Differential diagnosis and clinical relevance of ovarian carcinoma subtypes

Abstract

The five main subtypes of ovarian surface epithelial carcinoma (high-grade serous, low-grade serous, endometrioid, clear cell and mucinous) are different diseases, with differences in genetic and environmental risk factors, precursor lesions, molecular events during oncogenesis, patterns of spread and response to treatment. With recent advances in surgical pathology, it is possible to reproducibly diagnose these subtypes in routine surgical pathology practice. This review examines these subtypes of ovarian carcinoma, focusing on differential diagnosis, molecular features and current treatment strategies. The increasing understanding of the molecular abnormalities associated with each subtype is leading to exploration and introduction of more subtype-specific treatment of ovarian carcinoma.

Keywords::

• clear cell carcinoma
• endometrioid carcinoma
• mucinous carcinoma
• ovarian surface epithelial carcinoma
• serous carcinoma

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Release date: 24 December 2012; Expiration date: 24 December 2013

Learning objectives

Upon completion of this activity, participants will be able to:

• • Analyze the epidemiology and prognosis of ovarian cancer

• • Assess characteristics of high-grade serous carcinomas

• • Assess characteristics of low-grade serous carcinomas

• • Evaluate other subtypes of ovarian carcinoma

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK.

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD

Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Chris MJ Conklin, MD

Department of Pathology and Laboratory Medicine, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada.

Disclosure: Chris MJ Conklin, MD, has disclosed no relevant financial relationships.

C Blake Gilks, MD, FRCPC

Department of Pathology and Laboratory Medicine, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada.

Disclosure: C Blake Gilks, MD, FRCPC, has disclosed no relevant financial relationships.

Figure 1. Representative photomicrographs of the five main subtypes of ovarian carcinomas.

(A) High-grade serous carcinoma, (B) mucinous carcinoma, (C) low-grade serous carcinoma, (D) endometrioid carcinoma and (E) clear cell carcinoma.

Figure 2. Incidence of ovarian carcinomas by subtype.

Approximately 96% of ovarian carcinomas can be diagnosed as one of these five subtypes (HGSC [71% of cases], MC [3.2%], EC [8.3%], CCC [9.5%], LGSC [4.1%]), which have distinct molecular abnormalities and behaviors. These frequencies are based on data from British Columbia, Canada.

CCC: Clear cell carcinoma; EC: Endometrioid carcinoma; HGSC: High-grade serous carcinoma; LGSC: Low-grade serous carcinoma; MC: Mucinous carcinoma.

Data taken from [36].

Ovarian cancer is the seventh most commonly diagnosed female cancer worldwide, accounting for almost 4% of all female cancers [1,2]. Furthermore, the proportion of ovarian cancer is increasing due to effective Papanicolaou smear screening programs, leading to reduced incidence of cervical cancer [3]. Ovarian surface epithelial carcinomas are the most common malignant ovarian tumors, accounting for 90% of cases, and are the most lethal gynecological malignancies [4,5].

The majority of ovarian carcinomas are detected at advanced stage. Since the introduction of platinum/taxane-based therapy, the only progress in therapy has been the introduction of intraperitoneal chemotherapy and bevacizumab. Although the former is associated with prolonged survival, it is accompanied by serious adverse side effects, such that treatment cannot be completed as frequently as planned [6,7]. The latter treatment regimen is associated with a modest increase in progression-free survival, but not with overall survival [8,9]. Thus, there are unresolved issues around both of these new treatments and neither has entered widespread, routine use in ovarian cancer management. Currently, all histological subtypes of ovarian carcinoma are treated in a similar manner, with surgery and chemotherapy based on stage at diagnosis. Whereas patient prognosis has improved for many other solid cancers, the 5-year survival of women with ovarian cancer in developed countries has remained stable at 30–40% [1].

Recent advances have forced the medical community to change the way ovarian carcinoma is viewed. Historically, ovarian surface epithelial tumors were thought to arise from the ovarian surface mesothelial cells, and that subsequent metaplastic change led to the development of the four main ovarian carcinoma cell types (serous, endometrioid, mucinous and clear cell) [10]. However, it is now understood that different histological subtypes of ovarian carcinomas arise from distinct precursor lesions, which are not necessarily ovarian in origin. The majority of high-grade serous carcinomas (HGSCs) are now believed to arise from distal fallopian tube epithelium as serous tubal intraepithelial carcinoma [11–14]. Ovarian endometrioid carcinomas (ECs) and clear cell carcinomas (CCCs) are associated with endometriosis, the presumed precursor lesion, in 23–42% of cases [15,16]. A precursor lesion for primary ovarian mucinous carcinoma (MC) has not yet been identified.

Molecular genetic analyses have shown that different morphological subtypes of ovarian carcinoma have distinct mutation profiles. For example, low-grade serous carcinomas (LGSCs) and HGSCs were once thought to be part of a continuum of serous neoplasia; however, the majority of LGSCs have KRAS and BRAF mutations and are genomically stable [17], whereas HGSCs have abnormalities of BRCA1 or BRCA2 and TP53, and show chromosomal instability [18]. Furthermore, the response to treatment varies considerably across the ovarian carcinoma subtypes [19], which has led to recent subtype-specific treatment trials [20], emphasizing the importance of accurate subtype diagnosis.

Historically, diagnosis of ovarian carcinoma subtype has been only modestly reproducible [21–24]; however, recent studies have shown very high reproducibility in diagnostic subtyping of ovarian surface epithelial carcinomas [25,26]. A number of advances in diagnostic pathology have underpinned this progress. For example, the recognition that glandular lesions showing serous differentiation are best classified as HGSCs rather than ECs or mixed serous/endometrioid has increased diagnostic accuracy and is supported by molecular genetic analysis [26]. More than 98% of ovarian surface epithelial carcinomas can be assigned to one of the five major subtypes, HGSC, CCC, EC, MC and LGSC [25], based on routine pathological assessment (Figures 1 & 2). In this review, the authors outline the recent advances in histopathology, molecular genetics and immunohistochemistry, and therapy of these five main ovarian surface epithelial carcinoma subtypes.

Serous carcinomas

One of the most important advances in the understanding of ovarian carcinoma over the last 10 years is the recognition that HGSCs and LGSCs are distinct disease entities [10,27–29]. This discovery was initially based upon molecular differences; most LGSCs have mutations in KRAS and BRAF [29], alterations shared with serous borderline tumors (SBTs) [30], which are thought to be a precursor of LGSCs. Most HGSCs, by contrast, have somatic mutations in TP53 [31], and approximately half of all cases have abnormalities of BRCA1 or BRCA2 [32,33]. Furthermore, HGSCs are not related to SBTs, and are believed to originate from the distal fallopian tube epithelium [11,12,14]. Based solely on histological criteria, LGSCs and HGSCs can be reliably distinguished from one another. Because of these differences, HGSCs and LGSCs will be discussed separately.

High-grade serous carcinoma

HGSCs account for approximately 70% of malignant ovarian surface epithelial carcinomas in North America and in Europe, although this subtype is less common in other parts of the world [34,35]. Almost 90% of HGSCs present with advanced-stage (stage III or IV) disease [36,37]. Most HGSCs have spread beyond the pelvis at the time of diagnosis, accounting for low median survival times.

It is now believed that most HGSCs arise from the distal, fimbriated end of the fallopian tube, a finding supported by the observation that both familial or sporadic cases of HGSCs have synchronous tubal intraepithelial carcinoma in most cases and that these lesions share TP53 mutations and immunoreactivity for PAX8, a transcription factor expressed in secretory tubal epithelium; examination of telomere length in tubal intraepithelial carcinomas also supports the tubal lesions being precursors rather than metastases [35]. The propensity of HGSCs to spread transcelomically, with bulky intraperitoneal disease, makes it challenging to determine the primary site of the serous carcinoma (ovarian, peritoneal, fallopian tube, among others) in an individual case. The designation ‘pelvic HGSC’ has been suggested for such cases, to avoid speculation about the primary site. While the primary site (i.e., fallopian tube vs ovary) has profound implications for screening or prevention strategies, it does not impact on the management for advanced-stage HGSCs, making this a reasonable approach in clinical practice.

Morphology of HGSCs

Macroscopically, HGSCs of the ovary are usually large, bilateral and demonstrate a mix of solid, cystic and papillary growth. The solid regions are tan-white, and typically contain regions of necrosis and hemorrhage. The carcinoma often invades through the capsule and grows on the surface of the ovary. The fallopian tube may be overgrown and obliterated; however, sometimes a polypoid tumor growth is seen at the fimbriated end. The omentum often shows diffuse involvement with multiple discrete and coalescing tumor nodules (referred to as ‘omental cake’), and the peritoneal surface may be studded with metastatic carcinoma.

Microscopically, HGSC is characterized by a wide variety of architectural patterns, which may coexist within the same tumor and in the same tissue section. The most common pattern is ‘papillary’, consisting not of well-formed fibrovascular cores in most cases, but instead of highly stratified epithelium with a fenestrated, tufted, or slit-like architecture. Less common patterns include solid, glandular and transitional like. All growth patterns share the same cytological features; the tumor cells are usually intermediate to large in size, with prominent nucleoli visible at low magnification. The nuclei are distinctly pleomorphic, showing more than a threefold variation in size; the primary diagnostic criterion in distinguishing HGSCs from LGSCs. Sometimes, bizarre mononuclear giant cells are seen. High mitotic rate and abundant apoptotic bodies are characteristic of HGSCs. In cases where the nuclear pleomorphism is equivocal in establishing a diagnosis of HGSC versus LGSC, a mitotic rate of greater than 12/10 high-power field supports a diagnosis of HGSC [34,38].

Molecular features of HGSCs

Approximately half of all patients with ovarian HGSCs have either hereditary (germline) or somatic mutations in BRCA1 or BRCA2, or loss of BRCA1 expression in tumor cells as a result of methylation of its promoter (BRCA2 is not inactivated by promoter methylation). The prevalence of germline mutations varies between populations studied (16–26%) [32,33,39], with mutations in BRCA1 consistently being more common than BRCA2 mutations. BRCA1/2 mutations are almost exclusively seen in HGSC subtype of ovarian carcinoma. Given the high frequency of BRCA1/2 mutations in patients with HGSC, and the lack of sensitivity of family history in identifying these patients, it is believed that all such patients should be referred for genetic counseling and testing [40]. For those patients with mutations, there can then be counseling regarding breast cancer screening and risk-reducing surgery. Loss of BRCA1/2 is lethal to normal cells; however, 95% of HGSCs have TP53 mutations early in oncogenesis, permitting cells to survive subsequent loss of BRCA1/2 [37]. These two changes result in loss of ability to repair dsDNA breaks, resulting in chromosomal instability [31]. As a result, HGSCs are typically aneuploid with complex karyotypes. The landmark Cancer Genome Atlas study of HGSCs showed many somatic copy number alterations, which is a characteristic feature of this cancer subtype, but that recurrent mutations (apart from BRCA1, BRCA2 and TP53) are uncommon [41].

Among immunohistochemical markers, immunoreactivity to WT-1 is particularly useful in the distinction of serous ovarian carcinomas from other subtypes. Approximately 70% of LGSCs and 80% of HGSCs are positive for WT-1, compared with less than 5% positivity of other ovarian subtypes [42,43]. Estrogen receptor (ER) is positive in more than two-thirds of serous carcinomas, and is also expressed in ECs, but is negative in almost all CCCs and MCs [44]. With respect to the differential diagnosis between HGSCs and LGSCs, abnormal p53 staining (i.e., either strong diffuse staining or complete absence of staining) and a high Ki-67 index are supportive of a diagnosis of HGSC.

HGSC can be confused with LGSC, EC and CCC. The differential diagnosis with LGSC has been discussed previously, which is based primarily on identification of at least threefold nuclear variation in HGSCs (Table 1). The distinction between HGSCs and LGSCs is not usually problematic when multiple sections are available for review; however, with a very small sample, the differential diagnosis can be very problematic. p53 staining and Ki-67 index have been suggested in this circumstance, but a cutoff point for Ki-67 index to distinguish between HGSCs and LGSCs has not been established. The differential diagnosis between HGSCs and ECs has historically been very problematic, with considerable variability in practice in different centers [19,26,45]. As a result, a variable proportion of HGSCs with glandular pattern were erroneously diagnosed as EC in the past. The key morphological feature for distinction is the identification of high-grade nuclear atypia in HGSCs as well as coexistence with other HGSC patterns. In addition, squamous differentiation, when present, supports a diagnosis of EC. In morphologically challenging cases, WT-1 is immensely useful; it is positive in a large majority of HGSCs and negative in most ECs [26,45]. The distinction between HGSCs and CCCs can be challenging, especially in cases of HGSCs with clear cell changes [46]. The presence of more typical HGSC is strong evidence in support of a diagnosis of HGSC with clear cell change. A high mitotic rate favors HGSC [46]. Moreover, an immunohistochemical panel of three markers, ER, WT-1 and HNF-1b, a transcription factor related to glycogen metabolism, can be helpful, with negative staining for ER and WT-1, and positive staining for HNF-1b indicative of CCC [47].

Therapy

The initial therapeutic approach for HGSCs is usually surgical tumor debulking followed by chemotherapy. However, a recent randomized clinical trial has shown that for some patients with advanced-stage HGSC, equivalent outcomes can be obtained if they first receive three to four cycles of chemotherapy, followed by interval debulking [47]. With either strategy, optimal debulking, with no macroscopic residual disease, is the most important prognostic indicator. Most HGSCs (80%) respond well to platinum/taxane therapy initially, with drug resistance emerging during subsequent treatment cycles. A minority of cases of HGSCs (20%) are refractory to platinum-based chemotherapy from the time of presentation, but the basis for this drug resistance is not known. Poly (ADP-ribose) polymerase (PARP) inhibitors represent a possible therapeutic intervention. PARP is a key enzyme involved in ssDNA repair, and its inhibition can be used to exploit the loss of DNA double-strand break repair in HGSCs. PARP inhibitors cause the death of cells also lacking double-strand break repair capability, while normal cells are unaffected. Initial studies have shown that the PARP inhibitor, olaparib, extends survival in a BRCA2-mutated ovarian cancer xenograft model [48], and the results of an initial clinical trial show activity against HGSC in patients with BRCA mutations and also in patients without such mutations [49,50]. Unfortunately, routine use of PARP inhibitors remains some time in the future, with additional trial data needed (but not anticipated in the near future, based on currently active trials). As noted previously, targeting angiogenesis with bevacizumab has been used [8,9], but the improvements in outcome have been modest and there is a need for predictive biomarkers to identify those patients who stand to benefit from this therapy.

Low-grade serous carcinoma

LGSCs are uncommon, accounting for approximately 3% of ovarian surface epithelial carcinomas, and the average age at diagnosis is lower than for HGSCs [34]. When confined to the ovary (stage Ia), the prognosis is greater than 95%, achieved with surgical intervention alone; however, the majority of LGSCs present at an advanced stage, and although the disease is relatively indolent (mean survival: 4.2 years) [34,51], the long-term survival is similar to HGSC.

Morphology of LGSCs

Macroscopically, LGSCs are often bilateral, exhibiting fine papillary growths, which are often indistinguishable from SBTs. Compared with HGSCs, there is less necrosis and hemorrhage. Often there are firm extraovarian implants that have a gritty texture caused by abundant psammoma-body formation.

Microscopically, LGSCs grow in a well-developed papillary pattern with fibrovascular cores. Numerous psammoma bodies are evident, and nuclear uniformity is the key feature in the distinction from HGSC, with less than threefold variation in nuclear size. Nucleoli may be prominent; however, this is not a criterion used in diagnostic subtyping. By definition, the tumor cells are invasive, either in nests or in single cells. If the invasive foci measure less than 10 mm², the tumor is considered to be microinvasive [52]. Although rare, LGSCs can progress to high-grade carcinoma [53,54], although the relationship of these carcinomas to usual HGSCs is doubtful.

Molecular features of LGSCs

The molecular alterations of LGSCs are distinct from HGSCs. Instead, LGSCs share molecular changes with SBT [27], suggesting a continuum of disease from SBT to LGSC. Both LGSCs and SBTs lack TP53 mutations [27], and neither are associated with BRCA germline mutations nor other hereditary ovarian cancer syndromes. In addition, the majority of LGSCs and SBTs harbor somatic, activating mutations in KRAS and BRAF, resulting in constitutive activation of the MAP-kinase pathway, believed to be central to their pathogenesis [29,55–57]. Interestingly, recurrences of SBTs can present as LGSCs [58], and more than half of LGSCs are seen in association with SBT [34]. Furthermore, LGSCs are diploid or near diploid, do not have chromosomal instability and lack the complex mutations seen in HGSCs.

As previously stated, the majority of LGSCs and HGSCs are positive for WT-1, ER and progesterone receptors, and negative for HNF-1b [42,44]. The main differential is between LGSCs and SBTs. The distinction is based solely on histological evidence of invasion, and there are no immunohistochemical stains that can assist. The term ‘SBT with microinvasion’ is reserved for SBT with small invasive foci of less than 10 mm².

Therapy

It is generally believed that LGSCs do not respond to conventional platinum-based chemotherapy [58]; however, studies on the therapeutic response of this tumor are limited, as LGSC has only recently been recognized as a distinct ovarian carcinoma subtype [19]. Since the discovery of MAP-kinase mutations in LGSCs, there have been trials that have investigated targeted therapies. Cabozantinib, a potent MAP-kinase inhibitor, has shown positive treatment results in advanced ovarian cancer, irrespective of platinum-based chemotherapy response [59]. In addition, there is an ongoing Phase II study performed by the Gynecological Oncology Group investigating the effectiveness of AZD6244 (AstraZeneca), another MAP-kinase inhibitor [60].

Ovarian MCs

Ovarian mucinous tumors account for 10–15% of primary ovarian tumors; however, approximately 80% are benign mucinous tumors (cystadenomas or cystadenofibromas) [61], and most of the remainder are mucinous borderline tumors. The diagnosis of primary ovarian MCs is challenging and involves consideration of both clinical and pathological information, as metastatic gastrointestinal adenocarcinomas originating from the appendix, stomach, pancreas or colon enter the differential diagnosis [62]. Once metastases to the ovary are excluded, primary ovarian MCs comprise between 2 and 8% of ovarian surface epithelial carcinomas in North America [34,35,63,64].

More than 90% of MCs are low-grade tumors (grade 1 or 2), and approximately 80% are diagnosed at stage I or II [36]. The mortality associated with MCs is relatively low, as MCs, regardless of stage, have a 90% 5-year survival [62]. However, when diagnosed at an advanced stage, the outcome is poor compared with HGSCs due to its poor response rate to standard platinum-based chemotherapy [65,66].

Morphology of MCs

Macroscopically, MCs are usually large (15–20 cm), multilocular, cystic tumors [67,68]. Solid regions of firm, fleshy, white or tan tissue may be present, and in larger tumors, foci of hemorrhage or necrosis are often seen. More than 90% of MCs are unilateral without surface growth [69]. However, rupture is common because of the large size and mucin content of this tumor. Bilateral and small tumors (less than 10 cm) are likely to be metastatic, while large unilateral tumors are more commonly primary [63].

Microscopically, most MCs are intestinal type. The cells are columnar with eosinophilic cytoplasm and tend to stratify into two or more layers, and sometimes goblet cells are present. The nuclei are enlarged, vesicular and have coarse chromatin with prominent nucleoli. The frequency of mitotic figures ranges from few to many, and often atypical mitotic figures are present. The growth pattern is glandular and cystic, and often the glands are crowded and complex with irregular infoldings and protrusions into the surrounding stroma. Two patterns of invasion are described, and have potential clinical implications. The first is expansile type, characterized by confluent, back-to-back complex malignant glands with minimal to no intervening stroma, and exceeding 10mm² in area. This pattern of invasion is almost always associated with stage I disease and predicts an excellent prognosis [64]. The second pattern is termed infiltrative type and shows malignant glands, clusters or individual cells infiltrating the stroma, associated with a desmoplastic stromal response – a pattern associated with a worse prognosis [70].

Some MCs lack intestinal features, and instead have endocervical-like cells with columnar cells and prominent mucinous cytoplasm. The tumor cells line glands, cysts and papillae. Although endocervical-like mucinous borderline tumors are relatively common, MCs are almost exclusively of intestinal type. An important feature of MCs is intratumoral heterogeneity. Benign, borderline and intraepithelial carcinoma frequently coexist within a tumor, thus the need for adequate sampling. A minimum of one section per centimeter of tumor is required, focusing on the more solid regions. Mucinous borderline tumor with intraepithelial carcinoma is defined as tumors with malignant cytological features of the epithelium, but lacking invasive carcinoma, as defined previously. Although considered an in situ form of MCs, such tumors rarely recur (less than 5%), and the recurrence usually has the morphology of a high-grade MC and behaves in an aggressive fashion, with metastases to bone, lungs and other organs [64]. An unusual histological feature, apparently unique to MCs, is the occasional finding of mural nodules composed of ‘sarcoma-like’ reactive stromal proliferation, sarcoma or anaplastic carcinoma. If the mural nodules are localized to the wall of an unruptured cyst, the prognosis is more favorable [71,72]; however, despite complete surgical removal, some of these tumors recur, and when they do, the anaplastic component predominates.

Molecular features of MCs

The most common mutation in MC is the activation of KRAS, which occurs early in tumorigenesis, is present in up to 75% of cases [73,74] and is a molecular alteration shared with LGSC [56]. However, unlike LGSCs, MCs do not have BRAF mutations. Interestingly, KRAS mutations are also seen in mucinous cystadenomas and borderline mucinous tumors, supporting a stepwise progression from borderline tumors to MCs [73]. More than 50% of colorectal and more than 90% of pancreatic adenocarcinomas have KRAS mutations, so KRAS cannot be used to distinguish MCs from metastatic gastrointestinal carcinomas. Moreover, recent studies have shown that HER2 is amplified in 15–20% of MCs, representing an alternative means of activating the MAPK pathway [75–77]. Not surprisingly, given that the mutations in KRAS and HER2 target the same pathway, they are almost mutually exclusive [78].

Immunohistochemical staining has an important role in distinguishing primary ovarian MCs from metastatic MCs, and with current staining techniques, such a distinction is possible in a large majority of cases; where uncertainty remains after immunostaining, clinical investigations such as endoscopy or imaging can be undertaken. However, when interpreting the result, it is important to consider the nature of staining and not just whether the stain is positive or negative, as well as considering the clinical history. Almost all primary ovarian MCs are CK7-positive, compared with colorectal adenocarcinomas, which are typically CK7 negative [79]. However, the immunoreaction for CK7 is usually weak and focal, and staining for CDX-2 can be similar between ovarian MCs and colorectal adenocarcinomas (Table 2) [80]. By contrast, CK20 staining is often relatively weak and focal in ovarian MC, while appendiceal or colonic metastases typically show strong diffuse CK20 positivity. Metastatic pancreatic adenocarcinomas can be distinguished from primary ovarian MCs in some cases based on Dpc4 immunohistochemistry; Dpc4 staining is negative in 50% of pancreatic adenocarcinomas and is typically focally or diffusely positive in primary ovarian MCs [81]. Metastatic cervical adenocarcinomas in the ovaries can be distinguished by their strong, diffuse positivity for p16, and demonstration of human papilloma virus DNA [82]. Higher-grade MCs may show mucin depletion, and serous and ECs of the ovaries enter the differential diagnosis. MCs are typically negative for ER and WT-1, compared with ECs (ER-positive) and serous carcinomas (ER- and WT-1-positive) [42].

Therapy

Combined surgery and chemotherapy is currently the only approved treatment for advanced-stage ovarian MC [65]. It is difficult to determine the response rate of MCs to adjuvant chemotherapy because older studies invariably include a mix of metastatic and primary MCs. However, recent studies have shown a significantly lower response rate to platinum-based chemotherapy (<40%) compared with HGSCs [83], prompting a search for other therapies. Trastuzumab seems like an obvious treatment option in patients whose tumors show HER2 amplification and overexpression. However, to date, there are limited data on efficacy, consisting of individual cases; one patient with platinum-resistant disease had a complete remission with Herceptin^® (Genentech, CA, USA) treatment in combination with platinum-based chemotherapy [76]. Given that primary ovarian MCs and gastrointestinal adenocarcinomas share some molecular alterations, chemotherapeutic regimens traditionally used for gastrointestinal carcinomas have been tried for primary ovarian MCs. Oxaliplatin and 5-fluorouracil chemotherapy have shown activity in ovarian MC experimental models [84], and a Phase II trial involving patients with ovarian MCs treated with irinotecan and mitomycin-C showed a response rate of 52% with five complete responses [85]. The current standard of care for MCs, however, is platinum/taxane chemotherapy.

Ovarian ECs

The prevalence of ovarian ECs has apparently decreased recently, and it currently accounts for 10% of ovarian surface epithelial carcinomas [37]. The reduction in incidence is attributable to inappropriate classification in the past, where ovarian carcinomas with glandular morphology were frequently diagnosed as high-grade ECs. However, a significant proportion of these carcinomas were found to express WT-1 [26,42,86], be chromosomally unstable and have TP53 mutations; that is, they are molecularly indistinguishable from HGSCs, and thus are best diagnosed as HGSCs [87]. ECs represent the majority of low-grade ovarian carcinomas, and usually present with low-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage I or II) [37]. Most ECs are diagnosed in women during the perimenopausal or postmenopausal period [19]. Interestingly, there is a strong association with endometriosis, with the condition present in 20–40% of ECs. In some such cases, the ECs arise in an endometriotic cyst. 15–20% of cases of ovarian ECs are associated with endometrioid adenocarcinomas of the endometrium [88,89]. Although there is strong evidence linking endometriosis to ECs (and CCCs), there are no tools available at present to identify those patients with endometriosis who are more likely to develop carcinoma.

Morphology of ECs

Macroscopically, ECs are variably cystic and solid, and generally have smooth outer surfaces [90,91]. Regions of hemorrhage, necrosis and residual endometriosis are common. Between 80 and 90% of cases are unilateral [88,92].

Microscopically, the majority of ECs have a glandular or papillary architecture and resemble endometrioid adenocarcinomas of the uterus. The epithelium is composed of stratified, nonmucinous glandular epithelial cells; the nuclei may contain nucleoli. Squamous differentiation, in the form of morules, occurs in approximately 50% of cases. Clear cells sometimes occur in ECs and may be either glandular (secretory type) or squamous. Distinction from CCCs is based on the lower nuclear grade features of the ‘clear cells’ in ECs, and the architectural features of CCCs. The degree of atypia, amount of nuclear stratification and extent to which the glands coalesce to form solid foci increase as the grade increases. ECs can be graded using the same criteria as for endometrial adenocarcinomas of endometrioid type [93]. In addition to glandular architecture, ECs may have a villoglandular growth pattern. A rare variant of ECs can mimic sex cord-stromal tumors. Some tumors exhibit a microglandular growth pattern, characterized by round or small rosette-like glands, and can be mistaken for granulosa cell tumor [94]. Sertoliform ECs have regions characterized by long, branching, tubular glands or trabeculae. This variant can mimic a Sertoli or Sertoli–Leydig cell tumor, especially when the stroma is abundant and fibrous, and luteinized cells are present [94,95]. The oxyphilic variant of EC has prominent, large polygonal tumor cells with eosinophilic cytoplasm and round central nuclei with prominent nucleoli [96]. The spindle cell variant contains bland spindle cells in lobulated nests, admixed with ribbons and cords of tumor cells. The clinical, microscopic and immunohistochemical features all serve to distinguish these ovarian ECs from sex cord-stromal tumors. Ovarian ECs usually occur in post- or peri-menopausal women, and usually lack steroid hormone productions.

Molecular features of ECs

ECs are typically chromosomally stable. The most common genetic abnormalities detected in ovarian ECs are somatic mutations of CTNNB1 (b-catenin) and PTEN genes [97,98]. The incidence of CTNNB1 mutations in ovarian ECs ranges from 38 to 50%. Common locations for the mutations in CTNNB1 are phosphorylation sites of serine–threonine residues coded in exon 3, targeted by glycogen synthase kinase 3-B. These mutations probably render cellular b-catenin insensitive to adenomatous polyposis coli-mediated downregulation, resulting in increased nuclear and cytoplasmic levels of b-catenin. The end result is aberrant function of the Wnt-signaling pathway, which ultimately has antiapoptosis effects. Normal CTNNB1 results in membranous staining by immunohistochemistry. CTNNB1 mutations result in focal nuclear and cytoplasmic staining. This altered staining pattern is seen in up to 85% of ovarian ECs with squamous differentiation [99]. ECs of the ovary have similar frequencies of microsatellite instability compared with endometrial adenocarcinomas [97].

The prevalence of Lynch syndrome, with microsatellite instability, in patients with ovarian ECs is approximately 3%, making ECs, along with CCCs, the most common ovarian carcinomas in this patient population. This prevalence of microsatellite instability is similar to adenocarcinomas of the colon and endometrium [100], suggesting a need for mismatch repair testing on certain patients diagnosed with ovarian EC.

The coexistence of endometrial adenocarcinomas and ovarian ECs is well documented. These tumors behave as if they are independent synchronous low-stage primary tumors of ovary and endometrium, with a favorable prognosis. Almost all ovarian ECs express ER. The same is true for endometrial adenocarcinomas, suggesting a potential role of hormonal environment in the genesis of these two tumors, given the well-established role of unopposed estrogen stimulation as a risk factor for endometrioid endometrial adenocarcinoma.

Common differential diagnoses include HGSCs of the ovary, ovarian sex-cord tumors, and metastatic colon, endometrial and endocervical adenocarcinomas (Table 3). HGSCs of the ovaries can usually be distinguished based upon greater nuclear variability and high mitotic rate, and absence of squamous differentiation. However, high-grade nuclear atypia can occur in ovarian ECs; and in these cases, especially when there is no low-grade ECs present, WT-1 is a useful immunohistochemical marker, being positive in HGSCs and negative in ovarian ECs. Ovarian sex cord-stromal tumors are positive for WT-1, inhibin and calretinin, compared with negative staining in ovarian ECs [101–103]. Metastatic colonic adenocarcinoma is one of the most common metastatic carcinomas affecting the ovary. Immunohistochemically, colon carcinoma is positive for CDX-2 and generally negative for CK7. By contrast, ovarian ECs are positive for CK7 (97%) and rarely positive for CK20 (13%). Rare cases of ovarian ECs with extensive mucinous differentiation are positive for CDX-2 [104]. Endocervical adenocarcinomas sometimes metastasize to the ovaries. CK7 and CK20 staining pattern is similar between endocervical adenocarcinoma and ovarian ECs. However, p16 can be used, being diffusely positive in a large majority of endocervical adenocarcinomas and only focally positive in ovarian EC [105].

Therapy

Patients with ovarian ECs typically present at an earlier stage, with few presentations with ascites compared with other ovarian carcinoma subtypes [106] and a comparatively favorable prognosis. Stage I ovarian ECs have a greater than 90% 10-year disease-specific survival, compared with 70% for CCCs and 40% for ovarian serous carcinomas [26]. The grade of ovarian ECs does not appear to influence prognosis [26], however there is little data on grade 3 EC, which is rare. The standard of therapy for high-risk ovarian ECs is debulking surgery followed by platinum- and taxane-based chemotherapy, which has shown to have a better response rate than single agent or other platinum combinations [106].

The molecular profile of ovarian ECs has led to investigations regarding targeted therapy. Ovarian carcinoma, like breast and endometrial carcinoma, is considered to be estrogen responsive. Antiestrogenic effect, with either tamoxifen or progesterone therapy, has a disease stabilizing effect on endometrioid endometrial adenocarcinoma, and selective ER modulators may have a similar effect on ER-positive ovarian carcinomas, such as ECs. However, studies have shown mixed results. While some clinical trials have demonstrated that tamoxifen has a small but favorable effect on recurrent ovarian carcinoma [105,106], bazedoxifene, a selective estrogen receptor modulator, slowed invasion and growth of ovarian cancer cells in a mouse model, but showed no effect on tumor burden, metastatic nodule formation and ascites [99]. Aromatase is a major source of estrogen synthesis, converting androgens to estrogens [106]. Clinical studies have shown that aromatase inhibitors produce a clinical response in up to 35% of estrogen-sensitive ovarian carcinomas and stable disease rates of 20–42% in recurrent ovarian carcinoma cases [107–109].

Finally, histone deacetylation and acetylation act as epigenetic controls of gene expression and promoter functions. Alterations in histone deacytelases have been reported in several tumor entities, including ovarian ECs [110]. Preclinical studies using drugs that act as histone deacytelase inhibitors have shown increased induction of apoptosis in ovarian EC cell lines and reduction in tumor size in mouse models [111].

CCCs of the ovary

In North America, CCCs of the ovary is the second or third most common ovarian carcinoma, depending on the population studied, accounting for 5–10% of all ovarian tumors [37]. However, CCC is more common in East Asia, and especially Japan, at least relative to other ovarian carcinoma subtypes [112]. Similar to ovarian EC, CCC commonly presents at an early stage, with most CCCs presenting with FIGO stage I/II disease [36], and relatively few cases with peritoneal or nodal metastases [113,114]. Although survival rates of low-stage CCC are relatively favorable, stage-for-stage, CCC is considered an unfavorable histological subtype, with a poor response to platinum-based chemotherapy [112]. Paraneoplastic syndromes occur in women with CCC, including hypercalcemia [115] and thromboembolic events, such as deep venous thrombosis and pulmonary emboli [116].

At least 50% of CCCs are associated with endometriosis, especially atypical endometriosis [117,118]. Atypical endometriosis refers to a heterogeneous group of lesions, including endometriosis with atypical hyperplasia and endometriosis with hobnail metaplasia and nuclear atypia [119].

Morphology of ovarian CCCs

The most characteristic gross appearance of CCC is a solid and cystic tumor that may be accompanied by endometriosis. When endometriosis is present, the CCC component may take the form of mural nodules of papillary tumor protruding into the lumen of an endometriotic cyst. CCCs can show an adenofibromatous architecture with innumerable small cysts separated by fibrous stroma. Many CCCs are associated with surface adhesions due to chronic endometriosis. Tumors that are confined to the ovaries (FIGO stage I) are usually unilateral. However, when all stages of CCCs are considered, approximately 30% are bilateral.

The characteristic microscopic features of CCC include: multiple complex papillae, dense hyaline basement membrane material that expands the papillary cores, and hyaline bodies. In addition, tubules lined by cuboidal cells with clear cytoplasm and filled with eosinophilic secretions are particularly characteristic. A variety of cell types are present, including clear cells, cells with granular eosinophilic cytoplasm and hobnail cells with clear or eosinophilic cytoplasm. Usually a mixture of cell types is present. The clear cells are low columnar, cuboidal or polygonal and have abundant clear cytoplasm, central nuclei and prominent nucleoli. The cells contain glycogen and stain with periodic acid-Schiff stain. Mitotic activity is generally lower in CCCs compared with other ovarian carcinoma subtypes (with the exception of LGSCs), and the low rate has been proposed as a possible explanation for the poor response to chemotherapy [120]. In a study, a mitotic rate of 6 or greater per 10 high-power field was an adverse prognostic factor in CCC [120]. Grading is not of proven significance in CCCs and, in practice, all are considered high grade (grade 3) [26].

There are a number of differential diagnoses to be considered with CCCs (Table 4). The papillary architecture of CCCs can be confused with SBTs, especially at frozen section; however, the unilateral nature of CCCs and higher-grade cytological features should allow the correct diagnosis to be made [121]. In HGSCs, any clear cell has the same immunophenotype as the serous component, and usually have greater than threefold variability in nuclear size. In addition, these tumors with serous and clear cell components usually have a high mitotic rate, supporting the diagnosis of HGSCs with clear cell change, instead of mixed serous/CCCs or CCCs [46]. Finally, ovarian ECs with clear cell change do not have the high nuclear atypia observed in CCCs [122].

Molecular features of ovarian CCCs

CCCs are characterized by a low level of chromosomal instability and lack the complex karyotypes of HGSCs. In addition, CCCs are not associated with BRCA abnormalities [32]. Relatively little is known regarding the genetic alterations of CCCs. KRAS [123] and PTEN [123] mutations are reported in a minority of CCCs. In addition, microsatellite instability is present in some CCCs [124,125]. The most consistently demonstrated abnormality in CCC is mutation of the oncogene PIK3CA, which is reported to occur in up to 33% of cases [126]. This mutation activates the PI3K/AKT pathway, promoting increased cell proliferation, invasion and decreased apoptosis. Lynch syndrome is characterized by a germline mutation in mismatch repair proteins and is associated with increased incidence of tumors, including ovarian carcinomas. A recent study has shown that 17% of CCC cases occurring in women younger than 50 years of age had mismatch repair defects, making CCCs, along with ECs, the most common ovarian subtypes associated with Lynch syndrome [124]. In addition, ARID1A, a tumor suppressor gene, has recently been shown to be mutated in 46% of CCCs [127].

Immunohistochemistry is rarely required for the diagnosis of CCC. CCC is positive for CK7 and negative for CK20, whereas renal CCC is negative for both CK7 and CK20. CCC is negative for ER and WT-1 in more than 95% of cases [53]. TP53 staining can occur in CCC, but diffuse, string nuclear staining (as seen in HGSC) is distinctly uncommon [44,46]. HNF-1b is highly sensitive (82–100%) and a specific marker for CCC [128], with only rare focal positivity reported in ovarian EC, serous and MCs.

While both EC and CCC are thought to arise from endometriosis, the molecular abnormalities suggest different oncogenic pathways, with EC arising in a hormonally dependent manner and CCC arising through mechanisms independent of hormonal signaling, with HNF-1b playing a central role, analogous to type II endometrial carcinomas [129].

Therapy

CCCs do not respond as well to standard platinum-based chemotherapy, compared with HGSCs [112,130–132]. The reported differences in response rate (15–45%) may be due in part to the more genomically stable and lower mitotic rate of CCCs compared with HGSCs. Currently, there are no superior alternatives to platinum-based chemotherapy; however, a study showed that postoperative, whole abdominal radiotherapy was effective in improving disease-free survival and overall-survival in patients with stage Ic–III CCC compared with platinum-based chemotherapy alone [133]. Another retrospective study demonstrated improved outcomes for patients with CCC who received radiotherapy and chemotherapy, compared with patients who received chemotherapy alone [134], and inhibitors to VEGF signaling have shown promise in a preclinical model [133]. CCCs have the greatest frequency of PIK3CA mutations among ovarian carcinoma subtypes. However, attempts at targeted therapy have largely been unsuccessful due to the significant toxicity associated with PIK3CA inhibitors [135].

Conclusion

The advances in molecular genetics and immunohistochemistry have contributed significantly to our current situation, where it is possible to accurately and reproducibly subclassify ovarian surface epithelial carcinomas into five main subtypes: HGSC, CCC, EC, MC and LGSC. These subtypes show distinct genetic alterations, natural history and response to chemotherapy, and are best considered to be distinct diseases (Table 5). Accurate diagnosis will serve as the foundation as we progress towards subtype-specific therapy for ovarian carcinoma.

Expert commentary

There has been a dramatic shift in our understanding of ovarian carcinoma over the last 5 years, as we have moved away from the traditional ‘one disease, one treatment’ approach. This shift is underpinned by recognition that ovarian carcinoma is five different diseases, with differences in risk factors, patterns of spread, response to therapy and outcomes. These five ovarian carcinoma subtypes also have characteristic molecular abnormalities that are just starting to be documented, as subtype-specific research into ovarian carcinoma pathogenesis is now becoming the norm. Furthermore, in the past 5 years, there has been significant progress in diagnostic surgical pathology, such that it is now possible for ovarian carcinoma subtypes to be accurately and reproducibly diagnosed in routine surgical pathology practice.

Five-year view

Over the next 5 years, we will see a dramatic surge forward in our understanding of the molecular basis of the less-common subtypes of ovarian carcinoma (LGSC, EC, MC and CCC), which together account for 30% of cases. There will be increasing efforts to offer subtype-specific treatment for ovarian carcinoma, based on our improved understanding of the different biologies of these subtypes.

Table 1. High-grade serous carcinoma versus low-grade serous carcinoma.

Ovarian serous carcinoma subtype	Key morphological features	Key immunohistochemical features
HGSC	Pleomorphic nucleoli (>threefold variation in size); high mitotic rate (>12 mitoses/10 HPF)	WT-1 (80%); ER; PR positive high Ki-67 rate; diffuse p53 nuclear staining
LGSC	Uniform nuclei (<threefold variation in size); low mitotic rate; papillary architecture; psammoma bodies; serous borderline component	WT-1 (70%); ER; PR positive

ER: Estrogen receptor; HGSC: High-grade serous carcinoma; HPF: High-power field; LGSC: Low-grade serous carcinoma; PR: Progesterone receptor.

Table 2. Differential diagnosis of ovarian mucinous carcinoma.

	Key morphological features	Key immunohistochemical features
Ovarian mucinous carcinoma	Heterogeneous (intestinal type >endocervical type); 90% unilateral	CK7+; CK20- or weak+; CDX-2 weak+
Metastatic colon cancer	Usually bilateral; tumor necrosis	CK7-; CK20 strong+; CDX-2 strong+

+: Positive stain; -: Negative stain.

Table 3. Differential diagnosis of ovarian endometrioid carcinoma.

	Key morphological features	Key immunohistochemical features
Ovarian endometrioid carcinoma	Glandular differentiation with squamous differentiation; less commonly mucinous differentiation	EMA+; ER+; PR+; CK7+; WT-1-
Ovarian sex-cord tumors	Lacks glandular and squamous differentiation	Inhibin+; calretinin+; WT-1+
Metastatic colon cancer	Tumor necrosis; lacks squamous differentiation	CK7-
Metastatic endocervical cancer	Usually bilateral, more commonly mucinous	CK7+; p16 diffusely positive

+: Positive; -: Negative; EMA: Epithelial membrane antigen; ER: Estrogen receptor; PR: Progesterone receptor.

Table 4. Differential diagnosis of ovarian clear cell carcinoma.

	Key morphological features	Key immunohistochemical features
CCC	Papillary and tubulocystic pattern; hylaine bodies; hobnail cells with atypia; little cellular stratification;low mitotic rate	HNF-1+; WT-1-; ER-
HGSC	>threefold nuclear variation; high mitotic rate	WT-1+; ER+; HNF-1b-
LGSC	Nuclear uniformity; psammoma bodies; low mitotic rate	WT-1+; ER+; HNF-1b-
Ovarian EC with clear cell change	Lack nuclear atypia	ER+; WT-1-; HNF-1b-

CCC: Clear cell carcinoma; EC: Endometrial carcinoma; ER: Estrogen receptor; HGSC: High-grade serous carcinoma; LGSC: Low-grade serous carcinoma.

Table 5. Clinical and molecular differences between the main histological subtypes of ovarian carcinoma.

	HGSC	LGSC	MC	EC	CCC
Precursor lesions	Tubal intraepithelial carcinoma	SBT	Cystadenoma	Endometriosis	Endometriosis
Pattern of spread	Very early	Early	Often confined to ovary	Often confined to ovary	Often confined to pelvis
Molecular abnormalities	TP53; BRCA1/2; chromosomally unstable	BRAF/KRAS; chromosomally stable	KRAS/HER-2	PTEN, b-catenin; microsatellite instability	PIK3CA; KRAS; PTEN; ARID1A; microsatellite instability
Response to chemotherapy	High	Intermediate	Low	High	Low
Prognosis	Poor	Intermediate	Favorable	Favorable	Intermediate

CCC: Clear cell carcinoma; EC: Endometrial carcinoma; ER: Estrogen receptor; HGSC: High-grade serous carcinoma; LGSC: Low-grade serous carcinoma; MC: mucinous carcinoma; SBT: Serous borderline tumor.

Key issues

• • Ovarian surface epithelial carcinomas are the most common malignant ovarian tumors and the most lethal gynecological malignancies.

• • Advances in immunohistochemistry and molecular analyses have dramatically increased the diagnostic accuracy of ovarian surface epithelial carcinoma subtype diagnosis.

• • More than 98% of ovarian surface epithelial carcinomas can be assigned to one of five major subtypes: high-grade serous carcinoma, clear cell carcinoma, endometrioid carcinoma, mucinous carcinoma and low-grade serous carcinoma.

• • The five main subtypes have distinct molecular abnormalities and treatment responses, and are best regarded as distinct diseases.

• • New subtype-specific treatment strategies are being developed, targeting molecular abnormalities specific for each subtype.

• • Poly (ADP-ribose) polymerase P inhibitors have shown promise in the treatment of high-grade serous carcinoma, through exploitation of inherent double-strand break–repair defects.

• • MAPK inhibitors have been tested in low-grade serous carcinoma, PIK3CA inhibitors in clear cell carcinoma, tamoxifen in endometrioid carcinoma and Herceptin^® in mucinous carcinoma, with varying results.

• • Further subtype-specific therapeutic trials are required to improve outcomes for patients with ovarian carcinoma.

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Differential diagnosis and clinical relevance of ovarian carcinoma subtypes

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

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2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
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1. Which of the following statements regarding the epidemiology and prognosis of ovarian cancer is most accurate?

• □ A It is the second most common female cancer worldwide

• □ B Ovarian surface epithelial carcinomas are the most common form of ovarian cancer

• □ C Bevacizumab improves cancer-related and overall mortality outcomes

• □ D There is clear differentiation of treatment based on the type of ovarian cancer

2. Which of the following statements regarding the features and treatment of high-grade serous carcinoma (HGSC) is most accurate?

• □ A Half of cases have abnormalities of BRCA1 or BRCA2

• □ B The most common histologic pattern is glandular

• □ C HGSC can be differentiated from other subtypes by a lack of reactivity to WT-1

• □ D Initial response to platinum/taxane therapy is usually poor

3. What should you consider in managing patients with low-grade serous carcinomas (LGSCs)?

• □ A Surgery alone is effective for approximately 35% of patients with LGSC limited to the ovary

• □ B There is greater variability in nuclear size compared with HGSC

• □ C LGSCs share molecular changes associated with serous borderline tumors (SBT)

• □ D LGSC readily responds to platinum-based chemotherapy

4. Which of the following statements regarding ovarian carcinoma is most accurate?

• □ A Most mucinous carcinomas are high-grade tumors

• □ B The most common mutation in mucinous carcinomas is PIK3CA

• □ C Endometrioid carcinoma is always bilateral

• □ D At least 50% of cases of clear cell carcinoma are related to endometriosis