Functional Oncocytic Adrenocortical Carcinoma
Abdullah Essa Ali · Simon J. Raphael
Published online: 11 September 2007 C Humana Press Inc. 2007
Abstract We present a case of oncocytic adrenocortical carcinoma in a 25-year-old man who presented with persistent hypertension, hypokalemia, and a large right adrenal mass. Clinical workup revealed increased serum aldosterone level, suppressed serum ACTH level and high 24-h urine cortisol. Histologically the tumor showed several features of malig- nancy and electron microscopy confirmed oncocytic differ- entiation. This case is reported as the first case of an aldosterone and cortisol-producing malignancy with an oncocytic phenotype.
Keywords functional · adrenal · carcinoma · oncocytic . aldosterone
Introduction
The oncocytic variant of adrenocortical carcinoma (ACC) is exceedingly rare with only 16 cases having been reported [1, 4-6, 8, 9, 11]. By definition, oncocytic neoplasms consist exclusively of oncocytes whose light microscopic hallmark is abundant granular eosinophilic cytoplasm and ultrastruc- turally show cytoplasm filled with mitochondria [6]. We report a case of oncocytic ACC producing cortisol and aldosterone in a symptomatic patient; to our knowledge, this is the first time this has been reported in the literature.
A. E. Ali . S. J. Raphael Department of Pathology, Sunnybrook Health Science Centre, 2075 Bayview Avenue, Room E-432, Toronto, ON M4N 3M5, Canada e-mail: simon.raphael@sunnybrook.ca
S. J. Raphael Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Clinical History
A 25-year-old man presented with hypertension over a period of 2 years that was resistant to medical treatment. He was found to have hypokalemia. Physical examination was unremarkable apart from high blood pressure. Laboratory investigation showed a suppressed ACTH level of less than 2.0 pg/ml (8-10 pg/ml) and an A.M. serum cortisol within the normal range at 265 nmol/1 (82-958 nmol/l), but a 24-h urine- free cortisol excretion was elevated at 1,183 nmol/24 h (55- 248 nmol/24 h). Serum aldosterone level was elevated at 1,715 nmol/1 (110-860 nmol/1). His 24-h urine screening for pheochromocytoma was negative. CT scan of the abdomen revealed a large, lobulated, solid mass arising from the right adrenal gland. The patient underwent a right adrenalectomy. Postoperative hormone levels were not available.
Materials and Method
The specimen was fixed in 10% formalin, embedded in paraffin and cut at 5 um. Immunohistochemical staining was performed using the avidin-biotin peroxidase method. The antibodies used in this study were directed against: inhibin (1/50, monoclonal, Serotec), synaptophysin (1/100, mono- clonal, Vector), vimentin (1/1000, monoclonal, Zymed), pankeratin (1/300, monoclonal, Dako), cytokeratin 7 (1/4000, monoclonal, Dako), chromogranin (1/200, polyclonal, Dako), melan A (1/100, monoclonal, Zymed), EMA (1/1200, mono- clonal, Dako), CD117 (1/400, polyclonal, Dako), S100 protein (1/1500, polyclonal, Dako), hepar-1 (1/400, mono- clonal, Dako), p53 (1/500, monoclonal, Novocastra), and Ki67 (1/400, polyclonal, Neomarker). Tissue for electron microsco- py was routinely processed, stained with uranyl acetate, and examined in a ZEISS EM 109 electron microscope.
Results
The specimen weighed 90 g and measured 8.5x7.0x 4.5 cm. The tumor was lobulated and tan-brown with foci of hemorrhage and necrosis. A remnant of adrenal gland was noted adjacent to the tumor showing cortical flattening and atrophy. A total of 12 representative sections from the tumor were taken. Microscopically, the tumor was com- posed exclusively of polygonal cells with abundant gran- ular eosinophilic cytoplasm. These oncocytes grew in diffuse sheets with large foci of necrosis (Fig. 1). The tumor invaded outside its capsule and broad fibrous bands were noted within the tumor. There was focal marked nuclear pleomorphism. A maximum of seven mitoses were counted in 50 HPF, but no atypical mitoses were seen. Evidence of fresh and old hemorrhage was seen micro- scopically. Histochemically, the tumor was negative for PAS-D and Hale stains. Immunohistochemically, it was positive for synaptophysin, vimentin, and inhibin alpha (Fig. 2). The tumor was negative for calretinin, S100 protein, pankeratin, CK7, chromogranin, EMA, melan-A, hepar-1, CD117 and p53. Ki-67 was estimated to stain 10% of tumor cells. Electron microscopy showed tumor cells packed with mitochondria (Fig. 3).
The most important practical problem regarding oncocytic adrenocortical carcinomas concerns their biological behavior, that is their distinction form adrenocortical oncocytomas [2, 3, 9]. According to the Weiss criteria of malignancy for adrenocortical tumors, there are nine pathological findings: high nuclear grade (Fuhrman III or IV), less than 25% clear cells, diffuse architecture, tumor necrosis, five or more mitotic figures/50 HPF, atypical mitoses, capsular invasion, venous invasion, and sinusoidal invasion that can help define malignancy [12, 13]. The presence of three or more of the above findings correlates with subsequent malignant behav-
ior. Our case possessed six of these features. Therefore, we diagnosed our case as an oncocytic adrenocortical carcino- ma. Between our initial diagnosis and the submission of this case report, the patient developed extensive local recurrence with hepatic invasion. Hypertension also persisted postoper- atively. The histology of the recurrent tumor was similar to that of the primary lesion.
Discussion
Adrenocortical carcinoma (ACC) is a rare tumor accounting for 0.05-0.2% of all malignancies [3]. Several variants have been reported, including myxoid and oncocytic variants. Oncocytic adrenocortical neoplasms are extremely rare and are found predominantly in adults [5]. The majority of those reported have followed a benign clinical course and were called oncocytoma. To date, 16 cases of oncocytic adreno- cortical carcinomas have been described [1, 4-7, 9, 11]. The majority of oncocytic ACCs are non-functional and are usually detected incidentally, present as an abdominal mass or with pain [2, 5, 9].
The differential diagnosis of oncocytic ACC includes: adrenocortical oncocytomas, conventional ACC, pheochro- mocytoma, chromophobe renal cell carcinoma, and metastatic hepatocellular carcinoma [5]. Conventional ACC may have focal areas of oncocytic changes only, unlike oncocytic ACC. Pheochromocytomas are functional tumors producing episodic hypertension. They are chromogranin positive and ultrastructural examination shows neurosecretory granules rather than mitochondria. Chromophobe renal cell carcino- mas are EMA-positive and inhibin-negative. Electron micro- scopic examination shows cytoplasmic vesicles. Metastatic hepatocellular carcinoma is usually hepar-1 positive.
In the distinction of oncocytoma from oncocytic ACC, it is problematic to apply the Weiss criteria because both these tumor types generally contain less than 25% clear cells and show diffuse architecture. Only one additional histological finding is then needed to make a diagnosis of malignancy. Thus, it was suggested that oncocytic adreno- cortical neoplasms should be assessed conservatively in the absence of mitotic activity, necrosis, or invasion [9].
Markers such as P53 and Ki-67 have been proposed to be potential predictive markers of biological behavior [5]. Our case shows 10% of tumor cells positive for Ki-67 and was negative for P53. Studies have demonstrated low or absent P53 and Ki-67 immunoreactivity in adrenal adenomas; however, the rate of immunoreactivity among adrenocortical carcinomas has been highly variable, ranging from 5% to 52% [10].
Although our patient had a high level of urine-free cortisol, his early morning cortisol was within normal limits. This could be explained by episodic cortisol secretion by the tumor. In addition, the patient did not show Cushingoid features,
possibly because malignancy-associated factors may work against the development of such features.
In summary, we report the first case of an oncocytic adrenocortical carcinoma producing cortisol and aldosterone. This case adds to our knowledge of the wide morphologic range in these tumors and particularly our knowledge of the spectrum of functional malignant tumors of the adrenal cortex.
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