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2011 — August Case of the Month

Posted August 23, 2011

CLINICAL SUMMARY: Mediastinum, posterior  

CAP Foundation August 2011 Online Case of the Month

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

A 32-year-old man with no significant previous medical history presented with sweating, headaches, and palpitations. A CT scan revealed a mass in his posterior mediastinum. Grossly, the 125 g mass measured 7.9 x 6.5 x 5.3 cm and was partially encapsulated with a deep red to pink cut surface. Sectioning revealed a single 3.1 cm cyst filled with serosanguinous fluid surrounded by red-pink, soft parenchyma.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, Case 5, and is paraganglioma.

Criteria for Diagnosis and Comments: The histologic sections demonstrate a partially encapsulated, well-circumscribed mass with a nested architecture. The septa surrounding the nests are highly vascular and show sinusoidal dilatation with formation of blood lakes. The tumor cells are relatively monotonous with small, round to oval nuclei, fine and peripherally marginated chromatin, and small, eccentric eosinophilic nucleoli. Minimal nuclear pleomorphism and a moderate amount of eosinophilic cytoplasm are present. Rare mitotic figures are identified. The histologic features are diagnostic of a paraganglioma (extra-adrenal pheochromocytoma).

The differential diagnosis of posterior mediastinal tumors includes metastatic carcinoma, neurogenic tumors (schwannoma, neurofibroma, ganglioneuroma, and neuroblastoma), soft tissue tumors, and gastroenteric cysts. Mediastinal paragangliomas are extremely rare neoplasms, accounting for less than 10% of all mediastinal neuroendocrine tumors, and 0.3% of mediastinal tumors overall. They arise in association with the aorticopulmonary vascular root (“aortic body paragangliomas”, anterior and middle mediastinum) or in a paravertebral location (“paravertebral paraganglioma”, posterior mediastinum). Aortic body paragangliomas occur in a slightly older population (average age 46 years) and tend to be nonfunctioning, versus paravertebral lesions, which occur at a younger age (average age 29 years), may be functional in up to half of cases, and thus present similar to adrenal pheochromocytoma. Nonfunctioning paragangliomas usually present as an incidental radiographic finding or due to a mass effect on adjacent structures.

Paragangliomas are unusual non-epithelial neoplasms thought to arise from neural crest progenitor cells, while neuroendocrine tumors arise from separate (but closely related) neuroectoderm. They can arise at any site where paraganglia are normally found; in fact, 23% of patients with paravertebral paragangliomas and 10% of patients overall will have multiple tumors in different sites. Grossly, they are well-circumscribed, lobulated masses, ranging from 2 to 12 cm in greatest dimension. Large tumors tend to be invasive and firmly attached to adjacent structures, giving a macroscopic appearance of malignancy. On cut surface the tumor is soft, homogenous, and tan-white, with focal areas of hemorrhage. Necrosis rarely is seen.

Histologically, two cell types exist, chief and sustentacular cells. The chief cells are arranged in a characteristic “Zellballen” pattern, with compact cell nests. Tumor cell nuclei vary from round to fusiform to extremely pleomorphic; chromatin pattern is also variable, and can be dispersed, uniformly dense, or vesicular. Nucleoli may be seen. Mitoses are usually absent but can be present in scant numbers. The cytoplasm ranges from clear to eosinophilic; the tumors can be composed exclusively of cells of either cytoplasmic type, or have an admixture of both. Other unusual histologic variants include lesions with oncocytic granular cytoplasm, prominent spindling of tumor cells, or pigmentation. Chief cells are surrounded by sustentacular cells, which stain positive for S-100 protein. The presence and number of sustentacular cells has been correlated with clinical behavior in some studies.

Histochemistry is useful for diagnosis; however, most of the formerly used techniques have been rendered obsolete by immunohistochemistry. Immunohistochemical stains such as chromogranin, synaptophysin, neurofilament, and neuron-specific enolase are usually positive. Other studies have reported variable positivity with vimentin, corticotropin, glucagon, somatostatin, and calcitonin. Most importantly, paragangliomas are negative for wide-spectrum cytokeratins and EMA (with the exception of filum terminale lesions and gangliocytic paraganglioma), an important differentiating factor from carcinoid and other epithelial neoplasms.

Ultrastructurally, numerous dense core neurosecretory granules are present. There is marked variation in their size and shape, a feature which may be helpful in differentiation from carcinoid, which tend to have smaller, less variable granules. Sustentacular cells show a lack of dense core granules.

Paragangliomas usually behave as low-grade, indolent neoplasms. 10% of cases can metastasize to lung, lymph nodes, and bone. The most significant prognostic factor is staging at the time of diagnosis. Tumors arising in the mediastinum have been shown to have a higher incidence of aggressive tumor growth, with higher rates of morbidity and mortality as compared to other primary sites. Histologic findings such as nuclear pleomorphism and hyperchromasia, mitotic activity, capsular and vascular invasion, and the presence of necrosis have not been found to be predictive of behavior; however, in one study, tumors that were invasive at the time of diagnosis were shown to be associated with a more aggressive clinical behavior. Metastatic disease is currently the only reliable criterion for determination of malignancy. Diagnosis of metastatic disease must not be made in haste; as stated earlier, multifocal disease with multiple synchronous or metachronous lesions is not uncommon. A lesion can be ruled a metastasis only if it arises in a site where paraganglia are not normally located. Complete surgical excision is the treatment of choice.

The main differential diagnosis for mediastinal paraganglioma is with thymic carcinoid and metastatic carcinoma. Thymic carcinoid displays nuclear atypia, mitotic activity and necrosis to a degree usually not seen in paragangliomas. Also, carcinoids display histological growth patterns not seen in paraganglioma, such as rosettes, ribbons, trabeculae, microacini, and festoons. Metastatic carcinoma and carcinoid tumors are generally positive for cytokeratin, while mediastinal paragangliomas are uniformly negative.  Metastatic renal cell carcinoma must be carefully considered, especially when the patient has a relevant history and/or the tumor is composed exclusively of chief cells with clear cytoplasm. Renal cell carcinomas are usually positive for wide spectrum cytokeratin and EMA, both of which are negative in paraganglioma. Medullary thyroid carcinoma is an unlikely consideration in the posterior mediastinum; like renal cell carcinoma, it can be differentiated by its cytokeratin positivity. Angiosarcoma may be a consideration due to the striking vascular pattern seen in paraganglioma; immunohistochemically, angiosarcoma is positive for vascular markers (CD31, CD34) whereas paraganglioma is negative.

Paragangliomas have been shown to be familial in some cases, associated with succinate dehydrogenase (SDH) mutations, multiple endocrine neoplasia (MEN 2A and 2B), neurofibromatosis Type I (Von Recklinghausen disease), and von Hippel-Lindau syndrome. Functional mediastinal paragangliomas associated with epithelioid gastric stromal sarcoma and pulmonary chondroma have been described as Carney triad. Extraadrenal parasympathetic paragangliomas have been shown to be associated with germline mutations in the three succinate dehydrogenase subunits (SDHD, SHDB, and SDHC). It has been demonstrated that RET is expressed but not mutated in parasympathetic paragangliomas.

Supplementary Questions:

Question Diagnostic Set
1. Which of the following statements is incorrect? A. Mitotic activity, nuclear pleomorphism, and the presence of necrosis are poorly correlated with clinical behavior.
B. Paragangliomas can be differentiated from most epithelial tumors based upon their negativity for cytokeratin and EMA, and positivity for neuroendocrine markers.
C. Paragangliomas can be functional (catecholamine-secreting) or non-functional.
D. Paravertebral paragangliomas are more likely to be functional than aortic body paragangliomas.
E. The presence of multiple tumors along the vertebrae in the thorax and abdomen is indicative of metastasis.
2. Mitotic activity is diagnostic of malignancy in paraganglioma. A. True
B. False
3. Which of the following associations with paraganglioma is incorrect? A. Carney syndrome
B. Carney triad
C. MEN II
D. Neurofibromatosis Type 1 (Von Recklinghausen disease)
E. Von-Hippel Lindau syndrome

References

  1. DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. World Health Organization Classification of Tumours: Tumours of Endocrine Organs. Lyon, France: IARC Press; 2004.
  2. Fletcher CDM. Diagnostic Histopathology of Tumors. 3rd Ed. New York, NY: Elsevier Limited; 2007.
  3. Kliewer KE, Cochran AJ. A review of the histology, ultrastructure, immunohistology, and molecular biology of extra-adrenal paragangliomas. Arch Pathol Lab Med. 1989; 113:1209-1218.
  4. Mills E. Sternberg’s Diagnostic Surgical Pathology. 4th ed. Lippincott Williams & Wilkins; 2004.
  5. Moran C, Suster S, Fishback N, Koss M. Mediastinal paragangliomas. Cancer. 1993; 72(8):2358-2364.
  6. Rosai J. Rosai and Ackerman’s Surgical Pathology. 9th ed. Mosby; 2004.
  7. Suster S, Moran CA. Neuroendocrine Neoplasms of the Mediastinum. Am j Clin Pathol. 2001; 115(Suppl 1):S17-S27.

Author:
2008
Krista L. D’Amore, MD
Medical College of Wisconsin
Milwaukee, WI.

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