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CAP Home > Case of the Month > August 2009 - Thymus > Case Critique
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2009 — August Case of the Month

Updated July 30, 2009

CLINICAL SUMMARY: THYMUS  

CAP Foundation August 2009 Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

A 50-year-old man presented with chest pain and dyspnea. Chest X-ray revealed an anterior mediastinal mass. Biopsy was performed with subsequent resection of the tumor. A 6.0 x 5.0 x 4.0 cm circumscribed mass was received which had a firm, tan cut surface with focal areas of hemorrhage. Immunohistochemical studies were positive for keratin, chromogranin and synaptophysin.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2006, Case 22 and is a Thymic carcinoid.

Criteria for Diagnosis and Comments:

This is an example of a thymic carcinoid. The tumor is characterized by a relatively uniform population of oval to polygonal cells with moderately abundant eosinophilic cytoplasm and granular nuclear chromatin. The tumor grows primarily in an organoid pattern. Some sections may also show trabecular growth and rosette formation. The mitotic rate is low, and by definition is less than 10/10HPF. Necrosis may be present in some sections.

Thymic carcinoids are very rare and comprise less than 2% of thymic epithelial neoplasms. They occur primarily in the 5th and 6th decades with a male predominance. Approximately one quarter of patients have a positive family history of MEN-1. In the WHO classification, thymic carcinoids are divided into typical and atypical varieties utilizing the same criteria that have been established for pulmonary carcinoids, although whether this approach is justified has not been validated by scientific studies. Because of this, some authors recommend that all thymic carcinoids be classified as “well differentiated neuroendocrine carcinoma”. The majority of thymic carcinoids fall into the category of atypical carcinoid, defined as having between 2-10 mitoses per 10HPF and necrosis, the latter typically being focal and or punctuate.

Clinically, thymic carcinoids present as an anterior mediastinal mass. Many are incidental findings, but local symptoms such as chest pain or shortness of breath may be present. Carcinoid syndrome is quite rare but, curiously, Cushing's syndrome is present in a third of cases and is due to tumoral production of ACTH.

Thymic carcinoids are typically circumscribed but unencapsulated, although some may be grossly invasive. They are composed of a relatively uniform population of cells as described above, but, similar to pulmonary carcinoids, may have a wide range of morphologic patterns including spindle cell and oncocytic morphology. Thymic carcinoids, like carcinoids in other sites, are positive for cytokeratin and neuroendocrine markers such as chromogranin, synaptophysin and CD56 (NCAM). As most thymic carcinoids fall into the category of atypical carcinoid, mitoses and necrosis may be present, although by definition the mitotic rate is less than 10 per 10 HPF. Some tumors may have abundant amyloid and exhibit staining with calcitonin, thereby making them essentially indistinguishable from medullary carcinoma of the thyroid. Whether these rare tumors represent true thymic epithelial tumors or tumors of heterotopic thyroid C-cells is unclear.

As with all thymic epithelial tumors, stage is the most important predictor of prognosis. Half of thymic carcinoids are encapsulated or minimally invasive (T1 or T2) while half will show more extensive invasion or metastasis at the time of diagnosis. Metastases are most frequent in the mediastinal lymph nodes but hematogenous metastases to other organs may also be seen. Overall, the 5-year survival rate ranges from 50-80% depending on the study.

The most important entities in the differential diagnosis include thymoma, particularly the spindle cell (Type A) and cortical predominant (Type B3) subtypes, thymic carcinoma, paraganglioma and small cell carcinoma.

Thymomas are much more common than thymic carcinoids and are derived from thymic epithelial cells. The spindle cell subtype may be confused with the spindle cell variant of carcinoid, and epithelial thymomas may exhibit fairly pronounced rosette formation. The presence of admixed lymphocytes, perivascular spaces and lobular architecture are important morphologic clues. Thymomas are negative for chromogranin and synaptophysin. A noteworthy pitfall is that some thymomas may be positive for Leu-7 (CD57) so this marker should not be used as the sole support for neuroendocrine differentiation when distinguishing thymoma from thymic carcinoid.

Thymic carcinomas are cytologically malignant tumors which are most commonly squamous cell carcinomas or "lymphoepithelioma-like" carcinomas. Such tumors are generally not confused with carcinoid tumors, and immunohistochemical studies for neuroendocrine markers should readily sort out difficult cases.

Small cell carcinoma is a high grade neuroendocrine carcinoma that may arise primarily in the thymus, although most cases represent extension from a pulmonary primary. Small cell carcinoma, in contrast to carcinoid, is a high grade tumor which by definition has greater than 10 mitoses per 10 HPF, with most cases having in excess of 50 mitoses per 10 HPF. The cells additionally have scant or barely discernable cytoplasm in contrast to the more abundant cytoplasm of a carcinoid tumor.

Paraganglioma is a neuroendocrine tumor which more typically arises in the middle or posterior mediastinum; although around 20% occur in the anterior mediastinum. Paragangliomas grow in a nested "Zellballen" pattern and the neuroendocrine cells are surrounded by S-100 positive sustentacular cells. They do not typically grow in a trabecular pattern or form rosettes as carcinoids do. Additionally, cytokeratin is typically negative in paraganglioma, while it is positive in carcinoid tumors.

Supplementary Questions For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
Which tumor occurs more commonly in the middle or posterior mediastinum, is positive for neuroendocrine markers but is typically negative for cytokeratin? A. Paraganglioma
B. Small cell carcinoma
C. Thymic carcinoid
D. Thymic carcinoma
E. Thymoma
Which tumor occurs in the anterior mediastinum, is positive for neuroendocrine markers and cytokeratin, has a low mitotic rate and may be associated with Cushing's syndrome? A. Paraganglioma
B. Small cell carcinoma
C. Thymic carcinoid
D. Thymic carcinoma
E. Thymoma
Which tumor occurs as an anterior mediastinal mass, shows lobular growth with admixed lymphocytes, and is positive for keratin while being negative for chromogranin and synaptophysin? A. Paraganglioma
B. Small cell carcinoma
C. Thymic carcinoid
D. Thymic carcinoma
E. Thymoma

References

  1. Gal AA, Kornstein MJ, Cohen C, Duarte IG, Miller JI, Mansour KA. Neuroendocrine tumors of the thymus: a clinicopathological and prognostic study. Ann Thorac Surg. 2001;72(4):1179-1182.
  2. Klemm KM, Moran CA. Primary neuroendocrine carcinomas of the thymus. Semin Diagn Pathol. 1999;16(1):32-41.
  3. Marx A, Shimosato Y, Kuo TT, Chan JKC, Travis WD, Wick MR. Thymic neuroendocrine tumors. In: Travis WD. Brambilla E, Muller-Hermelink HK. Harris CC. eds. World Health Organization of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press: 2004:188-195.
  4. Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol. 2000;114(1):100-110.
  5. Soga J, Yakuwa Y, Osaka M. Evaluation of 342 cases of mediastinal/thymic carcinoids collected from literature: a comparative study between typical carcinoids and atypical varieties. Ann Thorac Cardiovasc Surg. 1999;5(5):285-292.
  6. Tiffet O, Nicholson AG, Ladas G, Sheppard MN, Goldstraw P. A clinicopathologic study of 12 neuroendocrine tumors arising in the thymus. Chest. 2003;124(1):141-146.

Author:
2006
Mary Beth Beasley, MD
Surgical Pathology Committee
Providence Portland Medical Center
Portland, OR
 
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