Nephrology Reviews 2010; volume 2:12
Adrenal-oncocytic tumor: an unusual cause of secondary hypertension in a young South African male Ikechi G. Okpechi,1 Ahmed Motala,2 Eugenio Panieri,3 Brian L. Rayner1 1
Department of Medicine, Groote Schuur Hospital, University of Cape Town; 2Department of Histopathology, University of Cape Town; 3Department of Surgery, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa
Correspondence: Ikechi G. Okpechi, E13 Renal Unit, Groote Schuur Hospital, University of Cape Town, Observatory 7925, Cape Town, South Africa. E-mail:
[email protected]
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Key words: adrenal, hypertension, oncocytic tumor. Contributions: IGO, AM, EP, BLR were all involved in the conception of the case report, data collection, review of the literature, and writing the manuscript; AM participated in the data collection and in rendering a pathological diagnosis. All authors read and approved the final manuscript. Conflict of interest: the authors report no conflicts of interest. Received for publication: 2 June 2010. Revision received: 18 July 2010. Accepted for publication: 27 July 2010. This work is licensed under a Creative Commons Attribution 3.0 License (by-nc 3.0). ©Copyright I.G. Okpechi et al., 2010 Licensee PAGEPress, Italy Nephrology Reviews 2010; 2:e12 doi:10.4081/nr.2010.e12
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perspiration, or muscle weakness. At first presentation (two months before visiting our clinic), he had been started on a diuretic (hydrochlorothiazide, 12.5 mg once daily), a calcium channel blocker (amlodipine, 10 mg once daily), an ACE inhibitor (enalapril, 10 mg twice daily), and a beta-blocker (atenolol, 50 mg daily) by his family physician. On general physical examination, the patient had an athletic build with no evidence of peripheral lymphadenopathy, palpable masses, peripheral edema, Cushingoid features, striae, petechiae, or abdominal tenderness. The average blood pressure recorded at his first visit was 148/98 mmHg (with the patient being on four anti-hypertensive agents). Postural hypotension was not present and a 24-hour ambulatory blood pressure monitoring had not shown any evidence of episodic hypertension. He had no features of hypertensive retinopathy. His serum biochemistry including cortisol, aldosterone and renin, aldosterone-to-renin ratio (ARR), glucose and electrolytes, urea and creatinine, and full blood count results were all normal. Urine dipsticks, microscopy, and urinary cortisol were also normal. Urinary metanephrines were slightly elevated initially (7.5 mol/24 hrs; reference range: 0-5 mol/24 hrs) but subsequent repeat tests showed that they were within normal limits. The first ECG performed on him at presentation showed features of left ventricular hypertrophy (LVH; Figure 1A). An abdominal ultrasound scan revealed a heterogeneous solid and cystic mass in the right upper quadrant between the right kidney and liver, measuring 84¥78¥81 mm. No other masses were detected in the liver or intra-abdominally. A computed tomography (CT) scan of the abdomen confirmed this to be a right adrenal mass (Figure 2) and did not show features suggestive of a metastatic disease. On the basis of the size and CT appearance of the mass, it was decided to perform a right adrenalectomy with the entire gland carefully dissected from surrounding structures. Following removal of the mass, the patient’s postoperative blood pressure was noted to
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Introduction
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Tumors with oncocytic features are characterized histologically by cells with eosinophilic granular cytoplasm. Ultrastructurally the presence of numerous closely packed mitochondria is evident. Adrenal oncocytomas are rare and are usually non-functioning tumors found predominantly in adults. About 30 cases of adrenal oncocytomas have been reported in the literature to date.1-10 Most of these have had a benign clinical manifestation, although in a few cases the histological findings indicated a low malignant potential, resulting in the tumors being classified as borderline.2 Here, we report the case of adrenal oncocytoma in a young man who was being evaluated for a possible secondary cause of hypertension, and we highlight its clinical, radiologic, histological, and immunohistochemical features.
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Tumors with oncocytic features are characterized histologically by cells with eosinophilic granular cytoplasm and by the ultrastructural presence of numerous closely packed mitochondria. Adrenal oncocytic tumors are very rare. We describe the case of a 36-year old white male who was newly diagnosed with hypertension and referred for evaluation. An abdominal computer tomography scan revealed a right adrenal tumor, which was removed surgically. The final diagnosis was made histologically on the excised tumor specimen. Hypertension in this patient was cured by the removal of the tumor. Adrenal oncocytic tumors are often benign, non-functional tumors that rarely cause hypertension. The diagnosis and assessment
of metastatic potential can be made with histology and appropriate immunohistochemical stains. Removal of the tumor is necessary as some may have a malignant potential. Longterm follow-up is important in these patients in view of the difficulty in accurately predicting biological behavior.
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Abstract
Case Report A 36-year-old white male, newly diagnosed with systemic arterial hypertension, was referred by his family physician for evalu ation, exclusion of secondary hypertension, and treatment at the hypertension clinic of the Groote Schuur Hospital. He had a oneand-a-half pack year smoking history and occasionally drank alcohol. He worked from his home, making pot wares from ceramic materials. He had a positive maternal history of hypertension. Besides a recent and occasional dull ache in his right subcoastal region, he felt very well and denied any history of headaches, palpitations, excessive
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Okpechi et al. have reduced significantly. All his anti-hypertensive medications were withdrawn subsequently, his blood pressure remained in the normotensive range, and a repeat ECG three months after his surgery was normal and exhibited no signs of LVH (Figure 1B).
Pathologic findings
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The tumor weighed 300 g and measured 100¥85¥70 mm. The cut surface revealed an encapsulated, well-circumscribed tumor that was 100 mm in its greatest dimension with capsular undulation and evidence of focal surface nodularity. It was firm in consistency with a fleshy tan-to-brown cut surface. Fibrous bands and cysts were evident but no necrosis or lymph nodes were identified.
Figure 1. Electrocardiogram of the subject before surgery (A), and 3 months after surgery (B) demonstrating reversal of left ventricular hypertrophy with normalization of blood pressure.
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Gross findings
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Figure 2. Imaging (computed tomography scan) features of the tumor. The well-circumscribed tumor mass is clearly seen (*) between the liver and right kidney, with compression of the latter.
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Sections of the tumor showed a diffuse architecture comprising sheets of cells with moderate to abundant granular eosinophilic cytoplasm. The cells had pleomorphic, hyperchromatic nuclei with focal prominent nucleoli. Multinucleate cells, hyaline globules, and eosinophlic nuclear pseudo-inclusions were present. There was prominent vascularization, with focal ectatic vessels lined by bland endothelial cells. There were no atypical mitotic figures and there was no evidence of vascular, capsular, or sinusoidal invasion (Figure 3A-C). The adjacent residual adrenal cortex appeared compressed and effaced and the medulla was normal. Phosphotungstic acid hematoxylin (PTAH) staining was consistent with an oncocytoma.
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Microscopic findings
Immunohistochemical analysis
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Immunohistochemical stains were performed and were negative for p53 and revealed a Ki-67 (proliferative) index of 6.5% (Figure 3D). S-100 staining was negative. Additional stains such as SF-1, tyrosine hydroxylase, and dopamine b-hydroxylase were not available at the time of assessment. However, other stains that were performed showed negative CAM 5.2, Hep Par 1, and chromogranin A. Isolated melan-A and inhibin stains showed the presence of positive cells while focal cytoplasmic synaptophysin positivity was also found to be present.
Discussion An oncocytoma refers to any tumor composed predominantly or exclusively of polyg[page 54]
Figure 3. Microscopic features of the adrenal oncocytoma. The dense fibrous capsule of the tumor is seen at low magnification (A). At higher magnification (B-D), the typically granular eosinophilic cytoplasm of the pleomorphic tumor cells are seen (B), with degenerative changes within the tumor and pink edematous fluid separating tumor cells (C), and immunohistochemical staining for Ki-67 found to be positive (brown nuclei) in 6.5% of the tumor cells (D). [Nephrology Reviews 2010; 2:e12]
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References
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1. Poretti D, Mazzarol G, Bonomo G, et al. Adrenocortical oncocytoma: case report. Clin Imaging 2003;27:426-30. 2. El-Naggar AK, Evans DB, Mackay B. Oncocytic adrenal cortical carcinoma. Ultrastruct Pathol 1991;15:549-56. 3. Macchi C, Rebuffat P, Blandamura S, et al. Adrenocortical oncocytoma: case report and review of the literature. Tumori 1998; 84:403-7. 4. Vara Castrodeza A, Ablanedo P, Garcia J, et al. Adrenal oncocytoma. Arch Esp Urol 1999;52:525-8. 5. Kitching PA, Patel V, Ruben Harach H. Adrenocortical oncocytoma. J Clin Pathol 1999;52:151-3. 6. Chang A, Harawi SJ. Oncocytes, oncocytosis and oncocytic tumors. Pathol Annu 1992;27:263-304. 7. Begin LR. Adrenocortical oncocytoma: case report with immunocytochemical and ultrastructural study. Virchows Arch A Pathol Anat Histopathol 1992;421:533-7. 8. Xiao GQ, Pertsemlidis DS, Unger PD. Functioning adrenocortical oncocytoma. A case report and review of the literature. Ann Diagn Pathol 2005;9:295-7. 9. Lee R, Al-Ahmadie HA, Boorjian SA, et al. A case of incidental adrenocortical oncocytoma. Nat Clin Pract Urol 2006;3:618-21. 10. Botsios D, Blouhos K, Vasiliadis K, et al. Adrenocortical Oncocytoma. A rare tumor of undefined malignant potential: report of a case. Surg Today 2007;37:612-7. 11. Kobayshi S, Seki T, Nonomura K, et al. Clinical experience of incidentally discovered adrenal tumor with particular reference to cortical function. J Urol 1993;150: 8-12. 12. Hoang MP, Ayala AG, Albores-Saavedra J. Oncocytic adrenocortical carcinoma: A morphologic, immunohistochemical and ultrastructural study of four cases. Mod Pathol 2002;15:973-8. 13. Disler DG, Chew FS. Adrenal pheochromocytoma. AJR Am J Roentgenol 1992;158: 1056. 14. Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989;13:202-6. 15. Bisceglia M, Ludovico O, Di Mattia A, et al. Adrenal oncocytic tumors: report of 10 cases and review of the literature. Int J Surg Pathol 2004;12:231-43. 16. Vargas MP, Vargas HI, Kleiner DE, et al. Adrenocortical neoplasms: role of prognostic markers MIB-1, p53, and RB. Am J Surg Pathol 1997;21:556-62.
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non-functioning adrenal adenoma was also improbable, as they are usually less than 5 cm in diameter.11 The management of adrenocortical tumors is difficult from the perspective of differentiating between a malignant and a benign tumor. Unfortunately, no single radiological or pathological parameter can predict outcome, therefore multiple parameters need to be considered carefully before deciding to label a tumor as benign, malignant, or of uncertain malignant potential. The most widely used histological criteria are the presence of three or more of the following features: 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.14,15 In the presence of the characteristic triad of venous invasion, atypical mitotic figures, and a mitotic rate higher than 5 mitotic figures per 50 high power fields, the tumor is described as malignant. These features were absent in our patient. An increase in the proliferative activity of tumor cells, as measured by nuclear overexpression of Ki-67 or p53, have been proposed to be potential predictive markers of biological behavior of adrenocortical neoplasms.16 However, the role of these proteins as biomarkers is still uncertain as only a few cases of these tumors have been reported. In our case, immunohistochemical staining for the Ki-67 protein was positive in 6.5% of tumor cells but was negative for p53 (Figure 3D). The normalization of our patient’s blood pressure immediately post-surgery, to the extent of not requiring any further anti-hypertensive agents, may suggest that the tumor contributed to the hypertension. However, with normal serum and urinary biochemistry, normal hormone assays, and absence of clinical features such as headaches, palpitations, and excessive sweating, the relationship between the presence of this tumor and hypertension in this patient still remains largely unknown. Compression of the right kidney by the tumor (Figure 2) possibly could have played a role through renal sympathetic nervous system activation. Finally, although adrenal oncocytic tumors are rare, we have shown as in this case that adrenal oncocytic tumor may be associated with secondary hypertension and that complete removal of the tumor may likely lead to complete cure of hypertension. Adrenal oncocytic tumors therefore should be considered as a cause of secondary hypertension.
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onal oncocytes with abundant granular and intensely eosinophilic cytoplasm.6 Oncocytic tumors are found commonly in the kidney, thyroid, and salivary gland, and rarely occur in other sites. Adrenal oncocytic tumors are rare with only a few cases described worldwide in the English literature to date. The age range at presentation has been 5-72 years, with more cases described in females. In many reported cases, the tumors were discovered incidentally during the evaluation of unrelated problems. These incidentalomas, which may occur in as high as 1-2% of patients who undergo abdominal CT scans for unrelated problems, have often been found to be cysts, cortical adenomas, cortical carcinomas, myelolipomas, ganglioneuromas, or adrenal metastases from other tumors.11 In gross anatomical terms, many of the tumors described are said to be rounded, well circumscribed, and with a brownish-tan color when cut. However, abnormal morphology and proliferation of the mitochondria to the exclusion of other organelles has been the defining microscopic feature of oncocytic neoplasms.7 A strongly eosinophilic and granular cytoplasm, because of the presence of abundant mitochondria, is present. The mitochondria can be seen on electron microscopy, and the cells can be arranged in alveolar, tubular, or solid patterns.6 Although the pathogenesis of adrenal oncocytomas is still unknown, the abnormal proliferation of mitochondria is thought to be the result of a compensatory mechanism owing to deficient organelle activity in oncocytic cells. Reported cases have shown patients that presented with symptoms of an abdominal mass, virilization, Cushing’s syndrome and neurological abnormalities owing to spinal cord involvement. Only in two previous cases has the tumor been discovered during the evaluation of hypertension. Although some cases have been reported as adrenal oncocytic carcinomas,2,12 most cases have been benign and non-functioning like in the present example. The finding of an incidental adrenal mass in a patient being evaluated for secondary hypertension raises the possibility of several differential diagnoses including an adrenal adenoma and pheochromocytoma. In our case, pheochromocytoma was considered in view of the initial mild elevation of urinary metanephrines. However, with repeat tests showing normal urinary metanephrine values, CT features that did not show a calcified rim with central necrosis of the tumor (commonly seen in pheochromocytoma),13 and a negative chromogranin A stain on histology, the diagnosis of pheochromocytoma was excluded. Metastatic malignant disease of the adrenal gland was unlikely in this case as no clinical primary sites could be found. A
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