Ovarian Cancer Pathology
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Pathology Manual: Gynecologic Oncology
Histologic Classification of Tumors of the Ovary
Jo Ann Benda, M.D. and Richard Zaino, M.D.
Peer Review Status: Internally Peer Reviewed
Comments on Ovarian Tumors for GOG
1) Ovarian tumors should be extensively sampled, one block for every 1-2 cm diameter
(an individual case may vary, but this is the general guideline).
2) Slides submitted should support the type of malignancy, the grade assigned,
and the extent of disease. Intraoperative rupture should be noted. All slides do
not have to be submitted. Documentation of tumor extent is necessary.
3) Primary peritoneal serous carcinoma patients are not eligible for ovarian
protocols. A single ovarian lesion greater than 0.5 cm (5 mm) has been
designated by GOG pathologists as the cutoff to be called ovarian primary (<0.5
cm eligible for primary peritoneal serous carcinoma protocols; >0.5 cm focus
eligible for ovarian primary protocols).
4) Microinvasive carcinoma in an otherwise low malignant potential tumor are not
acceptable for protocols for invasive ovarian carcinoma. The lesion will be
considered microinvasive using the following criteria:
a. Foci measuring 3 mm or less of invasion are microinvasive.
b. Foci are characterized by single cells or cell clusters composed of round to
cuboidal or columnar eosinophilic cells often displaying degenerate nuclear
features. Some "degree" of atypia is permissible, but the atypia is not severe.
c. There is no stromal reaction or there may be mildly reactive stroma.
Destructive stromal invasion is not present.
d. The cells and cell clusters may be separated from the stroma by artifactual
clefts, i.e. clear spaces.
Epithelial Ovarian Tumors
Introduction
The grading of ovarian carcinomas is subjective. The following definitions
consider both architectural and cytologic features. These features generally
parallel each other.
Serous
Grade 0:
Low Malignant Potential (LMP). These are serous tumors with no stromal
invasion characterized by branching papillae having fibrous cores. Cellular
stratification is present with several cell layers piled on top of each other. Cellular
budding or tufting, may appear as detached clusters at the end of papillae.
Cytologic atypia and mitotic activity are present(1,2,3).
Grade 1:
Well Differentiated Carcinoma. A serous carcinoma must have definite invasion
of stroma. Well-formed papillary processes and glands, minimal disorientation of
nuclei with only mild stratification, minimal nuclear pleomorphism and
hyperchromatism are characteristic. Less than 5% solid areas are present. If
invasive focus is less than 3 mm, this should be noted.
Grade 2:
Moderately Differentiated Carcinoma. This tumor forms more complex papillary
and glandular structures with more pronounced nuclear atypia. Small areas of
solid tumor growth may be seen (greater than 5% but less than 50%).
Grade 3:
Poorly Differentiated Carcinoma. This tumor is still recognizable as serous but
contains large areas of solid growth (more than 50%) with marked pleomorphism,
nuclear hyperchromasia, and giant cell formation.
Mucinous
Grade 0:
Low Malignant Potential (LMP) This mucinous tumor has a complex glandular
pattern with no stromal invasion. Up to three layers of cells exhihiting mild to
moderate atypia may be observed.* Tumors with severely anaplastic nuclei, solid
areas, papillary tufting, or cribriform intraglandular proliferations should not be
classified as being of low malignant potential.
Grade 1:
Well Differentiated Carcinoma. A mucinous carcinoma may show either stromal
invasion indicated by a desmoplastic host response, or epithelial stratification of 4
or more cell layers.* It should be clearly stated whether a mucinous carcinoma
demonstrates invasion as the criterion for diagnosis or only epithelial
stratification. Solid growth is less than 5%.
Grade 2:
Moderately Differentiated Carcinoma. More complex glands or smaller glands are
present with an increase in the degree of nuclear atypia. Stratification is greater
and invasion is generally present. Solid areas are greater than 5% and less than
50%.
Grade 3:
Poorly Differentiated Carcinoma. Marked nuclear atypia, pleomorphism, and
multinucleated cells are characteristic. The glands are poorly formed and large
sheets of tumor without glands or stroma are present (greater than 50% is solid).
Mucin secretion may be lost in a majority of the cells, or seen only with special
stains.
*Some data supports dividing LMP tumors and carcinoma based on invasion
alone. If a tumor is not called low malignant potential because cellular
stratification is 4 or more, this should be clearly stated as non-invasive carcinoma.
If invasion is present, this should be clearly stated.
Endometrioid Carcinoma
Grade 1:
Well Differentiated. This tumor resembles the typical villoglandular carcinoma of
the uterine corpus. The glands are well-formed. Less than 5% of the tumor is
solid. Squamous differentiation may be present.
Grade 2:
Moderately Differentiated. The glands present are more complex with increased
stratification. Occasional small solid nests of tumor are seen, but constitute a
component greater than 5% but less than 50% of the tumor. Squamous
differentiation may be present.
Grade 3:
Poorly Differentiated This tumor has poorly formed glands, nests, and large
sheets of cells with greater than 50% of the tumor solid. Squamous differentiation
may be present.
Brenner Tumors
Low Malignant Potential
Proliferation of transitional or squamous type epithelium on papillary stalks is
necessary. The papillary growth is generally intracystic. The nuclear atypia is
similar to that seen in grade 3 transitional cell carcinoma of the bladder or
squamous cell carcinoma in situ. Typical Brenner tumor must be identified. No
evidence of invasion is present(6).
Invasive
Stromal invasion with a desmoplastic response is necessary. Areas of benign,
metaplastic, or proliferating Brenner tumor must be identified. A well
differentiated tumor has low grade atypia of transitional epithelial type while
poorly differentiated tumors resemble high grade transitional cell carcinoma(7) .
Transitional Cell Carcinoma
Transitional cell carcinoma (TCC) is defined as those primary ovarian carcinomas
in which features of urothelial carcinoma are present, but no benign, metaplastic,
or proliferating Brenner tumor is identified. The predominant malignant
component closely resembles carcinoma of the urinary bladder, although minor
differentiation to squamous or adenocarcinoma is observed in about half. Tumors
are classified according to their predominant histology. Papillary type of
transitional cell carcinoma is histologically identified by the presence of thick
papillary proliferations with smooth luminal borders projecting into empty cystic
spaces. The epithelial cells forming the papillae are polygonal. Focal spindle cells
and glandular lumina are observed. The malignant Brenner-like type resembles a
malignant Brenner tumor, but no benign, metaplastic or proliferating Brenner
tumor is identified(8-11). Grading is done by the WHO and AFIP rules for
transitional cell carcinoma of the urinary bladder.
Mixed Epithelial Tumors
A tumor is classified as a mixed epithelial tumor if there are two components each
making up at least 10 percent of the tumor. The components should be specified.
Mullerian epithelial borderline tumor is a specifically recognized type of mixed
epithelial tumor. Though mucin containing cells are present, the proliferation is
often tufted more like a serous tumor. Serous or endometriod cells may be present
with the mucin containing cells.
Small Cell Carcinoma
Small cell carcinomas of the ovary have been recently divided into two types:
small cell associated with hypercalcemia and pulmonary (oat cell) types. These
tumors enter into the differential diagnosis of many poorly differentiated ovarian
cancers. These tumors are not eligible for epithelial ovarian carcinoma protocols
unless specifically included.
Clear Cell Carcinoma
Clear cell carcinomas are not graded.
Sex Cord-Stromal Tumors
Adult Type Granulosa Cell Tumor (Granulosa-theca cell tumor)
The adult type granulosa cell tumor has been subdivided according to growth
pattern into several types: macrofollicular, microfollicular, insular, trabecular,
cylindromatous, tubular, moire-silk, and diffuse or sarcomatoid. These patterns
are commonly mixed in the same neoplasm. The significance of grading is still
under investigation. Size is the only feature of granulosa cell tumor consistently
related to prognosis.
Juvenile Type Granulosa Cell Tumor
Juvenile granulosa cell tumors are characterized by a follicular or diffuse growth
pattern. The diffuse pattern is sometimes disorderly, often with extensive
lueteinization, and lipid present in the granulosa and/or the theca cell elements.
Nuclei are hyperchromatic and mitotes, which may be atypical, abundant. Nuclear
grooves are rare.
Sertoli-Leydig Cell Tumors (19)
Grade 1:
Well Differentiated
The well-differentiated form is composed of hollow or solid tubules composed of
benign appearting Sertoli cells interspersed with variable numbers of Leydig cells
that occasionally contain crystaloids of Reinke. These generally behave in a
benign fashion.
Grade 2:
Intermediate Differentiation
The lesions of intermediate differentiation have a wide variety of patterns.
Typically, they consist of immature Sertoli cells arranged diffusely in sheets,
aggregates, or cords resembling embryonic testicular sex cords. The stromal
component usually contains clusters of recognizable Leydig cells, but may be
composed of indifferent spindle cells.
Grade 3:
Poorly-Differentiated
The poorly-differentiated, or sarcomatoid type is largely composed of spindled
cells. These tumors may resemble sarcomas with prominent atypia and mitotic
activity. The presence of cords of Sertoli cells, aggregates of Leydig cells, or
other elements enables one to identify the lesion as a Sertoli-Leydig cell tumor.
Retiform pattern
This tumor is characterized by irregular slit-like spaces which may contain blunt
papillae with hyalinized or edematous cores. The spaces are lined by low cuboidal
cells with round, usually regular nuclei, and scant cytoplasm.
With heterologous elements:
Tumors of intermediate or poor differentiation may contain cell types foreign to
the gonad; these include tubules and cysts lined by mucinous epithelium,
cartilage, bone, skeletal muscle, smooth muscle, and fat. The tissue elements
should be specified.
Sex Cord-Stromal Tumors with Annular Tubules
In tumors where more than one pattern of differentiation exists, the tumor will be
graded by the predominant area. Those tumors associated with the Peutz-Jeghers
syndrome are typically benign, whereas those not associated with the syndrome
may behave aggressively.
Germ Cell Tumors of the Ovary
There is no generally accepted grading system for any of the germ cell tumors except for
teratomas. The presence of syncytiotrophoblastic giant cells in ovarian germ cell tumors
should be specified, though these should not be classified as choriocarcinoma. Where
mixed forms exist, the tumors should be listed in order of the proportion present.
Grading of ovarain teratomas.
Grade 0:
All tissues are mature and mitotic activity is rare or absent. Well sampled grade 0
primary teratomas are regarded as benign.
Grade 1:
Neoplasms have some immaturity that may involve any element. Immature neural
tissue or neuroepithelium is rare. An aggregate area of one low-power
microscopic field (4xobj and 10x eyepiece), even if only in one slide of the tumor,
exceeds the minor amount of immature brain or neuroepithelium acceptable for
Grade 1. Mitotic activity is low.
Grade 2:
Immaturity of any tissue and immature neural tissue/neuroepithelium are present
to a greater degree than grade 1. Immature neural tissue or neuroepithelium is
more common than grade 1 but does not exceed an aggregate area of three low-
power microscopic fields (4x objective) in any one slide. Mitotic activity is
moderate.
Grade 3:
Immaturity of any tissue and neuroepithelium are prominent. Immature neural
tissue/neuroepithelium occupies an aggregate area of more than 3 low-power
microscopic fields (4x objective) in any one slide of the tumor. Mitotic activity is
high.
The degree of immaturity of all elements should be considered in grading
immature teratoma. However, immature neural tissue and/or neuroepithelium is
generally agreed to be the most reproducible element.
Grading of metastases should be done independently of the primary grade.
FIGO Staging, Carcinoma of the Ovary
Stage, Description
I.
II.
III.
Growth limited to the ovaries
A. Growth limited to one ovary; no ascites. No tumor on the external surface,
capsule intact.
B.
Growth limited to both ovaries; no ascites. No tumor on the external
surface; capsule intact.
C.
* Tumor either Stage IA or Stage IB, but with tumor on the surface of one
or both ovaries; or with capsule ruptured; or with ascites present
containing malignant cells or with positive peritoneal washings.
Growth involving one or both ovaries with pelvic extension.
A. Extension and/or metastases to the uterus and/or tubes
B.
Extension to other pelvic tissues.
C.
* Tumor either Stage IIA or IIB but with tumor on the surface of one or
both ovaries; or with capsule(s) ruptured; or ascites present containing
malignant cells or with positive peritoneal washings.
Tumor involving one or both ovaries with peritoneal implants outside the pelvis
and/or positive retroperitoneal or inguinal nodes. Superficial liver metastasis
equals Stage III. Tumor is limited to the true pelvis with histologically verified
malignant extension to small bowel or omentum.
A. Tumor grossly limited to the true pelvis with negative nodes but with
histologically confirmed microscopic seeding of abdominal peritoneal
surfaces.
B.
Tumor of one or both ovaries with histologically confirmed implants of
abdominal peritoneal surfaces, none exceeding 2 cm in diameter. Nodes
negative.
C.
IV.
Abdominal implants >2 cm in diameter and/or positive retroperitoneal or
inguinal nodes.
Growth involving one or both ovaries with distant metastasis. If pleural effusion
is present there must be positive cytologic test results to allot a case to Stage IV.
Parenchymal liver metastasis equals Stage IV.
*In order to evaluate the impact on prognosis of the different criteria for allotting
cases to Stage IC or IIC, it would be of value to know if rupture of the capsule
was (1) spontaneous or (2) caused by the surgeon and if the source of malignant
cells detected was (1) peritoneal washings or (2) ascites.
Friedlander ML, Dembo AJ. Prognostic factors in ovarian cancer. Sem in Oncol
18:20-212, 1991.
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