REVIEW ARTICLE
Immunohistochemistry in the Diagnosis of Thymic Epithelial Neoplasms Annikka Weissferdt, MD, FRCPath and Cesar A. Moran, MD
features with tumors of other organ systems. Sufficient Abstract: The diagnosis of thymic epithelial neoplasms is nor- familiarity with the histologic characteristics of thymic mally rendered after careful evaluation of their histologic fea- epithelial neoplasms often allows diagnosis based on tures. In some cases, however, the morphological heterogeneity morphology alone, however, immunohistochemistry is or overlap with neoplasms of other organ systems can lead to sometimes used to confirm the diagnosis or, especially in diagnostic uncertainty. On the basis of this, the use of im- cases of thymic carcinoma, to exclude metastasis to the munohistochemical stains as a diagnostic adjunct has become a mediastinal compartment. Nevertheless it has to be noted popular tool. Although undoubtedly, immunohistochemistry that to date no specific marker exists that would un- has its role in the diagnosis of difficult cases, to date there are equivocally distinguish tumors of thymic epithelial origin no specific markers that would distinguish thymic epithelial from other epithelial tumors. On the basis of this, im- neoplasms from other tumors and interpretation of im- munohistochemistry plays a mere supportive role in this munohistochemical results should only ever be made in con- context making complete clinical evaluation the most im- junction with accurate morphologic analysis and careful clinical portant aspect in the diagnosis of these tumors. This article evaluation. This article will review the current knowledge of the will provide an overview of the immunohistochemical immunohistochemical phenotype of thymic epithelial neoplasms properties of thymic epithelial neoplasms with particular with particular emphasis on its use for diagnostic purposes and focus on their use for diagnostic purposes and will also the latest advances in this field. briefly review markers that have been implicated with a Key Words: thymic epithelial neoplasms, mediastinum, im- prognostic or predictive value in these tumors. munohistochemistry, thymoma, thymic carcinoma (Appl Immunohistochem Mol Morphol 2014;22:479–487) THYMOMA Similar to the normal thymic gland, thymomas ex- hibit an admixture of epithelial and lymphoid elements in he thymic gland is a lymphoepithelial organ com- varying proportions. On the basis of the shape of the Tposed of closely admixed epithelial and lymphoid epithelial cells and the proportion of lymphocytes the elements. The gland is divided into lobules each of which tumors are classified as spindle cell thymoma [World in turn contains 2 distinct areas, the cortex and the me- Health Organization (WHO) types A and AB], thymoma dulla. Whereas the cortex consists of closely packed T (B1 and B2), and atypical thymoma (B3).1 In addition, lymphocytes, the so-called thymocytes and only scattered there are special variants of thymoma that often defy dispersed epithelial cells, the medulla, comprises a large classification according to the letters and numbers pro- number of epithelial cells and only relatively few lym- posed by the WHO schema.1 Despite these histologic phocytes. Thymic epithelial neoplasms are tumors derived differences, the immunohistochemical characteristics of from the epithelial elements of the thymic gland. They are all types of thymoma are generally similar but may dis- divided into thymomas, neoplasms of low malignant po- play some special features depending on the subtype. tential and thymic carcinomas, outright malignant tu- True to their epithelial nature, the neoplastic cells of mors. Both thymomas and thymic carcinomas are tumors thymoma show positive staining for a range of keratins, that can display a wide morphologic spectrum. While for instance pancytokeratin (AE1/AE3) (Fig. 1A), thymomas are neoplasms composed of epithelial cells and low–molecular-weight cytokeratin (CAM5.2), high– thymocytes in varying numbers, thymic carcinomas are molecular-weight cytokeratin (34E12), and CK5/6.2–4 entirely epithelial tumors that share identical histologic Other carcinomatous markers such as BerEP4 and MOC31 show a more variable staining pattern decorating 3 Received for publication June 23, 2013; accepted July 15, 2013. up to a third of all cases, respectively. In the last few From the Department of Pathology, MD Anderson Cancer Center, years a range of novel markers have successfully been Houston, TX. applied to thymomas including Pax8, p63, FOXN1, and The authors declare no conflict of interest. CD205. Pax8 and p63 have been demonstrated to display Reprints: Annikka Weissferdt, MD, FRCPath, Department of Patho- diffuse and strong nuclear reactivity in up to 100% of logy, MD Anderson Cancer Center, Houston, TX 77030 (e-mail: 3,5–7 [email protected]). cases (Fig. 2A), whereas positive staining for FOXN1 Copyright r 2014 by Lippincott Williams & Wilkins and CD205 was found in 89% of spindle cell thymomas
Appl Immunohistochem Mol Morphol Volume 22, Number 7, August 2014 www.appliedimmunohist.com | 479 Weissferdt and Moran Appl Immunohistochem Mol Morphol Volume 22, Number 7, August 2014
FIGURE 1. A, Pancytokeratin decorating the epithelial cells in conventional thymoma in a typical “lace-like” pattern. B, Nuclear staining of immature T lymphocytes by TdT in con- ventional thymoma.
(WHO type A) and up to 100% of WHO type AB and B1-3 thymomas.8 Contrary to thymic carcinoma, ex- pression of c-kit and CD5 is only seen in a minority of thymoma cases.3,8–10 Finally, staining with D2-40, a lymphatic endothelial cell marker, has been identified in as much as 70% of thymomas, preferentially those types rich in epithelial cells (WHO types B2 and B3).11–12 The lymphocytic component of thymomas shows an immature T-cell phenotype and these thymocytes can be targeted with lymphocyte common antigen, CD3, CD1a, FIGURE 2. Nuclear Pax8 expression highlighting the epithelial terminal deoxynucleotidyl transferase (TdT) and CD99 cells in (A) conventional thymoma, (B) spindle cell thymoma, antibodies13–15 (Fig. 1B). However, it should be noted and (C) thymic carcinoma. that a small number of CD20-positive B lymphocytes can be found in thymomas, either as scattered single cells or relies on limited biopsy material obtained at mediastino- organized in germinal centers16 (Table 1). scopy. In this scenario, the most useful marker is a pan- One of the most commonly encountered problems cytokeratin stain: in cases of thymoma this will typically in mediastinal pathology is the distinction of thymoma, highlight a finely arborized network of interconnecting especially those with a rich lymphocytic component epithelial cell processes between the lymphocytes mani- (WHO types B1 and B2) from lymphoblastic lymphoma. festing a prominent lace-like pattern17–19 (Fig. 1A). This is mainly because of the fact that the diagnosis often Although lymphomas can entrap non-neoplastic
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TABLE 1. Immunophenotype of Thymic Epithelial Neoplasms TABLE 2. Differential Immunophenotype of Thymoma and Thymoma Thymic Carcinoma T-Cell Lymphoblastic Lymphoma Thymoma T-Cell Lymphoblastic Lymphoma CK + + CAM5.2 + + CK + À 34bE12 + + Pax8 + À CK5/6 + + CD1a + + p63 + + CD99 + + Pax8 + + LCA + + FOXN1 + + CD205 + + CK indicates cytokeratin; LCA, lymphocyte common antigen. c-kit À + CD5 +/À + CK7 +/À + TTF-1 +/ÀÀhowever, thyroglobulin antibody can help distinguish Napsin NK À between these neoplasms being positive in papillary tu- Synaptophysin +/À +/À mors of thyroid origin. Chromogranin À +/À NSE +/À +/À Adenomatoid spindle cell thymoma is a recently de- scribed variant of thymoma with a prominent glandular CK indicates cytokeratin; NK, not known; NSE, neuron-specific enolase; TTF-1, thyroid transcription factor 1. or microvesicular pattern resembling adenomatoid or yolk sac tumors.24 The spindled epithelial cells of these tumors will express epithelial markers such as CAM5.2 and epithelial membrane antigen (EMA), whereas alpha thymic epithelial cells that are visible on keratin im- fetoprotein (AFP) is negative. Calretinin on the other munostains, these cells will be widely separated and not hand, a marker known to label adenomatoid tumors may interconnecting allowing distinction from thymoma20 also show focal staining in the epithelial cells of ad- (Table 2). enomatoid spindle cell thymoma.24 Most of the existing literature on the im- Micronodular thymoma with lymphoid hyperplasia is munohistochemical pattern in thymomas is based on the a tumor composed of islands of spindled epithelial cells evaluation of the conventional types, that is, the so-called that are embedded in a prominent lymphoid stroma. The B-type thymomas. Only recently have some investigators epithelial cells have been shown to stain with cytokeratins specifically evaluated spindle cell and mixed-type thy- (CAM5.2 and AE1/AE3) and focally with bcl-2.25,26 The momas (WHO type A and AB).15,21 Generally, these more important aspect in this type of thymoma is the show a similar staining pattern as described above lymphoid stroma which is composed of a mixture of (Fig. 2B), however, the epithelial cells in these tumors can mature B (CD20+) and T (CD3+,CD5+) lymphocytes; also show expression of markers not usually associated immature T cells (CD1a+,CD99+) like commonly seen with these neoplasms: CD20 and CK7 reactivity has been in thymomas are present only in scattered form.15,25,26 identified in 90% and 83% of spindle cell thymomas, These tumors have the potential to be mistaken for respectively.15,21 Another important finding in these metastatic carcinoma or sarcoma to a lymph node; care- studies was the fact that focal staining for calretinin, ful search for cytologic atypia and increased mitotic ac- synaptophysin, bcl-2, and smooth muscle actin (SMA) tivity in the latter should help distinguish these tumors.25 can be seen in spindle cell thymomas21 and even thyroid Analogous to conventional thymoma, the so-called transcription factor 1 (TTF-1)-positive cases have been atypical thymoma with pseudosarcomatous stroma contains observed among isolated cases of spindle cell and mixed- an epithelial component that shows reactivity for cytoker- type thymomas21,22 (Figs. 3A–C) (Table 3). atin (CK), CAM5.2, EMA, AE1/AE3, p63, and e-cadher- Among the different subtypes of thymoma, several in.27 In addition, these tumors contain a second stromal deserve special mention with regard to their im- spindle cell component that shows a more variable im- munohistochemical properties. Familiarity not only with munophenotype and in addition to vimentin may show the unusual histologic features of these tumors but also focal staining with SMA or even epithelial markers.27–30 The their immunohistochemical phenotype is highly im- scarce lymphoid component is identical to that seen in portant to avoid diagnostic confusion with other neo- conventional thymomas and consists primarily of CD3+, plasms. CD99+,TdT+ T lymphocytes.27,29 Spindle cell thymoma with papillary or pseudopapil- As the name implies plasma cell–rich thymoma lary features is a spindle cell thymoma characterized by a contains abundant stromal plasma cells of polyclonal prominent papillary growth pattern.23 The main differ- nature.31 Although plasma cells may be present in the ential diagnosis for these cases includes papillary carci- normal thymus, their occurrence in thymomas is nomas of thymic or thyroid origin. The use of extremely rare and is often associated with autoimmune immunohistochemical markers in the former case will be disorders in this context.31–33 Cytokeratin will positively futile as both neoplasms express similar immunomarkers stain the epithelial cells of this thymoma, whereas kappa and cytologic features of malignancy should be sought to and lambda stains can be used to label the plasma cell distinguish the 2. In cases of papillary thyroid carcinoma, component and assess clonality.31 r 2014 Lippincott Williams & Wilkins www.appliedimmunohist.com | 481 Weissferdt and Moran Appl Immunohistochem Mol Morphol Volume 22, Number 7, August 2014
tumors primarily includes keratin-negative lesions such as sclerosing mediastinitis, solitary fibrous tumor, or Hodgkin lymphoma allowing for distinction between these entities.34,35 Two distinct cell populations characterize rhabdo- myomatous thymomas. In these tumors, epithelial and myoid elements are closely intermixed.36 The epithelial component can be targeted with stains such as AE1/AE3, CK, and BerEP4, whereas the myoid cells react with myoglobin, desmin, and vimentin.36,37 Awareness of this unusual tumor is important not to mistake this lesion for a tumor of pure skeletal muscle lineage or a carcino- sarcoma. Thymomawithsignetringcell-likefeaturesis a type of thymoma that strongly mimics signet ring cell ad- enocarcinoma or even yolk sac tumors.38 The tumor cells show reactivity for CK, AE1/AE3, CAM5.2, and CK5/6 and are negative for markers such as AFP, TTF-1, calreti- nin, CD31, S100, vimentin, and carcinoembryonic antigen (CEA). This staining patterntogetherwithanabsenceof cytologic atypia helps classify these tumors as thymoma.38,39 Finally, thymomas characterized by abundant stromal changes such as hyalinized or myxoid collagen admixed with a young fibroblastic proliferation exist (desmoplastic spindle cell thymoma).40 The spindled epi- thelial cells of these tumors show immunoreactivity for cytokeratin, CK5/6, vimentin, Pax8, and bcl-2 and lack expression of markers such as desmin, EMA, SMA, S100, and CD34 setting them apart from other tumors such as solitary fibrous tumor or synovial sarcoma.
THYMIC CARCINOMA Thymic carcinomas are a group of malignant epi- thelial tumors of the thymus that display a wide mor- phologic spectrum. Contrary to thymomas, these tumors show unequivocal cytologic features of malignancy and lack the typical lymphocytic component associated with the majority of thymomas. There are no specific histologic features that would distinguish thymic carcinomas from tumors of other organ systems and metastatic disease to the thymic gland needs to be ruled out clinically before a diagnosis of primary thymic carcinoma can be rendered. A wide range of thymic carcinoma subtypes exist of which squamous cell, high-grade undifferentiated and lym- phoepithelioma-like carcinoma types are the most com- mon.41 Although tumor subtype does not appear to have significant prognostic value, correct diagnosis in none- 41 FIGURE 3. Spindle cell thymomas can also demonstrate pos- theless required for appropriate classification. itive staining with markers not usually associated with these In general, the tumor cells in thymic carcinoma are neoplasms: (A) bcl-2, (B) thyroid transcription factor 1, and characterized by diffuse immunoreactivity for a range of (C) synaptophysin. cytokeratins including pancytokeratin, CK5/6 and CK7 as well as p633,42–47 (Figs. 4A, B). In a similar fashion to thymoma, 2 novel markers, Pax8 and FOXN1 have re- Ancient (sclerosing) thymoma shows extensive cently been shown to be expressed by the majority of stromal sclerosis that can obscure the epithelial elements thymic carcinomas (Figs. 2C, 4C). This immunoreactivity of these tumors making the use of a cytokeratin stain is a valuable tool especially in the differential diagnosis necessary to identify the epithelial nature of the tu- from non–small cell lung cancer as these markers are mor.34,35 Fortunately, the differential diagnosis for these usually negative in primary lung carcinoma cases
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TABLE 3. Differential Immunophenotype of Spindle Cell Thymic Epithelial Neoplasms and Other Spindle Cell Tumors Spindle Cell TEN Solitary Fibrous Tumor Synovial Sarcoma Spindle Cell Neuroendocrine TEN CK + À + (patchy) + Pax8 + ÀÀ +/À CD34 À + ÀÀ bcl-2 +/À ++ À EMA +/ÀÀ+ (patchy) +/À Synaptophysin +/À (patchy) À +/À (patchy) + (diffuse) Chromogranin +/À (patchy) ÀÀ + (diffuse)
CK indicates cytokeratin; EMA, epithelial membrane antigen; TEN, thymic epithelial neoplasms.
(Table 4).5,8,41 Contrary to thymoma, thymic carcinomas tion. As with thymomas, awareness of these entities is show more variation of staining with CD205 with only important in order not to mistake these tumors for neo- approximately 10% to 60% of cases showing expression plasms of a different grade or a metastatic process. of this marker.8,41 In contrast, thymomas and thymic Mucinous adenocarcinomas of the thymus are very carcinomas display a marked difference in their staining rare tumors that show morphologic overlap with meta- for c-kit; whereas thymomas are largely negative for this static mucinous carcinomas, especially those of colon or marker, thymic carcinomas have been shown to be pos- lung origin. Expression of CK and CK7 is usually iden- itive in up to 86% of cases9,41,48,49 (Fig. 4D). In the past, tified in these tumors; more variable reactivity is seen CD5 had received acclaim for its supposed high ex- with CK20, CD5, and CDX2 (Fig. 5). Negative markers pression in thymic carcinoma cells and negative ex- include TTF-1, surfactant protein-a, napsin, and pression in many other neoplasms.3,48,50–52 In the last few Pax8.59–62,41 years, however, it could be demonstrated that this marker Clear cell carcinomas of the thymus generally show a is also expressed by a range of other carcinomas as well as positive reaction for CK (both low–molecular-weight and atypical thymomas (WHO type B3), limiting the use of high–molecular-weight cytokeratins). Variable staining this antibody for the definitive diagnosis of primary has been described for CD5, CEA, and EMA, whereas thymic carcinoma.47,48,53 In addition, a study evaluating a Pax8, FOXN1, p63, CK5/6, and TTF-1 are ususally large series of thymic carcinoma showed that <40% of negative.41,63,64 cases of thymic carcinoma were positive for this marker41 Micronodular thymic carcinoma with lymphoid hy- (Fig. 4E). It should also be acknowledged that im- perplasia is the counterpart to micronodular thymoma, munohistochemical evidence of neuroendocrine differ- the discriminating factor being overt cytologic atypia in entiation is not an uncommon finding in thymic the epithelial cells of the former.65 Common to both tu- carcinomas54; patchy expression of synaptophysin, neu- mors is the prominent lymphoid stroma composed of a ron-specific enolase, and chromogranin has been identi- mixture of mature B (CD20+) and T (CD3+/TdTÀ) cells. fied in thymic carcinomas that lack the typical Kappa and lambda stains failed to demonstrate a mon- appearance of a neuroendocrine tumor. On that account oclonal proliferation.65 it has to be stressed that these carcinomas should not be Averyraretypeofthymictumoristheso-called regarded as neuroendocrine carcinomas but rather as hepatoid thymic carcinoma. This tumor strongly resembles thymic carcinomas with neuroendocrine differentiation, hepatocellular carcinoma based on its large polygonal tu- the prognosis of which does not appear to differ from mor cells.58 Expression of CK7, CK19, a-1-antitrypsin, a-1- conventional thymic carcinomas.54 Another important antichymotrypsin, and Hepar1 has been reported in this issue with thymic carcinomas is the fact that these tumors tumor in the absence of staining for AFP, placental alkaline can be positive for calretinin in a significant number of phosphatase, or CD5 among others. Intratumoral CD1a+ cases (Fig. 4F); this should be kept in mind when the or TdT+ lymphocytes were not identified.58 differential diagnosis includes mesothelial-derived le- Care should be taken not to mistake papillary thy- sions.3,41 Three additional markers that are deemed useful mic carcinoma for metastatic papillary carcinoma of for distinguishing thymoma from thymic carcinoma are thyroid or lung origin. The tumor cells in the former show glucose transporter 1 (GLUT-1), L-type amino acid reactivity for CEA, BerEP4, CD15, and variable staining transporter 1 (LAT1), and mucin 1 (MUC1); these for calretinin and CD5.66,67 Contrary to their thyroid or markers are significantly higher expressed in thymic car- lung counterparts, thyroglobulin and surfactant protein-a cinomas than in thymomas.49,55,56 TTF-1, napsin, and are reported to be negative in these tumors.66,67 CD30 have been consistently negative in thymic carci- Thymic carcinomas showing prominent rhabdoid nomas rendering these markers very useful for differential cytoplasmic inclusions have been named thymic carcino- diagnostic considerations3,46,47,50,57,58 (Tables 1 and 4). ma with rhabdoid features. These tumors are extremely Apart from the more common types of thymic rare and only few cases have been described in the liter- carcinoma, there are several tumor subtypes that show ature. Limited immunohistochemical studies in these tu- distinct morphologic features and can vary in their im- mors have revealed a CK+, FOXN1+ immunophenotype munohistochemical properties due to their cell composi- with focal staining also for CK7 and vimentin.41,57 r 2014 Lippincott Williams & Wilkins www.appliedimmunohist.com | 483 Weissferdt and Moran Appl Immunohistochem Mol Morphol Volume 22, Number 7, August 2014
FIGURE 4. Immunohistochemical phenotype of thymic carcinoma. A, Cytokeratin, (B) p63, (C) FOXN1, (D) c-kit, and (E) CD5. F, A small subset of tumors can also show focal staining with calretinin.
As the name implies spindle cell thymic carcinomas Other markers such as actin, desmin, S100 protein, are characterized by their fusiform cell morphology. HMB45, CD34, CD5, and CD99 are usually negative.68,69 These tumors are easily mistaken for mediastinal sarco- Another unique group of thymic carcinomas are mas. Immunohistocemically, however, the spindle cells salivary gland–type carcinomas. In the thymus, this group are positive for pancytokeratin and CAM5.2, whereas of tumors includes mucoepidermoid and adenoid cystic EMA and vimentin may show variable staining results. carcinoma. Although immunohistochemical analysis does
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described in tumors expressing p53,73 high–molecular- TABLE 4. Differential Immunophenotype of Thymic 74 55 49 Carcinoma and Non–Small Cell Lung Carcinoma weight cytokeratin 34bE12, LAT1, GLUT-1, IGF1R and p-AKT,75 c-kit,10 podoplanin,12 and Thymic Pulmonary Pulmonary MUC1.56 Contrary to that, expression of estrogen re- Carcinoma SCC Adenocarcinoma ceptors is inversely correlated to tumor size, clinical stage, CK + + + WHO type, and Ki67 labeling resulting in better prog- CK5/6 + + À 76 p63 + + À nosis. Like for many other solid tumors, epidermal CK7 +/ÀÀ + growth factor receptor and HER2 protein overexpression TTF-1 ÀÀ + has been demonstrated in both thymomas and thymic Napsin ÀÀ + carcinomas.77–83 However, contradicting results have Pax8 + ÀÀemerged with regard to prognostic utility.84–88 c-kit +/ÀÀ À CD5 +/À +/ÀÀ SUMMARY CK indicates cytokeratin; TTF-1, thyroid transcription factor 1; SCC, squ- amous cell carcinoma. In today’s practice of surgical pathology im- munohistochemistry plays a vital role by either estab- lishing or confirming a diagnosis. This also applies to the not usually play a major role in the diagnosis of salivary pathologic assessment of thymic epithelial neoplasms. gland–type tumors, thymic mucoepidermoid carcinomas Although unfortunately no specific marker exists for have been reported to express CK, CK7, CK20 with these tumors, a panel of several markers can be used with variable staining also for CD5, whereas TTF-1, syn- good success to differentiate these tumors from other aptophysin, chromogranin A, S100, CD99, and MUC2 neoplasms. Promising new markers to use in such a panel were negative.8,70 Thymic adenoid cystic carcinomas are include Pax8 and FoxN1 besides the more traditional even rarer than thymic mucoepidermoid carcinomas, cytokeratin and CD5 stains. Use of these markers in however, limited reports have demonstrated positive combination with relevant negative stains should aid in staining of the tumor cells for CK5/6, p63, 34bE12, along making the correct diagnosis in most cases, however, with focal synaptophysin reactivity. In contrast, CD5, c- clinical and radiologic findings should never be under- kit, chromogranin A, and CD56 appear to be uniformly estimated and still play a major role in the assessment of negative in these tumors.71,72 mediastinal masses.
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