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Neoplasma Ovarial
Neoplasma Ovarial
Introduction: Sex cord-stromal tumors are uncommon ovarian neoplasms, accounting for 5% to
12% of ovarian tumors, yet many of these tumors may mimic a range of more common epithelial
and germ cell tumors, both benign and malignant. Two growth patterns in ovarian tumors that
are problematic in terms of overlap between sex cord-stromal, epithelial and germ cell tumors are
1.) tubuloglandular growth and 2.) sex cord-like growth. A third but much less common pattern is
that of single infiltrative clusters or cells with signet ring features or vacuoles. This lecture will
focus on differential diagnosis of these three growth patterns, with emphasis on granulosa cell
tumors.
Outline of Lecture:
¾ Pattern 1: Tubuloglandular:
Granulosa Cell Tumor
Sertoli Cell Tumor / Sertoli Leydig Cell Tumor
Sex Cord Tumor with Annular Tubules
Endometrioid Adenocarcinoma
Carcinoid Tumor
Struma Ovarii
Strumal Carcinoid Tumor
Yolk Sac Tumor, glandular variant
Inhibin and calretinin are the traditional markers of ovarian sex cord-stromal differentiation.
Expression tends to be stronger and more diffuse in granulosa cell tumors, Sertoli and Sertoli-
Leydig cell tumors than in fibroma or thecoma. Ovarian steroid cell tumors will also mark with
inhibin and calretinin, as will ovarian hilus cells and cells of stromal hyperthecosis. Nuclear
expression of WT1 and membrane expression of CD99 also characterize many sex cord-stromal
tumors, but in our practice, we don’t use these markers since they are not as reliable as others in
our laboratory. ER and PR may be expressed in many granulosa cell tumors. When trying to
distinguish sex cord-stromal tumors from epithelial tumors, care must be exercised in selection of
epithelial markers: pan-keratin may mark granulosa cell tumors and Sertoli cell tumors to variable
degrees and this may cause confusion with adenocarcinoma. EMA (epithelial membrane
antigen) is a better choice since it is negative in sex cord-stromal tumors. Conversely, some
endometrioid adenocarcinomas may express inhibin, calretinin or WT-1, albeit in a weak, patchy
pattern.
Steroidenic factor 1 (SF 1) is a recently studied nuclear protein that appears to be a useful marker
of ovarian sex cord differentiation. It marks lesions of sex cord-stromal differentiation in a nuclear
pattern and is negative in epithelial tumors.56, 57 SF 1, also known as Adrenal Binding Protein 1,
is found in many of the same tissues that mark with inhibin. SF 1 is a transcription factor
regulating steroidogenesis of the adrenal and pituitary glands. Immunoexpression is observed in
adrenal cortical tumors and pituitary adenoma. It is also thought that SF 1 is involved in gonadal
development. In the testis, SF 1 marks Sertoli cells and Leydig cells. Recently it was
demonstrated that SF 1 marks ovarian sex cord tumors (granulosa cell tumor, Sertoli cell tumor,
Sertoli Leydig cell tumor, and fibroma/thecoma) but not endometrioid adenocarcinoma or
carcinoid tumor. 56, 57 The nuclear expression pattern makes it a preferred marker.
Recommended panel:
To confirm a diagnosis of granulosa cell tumor, we prefer the quartet of SF-1, inhibin, calretinin
and EMA and we avoid cytokeratin stains. The following table lists the results expected in most
tumors, keeping in mind that exceptions do occur.
Potential Pitfall: Nuclear grooves are not pathognomonic of granulosa cell tumor.
Nuclear grooves may be seen endometrioid adenocarcinoma.
Granulosa cell tumors range from small incidentally discovered nodules only a few millimeter in
diameter to large tumors more than 30 cm in diameter. Some are totally solid, but most are partly
cystic. The solid portions are pink, tan, brown, or light yellow and vary from soft to firm in
consistency. Rare granulosa cell tumors grow as large cysts with a wall only a few mm thick.
These are supposedly more likely than other granulosa cell tumors to be androgenic. 27, 36
Microscopically, the tumor cells resemble normal granulosa cells. They are small and round,
cuboidal, or fusiform with pale cytoplasm and ill-defined cell borders. The nuclei are round or
oval with fine chromatin and a single small nucleolus. Longitudinal folds or grooves are present
in many nuclei and are a characteristic feature of the adult type of granulosa cell tumor. Mitotic
figures are usually infrequent and pleomorphic or atypical nuclei are uncommon. Rare granulosa
cell tumors contain foci of cells with bizarre nuclei, but this does not appear to imply an adverse
prognosis. 13, 51 Extensive tumor cell luteinization is seen in about 1% of adult granulosa cell
tumors. Luteinized granulosa cells have abundant eosinophilic cytoplasm, well-defined cell
borders, and central nuclei, and resemble the luteinized granulosa cells of the corpus luteum.
Some luteinized granulosa cell tumors occur in pregnant women, 47 but they are also seen in
patients with androgenic granulosa cell tumors, 35 and as idiopathic findings. 48
A diverse range of growth patterns are exhibited by adult granulosa cell tumors, often mixed
together. The patterns do not have any prognostic significance, but because they may mimic
other tumor types, awareness of them is critical. The microfollicular pattern is the most typical
one and consists of nests and sheets of granulosa cells that contain small spaces filled with
eosinophilic secretions and cellular debris. The spaces resemble the Call-Exner bodies of
developing follicles. In the macrofollicular pattern, large, often irregularly shaped follicles are
lined by stratified granulosa cells. Granulosa cells grow in anastomosing bands, ribbons, and
cords in the trabecular pattern; and in irregular undulating ribbons in the gyriform or watered-silk
pattern. Nests and islands of tumor cells are surrounded by fibrous stroma in the insular pattern.
The cells grow in large irregular sheets with no organized substructure in the solid or diffuse
pattern. Many granulosa cell tumors contain large cysts lined by granulosa cells. The cysts may
contain blood and hemosiderin-laden macrophages are often present in the walls. Rare cystic
granulosa cell tumors grow as large unilocular cysts lined by stratified granulosa cells among
which are microfollicles or areas of trabecular growth.
Granulosa cell tumors have a variable amount of fibrous or thecomatous stroma. Tumors with a
prominent fibrothecomatous stroma have been called granulosa-theca cell tumors but when
granulosa cells comprise > 5-10% of the a tumor it can be classified as a granulosa cell tumor.
Tumors with only a minor granulosa cell component are best classified as a thecoma or fibroma
with minor sex cord elements (<5%). 52 Rarely, a granulosa cell tumor contains heterologous
mucinous epithelium. 4, 9, 37 Equally rare is the finding of foci of hepatic cell differentiation in a
granulosa cell tumor. 1
It is difficult to predict the prognosis of a granulosa cell tumor, 27 but some pathologic findings
correlate to a degree with the clinical outcome. 2, 12, 43 Unfavorable findings include a tumor
diameter > 15 cm, bilateral tumors, rupture, and spread beyond the ovary (FIGO stage > IA).
Diffuse moderate or marked nuclear atypia or a high mitotic rate (variably defined as greater than
2 or 4 mitotic figures per 10 high power fields) appears to predict a higher risk of recurrence. 24, 28,
30
The stage is the single most powerful predictor of prognosis. There is no correlation between
the microscopic pattern and the clinical outcome. More than 80% of granulosa cell tumors are
DNA diploid. Some authors have found ploidy or s-phase fraction to provide significant
prognostic information, 21, 25, 38 but others have not. 10, 20, 44
Fibroma / Thecoma
Ovarian fibroma is a benign stromal tumor in which spindle shaped stromal cells grow in abundant
collagenous stroma. Immunohistochemistry is rarely performed on fibromas because their
appearance on H&E stained slides is usually distinctive. Fibromas and related tumors such as
cellular fibromas and fibrosarcomas stain only infrequently for inhibin but most are calretinin
positive.8, 26, 33 They show patchy and weak to moderate staining for WT-1.17 SF-1 is positive,
though may have variable intensity/distribution.
Thecoma is a benign spindle cell stromal tumor that differs from fibroma in that it is often hormonally
active, usually secreting estrogen. There are morphologic differences as well, as the tumor cells in a
thecoma tend to be plump, with clear or vacuolated cytoplasm, and there is less collagen in the
background stroma than is present in a fibroma. Thecoma is usually positive for both inhibin and
calretinin.5, 7, 19, 26, 33 Strong positive staining for inhibin favors classifying a stromal tumor as a
thecoma rather than as a fibroma. Stains for myoid markers, such as smooth muscle actin, are often
positive as well.18, 45
The diagnosis of fibroma and thecoma is generally straightforward, however, in addition to distinction
from granulosa cell tumor, there is one problem that may occasionally present difficulty: presence of
mitoses and/or presence of cellularity. The differential diagnosis that is raised is fibrosarcoma, an
exceedingly rare tumor in the ovary.
Sertoli-Leydig cell tumors (SLCT) are tumors of young women and girls and are notable for virilizing
effects.46 They may be of well, intermediate, or poor differentiation and any of these may be
accompanied by heterologous elements or by retiform growth. In well differentiated variants Sertoli
cells line well formed tubules that grow in a fibrous stroma that contains clusters of polygonal Leydig
cells.53, 55 Immature stromal and Sertoli cells are not present. The more common intermediate and
poorly differentiated Sertoli-Leydig cell tumors contain variably mature Sertoli cells growing in
trabeculae or nests or lining round or retiform tubules.31, 50, 54, 55 The stroma is cellular and immature,
and Leydig cells, present either singly or in clusters, are present in most tumors. Most patients
present with tumors confined to the ovary and have a favorable prognosis.
Sclerosing stromal tumor is a rare though benign, hormonally inactive ovarian tumor with a distinct
low magnification growth pattern that arises almost exclusively in young women.3, 23 The tumor
shows a pseudolobular pattern of cellular, spindle cell zones alternating with paucicellular fibrous
zones. Scattered throughout are branched dilated blood vessels having a “hemangiopericytoma-
like” appearance. The tumor cells adjacent to the vessels are often polygonal, vacuolated (lipid, not
mucin) or vaguely myoid in appearance. In rare cases these cells may exhibit signet ring features.
The tumor cells are vimentin positive and they often stain for smooth muscle actin.40-42
Immunostains for inhibin and calretinin are positive in more than 50% of sclerosing stromal tumors.26,
33, 39
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