A Masculine Twist: Virilization Caused due to Adrenocortical Cancer

INTRODUCTION

Virilization or masculinization is the biological development of adult male characteristics in females. Most of these changes are produced by androgens. Symptoms include excess facial and body hair, deepening of the voice, baldness, acne, and increased muscularity.¹ Virilization could be associated with either benign or malignant conditions of the ovaries or the adrenal glands. Adrenal virilization syndrome is marked by excessive production of adrenal androgens, which leads to virilization. These growths usually secrete dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS), but not testosterone, which is normally produced by ovarian tumors. Adrenocortical carcinoma (ACC), one of the causes of Adrenal Virilization, is a rare malignancy and has a global incidence of one to two per million population annually.²

CASE DESCRIPTION

A 30-year-old female presented with a history of menstrual irregularities for the past 10 years. She had irregular menses for the first 2 years which improved with medications, however, she became amenorrheic for the past 8 years, despite taking various medications. She also complained of increased facial and body hair for the last 8 years, which would result in her needing to wax her skin repeatedly, with frequency increasing to once every week over the last few months. She also noticed a deepening of her voice, a broadening of shoulders, frontal hair loss, and a reduction in her breast size. She also complained of intermittent, dull aching, pain in the right upper half of the abdomen for the past 2−3 years which aggravated on exertion and relieved with over-the-counter medications. She also received homeopathic treatment for 2−3 years for the above complaints, with no results. The patient had attained menarche at 12 years of age and had regular menses before presenting with these symptoms. On examination, hyperpigmented areas were seen over both her arms, back, buttocks, and thighs. Terminal hair growth was seen over her face, abdomen, arms, legs, back, and pubis, along with frontal hair loss and acne (Fig. 1). Clitoromegaly and decreased breast size were also noted (Figs 2 and 3). The abdomen was soft, and non-tender and no mass per abdomen or organomegaly was appreciated.

She was worked up for secondary amenorrhea elsewhere. Her hormonal evaluation revealed high serum levels of testosterone and DHEAS with normal 17 hydroxyprogesterone (Table 1). Pelvic ultrasound did not show ovarian cysts and hence a triple phase, contrast-enhanced computed tomography (CT) of the abdomen with an adrenal protocol (Fig. 4) was done, which revealed a well-defined, lobulated, heterogeneously enhancing lesion of 10 × 9.6 × 11.8 cm in the right suprarenal region, replacing the right adrenal gland, and displacing the right kidney inferiorly. Internal areas of fat (~10%) and calcification were seen. Fat planes with adjacent structures were well maintained. The absolute washout of the lesion was 75% and the relative washout was 54% suggestive of ACC. Because of these findings, a biochemical workup for the adrenal lesion was done as summarized in Table 1.

As the adrenal mass was nonfunctional with a high suspicion of adrenocortical cancer, open transperitoneal right adrenalectomy was done. A 570-gm adrenal tumor measuring 12 × 8 × 6 cm was removed. Her intraoperative and postoperative course was uneventful. On histopathological examination, the cut surface showed a large area of necrosis measuring 4 × 3 × 1.5 cm along with areas of congestion. Solid and cystic growths were identified, and the rest of the gland showed unremarkable parenchyma (Fig. 5). Microscopic Examination showed a malignant neoplasm consisting of variably sized nests, sheets, and trabeculae of the tumor. Individual tumor cells were highly pleomorphic, having large-sized, round to oval nuclei, vesicular chromatin, conspicuous to prominent nucleoli, and moderate eosinophilic cytoplasm. Many binucleated, multinucleated, and bizarre cells, and mitosis (<20 per 50 high power fields) were noted. Lymphovascular invasion and capsular invasions were also present. Large hemorrhagic areas were also identified, which were intermixed with the tumor. The above findings were suggestive of a low grade, oncocytic variant of ACC (Fig. 6) pT3N0, stage III of 8th edition of American Joint Committee on Cancer (AJCC) staging manual. The patient was discharged on postoperative day 5. She is being planned for adjuvant radiotherapy after a discussion in a multidisciplinary meeting.

DISCUSSION

Secondary amenorrhea is the cessation of previously regular menses for 3 months or previously irregular menses for 6 months.³ Click or tap here to enter text. Once pregnancy has been ruled out, the evaluation of secondary amenorrhea is based on the anatomical pathologies of the uterus or the hypothalamic-pituitary-ovarian axis. The most common pathology to cause secondary amenorrhea in a woman of reproductive age-group is a polycystic ovarian syndrome (PCOS), characterized by irregular menses and features of hyperandrogenism like hirsutism, male-pattern hair loss, and acne. Another important differential, especially in women with severe virilization, is androgen-secreting tumors⁴ Serum Testosterone, DHEAS, and serum 17 hydroxyprogesterone should be tested. This is followed by a pelvic ultrasound to look for the ovaries. An adrenal CT is next done to look for identifying an androgen-secreting tumor, in women with high serum testosterone or DHEAS with a negative pelvic ultrasound.^5,6 This patient with severe virilization and hyperandrogenism had a high suspicion of an adrenal tumor which was eventually revealed in the CT scan.

Adrenocortical cancers are malignant tumors of the adrenal cortex with a 5-year survival of only 50%. Approximately 60% of ACCs are known to secrete, androgens, estrogens, cortisol, and various other hormones. Adrenocortical cancer has a bimodal age distribution, with the appearance of two peaks—in children less than 5 years old, and adults in the third or fourth decade of life, respectively. The presentation differs between adults and children. Most childhood tumors present most commonly with virilization, followed by Cushing’s syndrome and precocious puberty.⁷ In adults, Cushing’s syndrome is the most common manifestation, followed by combined Cushing’s and virilization (glucocorticoid and androgen overproduction). Feminization and Conn’s syndrome (mineralocorticoid excess) are rare and the incidence is less than 10% of all cases. Rarely, hypersecretion of pheochromocytoma-like catecholamines has also been noted. Histopathological variants of ACC include conventional, oncocytic, myxoid, and sarcomatoid types.⁸ Click or tap here to enter text. Mutations in TP53, CTNNB1, MEN1, PRKAR1A, RPL22, DAXX, telomerase gene TERT, ZNRF3, CDKN2A, p57kip2, h19, IGF-II, and c-myc gene expression are found to be increased in ACC.⁹

Cortisol non-secreting, pure virilizing ACC, accounts for fewer than 10% of cases of adrenal tumors. Moreover, virilization in the presence of adrenal neoplasm suggests an ACC rather than an adenoma.¹⁰ As the only potentially curative treatment for ACC is complete surgical resection, the patient underwent an open transperitoneal excision of the adrenal tumor which confirmed the diagnosis of an oncocytic variant of ACC. These tumors predominantly consist of oncocytes which are cells with abundant granular cytoplasm with tumors cells showing diffuse, nested, or trabecular patterns of pleomorphic cells with round nuclei, and prominent nucleoli.¹¹ Functionality in these tumors was thought to be rare but recent literature quotes functionality in approximately 30% of cases. Compared to conventional ACCs, oncocytic variants are thought to have a better prognosis with an overall median survival of 58 months.¹² Accurate classification of oncocytic adrenal neoplasms is important to predict the diagnosis of the disease. Lin−Weiss−Bisceglia system is frequently used. This includes the following major criteria: Mitotic rate of more than 5 mitoses per 50 high power fields, any atypical mitoses or venous invasion; Minor criteria: Large size > 10 cm/>200 gm, necrosis, capsular or sinusoidal invasion; Definitional criteria: Eosinophilic granular cytoplasm, high nuclear grade, and diffuse architectural pattern. The presence of any of the major criteria indicates malignancy, only minor criteria indicate uncertain malignant potential whereas the absence of all major and minor criteria indicates a benign course.¹²

The adjuvant treatment of stage III ACC is controversial with some studies recommending adjuvant treatment whereas others recommending only observation if the risk of recurrence is deemed to be low. Adjuvant mitotane may be appropriate in low-risk diseases with some features that suggest a potential risk of recurrence, such as in this patient with a low-grade, stage III disease, with a shorter duration of treatment (2 years) and a low threshold to discontinue mitotane if side effects are difficult to manage.¹³ However, due to the lack of availability of mitotane in our setup, economic constraints of the patient, and multidisciplinary team discussion between the departments of endocrine surgery, radiotherapy, and medical oncology; adjuvant radiotherapy was decided to be used as a risk reduction modality in this patient.

CONCLUSION

Secondary amenorrhea is a very common condition seen in women of reproductive age-group, however, severe virilization must raise suspicion for the evaluation of other pathologies such as adrenal tumors as ACC can be life-threatening if not treated at an early stage.

ORCID

Shubhajeet Roy https://orcid.org/0000-0003-1092-9668

Timil Suresh https://orcid.org/0000-0002-4988-9053

Ganesh Bhat https://orcid.org/0000-0002-4992-4322

Madhu Kumar https://orcid.org/0000-0001-9739-7793

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