Urological Science 22 (2011) 166e168

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Urological Science

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Case report Functional adrenal presenting as Cushing’s syndrome: Case report and literature review

Yung-Shu Lee a, Wun-Rong Lin b,*, Chi-Kuan Chen b, Yi-Wei Pai b, Marcelo Chen b a Department of Urology, Mackay Memorial Hospital, Taitung, Taiwan b Department of Pathology, Mackay Memorial Hospital, Taipei, Taiwan article info abstract

Article history: Adrenocortical are very rare, with only 47 cases reported in the English literature. They are Received 28 November 2010 usually benign and nonfunctional. Herein, we report on a 30-year-old female patient presenting with Received in revised form extreme weight gain (17 kg in a year), moon face, buffalo hump, central and edema in both legs. 26 January 2011 Computed tomography revealed a 3.2 cm solid left . A clipless laparoscopic adrenalectomy Accepted 17 February 2011 was performed. Pathology revealed an adrenocortical oncocytoma. Available online 15 November 2011 Copyright Ó 2011, Taiwan Urological Association. Published by Elsevier Taiwan LLC. All rights reserved.

Keywords: adrenal tumor Cushing’s syndrome oncocytoma

1. Introduction experienced palpitations, insomnia, anxiety and persistent swelling in her lower legs. She had irregular menstrual cycles with menor- Oncocytomas are comprised of cells replete with rhagia. Her body weight increased from 71 to 79 kg in 20 days. A eosinophilic granular cytoplasm packed with swollen mitochon- physical examination revealed a moon face, buffalo hump, central dria. They can arise in the kidney, thyroid, salivary , para- obesity and edema in both legs. thyroid, lung, pituitary and ovaries.1,2 The term “oncocyte” Blood tests showed that cortisol (morning, afternoon and dexa- was first used by Hamperl in 1950 to describe large, highly eosin- methasone suppression test), (standing and lying ophilic granular cells associated with a Hurthle cell tumor of the down), adenocorticotropic hormone, thyroid-stimulating hormone, thyroid gland.3 Adrenocortical oncocytomas are very rare, with luteinizing hormone, follicle-stimulating hormone and prolactin only 47 cases reported in the English literature.4 They are usually levels were all within normal ranges. Her testosterone level (1.43 ng/ benign and nonfunctional. Only seven cases of functional adrenal mL) was high. Her dehydroepiandrosterone (121.0 mg/dL) and free oncocytoma have been reported.5 Herein, we report on a rare case T4 (0.64 ng/dL) levels were low. Urine cortisol (638.40 mg/day), 17- of functional adrenal oncocytoma in a patient presenting with ketosteroids (27.6 mg/day) and 17-OH progesterone (43.2 mg/day) Cushing’s syndrome. levels were high. Adrenal computed tomography (CT) revealed a 3.2 cm well- fi 2. Case report de ned, nearly homogeneously solid mass with a mean Houns- field unit (HU) number of around 30 on precontrast scans, favoring A 30-year-old female patient presented with extreme weight a relatively lipid-poor (Fig. 1). An Adrenal scans with gain (17 kg in 1 year) and bilateral leg edema for 3 months. She had Radioiodine - Labeled Norcholesterol (NP-59) showed unilateral a history of essential since 2008 and obesity. The visualization of the left , and a left adrenal adenoma family history was noncontributory. She had complained of prox- was diagnosed. imal and thigh soreness for a year and of getting Due to the presenting symptoms and signs and the high urine fatter, especially in the face. In the past 3 months, she had cortisol level, the impression was of a functional adrenal adenoma with Cushing’s syndrome, and a clipless left laparoscopic adrenal- ectomy was performed via a retroperitoneal approach. On gross examination, the specimen was 3.5 cm 2.5 cm 2.0 cm and * Corresponding author. Department of Urology, Mackay Memorial Hospital, 92 Chung Shan North Road, Section 2, Taipei 104, Taiwan. weighed 16.5 g. Microscopically, the tumor was composed of E-mail address: [email protected] (W.-R. Lin). trabecular and solidly arranged oncocytic cells with mild nuclear

1879-5226/$ e see front matter Copyright Ó 2011, Taiwan Urological Association. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.urols.2011.02.001 Y.-S. Lee et al. / Urological Science 22 (2011) 166e168 167

Fig. 2. (A) Microscopically, tumor cells are abundantly eosinophilic with granular cytoplasm and are arranged in a nested pattern (hematoxylin and eosin stain 200x); and (B) tumor cells were diffusely strongly positive for cytoplasmic alpha-inhibin indicating adrenal cortical differentiation (alpha-inhibin 100x).

3. Discussion

Adrenal masses are usually silent and are incidentally detected in 12% of abdominal CT scans.6 These adrenal incidentalomas may be cortical , myelolipomas, , , Fig. 1. Adrenal CT revealing a well-defined 3.2 cm, nearly homogeneously solid mass , adrenocortical or adrenal metas- (arrow) with a mean HU number of around 30 on precontrast scans (A) and around 55 tases, with nonfunctioning cortical adenomas being the most on 10-min postcontrast images (>70% washout) (B), favoring a relatively lipid-poor common.7 In order to distinguish nonfunctional from functional adenoma. adrenal masses, a biochemical evaluation should be performed. Surgical removal is indicated for adrenal masses that are functional atypia and no mitotic activity. There was no tumor necrosis. or >6 cm in size. Extramedullary hematopoiesis was seen within the tumor and in Adrenal oncocytomas are very rare, and only 48 cases have the periadrenal soft tissue. Immunohistochemical staining showed been reported to date.4 Many such tumors are benign and that the tumor was strongly positive for alpha-inhibin and negative nonfunctional, and are detected incidentally. Adrenal oncocyto- for cytokeratin (AE1/AE3), vimentin, chromogranin A, epithelial mas are reported to be more common on the left-hand side (2:1), membrane antigen and HepPar1 antigen. The Ki-67 index was very with tumor size ranging from 3 cm to 15 cm (median 8 cm) and low. Pathological impressions were a left adrenal oncocytoma and weighing from 30 g to 865 g (mean 281 g). The mean age of extramedullary hematopoiesis (Fig. 2A and B). diagnosis is 46 years and the condition is prevalent in females. The patient’s postoperative recovery was uneventful. Intrave- Only two cases of a malignant adrenal oncocytoma have been re- nous hydrocortisone sodium succinate was given postoperatively, ported: one was an adrenal oncocytoma with local invasion and and on the second postoperative day the patient was switched to distant metastases8 and the other was a 51-year-old male with oral cortisone acetate. The patient had lost 4 kg of weight by the a 15.0 cm 16.0 cm 17.2 cm adrenal mass. In the latter case, the 30th postoperative day. man had enlarged periarterial lymph nodes, elevated serum 168 Y.-S. Lee et al. / Urological Science 22 (2011) 166e168

Table 1 profiles can be used to determine the tumor’s nature and predict its 13 Criteria of malignant oncocytoma proposed by Bisceglia et al. behavior. The presence of Ki-67(þ), p21(þ), p27(þ) and Mdm-2(-) Major criteria Minor criteria can be used to predict malignancy and distant spread of adrenal Mitotic rate >5 mitoses/50 Large tumor size: >10 cm and/or >200 g cortical tumors. The sensitivity of these proteins is low, however, high power fields and only 13% of adrenal cortical carcinomas expressed this pheno- Atypical mitosis Necrosis type.15 In the present case, the tumor was functional, 3.5 cm in size, Venous invasion Capsular invasion; sinusoidal invasion the Ki-67 proliferative index was very low, and no major or minor criteria were met. dehydroepiandrosterone sulfate, elevated serum cortisol following 4. Conclusion an overnight 1-mg dexamethasone test and increased urinary excretion of 17-hydroxycorticosteroids. The mass was unresect- In patients presenting with symptoms and signs of Cushing’s able due to tumor invasion of the inferior vena cava.9 syndrome, 24-h urine cortisol is a valuable test for the diagnosis of Tahar et al have reported that the clinical symptoms of func- Cushing’s syndrome if plasma cortisol levels are normal. Adreno- tional adrenocortical oncocytomas include in three cortical oncocytomas are rare and usually benign and nonfunc- female cases, Cushing’s syndrome in a male case, bilateral tional. A functional adrenal oncocytoma may, however, present as gynecomastia in two male cases and pseudopuberty in a female Cushing’s syndrome. This must therefore be taken into consider- child.5 A MEDLINE search revealed that only one case of Cushing’s ation in differential diagnosis. syndrome10 and two cases of subclinical Cushing’s syndrome have been reported.9,11 Our case is the second adrenocortical oncocy- toma presenting with Cushing’s syndrome. In our case, the patient References had irregular menstrual cycles with menorrhagia, moon face, buffalo hump, central obesity and edema in both legs. Cortisol 1. Chang A, Harawi SJ. Oncocytes, oncytosis and oncytotic tumors. Pathol Annu 1992;27:263e304. levels (morning, afternoon and on the dexamethasone suppression 2. Smirnova EA, Michailov IG. Electron microscopic characteristics of oncocytoma test) were normal, but urine cortisol (638.4 mg/day; reference of the lung, small intestine and adrenal gland. Arch Pathol 1968;48:79e81. m ’ 3. Hamperl H. Onkocytes and the so called Hurthle cell tumor. Arch Pathol range, 20.0 90.0 g/day) was high. According to Harrision s Prin- e 12 fi 1950;49:563 70. ciples of Internal Medicine, in dif cult cases, such as obese or 4. Bouasker I, Zoghlami A. Farah Klibi F. Adreno-cortical oncocytoma: a case depressed patients, 24-h urine free cortisol can be measured, and report. Tunis Med 2010;88:353e6. a level of >140 nmol/day (50 mg/day) is suggestive of Cushing’s 5. Tahar GT, Nejib KN, Sadok SS. Adrenocortical oncocytoma: a case report and review of literature. J Ped Surg 2008;43:E1e3. syndrome. 6. Ross NS, Aron DC. Hormonal evaluation of the patient with an incidentally A diagnosis of an oncocytoma is based on histological and discovered adrenal mass. N Engl J Med 1990;323:1401e5. immunohistochemical studies. Oncocytomas are neoplasms made 7. Copeland PM. The incidentally discovered adrenal mass. Ann Intern Med 1983;98:940e5. up of cells with large amounts of eosinophilic granular cytoplasm 8. El-Naggar AK, Evans DB, Mackay B. Oncocytic adrenal cortical . 2 filled with swollen mitochondria. In immunohistochemical Ultrastruct Pathol 1991;15:549e56. studies, vimentin and keratin are frequently identified, and the 9. Golkowski F, Buziak-Bereza M, Huszno B. The unique case of adrenocortical malignant and functioning oncocytic tumour. Exp Clin Endocrinol Diabetes tumors are strongly positive for antimitochondrial antibodies.13 In 2007;115(6):401e4. the present case, the tumor was composed of trabecular and solidly 10. Xiao GQ, Pertsemlidis DS, Unger PD. Functioning adrenocortical oncocytoma: arranged oncocytic cells, with mild nuclear atypia and no mitotic a case report and review of the literature. Ann Diagnostic Pathol 2005;9:295e7. activity. The tumor was strongly positive for alpha-inhibin and 11. Lee SS, Beek KH, Lee YS. Subclinical Cushing syndrome associated with an adrenocortical oncocytoma. J Endocrinol Invest 2008;31(7):675e9. negative for cytokeratin (AE1/AE3), vimentin, chromogranin A, 12. Williams GH, Dludy RG. Cushing’s syndrome, Harrision’s principles of internal epithelial membrane antigen and HepPar1. medicine. 17th ed. New York: McGraw-Hill; 2008. 2254e2257. Bisceglia et al14 have produced new criteria for the differentiation 13. Hoang MP, Ayala AG, Albores-Saavedra J. Oncocytic : a morphologic, immunohistochemical and ultrastructural study of four cases. of benign from malignant adrenocortical oncocytomas (Table 1). Mod Pathol 2002;15:973e8. If a tumor meets one or more major criteria, it is defined as malig- 14. Bisceglia M, Ludovico O, Di Mattia A. Adrenocortical oncocytic tumors: report nant. If the tumor meets one or more minor criteria, it is considered of 10 cases and review of the literature. Int J Surg Pathol 2004;12:231e4. 15. Stojadinovic A, Brennan MF, Hoos A, Omeroglu A, Leung DH, Dudas ME, et al. borderline malignant. If no major or minor criteria are met, and carcinoma: histopathological and molecular the oncocytoma is benign. Immunohistochemical and molecular comparative analysis. Mod Pathol 2003;16:742e51.