Ovarian Sex Cord Stromal Tumors: - Departments of Pathology and ...

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Ovarian Sex Cord Stromal Tumors: - Departments of Pathology and ...

Ovarian Sex Cord Stromal Tumors:

Uncommon Tumors That May Mimic A Variety of More Common Tumors

An Overview of Helpful Morphology and Immunomarkers

Joseph Rabban MD MPH

Associate Professor

UCSF Pathology Department

joseph.rabban@ucsf.edu

June 2010

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:

‣ Immunohistochemistry of Sex Cord-Stromal Ovarian Tumors

‣ 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

‣ Pattern 2: Sex cord-like:

Granulosa cell Tumor

Fibroma with sex cord elements

Endometrioid Adenocarcinoma (sex cord variant)

Adenofibroma/Adenosarcoma with sex cord-like elements

‣ Pattern 3: Single infiltrating cells/clusters +/- signet ring/mucin/vacuoles

Sclerosing Stromal Tumor

Metastatic Gastric / Breast Cancer

Mucinous Carcinoid (primary or metastatic)

Clinical Context, Gross Findings and Differential Diagnosis:

Patient age, clinical setting and gross findings are useful since many patients with ovarian sex

cord stromal tumors are young, have hormonal alterations (estrogenic or androgenic

manifestations, elevated serum markers (e.g. AFP) or syndromic associations (e.g. Peutz

Jeghers syndrome); the tumors are often unilateral, yellow/orange, and multicystic. In contrast,

many of the mimics, particularly adenocarcinoma, would be unusual in a young patient and would

not likely present with such clinical or gross features. Thus, discordance between the clinical

context and the pathologic impression should prompt for further confirmation of the pathologic

diagnosis. Generally, we prefer to confirm the morphologic diagnosis of granulosa cell tumor,

Sertoli cell tumor or Sertoli Leydig cell tumor with immunohistochemistry given the potential for

overlap with so many other tumor types.


Immunohistochemistry

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

56, 57

carcinoid tumor. 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.

Marker Granulosa Cell Sertoli Cell Endometrioid Carcinoid Struma

Tumor Tumor Adenocarcinoma Tumor Ovarii

SF-1 Positive Positive Negative Negative Negative

Calretinin Positive Positive Negative Negative Negative

Inhibin Positive Positive Negative Negative Negative

WT-1 Positive Positive Rarely Negative Negative

EMA Negative Negative Positive Rarely Positive

Keratin Variable Positive Positive Positive Positive

Chromogranin Negative Negative Negative Positive Negative

TTF-1 Negative Negative Negative Negative Positive


Differential Diagnosis by Patterns

PATTERN 1: TUBULOGLANDULAR GROWTH:

Granulosa Cell Tumor versus Endometrioid Adenocarcinoma

The microfollicular and solid pattern of granulosa cell tumor may resemble endometrioid

adenocarcinoma. Morphologic features favoring granulosa cell tumor include nuclear grooves,

Call-Exner bodies, a mixture of growth patterns including trabecular growth, and an absence of

squamous differentiation.

Potential Pitfall: Nuclear grooves are not pathognomonic of granulosa cell tumor.

Nuclear grooves may be seen endometrioid adenocarcinoma.

Endometrioid adenocarcinoma is favored by the presence of endometrioid appearing cells and

squamous differentiation. In questionable cases, immunostains may be helpful (positive EMA,

negative SF-1, calretinin, inhibin).

Granulosa Cell Tumor versus Sertoli Cell Tumor

Microfollicular growth in granulosa cell tumor may resemble the hollow packed tubules of Sertoli

cell tumor, however the latter usually does not exhibit the mixed array of other growth patterns

seen in granulosa cell tumor. In difficult cases, cytokeratin expression can be used to confirm a

diagnosis of Sertoli cell tumor.

Granulosa Cell Tumor versus Carcinoid Tumor

Microfollicular and trabecular growth can be seen in both these tumors but the typical cytologic

features of granulosa cell tumor (nuclear grooves, Call-Exner bodies) will not be seen in carcinoid

tumor. Teratomatous elements favor a diagnosis of carcinoid tumor, as does the presence of

nuclei with neuroendocrine type chromatin texture (stippled or so-called salt and pepper texture).

Neuroendocrine markers such as chromogranin and synaptophysin can be useful to identifiy

carcinoid tumor.

Granulosa Cell Tumor versus Struma Ovarii

Microfollicular growth of granulosa cell tumor may sometimes resemble the follicles of struma

ovarii but otherwise, each entity should show other morphology that clearly leads to the correct

diagnosis. Struma ovarii may be accompanied by other teratomatous elements, something not

expected in granulosa cell tumor. Generally the mixture of other growth patterns in the latter is

not seen in struma ovarii. The nuclear shape may also helpful. Struma ovarii usually exhibits a

uniform, monotonous round/oval nuclear shape without nuclear contour irregularities whereas

most granulosa cell tumors show more nuclear atypia, folds, and grooves.

Granulosa Cell Tumor versus glandular variant Yolk Sac Tumor

Microfollicular and trabecular growth of granulosa cell tumor can resemble the glandular variant of

yolk sac tumor but, again, there are usually other morphologic findings that allow for a

straightforward diagnosis. Yolk sac tumor often shows a mixture of growth patterns (i.e. reticular,

papillary, solid, microcystic) and may be mixed with other germ cell tumor components that are

not expected in granulosa cell tumor. Immunostaining for SALL-4, Glypican 3, AFP

PATTERN 2: SEX CORD LIKE GROWTH

Fibroma with sex cord elements versus Granulosa Cell Tumor

Some fibromas may contain foci of sex cord elements. Typically these are microscopic foci and

only a few foci are present; this does not alter the behavior.


Conversely, some granulosa cell tumors may show a fascicular, spindled growth pattern that

resembles thecoma or cellular fibroma. Though it is unusual for such a tumor to lack other

distinctive patterns of granulosa cell tumor growth (such as microfollicular or trabecular), rare

cases may be difficult to resolve based on morphology alone. Immunohistochemistry is not of

great value since calretinin, inhibin, WT-1, and SF 1 can be seen in both tumor groups. Reticulin

staining, however, is useful. In granulosa cell tumor, the reticulin fibers will highlight bundles,

fascicles and nests of tumor cells but the fibers will not surround individual cells. In contrast, the

reticulin fibers will surround individual spindle cells.

Adenofibroma/Adenosarcoma with sex cord elements versus Granulosa Cell Tumor

Similar to fibroma with sex cord elements, both adenofibroma and adenosarcoma may contain

these elements, typically in a microscopic amount. There usually is sufficient morphology present

to easily make the diagnosis of adenofibroma or adenosarcoma and these tumors are not

typically confused with granulosa cell tumor. Behavior is not affected by sex cord elements.

Endometrioid Adenocarcinoma, Corded and Hyalinized Variant, versus Granulosa Cell

Tumor

A rare variant of endometrioid adenocarcinoma of the ovary or uterus may contain a sex cord-like

or sertoliform growth pattern that resembles granulosa cell tumor. 34 The unusual growth zones

may be embedded in hyalinized stroma, thus giving the name “corded and hyalinized

endometrioid adenocarcinoma”. Such tumors generally exhibit clear cut areas of typical

endometrioid adenocarcinoma that allow for the correct diagnosis. However, we have

encountered some cases that lack such areas and truly resemble granulosa cell tumor.

Identification of squamous differentiation is a key clue to correctly diagnosis adenocarcinoma.

Immunostaining can be helpful in difficult cases.

PATTERN 3: INFILTRATING CLUSTERS/CELLS with SIGNET RING/MUCIN/VACUOLES

Sclerosing stromal tumor versus metastatic carcinoma

Lobular breast cancer and metastatic gastric carcinoma involving the ovary may grow as single

infiltrating polygonal tumor cells embedded within fibrotic stroma, resembling a sclerosing stromal

tumor. Such metastases generally lack the distinctive blood vessels and the pseudolobular growth

pattern of sclerosing stromal tumor. In addition, clinical history of a primary gastrointestinal or breast

cancer should be informative in the differential diagnosis. Because sclerosing stromal tumor affects

young women, the likelihood of a metastatic cancer to the ovaries is comparatively low. EMA

immunostaining should highlight metastatic carcinoma cells and confirm that diagnosis.

Sclerosing stromal tumor versus mucinous carcinoid tumor

A rare variant of carcinoid tumor is the mucinous carcinoid tumor, which may be primary to the ovary

or metastatic. A range of growth patterns can be seen. Infiltrative dispersed clusters or single tumor

cells with a mucin droplet or signet ring appearance may raise consideration of either sclerosing

stromal tumor or metastatic mucinous/signet ring adenocarcinoma. Generally, however, there will be

clear cut areas of carcinoid morphology in the tumor. Distinguishing primary versus metastatic origin

of mucinous carcinoid is important; appendiceal origin or other intestinal origin should be considered.

CK7 and CK20 may be helpful for that purpose. Keratin or EMA positivity will separate carcinoid

from sclerosing stromal tumor, as will calretinin and inhibin.


SUMMARY OF TUMOR TYPES

Granulosa Cell Tumor

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.

27, 36

These are supposedly more likely than other granulosa cell tumors to be androgenic.

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

13, 51

prognosis. 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 ( 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

24, 28,

2 or 4 mitotic figures per 10 high power fields) appears to predict a higher risk of recurrence. 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 10, 20, 44

but others have not.


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

5, 7, 19, 26, 33

calretinin. 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

18, 45

positive as well.

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.

Mitotically active cellular fibroma

A recent outcome study suggests that mitotic activity in cellular fibroma (that lacks nuclear atypia) is

not associated with recurrence or spread. The study had an average follow up period of 4.7 years.

Isolated case reports of similar tumors that did spread do exist, therefore the authors recommend

that mitotically active cellular fibromas be considered low malignant potential tumors and that careful

surveillance should be offered. 22 Ovarian fibrosarcoma should be reserved for the rare case in which

hypercellularity and unequivocal nuclear atypia are present.

Sertoli-Leydig Cell Tumor

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

53, 55

cells. 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

31, 50, 54, 55

trabeculae or nests or lining round or retiform tubules. 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.

SLCT versus sertoliform variant of endometrioid adenocarcinoma

Rare ovarian endometrioid adenocarcinomas may exhibit areas of growth that mimic Sertoli cell

proliferation. Because pan-keratin can be expressed in the Sertoli cells of SLCT, it is important to

use EMA in this particular differential diagnosis since Sertoli cells will be negative while

6, 15, 16, 29

adenocarcinoma will be positive. Because some SLCT will express estrogen and/or

progesterone receptors, these markers are less helpful in this setting. 11

Heterologous elements in SLCT

Two types of heterologous elements can create diagnostic problems. These are present in about

20% of cases, mostly consisting of gastrointestinal type epithelium. ; 49 If prominent, this component

14, 32

can be confused for a mucinous tumor. Less commonly, hepatoid differentiation can be found.

These cells can secrete alpha fetoprotein and this may lead to elevated serum AFP. Awareness of

this can prevent confusion with yolk sac tumor, which also results in elevated serum AFP.


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