typing of ovarian tumors
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Typing of ovariancarcinomas: an updateChristopher G Przybycin
Robert A Soslow
AbstractClassification of ovarian carcinomas into differentsubtypes is no longer only
an exercise in pattern recognition that lacks clinical and biological signifi-
cance. Biologically validated diagnostic criteria now separate ovarian carci-
nomas into specific disease types that have clinical relevance: high-grade
serous carcinoma, low-grade serous carcinoma, endometrioid carcinoma,
clear cell carcinoma and primary ovarian mucinous carcinoma. This review
summarizes the clinical and pathologic features of these types of ovarian
carcinoma and provides information about refined diagnostic criteria and
the use of ancillary diagnostic techniques for diagnosis.
Keywords clear cell; endometrioid; mucinous; ovarian carcinoma; serous
Introduction
Historically, the chief means of classifying ovarian carcinomas has
beenhistologicassessment of cell type. Thisapproach is reflected in
the current World Health Organizations ovarian carcinoma clas-
sification, which includes serous, mucinous, endometrioid, clear
cell, transitional cell, and squamous carcinomas. As the immuno-
histochemical characteristics and molecular underpinnings of these
ovarian tumours have been progressively elucidated, it has become
apparent that the different subtypes of ovarian carcinoma represent
distinct disease entities, rather than different manifestations of one
disease. Each ovarian carcinoma type has a specific predilection for
mode of presentation, with endometrioid and mucinous carci-
nomas usually presenting at FIGO stage I, clear cell carcinoma at
stage I or II and serous carcinoma at stage III or IV.1 These obser-
vations have elicited clinically justifiable interest in the accurate
subclassification of ovarian tumours. As an example, high-grade
and low-grade serous carcinomas are now known to be the prod-
ucts of two completely disparate tumorigenic pathways with only
rare intersection2,3 with distinct differences in prognosis and
chemotherapeutic sensitivity.
Nonspecific diagnoses are insufficient, as tumour cell type has
been shown to be prognostically significant independent of tumour
grade4,5 and certain carcinoma subtypes (low-grade serous,
mucinous, and clear cell carcinomas) are intrinsically resistant to
standard chemotherapeutic agents,6e10 while clear cell carcinoma
is relatively more radiosensitive than other types.11 A recent study
emphasizes that careful evaluation of morphologic features,
following guidelines outlined in this review, leads to reproducible
and clinically meaningful subclassification of ovarian carci-
nomas.12 These distinct morphologic features also correspond to
unique genetic profiles, aspects of which could potentially be
exploited by future targeted therapies.
High-grade serous carcinoma
Prevalence
Serous carcinomas (of which high-grade serous carcinomas
constitute the vast majority13) are the most common ovarian
carcinomas, representing 80e85% of all ovarian carcinomas in
the West, and are especially well represented among carcinomas
that present at high FIGO stage (III or IV).13
Tumour characteristics, immunophenotype, and genotype
Currently, high-grade and low-grade serous carcinomas are thought
to represent two distinct types of ovarian carcinoma, rather than
opposite ends of severity along a single trajectory of tumour
progression. The morphologic differences between these tumours
are a manifestation of their underlying biological and, ultimately,genetic, disparity. Specifically, it has been shown that high-grade
serous carcinomas are aggressive neoplasms with unstable
genetics, a very high prevalence ofTP53 mutations, and no well-
characterized ovarian precursor lesion. In contrast, low-grade
serous carcinomas follow a moresmouldering course, havea stable
genetic profile, usually have mutations inKRAS, BRAF, and ERBB2,
rather than TP53, are chemoresistant by comparison, and usually
arise in association with established precursors (serous cys-
tadenomas and serous borderline tumours).2,3
The discovery of biological differences between low-grade and
high-grade serous carcinomas has provided a basis for some
investigators to propose a dichotomous model of ovarian carcino-
genesis that recognizes type I and type II pathways.14
Low-grade serous carcinomas are an example of type I tumours, a group
that also includes mucinous carcinomas, malignant Brenner
tumours, clear cell carcinomas, and endometrioid carcinomas.
Tumours in the type I pathway are thought to arise in a stepwise
fashion from recognized benign or borderline precursors, are
genetically stable, are often confined to the ovary at the time of
presentation, and generally follow an indolent course. They char-
acteristically lack TP53 mutations, and instead each histologic
subtype has a characteristic genetic profile. High-grade serous
carcinomas, along with transitional and undifferentiated carci-
nomas and carcinosarcomas (malignant mixed mesodermal
tumours), are type II tumours, the hallmarks of which are advanced
stage at presentation, aggressive course, unstable genetics, and anextremely high prevalence of TP53 mutations. Many high-grade
serous carcinomas are now thought to arise from microscopic
precursor lesions in the distal fallopian tube.15,16 There can be rare
intersection between these tumorigenic pathways, in which a high-
grade serous carcinoma arises from a low-grade serous carcinoma.
High-grade serous carcinomas are morphologically heteroge-
neous and, while they usually contain at least focal papillary or
micropapillary areas, they can also have solid, glandular, micro-
cystic, or cribriform patterns, as well as areas that resemble tran-
sitional cell carcinomas (Figures 1 and 2) (Table 1). Slit-like spaces
are common, and can aid in the diagnosis. The cells characteristi-
cally have large, pleomorphic nuclei, often hyperchromatic or
Christopher G Przybycin MD is a Consultant Pathologist at Clin-Path
Associates, Tempe, AZ, USA. Conflict of interest: none.
Robert A SoslowMD is in the Department of Pathology at the Memorial
Sloan-Kettering Cancer Center, NY, USA. Conflict of interest: none.
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showing prominent nucleoli (Figure 3). Mitotic figures exceed
12 mitotic figures per 10 high power fields, by definition, and most
cases showsignificantly more thanthis.17,18 Atypical mitotic figures
can be seen. Tumour infiltrating lymphocytes can be conspicuous
in tumours lacking BRCA function, including those attributable to
a germline mutation in BRCA1.19
There is a high reported frequency ofTP53 mutations in high-
grade serous carcinomas20e22 with as many as 90% of high-grade
serous carcinomas having TP53 mutations. TP53 mutations come
in two general forms, those that result in abnormal proteins that
are detectable with commercially available antibodies and those
that are not. Between 60% and 70% of high-grade serous carci-
nomas show p53 overexpression (expression in more than
50e75% of tumour cell nuclei) and an additional 20e30% show
absolutely no expression, which has been referred to as a p53
null phenotype.23 Both the p53 null and overexpressing
phenotypes are good indicators ofTP53 mutation. Interestingly,
a possible prognostic significance of the p53 expression pattern
has been found in high-grade serous carcinomas. Tumours that
show expression by greater than 50% of the tumour nuclei have
a lower recurrence rate than those that show complete lack of
p53 expression.23 Expression of CK7, PAX8, EMA, B72.3, Ber
EP4, oestrogen receptor, and progesterone receptor is typical.
Differential diagnosis
Most high-grade serous carcinomas have at least focal areas with
slit-like spaces, small papillae, and high-grade pleomorphic nuclei,
but glandular or microcystic areas can create confusion with
endometrioid (Figure 4) or clear cell carcinomas (Figure 5), as can
the frequent presence of clear cells within high-grade serous carci-
nomas.24 The presence of broad papillae and solid architecture
often recalls the appearance of so-called transitional cell carci-
noma of the ovary25 and undifferentiated carcinomas. In all of
these cases, the presence of at least focal characteristic high-grade
serous morphology eliminatesthe other possibilities. Because high-
grade serous carcinomas enter into the differential diagnosis of
many ovarian carcinomas, specific means for distinction will bediscussed below in the context of those other tumour types.
Low-grade serous carcinoma
Prevalence
Low-grade serous carcinomas represent less than 5% of all
ovarian carcinomas and are usually disseminated at presentation.1
Figure 1 High-grade serous carcinoma. Note papillae, micropapillae,
tumour cell detachment and budding, high nuclear-to-cytoplasmic ratios
and high nuclear grade.
Figure 2 High-grade serous carcinoma. Predominantly solid tumour with
apparent slit-like spaces and severe nuclear pleomorphism.
High-grade serous carcinoma
A. Spectrum of growth patterns, including solid, glandular,
microcystic and cribriform patterns, and those resembling
transitional cell carcinoma. Papillae and micropapillae with
gaping and slit-like architectural features are present at least
focally.B. High nuclear grade, with extreme nuclear size variability (>5).
C. More than 12 mitotic figures per 10 high power fields.
D. Typically high stage at presentation.
E. WT1, p53 and/or p16 overexpression may be sought if the
differential diagnosis includes low-grade serous carcinoma,
endometrioid carcinoma or clear cell carcinoma.
Table 1
Figure 3 High-grade serous carcinoma. Note severe nuclear pleomorphism
and atypical mitotic figures.
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Tumour characteristics, immunophenotype, and genotype
Low-grade serous carcinomas are significantly less common than
high-grade serous carcinomas and represent a completely
different entity. In contrast to high-grade serous carcinomas, they
are often seen in association with non-invasive serous neoplasms,
such as serous borderline tumour, from which they must be
distinguished. Low-grade serous carcinomas are separated from
serous borderline tumour by the presence of stromal invasion
greater than microinvasion and from high-grade serous carcinoma
by the presence of a cytologically uniform population of neoplastic
cells with a low mitotic rate (Table 2). By convention, a focus of
destructive stromal invasion must exceed limits defined for
microinvasion: 5 mm in any dimension26 or an area of 10 mm2 for
a diagnosis of invasive low-grade serous carcinoma. Upon stromal
invasion (Figure 6), low-grade serous carcinomas show small,
round papillary clusters of cells often surrounded by retraction
artefact, resembling micropapillary carcinomas that have been
described in other organs, including breast and urinary bladder
(Figure 7). Other less commonly encountered architectural
patterns include microcystic, which can mimic mucinous and
endometrioid carcinomas, and macropapillary, which can
mimic serous adenofibroma at low power. To qualify for this
diagnosis, the tumour nuclei must be uniform, small, andround to
oval, and mitotic figures must be infrequent (less than 12 mitotic
figures per 10 high power fields)17 (Figure 8). Small nucleoli are
permitted, provided the nuclear size is uniform. Once these
criteria are violated, the diagnosis of a high-grade serous carci-
noma must be considered, even when the architecture and local
environment (e.g. associated serous borderline tumour) suggest
a low-grade serous carcinoma.
Low-grade serous carcinomas typically express WT1, but
since TP53 mutations are rare among them, diffuse nuclear
overexpression or complete lack of detectable expression of p53
is also rare. Unlike high-grade serous carcinomas, the most
common mutations are those affecting the KRAS, BRAF, or ERBB2
genes, not TP53 mutations.2,27e30 Expression of CK7, PAX8,
EMA, B72.3, Ber EP4, oestrogen receptor, and progesterone
receptor is typical.
Figure 4 High-grade serous carcinoma with cribriform architecture. The
differential diagnosis includes endometrioid carcinoma, but confirmatory
endometrioid features are lacking and the tumour expressed WT1
(not shown).
Figure 5 High-grade serous carcinoma with clear cytoplasm. The differ-
ential diagnosis includes clear cell carcinoma, but there is notable nuclear
pleomorphism, clear cell carcinoma architecture is lacking, and the
tumour expressed WT1 (not shown).
Low-grade serous carcinoma
A. Papillary, micropapillary and cribriform patterns typical. Intra-
luminal mucin frequently present.
B. Frequent association with serous borderline tumour (serous
tumour of low malignant potential).
C. Distinguished from serous borderline tumour by destructivestromal invasion exceeding 5 mm in any dimension in the
ovary.
D. Distinguished from high-grade serous carcinoma by the pres-
ence of uniform nuclei and a mitotic rate that does not exceed
12 mitotic figures per 10 high power fields. Atypical mitotic
forms are not seen. Nucleoli may be present.
Table 2
Figure 6 Invasive low-grade serous carcinoma. Invasive carcinoma is
present in a background of serous borderline tumour with micropapillary
features.
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Differential diagnosis
Serous borderline tumours with micropapillary architecture (SBT-MP) feature prominently in the differential diagnosis of low-grade
serous carcinoma. In contrast to typical serous borderline tumours,
which contain a hierarchical branching pattern of progressively
smaller papillary structures from larger parent papillae, the papillae
of SBT-MP are surrounded by filiform, micropapillae lacking
substantial stromal cores, emanating directly from the larger
papillae in a non-hierarchical fashion (so-called medusa head
appearance) (Figure 6). These micropapillae can collapse and fuse,
creating a cribriform configuration surrounding each papilla.31
Some pathologists consider SBT-MP to represent non-invasive
low-grade micropapillary serous carcinoma. As mentioned previ-
ously, stromal invasion that exceeds criteria for microinvasion
distinguishes SBT-MP from invasive low-grade serous carcinoma.Low-grade serous carcinomas with a microcystic architecture
can mimic endometrioid or mucinous carcinomas, although thor-
ough examination of the tumour usually discloses areas of typical
low-grade serous carcinoma morphology.
Rarely, the differential diagnosticproblem maybe thedistinction
between high-grade and low-grade serous carcinoma. Some high-
grade serous carcinomas have been shown to mimic low-grade
serous carcinomas architecturally, even arising within serous
borderline tumours. It is only upon close examination that nuclear
atypia and mitotic indices are seen that prohibit a low-grade diag-
nosis. Many of these tumourshave grade 2 nuclearatypia, but are
best classified as high-grade serous carcinomas provided there isobvious variation in nuclear size or a mitotic rate that exceeds 12
mitotic figures per 10 high power fields.32
Endometrioid carcinoma
Prevalence
There has been a decrease in the reported incidence of ovarian
endometrioid carcinoma as many of the high grade endometrioid
carcinomas have been reclassified as high-grade serous carci-
nomas. This still remains a relatively common tumour, especially
in the West, where it is the second most common subtype of
ovarian carcinoma, accounting for approximately 10e15% of all
ovarian carcinomas. It is the most common ovarian carcinoma to
present at FIGO stage I, probably representing at least 50% of suchcases. Most endometrioid carcinomas are FIGO stage I or II at
presentation.1 Ten to 15% of patients have synchronous endo-
metrioid carcinomas of endometrium, particularly when present-
ing before 45 years of age.33e35
Tumour characteristics, immunophenotype, and genotype
Ovarian endometrioid carcinomas are most commonly found to
be unilateral, especially after subtraction of misclassified serous
carcinomas from this category. Indeed, presentation with bilat-
eral disease and/or spread to extrapelvic sites should call into
question a diagnosis of endometrioid carcinoma.
The morphology of ovarian endometrioid carcinoma is identical
to that of its analogue in the endometrium, consisting of columnarcells arrangedas complex and fused glands, often with cribriformor
papillary areas showing a substantial degree of architectural
complexity (Figure 9) (Table 3). A solid component can be present
to a variable degree, and, as in the endometrium, its proportion
serves as the primary determinant of FIGO grade (Figure 10). The
Figure 7 Invasive low-grade serous carcinoma. Micropapillary and filiform
structures are surrounded by clefts as they invade stroma.
Figure 9 Endometrioid carcinoma. This grade 1 tumour, typical of ovarian
endometrioid carcinoma, shows confluent glandular growth, evidence of
expansile invasion.
Figure 8 Low-grade serous carcinoma. Nuclei are uniform in size and
shape. Occasional cells contain small nucleoli. No mitotic figures are
seen.
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degree of nuclearatypiais typicallyproportional to the architectural
grade, so that cells with mild to moderate atypia are commonly
arranged in simple glands and tubules (Figure 11) and cells with
severe nuclear atypia typically have a solid configuration; if simple
tubules or papillae are seen lined by cells with marked atypia and
extensive budding, the diagnosis of endometrioidcarcinoma should
be questioned.
There are several features that are seen so often in association
with ovarian endometrioid carcinomas that their presence in an
otherwise morphologically equivocal case provides strong support
for a diagnosis of endometrioid carcinoma, such that they could be
considered confirmatory endometrioid features. These include
metaplastic features (squamous, morular, hobnail, or mucinous)
(Figure 12) or other alterations of cellular phenotype (eosinophilic
or secretory change), associated endometriosis, associated ovarian
endometrioid adenofibroma or endometrioid borderline tumour,
or a synchronous endometrioid neoplasm of the endometrium.
This category of ovarian carcinomas can be graded using either
the ShimizueSilverberg36,37 or the FIGO system, where typical
cases would meet the criteria for grade 1 carcinoma.
Endometrioid carcinomas express CK7, PAX8, EMA, B72.3, Ber
EP4, oestrogen receptor, and progesterone receptor as well as
vimentin in most cases and beta-catenin in a subset. Lack of WT1
expression and p53 overexpression can often help to distinguish
them from serous carcinomas. Molecular findings that are consid-
ered typical of endometrioid carcinomas include mutations in
CTNNB-1 (beta-catenin),38,39 PIK3CA40,41 and PTEN38,42 as well as
high levelsof microsatellite instability.38,43 Many tumoursthat have
been diagnosed as high-grade or poorly differentiated endometrioid
carcinomas do not have any of these molecular findings, however,
and are more likely to have TP53 mutations instead.40 In addition,
they have been reported to express WT1 and overexpress p53, and
are rarely associated with confirmatory endometrioid features.
All of these data suggestthat at least some of these tumours actually
represent high-grade serous carcinomas with cribriform glandular
architecture rather than true endometrioid carcinomas.4
Endometrioid carcinoma
A. Cribriform, glandular and papillary architecture predominates.
B. At least one confirmatory endometrioid feature (see text) is
almost always present.
C. Nuclei show mild or moderate atypia with size variations that
do not exceed 5. Small nucleoli are allowed. Mitotic rate doesnot usually exceed 10 per 10 high power fields.
D. Bilateral presentation and/or extrapelvic spread is unusual.
E. High-grade serous carcinoma is excluded, specifically, either by
careful attention to morphologic features (see Table 1) or with
p53, WT1 and p16 immunohistochemical stains.
F. Metastatic endometrial carcinoma is excluded.
G. Mucinous carcinoma and clear cell carcinoma are excluded. ER
and PR stains may be used for this purpose, as mucinous and
clear cell carcinomas are negative or only very weakly positive.
H. Metastatic colorectal carcinoma is excluded.
Table 3
Figure 10 Endometrioid carcinoma. This grade 3 tumour, associated with
endometrioid adenofibroma (upper left), has a solid growth pattern.
These tumours are unusual.
Figure 11 Endometrioid carcinoma. This gland-forming tumour shows
nuclear features that are concordant with the architectural grade. Small
nucleoli are present in the context of columnar tumour cells, but neither
pleomorphic forms nor a high mitotic index is present.
Figure 12 Endometrioid carcinoma. Carcinoma demonstrates mucinous
and squamous differentiation.
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Differential diagnosis
The differential diagnosis mainly concerns carcinomas of other
ovarian epithelial cell types, although sex-cord stromal tumours,
germ cell tumours and metastases may give the mistaken
impression of endometrioid carcinoma in some instances. Primary
and metastatic mucinous carcinomas, including colorectal
adenocarcinoma, can create a diagnostic problem when cyto-
plasmic mucin is inconspicuous, but these tumours do not haveconfirmatory endometrioid features and generally have an
immunoprofile that differs considerably from that of endometrioid
carcinoma (i.e. they are usually negative for ER and PR, and may
have a profile that suggests a lower gastrointestinal tract metas-
tasis [CK7 negative, CK20 positive], or endocervical metastasis
[strong diffuse p16 expression]). Any moderately or poorly
differentiated adenocarcinoma resembling endometrioid carci-
noma should be suspected of being a metastasis or a primary high-
grade serous carcinoma (Figure 4), particularly when the tumour
is bilateral. Do not neglect to consider the possibility of metastatic
endometrioid carcinoma of endometrium, a tumour that more
frequently involves the ovarian surface, is bilateral and less well
differentiated as compared to primary ovarian endometrioidcarcinoma. Some endometrioid carcinomas have numerous clear
cells and so may cause concern for clear cell carcinoma, a tumour
that may also be associated with endometriosis, but in these cases
the clear cells are typically confined to areas of squamous meta-
plasia,44 the nuclear atypiais not severe, and thetumour generally
retains ER and PR expression. Gland-forming and papillary
endometrioid carcinoma with cytoplasmic clearing can be distin-
guished from clear cell carcinoma by attention to both immuno-
phenotype and also to the presence of columnar cells arranged in
patterns that are not characteristic of clear cell carcinoma.
Distinction from gland-forming low- and high-grade serous
carcinomas is possible by noting the presence of confirmatory
endometrioid features and a lack of WT1 expression and p53overexpression (in the case of high-grade serous carcinomas).
Although endometrioid borderline tumours are rare, it should
be noted that the presence of stromal invasion greater than what is
permitted for microinvasion (discussed previously) separates this
entity from endometrioid carcinoma.45,46 Most grade 1 endome-
trioid carcinomas demonstrate expansile invasion without signif-
icant destructive stromal invasion (Figure 9). Expansile invasion,
characterized by confluent glandular and papillary patterns, is
analogousto those patterns that permita diagnosisof FIGO grade 1
endometrioid carcinoma of endometrium in the presence of
atypical hyperplasia. Occasional endometrioid carcinomas show
destructive stromal invasion, reminiscent of myometrial invasive
endometrial cancer.47
The potential exists for confusion with sex-cord tumours, as
the tubules and glands in endometrioid carcinomas can assume
a sertoliform appearance.48,49 The most important factor in
avoiding this diagnostic pitfall is the awareness of the existence
of the phenomenon, after which attention to morphology and
immunohistochemistry can resolve the diagnosis. First, thorough
sampling of the tumour may reveal areas of typical endometrioid
carcinoma. Second, in contrast to endometrioid carcinomas, sex-
cord tumours do not express EMA and should express only focal
CK7.49,50 Sex-cord tumours are usually inhibin and calretinin
positive. Endometrioid spindle cell carcinomas have also been
described in the ovary51 (Figure 13), and if the low-grade nature
of the spindled areas are not appreciated, these tumours could be
misdiagnosed as carcinosarcomas. The very rare endometrioid
variant of yolk sac tumour should also be considered as
a possible diagnosis in young patients, especially when confir-
matory endometrioid features are lacking.
Clear cell carcinoma
Prevalence
In North America, clear cell carcinomas comprise approximately
5e10% of all ovarian tumours, whereas they account for a larger
proportion of ovarian tumours in Japan.7,52 They are most often
low stage at presentation, and account for approximately 25% of
all FIGO stage I and II ovarian carcinomas.1,53 Although clear cell
adenofibromas and clear cell borderline tumours exist, mostclear cell tumours are carcinomas.
Tumour characteristics, immunophenotype, and genotype
Grossly, ovarian clear cell carcinomas are almost always unilat-
eral and occur as a large, cystic and solid tumour, often with
associated endometriosis and surface adhesions.
Although its namesake implies a tumour composed of clear
cells, clear cell carcinoma should not be diagnosed primarily
based on cytoplasmic characteristics, because cells with clear
cytoplasm are often present in other ovarian tumours, for
example endometrioid carcinomas and high-grade serous carci-
nomas24 (Table 4). Rarely, a clear cell carcinoma may completely
lack clear cells, being composed entirely of cells with eosino-philic cytoplasm (Figure 14). Three classical architectural
patterns are seen in clear cell carcinomas: papillary (Figure 15),
tubulocystic (Figure 16) and solid. These are typically present as
a combination of patterns, most commonly papillary and tubu-
locystic patterns.54 Unlike the papillae of serous carcinomas,
clear cell carcinoma papillae are short and round with hyalinized
stroma and are lined by only one or two cell layers without
notable epithelial tufting (compare Figures 1 and 15). The
tubulocystic pattern (Figure 16) contains infiltrating tubular or
cystically dilated glands lined by a single flattened layer of cells,
a pattern that can be deceptively benign if attention is not given
to the characteristic architecture of the tumour. The solid pattern
Figure 13 Endometrioid carcinoma with spindle cell features. Low nuclear
grade and a well differentiated endometrioid carcinoma substrate are
against a diagnosis of malignant mixed mesodermal tumour.
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is composed of a flat sheet of square to rectangular tumour cells
with sharp cytoplasmic borders, imparting a cobblestone
appearance. Papillary and/or tubulocystic patterns are almost
always present elsewhere in a tumour with solid architecture,
facilitating recognition as a clear cell carcinoma. The tumour
cells themselves have clear, eosinophilic, or flattened cytoplasm
with large, atypical nuclei and prominent nucleoli, but generally
no significant pleomorphism. The atypia is therefore relatively
uniform. Nuclear hobnailing, while present in the majority of
clear cell carcinomas, is not specific for that diagnosis54
(Figure 17) Approximately 10e
30% of clear cell carcinomas
contain other features, including psammoma bodies, hyaline
globules, basophilic secretions, open tumour rings, nuclear
pseudoinclusions, targetoid bodies, intraluminal mucin, and
a lymphoplasmacytic infiltrate.54 Clear cell carcinoma is one of
the ovarian tumours associated with ovarian endometriosis, the
others being seromucinous (endocervical-type mucinous)
borderline tumours and endometrioid carcinomas. Evidence
exists that those clear cell carcinomas which arise in association
with a clear cell adenofibromatous tumour represent a subtype of
clear cell carcinomas with clinicopathologic characteristics that
are distinct from other clear cell carcinomas.55,56
Recent work has identified a specific immunophenotype for
clear cell carcinomas, namely expression of hepatocyte nuclear
factor 1-beta (HNF-1b), lack of WT1 and ER expression, and lack of
p53 overexpression.24,54,57e59 About one-third of ovarian clear cell
carcinomas have PIK3CA mutations, a higher frequency than
observed in other carcinoma subtypes.60 Mutations have also been
reported in PTEN42 as has high levels of microsatellite insta-
bility.61,62 A recent study detected mutations in the ARID1A gene,
Figure 14 Clear cell carcinoma with eosinophilic cytoplasm (oxyphilic
variant). Tumour cells are cuboidal, have round, large nuclei and nucleoli
of rather uniform size and a low mitotic rate. This tumour can be recog-
nized as clear cell carcinoma even though it lacks clear cytoplasm.
Figure 15 Clear cell carcinoma, papillary pattern. This clear cell carcinoma
has hyalinized fibrovascular cores surrounded by a monolayer of tumour
cells with clear cytoplasm and hobnail nuclei of uniform size.
Figure 16 Clear cell carcinoma, tubulocystic pattern. Note the flattened
tumour cells at the periphery of the cysts.
Clear cell carcinoma
A. Architectural, cytoplasmic and nuclear features together should
be used for diagnosis; clear cytoplasm by itself is insufficient
for diagnosis (and it is sometimes lacking).
B. Papillary patterns, typically with round, non-hierarchically
branched papillae lined by only one or two layers of cells, areusually present at least focally. Stromal hyaline can be
prominent.
C. Tumour cells are typically cuboidal, not high columnar.
Flattened and low columnar cells may also be seen.
D. Cytoplasm may be clear or eosinophilic (oxyphilic).
E. Nuclei in papillary tumours are round, tend to be uniform in size
and may have prominent nucleoli. Occasional, scattered larger
nuclei are present.
F. Tubulocystic tumours frequently have flattened or cuboidal
cells, with small nuclei.
G. Tumours with solid architecture are composed of cuboidal cells
arranged in a sheet resembling cobblestones. Nuclei may be
round and regular or resemble koilocytes.H. Mitotic rates exceeding 8e10 mitotic figures per 10 high power
fields are exceptional.
I. Serous and endometrioid tumours are specifically excluded;
immunohistochemistry, using WT1 and ER/PR, may be
necessary.
Table 4
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which encodes the BAF250 protein, in a high percentage of endo-
metriosis-associated ovarian carcinomas, specifically clear cell
carcinomas and endometrioid carcinomas, as well as in areas ofatypical endometriosis associated with these tumours.63 The
BAF250 protein is a key component of the SWI-SNF chromatin
remodelling complex, which uses ATP to mobilize nucleosomes,
controlling the availability of individual promoters for transcrip-
tional activation or repression. The gene encoding BAF250,
ARID1A, is thereby thought to act as a tumour suppressor gene.
Differential diagnosis
Among surface epithelial tumours, the differential diagnosis mainly
concerns high-grade serous carcinoma, endometrioid carcinoma,
and occasionally serous borderline tumour. Distinction from high-
grade serous carcinoma can be made by attention to the uniform
nuclear atypia of clear cell carcinoma and a low mitotic rate. Incontrast, high-grade serous carcinomas are pleomorphic and have
mitotic indices that significantly exceed 12 mitotic figures per 10
high power fields (compare Figure 14 with Figure 3). Further sup-
porting a clear cell carcinoma diagnosis would be papillae con-
taining hyalinized cores lined by only one or two cell layers, lack of
WT1and ER expression, lowstage at presentation, andthe presence
of associated endometriosis. Because many high-grade serous
carcinomas can contain clear cells that do not represent clear cell
carcinoma (Figure 5), a diagnosis of clearcellcarcinoma should not
be made if areas of recognizable high-grade serous carcinoma are
present elsewhere in a given tumour. While endometrioid carci-
nomas can contain cells with clear cytoplasm, particularly in areas
of squamous metaplasia or secretory change, the clear cell areas donot generally have the degree of nuclear atypia nor the character-
istic architectural features of clear cell carcinoma, andsuch tumours
generally contain other areas of easily recognizable endometrioid
carcinoma.44 Furthermore, the cells of clear cell carcinoma are
cuboidal, rather than the predominantly columnar shape of the
clear cells in an endometrioid carcinoma. Serous borderline tumour
can enter the differential diagnosis when the tumour has a papillary
architecture but nuclear atypia is not diffuse. In these cases, the
finding of characteristic architectural patterns of clear cell carci-
noma, associated endometriosis, and presentation at low stage can
help avoid an erroneous diagnosis of serous borderline tumour.
Yolk sac tumour, while more morphologically diverse than clear
cell carcinomaand typicallyoccurring in a much younger age range,
can have patterns that mimic clear cell carcinoma. The key to
diagnosing yolk sac tumour in thissetting is the recognition of more
primitive-appearing nuclei than are seen in clear cell carcinoma, as
well as a higher mitotic rate and possibly the presence of other germ
cell components, often in a patient with elevated serum AFP levels.
When uncertaintystill exists, a confirmatory immunohistochemical
panelcan be used to show expression of SALL4 and AFP and lack ofCK7 and EMA expression in yolk sac tumour and the reverse
immunoprofile (with the rare exception of AFP expression) in clear
cell carcinoma.64
Primary intestinal type mucinous carcinoma
Prevalence
Mucinous carcinomas involving the ovary are much more likely to
represent metastases than primary tumours; indeed, primary
ovarian mucinous carcinomas are rare, representing approximately
3% of all ovarian carcinomas.1,52 There are three broad categories
of primary ovarian mucinous tumours: the typical intestinal
mucinous tumours, the less common endocervical or Mulle-
rian or seromucinous tumours and the even rarer mucinousneoplasms that arise in the setting of another primary ovarian
neoplasm. The most common variety, the intestinal mucinous
tumours, resembles upper gastrointestinal tract tumours and
should not be confused with the substantially more common
metastatic mucinous carcinoma that, statistically speaking, tends to
originate in either the upper or lower gastrointestinal tract.
Tumour characteristics, immunophenotype, and genotype
Because a critical decision point will be the discrimination of
primary ovarian mucinous carcinomas from the more common
metastatic adenocarcinomas, certain characteristics of the clinical
and gross presentation should be taken into account, and have
been expressed as a triage algorithm65,66
(Table 5). With someexceptions, the diagnosis of a primary mucinous ovarian
neoplasm should be made with caution unless the tumour is
unilateral, larger than 10e12cm, and isoccurring in a patient with
no history of an extraovarianneoplasmand no alternative primary
site detectable upon intraoperative examination. Features that
favour metastasis to the ovary are bilateral tumours, a unilateral
tumour less than 10 cm, and/or a known alternative primary site.
Interestingly, mucinous carcinomas from extraovarian sites do not
always retain a frankly malignant appearance upon metastasis to
the ovary, and may, in fact, mimic exactly the appearance of
a mucinous cystadenoma or mucinous borderline tumour.67,68
Thus, proper diagnosis depends on addressing the possibility of
metastatic disease by thorough clinical and gross evaluation anda low threshold for submitting additional tissue for microscopic
examination and employing immunohistochemistry, especially
when any of the tumour characteristics are atypical for a primary
ovarian mucinous neoplasm.
As the name implies, the cells of intestinal type mucinous
carcinomas contain intracellular mucin, often with goblet cells
present at least focally. Importantly, the diagnosis of this subtype
is made based on the character of the epithelial cells constituting
the tumour, not on the presence of extracellular mucin alone.
Primary mucinous carcinomas, belonging to the type I pathway,
commonly arise in association with benign tumours of the same
cell type (i.e. mucinous cystadenomas and mucinous borderline
Figure 17 Clear cell carcinoma, tubular pattern. Note the abundant stromal
hyaline and hobnail nuclei.
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tumours). These three mucinous tumour types lie on
a continuum where tumour virulence increases with architec-
tural complexity from borderline tumour to carcinoma. Thus, the
distinction between mucinous carcinomas and mucinous
borderline tumours is primarily architectural. Specifically,
mucinous carcinomas show invasion, which has been described
in two main patterns.69e71
The most common form of invasion isthe expansile pattern (Figure 18), so called because it consists of
complex glands or papillary structures, often including cribriform
glands or glands with maze-like lumens arranged in a back-to-
back configuration, to the exclusion of stroma. This pattern can
usually be recognized easily if one applies architectural criteria
analogous to those used for the diagnosis of well differentiated
endometrioid carcinoma of the endometrium. The less common
pattern of invasion is that of destructive stromal invasion, which
resembles myoinvasive endometrioid carcinoma of the endo-
metrium (small, irregularly shaped glands and nests surrounded
by reactive stroma). When extensive destructive stromal inva-
sion is present, the possibility of metastasis to the ovary should
be entertained. For the diagnosis of carcinoma, areas of invasionshould be at least 5 mm in greatest linear dimension in any one
focus or greater than 10 mm2 in greatest area on any one slide.
On very rare occasions, atypical mucinous neoplasms may
arise in the setting of another primary ovarian neoplasm, such as
SertolieLeydig cell tumour, teratoma, small cell hypercalcemic
carcinoma, Brenner tumour and carcinoid. Only few teratoma-
associated mucinous carcinomas have been studied, but it should
be noted that many of these demonstrate features that are more
in keeping with lower intestinal-type tumours (i.e. colorectal-
type adenocarcinomas or appendiceal mucinous neoplasms)
than with the more typical ovarian mucinous neoplasms.
The immunophenotype of primary mucinous carcinomas
unassociated with teratoma is generally positive for CK7 (diffuse,strong) with variable CK20 expression, ranging from negative to
patchy, but generally not diffuse, like upper gastrointestinal tract
tumours.72e75 Oestrogen receptor, progesterone receptor,
CA-125, and p16 are generally not expressed72,76 SMAD4 (DPC4)
expression is retained73. From a molecular standpoint, primary
mucinous carcinomas are commonly found to have KRAS
mutations77,78 Up to 20% show overexpression and amplification
ofHer2, a possible therapeutic target.79 The rare intestinal-type
tumours that arise in teratomas would be expected to demon-
strate a lower intestinal immunophenotype (i.e. CK20 positive
and CK7 negative).80,81
Differential diagnosisWhen mucinous differentiation is obvious, the differential diag-
nosis is primarily focused on the exclusion of metastatic mucinous
carcinomas to the ovary. This cannot always be done solely based
on morphology, as metastatic carcinomas often mimic primary
mucinous carcinomas, and can even histologically simulate
mucinous cystadenomas and mucinous borderline tumours.67,68 As
mentioned earlier, attention to the presence of a previous or
concurrent extraovarian neoplasm as well as the size and laterality
of ovarian involvement can provide at least an initial impression of
the site of origin of a given mucinous ovarian tumour.
Certain histologic features point strongly to particular sites of
origin. For example, the finding of pseudomyxoma ovarii (dilated
mucinous glands, ruptured, with extravasated mucin dissectingthrough the ovarian stroma) is often seen in the case of a low-
grade adenomatous mucinous cystic neoplasm of the appendix
that has spread to the ovary or in the case of an enteric-type
mucinous cystic neoplasm arising in association with an ovarian
teratoma. Interestingly, both of these tumours have been associ-
ated with the clinical condition of pseudomyxoma peritonei.80,82
Immunohistochemistry can only help to exclude a few specific
metastatic entities, insofar as expression of CK20 with lack of
CK7 expression suggests the possibility of a metastasis of lower
gastrointestinal origin (with a few exceptions, including some
rectal carcinomas that show considerable CK7 expression, and
enteric-type somatic mucinous neoplasms arising within ovarian
Intestinal mucinous carcinoma
A. Primary ovarian adenocarcinoma with intracytoplasmic mucin
easily demonstrable.
B. Bilateral presentation, tumour size less than 12 cm, and/or
extrapelvic spread are very unusual and, if present, should
raise consideration for another diagnosis.C. Extensive mucin dissection, hilar invasion, extensive lympho-
vascular invasion, nodular growth pattern and signet ring cells
suggest metastatic mucinous carcinoma.
D. Metastatic mucinous carcinoma is excluded.
E. Adenocarcinoma arising in teratoma should be noted
specifically.
F. Endometrioid adenocarcinoma is excluded.
G. Mucinous borderline tumour (tumour of low malignant poten-
tial) is frequently present (but patterns resembling this may
also be seen in metastatic adenocarcinomas).
H. Distinguished from intestinal mucinous borderline tumour by
the presence of complex papillary or glandular architecture,
resembling well differentiated endometrioid adenocarcinomain the endometrium (also referred to as expansile invasion) or
destructive stromal invasion, resembling myometrial invasion,
measuring more than 5 mm in any dimension.
Table 5
Figure 18 Primary ovarian mucinous carcinoma. This well differentiated
tumour shows confluent glandular growth, evidence of expansile
invasion.
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teratomas, which have a lower gastrointestinal immunopheno-
type), lack of diffuse strong p16 expression rules out a metastasis
from a high risk HPV-associated endocervical adenocarcinoma,
and loss of SMAD4 expression suggests metastasis from a pan-
creaticobiliary carcinoma (although if SMAD4 expression is
retained, one has not excluded a pancreatic metastasis, because
SMAD4 expression is only lost in 50% of metastatic pancreatic
carcinomas involving the ovary).73
Paradoxically, metastaticpancreatic ductal carcinomas are more likely to express CA-125
than primary ovarian intestinal mucinous adenocarcinoma.
Because immunohistochemistry is of limited use in many situa-
tions, it is critical to obtain accurate clinical and intraoperative
findings, and to correlate these data with the gross and micro-
scopic findings.
Less often, the differential diagnosis also includes low-grade
endometrioid carcinoma, especially in cases in which the intracel-
lular mucin is largely inapparent, resulting in cells that contain only
eosinophilic cytoplasm. This problem is further complicated by the
fact that areas of mucinous metaplasia are not uncommon in
endometrioid carcinomas. For diagnostic purposes, at least 50% of
the cells should contain demonstrable mucin in a primary ovarianmucinous carcinoma, and this diagnosis is excluded if any
confirmatoryendometrioid features are present (seediscussionof
endometrioid carcinomas for a description of confirmatory endo-
metrioid features). Immunohistochemistry can help in this situa-
tion, because ER and/or PR expression favour a diagnosis of
endometrioid carcinoma.
Transitional cell carcinoma
Prevalence
Transitional cell carcinomas, which should, as implied by the
name, resemble urothelial carcinomas, are notoriously difficult to
diagnose reproducibly. The likely prevalence becomes vanish-
ingly small when the diagnosis is appropriately limited to those
tumours that are morphologically and immunohistochemically
separable from high-grade serous carcinomas.
Tumour characteristics, immunophenotype, and genotype
While the ideal transitional cell carcinoma looks like urothelial
carcinoma, containing well organized cells with uniform elon-
gated nuclei with grooves, arranged along broad papillae,
tumours with this morphology are rare, occurring chiefly in
association with a Brenner tumour, in which case the term
malignant Brenner tumour is used. Many tumours that have been
diagnosed as transitional cell carcinoma contain features that
suggest high-grade serous carcinoma, including slit-like spaces,
microcystic areas, and small papillae, while expressing WT1 andoften overexpressing p53.25,83 Given the rarity of this tumour and
the difficulty associated with accurately diagnosing it, data
describing any characteristic molecular abnormalities are not
widely available.
Differential diagnosis
High-grade serous carcinoma is the chief consideration in the
differential diagnosis of transitional cell carcinoma. Because many
tumours diagnosed as transitional cell carcinomas share morpho-
logic and immunohistochemical characteristics with high-grade
serous carcinomas (as described above), a logical approach would
seem to be restricting the diagnosis of transitional cell carcinoma to
those tumours that, after thoroughsampling, contain no areas, even
focally, that have features characteristic of high-grade serous
carcinoma. This rigorous approach may be clinically useful, as
true transitional cell carcinomas seem to have a better prognosis
and response to chemotherapy than high-grade serous
carcinomas.84e86 Endometrioid carcinomas may enter the
differential diagnosis. When typical endometrioid tubules, endo-
metriosis, squamous differentiation or an endometrioid adenofi-bromatous tumour is present, Brenner tumour is absent, and the
tumour expresses ER without WT1, the correct diagnosis can be
achieved.
Mixed epithelial ovarian tumour
True mixed epithelial tumours of the ovary are rare. Given the
usual heterogeneity of surface epithelial tumours and their ability
to mimic one another, a diagnosis of a mixed epithelial tumour
should only be considered when two separate components are
present in a given tumour, each having unequivocal morphologic
features and a supportive immunoprofile of a different subtype of
carcinoma, and each present as a substantial proportion of the
tumour (at least 10%). Mixed epithelial carcinomas, containingat least two separate areas that are fully diagnostic of different
carcinoma subtypes should be distinguished from hybrid carci-
nomas, that is, tumours that have features intermediate between
two established subtypes of ovarian carcinoma, but fully diag-
nostic of neither. When the pathologist is aware of common
mimics among ovarian surface epithelial tumours, for example,
the existence of clear cells in high-grade serous or endometrioid
carcinomas, the true incidence of mixed ovarian carcinomas
becomes quite low.
Undifferentiated carcinoma
Rare ovarian carcinomas lack any differentiating features. Inthis instance, after the exclusion of a solid or anaplastic high-
grade serous carcinoma and non-epithelial neoplasms, a diag-
nosis of undifferentiated ovarian carcinoma could be consid-
ered. This tumour is best characterized by the definition used
for its original characterization in the endometrium,87 namely,
a malignant epithelial neoplasm arising in the endometrium
or ovary characterized by a total absence of nests, papillae,
glands or trabeculae, lack of squamous or mucinous meta-
plasia, lack of a spindled growth pattern with a patternless
solid, sheet-like growth of tumour cells, with absent or
minimal neuroendocrine differentiation. While this diagnosis
is often, as mentioned above, reached after exclusion of other
entities, many examples have a somewhat characteristicappearance, being composed of uniform small cells resembling
lymphocytes, sometimes admixed with larger cells containing
abundant cytoplasm, and commonly showing an abrupt tran-
sition from an associated better differentiated carcinoma,
widespread necrosis with perivascular sparing, and foci of
abrupt keratinization. This characteristic appearance may
reflect a unique tumour biology, as a high proportion of cases
tested have shown loss of at least one DNA mismatch repair
protein.88 Recognition of this entity is important, because the
presence of even a focal component of undifferentiated carci-
noma within an otherwise well differentiated carcinoma
heralds a very poor prognosis.87,88 A
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