Answer: Paraganglioma

Histology: The lesion is characterized by nests of polygonal cells surrounded by fibrovascular septa and, in many areas, by bands of collagen. The tumor cells have ample pink cytoplasm and indistinct cell borders. The nuclei are randomly arranged and have no distinct polarity to adjacent vascular septa. There may be some variability in nuclear size and nuclear “pseudo-inclusions” may be found. Variations in histology may include spindle cells or a “pseudo-sarcomatous” arrangement of tumor cells. Other variations include stromal alteration with edema, proteinaceous pink fluid or dense stromal sclerosis. An excellent discussion of pathologic features can be found in Pathology of Adrenal and Extra-Adrenal Paraganglia by E.E. Lack (W.B. Saunders Co. 1994). The endocrine nature of paraganglioma can be established (by cytochemical or immunostains). Characteristically, the cells with pink cytoplasm react with antibodies too synaptophysin, chromogranin or NSE, and are characteristically negative for cytokeratins. Antibodies to S-100 protein will stain the sustentacular cells located in the cell nest between the pink tumor cells.

Discussion: The differential diagnosis of carotid body paragangliomas often includes primary or metastatic medullary thyroid carcinoma. The presence of stromal amyloid in a lesion favors medullary thyroid carcinoma strongly over paraganglioma. Immunocytochemical positivity for cytokeratin, calcitonin and CEA would also point to a diagnosis of medullary thyroid carcinoma. The presence of S-100 protein positive cells at the periphery of the cell nest is also a useful feature in the diagnosis of paraganglioma. Renal cell carcinoma is also a lesion that can form prominent cell nests. PAS-positivity and positive immunostaining for EMA RCC or CD-10 may be helpful in the pathologic differential diagnosis. Alveolar soft part sarcoma is yet another lesion with a cell nest pattern, and it appears that a majority of “chemodectomas” reported in unusual sites might in fact be alveolar soft part sarcoma. While many ASPSs have a characteristic alveolar pattern with apparent exfoliation into central spaces, a number of cases may lack this appearance and may present only an organoid pattern, which provides confusion with paraganglioma. The tumor cells of ASPS often have a single prominent nucleolus and may have intracytoplasmic crystalline material, which is characteristically PAS-positive and diastase-resistant. ASPS does not show cytoplasmic chromophilia, and lacks the neuroendocrine immunostaining markers and S-100 positive sustentacular cells seen in paraganglioma. Unfortunately, a small percentage of alveolar soft part sarcomas can be chromogranin-positive. It is possible that the TFE-3 (an immunostain for the fusion protein present in ASPS) may be helpful in the future.

This particular outpatient actually had familial paraganglioma. Actually, 10% of pheochromocytomas are familial and usually occur as part of multiple endocrine dysplasia type 2 (MEN 2), von Hippel Lindau (VHL) disease or neurofibromatosis type 1. A subset of non-pigmented paragangliomas are also familiar, and occur in patients with germ line mutations in genes that encode subunits of the mitochondrial complex II (SDHB, SDHC or SDHD genes).