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Adrenal Oncocytic Pheochromocytoma

Li, Maomi M.D., Ph.D.; Wenig, Bruce M. M.D.

American Journal of Surgical Pathology: November 2000 - Volume 24 - Issue 11 - pp 1552-1557
Case Reports

We report a case of adrenal oncoctyic pheochromocytoma in a 37-year-old woman. The patient presented with a 2-year history of an increase in abdominal girth. Computed tomographic studies revealed a large left adrenal mass, which was subsequently excised. Grossly, the tumor measured 17 [times] 14 [times] 8.5 cm, weighed 1150 g, and had a solid, brown cut surface. Histologically, it consisted of large polygonal tumor cells containing eosinophilic granular cytoplasm and arranged in nesting, alveolar, and trabecular patterns. Electron microscopy revealed closely packed mitochondria and dense-core membrane-bound granules in almost all tumor cells. The latter were immunohistochemically positive for chromogranin, synaptophysin, neuron-specific enolase, neurofilament, serotonin, bombesin, ACTH, vimentin, desmin, S-100 protein, and cytokeratins, including AE1/3, CAM 5.2, cytokeratin 7, and cytokeratin 20. To the best of our knowledge, this is the first reported case of adrenal oncocytic pheochromocytoma confirmed by ultrastructural study. The immunoreactivity of this tumor adds several unusual features to the wide immunohistochemical spectrum of pheochromocytoma.

From the Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York, U.S.A.

Address correspondence and reprint requests to Maomi Li, MD, PhD, Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, 1825 Eastchester Road, Room 338, Bronx, NY 10461, U.S.A.; e-mail[colon] maomili[commat]

Oncocytic tumors or tumors with oncocytic features are characterized histologically by cells with eosinophilic granular cytoplasm and ultrastructurally by the presence of numerous closely packed mitochondria. These tumors have been described in a variety of organs, most frequently in salivary glands, kidney, thyroid, parathyroid, and pituitary. 4 Tumors with oncocytic features were also infrequently reported in adrenal cortex. 2,6,15,22 However, oncocytic adrenal pheochromocytoma or oncocytic extra-adrenal paraganglioma are exceedingly rare. Two cases of extra-adrenal oncocytic paragangliomas were reported in the literature, one arising in the cauda equina 8 and the other in the carotid body. 19 One case of oncocytic pheochromocytoma was mentioned by Linnoila et al. 17 in a paper that included 120 cases of adrenal and extra-adrenal paragangliomas. However, in that case report, detailed description of histologic, immunohistochemical, and ultrastructural features were lacking. Because of unusual histology and rarity of this type of tumor, we report a case of adrenal oncocytic pheochromocytoma including its histologic, immunohistochemical, and ultrastructural features.

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A 37-year-old woman presented clinically in May 1998 with a 2-year history of an increase in abdominal girth. The patient did not have a family history of multiple endocrine neoplasia (MEN) syndrome and had no headaches, palpitation, sweating, or other symptoms. Her blood pressure and pulse were normal. Because a diagnosis of pheochromocytoma was not clinically suspected, evaluation for the presence of catecholamines was not performed. Computed tomographic (CT) studies revealed a left adrenal mass that measured 15 cm and was considered to be a malignant tumor because of the size and the presence of heterogeneous areas consistent with necrosis. No other masses were detected outside of the left adrenal gland. The radiographic appearance of the right adrenal gland was reported as within normal limits. At operation, the tumor was confined to the left adrenal gland without invasion of adjacent organs. No metastatic foci were found in the liver or other organs. The tumor was successfully removed and the patient maintained a stable blood pressure during the operation. The postoperative recovery was unremarkable. Follow up (22 mos) revealed no recurrent or metastatic disease.

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Tissue was fixed in buffered formalin, embedded in paraffin, and stained with hematoxylin and eosin. Immunohistochemical studies were performed on formalin-fixed, paraffin-embedded blocks with primary antibodies listed in Table 1 using a standard automated streptavidin-biotin-peroxidase detecting system (Ventana MedSys, Tuscon, AZ, USA). For electron micrography, tissue was fixed in glutaraldehyde, postfixed in osmium tetroxide, dehydrated, and embedded in epoxy resin. Thin sections stained with uranyl acetate and lead citrate were examined under a transmission electron microscope.

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Gross examination revealed a well-circumscribed tumor surrounded by a thin rim of fibrous capsule which measured 17 [times] 14 [times] 8.5 cm and weighed 1150 g. Residual adrenal tissue was seen focally. The cut surfaces were predominantly orange to brown punctuated by small yellow areas and foci of hemorrhage and myxoid degeneration (Fig. 1). There was no necrosis or cystic formation. Microscopically, the tumor cells were predominantly arranged in nests and trabeculae separated by delicate fibrovascular stroma (Fig. 2A). In some areas, alveolar and pseudoglandular patterns were seen. Foci of fibromyxoid degeneration with the absence of tumor cells were also present. Cytologically, the tumor cells were large, polygonal, and contained abundant eosinophilic granular cytoplasm (oncocytic features) (Fig. 2B). The nuclei were round and large with single prominent nucleolus. Occasional bizarre, highly pleomorphic nuclei and nuclear pseudoinclusions were also seen. Several small isolated areas in which a dimorphic tumor cell population consisting of intensive oncocytic cells and pale, stained cells with smaller nuclei were also noted (Fig. 2B). Mitoses were not seen and there was no evidence of necrosis, lymphovascular invasion, or extra-adrenal extension.

Immunohistochemical studies (Table 1) revealed that the tumor cells were diffusely and strongly positive for vimentin, cytokeratins, including AE1/3, CAM 5.2, and cytokeratin 7, neurofilament, desmin, chromogranin, synaptophysin, neuron-specific enolase (NSE), and bombesin (Fig. 3). Tumor cells were also reactive, although to a lesser degree, with cytokeratin 20, serotonin, and adrenocorticotropical hormone (ACTH). Staining for S-100 protein revealed diffuse staining in tumor cells and occasional staining of spindle cells located at the periphery of the neoplastic nests (that is, sustentacular cells). The tumor cells did not react with calcitonin, glial fibrillary acidic protein (GFAP), muscle specific actin, or smooth muscle actin.

Ultrastructurally, the tumor cells contained single large vesicular nuclei with prominent nucleoli. Numerous, closely packed mitochondria were seen in almost all tumor cells (Fig. 4). Round to oval membrane-bound, dense-core granules were present in a vast majority of the cells. They ranged from 150 to 310 nm in diameter but most were 230 to 280 nm. Other organelles such as rough endoplasmic reticulum, ribosomes and lysosomes, and lipid droplets were only sparsely seen. No tonofilaments or cell junctions were observed.

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Oncocytic tumors of adrenal gland are uncommon. Most reported cases are of adrenal cortical origin and include 20 cases of cortical oncocytoma, one case of cortical carcinoma, and two cases of cortical oncocytic neoplasm of undetermined malignant potential. 2 To the best of our knowledge, there is only one known case of adrenal oncocytic pheochromocytoma in the literature. 17

The major problem in the differential diagnosis of our current case was to determine its origin, that is, cortical or medullary. Because of the large size, the epicenter of the tumor could not be evaluated with certainty. The lack of symptoms and signs and the failure to measure catecholamine metabolites preoperatively further eliminated some clues for differential diagnosis. Although the histologic features, including trabecular and alveolar patterns, are more favorable for pheochromocytoma, these patterns also occur in cortical neoplasms as well. 13 However, we consider this tumor an oncocytic pheochromocytoma based on the immunohistochemical reactivity for multiple neuroendocrine markers and the ultrastructural findings of dense-core, membrane-bound granules. Although adrenal cortical tumors can be reactive with synaptophysin and NSE, they are negative for chromogranin and neural peptides. 1,12,14,15,20,23

Medline search revealed only two oncocytic paragangliomas and one oncocytic pheochromocytoma in the literature. Gaffney et al. 8 described an oncocytic paraganglioma of the cauda equina, which was locally aggressive with destruction of surrounding vertebral bone. The tumor contained numerous mitochondria and scattered dense-core, membrane-bound granules ultrastructurally and was immunoreactive for NSE, S-100 protein, keratin, and carcinoembryonic antigen. Michailow and Alexiew 19 reported an oncocytic paraganglioma of the carotid body in a 66-year-old woman that consisted of oncocytes and contained dense-core granules. The only case we could find of an oncocytic pheochromocytoma was included in a series of 120 cases of adrenal and extra-adrenal paragangliomas reported by Linnoila et al. 17 It was described as a tumor with well-developed oncocytic features throughout and characterized by cells with abundant granular eosinophilic cytoplasm. However, the clinical presentation, immunohistochemical features, and ultrastructural evidence of the oncocytes were not documented in the paper.

Oncocytic changes, either in nonneoplastic or neoplastic cells, are considered to be a cellular degenerative phenomenon. 4,9,16 It has been assumed that the accumulation of mitochondria is to compensate the uncoupling of oxidative phosphorylation. 4 This probably explains why most oncocytic tumors of endocrine organs, including the pituitary, 24 parathyroid, 3 and adrenal cortex, 22 are nonfunctional. It is probably the same mechanism that is responsible for the lack of symptoms and signs typically associated with pheochromocytoma in our current case. Unfortunately, the urine catecholamine metabolites were not measured preoperatively. Therefore, whether this tumor secreted catecholamines is unknown. Although the immunohistochemical stains for chromogranin and other neuroendocrine markers were strongly positive, dense-core granules as seen by ultrastructural study were relatively sparse.

Pheochromocytomas and paragangliomas are immunohistochemically characterized by the presence of neuroendocrine markers, including chromogranin, synaptophysin, NSE, neurofilament, and a variety of hormones. 7,10 S-100 protein is typically expressed in the sustentacular cells. However, expression of intermediate filaments has been variably reported. Kimura et al. 11 found that cytokeratin was focally positive in 13 of 37 cases of adrenal pheochromocytoma and negative in all eight cases of extra-adrenal paragangliomas. In contrast, Chetty et al. 5 detected expression of cytokeratin (CAM 5.2 and AE1/3) in three of 18 cases of extra-adrenal paragangliomas but none of the seven pheochromocytomas. Expression of cytokeratin in some cases of extra-adrenal paragangliomas was also found in two other studies. 10,21 Expression of GFAP has also been inconsistently reported. 7,10,21 Vimentin was found to be positive in some cases of pheochromocytomas as well as extra-adrenal paragangliomas. 7,10,11 Desmin was investigated in one study and found to be negative in all 29 cases of extra-adrenal paragangliomas. 10 The immunohistochemical profile of our current case reveals several interesting features[colon] positivity for desmin and S-100 protein (in chief cells) and diffuse strong staining for multiple cytokeratins. These results further illustrate the wide immunohistochemical spectrum of pheochromocytoma. Whether the concomitant expression of multiple immunologic markers in our current case is related to its oncocytic changes is unclear.

No well-defined pathologic criteria have been found to correlate malignant behavior of pheochromocytoma. The determination of malignancy in pheochromocytomas and paragangliomas is often dependent on the biologic behavior (that is, presence or absence of metastatic disease). Large tumor size and extensive necrosis were reported to be more frequently associated with malignant tumors in two large series. 17,18 Although our current tumor reached a significant size, there was no clinicopathologic evidence of malignancy. At 20-month follow up there has been no evidence of recurrence or metastasis. The large size of the tumor may be partly attributed to the delayed detection resulting from the absence of symptoms and signs. Further follow up is necessary to determine the nature of this tumor.

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Pheochromocytoma; Adrenal; Oncocytic; Mitochondria

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