Endocrine Journal 2009, 56 (6), 817-824 NOTE Corticomedullary Mixed Adrenal Tumor: Case Report and Literature Review KRYSTALLENIA I. ALEXANDRAKI*, OTHON P. MICHAIL**, AFRODITE NONNI***, DIMITRIOS DIamaNTIS**, IOANNA GIANNOPOULOU***, GREGORY A. KALTSAS*, SOFIA TSELENI-BALAFOUTA***, VASSILIKI SYRIOU* AND PANAYIOTIS O. MICHAIL** *Division of Endocrinology, Department of Pathophysiology, Laiko University Hospital, School of Medicine, National and Kapodistrian University of Athens, Mikras Asias 75, Athen, Greece **1 st Department of Surgery, Laiko University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece ***Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece Abstract. We report a 66-year-old woman with a mixed corticomedullary tumor of the left adrenal gland. The patient was found to harbor an adrenal incidentaloma while investigated for a spigelian hernia. Due to the atypical radiological features and the relatively large size of the adrenal lesion she underwent a left adrenalectomy following endocrine testing to exclude a functional lesion. Subclinical Cushing’s syndrome was suggested by the failure to obtain adequate cortisol suppression (less than 1.8 μg/dL) following dexamethasone administration pre-operatively; cortisol suppression was restored post- operatively following the excision of the tumor. Histology was consistent with a corticomedullary mixed adenoma, a lesion for which, there is paucity of published data regarding its natural history and long term outcome. The finding of this case highlights the importance of this extremely rare entity which should be included in the long list of causes of adrenal incidentaloma since cases with intra-operative complications have been described. The previously reported reappearance of this tumor in the contralateral adrenal gland emphasizes the need for prolonged follow-up. Key words: Corticomedullary mixed adrenal tumor, Cortical adenoma, Phaeochromocytoma (Endocrine Journal 56: 817-824, 2009) THE WIDESPREAD use of abdominal imaging, par- dices to distinguish potentially malignant from benign ticularly computed tomography (CT) and magnetic lesions [3]. resonance imaging (MRI), during diagnostic testing or Corticomedullary mixed tumor is a single adrenal treatment for many clinical conditions has resulted in tumor mass composed of an intimately admixed pop- the identification of previously unsuspected adrenal le- ulation of both adrenal cortical cells and phaeochro- sions defined as adrenal incidentalomas [1, 2]. Since mocytes [4]. Such tumors exhibit histologic features the management of adrenal incidentalomas is influ- of both adrenocortical adenoma and phaechromocy- enced by the functional status and malignant potential toma different from simultaneously tumors arising in of these lesions it is mandatory to exclude a hormo- the same gland [4]. Currently, no data has been pub- nal hypersecretory state, particularly the presence of a lished regarding the prevalence of these tumors. As pheochromocytoma, and use accurate radiological in- only a small number of cases has been described in the medical literature there is a lack of information re- garding their pathogenesis, optimal treatment and long Received Jan. 9, 2009; Accepted Apr. 10, 2009 as K09E-010 term outcome. Although these tumors are exclusively Released online in J-STAGE as advance publication May 20, 2009 derived from the adrenal glands they are currently not Correspondence to: Krystallenia ALEXANDRAKI, MD., MSc, MSc, Ph.D., Department of Endocrinology, Laiko General Hospital included in the long list of adrenal incidentalomas ae- School of Medicine, National & Kapodistrian University of Athens tiology [5, 6]. E-mail: [email protected] We present a 66-year-old woman with a left adre- 818 ALEXANDRAKI et al. nal incidentaloma identified by CT while being investi- gated for a spigelian hernia. Due to subclinical autono- mous glucocorticoid secretion and suspicious imaging characteristics she underwent a left adrenalectomy. The diagnosis of corticomedullary mixed tumor was an in- advertent discovery of the pathology report. Case Report A 66-year-old female was admitted to the Surgical Department for an elective repair of a spigelian her- nia [7]. Clinical examination and review of systems as well as family and past medical history were unre- markable. The patient reported occasionally a mild increase of blood pressure in the range of systolic blood pressure 140-145mmHg and diastolic blood pressure 85-90mmHg which was controlled by weight reduction and salt restriction; increased blood pres- sure was not confirmed in the present admission or previous medical recordings. Patient’s body mass in- dex (BMI) was 28.13 kg/m2 and waist circumference Fig. 1. Computed tomography imaging describing the adrenal was 92cm. Following an abdominal CT, a 4 cm left tumor with punctuated calcification pre-operatively. adrenal lesion was identified. Since the patient had no symptoms suggestive of a functioning adrenal neo- Pathology report plasm and no evidence of another systemic disease, a provisional diagnosis of an adrenal incidentaloma was Macroscopically, the tumor was well circum- made. However, the CT imaging described an adeno- scribed and encapsulated, weighing 65 g and measur- ma with punctuated calcification along with the pres- ing 4.2x3.7x3.4 cm. Histology was consistent with ence of two simple cysts in the liver and the spige- an adrenocortical adenoma that exhibited features of lian hernia of the anterior abdominal wall (Figure 1). neuroendocrine differentiation (Figure 3 A-D). The Due to the atypical CT imaging characteristics, MRI cut surface was yellow-orange in colour, with a few of the abdomen was also performed which confirmed foci of dark discoloration. Microscopically, sections the presence of a heterogeneous left adrenal mass, 3.5 showed clusters, cords or alveoli of cells with round cm in maximum diameter, with cystic components to oval, not pleomorphic nuclei (low grade- Fuhrman that were not compatible with an adenoma or myelol- 1 and 2) and abundant pale-staining cytoplasm (Figure ipoma raising the suspicion of malignancy (Figure 2) 3A). Focally, there were nests of cells having com- as well as the presence of simple liver cysts. As en- pact, eosinophilic cytoplasm. Mitoses were absent. docrine investigations revealed concomitant mild au- Among the above described cells, there were enlarged tonomous glucocorticoid secretion (Table 1) it was de- cells present, distributed either as single cells or as cided to proceed to surgical removal of the left adrenal small clusters. They were characterised by abundant and concomitant hernia repair. The patient was sub- eosinophilic cytoplasm, containing pigmented granu- mitted in a combined uneventful resection of left adre- lar material and enlarged nuclei with prominent nucle- nal and hernia repair; during the operation the patient oli or nuclear inclusions (Figure 3B). Mitotic activity was covered with hydrocortisone administration [8]. was not found in these areas. Immunohistochemically, The patient had an uneventful recovery and was dis- the enlarged cells were positive to synaptophysin charged after 5 days without any medications. (Figure 3C) and chromogranin A (Figure 3D). There was no evidence of vascular or capsular invasion in the encapsulated sections. CORTICOMEDULLARY MIXED ADRENAL TUMOR 819 PRE-OPERATIVE INVESTIGATION WITH MAGNETIC RESONANCE IMAGING POST-OPERATIVE INVESTIGATION WITH MAGNETIC RESONANCE IMAGING Fig. 2. Magnetic resonance imaging during the pre-operative and post-operative investigation. The white arrow is indicating the adrenal tumor pre-operatively and the black arrow the post-operative changes in the surgical area. Fig. 3. A. Nests of clear cells, low nuclear grade (Fuhrman 1 and 2) (Hematoxylin and Eosin x 200). B. Large cells with abundant cytoplasm and enlarged nuclei including prominent nucleoli. Brown granules within the cytoplasm are evidenced (Hematoxylin and Eosin x 200). C. Positive immunostaining of large cells for synaptophysin (Avidin Biotin Peroxidase Complex x 200). D. Positive immunostaining of large cells for chromogranin (Avidin Biotin Peroxidase Complex x 200). 820 ALEXANDRAKI et al. Table 1. The pre-operative investigation of the adrenal incidentaloma modified by the suspicion for malignancy and the post-operative investigation one year after the adrenalectomy. Values Hormonal Parameters (morning values) Reference Range Pre-operatively Post-operatively Adrenocorticotrophin (pmol/L) 1.93 9.4 0.22-11 Total cortisol (nmol/L) 382 281 260-720 Plasma Renin Activity (ng/ml/h) 0.66 1.88 0.15-2.33 Aldosterone (pmol/L) 425.2 192 27.70-443.2 Dehydroepiandrosterone Sulphate (μmol/L) 1.35 0.16 2.7-21.6 Carcinoembryonic antigen (mcg/L) 1.39 2.1 <5 Ca- 15.3 (U/mL) 15.7 19.6 3-28 Ca-125 (U/mL) 6.26 6.71 <30 Ca 19.9 (U/mL) 3.5 4.29 <37 Alpha-fetoprotein (ng/mL) 8.39 6.1 <6 Thyroid-stimulating hormone (mU/L) 2 2.45 0.3-4.0 Free thyroxine (pmol/L) 17.6 15.1 10-25 3,5,3’-triiodothyronine (nmol/L) 1.97 2.36 1.23-3.08 Calcitonin (mIU/L) 4.4 4.6 0-10 Biochemical parameters (morning values) Sodium (mmol/L) 141 142 135-144 Potassium (mmol/L) 4.5 4.2 3.6-4.8 Glucose (mmol/L) 5.44 4.88 3.89-6.66 Urea (mmol/L) 12.9 10.71 5-17.80 Creatinine (mmol/L) 0.11 0.8 0.07-1.12 Aspartate aminotransferase (U/L) 18 17 <45 Alanine aminotransferase (U/L) 15 13 <45 Gamma glutamyl transferase (U/L) 14 8 <32 Hormonal Parameters (afternoon values) Total cortisol (nmol/L)