Anterior mediastinum 

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2022, Case 02 and is micronodular thymoma with lymphoid stroma of the anterior mediastinum.  

The information provided in this case was accurate and correct at the time of publication in 2022. Any changes in terminology since the time of publication may not be reflected in this case. 

On low power examination, a biphenotypic growth pattern of nests and clusters of epithelioid cells surrounded by a lymphoid stroma is noted. Vague lymphoid follicles are present in the lymphoid stroma. The nests are composed of epithelial cells exhibiting ovoid to spindle morphology with eosinophilic cytoplasm and indistinct cell borders. Lymphoid cells infiltrate the nests. No epithelial cells are identified within the lymphoid stroma. Morphology and provided immunophenotype support the diagnosis of micronodular thymoma with lymphoid stroma (MNTL).  

Thymomas are rare but represent the most common mediastinal tumor in adults, with a peak incidence between 40 to 60 years. In the United States, the average incidence rate ranges from 1.3 to 1.5 per million persons whereas the incidence rate in Asians and Pacific Islanders is about three times higher. No definite etiological factors have been implicated in the development of thymomas, although a minor role for genetic risk factors is suggested. Thymomas may be incidentally discovered on imaging and/or present with compressive symptoms. A wide proportion of thymomas (6% to 70%,) present with myasthenia gravis and/or paraneoplastic syndromes, depending on the subtype.  

Thymomas are slow-growing and tend to be well-demarcated/encapsulated, tan-pink to grey-white masses; infiltration beyond the capsule into the surrounding adipose tissue or mediastinal structures may be seen. Several common histologic subtypes have been described (Table 1), based on “organotypical” features (ie, histologic resemblance to normal thymic development), growth pattern, and cellular composition. Many classification schemes using different terminologies for the subtypes exist; however, the World Health Organization nomenclature is followed in this write-up. In summary, the A subtype is characterized by a predominant spindle-cell type epithelial component, while the B subtypes are characterized by a varying proportion of epithelial cells admixed with immature T cells. B1, B2, and B3 subtypes differ from one another in the relative proportion of epithelium to lymphocyte ratio (Table 1). In addition, mixed patterns occur within the same tumor, necessitating the need for adequate sampling (1 block per cm of gross tumor). It is recommended that thymomas with heterogenous histologic patterns be classified by listing the predominant pattern, followed by the minor components in 10% increments.  

MNTL is a rare subtype that accounts for approximately 1% of all thymomas. Most tumors are incidentally found, and myasthenia gravis is usually absent. The vast majority (60% to 70%) are stage I tumors, and the remaining are minimally invasive (stage II) tumors. Grossly, these tumors are often soft and friable. by multiple, discrete solid nests or cords of tumor cells surrounded by abundant lymphoid stroma with lymphoid follicles. Germinal centers may be seen. The nests are composed of bland, spindle to ovoid epithelial cells with scant cytoplasm with finely dispersed chromatin and inconspicuous nucleoli. The epithelial cell nests can be highlighted using pancytokeratin, CK5/6, CK19, p63, and PAX8. Unlike type A thymoma, the spindled epithelial cells of MNTL lack aberrant expression of CD20. MNTL also possess a higher degree of lymphocytic infiltrate when compared to type A thymomas. The lymphoid stroma of MNTL lacks epithelial cells and is composed mostly of a mix of mature CD20+ positive B cells and mature, CD3+/ TdT- T cells. Sparse rimming of the nests by immature (CD3+/Tdt+) T cells may be seen.

The Masaoka–Koga staging system is the most frequently used staging system for thymic neoplasms; however, the American Joint Committee on Cancer Staging Manual 8th edition has implemented a staging system as of 2016, which is now part of the College of American Pathologists staging summary protocols. A staging summary needs to be provided not just for thymic carcinomas and thymic neuroendocrine tumors but also for all subtypes of thymomas. B2 and B3 thymomas are more likely to present as stage III (Masaoka–Koga stage) when compared to other subtypes.

Thymic follicular hyperplasia shows retained normal thymic weight and lobular thymic architecture with increased lymphoid follicles with germinal centers in the interstitium and corticomedullary junction. The epithelial component is inconspicuous. Thymic follicular hyperplasia is most often associated with myasthenia gravis. Thymic follicular hyperplasia may be idiopathic or secondary to autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis etc. On the other hand, true thymic hyperplasia is defined as increase in age-adjusted, weight and size of the thymus with retained lobular architecture. There is no influx of reactive inflammatory cells.

Typical carcinoid tumor of the thymus is a rare neuroendocrine neoplasm devoid of necrosis that shows fewer than 2 mitoses per 2 mm2. Thymic neuroendocrine tumors are classified similar to their lung counterparts. Twenty-five percent of thymic carcinoid tumors are associated with a family history of Multiple Endocrine Neoplasia syndrome, Type 1. These tumors show prototypical neuroendocrine features such as rosetting, nests, and trabecular growth pattern invested by a delicate vascular network. Like thymomas, carcinoid tumors show expression of cytokeratin; however, the latter are also strongly reactive for neuroendocrine markers (synaptophysin, chromogranin, INSM1, and CD56).

Thymic carcinomas account for 22% of all thymic neoplasms, of which squamous cell carcinomas are the predominant subtype. Thymic carcinomas show infiltrating, jagged islands in a desmoplastic stroma. Tumor cells are polygonal with a greater degree of nuclear atypia, such as vesicular or hyperchromatic nuclei with distinct nucleoli. Mitotic figures are appreciable, and necrosis may be seen. Akin to thymomas, thymic carcinomas are positive for keratins, p63, and PAX8; these are more likely to express CD5, CD117, GLUT1, and MUC1 (approximately 70% to 80%).

Mediastinal seminoma and granulomatous inflammation are easily distinguished from thymomas by their morphology and immunoprofile. Mediastinal seminomas are malignant germ cell tumors composed of nests of large, keratin negative, neoplastic cells with abundant clear cytoplasm, round nuclei and prominent nucleoli. These are associated with varying amounts of lymphoplasmacytic/granulomatous response. Seminoma is positive for OCT3/4, PLAP, and CD117.   

Non-necrotizing granulomatous inflammatory processes such as sarcoidosis may involve the anterior mediastinum. Sarcoid granulomas are typically well-formed, with sparse lymphocyte rimming (so called “naked” granulomas) and fibrosis. Multinucleated giant cells with intracytoplasmic inclusions may be present. Immunohistochemical stains are usually not needed to ascertain histogenesis but may be highlighted by CD68 and/CD163 immunostains in challenging cases.

Table 1. Common thymoma subtypes

1. Which of the following thymoma subtypes show a spindle cell epithelial proliferation with sparse lymphocytes? 
    
   1. Micronodular thymoma with lymphoid stroma
   2. Thymoma, type A
   3. Thymoma, type B1
   4. Thymoma, type B2
   5. Thymoma, type B3 
       
2. CD5 and CD117 expression is more likely to be expressed in which of the following anterior mediastinal lesions? 
    
   1. AMicronodular thymoma with lymphoid stroma
   2. Thymic carcinoma
   3. Thymic follicular hyperplasia
   4. Thymoma, type A
   5. Typical carcinoid tumor  
       
3. Myasthenia gravis is commonly associated with which of the following anterior mediastinal lesions? 
    
   1. Micronodular thymoma with lymphoid stroma
   2. Non-necrotizing granulomatous inflammation
   3. Seminoma
   4. Thymic carcinoma
   5. Thymic follicular hyperplasia 

1. Cheung AN, Kim KR, Longacre TA, Malpica A. “Tumours of the peritoneum.” WHO classification of tumours: female genital tumours, 5th edition, edited by the WHO Classification of Tumours Editorial Board, IARC, 2020, pp. 176-214.
2. Churg A, Cagle PT, Roggli VL, eds. Tumors of the serosal membranes. American Registry of Pathology (ARP) publishing. 2006.
3. Ferguson AW, Katabuchi H, Ronnett BM, Cho KR. Glial implants in gliomatosis peritonei arise from normal tissue, not from the associated teratoma. Am J Pathol. 2001;159(1):51-55.
4. Kwan M, Kalle W, Lau GTC, Chan JKC. Is gliomatosis peritonei derived from the associated ovarian teratoma? Hum Pathol. 2004;35(6):685-688.
5. Levy AD, Shaw JC, Sobin LH. Secondary tumors and tumor-like lesions of the peritoneal cavity: imaging features with pathologic correlation. Radiographics. 2009;29(2):347-373.
6. Liang L, Zhang Y, Malpica A, et al. Gliomatosis peritonei: a clinicopathologic and immunohistochemical study of 21 cases. Mod Pathol. 2015;28(12):1613-1620.  
7. Ordóñez NG. The diagnostic utility of immunohistochemistry and electron microscopy in distinguishing between peritoneal mesotheliomas and serous carcinomas: a comparative study. Mod Pathol. 2006;19(1):34-48.  
8. Toriyama A, Ishida M, Amano T, et al. Leiomyomatosis peritonealis disseminata coexisting with endometriosis within the same lesions: a case report with review of the literature. Int J Clin Exp Pathol. 2013;6(12):2949-2954.  

1. B- It is considered a World Health Organization grade 0 lesion
2. B- Immature neuroepithelial elements
3. E- Secondary involvement by metastases