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Immunohistochemistry in the Diagnosis of Thymic Epithelial Neoplasms Annikka Weissferdt, MD, Frcpath and Cesar A

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Immunohistochemistry in the Diagnosis of Thymic Epithelial Neoplasms Annikka Weissferdt, MD, Frcpath and Cesar A 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 480 | www.appliedimmunohist.com r 2014 Lippincott Williams & Wilkins Immunohistochemistry in the Diagnosis of Appl Immunohistochem Mol Morphol Volume 22, Number 7, August 2014 Thymic Epithelial Neoplasms 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
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