Ancuta-Augustina Gheorghisan-Galateanu  ( Department of Cellular and Molecular Biology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania )
Mara Carsote  ( Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania )
Dana Terzea  ( Onco Team, Monza Hospital, Bucharest, Romania )
Ana Valea  ( Department of Endocrinology & Clinical County Hospital, I.Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania )
Adina Ghemigian  ( Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania )

Rarity of Sertoli cell tumours contributes to a low index of suspicion and therefore a thorough knowledge of the clinicopathological and immunological characteristics of such tumours is essential to diagnosis and proper management of the treatment and follow-up. The current narrative review of literature was planned to focus on ovarian Sertoli cell tumours that arise from the sex cords cells, which are typically benign unilateral neoplasia incidentally detected, or associated with hormonal hyperactivity, in women of reproductive age. A priory unpublished case of a 35-year old female is also introduced as the base of discussion Abdominal massrelated syndrome and vaginal bleeding anomalies have been reported. Genetic background, if presented, is mostly related to Peutz-Jeghers syndrome caused by STK11/LKB1 mutation. The tumour displays a microscopic tubular pattern and rarely displays cords or trabecular, retiform, spindles, diffuse or areolar structures. Although immunohistochemistry can be helpful in establishing the diagnosis, the results are sometimes inconclusive and the current results require new research to establish a specific immunological panel.

Keywords: Sex cord tumour, Ovarian Sertoli cell tumour, Histology diagnosis, Immunohistochemistry. https://doi.org/10.5455/JPMA.1381

Introduction

Ovarian Sertoli cell tumours (OSCTs) are rare neoplasia associating a relatively large number of morphological aspects in addition to heterogeneous endocrine behaviour. Typically benign, they are frequently seen in women of reproductive age with ranges between first years of life to the seventh decade.¹ Their detection may be either incidental in women seeking fertility or having a routine gynaecological control, either due to associated hormonal hyperactivity which requires endocrine evaluation. Therefore, neoplasia is usually detected by a gynaecologist or an endocrinologist. The underlying histological reports include these tumours in the vast family of sex cord-stromal tumours, ^2,3 and some have a genetic background, as seen in Peutz-Jeghers syndrome or DICER mutation (the gene encoding endoribonuclease Dicer), the latter more frequently associated with Sertoli- Leydig cell tumours. ^4-6
Method

In the current narrative literature review, some examples are introduced based on a prior unpublished case diagnosed with unilateral OSCT and displayed as ovarian incidentaloma. The patient signed the informed written consent to anonymously use her medical data referring to the pathological report as well as medical history and hormonal profile. The research of literature is focused on clinical and histological aspects of OSCT, as a topic of gynaecological endocrinology. Most studies were found while searching on PubMed.

Results

Classification

According to the World Health Organisation (WHO) 2016 classification, OSCT, a subgroup of ovarian sex cordstromal tumours, are rare sex cord tumours of the ovary. Distinctive feature of OSCT is the lack of Leydig cells and immature stroma which is in contrast with Sertoli-Leydig cell tumours. ^7,8The report of cases has low level of statistical evidence because most of these tumours have been described in literature as series of cases.

Main characteristics

The onset age is between 2 and 79 years, with an average of about 30 years. Classically, they are considered tumours of reproductive age and, therefore, the possibility of detection during periodical gynaecological control. ⁹ Their hormonal profile can be of several types: completely negative or associated with an excess of oestrogens, androgens (less than oestrogen excess) or even progesterone, secondary to hormone secretion by the tumour cells. ^7,8 Recent studies suggested that a DICER1 mutation (or DICER mutation involving helicase with RNase motif ) as back ground induces a higher risk of androgen production rather than oestrogens. ¹⁰Two cases have been reported in association with rennin and aldosterone production. ¹¹ Virilisation potential is less seen than in tumours with Sertoli-Leydig cells (androblastoma) or Leydig cell profile. ¹² Sometimes, local symptoms as pain and  menstrual abnormalities lead to tumour detection.Postmenopausal vaginal bleeding in association with high cancer antigen 125 (CA125) levels mimicking an ovarian cancer has been described. ¹³ Cases completely as ymptomatic d is pl ay the sce nar io of ovar ian incidentaloma, a term that is still incompletely defined when it comes to ovaries and it subscribes various pathological reports. ^14-16 The case in question had a baseline ovarian ultrasound showing a solid tumour at the level of left ovary of 3.1 x 2.95 cm with penetrating vessels on a 35-year old non-smoking female with irrelevant family and personal clinical history who was detected with the mass during a routine endocrine and gynaecological exam, displaying the scenario of an ovarian incidentaloma. (Figure 1)



Pelvic computed tomography (CT) confirmed a solid, well-shaped left ovarian tumour of 3.13 x 2.93 cm. (Figure 2)



She had normal baseline hormones, including total and free testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (day 14 of menstrual c ycle), thyroid stimulating hormone ( TSH), free levothyroxine and prolactin, negative thyroid antibodies, and a level of progesterone of 11 ng/mL (day 21 of menstrual cycle), normal for ovulatory status (the level required for proving ovulation is above 10 ng/mL). The most common clinical presentation when occurring in children is isosexual precocity. ¹⁷Genetic syndromes, like Peutz-Jeghers, are associated especially with cases detected in young population, counting less than a fifth of subjects. Peutz-Jeghers syndrome is caused by STK11/LKB1 mutation which causes a higher risk of some digestive cancers as well as hamartomatous polyposis or hyperpigmentation of skin and mucosa. ^4,18New mutations as DICER or FOL2 (the gene encoding GTP cyclohydrolase I) are still incompletely described. DICER syndrome includes multinodular goitre (MNG) and it is linked in majority of cases with neoplasia displaying both Sertoli and Leydig cells. ^19-21 In addition to a complete physical examination, the patient should undergo imaging tests that may include ultrasonography (US), CT, and magnetic resonance imaging (MRI) of the pelvis to look for an ovarian tumour. Fine needle aspiration (FNA) is cited as useful in one large series of cases in order to appreciate the malignant potential as alternative of surgery. ²²Most OSCTs are stage I, following a non-aggressive clinical course. Therefore, the primary treatment is surgical (unilateral oophorectomy) and the prognosis is generally favourable. Histological and immunohistochemistr y feature Pathology and immunocytochemistry are basic tools for the diagnosis of OSCT, having also a prognostic value. Macroscopically, the tumour is yellow or brown, usually solid, with potential mix structure (solid-cyst). The diameter varies from <1 cm to 30 cm, usually between 4 cm and 12 cm. Most reported cases are unilateral.^7,8,23 Their morphological spectrum are not clearly established. Many other neoplasms of diverse types can closely simulate Sertoli cell tumours. ²⁴OSCT shows a histological resemblance to developing or adult testes, with follicle trans- differentiation to structures resembling

seminiferous tubules of the testis, with Sertoli-like cells. The neoplasia with Sertoli cells of gonads, ovary and testes, have common by the lobular aspect, but the lobulation is less evident in ovaries than the testis. ²⁵On microscopic exam, tubular pattern, a very distinctive profile rarely seen in other types of ovarian neoplasia, is most frequent but not exclusive. Other features have been identified in ovarian Sertoli cell tumours like cord or trabecular, retiform, spindles, diffuse or alveolar areas. Several pattern scan coexist in the same tumour. Thestroma devoid of Leydig cells can be abundant with marked hyalinisation. It can be noticed round or elongated tubules, hollow or solid, lined by columnar or cuboidal Sertoli-like cells, with moderate to abundant amounts of slightly eosinophilic cytoplasm, occasionally vacuolated. The nuclei of the tumoural cells usually lack atypical features or mitotic activity. Ultrastructurally, abundant trough endoplasmic reticulum, some cystically dilated smooth endoplasmic reticulum profile and mitochondria with tubular crystals visible. These, together with lipid droplets, suggest a potential or steroidhormone synthesis which is not always expressed clinically. The free border of cell show occasional cilia or microvili, considered to be a manifestation of focal metaplasia of the neoplastic Sertoli cell. Laterally, the cells show tight junc tions and desmosomes. ^26,27Long-term follow-up associates a good prognosis, but recurrences have rarely been found in cases with atypia or high mitotic index. ^17,23The good behaviour is predictable through pathological report, and even some atypical aspects mimicking other tumours have been reported. ^17,23Microscopic appearance requires a differential diagnosis, firstly with endometrioid carcinoma and carcinoid tumour. The immunohistochemical (IHC) panel can be helpful in establishing the diagnosis. Many IHC markers have been studied for diagnosis, but currently available markers are not 100% sensitive or specific. Some reports revealed calretinin-positive reaction in more than half of the cases, as well as vimentin, and inhibin. ^28-30In one study on 26 cases of Sertoli cell tumours, nuclear expression of Wilms tumour protein (WT1) was present in 96%.³¹ Negative staining for epithelial membrane antigen (EMA) was found to be most useful as discriminative element, while pan-cytokeratin (pan-CK) and Cluster of differentiation  99 (CD99) were not identified as being useful. In oneseries of 160 cases of ovarian tumours, including 40 of Sertoli cell type tumours, 7% had cytokeratin 7 (CK7) positive stain, 8%, were positive for oestrogen receptor, and 13% for progesterone receptor. ³² One study on 36 cases tried to find if a SOX9 (which is a key transcription factor during sex determination, and tumour growth) positive reaction may be highly suggestive in the IHC profile of ovarian Sertoli cells neoplasia since SOX9 is a transcription factor involved in Sertoli cell differentiation in the testes but its ovarian stain was irrelevant. ³³ Overall, there is no specific combination of immunostain to sustain 100% diagnosis. IHC report seems to be more useful in cases where classical tubular pattern is not clearly identified. In our case, tumour cells were positive for vimentin and CK7, but negative for inhibin, with a low Ki67 index of proliferation which is usually correlated with tumour progression. Pathological report after left laparoscopic ovarectomy on a 35-year-old asymptomatic female with ovarian incidentaloma showed a benign sex cord tumour with Sertoli cells (Figure 3A).



IHC report revealed positive vimentin and CK7 (Figure 3B) and a low index of proliferation (3%) into the tumour cells (Figure 3C). The tumour was negative for chromogran in ,carcinoembryonic antigen (CEA), cytokeratin 20 (CK20), inhibin, and high molecular weight cytokeratins 1,5,10 and 14 (34E12). Positive actin was found in stroma but not into the tumour cells. The patient was followed for the next 12 months assessing normal ovulation based on progesterone levels of 16 ng/mL (day 21 of menstrual cycle).

Limitations

Rarity of Sertoli cell tumours cases reported to date contributes to a low index of suspicion and therefore at thorough knowledge of the clinicopathological and immunological characteristics of such tumours is essential for diagnosis and proper management right up to treatment and patient follow-up. As current limits of the concept related to OSCT, we consider five aspects: the insufficient description of risk factors and genetic predisposition, especially in non-Peutz Jeghers syndrome cases, and the exact role of identifying DICER1 mutation s in selected cases; which is the driven force of endocrineactivity in relationship to a particular histological  expression; lack of high specificity markers regardingIHC features; the poor prognosis markers are still a matter of debate, an aspect that cannot be sustained based on small sample size studies; and, finally, which is the clear definition and multi-disciplinary protocol for ovarian

incidentaloma underlying various pathological reports, including OSCT. ^34,35The current level of evidence regarding OSC is essential for all concerned ( Table).



Conclusion

Sertoli cell tumour of the ovary is a rare neoplasia of low malignancy risk that typically occurs in women of reproductive age, and it has a good prognosis in association with the usual tubular pattern. IHC may be useful but current results require new research to establish a specific immunological panel. The detection of the tumour and its follow-up after removal may be done either by a gynaecologist or an endocrinologist.

Disclaimer: None.

Conflict of Interest: None.

Source of Funding: None.

Abbreviations
 

cm = centimetre, FSH = Follicle Stimulating Hormone,

LH = Luteinizing Hormone, TSH = Thyroid Stimulating

Hormone, CK7 = cytokeratin7, CEA = Carcinoembryonic

antigen, CK20 = cytokeratin 20, 34E12 = high molecular

weight cytokeratins 1,5,10 and 14, WT1 = Wilms tumour

protein, EMA = epithelial membrane antigen, CD99 =

Cluster of differentiation 99, pan-CK = pan-cytokeratin

References

 

1. Schultz KA, Harris AK, Schneider DT, Young RH, Brown J, Gershenson DM, et al. Ovarian Sex Cord-Stromal Tumours. J Oncol Pract 2016; 12: 940-6.

2. Gheorghisan-Galateanu AA, Terzea D, Valea A, Carsote M. Menopausal androgen excess-associated cardio-metabolic risk: clues for ovarian Leydig cell tumour (case report and mini-review of literature). Acta Endocrinologica 2017; XIII: 356-63.

3. Poiana C, Virtej I, Carsote M, Banceanu M, Sajin M, Stanescu B, et al. Virilising Sertoli-Leydig cell tumour associated with thyroid papillary carcinoma: case report and general considerations.Gynecol Endocrinol 2010; 26: 617-22.

4. Ravishankar S, Mangray S, Kurkchubasche A, Yakirevich E, Young RH. Unusual Sertoli Cell Tumour Associated With Sex Cord Tumour With Annular Tubules in Peutz-Jeghers Syndrome: Report of a Case and Review of the Literature on Ovarian Tumours in Peutz-Jeghers Syndrome. Int J Surg Pathol 2016; 24: 269-73.

5. Schultz KAP, Harris AK, Finch M, Dehner LP, Brown JB, Gershenson

DM, et al. DICER1- related Sertoli-Leydig cell tumour and gynandroblastoma: Clinical and genetic findings from the International Ovarian and Testicular Stromal Tumour Registry. Gynecol Oncol 2017; 147: 521-7.

6. Apellaniz-Ruiz M, deKock L, Sabbaghian N, Guaraldi F, Ghizzoni L, Beccuti G, et al. Familial multi nodular goiter and sertoli-Leydig cell tumours associated with a large intragenic in-frame DICER1 deletion. Eur J Endocrinol 2018; 178: K11-K19.

7. Oliva E, Alvarez T, Young RH. Sertoli cell tumours of the ovary: a clinicopathologic and immunohistochemical study of 54 cases. Am J Surg Pathol 2005; 29: 143-56.

8. Zizi-Sermpetzoglou A, Petrakopoulou N, Tepelenis N, Savvaidou V, Manoloudaki K, Katsoulis M. Pure Sertoli cell tumour. A case report and review of the literature. Eur J Gynecol Oncol 2010; 31: 117-9.

9. Young RH. Ovarian tumours and tumour-like lesions in the first three decades. Semin Diagn Pathol 2014; 31: 382-426.

10. Kato N, Kusumi T, Kamataki A, Tsunoda R, Fukase M, Kurose A. DICER

1 hot spot mutations in ovarian Sertoli-Leydig cell tumours: a potential association with androgenic effects. Hum Pathol 2017; 59: 41-7.

11. Perez Lana M, Demayo S, Monastero A, Nolting M. Ovarian tumors secreting androgens: an infrequent cause of hyperandrogenism. Minerva Ginecol 2019; 71: 72-7.
12. Shanbhogue AK, Shanbhogue DK, Prasad SR, Surabhi VR, Fasih N, Menias CO. Clinical syndromes associated with ovarian neoplasms: a comprehensive review. Radiographics 2010; 30: 903-19.

13. Al-Agha OM, Tahmasebi FC, Nicastri AD. A 67-year-old woman with abdominal distention, vaginal bleeding, and elevated CA 125 level. Pure Sertoli cell tumour of the ovary with differentiation varying from well-differentiated tubules, to intermediate foci, to sarcomatoid spindle cell areas. Arch Pathol Lab Med 2006; 130: e70-3.
14. Gheorghisan-Galateanu AA, Carsote M, Valea A. Incidentaloma: from general practice to specific endocrine frame. J Pak Med Assoc 2017; 67: 917-22.

15. Solnik MJ, Alexander C. Ovarian incidentaloma. Best Pract Res Clin Endocrinol Metab 2012; 26: 105-16.

16. O'Sullivan JW, Muntinga T, Grigg S, Ioannidis JPA. Prevalence and

outcomes of incidental imaging findings: umbrella review. BMJ 2018; 361: k2387.

17. D'Souza L, Burgis JT, Bacon JL, Camps JI. A pure Sertoli cell tumour of the ovary in a10-year-old female. J Pediatr Adolesc Gynecol 2007; 20: 257-9.

18. Meserve EE, Nucci MR. Peutz-Jeghers Syndrome: Pathobiology, Pathologic Manifestations, and Suggestions for Recommending Genetic Testing in Pathology Reports. Surg Pathol Clin 2016; 9: 243- 68.

19. deKock L, Terzic T, McCluggage WG, Stewart CJR, Shaw P, Foulkes WD, et al. DICER1 Mutations are Consistently Presenting Moderately and Poorly Differentiated Sertoli-Leydig Cell Tumours. Am J Surg Pathol 2017; 41: 1178-87.

20. Chiang S, Staats PN, Senz J, Kommoss F, DeNictolis M, Huntsman DG, et al. FOXL 2 mutation is absent in uterine tumours resembling ovarian sexcord tumours. Am J Surg Pathol 2015; 39: 618-23.

21. Boldorini R, Bozzola C, Ribaldone R, Tosoni A, Monga G. Pure Sertoli cell tumour of the ovary with Meig's syndrome. Pathology 2006; 38: 579-81.

22. Dey S, Datta S, Chaudhuri S, Paul PC, Khandakar B, Mandal S. Preoperative Ultrasound Guided Fine Needle Aspiration Cytology of Ovarian Lesions- Is It a Rapid and Effective Diagnostic Modality? J Clin Diagn Res 2016; 10: EC16-9.

23. Haroon S, Zia A, Idrees R, Memon A, Fatima S, Kayani N. Clinicopathological spectrum of ovarian sexcord-stromal tumours;

20 years' retrospective study in a developing country. J Ovarian Res 2013; 6: 87.
24. Young RH. Ovarian sex cord-stromal tumours and their mimics. Pathology 2018; 50: 5-15.

25. Roth LM, Lyu B, Cheng L. Perspectives on testicular sex cord-stromal tumors and those composed of both germ cells and sex cord-stromal derivatives with a comparison to corresponding ovarian neoplasms.

Hum Pathol 2017; 65: 1-14.

26. Boussios S, Moschetta M, Zarkavelis G, Papadaki A, Kefas A, Tatsi K. Ovarian sex-cord stromal tumours and small cell tumours: Pathological, genetic and management aspects. Crit Rev Oncol Hematol 2017; 120: 43-51.

27. Kato N, Fukase M, Ono I, Matsumoto K, Okazaki E, Motoyama T. Sertoli-stromal cell tumour of the ovary: immunohistochemical, ultrastructural, and genetic studies. Hum Pathol 2001; 32: 796-802.

28. Young RH. Ovarian Sex Cord-Stromal Tumors: Reflections on a 40- Year Experience With a Fascinating Group of Tumors, Including Comments on the Seminal Observations of Robert E. Scully, MD. Arch Pathol Lab Med 2018; 142: 1459-84.

29. Lim D, Oliva E. Ovarian sex cord-stromal tumours: an update in recent molecular advances. Pathology 2018; 50: 178-89.

30. Vang R, Herrmann ME, Tavassoli FA.Comparative immunohistochemical analysis of granulose and sertoli components in ovarian sexcord-stromal tumours with mixed differentiation: potential implications for derivation of sertoli differentiation in ovarian tumours. Int J Gynecol Pathol 2004; 23:151-61.

31. Zhao C, Bratthauer GL, Barner R, Vang R. Diagnostic utility of WT1 immuno staining in ovarian sertoli cell tumour. Am J Surg Pathol 2007; 31: 1378-86.

32. Zhao C, Bratthauer GL, Barner R, Vang R. Comparative analysis of alternative and traditional immunehistochemical markers for the distinction of ovarian sertoli cell tumour from endometrioid tumours and carcinoid tumour: A study of 160 cases.Am J Surg Pathol 2007; 31: 255-66.

33. Wang J, Li J, Chen R, Lu X. Contribution of lymph node staging method and prognostic factors in malignant ovarian sex cord-stromal tumors: A world wide database analysis. Eur J Surg Oncol 2018; 44: 1054-61.

34. Fuller PJ, Leung D, Chu S. Genetics and genomics of ovarian sex cordstromal tumours. Clin Genet 2017; 91: 285-91.

35. Stewart CJ, Charles A, Foulkes WD. Gynecologic Manifestations of the DICER1 Syndrome. Surg Pathol Clin 2016; 9: 227-41.