Neuroendocrine Tumors of the Thyroid Gland Zubair W

Pathology Patterns Reviews

Neuroendocrine Tumors of the Thyroid Gland Zubair W. Baloch, MD, PhD, and Virginia A. LiVolsi, MD

Key Words: Neuroendocrine tumors; C-cell hyperplasia; Medullary carcinoma; Paraganglioma; Parathyroid tumors; Insular carcinoma; Hyalinizing trabecular neoplasm Downloaded from https://academic.oup.com/ppr/article/115/suppl_1/S56/2291738 by guest on 01 October 2021

Abstract Neuroendocrine lesions of the thyroid are rare entities. The neuroendocrine lesions of the thyroid are few The most important subgroup includes those lesions derived in number and include C-cell lesions (C-cell from C cells (C-cell hyperplasia and medullary carcinoma hyperplasia and medullary carcinoma), mixed C-cell and its variants). Other intrathyroidal nodules and tumors that and follicular-derived tumors, paraganglioma, display neuroendocrine features include hyalinizing trabec- intrathyroidal parathyroid adenoma, and metastasis to ular neoplasms, insular carcinoma, true paraganglioma, the thyroid from neuroendocrine carcinoma arising parathyroid lesions, and tumors metastatic to the thyroid. elsewhere. However, some follicular-derived lesions of These entities will be discussed and illustrated in this review. the thyroid can show trabecular and nesting growth patterns characteristic of neuroendocrine tumors. These lesions should also be included in the differential C-Cell Lesions of the Thyroid diagnosis of primary and secondary neuroendocrine tumors of the thyroid. The C cells are derived from neural crest; it has been suggested that these first migrate to ultimobranchial body remnants before becoming a component of thyroid parenchyma.1-3 In the thyroid, they usually are found at the junction of the upper third and lower two thirds of the lateral lobes.2,4-6 Histologic sections stained with H&E usually fail to reveal C cells; however, Grimelius stain and neuroendocrine markers such as chromogranin A, synaptophysin, and neuron-specific enolase can readily identify them.2,5,7 The advent of immunostain for calcitonin, the hormone product of C cells, has made it the stain of choice.2 Other immunostains that can identify C cells include calcitonin-gene–related peptide, somatostatin, gastrin-releasing peptide, and serotonin.8-11

Medullary Thyroid Carcinoma This tumor is derived from C cells and constitutes about 10% of all malignant tumors of the thyroid.12-16 These tumors generate much interest among clinicians because of their hereditary predisposition and association with multiple endocrine neoplasia (MEN) syndromes.17-25 In addition, these

S56 Am J Clin Pathol 2001;115 (Suppl 1):S56-S67 © American Society of Clinical Pathologists Pathology Patterns Reviews lesions can be challenging to the pathologist owing to their carcinoma also can express a variety of other hormones varied morphologic patterns.24,26-30 C-cell hyperplasia has besides calcitonin, such as corticotropin, melatonin-stimu- been implicated as the precursor of in situ lesions of me- lating hormone, serotonin, and gastrin. This unique property dullary carcinoma compared with other tumors of the thyroid of this thyroid tumor may complicate the clinical picture and in which precursor lesions are yet to be defined.5,24,31,32 can pose problems in clinical diagnosis.10,24,69-72 Hazard and associates33 first coined the term medullary The familial medullary carcinoma can manifest in carcinoma; these authors also described in detail its morpho- different clinical settings. Medullary carcinoma in MEN type logic features, presence of amyloid, frequency of lymph 2A (MEN type 2 or Sipple syndrome) is associated with C- node metastases, and prognosis. Before the report by Hazard cell hyperplasia, adrenal pheochromocytoma, adrenal et al,33 Horn,34 in 1951, reported 7 cases of a distinct thyroid medullary hyperplasia, and parathyroid hyperplasia.21,73-75

tumor with a morphologic description similar to that for The latter is observed in only one third of cases. Medullary Downloaded from https://academic.oup.com/ppr/article/115/suppl_1/S56/2291738 by guest on 01 October 2021 medullary carcinoma; however, he did not designate it as carcinoma arising in MEN type 2B behaves in a much more medullary carcinoma. Williams16 identified C cells as the aggressive manner and can lead to demise at an early age due origin of medullary carcinoma, which has led to vast investi- to distant metastasis; however, some authors refute this gations into the origin, pathogenesis, and treatment of these outcome.65,67,68 The other components of this syndrome in- tumors. clude C-cell hyperplasia, pheochromocytoma, adrenal med- A majority of medullary carcinomas are sporadic, but up ullary hyperplasia, mucosal neuromas, gastrointestinal gangli- to 20% are familial.15,18,24,35-37 The latter are inherited in an oneuromas, and musculoskeletal abnormalities.53,65,67,72-74 autosomal dominant manner with high penetrance and can Gross pathologic examination reveals that the sporadic manifest as a component of MEN type 2A (MEN 2A or medullary cancer is usually a solitary nodule, whereas the Sipple syndrome), type 2B (MEN 2B, MEN 3, or mucosal familial cases are multiple and bilateral.8,13,14,76 These neuroma syndrome), or familial non-MEN medullary thyroid tumors usually are situated in the lateral upper two thirds carcinoma (FMTC). 25,26,38 of the thyroid, the site of highest C-cell concentra- Mutations in the RET proto-oncogene, which codes for tion.2,8,13,14,16,35,77 The tumor size may vary from a microcar- a tyrosine kinase receptor, have been implicated in familial cinoma (<1 cm) to a size that will replace the entire thyroid medullary cancer syndromes by linkage analysis.25,39,40 The with extension into the surrounding soft tissues.13,14,26,63,78,79 identification of a specific mutation has important implica- The histologic appearance of medullary carcinoma can tions for clinical management, which includes prophylactic be extremely variable.13,14 The most commonly encountered surgical excision of the thyroid.41-44 RET mutations in fami- pattern consists of sheets and solid nests of round cells with lies with MEN 2A (95% of families) and FMTC (85% of granular eosinophilic cytoplasm and a prominent eccentric families) have been seen in 1 of the 5 cysteine codons in nucleus with evenly dispersed chromatin ❚Image 1❚.13,14,26,80 exons 10 and 11. Cases of FMTC also can demonstrate 2 In some cases the tumor cells also can show prominent additional mutations involving codon 768 (exon 13) and nuclear grooves and even inclusions, which can be mistaken codon 804 (exon 14). A point mutation at codon 918 (exon for papillary thyroid carcinoma,80-84 while in other cases the 160) has been noted in 95% of cases of MEN 2B.25,40,45-47 tumor cells can exhibit marked nuclear pleomorphism, a Because medullary carcinoma generally is considered a prominent central nucleolus, and eosinophilic granular cyto- lethal tumor, it is recommended that first-degree relatives of plasm; such cases can be mistaken for Hürthle cell tumors.85 the affected family member undergo genetic screening; a Medullary carcinoma also can exhibit spindle cell positive result should be followed be prophylactic total morphologic features; this was reported originally by Hazard thyroidectomy. This radical management can be undertaken et al.33 The spindle cell pattern can form a part of the usual before the age of 6 years.43,44,48-53 aforementioned pattern or, in some cases, the entire tumor is RET mutations also can be seen in sporadic medullary composed of spindle cells ❚Image 2❚. These cases can mimic cancer and may affect the prognosis. The mutations in primary or metastatic mesenchymal tumors of the thyroid, sporadic cases are usually seen in codon 918 (23%-66%); the anaplastic carcinoma, or thyroid tumors of thymic origin.86-90 other less frequent ones involve cysteine codons 768 and In some cases of medullary carcinoma, the entire tumor is 883. 40,54-58 composed of small cells, resembling small cell carcinoma of Medullary carcinoma usually manifests as a firm pain- the lung.13,14 Several other histologic patterns of this tumor less thyroid nodule, with half of the cases showing lymph have been described, which include oxyphil and squamous node metastases and up to 15% showing distant metas- cell, giant cell ❚Image 3❚, pseudopapillary, carcinoid-like, and tases.13,14,18,26,33,59-62 Sporadic tumors are more common mixed medullary and papillary. 18,29,85,91-98 in females and usually manifest at older age (45 years) than Amyloid can be seen in up to 80% of medullary the familial cases.13,61,63-68 The tumor cells of medullary cancers; therefore, Congo red staining and polarized light

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❚ ❚ C Image 1 A, Low-power view showing medullary thyroid carcinoma with sclerosis and amyloid containing stroma (H&E, ×40). B, High-power view showing amyloid appearing as a pink amorphous substance (H&E, ×100). C, High-power view showing tumor cells with neuroendocrine-type nuclear chromatin (H&E, ×200).

microscopy are used to diagnose these tumors.13,14,99 associated with C-cell hyperplasia.108 The other marker that However, lack of amyloid does not exclude medullary carci- can be used for this diagnosis is immunostain for calcitonin- noma.14,18,100 Amyloid is usually scant or absent in cases of gene–related peptide.24,109 However, both markers also can medullary carcinoma that demonstrate a diffuse spindle cell stain other tumors of nonthyroid origin (eg, islet cell tumors, pattern.24,26,100 small cell carcinoma of lung). Medullary carcinomas also Tumor necrosis and mitoses can be seen in large tumors. stain positive for carcinoembryonic antigen (CEA); Up to 50% of cases can demonstrate lymph node metastases increased levels of serum CEA along with calcitonin values involving regional and mediastinal nodes. These tumors also often are used for follow-up in patients at risk for recurrent show a propensity toward extrathyroidal extension and or metastatic disease.107 Some authors have reported that involvement of the contralateral lobe. The common sites immunoreactivity for calcitonin in 25% or fewer tumor cells for distant metastasis include lung, bone, liver, and and a marked increase in CEA positivity indicate a guarded adrenals.18,101-106 prognosis; however, other authors have not been able to The “gold standard” for the diagnosis of medullary reproduce these findings.107,110,111 carcinoma is the immunostain for calcitonin.107 Calcitonin stains both the tumor cells and the amyloid.107 Calcitonin- C-Cell Hyperplasia negative medullary cancers have been reported; however, The familial medullary cancers often are associated with these tumors usually occur in the familial setting and/or are C-cell hyperplasia; however, it also can be seen in sporadic

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❚Image 2❚ Spindle cell variant of medullary carcinoma (H&E, ❚Image 3❚ Giant cell variant of medullary carcinoma (H&E, ×100). ×100). medullary cancer, follicular-derived tumors, autoimmune The nodal metastases from these tumors also exhibit both thyroiditis, hyperparathyroidism, and hypercalcemia due to follicular and medullary components.121,122,124-126 other causes.5,24,32,49,112-117 Several hypotheses have been suggested about the origin What constitutes a lesion to be designated as C-cell of these tumors; some authors have proposed that these hyperplasia? Various authors have proposed several sugges- tumors develop from an uncommitted stem cell capable of tions.4,113,118,119 Wolfe et al118 studied normal thyroids and producing both follicular and C-cell progeny.121,122,127 found clusters of 4 to 10 C cells in the central regions of the Volante et al128 microdissected the individual components of upper and middle thirds of the lateral lobes. These authors 12 mixed tumors, performed genetic analysis for RET proto- suggested that multiple large clusters of C cells should be oncogene and allelic losses of 9 loci on chromosome 6, and designated as hyperplasia.118 Some authors have suggested studied the clonal composition of tumor cells in female the presence of more than 20 cells, while others have said patients. Their results showed that the follicular and that 2 to 5 C cells with more than 50 cells per low-power medullary components of the mixed tumors are not derived field indicate hyperplasia ❚Image 4❚.119 As mentioned, C-cell hyperplasia can be seen in thyroid from non-MEN cases.117 It has been reported that immunostains for the polysialic acid component of the neural cell adhesion molecule can differentiate between primary and secondary C-cell hyperplasia.120 However, genetic testing has proven to be the gold standard for identifying familial C- cell lesions.25

Mixed Medullary and Follicular and Composite Tumors These tumors are rare and exhibit both C-cell and follicular differentiation.91,121,122 Mixed tumors show admixture of medullary and follicular growth patterns and rarely foci of papillary thyroid carcinoma.121-123 The follicular-patterned areas express thyroglobulin, and the medullary regions express calcitonin. Occasionally the medullary carcinoma ❚Image 4❚ Calcitonin immunostains highlighting the focus of cells in these tumors also coexpress thyroglobulin.121,122,124-126 C-cell hyperplasia (H&E, ×100).

© American Society of Clinical Pathologists Am J Clin Pathol 2001;115 (Suppl 1):S56-S67 S59 Baloch and LiVolsi / NEUROENDOCRINE TUMORS OF THE THYROID GLAND from the single stem cells. In addition, the follicular- stains positive for neuron-specific enolase, chromogranin, patterned areas were oligoclonal or polyclonal and most and synaptophysin, and S-100 protein highlights the susten- likely hyperplastic rather than neoplastic.128 tacular cells; the tumor cells are negative for thyroglobulin, Apel et al129 described a composite tumor of the thyroid. epithelial membrane antigen, cytokeratins, calcitonin, and Two distinct cell populations consisting of papillary carci- CEA. These immunohistochemical features of thyroid para- noma and medullary carcinoma characterize these tumors. It ganglioma are helpful for differentiating it from other tumors is claimed that these tumors are distinct from mixed tumors of the thyroid that can show a partly similar growth pattern. because follicular and parafollicular lineage is demonstrated The tumors in the differential diagnoses of thyroid paragan- in 2 different cell populations rather in a single cell as seen in glioma include medullary carcinoma, metastatic neuroen- some cases of mixed tumors.129 docrine neoplasm, hyalinizing trabecular adenoma, Hürthle 138 cell carcinoma, and insular carcinoma. Downloaded from https://academic.oup.com/ppr/article/115/suppl_1/S56/2291738 by guest on 01 October 2021 Thyroid Paraganglioma Intrathyroidal Parathyroid Adenoma Paragangliomas of the thyroid are rare; to date, fewer than 20 cases have been described as single case reports and The parathyroid glands develop from the fourth and fifth small series.130-138 These tumors are believed to arise from branchial pouches and descend, along with thyroid anlage and inferior laryngeal paraganglia, which can be found within the thymus, to their various final destinations in the neck. Abnor- thyroid capsule. malities in the descent of the parathyroids can cause the glands All reported cases of paraganglioma of the thyroid to reside anywhere along their embryologic pathway.140,141 occurred in women, manifested as a solitary mass, and Variability in location is found most often in the inferior ranged in size from 1.5 to 10 cm.138 They can be confined to parathyroids.141 These usually are located around the lower the thyroid, or some cases can exhibit infiltration into pole of the thyroid; however, in some cases they can be truly surrounding tissue. Light microscopy of these tumors intrathyroidal.142 revealed the hallmark nesting (Zellballen) growth pattern Parathyroid adenomas embedded within thyroid seen in paragangliomas arising in sites other than thyroid.138 parenchyma can be seen in 2% to 5% of cases.142-145 Some The other histologic characteristics include prominent vascu- of these tumors can be detected preoperatively by ultrasound larity and tumor cells with oncocytic cytoplasm and round to examination; however, some may be difficult to separate oval nuclei with finely dispersed chromatin and inconspic- from a thyroid nodule. Similarly, preoperative fine-needle uous nucleoli. Some of these tumors also can exhibit isolated aspiration procedures may not be able to distinguish between bizarre cells; mitoses are usually rare ❚Image 5❚.138,139 parathyroid and thyroid origin, since the parathyroid cells Amyloid is not seen in these tumors. Thyroid paraganglioma in cytologic preparations may look similar to the thyroid

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❚Image 5❚ A, Low-power view of thyroid paraganglioma showing tumor cells arranged in nests separated by a prominent vasculature (H&E, ×50). B, High-power view showing tumor cells with oncocytic cytoplasm and random nuclear atypia (H&E, ×150).

S60 Am J Clin Pathol 2001;115 (Suppl 1):S56-S67 © American Society of Clinical Pathologists Pathology Patterns Reviews follicular cells.146,147 In such instances, immunostaining for but by their growth patterns can mimic neuroendocrine parathyroid hormone may prove helpful. Some of these tumors, especially medullary carcinoma. tumors can undergo cystification and give rise to clear translucent fluid, which on fine-needle aspiration is diag- Hyalinizing Trabecular Adenoma (Paraganglioma-like nostic of a parathyroid lesion, and confirmation of the Adenoma of the Thyroid) morphologic impression can be made by performing the Carney et al155 first described hyalinizing trabecular biochemical assay for parathyroid hormone on the cyst adenoma (HTA), an unusual tumor of the thyroid. It is an fluid.147-151 encapsulated tumor that shows elongated follicular cells By light microscopy, a majority of these tumors are nested around capillaries in a background of hyaline and encapsulated and show typical morphologic features of occasionally calcified extracellular matrix. The tumor cells

parathyroid adenoma. Immunostains for parathyroid can show nuclear grooves and inclusions, which can be Downloaded from https://academic.oup.com/ppr/article/115/suppl_1/S56/2291738 by guest on 01 October 2021 hormone and thyroglobulin are helpful for confirming the mistaken for papillary thyroid carcinoma ❚Image 6❚. These cell of origin.144,152 tumors stain positive for thyroglobulin and are negative for calcitonin.155-158 Recently, yellow, cytoplasmic inclusions containing glycosaminoglycan, proteoglycan, and lipid were described in these tumors.159 Secondary Neuroendocrine Tumors of The trabecular growth pattern also can be seen in follic- the Thyroid ular adenoma, follicular carcinoma, and papillary thyroid Neuroendocrine neoplasms occur throughout the body carcinoma.13,157 Owing to this growth pattern, some authors and range from the bland-appearing carcinoid to the more have suggested that these tumors should not be classified as a ominous small cell carcinoma. Metastasis to the thyroid from separate entity of thyroid tumors, while others have these tumors can mimic primary neuroendocrine tumors of suggested that this tumor is closely related to or is an encap- the thyroid, especially medullary carcinoma.87,153,154 A sulated form of papillary carcinoma because of its nuclear majority of these tumors are of pulmonary origin and can cytology and immunoprofile.157 Fonseca et al160 showed that include carcinoid, atypical carcinoid, or neuroendocrine there are no differences in the expression of stratified epithe- carcinoma.87 Metastasis to the thyroid from these tumors lial-type cytokeratins between HTA and papillary carcinoma. usually manifests as multiple tumor nodules infiltrating and However, Hirokawa et al161 failed to reproduce these results. undermining the thyroid parenchyma with multiple foci of Recently Papotti et al162 showed RET/PTC expression in vascular and lymphatic invasion.154 Immunohistochemical 28.6% of HTAs in their series of 14 cases, whereas follicular examination usually is helpful for separating metastatic adenomas with a trabecular growth pattern failed to show disease from medullary carcinoma; secondary neuroen- RET proto-oncogene alterations. docrine tumors of the thyroid usually are negative for calci- A majority of pathologists believe that HTA is a benign tonin and CEA. However, calcitonin can be positive in cells tumor owing to its clinical behavior; however, a few reports of small cell carcinoma of the lung, but CEA is usually nega- have described similar tumors with capsular and vascular tive. Thyroid paraganglioma also should be considered in the invasion.155,163,164 differential diagnosis of secondary neuroendocrine tumors of the thyroid. Usually paragangliomas manifest as a solitary Insular Carcinoma mass and lack mitoses and necrosis, which is more common This follicular-derived tumor was named as such by in metastatic tumors. Besides evaluating these features, Carcangiu et al165 owing to its peculiar growth pattern, in obtaining a detailed history is always crucial; isolated metas- which the tumor cells are arranged in well-formed nests or tases to the thyroid from neuroendocrine tumors are rare, and islands (insulae). This tumor is similar to what had been these patients usually have metastases to other organs and described by Langhans in 1907 as “wuchernde Struma.”165 can have symptomatology characteristic of a neuroendocrine This is a rare thyroid tumor; however, in some geographic neoplasm (eg, diarrhea, flushing, weight loss).87,153,154 regions, its incidence has been reported as high as 5%.166 These tumors usually occur in an older age group and are twice as common in women as in men.165,167 Gross examination reveals insular carcinoma as large Primary Thyroid Lesions That Can Mimic tumors, and the tumors can exhibit areas of necrosis. Besides Primary Neuroendocrine Tumors of the a nesting pattern, light microscopy reveals prominent vascu- Thyroid larization, mitoses, and areas of necrosis ❚Image 7❚. Vascular We believe that it is also important to briefly mention invasion is common; regional and distant metastases are tumors of the thyroid that are not of neuroendocrine origin commonly present at the time of diagnosis. Clinically these

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❚Image 6❚ A, Hyalinizing trabecular adenoma of the thyroid showing an encapsulated tumor consisting of tumor cells forming trabeculae and nests (H&E, ×50). B, High-power view showing nests of tumor cells separated by thin-walled vessels (H&E, ×150). tumors are aggressive, and up to half of the patients die of stain positive for thyroglobulin and are negative for calci- their tumors 1 to 8 years after therapy. These tumors stain tonin and CEA.13,14,172 positive for thyroglobulin and are negative for calcitonin, which helps distinguish them from medullary carcinoma.166-171 Summary Besides the aforementioned entities (HTA and insular carcinoma), follicular adenoma, follicular carcinoma, and This article has reviewed the thyroid lesions of known papillary carcinoma can exhibit a trabecular growth pattern neuroendocrine derivation and those that mimic such tumors. with prominent vascularity. Some of these cases may show Differential diagnostic features and helpful clues for the focal staining for neuroendocrine markers such as chromo- workup of such lesions are discussed. granin and synaptophysin. However, these tumors usually

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❚Image 7❚ A, Insular carcinoma of thyroid showing tumor cells arranged in insulae and prominent vessels (H&E, ×40). B, High- power view demonstrating tumor cells with small, dark, and round nuclei (H&E, ×100).

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