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Abstract
A nulligravida in her 30s presented with primary infertility and secondary amenorrhoea. General examination revealed virilisation; sonological examination detected a right ovarian solid mass. International Ovarian Tumour Analysis (IOTA) was suggestive of malignancy and serum testosterone was raised. A strong clinical suspicion and negative tumour markers pointed towards androgen producing sex cord stromal ovarian neoplasm. MRI excluded pelvic lymphadenopathy. Given the patient’s desire for conception, fertility sparing staging laparotomy was done. Histopathology confirmed Sertoli-Leydig cell tumour (SLCT) International Federation of Gynaecology and Obstetrics stage IA. Serum testosterone fell drastically by day 10. Spontaneous menstruation resumed within 30 days. The significance of SLCTs as a differential diagnosis in young women with secondary amenorrhoea and virilising features underscores the role of fertility-preserving surgery in certain circumstances. Here we discuss the clinical features, diagnostic challenges and management strategies for SLCTs, emphasising the need for multidisciplinary collaboration and option of fertility preservation in early stages.
- Obstetrics, gynaecology and fertility
- Immunohistochemistry
- Reproductive medicine
- Endocrine cancer
- Gynecological cancer
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- Obstetrics, gynaecology and fertility
- Immunohistochemistry
- Reproductive medicine
- Endocrine cancer
- Gynecological cancer
Background
Of all ovarian neoplasms, 0.2%–0.5% are Sertoli-Leydig cell tumours (SLCTs) arising from sex cord (Sertoli) and stromal (Leydig) cells that can present over a wide range of age groups ranging from 1 to 84 years with maximum incidence seen in second and third decade of life. Patients may present with various clinical manifestations, including irregular menstrual cycles or amenorrhoea, hirsutism, virilisation associated with pelvic mass, pelvic pain, ascites or tumour rupture. SLCTs are divided into four types according to the WHO’s 2014 histological categorisation of female reproductive neoplasms: well differentiated, moderately differentiated/intermediate grade, poorly differentiated and retiform variation. A high degree of suspicion helps in early diagnosis. This case illustrated here, highlights the role of fertility sparing surgical management in cases which are diagnosed at a young age in order to meet the reproductive goals of such patients.
Case presentation
Nulligravida in her 30s married for 1.5 years presented with primary infertility and secondary amenorrhoea for a duration of 3 months. She had a history of excessive growth of coarse hair since pubarche, accelerated since 6 months with no history of intake of anabolic steroids. She underwent five cycles of ovulation induction with oral ovulogens and follicular monitoring in two cycles prior to her missed cycle when she was not diagnosed with any ovarian pathology. A negative progesterone challenge test following a negative pregnancy test was noteworthy. Clinical examination revealed hirsutism with a modified Ferriman-Gallwey score of 12/36, husky voice, broad shoulders, breast and pubic hair development of Tanner stage V with no cushingoid features. Abdominal examination as well as other systemic examinations were normal. Pelvic examination revealed clitoromegaly with CI: 94 mm2, a normal sized anteverted mobile uterus with fullness in anterior fornix; other fornixes were free.
Investigations
Transvaginal ultrasound with Doppler showed a normal appearing uterus measuring 8.7×4.7×5.2 cm, a right ovarian solid mass measuring 6×5 cm with regular borders (figure 1) and increased vascularity with a colour score of 4 seen in periphery and within (figure 2). A clear cyst measuring 3.2×2.7 cm was seen with minimal peripheral vascularity, left ovary appeared normal. The number of follicles per ovary was 13 in the left ovary and 6 in the right. Pouch of Douglas contained a moderate amount of free fluid, which was suggestive of ascites. International Ovarian Tumour Analysis suggestive of malignancy with three out of five signs present (M1: solid tumour, M2: presence of ascites, M5: very strong blood flow: colour score—4). Hormonal evaluation showed raised serum testosterone of 567 ng/dL (8.4–48.1 ng/dL), DHEA-S (dehydroepiandrosterone-sulfate) of 474.20 µg/dL (98.8–340 µg/dL), 17-hydroxy progesterone of 4.99 nmol/L (0.2–4.5 nmol/L), estradiol of 84.4 pg/mL (40–60 pg/mL), Inhibin B of 24.4 pg/mL (12.13–99.20 pg/mL). It was found that tumour markers such as β-human chorionic gonadotrophin, lactate dehydrogenase, alpha fetoprotein, CA-125 (cancer antigen), carcinoembryonic antigen and CA 19-9 were negative. Her ovarian reserve was biochemically assessed using serum AMH (anti-Mullerian hormone), and it was reported to be 1.42 ng/mL.
3D-ultrasonographic picture of the right ovary depicting the solid mass in it.
2D ultrasonographic picture of the right ovary with colour doppler.
Serum electrolytes, renal and liver function tests were normal. MRI confirmed an enlarged right ovary measuring 5.4×6.6×7.1 cm, a solid heterogeneous lesion measuring 5.2×6.4×5.2 cm seen in lateral aspect of the right ovary, prominent vessels seen entering from the right superolateral aspect of the tumour supplying it, indicating increased vascularity of the tumour. The lesion showed restricted diffusion with type III pattern of enhancement of the dynamic contrast imaging. In addition, a unilocular cyst with faint smooth wall enhancement seen within the medial aspect of the enlarged ovary is suspected to represent part of the ovarian tumour or a follicular cyst. There were no significant pelvic lymphadenopathy. MRI features were more in favour of ORADS-5 (Ovarian-Adnexal Reporting and Data System) lesion.
Differential diagnosis
In view of her antecedent history of secondary amenorrhoea and virilising features a differential diagnosis of non-classic congenital adrenal hyperplasia, Cushing’s syndrome, polycystic ovarian syndrome, androgen secreting ovarian tumours were contemplated. The presence of a solid right ovarian mass with hyperandrogenic features raised clinical suspicion towards an androgen producing tumour. Initial workup aimed at detecting any hormonal disturbances. Raised testosterone and DHEA-S levels confirmed androgen producing ovarian tumour. However, negative tumour markers were more in favour of a non-epithelial, non-germ cell origin tumour; most likely sex-cord stromal cell in nature. Transvaginal ultrasound and MRI findings raised the suspicion of malignancy.
Treatment
The couple were counselled about the diagnosis and management options. As they were keen on conception, the couple were counselled about the effect of the condition on her fertility and risks associated with the same. They were given the option for fertility sparing staging procedure and need for a second surgery if histopathology confirms malignancy. The same was discussed in tumour board and decision for fertility sparing staging laparotomy was taken. She was planned for right salphingo-oophorectomy with unilateral right pelvic lymphadenectomy and infracolic omentectomy. It was essential to conserve her contralateral ovary in view of her young age and nulliparity. Intraoperatively there were moderate ascites—100 mL straw coloured peritoneal fluid was aspirated and sent for cytological evaluation. Right ovarian solid mass measuring 5.5×4.8×2.7 cm was retrieved and sent for frozen section (figure 3). Right salpinx, left ovary and salpinx were found to be healthy. None of the lymph nodes were palpable. All peritoneal surfaces were thoroughly inspected and found to be normal, under surface of diaphragm was free. All samples were sent for histopathological examination. The frozen section was generally benign and suggested the possibility of a Leydig cell tumour. Macroscopically the mass was smooth on surface. Cut section showed solid cystic areas of yellowish discolouration (figure 3). Microscopically right ovarian tissue showed polygonal cells with clear cut margins, centrally placed nuclei with eosinophilic cytoplasm without haemorrhage or necrosis (figure 4). The stroma had an oedematous appearance and included pale cytoplasmic Leydig cells scattered throughout (figure 5), which indicated an intermediate-grade SLCT. Capsule of the tumour was intact and ascitic fluid was found to be negative for malignant cells. Pathologically the tumour was staged T1a, N could not be assigned, M not applicable; International Federation of Gynaecology and Obstetrics stage IA. After immunohistochemistry, the tumour cells showed positive signals for CD99 and Inhibin but negative signals for WT1, suggesting that they were ovarian tumours with sex cord stromal origin (figure 6).
Image of the right ovary showing yellowish mass.
Sertoli cells stained in blue (eosin-nigrosin staining).
Interspread lipid-laden Leydig cells.
Immunohistochemistry depicting brown staining—positive for Inhibin.
Outcome and follow-up
Her blood testosterone levels fell sharply during follow-up, reaching 26 ng/dL 48 hours after surgery and 16 ng/dL 10 days later. She had an uneventful recovery and resumed spontaneous menstruation after 30 days of follow-up. In addition, she observed a reduction in the frequency of hair removal, and it was advised that she can attempt spontaneous conception for a few months. She has been having regular cycles for the past year, every 28 days. They were unable to try for a child because her partner had to travel overseas for work. A year later on evaluation, her modified Ferriman-Gallwey score of 6/36 indicated a considerable reduction in hirsutism and follow-up measurements of serum testosterone and serum AMH were determined to be 6.94 ng/dL and 0.935 ng/mL, respectively. She was counselled for ovulation induction with intrauterine insemination in view of decreased ovarian reserve and male factor. Currently, the male partner is receiving medical management for the same.
Discussion
It is extremely uncommon for an SLCT with an ovarian mass to manifest with fully developed hyperandrogenic characteristics; their prevalence is between 0.2% and 0.5% of all ovarian neoplasms.1 2 Majority of women present at an average age of 25 years. A third of SLCTs exhibit hirsutism, acne and oligomenorrhoea-amenorrhoea, which are signs of androgen excess. Occasionally, SLCTs could exhibit estrogenic effects. Endometrial cancer may be caused by excessive oestrogen released by the tumour cells. The tumour may not be functionally active in 50% of patients. This complicates the diagnosis of SLCTs prior to surgery. Hence in those cases hormonal evaluation may aid in diagnosing them accurately.3 4 The majority of SLCTs are identified at stage I, when the lesion is limited to one ovary.5 Our patient presented in her early 30s with a hoarse voice, broad shoulders, hirsutism, clitoromegaly and secondary amenorrhoea. On hormonal evaluation, raised serum testosterone and DHEA-S levels were detected and transvaginal ultrasound detected right ovarian involvement. Sonologically SLCTs may be viewed as a wide spectrum ranging from solid to cystic. In a study done by Young et al SLCTs were identified in 207 cases, of which 38% of the tumours were solid, 4% were cystic and 58% of the tumours were both solid and cystic.5 However, according to Demidov et al ultrasonography examination revealed that SLCTs were either solid tumours or multilocular solid masses.6 We observed solid pattern of tumour in our patient. We are presenting this case due to the rarity of SLCTs and the current treatment guidelines available for which are less clear. The modality of treatment is influenced by the tumour stage, degree of differentiation, age of the patient and her need for fertility. Even though surgical excision is the mainstay to treat SLCTs, fertility sparing surgeries are preferred for stage Ia disease in young patients due to the similar recurrence rate in both conservative and radical surgeries. Recurrence rate is 8% in fertility-preserving surgeries versus 3% in radical surgeries. The prognosis is bad at advanced stages, such as stage Ic and above, because they are linked to a high recurrence rate (around 30%) and high mortality (about 54%). Hence advanced stage or tumour rupture may be considered as contraindications for a fertility sparing surgery.7 The results of 21 SLCTs in a retrospective MITO study revealed that the 5-year survival rate for stage I illness was 92.3%, whereas the rate for advanced stage tumour was 67%.8 Our patient was staged Ia and a meticulous surgery was carried over by combined team of Reproductive Medicine and a Gynae-Oncologist so as to avoid any tumour rupture or spillage. This is supported by European Society for Medical Oncology guidelines for stage Ia, well-differentiated tumours in young patients. However, adjuvant treatment with BEP (bleomycin, etoposide and cisplatin), etoposide and cisplatin if the patient is older than 40, or carboplatin/paclitaxel for six rounds is advised for poorly differentiated tumours or those containing heterologous elements.9 National Comprehensive Cancer Network guidelines state to perform fertility sparing surgery if fertility is desired and complete staging if fertility is not desired in cases of sex cord stromal tumours.10
Apart from stage, the degree of differentiation is also an important prognostic factor. It was shown that the 5-year survival rate for intermediate or poorly differentiated SLCTs was 92% in a study including 64 patients. According to a different study, patients with grade 2–3 tumours had a 5-year survival rate of 77%, compared with 100% for grade 1.8 Relapse rates at stage Ia were marginally lower (7% vs 30%) than those of SLCTs at stage Ic in a study of 13 publications.7 Despite research showing that retiform pattern has a worse prognosis and is more likely to show endocrine function, our patient who exhibited significant endocrine spectrum was diagnosed to have an intermediate grade of differentiation on histopathology. Hence further studies are required to accurately gauge the disease according to their degree of differentiation. According to a recent research, DICER1 mutations are linked to the prognosis and pathophysiology of ovarian SLCTs. Consequently, it is critical to determine the DICER1 mutation for the patient, their family, and any prospective progeny.11 12 Even though genetic testing for DICER1 mutation is recommended, due to unavailability of resources it could not be tested in our patient. We observed completeness of the procedure in our patient with swift fall in serum testosterone levels within days and resumption of spontaneous menstrual cycles. As spontaneous conception has been reported in few cases after surgery, hence she was advised to try for natural conception prior to proceeding with further management of her primary infertility.13 14
Several case reports have been published on the fertility of SLCT patients. A highly uncommon instance of spontaneous pregnancy in a 26-year-old patient with a tiny virilising SLCT was described by Moltz et al. The patient was expecting when she was suspected to have SLCT; but the pregnancy had to be terminated. She underwent a left oophorectomy and right ovarian wedge resection at 14 weeks of gestation. Thereafter she conceived spontaneously within 3 years and delivered a healthy female infant.15
Additionally, Gowri et al reported a successful term pregnancy following the laparoscopic removal of an ovarian tumour with poorly differentiated SLCT. The couple refused to undergo a staging laparotomy, hence just the pedunculated ovarian mass was removed laparoscopically, leaving the remaining ovary intact. She then sought a second opinion and was thereafter managed conservatively by the medical oncologist. In the intervening time, she conceived twice on her own and gave birth to two healthy infants vaginally at term.14
According to Han et al, a 22-year-old nulliparous woman with SLCT and heterologous elements of left ovary stage Ic underwent staging laparotomy with preservation of the contralateral ovary. She then had adjuvant chemotherapy with docetaxel and cisplatin, which was given for six cycles. To maintain the patient’s fertility, triptorelin (3.75 mg per time for three cycles) was injected intramuscularly every 28 days prior to and during the chemotherapy. Within 3 years, the patient conceived spontaneously but later developed SLCT in the preserved ovary.16
Stavrakis et al described a young woman in her 20s who was diagnosed with SLCT of the left ovary and underwent fertility sparing staging laparotomy and unilateral salphingo-oophorectomy followed by adjuvant chemotherapy for a poorly differentiated tumour; she then conceived spontaneously within 23 months of follow-up.17
A primigravida with no signs of virilisation was unexpectedly detected to have bilateral SLCT. She underwent bilateral salphingo-oophorectomy and was found to have an intermediate to poor differentiation of tumour. She was then initiated on adjuvant chemotherapy containing BEP, at 3 weekly intervals. However, she miscarried in the midst of the second cycle. In such instance, there was no longer any chance of spontaneous conception because she had undergone a B/L salpingo- oophorectomy.18
In cases of SLCTs when at least one ovary is preserved, we believe spontaneous pregnancies are conceivable provided that’s the only reason contributing to the couple’s infertility. In our case, the male partner’s semen examination revealed mild oligoasthenoteratozoospermia with a sperm concentration of 10 million/mL, total motility of 30% and morphology of 2% at first consultation. At that time due to their lack of interest in pursuing reproductive treatments and desire for a natural conception; the male partner did not pursue any further management. When we re-evaluated him after a year of failing to conceive naturally, his semen parameters were found to have deteriorated to the point of severe oligoasthenoteratozoospermia with a sperm concentration of 5 million/mL, total motility of 22% and morphology of 2%, for which he is currently receiving medical management.
Fertility is a team effort, and while one partner may have been able to overcome their challenges, the other partner may require medical assistance.
Perhaps they could have conceived naturally by now if the male partner in our scenario had not had shortcomings in his semen parameters.
It remains to be seen whether they will conceive spontaneously or via medically assisted reproduction.
Tumours with Sertoli-Leydig cells typically recur after 36 months. Though recurrences as late as 35 years have also been documented. As a result, they are advised lifelong follow-up.
Although distant metastatic deposits in bones, lungs and lymph nodes have also been documented, recurrences are limited to the pelvis and abdomen.5 19 20
Our patient is still under follow-up at fourth monthly interval and is doing well. We look forward to being able to help her in achieving her dream of becoming a mother.
Patient’s perspective
I was clueless about my condition when I came for my first visit. All I wanted was to conceive. I never paid much heed to excess hair growth. Some of my friends also suffer from the same, so it never occurred to me that this could be grave. Weekly removal of my excess hair was all that I did to address the issue. Never in my dreams did I think I might have a tumour growing inside me. I am thankful to have met the right doctor at the right time. Now I don’t have to shave so often; also my periods have become regular. Since then I had not have to worry about my period dates. We are looking forward to conceive on our own; wish us luck.
Learning points
A high index of suspicion of Sertoli-Leydig cell tumours particularly in cases of secondary amenorrhoea associated with adnexal mass and hyperandrogenism helps in early diagnosis.
Option of fertility sparing surgery and follow-up should be considered and discussed with the couple before planning for definitive surgery.
Surgical removal of tumour halts further progression of virilising features, patient resumes regular menstrual cycles and this promotes spontaneous conception.
Prior to initiating fertility treatment, other factors such as the male and tubal factors must be taken into account.
Since they are at risk of a late recurrence, long-term follow-up with serum inhibin, testosterone and transvaginal ultrasound is preferred.
Ethics statements
Patient consent for publication
Acknowledgments
Vijaya Shanthi assisted in the case. Sushruthan provided histopathology report.
Footnotes
Contributors The following authors were responsible for drafting the text, sourcing and editing clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: DESA wrote the manuscript under supervision of RV supported in collecting reviewing articles and management plans. RV operated the case.MP and NSR contributed to the final version of the manuscript. The following authors gave final approval of the manuscript: RV, NSR.
Funding It is self funding .
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.