MINI-SYMPOSIUM: OVARIAN PATHOLOGY

Typing of ovarian carcinomas: an update

Christopher G Przybycin Robert A Soslow

following guidelines outlined in this review, leads to reproducible and clinically meaningful subclassication of ovarian carcinomas.12 These distinct morphologic features also correspond to unique genetic proles, 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. Specically, it has been shown that high-grade serous carcinomas are aggressive neoplasms with unstable genetics, a very high prevalence of TP53 mutations, and no wellcharacterized ovarian precursor lesion. In contrast, low-grade serous carcinomas follow a more smouldering course, have a stable genetic prole, usually have mutations in KRAS, BRAF, and ERBB2, rather than TP53, are chemoresistant by comparison, and usually arise in association with established precursors (serous cystadenomas 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 carcinogenesis that recognizes type I and type II pathways.14 Lowgrade 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 conned to the ovary at the time of presentation, and generally follow an indolent course. They characteristically lack TP53 mutations, and instead each histologic subtype has a characteristic genetic prole. High-grade serous carcinomas, along with transitional and undifferentiated carcinomas and carcinosarcomas (malignant mixed mesodermal tumours), are type II tumours, the hallmarks of which are advanced stage at presentation, aggressive course, unstable genetics, and an extremely 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 highgrade serous carcinoma arises from a low-grade serous carcinoma. High-grade serous carcinomas are morphologically heterogeneous and, while they usually contain at least focal papillary or micropapillary areas, they can also have solid, glandular, microcystic, or cribriform patterns, as well as areas that resemble transitional cell carcinomas (Figures 1 and 2) (Table 1). Slit-like spaces are common, and can aid in the diagnosis. The cells characteristically have large, pleomorphic nuclei, often hyperchromatic or

Abstract
Classication of ovarian carcinomas into different subtypes is no longer only an exercise in pattern recognition that lacks clinical and biological signicance. Biologically validated diagnostic criteria now separate ovarian carcinomas into specic 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 rened 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 been histologic assessment of cell type. This approach is reected in the current World Health Organizations ovarian carcinoma classication, which includes serous, mucinous, endometrioid, clear cell, transitional cell, and squamous carcinomas. As the immunohistochemical 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 specic predilection for mode of presentation, with endometrioid and mucinous carcinomas usually presenting at FIGO stage I, clear cell carcinoma at stage I or II and serous carcinoma at stage III or IV.1 These observations have elicited clinically justiable interest in the accurate subclassication of ovarian tumours. As an example, high-grade and low-grade serous carcinomas are now known to be the products of two completely disparate tumorigenic pathways with only rare intersection2,3 with distinct differences in prognosis and chemotherapeutic sensitivity. Nonspecic diagnoses are insufcient, as tumour cell type has been shown to be prognostically signicant 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,

Christopher G Przybycin MD is a Consultant Pathologist at Clin-Path Associates, Tempe, AZ, USA. Conict of interest: none. Robert A Soslow MD is in the Department of Pathology at the Memorial Sloan-Kettering Cancer Center, NY, USA. Conict of interest: none.

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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 gures per 10 high power elds. 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. Figure 1 High-grade serous carcinoma. Note papillae, micropapillae, tumour cell detachment and budding, high nuclear-to-cytoplasmic ratios and high nuclear grade. Table 1

showing prominent nucleoli (Figure 3). Mitotic gures exceed 12 mitotic gures per 10 high power elds, by denition, and most cases show signicantly more than this.17,18 Atypical mitotic gures can be seen. Tumour inltrating 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 of TP53 mutations in highgrade 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 carcinomas 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 of TP53 mutation. Interestingly, a possible prognostic signicance 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 carcinomas.24 The presence of broad papillae and solid architecture often recalls the appearance of so-called transitional cell carcinoma of the ovary25 and undifferentiated carcinomas. In all of these cases, the presence of at least focal characteristic high-grade serous morphology eliminates the other possibilities. Because highgrade serous carcinomas enter into the differential diagnosis of many ovarian carcinomas, specic means for distinction will be discussed 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 2 High-grade serous carcinoma. Predominantly solid tumour with apparent slit-like spaces and severe nuclear pleomorphism.

Figure 3 High-grade serous carcinoma. Note severe nuclear pleomorphism and atypical mitotic gures.

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Low-grade serous carcinoma

A. Papillary, micropapillary and cribriform patterns typical. Intraluminal mucin frequently present. B. Frequent association with serous borderline tumour (serous tumour of low malignant potential). C. Distinguished from serous borderline tumour by destructive stromal invasion exceeding 5 mm in any dimension in the ovary. D. Distinguished from high-grade serous carcinoma by the presence of uniform nuclei and a mitotic rate that does not exceed 12 mitotic gures per 10 high power elds. Atypical mitotic forms are not seen. Nucleoli may be present. Figure 4 High-grade serous carcinoma with cribriform architecture. The differential diagnosis includes endometrioid carcinoma, but conrmatory endometrioid features are lacking and the tumour expressed WT1 (not shown). Table 2

Tumour characteristics, immunophenotype, and genotype Low-grade serous carcinomas are signicantly 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 dened 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 adenobroma at low power. To qualify for this diagnosis, the tumour nuclei must be uniform, small, and round to oval, and mitotic gures must be infrequent (less than 12 mitotic gures per 10 high power elds)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 carcinoma 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 5 High-grade serous carcinoma with clear cytoplasm. The differential diagnosis includes clear cell carcinoma, but there is notable nuclear pleomorphism, clear cell carcinoma architecture is lacking, and the tumour expressed WT1 (not shown).

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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Rarely, the differential diagnostic problem may be the distinction between high-grade and low-grade serous carcinoma. Some highgrade 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 diagnosis. Many of these tumours have grade 2 nuclear atypia, but are best classied as high-grade serous carcinomas provided there is obvious variation in nuclear size or a mitotic rate that exceeds 12 mitotic gures per 10 high power elds.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 reclassied as high-grade serous carcinomas. 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 such cases. Most endometrioid carcinomas are FIGO stage I or II at presentation.1 Ten to 15% of patients have synchronous endometrioid carcinomas of endometrium, particularly when presenting 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 misclassied serous carcinomas from this category. Indeed, presentation with bilateral 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 columnar cells arranged as complex and fused glands, often with cribriform or 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 liform structures are surrounded by clefts as they invade stroma.

Differential diagnosis Serous borderline tumours with micropapillary architecture (SBTMP) 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 liform, 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 conguration surrounding each papilla.31 Some pathologists consider SBT-MP to represent non-invasive low-grade micropapillary serous carcinoma. As mentioned previously, 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 thorough examination of the tumour usually discloses areas of typical low-grade serous carcinoma morphology.

Figure 8 Low-grade serous carcinoma. Nuclei are uniform in size and shape. Occasional cells contain small nucleoli. No mitotic gures are seen.

Figure 9 Endometrioid carcinoma. This grade 1 tumour, typical of ovarian endometrioid carcinoma, shows conuent glandular growth, evidence of expansile invasion.

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Endometrioid carcinoma
A. Cribriform, glandular and papillary architecture predominates. B. At least one conrmatory 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 does not usually exceed 10 per 10 high power elds. D. Bilateral presentation and/or extrapelvic spread is unusual. E. High-grade serous carcinoma is excluded, specically, 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 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.

degree of nuclear atypia is typically proportional 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 conguration; if simple tubules or papillae are seen lined by cells with marked atypia and extensive budding, the diagnosis of endometrioid carcinoma 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 conrmatory 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 adenobroma 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 ndings that are considered typical of endometrioid carcinomas include mutations in CTNNB-1 (beta-catenin),38,39 PIK3CA40,41 and PTEN38,42 as well as high levels of microsatellite instability.38,43 Many tumours that have been diagnosed as high-grade or poorly differentiated endometrioid carcinomas do not have any of these molecular ndings, 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 conrmatory endometrioid features. All of these data suggest that at least some of these tumours actually represent high-grade serous carcinomas with cribriform glandular architecture rather than true endometrioid carcinomas.4

Figure 10 Endometrioid carcinoma. This grade 3 tumour, associated with endometrioid adenobroma (upper left), has a solid growth pattern. These tumours are unusual.

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 cytoplasmic mucin is inconspicuous, but these tumours do not have conrmatory endometrioid features and generally have an immunoprole that differs considerably from that of endometrioid carcinoma (i.e. they are usually negative for ER and PR, and may have a prole that suggests a lower gastrointestinal tract metastasis [CK7 negative, CK20 positive], or endocervical metastasis [strong diffuse p16 expression]). Any moderately or poorly differentiated adenocarcinoma resembling endometrioid carcinoma should be suspected of being a metastasis or a primary highgrade 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 endometrioid carcinoma. 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 conned to areas of squamous metaplasia,44 the nuclear atypia is not severe, and the tumour generally retains ER and PR expression. Gland-forming and papillary endometrioid carcinoma with cytoplasmic clearing can be distinguished from clear cell carcinoma by attention to both immunophenotype 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 conrmatory endometrioid features and a lack of WT1 expression and p53 overexpression (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 endometrioid carcinomas demonstrate expansile invasion without significant destructive stromal invasion (Figure 9). Expansile invasion, characterized by conuent glandular and papillary patterns, is analogous to those patterns that permit a diagnosis of 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, sexcord 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

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.

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 conrmatory 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 adenobromas and clear cell borderline tumours exist, most clear cell tumours are carcinomas. Tumour characteristics, immunophenotype, and genotype Grossly, ovarian clear cell carcinomas are almost always unilateral 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 carcinomas24 (Table 4). Rarely, a clear cell carcinoma may completely lack clear cells, being composed entirely of cells with eosinophilic 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 tubulocystic 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 inltrating tubular or cystically dilated glands lined by a single attened 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

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Clear cell carcinoma

A. Architectural, cytoplasmic and nuclear features together should be used for diagnosis; clear cytoplasm by itself is insufcient 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, are usually 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 attened 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 gures per 10 high power elds are exceptional. I. Serous and endometrioid tumours are specically excluded; immunohistochemistry, using WT1 and ER/PR, may be necessary. Table 4

Figure 15 Clear cell carcinoma, papillary pattern. This clear cell carcinoma has hyalinized brovascular cores surrounded by a monolayer of tumour cells with clear cytoplasm and hobnail nuclei of uniform size.

is composed of a at 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 attened cytoplasm with large, atypical nuclei and prominent nucleoli, but generally no signicant pleomorphism. The atypia is therefore relatively uniform. Nuclear hobnailing, while present in the majority of

clear cell carcinomas, is not specic for that diagnosis54 (Figure 17) Approximately 10e30% 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 inltrate.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 adenobromatous tumour represent a subtype of clear cell carcinomas with clinicopathologic characteristics that are distinct from other clear cell carcinomas.55,56 Recent work has identied a specic 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 instability.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 recognized as clear cell carcinoma even though it lacks clear cytoplasm.

Figure 16 Clear cell carcinoma, tubulocystic pattern. Note the attened tumour cells at the periphery of the cysts.

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cell carcinoma and typically occurring in a much younger age range, can have patterns that mimic clear cell carcinoma. The key to diagnosing yolk sac tumour in this setting 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 uncertainty still exists, a conrmatory immunohistochemical panel can be used to show expression of SALL4 and AFP and lack of CK7 and EMA expression in yolk sac tumour and the reverse immunoprole (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 Mullerian or seromucinous tumours and the even rarer mucinous neoplasms 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 some exceptions, the diagnosis of a primary mucinous ovarian neoplasm should be made with caution unless the tumour is unilateral, larger than 10e12 cm, and is occurring in a patient with no history of an extraovarian neoplasm and 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 and a 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.

which encodes the BAF250 protein, in a high percentage of endometriosis-associated ovarian carcinomas, specically clear cell carcinomas and endometrioid carcinomas, as well as in areas of atypical 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 transcriptional 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 highgrade serous carcinoma can be made by attention to the uniform nuclear atypia of clear cell carcinoma and a low mitotic rate. In contrast, high-grade serous carcinomas are pleomorphic and have mitotic indices that signicantly exceed 12 mitotic gures per 10 high power elds (compare Figure 14 with Figure 3). Further supporting a clear cell carcinoma diagnosis would be papillae containing hyalinized cores lined by only one or two cell layers, lack of WT1 and ER expression, low stage at presentation, and the 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 clear cell carcinoma should not be made if areas of recognizable high-grade serous carcinoma are present elsewhere in a given tumour. While endometrioid carcinomas can contain cells with clear cytoplasm, particularly in areas of squamous metaplasia or secretory change, the clear cell areas do not generally have the degree of nuclear atypia nor the characteristic architectural features of clear cell carcinoma, and such 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 nding of characteristic architectural patterns of clear cell carcinoma, 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

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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 lymphovascular 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 specically. F. Endometrioid adenocarcinoma is excluded. G. Mucinous borderline tumour (tumour of low malignant potential) 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 adenocarcinoma in 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

tumours). These three mucinous tumour types lie on a continuum where tumour virulence increases with architectural complexity from borderline tumour to carcinoma. Thus, the distinction between mucinous carcinomas and mucinous borderline tumours is primarily architectural. Specically, mucinous carcinomas show invasion, which has been described in two main patterns.69e71 The most common form of invasion is the 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-toback conguration, 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 endometrium (small, irregularly shaped glands and nests surrounded by reactive stroma). When extensive destructive stromal invasion is present, the possibility of metastasis to the ovary should be entertained. For the diagnosis of carcinoma, areas of invasion should 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 teratomaassociated 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. colorectaltype 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 amplication of Her2, a possible therapeutic target.79 The rare intestinal-type tumours that arise in teratomas would be expected to demonstrate a lower intestinal immunophenotype (i.e. CK20 positive and CK7 negative).80,81 Differential diagnosis When mucinous differentiation is obvious, the differential diagnosis 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 nding of pseudomyxoma ovarii (dilated mucinous glands, ruptured, with extravasated mucin dissecting through the ovarian stroma) is often seen in the case of a lowgrade 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 associated with the clinical condition of pseudomyxoma peritonei.80,82 Immunohistochemistry can only help to exclude a few specic 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

Figure 18 Primary ovarian mucinous carcinoma. This well differentiated tumour shows conuent glandular growth, evidence of expansile invasion.

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teratomas, which have a lower gastrointestinal immunophenotype), 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 pancreaticobiliary 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, metastatic pancreatic ductal carcinomas are more likely to express CA-125 than primary ovarian intestinal mucinous adenocarcinoma. Because immunohistochemistry is of limited use in many situations, it is critical to obtain accurate clinical and intraoperative ndings, and to correlate these data with the gross and microscopic ndings. Less often, the differential diagnosis also includes low-grade endometrioid carcinoma, especially in cases in which the intracellular 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 ovarian mucinous carcinoma, and this diagnosis is excluded if any conrmatory endometrioid features are present (see discussion of endometrioid carcinomas for a description of conrmatory endometrioid features). Immunohistochemistry can help in this situation, because ER and/or PR expression favour a diagnosis of endometrioid carcinoma.

those tumours that, after thorough sampling, 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, endometriosis, squamous differentiation or an endometrioid adenobromatous 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 immunoprole of a different subtype of carcinoma, and each present as a substantial proportion of the tumour (at least 10%). Mixed epithelial carcinomas, containing at least two separate areas that are fully diagnostic of different carcinoma subtypes should be distinguished from hybrid carcinomas, that is, tumours that have features intermediate between two established subtypes of ovarian carcinoma, but fully diagnostic 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.

Transitional cell carcinoma

Prevalence Transitional cell carcinomas, which should, as implied by the name, resemble urothelial carcinomas, are notoriously difcult to diagnose reproducibly. The likely prevalence becomes vanishingly 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 elongated nuclei with grooves, arranged along broad papillae, tumours with this morphology are rare, occurring chiey 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 and often overexpressing p53.25,83 Given the rarity of this tumour and the difculty 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 morphologic 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

Undifferentiated carcinoma
Rare ovarian carcinomas lack any differentiating features. In this instance, after the exclusion of a solid or anaplastic highgrade serous carcinoma and non-epithelial neoplasms, a diagnosis of undifferentiated ovarian carcinoma could be considered. This tumour is best characterized by the denition 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 metaplasia, 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 characteristic appearance, being composed of uniform small cells resembling lymphocytes, sometimes admixed with larger cells containing abundant cytoplasm, and commonly showing an abrupt transition from an associated better differentiated carcinoma, widespread necrosis with perivascular sparing, and foci of abrupt keratinization. This characteristic appearance may reect 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 carcinoma within an otherwise well differentiated carcinoma heralds a very poor prognosis.87,88 A
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