Ovarian Leydig Cell Tumor Associated with Recurrent Torsion and Virilization in an Adolescent Patient.

Ovarian tumors are rare in children; however, their incidence increases with age. Of these ovarian tumors, Leydig cell tumors are some of the rarest, accounting for less than 0.1% of all ovarian tumors across all ages. Leydig cell tumors predominantly occur in postmenopausal women and are characterized by nodular proliferation of Leydig cells in the ovarian hilum with intracytoplasmic Reinke crystals. These tumors secrete androgens, which can disrupt ovarian function, clinically presenting with abnormal uterine bleeding and virilization. Although they are generally benign, current recommendations are for treatment with a unilateral salpingo-oophorectomy. In adolescents, hyperandrogenism is most commonly caused by polycystic ovarian syndrome (PCOS); however, the differential for hyperandrogenism is broad. We present a case of a 15-year-old girl with a history of primary amenorrhea who presented with a Leydig cell tumor associated with recurrent ovarian torsion and virilization. This case reviews the challenges with diagnosis, management, and future implications of a rare androgen-secreting tumor in young patients.

Ovarian Leydig Cell Tumor and Ovarian Hyperthecosis in a Postmenopausal Woman: A Case Report and Literature Review.

Ovarian Leydig cell tumor is a rare type of ovarian steroid cell neoplasms, presenting in only 0.1% of all ovarian tumor cases, and is generally androgen-secreting and unilateral. Although they are often malignant non-spreading tumors, which have excellent prognosis, benign ovarian Leydig cell tumors with low-risk malignancy can be also detected. Ovarian hyperthecosis is a rare non-neoplastic disorder, in most cases bilateral. Ovarian tumors and ovarian hyperthecosis are one of the main causes of hyperandrogenism in postmenopausal women, a condition strongly associated with both hormonal and metabolic changes. Here, we report a 65-year-old patient with complaints of excessive body hairiness and alopecia. The laboratory investigation showed increased levels of serum testosterone and dehydroepiandrosterone sulfate (DHEA-S). Imaging, including transvaginal ultrasound and pelvic MRI revealed the presence of two masses in the ovaries. The patient underwent a laparoscopic bilateral salpingo-oophorectomy due to the ovarian tumors unknown etiology, and histopathological examination revealed a unilateral benign left ovarian Leydig cell tumor with bilateral ovarian stromal hyperplasia and ovarian hyperthecosis. Making differential diagnosis between ovarian tumors and ovarian hyperthecosis is difficult. Bilateral salpingo-oophorectomy is the treatment of choice in postmenopausal women with benign Leydig cell ovarian tumor, as well as ovarian hyperthecosis, as it offers both a cure and diagnostic confirmation.

Leydig cell tumor of the testis with characteristic contrast patterns of tumor and non-tumorous testicular parenchyma on MRI: a case report.

PURPOSE: Testicular Leydig cell tumor (LCT) is a rare subtype of testicular neoplasms that occurs in the interstitial tissue of testes, accounting for 1-3% of total testicular masses removed annually. We report a case of 70-year-old man diagnosed as testicular LCT. This report demonstrates a testicular LCT with intratumoral and non-tumorous testicular parenchymal enhancement in the affected testis, which should be considered characteristic findings of LCT. METHODS: Ultrasonography showed a hypoechoic mass. On magnetic resonance imaging, the tumor showed low signal intensity comparable to the surrounding testicular tissue on T1-weighted images (T1WI) and low signal intensity on T2-weighted images (T2WI). On gadolinium contrast-enhanced T1WI (CE-T1WI), the tumor showed a rapid and marked wash-in and subsequent prolonged washout. The spared, non-tumorous testicular parenchyma showed slow and progressive enhancement in the early phase, which was as strong as or stronger than that of the mass in the delayed phase. The patient underwent right orchiectomy. RESULTS: Pathologically, the tumor was diagnosed as a testicular Leydig cell tumor (LCT). Leydig cell proliferation was observed with well-developed microvessels, atrophy of the seminiferous tubules, and stromal edema in the non-tumorous testicular parenchyma. Leydig cells in the non-tumorous parenchyma were positive for estrogen receptors. CONCLUSION: Since the contrast findings in the non-tumorous testicular parenchymal region on CE-T1WI likely match the histopathological features of LCT, our case suggests that the presence of non-tumorous testicular parenchymal enhancement on imaging might indicate a diagnosis of LCT.

Histidine decarboxylase inhibitors: a novel therapeutic option for the treatment of leydigioma.

Recent reports indicate an increase in Leydig cell tumor (LCT) incidence. Radical orchiectomy is the standard therapy in children and adults, although it entails physical and psychosocial side effects. Testis-sparing surgery can be a consideration for benign LCT of 2.5 cm or less in size. Malignant LCTs respond poorly to conventional chemotherapy, so new treatment modalities are needed. In this study, we observed increased histidine decarboxylase expression and pro-angiogenic potential in LCT surgically resected from pediatric patients (fetal to pubertal) vs control samples from patients without endocrine or metabolic disorders which were collected at necropsy. We, therefore, evaluated for the first time the antitumor efficacy of two histidine decarboxylase inhibitors (α-methyl-dl-histidine dihydrochloride (α-MHD) and epigallocatechin gallate (EGCG)), alone and combined with carboplatin, in two preclinical models of LCT. MA-10 and R2C Leydig tumor cells, representing two different LCT subtypes, were used to generate syngeneic and xenograft mouse LCT models, respectively. In the syngeneic model, monotherapy with α-MHD effectively reduced tumor growth and angiogenesis. In the xenografts, which showed co-expression of histidine decarboxylase and CYP19, the combination of EGCG plus carboplatin was the most effective therapy, leading to LCT growth arrest and undetectable levels of plasmatic estradiol. Testicular and body weights remained unaltered. On the basis of this study, histidine decarboxylase may emerge as a novel pharmacological target for LCT treatment.

Is testis sparing surgery safe in patients with incidental small testicular lesions referring to a fertility center? A retrospective analysis reporting factors correlated to malignancy and long-term oncological outcomes.

PURPOSE: To define predictors of malignancy after Testis sparing surgery (TSS) in patients referring to a fertility center with incidental small testicular lesions. Sub analyses were performed to assess predictors of Leydig cell hyperplasia and Leydig cell tumor. MATERIALS AND METHODS: We performed a retrospective analysis of a single institutional database including patients treated with TSS between 2002 and 2020. All patients who underwent TSS as a first line surgical approach for incidentally detected lesions found during fertility evaluation were included. RESULTS: Data of 64 patients were collected. The median follow up was 58 months and no recurrences were observed. At univariable logistic regression multifocal lesions, hypervascularization, microlithiasis, age and lesion size were significantly associated with malignancy. At multivariable logistic regression lesion dimension, hypervascularization and multifocal lesions were predictors of malignancy. Lesions smaller than 5 mm proved to be benign in 96.6% of the cases (32/33). Intraoperative color of the lesion and US pattern of vascularization were predictors at multivariable logistic regression for Leydig cell hyperplasia and Leydig cell tumor. CONCLUSION: Ultrasonographic characteristics and intraoperative appearance of the lesion can predict the malignant nature of small testicular lesions, guiding their surgical management in patients referring to a fertility center. Based on our experience, clinicians may safely perform TSS in carefully selected patients.

Hyperandrogenism due to ovarian Leydig cell tumour presenting with polycythaemia.

A postmenopausal woman in her 60s was referred due to an elevated haemoglobin value found during her annual check-up. On physical examination, characteristic features of hyperandrogenism were observed which were not earlier mentioned. Laboratory investigations revealed polycythaemia accompanied by a normal erythropoietin and a negative analysis for JAK2-V617F mutation. A disproportionally and markedly elevated testosterone in combination with normal levels of adrenal androgens raised the suspicion of an ovarian source. CT scan showed nodular hyperdense lesions in both ovaries. A bilateral oophorectomy was performed and histological evaluation unfolded a Leydig cell ovarian tumour. Testosterone levels and haematological parameters normalised after surgery. Polycythaemia secondary to hyperandrogenism in postmenopausal women is an extremely rare condition and patients should be carefully analysed for the presence of androgen-secreting neoplasms. Diagnosis of the underlying pathology requires careful history, physical examination and comprehensive investigation. Treatment for this condition is surgery and resolves polycythaemia.

Ultrasound examination assisted clinical diagnosis of Leydig cell tumor of ovary: An extremely rare case report.

INTRODUCTION: Leydig cell tumor (LCT) is a sex cord-stromal tumor, which is a clinically rare ovarian tumor. It is characterized by endocrine hormonal changes and usually occurs in postmenopausal women. PATIENT CONCERNS: We report the clinical case of a 38-year-old female of childbearing age with LCT of the right ovary who presented with significantly decreased menstrual flow and elevated androgen levels, with persistent hypoechoic areas in the ovary as demonstrated by transvaginal ultrasound. DIAGNOSIS: The transvaginal ultrasound suggested the presence of a hypoechoic area in the right ovary with elevated androgens, interstitial tumor of the ovarian sex cord may be considered. INTERVENTIONS: The patient underwent laparoscopic right adnexectomy. OUTCOMES: Postoperative pathology confirmed the morphology and immunohistochemistry of the right adnexa consistent with LCT, and no areas of malignant transformation were found on multiple sections of the surgical specimen. The patient had normal androgen levels at postoperative day 2, day 45 and month 3. There was no sign of recurrence. CONCLUSION: This case suggests that when women of childbearing age have abruptly decreased menstrual flow with increased testosterone, clinicians should pay attention to intra-ovarian occupying lesions and consider the possibility of LCT. In such cases, ultrasound examination can determine the presence, location, shape and size of occupying ovarian lesions and play an important role in the diagnosis of condition.

Ovarian Leydig Cell Tumor: Cause of Virilization in a Postmenopausal Woman.

BACKGROUND Only 0.5% of all ovarian tumors are Leydig cell tumors and they are generally benign and unilateral. These androgen-secreting tumors lead to virilizing symptoms, most often in postmenopausal women. Because Leydig cell tumors are typically small, diagnosing them accurately can be challenging. CASE REPORT We report the case of a 77-year-old woman who was referred to our Endocrinology Clinic because of a 5-year history of hirsutism (Ferriman-Gallwey score of 11) with no discernible cause. The patient had high levels of serum testosterone and a normal level of dehydroepiandrosterone sulfate. Imaging, including transvaginal ultrasound and pelvic magnetic resonance, revealed a 16-mm uterine nodule, which was suspected to be a submucous leiomyoma, but no adrenal or ovarian lesions. Despite the lack of findings on imaging and because of the high suspicion for an androgen-secreting ovarian tumor, bilateral laparoscopic oophorectomy was performed. Histological examination of the specimen revealed a non-hilar Leydig cell tumor that measured 8 mm in its largest axis. After the surgery, the patient had significant clinical improvement and her laboratory test results normalized. Her sister had the same symptoms and laboratory findings at a similar age, which raised the suspicion of a possible familial genetic syndrome. No genetic testing was performed, however, because the patient's sister declined further diagnostic investigation. CONCLUSIONS Leydig cell tumors are rare, and even when they are small, they can cause symptoms related to androgen excess. As a result, diagnosing them often is challenging.

Occult symptomatic bilateral pure Leydig cell tumors in a postmenopausal woman: a case report.

BACKGROUND: Pure Leydig cell tumors (LCTs) represent 0.1% of ovarian masses. Postmenopausal patients typically present with virilization. Although LCTs can be challenging to locate on conventional imaging, positron emission tomography (PET) has been demonstrated to be effective. CASE: A 64-year-old postmenopausal woman presented with alopecia, facial hirsutism, and clitoromegaly. Laboratory findings included elevated testosterone and androstenedione. Ultrasound, computed tomography, and magnetic resonance imaging showed no adnexal masses. PET did not demonstrate ovarian fludeoxyglucose-avidity. Histopathology after bilateral salpingo-oophorectomy revealed bilateral Leydig cell tumors. Her testosterone normalized 2 weeks postoperatively. CONCLUSION: We describe the occult, symptomatic, bilateral ovarian Leydig cell tumors, an occurrence that has not been described in the literature. Virilizing tumors must be considered in patients with evidence of hyperandrogenism, even without pelvic masses on imaging.

Role of contrast-enhanced ultrasound with Sonazoid in management of small testicular Leydig cell tumours: A case report with literature review.

Small testicular solid lesions are discovered accidentally due to the extensive use of ultrasound in urology and andrology. Early differentiation between benign and malignant testicular neoplasms is crucial for the determination of treatment options, especially for sub-centimetre lesions. We report a case of a male patient with an incidental discovery of a small testicular lesion on ultrasonography with the chief complaint of left testicular discomfort. The blood-flow distribution and microbubble dynamics in the lesion were evaluated through contrast-enhanced ultrasound using Sonazoid intravenous bolus injection, the rapid and intense enhancement pattern tended to be testicular Leydig cell tumour. Through testicular-sparing surgery, the lesion was excised, and benign testicular Leydig cell tumour was confirmed by post-operative pathology and immunohistochemical pathology. No sign of recurrence or metastasis was detected during follow-up.

Management and outcome of paediatric testicular tumours - A 20 year experience.

OBJECTIVE: To report a 20-year experience highlighting management and outcome(s) of paediatric testicular tumours. PATIENTS AND METHODS: All males (< 19 years) with an index diagnosis of testicular tumours during the era(s) 1998-2018 in North West England were identified. Data were collected regarding age at diagnosis, disease stage, surgical operations, tumour biology and outcome(s). RESULTS: A total of 34 male patients were identified. Median age at primary diagnosis was 94 months (range: 0-229 months). Eighteen tumours were benign and 16 malignant. Twenty cases (59%) were recorded in pre pubertal children and 14 (41%) in post pubertal males . In the pre pubertal group (0-11 years) - 15 cases of germ cell tumours (unrelated to germ cell neoplasia in situ - non-GCNIS derived) were recorded, including six yolk sac lesions, eight teratomas and one mixed teratoma/yolk sac tumour (pre-pubertal type). Four males with sex cord-stromal tumours included one juvenile granulosa cell tumour, two Sertoli cell tumours and one Leydig cell tumour. One miscellaneous type tumour notably a papillary cyst adenoma was also identified. In the post pubertal male cohort (>12 years) (n = 14) - four non-GCNIS derived tumours were identified (3 epidermoid cysts and one teratoma), eight cases of germ cell tumour derived from germ cell neoplasia in situ (GCNIS derived) included one teratoma, six with mixed germ cell tumours and one embryonal carcinoma. Two males had sex cord stromal tumours: (Leydig cell and granulosa cell biology). Twenty-eight patients underwent high radical inguinal orchidectomy(s) with one male also requiring retroperitoneal surgery to clear distant locoregional disease and a further single case thoracotomy and metastasectomy. Six patients had lesions suitable for 'testicular sparing' surgery. Six patients had metastatic disease at presentation (18%). Overall study survival was 97%. A single fatality occurred in an adolescent male with a mixed GCT harbouring liver, lung and para-aortic disease who died 48 months after initiating treatment. CONCLUSION: We highlight one of the largest study series of paediatric testicular tumours in the UK and Europe. Non-GCNIS derived tumours accounted for the most common tumour biology (56%). Survival for paediatric testicular tumours is reassuringly generally excellent. Delayed presentation however with a malignant testicular tumour may be associated with poor outcome(s).

Ovarian Leydig cell tumor and postmenopausal hirsutism with signs of virilisation.

A 71-year-old woman was referred to the endocrinology clinic to investigate postmenopausal hirsutism with 10 years of evolution. She had history of regular menses and menopause with 50 years old. Physical examination showed a male pattern facies, deepening of the voice, androgenic alopecia and hirsutism with a score of 23 according to the modified Ferriman-Gallwey scale. Testosterone and androstenedione were increased. Transvaginal ultrasound, abdominal and pelvic CT showed uterine fibroids with no pathological findings in the adrenals or ovaries. Since she had postmenopausal vaginal bleeding, uterine fibroids and suspicion of an ovarian source for her hyperandrogenism, total hysterectomy and bilateral oophorectomy were performed. Histopathological diagnosis was a Leydig cell tumour located in left ovary and endometrial carcinoma. Improvement of hirsutism was started to notice 1 month after the surgery and she was referred to the oncology clinic for adjuvant treatment.

[Leydig Cell Tumor in a Patient with Contralateral Cryptorchidism: A Rare Association]. / Tumor de Células de Leydig num Doente com Criptorquidia Contralateral: Uma Associação Rara.

Gynecomastia is a frequent sign that may be physiological or caused by various benign or malignant diseases. In rare cases, it may be caused by testicular tumors. We describe a case of progressive gynecomastia at age 20 due to a Leydig cell tumor of the right testicle in a patient with a previous history of left-sided cryptorchidism. The patient underwent orchidectomy and testicular prosthesis placement, with subsequent improvement of gynecomastia and normalization of estrogen. Our case, in addition to demonstrating that gynecomastia may regress if the underlying cause is treated in a timely manner, shows that cryptorchidism may be related with the development of Leydig cell tumors in the same way as it is in other testicular tumors.

A ginecomastia é um sinal frequente que pode ser fisiológica ou causada por várias doenças benignas ou malignas. Em casos raros pode ser originada por tumores testiculares. Nós descrevemos um caso de ginecomastia de início rapidamente progressivo aos 20 anos por um tumor de células de Leydig do testículo direito em doente com história pregressa de criptorquidia esquerda. O doente foi submetido a orquidectomia e colocação de prótese testicular assistindo-se a melhoria da ginecomastia e normalização dos valores de estrogénio. O nosso caso, além de demonstrar que a ginecomastia pode regredir se a causa subjacente for tratada atempadamente, mostra que a criptorquidia poderá estar associada ao aparecimento de tumores de células de Leydig à semelhança do que acontece com outros tumores testiculares.

Testis-sparing surgery for testicular tumors in children: a 20 year single center experience and systematic review of the literature.

PURPOSE: Although surgical therapy for testicular tumors (TT) is often radical orchidectomy, tumor resection with preservation of healthy testicular parenchyma has been proposed. This study herein reports a 20 year single center experience applying testicular sparing surgery (TSS) as a primary operative strategy in pediatric patients. A systematic literature review summarizes the utility and outcomes of TSS in appropriately selected patients. METHODS: Pediatric patients with TT who underwent TSS between 1997 and 2018 were studied. TSS was indicated if patients presented evidence of adequately spared healthy testicular parenchyma on preoperative ultrasound and negative serum tumor markers. A systematic review of the literature was also performed. RESULTS: 12 cases met full inclusion criteria with 10 of 12 subjects in the prepubertal age group. Follow-up was 73 months (range 18-278 months). Only a single male patient (GSCCT) presented with early recurrence and orchidectomy was then performed. No cases of postoperative testicular atrophy were identified. Sexual maturation (Tanner stage) expected for age in each patient was documented. Review of the literature identified 34 published studies including 269 patients (94% prepubertal). Pathologic lesions here were mainly mature teratoma(s)-(62%) with a follow-up period of 4 years. Recurrent tumors were observed in only three patients (1.1%) notably two Leydig Cell Tumors and one Teratoma. Testicular atrophy reportedly occurred in only one single case (0.37%). DISCUSSION: TSS is a feasible alternative to radical orchidectomy in pediatric male patients with localized TT and negative tumor markers. Long term follow-up is essential to monitor testicular growth, puberty with sexual development and psychological male health.

Spermatogenesis in pre-pubertal boys with Leydig cell neoplasms suggests paracrine stimulation by testosterone.

INTRODUCTION: Pediatric Leydig cell tumors (LCTs) represent approximately 4% of pre-pubertal testicular tumors and are known to cause precocious puberty secondary to testosterone production. While gonadotropins and testosterone are known to initiate spermatogenesis beginning in puberty, it is yet to be determined if a similar phenomenon is triggered by isolated testosterone production in prepubescent boys. OBJECTIVE: To determine if testicular pathology in pre-pubertal pediatric patients with LCTs exhibit spermatogenesis secondary to paracrine testosterone stimulation. STUDY DESIGN: We reviewed patients who underwent orchiectomy for a testicular tumor from 2003-17. We included patients with LCTs and compared them to children with non-LCT pathology (teratomas and epidermoid cysts). We excluded other pathologies and tumors in pubertal patients. Data were collected on the presence of spermatogenesis on pathology, tumor markers and serum hormone results. RESULTS: Orchiectomy for testicular tumors were completed in 66 patients, of which 20 were included in the non-LCT group and 9 in the LCT group. Two of the 9 LCT patients had bilateral pathology. Age at presentation was 6.3 ± 5.8 years for the non-LCT group vs. 8.4 ± 1.6 years for LCTs (p = 0.261). Spermatogenesis was detected in 7 (64%) LCT specimens vs 2 (10%) non-LCT specimens (p = 0.002). Age of the spermatogenesis patients in the non-LCT group (11.08 ± 2.5 years) was older than LCT ones (8.3 ± 2.0 years), suggesting that spermatogenesis in the non-LCT group may be due to early pubertal development. The summary figure demonstrates spermatogenesis identified in a pre-pubertal LCT patient. DISCUSSION: In this study, pre-pubertal males with LCTs were identified to have pathology evidence of spermatogenesis compared to controls with non-LCT pathology. This represents the first study assessing paracrine testosterone effects on spermatogenesis in pre-pubertal patients with LCTs. In contrast, adult literature on LCTs primarily report on resulting concerns for fertility, gynecomastia and testicular atrophy. CONCLUSION: LCTs can induce spermatogenesis in prepubertal patients. This reinforces the hypothesis that paracrine testosterone signaling plays a role in spermatogenesis. Our findings could help explore novel fertility preservation opportunities in children.

The Masquerading, Masculinizing Tumor: A Case Report and Review of the Literature.

Androgen-producing tumors in women are rare neoplasms that can cause secondary virilizing characteristics. Of patients presenting with symptoms of hyperandrogenism, these tumors are found in ∼0.2% of cases. Androgen-producing tumors can arise from the ovary or the adrenal gland. Those arising from the ovary are rare, accounting for <5% of all ovarian tumors. This case presents a hilar Leydig cell tumor of the ovary, which resulted in secondary virilization of a 45-year-old female 2 months after cessation of combined oral contraceptives (COC). Laboratory findings showed markedly elevated total and free testosterone concentrations with normal dehydroepiandrosterone sulfate, however neither pelvic ultrasound nor magnetic resonance imaging demonstrated any masses. Venous sampling under fluoroscopy revealed supraphysiologic testosterone concentrations from the right ovarian vein suggesting the source. The patient underwent bilateral salpingo-oophorectomy revealing a 1.3 cm hilar cell tumor of the right ovary. This article reviews the clinical features, diagnosis, and treatment of hilar Leydig cell tumors and describes the long-term complications of supraphysiologic testosterone levels. As the tumor presented after cessation of COC, we also review the mechanisms by which COC might suppress supraphysiologic androgen levels and mask the secondary virilizing effects of androgen-producing tumors.

Bilateral microscopic Leydig cell ovarian tumors in the postmenopausal woman.

A 64-year-old postmenopausal female patient presented with approximately 5 years of intermittent spotting, progressive hirsutism and significantly increased libido and clitoral hypersensitivity with spontaneous orgasms multiple times a day beginning a few months prior. Initial hormone work-up revealed elevated total serum testosterone, androstenedione and 17-hydroxyprogesterone. Luteinising hormone, follicle stimulating hormone, estradiol, dehydroepiandrosterone-sulfate, thyroid stimulating hormone and prolactin were all within normal limits. Initial suspicions suggested an androgen-secreting tumour, likely in the ovary. The lesion was undetectable on transvaginal ultrasound and abdominal-pelvic CT scan. Laparoscopic bilateral salpingo-oophorectomy was performed to remove the likely source of excess androgens. Visible gross lesions were not observed intraoperatively; however, bilateral Leydig (hilus cell) tumours were confirmed by histopathology. Serum testosterone, androstenedione and 17-hydroxyprogesterone levels were normalised postoperatively within 2 weeks and 1 month, respectively.

Hyperandrogenism caused by ovarian Leydig cell tumour: finding the needle in a haystack.

Leydig cell tumours (LCTs) of the ovary are rare ovarian tumours that usually present with hyperandrogenism. Conventional radiological imagings are helpful in localising these tumours. However, some tumours may be too small to be localised before curative surgical removal. It is important to identify these androgen-secreting neoplasms which originate mostly from adrenals or ovaries because they are potentially malignant and require specific treatment. When conventional imagings are unrevealing, selective ovarian and adrenal venous sampling (SOAVS) is the next option. We report a case of LCT that was localised by SOAVS after results from other imaging modalities remained inconclusive.