College of American Pathologists

2011—June Case of the Month

Posted June 17, 2011


CAP Foundation April 2010 Online Case of the Month

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A 55-year-old man, with a history of myasthenia gravis for two years, presented with an anterior mediastinal mass, recently noted on CT scan. Grossly, the thymus is 118 g, 12.0 x 10.0 x 2.5 cm and shows an encapsulated, nodular, tan-white, firm cut surface.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, Case 18, and is lymphoepithelial thymoma (WHO B2).

Criteria for Diagnosis and Comments: The histologic sections demonstrate an encapsulated tumor with a lobular architecture. Lobules are irregular in configuration, separated by thick, fibrous septae, and are composed of an admixture of large epithelioid cells with plump ovoid nuclei, vesicular chromatin, and small nucleoli, and a population of small, round lymphocytes with mature chromatin, scant cytoplasm, and regular nuclear contours. Many vessels show prominent dilated perivascular spaces displaying proteinaceous fluid and lymphocytes. These histologic features are diagnostic of lymphoepithelial thymoma, corresponding to the WHO classification Type B2.

The differential diagnosis of anterior mediastinal tumors includes thymic epithelial tumors, thymic cysts, germ cell tumors, lymphomas, thyroid and parathyroid lesions, paragangliomas, and soft tissue tumors, with thymomas representing the most common tumor in this location. Thymomas are largely a tumor of adulthood, rarely diagnosed in the pediatric population. They can be incidental findings or may be seen in association with myasthenia gravis and other systemic diseases, including red cell aplasia, hypogammaglobulinemia, collagen vascular disorders, and hematopoietic malignancies. Approximately 10% of patients with myasthenia gravis will have associated thymomas; however, follicular hyperplasia is a more common histologic finding within the thymus in this population.

Thymomas are epithelial neoplasms with a variable, coexisting, non-neoplastic lymphocytic component. The neoplastic epithelial cells may recapitulate the normal mature thymus of infants and adolescents or the involuted morphology of the thymus in adults. Tumor cells stain positive for cytokeratins. With the exception of those existing in germinal centers (usually only seen in myasthenia gravis cases and a rare thymoma variant), the non-neoplastic lymphocytes are of T-cell origin and have a maturing T-cell immunophenotype, predominating consisting of immature forms and demonstrating a reproducible maturation pattern of CD1a, CD3, CD4, and CD8 expression by flow cytometry.

Many classification schemes for thymic epithelial neoplasms exist, and thus classification is complicated. The most recent WHO classification (2004) divides these tumors into two major categories based on the morphology of the epithelial cell: type A (spindle/oval) and type B (round/polygonal). Type B thymomas are further subdivided into the following: type B1, resembling normal thymic cortex admixed with areas resembling thymic medulla; type B2, a near equal admixture of plump epithelial cells and lymphocytes; and type B3, predominance of epithelial cells with round or polygonal shape with mild to moderate atypia and with a minor component of lymphocytes. Mixed thymomas, containing foci of both type A and type B thymomas, are categorized as type AB thymoma. Thymic carcinomas (formerly type C) are classified separately. The latest WHO schema has also added a number of unusual types of thymoma that do not fit into any of the above categories, including “metaplastic” thymoma, micronodular thymoma with B-cell hyperplasia, sclerosing thymoma, etc.

Prognostic factors in thymoma include clinical stage, histologic type, and the completeness of surgical resection. The most commonly used staging system is one proposed by Koga, et al. in 1994, which is a modification of an earlier system by Masaoka, wherein clinical stages are assigned based on tumor invasiveness, as follows: complete tumor encapsulation, including tumors with incomplete capsular invasion (I), microscopic transcapsular invasion (II 1), macroscopic invasion into surrounding soft tissue (II 2), invasion into neighboring organs (III), pleural/pericardial dissemination (IVa), and lymphovascular metastases (IVb). Pathology reports of thymomas must therefore include commentary on encapsulation, extent of capsular invasion, and lymphovascular invasion, when present. Many studies have established tumor invasiveness, thus clinical staging, as the most important prognostic factor in predicting biologic behavior in these tumors; i.e., clinically aggressive tumors are more likely to show evidence of invasion. Prognostic stratification by histologic subtype of thymoma, on the other hand, remains somewhat controversial. As such, some groups have advocated a more simplified, three-tiered morphologic classification, whereby low grade tumors/well differentiated thymomas (WHO types A, AB, B1, and B2) are distinguished from intermediate grade tumors/atypical thymomas (WHO type B3) and high grade neoplasms (thymic carcinoma). Indeed, all histologic subtypes can exhibit invasion; thus, regardless of morphology, all thymomas should be regarded as neoplasms capable of local spread and metastasis.

Given the patient’s history of myasthenia gravis, follicular hyperplasia is a consideration in the differential diagnosis. The majority of myasthenia gravis patients do have thymic histopathology, with 65% displaying follicular hyperplasia, defined as thymic tissue with prominent lymphoid follicles demonstrating germinal center formation. Though an organ of T-cell development, occasional germinal centers may be seen in the thymus, and therefore this diagnosis is reserved for cases with significant numbers of follicles. Follicular hyperplasia has also been described in association with hyperthyroidism, HIV, and post-chemotherapy.

Due to the prominent lymphocytic component seen in most thymomas, one of the most important differential diagnoses is lymphoma, including both Hodgkin and non-Hodgkin lymphomas (NHL). Mediastinal involvement is most common in the nodular sclerosis variant of Hodgkin lymphoma (NSHL). Low power examination of this variant of classical HL reveals a nodular architecture, with nodules separated by thick fibrous bands, which may simulate the architecture of a thymoma. In NSHL, the nodules are composed of an admixture of lymphocytes, eosinophils, histiocytes, and variants of Reed-Sternberg cells known as lacunar cells. Immunohistochemical staining with CD15 and CD30 highlight these diagnostic cells.

Several NHLs occur with frequency in the mediastinum, including mediastinal (thymic) diffuse large B-cell lymphoma (Med-DLBCL) and lymphoblastic lymphoma (LBL). Med-DLBCL is a variant of diffuse large B-cell lymphoma which has a predilection for middle-aged females and presents with a large anterior mediastinal mass. Histologically, this tumor consists of large cells with pleomorphic nuclei, mature chromatin, and pale cytoplasm, admixed with a variable amount of small, mature lymphocytes, which are compartmentalized into nests by thin bands of fibrous tissue. The large tumor cells can be identified by positive immunohistochemical staining for CD20, CD30, and CD45.

In the mediastinum, LBLs are also a strong consideration, especially T-cell LBL in pediatric and adolescent males. Characteristically, these lesions are composed of medium-sized cells with high nuclear/cytoplasmic ratios, frequent nuclear irregularities, and chromatin varying from delicate, immature to condensed and mature. Difficulty may be encountered in distinguishing T-cell LBL from the non-neoplastic T-cell infiltrate characteristic of lymphocyte-rich thymomas, particularly in small biopsies. However, in comparison, the neoplastic infiltrate of LBL is morphologically atypical and immunophenotypically aberrant.

Thymic carcinomas are rare and comprise a heterogeneous group of malignant thymic epithelial tumors, which are characterized by significant cytologic atypia and complete loss of thymic organotypical features, mimicking carcinomas seen in other locations. The WHO recognizes several morphologic variants, including squamous cell, basaloid, mucoepidermoid, clear cell, papillary, sarcomatoid, lymphoepithelioma-like, and undifferentiated carcinomas. The present case lacked the degree of cytologic atypia observed in thymic carcinoma, and retained most of the characteristic organotypical features of thymoma.

Approximately 20% of mediastinal tumors in children and adults are germ cell neoplasms. All types of germ cell tumors have been reported in this location, arising within or adjacent to the thymus. Primordial germ cells, present within midline structures during early development, are thought to represent the cell of origin for mediastinal, retroperitoneal, sacral, and pineal gland germ cell tumors. Seminomas show the same histologic features of those originating in the testes, namely uniform round to polygonal cells with abundant clear cytoplasm and well-defined cell borders, separated into nests by thin, fibrous septa with infiltrating lymphocytes and plasma cells. Tumor cells stain positive for PLAP and CD117 and are often focally, weakly positive for pan-cytokeratin. A seminomatous component can also exist as part of a mediastinal mixed germ cell tumor, much like their gonadal counterpart. The majority of mediastinal germ cell tumors, as in such neoplasms in other locations, exhibit an isochromosome 12p.

The WHO classification categorizes spindle cell thymoma as a type A thymoma. These lesions are characterized by a proliferation of spindle/oval epithelial cells, which lack cytologic atypia and are arranged in either sheets or a storiform pattern. Lymphocytes are usually scant. The histology of these tumors may simulate that of mesenchymal neoplasms, although the thymoma tumor cells are strongly cytokeratin positive. The present case would not be classified in this category, as it consists of plump, oval epithelial cells admixed with an abundance of lymphocytes rather than being primarily composed of spindle cells.

Supplementary Questions:

Question Diagnostic Set
1. Which of the following lesions is LEAST likely encountered in the anterior mediastinum? A. Germ cell tumor
B. Mediastinal (thymic) large B-cell lymphoma
C. Schwannoma
D. Thymic cyst
E. Thymoma
2. Capsular invasion in thymic epithelial tumors is diagnostic of thymic carcinoma. A. True
B. False
3. Which of the following associations is most correct? A. Myasthenia gravis and thymic follicular hyperplasia
B. Nodular sclerosis variant of Hodgkin lymphoma and CD45 expression
C. Seminomas and elevated serum AFP
D. Spindle cell thymoma and cytologic atypia
E. Thymomas and immunophenotypically aberrant T-cells


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  2. Koga K, Matsuno Y, Noguchi M, et al. A Review of 79 thymomas: Modification of staging system and reappraisal of conventional division into invasive and non-invasive thymoma. Pathology International. 1994; 44:359-367.
  3. Suster S, Moran CA. Problem areas and inconsistencies in the WHO classification of thymoma. Semin Diagn Pathol. 2005; 22:188-197.
  4. Rosai J. Rosai and Ackerman’s Surgical Pathology. 9th edition. Mosby; 2004.
  5. Suster S, Moran CA. Thymoma Classification. Current Status and Future Trends. Am J Surg Pathol. 2006; 125:542-554.
  6. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. World Health Organization Classification of Tumours. Pathology & Genetics: Tumours of the Lung, Pleura, Thymus, and Heart. Lyon, France: IARC Press; 2004.
Alexandra Harrington, MD
Medical College of Wisconsin
Milwaukee, WI.

Saul Suster, MD, FCAP
Surgical Pathology Committee
Medical College of Wisconsin
Milwaukee, WI.