Thyroid and Parathyroid John K

Home , Medullary thyroid cancer, Parafollicular cell, Parathyroid adenoma, Parathyroid carcinoma, Parathyroid chief cell, Parathyroid gland

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Thyroid and Parathyroid John K. C. Chan

The Thyroid Gland NON-NEOPLASTIC LESIONS NEOPLASTIC LESIONS Incidental and Insignificant Findings in the Thyroid Classification Gland General Considerations Cysts Follicular Adenoma Thyroid Tissue in the Lateral Neck Follicular Carcinoma Thyroiditis Papillary Carcinoma Graves’ Disease Poorly Differentiated Thyroid Carcinoma Nodular Goiter Anaplastic (Undifferentiated) Carcinoma Dyshormonogenetic Goiter Columnar Cell Carcinoma Fine-Needle Aspiration–Associated Changes in the Mucoepidermoid Carcinoma Thyroid Gland Sclerosing Mucoepidermoid Carcinoma with Amyloid Goiter Eosinophilia Black Thyroid Mucinous Carcinoma Uncommon Lesions of the Thyroid Gland Medullary Thyroid Carcinoma The Parathyroid Gland Collision Tumor NEOPLASTIC LESIONS Mixed Follicular-Parafollicular Carcinoma Classification Thymic and Related Branchial Pouch Tumors of the General Considerations Thyroid Parathyroid Adenoma Intrathyroid Parathyroid Tumor Parathyroid Carcinoma Malignant Lymphoma Contents of the Final Surgical Pathology Report Plasmacytoma of the Thyroid NON-NEOPLASTIC LESIONS Langerhans Cell Histiocytosis (Histiocytosis X) Primary Parathyroid Chief Cell Hyperplasia Angiosarcoma Primary Water-Clear Cell Hyperplasia Solitary Fibrous Tumor Secondary Parathyroid Hyperplasia Other Mesenchymal Tumors Parathyroid Cyst Paraganglioma Periparathyroid Salivary Heterotopia–Cyst Unit Teratoma Amyloidosis Metastatic Malignant Neoplasms in Thyroid Contents of the Final Surgical Pathology Report

A. The Thyroid Gland

NEOPLASTIC LESIONS Tumors of Thyroid Follicular Epithelium Classiﬁcation Follicular adenoma, including Hu¨ rthle cell adenoma The primary tumors of the thyroid gland, grouped Follicular carcinoma, including Hu¨ rthle cell car- according to the line of differentiation, include the cinoma following.1 Papillary carcinoma short standard 3 long

top of RH ϩ ϩ ϩ ; S-100 ϩ Ϫ and other ϩ sustentacular ϩ ϩ sustentacular cells may be present in hereditary form lymphoid markers cells; CEA lial markers, such as CD31, CD34, factor VIII antigen tigen (CEA) Thyroid Transcription Factor 1 Other Markers Negative Negative Negative Usually negative — Negative Negative Negative Negative Positive for endothe- Pan-neuroendocrine Markers (such as synaptophysin, chromogranin) Thyroglobulin Calcitonin 50% ϳ of cases) but sometimes positive) Positive Positive Positive Positive Positive — Positive Negative PositivePositive Negative Positive Negative — Negative Negative Negative CD5 Immunohistochemical Staining Proﬁle of the Various Thyroid Neoplasms carcinoma adenoma-carcinoma; poorly differentiated thyroid carcinoma; columnar cell carcinoma like element (CASTLE) Angiosarcoma Variable (usually negative, Mixed follicular-parafollicular Anaplastic carcinoma Variable (positive in Malignant lymphoma Negative Negative Negative Negative Negative Leukocyte common Medullary carcinoma Positive Positive Negative Positive Positive Carcinoembryonic an- TABLE 44–1. Tumor TypePapillary carcinoma; follicular Cytokeratin Carcinoma showing thymus- Intrathyroid parathyroid tumorParaganglioma Positive Negative Positive Positive Negativeshort Negative Negative Negative Negative Negative Parathyroid hormone S-100 standard 4 long

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Poorly differentiated thyroid carcinoma, includ- documented factor.6 External radiation was once ing insular carcinoma popularly used to treat patients with a variety of Anaplastic carcinoma, squamous cell carcinoma, benign disorders of the head and neck region, such and carcinosarcoma as acne, tinea capitis, cervical tuberculous lymphad- Rare tumor types: columnar cell carcinoma, mu- enitis, and thymic enlargement; such patients have coepidermoid carcinoma, sclerosing muco- an increased chance of developing thyroid cancer. epidermoid carcinoma with eosinophilia, Cancer patients treated with radiation have been mucinous carcinoma shown to have an excess of thyroid cancer compared with control subjects. Survivors of the Hiro- Tumors Showing C Cell or shima atomic bomb have a high risk for develop- Simultaneous Follicular and C Cell ment of thyroid cancer; persons who were younger Differentiation than 10 years when they were exposed have an excess relative risk of 9.46. The Chernobyl nuclear ac- Medullary carcinoma cident in 1986 provides further evidence of the im- Collision tumor: follicular and medullary carci- portance of radiation in thyroid carcinogenesis; in nomas or papillary and medullary carcino- some exposed areas, the incidence of thyroid cancer mas in children increased from 0.5 per million per year Mixed follicular-parafollicular carcinoma (differ- to 96.4 per million per year. The clinicopathologic entiated thyroid carcinoma, intermediate features of the Chernobyl accident–associated thy- type) roid cancers are listed in Table 44–2. Ectopic Tumors Iodine deficiency and endemic goiter are associated with an increased risk of thyroid carcinoma Ectopic thymoma and angiosarcoma. It has been postulated that the Spindle epithelial tumor with thymus-like ele- tumors may result from prolonged stimulation of ment (SETTLE) the thyroid tissues by thyroid-stimulating hormone.7 Carcinoma showing thymus-like element (CAS- Hashimoto’s thyroiditis and lymphocytic thy- TLE) roiditis are associated with an increased risk for ma- Intrathyroid parathyroid adenoma and carci- lignant lymphoma. In addition, sclerosing mucoepi- noma dermoid carcinoma with eosinophilia almost always arises in a setting of fibrosing Hashimoto’s thyroidi- Tumors of Hematolymphoid Cells tis. Hashimoto’s thyroiditis may slightly increase the risk for development of papillary carcinoma.8 Malignant lymphoma Plasmacytoma Langerhans cell histiocytosis Mesenchymal and Other Tumors TABLE 44–2. Features of Chernobyl Nuclear Accident- Benign and malignant mesenchymal tumors, Associated Thyroid Cancer such as solitary fibrous tumor, smooth muscle tumor, peripheral nerve sheath tumor, It is caused by exposure to radioactive iodine fallout; the accident occurred on April 26, 1986. angiosarcoma Most cases are papillary carcinomas (ϳ95%). The papillary car- Paraganglioma cinomas often show a follicular, solid, or mixed follicular- Teratoma papillary-solid pattern, contrasting with the typical papillary pattern seen in sporadic papillary carcinomas in children. The most common primary thyroid cancer is The incidence of thyroid cancer in areas around Chernobyl has papillary carcinoma, which accounts for 60% to 80% increased 6- to 500-fold compared with previous years, de- of all cases, followed by follicular carcinoma, which pending on the distance from the accident site. The greatest number of cases occur in areas where the thyroid radiation accounts for 10% to 20% of cases. Most thyroid tu- dose is Ն0.5 gy. mors can be readily diagnosed on morphologic as- The tumors show greater aggressiveness at presentation, such sessment alone. Nonetheless, in some circumstances, as extrathyroidal extension, venous invasion, and lymph especially with medullary carcinoma or unusual- node metastasis. Thus, treatment often entails total thyroid- looking tumors, immunohistochemical studies are ectomy and lymph node dissection. Lymphocytic thyroiditis and antithyroperoxidase antibody are required for a definitive classification. The immuno- more common than in sporadic cases. histochemical profiles of the more common thyroid Age at diagnosis is usually Յ14 years, which is younger than tumors are shown in Table 44–1.2–5 for the sporadic thyroid cancers in children not related to a nuclear accident. The time interval between the nuclear accident and the diagnosis of thyroid cancer is ϳ6–7 years. General Considerations Subjects younger than 5 years or in utero at the time of the nuclear accident account for the majority of cases. PATHOGENESIS Papillary carcinomas occurring in this setting show a much higher frequency of RET/PTC (especially RET/PTC3) gene rear- Some risk factors for development of thyroid cancer rangement compared with sporadic cases. short have been identified; radiation exposure is the best standard long

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Thyroid cancer can occur as a component of component of Cowden’s disease and may include some heritable syndromes.8, 9 Medullary carcinoma follicular adenoma, follicular carcinoma, and papil- is a key component of multiple endocrine neoplasia lary carcinoma. There are also less well deﬁned fa- type 2 (MEN 2) or familial medullary thyroid carci- milial nonmedullary thyroid cancer syndromes. noma. Thyroid adenoma or carcinoma sometimes occurs as a component of MEN type 1 (MEN 1). GRADING AND STAGING Some patients with familial adenomatous polyposis The TNM staging is the most widely used staging develop thyroid cancer, most commonly papillary system for thyroid cancer (Table 44–3). There are no carcinoma of the cribriform-morular variant (so- universally accepted grading systems for thyroid called familial adenomatous polyposis–associated cancers, although the histologic grade may be im- thyroid carcinoma). Thyroid tumors also constitute a plied from the histologic type (e.g., low grade for

TABLE 44–3. Staging of Thyroid Tumors

TNM Staging

Primary Tumor (T) All categories may be subdivided: (a) solitary; (b) multifocal—the largest is measured for classiﬁcation TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumors Յ1 cm, limited to the thyroid T2 Tumor 1–4 cm, limited to the thyroid T3 Tumor Ͼ4 cm, limited to the thyroid T4 Tumor of any size extending beyond thyroid capsule Lymp Node (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis N1a Metastasis in ipsilateral cervical lymph nodes N1b Metastasis in bilateral, midline or contralateral cervical, or upper mediastinal lymph nodes Distant Metastasis (M) MX Presence of distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

Stage Grouping

Papillary or Follicular Carcinoma

Stage Ͻ45 y Ն45 y

I Any T, any N, M0 T1, N0, M0 II Any T, any N, M1 T2, N0, M0 T3, N0, M0 III — T4, N0, M0 AnyT,N1,M0 IV — Any T, any N, M1

Medullary Carcinoma

Stage TNM status

I T1, N0, M0 II T2, N0, M0 T3, N0, M0 T4, N0, M0 III Any T, N1, M0 IV Any T, any N, M1

Anaplastic Carcinoma All cases are stage IV (i.e., any T, any N, any M) short standard long

Thyroid and Parathyroid 7 top of RH papillary and follicular carcinomas, and high grade commonly given postoperatively to suppress thy- for anaplastic carcinoma). roid-stimulating hormone activity in the hope of re- ducing tumor recurrence. External radiation therapy PROGNOSTIC FEATURES and chemotherapy are often reserved for uncontrol- The different types of thyroid cancers have a num- lable disease or highly aggressive tumors. ber of significant prognostic factors in common. TISSUE PROCUREMENT • Age younger than 40 years is a highly favorable Fine-Needle Aspiration prognostic factor.10 • Small tumor size (especiallyϽ1 cm) is a favorable In recent years, fine-needle aspiration cytology prognostic factor. has become the first-line screening or diagnostic pro- • Tumor stage (intrathyroid tumor versus presence cedure for patients presenting with a thyroid 13, 14 of extrathyroidal extension; presence or absence of mass. The technique is popular because the pro- metastasis) is a highly significant prognostic fac- cedure is simple and relatively nontraumatic, with tor.10–12 good acceptance by patients. In experienced hands, the false-positive rate(ϳ0%) and false-negative rate According to the Surveillance, Epidemiology, (7% to 10%) are low.15 The diagnostic categories and and End Results study,10 the 10-year relative sur- their rationale are listed in Table 44–4. By use of the vival rates of the major thyroid carcinomas are as cytologic diagnosis for triage, patients with a diag- follows: papillary carcinoma, 0.98; follicular carci- nosis of tumor or who are suspected of having tu- noma, 0.92; medullary carcinoma, 0.80; and anaplas- mor can be selected for early operation. Those tic carcinoma, 0.13. Papillary carcinoma and follicu- shown on cytologic assessment to have non-neoplas- lar carcinoma are sometimes lumped together in one tic lesions (such as cyst or colloid nodule) can be category of “differentiated thyroid carcinoma” in followed up; repeated fine-needle aspiration may be clinical studies, but this is not advisable because required during follow-up to rule out a missed neo- they show different clinical and biologic features. plasm.15, 16 THERAPY Core Needle Biopsy The mainstay of therapy for thyroid tumors is surgi- Core or large needle biopsy is performed in cal excision, and the extent of surgery depends on some centers either as the sole procedure or as a the tumor type. For thyroid carcinomas that can complementary procedure to fine-needle aspiration take up iodine (such as follicular carcinoma, papil- for the initial investigation of thyroid nodules.17–22 lary carcinoma, and poorly differentiated thyroid The procedure is more traumatic than fine-needle carcinoma), radioactive iodine is sometimes adminis- aspiration, but the yield is generally higher, permit- tered after total thyroidectomy so that residual mi- ting more accurate diagnosis to be made in some croscopic tumor can be eradicated. Thyroxine is also cases.

TABLE 44–4. Diagnostic Categories from Fine-Needle Aspiration Cytology of the Thyroid

Cytologic Diagnosis Rationale

Inadequate for diagnosis With the exception of cyst (which can be hypocellular, with only macrophages being identified), the minimal criterion for adequacy of a specimen is the presence of 5–6 groups of thyroid follicular epithelium with Ͼ10 cells per group. Benign, e.g., nodular goiter, cyst, Hashi- Nodular goiter can usually be recognized by features such as abundant thick moto’s thyroiditis colloid, low cellularity, large follicles, and honeycombed arrangement of nuclei in the epithelial fragments. Follicular lesion It can be difficult to make a distinction between cellular adenomatoid nodule and follicular neoplasm. In such situations, the descriptive term follicular lesion is applicable. Follicular neoplasm It is not possible to make a distinction between follicular carcinoma and follicular adenoma on the basis of fine-needle aspiration cytology because diagnosis of follicular carcinoma requires demonstration of vascular or capsular invasion. Suspicious of malignancy A diagnosis of “suspicious of malignancy” is justified if there are cytologic features suggestive of but not diagnostic of malignancy. Malignant neoplasm, e.g., papillary carci- Papillary carcinoma, medullary carcinoma, anaplastic carcinoma, and malignant noma, medullary carcinoma, anaplastic lymphoma can often be diagnosed on the basis of fine-needle aspiration sam- carcinoma, lymphoma ples because they exhibit distinctive cytologic and sometimes architectural features. Immunohistochemical studies on the aspirate smears or cell blocks pre- pared from the aspirated materials are particularly helpful in supporting a diagnosis of medullary carcinoma or lymphoma. Definitive treatment can pro- ceed on the basis of the cytologic diagnosis. A diagnosis of follicular carcinoma cannot be made from fine-needle aspiration cytology. short standard long

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radial cuts are made to produce wedge-shaped pieces, like cutting slices of an orange.25 Intraoperative Frozen Section Diagnosis of thyroid tumors is usually not difficult on frozen sections; the greatest difficulty lies in the distinction between follicular adenoma and follicular carcinoma because the invasive component is often focal and thus not seen in random frozen sections. Touch preparations form an important adjunct at intraoperative assessment and are particularly helpful for recognizing the characteristic nuclear features of papillary carcinoma and medullary carcinoma. The role of intraoperative frozen section has FIGURE 44–1. Follicular adenoma. The tumor is enveloped by a much diminished in recent years because of the thin fibrous capsule. There is no capsular or vascular invasion. widespread use of fine-needle aspiration cytology for preoperative screening or diagnosis. It is currently used mostly when fine-needle aspiration findings are suggestive of malignancy or are inconclusive. Intraoperative frozen section is of limited use and cost-effectiveness for follicular neoplasms be- Surgical Excision cause of the high deferral rate (“follicular neoplasm; Surgical excision is the standard treatment of defer diagnosis to permanent sections”).26–29 After thyroid tumors, providing ample tissue for histo- frozen section is performed, the remaining tissue logic examination and special studies. It is most im- should be fixed and further sampled for histologic portant to sample the specimen adequately so that examination. an accurate diagnosis can be reached and all prognostic information can be provided. Sampling is most critical for encapsulated follicular neoplasm be- Follicular Adenoma cause a diagnosis of follicular carcinoma can be missed owing to the focal nature of the invasive CLINICAL CONSIDERATIONS foci. Some authors recommend a minimum of 10 blocks.23 Others recommend at least five blocks ini- Presentation tially, with five or more additional blocks being Follicular adenoma occurs most commonly in taken if the tumor is found to be cellular on initial adult women aged 20 to 50 years, although no age histologic examination.24 Most blocks should be or sex is exempt. Most patients present with a pain- taken from the peripheral portions of the tumor, less thyroid nodule (“cold” nodule on iodine scan). including the interface with the normal thyroid, Rare tumors show increased iodine uptake (“hot” rather than from the central portion. For optimal nodules) and may be associated with hyperthyroid- assessment of the capsule in all histologic sections, ism. Follicular adenomas are benign and are ade- after bisection of the nodule through the equator, quately treated by lobectomy.

FIGURE 44–2. Follicular adenoma. A. This tumor is composed of small follicles lined by cells with short uniform dark nuclei. B. This tumor shows a trabecular to microfollicular growth pattern and com- standard prises cells with mildly atypical nuclei. long

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FIGURE 44–3. Hyalinizing trabecular adenoma. A. The tumor typically forms wavy trabeculae interspersed with lumpy hyaline material. There are interspersed small cystic spaces representing abortive follicle formation. B. The tumor cells possess pale oval nuclei that are sometimes grooved, mimicking the cytologic features of papillary carcinoma. Perinucleolar haloes are present. Some tumor cells contain distinctive cytoplasmic “yellow bodies” that stain dull pink and are surrounded by a halo.

Macroscopic Findings The lining cells often have uniform, dark, round nu- Follicular adenomas are almost invariably soli- clei, although occasional enlarged hyperchromatic tary. They are round or oval and are enveloped in a nuclei can be interspersed (Fig. 44–2). fibrous capsule, which is often thin. The cut surface The many histologic variants of follicular ade- shows homogeneous tan-brown fleshy tumor, some- noma are listed in Table 44–5 (Figs. 44–3 to 44–10). times with a glistening quality. Secondary changes By definition, capsular or vascular invasion must be such as hemorrhage and cystic degeneration may be absent; if invasion is found, the tumor has to be 23, 30–56 present. Hu¨ rthle cell adenomas are typically mahog- diagnosed as follicular carcinoma. The nature any brown. of hyalinizing trabecular adenoma has been most controversial. The hyalinizing trabecular pattern is DIAGNOSTIC CONSIDERATIONS not specific for follicular adenoma; it can be observed in papillary carcinoma and follicular carci- Microscopic Findings noma as well as focally in various thyroid lesions, Follicular adenoma is typically enclosed in a fi- such as colloid nodule and thyroiditis.57–59 Some in- brous capsule of variable thickness, often with com- vestigators consider hyalinizing trabecular adenoma pression of the surrounding thyroid tissue (Fig. to represent a peculiar variant of papillary carci- 44–1). It can show a wide spectrum of architectural noma because of merging with typical papillary features, but a follicular pattern is most common. carcinoma in some cases, similarities in cytologic

TABLE 44–5. Variants of Follicular Adenoma

Entity for Which the Variant May be Variant* Deﬁning Morphologic Features Mistaken

Macrofollicular Most follicles in the neoplasm are large. Nodular goiter Microfollicular Most follicles in the neoplasm are small. Poorly differentiated (insular) carcinoma Trabecular (embryonal) The tumor cells form straight trabeculae Poorly differentiated (insular) carcinoma separated by a delicate vasculature. Medullary carcinoma Hyalinizing trabecular The tumor forms wavy trabeculae with in- Papillary carcinoma terspersed microcystic spaces representing Paraganglioma abortive follicle formation. Medullary carcinoma The elongated tumor cells are aligned perpendicularly in the trabeculae. The nuclei are often grooved and show pseudoinclusions. Unique cytoplasmic yellow bodies are present. Lumpy hyaline material is interspersed throughout the tumor. Calciﬁed colloid short may be present. standard Table continues on following page long

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TABLE 44–5. Variants of Follicular Adenoma (Continued)

Entity for Which the Variant May be Variant* Deﬁning Morphologic Features Mistaken

Hu¨ rthle cell Follicular neoplasm; most tumor cells have Medullary carcinoma, oxyphilic variant abundant oxyphilic cytoplasm because of Papillary carcinoma, oxyphilic variant accumulation of mitochondria. Nucleoli are often distinct. Some nuclei can be grooved. The tumor often shows a microfollicular or trabecular pattern of growth. Clear cell Follicular neoplasm; the tumor cells possess Other primary thyroid neoplasms with clear clear cytoplasm because of ballooning of cell change mitochondria, accumulation of lipid or Metastatic renal cell carcinoma glycogen, or deposition of intracellular Intrathyroid parathyroid neoplasm thyroglobulin. The clear cytoplasm often retains a ﬁnely reticulated or granular quality, instead of being water-clear. Signet ring cell The tumor cells exhibit discrete cytoplasmic Metastatic adenocarcinoma vacuoles that displace the nuclei to one side. The cytoplasmic vacuoles are thyroglobulin immunoreactive and often show the staining properties of mucosubstances. They correspond ultrastructurally to intracellular lumina lined by microvilli. Signet ring cell changes can be focal or diffuse, and this pattern may merge into microcystic spaces ﬁlled with extracellular mucin. Mucinous The tumor shows abundant extracellular ba- Metastatic adenocarcinoma sophilic mucinous material, often accompanied by a microcystic or reticular growth pattern in the follicular epithelium. Some tumor cells may exhibit signet ring appearance. Follicular adenoma with papillary The tumor is encapsulated and partially cys- Papillary carcinoma hyperplasia (papillary variant tic. It is composed of papillae and follicles of follicular adenoma) lined by cells with uniform, round, and hyperchromatic nuclei regularly aligned at the base. Hot adenoma (toxic adenoma) Follicular adenoma producing symptoms of — hyperthyroidism. On histologic examination, the follicles often show papillary infoldings, similar to the follicles seen in Graves’ disease. Adenolipoma Follicular adenoma accompanied by a — stroma containing adipose cells Follicular adenoma with bizarre An otherwise typical follicular adenoma Follicular carcinoma nuclei with interspersed huge monstrous cells Anaplastic carcinoma Atypical adenoma Follicular neoplasm shows generalized nu- Follicular carcinoma clear atypia, giant cells, or unusual histo- Medullary carcinoma logic patterns (such as spindle cell fasci- Anaplastic carcinoma cles) but lacks vascular and capsular invasion after thorough sampling. It pursues a benign course.

* All tumors have to be assessed for vascular or capsular invasion, which, if present, is indicative of a diagnosis of follicular carcinoma.

features, and similarities in immunohistochemi- ular adenoma (high-molecular-weight cytokeratin cal proﬁle (such as expression of high-molecular- and cytokeratin 19 are often negative or only focally weight cytokeratin and basement membrane deposi- positive) to be different from that of papillary carci- tion) 49, 56, 59, 60 (see Fig. 44–3). Nonetheless, a study noma, and thus it does not support a histogenetic short showed the cytokeratin proﬁle of hyalinizing trabec- link between the two tumors.61 Recent molecular standard long

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FIGURE 44–4. Hu¨rthle cell adenoma. A. This tumor shows a follicular growth pattern. The cells possess abundant eosinophilic granular cytoplasm. Nucleoli are often but not invariably distinct in Hu¨ rthle cells. B. This tumor shows a solid to trabecular growth pattern. The calciﬁed colloid (left ﬁeld) can potentially be mistaken for psammoma bodies. In contrast to psammoma bodies, they occur within follicular lumina rather than in the stroma.

studies demonstrated a high frequency of RET/PTC the Cowden disease gene, PTEN, is found in 26% of translocation, suggesting a histogenetic relationship follicular adenomas.64 Activating mutations of the of hyalinizing trabecular adenoma with papillary genes coding for the thyrotropin receptor and ␣- carcinoma.61a–61c subunit of the stimulatory G protein have been detected in some follicular adenomas, especially the 62, 65–70 Immunohistochemistry hyperfunctioning ones. Follicular adenomas are immunoreactive for cy- Differential Diagnosis tokeratin and thyroglobulin but not for calcitonin COLLOID (ADENOMATOID)NODULE. It can be and pan-neuroendocrine markers. Hyalinizing tra- difficult to distinguish between follicular adenoma becular adenoma is peculiar in that it often shows and adenomatoid nodule (hypercellular colloid nod- an unusual cell membrane pattern of staining for ule); the distinction is sometimes arbitrary. In gen- Ki-67. eral, adenomatoid nodules are multiple, lack a well- defined fibrous capsule, and are composed of Molecular Biology follicles morphologically similar to those in the sur- Mutations in the ras gene are found in some rounding thyroid tissue. follicular adenomas, at a frequency lower than in PAPILLARY CARCINOMA. Pale or clear nuclei follicularcarcinomas.62, 63 Hemizygous deletion of are not uncommonly encountered in follicular ade-

FIGURE 44–5. Follicular adenoma, clear cell variant. The clear cytoplasm is not water-clear but retains a ﬁnely reticulated qual- short ity. FIGURE 44–6. Follicular adenoma, signet ring cell variant. standard long

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nomas, most probably owing to delayed ﬁxation because they are often most prevalent in the central portions of the tumor (Fig. 44–11). Other cytologic features of papillary carcinoma, such as nuclear crowding and nuclear grooving, are lacking, however.

INTRATHYROID PARATHYROID TUMOR. Parathy- roid adenoma can sometimes arise within the thyroid gland and thus can be mistaken for microfollicular adenoma, clear cell follicular adenoma, or Hu¨ rthle cell adenoma. The presence of clear cells is a most useful clue that the tumor in question might be of parathyroid origin. The diagnosis can be con- ﬁrmed by the clinical information (hypercalcemia) FIGURE 44–7. Follicular adenoma, mucinous variant. Intercellu- and positive immunostaining for parathyroid hor- lar pools of mucin are evident. mone.

FIGURE 44–8. Follicular adenoma with papillary hyperplasia, so-called papillary adenoma. A. The tumor is surrounded by a well-deﬁned ﬁbrous capsule. Arborizing papillae are present. B. In contrast to papillary carcinoma, the tumor cells have regularly aligned, basal, dark-staining nuclei.

FIGURE 44–10. Atypical follicular adenoma. Many tumor cells FIGURE 44–9. Follicular adenoma, adenolipoma variant. have enlarged hyperchromatic nuclei. short standard long

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higher than that of those with follicular adenoma. It usually manifests as a solitary thyroid mass or, less commonly, as metastatic tumor, in particular in bone.71–74 The main mode of spread is hematogenous (predilection sites are bone and lung) rather than lymphatic.75 The differences in clinicopathologic and biologic features between follicular carcinoma and papillary carcinoma are listed in Table 44–6. Macroscopic Findings and Major Subtypes of Follicular Carcinoma Follicular carcinoma is categorized into minimally invasive and widely invasive types, which show different clinical outcome (Table 44–7). The minimally invasive type is more common.1, 24, 44, 76–80 FIGURE 44–11. Follicular adenoma showing nuclear clearing. Minimally invasive carcinomas are macroscopi- Although the nuclei show clearing, they are not crowded and do cally indistinguishable from follicular adenoma, al- not exhibit grooves. This is a common finding confined to the though the capsule tends to be thicker. Vascular or central portion of follicular adenoma, where fixation is delayed. capsular invasion is identified only on histologic assessment (Fig. 44–12). The prognosis is excellent, and thus treatment can be conservative.24, 72, 73, 81–88 The less common widely invasive follicular carcinoma shows obvious invasion of the adjacent thy- Follicular Carcinoma roid parenchyma (Fig. 44–13). The tumor can extend into the perithyroid tissues, and plugging of 1, 44 CLINICAL CONSIDERATIONS blood vessels by tumor may also be evident. There is a significant risk of distant metastasis, and Presentation the prognosis is much worse than for minimally in- Follicular carcinoma is a malignant thyroid neo- vasive follicular carcinoma.44, 89 Of note, many cases plasm showing follicular cell differentiation but lack- reported in the literature as “widely invasive follicu- ing the diagnostic features of papillary carcinoma.1 lar carcinomas” are now reclassifiable as poorly dif- It generally occurs in patients with a mean age ferentiated thyroid carcinomas.

TABLE 44–6. Comparison Between Papillary and Follicular Carcinoma

Papillary Carcinoma Follicular Carcinoma

Frequency Ͼ70% of thyroid cancers Ͻ20% of thyroid cancers Age Wide age range (mean, 43 y) Minimally invasive type: mean, 48 y Widely invasive type: mean, 55 y Presentation Slow-growth thyroid mass; cervical lymphadenopa- Slow-growing thyroid mass; fast-growing thyroid thy; incidental finding mass (less common); distant metastasis (such as bone) Multifocal disease Common Uncommon Clinical behavior Tumor is locally invasive; typically spreads by lym- Tumor spreads predominantly by bloodstream; bone phatic route to lymph nodes (ϳ40%). is the predilection site. Distant metastasis (such as to lungs) is rare. Lymph node metastasis is uncommon. The tumor is indolent; the cancer-related mortality The cumulative mortality rates of the minimally in- is only 6.5%—often confined to older patients vasive and widely invasive types are 3% and 32%, with extensive extrathyroid disease or distant me- respectively. tastasis. Basis of diagnosis Diagnosis is mostly based on the nuclear characteris- A follicular neoplasm demonstrating vascular or tics (crowded, ground-glass, grooved nuclei with capsular invasion, and nuclear features of papil- pseudoinclusions), and demonstration of invasion lary carcinoma must be lacking. Therefore, distinc- is not required for the diagnosis. Therefore, this tion from follicular adenoma cannot be made on tumor is diagnosable by fine-needle aspiration cy- fine-needle aspiration cytology; only a diagnostic tology. label of “follicular neoplasm” can be given. Genetic basis Overexpression of RET proto-oncogene due to fu- Somatic mutation of ras oncogene in ϳ50% of sion with PTC1, PTC2, or PTC3 gene, or overex- cases, most commonly involving codon 61 CAA : pression of NTRK1 gene due to fusion with other CGA (Gln : Arg). t(2;3)(q13 5) resulting inPAX8- genes such as TPM3 PPAR␷1 fusion is found in Ͼ50% of cases. short standard long

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TABLE 44–7. Categories of Follicular Carcinoma

Minimally Invasive Widely Invasive

Deﬁnition Totally encapsulated tumor with no gross invasion; Tumor shows obvious invasion of adjacent thyroid tissue. vascular or capsular invasion is identiﬁed on histologic examination. Age Younger (mean, ϳ48 y) Older (mean, ϳ56 y) Metastases Regional lymph node or distant metastasis is rare Regional lymph node metastasis occurs in 13%–24% of and occurs late if it does. cases. Distant metastasis (such as to lung, bone, brain, liver) is common (29%–60%). Outcome Excellent prognosis. The long-term mortality is Long-term mortality is 30%–50%. only 3%–5%. Treatment Curable by lobectomy or subtotal thyroidectomy, Total thyroidectomy, radioactive iodine, and suppressive with or without suppressive dose of thyroxine. dose of thyroxine For high-risk patients, such as old patients and those with large tumors, total thyroidectomy and radioactive iodine therapy may have to be considered.

DIAGNOSTIC CONSIDERATIONS tures like those listed for follicular adenomas31, 34, 90– Microscopic Findings 93 (see Table 44–5). The only feature that distinguishes a follicular Follicular carcinomas are often surrounded by a carcinoma from a follicular adenoma is the presence thick, dense fibrous capsule, although some widely of vascular or capsular invasion.1 Strict criteria must invasive follicular carcinomas may not have a fi- be applied in the assessment of invasion.94–98 The brous capsule (see Figs. 44–12 and 44–13). The histologic features that should heighten the suspi- tumors comprise cuboid cells forming closely cion for follicular carcinoma are listed in Table packed follicles, trabeculae, or solid sheets. The folli- 44–8, but they are by themselves insufficient for a cles are mostly small, but large follicles can also be diagnosis of malignancy. present. The tumor cells often have uniform, dark- To qualify for vascular invasion, the following staining or pale-staining, round nuclei, but signifi- two criteria must be satisfied24: cant nuclear atypia can be observed in some cases (Fig. 44–14). The cytoplasm is eosinophilic, oxy- • Involved blood vessels have to be located within philic, or clear. Mitotic figures range from being or outside the fibrous capsule. scanty to easily found. Secondary changes such as • The intravascular polypoid tumor plug has to be hemorrhage, hemosiderin deposition, sclerosis, covered by endothelium; if it is not endothelial- edema, necrosis, and cystic change are not uncom- ized, it must be associated with thrombus forma- mon. The tumors may show variant histologic fea- tion (Fig. 44–15; see also Fig. 44–12).

FIGURE 44–13. Follicular carcinoma, widely invasive type. FIGURE 44–12. Follicular carcinoma, minimally invasive type. There is frank invasion of the thyroid tissue in the form of multi- The tumor is typically surrounded by a thick fibrous capsule. ple cellular tumor nodules. The upper field shows vascular inva- short Vascular invasion is present (upper field). sion. standard long

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FIGURE 44–14. Follicular carcinoma. A. This tumor shows a trabecular growth pattern and comprises cells with fairly uniform, dark, round nuclei. B. This tumor exhibits generalized nuclear atypia. This is a feature that should alert one to the possibility of carcinoma for a follicular neoplasm.

An invasive bud frequently pushes into the fi- dislodgment of tumor during sectioning of the speci- brous capsule and then into a capsular blood vessel men.24 Intravascular endothelial hyperplasia occur- lumen (Fig. 44–16). Mere bulging of follicles against ring in capsular blood vessels should also not be the thin-walled capsular vessels is not sufficient for mistaken for vascular invasion; the intravascular a designation of vascular invasion (Fig. 44–17). Re- polypoid plug is formed by plump spindly endothe- traction spaces around tumor islands should not be lial cells and pericytes instead of follicular epithelial mistaken for vascular invasion, and they can be rec- cells99 (Fig. 44–18). ognized by the lack of endothelial lining. The pres- To qualify for capsular invasion, there must be ence of ragged clusters of nonendothelialized tumor complete transgression of the fibrous capsule by tu- within blood vessels does not count for vascular mor. That is, the tumor bud must have extended invasion. This is believed to result from artifactual beyond an imaginary line drawn through the exter-

TABLE 44–8. Key Points and Caveats in Diagnosis of Follicular Adenoma and Carcinoma

There is a tendency to overdiagnose follicular carcinoma. To qualify for follicular carcinoma, the following criteria must be satisfied: • Follicular neoplasm lacking nuclear features of papillary carcinoma • Capsular or vascular invasion, which must be unequivocal Histologic features in a follicular neoplasm warranting more careful sampling to look for invasion (these features are not diagnostic of carcinoma per se): • Thick fibrous capsule • High cellularity, i.e., tumors that are predominantly solid, trabecular, or microfollicular • Diffuse nuclear atypia (as opposed to presence of occasional bizarre cells) • Readily identifiable mitotic figures • Perpendicularly aligned neoplastic follicles or mushroom-shaped tumor bud in fibrous capsule • Hu¨ rthle cell neoplasm (ϳ35% of all Hu¨ rthle cell neoplasms are malignant, a percentage higher than that of non–Hu¨ rthle cell neoplasms) Do not mistake capsular rupture associated with prior fine-needle aspiration as true capsular invasion. Capsular rupture can be recognized by the following features: • Tumor buds within fibrous capsule (at most one or two sites) are tiny and lack a “mushroom” contour. • Tumor buds are associated with blood, chronic inflammatory cells, and hemosiderin deposit. • Tumor cells often have a degenerated appearance. • Hemorrhagic track (with or without reparative features) is often identifiable in the vicinity. If prominent delicate fibrovascular septa are present, consider the alterantive possibilities: • Medullary carcinoma • Intrathyroid parathyroid neoplasm • Paraganglioma If a Hu¨ rthle cell neoplasm appears unusual, it may represent oxyphilic variant of the following tumors: • Medullary carcinoma • Intrathyroid parathyroid neoplasm • Papillary carcinoma short standard long

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FIGURE 44–15. Follicular carcinoma showing vascular invasion. A. A tumor plug projects into a capsular blood vessel, and it is clothed by endothelium. B. The intravascular tumor plug has a jagged outline and is not clothed by endothelium. However, this satisfies the criterion for vascular invasion because there is associated fibrin thrombus (left field).

FIGURE 44–16. Follicular carcinoma. The tumor (lower ﬁeld) ex- FIGURE 44–17. Follicular adenoma. Bulging of tumor against tends into the ﬁbrous capsule and then projects into a vascular blood vessels within the tumor proper does not constitute vascu- lumen in the capsule. lar invasion.

FIGURE 44–18. Follicular adenoma with intravascular endothelial hyperplasia in the capsule, mimicking vascular invasion. A. Cellular proliferation is seen in the capsular blood vessel (upper ﬁeld). B. Closer examination reveals that the intravascular proliferation consists of small blood vessels and not tumor cells. short standard long

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FIGURE 44–19. Follicular carcinoma showing capsular invasion. A. In this case, there is total penetration of the fibrous capsule. The invasive bud does not have a fibrous cap. B. In this case, the invasive bud has penetrated the fibrous capsule, reaching beyond an imaginary line drawn along the external contour of the capsule. This invasive bud is clothed by a newly formed, thin fibrous cap.

nal contour of the capsule (Fig. 44–19). The invasive Hu¨ rthle Cell Carcinoma bud may be “naked” (without a fibrous capsule) or Hu¨ rthle cell carcinoma is a variant of follicular clothed by a thinner, newly formed fibrous cap- carcinoma characterized by mitochondria-rich cells,75 24, 71, 78, 100 sule (Fig. 44–19). A tumor bud that shows although some investigators consider it to be a dis- incomplete penetration of the capsule despite exami- tinct entity.45 There is new evidence that the pattern nation of multiple levels of the tissue block can be of chromosome allelic alteration in Hu¨ rthle cell car- disregarded. Follicles entrapped in the capsule by a cinomas differs from that of conventional follicular sclerotic process are often aligned parallel to the fi- carcinomas.102 bers of the capsule (Fig. 44–20), whereas follicles oriented perpendicular to the fibers or forming a On gross evaluation, the tumor is bright brown. mushroom-shaped bud are more indicative of an A size of 4 cm or larger is strongly correlated with 103 active invasive process, mandating examination of malignancy. On histologic examination, the tumor multiple levels and multiple blocks for more definite shows a trabecular, microfollicular, diffuse, or rarely evidence of capsular invasion (Fig. 44–21). Fine-nee- papillary growth pattern. The tumor cells possess dle aspiration can result in capsular rupture, mim- abundant brightly eosinophilic granular cytoplasm, icking capsular invasion; see Table 44–8 for features which can exhibit partial to complete clearing as supportive of this interpretation101 (Fig. 44–22). a result of ballooning of the mitochondria (Fig.

FIGURE 44–20. Follicular adenoma. A. Bosselations of the tumor on the inner aspect of the fibrous capsule should not be interpreted as capsular invasion. B. In the fibrous capsule, there are atrophic follicles aligned in the direction of the fibrous capsule. This phenomenon results from passive entrap- ment of follicles in the fibrotic process and does not indicate capsular invasion. short standard long

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FIGURE 44–21. Follicular carcinoma. Not uncommonly, an invasive bud takes the shape of a mushroom, indicating an active invasive process. This field, however, is insufficient to qualify for full capsule penetration because the bud has not extended beyond the external contour of the fibrous capsule. Nonetheless, this finding should prompt careful examination of deeper levels and multiple blocks for more definite evidence of capsular or vascular invasion. FIGURE 44–22. Follicular adenoma with fine-needle aspiration– associated capsular rupture. The bud in the fibrous capsule is small and accompanied by hemorrhage and chronic inflammatory cells. 44–23). The nuclei are round or sometimes grooved. The chromatin is granular to coarse, and nucleoli are often prominent. Some degree of nuclear pleomor- they show a higher frequency of extrathyroidal ex- phism is common. The colloid can undergo calcifica- tension, local recurrence, and metastasis to lymph tion and thus may be mistaken for psammoma bod- nodes, and the survival rate is lower.75, 96, 100, 122, 123 ies. Hu¨ rthle cell neoplasms are particularly prone to However, with stratification by the extent of inva- infarction after fine-needle aspiration.101, 104–106 sion, the differences are obliterated.75 It has been Some previous studies have proposed aggressive suggested that the presence of a solid or trabecular treatment for all Hu¨ rthle cell neoplasms, irrespective pattern in more than 75% of the tumor area identi- of whether invasion could be demonstrated histolog- fies a poorly differentiated subgroup with worse ically, on the basis of the belief that all were poten- prognosis—30% died of disease or were alive tially malignant.107–110 However, many later studies with recurrent disease, compared with a 2.5% mor- have challenged this misconception and shown that tality rate for the non–poorly differentiated sub- the behavior of Hu¨ rthle cell neoplasms can be accu- group.124 rately predicted by histologic features (i.e., whether there is vascular or capsular invasion, as in follicular neoplasms).* Only those showing invasion are diagnosed as carcinoma (see Fig. 44–15A). Such tumors can recur locally, metastasize to regional lymph nodes, or show distant metastasis (especially to bone and lungs).71, 98, 100, 119, 120 When a Hu¨ rthle cell neoplasm shows some but inconclusive evidence of invasion, the term Hu¨rthle cell tumor of uncertain malignant potential is sometimes applied. Clinical follow-up shows a benign evolution in all cases. It may therefore be more appropriate to simply label such cases “Hu¨ rthle cell adenoma.”100, 121 The overall mortality rate of Hu¨ rthle cell carcinomas is 30% to 70%.71, 98, 100 Compared with conventional follicular carcinomas, Hu¨ rthle cell carcinomas take up radioactive iodine less satisfactorily;

FIGURE 44–23. Hu¨rthle cell carcinoma. The tumor comprises trabeculae of tumor cells with abundant eosinophilic granular short *References 71, 94, 95, 98, 100, 107, 111–119. cytoplasm. There is mild nuclear pleomorphism. standard long

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Immunohistochemistry antigen, oncogene products (Ras p21, c-Myc), cyclin Follicular carcinoma is immunoreactive for cyto- D1, cyclin-dependent kinase inhibitor (p27), prolifer- keratin and thyroglobulin but not for pan-neuroen- ation marker (Ki-67), epidermal growth factor, P- docrine markers.125 Immunohistochemical studies are glycoprotein, high-mobility group I HMGI(Y) pro- rarely required for diagnosis of this tumor with the tein, and telomerase activity, have not been shown 121, 125, 143–149 exception of two scenarios: to be sufficiently discriminatory either. DNA ploidy analysis also fails to distinguish follicu- • Unusual-looking thyroid neoplasm—thyroglobulin lar carcinoma from follicular adenoma.150–154 immunoreactivity confirms the presence of thyroid HASHIMOTO’S THYROIDITIS AND DYSHORMON- follicular cell differentiation and is helpful for dis- OGENESIS. In Hashimoto’s thyroiditis or dyshor- tinction from medullary carcinoma. monogenetic goiter, multiple cellular hyperplastic • Metastatic neoplasm suspected to represent meta- nodules can be present, raising a concern for follicu- static follicular carcinoma—thyroglobulin immu- lar carcinoma. However, vascular invasion is not noreactivity confirms the thyroid origin of the car- found, and the different cellular nodules often ex- cinoma. hibit different cellularities and follicle size. Molecular Biology and Special Studies MEDULLARY CARCINOMA. Some variants of Clonal chromosome abnormalities, such as nonmedullary carcinoma can mimic follicular or Hu¨ rthle disjunctional chromosome loss and deletions in 3p25 cell carcinoma. The presence of prominent delicate : pter, are common in follicular carcinomas.126–129 fibrovascular septa should always raise the possibil- Comparative genomic hybridization studies reveal ity of medullary carcinoma. If there is any uncer- frequent DNA copy number changes; loss of chro- tainty about the diagnosis, immunohistochemical mosome 22 is associated with the widely invasive studies should be performed. type and old age at presentation.130 Molecular stud- PAPILLARY CARCINOMA. Some follicular carci- ies show frequent loss of heterozygosity on chromo- nomas may show nuclear clearing, mimicking papil- somes 3p (86%), 17p (72%), and 10q (57%); 17p lary carcinomas. However, this phenomenon is often change is correlated with mortality.131, 132 confined to the central portion of the tumor, where A high frequency of activating point mutations there is delayed fixation. Hu¨ rthle cell carcinomas in the family of ras genes is found in follicular carci- can show nuclear grooving, but this is often a focal nomas, although similar mutations can also be phenomenon and other cytologic features of papil- found in some follicular adenomas.62, 63 N-ras muta- lary carcinoma are lacking. tion is found in 50% of follicular carcinomas, most commonly involving codon 61 with CAA : CGA PROGNOSTIC CONSIDERATIONS (Gln : Arg); this mutation is observed in approxi- The most important prognostic factors for follicular mately 25% of anaplastic carcinomas but not in pap- carcinoma are age, degree of invasiveness, and pres- illary carcinomas.133 H-ras codon 12 mutation is ence or absence of distant metastasis. 134 found in 33% of follicular carcinomas. Alteration AGE. The prognosis is excellent for patients in the TP53 gene is uncommon, but its presence is younger than 30 to 40 years.* associated with an increased risk of metastasis.135 Recently, t(2;3)(q13; p25), which results in fusion of MINIMALLY INVASIVE VERSUS WIDELY INVA- PAX8 gene with peroxisome proliferator-activated SIVE TYPE. The prognosis of the widely invasive receptor gamma 1 (PPAR␥1) gene, has been shown follicular carcinoma is much worse than that of to be a characteristic genetic aberration of follicular the minimally invasive type (see Table 44–7). carcinoma. The fusion transcript is detected in 5 of 8 Tumor invasion of the soft tissues of the neck is associated with a particularly unfavorable progno- follicular carcinomas, but not in 20 follicular adeno- 44, 82, 96, 111, 123 mas, 10 papillary carcinomas and 10 cases of multi- sis. nodular hyperplasia.135a METASTASIS. Distant metastasis at presentation is a highly unfavorable prognostic factor.† Differential Diagnosis SEX. Some studies have shown the male sex to FOLLICULAR ADENOMA. The current “gold be associated with a worse outcome.82, 100, 156 standard” for distinguishing between follicular carci- HISTOLOGIC TYPE OR PATTERN. As a group, noma and follicular adenoma is identification of vas- Hu¨ rthle cell carcinomas have a worse progno- cular or capsular invasion in follicular carcinoma sis than that of conventional follicular carcino- (see “Microscopic Findings”). Although some anti- mas.71, 75, 100, 123 Presence of a solid or trabecular pat- bodies, such as Leu-7, thyroid peroxidase (monoclo- tern in more than 75% of the tumor area is nal antibody 47), HBME-1, tissue polypeptide anti- associated with a worse prognosis.124 gen, dipeptidyl aminopeptidase IV (CD26), and topoisomerase II, have been reported to stain follicular carcinomas and follicular adenomas with differ- 136–142 ent frequencies, the discriminatory power is *References 44, 71, 78, 82, 100, 111, 123, 155, 156. not high enough for routine diagnostic application. short Various tumor markers, such as carcinoembryonic †References 44, 71, 81, 100, 111, 123, 156–158. standard long

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TUMOR SIZE. Some studies have reported a illary carcinoma can also be discovered incidentally large tumor (Ͼ 4 cm) to be associated with a worse in thyroid glands excised for various reasons (latent prognosis.78, 100, 123, 155, 156 papillary carcinoma).166, 167 VASCULAR INVASION. Follicular carcinomas showing capsular invasion alone in the absence of Macroscopic Findings vascular invasion have a negligible risk of metasta- The macroscopic appearances of papillary carci- sis.81, 121, 156, 159 noma are highly variable, mirroring the myriad his- E-CE-CADHERIN EXPRESSION. Lack of E-cadherin tologic patterns that this tumor can assume. The expression is reported to be an unfavorable prognos- classic examples exhibit firm to hard white-tan tu- tic factor.160 mors with invasive borders. The tumor often has a granular quality on the cut surface due to the pres- DNADNA A NEUPLOIDY. Whereas some studies sug- ence of papillae. The presence of psammoma bodies gest that aneuploid follicular carcinomas are more can impart a gritty sensation on cutting of the tu- aggressive, other studies have not been able to con- 150, 151, 161 mor. Tumors with a predominantly follicular archi- firm this observation. tecture are often tan-brown and fleshy, similar to P5353 A BERRATION. Presence of p53 aberration follicular neoplasms. Some tumors can be encapsu- may confer an increased chance of metastasis.124, 135 lated. Cystic change can occur.

DIAGNOSTIC CONSIDERATIONS Papillary Carcinoma Microscopic Findings CLINICAL CONSIDERATIONS Papillary carcinoma is deﬁned as a malignant epithelial tumor showing evidence of follicular Presentation cell differentiation, typically with papillary and fol- Papillary carcinoma can occur in patients of any licular structures as well as characteristic nuclear age, including children. The mean age is 43 years, changes.1, 168, 169 The diagnosis is based on the nu- and there is a female predilection162–165 (see Table clear characteristics, which include large size, pallor, 44–6). The patients usually present with a thyroid ground-glass appearance, irregular outline, deep mass or cervical lymph node metastasis. Small pap- grooves, and pseudoinclusions169–172 (Fig. 44–24).

FIGURE 44–24. Papillary carcinoma showing the spectrum of cytologic features. A. The papillae are covered by cells with pale nuclei, some of which are optically clear (left ﬁeld). The nuclei also exhibit crowding. B. The nuclei are comparatively chromatin rich, although still pale. They are ovoid, with grooving and distinct nucleoli. Note the lack of polarity. C. The nuclei are pale, and some nuclear pseudoinclusions are seen. Portion of a multinucle- short ated histiocyte is seen in the lumen (lower ﬁeld). standard long

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anastomosing tubular, trabecular, and solid.171, 175 Multinucleated histiocytes with deeply eosinophilic cytoplasm can be found in the luminal space of some follicles and papillae in approximately 50% of cases and can aid in the diagnosis of papillary carcinoma because they are extremely rare in other thyroid lesions or tumors176 (see Fig. 44–24C). There is commonly an abundant sclerotic stroma,177, 178 and desmoplastic stroma is often confined to the invasive fronts170 (Fig. 44–27; see also Fig. 44–25). The stroma commonly shows patchy infiltration of lymphocytes, plasma cells, and macrophages. Psammoma bodies are found in the stalks of the papillae, in the fibrous stroma, or among the tumor cells in about 50% of cases; they are vir- FIGURE 44–25. Papillary carcinoma. A typical example showing tually pathognomonic of papillary thyroid carci- 170, 179, 180 infiltrative growth, prominent branching papillae, and sclerotic noma (see Fig. 44–26A). stroma. The nuclei of papillary carcinoma are characteristically large, crowded, ovoid, ground-glass (“Or- phan Annie” eye), and grooved and contain small distinct nucleoli171, 181 (see Fig. 44–24). Nuclear pseu- Papillary carcinomas are usually infiltrative, but doinclusions may be identified in a small proportion some may be circumscribed or even encapsulated of tumor cells181–184 (see Fig. 44–24C). Mitotic figures (Fig. 44–25). are usually sparse. In some papillary carcinomas, The papillae are usually arborizing, with deli- the typical nuclear features may not be well devel- cate fibrovascular cores (Fig. 44–26A; see also Fig. oped, and thus the diagnosis of papillary carcinoma 44–25). However, the papillae can be broad, with would have to depend on the architectural features the cores being formed by fibrocellular, edematous, and on the identification of foci showing more typi- or hyalinized tissue, which may contain foamy mac- cal nuclear features (Fig. 44–28). rophages, adipose cells, or small neoplastic folli- The neoplastic cells are cuboid, polygonal, co- cles.38, 173, 174 Micropapillae comprising cellular tufts lumnar, flattened, dome shaped, or hobnailed. The are sometimes formed. Follicles are frequently cytoplasm is lightly eosinophilic to amphophilic, but present. They vary in size and contour but are com- it can be oxyphilic or clear.31, 34, 185–187 Cytoplasmic monly elongated or irregularly shaped and contain mucin can be demonstrated by histochemical stains dark-staining colloid. Some follicles can be large and in a proportion of cases.188, 189 Focal squamous differ- markedly distended with colloid. Intrafollicular entiation is common, and such foci usually do not hemorrhage is common. There is often an intricate exhibit the characteristic nuclear features of papil- blending of the follicles and papillae, resulting in a lary carcinoma (Fig. 44–29). complex tubulopapillary pattern (Fig. 44–26B). Less Many variants of papillary carcinoma have been common patterns are microglandular, cribriform, recognized, but only some are of prognostic signifi-

FIGURE 44–26. Papillary carcinoma. A. Arborizing papillae are evident. Psammoma bodies are seen short in the cores of some papillae. B. Complex tubulopapillary architecture is a common growth pattern. standard long

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FIGURE 44–27. Papillary carcinoma with extrathyroidal exten- FIGURE 44–29. Papillary carcinoma showing focal squamous sion. The tumor extends into the skeletal muscle of the anterior metaplasia. neck and is accompanied by a desmoplastic stroma. cance.* They are listed in Table 44–9 (Figs. 44–30 to even without excision.261 The lack of female predom- 44–42). inance in latent papillary carcinomas and the dis- sociation between the prevalence rates of latent Latent Papillary Carcinoma and clinical thyroid carcinomas suggest that most Latent papillary carcinomas are cancers inciden- latent papillary carcinomas remain dormant and tally found in thyroidectomy specimens or at au- do not grow to become clinically apparent tu- topsy. In autopsy series, they are found in approxi- mors.180, 250, 254, 262 Because latent papillary carcinomas mately 5% to 10% of cases, but the frequency ranges are innocuous, no additional therapy is required. from as high as 36% in Finland to as low as 1.2% Latent papillary carcinomas are almost always inSwitzerland.171, 248–257 Latent papillary carcinomas tiny and commonly show a predominantly follicular usually appear after puberty, and the prevalence architecture. Most cases exhibit an invasive stellate does not show a signiﬁcant increase with age there- contour and sclerosis; others comprise a circum- after.250, 258–260 A small proportion of cases can show scribed or encapsulated collection of neoplastic folli- regional lymph node metastasis, but the deposits are cles without intratumoral sclerosis245, 263 (Figs. 44–43 often microscopic and probably remain dormant and 44–44). Immunohistochemistry The immunohistochemical proﬁle of papillary *References 45, 72, 76, 164, 165, 170, 171, 180, 185, 190–247. carcinoma is listed in Table 44–1. The staining for

FIGURE 44–28. Papillary carcinoma. In this tumor, the nuclear features of papillary carcinoma are poorly developed. A diagnosis FIGURE 44–30. Papillary carcinoma, follicular variant. This tu- of papillary carcinoma is made because the tumor exhibits a pap- mor is composed exclusively of follicles. It is inﬁltrative and ac- illary architecture and frank invasion into the soft tissues of the companied by a sclerotic stroma, and thus recognition of the short neck. malignant nature of the neoplasm is easy. standard long

Thyroid and Parathyroid 23 top of RH

TABLE 44–9. Variants of Papillary Carcinoma

Entity for Which the Variant Variant* Deﬁning Morphologic Features May Be Mistaken Clinical Signiﬁcance

Follicular variant Composed exclusively or almost Follicular adenoma No prognostic implications exclusively of follicles Follicular carcinoma The follicles are often elongated and irregularly shaped, with abortive papillae. The colloid is often dark staining. Encapsulated variant Tumor with a distinct fibrous Follicular adenoma Highly favorable prognosis: no capsule Follicular carcinoma tumor relapse after nodulec- Capsular or vascular invasion tomy or lobectomy may or may not be present. Cystic variant Prominent cyst formation Cystic degeneration of colloid No prognostic implications There may or may not be neo- nodule plastic papillae projecting into the cystic space. Encapsulated follicu- Encapsulated tumor composed Follicular adenoma Highly favorable prognosis: no lar variant exclusively or almost exclu- Follicular carcinoma tumor relapse after treat- sively of follicles ment Diffuse sclerosing Diffuse extensive involvement Thyroiditis, especially because Some studies have reported variant of one or both lobes without of the diffuse nature of the this variant to be more ag- forming a gross tumor nod- process and frequent pres- gressive, with frequent ule ence of circulating antithy- lymph node and sometimes Thyroid parenchyma shows roid antibodies distant metastases, but out- sclerosis and lymphoid infil- come is still favorable be- tration. Tumor islands are of- cause of the young age of ten small and dispersed, with patients (favorable prognos- many lying within lymphatic tic factor). spaces. Some studies have not shown Tumor commonly shows squa- this variant to exhibit a high mous metaplasia and promi- metastatic rate. nent psammoma body formation. Diffuse follicular Diffuse involvement of the en- Colloid goiter More aggressive, with frequent variant tire thyroid without forma- lymph node and distant me- tion of discrete tumor nod- tastases, but outcome is still ules, and composed entirely favorable because of the of follicles young age of patients (favor- No fibrosis able prognostic factor) and good response to radioactive iodine therapy. Macrofollicular vari- Presence of many large folli- Nodular goiter No prognostic implications ant cles, mimicking colloid nodule Tall cell variant Ͼ50% of tumor cells with a Columnar cell carcinoma As a group, tall cell variant is height of more than twice more aggressive than con- the breadth ventional papillary carci- Tumor cells often possess oxy- noma, with larger tumors, philic cytoplasm. more frequent extrathyroidal extension, higher recurrence rate, and higher mortality (reported 9%–25%). For intrathyroidal tumors occurring in young patients, however, the prognosis appears to be similar to that of conventional papillary carcinoma. Oxyphil cell variant Ͼ50% of tumor cells with Hu¨ rthle cell adenoma or carci- No prognostic implications abundant oxyphilic cytoplasm noma Solid variant Ͼ50% of tumor showing a Poorly differentiated (insular) No prognostic implications solid growth pattern carcinoma The sheets and nests of tumor are often traversed by delicate fibrovascular septa. short Table continued on following page standard long

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TABLE 44–9. Variants of Papillary Carcinoma Continued

Entity for Which the Variant Variant* Deﬁning Morphologic Features May Be Mistaken Clinical Signiﬁcance

Trabecular variant Ͼ5% of tumor showing a tra- Follicular adenoma or carci- Some studies have shown this becular growth pattern noma, trabecular (embryonal) variant to have a less favor- type able outcome. Cribriform-morular An intricate admixture of crib- Columnar cell carcinoma Familial adenomatous polyposis variant riform structures, closely Tall cell variant of papillary car- should be excluded because packed small follicles, papil- cinoma the papillary carcinomas as- lae, and squamoid islands sociated with the syndrome (morulas) commonly exhibit histologic Colloid is usually scanty or ab- features of this variant. sent. By itself, the variant has no Some tumor cells in the morula prognostic implications. contain nuclei with a lightly eosinophilic homogeneous appearance caused by biotin accumulation. The tumor cell nuclei are often more hyperchromatic and pseudostratified compared with classic papillary carcinoma. Variant with nodu- Presence of abundant nodular Nodular fasciitis No prognostic implications lar fasciitis–like fasciitis–like or fibromatosis- Fibromatosis stroma like reactive stroma Benign mesenchymal neoplasm The papillary carcinoma component can be masked by the stromal component or shows peculiar architectural features reminiscent of fibro- cystic disease or phyllodes tumor of the breast. Warthin tumor–like Presence of broad papillae cov- Hashimoto’s thyroiditis No prognostic implications variant ered by oxyphilic neoplastic cells, with the cores being packed with lymphoid cells, reminiscent of Warthin tumor of salivary gland Papillary microcarci- Small tumor, Ͻ1 cm Multifocal fibrosing thyroiditis Highly favorable prognosis noma Hyperplastic adenomatoid nod- Virtually all patients remain ule well on long-term follow-up. The rare patients who have an unfavorable outcome are those with lymphadenopathy Ͼ3 cm and a nonencapsulated type of primary lesion. Dedifferentiated Papillary carcinoma accompa- — High mortality rate papillary carci- nied by an anaplastic carcinoma noma or poorly differentiated thyroid carcinoma, indicating transformation to a higher-grade neoplasm

* All variants show the typical nuclear characteristics of papillary carcinoma, at least in some areas of the tumor. thyroglobulin is patchy, and it is often absent in roid lesions in difﬁcult cases,264–267 the results are areas of squamous differentiation. The main applica- not consistent enough for routine application. tion of immunohistochemical staining is in conﬁrma- tion of the thyroid origin of metastatic carcinoma, Cytogenetics and Molecular Biology such as cystic metastasis of papillary thyroid carci- The key molecular change in papillary carcinoma in a cervical lymph node. Although staining noma involves activation of the proto-oncogene RET for high-molecular-weight cytokeratin or cytokeratin or NTRK1 by intrachromosome inversion or chromo- 19 has been suggested to be of value in supporting a some translocation.268–270 Constitutive activation of diagnosis of papillary carcinoma versus benign thy- RET (a receptor tyrosine kinase) occurs through fu- short standard long

Thyroid and Parathyroid 25 top of RH

FIGURE 44–31. Papillary carcinoma, encapsulated follicular variant. A. The encapsulated tumor is composed exclusively of follicles, rendering distinction from follicular adenoma or follicular carcinoma difﬁcult. The clues to diagnosis are dark-staining colloid, elongated follicles, and presence of abortive papillae. B. The follicles are lined by cells with crowded, pale, and grooved nuclei, compatible with papillary carcinoma. sion of the RET gene with a gene commonly ex- The RET/PTC translocation occurs in approximately pressed in thyroid epithelial cells, such as PTC1 30% to 40% of papillary carcinomas, but the fre- through inv(10)(q11.2q21), PTC2 through t(10;17) quency is higher in children and young patients, (q11.2;q23), and PTC3 through cytogenetically unde- Chernobyl accident–associated tumors, and patients tectable paracentric inversion within 10q11.2.271–277 who received external radiation during child-

FIGURE 44–32. Papillary carcinoma, cystic variant. A. The cyst has a ﬁbrous wall lined by attenuated epithelium and can potentially be mistaken for cystic degeneration of colloid nodule. B. In the wall, there are occasional follicles lined by cells with active- looking and crowded nuclei. C. Focally, short papillae lined by cells exhibiting features of papillary carcinoma are identiﬁed, per- mitting the correct diagnosis to be made. short standard long

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FIGURE 44–33. Papillary carcinoma, diffuse sclerosing variant. A. The thyroid gland shows sclerosis and chronic inflammation, mimicking thyroiditis. However, linear scratches on the slide suggest the presence of calcified psammoma bodies. B. Hiding within the gland are islands of papillary carcinoma. A psammoma body is seen in the left lower field.

FIGURE 44–34. Papillary carcinoma, diffuse follicular variant. A. The neoplasm shows extensive involvement of the thyroid without discrete nodule formation or sclerosis and thus can be mistaken for a diffuse goiter, especially because some follicles are large. B. Careful examination of the smaller follicles reveals cytologic features of papillary carcinoma.

FIGURE 44–35. Papillary carcinoma, tall cell variant. A. The neoplastic cells are tall columnar and exhibit oncocytic cytoplasmic features. The nuclear features are no different from those of conventional papillary carcinoma. B. In this unusual example, the cells show cytoplasmic clearing. short standard long

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FIGURE 44–36. Papillary carcinoma, oncocytic variant. The cu- FIGURE 44–37. Papillary carcinoma, solid variant. Solid islands boid and polygonal tumor cells possess abundant eosinophilic of tumor are often traversed by delicate capillaries. The character- granular cytoplasm. istic nuclear features of papillary carcinoma are present.

hood.62, 278–296 Activation of the NTRK1 gene product (a receptor for nerve growth factor) occurs through fusion with widely expressed “housekeeping” genes, such as TPM3 (tropomyosin gene), TPR, and TAG.268, 280, 281, 285, 297–299 Differential Diagnosis The main criteria and problems in diagnosis of papillary carcinoma are listed in Table 44–10.300 Some immunohistochemical markers, such as expression of high-molecular-weight cytokeratin (34␤E12, cytokeratin 1), cytokeratin 19, vimentin, mesothelium-associated antibody HBME-1, Leu-7 (CD57), CD15 (Leu-M1), or CD44, and loss of expression of thyroid peroxidase or retinoblastoma FIGURE 44–38. Papillary carcinoma, trabecular variant. protein have been reported to be of value in distin-

FIGURE 44–39. Papillary carcinoma, cribriform-morular variant. A. There is an intricate blend of cribriform structures, empty follicles, and solid foci. B. Papillae merge into a morular structure. Highly characteristic homogeneous, lightly eosinophilic biotin inclusions are seen in the nuclei of the morula. The tumor cells are often more chromatin rich than in a usual case of papillary carcinoma. short standard long

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FIGURE 44–40. Papillary carcinoma, variant with nodular fasciitis–like stroma. A. The interaction of the abundant fibrocellular stroma with the papillary carcinoma results in a peculiar pattern mimicking sclerosing adenosis of the breast. B. The stroma comprises loose fascicles of active-looking myofibroblasts, mimicking nodular fasciitis or fibromatosis.

FIGURE 44–41. Papillary carcinoma, Warthin tumor–like vari- FIGURE 44–42. Papillary carcinoma, dedifferentiated variant. ant. The resemblance to Warthin tumor of the salivary gland is Papillary carcinoma component is shown on the left; the anaplas- striking. The neoplastic cells show oncocytic change. tic carcinoma comprising pleomorphic spindly cells is shown on the right.

FIGURE 44–43. Latent papillary carcinoma as an incidental finding. A. Near the central field, there is a collection of small follicles representing latent papillary carcinoma. It is not accompanied by a sclerotic stroma. B. The follicles are lined by cells with large pale nuclei lacking polarity (left field), characteristic of papillary carcinoma. Note the abrupt difference in nuclear features compared with the adjoining normal follicles (right field). short standard long

Thyroid and Parathyroid 29 top of RH

toid nodules are often broad, with small follicles in the loose core. The cells are usually columnar, with dark round nuclei regularly aligned at the base of the cells. In some colloid or adenomatoid nodules, there can be collections of follicles with pale or clear nuclei, raising a concern for papillary carcinoma. However, a diagnosis of papillary carcinoma (follicular variant) should not be made unless there are totally convincing nuclear features (see Figs. 44–24 and 44–31 and Table 44–10). The neoplastic follicles of papillary carcinoma should show an abrupt change from the surrounding benign follicles, often accompanied by enlargement of the nuclei (see Fig. 44–43). In contrast, the atypical follicles of adenomatoid nodule typically show gradual transition with FIGURE 44–44. Latent papillary carcinoma as an incidental ﬁnd- the surrounding benign follicles. ing. This microcarcinoma shows a papillary architecture. FOLLICULAR ADENOMA WITH PAPILLARY HY- PERPLASIA. Distinguishing features from papillary carcinoma are the same as those for colloid nodule. guishing papillary carcinoma from benign thyroid lesions and other thyroid tumors, but so far none of FOLLICULAR ADENOMA. Some follicular adeno- these makers is reliable enough to aid in routine mas may have some pale or clear nuclei, raising the 138, 139, 265, 266, 301–314 diagnosis of papillary carcinoma. possibility of follicular variant of papillary carci- Future studies are required to determine whether noma. The nuclear clearing is often artifactual be- overexpression of RET by in situ hybridization or cause of delayed ﬁxation, with “blowing up” of the immunohistochemistry can aid in the diagnosis of nuclei (see Fig. 44–11). Convincing nuclear features papillary carcinoma. Currently, morphologic assess- must be present in rendering a diagnosis of papil- ment remains the gold standard in rendering a diag- lary carcinoma in an encapsulated follicular neo- nosis of papillary carcinoma. plasm because there is no harm in missing an en- COLLOID NODULE. In contrast to papillary car- capsulated papillary carcinoma, which has an cinoma, the papillae found in colloid or adenoma- excellent prognosis (see Table 44–9).

TABLE 44–10. Key Points and Caveats in Diagnosis of Papillary Carcinoma

Diagnostic criteria for papillary carcinoma are based on a constellation of features, no single one of which is pathognomonic. For a noninvasive tumor, the diagnostic label “papillary carcinoma” should be applied only when the typical cytologic features are well developed. Basic criteria • Cytologic features: ovoid nuclei that are crowded, without polarization, clear or pale, and grooved, with or without pseudoinclusions • Demonstration of vascular or capsular invasion is not required Strong supporting feature, if present • Psammoma bodies Other supporting histologic features • Papillae (including abortive papillae) • Follicles that are elongated or irregularly shaped • Dark-staining colloid • Multinucleated histiocytes in lumina of follicles or papillae Deceptively “benign” patterns warranting serious consideration of the possibility of papillary carcinoma: • “Colloid nodule” with delicate papillary budding in some follicles, or psammoma bodies, or many clear nuclei (papillary carcinoma, macrofollicular variant) • Hashimoto’s or lymphocytic thyroiditis–like picture, but with many “knife marks” on the histologic section due to presence of psammoma bodies (diffuse sclerosing variant of papillary carcinoma) • “Follicular adenoma” with many elongated follicles and dark-staining colloid or abortive papillae (papillary carcinoma, encapsulated follicular variant) • “Degenerate cyst,” but with occasional small papillary tufts projecting into the lumen or some follicles in the ﬁbrous wall lined by cells with high nuclear-to-cytoplasmic ratio (cystic variant of papillary carcinoma) • Spindle cell proliferation resembling nodular fasciitis or ﬁbromatosis (papillary carcinoma variant with exuberant nodular fasciitis–like stroma) short standard long

30 Endocrine System top of RH

COLUMNAR CELL CARCINOMA. See later. MEDULLARY CARCINOMA WITH PSEUDOPAPIL- LARY PATTERN. See later. PROGNOSTIC CONSIDERATIONS Papillary carcinoma is an indolent neoplasm. Ac- cording to a long-term follow-up study from the Mayo Clinic, the cancer-related mortality is only 6.5%.164 The tumor is locally invasive and has a pro- pensity to metastasize to regional lymph nodes, but distant metastasis is uncommon and often late (ϳ 10%).73, 192, 193, 315, 316 The most significant prognostic factors are age, stage, and tumor size. To aid in prediction of outcome and selection of therapy, a number of parameters (such as age, metastasis, extent of primary can- FIGURE 44–45. Papillary carcinoma with marked cellular atypia cer, and tumor size) are taken into consideration (grade 2). Some studies have shown this feature to be associated to divide patients into low-risk and high-risk with a worse prognosis. groups.317–320 The low-risk group has an excellent prognosis, and conservative therapy can be considered. The high-risk group has a worse outcome, and thus more aggressive therapy is required. necrosis, or vascular invasion, has been reported to be associated with a worse prognosis.339, 343 AGE. Young age is an important favorable prognostic factor. Few patients younger than 40 years die STROMAL REACTION. Chronic thyroiditis in the of papillary carcinoma.164, 165, 241, 321–329 background thyroid tissue and stromal bone formation have been reported to be favorable prognostic SEX. The male sex is often associated with a factors.178, 329 worse prognosis.226, 323, 325, 326, 329–332 VASCULAR INVASION. Invasion of sizable blood TUMOR SIZE. Risk of death from papillary carci- vessels is an unfavorable prognostic factor.77, 192 noma increases with the size of the primary tumor.164 Microcarcinomas (Ͻ 1 to 1.5 cm) have an ex- IMMUNOHISTOCHEMICAL FEATURES. High den- cellent prognosis, whereas tumors larger than 4 cm sity of S-100 protein–positive histiocytes is a favor- 344 fare worse.78, 164, 241, 325, 333 able prognostic factor. The features associated with a worse prognosis are Leu-M1 positivity, epi- TUMOR STAGE. Extrathyroidal extension wors- thelial membrane antigen positivity, p53 protein ens the prognosis, which is even worse when there 164, 325, 327, 334, 335 immunoreactivity, lack of E-cadherin expression, is invasion of the esophagus or trachea. and low-level expression of retinoblastoma pro- Presence of distant metastasis is a highly unfavor- tein.160, 303, 345–348 able prognostic feature.157 Papillary carcinoma is unique among carcinomas in that most studies have TUMOR ANGIOGENESIS. Whereas some studies not found lymph node metastasis to be of prognos- have suggested that a high microvessel count (intra- tic significance.* tumoral microvessel count as highlighted by immunostaining for vascular markers) correlates with a TUMOR ENCAPSULATION. Encapsulated papil- worse prognosis, other studies cannot confirm this lary carcinomas have an excellent prognosis. There finding.349–351 is no recurrence after excision of the tumor.72, 192, 196 DNADNA P LOIDY. Multiploidy or aneuploidy is an HISTOLOGIC VARIANTS. The prognostic signifi- unfavorable prognostic factor.178, 352 cance of the variants is listed in Table 44–9.340 N-N-RAS MUTATION. N-ras mutation at codon 61, COMPLETENESS OF EXCISION. Incomplete tumor 319, 341 which is uncommon, is associated with a more ag- excision increases the probability of recurrence. gressive behavior.353 HISTOLOGIC FEATURES. The histologic features shown in some studies to be associated with a worse prognosis are marked cellular atypia (multi- Poorly Differentiated Thyroid layered cells with marked variation in cellular and Carcinoma nuclear size and shape, uneven distribution of chro- 237, 331, 332, 342 matin) and trabecular growth pattern CLINICAL CONSIDERATIONS (Fig. 44–45). High tumor grade (grade 2), as defined by the presence of marked nuclear atypia, tumor Presentation Poorly differentiated thyroid carcinoma shows histologic and biologic features intermediate between differentiated thyroid carcinomas and ana- short *References 77, 164, 321, 324, 325, 328, 329, 336–339. plastic carcinomas.342, 354–357 It retains sufficient dif- standard long

Thyroid and Parathyroid 31 top of RH ferentiation to form small follicular structures and to numbers of small abortive follicles (Fig. 44–46). It is produce thyroglobulin, but it lacks the usual mor- common to observe retraction artifacts around the phologic characteristics of papillary and follicular tumor islands. The frequent presence of coagulative carcinoma.358 The morphologic spectrum of poorly necrosis results in a characteristic “peritheliomatous” differentiated thyroid carcinoma is broad, and insu- appearance. The tumor can also form diffuse sheets, lar carcinoma is the best characterized form.354 An trabeculae, festoons, and papillae (Fig. 44–47). Vas- alternative designation of “primordial cell carci- cular invasion is common.354, 360 Some cases may noma” has also been proposed in view of the cy- show transition with typical papillary carcinoma or toarchitectural resemblance to the fetal thyroid.355 follicular carcinoma. The tumor cells are relatively Poorly differentiated carcinomas can arise de small, with uniform round, hyperchromatic nuclei, novo or transform from differentiated thyroid carci- indistinct nucleoli and scanty cytoplasm355 (Fig. 44– nomas, either after repeated recurrences or with the 48). Some mitotic figures can often be identified. two components being discovered simultaneously at There is a morphologic range of poorly differen- diagnosis.238, 359 They can further transform to ana- tiated thyroid carcinomas that do not fit the histo- plastic carcinoma. logic description of insular carcinoma. They are The tumor predominantly affects middle- composed of large cells growing in a trabecular, aged and elderly adults, with a mean age of 54 cribriform, solid, or focally follicular pattern355 (Fig. years.89, 354, 355, 358 Women are more commonly af- 44–48B). fected than are men (male-to-female ratio ϭ 1 : 2). Most patients present with an enlarging thyroid Immunohistochemistry mass, and there may be a preceding history of long- Poorly differentiated thyroid carcinoma is im- standing goiter. Rare patients present with bone me- munoreactive for cytokeratin, thyroglobulin, and tastasis. The disease is often locally advanced at pre- thyroid transcription factor 1. The positive staining sentation, with extrathyroidal extension in more for thyroglobulin may be confined to the abortive 89 than 50% of cases. Lymph node and distant metas- follicles and isolated cells in the form of paranuclear tases are already present at presentation in approxi- globules.354, 355, 361 There is reduced expression of the mately 40% and approximately 30% of cases, respec- cyclin-dependent kinase inhibitor p27 and a higher 89, 354, 358 tively. Ki-67 index compared with differentiated thyroid 357, 362 Macroscopic Findings carcinomas. Positive staining for Bcl-2 is common (84%), contrasting with the infrequent positive The tumor is partially encapsulated or frankly staining in anaplastic carcinomas (14%).363 invasive. It is often large, with a mean size of 358 4.7 cm. The cut surface is solid, firm, and fleshy, Molecular Biology often punctuated by areas of necrosis and hemorrhage. Approximately half of the cases of poorly differentiated thyroid carcinomas show immunoreactivity for p53 protein, whereas this feature is uncommon DIAGNOSTIC CONSIDERATIONS in well-differentiated thyroid carcinomas but common in anaplastic carcinomas. Thus, it appears that Microscopic Findings TP53 gene mutation may play a role in the genesis Insular carcinoma typically grows in the form of of some cases.363, 364 The finding of point mutations large solid nests (insulae) decorated with variable in the ras oncogene in a proportion of cases suggests

FIGURE 44–46. Insular carcinoma. A. The tumor is inﬁltrative and highly cellular. B. The tumor short frequently forms islands punctuated by small follicles. standard long

32 Endocrine System top of RH

FIGURE 44–47. Insular carcinoma. A. A “peritheliomatous” pattern results from degeneration and necrosis of tumor away from the blood vessels. B. A festooning pattern is also common. C. A papillary pattern is occasionally observed.

FIGURE 44–48. Poorly differentiated carcinoma. A. In insular carcinoma, the tumor cells are typically small and monotonous, with fairly uniform dark-staining nuclei. Some mitotic figures can often be identified. Note the focal differentiation into small follicles. B. In this poorly differentiated thyroid carcinoma, the right lower field shows cytologic features characteristic of insular carcinoma. In the left upper field, the cells are slightly larger and more pleomorphic, with brisk mitotic activity. This component is still a form of poorly differentiated rather than anaplastic carcinoma because there is organoid arrangement of the tumor cells and immunoreactivity for thyroglobulin. short standard long

Thyroid and Parathyroid 33 top of RH a relationship with follicular carcinoma in such Macroscopic Findings 89, 365 cases. Anaplastic thyroid carcinoma typically shows infiltration of the perithyroid soft tissues and adjacent Differential Diagnosis structures, such as the larynx and pharynx. The tu- MEDULLARY CARCINOMA. Insular carcinoma mor is fleshy, with areas of necrosis and hemor- may mimic medullary carcinoma as a result of the rhage. growth pattern and amyloid-like sclerosis. The distinction can be readily made by immunostaining for DIAGNOSTIC CONSIDERATIONS thyroglobulin and calcitonin (see Table 44–1). Microscopic Findings ANAPLASTIC THYROID CARCINOMA. Poorly differentiated carcinoma lacks the prominent nuclear Anaplastic thyroid carcinoma is characterized by pleomorphism and frequent mitoses of anaplastic highly pleomorphic tumor cells that lack any orga- 238, 374 carcinoma and furthermore shows abortive follicles noid growth pattern (Fig. 44–49). The tumor and thyroglobulin immunoreactivity. grows in diffuse sheets, irregular islands, cords, and fascicles. The tumor cells are large and are polygo- SOLID VARIANT OF PAPILLARY CARCINOMA. nal, ovoid, or spindly; some foci can show squa- See Table 44–9. mous differentiation229 (Fig. 44–50). A pseudoan- PROGNOSTIC CONSIDERATIONS giomatoid pattern resembling angiosarcoma can be seen in some cases (Fig. 44–51). Mitotic figures are Recurrence or metastasis develops in approximately frequent, and coagulative tumor necrosis is often ex- 60% of cases after treatment.89, 354, 355 In contrast to tensive (see Fig. 44–49). There is a tendency for the the rapidly fatal course of anaplastic carcinoma, tumor cells to permeate and replace the walls of poorly differentiated carcinoma causes death after blood vessels, obliterating their lumina238 (Fig. several years (mean survival, 3.9 years). The long- 44–52). There are commonly some admixed inflam- term survival rate is around 40%.89, 354–356, 366 Death matory cells, particularly neutrophils. is often attributable to metastasis rather than to un- A component of papillary carcinoma, follicular controllable local disease. The treatment usually con- carcinoma, or poorly differentiated thyroid carci- sists of total thyroidectomy, radioactive iodine, and noma can be found in approximately 50% of cases, suppressive thyroxine.354 Radiotherapy and chemo- suggesting that the anaplastic carcinoma arises therapy may also be considered in view of the unfa- through a process of “dedifferentiation”238, 354, 366, 373–377 vorable prognosis. Poor prognostic factors include (Fig. 44–53). advanced age, large tumor size, extrathyroidal ex- The morphologic variants of anaplastic carci- tension, lymph node metastasis, and presence of an noma are listed in Table 44–11 (Figs. 44–54 and anaplastic carcinoma component.356 44–55).300, 373, 378–391 True “small cell” anaplastic carci- Whether the presence of a minor component of nomas are extremely rare; most cases diagnosed as poorly differentiated carcinoma worsens the progno- such in the past represent malignant lymphoma, sis of an otherwise typical differentiated thyroid car- medullary carcinoma, or poorly differentiated thy- cinoma remains controversial.360, 367–369 The outcome roid carcinoma.238, 373, 374, 392–396 will probably be worsened if the poorly differentiated carcinoma component is found in the invasive portions of the tumor but not if the component is confined to an encapsulated tumor.

Anaplastic (Undifferentiated) Carcinoma

CLINICAL CONSIDERATIONS Presentation Anaplastic carcinoma is predominantly a disease of older adults with a mean age of 67 years; there is a slight female predominance.238, 370–372 The patients present with a rapidly enlarging thyroid mass or metastatic tumor in cervical lymph nodes or distant sites. The mass lesion is frequently accompanied by hoarseness, dysphagia, and dyspnea. Some patients have a history of long-standing goiter or well-differ- 238, 359, 370, 373, 374 entiated thyroid carcinoma. Squamous FIGURE 44–49. Anaplastic carcinoma. The tumor is solid grow- cell carcinoma and carcinosarcoma can be consid- ing, lacking organoid features. Coagulative necrosis is a common ered variants of anaplastic carcinoma. ﬁnding. short standard long

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FIGURE 44–50. Anaplastic carcinoma. A. This tumor is composed of ovoid and plump spindly cells with signiﬁcant nuclear pleomorphism. Many tumor cells possess multiple large nucleoli. B. This tumor is composed of spindly cells with distinct nucleoli.

FIGURE 44–51. Anaplastic carcinoma. This tumor shows cellular FIGURE 44–52. Anaplastic carcinoma. A highly characteristic dehiscence and interstitial hemorrhage, mimicking angiosarcoma. feature is obliteration of the wall and lumen of large blood vessels by tumor cells.

FIGURE 44–53. Anaplastic carcinoma. A. A component of Hu¨ rthle cell neoplasm (left ﬁeld)isfound in this anaplastic carcinoma. B. At the interface between the two components, there are highly atypical Hu¨ rthle cells that merge into the anaplastic carcinoma, suggesting transformation of Hu¨ rthle short cell neoplasm into anaplastic carcinoma. standard long

Thyroid and Parathyroid 35 top of RH

TABLE 44–11. Variants of Anaplastic Thyroid Carcinoma

Entity for Which the Variant May be Variant* Deﬁning Morphologic Features Mistaken

Angiomatoid variant Presence of irregular cleftlike tumor cell–lined Angiosarcoma spaces mimicking vascular spaces Osteoclastic variant Reactive osteoclastic giant cells are interspersed in Giant cell tumor of larynx (thyroid cartilage) an otherwise typical anaplastic carcinoma Paucicellular variant Low-cellularity tumor with large areas of sclerosis Riedel’s thyroiditis and infarction. A sprinkling of lymphocytes is often present. Focally, spindly tumor cells with mild to moderate nuclear atypia can be identi- ﬁed. These spindle cells also obliterate the wall and lumina of blood vessels. Lymphoepithelioma-like Irregular inﬁltrative islands and sheets of syncytial- CASTLE variant appearing pleomorphic tumor cells, heavily intermingled with lymphocytes and plasma cells Squamous cell carcinoma Identical to squamous cell carcinoma occurring in CASTLE other sites Adenosquamous carcinoma Squamous cell carcinoma with areas of mucin pro- — duction Carcinosarcoma Anaplastic carcinoma accompanied by a sarcoma- — tous component with muscle, fat, cartilage, or bone differentiation

* None of these variants has clinical or prognostic signiﬁcance.

Immunohistochemistry for factor VIII–related antigen has been reported, In anaplastic carcinoma, epithelial markers can- possibly indicating focal divergent endothelial differ- 398 not be consistently demonstrated, except in areas of entiation. squamous differentiation. Cytokeratin is positive in Molecular Biology only approximately half of the cases, whereas epithelial membrane antigen is positive in only 33% to Aberrations in the p53 pathways have been im- 55%.238, 370, 372, 397, 398 Vimentin is positive in 50% to plicated in the transformation of differentiated thy- 364, 377, 400–404 100% but has no diagnostic value.372, 397 roid carcinoma to anaplastic carcinoma. Thyroglobulin and thyroid transcription factor 1 The anaplastic carcinoma component commonly are negative in the anaplastic carcinoma component, shows strong immunoreactivity for p53 protein, but immunostaining for these markers can some- whereas the differentiated thyroid carcinoma com- ␤ times highlight the preexisting differentiated thyroid ponent is negative. The -catenin gene commonly carcinoma component if it is present.2, 3, 370, 393, 399 shows somatic mutations in anaplastic carcinoma Calcitonin is negative.238, 370 Focal immunoreactivity and may thus play a key role in the development of this tumor type.405 Differential Diagnosis The main pitfalls in diagnosis of anaplastic carcinoma are listed in Table 44–12. SARCOMA. Anaplastic carcinomas composed predominantly of spindly cells are difficult to distinguish from sarcomas. However, because primary sarcomas of the thyroid are rare, they should be diagnosed only when there is strong proof of a definite line of differentiation, such as smooth muscle or nerve sheath differentiation.238 LARGE CELL LYMPHOMA. Large cell lymphoma can be distinguished from anaplastic carcinoma by the poor cellular cohesion, presence of plasmacytoid or amphophilic cytoplasm, infiltration of thyroid follicular epithelium, stuffing of follicular lumina by tumor cells, and immunohistochemical expression of leukocyte markers. FIGURE 44–54. Anaplastic carcinoma, osteoclastic variant. Non- neoplastic osteoclast giant cells are dispersed among the highly METASTATIC CARCINOMA. Clinical correlation short pleomorphic ovoid tumor cells. is required to distinguish anaplastic carcinoma from standard long

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FIGURE 44–55. Anaplastic carcinoma, paucicellular variant. A. The tumor infiltrates and replaces the thyroid parenchyma. The extremely low cellularity, fibrosis, and sprinkling of chronic inflammatory cells impart an impression of thyroiditis. B. In areas, there is dense fibrous tissue with ghost shadows of blood vessels, indicating prior infarction of the tissue. C. Careful scrutiny of the less hypocellular areas reveals myofibroblast-like spindly cells that are in fact tumor cells. Mild nuclear atypia is evident. D. Identification of blood vessels showing obliteration by atypical spindly cells provides the best clue to the diagnosis of anaplastic carcinoma.

metastatic carcinoma, although metastatic carcinoma with the adjacent tissue, and cytokeratin immunore- should be suspected if the bulk of the tumor lies activity. within lymphovascular spaces. The presence of a ANGIOSARCOMA. See later. component of differentiated thyroid carcinoma strongly favors the diagnosis of anaplastic carci- SOLID VARIANT OF PAPILLARY CARCINOMA. noma. The solid variant of papillary carcinoma can be distinguished from anaplastic carcinoma by the typical PARATHYROID CARCINOMA. Parathyroid carci- nuclear features, lack of bizarre cells, and paucity of noma presenting as a thyroid mass is not uncom- mitotic figures. monly misdiagnosed as anaplastic thyroid carcinoma. The distinction is important because POORLY DIFFERENTIATED THYROID CARCI- parathyroid carcinoma is a much more indolent neo- NOMA. Poorly differentiated thyroid carcinoma usu- plasm. Histologic clues to the correct diagnosis are ally shows definite cellular organization into islands presence of clear cells, mixture of cell types, paucity with microfollicles, relatively small cells, fairly uni- of mitotic figures, and prominent delicate vascula- form nuclei, lack of bizarre cells, and thyroglobulin ture. immunoreactivity. RIEDEL’S THYROIDITIS. The paucicellular variant THYMIC AND RELATED TUMORS. See later. of anaplastic carcinoma can be mistaken for Riedel’s thyroiditis, which has a favorable prognosis. Fea- PROGNOSTIC CONSIDERATIONS tures favoring the diagnosis of a paucicellular vari- Anaplastic carcinoma is inoperable in about half of ant of anaplastic carcinoma are presence of infarc- the cases because of extensive local disease. Regional tion, cytologic atypia (albeit focal and often subtle), lymph node and distant metastases (mostly lungs, short vascular occlusion by spindle cells, discrete interface sometimes bones) are common. The cause of death standard long

Thyroid and Parathyroid 37 top of RH

TABLE 44–12. Main Pitfalls in Diagnosis of Anaplastic for anaplastic carcinoma include large tumor size Thyroid Carcinoma (Ͼ 6 cm), extension of tumor beyond the neck, old age at diagnosis, male gender, and dyspnea as a Entities That May Cause the presenting symptom.406 Main Diagnostic Pitfall Diagnostic Confusion

Benign lesions mimicking an- Reparative cellular atypia in aplastic thyroid carcinoma benign tumor attributable Columnar Cell Carcinoma to infarction or fine-needle aspiration injury CLINICAL AND PROGNOSTIC Florid granulation tissue for- CONSIDERATIONS mation resulting from organization of infarcted tu- Although columnar cell carcinoma was originally re- mor ported as an aggressive neoplasm,413 studies have Inflammatory pseudotumor shown that aggressive behavior is observed only in Low-grade malignant tumors Papillar carcinoma, solid vari- the frankly invasive tumors. For invasive tumors, mimicking anaplastic thy- ant there is slight male predilection and the mean age is roid carcinoma Mucoepidermoid carcinoma 55.6 years.413–422 There is a high frequency of re- Sclerosing mucoepidermoid carcinoma with eosino- gional lymph node and distant metastases. The mor- philia tality rate, which is at least 75%, is high. In contrast, Thymic and branchial pouch– for encapsulated tumors, there is marked female related tumors (ectopic predominance and patients are younger (mean, thymoma, SETTLE, CASTLE) 414, 422–425 Parathyroid carcinoma 42.7years). Most patients remain well on Malignant lymphoma follow-up. Anaplastic thyroid carcinoma Paucicellular variant, which There are divergent views on the nature of co- variant potentially misdi- may be mistaken for Rie- lumnar cell carcinoma: a distinct tumor type versus agnosed as benign or low- del’s thyroiditis a variant of thyroid carcinoma. In fact, occasional grade malignant lesions Lymphoepithelioma-like car- cases show merging with tall cell papillary carci- cinoma variant, which may noma.419, 421, 422, 426, 427 There is also some morphologic be mistaken for CASTLE or malignant lymphoma overlap with the cribriform-morular variant of papillary carcinoma and familial adenomatous polyposis– associated thyroid carcinoma. DIAGNOSTIC CONSIDERATIONS is usually upper airway obstruction from extensive Microscopic Findings local disease or a combination of the effects of local Columnar cell carcinoma shows heterogeneous and metastatic disease.406 The median survival is growth patterns, including papillary, complex glan- only 3 to 4 months, and the 5-year survival rate dular, cribriform, and solid. The cells are tall colum- is 5% to 10%.366, 377, 407–409 The rare patients who nar and characteristically show marked nuclear can achieve a cure usually have relatively small pseudostratification and hyperchromasia, reminis- (Ͻ 5 cm) tumors confined to the thyroid gland and cent of colorectal adenocarcinoma or endometrioid have been treated with aggressive local interven- adenocarcinoma (Fig. 44–56). Subnuclear vacuoles tion.374, 406, 407, 410–412 Unfavorable prognostic factors and diffuse cytoplasmic clearing can sometimes oc-

FIGURE 44–56. Columnar cell carcinoma. A. Complex tubulopapillary structures characterize the growth pattern of this tumor. B. The lining cells are markedly pseudostratiﬁed cells and possess short chromatin-rich nuclei. standard long

38 Endocrine System top of RH cur. Short fascicles of spindle cells can also be nent, if present, is immunoreactive for thyroglobu- present. The follicular epithelial nature of the tumor lin.428–432, 435, 438, 441a is evidenced by thyroglobulin immunoreactivity. Differential Diagnosis Sclerosing Mucoepidermoid Columnar cell carcinoma can be distinguished Carcinoma with Eosinophilia from tall cell papillary carcinoma by the features of taller cells, striking nuclear pseudostratification, nu- CLINICAL AND PROGNOSTIC clear hyperchromasia, and lack of oxyphilic change. CONSIDERATIONS Sclerosing mucoepidermoid carcinoma with eosinophilia is a low-grade malignant neoplasm that usu- Mucoepidermoid Carcinoma ally arises in a background of fibrosing Hashimoto’s thyroiditis.443 It affects adults with a mean age of 55 CLINICAL AND PROGNOSTIC years, and there is a marked female predomi- CONSIDERATIONS nance.436, 441a, 443–447 Regional or distant metastases This is a rare tumor showing female predominance. are uncommon, and the outcome is generally favor- The mean age is 37.9 years.428–441a The patients able.436, 441a, 443–446 present with a thyroid mass. Lymph node metasta- DIAGNOSTIC CONSIDERATIONS sis is common (60%), but distant metastasis is rare (13%). This is a low-grade malignant neoplasm; Microscopic Findings and most patients remain well after treatment. Immunohistochemistry The nature of mucoepidermoid carcinoma is Sclerosing mucoepidermoid carcinoma with eo- controversial: origin from ultimobranchial body,442 sinophilia is typically infiltrative, and there may be origin from thyroglossal duct,436 or merely a meta- extrathyroidal extension. Anastomosing cords and plastic variant of papillary carcinoma. In some cases, nests of tumor cells are associated with a sclerotic a component of conventional papillary carcinoma stroma infiltrated by eosinophils. The tumor cells are can be identified.434, 435, 437–441a polygonal, with mild to moderate nuclear pleomorphism and distinct nucleoli. There can sometimes be DIAGNOSTIC CONSIDERATIONS foci of squamous differentiation and small pools of The tumor comprises tumor cell islands that infil- mucin (Fig. 44–58). Tumor cell dehiscence may pro- trate a sclerotic stroma. The tumor cells are squa- duce a pseudoangiomatous appearance. The tumor moid to squamous, and there are interspersed mu- cells are immunoreactive for cytokeratin but not for cin-secreting cells (Fig. 44–57A). In areas, a thyroglobulin and calcitonin. cribriform pattern with elongated lumina containing colloidlike material can be found. The nuclei are hy- Differential Diagnosis perchromatic or pale; nuclear pleomorphism is mild The most important reasons to recognize scleros- to moderate (Fig. 44–57B). Comedo-type necrosis or ing mucoepidermoid carcinoma with eosinophilia psammoma bodies can sometimes be found. The tu- are not to mistake it for the vastly more aggressive mor usually does not show immunoreactivity for anaplastic or squamous carcinomas of the thyroid thyroglobulin while the papillary carcinoma compo- on the one hand and not to misdiagnose it as be-

FIGURE 44–57. Mucoepidermoid carcinoma. A. Irregular islands of tumor inﬁltrate a desmoplastic stroma. Multiple mucin-containing cystic spaces are interspersed within the tumor islands. B. The tumor cells often have bland-looking and pale-staining nuclei. short standard long

Thyroid and Parathyroid 39 top of RH

FIGURE 44–58. Sclerosing mucoepidermoid carcinoma with eosinophilia. A. Cords of polygonal tumor cells with distinct nucleoli infiltrate a sclerotic stroma richly infiltrated by eosinophils and lymphocytes. B. Irregular islands of squamoid cells are intermingled with eosinophils and lymphocytes. The mucinous component is usually difficult to appreciate without recourse to mucin stain. nign squamous metaplasia on the other. In contrast 44–13). Germline mutation in the RET gene is the to anaplastic or squamous cell carcinoma, the underlying molecular event.462–464 Thyroidectomy is growth pattern is more diffuse with formation of usually performed for the mutant RET gene carriers cords or large islands; nuclear atypia is generally identified through screening of family members, and not striking, and the inflammatory component is the medullary carcinomas diagnosed in such circum- usually eosinophilic rather than neutrophilic. stances are often small and at an early stage. Macroscopic Findings Mucinous Carcinoma Medullary carcinoma has a predilection for the middle third of the lateral lobe, where normal C Primary mucinous carcinoma of the thyroid is ex- cells are most prevalent.460 It is infiltrative, circum- tremely rare; only four cases have been reported in scribed, or encapsulated474, 475 (Fig. 44–59). It is firm the literature.448–451 It is histologically identical to and grayish white, tan, or reddish brown. Hemor- colloid carcinoma of other sites, except that thyro- rhage and necrosis can be seen in larger tumors.476 globulin is usually positive. DIAGNOSTIC CONSIDERATIONS Microscopic Findings Medullary Thyroid Carcinoma Medullary carcinoma typically grows in the form of sheets, packets, or irregular islands tra- CLINICAL CONSIDERATIONS Presentation Medullary thyroid carcinoma is a malignant neoplasm exhibiting parafollicular C cell differentiation.452 The patients are mostly adults with slight female predominance.453–464 Most patients present with a thyroid mass or cervical lymphadenopathy.465 Some patients may have diarrhea or, more rarely, Cushing’s syndrome.454, 466 The stage distribution at presentation is as follows: stage I, 21%; stage II, 21%; stage III, 47%; and stage IV, 12%.467 In some centers, routine screening of the calcitonin level in patients with nodular thyroid disease allows early diagnosis of unsuspected sporadic medullary thyroid carcinoma.468–470 Approximately 20% to 30% of medullary carcinomas are heritable (autosomal dominant with high penetrance).453, 455 The tumor often appears at an earlier age, multicentrically and bilaterally, and on a FIGURE 44–59. Medullary carcinoma. This tumor exhibits inva- background of C cell hyperplasia454–461, 471–473 (Table sive borders, but other cases can have circumscribed borders. short standard long

top of RH ᭤ ᭤ ACG (me- : threonine) : don 918), with ATG thionine Pheochromocytoma Mucosal neuromas Marfanoid appearance Lymph node: 38% Distant: 20% 1.1 : Frequent Hereditary MTC Male-Female 1 Parathyroid hyperplasia Mutation involving exon 10 or 11 Mutation involving exon 16 (co- 0%–17% 50% (most aggressive) Lymph node: 14% Distant: 0%–3% 11, 13, or 14 the various types) 0% (most indolent among ᭣ Lymph node: 10%–20% Distant: 0% ϳ Familial MTC MEN 2A MEN 2B ᭣ 1.4 : 30% Uncommon NilNilDistant: 12% ϳ Nil Mutation involving exon 10, Pheochromocytoma Sporadic MTC RET Sporadic and Hereditary Forms of Medullary Thyroid Carcinoma (MTC) MEN, multiple endocrine neoplasia. sia in the background drome proto-oncogene short Bilaterality and C cell hyperpla- Other components of the syn- Germline mutation in Metastases at diagnosisTumor-related mortality Lymph node: 40%–50% TABLE 44–13. Mean age at diagnosisSex ratio 44–50 y Male-female 1 29–43 y 21–38 ystandard 12–23 y 40 long

Thyroid and Parathyroid 41 top of RH

FIGURE 44–60. Medullary carcinoma. A and B. Medullary carcinoma typically grows in the form of sheets and islands traversed by delicate ﬁbrovascular septa.

versed by delicate fibrovascularsepta477, 478 (Fig. prognostic importance (Fig. 44–65; Table 44–14). It 44–60). On occasion, a trabecular, pseudopapillary, is usually not too difficult to render a correct diag- whorled, rosette, tubular, microglandular, or cribri- nosis for such variants because a component of con- form pattern can beobserved.455, 475 Cellular dehis- ventional medullary carcinoma can often be identi- cence and interstitial edema are common (Fig. fied on careful search.476, 478, 481–497 44–61A). The tumor cells are polygonal or spindly. Their round or oval nuclei exhibit finely stippled chromatin and indistinct nucleoli. The nuclei often Immunohistochemistry appear uniform, with occasional interspersed larger A diagnosis of medullary carcinoma should al- hyperchromatic nuclei (Fig. 44–61B). The cytoplasm ways be confirmed by immunohistochemistry. Al- is finely granular. Cytoplasmic mucin is demonstra- most all cases are immunoreactive for calcitonin, ble in some tumor cells in up to 50% of cases189, 479 and a low percentage of positive cells is correlated (Fig. 44–62). with a more aggressivebehavior493, 498–501 (Fig. Amyloid, in the form of globules or massive 44–66A). If the staining is equivocal or difficult to deposits, is found in 80% to 85% of cases476 (Fig. interpret, immunostaining with a pan-neuroendo- 44–63). It may show calcification or foreign body crine marker such as chromogranin can readily con- giant cell reaction. In microcarcinomas, amyloid is firm the diagnosis (Fig. 44–66B). Carcinoembryonic less common, being found in 27% of cases480 (Fig. antigen is positive in 88% to 100% of cases; this is a 44–64). highly useful diagnostic marker for poorly differen- Many histologic variants of medullary carci- tiated or small cell medullary carcinoma, when calci- noma have been recognized, but most are of no tonin may be negative.476, 478, 489, 493, 501, 502

FIGURE 44–61. Medullary carcinoma. A. The tumor cells are polygonal and exhibit finely granular chromatin and finely granular cytoplasm. Note the characteristic delicate fibrovascular septa. B. Cellu- short lar dehiscence is a common feature within the tumor islands. standard long

42 Endocrine System top of RH

FIGURE 44–62. Medullary carcinoma. Staining with periodic FIGURE 44–63. Medullary carcinoma. Abundant amyloid depos- acid–Schiff shows presence of mucin vacuoles in some tumor its (upper ﬁeld) are evident in this tumor. cells.

TABLE 44–14. Variants of Medullary Thyroid Carcinoma

Entities for Which the Variant May Be Variant* Deﬁning Morphologic Features Mistaken

Glandular-follicular Presence of glandular or follicular structures which Follicular adenoma or carcinoma may contain eosinophilic secretion in the lumina Poorly differentiated (insular) thyroid carci- The cytoplasm toward the luminal aspect is often noma more deeply eosinophilic due to polarization of neurosecretory granules. Papillary Presence of pseudopapillae due to cellular dehis- Papillary carcinoma cence, and only rarely are there true papillary for- mations Oxyphilic Tumor cells with abundant eosinophilic granular cyto- Hu¨ rthle cell neoplasm plasm due to accumulation of mitochondria Clear cell Presence of tumor cells with water-clear cytoplasm Other clear cell tumors Spindle cell Presence of spindly tumor cells arranged in fascicles Mesenchymal tumors or whorls Pigmented Presence of brown melanin pigment in some tumor — cells Squamous Presence of squamous differentiation Squamous cell carcinoma Small cell Tumor composed predominantly of small cells, often Malignant lymphoma with nuclear molding, resembling small cell carcinoma of lung Giant cell (anaplastic) Presence of large cells with bizarre and pleomorphic Anaplastic carcinoma nuclei, but mitotic figures are rare Neuroblastoma-like Presence of fibrillary matrix or rosettes, resembling Malignant lymphoma neuroblastoma Metastatic neuroblastoma Peripheral primitive neuroectodermal tumor Carcinoid-like Histologic features resembling intestinal carcinoid, Metastatic carcinoid with tumor islands, trabeculae, or glands separated Paraganglioma by fibrohyaline stroma Follicular neoplasm Hyalinizing trabecular Wavy trabeculae of tumor cells, which merge into Hyalinizing trabecular adenoma adenoma–like abundant extracellular hyaline material, mimicking Paraganglioma hyalinizing trabecular adenoma Paraganglioma-like Tumor forming packets delineated by a delicate vas- Paraganglioma culature

* The listed variants have no clinical or prognostic signiﬁcance, except the small cell type, which is more aggressive. The prognostic implication of the giant cell variant is still unsettled. short standard long

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(Met : Thr).513–515 Molecular study is currently the most reliable way to diagnose the hereditary form of medullary thyroid carcinoma—germline mutation in RET can be conveniently demonstrated on DNA ex- tracted from peripheral blood leukocytes or paraffin- embedded nontumor tissues. After exons 10, 11, and 16 are amplified by the polymerase chain reaction, mutation screening can be performed by the single- stranded conformation polymorphism or heterodu- plex technique; the site of mutation can be confirmed by DNA sequencing or restriction endonuclease cleavage. If the patient is confirmed to show germline mutation in RET, all family members should be screened to detect carriers of the RET mutation, who should be counseled, offered thyroid- 516–518 FIGURE 44–64. Medullary carcinoma as an incidental finding. ectomy, and closely followed up. As is characteristic of microcarcinoma, amyloid is often absent or In sporadic medullary carcinomas, somatic mu- scanty. tations in RET are found in 26% to 69% of cases, most commonly involving codon 918 of exon 16 (ATG : ACG).514, 519–522

S-100 protein–positive sustentacular cells are Differential Diagnosis usually absent, except in the setting of multiple en- POORLY DIFFERENTIATED (I(INSULAR)THYROID docrine neoplasia or familial medullary carcinoma, CARCINOMA. See earlier. when 62.5% of cases can show a population of sustentacular cells.503 HYALINIZING TRABECULAR ADENOMA. Hyalin- The hereditary form of medullary carcinoma izing trabecular adenoma can mimic medullary car- typically arises in a background of C cell hyperpla- cinoma architecturally, but long wavy trabeculae are sia, which has been classified into a diffuse type and most uncommon in medullary carcinoma, and the a nodular type. However, there are no universally nuclear features (nuclear grooves, nuclear pseudoin- accepted criteria for the diffuse type of C cell hyper- clusions, perinucleolar haloes) are also different. plasia, and a similar degree of C cell proliferation PARAGANGLIOMA. There is significant morpho- can be seen in normal subjects, around various types logic overlap between paraganglioma and medullary of thyroid tumors, and in thyroiditis504–509 (Fig. carcinoma, such as packeting pattern, rich vascular- 44–67). The nodular type of C cell hyperplasia is ity, and granular cytoplasm. Paraganglioma differs defined as “complete obliteration of follicular space in being negative for cytokeratin, calcitonin, and car- by C cells with production of solid intrafollicular cinoembryonic antigen. aggregates,” but distinction from a minute medul- METASTATIC NEUROENDOCRINE CARCINOMA. lary carcinoma or intrathyroid spread of medullary 507, 510 Metastatic neuroendocrine carcinoma (carcinoid and carcinoma can be difficult (Fig. 44–68). atypical carcinoid) from the bronchus or intra-ab- Molecular Biology dominal sites can present initially as thyroid tumor and is often misdiagnosed as medullary carci- The RET proto-oncogene on chromosome 10q11 noma.523 The neuroendocrine carcinoma forms nests, plays a key role in the genesis of medullary carci- ribbons, islands, rosettes, and sheets traversed by noma. The RET gene, which comprises 21 exons, delicate fibrovascular stroma. Clues to the diagnosis encodes a receptor tyrosine kinase with a cysteine- are predominantly interstitial growth, multiple tu- rich extramembrane domain, a transmembrane do- mor foci, absence of C cell hyperplasia, presence of main, and an intracellular tyrosine kinase compo- peculiar protrusions into thyroid follicles in the form nent. Germline mutations of RET are found in of subepithelial cell balls, and lack of amyloid. The patients with MEN 2 or familial medullary thyroid tumor cells lack immunoreactivity for calcitonin and carcinoma. The mutations result in constitutive acti- carcinoembryonic antigen. vation of the receptor owing to dimerization or alteration in the tyrosine kinase substrate specific- HU¨ RTHLE CELL NEOPLASM. Medullary carci- ity.274, 511, 512 In MEN 2A, the mutations involve the noma with oncocytic change is not uncommonly cysteine-rich region of the extracellular domain, re- misdiagnosed as Hu¨ rthle cell neoplasm. The most sulting in substitution of cysteine by another amino helpful clue is the presence of the delicate fibrovas- acid, the most common being TGC : CGC (Cys : cular septa; identification of areas of conventional Arg) at codon 634.513, 514 The sites of mutation are medullary carcinoma is also helpful. more varied in familial medullary thyroid carci- ANAPLASTIC CARCINOMA. Bizarre and highly noma.274 MEN 2B is always caused by the same atypical cells may occur in an otherwise typical mutation in codon 918 of exon 16: ATG : ACG medullary carcinoma; this tumor can be distin- short standard long

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FIGURE 44–65. Variants of medullary carcinoma. A. Glandular- follicular variant, which can potentially be mistaken for a follicular neoplasm. B. Papillary variant comprising pseudopapillae produced by cellular dehiscence. The tumor cells lack the typical nuclear features of papillary carcinoma. C. Oncocytic variant, which can be mistaken for Hu¨ rthle cell follicular neoplasm. D. Clear cell variant. E. Spindle cell variant, which may be mistaken for a mesenchymal neoplasm. F. Small cell variant. G. Giant cell variant. short standard long

Thyroid and Parathyroid 45 top of RH

FIGURE 44–66. Medullary carcinoma, immunohistochemical staining. A. All tumor cells show positive staining for calcitonin. B. Strong positive granular staining for chromogranin is observed.

guished from anaplastic carcinoma by the presence lent and not rapidly lethal. However, there is still an of many bland-looking cells among the bizarre cells excess mortality 10 years after a diagnosis of medul- and the paucity of mitotic figures. lary carcinoma.527 Because medullary carcinoma is PARATHYROID NEOPLASM. See later. not radiosensitive, adequate surgical clearance (total thyroidectomy) is the mainstay of primary treat- PROGNOSTIC CONSIDERATIONS ment.528, 529 The tumor tends to spread by lymphatics to lymph Tumor stage is the single most important prog- 453, 473, 524–527 nodes of the neck (one third to two thirds) and nostic factor on multivariate analysis. upper mediastinum.454, 465, 524 Local recurrence devel- STAGE OF DISEASE. Extrathyroidal extension is ops in about one third of cases after treatment.465 associated with a high risk of recurrence, disease Late in the course, the tumor may metastasize to progression, and worsened survival.526, 529, 530 Pres- other sites, such as lungs, liver, adrenal, and bone, ence of lymph node metastasis at diagnosis greatly although distant metastasis is already present in 8% worsens the prognosis, with 10-year survival drop- of patients at presentation.524 Patients may still sur- ping from 86% to 95% (node negative) to 46% to vive for many years despite the presence of distant 55% (node positive).* Distant metastasis is associated metastases. The 5-year, 10-year, and 15-year survival with a poor survival.529 rates are 65% to 87%, 51% to 78%, and 65%, respec- AGE. Older patients (Ͼ 50 to 60 years) have a 453, 465, 525–527 tively, indicating that this tumor is indo- worse outcome.† SEX. Some studies have shown the female sex to be associated with a better prognosis,493, 526 but this factor loses prognostic significance on multivariate analysis according to some series.524, 525 MEDULLARY CARCINOMA OF MENMEN 2 2.. MEN 2A–associated medullary carcinoma has a better prognosis than the sporadic variety does; MEN 2B– associated medullary carcinoma is associated with a worse prognosis.455, 471, 527, 531 Nonetheless, this factor is apparently not significant after multivariate analysis according to one study.453 TUMOR SIZE. Small tumors less than 1 cm have an excellentprognosis.461, 468, 474, 527, 532 Unfavorable outcome in microcarcinomas is virtually confined to patients who are symptomatic (such as palpable microcarcinoma, diarrhea, or metastatic disease at presentation).532 FIGURE 44–67. C cell hyperplasia, diffuse type, found adjacent to a follicular adenoma. This form of C cell hyperplasia cannot be appreciated in conventional histologic sections. Immunostaining *References 455, 465, 493, 524, 526, 528, 530. for calcitonin shows increased isolated C cells (stained brown). These cells lie within the basal lamina of the follicles. †References 453, 455, 465, 473, 493, 524, 526, 528. short standard long

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FIGURE 44–68. C cell hyperplasia, nodular type, associated with MEN 2A. A. Small nodular clusters of cells are found among the follicles, sometimes obliterating their lumina. B. A corresponding ﬁeld stained for calcitonin clearly delineates the hyperplastic C cells.

BIOCHEMICAL CURE. Achievement of biochemi- N-N-MYC EXPRESSION. Increased expression of cal cure predicts good survival (98% at 10 years N-myc has been reported to be an unfavorable prog- versus 70% for those not achieving biochemical nostic factor.541 cure).525, 530 TUMOR ANGIOGENESIS. A high microvessel HISTOLOGIC FEATURES. Features associated count is associated with a poorer prognosis.542 with a worse prognosis include high mitotic count (more than 1 mitotic ﬁgure per 25 high-power DNADNA PLOIDY. Aneuploid tumors behave more 493, 527, 543, 544 ﬁelds), coagulative necrosis, absence of amyloid, and aggressively than diploid ones do. small cell variant474, 475, 486, 526, 527, 533 (Fig. 44–69). IMMUNOHISTOCHEMICAL FEATURES. Calcitonin- poor medullary carcinomas fare worse than calcito- Collision Tumor nin-rich tumors.534–536 The calcitonin content of the tumor may decrease at relapse. Strong expression of Collision tumors are neoplasms comprising two CD15/Leu-M1 is correlated with a higher risk of components: medullary carcinoma and a carcinoma 537, 538 local recurrence and tumor mortality. Low ex- of follicular cell derivation (follicular carcinoma or pression of chromogranin B or Bcl-2 is associated papillary carcinoma).545–552 The two components can 539, 540 with a more aggressive course. be intermingled, contiguous, or separate. Most probably represent coincidental occurrence of two neoplasms in proximity.

Mixed Follicular-Parafollicular Carcinoma

CLINICAL CONSIDERATIONS Mixed follicular-parafollicular carcinoma, also known as differentiated carcinoma of intermediate type, is an uncommon tumor of the thyroid comprising closely intermingled follicular and parafollicular cells. The follicular cells secrete thyroglobulin, and the parafollicular cells secrete calcitonin or other hormone products such as somatostatin and neuro- tensin; on occasion, both hormone products can be produced by the same cell.553–556 The patients have a FIGURE 44–69. Medullary carcinoma showing “aggressive” his- median age of 48 years. They present with a thyroid tologic features, such as diffuse cellular atypia, coagulative necro- nodule, and lymph node involvement is common sis, and mitotic ﬁgures. (ϳ 75%). The mean size of the tumor is 3.7 cm.556 short standard long

Thyroid and Parathyroid 47 top of RH

Immunohistochemistry Thyroglobulin immunoreactivity is characteristically seen in the follicular and cribriform areas and sometimes in the solid component; calcitonin immunoreactivity is most conspicuous in the solid areas553, 555 (Fig. 44–71). Rare cells with dual hormone production can be identified in some cases. Differential Diagnosis This tumor histologically mimics the less well differentiated examples of follicular carcinoma or insular carcinoma. Immunohistochemical confirmation is therefore essential for diagnosis. However, the possibilities of entrapped benign follicles and diffu- sion of thyroglobulin from surrounding thyroid tis- FIGURE 44–70. Mixed follicular-parafollicular carcinoma. It sue have to be excluded. shows a solid growth interspersed with follicles. Molecular Biology Although it has been thought that mixed follicular-parafollicular carcinoma results from an uncom- mitted stem cell capable of differentiating toward both follicular cells and C cells, molecular studies 556 DIAGNOSTIC CONSIDERATIONS have failed to confirm such a hypothesis. Studies of gene mutation, allelic loss, and clonal composition Microscopic Findings on microdissected tumor tissue show that the follic- Mixed follicular-parafollicular carcinomas are of- ular and parafollicular components belong to differ- ten completely or partially encapsulated. They show ent clones.560 Furthermore, the follicular component solid, nested, or cribriform growth with intermin- is often oligoclonal or polyclonal. gled follicles553, 557–559 (Fig. 44–70). It is important not to mistake entrapped thyroid follicles in a con- PROGNOSTIC CONSIDERATIONS ventional medullary carcinoma for a mixed follicu- Mixed follicular-parafollicular carcinomas spread by lar-parafollicular carcinoma. Cytologic comparison both the lymphatic and hematogenous routes and of the cells lining the follicles with those of the sur- are more aggressive than differentiated thyroid car- rounding follicles is most helpful. The most defini- cinomas. In the series of 18 patients reported by tive evidence of follicular differentiation is identifi- Ljungberg,553 6 developed metastasis, and 4 died of cation of follicles in metastatic deposits. Amyloid is the tumor 1 month to 15 years after surgery. Ac- occasionally present. On ultrastructural examination, cording to the review of Papotti and colleagues,556 neurosecretory granules, follicular cells, cells with 56% of patients (N ϭ 25) were alive with disease or intermediate features, and indifferent cells are iden- dead of disease up to 10 years after diagnosis. The tified.553 results contrast with those of otherwise typical med-

FIGURE 44–71. Mixed follicular-parafollicular carcinoma, immunohistochemical staining. A. The solid component shows immunoreactivity for calcitonin. B. Thyroglobulin immunoreactivity is con- ﬁned to the follicles. short standard long

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TABLE 44–15. Clinicopathologic Features of Thymic and Related Branchial Pouch Tumors in the Thyroid

Spindle Epithelial Tumor with Carcinoma Showing Thymus- Ectopic Thymoma Thymus-like Element (SETTLE) like Element (CASTLE)

Age Middle age Children and young adults, Middle and old age, with a with a mean age of 18 y mean age of 49 y Sex F Ͼ MMϾ FMՅ F Presentation Thyroid mass Thyroid mass Thyroid mass, with or without cervical node enlargement Pathology Encapsulated tumor with jig- The tumor is demarcated into The tumor usually involves the saw puzzle–type lobulation incomplete lobules by scle- lower pole of the thyroid Composed of a variable admix- rotic stroma. It is highly cel- and invades in pushing ture of pale-staining plump lular, with compact interlac- fronts. Variably sized, often epithelial cells and small lym- ing to reticulated fascicles of smooth-contoured lobules of phocytes spindle cells merging imper- tumor cells are demarcated ceptibly into epithelial struc- by desmoplastic fibrous tures that can be in the form stroma. of cords, tubules, or papillae. The tumor cells have indistinct The spindle cells possess cell borders, vesicular nuclei, elongated bland-looking nu- and prominent nucleoli or clei with fine chromatin; mi- show a squamous or squa- tosis is infrequent. moid appearance. In some cases, discrete glandu- The tumor cells and fibrous lar structures lined by muci- septa show scanty to heavy nous or respiratory-type epi- infiltration by lymphocytes thelium are found. and plasma cells. Lymphocytes are sparse or absent. Immunohistochemistry Epithelial component is cyto- Both glandular and spindle cell Cytokeratin and CD5 positive keratin positive components are cytokeratin Lymphoid component com- positive prises mostly immature T CD5 negative cells (TdTϩ). Clinical behavior Benign in all reported cases Behavior is unpredictable, but Extrathyroidal extension is a significant proportion of common. Regional lymph patients develop delayed dis- node metastasis occurs in tant metastasis (ϳ70% with about half of the cases. long-term follow-up), espe- The tumor is indolent; most pa- cially to the lungs. tients enjoy long survivals af- Even in the presence of metas- ter surgery or radiation ther- tasis, this indolent tumor can apy, although occasional pursue a protracted course cases can pursue a more ag- for many years before killing gressive course. the patient.

FIGURE 44–72. Spindle epithelial tumor with thymus-like element. A. The tumor forms lobules demarcated by sclerotic septa, reminiscent of the architectural features of thymoma. B. Compact and reticulated fascicles of spindly cells merge imperceptibly into tubulopapillary epithelial structures short (right ﬁeld). This tumor type shows cytoarchitectural resemblance to synovial sarcoma. standard long

Thyroid and Parathyroid 49 top of RH

DIAGNOSTIC CONSIDERATIONS Ectopic thymoma is histologically identical to the mediastinal counterpart. For CASTLE, the morphologic features and expression of CD5 (a lymphocyte- associated marker commonly expressed in thymic carcinomas but not in nonthymic carcinomas) strongly suggest that this is an intrathyroid thymic carcinoma.582–584 The histogenesis of SETTLE currently remains elusive.581 The most important reason for recognizing this group of neoplasms is that they are benign to low- grade malignant and should not be mistaken for lymphoma or the vastly more aggressive anaplastic carcinoma. Follicular dendritic cell tumor can also potentially be misdiagnosed as CASTLE.585 FIGURE 44–73. Spindle epithelial tumor with thymus-like element. The spindly cells have fairly uniform nuclei and scanty cytoplasm. The glandular structures (left upper ﬁeld) exhibit bland- Intrathyroid Parathyroid Tumor looking, pale-staining nuclei. Because the parathyroid glands are close to or are embedded in the thyroid gland, parathyroid ade- ullary carcinoma shown on immunohistochemical noma or carcinoma can occur as primary thyroid staining to be thyroglobulin positive, which has a tumor.586, 587 These tumors are not uncommonly mis- prognosis similar to or better than that of conven- diagnosed as follicular adenoma, follicular carci- tional medullary carcinoma.561 noma, or anaplastic carcinoma (Fig. 44–75A). A parathyroid origin should be suspected when there are clear cells, prominent delicate vasculature, and regi- Thymic and Related Branchial mentation of nuclei along the vascular septa. The Pouch Tumors of the Thyroid diagnosis can be conﬁrmed by immunostaining for parathyroid hormone (Fig. 44–75B). CLINICAL CONSIDERATIONS The occasional presence of sequestered thymic tissue Malignant Lymphoma or branchial pouch remnants in the thyroid gland may explain the occurrence of ectopic thymic tu- CLINICAL CONSIDERATIONS mors in the thyroid. These rare tumors include ectopic thymoma, spindle epithelial tumor with thy- Presentation mus-like element (SETTLE), and carcinoma showing Primary lymphoma of the thyroid accounts for thymus-like element (CASTLE); their clinicopathol- approximately 5% of all thyroid cancers.588 It affects ogic features are summarized in Table 44–15 (Figs. mostly adults, and there is a female predominance 44–72 to 44–74).562–581 (male-to-female ratio ϭ 1 : 2.5).589–599 Hashimoto’s

FIGURE 44–74. Carcinoma showing thymus-like element. A. The tumor invades the thyroid predominantly in the form of smooth-contoured cell islands, different from the extensive permeative growth of anaplastic carcinoma. B. The tumor island comprises squamoid cells with moderate nuclear atypia. short The cytoarchitectural features are identical to those of squamous cell carcinoma of the thymus. standard long

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FIGURE 44–75. Intrathyroid parathyroid adenoma. A. The presence of follicle structures creates a strong mimicry of follicular neoplasm. B. The diagnosis can be readily conﬁrmed by positive immunoreactivity for parathyroid hormone.

thyroiditis and lymphocytic thyroiditis are recog- groups, are commonly found among the lymphoma nized predisposing factors.589, 593, 598 cells. Invasion of the thyroid follicles by lymphoma Some patients present with a rapidly enlarging cells results in formation of lymphoepithelial lesions thyroid mass, which may be accompanied by dys- and plugging of the follicular lumina by lymphoma phagia or hoarseness, simulating the presentation of cells589, 599, 608 (Fig. 44–77; see also Fig. 44–76B). Col- anaplastic carcinoma. Others present with gradual onization of the reactive lymphoid follicles can re- enlargement of the thyroid gland or a slow-growing sult in a pattern reminiscent of follicular lymphoma thyroid nodule. The tumor can be confined to the (see Fig.44–76C).599, 608, 609 Immunohistochemical thyroid or show extrathyroidal extension. Regional staining shows expression of B markers; CD5, CD10, lymph nodes are sometimes involved. CD23, and cyclin D1 are negative.599, 607 Monotypic immunoglobulin can be demonstrated in the plasma Macroscopic Findings cells in approximately 30% of cases.608, 610 The lymphoma forms a noncircumscribed rubbery to soft mass in one or both lobes of the thy- Diffuse Large B Cell Lymphoma With roid. The cut surfaces are slightly bulging, fleshy, or Without a Component of light tan, and often homogeneous, with or without Extranodal Marginal Zone B Cell necrosis and hemorrhage. The size ranges from less Lymphoma than 1 cm to 19.5 cm.592, 600 Diffuse large B cell lymphoma accounts for more than 60% of all thyroid lymphomas. In some DIAGNOSTIC CONSIDERATIONS cases, there is a component of extranodal marginal Histologic Types zone B cell lymphoma, suggesting transformation 590, 591, 593, 599, 611, 612 Hodgkin’s lymphoma of the thyroid is ex- from it. The lymphomatous growth tremely rare.601 Among non-Hodgkin’s lymphomas, effaces the architecture of the thyroid tissue (Fig. diffuse large B cell lymphoma and extranodal mar- 44–78A). The lymphoma cells are large, with round ginal zone B cell lymphoma of mucosa-associated vesicular nuclei, distinct nucleoli, and a moderate lymphoid tissue (MALT) type constitute almost all amount of amphophilic cytoplasm that may some- cases.589, 596, 599, 602 Exceptional examples of follicular times be plasmacytoid (Fig. 44–78B). Mitotic figures lymphoma, intravascular lymphomatosis, and T cell and apoptotic bodies are common. Invasion of the lymphomas have been reported.599, 603–607 thyroid epithelium to produce lymphoepithelial lesions is common, whereas plugging of follicu- Extranodal Marginal Zone B Cell lar lumina by lymphoma cells is much less fre- Lymphoma of MALT Type quent.590, 592, 599, 613 Vascular invasion can sometimes 590, 592 The histologic features of extranodal marginal be identified (Fig. 44–78C). Immunohistochemi- zone B cell lymphoma involving the thyroid are cal analysis shows positive staining for leukocyte similar to those of this lymphoma type occurring common antigen and B markers. elsewhere. Within the diffuse lymphomatous infil- Differential Diagnosis trate, some reactive lymphoid follicles are often interspersed (Fig. 44–76A). The lymphoma cells are HASHIMOTO’S THYROIDITIS. When Hashimoto’s small to medium sized, resembling small lympho- thyroiditis shows a florid chronic inflammatory cell cytes, centrocytes, or monocytoid B cells; the cellular infiltrate, it can be difficult to tell whether there is short composition is often mixed. Plasma cells, often in superimposed extranodal marginal zone B cell lym- standard long

Thyroid and Parathyroid 51 top of RH

FIGURE 44–76. Extranodal marginal zone B cell lymphoma of the thyroid. A. An intense lymphoid infiltrate characterizes lymphoma. B. The infiltrate comprises centrocyte-like cells with irregular nuclei, plasma cells, and plasmacytoid cells. The lymphoid cells infiltrate into the thyroid follicles (lymphoepithelial lesions) and characteristically plug up the lumina of the follicles. C. The preexisting reactive lymphoid follicles are colonized by monotonous-appearing lymphoma cells, resulting in a resemblance to follicular lymphoma.

phoma.608 A dense lymphoid inﬁltrate, broad bands ANAPLASTIC CARCINOMA. Features favoring a of centrocyte-like cells or clear cells, and prominent diagnosis of lymphoma are lack of cellular co- lymphoepithelial lesions are histologic features hesion, plasmacytoid cytoplasm, presence of lym- strongly favoring a diagnosis of lymphoma, which phoepithelial lesions, and plugging of follicular lu- can be further supported by immunohistochemical mina by tumor cells. The diagnosis can be readily studies to demonstrate sheets of B cells, aberrant conﬁrmed by immunohistochemical studies (see Ta- coexpression of CD43, or light chain restriction.300 ble 44–1).

FIGURE 44–77. Extranodal marginal zone B cell lymphoma of the thyroid. A. The lymphoma cells show prominent infiltration and expansion of the thyroid follicles to produce lymphoepithelial lesions (right field). B. Cytokeratin immunostaining of a corresponding field clearly shows follicular destruc- short tion and expansion by the neoplastic infiltrate. standard long

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FIGURE 44–78. Diffuse large B cell lymphoma of the thyroid. A. The neoplasm is permeative and destructive. Residual follicles are evident in the left lower ﬁeld. B. The noncohesive neoplastic cells are large and possess round or irregular nuclei, distinct nucleoli, and amphophilic cytoplasm. C. The neoplastic cells commonly inﬁltrate the epithelial lining of the follicles, but they rarely ag- gregate within the central colloid material.

PROGNOSTIC CONSIDERATIONS ponent of extranodal marginal zone B cell lym- The 5-year survival rate for thyroid lymphoma is phoma, similar to the findings in other mucosal sites 50% to 79%.* The most important prognostic factors such as the stomach, although conflicting results are 599, 618 are tumor stage and histologic type. reported by Skacel and coworkers. AGE. Advanced age (older than 60 to 65 years) TUMOR STAGE. Stage IIE or higher is associated with a much worse prognosis than is stage I dis- has been shown in some studies to be associated E 590, 591 ease; almost all mortalities are confined to the stage with a worse prognosis. 591, 592, 599 Ͼ IIE and higher group. Most studies have also TUMOR SIZE. A large tumor ( 10 cm) is re- shown extrathyroidal extension to worsen the prog- ported to be associated with a worse prognosis ac- nosis, with a 5-year survival of 40% compared with cording to some but not all studies.590, 596, 599 590–593, 596, 599 85% for intrathyroidal tumor. VASCULAR INVASION. Vascular invasion is as- HISTOLOGIC TYPE. Although some studies have sociated with a worse prognosis.592, 599 not found the histologic type to correlate with prog- HISTOLOGIC FEATURES. High mitotic count and 589, 591, 593, 594, 616 nosis, other studies have shown the high apoptotic count are associated with a worse prognosis of extranodal marginal zone B cell lym- prognosis.599 Tumor necrosis is associated with a phoma of MALT type to be much superior to that of worse prognosis according to one study but not an- 590, 599, 612, 617 diffuse large B cell lymphoma. According other.592, 599 to the series from the Armed Forces Institute of Pa- thology, none of 30 patients with pure extranodal marginal zone B cell lymphoma died of lymphoma, Plasmacytoma of the Thyroid whereas 20 (26%) of 77 patients with a diffuse large 599 B cell lymphoma component died of the disease. Plasmacytoma of the thyroid is uncommon, and the There is no difference in outcome for diffuse large B prognosis is excellent592, 619 (Table 44–16). The neo- cell lymphoma with or without an identifiable com- plastic infiltrate comprises a monotonous population of mature-looking, immature-looking, pleomorphic, or plasmablastic plasma cells. It has been suggested short *References 589–591, 593, 600, 610, 611, 614, 615. that thyroid plasmacytoma may represent an ex- standard long

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TABLE 44–16. Comparison Between Plasmacytoma and Malignant Lymphoma of Thyroid

Plasmacytoma Malignant Lymphoma

Sex Slight male predominance (male-female 1.4 : 1) Female predominance (male-female 1 : 2.5) Age (mean) 58 y 62 y Presentation Usually slowly growing thyroid mass Rapidly or slowly growing thyroid mass 5-year survival More favorable: 85% Less favorable: overall ϳ60%, but much more favorable for extranodal marginal zone B cell lymphoma of MALT type

treme (mature) form of extranodal marginal zone Angiosarcoma of the thyroid is extremely ag- B cell lymphoma with prominent plasmacytic differ- gressive, and metastatic spread is common, such as entiation.600, 620 The major differential diagnoses are to the lung, pleura, lymph node, adrenal, gastroin- inﬂammatory pseudotumor (plasma cell granu- testinal tract, and bone.629 The median survival is loma)621, 622 and malignant lymphoma. only 3.5 months, and the rare survivors all have small tumors lacking extrathyroidal extension.630

Langerhans Cell Histiocytosis Macroscopic Findings (Histiocytosis X) The tumor is usually solitary and infiltrative, with a fleshy gray-tan appearance punctuated by CLINICAL AND PROGNOSTIC areas of necrosis and hemorrhage. There can be a CONSIDERATIONS central cavity filled with coagulated or fluid blood.629 The thyroid gland can be involved by Langerhans cell histiocytosis as the sole lesion or as part of dis- DIAGNOSTIC CONSIDERATIONS seminated disease. The patients show a wide age Microscopic Findings range (median, 37 years), and there is no sex predilection.623–628 The disease presents either as an inci- Angiosarcomas of the thyroid are often poorly dental finding in the thyroid removed for other rea- differentiated. The tumors grow in solid sheets and sons or at autopsy or as a large thyroid. The irregular anastomosing channels that contain blood. prognosis is excellent for disease limited to the thy- The tumor cells often exhibit significant nuclear roid but poor for patients with disseminated disease. pleomorphism; some of them have cytoplasmic vac- uolation. Some cases can show epithelioid morpho- DIAGNOSTIC CONSIDERATIONS logic features, with polygonal tumor cells and abundant eosinophilic hyaline cytoplasm630–632 (Fig. 44– The thyroid is infiltrated by Langerhans cells in a 79). patchy or extensive pattern, and there can be extrathyroidal extension. The Langerhans cells possess Immunohistochemistry grooved or highly contorted nuclei, thin nuclear A diagnosis of angiosarcoma has to be substanti- membrane, delicate chromatin, and moderate ated by positive immunohistochemical staining for amount of eosinophilic cytoplasm. They can infiltrate and destroy the thyroid follicular epithelium. There are variable numbers of admixed eosinophils, sometimes with formation of eosinophil abscesses. The diagnosis should be confirmed by positive immunostaining for S-100 protein and CD1a.

Angiosarcoma

CLINICAL AND PROGNOSTIC CONSIDERATIONS Presentation Angiosarcoma of the thyroid, also known as malignant hemangioendothelioma, is rare. It affects mostly old patients with a slight male predominance.629 The patients usually present with rapid onset of a neck mass, which may cause difﬁculties in FIGURE 44–79. Epithelioid angiosarcoma. Cords and islands of breathing and swallowing. They may have a history polygonal cells with voluminous hyaline cytoplasm show cyto- of long-standing goiter. Some patients may present plasmic vacuoles and occasional irregular narrow vascular chan- short with distant metastasis. nels. standard long

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Other Mesenchymal Tumors

Smooth muscle tumors of the thyroid gland are rare, and most are malignant.640 Leiomyomas are encapsulated and confined to the thyroid gland, with no cellular atypia, necrosis, or mitotic activity. Leiomyo- sarcomas often affect older patients and are often larger. On histologic examination, they exhibit cellular pleomorphism, mitotic activity, necrosis, hemorrhage, invasive growth, and extrathyroidal extension. The diagnosis has to be confirmed by immunohistochemical or ultrastructural studies, especially for distinction from anaplastic carcinoma. These tumors are aggressive; most patients die within 2 years. Metastases to the lungs and other 640–645 FIGURE 44–80. Solitary fibrous tumor. Nondescript spindly cells sites develop early in the course of disease. with scanty cytoplasm and in close interaction with delicate colla- Rare mesenchymal tumors reported to occur in gen fibrils characterize solitary fibrous tumor. Some entrapped the thyroid include hemangioma, lymphangioma, follicles are seen in the peripheral portion of the tumor. peripheral nerve sheath tumors, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, and follicular dendritic cell sarcoma.624, 646–654 endothelial markers, such as factor VIII–related anti- Paraganglioma gen, CD31, and CD34.397, 398 Some cases can exhibit immunoreactivity for cytokeratin.631 CLINICAL CONSIDERATIONS Rarely, paragangliomas can occur within the thyroid Differential Diagnosis gland, probably from the inferior laryngeal paragan- Because anaplastic carcinoma can exhibit angio- glia. There is a female predominance, and most pa- sarcoma-like morphologic features focally (angioma- tients are aged between 40 and 60 years.262, 655 The toid carcinoma), distinction between anaplastic carci- patients present with a neck mass. The tumors are noma and pure angiosarcoma can be difficult.633–635 circumscribed or can extend into the adjacent larynx The distinction is not too important from a clini- or trachea. All patients have remained well after cal point of view, however, because both are surgical excision. highly aggressive neoplasms with similar survival DIAGNOSTIC CONSIDERATIONS figures. Fine-needle aspiration changes such as reactive The tumors usually have a size of approximately 2 vascular proliferation or pseudoangiosarcomatous cm.262, 656 Alveolar packets of ovoid cells with finely change in the damaged thyroid follicular epithelium granular cytoplasm are surrounded by an inconspic- can mimic angiosarcoma. uous layer of sustentacular cells (Fig. 44–81; see Ta- Sclerosing mucoepidermoid carcinoma with eo- ble 44–1). The stroma is typically richly vascular- sinophilia can exhibit a pseudoangiomatous pattern, focally mimicking angiosarcoma.

Solitary Fibrous Tumor

Solitary ﬁbrous tumor can rarely occur as a primary thyroid tumor.636–639 All patients have remained well after surgical excision. The histologic features are identical to those of the pleural counterpart. The tumor is well circumscribed, although some thyroid follicles can be entrapped in the periphery. It shows alternating hypercellular and hypocellular areas, with haphazardly distributed bland-looking spindly or stellate cells in- timately intermingled with delicate to thick collagen ﬁbers (Fig. 44–80). A pericytomatous vascular pattern is common. The tumor cells are immunoreactive FIGURE 44–81. Paraganglioma. Oval islands of tumor are sepa- for CD34 but are negative for cytokeratin and S-100 rated by a richly vascularized stroma. This tumor can potentially short protein. be mistaken for medullary carcinoma. standard long

Thyroid and Parathyroid 55 top of RH ized. Tumors with enlarged, hyperchromatic, or bizarre nuclei can potentially be misdiagnosed as a ✒ TABLE 44–17. Contents of the Final Report: malignant neoplasm. Other major differential diag- Thyroid Excision Specimens noses are medullary carcinoma and hyalinizing trabecular adenoma. Specimen type/operation procedure Diagnosis Teratoma Histologic type, and variant if applicable Histologic grade, if relevant CLINICAL AND PROGNOSTIC Other tumor features Tumor location (right lobe, left lobe, isthmus) CONSIDERATIONS Tumor size There are two distinct age peaks for the occurrence Solitary or multicentric of thyroid teratomas. The first and higher peak is in Encapsulated or nonencapsulated Capsular invasion (absent, present, extensive) the newborn period to the age of 2 years; the second Vascular invasion (absent, present, extensive) smaller peak is in older children and adults, mostly Extrathyroidal extension (structures invaded, if applicable) between the ages of 20 and 50 years.600, 657–662 These Mitotic activity tumors are more common in females than in males. Surgical margins: free, close to surgical margin (specify dis- Most patients present with a large thyroid or neck tance), or margin involved (specify site) mass, which may be accompanied by respiratory Non-neoplastic thyroid: normal, nodular goiter, lymphocytic difficulties. thyroiditis, Hashimoto’s thyroiditis, atrophy, fibrosis Thyroid teratomas occurring before the age of 2 Lymph nodes years usually pursue a benign course after surgical Number of lymph nodes found, and their location (level) excision, although some patients may die of respira- Number of involved lymph nodes tory obstruction. Thyroid teratomas occurring in Size of largest metastatic deposit adults are more likely to be malignant, with local Presence or absence of extracapsular extension recurrence, cervical lymph node metastasis, and pulmonary metastasis. Nonetheless, long-term survival is possible with aggressive treatment including chemotherapy and surgery.600, 663, 664 thyroid, but it can be recognized by the presence of multiple tumor nodules, distinct cell membranes, DIAGNOSTIC CONSIDERATIONS water-clear cytoplasm, sinusoidal vascular pattern, fresh hemorrhage in the glandular lumina, and neg- The teratomas are most often immature, although 31 some may be of the mature type. Tissues from the ative immunostaining for thyroglobulin. various germ layers are present, and neuroectodermal tissue may be prominent. The presence of neu- ral tissue provides a strong point against the differ- Contents of the Final Surgical ential diagnosis of anaplastic carcinoma. Pathology Report Tumors occurring in neonates and infants are often immature (grade 1 or 2), but they are some- In the surgical pathology report of thyroid excision times mature. Those occurring in adults most often specimens for tumors, it is important to include all show grade 3 immaturity (“malignant”).600 information relevant for staging and prognostication in addition to the diagnosis15, 45, 46 (Table 44–17). Metastatic Malignant Neoplasms in Thyroid NON-NEOPLASTIC LESIONS

Because the thyroid gland is rich in blood vessels Incidental and Insignificant and lymphatics, it is not infrequently involved by Findings in the Thyroid Gland metastatic cancer in patients with carcinomatosis, most commonly due to pulmonary carcinoma (usu- Skeletal muscle fibers may be intermingled with the ally adenocarcinoma), breast carcinoma, malignant thyroid follicles in the region beneath the thyroid melanoma, and renal cell carcinoma.665–669 The meta- capsule. Adipose cells and hyaline cartilage rest are static deposits are often small and asymptomatic occasionally found incidentally in the thyroid and are associated with obvious widespread meta- gland.670 Ectopic parathyroid tissue, ectopic thymic static tumor elsewhere.665 tissue, and ectopic salivary gland tissue can also Renal cell carcinoma can metastasize to the thy- sometimes be found within the thyroid. roid gland as the initial manifestation of the tumor Rarely, there can be columnar ciliated epithe- or as the first evidence of relapse many years after lium replacing part of the follicular epithelium.670 resection of the renal primary.31, 665 It can potentially The thyroid follicular epithelium can also undergo short be misdiagnosed as primary clear cell tumor of the squamous metaplasia or oncocytic metaplasia.671 standard long

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Crystals are commonly found in the colloid of situated below the hyoid bone but above the thyroid the thyroid follicles. They are most commonly seen isthmus. When it is complicated by infection, there in nodular goiters, but they can be seen in various can be tenderness and pain. Histologic examination non-neoplastic and neoplastic lesions of the thyroid. shows the cyst to be lined by respiratory or strati- The crystals vary in geometric shapes and are most fied squamous epithelium. The wall consists of fi- often composed of calcium oxalate.672–674 brous tissue, which may be infiltrated by chronic Solid cell nests, common incidental findings in inflammatory cells. Mucous glands can be present in the thyroid, are often detected at low-magnification the wall. Some thyroid follicles are often but not scanning as a blue-staining cellular focus.671, 675–679 invariably identified in the vicinity. Rarely, carcino- They appear as a small collection of solid epithelial mas can develop in a thyroglossal duct cyst. Papil- islands resembling transitional epithelium (Fig. lary carcinoma is the most common histologic type, 44–82). Some islands can show cystic change and but squamous cell carcinoma can also rarely occur contain mucinous substance. The epithelial cells pos- in this setting.681–683 sess oval grooved nuclei. The solid cell nests are Multiple branchial cleft–like cysts are rarely believed to be remnants of ultimobranchial bodies, found in association with Hashimoto’s thyroiditis. and many scattered C cells are associated with these The cysts are lined by squamous or respiratory epi- nests.508, 677 thelium and are surrounded by a band of dense Palpation granuloma (palpation thyroiditis) is a lymphoid infiltrate.684 Postulated pathogenetic mech- common incidental finding of no consequence and is anisms include metaplastic and cystic change of the believed to result from the mechanical trauma of thyroid follicles in the setting of thyroiditis and palpation.680 One or two thyroid follicles appear to origin from developmental rests.684, 685 have ruptured and are replaced by histiocytes and multinucleated histiocytes. They are not associated with fibrous scarring. Thyroid Tissue in the Lateral Neck

Cysts LATERAL ABERRANT THYROID Thyroid tissue occurring in the lateral neck separate The most common cyst of the thyroid gland is de- from the thyroid gland has often been referred to as generate cyst resulting from cystic degeneration of lateral aberrant thyroid. This can occur in several nodular goiter. Cystic degeneration can also occur in circumstances46: 1) sequestered nodule in nodular various thyroid tumors, such as follicular adenoma. goiter; the nodule may still be connected by a nar- The cystic variant of papillary carcinoma is charac- row strand of tissue to the main gland; 2) regrowth terized by the presence of a prominent cystic com- of thyroid tissue that has been implanted in the soft ponent lined by neoplastic cells. tissues of the neck from prior surgery; and 3) se- Thyroglossal duct cyst represents cystic dilata- questered thyroid tissue involved by Hashimoto’s tion of the persistent thyroglossal duct. The patient thyroiditis or Graves’ disease. It is most important, usually present in the ﬁrst 3 decades of life with a however, to rule out the possibility of metastatic swelling in the midline of the neck that typically thyroid carcinoma (most commonly papillary carci- moves upward with swallowing. The cyst is usually noma) in cervical lymph nodes.

FIGURE 44–82. Solid cell nest of the thyroid. A. Small, blue-staining islands of epithelium are disposed in a stellate conﬁguration among the thyroid follicles. Occasional epithelial islands show cyst formation with secretion. B. The epithelial cells resemble transitional epithelium, and nuclear grooves short are common. standard long

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THYROID INCLUSIONS IN CERVICAL the first clinical manifestation of an occult papillary LYMPH NODE thyroid carcinoma—the thyroid primary is almost Benign thyroid follicles can rarely occur in cervical always located on the ipsilateral side. The node can lymph nodes. Nonetheless, this belief is not univer- be cystic or show sudden enlargement because of sally accepted; some investigators consider all thy- hemorrhage. On histologic examination, a diagnosis roid tissues within lymph nodes to represent metas- of metastatic papillary thyroid carcinoma can be ob- tasis from clinically undetected thyroid carcinoma.686 vious because of presence of recognizable lymph Because the distinction between benign thyroid in- node tissue and papillary carcinoma. However, in clusions and metastasis from an occult thyroid carci- some cases, the cyst wall is formed by dense fibrous noma can be extremely difficult owing to the almost tissue with scanty lymphoid tissue underneath and normal histologic appearances of some thyroid carci- lined by attenuated nondescript cells, and thus it nomas, strict criteria must be used in the diagnosis may be mistaken for a branchial cyst (Fig. 44–83). of benign thyroid inclusions46, 687, 688: Careful search may be required to uncover small papillae projecting into the lumen or some elongated • They consist of only a small conglomerate of thy- follicles in the wall, with the cells exhibiting the roid follicles. typical nuclear features of papillary carcinoma (Fig. • They are limited to the periphery of one or two 44–83B, C). A diagnosis can be readily confirmed by lymph nodes. positive immunostaining for thyroglobulin. • Nuclear features of papillary carcinoma are lacking, that is, nuclei are not enlarged, with fine chro- MIMICKER OF METASTATIC THYROID matin and inconspicuous nucleoli. CARCINOMA IN CERVICAL LYMPH NODE • Psammoma bodies are absent. A sequestered thyroid nodule involved by florid • There is lack of a desmoplastic reaction. Hashimoto’s thyroiditis can potentially be mistaken for metastatic thyroid carcinoma in lymph node be- METASTATIC THYROID CARCINOMA IN cause the lymphoplasmacytic infiltrate with germi- CERVICAL LYMPH NODE nal center formation imparts a lymph node–like ap- Papillary carcinoma commonly metastasizes to pearance and the thyroid follicles can exhibit nuclear lymph nodes, whereas follicular carcinoma rarely atypia or pallor. However, subcapsular sinuses, a does. Cervical lymph node metastasis is sometimes hallmark of lymph node, are lacking.

FIGURE 44–83. Cystic metastasis of papillary thyroid carcinoma in lymph node. A. This cyst excised from the lateral neck can be mistaken for a developmental cyst because of its innocuous appearance. The wall is formed by ﬁbrous tissue with only focal lining by attenuated epithelium. B. In areas, more plump and slightly pseudostratiﬁed epithelial cells are seen lining the cyst. C. On careful search, a small focus with papillary structures is short found, clinching the diagnosis of metastatic papillary carcinoma. standard long

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Thyroiditis berculosis, actinomycosis, and fungal infection. The patients are often immunocompromised. Granulo- ACUTE THYROIDITIS mas with or without caseation are found in the thyroid, although they can be poorly formed in im- Acute thyroiditis is rare. It is caused by bacterial munocompromised hosts. The main differential infection, such as Staphylococcus, Streptococcus pyoge- diagnoses are sarcoidosis and de Quervain’s thy- nes, and Haemophilus influenzae. The patients are of- roiditis. ten immunosuppressed, or there is a regional infective focus, such as piriform sinus fistula. They DE QUERVAIN’S THYROIDITIS (SUBACUTE present with painful swelling of the thyroid and GRANULOMATOUS THYROIDITIS) fever. Histologic examination shows polymorph inde Quervain’s thyroiditis is thought to be caused by filtration associated with destruction of the thyroid viral infection, although no specific virus has been follicles. incriminated. The main features are summarized in Table 44–18.689, 690 In contrast to the randomly dis- INFECTIOUS GRANULOMATOUS tributed granulomas in infectious granulomatous THYROIDITIS thyroiditis, the granulomas in de Quervain’s thy- Granulomatous inflammation can be produced in roiditis are centered around residual colloid (Fig. the thyroid by some infective processes, such as tu- 44–84).

TABLE 44–18. Major Types of Thyroiditis

Hashimotos’ Thyroiditis de Quervain’s Thyroiditis Riedel’s Thyroiditis

Nature of disease Autoimmune thyroiditis, with au- A subacute thyroiditis An inflammatory fibrosclerosing process toantibodies against thyro- Possibly related to viral infection lesion globulin, thyroid peroxidase, or postviral inflammatory pro- A small proportion of patients thyrotropin receptor, and io- cess subsequently develop inflam- dine transporter, as well as matory fibrosclerosis of other cell-mediated immunity sites, e.g., retroperitoneal fi- against thyroid tissue compo- brosis, mediastinal fibrosis, or- nents bital pseudotumor, sclerosing cholangitis Age Most commonly 45–65 y Most commonly 30–50 y Broad age range, with a mean of 48 y Sex F ϾϾ M (15 : 1) F Ͼ M(4: 1) F Ͼ M(5: 1) Presentation Painless thyroid swelling Sudden or gradual onset of pain Recent enlargement of thyroid Some may have evidence of hy- in the neck gland, which may be accompa- pothyroidism, whereas some May have transient hyperthyroid- nied by pressure symptoms, may have transient hyperthy- ism e.g, dyspnea, dysphagia roidism Can be accompanied by fever Most patients are euthyroid, but and systemic symptoms some can be hypothyroid May have a history of preceding upper respiratory infection Pattern of in- Diffuse, with involvement of Unilateral or bilateral involve- Focal involvement of thyroid, as- volvement of both lobes ment sociated with extrathyroidal the thyroid No extrathyroidal extension Usually a patchy process (1 cm to extension gland several centimeters in diame- ter), but there is no extrathyroidal extension Antithyroid anti- Always Usually negative Approximatelly two thirds of pa- bodies in se- tients rum Major histologic Lymphoplasmacytic infiltration Disrupted follicles Invasive process, and may entrap features Follicular infiltration and destruc- Histiocytes and multinucleated skeletal muscle fibers tion by lymphocytes giant cells around pools of re- Focal replacement of thyroid pa- Widespread oncocytic change in sidual colloid renchyma by hypocellular fi- thyroid epithelium Lymphocytic infiltration brous tissue Patchy fibrosis Patchy chronic inflammation with or without lymphoid follicle formation Phlebitis Clinical outcome Gradual loss of thyroid function, May have transient hyperthyroid- Disease appears to be self-lim- i.e., hypothyroidism ism ited Disease usually resolves in a few Prognosis after subtotal removal short months of the fibrotic mass is excellent standard long

Thyroid and Parathyroid 59 top of RH

follicles, and the remaining ones are often small. The thyroid follicular epithelium shows extensive oncocytic (Hu¨ rthle cell) change and can have enlarged or pale nuclei (Fig. 44–85). Those examples with heavy lymphoplasmacytic infiltration can be difficult to distinguish from extranodal marginal zone B cell lymphoma or plasmacytoma arising in Hashimoto’s thyroiditis; see the relevant sections for distinguishing features. Nodular Hashimoto’s thyroiditis refers to the presence of superimposed nodules comprising closely packed small follicles or trabeculae, most of which are lined by Hu¨ rthle cells (Fig. 44–86). The multiplicity of nodules and the frequent presence of isolated pleomorphic nuclei can potentially lead to FIGURE 44–84. de Quervain’s thyroiditis. The thyroid shows in- an erroneous diagnosis of Hu¨ rthle cell carcinoma. filtration by chronic inflammatory cells and mild fibrosis. The Vascular invasion is absent, however. most characteristic feature is the presence of foreign body–type The fibrosing variant accounts for 12.5% of all giant cells engulfing colloid material, indicating that there has cases of Hashimoto’s thyroiditis. It is defined by the been destruction of follicles. presence of broad bands of dense hyaline fibrous tissue occupying more than one third of the thyroid gland, separating islands of thyroid parenchyma ex- HASHIMOTO’S THYROIDITIS hibiting typical histologic features of Hashimoto’s thyroiditis (oxyphilic change, follicular cell damage, Clinical Considerations and lymphoid infiltration)692 (Fig. 44–87). Squamous Hashimoto’s thyroiditis, also known as struma metaplasia in the thyroid follicles is common. Clini- lymphomatosa, is the prototype of autoimmune thy- cally, the thyroid gland feels firm or hard, and pres- roiditis. The salient clinical features are summarized sure symptoms can be present. The antithyroid anti- in Table 44–18.689–691 There is an increased risk for body titers are often high. Clinical evidence of development of malignant lymphoma and papillary hypothyroidism is present in approximately 50% of carcinoma. cases. The thyroid is usually symmetrically enlarged, with a firm or rubbery consistency. The cut surface LYMPHOCYTIC THYROIDITIS AND is tan or tan-brown, with a homogeneous or vaguely PAINLESS THYROIDITIS lobulated appearance. The term lymphocytic thyroiditis is often applied when there is diffuse or multifocal lymphoplas- Diagnostic Considerations macytic infiltration in the absence of oncocytic On histologic examination, there is heavy infil- change in the thyroid follicular epithelium. There is tration of the interstitium and some thyroid follicles no significant atrophy of the thyroid follicles. How- by lymphocytes and plasma cells. Reactive lymphoid ever, during the active phase, there can be follicular follicles are often present. There is loss of thyroid destruction and hyperplastic change in the follicles.

FIGURE 44–85. Hashimoto’s thyroiditis. A. There is frequently an accentuated lobulated architecture. Lymphoid inﬁltration with lymphoid follicle formation is evident. The pink appearance in areas not inﬁltrated by lymphoid cells results from oncocytic change in the follicular epithelium. B. The follicles short are typically small and lined by oncocytic (Hu¨ rthle) cells. There are many intermingled lymphocytes standard and plasma cells. long

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FIGURE 44–86. Nodular Hashimoto’s thyroiditis. In the back- FIGURE 44–88. Riedel’s thyroiditis. The ﬁbroproliferative pro- ground Hashimoto’s thyroiditis, variably sized nodules composed cess replaces the thyroid parenchyma and extends into the sur- of follicles lined by Hu¨ rthle cells are present. These nodules con- rounding tissue. In addition to a sprinkling of chronic inﬂamma- tain few lymphoplasmacytic cells. tory cells, small aggregates of lymphocytes are present.

The disease is believed to have an autoimmune past few decades.701 Although steroid treatment may basis. sometimes be effective, surgical excision is usually The clinical counterpart is variously known as required to relieve the pressure symptoms and to painless thyroiditis, silent thyroiditis, juvenile thy- exclude malignancy. roiditis, or postpartum thyroiditis, depending on the The most important differential diagnosis is clinical scenario.693–698 In most patients, there is tran- paucicellular variant of anaplastic carcinoma because sient hyperthyroidism followed by hypothyroidism of marked differences in outcome (see “Anaplastic and spontaneous evolution. Some patients present Carcinoma”).381 Riedel’s thyroiditis can also be dis- with thyroid swelling. The entire clinical course usu- tinguished from fibrosing Hashimoto’s thyroiditis by ally lasts less than 1 year. Only rarely do the pa- the features of extrathyroidal extension of the fibro- tients eventually become hypothyroid. proliferative process, presence of phlebitis, and relatively normal surviving thyroid tissue.700 RIEDEL’S THYROIDITIS The main features of Riedel’s thyroiditis are summa- FOCAL LYMPHOCYTIC THYROIDITIS rized in Table 44–18 (Fig. 44–88).689, 699–701 The clini- (NONSPECIFIC LYMPHOCYTIC THYROIDITIS) cal impression is usually that of thyroid cancer be- Focal lymphoid infiltration in the thyroid gland is a cause of the presence of a stony hard thyroid mass. fairly common incidental finding in thyroidectomy Riedel’s thyroiditis is rare; for unknown reasons, its specimens and at autopsy.702–705 This is also a com- incidence has decreased dramatically during the mon finding in the vicinity of various thyroid tumors, especially papillary carcinoma. The lymphoid cells tend to be localized to the interlobular areas, with little evidence of destruction of thyroid follicles. The pathogenesis is unknown, but the lesion is probably of no consequence. MULTIFOCAL FIBROSING THYROIDITIS Multifocal fibrosing thyroiditis is a peculiar form of thyroiditis characterized by many microscopic foci of stellate cellular fibrosis with some entrapped thyroid follicles, mimicking the low-magnification architecture of papillary microcarcinoma.45 The pathogenesis is not known.

Graves’ Disease

CLINICAL CONSIDERATIONS FIGURE 44–87. Fibrosing Hashimoto’s thyroiditis. Broad ﬁbrous bands traverse the thyroid gland involved by Hashimoto’s thy- Graves’ disease is the most common cause of hyper- roiditis. In contrast to Riedel’s thyroiditis, the process does not thyroidism. It is an organ-speciﬁc autoimmune dis- short extend beyond the thyroid capsule. ease produced by thyroid-stimulating antibodies— standard long

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The endemic form (endemic goiter) is due to iodine deficiency in the diet or water and hence a low production of thyroid hormones, leading to compensatory increase in thyroid-stimulating hormone, which stimulates the thyroid follicles to undergo hyperplasia (parenchymatous goiter). Subse- quently, some follicles undergo involution with massive accumulation of colloid (diffuse colloid goiter), and nodule formation supervenes. The sporadic form of nodular goiter is of unknown pathogenesis. The patients usually present with an enlarged multinodular thyroid gland, which may be accompanied by compression symptoms. Extension into the mediastinum can occur, producing additional FIGURE 44–89. Graves’ disease. The follicles are mostly me- symptoms related to the mediastinal location. There dium sized and lined by columnar cells that form papillary in- can be pain and sudden enlargement of the thyroid foldings. gland due to hemorrhage. Some patients present with a solitary thyroid mass, but additional nodules are often evident on ultrasound examination. Most thyrotropin receptor antibody, which stimulates patients are euthyroid, but rare patients may have hormone production, and thyroid growth–stimulat- hyperthyroidism (toxic nodular goiter). ing immunoglobulin, which promotes parenchymal hyperplasia. Macroscopic Findings Graves’ disease mostly affects adults in their 20s The thyroid gland is enlarged, sometimes to an and 30s with a marked female predominance. The enormous size. The external contour is often dis- patients present with hyperthyroidism, diffuse swell- torted. There are multiple nodules, which often lack ing of the thyroid gland, and exophthalmos. fibrous capsules (Fig. 44–90A). The nodules exhibit variable appearances ranging from colloid-rich with DIAGNOSTIC CONSIDERATIONS brown color and glistening quality to solid, tan, and Thyroid gland involved by Graves’ disease is typi- fleshy. Secondary changes such as fibrosis, hemor- cally diffusely and symmetrically enlarged, with a rhage, cystic degeneration, and calcification are com- meaty quality on the cut surface. An accentuated mon. In some cases, there is an apparently solitary lobular architecture is evident histologically. The fol- nodule surrounded by a thin capsule, making dis- licles are mostly medium sized. The lining columnar tinction from follicular neoplasm difficult (Fig. cells form papillary projections into the luminal 44–90B). Careful examination of the background spaces, with some lumina appearing star shaped thyroid often reveals multiple vague nodules with a (Fig. 44–89). The nuclei often show some variation colloid-rich quality. in size, and some can appear pale. Colloid is scanty, pale, and scalloped. There is a patchy light lym- DIAGNOSTIC CONSIDERATIONS phoid infiltrate in the interstitium. Microscopic Findings The typical histologic features are now rarely seen in surgical pathology practice because the pa- In most cases, multiple, variably sized nodules tients have been treated with drugs to control the are evident. The different nodules often exhibit dif- hyperthyroidism before the operation. With such ferent degrees of cellularity and variations in follicle treatment, the follicles show greater variation in size (Fig. 44–91). size, and some follicles may appear involuted. The The typical nodule comprises large follicles lined follicular epithelium becomes less tall, and colloid by regular low cuboidal epithelium and distended can often be seen. Nonetheless, the hyperplastic ap- with colloid (colloid nodule) (Fig. 44–92). There are pearance with papillary infoldings is often still evi- frequently some broad papillae projecting into the dent in focal areas. large follicles, so-called Sanderson polsters (Fig. 44–93). In contrast to papillary carcinoma, the papillae have broad edematous cores and are lined by Nodular Goiter columnar cells with dark round nuclei regularly aligned at the base of the cells. Smaller “daughter” CLINICAL CONSIDERATIONS follicles are present in the cores of these papillae. Hemosiderin-laden macrophages are commonly Presentation found within the follicular lumina or in the intersti- Nodular goiter is the most common thyroid le- tium, providing evidence of prior hemorrhage. sion encountered in surgical pathology practice. It is Patchy fibrosis and calcification are common (Fig. characterized by nodule formation in the thyroid, 44–94A). Some areas may undergo infarction, with short with hyperplastic as well as involuted areas. only “ghost” follicles being identifiable. There can be standard long

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FIGURE 44–90. Nodular goiter. A. In this case, multiple nodules with a glistening colloid (gelati- nous) quality are evident. B. In this case, the nodule is apparently solitary and enveloped by a thin capsule. It has a variegated appearance with colloidlike areas, small cysts, hemorrhagic areas, fibrosis, and calcification. interspersed cysts comprising a fibrous wall with Differential Diagnosis or without lining by attenuated epithelium (Fig. 44–94B). The lining epithelium and entrapped folli- FOLLICULAR ADENOMA. The distinction be- cles in the fibrous wall may show reactive atypia or tween nodular goiter presenting as a solitary nodule squamous metaplasia. In some cysts, collections of and follicular adenoma can be difficult and some- residual large follicles project into the cyst lumen. times arbitrary. The distinction is not critical, how- Some nodules can be highly cellular, being com- ever, as long as there is no capsular or vascular posed of small follicles and trabeculae (Fig. 44–95; invasion. In general, an adenoma is solitary, is com- see also Fig. 44–92C). The nuclei of the thyroid epi- pletely enveloped by a fibrous capsule, is expansile thelial cells appear uniform or atypical. Oncocytic, and produces a compression effect on the surround- clear cell, and signet ring change can occur. There ing tissues, and shows cytoarchitectural features dis- can also be areas resembling hyalinizing trabecular similar from the surrounding parenchyma. 57 adenoma. These cellular nodules (adenomatoid FOLLICULAR CARCINOMA. See earlier. nodules) can be difficult to distinguish from follicular neoplasm or even insular carcinoma. When the PAPILLARY CARCINOMA. See earlier follicles exhibit large pale nuclei, the additional dif- INSULAR CARCINOMA. See earlier. ferential diagnosis of papillary carcinoma may be raised; these follicles show gradual transition with DYSHORMONOGENESIS. For young patients not the normal or benign follicles, and they lack the living in areas of endemic goiter and presenting sharp demarcation from the non-neoplastic follicles with large multinodular goiter, the possibility of as seen in papillary carcinoma. dyshormonogenesis should be entertained.

FIGURE 44–91. Nodular goiter. Multiple nodules with variable cellularities and follicle sizes are short seen. A. In this case, most follicles are large. B. In this case, there are large as well as small follicles. standard long

Thyroid and Parathyroid 63 top of RH

FIGURE 44–92. Nodular goiter. A. The large follicles are distended with colloid and are lined by uniform cells with small dark nuclei. B. Small and closely packed follicles (left field) can be found in some nodules. C. Although the cells lining the smaller follicles may have pale nuclei (left field), raising the possibility of papillary carcinoma, they show gradual transition with the benign follicles in the right field instead of forming a distinct neoplastic population.

Dyshormonogenetic Goiter dle age.706 The enlarged multinodular thyroid can weigh up to 600 g. There can be a slightly increased CLINICAL CONSIDERATIONS risk for thyroid carcinoma.706 Dyshormonogenesis is a form of familial goiter DIAGNOSTIC CONSIDERATIONS caused by genetic enzyme defects in thyroid hormone synthesis.297 The patients usually present with Microscopic Findings congenital hypothyroidism or early-onset goiter. The most salient feature of dyshormonogenetic However, some patients may not present until mid- goiter is the presence of highly cellular nodules ex-

FIGURE 44–93. Nodular goiter. A. Sanderson polsters and papillary structures project into a large colloid-ﬁlled follicle. B. Sanderson polster is a broad protuberance with daughter follicles in the core. short The lining cells have uniform and regularly aligned nuclei. standard long

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FIGURE 44–94. Nodular goiter. A. Nodular goiter showing patchy fibrosis, with infiltration of histiocytes and chronic inflammatory cells. B. Cystic degeneration in nodular goiter. The cyst has a fibrous wall lined by attenuated epithelium.

FIGURE 44–95. Nodular goiter with cellular nodules (adenomatoid nodules). A. The follicles are small, and distinction from follicular neoplasm can be difﬁcult. B. A solid appearance can also be produced.

FIGURE 44–96. Dyshormonogenesis. A. A multinodular pattern is evident. B. The follicles are often small with no or scanty colloid. There are interspersed cells with large hyperchromatic nuclei. short standard long

Thyroid and Parathyroid 65 top of RH hibiting a variety of architectural features (Fig. TISSUE INJURY 44–96A). The nodules can show a microfollicular, In the track of the needle pass, a linear hemorrhagic trabecular, solid, papillary, insular, or mixed growth track or an irregularly shaped hematoma is formed pattern. Follicles, when present, are small and fre- (Fig. 44–97A). The thyroid follicles in the vicinity quently devoid of colloid. There are commonly in- can undergo partial disruption or necrosis. terspersed cells with large hyperchromatic nuclei or vesicular nuclei. Cells with hyperchromatic pleomor- REPARATIVE CHANGE phic nuclei are most commonly found in the inter- Organization of the hematoma and damaged tissue nodular tissue in association with streaming of folli- leads to granulation tissue formation, chronic in- cles (Fig. 44–96B). There is often prominent fibrosis flammatory cell infiltration, hemosiderin deposition, between the nodules. Because of the presence of and subsequently fibrous scarring. multiple highly cellular nodules, cellular atypia, and pseudoinfiltrative pattern created by the fibrosis, TISSUE INJURY OR REPAIR-ASSOCIATED dyshormonogenetic goiter can be mistaken for follic- REACTIVE CHANGES THAT MAY LEAD TO ular carcinoma.706 A MISDIAGNOSIS OF MALIGNANCY The stromal reparative reaction to the trauma of Differential Diagnosis fine-needle aspiration can be exuberant. Active-look- FOLLICULAR CARCINOMA. In contrast to follicu- ing plump spindly myofibroblasts are admixed with lar carcinoma, the different nodules exhibit different thin-walled blood vessels, histiocytes, and hemosid- degrees of cellularity and architectural features, and erin (Fig. 44–97B). The lesion can be mistaken for genuine vascular invasion is lacking.707 Kaposi’s sarcoma or other sarcomas; the term post– ODULAR OITER fine-needle aspiration spindle cell nodule has also been N G . In contrast to nodular 708 goiter, there is scanty colloid, less degenerative applied to this lesion. change, presence of prominent nuclear atypia, and Tumor infarction complicating fine-needle aspi- absence of normal internodular tissue.706 ration can be accompanied by exuberant fibrogranu- lation tissue that begins in the peripheral zone and THYROID TREATED WITH RADIOACTIVE IODINE. gradually extends inward. This reparative process The thyroid glands in patients treated with radioac- can potentially be mistaken for anaplastic carcinoma, tive iodine can be indistinguishable from dyshor- attributable to the poorly defined contour of the monogenetic goiter histologically. The clinical his- lesion and reactive atypia of the spindly cells (Fig. tory is essential for making the distinction. 44–98). Organization of the fine-needle aspiration–associated hematoma can result in an exuberant, Masson Fine-Needle Aspiration–Associated tumor–like reaction, which can potentially be mis- Changes in the Thyroid Gland taken for angiosarcoma.709 The follicles around the areas of tissue injury or Fine-needle aspiration of the thyroid gland can lead infarction can exhibit reactive atypia, such as nuclear to a variety of histologic changes, some mundane enlargement and prominent nucleoli, and can poten- and some potentially causing diagnostic prob- tially be mistaken for high-grade carcinoma. These lems.101, 106 reactive follicles can show anastomosis and intrafol-

FIGURE 44–97. Fine-needle aspiration–associated changes in the thyroid. A. A linear hemorrhagic needle track is evident. B. Exuberant fibroblastic-myofibroblastic reaction in an area of tissue injury, so-called post–fine-needle aspiration spindle cell nodule. short standard long

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FIGURE 44–98. Fine-needle aspiration–associated infarction of papillary carcinoma. A. In most areas of the resection specimen, there is prominent myofibroblastic proliferation associated with histiocytes and deposits of hematoidin and hemosiderin. This represents organization of the infarct. B. Residual papillary carcinoma is identified focally (right upper field). Note the adjacent reparative reaction and infarcted tumor (lower field). licular hemorrhage, resulting in an angiosarcoma- dle aspiration (see Fig. 44–98). It can be difficult to like appearance106, 709, 710 (Fig. 44–99). arrive at a definitive diagnosis in the excision specimen if the tumor shows complete infarction. TUMOR IMPLANTATION IN NEEDLE TRACK At the site of needle puncture of the fibrous capsule of a thyroid neoplasm, some tumor islands can her- Amyloid Goiter niate into the capsule. This phenomenon (capsular rupture) can potentially lead to an erroneous inter- The thyroid gland is a common site for deposition pretation of capsular invasion (see Fig. 44–22 and of amyloid in systemic amyloidosis, but this usually Table 44–8). does not result in enlargement of the thyroid or clinical symptoms. However, on occasion, amyloid TUMOR INFARCTION deposits are so extensive that the patients present Among the various types of thyroid tumors, Hu¨ rthle with a nontender, rapidly enlarging neck mass, cell tumor is particularly prone to undergo infarc- which may be associated with dysphagia, dyspnea, tion after fine-needle aspiration, probably because of and hoarseness. There is usually no clinical or bio- the high energy requirements of the mitochondria- chemical evidence of thyroid dysfunction.711, 712 rich tumor cells104 (Fig. 44–100). Papillary carcinoma On histologic examination, amyloid is deposited also occasionally undergoes infarction after fine-nee- between and around the follicles, accompanied by

FIGURE 44–100. Fine-needle aspiration–associated infarction of FIGURE 44–99. Fine-needle aspiration–associated reactive cellu- Hu¨ rthle cell adenoma. Virtually the entire tumor has undergone lar atypia. Around the hemorrhagic needle track, the follicles infarction. Necrotic ghost cells are seen in the left field, and only anastomose to produce branching clefts, which in association with a thin rim of viable tumor is seen in the right field. The interven- short the extravasated blood mimic angiosarcoma. ing zone shows histiocytic infiltration and reparative changes. standard long

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FIGURE 44–101. Amyloid goiter. There is interstitial deposition FIGURE 44–102. Black thyroid associated with minocycline in- of eosinophilic-staining amyloid. Commonly, there are inter- take. The follicular epithelial cells contain bright brown granules spersed adipose cells. The follicles are atrophic and lined by atin the cytoplasm. tenuated epithelium.

atrophy of the follicles (Fig. 44–101). Amyloid is 44–102). The pigment is currently believed to result also deposited in the blood vessel walls. Adipose from oxidative interaction between thyroid peroxi- cells are commonly interspersed within the amyloid. dase and the drug; it resembles neuromelanin in The amyloid can be of AA or AL type. histochemical properties.713–720 Of interest, when a tumor arises in a black thyroid, the tumor is often nonpigmented.721–723 Black Thyroid

Black thyroid is an uncommon but dramatic condi- Uncommon Lesions of the Thyroid tion caused by administration of minocycline, a Gland form of tetracycline. There are no clinical symptoms. On gross evaluation, the thyroid is black. On histo- Exceptional examples of Rosai-Dorfman disease, ma- logic examination, the follicular cells contain ﬁne, lacoplakia, extramedullary hematopoiesis, and in- dark brown granules, and ultrastructural analysis ﬂammatory pseudotumor (plasma cell granuloma) shows the pigment to be located in lysosomes (Fig. have been reported in the thyroid.621, 724–730

B. The Parathyroid Gland

NEOPLASTIC LESIONS Parathyroid neoplasm of uncertain malignant potential Classiﬁcation

Few tumor types are known to affect the parathy- General Considerations roid gland, and they include the following: Parathyroid adenoma PATHOGENESIS Typical Parathyroid adenomas and carcinomas usually occur Variants sporadically, but they can sometimes occur as a Lipoadenoma component of multiple endocrine neoplasia (MEN 1 Papillary variant and MEN 2) or familial idiopathic hyperparathy- Water-clear variant roidism.731–733 Radiation to the head and neck region Follicular variant has also been implicated as a possible etiologic fac- Oxyphil variant tor of parathyroid adenoma.734, 735 Parathyroid carci- Parathyroid carcinoma (functional or nonfunc- noma can occasionally supervene on parathyroid ad- short tional) enoma or parathyroid hyperplasia.736 standard long

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HYPERPARATHYROIDISM AS THE MAIN common), malabsorption, vitamin D deficiency, and CLINICAL MANIFESTATION OF renal tubular acidosis. PARATHYROID NEOPLASMS Parathyroid neoplasms typically present with fea- Tertiary Hyperparathyroidism tures of hyperparathyroidism, although some pa- Tertiary hyperparathyroidism is defined as au- tients are asymptomatic. There are three forms of tonomous parathyroid hyperfunction supervening hyperparathyroidism: primary, secondary, and terti- on secondary hyperparathyroidism. As a result, the ary. Only the primary and tertiary forms are associ- serum calcium concentration is elevated. The auton- ated with hypercalcemia and its related complica- omous parathyroid hyperfunction is most often tions, such as polyuria and polydipsia, muscle caused by nodular hyperplasia; it is only uncom- weakness, renal stone, and mental disturbance, but monly due to superimposed parathyroid adenoma all three forms can be associated with hyperparathy- or carcinoma. roid bone disease manifesting as bone pain or fracture.733, 737–748 Primary Hyperparathyroidism Parathyroid Adenoma Primary hyperparathyroidism is defined as over- CLINICAL CONSIDERATIONS production of parathyroid hormone as a result of intrinsic abnormality of the parathyroid glands. In Presentation more than 85% of cases, the underlying pathologic Parathyroid adenoma is the most common cause process is a parathyroid neoplasm. The remaining of primary hyperparathyroidism (Ͼ 85%).749, 750 It oc- cases result from primary parathyroid hyperplasia, curs in patients with a mean age of 56 to 62 years. which can be sporadic or syndromatic (Table Women are more commonly affected than are men. 44–19). Approximately 50% of patients are asymptomatic, being incidentally found to have hypercalcemia on Secondary Hyperparathyroidism routine blood chemistry.750, 751 Others present with Secondary hyperparathyroidism is defined as renal stone (30%) or parathyroid bone disease (20%), compensatory hyperplasia of parathyroid glands but simultaneous renal and skeletal disease is ex- with overproduction of parathyroid hormone due to tremely rare.750–755 Surgical excision of the single in- hypocalcemia. As a result, the serum calcium con- volved parathyroid gland is curative.749, 756 centration is often normalized. Nonetheless, the para- Although parathyroid adenoma typically in- thyroid hormone can stimulate bone resorption, re- volves a single gland, occasionally two of the four sulting in parathyroid bone disease. Underlying glands are simultaneously involved (double ade- disorders include chronic renal failure (the most noma) on both sides or on the same side of the

TABLE 44–19. Syndromes Associated with Hyperparathyroidism

Familial Isolated MEN 1 MEN 2A Hyperparathyroidism

Endocrine organ Parathyroid hyperplasia or neo- Parathyroid hyperplasia or neo- Parathyroid hyperplasia or neo- disease plasm plasm plasm Thyroid nodule or follicular ade- Thyroid medullary carcinoma noma Pheochromocytoma Adrenal nodule or adenoma Islet cell tumor Pituitary adenoma Thymic carcinoid Bronchial carcinoid Other clinical Facial angioﬁbromas Lichen amyloidosis (some cases) Some kindreds also have jaw tu- features Collagenomas mors (hyperparathyroidism– Multiple lipomas jaw tumor syndrome) Natural history Hyperparathyroidism is com- Hyperparathyroidism occurs in Hyperparathyroidism is often di- of hyperpara- monly the ﬁrst presentation. 20%–30% of cases and is usu- agnosed at an early age. thyroidism Serum calcium level tends to be ally mild and asymptomatic. Incidence of renal stone is high. lower than that of parathyroid Recurrent or persistent hyper- adenoma, but incidence of re- parathyroidism is common. nal or bone involvement is similar. Genetic basis Germline mutation in MEN1 lo- Germline gain-of-function muta- Genetic locus linked to 1q21–32 cus on chromosome 11q13 tion in RET proto-oncogene on (HPT-JT or HRPT2 gene) chromosome 10q11 short standard long

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in ectopic locations, such as the mediastinum, thyroid, or esophagus.761–766 When they occur within the thyroid gland, they can potentially be mistaken for thyroid follicular adenoma or medullary carcinoma.761, 767 Macroscopic Findings Parathyroid adenomas usually weigh less than 1g,with size ranging from less than 1 cm to several centimeters.768 The degree of hypercalcemia is generally correlated with the weight of the tumor.768 Para- thyroid adenoma forms a solitary circumscribed nodule, which is usually soft and orange-brown or reddish yellow to mahogany brown. Hemorrhage or cystic degeneration can sometimes be seen. The un- FIGURE 44–103. Parathyroid adenoma. The well-circumscribed affected parathyroid glands are normal in size or tumor exhibits a solid growth pattern punctuated by edematous areas (left field). Residual normal parathyroid tissue is seen in the small. right upper field. DIAGNOSTIC CONSIDERATIONS Microscopic Findings Parathyroid adenomas are typically well circumscribed and solitary, although exceptionally they neck.751, 757–760 These patients are often symptomatic may be multinodular (Fig. 44–103). Vague lobula- and have a significantly higher parathyroid hor- tion may be present.769, 770 A thin rim of compressed mone level and tumor weight than with solitary ad- parathyroid tissue can be present at the periphery. enoma. Because distinction from asymmetric pri- In contrast to the normal parathyroid gland, inter- mary hyperplasia of the parathyroid glands can be spersed adipose cells are absent or scanty. difficult, strict criteria must be applied for its diag- The tumor cells form solid sheets, cords, acini, nosis757, 758: follicles, and microcysts traversed by a delicate cap- • Two enlarged parathyroid glands are confirmed illary or sinusoidal network (Fig. 44–104). They are histologically to be hypercellular. polygonal, and the cytoplasm can be clear, eosino- • The remaining parathyroid glands are confirmed philic, or oxyphilic. The nuclei are usually dark, intraoperatively to be normal (preferably con- round, and uniform, but there can be interspersed firmed histologically by biopsy). nuclei that are large, hyperchromatic, or even bi- 768 (Fig. 44–105). The nuclei also show a ten- • No clinical evidence or family history of multiple zarre dency to be polarized toward the vascular aspect of endocrine neoplasia or familial hyperparathyroid- the cells (Fig. 44–106). Mitotic figures are rare or ism is found. absent. Vague nodular foci are sometimes seen • Permanent cure of hypercalcemia is achieved by within the tumor.771 excision of the two enlarged glands alone. Fibrosis, hemorrhage, infarction, or cystic change Parathyroid adenomas can sometimes cause can occur, but there should not be coagulative tu- problems in their localization because of occurrence mor necrosis; if it is present, coagulative tumor ne-

FIGURE 44–104. Parathyroid adenoma. A. Clear cells grow in a diffuse pattern and are characteristi- short cally traversed by delicate blood vessels. B. The tumor shows a complex acinar growth pattern. standard long

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FIGURE 44–105. Parathyroid adenoma. A. The tumor cells possess clear or eosinophilic cytoplasm. The nuclei appear uniform and dark staining. B. In focal areas, there are cells with large hyperchromatic nuclei. Presence of these large nuclei is not indicative of malignancy. C. In this example, most nuclei are mildly atypical.

crosis strongly suggests parathyroid carcinoma. Rare Rarely, intrafollicular or interstitial amyloid can be cases show a lymphoid infiltrate in the peripheral found767, 774, 775 (Fig. 44–107). The morphologic vari- portion in the form of lymphoid follicles or in the ants are listed in Table 44–20 (Figs. 44–107 to parenchyma in the form of isolated cells.772, 773 44–109).775–788 Immunohistochemistry The tumor cells of parathyroid adenoma are immunoreactive for cytokeratin, pan-neuroendocrine markers (such as synaptophysin, chromogranin, and neurofilament), and parathyroid hormone.789–791 The Ki-67 proliferative index is low (0.5% to 5.1%, with a mean of 2% to 3%), but the nodular foci may show a higher index.771, 792–794 Immunohistochemical staining for parathyroid hormone is rarely required for diagnostic purposes, except when there are difficulties in distinction from a thyroid follicular adenoma or when the tumor occurs in an ectopic location. Molecular Biology and Genetics Molecular evidence of monoclonality can be demonstrated in most parathyroid adenomas by use of X-linked restriction fragment length polymor- FIGURE 44–106. Parathyroid adenoma. A characteristic feature 795–797 commonly seen in the normal parathyroid gland, parathyroid ad- phism studies. Furthermore, some cases exhibit enoma, and parathyroid carcinoma is palisading of nuclei along tumor-specific DNA alterations in the parathyroid the vascular pole of the cells. hormone gene.795 short standard long

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TABLE 44–20. Morphologic Variants of Parathyroid Adenoma

Variant Major Pathologic Findings Potential Diagnostic Pitfall

Lipoadenoma Often large size; chief and oxyphil cells are intermingled Without information on the gross appearance (“parathyroid with many mature adipose cells, which occupy 20%– (circumscribed and large), it can be mis- hamartoma”) 90% of the tissue area; loose ﬁbromyxoid stroma can taken histologically for normal parathyroid be present in some cases Papillary Prominent papillary pattern May be mistaken for papillary thyroid carcinoma Water-clear cell Composed of tumor cells with clear cytoplasm and dis- — tinct cell membranes Follicular Prominent follicular-acinar pattern May be mistaken for follicular thyroid neoplasm Oxyphilic Composed entirely of oxyphilic cells with abundant eo- May be mistaken for Hu¨ rthle cell neoplasms sinophilic granular cytoplasm of thyroid

FIGURE 44–107. Parathyroid adenoma, oxyphilic type. A. The tumor cells form trabeculae and acini. Amyloid is found in the lumina of the acini. B. This example shows a diffuse growth pattern. In contrast to Hu¨ rthle (oxyphilic) cells of the thyroid, the cell membranes are typically distinct.

FIGURE 44–108. Parathyroid lipoadenoma. Islands of parathyroid parenchymal cells are interspersed among abundant adipose FIGURE 44–109. Parathyroid adenoma, papillary variant. The cells. The circumscribed border of the large tumor is seen in the papillary processes are not genuine papillae but represent pseu- left upper ﬁeld. dopapillae formed by dehiscence of the tumor tissue. short standard long

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On cytogenetic analysis, rare cases of parathy- Intraoperative Frozen Section roid adenoma show pericentric inversion of chromo- Diagnosis of Parathyroid Adenoma some 11, which results in translocation of the cyclin Intraoperative frozen section evaluation of pa- D1 (PRAD1) gene with the parathyroid hormone tients presenting with hyperparathyroidism aims to gene, causing overexpression of cyclin D1 and hence achieve the following806, 807: increased cellular proliferation.795, 796, 798–801 Immu- • nohistochemical expression of cyclin D1 occurs at a Confirm that the tissue removed for examination higher frequency (ϳ 25% of cases), suggesting indeed represents parathyroid tissue, not lymph deregulation of cyclin D1 by mechanisms other node, thyroid, or ectopic thymus. • than pericentric chromosome inversion in such Determine whether the abnormal parathyroid tis- cases.798, 802 The MEN 1–associated MEN1 gene sue represents parathyroid adenoma (removal of shows somatic mutation in 10% to 23% of sporadic the diseased gland alone is sufficient), parathyroid parathyroid adenomas.803, 804 Chromosome abnormal- hyperplasia (removal of 3.5 glands is required), or ities identified by comparative genomic hybridiza- parathyroid carcinoma (en bloc radical excision is 749, 756 tion include loss of 11p, 11q, 1p, and 1q and gain of required). 805 16p and 19p. The gland should be measured, weighed, and examined histologically. It is usually easy to confirm Differential Diagnosis that the excised tissue is parathyroid gland on histologic examination, except that a small biopsy speci- PRIMARY OR SECONDARY PARATHYROID HY- men of lymph node may occasionally be misinter- PERPLASIA. In parathyroid hyperplasia, all the para- preted as parathyroid tissue because of artifactual thyroid glands should be enlarged, although they spaces created by freezing that mimic adipose are unevenly enlarged in some cases. Not uncom- cells.808 A parathyroid gland with few or no inter- monly, the individual enlarged glands have a multi- spersed adipose cells is supportive of a diagnosis of nodular appearance. “hypercellular parathyroid gland, consistent with PARATHYROID CARCINOMA. See subsequent parathyroid adenoma or hyperplasia” (Table section. 44–21). Some investigators consider lipid staining (Sudan II or IV, oil red O) on frozen sections or THYROID FOLLICULAR ADENOMA. When the imprint smears to be helpful in identifying an ab- parathyroid tumor is inside the thyroid gland and normal parathyroid gland797, 809–812 because the nor- shows a microfollicular pattern, it can be mistaken mal parathyroid cells contain abundant intracyto- for a follicular adenoma. Parathyroid adenoma is plasmic lipid droplets, whereas the hyperplastic or immunoreactive for parathyroid hormone, whereas adenomatous cells are often devoid of intracyto- thyroid follicular adenoma is immunoreactive for plasmic lipid. An exception is the oxyphil cell, thyroglobulin. which always contains no or scanty intracytoplasmic 770 OXYPHIL CELL NODULE. Oxyphil cell nodules lipid droplets. Adenomatous or hyperplastic are a common incidental finding in the parathyroid glands may occasionally contain intracytoplasmic gland, especially in an older subject. They are small lipid, albeit weakly and focally.813–816 and commonly multifocal (Fig. 44–110). After it is confirmed that the parathyroid gland is hypercellular, the next step is to determine whether it represents an adenoma or hyperplastic process. Although a compressed rim of normal parathyroid gland is characteristic of parathyroid adenoma, it is not always found and it can be mim- icked by the compressed intervening parenchyma in multinodular parathyroidhyperplasia.817, 818 The most reliable way to make the distinction is by de-

TABLE 44–21. Features Indicative of a Hypercellular (Neoplastic or Hyperplastic) Parathyroid Gland

Weight: single gland weighing Ͼ100 mg (normal weight, ϳ30 mg) Adipose cells in gland: few or absent (on average, ϳ17% of a normal parathyroid gland is composed of adipose cells) FIGURE 44–110. Oxyphil cell nodule. Small nodule composed Intracytoplasmic lipid droplets as demonstrated by lipid stain: entirely of oxyphilic cells is a common incidental ﬁnding in the absent or scanty parathyroid gland. short standard long

Thyroid and Parathyroid 73 top of RH termining the status of the other parathyroid glands. TABLE 44–22. Clues for Recognizing Parathyroid If they are all normal in size or small, a diagnosis of Carcinoma Versus Parathyroid Adenoma adenoma is favored. If all are enlarged, a diagnosis of parathyroid hyperplasia is favored. Simple in- Clinical Clues* Clues at Operation spection is not reliable because some hyperplastic processes affect the glands unequally; it is preferable High serum calcium level Firm consistency (Ͼ3.5 mmol/L or 14 mg/dL) Thick capsule to take an incisional biopsy specimen of one or Simultaneous parathyroid Adherence and invasion to more glands for histologic confirmation to ascertain bone disease and renal adjacent organs, e.g., thy- whether they are normal-suppressed or hyper- stone (found in ϳ40%) roid, muscle, nerve, esoph- plastic.819 Palpable neck mass (found in agus ϳ40%) Intraoperative assay of the parathyroid hormone Vocal cord paralysis level is an alternative way for guiding the extent of Presence of metastasis surgery, taking advantage of the fact that the hor- 807, 820–822 mone has a short half-life. If preoperative * The clinical clues actually reflect a large tumor or a tumor with imaging studies can identify an enlarged parathy- invasive properties. roid gland, a more limited unilateral procedure can be performed in place of bilateral neck exploration. Approximately 15 minutes after removal of the en- mors are nonfunctional.* The clues for recognizing larged gland, a serum sample is taken for parathy- the malignant nature of a parathyroid neoplasm are roid hormone assay. A significant drop in the hor- listed in Table 44–22. mone level (Ͼ 50%) suggests successful removal of the hypersecreting tissue, and thus cure is reasona- Macroscopic Findings bly ensured. The other parathyroid glands have to The carcinomas are usually hard because of the be explored for hyperplasia if the parathyroid hor- presence of fibrous trabeculae. The size ranges from mone level remains elevated after removal of one 1 cm to several centimeters.752 They are often much enlarged gland. larger than parathyroid adenomas, with an average weight of 12 g (versus less than 1 g for parathyroid adenoma).768 They can be circumscribed or invasive. Parathyroid Carcinoma Necrosis and calcification can be present.834

CLINICAL CONSIDERATIONS DIAGNOSTIC CONSIDERATIONS Presentation Microscopic Findings The tumor shows frank invasive features or is Parathyroid carcinomas are rare, constituting 736 only about 2% of all parathyroid neoplasms. Com- surrounded by a thick ﬁbrous capsule (Fig. 44–111). It comprises polygonal cells forming solid pared with parathyroid adenoma, the patients with 755 parathyroid carcinoma have a lower mean age (45 to sheets, trabeculae, acini, and packets. In some 54 years), there is no sex predilection, and virtually all patients are symptomatic because of the high serum calcium level (3.5 to 4 mmol/L). Only rare tu- *References 731, 736, 752–754, 767, 823–833.

FIGURE 44–111. Parathyroid carcinoma. A. The tumor shows frank infiltration into the surrounding fibrofatty tissue. B. In this example, the tumor grows in the form of irregular infiltrative islands. The stroma is desmoplastic. short standard long

74 Endocrine System top of RH

FIGURE 44–112. Parathyroid carcinoma showing the spectrum of cytologic features. A. In this example, the cells have fairly uniform nuclei. B. In this example, interspersed cells with large hyperchromatic nuclei are present. Mitotic ﬁgures are also evident. C. In this example, many tumor cells are atypical and have macronucleoli.

cases, the nuclei are uniform and bland-looking, to-cytoplasmic ratio can dominate (Fig. 44–113). Co- with or without interspersed large hyperchromatic agulative necrosis can be present.835 or bizarre nuclei731 (Fig. 44–112). In other cases, the The features for diagnosing parathyroid carci- nuclei are overtly pleomorphic (Fig. 44–112C). Nu- noma are outlined in Table 44–23.838 Stringent crite- cleoli are sometimes prominent.835 The cytoplasm is ria must be used in the assessment of capsular or clear, lightly eosinophilic, or oxyphilic.834, 836, 837 On vascular invasion, similar to those applied for follic- occasion, monotonous small cells with high nuclear- ular neoplasms of the thyroid. Broad ﬁbrous septa

FIGURE 44–113. Parathyroid carcinoma. A. Monotonous small cells are seen in the left field of this tumor. B. Higher magnification shows small cells with high nuclear-to-cytoplasmic ratio. A mitotic short figure is seen near the central field. standard long

Thyroid and Parathyroid 75 top of RH

TABLE 44–23. Histologic Criteria for Diagnosis of Parathyroid Carcinoma in a Parathyroid Neoplasm

Absolute Criteria of Malignancy Features Associated with Malignancy

Presence of any one of the following criteria is sufficient for a When the absolute criteria are lacking, at least 2 and prefera- diagnosis of malignancy: bly 3 or more of the following features have to be present —Invasion into surrounding tissues to establish a diagnosis of malignancy: ● Thyroid —Vascular invasion ● Esophagus —Capsular invasion ● Nerves —Broad fibrous bands splitting the parenchyma and de- ● Soft tissues lineating expansile nodules —Regional or distant metastasis —Coagulative tumor necrosis —Mitotic count Ͼ5 per 10 high-power fields —Sheetlike monotonous small cells with high nuclear-to-cytoplasmic ratio —Generalized cellular atypia —Frequent macronucleoli Ancillary studies that may help in supporting a diagnosis of parathyroid carcinoma over adenoma: Immunostaining for Ki-67: high Ki-67 index (mean Ki-67 index for carcinoma is 6.1%–8.4%; that for adenoma is 2.0%–3.3%) Immunostaining for retinoblastoma protein (lack of nuclear staining in tumor cells, provided that appropriate internal positive control is found) or molecular analysis of retinoblastoma gene in tumor (allelic loss) Immunostaining for p27: low percentage of positive cells (mean labeling index 13.9% for carcinoma versus 56.8% for adenoma) In some cases, there are some features associated with malignancy, but they are insufficient for a definite diagnosis of carcinoma to be made. A designation “parathyroid neoplasm of uncertain malignant potential” may be appropriate in such circumstances.

traversing the tumor must be accompanied by ex- markers, and parathyroid hormone. Immunostaining pansile nodules before they are considered signifi- for parathyroid hormone is most helpful for con- cant to distinguish them from the focal scarring due firming a diagnosis of nonfunctioning or ectopic to previous hemorrhage or surgery752 (Fig. 44–114). parathyroid carcinoma. Although mitotic figures have been emphasized as being the single most important criterion of malig- Molecular Biology nancy,752 they are now recognized as being signifi- In most parathyroid carcinomas, allelic loss of cant only when they are present in considerable the retinoblastoma (RB) tumor suppressor gene is numbers736, 838–840 (see Fig. 44–112B). Conversely, found.800, 838, 841 On immunohistochemical staining, some carcinomas may show no or few mitotic fig- lack of immunoreactivity for the RB protein occurs ures.752, 835, 838 in 20% to 88% of cases.792, 841, 842 Cyclin D1 overexpression is also common (91% of cases).798, 802 There Immunohistochemistry is commonly reduced expression of the cyclin-de- The tumor cells of parathyroid carcinoma are pendent kinase inhibitor protein p27 (mean labeling immunoreactive for cytokeratin, pan-neuroendocrine index of 14% versus 57% for parathyroid adenoma).794 Differential Diagnosis The main problem in diagnosis of parathyroid carcinoma is to recognize its malignant nature. The difficulty lies in the fact that some apparently bland- looking tumors may declare themselves to be malignant by subsequent recurrence or metastasis.836, 843 In some cases, the malignant nature of the tumor is obvious by virtue of the frankly invasive growth, significant cellular pleomorphism, and frequent mitoses. However, in other cases, it is essential to consider a number of features to render a diagnosis of malignancy (see Table 44–23). Immunostaining for the proliferation marker Ki-67 can sometimes be helpful because the index is higher in parathyroid carcinoma than in adenoma.792–794 Nonetheless, it cannot be used as the sole criterion because there is overlap in the counts between adenomas and carcinomas.844 Whereas a FIGURE 44–114. Parathyroid carcinoma. The tumor is traversed Ͼ by dense fibrous bands associated with expansile nodules of tu- high Ki-67 index ( 5%) suggests a diagnosis of car- short mor tissue. cinoma, a low index does not exclude this possibil- standard long

76 Endocrine System top of RH ity. The role of flow cytometric analysis of DNA in the diagnosis of parathyroid carcinoma remains con- ✒ TABLE 44–24. Contents of the Final Report: troversial.845–848 A study employing a static DNA Parathyroid Excision Specimens fluorometric method has reported a high nuclear Specimen type/operation procedure DNA content and aneuploidy to favor a diagnosis of parathyroid carcinoma over parathyroid adenoma.849 Diagnosis When there are some but inconclusive features Histologic diagnosis associated with malignancy, the designation “para- Other tumor features Tumor location thyroid neoplasm of uncertain malignant potential” Tumor size or “atypical parathyroid adenoma” can be ap- Encapsulated or nonencapsulated plied.850 Follow-up with regular monitoring of the Capsular invasion (absent, present, extensive) serum calcium level will be helpful for such pa- Vascular invasion (absent, present, extensive) tients. Firm data on the outcome of these cases are Tissues or structures invaded by the carcinoma Mitotic count lacking. Immunohistochemical expression of RB, cyclin D1, p27 (op- tional) PROGNOSTIC CONSIDERATIONS Surgical margins: free, close to surgical margin, or margin in- General Behavior volved (specify site) Parathyroid carcinoma generally pursues an in- Non-neoplastic parathyroid: normal, diffuse hyperplasia, nodu- dolent clinical course. It can invade contiguous lar hyperplasia 754, 830, 851 structures, particularly the thyroid. Surgery Lymph nodes is the mainstay of treatment. Local recurrence devel- Number of lymph nodes found, and their location (level) ops in approximately one third of patients, usually Number of involved lymph nodes within 3 years833; this occurrence may be reduced by Size of largest metastatic deposit Presence or absence of extracapsular extension postoperative radiotherapy.826 About one third of patients develop metastasis, usually relatively late in the course; the favored sites are regional lymph nodes of the neck and mediastinum, lungs, liver, and bones. The relapse usually manifests as recur- NON-NEOPLASTIC LESIONS rent hypercalcemia, and symptomatic control or even occasionally cure can still be achieved by fur- Primary Parathyroid Chief Cell ther operations.* The 5-year and 10-year survival Hyperplasia rates are 60% and 40%, respectively. Death is usually caused by metabolic complications of hyper- CLINICAL CONSIDERATIONS calcemia rather than by organ replacement by tumor.752–754, 834, 853 Primary parathyroid chief cell hyperplasia is a de novo hyperplastic process involving all the parathy- Prognostic Factors roid glands, producing the clinical features of pri- 737, 756, 769, 854 Data on prognostic factors of parathyroid carci- maryhyperparathyroidism. Approxi- noma are limited. Adequate en bloc excision (re- mately 80% of cases are sporadic; the other cases moval of the tumor, adjacent thyroid lobe, paratra- occur as a component of MEN 1, MEN 2, familial cheal soft tissues and lymph nodes, and ipsilateral isolated hyperparathyroidism, or hyperparathyroid- thymus) on recognition of the malignant nature of ism–jaw tumor syndrome. The condition is more the tumor at the initial operation offers the best common in females than in males. Treatment con- chance of cure.824, 827, 833, 852 Nonfunctioning parathy- sists of subtotal parathyroidectomy (removal of 3.5 roid carcinomas appear to behave more aggressively glands); the remaining gland is sometimes autoim- than functioning ones.823 The triad of macronucleoli, planted in the forearm. more than 5 mitoses per 50 high-power fields, and DIAGNOSTIC CONSIDERATIONS necrosis is correlated with a more aggressive outcome. High nuclear DNA content is correlated with Although all parathyroid glands are involved, they a less favorable survival.835 may be unevenly enlarged, with some glands apparently having a “normal size”—and hence leading to a misdiagnosis of parathyroid neoplasm. The com- Contents of the Final Surgical bined weight of the parathyroid glands ranges from Pathology Report less than 1 g to 10 g. In primary chief cell hyperplasia, the parathy- The checklist of contents of the final report of para- roid glands are hypercellular, with marked reduc- thyroid carcinoma excision specimens is listed in tion in interposed adipose cells. The proliferated Table 44–24. parathyroid cells include predominantly chief cells, but water-clear cells and oxyphil cells are often present. The parathyroid cells show a solid, trabecular, follicular, or cordlike growth. In areas, it is com- short *References 753, 754, 823, 828, 830, 843, 852. mon to see the characteristic palisading of the nuclei standard long

Thyroid and Parathyroid 77 top of RH along the vascular septa. The pathologic process is weight of the gland is frequently above 10 g. The initially diffuse, but with time, nodules will super- upper glands are often larger than the lower ones. vene on the background of diffuse hyperplasia. The On histologic examination, the hyperplastic parathy- various nodules often show different cellular compo- roid cells are large and possess water-clear cyto- sitions and different patterns of cellular organiza- plasm. They form solid sheets and acini. tion. Secondary Parathyroid Hyperplasia Primary Water-Clear Cell Hyperplasia CLINICAL CONSIDERATIONS Secondary parathyroid hyperplasia is a hyperplastic CLINICAL CONSIDERATIONS condition of the parathyroid glands in response to Water-clear cell hyperplasia is a rare form of pri- hypocalcemia or hyperphosphatemia. The most com- mary parathyroid hyperplasia. It shows no familial mon cause is chronic renal failure. The patients incidence or association with multiple endocrine present with features of secondary hyperparathy- neoplasia. Of interest, for unknown reasons, this roidism (mostly with parathyroid bone disease) or entity has virtually disappeared in the past few tertiary hyperparathyroidism (mostly with complica- decades.737, 738, 855, 856 tions of hypercalcemia). Treatment consists of subto- The condition occurs mostly in older adults, but tal parathyroidectomy. any age can be affected. It is slightly more common in males than in females. The patients present with DIAGNOSTIC CONSIDERATIONS features of primary hyperparathyroidism. In general, There is uniform or uneven enlargement of all para- the hypercalcemia is more severe than in chief cell thyroid glands, indistinguishable from that seen in hyperplasia. primary parathyroid hyperplasia. A multinodular pattern is seen in the majority of cases. The prolifer- DIAGNOSTIC CONSIDERATIONS ation involves chief cells, clear cells, and oxyphil In water-clear cell hyperplasia, the parathyroid cells, which are arranged in sheets, trabeculae, or glands are usually markedly enlarged; the combined acini (Fig. 44–115). There can be ﬁbrous bands

FIGURE 44–115. Secondary parathyroid hyperplasia in chronic renal failure. A. The enlarged parathyroid gland is converted into multiple hyperplastic nodules. B. The nodules show different cell compositions. This ﬁeld may give a false impression of an adenoma surrounded by compressed residual parathyroid tissue. C. short The nodules often show a mixture of cell types. standard long

78 Endocrine System top of RH

dant amyloid deposition, parenchymal cells may be lost, leading to the development of mild hypocalcemia.

REFERENCES

1. Hedinger C, Williams ED, Sobin LH: Histological Typing of Thyroid Tumors. WHO International Histological Classifica- tion of Tumors. 2nd ed. Berlin, Springer-Verlag, 1988. 2. Ordonez NG: Thyroid transcription factor-1 is a marker of lung and thyroid carcinomas. Adv Anat Pathol 7:123–127, 2000. 3. Katoh R, Kawaoi A, Miyagi E, et al: Thyroid transcription factor-1 in normal, hyperplastic, and neoplastic follicular thyroid cells examined by immunohistochemistry and nonra- dioactive in situ hybridization. Mod Pathol 13:570–576, 2000. FIGURE 44–116. Parathyroid cyst. The cyst is lined by a single 4. Chan JKC: Tumors of the thyroid and parathyroid glands. In layer of parathyroid cells. Normal parathyroid tissue is identified Fletcher CDM (ed): Diagnostic Histopathology of Tumors. in the wall (lower field). 2nd ed. Edinburgh, Churchill Livingstone, 2000, pp 959– 1056. 5. Katoh R, Miyagi E, Nakamura N, et al: Expression of thyroid transcription factor-1 (TTF-1) in human C cells and medullary thyroid carcinomas. Hum Pathol 31:386–393, 2000. around the nodules, hemosiderin deposition, and 6. Figge J, Jennings T, Gerasimov G: Radiation and thyroid cystic change. Calcification can be present. cancer. In Wartofsky L (ed): Thyroid Cancer, A Comprehen- sive Guide to Clinical Management. Totowa, NJ, Humana Press, 2000, pp 85–116. 7. Figge J: Epidemiology of thyroid cancer. In Wartofsky L (ed): Parathyroid Cyst Thyroid Cancer, A Comprehensive Guide to Clinical Man- agement. Totowa, NJ, Humana Press, 2000, pp 77–81. Parathyroid cyst manifests clinically as a mass lesion 8. Williams ED: The aetiology of thyroid tumours. Clin Endo- or hypercalcemia, but it can also be an incidental crinol Metab 8:193–207, 1979. 9. Feilotter H, Mulligan L: Endocrine cancers. In Foulkes WD, finding. Its size can range from a few millimeters to Hodgson SV (eds): Inherited susceptibility to cancer: clinical, 10 cm. The wall is thin and translucent.857 A diagno- predictive and ethical perspectives. Cambridge, UK, Cam- sis can be made by fine-needle aspiration, either by bridge University Press, 1998, pp 326–354. identification of parathyroid cells or by demonstra- 10. Gilliland FD, Hunt WC, Morris DM, Key CR: Prognostic factors for thyroid carcinoma. A population-based study of tion of elevated levels of parathyroid hormone in 15,698 cases from the Surveillance, Epidemiology and End 858 the cystic fluid. On histologic examination, it is Results (SEER) program 1973–1991. Cancer 79:564–573, 1997. often lined by attenuated parathyroid cells and sur- 11. Brierley JD, Panzarella T, Tsang RW, et al: A comparison of rounded by islands of normal, hyperplastic, or ade- different staging systems predictability of patient outcome. nomatous parathyroid tissue (Fig. 44–116). That is, Thyroid carcinoma as an example. Cancer 79:2414–2423, 1997. some cases represent cystic change of a parathyroid 12. Gemsenjager E, Heitz PU, Martina B: Selective treatment of adenoma and are thus associated with hypercal- differentiated thyroid carcinoma. World J Surg 21:546–551, cemia. discussion 551–552, 1997. 13. Oertel YC, Oertel JE: Diagnosis of malignant epithelial thyroid lesions: fine needle aspiration and histopathologic correlation. Ann Diagn Pathol 2:377–400, 1998. Periparathyroid Salivary 14. Oertel YC: Fine-needle aspiration and the diagnosis of thy- Heterotopia–Cyst Unit roid cancer. Endocrinol Metab Clin North Am 25:69–91, 1996. 15. Silver CE, Owen RP: Year 2000 update: what the head and An uncommon lesion occurring in a periparathyroid neck surgeon expects of the pathologist. Pathol Case Rev 5: location is the salivary heterotopia–cyst unit.859 It is 183–188, 2000. usually small, measuring 1 to 6 mm, comprising 16. Chang HY, Lin JD, Chen JF, et al: Correlation of fine needle small lobules of salivary acini and cysts. The cysts aspiration cytology and frozen section biopsies in the diagnosis of thyroid nodules. J Clin Pathol 50:1005–1009, 1997. are lined by flattened, ciliated, or columnar cells, 17. Quinn SF, Nelson HA, Demlow TA: Thyroid biopsies: fine- without parathyroid cell lining. The salivary hetero- needle aspiration biopsy versus spring-activated core biopsy topia–cyst unit has been postulated to be of third needle in 102 patients. J Vasc Interv Radiol 5:619–623, 1994. and fourth-fifth branchial pouch derivation. 18. Munn JS, Castelli M, Prinz RA, Walloch JL: Needle biopsy of nodular thyroid disease. Am Surg 54:438–443, 1988. 19. Lo Gerfo P: The value of coarse needle biopsy in evaluating thyroid nodules. Thyroidology 6:1–4, 1994. Amyloidosis 20. Wang C, Guyton SP, Vickery AL Jr: A further note on the large needle biopsy of the thyroid gland. Surg Gynecol Ob- The parathyroid glands can be involved in systemic stet 156:508–510, 1983. 21. Miller JM: Evaluation of thyroid nodules. Accent on needle amyloidosis. The glands are enlarged and histologi- biopsy. Med Clin North Am 69:1063–1077, 1985. cally show deposition of amyloid in blood vessel 22. Broughan TA, Esselstyn CB Jr: Large-needle thyroid biopsy: short walls and the interstitium.860 When there is abun- still necessary. Surgery 100:1138–1141, 1986. standard long

Thyroid and Parathyroid 79 top of RH

23. Lang W, Georgii A, Stauch G, Kienzle E: The differentiation 48. Hirokawa M, Shimizu M, Manabe T, et al: Hyalinizing tra- of atypical adenomas and encapsulated follicular carcinomas becular adenoma of the thyroid: its unusual cytoplasmic im- in the thyroid gland. Virchows Arch Pathol Anat 385:125– munopositivity for MIB1. Pathol Int 45:399–401, 1995. 141, 1980. 49. Papotti M, Riella P, Montemurro F, et al: Immunophenotypic 24. Franssila KO, Ackerman LV, Brown CL: Follicular carci- heterogeneity of hyalinizing trabecular tumours of the thy- noma. Semin Diagn Pathol 2:101–122, 1985. roid. Histopathology 31:525–533, 1997. 25. Yamashina M: Follicular neoplasms of the thyroid. Total cir- 50. Rothenberg HJ, Goellner JR, Carney JA: Hyalinizing trabecu- cumferential evaluation of the fibrous capsule. Am J Surg lar adenoma of the thyroid gland: recognition and character- Pathol 16:392–400, 1992. ization of its cytoplasmic yellow body. Am J Surg Pathol 26. McHenry CR, Raeburn C, Strickland T, Marty JJ: The utility 23:118–125, 1999. of routine frozen section examination for intraoperative diag- 51. Carney JA, Ryan J, Goellner JR: Hyalinizing trabecular adenosis of thyroid cancer. Am J Surg 172:658–661, 1996. noma of the thyroid gland. Am J Surg Pathol 11:583–591, 27. Gibb GK, Pasieka JL: Assessing the need for frozen sections: 1987. still a valuable tool in thyroid surgery. Surgery 118:1005– 52. Sambade C, Sarabando F, Nesland JM, Sobrinho-Simoes M: 1009, discussion 1009–1010, 1995. Hyalinizing trabecular adenoma of the thyroid (case of the 28. Sabel MS, Staren ED, Gianakakis LM, et al: Use of fine- Ullensvang course). Hyalinizing spindle cell tumor of the needle aspiration biopsy and frozen section in the manage- thyroid with dual differentiation (variant of the so-called ment of the solitary thyroid nodule. Surgery 122:1021–1026, hyalinizing trabecular adenoma). Ultrastruct Pathol 13:275– discussion 1026–1027, 1997. 280, 1989. 29. Mulcahy MM, Cohen JI, Anderson PE, et al: Relative accu- 53. Katoh R, Jasani B, Williams ED: Hyalinizing trabecular ade- racy of fine-needle aspiration and frozen section in the diag- noma of the thyroid. A report of three cases with immuno- nosis of well-differentiated thyroid cancer. Laryngoscope histochemical and ultrastructural studies. Histopathology 108:494–496, 1998. 15:211–224, 1989. 30. Deligdisch L, Subhani Z, Gordon RE: Primary mucinous car- 54. Bronner MP, LiVolsi VA, Jennings TA: PLAT: paragangli- cinoma of the thyroid gland: report of a case and ultrastruc- oma-like adenoma of the thyroid. Surg Pathol 1:383–389, tural study. Cancer 45:2564–2567, 1980. 1988. 31. Carcangiu ML, Sibley RK, Rosai J: Clear cell change in pri- 55. Schmid KW, Mesewinkel F, Bocker W: Hyalinizing trabecu- mary thyroid tumors. A study of 38 cases. Am J Surg Pathol lar adenoma of the thyroid—morphology and differential 9:705–722, 1985. diagnosis. Acta Med Austriaca 23:65–68, 1996. 32. Schroder S, Husselmann H, Bocker W: Lipid-rich cell ade- 56. Chetty R, Beydoun R, LiVolsi VA: Paraganglioma-like (hy- noma of the thyroid gland. Report of a peculiar thyroid alinizing trabecular) adenoma of the thyroid revisited. Pa- tumour. Virchows Arch A Pathol Anat Histopathol 404:105– thology 26:429–431, 1994. 108, 1984. 57. Chan JKC, Tse CCH, Chiu HS: Hyalinizing trabecular ade- 33. Toth K, Peter I, Kremmer T, Sugar J: Lipid-rich cell thyroid noma–like lesion in multinodular goiter. Histopathology adenoma: histopathology with comparative lipid analysis. 16:611–614, 1990. Virchows Arch A Pathol Anat Histopathol 417:273–276, 58. Li M, Rosai J, Carcangiu ML: Hyalinizing trabecular ade- 1990. noma of the thyroid: a distinct tumor type or a pattern of 34. Schroder S, Bocker W: Clear-cell carcinomas of thyroid growth? Evaluation of 28 cases (abstract). Mod Pathol 8:54A, gland: a clinicopathological study of 13 cases. Histopathol- 1995. ogy 10:75–89, 1986. 59. Fonseca E, Nesland JM, Sobrinho-Simoes M: Expression of 35. Vuitch F, Leavitt A: Papillary variant of follicular adenoma stratified epithelial-type cytokeratins in hyalinizing trabecu- of thyroid (abstract). Mod Pathol 3:104A, 1990. lar adenomas supports their relationship with papillary car- 36. Hjorth L, Thomsen LB, Nielsen VT: Adenolipoma of the cinomas of the thyroid. Histopathology 31:330–335, 1997. thyroid gland. Histopathology 10:91–96, 1986. 60. Li M, Carcangiu ML, Rosai J: Abnormal intracellular and 37. Laforga JB, Vierna J: Adenoma of thyroid gland containing extracellular distribution of basement membrane material in fat (thyrolipoma). Report of a case. J Laryngol Otol 110: papillary carcinoma and hyalinizing trabecular tumors of the 1088–1089, 1996. thyroid: implication for deregulation of secretory pathways. 38. Gnepp DR, Ogorzalek JM, Heffess CS: Fat-containing lesions Hum Pathol 28:1366–1372, 1997. of the thyroid gland. Am J Surg Pathol 13:605–612, 1989. 61. Hirokawa M, Carney JA, Ohtsuki Y: Hyalinizing trabecular 39. Gherardi G: Signet ring cell ’mucinous’ thyroid adenoma: a adenoma and papillary carcinoma of the thyroid gland follicle cell tumour with abnormal accumulation of thyro- express different cytokeratin patterns. Am J Surg Pathol globulin and a peculiar histochemical profile. Histopathology 24:877–881, 2000. 11:317–326, 1987. 61a. Papotti M, Volante M, Giuliano A, et al: RET/PTC activa- 40. Mendelsohn G: Signet-cell–simulating microfollicular ade- tion in hyalinizing trabecular tumors of the thyroid. Am J noma of the thyroid. Am J Surg Pathol 8:705–708, 1984. Surg Pathol 24:1515–1621, 2000. 41. Rigaud C, Peltier F, Bogomoletz WV: Mucin producing mi- 61b. Cheung CC, Boerner SL, MacMillan CM, et al: Hyalinizing crofollicular adenoma of the thyroid. J Clin Pathol 38:277– trabecular tumor of the thyroid: a variant of papillary carci- 280, 1985. noma proved by molecular genetics. Am J Surg Pathol 24: 42. Alsop JE, Yerbury PJ, O’Donnell PJ, Heyderman E: Signet- 1622–1626, 2000. ring cell microfollicular adenoma arising in a nodular ectopic 61c. LiVolsi VA: Hyalinizing trabecular adenoma of the thyroid: thyroid. A case report. J Oral Pathol 15:518–519, 1986. adenoma, carcinoma or neoplasm of uncertain malignant po- 43. Hazard JB, Kenyon R: Atypical adenoma of the thyroid. tential? Am J Surg Pathol 24:1683–1684, 2000. Arch Pathol 58:554–563, 1954. 62. Schlumberger MJ: Papillary and follicular thyroid carcinoma 44. Lang W, Choritz H, Hundeshagen H: Risk factors in follicu- (review). N Engl J Med 338:297–306, 1998. lar thyroid carcinomas. A retrospective follow-up study cov- 63. Wright PA, Lemoine NR, Mayall ES, et al: Papillary and ering a 14-year period with emphasis on morphological find- follicular thyroid carcinomas show a different pattern of ras ings. Am J Surg Pathol 10:246–255, 1986. oncogene mutation. Br J Cancer 60:576–577, 1989. 45. Rosai J, Carcangiu ML, DeLellis RA: Tumors of the Thyroid 64. Dahia PL, Marsh DJ, Zheng Z, et al: Somatic deletions and Gland. Atlas of Tumor Pathology. Third Series, Fascicle 5. mutations in the Cowden disease gene, PTEN, in sporadic Washington, DC, Armed Forces Institute of Pathology, 1992. thyroid tumors. Cancer Res 57:4710–4713, 1997. 46. Rosai J: Ackerman’s Surgical Pathology. 8th ed. St. Louis, CV 65. Porcellini A, Ciullo I, Pannain S, et al: Somatic mutations in Mosby, 1996. the VI transmembrane segment of the thyrotropin receptor 47. Hirokawa M, Carney JA: Cell membrane and cytoplasmic constitutively activate cAMP signalling in thyroid hyperfunc- staining for MIB-1 in hyalinizing trabecular adenoma of the tioning adenomas. Oncogene 11:1089–1093, 1995. short thyroid gland. Am J Surg Pathol 24:575–578, 2000. 66. Porcellini A, Ciullo I, Laviola L, et al: Novel mutations of standard long

80 Endocrine System top of RH

thyrotropin receptor gene in thyroid hyperfunctioning ade- A, et al: Hyalinizing trabecular carcinoma of the thyroid nomas. Rapid identiﬁcation by ﬁne needle aspiration biopsy. gland: report of two cases of follicular cell thyroid carcinoma J Clin Endocrinol Metab 79:657–661, 1994. with hyalinizing trabecular pattern. Ultrastruct Pathol 22:39– 67. Krohn K, Fuhrer D, Holzapfel HP, Paschke R: Clonal origin 46, 1998. of toxic thyroid nodules with constitutively activating thyro- 92. McCluggage WG, Sloan JM: Hyalinizing trabecular carci- tropin receptor mutations. J Clin Endocrinol Metab 83:130– noma of thyroid gland. Histopathology 28:357–362, 1996. 134, 1998. 93. Ishimaru Y, Fukuda S, Kurano R, et al: Follicular thyroid 68. Pinducciu C, Borgonovo G, Arezzo A, et al: Toxic thyroid carcinoma with clear cell change showing unusual ultra- adenoma: absence of DNA mutations of the TSH receptor structural features. Am J Surg Pathol 12:240–246, 1988.

and Gs alpha. Eur J Endocrinol 138:37–40, 1998. 94. LiVolsi VA: Current concepts in follicular tumors of the thy- 69. Tonacchera M, Chiovato L, Pinchera A, et al: Hyperfunction- roid. Monogr Pathol 35:118–137, 1993. ing thyroid nodules in toxic multinodular goiter share acti- 95. Gosain AK, Clark OH: Hu¨ rthle cell neoplasms. Malignant vating thyrotropin receptor mutations with solitary toxic ad- potential. Arch Surg 119:515–519, 1984. enoma. J Clin Endocrinol Metab 83:492–498, 1998. 96. Watson RG, Brennan MD, Goellner JR, et al: Invasive 70. Esapa C, Foster S, Johnson S, et al: G protein and thyrotro- Hu¨ rthle cell carcinoma of the thyroid: natural history and pin receptor mutations in thyroid neoplasia. J Clin Endocri- management. Mayo Clin Proc 59:851–855, 1984. nol Metab 82:493–496, 1997. 97. Evans HL: Follicular neoplasms of the thyroid. A study of 44 71. Crile G Jr, Pontius KI, Hawk WA: Factors influencing the cases followed for a minimum of 10 years, with emphasis on survival of patients with follicular carcinoma of the thyroid differential diagnosis. Cancer 54:535–540, 1984. gland. Surg Gynecol Obstet 160:409–413, 1985. 98. Bronner MP, LiVolsi VA: Oxyphilic (Askanazy/Hu¨ rthle cell) 72. Schroder S, Bocker W, Dralle H, et al: The encapsulated tumors of the thyroid: microscopic features predict biologic papillary carcinoma of the thyroid. A morphologic subtype behavior. Surg Pathol 1:137–150, 1988. of the papillary thyroid carcinoma. Cancer 54:90–93, 1984. 99. Baloch ZW, LiVolsi VA: Intravascular Kaposi’s-like spindle 73. Shaha AR, Shah JP, Loree TR: Differentiated thyroid cancer cell proliferation of the capsular vessels of follicular-derived presenting initially with distant metastasis. Am J Surg thyroid carcinomas. Mod Pathol 11:995–998, 1998. 174:474–476, 1997. 100. Carcangiu ML, Bianchi S, Savino D, et al: Follicular Hu¨ rthle 74. Lo CY, Lorentz TG, Wan KY: Follicular carcinoma of the cell tumors of the thyroid gland. Cancer 68:1944–1953, 1991. thyroid gland in Hong Kong Chinese. Br J Surg 82:1095– 101. Chan JK, Tang SK, Tsang WY, et al: Histologic changes in- 1097, 1995. duced by fine-needle aspiration. Adv Anat Pathol 3:71–90, 75. Evans HL, Vassilopoulou-Sellin R: Follicular and Hu¨ rthle cell 1996. carcinomas of the thyroid: a comparative study. Am J Surg 102. Segev DL, Saji M, Phillips GS, et al: Polymerase chain reac- Pathol 22:1512–1520, 1998. tion–based microsatellite polymorphism analysis of follicular 76. Woolner LB: Thyroid carcinoma: pathologic classification and Hu¨ rthle cell neoplasms of the thyroid. J Clin Endocrinol with data on prognosis. Semin Nucl Med 1:481–502, 1971. Metab 83:2036–2042, 1998. 77. Franssila KO: Prognosis in thyroid carcinoma. Cancer 103. Chen H, Nicol TL, Zeiger MA, et al: Hu¨ rthle cell neoplasms 36:1138–1146, 1975. of the thyroid: are there factors predictive of malignancy? 78. Schroder S, Pfannschmidt N, Dralle H, et al: The encapsu- Ann Surg 227:542–546, 1998. lated follicular carcinoma of the thyroid. A clinicopathologic 104. Kini SR, Miller JM: Infarction of thyroid neoplasms following study of 35 cases. Virchows Arch A Pathol Anat Histopathol aspiration biopsy (abstract). Acta Cytol 30:591, 1986. 402:259–273, 1984. 105. Jones JD, Pittman DL, Sandes LR: Necrosis of thyroid nod- 79. Lang W, Georgii A: Minimal invasive cancer in the thyroid. ules after fine needle aspiration. Acta Cytol 29:29–31, 1985. Clin Oncol 1:527–537, 1982. 106. LiVolsi VA, Merino MJ: Worrisome histologic alterations fol- 80. Crile G Jr, Hawk WA: Carcinomas of the thyroid. Cleve Clin lowing fine-needle aspiration of the thyroid (WHAFFT). Q 38:97–104, 1971. Pathol Annu 29:99–120, 1994. 81. van Heerden JA, Hay ID, Goellner JR, et al: Follicular thy- 107. Flint A, Lloyd RV: Hu¨ rthle-cell neoplasms of the thyroid roid carcinoma with capsular invasion alone: a nonthreaten- gland. Pathol Annu 25:37–52, 1990. ing malignancy. Surgery 112:1130–1136, discussion 1136– 108. Thompson NW, Dunn EL, Batsakis JG, Nishiyama RH: 1138, 1992. Hu¨ rthle cell lesions of the thyroid gland. Surg Gynecol Ob- 82. Rossi RL, Nieroda C, Cady B, Wool MS: Malignancies of the stet 139:555–560, 1974. thyroid gland. The Lahey Clinic experience. Surg Clin North 109. Gundry SR, Burney RE, Thompson NW, Lloyd R: Total thy- Am 65:211–230, 1985. roidectomy for Hu¨ rthle cell neoplasm of the thyroid. Arch 83. Brooks JR, Starnes HF, Brooks DC, et al: Surgical therapy for Surg 118:529–532, 1983. thyroid carcinoma: a review of 1249 solitary thyroid nodules. 110. Miller RH, Estrada R, Sneed WF, Mace ML: Hu¨ rthle cell Surgery 104:940–946, 1988. tumors of the thyroid gland. Laryngoscope 93:884–888, 1983. 84. Van Nguyen K, Dilawari RA: Predictive value of AMES 111. Jorda M, Gonzalez-Campora R, Mora J, et al: Prognostic scoring system in selection of extent of surgery in well dif- factors in follicular carcinoma of the thyroid. Arch Pathol ferentiated carcinoma of thyroid. Am Surg 61:151–155, 1995. Lab Med 117:631–635, 1993. 85. Shah JP, Loree TR, Dharker D, Strong EW: Lobectomy ver- 112. Rosen IB, Luk S, Katz I: Hu¨ rthle cell tumor behavior: di- sus total thyroidectomy for differentiated carcinoma of the lemma and resolution. Surgery 98:777–783, 1985. thyroid: a matched-pair analysis. Am J Surg 166:331–335, 113. Heppe H, Armin A, Calandra DB, et al: Hu¨ rthle cell tumors 1993. of the thyroid gland. Surgery 98:1162–1165, 1985. 86. Wax MK, Briant TD: Completion thyroidectomy in the man- 114. Arganini M, Behar R, Wu TC, et al: Hu¨ rthle cell tumors: a agement of well-differentiated thyroid carcinoma. Otolaryn- twenty-five-year experience. Surgery 100:1108–1115, 1986. gol Head Neck Surg 107:63–68, 1992. 115. Caplan RH, Abellera RM, Kisken WA: Hu¨ rthle cell tumors 87. Loh KC: Familial nonmedullary thyroid carcinoma: a meta- of the thyroid gland. A clinicopathologic review and long- review of case series. Thyroid 7:107–113, 1997. term follow-up. JAMA 251:3114–3117, 1984. 88. Lerch H, Schober O, Kuwert T, Saur HB: Survival of differ- 116. Gonzalez-Campora R, Herrero-Zapatero A, Lerma E, et al: entiated thyroid carcinoma studied in 500 patients. J Clin Hu¨ rthle cell and mitochondrion-rich cell tumors. A clinico- Oncol 15:2067–2075, 1997. pathologic study. Cancer 57:1154–1163, 1986. 89. Pilotti S, Collini P, Mariani L, et al: Insular carcinoma: a 117. Saull SC, Kimmelman CP: Hu¨ rthle cell tumors of the thyroid distinct de novo entity among follicular carcinomas of the gland. Otolaryngol Head Neck Surg 93:58–62, 1985. thyroid gland. Am J Surg Pathol 21:1466–1473, 1997. 118. Bondeson L, Bondeson AG, Ljungberg O, Tibblin S: Oxyphil 90. Molberg K, Albores-Saavedra J: Hyalinizing trabecular carci- tumors of the thyroid: follow-up of 42 surgical cases. Ann noma of the thyroid gland. Hum Pathol 25:192–197, 1994. Surg 194:677–680, 1981. short 91. Gonzalez-Campora R, Fuentes-Vaamonde E, Hevia-Vazquez 119. Wasvary H, Czako P, Poulik J, Lucas R: Unilateral lobectomy standard long

Thyroid and Parathyroid 81 top of RH

for Hu¨ rthle cell adenoma. Am Surg 64:729–732, discussion 141. Kotani T, Asada Y, Aratake Y, et al: Diagnostic usefulness of 732–733, 1998. dipeptidyl aminopeptidase IV monoclonal antibody in paraf- 120. Grant CS, Barr D, Goellner JR, Hay ID: Benign Hu¨ rthle cell fin-embedded thyroid follicular tumours. J Pathol 168:41–45, tumors of the thyroid: a diagnosis to be trusted? World J 1992. Surg 12:488–495, 1988. 142. Aratake Y, Kotani T, Tamura K, et al: Dipeptidyl aminopep- 121. Erickson LA, Jin L, Goellner JR, et al: Pathologic features, tidase IV staining of cytologic preparations to distinguish proliferative activity, and cyclin D1 expression in Hu¨ rthle benign from malignant thyroid diseases. Am J Clin Pathol cell neoplasms of the thyroid. Mod Pathol 13:186–192, 2000. 96:306–310, 1991. 122. Tollefsen HR, Shah JP, Huvos AG: Hu¨ rthle cell carcinoma of 143. Johnson TL, Lloyd RV, Thor A: Expression of ras oncogene the thyroid. Am J Surg 130:390–394, 1975. p21 antigen in normal and proliferative thyroid tissues. Am J 123. Shaha AR, Loree TR, Shah JP: Prognostic factors and risk Pathol 127:60–65, 1987. group analysis in follicular carcinoma of the thyroid. Surgery 144. Johnson TL, Lloyd RV, Burney RE, Thompson NW: Hu¨ rthle 118:1131–1136, discussion 1136–1138, 1995. cell thyroid tumors. An immunohistochemical study. Cancer 124. Papotti M, Torchio B, Grassi L, et al: Poorly differentiated 59:107–112, 1987. oxyphilic (Hu¨ rthle cell) carcinomas of the thyroid. Am J Surg 145. Mizukami Y, Nonomura A, Hashimoto T, et al: Immunohis- Pathol 20:686–694, 1996. tochemical demonstration of epidermal growth factor and 125. Davila RM, Bedrossian CW, Silverberg AB: Immunocyto- c-myc oncogene product in normal, benign and malignant chemistry of the thyroid in surgical and cytologic specimens. thyroid tissues. Histopathology 18:11–18, 1991. Arch Pathol Lab Med 112:51–56, 1988. 146. Erickson LA, Jin L, Wollan PC, et al: Expression of p27kip1 126. Roque L, Clode A, Belge G, et al: Follicular thyroid carci- and Ki-67 in benign and malignant thyroid tumors. Mod noma: chromosome analysis of 19 cases. Genes Chromo- Pathol 11:169–174, 1998. somes Cancer 21:250–255, 1998. 147. Loy TS, Gelven PL, Mullins D, Diaz-Arias AA: Immunostain- 127. Pierotti MA, Bongarzone I, Borello MG, et al: Cytogenetics ing for P-glycoprotein in the diagnosis of thyroid carcinomas and molecular genetics of carcinomas arising from thyroid [see comments]. Mod Pathol 5:200–202, 1992. epithelial follicular cells. Genes Chromosomes Cancer 16:1– 148. Chiappetta G, Tallini G, De Biasio MC, et al: Detection of 14, 1996. high mobility group I HMGI(Y) protein in the diagnosis of 128. Tung WS, Shevlin DW, Kaleem Z, et al: Allelotype of follicu- thyroid tumors: HMGI(Y) expression represents a potential lar thyroid carcinomas reveals genetic instability consistent diagnostic indicator of carcinoma. Cancer Res 58:4193–4198, with frequent nondisjunctional chromosomal loss. Genes 1998. Chromosomes Cancer 19:43–51, 1997. 149. Umbricht CB, Saji M, Westra WH, et al: Telomerase activity: 129. Roque L, Castedo S, Clode A, Soares J: Deletion of 3p25 : a marker to distinguish follicular thyroid adenoma from car- pter in a primary follicular thyroid carcinoma and its metas- cinoma. Cancer Res 57:2144–2147, 1997. tasis. Genes Chromosomes Cancer 8:199–203, 1993. 150. Backdahl M, Wallin G, Akensten U, et al: Nuclear DNA 130. Hemmer S, Wasenius VM, Knuutila S, et al: DNA measurements in follicular thyroid adenomas. Eur J Surg copy number changes in thyroid carcinoma. Am J Pathol Oncol 15:125–129, 1989. 154:1539–1547, 1999. 151. Hruban RH, Huvos AG, Traganos F, et al: Follicular neo- 131. Grebe SK, McIver B, Hay ID, et al: Frequent loss of hetero- plasms of the thyroid in men older than 50 years of age. A zygosity on chromosomes 3p and 17p without VHL or p53 DNA flow cytometric study. Am J Clin Pathol 94:527–532, mutations suggests involvement of unidentified tumor sup- 1990. pressor genes in follicular thyroid carcinoma. J Clin Endocri- 152. Schurmann G, Mattfeldt T, Feichter G, et al: Stereology, nol Metab 82:3684–3691, 1997. flow cytometry, and immunohistochemistry of follicular 132. Zedenius J, Wallin G, Svensson A, et al: Deletions of the neoplasms of the thyroid gland. Hum Pathol 22:179–184, long arm of chromosome 10 in progression of follicular thy- 1991. roid tumors. Hum Genet 97:299–303, 1996. 153. Oyama T, Vickery AL Jr, Preffer FI, Colvin RB: A compara- 133. Oyama T, Suzuki T, Hara F, et al: N-ras mutation of thyroid tive study of flow cytometry and histopathologic findings in tumor with special reference to the follicular type. Pathol Int thyroid follicular carcinomas and adenomas. Hum Pathol 45:45–50, 1995. 25:271–275, 1994. 134. Bouras M, Parvaz P, Berger N, et al: Ha-ras oncogene (codon 154. Joensuu H, Klemi P, Eerola E: DNA aneuploidy in follicular 12) mutation in thyroid carcinogenesis: analysis of 60 benign adenomas of the thyroid gland. Am J Pathol 124:373–376, and malignant thyroid tumors. Ann Biol Clin 53:549–555, 1986. 1995. 155. Schmidt RJ, Wang CA: Encapsulated follicular carcinoma 135. Sapi Z, Lukacs G, Sztan M, et al: Contribution of p53 gene of the thyroid: diagnosis, treatment and results. Surgery alterations to development of metastatic forms of follicular 100:1068–1076, 1986. thyroid carcinoma. Diagn Mol Pathol 4:256–260, 1995. 156. Segal K, Arad A, Lubin E, et al: Follicular carcinoma of the 135a. Kroll TG, Sarraf P, Pecciarini L, et al: PAX8-PPAR gamma 1 thyroid. Head Neck 16:533–538, 1994. fusion oncogene in human thyroid carcinoma. Science 289: 157. Zohar Y, Strauss M: Occult distant metastases of well- 1357–1360, 2000. differentiated thyroid carcinoma. Head Neck 16:438–442, 136. Ghali VS, Jimenez EJ, Garcia RL: Distribution of Leu-7 anti- 1994. gen (HNK-1) in thyroid tumors: its usefulness as a diagnos- 158. Marcocci C, Pacini F, Eliseri R, et al: Clinical and biologic tic marker for follicular and papillary carcinomas. Hum behavior of bone metastasis from differentiated thyroid car- Pathol 23:21–25, 1992. cinoma. Surgery 106:960–966, 1989. 137. De Micco C, Ruf J, Chrestian MA, et al: Immunohistochemi- 159. Goldstein NS, Czako P, Neill JS: Metastatic minimally inva- cal study of thyroid peroxidase in normal, hyperplastic, and sive (encapsulated) follicular and Hu¨ rthle cell thyroid carci- neoplastic human thyroid tissues. Cancer 67:3036–3041, 1991. noma: a study of 34 patients. Mod Pathol 13:123–130, 2000. 138. Sack MJ, Astengo-Osuna C, Lin BT, et al: HBME-1 immuno- 160. von Wasielewski R, Rhein A, Werner M, et al: Immunohisto- staining in thyroid fine-needle aspirations: a useful marker chemical detection of E-cadherin in differentiated thyroid in the diagnosis of carcinoma. Mod Pathol 10:668–674, 1997. carcinomas correlates with clinical outcome. Cancer Res 139. Miettinen M, Karkkainen P: Differential reactivity of HBME- 57:2501–2507, 1997. 1 and CD15 antibodies in benign and malignant thyroid 161. Joensuu H, Klemi P, Eerola E, Tuominen J: Influence of tumours. Preferential reactivity with malignant tumours. Vir- cellular DNA content on survival in differentiated thyroid chows Arch 429:213–219, 1996. cancer. Cancer 58:2462–2467, 1986. 140. Tuccari G, Barresi G: Tissue polypeptide antigen in thyroid 162. Beaugie JM, Brown CL, Doniach I, Richardson JE: Primary tumours of follicular cell origin: an immunohistochemical re- malignant tumours of the thyroid: the relationship between evaluation for diagnostic purposes. Histopathology 16:377– histological classification and clinical behaviour. Br J Surg short 381, 1990. 63:173–181, 1976. standard long

82 Endocrine System top of RH

163. Hirabayashi RN, Lindsay S: Carcinoma of the thyroid gland: 188. Chan JK, Tse CC: Mucin production in metastatic papillary a statistical study of 390 patients. J Clin Endocrinol Metab carcinoma of the thyroid. Hum Pathol 19:195–200, 1988. 21:1596–1610, 1961. 189. Mlynek ML, Richter HJ, Leder LD: Mucin in carcinomas of 164. McConahey WM, Hay ID, Woolner LB, et al: Papillary thy- the thyroid. Cancer 56:2647–2650, 1985. roid cancer treated at the Mayo Clinic, 1946 through 1970: 190. Chen KT, Rosai J: Follicular variant of thyroid papillary car- initial manifestations, pathologic findings, therapy, and out- cinoma: a clinicopathologic study of six cases. Am J Surg come. Mayo Clin Proc 61:978–996, 1986. Pathol 1:123–130, 1977. 165. Meissner WA, Adler A: Papillary carcinoma of the thyroid, a 191. Rosai J, Zampi G, Carcangiu ML: Papillary carcinoma of the study of the pattern in 226 patients. Arch Pathol 66:518–525, thyroid. A discussion of its several morphologic expressions, 1958. with particular emphasis on the follicular variant. Am J Surg 166. Verge J, Guixa J, Alejo M, et al: Cervical cystic lymph node Pathol 7:809–817, 1983. metastasis as first manifestation of occult papillary thyroid 192. Carcangiu ML, Zampi G, Pupi A, et al: Papillary carcinoma carcinoma: report of seven cases. Head Neck 21:370–374, of the thyroid. A clinicopathologic study of 241 cases treated 1999. at the University of Florence, Italy. Cancer 55:805–828, 167. al-Talib RK, Wilkins BS, Theaker JM: Cystic metastasis of 1985. papillary carcinoma of the thyroid—an unusual presenta- 193. Franssila KO: Is the differentiation between papillary and tion. Histopathology 20:176–178, 1992. follicular thyroid carcinoma valid? Cancer 32:853–864, 1973. 168. Hedinger C, Sobin L: Histological Typing of Thyroid Tu- 194. Moreno A, Rodriguez JM, Sola J, et al: Encapsulated papil- mors. Geneva, World Health Organization, 1974. lary neoplasm of the thyroid: retrospective clinicopathologi- 169. Hedinger C, Williams ED, Sobin LH: The WHO histological cal study with long term follow up. Eur J Surg 162:177–180, classification of thyroid tumors: a commentary on the second 1996. edition. Cancer 63:908–911, 1989. 195. Vickery AL Jr: Thyroid papillary carcinoma. Pathological 170. Carcangiu ML, Zampi G, Rosai J: Papillary thyroid carci- and philosophical controversies. Am J Surg Pathol 7:797– noma: a study of its many morphologic expressions and 807, 1983. clinical correlates. Pathol Annu 20:1–44, 1985. 196. Evans HL: Encapsulated papillary neoplasms of the thyroid. 171. Chan JK: Papillary carcinoma of thyroid: classical and vari- A study of 14 cases followed for a minimum of 10 years. ants. Histol Histopathol 5:241–257, 1990. Am J Surg Pathol 11:592–597, 1987. 172. Rosai J, Carcangiu ML: Pitfalls in the diagnosis of thyroid 197. Chan JK, Carcangiu ML, Rosai J: Papillary carcinoma of thy- neoplasms. Pathol Res Pract 182:169–179, 1987. roid with exuberant nodular fasciitis–like stroma. Report of 173. Bruno J, Ciancia EM, Pingitore R: Thyroid papillary adeno- three cases. Am J Clin Pathol 95:309–314, 1991. carcinoma; lipomatous-type. Virchows Arch A Pathol Anat 198. Michal M, Chlumska A, Fakan F: Papillary carcinoma of Histopathol 414:371–373, 1989. thyroid with exuberant nodular fasciitis–like stroma. Histo- 174. Vestfrid MA: Papillary carcinoma of the thyroid gland with pathology 21:577–579, 1992. lipomatous stroma: report of a peculiar histological type of 199. Mizukami Y, Nonomura A, Matsubara F, et al: Papillary thyroid tumour. Histopathology 10:97–100, 1986. carcinoma of the thyroid gland with fibromatosis-like 175. Chan JK, Loo KT: Cribriform variant of papillary thyroid stroma. Histopathology 20:355–357, 1992. carcinoma. Arch Pathol Lab Med 114:622–624, 1990. 200. Terayama K, Toda S, Yonemitsu N, et al: Papillary carci- 176. Guiter GE, DeLellis RA: Multinucleate giant cells in papillary noma of the thyroid with exuberant nodular fasciitis–like thyroid carcinoma. A morphologic and immunohistochemi- stroma. Virchows Arch 431:291–295, 1997. cal study. Am J Clin Pathol 106:765–768, 1996. 201. Acosta J, Rodriguez JM, Sola J, et al: Nodular fasciitis–type 177. Isarangkul W: Dense fibrosis. Another diagnostic criterion papillary thyroid carcinoma. Presentation of a new case. Eur for papillary thyroid carcinoma. Arch Pathol Lab Med J Surg Oncol 24:80–81, 1998. 117:645–646, 1993. 202. Mizukami Y, Kurumaya H, Kitagawa T, et al: Papillary car- 178. Yamashita H, Noguchi S, Murakami N, et al: DNA ploidy cinoma of the thyroid gland with fibromatosis-like stroma: a and stromal bone formation as prognostic indicators of thy- case report and review of the literature. Mod Pathol 8:366– roid papillary carcinoma in aged patients: a retrospective 370, 1995. study. Acta Pathol Jpn 43:22–27, 1993. 203. Chan JK, Tsui MS, Tse CH: Diffuse sclerosing variant of 179. Johannessen JV, Sobrinho-Simoes M: The origin and signifi- papillary carcinoma of the thyroid: a histological and immu- cance of thyroid psammoma bodies. Lab Invest 43:287–296, nohistochemical study of three cases. Histopathology 11:191– 1980. 201, 1987. 180. Vickery AL, Carcangiu ML, Johannessen JV: Papillary carci- 204. Hayashi Y, Sasao T, Takeichi N, et al: Diffuse sclerosing noma. Semin Diagn Pathol 2:90–100, 1985. variant of papillary carcinoma of the thyroid. A histopatho- 181. Chan JK, Saw D: The grooved nucleus. A useful diagnostic logical study of four cases. Acta Pathol Jpn 40:193–198, 1990. criterion of papillary carcinoma of the thyroid. Am J Surg 205. Fujimoto Y, Obara T, Ito Y, et al: Diffuse sclerosing variant Pathol 10:672–679, 1986. of papillary carcinoma of the thyroid. Clinical importance, 182. Glant MD, Berger EK, Davey DD: Intranuclear cytoplasmic surgical treatment, and follow-up study. Cancer 66:2306– inclusions in aspirates of follicular neoplasms of the thyroid. 2312, 1990. A report of two cases. Acta Cytol 28:576–580, 1984. 206. Albareda M, Puig-Domingo M, Wengrowicz S, et al: Clinical 183. Oyama T: A histopathological, immunohistochemical and ul- forms of presentation and evolution of diffuse sclerosing trastructural study of intranuclear cytoplasmic inclusions in variant of papillary carcinoma and insular variant of follicu- thyroid papillary carcinoma. Virchows Arch A Pathol Anat lar carcinoma of the thyroid. Thyroid 8:385–391, 1998. Histopathol 414:91–104, 1989. 207. Carcangiu ML, Bianchi S: Diffuse sclerosing variant of papil- 184. Scopa CD, Melachrinou M, Saradopoulou C, Merino MJ: The lary thyroid carcinoma. Clinicopathologic study of 15 cases significance of the grooved nucleus in thyroid lesions. Mod [see comments]. Am J Surg Pathol 13:1041–1049, 1989. Pathol 6:691–694, 1993. 208. Carcangiu ML, Bianchi S, Rosai J: Diffuse sclerosing papil- 185. Hazard JB: Nomenclature of thyroid tumors. In Young S, lary carcinoma: report of 8 cases of a distinctive variant of Inman DR (eds): Thyroid Neoplasia. London, Academic thyroid malignancy (abstract). Lab Invest 56:10A, 1987. Press, 1968, pp 3–37. 209. Soares J, Limbert E, Sobrinho-Simoes M: Diffuse sclerosing 186. Dickersin GR, Vickery AL Jr, Smith SB: Papillary carcinoma variant of papillary thyroid carcinoma. A clinicopathologic of the thyroid, oxyphil cell type, “clear cell” variant: a light- study of 10 cases. Pathol Res Pract 185:200–206, 1989. and electron-microscopic study. Am J Surg Pathol 4:501–509, 210. Schroder S, Bay V, Dumke K, et al: Diffuse sclerosing variant 1980. of papillary thyroid carcinoma. S-100 protein immunocyto- 187. Variakojis D, Getz ML, Paloyan E, Straus FH: Papillary clear chemistry and prognosis. Virchows Arch A Pathol Anat His- cell carcinoma of the thyroid gland. Hum Pathol 6:384–390, topathol 416:367–371, 1990. short 1975. 211. Gomez-Morales M, Aneiros J, Alvaro T, Navarro N: Langer- standard long

Thyroid and Parathyroid 83 top of RH

hans’ cells and prognosis of thyroid carcinoma (letter). Am J 234. Perrier ND, van Heerden JA, Goellner JR, et al: Thyroid Clin Pathol 91:628–629, 1989. cancer in patients with familial adenomatous polyposis. 212. Gomez-Morales M, Alvaro T, Munoz M, et al: Diffuse scle- World J Surg 22:738–742, discussion 743, 1998. rosing papillary carcinoma of the thyroid gland: immunohis- 235. Soravia C, Sugg SL, Berk T, et al: Familial adenomatous tochemical analysis of the local host immune response. His- polyposis–associated thyroid cancer: a clinical, pathological, topathology 18:427–433, 1991. and molecular genetics study. Am J Pathol 154:127–135, 213. Sobrinho-Simoes M, Soares J, Carneiro F: Diffuse follicular 1999. variant of papillary carcinoma of the thyroid: report of eight 236. Cetta F, Pelizzo MR, Curia MC, Barbarisi A: Genetics and cases of a distinct aggressive type of thyroid tumor. Surg clinicopathological findings in thyroid carcinomas associated Pathol 3:189–203, 1990. with familial adenomatous polyposis. Am J Pathol 155:7–9, 214. Mizukami Y, Nonomura A, Michigishi T, et al: Diffuse follic- 1999. ular variant of papillary carcinoma of the thyroid. Histopa- 237. Mizukami Y, Noguchi M, Michigishi T, et al: Papillary thy- thology 27:575–577, 1995. roid carcinoma in Kanazawa, Japan: prognostic significance 215. Hawk WA, Hazard JB: The many appearances of papillary of histological subtypes. Histopathology 20:243–250, 1992. carcinoma of the thyroid. Cleve Clin Q 43:207–215, 1976. 238. Carcangiu ML, Steeper T, Zampi G, Rosai J: Anaplastic thy- 216. Johnson TL, Lloyd RV, Thompson NW, et al: Prognostic roid carcinoma. A study of 70 cases. Am J Clin Pathol implications of the tall cell variant of papillary thyroid carci- 83:135–158, 1985. noma. Am J Surg Pathol 12:22–27, 1988. 239. Kawahara E, Ooi A, Oda Y, et al: Papillary carcinoma of the 217. Ostrowski ML, Merino MJ: Tall cell variant of papillary thy- thyroid gland with anaplastic transformation in the meta- roid carcinoma: a reassessment and immunohistochemical static foci. An immunohistochemical study. Acta Pathol Jpn study with comparison to the usual type of papillary carci- 36:921–927, 1986. noma of the thyroid. Am J Surg Pathol 20:964–974, 1996. 240. D’Antonio A, De Chiara A, Santoro M, et al: Warthin-like 218. Ruter A, Dreifus J, Jones M, et al: Overexpression of p53 tumour of the thyroid gland: RET/PTC expression indicates in tall cell variants of papillary thyroid carcinoma. Surgery it is a variant of papillary carcinoma. Histopathology 36:493– 120:1046–1050, 1996. 498, 2000. 219. Apel RL, Asa SL, LiVolsi VA: Papillary Hu¨ rthle cell carci- 241. Ito J, Noguchi S, Murakami N, Noguchi A: Factors affecting noma with lymphocytic stroma. “Warthin-like tumor” of the the prognosis of patients with carcinoma of the thyroid. Surg thyroid [see comments]. Am J Surg Pathol 19:810–814, 1995. Gynecol Obstet 150:539–544, 1980. 220. Vera-Sempere FJ, Prieto M, Camanas A: Warthin-like tumor 242. Chen KT: Minute (less than 1 mm) occult papillary thyroid of the thyroid: a papillary carcinoma with mitochondrion- carcinoma with metastasis (letter). Am J Clin Pathol 91:746, rich cells and abundant lymphoid stroma. A case report. 1989. Pathol Res Pract 194:341–347, 1998. 243. Kasai N, Sakamoto A: New subgrouping of small thyroid 221. Ozaki O, Ito K, Mimura T, et al: Papillary carcinoma of the carcinomas. Cancer 60:1767–1770, 1987. thyroid. Tall-cell variant with extensive lymphocyte infiltra- 244. Laskin WB, James LP: Occult papillary carcinoma of the tion. Am J Surg Pathol 20:695–698, 1996. thyroid with pulmonary metastases. Hum Pathol 14:83–85, 221a. Baloch ZW, LiVolsi VA: Warthin-like papillary carcinoma 1983. of the thyroid. Arch Pathol Lab Med 124:1192–1195, 2000. 245. Sampson RJ, Key CR, Buncher CR, Iijima S: Smallest forms 222. Nakamura T, Moriyama S, Nariya S, et al: Macrofollicular of papillary carcinoma of the thyroid. A study of 141 micro- variant of papillary thyroid carcinoma. Pathol Int 48:467– carcinomas less than 0.1 cm in greatest dimension. Arch 470, 1998. Pathol 91:334–339, 1971. 223. Albores-Saavedra J, Gould E, Vardaman C, Vuitch F: The 246. Strate SM, Lee EL, Childers JH: Occult papillary carcinoma macrofollicular variant of papillary thyroid carcinoma: a of the thyroid with distant metastases. Cancer 54:1093–1100, study of 17 cases. Hum Pathol 22:1195–1205, 1991. 1984. 224. Albores-Saavedra J, Housini I, Vuitch F, Snyder WH 3rd: 247. Sugitani I, Yanagisawa A, Shimizu A, et al: Clinicopathologic Macrofollicular variant of papillary thyroid carcinoma with and immunohistochemical studies of papillary thyroid mi- minor insular component. Cancer 80:1110–1116, 1997. crocarcinoma presenting with cervical lymphadenopathy. 225. Sobrinho-Simoes MA, Nesland JM, Holm R, et al: Hu¨ rthle World J Surg 22:731–737, 1998. cell and mitochondrion-rich papillary carcinomas of the thy- 248. Fukunaga FH, Yatani R: Geographic pathology of occult thyroid gland: an ultrastructural and immunocytochemical roid carcinomas. Cancer 36:1095–1099, 1975. study. Ultrastruct Pathol 8:131–142, 1985. 249. Harach HR, Franssila KO, Wasenius VM: Occult papillary 226. Tscholl-Ducommun J, Hedinger CE: Papillary thyroid carci- carcinoma of the thyroid. A “normal” finding in Finland. A systematic autopsy study. Cancer 56:531–538, 1985. nomas. Morphology and prognosis. Virchows Arch Pathol 250. Sampson RJ: Prevalence and significance of occult thyroid Anat 396:19–39, 1982. cancer. In DeGroot LJ, Frohman LA, Kaplan DL (eds): Radia- 227. Beckner ME, Heffess CS, Oertel JE: Oxyphilic papillary thy- tion-Associated Thyroid Carcinoma. New York, Grune & roid carcinomas. Am J Clin Pathol 103:280–287, 1995. Stratton, 1977, pp 137–153. 228. Berho M, Suster S: The oncocytic variant of papillary carci- 251. Arellano L, Ibarra A: Occult carcinoma of the thyroid gland. noma of the thyroid: a clinicopathologic study of 15 cases. Pathol Res Pract 179:88–91, 1984. Hum Pathol 28:47–53, 1997. 252. Bondeson L, Ljungberg O: Occult thyroid carcinoma at au- 229. Katoh R, Sakamoto A, Kasai N, Yagawa K: Squamous differ- topsy in Malmo, Sweden. Cancer 47:319–323, 1981. entiation in thyroid carcinoma. With special reference to his- 253. Fukunaga FH, Lockett LJ: Thyroid carcinoma in the Japanese togenesis of squamous cell carcinoma of the thyroid. Acta in Hawaii. Arch Pathol 92:6–13, 1971. Pathol Jpn 39:306–312, 1989. 254. Lang W, Borrusch H, Bauer L: Occult carcinomas of the 230. Cameselle-Teijeiro J, Chan JK: Cribriform-morular variant of thyroid. Evaluation of 1,020 sequential autopsies. Am J Clin papillary carcinoma: a distinctive variant representing the Pathol 90:72–76, 1988. sporadic counterpart of familial adenomatous polyposis–as- 255. Ludwig G, Nishiyama RH: The prevalence of occult papil- sociated thyroid carcinoma? Mod Pathol 12:400–411, 1999. lary thyroid carcinoma in 100 consecutive autopsies in an 231. Yamashita T, Hosoda Y, Kameyama K, et al: Peculiar nuclear American population. Lab Invest 34:320–321, 1976. clearing composed of microfilaments in papillary carcinoma 256. Ottino A, Pianzola HM, Castelletto RH: Occult papillary thy- of the thyroid. Cancer 70:2923–2928, 1992. roid carcinoma at autopsy in La Plata, Argentina. Cancer 232. Harach HR, Williams GT, Williams ED: Familial adenoma- 64:547–551, 1989. tous polyposis associated thyroid carcinoma: a distinct type 257. Sobrinho-Simoes MA, Sambade MC, Goncalves V: Latent of follicular cell neoplasm. Histopathology 25:549–561, 1994. thyroid carcinoma at autopsy: a study from Oporto, Portu- 233. Cetta F, Toti P, Petracci M, et al: Thyroid carcinoma associ- gal. Cancer 43:1702–1706, 1979. ated with familial adenomatous polyposis. Histopathology 258. Mills SE, Allen MS Jr: Congenital occult papillary carcinoma short 31:231–236, 1997. of the thyroid gland. Hum Pathol 17:1179–1181, 1986. standard long

84 Endocrine System top of RH

259. Komorowski RA, Hanson GA: Occult thyroid pathology in 279. Lam AK, Montone KT, Nolan KA, Livolsi VA: Ret oncogene the young adult: an autopsy study of 138 patients without activation in papillary thyroid carcinoma: prevalence and clinical thyroid disease. Hum Pathol 19:689–696, 1988. implication on the histological parameters. Hum Pathol 260. Franssila KO, Harach HR: Occult papillary carcinoma of the 29:565–568, 1998. thyroid in children and young adults. A systemic autopsy 280. Delvincourt C, Patey M, Flament JB, et al: Ret and trk proto- study in Finland. Cancer 58:715–719, 1986. oncogene activation in thyroid papillary carcinomas in 261. Rassel H, Thompson LD, Heffess CS: A rationale for con- French patients from the Champagne-Ardenne region. Clin servative management of microscopic papillary carcinoma of Biochem 29:267–271, 1996. the thyroid gland: a clinicopathologic correlation of 90 cases. 281. Kitamura Y, Minobe K, Nakata T, et al: Ret/PTC3 is the Eur Arch Otorhinolaryngol 255:462–267, 1998. most frequent form of gene rearrangement in papillary thy- 262. LaGuette J, Matias-Guiu X, Rosai J: Thyroid paraganglioma: roid carcinomas in Japan. J Hum Genet 44:96–102, 1999. a clinicopathologic and immunohistochemical study of three 282. Santoro M, Dathan NA, Berlingieri MT, et al: Molecular cases. Am J Surg Pathol 21:748–753, 1997. characterization of RET/PTC3; a novel rearranged version of 263. Schroder S, Pfannschmidt N, Bocker W, et al: Histopatho- the RET proto-oncogene in a human thyroid papillary carci- logic types and clinical behaviour of occult papillary carcinoma. Oncogene 9:509–516, 1994. noma of the thyroid. Pathol Res Pract 179:81–87, 1984. 283. Lee CH, Hsu LS, Chi CW, et al: High frequency of rear- 264. Fonseca E, Nesland JM, Hoie J, Sobrinho-Simoes M: Pattern rangement of the RET protooncogene (RET/PTC) in Chinese of expression of intermediate cytokeratin filaments in the papillary thyroid carcinomas. J Clin Endocrinol Metab thyroid gland: an immunohistochemical study of simple 83:1629–1632, 1998. and stratified epithelial-type cytokeratins. Virchows Arch 284. Bongarzone I, Butti MG, Coronelli S, et al: Frequent activa- 430:239–245, 1997. tion of ret protooncogene by fusion with a new activating 265. Raphael SJ, McKeown-Eyssen G, Asa SL: High-molecular- gene in papillary thyroid carcinomas. Cancer Res 54:2979– weight cytokeratin and cytokeratin-19 in the diagnosis of 2985, 1994. thyroid tumors. Mod Pathol 7:295–300, 1994. 285. Bongarzone I, Fugazzola L, Vigneri P, et al: Age-related acti- 266. Raphael SJ, Apel RL, Asa SL: Brief report: detection of high- vation of the tyrosine kinase receptor protooncogenes RET molecular-weight cytokeratins in neoplastic and non-neoplas- and NTRK1 in papillary thyroid carcinoma. J Clin Endocri- tic thyroid tumors using microwave antigen retrieval. Mod nol Metab 81:2006–2009, 1996. Pathol 8:870–872, 1995. 286. Zou M, Shi Y, Farid NR: Low rate of ret proto-oncogene 267. Schelfhout LJ, Van Muijen GN, Fleuren GJ: Expression of activation (PTC/retTPC) in papillary thyroid carcinomas keratin 19 distinguishes papillary thyroid carcinoma from from Saudi Arabia. Cancer 73:176–180, 1994. follicular carcinomas and follicular thyroid adenoma. Am J 287. Tallini G, Ghossein RA, Emanuel J, et al: Detection of thyro- Clin Pathol 92:654–658, 1989. globulin, thyroid peroxidase, and RET/PTC1 mRNA tran- 268. Pierotti MA, Vigneri P, Bongarzone I: Rearrangements of scripts in the peripheral blood of patients with thyroid dis- RET and NTRK1 tyrosine kinase receptors in papillary thy- ease. J Clin Oncol 16:1158–1166, 1998. roid carcinomas. Recent Results Cancer Res 154:237–247, 288. Mayr B, Potter E, Goretzki P, et al: Expression of Ret/PTC1, 1998. -2, -3, -delta3 and -4 in German papillary thyroid carcinoma. 269. Smanik PA, Furminger TL, Mazzaferri EL, Jhiang SM: Break- Br J Cancer 77:903–906, 1998. point characterization of the ret/PTC oncogene in human 289. Mayr B, Potter E, Goretzki P, et al: Expression of wild-type papillary thyroid carcinoma. Hum Mol Genet 4:2313–2318, ret, ret/PTC and ret/PTC variants in papillary thyroid carci- 1995. noma in Germany. Langenbecks Arch Surg 384:54–59, 1999. 270. Santoro M, Carlomagno F, Hay ID, et al: Ret oncogene acti- 290. Soares P, Fonseca E, Wynford-Thomas D, Sobrinho-Simoes vation in human thyroid neoplasms is restricted to the papil- M: Sporadic ret-rearranged papillary carcinoma of the thy- lary cancer subtype. J Clin Invest 89:1517–1522, 1992. roid: a subset of slow growing, less aggressive thyroid neo- 271. Sozzi G, Bongarzone I, Miozzo M, et al: A t(10;17) transloca- plasms? J Pathol 185:71–78, 1998. tion creates the RET/PTC2 chimeric transforming sequence 291. Nikiforov YE, Rowland JM, Bove KE, et al: Distinct pattern in papillary thyroid carcinoma. Genes Chromosomes Cancer of ret oncogene rearrangements in morphological variants of 9:244–250, 1994. radiation-induced and sporadic thyroid papillary carcinomas 272. Minoletti F, Butti MG, Coronelli S, et al: The two genes in children. Cancer Res 57:1690–1694, 1997. generating RET/PTC3 are localized in chromosomal band 292. Sugg SL, Ezzat S, Zheng L, et al: Oncogene profile of papil- 10q11.2. Genes Chromosomes Cancer 11:51–57, 1994. lary thyroid carcinoma. Surgery 125:46–52, 1999. 273. Fugazzola L, Pierotti MA, Vigano E, et al: Molecular and 293. Klugbauer S, Lengfelder E, Demidchik EP, Rabes HM: High biochemical analysis of RET/PTC4, a novel oncogenic rear- prevalence of RET rearrangement in thyroid tumors of chil- rangement between RET and ELE1 genes, in a post-Cherno- dren from Belarus after the Chernobyl reactor accident. On- byl papillary thyroid cancer. Oncogene 13:1093–1097, 1996. cogene 11:2459–2467, 1995. 274. Ponder BAJ: Multiple endocrine neoplasia type 2. In Vogel- 294. Fugazzola L, Pilotti S, Pinchera A, et al: Oncogenic rear- stein B, Kinzler KW (eds): The Genetic Basis of Human Can- rangements of the RET proto-oncogene in papillary thyroid cer. New York, McGraw-Hill, 1998, pp 475–487. carcinomas from children exposed to the Chernobyl nuclear 275. Klugbauer S, Demidchik EP, Lengfelder E, Rabes HM: Mo- accident. Cancer Res 55:5617–5620, 1995. lecular analysis of new subtypes of ELE/RET rearrange- 295. Pisarchik AV, Ermak G, Demidchik EP, et al: Low preva- ments, their reciprocal transcripts and breakpoints in papil- lence of the ret/PTC3r1 rearrangement in a series of papillary thyroid carcinomas of children after Chernobyl. lary thyroid carcinomas presenting in Belarus ten years post- Oncogene 16:671–675, 1998. Chernobyl. Thyroid 8:1003–1008, 1998. 276. Klugbauer S, Demidchik EP, Lengfelder E, Rabes HM: Detec- 296. Bounacer A, Wicker R, Schlumberger M, et al: Oncogenic tion of a novel type of RET rearrangement (PTC5) in thyroid rearrangements of the ret proto-oncogene in thyroid tumors carcinomas after Chernobyl and analysis of the involved induced after exposure to ionizing radiation. Biochimie RET-fused gene RFG5. Cancer Res 58:198–203, 1998. 79:619–623, 1997. 277. Bongarzone I, Butti MG, Fugazzola L, et al: Comparison of 297. Kopp P, Jameson JL: Thyroid disorders. In Jameson JL (ed): the breakpoint regions of ELE1 and RET genes involved in Principles of Molecular Medicine. Totowa, NJ, Humana the generation of RET/PTC3 oncogene in sporadic and in Press, 1998, pp 459–473. radiation-associated papillary thyroid carcinomas. Genomics 298. Bongarzone I, Vigneri P, Mariani L, et al: RET/NTRK1 rear- 42:252–259, 1997. rangements in thyroid gland tumors of the papillary carci- 278. Williams GH, Rooney S, Thomas GA, et al: RET activation in noma family: correlation with clinicopathological features. adult and childhood papillary thyroid carcinoma using a Clin Cancer Res 4:223–228, 1998. reverse transcriptase-n-polymerase chain reaction approach 299. Beimfohr C, Klugbauer S, Demidchik EP, et al: NTRK1 rear- short on archival-nested material. Br J Cancer 74:585–589, 1996. rangement in papillary thyroid carcinomas of children after standard long

Thyroid and Parathyroid 85 top of RH

the Chernobyl reactor accident. Int J Cancer 80:842–847, nation of risk groups and outcome of treatment. Arch Surg 1999. 133:419–425, 1998. 300. Chan JKC, Tsang WYW: Endocrine malignancies that may 321. Woolner LB, Beahrs OH, Black BM, et al: Thyroid carcinoma: mimic benign lesions. Semin Diagn Pathol 12:45–63, 1995. general considerations and follow-up data on 1181 cases. In 301. Cheifetz RE, Davis NL, Robinson BW, et al: Differentiation Young S, Inman DR (eds): Thyroid Neoplasia. London, Aca- of thyroid neoplasms by evaluating epithelial membrane an- demic Press, 1968, pp 51–76. tigen, Leu-7 antigen, epidermal growth factor receptor, and 322. Tubiana M, Schlumberger M, Rougier P, et al: Long-term DNA content. Am J Surg 167:531–534, 1994. results and prognostic factors in patients with differentiated 302. Viale G, Dell’Orto P, Coggi G, Gambacorta M: Coexpression thyroid carcinoma. Cancer 55:794–804, 1985. of cytokeratins and vimentin in normal and diseased thyroid 323. Mazzaferri EL: Papillary thyroid carcinoma: factors influenc- glands. Lack of diagnostic utility of vimentin immunostaining prognosis and current therapy. Semin Oncol 14:315–332, ing. Am J Surg Pathol 13:1034–1040, 1989. 1987. 303. Yamamoto Y, Izumi K, Otsuka H: An immunohistochemical 324. Beenken S, Guillamondegui O, Shallenberger R, et al: Prog- study of epithelial membrane antigen, cytokeratin, and vi- nostic factors in patients dying of well-differentiated thyroid mentin in papillary thyroid carcinoma. Recognition of lethal cancer. Arch Otolaryngol Head Neck Surg 115:326–330, and favorable prognostic types [see comments]. Cancer 1989. 70:2326–2333, 1992. 325. Shaha AR, Shah JP, Loree TR: Risk group stratification and 304. Damiani S, Fratamico F, Lapertosa G, et al: Alcian blue and prognostic factors in papillary carcinoma of thyroid. Ann epithelial membrane antigen are useful markers in differenti- Surg Oncol 3:534–538, 1996. ating benign from malignant papillae in thyroid lesions. Vir- 326. Salvesen H, Njolstad PR, Akslen LA, et al: Papillary thyroid chows Arch A Pathol Anat Histopathol 419:131–135, 1991. carcinoma: a multivariate analysis of prognostic factors in- 305. Lucas SD, Ek B, Rask L, et al: Aberrantly expressed cytoker- cluding an evaluation of the p-TNM staging system. Eur J atin 1, a tumor-associated autoantigen in papillary thyroid Surg 158:583–589, 1992. carcinoma. Int J Cancer 73:171–177, 1997. 327. Bellantone R, Lombardi CP, Boscherini M, et al: Prognostic 306. Miettinen M, Kovatich AJ, Karkkainen P: Keratin subsets factors in differentiated thyroid carcinoma: a multivariate in papillary and follicular thyroid lesions. A paraffin sec- analysis of 234 consecutive patients. J Surg Oncol 68:237– tion analysis with diagnostic implications. Virchows Arch 241, 1998. 431:407–413, 1997. 328. Noguchi S, Murakami N, Kawamoto H: Classification of 307. Tanaka T, Umeki K, Yamamoto I, et al: Immunohistochemi- papillary cancer of the thyroid based on prognosis. World J cal loss of thyroid peroxidase in papillary thyroid carcinoma: Surg 18:552–557, discussion 558, 1994. strong suppression of peroxidase gene expression. J Pathol 329. Kashima K, Yokoyama S, Noguchi S, et al: Chronic thyroidi- 179:89–94, 1996. tis as a favorable prognostic factor in papillary thyroid carci- 308. Umeki K, Tanaka T, Yamamoto I, et al: Differential expres- noma. Thyroid 8:197–202, 1998. sion of dipeptidyl peptidase IV (CD26) and thyroid peroxi- 330. Frauenhoffer CM, Patchefsky AS, Cobanoglu A: Thyroid car- dase in neoplastic thyroid tissues. Endocr J 43:53–60, 1996. cinoma: a clinical and pathologic study of 125 cases. Cancer 309. Khan A, Baker SP, Patwardhan NA, Pullman JM: CD57 43:2414–2421, 1979. (Leu-7) expression is helpful in diagnosis of the follicular 331. Tennvall J, Biorklund A, Moller T, et al: Prognostic factors of variant of papillary thyroid carcinoma. Virchows Arch papillary, follicular and medullary carcinomas of the thyroid 432:427–432, 1998. gland. Retrospective multivariate analysis of 216 patients 310. Loy TS, Darkow GV, Spollen LE, Diaz-Arias AA: Immuno- with a median follow-up of 11 years. Acta Radiol Oncol 24:17–24, 1985. staining for Leu-7 in the diagnosis of thyroid carcinoma. 332. Tennvall J, Biorklund A, Moller T, et al: Is the EORTC prog- Arch Pathol Lab Med 118:172–174, 1994. nostic index of thyroid cancer valid in differentiated thyroid 311. Chhieng DC, Ross JS, McKenna BJ: CD44 immunostaining of carcinoma? Retrospective multivariate analysis of differenti- thyroid fine-needle aspirates differentiates thyroid papillary ated thyroid carcinoma with long follow-up. Cancer 57:1405– carcinoma from other lesions with nuclear grooves and in- 1414, 1986. clusions. Cancer 81:157–162, 1997. 333. Rodriguez JM, Moreno A, Parrilla P, et al: Papillary thyroid 312. Ross JS, del Rosario AD, Sanderson B, Bui HX: Selective microcarcinoma: clinical study and prognosis. Eur J Surg expression of CD44 cell-adhesion molecule in thyroid papil- 163:255–259, 1997. lary carcinoma fine-needle aspirates. Diagn Cytopathol 334. Vickery AL Jr, Wang CA, Walker AM: Treatment of in- 14:287–291, 1996. trathyroidal papillary carcinoma of the thyroid. Cancer 313. van Hoeven KH, Kovatich AJ, Miettinen M: Immunocyto- 60:2587–2595, 1987. chemical evaluation of HBME-1, CA 19-9, and CD-15 (Leu- 335. McCaffrey TV, Bergstralh EJ, Hay ID: Locally invasive papil- M1) in fine-needle aspirates of thyroid nodules. Diagn Cyto- lary thyroid carcinoma: 1940–1990 [see comments]. Head pathol 18:93–97, 1998. Neck 16:165–172, 1994. 314. Anwar F, Emond MJ, Schmidt RA, et al: Retinoblastoma 336. Yasumoto K, Miyagi C, Nakashima T, et al: Papillary and expression in thyroid neoplasms. Mod Pathol 13:562–569, follicular thyroid carcinoma: the treatment results of 357 pa- 2000. tients at the National Kyushu Cancer Centre of Japan. J 315. Gimm O, Rath FW, Dralle H: Pattern of lymph node metas- Laryngol Otol 110:657–662, 1996. tases in papillary thyroid carcinoma. Br J Surg 85:252–254, 337. Hughes CJ, Shaha AR, Shah JP, Loree TR: Impact of lymph 1998. node metastasis in differentiated carcinoma of the thyroid: a 316. Lindsay A: Papillary thyroid carcinoma revisited. In Hedin- matched-pair analysis. Head Neck 18:127–132, 1996. ger CE (ed): Thyroid Cancer. Berlin, Springer-Verlag, 1969, 338. Scheumann GF, Gimm O, Wegener G, et al: Prognostic signif- pp 29–32. icance and surgical management of locoregional lymph node 317. Cady B, Rossi R: An expanded view of risk-group definition metastases in papillary thyroid cancer. World J Surg 18:559– in differentiated thyroid carcinoma. Surgery 104:947–953, 567, discussion 567–568, 1994. 1988. 339. Akslen LA, LiVolsi VA: Prognostic significance of histologic 318. Cady B: Papillary carcinoma of the thyroid gland: treatment grading compared with subclassification of papillary thyroid based on risk group definition. Surg Oncol Clin North Am carcinoma [see comments]. Cancer 88:1902–1908, 2000. 7:633–644, 1998. 340. Pilotti S, Collini P, Manzari A, et al: Poorly differentiated 319. Hay ID, Bergstralh EJ, Goellner JR, et al: Predicting outcome forms of papillary thyroid carcinoma: distinctive entities or in papillary thyroid carcinoma: development of a reliable morphological patterns? Semin Diagn Pathol 12:249–255, prognostic scoring system in a cohort of 1779 patients surgi- 1995. cally treated at one institution during 1940 through 1989. 341. Andersen PE, Kinsella J, Loree TR, et al: Differentiated carci- Surgery 114:1050–1057, discussion 1057–1058, 1993. noma of the thyroid with extrathyroidal extension. Am J short 320. Sanders LE, Cady B: Differentiated thyroid cancer: reexami- Surg 170:467–470, 1995. standard long

86 Endocrine System top of RH

342. Sakamoto A, Kasai N, Sugano H: Poorly differentiated carci- ies that segregates immunocytochemically poorly differenti- noma of the thyroid. A clinicopathologic entity for a high- ated carcinoma from undifferentiated carcinoma of the thy- risk group of papillary and follicular carcinomas. Cancer roid gland. Am J Surg Pathol 18:1054–1064, 1994. 52:1849–1855, 1983. 364. Dobashi Y, Sakamoto A, Sugimura H, et al: Overexpression 343. Akslen LA: Prognostic importance of histologic grading in of p53 as a possible prognostic factor in human thyroid papillary thyroid carcinoma. Cancer 72:2680–2685, 1993. carcinoma. Am J Surg Pathol 17:375–381, 1993. 344. Schroder S, Schwarz W, Rehpenning W, et al: Dendritic/ 365. Manenti G, Pilotti S, Re FC, et al: Selective activation of ras Langerhans cells and prognosis in patients with papillary oncogenes in follicular and undifferentiated thyroid carcino- thyroid carcinomas. Immunocytochemical study of 106 thy- mas. Eur J Cancer 7:987–993, 1994. roid neoplasms correlated to follow-up data. Am J Clin 366. Lam KY, Lo CY, Chan KW, Wan KY: Insular and anaplastic Pathol 89:295–300, 1988. carcinoma of the thyroid: a 45-year comparative study at a 345. Schroder S, Schwarz W, Rehpenning W, et al: Prognostic single institution and a review of the significance of p53 and significance of Leu-M1 immunostaining in papillary carcino- p21. Ann Surg 231:329–338, 2000. mas of the thyroid gland. Virchows Arch A Pathol Anat 367. Johnson MW, Hunnicutt JW, Bilbao JE, et al: Poorly differen- Histopathol 411:435–439, 1987. tiated thyroid carcinoma with focal insular pattern: clinico- 346. Goldenberg JD, Portugal LG, Wenig BL, et al: Well-differen- pathologic correlation (abstract). Am J Clin Pathol 94:497– tiated thyroid carcinomas: p53 mutation status and micro- 498, 1990. vessel density. Head Neck 20:152–158, 1998. 368. Sasaki A, Daa T, Kashima K, et al: Insular component as a 347. Godballe C, Asschenfeldt P, Jorgensen KE, et al: Prognostic risk factor of thyroid carcinoma. Pathol Int 46:939–946, 1996. factors in papillary and follicular thyroid carcinomas: p53 369. Ashfaq R, Vuitch F, Delgado R, Albores-Saavedra J: Papillary expression is a significant indicator of prognosis. Laryngo- and follicular thyroid carcinomas with an insular compo- scope 108:243–249, 1998. nent. Cancer 73:416–423, 1994. 348. Omura K, Nagasato A, Kanehira E, et al: Retinoblastoma 370. LiVolsi VA, Brooks JJ, Arendash-Durand B: Anaplastic thy- protein and proliferating-cell nuclear antigen expression as roid tumors. Immunohistology. Am J Clin Pathol 87:434–442, predictors of recurrence in well-differentiated papillary thy- 1987. roid carcinoma. J Clin Oncol 15:3458–3463, 1997. 371. Nishiyama RH, Dunn EL, Thompson NW: Anaplastic spin- 349. Dhar DK, Kubota H, Kotoh T, et al: Tumor vascularity pre- dle-cell and giant-cell tumors of the thyroid gland. Cancer dicts recurrence in differentiated thyroid carcinoma. Am J 30:113–127, 1972. Surg 176:442–447, 1998. 372. Venkatesh YS, Ordonez NG, Schultz PN, et al: Anaplastic 350. Ishiwata T, Iino Y, Takei H, et al: Tumor angiogenesis as an carcinoma of the thyroid. A clinicopathologic study of 121 independent prognostic indicator in human papillary thyroid cases. Cancer 66:321–330, 1990. carcinoma. Oncol Rep 5:1343–1348, 1998. 373. Rosai J, Saxen EA, Woolner L: Undifferentiated and poorly 351. Akslen LA, Livolsi VA: Increased angiogenesis in papillary differentiated carcinoma. Semin Diagn Pathol 2:123–126, thyroid carcinoma but lack of prognostic importance [see 1985. comments]. Hum Pathol 31:439–442, 2000. 374. Aldinger KA, Samaan NA, Ibanez M, Hill CS Jr: Anaplastic 352. Hamming JF, Schelfhout LJ, Cornelisse CJ, et al: Prognostic carcinoma of the thyroid: a review of 84 cases of spindle and value of nuclear DNA content in papillary and follicular giant cell carcinoma of the thyroid. Cancer 41:2267–2275, thyroid cancer. World J Surg 12:503–508, 1988. 1978. 353. Hara H, Fulton N, Yashiro T, et al: N-ras mutation: an inde- 375. Spires JR, Schwartz MR, Miller RH: Anaplastic thyroid carci- pendent prognostic factor for aggressiveness of papillary noma. Association with differentiated thyroid cancer. Arch thyroid carcinoma. Surgery 116:1010–1016, 1994. Otolaryngol Head Neck Surg 114:40–44, 1988. 354. Carcangiu ML, Zampi G, Rosai J: Poorly differentiated (“in- 376. Galera-Davidson H, Bibbo M, Dytch HE, et al: Nuclear DNA sular”) thyroid carcinoma. A reinterpretation of Langhans’ in anaplastic thyroid carcinoma with a differentiated compo- “wuchernde Struma.” Am J Surg Pathol 8:655–668, 1984. nent. Histopathology 11:715–722, 1987. 355. Papotti M, Botto Micca F, Favero A, et al: Poorly differenti- 377. Lo CY, Lam KY, Wan KY: Anaplastic carcinoma of the thy- ated thyroid carcinomas with primordial cell component. A roid. Am J Surg 177:337–339, 1999. group of aggressive lesions sharing insular, trabecular, and 378. Cibull ML, Gray GF: Ultrastructure of osteoclastoma-like gi- solid patterns. Am J Surg Pathol 17:291–301, 1993. ant cell tumor of thyroid. Am J Surg Pathol 2:401–405, 1978. 356. van den Brekel MW, Hekkenberg RJ, Asa SL, et al: Prognos- 379. Silverberg SG, DeGiorgi LS: Osteoclastoma-like giant cell tu- tic features in tall cell papillary carcinoma and insular thy- mor of the thyroid. Report of a case with prolonged survival roid carcinoma. Laryngoscope 107:254–259, 1997. following partial excision and radiotherapy. Cancer 31:621– 357. Tallini G, Garcia-Rostan G, Herrero A, et al: Downregulation 625, 1973. of p27KIP1 and Ki67/Mib1 labeling index support the classi- 380. Gaffey MJ, Lack EE, Christ ML, Weiss LM: Anaplastic thy- fication of thyroid carcinoma into prognostically relevant cat- roid carcinoma with osteoclast-like giant cells. A clinicopath- egories. Am J Surg Pathol 23:678–685, 1999. ologic, immunohistochemical, and ultrastructural study. Am 358. Ringel MD, Burman KD, Shmookler BM: Clinical aspects of J Surg Pathol 15:160–168, 1991. miscellaneous and unusual types of thyroid cancers. In War- 381. Wan SK, Chan JK, Tang SK: Paucicellular variant of anaplas- tofsky L (ed): Thyroid Cancer, A Comprehensive Guide tic thyroid carcinoma. A mimic of Reidel’s thyroiditis. Am J to Clinical Management. Totowa, NJ, Humana Press, 2000, Clin Pathol 105:388–393, 1996. pp 421–451. 382. Blasius S, Edel G, Grunert J, et al: Anaplastic thyroid carci- 359. Kapp DS, LiVolsi VA, Sanders MM: Anaplastic carcinoma noma with osteosarcomatous differentiation. Pathol Res Pract following well-differentiated thyroid cancer: etiological con- 190:507–510, discussion 511–512, 1994. siderations. Yale J Biol Med 55:521–528, 1982. 383. Bakri K, Shimaoka K, Rao U, Tsukada Y: Adenosquamous 360. Flynn SD, Forman BH, Stewart AF, Kinder BK: Poorly differ- cell carcinoma of the thyroid after radiotherapy for Hodg- entiated (“insular”) carcinoma of the thyroid gland: an ag- kin’s disease. Cancer 52:465–470, 1983. gressive subset of differentiated thyroid neoplasms. Surgery 384. Harada T, Katagiri M, Tsukayama C, et al: Squamous cell 104:963–970, 1988. carcinoma with cyst of the thyroid. J Surg Oncol 42:136–143, 361. Pietribiasi F, Sapino A, Papotti M, Bussolati G: Cytologic 1989. features of poorly differentiated ’insular’ carcinoma of the 385. Huang TY, Assor D: Primary squamous cell carcinoma of thyroid, as revealed by fine-needle aspiration biopsy. Am J the thyroid gland: a report of four cases. Am J Clin Pathol Clin Pathol 94:687–692, 1990. 55:93–98, 1971. 362. Resnick MB, Schacter P, Finkelstein Y, et al: Immunohisto- 386. Huang TY, Lin SG: Primary squamous cell carcinoma of the chemical analysis of p27/kip1 expression in thyroid carci- thyroid. Indiana Med 79:763–764, 1986. noma. Mod Pathol 11:735–739, 1998. 387. Sarda AK, Bal S, Arunabh, et al: Squamous cell carcinoma of short 363. Pilotti S, Collini P, Del Bo R, et al: A novel panel of antibod- the thyroid. J Surg Oncol 39:175–178, 1988. standard long

Thyroid and Parathyroid 87 top of RH

388. Simpson WJ, Carruthers J: Squamous cell carcinoma of the 411. Tan RK, Finley RK 3rd, Driscoll D, et al: Anaplastic carci- thyroid gland. Am J Surg 156:44–46, 1988. noma of the thyroid: a 24-year experience. Head Neck 17:41– 389. Shimaoka K, Tsukada Y: Squamous cell carcinomas and ade- 47, discussion 47–48, 1995. nosquamous carcinomas originating from the thyroid gland. 412. Nilsson O, Lindeberg J, Zedenius J, et al: Anaplastic giant Cancer 46:1833–1842, 1980. cell carcinoma of the thyroid gland: treatment and survival 390. Theander C, Loden B, Berglund J, Seidal T: Primary squa- over a 25-year period. World J Surg 22:725–730, 1998. mous carcinoma of the thyroid—a case report. J Laryngol 413. Evans HL: Columnar-cell carcinoma of the thyroid. A report Otol 107:1155–1158, 1993. of two cases of an aggressive variant of thyroid carcinoma. 391. Harada T, Shimaoka K, Katagiri M, et al: Rarity of squamous Am J Clin Pathol 85:77–80, 1986. cell carcinoma of the thyroid: autopsy review. World J Surg 414. Ferreiro JA, Hay ID, Lloyd RV: Columnar cell carcinoma of 18:542–546, 1994. the thyroid: report of three additional cases. Hum Pathol 392. Burt A, Goudie RB: Diagnosis of primary thyroid carcinoma 27:1156–1160, 1996. by immunohistological demonstration of thyroglobulin. His- 415. Sobrinho-Simoes M, Nesland JM, Johannessen JV: Columnar- topathology 3:279–286, 1979. cell carcinoma. Another variant of poorly differentiated car- 393. Ralfkiaer N, Gatter KC, Alcock C, et al: The value of immu- cinoma of the thyroid. Am J Clin Pathol 89:264–267, 1988. nocytochemical methods in the differential diagnosis of ana- 416. Mizukami Y, Nonomura A, Michigishi T, et al: Columnar plastic thyroid tumours. Br J Cancer 52:167–170, 1985. cell carcinoma of the thyroid gland: a case report and review 394. Myskow MW, Krajewski AS, Dewar AE, et al: The role of of the literature. Hum Pathol 25:1098–1101, 1994. immunoperoxidase techniques on paraffin embedded tissue 417. Berends D, Mouthaan PJ: Columnar-cell carcinoma of the in determining the histogenesis of undifferentiated thyroid thyroid. Histopathology 20:360–362, 1992. neoplasms. Clin Endocrinol 24:335–341, 1986. 418. Gaertner EM, Davidson M, Wenig BM: The columnar cell 395. Eusebi V, Damiani S, Riva C, et al: Calcitonin free oat-cell variant of thyroid papillary carcinoma. Case report and dis- carcinoma of the thyroid gland. Virchows Arch A Pathol cussion of an unusually aggressive thyroid papillary carci- Anat Histopathol 417:267–271, 1990. noma. Am J Surg Pathol 19:940–947, 1995. 396. Wolf BC, Sheahan K, DeCoste D, et al: Immunohistochemical 419. Akslen LA, Varhaug JE: Thyroid carcinoma with mixed tall- analysis of small cell tumors of the thyroid gland: an Eastern cell and columnar-cell features. Am J Clin Pathol 94:442–445, Cooperative Oncology Group study. Hum Pathol 23:1252– 1990. 1261, 1992. 420. Genton CY, Dutoit M, Portmann L, et al: Pathologic fracture 397. Totsch M, Dobler G, Feichtinger H, et al: Malignant heman- of the femur neck as first manifestation of a minute colum- gioendothelioma of the thyroid. Its immunohistochemical nar cell carcinoma of the thyroid gland. Pathol Res Pract discrimination from undifferentiated thyroid carcinoma [see 194:861–863, 1998. comments]. Am J Surg Pathol 14:69–74, 1990. 421. Shimizu M, Hirokawa M, Manabe T: Tall cell variant of 398. Eckert F, Schmid U, Gloor F, Hedinger C: Evidence of vascu- papillary thyroid carcinoma with foci of columnar cell com- lar differentiation in anaplastic tumours of the thyroid—an ponent. Virchows Arch 434:173–175, 1999. immunohistological study. Virchows Arch A Pathol Anat 422. Wenig BM, Thompson LD, Adair CF, et al: Thyroid papillary Histopathol 410:203–215, 1986. carcinoma of columnar cell type: a clinicopathologic study of 399. Albores-Saavedra J, Nadji M, Civantos F, Morales AR: Thy- 16 cases. Cancer 82:740–753, 1998. roglobulin in carcinoma of the thyroid: an immunohisto- 423. Hui PK, Chan JK, Cheung PS, Gwi E: Columnar cell carci- chemical study. Hum Pathol 14:62–66, 1983. noma of the thyroid. Fine needle aspiration findings in a 400. Matias-Guiu X, Villanueva A, Cuatrecasas M, et al: p53 in a case. Acta Cytol 34:355–358, 1990. thyroid follicular carcinoma with foci of poorly differentiated 424. Evans HL: Encapsulated columnar-cell neoplasms of the thy- and anaplastic carcinoma. Pathol Res Pract 192:1242–1249, roid. A report of four cases suggesting a favorable prognosis. discussion 1250–1251, 1996. Am J Surg Pathol 20:1205–1211, 1996. 401. Holm R, Nesland JM: Retinoblastoma and p53 tumour sup- 425. Fukunaga M, Shinozaki S, Miyazawa Y, Ushigome S: Colum- pressor gene protein expression in carcinomas of the thyroid nar cell carcinoma of the thyroid. Pathol Int 47:489–492, gland. J Pathol 172:267–272, 1994. 1997. 402. Soares P, Cameselle-Teijeiro J, Sobrinho-Simoes M: Immu- 426. Putti TC, Bhuiya TA, Wasserman PG: Fine needle aspiration nohistochemical detection of p53 in differentiated, poorly cytology of mixed tall and columnar cell papillary carcinoma differentiated and undifferentiated carcinomas of the thy- of the thyroid. A case report. Acta Cytol 42:387–390, 1998. roid. Histopathology 24:205–210, 1994. 427. Smith AE, Couch M, Argani P: Pathologic quiz case 1. Papil- 403. Dobashi Y, Sugimura H, Sakamoto A, et al: Stepwise partici- lary thyroid carcinoma (PTC), combined tall cell and colum- pation of p53 gene mutation during dedifferentiation of hu- nar variants. Arch Otolaryngol Head Neck Surg 124:1170, man thyroid carcinomas. Diagn Mol Pathol 3:9–14, 1994. 1172, 1998. 404. Pollina L, Pacini F, Fontanini G, et al: bcl-2, p53 and prolifer- 428. Franssila KO, Harach HR, Wasenius VM: Mucoepidermoid ating cell nuclear antigen expression is related to the degree carcinoma of the thyroid. Histopathology 8:847–860, 1984. of differentiation in thyroid carcinomas. Br J Cancer 73:139– 429. Katoh R, Sugai T, Ono S, et al: Mucoepidermoid carcinoma 143, 1996. of the thyroid gland. Cancer 65:2020–2027, 1990. 405. Garcia-Rostan G, Tallini G, Herrero A, et al: Frequent muta- 430. Rhatigan RM, Roque JL, Bucher RL: Mucoepidermoid carci- tion and nuclear localization of beta-catenin in anaplastic noma of the thyroid gland. Cancer 39:210–214, 1977. thyroid carcinoma. Cancer Res 59:1811–1815, 1999. 431. Mizukami Y, Matsubara F, Hashimoto T, et al: Primary mu- 406. Sherman SI: Anaplastic carcinoma: prognosis. In Wartofsky L coepidermoid carcinoma in the thyroid gland. A case report (ed): Thyroid Cancer, A Comprehrensisve Guide to Clinical including an ultrastructural and biochemical study. Cancer Management. Totowa, NJ, Humana Press, 2000, pp 345–348. 53:1741–1745, 1984. 407. Kobayashi T, Asakawa H, Umeshita K, et al: Treatment of 37 432. Harach HR, Day ES, de Strizic NA: Mucoepidermoid carci- patients with anaplastic carcinoma of the thyroid. Head noma of the thyroid. Report of a case with immunohisto- Neck 18:36–41, 1996. chemical studies. Medicina (B Aires) 46:213–216, 1986. 408. Passler C, Scheuba C, Prager G, et al: Anaplastic (undifferen- 433. Tanda F, Massarelli G, Bosincu L, et al: Primary mucoepider- tiated) thyroid carcinoma (ATC). A retrospective analysis. moid carcinoma of the thyroid gland. Surg Pathol 3:317–324, Langenbecks Arch Surg 384:284–293, 1999. 1990. 409. Lu WT, Lin JD, Huang HS, Chao TC: Does surgery improve 434. Bondeson L, Bondeson AG, Thompson NW: Papillary carci- the survival of patients with advanced anaplastic thyroid noma of the thyroid with mucoepidermoid features. Am J carcinoma? Otolaryngol Head Neck Surg 118:728–731, 1998. Clin Pathol 95:175–179, 1991. 410. Nel CJ, van Heerden JA, Goellner JR, et al: Anaplastic carci- 435. Sambade C, Franssila K, Basilio-de-Oliveirz C: Mucoepider- noma of the thyroid: a clinicopathologic study of 82 cases. moid carcinoma of the thyroid revisited. Surg Pathol 3:271– short Mayo Clin Proc 60:51–58, 1985. 280, 1990. standard long

88 Endocrine System top of RH

436. Wenig BM, Adair CF, Heffess CS: Primary mucoepidermoid 456. Rosenberg-Bourgin M, Gardet P, de Sahb R, et al: Compari- carcinoma of the thyroid gland: a report of six cases and a son of sporadic and hereditary forms of medullary thyroid review of the literature of a follicular epithelial-derived tu- carcinoma. Henry Ford Hospital J 37:141–143, 1989. mor. Hum Pathol 26:1099–1108, 1995. 457. Donovan DT, Levy ML, Frust EJ: Familial cutaneous lichen 437. Arezzo A, Patetta R, Ceppa P, et al: Mucoepidermoid carci- amyloidosis in association with MEN2A: a new variant. noma of the thyroid gland arising from a papillary epithelial Henry Ford Hospital J 37:147–150, 1989. neoplasm. Am Surg 64:307–311, 1998. 458. Sobol H, Narod SA, Schuffenecker I, et al: Hereditary medul- 438. Viciana MJ, Galera-Davidson H, Martin-Lacave I, et al: Papil- lary thyroid carcinoma: genetic analysis of three related syn- lary carcinoma of the thyroid with mucoepidermoid differ- dromes. Henry Ford Hospital J 37:109–111, 1989. entiation. Arch Pathol Lab Med 120:397–398, 1996. 459. Farndon JR, Leight GS, Dilley WG: Familial medullary thy- 439. Miranda RN, Myint MA, Gnepp DR: Composite follicular roid carcinoma without associated endocrinopathies: a dis- variant of papillary carcinoma and mucoepidermoid carci- tinct clinical entity. Br J Surg 73:278–281, 1986. noma of the thyroid. Report of a case and review of the 460. Wolfe HJ, DeLellis RA: Familial medullary thyroid carci- literature. Am J Surg Pathol 19:1209–1215, 1995. noma and C cell hyperplasia. Clin Endocrinol Metab 10:351– 440. Cameselle-Teijeiro J, Febles-Perez C, Sobrinho-Simoes M: 365, 1981. Papillary and mucoepidermoid carcinoma of the thyroid 461. Carney JA, Sizemore GW, Hayles AV: C-cell disease of the with anaplastic transformation: a case report with histologic thyroid gland in multiple endocrine neoplasia, type 2b. Can- and immunohistochemical findings that support a provoca- cer 44:2173–2183, 1979. tive histogenetic hypothesis. Pathol Res Pract 191:1214–1221, 462. Mulligan LM, Kwok JB, Healey CS, et al: Germ-line muta- 1995. tions of the RET proto-oncogene in multiple endocrine neo- 441. Cameselle-Teijeiro J, Febles-Perez C, Sobrinho-Simoes M: Cy- plasia type 2A. Nature 363:458–460, 1993. tologic features of fine needle aspirates of papillary and mu- 463. Mulligan LM, Eng C, Healey CS, et al: Specific mutations of coepidermoid carcinoma of the thyroid with anaplastic trans- the RET proto-oncogene are related to disease phenotype in formation. A case report. Acta Cytol 41:1356–1360, 1997. MEN 2A and FMTC. Nat Genet 6:70–74, 1994. 441a. Baloch ZW, Solomon AC, LiVolsi VA: Primary mucoepider- 464. Hofstra RM, Landsvater RM, Ceccherini I, et al: A mutation moid carcinoma and sclerosing mucoepidermoid carcinoma in the RET proto-oncogene associated with multiple endo- with eosinophilia of the thyroid gland: a report of nine crine neoplasia type 2B and sporadic medullary thyroid car- cases. Mod Pathol 13:802–807, 2000. cinoma [see comments]. Nature 367:375–376, 1994. 442. Harach HR: A study on the relationship between solid cell 465. Chong GC, Beahrs OH, Sizemore GW, Woolner LH: Medul- nests and mucoepidermoid carcinoma of the thyroid. Histo- lary carcinoma of the thyroid gland. Cancer 35:695–704, pathology 9:195–207, 1985. 1975. 443. Chan JK, Albores-Saavedra J, Battifora H, et al: Sclerosing 466. Mure A, Gicquel C, Abdelmoumene N, et al: Cushing’s syn- mucoepidermoid thyroid carcinoma with eosinophilia. A dis- drome in medullary thyroid carcinoma. J Endocrinol Invest tinctive low-grade malignancy arising from the metaplastic 18:180–185, 1995. follicles of Hashimoto’s thyroiditis. Am J Surg Pathol 15:438– 467. Modigliani E: Medullary thyroid carcinoma. Curr Ther En- 448, 1991. docrinol Metab 5:112–117, 1994. 444. Sim SJ, Ro JY, Ordonez NG, et al: Sclerosing mucoepider- 468. Henry JF, Denizot A, Puccini M, et al: Latent subclinical moid carcinoma with eosinophilia of the thyroid: report of medullary thyroid carcinoma: diagnosis and treatment. two patients, one with distant metastasis, and review of the World J Surg 22:752–756, discussion 756–757, 1998. literature. Hum Pathol 28:1091–1096, 1997. 469. Rieu M, Lame MC, Richard A, et al: Prevalence of sporadic 445. Geisinger KR, Steffee CH, McGee RS, et al: The cytomorpho- medullary thyroid carcinoma: the importance of routine logic features of sclerosing mucoepidermoid carcinoma measurement of serum calcitonin in the diagnostic evalua- of the thyroid gland with eosinophilia. Am J Clin Pathol tion of thyroid nodules [see comments]. Clin Endocrinol 109:294–301, 1998. (Oxf) 42:453–460, 1995. 446. Chung J, Lee SK, Gong G, et al: Sclerosing mucoepidermoid 470. Kaserer K, Scheuba C, Neuhold N, et al: C-cell hyperplasia carcinoma with eosinophilia of the thyroid glands: a case and medullary thyroid carcinoma in patients routinely report with clinical manifestation of recurrent neck mass. J screened for serum calcitonin. Am J Surg Pathol 22:722–728, Korean Med Sci 14:338–341, 1999. 1998. 447. Cavazza A, Toschi E, Valcavi R, et al: Sclerosing mucoepi- 471. Kakudo K, Carney JA, Sizemore GW: Medullary carcinoma dermoid carcinoma with eosinophilia of the thyroid: descrip- of thyroid. Biologic behavior of the sporadic and familial tion of a case. Pathologica 91:31–35, 1999. neoplasm. Cancer 55:2818–2821, 1985. 448. Diaz-Perez R, Quiroz H, Nishiyama RH: Primary mucinous 472. Carney JA, Sizemore GW, Hayles AB: Multiple endocrine adenocarcinoma of thyroid gland. Cancer 38:1323–1325, neoplasia, type 2b. Pathobiol Annu 8:105–153, 1978. 1976. 473. Kebebew E, Ituarte PH, Siperstein AE, et al: Medullary 449. Sobrinho-Simoes M, Stenwig AE, Nesland JM, et al: A muci- thyroid carcinoma: clinical characteristics, treatment, prog- nous carcinoma of the thyroid. Pathol Res Pract 181:464–471, nostic factors, and a comparison of staging systems. Cancer 1986. 88:1139–1148, 2000. 450. Sobrinho-Simoes MA, Nesland JM, Johannessen JV: A mu- 474. Bigner SH, Cox EB, Mendelsohn G, et al: Medullary carci- cin-producing tumor in the thyroid gland. Ultrastruct Pathol noma of the thyroid in the multiple endocrine neoplasia IIA 9:277–281, 1985. syndrome. Am J Surg Pathol 5:459–472, 1981. 451. Cruz MC, Marques LP, Sambade CC, et al: Primary mucinous carcinoma of the thyroid gland. Surg Pathol 4:266–273, 475. Ibanez ML: Medullary carcinoma of the thyroid gland. 1991. Pathol Annu 9:263–290, 1974. 452. Williams ED: Histogenesis of medullary carcinoma of the 476. Albores-Saavedra J, LiVolsi VA, Williams ED: Medullary car- thyroid. J Clin Pathol 19:114–118, 1966. cinoma. Semin Diagn Pathol 2:137–146, 1985. 453. Raue F, Kotzerke J, Reinwein D, et al: Prognostic factors in 477. Hazard JB: The C cells (parafollicular cells) of the thyroid medullary thyroid carcinoma: evaluation of 741 patients gland and medullary thyroid carcinoma. A review. Am J from the German Medullary Thyroid Carcinoma Register. Pathol 88:213–250, 1977. Clin Invest 71:7–12, 1993. 478. Uribe M, Fenoglio-Preiser CM, Grimes M, Feind C: Medul- 454. Williams ED: Medullary carcinoma of the thyroid. In De- lary carcinoma of the thyroid gland. Clinical, pathological, Groot LJ (ed): Endocrinology. New York, Grune & Stratton, and immunohistochemical features with review of the litera- 1979, pp 777–792. ture. Am J Surg Pathol 9:577–594, 1985. 455. Saad MF, Ordonez NG, Rashid RK, et al: Medullary carci- 479. Zaatari GS, Saigo PE, Huvos AG: Mucin production in med- noma of the thyroid. A study of the clinical features and ullary carcinoma of the thyroid. Arch Pathol Lab Med prognostic factors in 161 patients. Medicine (Baltimore) 107:70–74, 1983. short 63:319–342, 1984. 480. Krueger JE, Maitra A, Albores-Saavedra J: Inherited medul- standard long

Thyroid and Parathyroid 89 top of RH

lary microcarcinoma of the thyroid: a study of 11 cases. Am for differentiation between familial and sporadic medullary J Surg Pathol 24:853–858, 2000. thyroid carcinoma. Dan Med Bull 30:353–356, 1983. 481. Harach HR, Williams ED: Glandular (tubular and follicular) 505. Albores-Saavedra J, Monforte H, Nadji M, Morales AR: variants of medullary carcinoma of the thyroid. Histopathol- C-cell hyperplasia in thyroid tissue adjacent to follicular cell ogy 7:83–97, 1983. tumors. Hum Pathol 19:795–799, 1988. 482. Sambade C, Baldaque-Faria A, Cardoso-Oliveira M, Sob- 506. Santensanio G, Iafrate E, Partenzi A, et al: A critical reassess- rinho-Simoes M: Follicular and papillary variants of medul- ment of the concept of C-cell hyperplasia of the thyroid—a lary carcinoma of the thyroid. Pathol Res Pract 184:98–107, quantitative immunohistochemical study. Appl Immunohis- 1988. tochem 5:160–172, 1997. 483. Dominguez-Malagon H, Delgado-Chavez R, Torres-Najera 507. DeLellis RA, Wolfe HJ: The pathobiology of the human calci- M, et al: Oxyphil and squamous variants of medullary thy- tonin (C)–cell: a review. Pathol Annu 16:25–52, 1981. roid carcinoma. Cancer 63:1183–1188, 1989. 508. Chan JKC, Tse CCH: Solid cell nest-associated C-cells: an- 484. Harach HR, Bergholm U: Medullary (C cell) carcinoma of other possible explanation for “C-cell hyperplasia” adjacent the thyroid with features of follicular oxyphilic cell tumours. to follicular cell tumors (letter). Hum Pathol 10:498, 1989. Histopathology 13:645–656, 1988. 509. Baschieri L, Castagna M, Fierabracci A, et al: Distribution of 485. Kakudo K, Miyauchi A, Ogihara T, et al: Medullary carci- calcitonin- and somatostatin-containing cells in thyroid lym- noma of the thyroid. Giant cell type. Arch Pathol Lab Med phoma and in Hashimoto’s thyroiditis. Appl Pathol 7:99– 102:445–447, 1978. 104, 1989. 486. Mendelsohn G, Baylin SB, Bigner SH, et al: Anaplastic vari- 510. Perry A, Molberg K, Albores-Saavedra J: Physiologic versus ants of medullary thyroid carcinoma: a light-microscopic and neoplastic C-cell hyperplasia of the thyroid: separation of immunohistochemical study. Am J Surg Pathol 4:333–341, distinct histologic and biologic entities. Cancer 77:750–756, 1980. 1996. 487. Bussolati G, Monga G: Medullary carcinoma of the thyroid 511. Komminoth P: The RET proto-oncogene in medullary and with atypical patterns. Cancer 44:1769–1777, 1979. papillary thyroid carcinoma. Molecular features, pathophysi- 488. Landon G, Ordonez NG: Clear cell variant of medullary ology and clinical implications. Virchows Arch 431:1–9, carcinoma of the thyroid. Hum Pathol 16:844–847, 1985. 1997. 489. Holm R, Sobrinho-Simoes M, Nesland JM, et al: Medullary 512. Lloyd RV: RET proto-oncogene mutations and rearrange- carcinoma of the thyroid gland: an immunocytochemical ments in endocrine diseases. Am J Pathol 147:1539–1544, study. Ultrastruct Pathol 8:25–41, 1985. 1995. 490. Marcus JN, Dise CA, LiVolsi VA: Melanin production in a 513. Mulligan LM, Marsh DJ, Robinson BG, et al: Genotype- medullary thyroid carcinoma. Cancer 49:2518–2526, 1982. phenotype correlation in multiple endocrine neoplasia type 491. Beerman H, Rigaud C, Bogomoletz WV, et al: Melanin pro- 2: report of the International RET Mutation Consortium. J duction in black medullary thyroid carcinoma (MTC). Histo- Intern Med 238:343–346, 1995. pathology 16:227–233, 1990. 514. Komminoth P, Kunz EK, Matias-Guiu X, et al: Analysis of 492. Ikeda T, Satoh M, Azuma K, et al: Medullary thyroid carci- RET protooncogene point mutations distinguishes heritable noma with a paraganglioma-like pattern and melanin pro- from nonheritable medullary thyroid carcinomas. Cancer duction: a case report with ultrastructural and immunohisto- 76:479–489, 1995. chemical studies. Arch Pathol Lab Med 122:555–558, 1998. 515. Eng C, Mulligan LM: Mutations of the RET protooncogene 493. Schroder S, Bocker W, Baisch H, et al: Prognostic factors in in the multiple endocrine neoplasia type 2 syndromes, re- medullary thyroid carcinomas. Survival in relation to age, lated sporadic tumors, and Hirschsprung disease. Hum Mu- sex, stage, histology, immunocytochemistry, and DNA con- tat 9:97–109, 1997. tent. Cancer 61:806–816, 1988. 516. Lallier M, St-Vil D, Giroux M, et al: Prophylactic thyroidec- 494. Kakudo K, Miyauchi A, Takai S, et al: C cell carcinoma of tomy for medullary thyroid carcinoma in gene carriers of the thyroid—papillary type. Acta Pathol Jpn 29:653–659, MEN2 syndrome. J Pediatr Surg 33:846–848, 1998. 1979. 517. Hinze R, Holzhausen HJ, Gimm O, et al: Primary hereditary 495. Harach HR, Bergholm U: Small cell variant of medullary medullary thyroid carcinoma—C-cell morphology and corre- carcinoma of the thyroid with neuroblastoma-like features. lation with preoperative calcitonin levels. Virchows Arch Histopathology 21:378–380, 1992. 433:203–208, 1998. 496. Huss LJ, Mendelsohn G: Medullary carcinoma of the thyroid 518. Dralle H, Gimm O, Simon D, et al: Prophylactic thyroidec- gland: an encapsulated variant resembling the hyalinizing tomy in 75 children and adolescents with hereditary medul- trabecular (paraganglioma-like) adenoma of thyroid. Mod lary thyroid carcinoma: German and Austrian experience. Pathol 3:581–585, 1990. World J Surg 22:744–750, discussion 750–751, 1998. 497. Harach HR, Bergholm U: Medullary carcinoma of the thy- 519. Eng C, Mulligan LM, Smith DP, et al: Mutation of the RET roid with carcinoid-like features. J Clin Pathol 46:113–117, protooncogene in sporadic medullary thyroid carcinoma. 1993. Genes Chromosomes Cancer 12:209–212, 1995. 498. Butler M, Khan S: Immunoreactive calcitonin in amyloid fi- 520. Bugalho MJ, Frade JP, Santos JR, et al: Molecular analysis of brils of medullary carcinoma of the thyroid gland. An im- the RET proto-oncogene in patients with sporadic medullary munogold staining technique. Arch Pathol Lab Med 110:647– thyroid carcinoma: a novel point mutation in the extracellu- 649, 1986. lar cysteine-rich domain. Eur J Endocrinol 136:423–426, 1997. 499. Krisch K, Krisch I, Horvat G, et al: The value of immunohistochemistry in medullary thyroid carcinoma: a systematic 521. Romei C, Elisei R, Pinchera A, et al: Somatic mutations of study of 30 cases. Histopathology 9:1077–1089, 1985. the ret protooncogene in sporadic medullary thyroid carci- 500. Schmid KW, Fischer-Colbrie R, Hagn C, et al: Chromogranin noma are not restricted to exon 16 and are associated with A and B and secretogranin II in medullary carcinomas of the tumor recurrence. J Clin Endocrinol Metab 81:1619–1622, thyroid. Am J Surg Pathol 11:551–556, 1987. 1996. 501. Lloyd RV, Sisson JC, Marangos PJ: Calcitonin, carcinoembry- 522. Marsh DJ, Learoyd DL, Andrew SD, et al: Somatic mutations onic antigen and neuron-specific enolase in medullary thy- in the RET proto-oncogene in sporadic medullary thyroid roid carcinoma. Cancer 51:2234–2239, 1983. carcinoma. Clin Endocrinol (Oxf) 44:249–257, 1996. 502. Schroder S, Kloppel G: Carcinoembryonic antigen and non- 523. Matias-Guiu X, LaGuette J, Puras-Gil AM, Rosai J: Metastatic specific cross-reacting antigen in thyroid cancer. An immu- neuroendocrine tumors to the thyroid gland mimicking med- nocytochemical study using polyclonal and monoclonal anti- ullary carcinoma: a pathologic and immunohistochemical bodies. Am J Surg Pathol 11:100–108, 1987. study of six cases. Am J Surg Pathol 21:754–762, 1997. 503. Matias-Guiu X, Machin P, Pons C, et al: Sustentacular cells 524. Girelli ME, Nacamulli D, Pelizzo MR, et al: Medullary thy- occur frequently in the familial form of medullary thyroid roid carcinoma: clinical features and long-term follow-up of carcinoma. J Pathol 184:420–423, 1998. seventy-eight patients treated between 1969 and 1986. Thy- short 504. Emmertsen K, Ernø H, Henriques U, Schrøder HD: C-cells roid 8:517–523, 1998. standard long

90 Endocrine System top of RH

525. Modigliani E, Cohen R, Campos JM, et al: Prognostic factors cinoma, an occult papillary carcinoma and a medullary car- for survival and for biochemical cure in medullary thyroid cinoma in the same patient. Histopathology 21:380–382, carcinoma: results in 899 patients. The GETC Study Group. 1992. Groupe d’etude des tumeurs a calcitonine. Clin Endocrinol 546. Sobrinho-Simoes M: Mixed medullary and follicular carci- (Oxf) 48:265–273, 1998. noma of the thyroid. Histopathology 23:287–289, 1993. 526. Scopsi L, Sampietro G, Boracchi P, et al: Multivariate analy- 547. Pfaltz M, Hedinger CE, Muhlethaler JP: Mixed medullary sis of prognostic factors in sporadic medullary carcinoma of and follicular carcinoma of the thyroid. Virchows Arch A the thyroid. A retrospective study of 109 consecutive pa- Pathol Anat Histopathol 400:53–59, 1983. tients. Cancer 78:2173–2183, 1996. 548. Parker LN, Kollin J, Wu SY, et al: Carcinoma of the thyroid 527. Bergholm U, Bergstrom R, Ekbom A: Long-term follow-up of with a mixed medullary, papillary, follicular, and undifferen- patients with medullary carcinoma of the thyroid. Cancer tiated pattern. Arch Intern Med 145:1507–1509, 1985. 79:132–138, 1997. 549. Apel RL, Alpert LC, Rizzo A, et al: A metastasizing compos- 528. Rossi RL, Cady B, Meissner WA, et al: Nonfamilial medul- ite carcinoma of the thyroid with distinct medullary and lary thyroid carcinoma. Am J Surg 139:554–560, 1980. papillary components. Arch Pathol Lab Med 118:1143–1147, 529. Fuchshuber PR, Loree TR, Hicks WL Jr, et al: Medullary 1994. carcinoma of the thyroid: prognostic factors and treatment 550. Lax SF, Beham A, Kronberger-Schonecker D, et al: Coexis- recommendations. Ann Surg Oncol 5:81–86, 1998. tence of papillary and medullary carcinoma of the thyroid 530. Brierley J, Tsang R, Simpson WJ, et al: Medullary thyroid gland—mixed or collision tumour? Clinicopathological anal- cancer: analyses of survival and prognostic factors and the ysis of three cases. Virchows Arch 424:441–447, 1994. role of radiation therapy in local control. Thyroid 6:305–310, 551. Albores-Saavedra J, Gorraez de la Mora T, de la Torre-Ren- 1996. don F, Gould E: Mixed medullary-papillary carcinoma of the 531. Norton JA, Froome LC, Farrell RE, et al: Multiple endocrine thyroid: a previously unrecognized variant of thyroid carci- neoplasia type IIb: the most aggressive form of medullary noma. Hum Pathol 21:1151–1155, 1990. thyroid carcinoma. Surg Clin North Am 59:109–118, 1979. 552. Pastolero GC, Coire CI, Asa SL: Concurrent medullary and 532. Guyetant S, Dupre F, Bigorgne JC, et al: Medullary thyroid papillary carcinomas of thyroid with lymph node metastases. microcarcinoma: a clinicopathologic retrospective study of 38 A collision phenomenon. Am J Surg Pathol 20:245–250, 1996. patients with no prior familial disease. Hum Pathol 30:957– 553. Ljungberg O: Biopsy Pathology of the Thyroid and Parathy- 963, 1999. roid. London, Chapman & Hall, 1992. 533. Williams ED, Brown CL, Doniach I: Pathological and clinical 554. Burt AD, MacGuire J, Lindop GB, et al: Mixed follicular- ﬁndings in a series of 67 cases of medullary carcinoma of the parafollicular carcinoma of the thyroid. Scott Med J 32:50– thyroid. J Clin Pathol 19:103–113, 1966. 51, 1987. 534. Ruppert JM, Eggleston JC, deBustros A, Baylin SB: Dissemi- 555. Papotti M, Negro F, Carney JA, et al: Mixed medullary- nated calcitonin-poor medullary thyroid carcinoma in a pa- follicular carcinoma of the thyroid. A morphological, immu- tient with calcitonin-rich primary tumor. Am J Surg Pathol nohistochemical and in situ hybridization analysis of 11 10:513–518, 1986. cases. Virchows Arch 430:397–405, 1997. 535. Saad MF, Ordonez NG, Guido JJ, Samaan NA: The prognos- 556. Papotti M, Volante M, Komminoth P, et al: Thyroid carcino- tic value of calcitonin immunostaining in medullary carci- mas with mixed follicular and C-cell differentiation patterns. noma of the thyroid. J Clin Endocrinol Metab 59:850–856, Semin Diagn Pathol 17:109–119, 2000. 1984. 557. Ljungberg O, Ericsson UB, Bondeson L, Thorell J: A com- 536. Mendelsohn G, Wells SA Jr, Baylin SB: Relationship of tissue pound follicular-parafollicular cell carcinoma of the thyroid: carcinoembryonic antigen and calcitonin to tumor virulence a new tumor entity? Cancer 52:1053–1061, 1983. in medullary thyroid carcinoma. An immunohistochemical 558. Ljungberg O, Bondeson L, Bondeson AG: Differentiated thy- study in early, localized, and virulent disseminated stages of roid carcinoma, intermediate type: a new tumor entity with disease. Cancer 54:657–662, 1984. features of follicular and parafollicular cell carcinoma. Hum 537. Schroder S, Schwarz W, Rehpenning W, et al: Leu-M1 im- Pathol 15:218–228, 1984. munoreactivity and prognosis in medullary carcinomas of 559. Mizukami Y, Nonomura A, Michigishi T, et al: Mixed med- the thyroid gland. J Cancer Res Clin Oncol 114:291–296, ullary-follicular carcinoma of the thyroid gland: a clinico- 1988. pathologic variant of medullary thyroid carcinoma. Mod 538. Langle F, Soliman T, Neuhold N, et al: CD15 (LeuM1) im- Pathol 9:631–635, 1996. munoreactivity: prognostic factor for sporadic and hereditary 560. Volante M, Papotti M, Roth J, et al: Mixed medullary-follicu- medullary thyroid cancer? Study Group on Multiple Endo- lar thyroid carcinoma. Molecular evidence for a dual origin crine Neoplasia of Austria. World J Surg 18:583–587, 1994. of tumor components. Am J Pathol 155:1499–1509, 1999. 539. Viale G, Roncalli M, Grimelius L, et al: Prognostic value of 561. Holm R, Sobrinho-Simoes M, Nesland JM, et al: Medullary bcl-2 immunoreactivity in medullary thyroid carcinoma. thyroid carcinoma with thyroglobulin immunoreactivity. A Hum Pathol 26:945–950, 1995. special entity? Lab Invest 57:258–268, 1987. 540. Scopsi L, Sampietro G, Boracchi P, Collini P: Argyrophilia 562. Chan JK, Rosai J: Tumors of the neck showing thymic or and chromogranin A and B immunostaining in patients with related branchial pouch differentiation: a unifying concept. sporadic medullary thyroid carcinoma. A critical appraisal of Hum Pathol 22:349–367, 1991. their prognostic utility. J Pathol 184:414–419, 1998. 563. Lewis JE, Wick MR, Scheithauer BW, et al: Thymoma, a 541. Roncalli M, Viale G, Grimelius L, et al: Prognostic value of clinicopathologic review. Cancer 60:2727–2743, 1987. N-myc immunoreactivity in medullary thyroid carcinoma. 564. Murao T, Nakanishi M, Toda K, et al: Malignant teratoma of Cancer 74:134–141, 1994. the thyroid gland in an adolescent female. Acta Pathol Jpn 542. Fontanini G, Vignati S, Pacini F, et al: Microvessel count: an 29:109–117, 1979. indicator of poor outcome in medullary thyroid carcinoma 565. Levey M: An unusual thyroid tumor in a child. Laryngo- but not in other types of thyroid carcinoma. Mod Pathol scope 86:1864–1868, 1976. 9:636–641, 1996. 566. Weigensberg C, Dalsley H, Asa SL, et al: Thyroid thymoma 543. el-Naggar AK, Ordonez NG, McLemore D, et al: Clinico- in childhood. Endocrinol Pathol 1:123–127, 1990. pathologic and ﬂow cytometric DNA study of medullary 567. Harach HR, Saravia Day E, Franssila KO: Thyroid spindle- thyroid carcinoma. Surgery 108:981–985, 1990. cell tumor with mucous cysts. An intrathyroid thymoma? 544. Ekman ET, Bergholm U, Backdahl M, et al: Nuclear DNA Am J Surg Pathol 9:525–530, 1985. content and survival in medullary thyroid carcinoma. Swed- 568. Kingsley DPE, Elton A, Bennett MH: Malignant teratoma of ish Medullary Thyroid Cancer Study Group. Cancer 65:511– the thyroid, case report and a review of the literature. Br J 517, 1990. Cancer 22:7–11, 1968. 545. Gonzalez-Campora R, Lopez-Garrido J, Martin-Lacave I, et 569. Hofman P, Mainguene C, Michiels JF, et al: Thyroid spindle short al: Concurrence of a symptomatic encapsulated follicular car- epithelial tumor with thymus-like differentiation (the “SET- standard long

Thyroid and Parathyroid 91 top of RH

TLE” tumor). An immunohistochemical and electron micro- phoproliferative disorders of the thyroid gland. A clinico- scopic study. Eur Arch Otorhinolaryngol 252:316–320, 1995. pathologic study of 245 cases. Am J Clin Pathol 74:1–11, 570. Saw D, Wu D, Chess Q, Shemen L: Spindle epithelial tumor 1980. with thymus-like element (SETTLE), a primary thyroid tu- 593. Devine RM, Edis AJ, Banks PM: Primary lymphoma of the mor. Int J Surg Pathol 4:169–174, 1997. thyroid: a review of the Mayo Clinic experience through 571. Chetty R, Goetsch S, Nayler S, Cooper K: Spindle epithelial 1978. World J Surg 5:33–38, 1981. tumour with thymus-like element (SETTLE): the predomi- 594. Rasbach DA, Mondschein MS, Harris NL, et al: Malignant nantly monophasic variant. Histopathology 33:71–74, 1998. lymphoma of the thyroid gland: a clinical and pathologic 572. Kirby PA, Ellison WA, Thomas PA: Spindle epithelial tumor study of twenty cases. Surgery 98:1166–1170, 1985. with thymus-like differentiation (SETTLE) of the thyroid 595. Woolner LB, McConahey WM, Beahrs OH, Black BM: Pri- with prominent mitotic activity and focal necrosis. Am J mary malignant lymphoma of the thyroid. Review of forty- Surg Pathol 23:712–716, 1999. six cases. Am J Surg 111:502–523, 1966. 573. Asa SL, Dardick I, Van Nostrand AW, et al: Primary thyroid 596. Singer JA: Primary lymphoma of the thyroid. Am Surg thymoma: a distinct clinicopathologic entity. Hum Pathol 64:334–337, 1998. 19:1463–1467, 1988. 597. Pledge S, Bessell EM, Leach IH, et al: Non-Hodgkin’s lym- 574. Kakudo K, Mori I, Tamaoki N, Watanabe K: Carcinoma of phoma of the thyroid: a retrospective review of all patients possible thymic origin presenting as a thyroid mass: a new diagnosed in Nottinghamshire from 1973 to 1992. Clin Oncol subgroup of squamous cell carcinoma of the thyroid. J Surg 8:371–375, 1996. Oncol 38:187–192, 1988. 598. Hamburger JI, Miller JM, Kini SR: Lymphoma of the thyroid. 575. Miyauchi A, Kuma K, Matsuzuka F, et al: Intrathyroidal Ann Intern Med 99:685–693, 1983. epithelial thymoma: an entity distinct from squamous cell 599. Derringer GA, Thompson LD, Frommelt RA, et al: Malignant carcinoma of the thyroid. World J Surg 9:128–135, 1985. lymphoma of the thyroid gland: a clinicopathologic study of 576. Miyauchi A, Ishikawa H, Maedea M: Intrathyroid epithelial 108 cases. Am J Surg Pathol 24:623–639, 2000. thymoma: a report of six cases with immunohistochemical 600. Thompson LD, Rosai J, Heffess CS: Primary thyroid terato- and ultrastructural studies [in Japanese]. Endocrinol Surg mas: a clinicopathologic study of 30 cases. Cancer 88:1149– 6:289–295, 1989. 1158, 2000. 577. Mizukami Y, Kurumaya H, Yamada T, et al: Thymic carci- 601. Luboshitzky R, Dharan M, Nachtigal D, et al: Syncytial vari- noma involving the thyroid gland: report of two cases. Hum ant of nodular sclerosing Hodgkin’s disease presenting as a Pathol 26:576–579, 1995. thyroid nodule. A case report. Acta Cytol 39:543–546, 1995. 578. Watanabe I, Tezuka F, Yamaguchi M, et al: Thymic carci- 602. Aozasa K, Inoue A, Yoshimura H, et al: Intermediate lym- noma of the thyroid. Pathol Int 46:450–456, 1996. phocytic lymphoma of the thyroid. An immunologic and 579. Attaran SY, Omrani GH, Tavangar SM: Lymphoepithelial- immunohistologic study. Cancer 57:1762–1767, 1986. like intrathyroidal thymic carcinoma with foci of squamous 603. Coltrera MD: Primary T-cell lymphoma of the thyroid. Head differentiation. Case report. APMIS 104:419–423, 1996. Neck 21:160–163, 1999. 580. Damiani S, Filotico M, Eusebi V: Carcinoma of the thyroid 604. Abdul-Rahman ZH, Gogas HJ, Tooze JA, et al: T-cell lym- showing thymoma-like features. Virchows Arch A Pathol phoma in Hashimoto’s thyroiditis. Histopathology 29:455– Anat Histopathol 418:463–466, 1991. 459, 1996. 581. Cheuk W, Jacobson AA, Chan JKC: Spindle epithelial tumor 605. Yamaguchi M, Ohno T, Kita K: Gamma/delta T-cell lym- with thymus-like element: a distinctive malignant thyroid phoma of the thyroid gland (letter). N Engl J Med 336:1391– tumor with significant metastatic potential. Mod Pathol 13: 1392, 1997. 1150–1155, 2000. 606. Shanks JH, Harris M, Howat AJ, Freemont AJ: Angiotropic 582. Dorfman DM, Shahsafaei A, Miyauchi A: Intrathyroidal epi- lymphoma with endocrine involvement. Histopathology thelial thymoma (ITET)/carcinoma showing thymus-like dif- 31:161–166, 1997. ferentiation (CASTLE) exhibits CD5 immunoreactivity: new 607. Isaacson PG: Lymphomas of mucosa-associated lymphoid evidence for thymic differentiation. Histopathology 32:104– tissue (MALT). Histopathology 16:617–619, 1990. 109, 1998. 608. Hyjek E, Isaacson PG: Primary B cell lymphoma of the thy- 583. Berezowski K, Grimes MM, Gal A, Kornstein MJ: CD5 im- roid and its relationship to Hashimoto’s thyroiditis. Hum munoreactivity of epithelial cells in thymic carcinoma and Pathol 19:1315–1326, 1988. CASTLE using paraffin-embedded tissue. Am J Clin Pathol 609. Isaacson PG, Androulakis-Papachristou A, Diss TC, et al: 106:483–486, 1996. Follicular colonization in thyroid lymphoma. Am J Pathol 584. Tse LLY, Shek TWH, Lam KY, et al: Carcinoma showing 141:43–52, 1992. thymus-like differentiation (CASTLE) of the thyroid: an in- 610. Mizukami Y, Michigishi T, Nonomura A, et al: Primary lym- trathyroid thymic carcinoma (abstract). Int J Surg Pathol phoma of the thyroid: a clinical, histological and immunohistochemical study of 20 cases. Histopathology 17:201–209, (in press). 1990. 585. Choi P, To KF, Lai FM, et al: Follicular dendritic cell tumor 611. Rosen IB, Sutcliffe SB, Gospodarowicz MK, et al: The role of of the neck: a report of two cases complicated by pulmonary surgery in the management of thyroid lymphoma. Surgery metastasis. Cancer 89:664–672, 2000. 104:1095–1099, 1988. 586. Sawady J, Mendelsohn G, Sirota RL, Taxy JB: The intrathy- 612. Maurer R, Taylor CR, Terry R, et al: Non-Hodgkin’s lym- roidal hyperfunctioning parathyroid gland. Mod Pathol phoma of the thyroid, a clinicopathological review of 29 2:652–657, 1989. cases applying the Lukes-Collins classification and an immu- 587. de la Cruz Vigo F, Ortega G, Gonzalez S, et al: Pathologic noperoxidase method. Virchows Arch A Pathol Anat Histo- intrathyroidal parathyroid glands. Int Surg 82:87–90, 1997. pathol 383:293–317, 1979. 588. Freeman C, Berg JW, Cutler SJ: Occurrence and prognosis of 613. Bateman AC, Wright DH: Epitheliotropism in high-grade extranodal lymphomas. Cancer 29:252–260, 1972. lymphomas of mucosa-associated lymphoid tissue. Histopa- 589. Anscombe AM, Wright DH: Primary malignant lymphoma thology 23:409–415, 1993. of the thyroid—a tumour of mucosa-associated lymphoid 614. Tennvall J, Cavallin-Stahl E, Akerman M: Primary localized tissue: review of seventy-six cases. Histopathology 9:81–97, non-Hodgkin’s lymphoma of the thyroid: a retrospective 1985. clinicopathological review. Eur J Surg Oncol 13:297–302, 590. Aozasa K, Inoue A, Tajima K, et al: Malignant lymphomas 1987. of the thyroid gland. Analysis of 79 patients with emphasis 615. Stone CW, Slease RB, Brubaker D, et al: Thyroid lymphoma on histologic prognostic factors. Cancer 58:100–104, 1986. with gastrointestinal involvement: report of three cases. Am 591. Burke JS, Butler JJ, Fuller LM: Malignant lymphomas of the J Hematol 21:357–365, 1986. thyroid: a clinical pathologic study of 35 patients including 616. Pedersen RK, Pedersen NT: Primary non-Hodgkin’s lym- ultrastructural observations. Cancer 39:1587–1602, 1977. phoma of the thyroid gland: a population based study. His- short 592. Compagno J, Oertel JE: Malignant lymphoma and other lym- topathology 28:25–32, 1996. standard long

92 Endocrine System top of RH

617. Laing RW, Hoskin P, Hudson BV, et al: The significance of study of five cases of anaplastic carcinoma. Cancer 62:2558– MALT histology in thyroid lymphoma: a review of patients 2563, 1988. from the BNLI and Royal Marsden Hospital. Clin Oncol (R 642. Iida Y, Katoh R, Yoshioka M, et al: Primary leiomyosarcoma Coll Radiol) 6:300–304, 1994. of the thyroid gland. Acta Pathol Jpn 43:71–75, 1993. 618. Skacel M, Ross CW, Hsi ED: A reassessment of primary 643. Chetty R, Clark SP, Dowling JP: Leiomyosarcoma of the thy- thyroid lymphoma: high-grade MALT-type lymphoma as a roid: immunohistochemical and ultrastructural study. Pathol- distinct subtype of diffuse large B-cell lymphoma. Histopa- ogy 25:203–205, 1993. thology 37:10–18, 2000. 644. Ozaki O, Sugino K, Mimura T, et al: Primary leiomyosar- 619. Aozasa K, Inoue A, Yoshimura H, et al: Plasmacytoma of the coma of the thyroid gland. Surg Today 27:177–180, 1997. thyroid gland. Cancer 58:105–110, 1986. 645. Tulbah A, Al-Dayel F, Fawaz I, Rosai J: Epstein-Barr virus– 620. Hussong JW, Perkins SL, Schnitzer B, et al: Extramedullary associated leiomyosarcoma of the thyroid in a child with plasmacytoma. A form of marginal zone cell lymphoma? congenital immunodeficiency: a case report. Am J Surg Am J Clin Pathol 111:111–116, 1999. Pathol 23:473–476, 1999. 621. Yapp R, Linder J, Schenken JR, Karrer FW: Plasma cell gran- 646. Andrion A, Bellis D, Delsedime L, et al: Leiomyoma and uloma of the thyroid. Hum Pathol 16:848–850, 1985. neurilemoma: report of two unusual non-epithelial tumours 622. Mizukami Y, Nonomura A, Michigishi T, et al: Pseudolym- of the thyroid gland. Virchows Arch A Pathol Anat Histo- phoma of the thyroid gland. A case report. Pathol Res Pract pathol 413:367–372, 1988. 192:166–169, discussion 170–171, 1996. 647. Galati LT, Barnes EL, Myers EN: Dendritic cell sarcoma of 623. Thompson LD: Langerhans cell histiocytosis isolated to the the thyroid. Head Neck 21:273–275, 1999. thyroid gland. Eur Arch Otorhinolaryngol 253:62–65, 1996. 648. Pickleman JR, Lee JF, Straus FHd, Paloyan E: Thyroid he- 624. Thompson LDR, Wenig BM, Adair CF, Heffess CS: Periph- mangioma. Am J Surg 129:331–333, 1975. eral nerve sheath tumors of the thyroid gland, a series of 649. Andrion A, Gaglio A, Dogliani N, et al: Liposarcoma of the four cases and a review of the literature. Endocr Pathol thyroid gland. Fine-needle aspiration cytology, immunohis- 7:309–318, 1996. tology, and ultrastructure. Am J Clin Pathol 95:675–679, 625. Tsang WY, Lau MF, Chan JK: Incidental Langerhans’ cell 1991. histiocytosis of the thyroid. Histopathology 24:397–399, 1994. 650. Nielsen VT, Knudsen N, Holm IE: Liposarcoma of the thy- 626. Coode PE, Shaikh MU: Histiocytosis X of the thyroid mas- roid gland. Tumori 72:499–502, 1986. querading as thyroid carcinoma. Hum Pathol 19:239–241, 651. Tseleni-Balafouta S, Arvanitis D, Kakaviatos N, Paraske- 1988. vakou H: Primary myxoid chondrosarcoma of the thyroid 627. Wang WS, Liu JH, Chiou TJ, et al: Langerhans’ cell histiocy- gland. Arch Pathol Lab Med 112:94–96, 1988. tosis with thyroid involvement masquerading as thyroid car- 652. Nitzsche EU, Seeger LL, Klosa B, et al: Primary osteosar- cinoma. Jpn J Clin Oncol 27:180–184, 1997. coma of the thyroid gland. J Nucl Med 33:1399–1401, 1992. 628. Kitahama S, Iitaka M, Shimizu T, et al: Thyroid involvement 653. Sichel JY, Wygoda M, Dano I, et al: Fibrosarcoma of the by malignant histiocytosis of Langerhans’ cell type. Clin En- thyroid in a man exposed to fallout from the Chernobyl docrinol (Oxf) 45:357–363, 1996. accident. Ann Otol Rhinol Laryngol 105:832–834, 1996. 629. Egloff B: The hemangioendothelioma of the thyroid. Vir- 654. Berthelsen A: Fibrosarcoma in the thyroid gland: recurrence chows Arch A Pathol Anat Histopathol 400:119–142, 1983. treated with radiotherapy. J Laryngol Otol 92:933–936, 1978. 630. Maiorana A, Collina G, Cesinaro AM, et al: Epithelioid an- 655. Heffess CS, Adair FF, Wenig BM: Paragangliomas of the giosarcoma of the thyroid. Clinicopathological analysis of thyroid gland (abstract). Int J Surg Pathol 2(suppl):188, 1995. seven cases from non-Alpine areas. Virchows Arch 429:131– 656. de Vries EJ, Watson CG: Paraganglioma of the thyroid. Head 137, 1996. Neck 11:462–465, 1989. 631. Eusebi V, Carcangiu ML, Dina R, Rosai J: Keratin-positive 657. Bale GF: Teratoma of the neck in the region of the thyroid epithelioid angiosarcoma of thyroid. A report of four cases. gland, a review of the literature and report of four cases. Am J Surg Pathol 14:737–747, 1990. Am J Pathol 26:565–580, 1950. 632. Lamovec J, Zidar A, Zidanik B: Epithelioid angiosarcoma of 658. Fisher JE, Cooney DR, Voorhess ML, Jewett TC Jr: Teratoma the thyroid gland. Report of two cases. Arch Pathol Lab Med of thyroid gland in infancy: review of the literature and two 118:642–646, 1994. case reports. J Surg Oncol 21:135–140, 1982. 633. Ritter JH, Mills SE, Nappi O, Wick MR: Angiosarcoma-like 659. Kimler SC, Muth WF: Primary malignant teratoma of the neoplasms of epithelial organs: true endothelial tumors or thyroid: case report and literature review of cervical terato- variants of carcinoma? Semin Diagn Pathol 12:270–282, mas in adults. Cancer 42:311–317, 1978. 1995. 660. Hajdu SI, Hajdu EO: Malignant teratoma of the neck. Arch 634. Mills SE, Stallings RG, Austin MB: Angiomatoid carcinoma Pathol 83:567–570, 1967. of the thyroid gland. Anaplastic carcinoma with follicular 661. Bowker CM, Whittaker RS: Malignant teratoma of the thy- and medullary features mimicking angiosarcoma. Am J Clin roid: case report and literature review of thyroid teratoma in Pathol 86:674–678, 1986. adults. Histopathology 21:81–83, 1992. 635. Mills SE, Gaffey MJ, Watts JC, et al: Angiomatoid carcinoma 662. Buckley NJ, Burch WM, Leight GS: Malignant teratoma in and ’angiosarcoma’ of the thyroid gland. A spectrum of en- the thyroid gland of an adult: a case report and a review of dothelial differentiation. Am J Clin Pathol 102:322–330, the literature. Surgery 100:932–937, 1986. 1994. 663. Ueno NT, Amato RJ, Ro JJ, Weber RS: Primary malignant 636. Taccagni G, Sambade C, Nesland J, et al: Solitary fibrous teratoma of the thyroid gland: report and discussion of two tumour of the thyroid: clinicopathological, immunohisto- cases. Head Neck 20:649–653, 1998. chemical and ultrastructural study of three cases. Virchows 664. Chen JS, Lai GM, Hsueh S: Malignant thyroid teratoma of an Arch A Pathol Anat Histopathol 422:491–497, 1993. adult: a long-term survival after chemotherapy. Am J Clin 637. Cameselle-Teijeiro J, Varela-Duran J: CD34 and thyroid fi- Oncol 21:212–214, 1998. brous tumor (letter). Am J Surg Pathol 19:1096, 1995. 665. Ivy HK: Cancer metastatic to the thyroid: a diagnostic prob- 638. Cameselle-Teijeiro J, Varela-Duran J, Fonseca E, et al: Soli- lem. Mayo Clin Proc 59:856–859, 1984. tary fibrous tumor of the thyroid. Am J Clin Pathol 101:535– 666. McCabe DP, Farrar WB, Petkov TM, et al: Clinical and path- 538, 1994. ologic correlations in disease metastatic to the thyroid gland. 639. Kie JH, Kim JY, Park YN, et al: Solitary fibrous tumour of Am J Surg 150:519–523, 1985. the thyroid. Histopathology 30:365–368, 1997. 667. Lam KY, Lo CY: Metastatic tumors of the thyroid gland: a 640. Thompson LD, Wenig BM, Adair CF, et al: Primary smooth study of 79 cases in Chinese patients. Arch Pathol Lab Med muscle tumors of the thyroid gland. Cancer 79:579–587, 122:37–41, 1998. 1997. 668. Nakhjavani MK, Gharib H, Goellner JR, van Heerden JA: 641. Kawahara E, Nakanishi I, Terahata S, Ikegaki S: Leiomyosar- Metastasis to the thyroid gland. A report of 43 cases. Cancer short coma of the thyroid gland. A case report with a comparative 79:574–578, 1997. standard long

Thyroid and Parathyroid 93 top of RH

669. Shimaoka K, Sokal JE, Pickren JW: Metastatic neoplasms of thyroiditis. A clinical, histologic, and immunopathologic the thyroid. Cancer 15:557–565, 1962. study of 15 cases. Am J Clin Pathol 100:200–205, 1993. 670. Carpenter GR, Emery JL: Inclusions in the human thyroid. J 696. Roti E, Emerson CH: Clinical review 29: Postpartum thyroid- Anat 122:77–89, 1976. itis. J Clin Endocrinol Metab 74:3–5, 1992. 671. LiVolsi VA, Merino MJ: Squamous cells in the human thy- 697. Mizukami Y, Michigishi T, Hashimoto T, et al: Silent thyroid gland. Am J Surg Pathol 2:133–140, 1978. roiditis: a histologic and immunohistochemical study. Hum 672. Reid JD, Choi CH, Oldroyd NO: Calcium oxalate crystals in Pathol 19:423–431, 1988. the thyroid. Their identification, prevalence, origin, and pos- 698. Inada M, Nishikawa M, Naito K, et al: Reversible changes of sible significance. Am J Clin Pathol 87:443–454, 1987. the histological abnormalities of the thyroid in patients with 673. Katoh R, Suzuki K, Hemmi A, Kawaoi A: Nature and signif- painless thyroiditis. J Clin Endocrinol Metab 52:431–435, icance of calcium oxalate crystals in normal human thyroid 1981. gland. A clinicopathological and immunohistochemical 699. Woolner LB, McConahey WM, Beahrs OH: Invasive fibrous study. Virchows Arch A Pathol Anat Histopathol 422:301– thyroiditis (Riedel’s struma). J Clin Endocrinol Metab 306, 1993. 17:201–220, 1957. 674. Katoh R, Kawaoi A, Muramatsu A, et al: Birefringent (cal- 700. Harach HR, Williams ED: Fibrous thyroiditis—an immuno- cium oxalate) crystals in thyroid diseases. A clinicopathologi- pathological study. Histopathology 7:739–751, 1983. cal study with possible implications for differential diagno- 701. Schwaegerle SM, Bauer TW, Esselstyn CB Jr: Riedel’s thy- sis. Am J Surg Pathol 17:698–705, 1993. roiditis. Am J Clin Pathol 90:715–722, 1988. 675. Yamaoka Y: Solid cell nest (SCN) of the human thyroid 702. Williams ED, Doniach I: The postmortem incidence of focal gland. Acta Pathol Jpn 23:493–506, 1973. thyroiditis. J Pathol 83:255–264, 1962. 676. Harach HR: Solid cell nests of the thyroid. J Pathol 155:191– 703. Mitchell JD, Kirkham N, Machin D: Focal lymphocytic thy- 200, 1988. roiditis in Southampton. J Pathol 144:269–273, 1984. 677. Ozaki O, Ito K, Sugino K, et al: Solid cell nests of the thy- 704. Okayasu I, Hatakeyama S, Tanaka Y, et al: Is focal chronic roid gland. Virchows Arch A Pathol Anat Histopathol autoimmune thyroiditis an age-related disease? Differences 418:201–205, 1991. in incidence and severity between Japanese and British. J 678. Beckner ME, Shultz JJ, Richardson T: Solid and cystic ulti- Pathol 163:257–264, 1991. mobranchial body remnants in the thyroid [see comments]. 705. Weaver DR, Deodhar SD, Hazard JB: A characterization of Arch Pathol Lab Med 114:1049–1052, 1990. focal lymphocytic thyroiditis. Cleve Clin Q 33:59–72, 1966. 679. Harach HR: Solid cell nests of the human thyroid in early 706. Ghossein RA, Rosai J, Heffess C: Dyshormonogenetic goiter: stages of postnatal life. Systematic autopsy study. Acta Anat a clinicopathologic study of 56 cases. Endocr Pathol 8:283– 127:262–264, 1986. 292, 1998. 680. Carney JA, Moore SB, Northcutt RC, et al: Palpation thyroid- 707. Fadda G, Baloch ZW, LiVolsi VA: Dyshormonogenetic goiter itis (multifocal granulomatous folliculitis). Am J Clin Pathol pathology, a review. Int J Surg Pathol 7:125–131, 1999. 64:639–647, 1975. 708. Baloch ZW, Wu H, LiVolsi VA: Post–fine-needle aspiration 681. Fernandez JF, Ordonez NG, Schultz PN, et al: Thyroglossal spindle cell nodules of the thyroid (PSCNT). Am J Clin duct carcinoma. Surgery 110:928–934, discussion 934–935, Pathol 111:70–74, 1999. 1991. 709. Tsang K, Duggan MA: Vascular proliferation of the thyroid. 682. Heshmati HM, Fatourechi V, van Heerden JA, et al: Thyro- A complication of fine-needle aspiration. Arch Pathol Lab glossal duct carcinoma: report of 12 cases. Mayo Clin Proc Med 116:1040–1042, 1992. 72:315–319, 1997. 710. Axiotis CA, Merino MJ, Ain K, Norton JA: Papillary endo- 683. O’Connell M, Grixti M, Harmer C: Thyroglossal duct carci- thelial hyperplasia in the thyroid following fine-needle aspi- noma: presentation and management, including eight case ration. Arch Pathol Lab Med 115:240–242, 1991. reports. Clin Oncol 10:186–190, 1998. 711. Hamed G, Heffess CS, Shmookler BM, Wenig BM: Amyloid 684. Louis DN, Vickery AL Jr, Rosai J, Wang CA: Multiple bran- goiter. A clinicopathologic study of 14 cases and review of chial cleft–like cysts in Hashimoto’s thyroiditis [see com- the literature. Am J Clin Pathol 104:306–312, 1995. ments]. Am J Surg Pathol 13:45–49, 1989. 712. Villamil CF, Massimi G, D’Avella J, Cole SR: Amyloid goiter 685. Wenig BM, Heffess CS, Adair CF: Atlas of Endocrine Pathol- with parathyroid involvement: a case report and review of ogy. Philadelphia, WB Saunders, 1997. the literature. Arch Pathol Lab Med 124:281–283, 2000. 686. Sampson RJ, Oka H, Key CR, et al: Metastases from occult 713. Landas SK, Schelper RL, Tio FO, et al: Black thyroid syn- thyroid carcinoma. An autopsy study from Hiroshima and drome: exaggeration of a normal process? Am J Clin Pathol Nagasaki, Japan. Cancer 25:803–811, 1970. 85:411–418, 1986. 687. Meyer JS, Steinberg LS: Microscopically benign thyroid folli- 714. Saul SH, Dekker A, Lee RE, Breitfeld V: The black thyroid. cles in cervical lymph nodes. Serial section study of lymph Its relation to minocycline use in man. Arch Pathol Lab Med node inclusions and entire thyroid glands in 5 cases. Cancer 107:173–177, 1983. 24:302–311, 1969. 715. Reid JD: The black thyroid associated with minocycline ther- 688. Gerard-Marchant R, Caillou B: Thyroid inclusions in cer- apy. A local manifestation of a drug-induced lysosome/sub- vical lymph nodes. Clin Endocrinol Metab 10:337–349, strate disorder. Am J Clin Pathol 79:738–746, 1983. 1981. 716. Medeiros LJ, Federman M, Silverman ML, Balogh K: Black 689. Hazard JB: Thyroiditis: a review. Part II. Am J Clin Pathol thyroid associated with minocycline therapy. Arch Pathol 25:399–423, 1955. Lab Med 108:268–269, 1984. 690. Volpe R: The pathology of thyroiditis. Hum Pathol 9:429– 717. Matsubara F, Mizukami Y, Tanaka Y: Black thyroid. Mor- 438, 1978. phological, biochemical and geriatric studies on the brown 691. Woolner LB, McConahey WM, Beahrs OH: Struma lym- granules in the thyroid follicular cells. Acta Pathol Jpn phomatosa (Hashimoto’s thyroiditis) and related thyroidal 32:13–22, 1982. disorders. J Clin Endocrinol Metab 19:53–83, 1959. 718. Barsoum GH, Ryley NG, Barros D’Sa AA: Minocycline and 692. Katz SM, Vickery AL: The fibrous variant of Hashimoto’s black thyroid. J R Coll Surg Edinb 35:387–388, 1990. thyroiditis. Hum Pathol 5:161–170, 1974. 719. Senba M, Toda Y, Yamashita H: Black thyroid associated 693. Greenberg AH, Czernichow P, Hung W, et al: Juvenile with minocycline therapy: histochemical and ultrastructural chronic lymphocytic thyroiditis: clinical, laboratory and his- studies on the brown pigment. Isr J Med Sci 24:51–53, 1988. tological correlations. J Clin Endocrinol Metab 30:293–301, 720. Hecht DA, Wenig BM, Sessions RB: Black thyroid: a collabo- 1970. rative series. Otolaryngol Head Neck Surg 121:293–296, 694. Rallison ML, Dobyns BM, Keating FR, et al: Occurrence and 1999. natural history of chronic lymphocytic thyroiditis in child- 721. Landas SK, Marsh WL Jr, Schuller DE, et al: Nonpigmented hood. J Pediatr 86:675–682, 1975. papillary carcinoma in a black thyroid gland. Arch Otolaryn- short 695. Mizukami Y, Michigishi T, Nonomura A, et al: Postpartum gol Head Neck Surg 116:735–737, 1990. standard long

94 Endocrine System top of RH

722. Onyia JN, Forrest LA, Forsthoefel K: Papillary carcinoma parathyroidism in multiple endocrine neoplasia type IIa: ret- associated with black thyroid gland. Am J Otolaryngol rospective French multicentric study. Groupe d’Etude des 17:299–302, 1996. Tumeurs a Calcitonine (GETC, French Calcitonin Tumors 723. Thompson AD, Pasieka JL, Kneafsey P, DiFrancesco LM: Hy- Study Group), French Association of Endocrine Surgeons. popigmentation of a papillary carcinoma arising in a black World J Surg 20:808–812, discussion 812–813, 1996. thyroid. Mod Pathol 12:1181–1185, 1999. 748. Fitzpatrick LA: Hypercalcemia in the multiple endocrine 724. Katoh R, Ishizaki T, Tomichi N, et al: Malacoplakia of the neoplasia syndromes. Endocrinol Metab Clin North Am thyroid gland. Am J Clin Pathol 92:813–820, 1989. 18:741–752, 1989. 725. Larkin DFP, Dervan PA, Munnelly J, et al: Sinus histiocytosis 749. Wang CA, Castleman B, Cope O: Surgical management of with massive lymphadenopathy simulating subacute thyroid- hyperparathyroidism due to primary hyperplasia. Ann Surg itis. Hum Pathol 17:321–324, 1986. 195:384–392, 1982. 726. Chan KW, Poon GP, Choi CH: Plasma cell granuloma of the 750. Dolgin C, Lo Gerfo P, LiVolsi V, Feind C: Twenty-five year thyroid. J Clin Pathol 39:1105–1107, 1986. experience with primary hyperparathyroidism at Columbia 727. Holck S: Plasma cell granuloma of the thyroid. Cancer Presbyterian Medical Center. Head Neck Surg 2:92–98, 1979. 48:830–832, 1981. 751. Heath H, Hodgson SF, Kennedy MA: Primary hyperparathy- 728. Zingrillo M, Tardio B, Bisceglia M: Plasma cell granuloma of roidism, incidence, morbidity and potential economic impact the thyroid associated with Hashimoto’s thyroiditis. J Endo- in a community. N Engl J Med 302:189–193, 1980. crinol Invest 18:460–464, 1995. 752. Schantz A, Castleman B: Parathyroid carcinoma. A study of 729. Schmid C, Beham A, Seewann HL: Extramedullary haemato- 70 cases. Cancer 31:600–605, 1973. poiesis in the thyroid gland. Histopathology 15:423–425, 753. Holmes EC, Morton DL, Ketcham AS: Parathyroid carci- 1989. noma: a collective review. Ann Surg 169:631–640, 1969. 730. Larsimont D, Hamels J, Fortunati D: Thyroid-gland malako- 754. Shane E, Bilezikian JP: Parathyroid carcinoma: a review of 62 plakia with autoimmune thyroiditis. Histopathology 23:491– patients. Endocr Rev 3:218–226, 1982. 494, 1993. 755. van Heerden JA, Weiland LH, ReMine WH, et al: Cancer of 731. Wynne AG, van Heerden J, Carney JA, Fitzpatrick LA: Para- the parathyroid glands. Arch Surg 114:475–480, 1979. thyroid carcinoma: clinical and pathologic features in 43 pa- 756. Roth SI, Wang CA, Potts JT: The team approach to primary tients. Medicine (Baltimore) 71:197–205, 1992. hyperparathyroidism. Hum Pathol 6:645–648, 1975. 732. Jenkins PJ, Satta MA, Simmgen M, et al: Metastatic parathy- 757. Harness JK, Ramsburg SR, Nishiyama RH, Thompson NW: roid carcinoma in the MEN2A syndrome. Clin Endocrinol Multiple adenomas of the parathyroids: do they exist? Arch (Oxf) 47:747–751, 1997. Surg 114:468–474, 1979. 733. Yoshimoto K, Endo H, Tsuyuguchi M, et al: Familial isolated 758. Verdonk CC, Edias AJ: Parathyroid “double adenomas”: fact primary hyperparathyroidism with parathyroid carcinomas: or fiction? Surgery 90:523–526, 1981. clinical and molecular features. Clin Endocrinol (Oxf) 48:67– 759. Bartsch D, Nies C, Hasse C, et al: Clinical and surgical as- 72, 1998. pects of double adenoma in patients with primary hyper- 734. Prinz RA, Barbato AL, Braithwaite SS, et al: Prior irradiation parathyroidism. Br J Surg 82:926–929, 1995. and the development of coexistent differentiated thyroid can- 760. Szabo E, Lundgren E, Juhlin C, et al: Double parathyroid cer and hyperparathyroidism. Cancer 49:874–877, 1982. adenoma, a clinically nondistinct entity of primary hyper- 735. Russ JE, Scanlon EF, Sener SF: Parathyroid adenomas follow- parathyroidism. World J Surg 22:708–713, 1998. ing radiation. Cancer 43:1078–1083, 1979. 761. Sawady J, Mendelsohn G, Sirota RL, et al: The intrathyroid 736. Evans HL: Criteria for diagnosis of parathyroid carcinoma: a hyperfunctioning parathyroid gland. Mod Pathol 2:652–657, critical study. Surg Pathol 4:244–265, 1991. 1989. 737. DeLellis RA: Tumors of the Parathyroid Gland. Atlas of Tu- 762. Russell CF, Edis AJ, Scholz DA, et al: Mediastinal parathy- mor Pathology. Third Series, Fascicle 6. Washington, DC, roid tumors: experience with 38 tumors requiring mediasti- Armed Forces Institute of Pathology, 1993. notomy for removal. Ann Surg 193:805–809, 1981. 738. Grimelius L, Akerstrom G, Johansson H, et al: The parathy- 763. Spiegel AM, Marx SJ, Doppman JL, et al: Intrathyroidal roid glands. In Kovacs K, Asa SL (eds): Functional Endocrine parathyroid adenoma or hyperplasia. An occasionally over- Pathology. 2nd ed. Malden, MA, Blackwell Science, 1998, looked cause of surgical failure in primary hyperparathy- pp 381–414. roidism. JAMA 234:1029–1033, 1975. 739. Matsushita H: Pathology of the parathyroid glands. In Lech- 764. Nathaniels EK, Nathaniels AM, Wang C: Mediastinal para- ago J, Gould VE (eds): Bloodworth’s Endocrine Pathology. thyroid tumours: a clinical and pathological study of 84 3rd ed. Baltimore, Williams & Wilkins, 1997, pp 249–272. cases. Ann Surg 171:165–170, 1970. 740. Tominaga Y, Kohara S, Namii Y, et al: Clonal analysis of 765. de la Cruz Vigo F, Ortega G, Gonzalez S, et al: Pathologic nodular parathyroid hyperplasia in renal hyperparathyroid- intrathyroidal parathyroid glands. Int Surg 82:87–90, 1997. ism. World J Surg 20:744–750, discussion 750–752, 1996. 766. Summers GW: Parathyroid update: a review of 220 cases. 741. Barry MK, van Heerden JA, Grant CS, et al: Is familial hy- Ear Nose Throat J 75:434–439, 1996. perparathyroidism a unique disease? Surgery 122:1028–1033, 767. Ordonez NG, Ibanez ML, Samaan NA, Hickey RC: Immuno- 1997. peroxidase study of uncommon parathyroid tumors. Report 742. Teh BT, Farnebo F, Twigg S, et al: Familial isolated hyper- of two cases of nonfunctioning parathyroid carcinoma and parathyroidism maps to the hyperparathyroidism–jaw tumor one intrathyroid parathyroid tumor producing amyloid. Am locus in 1q21–q32 in a subset of families. J Clin Endocrinol J Surg Pathol 7:535–542, 1983. Metab 83:2114–2120, 1998. 768. Castleman B, Roth S: Tumors of the Parathyroid Glands. 743. Huang SM, Duh QY, Shaver J, et al: Familial hyperparathy- Atlas of Tumor Pathology. Second Series, Fascicle 14. Wash- roidism without multiple endocrine neoplasia. World J Surg ington, DC, Armed Forces Institute of Pathology, 1978. 21:22–28, discussion 29, 1997. 769. Castleman B, Schantz A, Roth S: Parathyroid hyperplasia in 744. Harach HR, Jasani B: Parathyroid hyperplasia in tertiary hy- primary hyperparathyroidism: a review of 85 cases. Cancer perparathyroidism: a pathological and immunohistochemical 38:1668–1675, 1976. reappraisal. Histopathology 21:513–519, 1992. 770. Grimelius L, Bondeson L: Histopathological diagnosis of 745. Dotzenrath C, Goretzki PE, Farnebo F, et al: Molecular ge- parathyroid diseases. Pathol Res Pract 191:353–365, 1995. netics of primary and secondary hyperparathyroidism. Exp 771. Loda M, Lipman J, Cukor B, et al: Nodular foci in parathy- Clin Endocrinol Diabetes 104:105–107, 1996. roid adenomas and hyperplasias: an immunohistochemical 746. Agarwal SK, Kester MB, Debelenko LV, et al: Germline mu- analysis of proliferative activity. Hum Pathol 25:1050–1056, tations of the MEN1 gene in familial multiple endocrine 1994. neoplasia type 1 and related states. Hum Mol Genet 6:1169– 772. Lawton TJ, Feldman M, LiVolsi VA: Lymphocytic infiltrates 1175, 1997. in solitary parathyroid adenomas, a report of four cases with short 747. Kraimps JL, Denizot A, Carnaille B, et al: Primary hyper- review of the literature. Int J Surg Pathol 6:5–10, 1998. standard long

Thyroid and Parathyroid 95 top of RH

773. Veress B, Nordenstrom J: Lymphocytic infiltration and de- 797. Grimelius L, Johansson H: Pathology of parathyroid tumors. struction of parathyroid adenomas: a possible tumour-spe- Semin Surg Oncol 13:142–154, 1997. cific autoimmune reaction in two cases of primary hyper- 798. Hsi ED, Zukerberg LR, Yang WI, Arnold A: Cyclin D1/ parathyroidism. Histopathology 25:373–377, 1994. PRAD1 expression in parathyroid adenomas: an immunohis- 774. Leedham PW, Pollock DJ: Intrafollicular amyloid in primary tochemical study. J Clin Endocrinol Metab 81:1736–1739, hyperparathyroidism. J Clin Pathol 23:811–817, 1970. 1996. 775. Sahin A, Robinson RA: Papillae formation in parathyroid 799. Abati A, Skarulis MC, Shawker T, Solomon D: Ultrasound- adenoma, a source of possible diagnostic error. Arch Pathol guided fine-needle aspiration of parathyroid lesions: a mor- Lab Med 122:99–100, 1988. phological and immunocytochemical approach. Hum Pathol 776. Abdul-Haj SK, Conklin H, Hewitt WC: Functioning lipoad- 26:338–343, 1995. enoma of the parathyroid gland, report of a unique case. N 800. Arnold A: Molecular mechanisms of parathyroid neoplasia. Engl J Med 266:121–123, 1962. Endocrinol Metab Clin North Am 23:93–107, 1994. 777. Daroca PJ Jr, Landau RL, Reed RJ, Kappelman MD: Func- 801. Arnold A, Motokura T, Bloom T, et al: PRAD1 (cyclin D1): a tioning lipoadenoma of the parathyroid gland. Arch Pathol parathyroid neoplasia gene on 11q13. Henry Ford Hosp Med Lab Med 101:28–29, 1977. J 40:177–180, 1992. 778. Obara T, Fujimoto Y, Ito Y, et al: Functioning parathyroid 802. Vasef MA, Brynes RK, Sturm M, et al: Expression of cyclin lipoadenoma—report of four cases: clinicopathological and D1 in parathyroid carcinomas, adenomas, and hyperplasias: ultrasonographic features. Endocrinol Jpn 36:135–145, 1989. a paraffin immunohistochemical study. Mod Pathol 12:412– 779. Perosio P, Brooks JJ, LiVolsi VA: Orbital brown tumor as 416, 1999. initial manifestation of parathyroid lipoadenoma. Surg 803. Heppner C, Kester MB, Agarwal SK, et al: Somatic mutation Pathol 1:77–82, 1988. of the MEN1 gene in parathyroid tumours. Nat Genet 780. Turner WJ, Baergen RN, Pellitteri PK, Orloff LA: Parathyroid 16:375–378, 1997. lipoadenoma: case report and review of the literature. Otola- 804. Shan L, Nakamura Y, Nakamura M, et al: Somatic mutations ryngol Head Neck Surg 114:313–316, 1996. of multiple endocrine neoplasia type 1 gene in the sporadic 781. Weiland LH, Garrison RC, ReMine WH, Scholz DA: Lipoad- endocrine tumors. Lab Invest 78:471–475, 1998. enoma of the parathyroid gland. Am J Surg Pathol 2:3–7, 805. Palanisamy N, Imanishi Y, Rao PH, et al: Novel chromo- 1978. somal abnormalities identified by comparative genomic hy- 782. Wolff M, Goodman EN: Functioning lipoadenoma of a su- bridization in parathyroid adenomas. J Clin Endocrinol Me- pernumerary parathyroid gland in the mediastinum. Head tab 83:1766–1770, 1998. Neck Surg 2:302–307, 1980. 806. LiVolsi VA, Hamilton R: Intraoperative assessment of para- 783. Ho KJ: Papillary parathyroid adenoma. A rare occurrence thyroid gland pathology. A common view from the surgeon and its importance in differentiation from papillary carci- and the pathologist. Am J Clin Pathol 102:365–373, 1994. noma of the thyroid. Arch Pathol Lab Med 120:883–884, 807. Silver CE, Owen RP: Year 2000 update: what the head and 1996. neck surgeon expects of the pathologist. Pathol Case Rev 784. Roth SI: Water-clear cell ’adenoma.’ A new entity in the 5:183–188, 2000. pathology of primary hyperparathyroidism (editorial; com- 808. Westra WH, Pritchett DD, Udelsman R: Intraoperative con- ment). Arch Pathol Lab Med 119:996–997, 1995. firmation of parathyroid tissue during parathyroid explora- 785. Grenko RT, Anderson KM, Kauffman G, Abt AB: Water- tion: a retrospective evaluation of the frozen section. Am J clear cell adenoma of the parathyroid. A case report with Surg Pathol 22:538–544, 1998. immunohistochemistry and electron microscopy. Arch Pathol 809. Dekker A, Watson CG, Barnes EL: The pathologic assess- Lab Med 119:1072–1074, 1995. ment of primary hyperparathyroidism and its impact on 786. Bedetti CD, Dekker A, Watson CG: Functioning oxyphil cell therapy, a prospective evaluation of 50 cases with oil-red-O adenoma of the parathyroid gland: a clinicopathologic study stain. Ann Surg 190:671–675, 1979. of ten patients with hyperparathyroidism. Hum Pathol 15: 810. Ljungberg O, Tibblin S: Perioperative fat staining of frozen 1121–1126, 1984. sections in primary hyperparathyroidism. Am J Pathol 787. Natsui K, Tanaka K, Suda M, et al: Oxyphil parathyroid 95:633–641, 1979. adenoma associated with primary hyperparathyroidism and 811. Roth SI, Gallagher MJ: The rapid identification of “normal” marked postoperative hungry bone syndrome. Intern Med parathyroid glands by the presence of intracellular fat. Am J 35:545–549, 1996. Pathol 84:521–528, 1976. 788. Wolpert HR, Vickery AL Jr, Wang CA: Functioning oxyphil 812. Sasano H, Geelhoed GW, Silverberg SG: Intraoperative cyto- cell adenomas of the parathyroid gland. A study of 15 cases. logic evaluation of lipid in the diagnosis of parathyroid ade- Am J Surg Pathol 13:500–504, 1989. noma. Am J Surg Pathol 12:282–286, 1988. 789. Weiler R, Fischer-Colbrie R, Schmid KW, et al: Immunologi- 813. Dufour DR, Durkowski C: Sudan IV stain. Its limitations in cal studies on the occurrence and properties of chromo- evaluating parathyroid functional status. Arch Pathol Lab granin A and B and secretogranin II in endocrine tumors. Med 106:224–227, 1982. Am J Surg Pathol 12:877–884, 1988. 814. Kasdon EJ, Rosen S, Cohen RB, Silen W: Surgical pathology 790. Miettinen M, Clark R, Lehto VP, et al: Intermediate-filament of hyperparathyroidism. Usefulness of fat stain and prob- proteins in parathyroid glands and parathyroid adenomas. lems in interpretation. Am J Surg Pathol 5:381–384, 1981. Arch Pathol Lab Med 109:986–989, 1985. 815. King DT, Hirose FM: Chief cell intracytoplasmic fat used to 791. Mendelsohn G: Pathology of the parathyroid glands. In Men- evaluate parathyroid disease by frozen section. Arch Pathol delsohn G (ed): Diagnosis and Pathology of Endocrine Dis- eases. Philadelphia, JB Lippincott, 1988, pp 139–177. Lab Med 103:609–612, 1979. 792. Vargas MP, Vargas HI, Kleiner DE, Merino MJ: The role of 816. Clarke MR, Hoover WW, Carty SE, et al: Atypical fat stain- prognostic markers (MiB-1, RB, and bcl-2) in the diagnosis of ing patterns in hyperparathyroidism. Int J Surg Pathol 3:163– parathyroid tumors. Mod Pathol 10:12–17, 1997. 168, 1996. 793. Abbona GC, Papotti M, Gasparri G, Bussolati G: Proliferative 817. Black WC, Utley JR: The differential diagnosis of parathyroid activity in parathyroid tumors as detected by Ki-67 immuno- adenoma and chief cell hyperplasia. Am J Pathol 49:761–775, staining. Hum Pathol 26:135–138, 1995. 1968. 794. Erickson LA, Jin L, Wollan P, et al: Parathyroid hyperplasia, 818. Kay S: The abnormal parathyroid. Hum Pathol 7:127–138, adenomas, and carcinomas: differential expression of 1976. p27/KipI protein. Am J Surg Pathol 23:288–295, 1999. 819. Black WC, Haff RC: The surgical pathology of parathyroid 795. Arnold A, Staunton CE, Kim HG, et al: Monoclonality and chief cell hyperplasia. Am J Clin Pathol 53:565–579, 1970. abnormal parathyroid hormone genes in parathyroid adeno- 820. Sofferman RA, Standage J, Tang ME: Minimal-access para- mas. N Engl J Med 318:658–662, 1988. thyroid surgery using intraoperative parathyroid hormone 796. Marx SJ: Genetic defects in primary hyperparathyroidism assay. Laryngoscope 108:1497–1503, 1998. short (editorial). N Engl J Med 318:699–701, 1988. 821. Garner SC, Leight GS Jr: Initial experience with intraopera- standard long

96 Endocrine System top of RH

tive PTH determinations in the surgical management of 130 human parathyroid carcinoma. J Clin Endocrinol Metab consecutive cases of primary hyperparathyroidism. Surgery 78:1320–1324, 1994. 126:1132–1137, discussion 1137–1138, 1999. 843. Vainas IG, Tsilikas C, Grecu A, et al: Metastatic parathyroid 822. Chapuis Y, Fulla Y, Bonnichon P, et al: Values of ultrasonog- carcinoma (mPCa): natural history and treatment of a case. J raphy, sestamibi scintigraphy, and intraoperative measure- Exp Clin Cancer Res 16:429–432, 1997. ment of 1–84 PTH for unilateral neck exploration of primary 844. DeLellis RA: Proliferation markers in neuroendocrine tu- hyperparathyroidism. World J Surg 20:835–839, discussion mors: useful or useless? A critical reappraisal. Verh Dtsch 839–840, 1996. Ges Pathol 81:53–61, 1997. 823. Aldinger KA, Hickey RC, Ibanez ML, Samaan NA: Parathy- 845. Bowlby LS, DeBault LE, Abraham SR: Flow cytometric DNA roid carcinoma: a clinical study of seven cases of functioning analysis of parathyroid glands. Relationship between nuclear and two cases of nonfunctioning parathyroid cancer. Cancer DNA and pathologic classifications. Am J Pathol 128:338– 49:388–397, 1982. 344, 1987. 824. Shortell CK, Andrus CH, Phillips CE Jr, Schwartz SI: Carci- 846. Bocsi J, Perner F, Szucs J, et al: DNA content of parathyroid noma of the parathyroid gland: a 30-year experience. Sur- tumors. Anticancer Res 18:2901–2904, 1998. gery 110:704–708, 1991. 847. Obara T, Fujimoto Y, Hirayama A, et al: Flow cytometric 825. Park ST, Condemi G, Shakir KM, et al: Parathyroid carci- DNA analysis of parathyroid tumors with special reference noma: report of three cases and review of the literature. Mil to its diagnostic and prognostic value in parathyroid carci- Med 163:246–249, 1998. noma. Cancer 65:1789–1793, 1990. 826. Chow E, Tsang RW, Brierley JD, Filice S: Parathyroid carci- 848. Obara T, Fujimoto Y, Kanaji Y, et al: Flow cytometric DNA noma—the Princess Margaret Hospital experience. Int J Ra- analysis of parathyroid tumors. Implication of aneuploidy diat Oncol Biol Phys 41:569–572, 1998. for pathologic and biologic classification. Cancer 66:1555– 827. Cohn K, Silverman M, Corrado J, Sedgewick C: Parathyroid 1562, 1990. carcinoma: the Lahey Clinic experience. Surgery 98:1095– 849. Levin KE, Chew KL, Ljung BM, et al: Deoxyribonucleic acid 1100, 1985. cytometry helps identify parathyroid carcinomas. J Clin En- 828. Cordeiro AC, Montenegro FL, Kulcsar MA, et al: Parathy- docrinol Metab 67:779–784, 1988. roid carcinoma. Am J Surg 175:52–55, 1998. 850. Levin KE, Galante M, Clark OH: Parathyroid carcinoma ver- 829. McPheeters GO, Bender CA: Parathyroid carcinoma: a case sus parathyroid adenoma in patients with profound hyper- report and review. Hawaii Med J 44:104–108, 1985. calcemia. Surgery 101:649–660, 1987. 830. Shane E: Parathyroid carcinoma. Curr Ther Endocrinol Me- 851. Fujimoto Y, Obara T, Ito Y, et al: Surgical treatment of ten tab 6:565–568, 1997. cases of parathyroid carcinoma: importance of an initial en 831. Vetto JT, Brennan MF, Woodruff J, Burt M: Parathyroid car- bloc tumor resection. World J Surg 8:392–400, 1984. cinoma: diagnosis and clinical history. Surgery 114:882–892, 852. Obara T, Okamoto T, Kanbe M, Iihara M: Functioning para- 1993. thyroid carcinoma: clinicopathologic features and rational 832. Vazquez-Quintana E: Parathyroid carcinoma: diagnosis and treatment. Semin Surg Oncol 13:134–141, 1997. management. Am Surg 63:954–957, 1997. 853. Stevenson HU: Malignant tumours of the parathyroid gland: 833. Wang CA, Gaz RD: Natural history of parathyroid carci- a review of the literature with report of a case. Arch Surg noma. Diagnosis, treatment, and results. Am J Surg 149:522– 60:247–266, 1950. 527, 1985. 854. Palmer M, Ljunghall S, Akerstrom G, et al: Patients with 834. Anderson BJ, Samaan NA, Vassilopoulou-Sellin R, et al: Par- primary hyperparathyroidism operated on over a 24-year pe- athyroid carcinoma: features and difficulties in diagnosis and riod: temporal trends of clinical and laboratory findings. J management. Surgery 94:906–915, 1983. Chronic Dis 40:121–130, 1987. 835. Bondeson L, Sandelin K, Grimelius L: Histopathological vari- 855. Roth SI: The ultrastructure of primary water-clear cell hyper- ables and DNA cytometry in parathyroid carcinoma. Am J plasia of the parathyroid glands. Am J Pathol 61:233–248, Surg Pathol 17:820–829, 1993. 1970. 836. Obara T, Fujimoto Y, Yamaguchi K, et al: Parathyroid carci- 856. Dawkins RL, Tashjian AH Jr, Castleman B, Moore EW: Hy- noma of the oxyphil cell type. A report of two cases, light perparathyroidism due to clear cell hyperplasia. Serial deter- and electron microscopic study. Cancer 55:1482–1489, 1985. minations of serum ionized calcium, parathyroid hormone 837. Nasser G, Loberant N, Salameh A, et al: Oxyphil cell carci- and calcitonin. Am J Med 54:119–126, 1973. noma of the parathyroid: a rare cause of hyperparathyroid- 857. Rangnekar N, Bailer WJ, Ghani A, et al: Parathyroid cysts. ism. Clin Oncol 7:323–324, 1995. Report of four cases and review of the literature. Int Surg 838. Chan JK, Tsang WY: Endocrine malignancies that may 81:412–414, 1996. mimic benign lesions. Semin Diagn Pathol 12:45–63, 1995. 858. Alvi A, Myssiorek D, Wasserman P: Parathyroid cyst: cur- 839. Chaitin BA, Goldman RL: Mitotic activity in benign parathy- rent diagnostic and management principles. Head Neck roid disease (letter). Am J Clin Pathol 76:363–364, 1981. 18:370–373, 1996. 840. Snover DC, Foucar K: Mitotic activity in benign parathyroid 859. Carney JA: Salivary heterotopia, cysts, and the parathyroid disease. Am J Clin Pathol 75:345–347, 1981. gland: branchial pouch derivatives and remnants. Am J Surg 841. Cryns VL, Thor A, Xu HJ, et al: Loss of the retinoblastoma Pathol 24:837–845, 2000. tumor-suppressor gene in parathyroid carcinoma [see com- 860. Koelmeyer TD: Generalised amyloidosis with involvement ments]. N Engl J Med 330:757–761, 1994. of the parathyroids: case report. N Z Med J 85:372–373, 842. Cryns VL, Rubio MP, Thor AD, et al: p53 abnormalities in 1977.

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