Adrenocortical Oncocytoma - Springer Link

Surg Today (2007) 37:612–617 DOI 10.1007/s00595-006-3458-4

Adrenocortical Oncocytoma — A Rare Tumor of Undefined Malignant Potential: Report of a Case Dimitrios Botsios1, Konstantinos Blouhos1, Konstantinos Vasiliadis1, Anthoula Asimaki2, Konstantinos Tsalis1, and Dimitrios Betsis1 1 2

Fourth Department of Surgery, Aristotle University of Thessaloniki, Exohi 570 10, Thessaloniki, Greece Department of Histopathology, General Regional Hospital “George Papanikolaou,” Exohi 570 10, Thessaloniki, Greece

Abstract Adrenocortical oncocytomas are exceptionally rare. To our knowledge, only 23 cases have been reported in the world literature, most of which were benign and nonfunctioning. We report a case of adrenocortical oncocytoma diagnosed by pathological examination of an extirpated right adrenal mass in a young woman. We discuss this case and review the literature on this unusual entity. Key words Adrenocortical neoplasm · Oncocytoma

Introduction 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 the salivary glands, kidney, thyroid, parathyroid, and pituitary.1,2 An oncocytoma arising in the adrenal gland is an extremely rare finding. We are aware of only 23 cases reported in the English literature.3–16 In all the reported cases, a benign clinical behavior was observed, except for one case, which stood out for its local malignant behavior.11 Nevertheless, the histological findings seemed to indicate malignant potential in a few cases, leading to a borderline and nondefinitive diagnosis of benignity.4 Because of its unusual histology and rarity, we report a case of adrenocortical oncocytoma, detailing its histologic, immunohistochemical, and ultrastructural features.

Reprint requests to: K. Vasiliadis, Dorileou 3, 55133 Thessaloniki, Greece Received: Oct 4, 2006 / Accepted: Nov 18, 2006

Case Report A 36-year-old woman was found to have a right upper pole renal mass during an evaluation for flank pain and emesis. The patient denied a history of smoking, hematuria, headaches, palpitation, or excessive and inappropriate perspiration. Physical examination revealed mild left flank tenderness, but no palpable mass. She had no Cushingoid features, petechiae, or abdominal striae. An abdominal computed tomography (CT) scan showed a 6.2 × 5.5-cm mass in the superior aspect of the right kidney (Fig. 1). A pelvic CT scan and chest roentgenogram were normal. Her serum electrolytes, blood urea nitrogen, creatinine level, and complete blood count were also normal. Urinalysis showed two to four red cells per high-power field. At the same time, screening for Cushing’s syndrome, aldosteronoma, and pheochromocytoma proved negative. Subsequent biochemical testing for urinary free cortisol, serum aldosterone, and urinary catecholamine metabolites was normal. The tumor size remained unchanged on repeat imaging scans. Her family history was noncontributory. We suspected that the tumor was of adrenal origin, because of its position, but the gland could not be detected. Thus we performed magnetic resonance imaging (MRI), which confirmed the inhomogeneous pattern of the lesion and the possible presence of a capsule, but again, the right adrenal gland could not be identified (Fig. 2). There were no features suggesting invasion of the surrounding structures, or enlarged lymph nodes. We made a provisional diagnosis of retroperitoneal neoplasm of uncertain origin. Considering the regular margins of the tumor, the presence of a capsule, and the lack of lymph node enlargement or other organ metastasis, we assumed low aggressive potential. The patient underwent an open anterior surgical resection of the neoplasm with no further diagnostic procedures, such as aspiration cytology or fine-needle biopsy. At the operation the tumor seemed to originate

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Fig. 1. Magnetic resonance imaging (MRI) showed a 6.2 × 5.5-cm mass in the superior aspect of the right kidney. There were no features suggesting the invasion of surrounding structures, or enlarged lymph nodes

Fig. 3A,B. Tumor cells with abundant granular cytoplasm and moderately pleomorphic nuclei (H&E; A ×400, B ×1600). Inset: The tumor cell cytoplasm is packed with mitochondria (electron microscopy, ×15 640)

Fig. 2. Magnetic resonance imaging (MRI), which confirmed the inhomogeneous pattern of the lesion and the possible presence of a capsule. Again, the right adrenal gland could not be identified

from the adrenal gland, which was partially distorted by the mass and closely attached to it. It did not invade the surrounding structures, and was surrounded by a capsule. The neoplasm measured 6.2 cm in its major axis and weighed 35 g. Pathologic Findings Gross examination revealed a well-circumscribed tumor surrounded by a thin rim of fibrous capsule, which

measured 5 × 6.2 × 4 cm. Residual adrenal tissue was seen focally. The cut surface was predominantly orange to brown. There was no necrosis or cystic formation. Microscopically, the tumor cells were predominantly arranged in nests and trabeculae, separated by delicate fibrovascular stroma. Cytologically, the tumor cells were large, polygonal, and contained abundant eosinophilic granular cytoplasm, representing oncocytic features. The nuclei were round and large with a single prominent nucleolus (Fig. 3). Occasional bizarre, highly pleomorphic nuclei and nuclear pseudoinclusions were also seen. Mitoses were not seen and there was no evidence of necrosis, lymphovascular invasion, or extraadrenal extension (Fig. 4). Immunohistochemical studies revealed that the tumor cells were diffusely and strongly positive for vimentin, neuron-specific enolase, and synaptophysin (Fig. 5);

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Fig. 4A,B. The interface of the tumor and normal adrenal parenchyma (H&E, ×100)

Fig. 5A,B. The tumor cells displayed strong cytoplasmic positivity for vimentin and synaptophysin (×1600)

and to a lesser degree, for chromogranin. Staining for S-100 protein revealed occasional staining of spindle cells located at the periphery of neoplastic nests; namely, systentacular cells. The tumor cells did not react with calcitonin, glial fibrillary acidic protein, or musclespecific aptin cytokeratins, including AE1/AE3, and CK7. Tissue previously formalin fixed was resin embedded and examined under electron microscopy, which revealed tumor cells packed with mitochondria (Fig. 3, inset). On the basis of these findings, we made a final diagnosis of an adrenocortical oncocytoma. The patient had an uneventful postoperative course and was discharged 5 days after surgery. Because the tumor was deemed to be benign, she received no further treatment. However, she is being followed up by a physical examination and ultrasound scan of the abdomen 6-monthly for the first year, then yearly for the next 5 years.

Discussion Tumors composed entirely of oncocytes are well described in the kidney, thyroid, and salivary glands, and less commonly in other sites, including the pituitary and parathyroid glands, lachrymal gland, respiratory tract, and choroid plexus.1 Oncocytoma refers to any tumor composed predominantly or exclusively of polygonal oncocytes with abundant granular and intensely eosinophilic cytoplasm.1 Oncocytic adrenal cortical neoplasms are extremely rare. Our search of the English literature found only 23 cases reported to date.3–16 Most of these adrenocortical oncocytomas were well circumscribed, ranging in size from 2.2 to 15 cm in greatest dimension (average 8.4 cm), with a mean weight of 281 g (range 8– 865 g). The mean age of the patients was 43.5 years (range, 27–72 years), with a female predominance of 2 : 1. With the exception of one adrenocortical oncocy-


toma that originated in heterotopic supra-adrenal retroperitoneal tissue,10 all arose in the adrenal glands, with a predilection for the left (7 : 5). Our patient was a 36-year-old woman, and the tumor was located in the right adrenal gland. Most of these reported tumors were “incidentalomas,” in that they were detected during the evaluation of unrelated problems. It is estimated that an incidental adrenal mass will be discovered in at least 1%–2% of patients who undergo abdominal CT scans for unrelated reasons.17 These adrenal “incidentalomas”18 may be cortical adenomas, cysts, myelolipomas, ganglioneuromas, cortical carcinomas, pheochromocytomas, or adrenal metastases from other tumors. In patients with a known extra-adrenal malignancy, the most common cause of an incidental adrenal mass is metastasis. Excluding this patient population, most adrenal incidentalomas are non-functioning cortical adenomas.19 Nevertheless, a careful biochemical evaluation should be performed to eliminate the presence of functioning cortical adenomas, carcinomas, or pheochromocytomas. Any evidence of hormone hypersecretion is an indication for surgical extirpation. An incidental nonfunctioning adrenal mass presents a clinical dilemma and its management is controversial, although it is widely accepted that adrenal lesions greater than 6 cm must be removed.16,19 In all cases but two, the tumors were detected incidentally during investigation of symptoms not attributable to the tumor. In one reported patient,11 the tumor had infiltrated the adjacent vena cava and liver, which may have caused the abdominal pain that led to its discovery. Oncocytic metaplasia is not uncommon in epithelial cells with high metabolic activity and it may be associated with inflammation, degeneration, or cellular aging.1 Oncocytes are defined ultrastructurally by the abnormal accumulation of mitochondria in the cytoplasm, almost to the exclusion of other organelles.1 Although the relationship between the accumulation of mitochondria and the development of these tumors is unclear, many investigators believe that mitochondria multiply as a compensatory response to a functional impairment.20 The mitochondrial abnormalities in size, shape, and cristae structure with a several-fold increase in mitochondrial DNA without a parallel increase in mitochondrial RNA transcription20 support a functional or epigenetic impairment, which results in a compensatory proliferation in oncocytes.20 Evidence of endocrine overactivity was detected in only two tumors,9,16 But the underlying mechanisms of the hyperfunction in these two adrenocortical oncocytomas are as yet unexplained. A definite diagnosis of adrenocortical oncocytoma was made by the electron-microscopic finding of numerous mitochondria in the tumor cell cytoplasm. The cytoarchitectural features of adrenocortical onco-

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cytomas1,14,16 may closely resemble the following tumors: pheochromocytoma, which was excluded in this case by negative chromogranin A immunoreactivity and the absence of neurosecretory granules on electron microscopy; adrenocortical adenoma, where the tumor cell cytoplasm is not packed with mitochondria; renal oncocytoma; and metastatic oncocytic carcinoma, both of which were excluded, as no primary was found in the right kidney or in other organs on clinical and radiological examination. It is often difficult to differentiate benign from malignant adrenal cortical tumors, and no single feature has been reported to be predictive of their behavior. Although tumor size and patient age have been suggested as reliable indicators of adenoma versus adrenocortical carcinoma among patients with adrenal Cushing’s syndrome, there is only a marginally statistical difference not predictive of biologic behavior.16 Most studies have demonstrated that a combination of clinical, biochemical, and in particular, histological features can distinguish most adrenocortical adenomas from carcinomas based on well-defined pathological criteria. The most widely used histologic criteria, as proposed by Weiss et al.,21 were three or more of the following: a high nuclear grade, eosinophilic cytoplasm, diffuse architecture, and the presence of necrosis, mitotic figures (>5 per 50 high-power fields), atypical mitotic figures, capsular invasion, venous invasion, and sinusoidal invasion. Among these, a mitotic rate greater than 5 per 50 high-power fields, atypical mitotic figures, and venous invasion were found only in malignant tumors. Although immunohistochemical and molecular profiles have become popular for identifying the tumor nature and predicting its behavior; their validity in adrenocortical tumors is limited.22 Histologic assessment remains the cornerstone of the diagnosis and of the biologic behavior of adrenocortical neoplasms. Although adrenocortical oncocytoma is generally considered benign, one locally invasive malignant case was reported. This tumor had metastasized to the liver and invaded the inferior vena cava;11 however, although it exhibited malignant behavior, the microscopic appearance was that of a benign lesion with no evidence of pleomorphic nuclei or multiple mitoses. Two other reported tumors4 were classified as uncertain malignant potential because of increased proliferative activity and necrosis despite an absence of invasion. The malignant potential of such neoplasms might not correlate with the histologic presentation. Furthermore, because of its extremely low incidence and the limited numbers of reports, little is known in terms of its long-term natural history. Hence, pathologists need to be vigilant about sampling these tumors and clinicians must commit to long-term followup of the patients to promote a better understanding of the biology of adrenocortical oncocytomas.

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We excluded a diagnosis of metastatic disease in our patient because no primary lesion was identified on imaging work-up. Monolateral adrenal metastases without a detected primary, although rare, have been described; thus, we suspected a primitive adrenal tumor. The radiological features and biochemical evaluation ruled out the diagnosis of pheocromocytoma, which is the most frequent monolateral adrenal neoplasm.23 A specific finding of oncocytomas is the presence of a central fibrous scar, leading to the “spoke wheel” pattern seen on CT and MRI scans in about one third of the patients.24 This feature was not observed in our patient. We made a preoperative diagnosis of a minimally aggressive retroperitoneal tumor of unknown origin; possibly an adrenal myelolipoma, but with no evidence of fat.25 However, the final diagnosis was an adrenocortical oncocytoma. Fine-needle aspiration (FNA) cytology could have shown the oncocytic nature of the tumor, and the correct diagnosis would have been confirmed with radiological, clinical, and biochemical findings. However, FNA cytology is currently restricted to patients with a known extra-adrenal malignancy and suspected adrenal metastasis, because of the risks of serious complications and the relatively low sensitivity of the cytology procedure.26 We think that FNA cytology should not be performed on large adrenal tumors. Besides, this additional preoperative diagnostic modality would not have changed the surgical management.27 Over the past decade, laparoscopic adrenalectomy (LA) has become the operation of choice for the surgical treatment of adrenal tumors, as it results in less postoperative discomfort, a shorter hospital stay, less postoperative disability, and a lower rate of complications than open adrenalectomy.28,29 Indeed, there is consensus that LA is preferred over an open anterior operation for the resection of small, benign adrenal tumors.30 However, there is still controversy regarding the appropriateness of laparoscopy for the resection of adrenal tumors of uncertain malignant potential. While some authors have argued that LA can be performed safely in selected patients with potentially malignant tumors,28,31,32 others have urged caution, based partly on anecdotal experience with high rates of locoregional recurrence, including the development of carcinomatosis.33,34 Hand-assisted LA provides surgeons with an alternative to open adrenalectomy. This technique allows the surgeon to palpate the adrenal tumor and resection bed directly, and to remove large tumors, but it does not require as extensive an incision as open adrenalectomy. Unfortunately, the safety of hand-assisted LA for adrenal malignancies has not been proven.35,36 Furthermore, when laparoscopic surgery is performed for adrenal tumors larger than 6 cm or for potentially malignant tumors, it should be carried out by only a highly skilled laparoscopic surgeon.28


Taking into account the above-mentioned data, we believe that open adrenalectomy should remain the standard of care for resection of adrenal cortical neoplasms, for which adrenal cortical carcinoma remains in the differential diagnosis. Moreover, the morbidity associated with the presence of an abdominal incision may be relatively insignificant, compared with the oncologic importance of performing a complete tumor resection without peritoneal dissemination. We performed an open anterior adrenalectomy for our patient, considering the risk of malignancy and our lack of advanced surgical experience and skills in laparoscopic techniques. In conclusion, oncocytomas, although extremely rare in the adrenal cortex, must be taken into consideration while facing the differential diagnosis of tumors in this site. Knowledge of the mechanisms that lead to oncocytosis in general, and in adrenocortical cells in particular, is limited. The biologic behavior of oncocytic neoplasms of the adrenal cortex should be assessed by validated clinical, pathological, and molecular biological criteria in a series.

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