A 45-year-old man presents with refractory hypertension, hyperhidrosis, headaches, palpitations, and anxiety. Laboratory workup reveals markedly elevated norepinephrine levels at 14,900 pg/ml, total metanephrines at 24.4 mg per 24 hours, and total vanillylmandelic acid at 60.2 mg per 24 hours. Imaging studies show a well-circumscribed and highly vascular 15.0 cm mass at the superior pole of the right kidney, extending into the retroperitoneum.
The resection specimen includes the right kidney with an associated retroperitoneal mass. Examination reveals a 15.0 x 14.0 x 14.0 cm mass weighing 830 grams, with a multilobular, variegated yellow-tan and brown cut surface, which is soft and appears necrotic in places. The mass is densely adherent to the perinephric adipose tissue, but it does not appear grossly to invade the renal parenchyma. No adrenal gland is identified grossly. The remaining renal parenchyma is unremarkable.
Immunohistochemically, the tumor cells are positive for chromogranin, synaptophysin and neuron-specific enolase. The tumor is negative for renal cell carcinoma antibody, CD117, CK7, and TFE3. The tumor is mostly negative for pancytokeratin, with occasional positive foci. The tumor cells are not positive for S100; however, the supporting network of stromal cells (the sustentacular cells) surrounding the tumor cell nests are positive for S100.
Master List of Diagnoses
- Adrenal cortical adenoma
- Adrenal cortical carcinoma
- Alveolar soft part sarcoma
- Chromophobe renal cell carcinoma
- Oncocytoma (adrenocortical)
- Papillary renal cell carcinoma
Archive Case and Diagnosis
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 28, and is pheochromocytoma of the kidney and peritoneum.
Criteria for Diagnosis and Comments
The histological sections reveal a circumscribed mass with a multilobular, alveolar and trabecular architecture. The tumor cells are present in nests and sheets, with some foci having a follicular or glandular structure. The surrounding stroma is composed of a highly vascular fine capillary meshwork. Necrotic and hemorrhagic foci are present. The tumor cells are intermediate in size with predominantly polygonal cells and areas of spindled cells. Many tumor cells have an eosinophilic and granular cytoplasm, though clear cells are present occasionally. Eosinophilic hyaline globules are variably present within the tumor cell cytoplasm. The tumor nuclei are round to ovoid and hyperchromatic with coarse, stippled chromatin with marked nuclear pleomorphism and prominent nucleoli. The nuclear to cytoplasmic ratio is slightly increased. Nuclear pseudoinclusions are occasionally present. Mitotic figures are rare and normal in appearance. There is no involvement of the renal parenchyma by the tumor and there is no evidence of normal adrenal tissue in association with the tumor.
Overall, these are features of pheochromocytoma, confirmed by the immunohistochemical results reported above.
Pheochromocytomas are rare tumors of the catecholamine-secreting chromaffin cells of the adrenal medulla. As such, it is not surprising that patients with pheochromocytoma typically present with signs and symptoms of catecholamine hypersecretion: headache, hyperhidrosis, palpitations, anxiety, and sustained, refractory hypertension. Laboratory diagnosis is facilitated by measurement of serum and urine measurements of catecholamines and catecholamine metabolites (metanephrines and vanillylmandelic acid). The most sensitive diagnostic test for pheochromocytoma is plasma-free metanephrines, which represents the recommended first-line test; however, the most specific test is urinary vanillylmandelic acid.
Pheochromocytomas are usually benign, and surgical excision is curative. Malignant pheochromocytomas (approximately 10% of all pheochromocytomas) are diagnostically challenging, with the only absolute criterion defining malignancy as the presence of nodal or distant metastases. Focal invasion is a poor predictor of metastatic behavior, as is mitotic rate or nuclear pleomorphism; the highly vascular nature of the tumor makes hemorrhage and necrosis common, even in very benign-appearing tumors. A recent case series demonstrated that induction of angiogenesis-driving genes (VEGF, endothelin receptor, etc) does appear to be more common in metastatically proven malignant pheochromocytomas than in benign pheochromocytomas. Malignant pheochromocytomas have a poor prognosis, with a 5-year survival at less than 50%.
About 10% of pheochromocytomas are familial and these tumors are commonly seen in several genetic syndromes, including the subtypes of multiple endocrine neoplasia type 2 (MEN2A and MEN2B) and von Hippel-Lindau (VHL) disease. Pheochromocytomas in the MEN2 syndromes and VHL disease are usually benign but have a tendency to recur; they are bilateral in 50% of cases. The genes involved in the pathogenesis of pheochromocytoma include the RET proto-oncogene (mutated in MEN2) and the VHL tumor suppressor (mutated in VHL disease). The NF1 tumor suppressor gene is also involved, but in spite of the NF1 gene mutations present in neurofibromatosis type 1, pheochromocytomas are not a characteristic tumor of this syndrome. Other less-well understood genes that have been implicated in pheochromocytoma pathogenesis include TMEM127, MAX, H-RAS, and KIF1B.
The differential diagnosis includes neoplasms of adrenal origin (such as adrenal cortical adenoma or adrenocortical oncocytoma), renal origin (such as chromophobe renal cell carcinoma or papillary renal cell carcinoma), or neoplasms of the soft tissues (such as alveolar soft part sarcoma).
Adrenal tumors of any type should lead the list of differential diagnoses, given the apparent lack of involvement of the renal parenchyma. Adrenocortical neoplasms are typically well-circumscribed with a widely variable gross appearance from pink to yellow-tan. Adenomas tend to be smaller and homogenous, whereas carcinomas tend to be larger with gross necrosis. Functional tumors are common; the most common clinical presentations in these cases are hyperaldosteronism and virilization. Microscopically, these tumors have an admixture of trabecular, alveolar, and solid architecture. The nests are composed of polygonal cells with a vacuolated to eosinophilic and granular cytoplasm. The nuclei are round (or more variable in carcinomas), with coarse, stippled chromatin and prominent central nucleoli. Nuclear pseudoinclusions are variably present. Immunohistochemically, these tumors are weakly positive for synaptophysin and neuron-specific enolase; however, they are negative for chromogranin. The majority of tumors are positive for pancytokeratin, and an S100 stain will fail to highlight the sustentacular network of a pheochromocytoma.
An adrenocortical oncocytoma (an oncocytic variant of the adrenal cortical adenoma) is typically well-circumscribed with a classic "mahogany brown" surface. These tumors are composed of densely eosinophilic cells in nests with regular nuclei and central nucleoli, though some degree of nuclear pleomorphism can be present. However, necrosis is not seen, and these tumors show the same immunohistochemical profile as adrenal cortical adenomas.
Though the tumor does not appear to involve the renal parenchyma at all, by virtue of this tumor's proximity to the kidney, renal tumors must be considered in the differential diagnosis. Papillary renal cell carcinomas are usually well-circumscribed, often with a pseudocapsule in the renal parenchyma; they can have a widely variable tan to yellow to brown gross appearance. Microscopically, these tumors are composed of papillary to papillary-trabecular and solid architecture. The tumor cells are cuboidal to polygonal with amphophilic cytoplasm and varying degrees of nuclear pleomorphism and nucleolar prominence. Cells can be variably oncocytic or cleared, and hemorrhage and necrosis are common. Immunohistochemically, these tumors are usually positive for renal cell carcinoma antibody and pancytokeratin, and negative for chromogranin, synaptophysin, and neuron-specific enolase, a pattern opposite that of the pheochromocytoma in this case.
Chromophobe renal cell carcinomas are also usually well-circumscribed with a tan to brown appearance. They are usually unencapsulated and solid with alveolar and nested foci. The nests are composed of polygonal cells with granular eosinophilic to cleared-out cytoplasm and stark cytoplasmic borders (the "plant cell wall" appearance). Immunohistochemically, these tumors usually express strong and positive CK7 and CD117, while they are negative for synaptophysin, in contrast to pheochromocytomas.
A soft tissue neoplasm, such as alveolar soft part sarcoma, should also be considered. These tumors are most common in the deep soft tissues of the thigh (in adults) and have a widely variable gross appearance. Microscopically, the cells of alveolar soft part sarcoma are present as large polygonal cells in alveolar nests surrounded by a thin microvasculature. The cells have uniform, round nuclei and abundant granular cytoplasm. The nuclei have clumped chromatin with variable nucleoli and rare mitotic figures. Immunohistochemically, these tumors show a myogenic origin and are negative for neuroendocrine markers. Also, these tumors are characterized by der(17)t(X;17) translocation producing an ASPSCR1-TFE3 fusion gene, which results in TFE3 overexpression. In the index case, a lack of TFE3 overexpression by immunohistochemistry is helpful in ruling out alveolar soft part sarcoma in favor of pheochromocytoma.
- Which of the following laboratory tests is recommended as the first-line test for excluding or confirming the diagnosis of pheochromocytoma?
- Plasma catecholamines
- Plasma-free metanephrines
- Urinary catecholamines
- Urinary-free metanephrines
- Urinary vanillylmandelic acid
- Which genetic syndrome is most commonly associated with pheochromocytomas?
- Cowden syndrome
- Multiple endocrine neoplasia type 1
- Multiple endocrine neoplasia type 2
- Neurofibromatosis type 2
- Tuberous sclerosis
- Which of the following histologic findings allows for a definitive diagnosis of malignant pheochromocytoma?
- Distant metastases
- Focal invasion
- Increased mitotic rate
- Marked nuclear pleomorphism
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- Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA. 2002;287(11):1427-1434.
- Mills SE, Greenson JK, Hornick JL, Longacre TA, Reuter VE, eds. Sternberg's Diagnostic Surgical Pathology, 6th ed. Philadelphia, PA: Wolters Kluwer Health. 2015;209-210;633-639;1980-1989.
- Neumann HP, Berger DP, Sigmund G, et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med. 1993;329(21):1531-1538.
William R. Borch, MD
Surgical Pathology Resident
Walter Reed National Military Medical Center
Justin M. Wells, MD
Surgical Pathology Committee
Walter Reed National Military Medical Center
- Plasma-free metanephrines (b)
- Multiple endocrine neoplasia type 2 (c)
- Distant metastases (a)