Clinics and Practice 2014; volume 4:651

Feminizing adrenocortical (either or feminization), although mixed clinical features can be observed.1,5 Correspondence: Alessandro Fancellu, Unit of with distant Feminizing ACCs, i.e. malignant adrenal General Surgery 2 - Clinica Chirurgica, metastases: can surgery tumors causing features of excess, Department of Clinical and Experimental be considered? are an extremely rare cause of abdominal Medicine, University of Sassari, v.le San Pietro mass. 43, 07100 Sassari, Italy. Tel.: +39.079.228432 - Fax: +39.079 228394. Alessandro Fancellu, Antonio Pinna, We herein present a case of a young man E-mail: [email protected] Alberto Porcu having a giant feminizing ACC with distant metastases, which posed serious management Key words: adrenocortical carcinoma, feminizing, Unit of General Surgery 2, Department problems principally related to the burden of treatment, , rare tumor. of Clinical and Experimental Medicine, the primary tumor. University of Sassari, Italy Conflicts of interest: the authors declare no potential conflicts of interest.

Case Report Contributions: the authors contributed equally. Abstract Received for publication: 9 May 2014. A 41-year-old gentleman presented com- Accepted for publication: 12 June 2014. plaining of a 6-month history of bilateral Functioning adrenocortical are gynecomastia without galactorrhea, and a sig- This work is licensed under a Creative Commons rare diseases with dismal prognosis. A 41-year- Attribution NonCommercial 3.0 License (CC BY- nificant weight loss (8 kg in the last three old man presenting with gynecomastia had a NC 3.0). months). In the last two months he also giant feminizing adrenocortical carcinoma at noticed abdominal and back pain, dyspepsia, stage IV. Although surgical resection was con- ©Copyright A. Fancellu et al., 2014 and some episodes of vomiting, bloating and Licensee PAGEPress, Italy troversial, we removed the primary tumor to difficult passage of stools. The rest of his med- Clinics and Practice 2014; 4:651 reduce the mass effects. He lived for 12 ical history was not relevant and he was on no doi:10.4081/cp.2014.651 months with an acceptable quality of life. medications. His family history revealed the Gynecomastia may be the first sign of feminiz- presence of a 37-year-old sister with an estab- ing adrenal malignancies. Surgery may ame- lished diagnosis of MEN1 (primary hyper- liorate the quality of life in selected patients parathyroidism, pancreatic , and , in an attempt to reduce the with metastatic disease. ) with germline mutation 894-9 symptoms related to the mass, principally pain GA, and a 50-year-old brother affected by an and recurrent subocclusive episodes. Before adrenocorticotropic hormone (ACTH)-secret- the operation, a medication with ketoconazole ing pituitary causing Cushing’s dis- was started for hypercortisolemia; however, Introduction ease. As the patient was in good health before replacement of ketaconazole with metyrapone the appearance of gynecomastia, he had previ- was necessa ry to normalize the levels. While adrenal are quite frequent ously refused to undergo laboratory and genet- The patient underwent an exploratory celioto- in the general population, adrenal cortical car- ic testing. Laboratory tests showed: i) extreme- my where a large encapsulated mass was cinomas (ACCs) are rare malignancies affect- ly high estradiol plasma levels (E2>500), encountered, displacing the kidney inferiorly ing only 2 per million per year in the world pop- together with undetectable gonadotropin levels and the distal and spleen superiorly. ulation.1,2 A bimodal age distribution has been and low testosterone; ii) the likely coexistence The mass and the left kidney were resected en recognized, with first peak in childhood (<5 of Cushing’s disease (hypercortisolemia with bloc. On surgical exploration, the right adrenal years of age) and second peak in 4th-5th decade increased ACTH levels) (Table 1). In relation also appeared increased in size, thus a bilater- of life. Most of the ACCs are sporadic; however to the latter, an overnight dexamethasone sup- al adrenalectomy was performed. On gross they may also arise within the context of famil- pression test (1 mg at 11.00 p.m.) was carried pathology examination, the left adrenal tumor ial or hereditary diseases.2-4 out, which failed to show serum cortisol sup- (which included approximately half of the left Although different studies have been under- pression (19 g/dL at 08.00 a.m.). On abdomi- kidney, with diffusely infiltrated areas) taken in order to elucidate the molecular nal examination, a large, firm mass adherent weighed 3.3 kg, and measured 27×17×12 cm pathogenesis of sporadic ACCs, to date none of to the deep layers was palpable in the left quad- (Figure 2). The histological examination them has been proven to be completely rants. The total body computed tomographic revealed an ACC with oncocytic changes with a exhaustive.2,4 In particular, the genetic alter- (CT) scan showed a large tumor of the left Weiss score of 8 (Figure 3). Based on the his- ations characteristic of the adenoma-carcino- adrenal (25 cm in its maximum diameter) tological finding, the laboratory tests, and the ma sequence has not clearly established. To with colliquative areas infiltrating the left kid- presence of distant metastases, we made the date, modification in three main molecular ney (Figure 1), left renal vein thrombosis, and diagnosis of fe minizing adrenocortical carci- patterns has been identified: insulin-like multiple and metastases. No pancre- noma at stage IV according to the American growth factor (IGF)-2, the metabolic pathway atic lesions were visible. Pelvic CT scan Joint Committee on (AJCC) classifica- Wnt/-catenin and TP53.4 ACCs can be either revealed no abnormality, while breast and tes- tion. The right adrenal weighed 14 g and had functioning (i.e. producing hormones of the ticular ultrasound confirmed the presence of aspects of cortical hyperplasia. ) or non-functioning. Adrenal gynecomastia and reduced testicular volume. The postoperative course was uneventful, malignancies are more likely to be functioning Neck ultrasound showed neither enlarged and the patient was discharged on postopera- with respect to adenomas and can have differ- parathyroid nor thyroid alterations. tive day 12. He was given replacement therapy ent clinical presentations, depending on the Pituitary magnetic resonance imaging and with hydrocortisone, fludrocortisone, and type of hormonal secretion. In fact, patients parathyr oid sestamibi scan were also normal. therapy without any importan t side may have symptoms of hypercortisolism, After a multidisciplinary discussion, it was effects. Six months after surgery, laboratory hyperaldosteronism, or sex hormone excess decided to operate on the patient to remove the tests showed a normalization of cortisol and

[page 30] [Clinics and Practice 2014; 4:651] Article levels. Gynecomastia was markedly The main presenting signs and symptoms of patient.6 While AACs are for the most part spo- improved, and a mild reduction of the size of feminizing ACC are gynecomastia, testicular radic, they can occur as part of various familial liver and lung was observed. He atrophy, decreased and impotence. In tumor syndromes, such as MEN1, Li-Fraumeni went on to live 12 months with an acceptable line with other reported cases, gynecomastia syndrome, Beckwith-Wiedemann syndrome, quality of life before dying from metastatic dis- was the presenting symptom of ACC in our and .2,4 The familiar history of ease. patient.5,7 Gynecomastia recognizes various our patient denoted the presence of well- causes, being most commonly due to medica- defined endocrine pathologies (MEN1 and tions, imbalance between testosterone/estro- ACTH-producing ). Adrenal gen levels, kidney failure, cirrhosis, and much neoplasms are not commonly included in Discussion and Conclusions more rarely to pituitary and adrenal tumors.7 It MEN1; however, non-functioning macronodu- has been suggested that feminizing symptoms lar hyperplasia is observed in up to 40% of Feminizing ACCs are very rare, accounting can be linked to aberrant aromatization of patients with MEN1 and, even rarely, ACCs can for only 1-2% of all malignant neoplasms of adrenal in estrogens, principally occur.4 As a consequence, we investigated the 1 adrenal cortex. In 1994, Zayed reported fewer E1.6 Feminization is often combined with existence of MEN1 syndrome in our patient, 6 than 100 cases described in male sex. Since hypercortisolism, as we observed in our but the laboratory and imaging studies pre- then, only a few cases have been added to the literature. Clinical features related to excess occur in about 60% of ACCs, while feminizing symptoms due to estrogen secretion are extremely uncommon.1,5

Figure 1. Computed tomographic scan of the abdomen revealed a large tumor of the left adrenal (25 cm in its maximum diame- ter) with colliquative areas, occupying almost entirely the hemiabdomen.

Figure 2. The adrenal mass measured Figure 3. Histological examination with standard hematoxylin and eosin showing a pro- 25×17 cm, and appeared encapsulated, yel- liferation of large epithelial cells and pleomorphic oxyphil nuclei (A, 200×; B, 400×), lowish with extensive areas of and with large areas of necrosis and endovascular embolization (C, 100×; D, 200×). mucoid degeneration, encompassing the Immunohistochemistry showing strong positivity for Melan-A and Synaptophysin in the left kidney (black arrow). tumor cells (E, 200×; F, 200×).

[Clinics and Practice 2014; 4:651] [page 31] Case Report vented us from confirming this hypothesis. Table 1. Preoperative laboratory tests. In the described case, invasion of surround- Test Result Unit Normal values ing organs and distant metastases defined the neoplasm as a carcinoma. However, differenti- LH <0.1 mUI/mL 1.7-8.6 ation between benign tumors (adenomas) of FSH <0.1 mUI/mL 1.5-12.6 the adrenal cortex and ACCs is not always sim- Estradiol 577 pg/mL 7.63-42.6 ple to achieve.3 The likelihood of being malig- nant is very high for adrenal tumors producing Prolactin 26 ng/mL 2.5-17 sex hormones; in particular, feminization is Testosterone 5.98 ng/mL 2.8-8.0 quite consistent with malignancy more often Free testosterone 6.38 pg/mL 9-40 than virilization.5,8,9 As for the histological cri- DHEA-sulphate >1000 g/mL 89-427 teria, the model proposed by Weiss in 1984 still 17OH-progesterone 13,762 pg/mL 400-3300 remains the most accurate and the one that CEA 1.5 ng/mL 0-4.4 best correlates with the prognosis of ACCs.10 This model includes nine histological features -fetoprotein 18.8 UI/mL 0-5.8 distinguishing benign from malignant tumors. -HCG 0 mUI/mL 0-3 In our patient, 8 out of nine Weiss criteria PTH 53 pg/mL 12-60 were satisfied. Calcium 10.02 mg/dL 8.10-10.40 ACCs are notoriously aggressive tumors Phosphorus 2.5 mg/dL 2.7-4.5 associated with poor prognosis. One cause for 25hydroxy vitamin D 55 ng/mL 40-60 this finding is certainly the fact that many ACCs are detected at advanced stage. Preferred Cortisol (08.00 a.m.) 25 g/mL 5-23 sites of metastatic spread are liver, , and Cortisol (04. p.m.) 22 g/mL 3-16 lymph nodes. ACTH (08.00 a.m.) 72 pg/mL 9-52 According to the literature, only 25-30% of Free urinary cortisol 623±33.3 g/24/h 4.3-176 patients present with stage I-II (disease con- LH, luteinizing hormone; FSH, follicle-stimulating hormone; DHEA, ; CEA, carcinoembryonic antigen; HCG, human fined to the adrenal), whereas about 70% pres- chorionic gonadotropin; PTH, parathyroid hormone; ACTH, adrenocorticotropic hormone. ent with stage III-IV (disease extending beyond the adrenal).2 The two most important prognostic factors have been identified in role in metastatic ACCs providing that greater sus and mitotane) showed no dif- stage at diagnosis and surgical radicality, than 90% of the tumor and metastases can be ference between the two regimens in terms of though age, mitotic count, and Ki67 expres- removed, according to the National overall survival (14.8 vs 12.0 months; P=0.07).16 3,9,11,12 sion have also been considered. Comprehensive Cancer National guidelines. Individualized therapies based on genomic Historically, overall 5-year survival rates in In the case described herein, the manage- and expression profiling of ACCs represent patients with ACCs range between15% and ment decision was quite complex, as a result of other promising perspectives.2,14 As knowledge 20%. In a study from the Memorial Sloan the patient’s young age, the presence of wide- of the molecular mechanisms of ACCs contin- Kettering Cancer Center, patients with stage I- spread disease and the local extension of the ues to improve, it is likely that targeted thera- II disease and with III-IV disease had 5-year primary tumor. Following a multi-disciplinary pies will improve survival outcomes in the near survival of 60% and 10%, respectively.13 approach, we decided to operate on the patient future. Numerous trials are investigating tar- Complete surgical resection is the only poten- because of the local effects of tumor. Medical geted agents such as epidermal growth factor tially curative treatment, and nowadays treatments had failed to alleviate these symp- inhibitors, antiangiogenic agents, tyrosine remains the mainstay in the treatment of toms. The intention was obviously not to cure kinase inhibitors, IGF-1 inhibitors, and fibrob- localized ACCs (stage I-III), even in patients the patient with surgery, but to ameliorate his last growth factor receptor inhibitors.2,14 with extension to adjacent organs and positive quality of life, and thus obtain a good palliation In our opinion, this report contains two local lymph nodes. Five-year survival after sur- for mass effects and hormonal symptoms. To principal points of interest. First, we empha- gical resection is approximately 40%.12 Even note, he lived with an acceptable quality of life size the fact that feminizing ACC should be patients who undergo radical surgery bear for 12 months after the surgical removal of the taken into account as a possible diagnosis in high risk (about 80%) of local relapse and adrenal mass. We can reasonably speculate patients presenting with gynecomastia, espe- metastases, which typically occur within 2 that, in this case, surge ry might have pro- cially when the common causes for this disor- years.2 When surgical removal is not achieved longed the overall patient survival. der have been ruled out. Second, surgery may with radical intent, the prognosis is very poor Mitotane, alone or in combination with (median survival <1 year). other chemiotherapics has historically been have a role even in patients with functioning Although the use of laparoscopic adrenalec- the main medicament used in the adjuvant ACCs at stage IV, with the aim of improving tomy for malignant AACs has been reported to setting following radical surgery as well as in quality of life by relieving symptoms of hor- be safe by some authors, there is a common metastatic disease. Its use is limited by signif- monal excess and mass effects. agreement that open surgery should be pre- icant, dose-dependent gastrointestinal and ferred in this setting.14,15 neurologic toxicity; in our case the mitotane Our patient had stage IV disease because of therapy was quite well tolerated. distant metastases (lungs and liver) and inva- Survival rates from ACC have not substantial- References sion of adjacent tissues. ly changed over the last 20 years, and systemic In stage IV disease, or pallia- treatment, to date, is unsatisfactory. 1. Kidd MT, Karlin NJ, Cook CB. Feminizing tive cures have been the common options.3 The phase III FIRM-ACT trial comparing two adrenal neoplasms: case presentations Surgical resection of metastatic ACC remains different regimens in metastatic ACCs (etopo- and review of the literature. J Clin Oncol controversial, although surgery may have a side, , , and mitotane ver- 2011;29:e127-30.

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