Initial presentation and work-up: A 42-year-old man was referred to the endocrinologist because of an incidentaloma of the right adrenal with a maximum diameter of 4.2 cm on echography of the abdomen. Echography was performed because the patient presented with icterus. An abdominal CT scan confirmed a right adrenal mass with a maximum diameter of 5.1 cm. The intensity of the adrenal adenoma amounted 39 Hounsfield units. The patient did not have a significant medical history, especially no arterial hypertension. He did not use any medication. The patient did not have palpitations, headaches or sweat attacks. The last 3 months he lost 5 kg of weight which he attributed to stress and diet. He did not have spontaneous ecchymosis, colored striae or tiredness. He spontaneously complained about bilateral breast development since 5 months. His libido was normal and he did not have erection problems. Clinical examination showed a normal blood pressure and no Cushingoid stigmata. Bilateral gynecomastia was notified, which was confirmed on echo-mammography. Screening for hormonal activity of the incidentaloma showed no arguments for primary hyperaldosteronism, autonomous hypercortisolism or phaeochromocytoma. DHEAS was normal (278 μg/dl). Blood tests performed because of the bilateral gynecomastia showed a hypogonadotropic hypogonadism and a slightly elevated oestradiol of 44 ng/l. Prolactin level was normal. Hyperthyroidism, liver disease, testicular tumors and renal disease were excluded. Further examination by MRI of the adrenal glands did not show pronounced hypervascularization of the mass. A PET/CT scan showed a mild heterogeneous tracer capitation of the adrenal mass and did not show enlarged retroperitoneal gland complexes or distant metastases. Since the incidentaloma of the right adrenal was larger than 4 cm, the patient was referred to the endocrine surgeon to perform a right adrenalectomy.
Diagnosis and treatment: Histological examination of the right adrenal showed a completely resected adrenocortical carcinoma (ACC) (the tumor satisfied 4 of 9 items in the Weiss criteria) with a diameter of 2.8 cm with growth in the adrenal capsule and surrounding fatty tissue. TNM showed a pT3L0V0Pn0R0 classification. Due to growth in the surrounding tissue we diagnosed a stage 3 ACC based on the ENSAT (European Network for the Study of Adrenal Tumor) classification. Decision to start adjuvant treatment with mitotane was made during a multidisciplinary consultation. Patient mentioned disappearance of gynecomastia 2 weeks after surgery which was confirmed by clinical examination. Laboratory tests showed a decline in oestradiol level form 44 ng/l pre-operative to 9 ng/l postoperative and an almost complete recovery of the gonadotropic axis. DHEAS post-operatively was 125 μg/dl. Final diagnosis of an estrogen-producing ACC was made.
Discussion: ACC stays a rare endocrine malignancy with estrogen-producing feminizing ACC being even more rare with an incidence of 2% among all adrenocortical carcinomas1. They are mainly observed in men and children2. A normal adrenal gland has little aromatase activity. Oncogenesis leads to aromatase expression and induces estrogen synthesis. Excessive transformation of androgens to estrogens leads to an increase in estrogens/androgens ratio responsible for gynecomastia and other hypogonadism features and an inhibition of the hypothalamic-pituitary-gonadal axis causing a lack of luteinizing hormone-releasing hormone pulsatility inducing a low luteinizing hormone and follicle-stimulating hormone secretion1,2,3,4. The management of estrogen-producing ACC is similar to the management of other adrenal tumors. The guidelines of ENSAT conclude to give mitotane as adjuvant treatment to patients with high risk of recurrence (stage 3, R1 resection, or Ki67 >10%)5. In case of incomplete resection of estrogen-producing ACC, aminoglutethimide can be used as a complementary treatment. It blocks cortisol, aldosterone and androgens synthesis and also inhibits peripheral aromatization of androgens to estrogens2,5.
References: 1. Hatano M, Takenaka Y, et al. Feminizing Adrenocortical Carcinoma with Distinct Histopathological Findings. Intern Med. 2016; 55: 33013307.
2. Chentli F, Bekkaye I, et al. Feminizing adrenocortical tumors: Literature review. Indian J Endocrinol Metab. 2015; 19: 332339.
3. Nakamaru Y, Yamazaki Y, et al. Adrenocortical carcinoma: review of the pathologic features, production of adrenal steroids, and molecular pathogenesis. Endocrinol Metab Clin North Am. 2015; 44: 399410.
4. Saito T, Tojo K, et al. Feminizing adrenocortical carcinoma with selective suppression of follicle-stimulating hormone secretion and disorganized steroidogenesis: a case report and literature review. Intern Med. 2011; 50: 14191424.
5. Fassnacht M, Dekkers OM, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018; 179: 146.
21 Oct 2019
Belgian Endocrine Society