ovarian Sertoli cell tumor

Digital cases

Case 39 : Oxyphilic Sertoli cell tumor

Definition: Ovarian Sertoli cell tumors are rare, and their morphologic spectrum, behavior, and factors influencing the latter are not clearly established. Pure Sertoli cell tumors are rare ovarian tumors of the sex-cord stromal cell origin as designated by the World Health Organization. They account for about 0.5 % of all ovarian neoplasm.

Ovarian SCTs are rare, accounting for only approximately 4% of the tumors in the category of Sertoli-stromal cell tumors of the ovary, which themselves are overall uncommon.

Ovarian SCTs typically occur in women of reproductive age, but a few occur in children in whom the most common clinical presentation is isosexual pseudoprecocity.

Women of reproductive age and postmenopausal women frequently present with abdominal pain or swelling, menstrual abnormalities, or the tumor is an incidental finding.

However, these patients may have associated endocrine manifestations, more commonly estrogenic, and less frequently androgenic secondary to hormone secretion by the tumor cells. In the literature, endocrine manifestations have been reported to occur in two thirds of the patients, but only 34% of the patients in one series had such manifestations.

Estrogen production may result in menstrual abnormalities or postmenopausal bleeding and endometrial hyperplasia, depending on the menopausal status of the patient.

Rarely, endocrine disorders are due to progesterone production resulting in decidualization of the endometrium or peritoneum or increased levels of testosterone, the latter resulting in amenorrhea or virilization.

Evidence of androgen secretion suggests the possible presence of unsampled Leydig cells in an otherwise pure SCT, although pure SCTs seem to have this capacity.

SCTs also may cause endocrine manifestations by inducing peripheral stromal luteinization. Two SCTs in the literature have been associated with secretion of renin and aldosterone.

Epidemiology

The tumors typically occur in young females, sometimes children who typically present with sexual precocity, and occasional patients have Peutz-Jeghers syndrome.

They are almost always unilateral, occurring in women 30 year old or younger.

Fewer than 10% of the patients are over 50 years of age. About 30-40% of patients show virilization.

One striking association of occasional SCTs is with the Peutz-Jeghers syndrome, an autosomal dominant disorder characterized by mucocutaneous pigmentation, hamartomatous polyps, and occasionally carcinomas of the gastrointestinal tract, adenoma malignum of the uterine cervix, sex cord tumors of the ovary, and unusual testicular sex cord lesions. Between 5% and 15% of women with Peutz-Jeghers syndrome have sex cord-stromal tumors of the ovary, the most common being the sex cord tumor with annular tubules; a second type has a heterogeneous growth characterized by an admixture of diffuse areas, tubules, microcysts, retiform structures, and papillae with psamomma bodies, only encountered in patients with the PJS, both presenting with sexual precocity and finally SCTs.

Macroscopy

Grossly, SCTs are typically solid with a tan to yellow lobulated appearance. It is not infrequent to see focal cystic areas secondary to degeneration, but a mainly cystic tumor is rare.

In the testis, cysts up to 2.5 cm were described in up to 30% of SCTs in the largest series reported in the literature, but none of the tumors was predominantly cystic.

The gross appareance reflects varied components: solid, solid/cystic (the most common) or totally cystic.

Microscopy

The Sertoli-stromal cell tumor (SSCT) of the ovary shows a histologic resemblance to developing or adult testes and is often associated with virilization caused by tumor-produced androgenic hormone.

A tubular growth is the most common microscopic pattern seen, including that on testicular SCTs. The hollow or solid tubules present in these tumors are the major clue to their nature as they are practically always present at least focally.

Microscopically, they range from well to poorly differentiated. SCT are classified based on histological pattern:
simple tubular
complex tubular
lipid rich type.

The tubules, cords, and trabeculae are lined or composed of cuboidal to columnar cells.
Typically, the cells had moderate amounts of pale pink cytoplasm, but in some tumors the cells can have abundant deeply eosinophilic cytoplasm (oxyphilic cells).
Vacuolated cells can be seen. This appearance is diffuse throughout the neoplasm; in other cases, it was seen only focally. In these areas, the cells typically contained multiple small vacuoles that frequently pushed the nucleus to the side. Fat stains are positive to a variable extent. These cases are qualified as the lipid-rich variant of SCT.
Intracytoplasmic hyaline globules are identified in rare tumors.
Round to oval regular nuclei with inconspicuous nucleoli and no appreciable cytologic atypia are seen.
Nuclear grooves can be seen.
Rares tumors can have focally bizarre nuclei characterized by large mononucleate or multinucleated cells with smudgy chromatin with a patchy distribution. This change is unaccompanied by appreciable mitotic activity and is considered degenerative.
Moderate to severe cytologic atypia of conventional type, including vesicular nuclei with coarse chromatin and prominent nucleoli, are present in some tumors.
Rare tumors with severe cytologic atypia contain malignant giant cells.
Mitotic activity ranges from 0 to 34/10 high power fields (HPFs).
The stroma of the tumors varies from negligible to delicate fibrous septa to conspicuous and hyalinized.
Delicate fibrous septa in foci with a diffuse background imparte, particularly in 1 case an alveolar arrangement.
Abundant stroma is present in some tumors. It can undergo marked hyalinization compressing the tubules.
Calcification is seen in rare tumors and can be extensive forming irregular calcified plaques.
Scant groups of cells consistent with Leydig cells can be identified, but crystals of Reinke are very rare.
Additional findings can include a granulosa cell tumor, fibroma, Brenner tumor, and mature cystic teratoma in the opposite ovary, or grade 2 endometrial adenocarcinoma of endometrioid type.

Nota bene: By definition pure Sertoli cell tumors lack Leydig cell in the stroma. However, heterologous elements such as mucinous glands, bone, skeletal muscle and cartilage may be present in some tumors.

Immunochemistry

Immunohistochemical staning of SCT typically shows reactivity for citokeratin and α-inhibin. Positivity for melan A has also been described as a useful marker.

The tumor is typically negative for epithelial membrane antigen, carcinoembryonic antigen, placental alkaline phosphatase and S100.

Differential diagnosis of SCT includes:

mucinous tumors,
low grade endometrioid carcinoma
carcinosarcoma when heterologous elements are present
tubular Krukenberg tumor
tubular carcinoid and ovarian tumors of probable Wolffian origin

Physiopathology

Some tumor cells of a SSCT show simultaneous differentiation into both Sertoli cells and cells of rete testis. SRY gene was not detected in any cases, and the X chromosome activation pattern was the same as that of the female control. (#11521222#)

Predisposition

Peutz-Jeghers syndrome (10%)

Synopsis

Age: from 2 to 76 years of age (mean, 30 years)
estrogenic or androgenic manifestations
The tumors range from 0.8 to 30 cm, with the majority being in the range of 4 to 12 cm.
They are all unilateral, usually solid, and often yellow.
The predominant microscopic pattern iss tubular, seen, albeit often only focally, in all tumors; other patterns were cords or trabeculae, diffuse, pseudopapillary, retiform, islands or alveolar arrangements, and spindled.
The tubules are solid or hollow with the former being somewhat more common.
Delicate septa are occasionally seen and are conspicuous in areas of one tumor.
The stroma can be abundant with marked sclerosis.
The cells usually have pale to occasionally densely eosinophilic cytoplasm.
Some tumors are composed of cells with prominent foamy cytoplasm, falling in the category of "lipid-rich" Sertoli cell tumor, and one had cells with clear non-foamy cytoplasm.

Although Sertoli cell tumors usually have a distinctive tubular pattern that facilitates the diagnosis, other patterns may occasionally predominate, causing confusion with various other primary and metastatic ovarian tumors.

EMA, inhibin, and chromogranin represent the most helpful triad of immunomarkers serving to exclude two common mimics of Sertoli cell tumors (endometrioid carcinoma [inhibin-; EMA+; chromogranin-] and carcinoid tumor [inhibin-; EMA+; chromogranin+]).

Although CD99 and calretinin are often expressed in these tumors, they are much less specific and not as helpful in the differential diagnosis.

Most Sertoli cell tumors are stage I, unilateral, cytologically bland, and clinically benign, but occasional examples are high stage, and about 11% of stage I tumors have worrisome histologic features that may portend an adverse outcome.

Microscopy

Sertoli cell tumor shows closely packed hollow and solid tubules lined by well-differentiated cuboidal-to-columnar epithelial cells.
Leydig cell are absent

Immunochemistry

strong cytoplasmic staining for inhibin in tumoral Sertoli cells.
WT1 immunostaining (#17721194#)

Variants

oxyphilic sertoli cell tumor of the ovary

Differential diagnosis

Ovarian Sertoli cell tumors may be mimicked by many different tumors, some of them more frequent than Sertoli cell tumors.

ovarian Sertoli-Leydig cell tumor (SLCT)
ovarian granulosa cell tumor
ovarian steroid cell tumor
ovarian endometrioid adenocarcinoma

ovarian Sertoli-Leydig cell tumor (SLCT)

As SCTs may have a few luteinized cells or bona fide Leydig cells admixed with the Sertoli component, they may be misdiagnosed as a SLCT. The distinction of SCT from well-differentiated SLCT is based simply on the finding of more than rare cells consistent with Leydig cells in SLCTs. Two morphologic features of SLCTs, a retiform pattern and heterologous elements, strongly favor SLCT rather than SCT. Some SCTs had minor retiform foci, but it was less conspicuous than seen in SLCTs. The presence of heterologous components strongly supports the diagnosis of SLCT, as no SCT of the ovary with heterologous elements has been reported.

ovarian granulosa cell tumor

Among other sex cord tumors of the ovary that may enter in the differential diagnosis is an adult granulosa cell tumor. SCTs may grow in cords, trabeculae, solid tubules, or islands that may mimic the growth of an adult granulosa cell tumor, and the nuclei of SCTs may be grooved as in 18 of our cases and as reported in the literature.
The presence of well-formed solid or hollow tubules should alert the pathologist to a SCT even though some tubules are allowed in a granulosa cell tumor.
This overlap, an inherent aspect of sex cord tumors not withstanding, the great majority of SCTs and granulosa cell tumors are readily distinguished.
That distinction has some prognostic significance in that there is no current evidence to suggest that a SCT has the same propensity for late recurrence as a granulosa cell tumor.
Some categorize the pattern of sex cord tumor with annular tubules in the SCT family.
The presence of bizarre nuclei, a feature more often seen in granulosa cell tumors, was observed in rare SCT in one series but has not been previously reported in the literature or in the testicular counterpart of this tumor.

ovarian endometrioid adenocarcinoma

Probably the most important differential diagnosis is with an endometrioid carcinoma (EC) of the ovary, a much more common tumor than the one under discussion. It is well known that ECs may have a Sertoli-like appearance, leading some to even use the descriptive term “sertoliform endometrioid carcinoma.”
In these cases, typical areas of EC are almost always present merging with the Sertoli-like areas, and there is often focal squamous metaplasia or a background of adenofibroma or endometriosis.
Some ECs may have a predominant spindle cell growth pattern.
They may have an extensive component of oxyphilic cells, a feature seen in some SCTs.

ovarian carcinoid tumor

The second most common pattern encountered is cords and trabeculae.
In most cases, this was a minor component of the tumor but noticeable enough to bring carcinoid tumor into the differential diagnosis in some cases.
Moreover, the acini of a carcinoid tumor may be confused with well-differentiated Sertoli tubules.
The cells in the acini of carcinoids typically have a brush border, contain prominent neuroendocrine granules, and have nuclei with “salt and pepper” chromatin.
The stroma of carcinoid tumors is often much more prominent and frequently more extensively fibrotic than that seen in most SCTs.
Primary ovarian carcinoids are typically associated with a component of teratoma or mucinous tumor, and the trabecular pattern in particular is commonly associated with a strumal component.

female adnexal tumor of probable Wolffian origin (FATPWO)

Some SCTs may be mimicked by a female adnexal tumor of probable Wolffian origin (FATPWO). The latter tumor, although more frequently seen in the broad ligament, has also been described in the ovary.
Solid tubules containing slightly elongated cells with oval nuclei seen in some FATPWO may be reminiscent of those seen in SCTs.
However, the FATPWO is characterized by an admixture of other histologic patterns, particularly cysts with a sieve-like appearance, which are distinctive and rule out a SCT.
In difficult cases, immunostains may be helpful in the differential diagnosis.

Prognosis

The prognosis of SCT is usually good and correlates with the stage and degree of differentiation of the tumor.

Very rarely SCTs show malignant histological features including high mitotic rate, necrosis, marked cytological and nuclear atypia, and lymphovascular invasion.

Adjuvant therapy is considered based on the histological classification and staging of the tumor.

Poorly differentiated or metastasic tumors have noted to have a poor prognosis without chemotherapy.

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ovarian Sertoli cell tumor

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