THYROID

Virilising Sertoli–Leydig cell tumour associated with thyroid papillarycarcinoma: case report and general considerations

CATALINA POIANA1, IOANA VIRTEJ2, MARA CARSOTE3, GABRIEL BANCEANU4,

MARIA SAJIN5, BOGDAN STANESCU6, DUMITRU IOACHIM7, DAN HORTOPAN8, &

MIHAIL COCULESCU1

1Department of Endocrinology, C.I. Parhon Institute of Endocrinology, ‘Carol Davila’ University of Medicine and Pharmacy,

Bucharest, Romania, 2Endocrine Private Medical Center, Trikala, Greece, 3Department of Endocrinology, ‘Carol Davila’

University of Medicine and Pharmacy, Bucharest, Romania, 4Department of Obstetrics and Gynecology, Polizu Hospital,

‘Carol Davila’ University of Medicine and Pharmacy, Bucharest, Romania, 5Department of Pathology, University Hospital,

‘Carol Davila’ University of Medicine and Pharmacy, Bucharest, Romania, 6Deparment of Surgery, C.I. Parhon Institute of

Endocrinology, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest, Romania, 7Department of Pathology, and8Department of Radiology, C.I. Parhon Institute of Endocrinology, Bucharest, Romania

(Received 1 October 2009; revised 13 January 2010; accepted 20 January 2010)

AbstractWe present a case of a Sertoli–Leydig cell tumour manifested with progressive hirsutism, frontal alopecia and secondaryamenorrhea in a 46-years-old female, evolving for 6 years until presentation. Serum testosterone level was 8.01 ng/ml andgonadotropic hormones were LH 8.57 mIU/ml and FSH 9.52 mIU/ml. Computed tomography revealed a dense, solid,heterogeneous mass of 3.5/2.8 cm in the right ovary. Bilateral ovariectomy and hysterectomy were performed. Thehistopathological report mentioned a Sertoli-Leydig cell tumor with intermediate grade of differentiation. Immunohisto-chemical stains showed positive reaction for a-inhibin, calretin and for progesterone receptor. The testosterone levelsdramatically decreased after surgery (0.31 ng/ml) while levels of gonadotropes increased: LH 40.98 mIU/ml and FSH 50.41mIU/ml. At 6 months follow-up the diagnosis of a left lobe thyroid nodule leaded to fine needle aspiration biopsy withsuspicion of papillary carcinoma. Total thyroidectomy established the diagnosis of thyroid papillary carcinoma (2.17/2.18 cm) T2N0M0, stage II, followed by radioiodine administration. This is to our knowledge the first presented case ofovarian Sertoli–Leydig cell tumour associated with papillary thyroid carcinoma. This could suggest a common geneticbackground.

Keywords: Sertoli–Leydig cell tumour, amenorrhea, hirsutism, testosterone, thyroid carcinoma

Introduction

Sertoli–Leydig cell tumour is an ovarian tumour of the

sex cord-stromal type. Described more than 70 years

ago [1] and named originally arrhenoblastoma or

androblastoma in order to highlight their functional

‘masculinisation’ and structural homology to the male

blastema, it is still an intriguing tumour due to its

heterogenic presentation and biology. The term

Sertoli–Leydig cell tumour (SLCT) was adopted later

because virilisation is present only in about half of

the cases and estrogenic excess may also predominate

[2–4].

This functioning ovarian neoplasm is a rare tumour

comprising up to 0.5% of all ovarian tumours. It is

usually unilateral, variable in size (up to 15 cm

described), typically occurring in young female with

a mean age of occurrence under 30 years [5]. The

ovarian cells originate from the sex cords and

mesenchyme of the embryonic gonad. The sex cords

produce Sertoli and granulosa cells while the me-

senchyme gives origin to the Leydig cells, theca cells

and fibroblasts. Tumours of these cells, generally

called sex cord-stromal tumours, account for about

7% of malignant ovarian neoplasms (Table I). Only

about 3% of sex cord-stromal tumours are SLCTs [6].

Correspondence: Catalina Poiana, Department of Endocrinology, C.I. Parhon Institute of Endocrinology, ‘Carol Davila’ University of Medicine and Pharmacy,

PO: Box: 38-21, Bucharest 023573, Romania. E-mail: endoparhon@gmail.com

Gynecological Endocrinology, August 2010; 26(8): 617–622

ISSN 0951-3590 print/ISSN 1473-0766 online ª 2010 Informa UK Ltd.

DOI: 10.3109/09513591003686361

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Case report

We present the case of a 46-year-old female having for

the last 6 years progressive diffuse hirsutism, frontal

alopecia and secondary amenorrhea. She had no

significant personal and family history. Physical

examination revealed increased hair growth on the

abdomen, thorax, and chin and marked frontal

alopecia. (Figure 1) The patient’s BMI was 25 kg/

m2, waist to hip ratio was 0.9 and she had mild

hypertension (160/95 mmHg). She presented a mild

goitre. The blood examination showed poliglobulia

increase in haemoglobin levels 16.2 g/dl, haematocrit

48.2% and the absolute number of red blood cells

5.36106/ml, increased total cholesterol (225 mg/dl)

and hyperuricemia (6 mg/dl). Serum alpha fetopro-

tein (AFP) was normal, so were electrophoresis of

serum proteins, hepatic enzymes and alkaline phos-

phatase.

Hormonal profile revealed total serum testosterone

of 10 times above normal 8.01 ng/ml (normal values

0.14–0.76), increased levels of 24 h urinary 17

ketosteroids (8.69 mg/24 h, with normal va-

lues57 mg/24 h). The levels of gonadotropes were

inappropriately low, LH 8.57 mIU/ml and FSH

9.52 mIU/ml. Thyroid stimulating hormone

(TSH), antithyroid antibodies, prolactin and cortisol

with 1 mg overnight dexamethasone test were

normal. Thyroid ultrasound was performed with

the identification of a solid hypoechoic nodule of 1.4/

1.3 cm in the left lobe, with no cervical lymph nodes.

Endovaginal ultrasonography showed a hypoechoic

mass in the right ovary of 29/19 mm. Computed

tomography revealed a dense, solid, heterogeneous

mass of 3.5/2.8 cm in the right ovary with no

metastatic lesions or lymph node involvement

(Figure 2).

Bilateral resection of the ovaries with hysterectomy

was practiced. Macroscopic examination revealed

encapsulated yellow solid tumour of 2.5/2 cm in

the right ovary. Microscopic examination showed

tubules of cylindrical epithelium and interstitial

cells with eosinophilic cytoplasm suggesting SLCT

with intermediate grade of differentiation-stage II

(Figure 3). Immunohistochemical stains showed

highly reactive a-inhibin and intensely positive

calretinin. Epithelial membrane antigen (EMA),

synaptophysin and CD 99 had a weak reaction,

while pancytokeratin and progesterone receptor were

positive. Negative reactions were for cytokeratin 7,

CD 10 and oestrogen receptor.

The increased cardio-vascular risk due to hyper-

androgenemia expressed as hypercholesterolemia,

arterial hypertension, hyperuricemia and polyglobu-

lia caused post-operative profound venous thrombo-

sis of the right pelvic vein. Oral anticoagulation was

added for the following 6 months. After surgery the

levels of testosterone dramatically decreased to

normal levels (0.31 ng/ml) while the gonadotropes

increased LH 40.98 mIU/ml and FSH 50.41 mIU/

ml. Also, the blood pressure, cholesterol, uric acid

and haemoglobin decreased to normal.

Remarkably, when the patient was revalued 6

months after surgery, the anterior cervical ultrasound

was repeated and it showed that the node in the left

thyroid lobe increased considerably (at 2.17/2.18 cm)

Table I. Classification of ovarian sex cord-stromal tumours.

1. Testicular type

Sertoli cell tumours

Sertoli–Leydig tumours

Leydig tumours

2. Ovarian type

Thecofibromas

Granulose cell tumours

Sclerosing stromal tumours

Figure 1. Arrhenoblastoma. (a) virilising syndrome with frontal

alopecia. (b) virilising syndrome with frontal alopecia. (c) virilising

syndrome with frontal alopecia.

618 C. Poiana et al.

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with signs of partial necrosis and elevated peri-

nodal blood circulation with Doppler sonography

(Figure 4). Fine needle aspiration biopsy was per-

formed with suspicion of thyroid papillary carcinoma

(Figure 5). Total thyroidectomy with total neck

lymphadenectomy was practiced and the diagnosis

of papillary carcinoma was confirmed with no

local spreading of the tumour (T2N0M0, stage II)

(Figure 6), followed by radioiodine 131I administra-

tion. Suppressive levothyroxine therapy was initiated.

Discussions

SLCTs are very rare ovarian tumours, 0.5% of all

ovarian neoplasms [7] and an extremely rare cause of

hirsutism. The pathogenesis of SLCTs is unknown.

Some molecular defects in sex cord stromal tumours

have been reported, such as mutations in the a-inhibin

gene that normally acts as a suppressor of granulose

tumorigenesis [8]. Trisomy 12 was detected in a series

of benign sex cord stromal tumours, mainly in

thecomas [9]. The finding that many sex cord stromal

tumours are hormonally active, led to the assumption

that alterations in the signalling cell pathway could play

a role in the development of these tumours. Interest-

ingly, gsp- and gip2- activating mutations of the G

protein genes were recently described in ovarian and

testicular Leydig cell tumours [10], because until then

gsp mutations have only been described in gonadal

tumours associated with McCune-Albright syndrome.

Recent studies investigated the role of Sox 9 in the

pathogenesis of ovarian Sertoli cell tumour, knowing

its importance as transcription factor involved in

Sertoli cell differentiation in the testis. No consistent

data were found [11].

Although the peak incidence is under 30 years, in

our case it occurred in the fifth decade of life. The

particularities of our case are the long medical

history and the onset of amenorrhea at an expected

menopausal age, which made more difficult the

diagnosis and delayed the presentation to the doctor.

Despite the intermediate grading of the tumour in

our case, there was a slow progression of more than

6 years. Also, the long standing hyperandrogenemia

increased the peri- and post-operative risks for com-

plications: the patient had profound venous throm-

bosis after surgery.

The endocrine function of SLCT mirrors the

cellular components of these tumours. Tumours

containing both Sertoli and Leydig cells have variable

effects, depending on the proportion of the tumour

elements and the degree of histologic differentiation.

Overt virilisation occurs in about half of patients

Figure 3. (a) Microscopic examination of the ovarian tumour (hematoxiline-eosine)-tubular pattern SLCT (65). (b) Microscopic

examination of the ovarian tumour (hematoxiline-eosine)-tubular pattern SLCT (620).

Figure 2. Computed tomography – right ovarian tumour 3.5/

2.8 cm.

Virilising Sertoli–Leydig cell tumour 619

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with SLCTs. As with the pure Leydig cell tumors,

estrogenic manifestations can also be present [5],

such as irregular menses, hyperplastic endometrium

or postmenopausal bleeding (5). Oestrogens are

produced directly by the tumour [12], occasionally

producing isosexual precocious puberty in children

[13,14], or by peripheral conversion of androgens.

Patients with SLCTs who have virilising clinical signs

invariably have elevated blood testosterone levels.

Our case had significant elevated serum testosterone,

as high as 10 times the normal value, ranges that are

often described in these tumours [15]. There are

exceptional endocrine profiles described, as there is a

case with adrenocorticotropic hormone (ACTH)

excess syndrome due to bilateral ovarian 8 andro-

blastoma and fulminate evolution [16], human

chorionic gonadotropin (HCG) secretion causing

precocious pseudo-puberty [17] or renin producing

with resulting hypokalemia and hypertension [18].

Alpha feto protein (APF) may be high [19,20], but

our case had normal values.

Most SLCTs are unilateral, bilateral cases being

exceptional (less than 1.5% of cases) [21]. Grossly,

almost half of these tumours are less than 5 cm

diameter but some may be up to 18 cm or even

more. In our case, the tumour size was average 2 cm.

The size is not correlated with the duration and the

severity of clinical manifestations. Most tumours

are solid or solid-cystic. Their cut surface may be

coloured in brown, pink, yellow or grey. As we

described, our tumour was solid, yellow. The micro-

scopic patterns are tubular (as our case), trabecular,

diffuse, pseudopapillary, alveolar, spindled, retiform

[19,20]. Most of the sex-cord stromal tumours are

benign, stage I and only less than 15% are poorly

differentiated [19,20]. Our case was intermediately

aggressive. Stage of the disease and degree of tumour

differentiation are the major factors for prognosis.

Ovarian sex cord-stromal tumours are morpholo-

gically heterogeneous neoplasms and the diagnosis

can be often difficult. Immunohistochemical staining

is a helpful, adjuvant tool for establishing the diag-

nosis in problematic cases. We examined a panel of

Immunohistochemical markers: a-inhibin, calretin,

EMA, pancytokeratin, synaptophysin, CD 99, oes-

trogen and progesterone receptors, cytokeratin-7

and CD 10. In our case a-inhibin antibodies and

calretinin had intense positive staining reactions,

pattern which is encountered in most ovarian sex

cord-stromal tumours [22,23]. a-inhibin Immuno-

histochemical staining is positive in the vast majority

of sex cord-stromal tumours, regardless of primary,

recurrent or metastatic. Calretinin, a calcium-bind-

ing protein, is positive in the majority of sex cord-

stromal tumours where it is generally appreciated as

more sensitive but less specific than a-inhibin. The

expression of calretinin in hilus cell tumours, theca

interna cells normal Leydig cells and the Leydig cell

Figure 5. FNAB cytology of the thyroid nodule: proliferation of

oxyphil cells, with nuclear inclusions, moderate anisocaryosis

suggesting papillary carcinoma oxyphil type.

Figure 6. Histopathology of the thyroid nodule: papillary

carcinoma, cystic type, with oxyphil component, capsular invasion.

Figure 4. Thyroid ultrasound-solitary node in the left thyroid lobe.

620 C. Poiana et al.

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from SLCTs suggests its correlation with androgen

production. Calretinin is particularly useful in the

diagnosis of sex cord-stromal tumours that are a-

inhibin negative [24].

An extraordinary feature of this case is the

association with thyroid papillary carcinoma. The

clinical pattern is typical for thyroid papillary

carcinoma, a frequent type of cancer (reported

annual incidence in the United States 1/100 000

people): 60–80% are females, aged between 30 and

50 years with a single nodule average 2–3 cm. RET/

PTC oncogene and TRK rearrangement have been

identified and characterised as specific events in

papillary thyroid carcinogenesis [25]. Recently, a

somatic point mutation in the BRAF gene has been

identified as the most common genetic event in

papillary thyroid carcinoma [26].

Our patient had both ovarian SLCT and thyroid

papillary carcinoma. We did not perform genetic,

molecular studies to establish the genetic relationship

between these two forms of malignancies. The patient

may have the association of the two tumours spor-

adically. However, in the literature there are described a

few cases of familial clustering of SLCTs with thyroid

adenoma [27,28], with an autosomal dominant mode

of inheritance, none of these mentioning thyroid

carcinoma. In these families ovarian SLCT were

present among with multiple thyroid adenomas in the

probands, in some of the relatives with ovarian tumours

as well as in relatives without these tumours. A

mucinous cystadenoma was reported twice in these

families and one case of Wilms’ tumour was also

reported. In one case [28] a hamartous polyp of the

small intestine was also associated. These disorders

could be considered as a variant of Cowden syndrome

or Peutz-Jeghers syndrome. Other type of familial

clustering shows intestinal adenomatous polyposis

associated with thyroid carcinoma, probably due to

common predisposing genes [29].

Conclusion

This is to our knowledge the first presented case of

ovarian SLCT associated with papillary thyroid

carcinoma. This could suggest a common genetic

background. Further studies are needed to elucidate

the molecular alterations that underlie the develop-

ment of these tumours.

Declaration of interest: The authors report no

conflicts of interest. The authors alone are respon-

sible for the content and writing of the paper.

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