Corticomedullary Mixed Adrenal Tumor: Case Report and Literature Review

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 postoperatively 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 regarding 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 investigated for a spigelian hernia. Due to subclinical autonomous 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 hernia [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 pressure 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) 293 N/P Overnight Dexamethasone Test (post 1mg Dexamethasone at 23:00 hrs and total cortisol measurement next morning at 9:00 hrs) Total cortisol (nmol/L) 104 13.8 <50 Urine collections Urinary Free Cortisol (nmol/24h) 204 N/P 38-208 Catecholamines (nmol/24h) 24.2 N/P 11.00-87.13 Vanillymandelic acid (mg/24hrs, twice tested) N/P 4.4/ 6.4 1.8-6.7 Metanephrine (μg/24hrs, twice tested) N/P 121/ 63 52-341 Normetanephrine (μg/24hrs, twice tested) N/P 404/ 284 88-444 Ca: cancer antigen; N/P: not performed

Summarizing, the tumor represented an adrenal cor- receiving any medication although still reported occa- tical neoplasm with histological features suggestive sional mild elevations of her blood pressure in periods of benign biologic behaviour according to the Weiss of non compliance to weight control and salt restric- histopathologic criteria (modified by Aubert), namely tion. The post-surgical MRI revealed post-operative adrenocortical adenoma [9]. Because of the presence changes in the surgical area, the presence of the same of focal neuroendocrine differentiation, the neoplasm liver cysts and gallstones. The biochemical profile was classified as corticomedullary mixed tumor. was negative for a functioning cortical adenoma and/ or phaechromocytoma and the overnight dexametha- Follow up Investigation sone test revealed adequate cortisol suppression (Table 1). The patient was advised to undergo repeated bio- Biochemical and imaging studies were performed chemical and imaging assessment in regular intervals, following the surgical resection of the tumor. One every 6 months for three years and every year thereaf- year later the patient remained clinically well without ter due to the paucity of the information regarding this Corticomedullary mixed adrenal tumor 821

Table 2. Summary of the data retrieved from the literature regarding clinical and biochemical features of previously presented case compared to the present one. Date of the Cushing’s Other Biochemical Biochemical Biochemical published Gender Age Size Symptoms Hypertension Syndrome Hyperglycemia specific hypercortiso- phaeochro- hyperaldos- Co-existant case (years) (cm) features symptoms laemia mocytoma teronism morbidities 1969 F 39 4 YES Lability YES NO N/R YES YES N/R N/R 1993 F 61 3.5 YES YES NO YES N/R YES YES N/R N/R 1995 M 32 N/R YES N/R YES N/R N/R YES N/R N/R N/R Spindle cell 1996 F 56 N/R YES Paroxysmal YES N/R N/R N/R N/R YES sarcoma 1996 F 32 N/R YES Paroxysmal YES N/R N/R N/R N/R YES N/R 1998 N/R N/R N/R YES YES N/R N/R N/R N/R NO YES N/R 2001 F 34 4.5 YES YES YES YES N/R N/R N/R N/R N/R 2001 F 52 2.5 YES NO NO NO Flank pain N/R N/R N/R N/R 2002 N/R N/R N/R YES YES N/R N/R N/R N/R YES N/R N/R 2002 N/R N/R N/R YES YES N/R N/R N/R N/R N/R YES N/R 2002 N/R N/R N/R YES YES N/R N/R N/R N/R N/R YES N/R 2002 N/R N/R N/R YES YES N/R N/R N/R N/R N/R YES N/R Adrenal 2003 F 55 2.5 YES N/R YES YES N/R YES N/R N/R myelolypoma 2007 F 41 4 YES YES YES N/R N/R YES N/R N/R N/R Contralateral phaeocromocy- 2008 F 25 N/R YES Lability YES YES N/R YES YES N/R toma and ganglioneuroma Occasionally, current F 66 4 NO NO NO NO NO NO NO Spigelian hernia mild N/R: not reported rare clinical entity. thesis via a paracrine effect [24]. In addition, glucocorticoids appear to regulate the expression of the Discussion key-enzymes for catecholamines synthesis, such as β-hydroxylase, tyrosine hydroxylase and phenyleth- Approximately fifteen corticomedullary mixed ad- anolamine-N-methyl transferase [24-27], enhancing renal tumors have been described up-to-date, mainly further a vicious cycle. However, the possibility that as case reports or small series [4, 10-17]. The exist- a ‘hybrid’ population might have been created early in ence of a number of them has been doubted by some fetal life by the action of unknown factors resulting in authors [18], since in some cases the presence of two the development of hyperplastic cells cannot be ruled simultaneous tumors was described using the same out and it might also explain the different clinical pres- terminology [19], whereas some cases were not histo- entations of the reported cases. Some investigators logically confirmed [20, 21]. The characteristic fea- support a ‘collision’ theory [4] or an early genetic de- ture of these masses is the presence of cortical and fect [18] that results in the co-expression of these cells. neuroendocrine cells in the same tumor by patholog- Regarding the differences in clinical presentation, ic criteria and not their simple coincidental coexist- histology and outcome of the cases described in the ence [4]. The distinct embryogenetic origin of these literature, the clinical validity of the present case was two different components makes the pathogenesis of its coincidental finding in an older age than the previ- these tumors obscure. The simultaneous presence ously reported cases. According to the available liter- of two distinct tumors can be supported more easily. ature this tumor is considered to be of benign biologi- Pheochromocytomas can produce ectopically ACTH cal behaviour. However, only few reported cases had [22] whereas catecholamines stimulate pituitary cor- a long term follow-up [4]; one patient was still alive ticotroph cells to produce ACTH [23]. Both mecha- 30 years postoperatively whereas another died from nisms may lead to adrenocortical hyperplasia whereas unrelated reasons 23 years postoperatively. A further catecholamines may stimulate glucocorticoids syn- case that developed a similar mass in the contralateral 822 Alexandraki et al. adrenal 18 months after the removal of the first tumor ochromocytoma, and positron emission tomography has also been described [14]. This latter finding high- were not employed as these are not widely available, lights the necessity for prolonged follow-up of pa- and data on their clinical usefulness are insufficient to tients harbouring such tumors. support their standard performance; the described pa- From the clinical point of view, symptoms sugges- tients did not have any clinical or biochemical feature tive of Cushing’s syndrome seem to be common pre- suggesting the necessity of these imaging tests [3]. senting symptoms whereas four cases had biochemical Regarding the post-operative investigation, the bio- evidence of catecholamine hypersecretion (Table 2). chemical follow-up revealed no evidence of residual However, besides one case with increased urine cat- autonomous cortisol secretion and fractionated urine echolamine levels, manifestated as hypertensive crisis metanephrine were performed instead of urine cate- during the operation, another patient with the preop- cholamines [30] with no evidence for pheochromocy- erative diagnosis of Cushing’s syndrome developed toma. Furthermore, no genetic testing was performed a hypertensive crisis [10, 16]. It is of note, that bio- since in patients with apparently sporadic pheochro- chemical hypercortisolaemia when was investigated, it mocytoma this is optional when they are more than 20 has been observed in all the reported cases (Table 2). years, without family history or features suggestive In the present case the distorted glucocorticoid secre- of hereditary pheochromocytoma and without clinical tion dynamics was confirmed by the absence of corti- characteristics, such as presence of malignant, extra- sol circadian rhythm (morning and afternoon values) adrenal, bilateral or multiple tumors [31]. and by the fact that the patient did not obtain adequate Regarding other pathological features of the mass, cortisol suppression following the overnight dexam- the size of the tumor does not seem to predict the ethasone suppression. Therefore, the present case symptoms since in the present asymptomatic case represents an asymptomatic patient with biochemi- the mass had diameter 4 cm and hypercortisolaemic cal suspicion of subclinical Cushing’s syndrome but symptoms or blood pressure lability have been de- with imaging features that require surgical manage- scribed with a wide range of tumor size from 2 to 4.5 ment even if the patient was not suffering from any cm (Table 2). Although there is no evidence that there target organ complication [3]. However, it cannot be could be an association between the adrenomedullary excluded whether the mild metabolic syndrome of the mixed tumor and the spigelian hernia, other concomi- present patient was only due to the presence of adre- tant pathologies in the ipsilateral or contralateral ad- nal incidentaloma as previously reported [28, 29]. In renal such as spindle cell sarcoma, or ganglioneuroma addition, it has to be underlined that in cases present- with phaeocromocytoma, or myelolypoma have been ing as adrenal incidentaloma the main point of the in- described [7, 13, 15 ,17]. vestigation is to decide whether the mass has to be re- Incidentally-discovered adrenal masses are seen moved; when a single adrenal lesion is present with increasingly frequently, and all clinicians need to be atypical radiological features it has to be treated sur- aware of their aetiology since each case needs to be gically. However, for a safe procedure, the identifica- treated individually, taking into consideration patient’s tion of autonomous cortisol secretion has to be dealt age and general condition and having in mind the pos- with hydrocortisone administration to avoid the hy- sibility of intraoperative complications even following poadrenalism by a suppressed contralateral adrenal a negative biochemical work up. Adrenomedullary gland and pheochromocytoma has to be excluded bio- mixed tumor is a candidate diagnosis in cases of ad- chemically to avoid an hypertensive crisis during the renal incidentalomas which imply the adoption of a operation. In the present case, an immediate resection structured protocol for these masses with adequate of the adrenal mass was dictated by the presence of combination of clinical, biochemical and imaging data suspicious imaging of malignant disease and therefore in order to obtain a precise diagnosis. The presence of no further biochemical investigation for Cushing’s these tumors with the mysterious pathogenesis and the syndrome diagnosis or imaging study were performed necessity for specific pathological and genetic investi- pre-operatively [3]. Radionuclide scintigraphy using gation imply the value of a common international reg- iodocholesterol for evaluating adrenocortical lesions, istry of rare tumors. I-123 metaiodobenzyl guanidine for evaluating phe- Corticomedullary mixed adrenal tumor 823

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