Typing of Ovarian Tumors

8/3/2019 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.

MINI-SYMPOSIUM: OVARIAN PATHOLOGY

DIAGNOSTIC HISTOPATHOLOGY 17:4 165 2011 Elsevier Ltd. All rights reserved.
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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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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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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


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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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.


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.


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.


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.




10/13

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.


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.


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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Typing of Ovarian Tumors

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