Leydig Cell Tumor of Ovary Non-Hilar Type: An Uncommon Histopathological Variant - Case Report and Literature Review

Introduction

The recent World Health Organization classification of tumors of female reproductive organs, Hilus cell tumors were classified as a separate entity in the category of Sex Cord-Stromal Tumors (SCST) - pure stromal tumors [1].

Leydig cell tumors are rare, sex-cord stromal tumors. They account for 0.1% of ovarian tumors. The majority of these tumors are unilateral [2]. These are almost always benign in nature. There are approximately 150 reported cases of Leydig cell ovarian tumors in the literature to date [3, 4].

Leydig cell tumors of the ovary may produce androgens and cause virilization. The diagnosis is challenging and requires is proper clinical history, laboratory findings, histomorphological features and imaging.

We report a case of a 45-year-old postmenopausal woman who presented with a history of acne, increased muscle bulk, balding, virilization, polymenorrhea, dysmenorrhea, dysfunctional uterine bleeding of 6 month duration.

On ultrasonography abdomen-pelvis showed bulky uterus with three hypo echoic lesions, larger measuring 5.2x.5x3.5 cm, reported as intramural fibroid. The right ovary measured 2.8 x 2 x 1 cm showed nonspecific well-defined, solid mass with tiny cyst. The left ovary was 2.0 x 1.5 x 1 cm with 1cm cystic lesion.

The patient had increased levels of serum total testosterone 240 ng/dL (normal range, <41 ng/dL), free testosterone 5.10 ng/mL (normal range, 0.10–4.70), and a normal level of dehydroepiandrosterone sulfate 48 ug/dL (normal range, 26–460).

She underwent an exploratory laparatomy, total hysterectomy with bilateral salpingo-oophorectomy. Following the surgery, her hirsutism gradually disappeared and serum testosterone were of normal levels.

Discussion

Leydig stromal cell tumor are rare ovarian tumor that belongs to the group of sex-cord stromal tumors. Hilus or Leydig cell tumors are included in the WHO classification under the heading of “Steroid Tumors” Leydig cell tumors typically occurring in postmenopausal women. They cause hirsutism and virilization in 75% of cases. In addition, approximately 10–20% are also associated with some degree of estrogenic effect such as endometrial hyperplasia [5, 6].

Scully described a distinctive form of lipid cell tumor which closely resemble the stromal luteoma includes all neoplasms that are composed exclusively of cells with structural features common to adrenal cortical cells, Leydig cells, luteinized ovarian stromal cells, and luteinized theca interna cells [7]. Leydig cell tumors is distinguished from a stromal luteoma by the presence of characteristic crystalloids of Reinke within the tumor cells.

Leydig stromal tumor accounts for less than 0.1% of all ovarian tumors [8]. In most patients the etiology of Leydig cell tumor is unknown. Few cases sporadically observed mutations in the fumarate hydratase gene, while few cases area associated with hereditary leiomyomatosis and renal cell carcinoma syndrome. The Leydig cell tumor tumors are generally associated with a benign course. When hyperandrogenism with rapid progression or with signs of virilization an androgen-secreting tumor, origin from the adrenal glands, ovaries, or be ectopic are suspected.

Proper evaluation of women with postmenopausal hyperandrogenism requires a specific investigation protocol. The combined ovarian and adrenal venous blood sampling is a useful method to determine the site of androgen secretion. New-onset virilization in a postmenopausal woman is usually of acute or sub acute onset and is almost always due to tumors of the ovary than adrenal.

There is increased production of testosterone leading to hyperandrogenism and virilization. It shows clinical effect like growth of facial and body hair, voice deepening, clitoromegaly, hirsutism, breast atrophy, increased muscle mass in woman who are mostly postmenopausal [8].

Bancos I et al, observed that about 30% of patients may have endometrial hyperplasia and dysfunctional uterine bleeding. In our case patient presented with dysfunctional uterine bleeding [9]. Muechler EK reported a case of a hilar cell tumor resulting in erythrocytosis and bilateral deep venous thrombosis. [10].

These tumors are typically very small. These tumors are unilateral and confined to the ovary in about 90% of cases. Tumors are  well-circumscribed  with a  smooth lobulated outer surface, homogenous, solid, firm, tan-yellowish on cut surface. In our case tumors are unilateral and confined to the ovary (Figure 1).

On histopatholical examination tumor is composed of nodules of leydig cells with a neoplastic stromal proliferation. The tumor  is composed of Leydig cell which are arranged in diffuse sheets. The neoplatic cells are of uniform round or polygonal cells  with  abundant eosinophilic cytoplasm. The  nuclei are round, uniform, having prominent central nucleoli (Figures 2 & 3) there is no cellular atypia. The mitotic activity is not increased. The stromal component resembles the theca cell tumor, and the presence of crystals reinke: cylindrical crystalloid eosinophilic cytoplasmic bodies in the leydig cells. The tumor cells are surrounded by delicate vasculature. The lipid-rich Leydig cell tumors  have  finely vacuolated or foamy cytoplasm. Other histomorphological patterns include pseudoglandular, spindle insular, nested, trabecular, ribbon-like, and microcystic.

In histopathological reporting carefully look for the features of malignancy in Leydig cell tumors. These are cells showing nuclear atypia, large tumor size, infiltrative margins, evidence of necrosis and increased mitoses (>3/10 HPF).In our case there were no any features of malignancy.

The ovarian leydig cell tumors are of hilar, non hilar, leydig cell not otherwise specified . The hilar leydig cell tumors arise in the hilus from hilar leydig cells mostly (80%). Other leydig cells tumors that are located within the ovarian stroma are referred to as non hilar leydig cell tumors. While the term leydig cell not otherwise specified is used when it is uncertain about the origin [11]. Non-hilar Leydig cell tumors, as in our patient, occur in ovarian cortical stroma and can be difficult to distinguish from other stromal tumors.

Hilus cell tumors may be associated with other female genital tract’s benign and malignant neoplasms such as granulosa cell tumor of the ovary, polycystic ovaries, leiomyoma uterus, endometrial adenocarcinoma etc [12]. The differential for Leydig cell tumor are hyperplastic/ hamartomatous nodules. It is observed in Klinefelter syndrome, adrenogenital syndrome, elevated gonadotropin levels Nelson syndrome etc. Other differential are stromal  luteoma, stromal hyperthecosis, fibrothecoma, Leydig cell hyperplasia [13, 14]. Leydig cell tumors on immunochistochemistry are -alpha, calretinin, CD56, and vimentin positive.

A mutation in the DICER1 gene is associated with Sertoli- Leydig tumors as noted in recent data that indicate germline or somatic mutations in some genes are responsible for the development of some types of sex cord-stromal ovarian tumors [15].

The surgical resection of ovary is treatment for the sex cord –stromal ovarian tumors [16]. In patient who wants preserve their fertility conservative surgery with unilateral salpingo-oophorectomy is choice. The abdominal hysterectomy and bilateral salpingo-oophorectomy should be performed for the bilateral ovarian involvement, and patient who patient does not want to preserve her reproductive potential. On follow up our case showed well response to treatment.

Conclusion

Leydig cell tumors are rare, challenging to diagnose, and should be considered in the differential for virilizing symptoms in postmenopausal women. The histomorphological features play important role. Leydig cell tumors are rare, usually small size, seen in elderly women and having excellent prognosis. We report a rare case of a Leydig cell tumor - non- hilar type of right ovary for its clinical, radio imaing and histomorphological features.