Histological and Molecular Correlates in Ovarian Epithelial Neoplasia
Vancouver General Hospital
Surface epithelial carcinomas are a large and heterogeneous group of tumors that can be further
subclassified based on cell type and grade. The objective of this presentation is to examine the
correlations between molecular pathology data accrued over the past 3-4 years and the traditional
histopathological classification of surface epithelial carcinomas. By doing so, distinct subsets of
ovarian epithelial neoplasia can be identified with potential treatment implications.
The surface epithelial carcinomas and borderline tumors can be classified histopathologically into a
simple 6 x 4 matrix. This does not address the relationship between different cells within the matrix or
how these cells might be logically grouped,
the subject of this presentation. Both assignment of tumor
grade and tumor cell type have historically been fraught with reproducibility problems. With regards to
tumor grading, the recent introduction of a grading scheme for ovarian epithelial carcinomas based on
tumor architecture, nuclear pleomorphism, and mitotic activity (reviewed in ref. 1) provides a
significant advance in terms of both reproducibility and prognostication
. Uniform application of
grading will enhance our ability to reproducibly subclassify tumors and represents an important new tool
in ovarian cancer translational research. Assignment of tumor cell type is highly "impressionistic", as
noted by Hendrickson and Longacre, resulting in suboptimal reproducibility
. It is likely that
this lack of reproducibility is related to the difficulties in classification of higher grade carcinomas
tumors rather than the low grade carcinomas; distinction between the cell type of low grade serous,
mucinous and endometrioid tumors is usually straightforward, while grade 3 carcinomas lack the overt
lineage specific differentiation that would allow their reproducible classification. One result of the
difficulty in reproducibly subclassifying ovarian carcinomas is that tumor cell type typically does not
influence treatment, independent of stage and grade. This does not mean that cell type is irrelevant.
For example, grouping all borderline tumors together, as has been done in some studies, obscured
important clinical and biological differences between different subtypes, e.g. serous borderline tumors
vs. mucinous borderline tumors of intestinal type. Silverberg noted decreased chemoresponsiveness of
mucinous and clear cell carcinomas, compared to serous or transitional cell carcinomas, and concluded
that cell type, rather than grade may be a superior predictor of response to chemotherapy . For tumor
cell type to enter routine use in guiding patient treatment, however, it must be used in a way that
allows more reproducible subclassification than is presently achieved.
High Grade Serous, Endometrioid, and Undifferentiated Carcinomas
Most ovarian carcinomas are high-grade serous, endometrioid or undifferentiated carcinomas. Seidman
et al. reviewed 220 consecutive invasive ovarian epithelial carcinomas seen at Washington Hospital Center
and found that 85% were of serous, endometrioid, or undifferentiated types, with a further 5% being of
mixed type . (The large majority of these tumors were considered to be of serous type). Considering
only the advanced stage tumors (stage III and IV), the proportion considered serous, endometrioid,
undifferentiated or mixed increased to 93%. A series of 102 cases of advanced stage ovarian epithelial
carcinoma from our center were systematically reviewed with respect to tumor cell type and grade, and 93%
were high grade (grade 2 or 3 by the Silverberg grading system) serous, endometrioid, undifferentiated or
mixed carcinomas . There were 5 cases of clear cell carcinoma and one each of low grade serous
carcinoma and mucinous carcinoma in this series.
Our understanding of genetic events underlying the genesis of this subset of ovarian tumors, that
account for a disproportionate share of ovarian cancer mortality, was dramatically advanced with the
discovery in the mid 1990s of the BRCA1 and BRCA2 genes. It is now appreciated that hereditable cases of
ovarian carcinoma are more common than was originally thought, but it remains that the large majority of
cases of ovarian cancer are sporadic, occurring in patients without a family history of ovarian cancer or
any other identifiable risk factors.
The breast carcinomas arising in patients with germline BRCA1 or BRCA2 mutations are morphologically
distinct compared to sporadic breast cancers, are separable from sporadic breast cancers based on gene
expression profiling, and respond differently to chemotherapeutic agents
. In striking contrast,
the ovarian carcinomas associated with germline BRCA1 or BRCA2 mutations are indistinguishable from
sporadic high grade ovarian carcinomas, based on morphology, gene expression profiling, and p53 mutation
; the prognosis of familial vs. sporadic ovarian cancer remains controversial
The molecular basis for this has been demonstrated by the studies of Hilton et al. and Geisler et al.,
who showed evidence of BRCA1 and/or BRCA2 loss of function in a large majority (84%) of ovarian
. In these important studies, a series of patients with high-grade ovarian carcinomas
were characterized in detail with respect to BRCA1 and BRCA2 through assessment of mRNA levels, gene
sequencing to identify both germ line and somatic mutations, loss of heterozygosity studies to identify
allelic loss, and promoter hypermethylation assays to identify gene silencing through epigenetic means.
In this series, 89% of the tumors were of serous or endometrioid type, 85% were stage III or IV, and 88%
were grade 2 or 3. As expected, germ line and somatic mutations in BRCA1 or BRCA2 were relatively
uncommon. Loss of function more commonly occurred through a combination of loss of heterozygosity and
promoter hypermethylation, but the end result is that in most cases of high grade, advanced stage ovarian
carcinoma there is loss of BRCA1 and/or BRCA2 function.
We have recently shown that EMSY, a gene encoding a protein that binds and inactivates BRCA2, is
amplified in 17% of high-grade ovarian cancers, thus identifying a relatively common genetic mechanism
unrelated to the BRCA2 locus that can result in loss of BRCA2 function
. EMSY amplification was
not seen in grade 1 carcinomas, borderline tumors or mucinous carcinomas.
The data presented demonstrate clearly that a central abnormality in the most common and lethal subset
of ovarian carcinomas of both familial and sporadic type is loss of BRCA1/BRCA2 function with resulting
inability to repair double strand DNA breaks. This correlates well with the very complex cytogenetic
profiles of usual high grade ovarian carcinomas . We have no reliable prognostic indicators for this
group of patients and we have probably reached the limits of morphological subclassification so that
meaningful stratification of patients within this group, with respect to either prognosis or prediction
of response to therapy, will require molecular analysis.
Low Grade Serous Carcinomas and Serous Borderline Tumors
Serous carcinomas are predominantly high-grade tumors but rarely may be low grade. The low-grade
serous carcinomas (and serous borderline tumors) frequently have mutations in BRAF and KRAS, which are
rarely encountered in the high-grade carcinomas
. As well they lack p53 mutations, which are very
commonly encountered in their high-grade counterparts . Low grade serous carcinomas show fewer
molecular abnormalities by both cytogenetic  and single nucleotide polymorphism  analysis, in
comparison to high grade serous carcinomas. Gene expression profiling allows separation of both low
grade serous carcinomas  and serous borderline tumors  from high grade serous carcinomas. It is
clear that low-grade serous carcinomas are more closely related to serous borderline tumors than usual
serous carcinomas, both in terms of clinical outcome and genetic events during carcinogenesis. What is
less clear is whether we are able to reliably separate these two groups of tumors based on
histopathological assessment. Based on the work of Singer et al., only tumors with grade 1 nuclear
atypia, low grade architecture (typically micropapillary) and low-mitotic activity fall into the
low-grade group, with respect to their genetic profile. We have recently, however, encountered two cases
of high grade carcinoma in the recurrences of conventional serous borderline tumors. Both recurrences
were of high architectural grade, intermediate nuclear grade and with intermediate numbers of mitotic
figures (10 and 20 MF/10 HPF, respectively) . While these cases show that progression to higher grade
carcinoma can occur in serous borderline tumors or low grade carcinomas, this appears to be a rare event
and in most cases separation of serous carcinomas into two groups should be possible based on routine
histopathological assessment. The challenge then becomes determining the optimal therapy for advanced
stage, low grade serous carcinomas.
Mucinous Carcinomas and Borderline Tumors (of intestinal type)
In an ongoing review of 3500 cases of ovarian carcinoma seen in Vancouver over the past 20 years it
has become evident that in the 1980's, in particular, ovarian metastases of mucin producing
adenocarcinomas from other body sites were frequently classified as primary ovarian mucinous carcinomas.
There remain mucinous carcinomas that are true primary ovarian tumors rather than metastases, but they
are uncommon. Seidman et al. found that only 6 of 220 carcinomas were mucinous carcinomas, and only one
of these presented with advanced stage disease . In our review of 102 advanced stage ovarian
carcinomas seen at our institution, only one was mucinous . Thus, with careful exclusion of
metastases, mucinous carcinomas of the ovary are uncommon and the large majority are stage I tumors,
requiring no additional therapy beyond surgical removal. Mucinous borderline tumors of intestinal type
and mucinous carcinomas show an increasing frequency of KRAS mutations
and, unlike the situation
for serous tumors, individual tumors frequently show intratumoral heterogeneity with benign, borderline,
and frankly malignant areas. Mucinous carcinomas have been reported to be less chemoresponsive than
other ovarian carcinomas, but these older data must be interpreted with caution as an unknown number of
these cases are probably metastatic and not primary ovarian carcinomas. We recently encountered a case
of recurrent mucinous carcinoma in which conventional platinum/taxane chemotherapy had been ineffective;
the tumor showed strong membranous immunoreactivity for Her-2 and a trial of Herceptin therapy resulted
in a prompt response . As for low grade serous carcinomas, optimal treatment of advanced stage
mucinous carcinomas is not known, but consistent recognition of this group of tumors will allow
assessment of response rates to conventional chemotherapy and trials of novel therapies to occur.
Low Grade Endometrioid Carcinomas and Borderline
Borderline and malignant endometrioid tumors arise in association with endometriosis in a significant
percentage of cases, suggesting that they may arise from ectopic endometrial tissue rather than the
ovarian surface epithelium. The low-grade endometrioid carcinomas of the ovary are characterized by
mutations in the beta-catenin gene, an uncommon abnormality in high-grade ovarian carcinoma
These low-grade endometrioid tumors typically present with early stage disease and have a favourable
prognosis . The diagnosis of high-grade endometrioid carcinomas is, based on our experience,
irreproducible, with considerable morphological overlap with high-grade serous carcinomas. While
endometrioid carcinomas accounted for 2-3% of advanced stage ovarian carcinomas in the Washington and
, 23% of tumors were considered endometrioid in the Iowa series . High-grade
endometrioid carcinomas of the ovary are not separable from high-grade serous carcinomas based on either
studies of genetic events or gene expression profiling
. Based on the available evidence it is
doubtful whether there is a consistently recognizable set of high-grade endometrioid carcinomas that
differ in any substantive way from high-grade papillary serous carcinomas. The challenge will be to
define the boundary between the (usually) low grade tumors associated with endometriosis and beta-catenin
deregulation and higher grade tumors associated with BRCA1/BRCA2 loss of function.
Clear Cell Carcinomas
Clear cell carcinomas are uncommon, often occur in association with endometriosis, and not
infrequently are observed to arise in endometriotic cysts. Although depicted in the figure at right as
showing a range of grades from borderline to grade 3, they are quite stereotypical in their appearance;
even the "borderline" tumors, which lack invasion, show high grade cytological features, at least
focally, and a consistent feature of clear cell carcinomas is a relatively low mitotic rate compared to
other high grade ovarian carcinomas . It is doubtful whether grading contributes significantly to
subclassification of clear cell carcinomas, and according to WHO guidelines, these tumors are not
graded. The gene expression profile of clear cell carcinomas is distinct from other types of ovarian
. Clear cell carcinomas occur in BRCA1 and BRCA2 mutation carriers. Although they
frequently present with early stage disease, the prognosis of patients with clear cell carcinoma, when
corrected for stage, appears to be somewhat worse than for patients with other subtypes of ovarian
carcinoma . Although this appears to be a well-defined subgroup of ovarian carcinoma, there are a
number of unresolved questions. For example, do pure clear cell carcinoma differ significantly from
those tumors showing mixed growth patterns (e.g. clear cell and serous differentiation)? Is BRCA1/BRCA2
loss of function as common as in high grade serous carcinomas? Do the tumors arising in endometriosis
differ from those unassociated with endometriosis? Until these questions are answered it is uncertain
whether this is a homogeneous group of tumors of whether there are clinically relevant subsets within
Transitional Cell Carcinomas
Transitional cell carcinomas are the most recent addition to the WHO and ISGP classification of
ovarian carcinomas so it is not surprising that they are the least characterized subtype. These are rare
tumors; Silva et al. estimated that they account for 1% of ovarian carcinomas . Transitional cell
carcinomas may show a more favourable response to chemotherapy than other ovarian carcinomas, but this
has not been a uniform finding
. With a recently recognized tumor subtype there will be
problems with reproducibility in diagnosis. Genetic abnormalities associated with transitional cell
carcinomas have not been characterized and the immunophenotype of transitional cell carcinomas is not
related to transitional cell carcinomas of the bladder . Thus, definition of this subtype of ovarian
carcinoma remains purely morphological . How these tumor relate to other ovarian carcinomas remains
to be determined.
Guided by recently gained insights into the genetic basis of different ovarian cancer subtypes it is
possible, based on routine histopathological assessment of cell type and grade, to group ovarian
carcinomas into clinically relevant subsets.
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