ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Histopathology

Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Histopathology
Literature review current through: Jan 2024.
This topic last updated: Feb 18, 2022.

INTRODUCTION — Epithelial carcinoma is the most common histologic type of cancer of the ovary, fallopian tube, and peritoneum, accounting for 90 percent of all cancers at these sites [1,2]. Ovarian carcinoma is traditionally referred to as a single entity, but it consists of a heterogeneous group of neoplasms with multiple histologic subtypes [3].

Management of these neoplasms is largely dependent on factors such as tumor grade and stage. It is important, however, to accurately subclassify these neoplasms since each is a biologically different disease with different epidemiologic and genetic risk factors, precursor lesions, patterns of spread, molecular biology, response to therapy, and prognosis [4,5]. Moreover, as new therapies are developed, it will be essential to determine which subtypes of ovarian, fallopian tube, and peritoneal carcinomas respond to which treatment modalities.

The incidence, histopathology, and molecular biology of histologic subtypes of epithelial ovarian, fallopian tube, and peritoneal carcinomas and borderline neoplasms will be reviewed here. The pathogenesis, diagnosis, and treatment of these neoplasms are discussed in detail separately. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis".)

OVERVIEW — Based on histopathology, immunohistochemistry, and molecular genetic analysis, the five main subtypes of epithelial ovarian, fallopian tube, and peritoneal carcinomas and their relative proportions are [3]:

High-grade serous carcinoma (HGSC; 70 to 80 percent)

Endometrioid carcinoma (10 percent)

Clear cell carcinomas (10 percent)

Mucinous carcinoma (3 percent)

Low-grade serous carcinoma (LGSC; <5 percent)

It is now accepted that HGSC and LGSC are fundamentally different neoplasms from each other with different molecular pathogenesis [6,7]. However, it has been proposed that both may originate from fallopian tube precursors, serous tubal intraepithelial neoplasia/carcinoma in the case of HGSC and endosalpingiosis/müllerian rests in the case of LGSC [8-15]. The pathogenesis of serous ovarian, fallopian tube, and peritoneal carcinomas are discussed separately. (See "Endosalpingiosis".)

Transitional cell carcinoma had historically been included as a distinct subtype, although recent molecular evidence supports this as a subset of serous carcinoma. (See 'Transitional cell carcinoma' below.)

Noninvasive or borderline neoplastic counterparts exist for some subtypes of ovarian carcinomas. (See 'Overview of borderline neoplasms' below.)

The immunohistochemical profiles and molecular biology differ among the histologic subtypes as do the prognoses. HGSCs typically have TP53 and BRCA mutations [16]. LGSCs often carry KRAS and BRAF mutations. Common immunohistochemical profiles and gene mutations for different histologic subtypes are shown in the table (table 1).

HIGH-GRADE SEROUS CARCINOMA

Prevalence and disease characteristics — High-grade serous carcinoma (HGSC) is the most common type of ovarian cancer and accounts for approximately 70 to 80 percent of all malignant ovarian neoplasms. The peak age range is 45 to 65 years with a mean of 57 years [17]. Most HGSC is diagnosed at an advanced stage (stage III or IV) and has a poor overall prognosis. HGSC that is confined to the ovary at diagnosis is rare (<10 percent) [18].

Gross pathology — HGSC can range in size from microscopic to greater than 20 cm in diameter [19]. The external surfaces of the neoplasm may be smooth or have friable surface papillae. The mass is typically cystic and multilocular with serous or bloody fluid and soft friable papillary excrescences (picture 1). Other areas may be solid and range from soft to firm, depending on the tumor stroma. Hemorrhage and necrosis are frequently present.

Gross metastases are often found throughout the peritoneum and the omentum. These are typically firm nodules of various sizes that may coalesce into larger masses, often an omental cake. In up to 25 percent of cases, however, the omentum may appear grossly normal, but microscopic neoplasm is identified [19].

Microscopic pathology — Microscopically, HGSC may have a variety of architectural patterns. These include: complex papillary, glandular, microcystic, and solid patterns. HGSC infiltrates, destroys, and/or replaces the normal stroma. Psammoma bodies may be present, but are rarely as numerous as in low-grade serous carcinoma (LGSC). (See 'Low-grade serous carcinoma' below.)

The key feature of HGSC, regardless of the overall architectural pattern, is the marked cytologic atypia with prominent mitotic activity. The atypical nuclei are hyperchromatic with a threefold or greater variation in nuclear size, and tumor giant cells are common. The mitotic rate is often very high, with the threshold for HGSC defined as ≥12 mitotic figures per 10 high-powered fields (HPF); if mitotic rate is low, LGSC or other diagnosis must be considered [19,20]. Atypical mitotic figures are frequently seen (picture 2).

The cytoplasm of the HGSC cells may demonstrate focal "clear cell change," but care should be taken in diagnosing mixed HGSC and clear cell carcinoma, as these neoplasms have different molecular etiologies and a true mixed neoplasm containing serous and clear cell carcinoma is rare.

Immunophenotype — Immunophenotypically, HGSC typically strongly and diffusely expresses p53 and p16 (picture 2). HGSC also expresses WT-1, estrogen receptor, and PAX-8 in most cases. It does not express HNF-1 beta and calretinin and has a high Ki67 proliferative index.

Molecular biology — Molecular studies have identified BRCA1 or BRCA2 germline mutations in up to 10 percent of patients with HGSC [21-27]. Conversely, patients with these germline mutations have a 30 to 50 percent risk of developing ovarian carcinoma, mainly HGSC, by age 70. The possible role of fallopian tube neoplasia in the development of apparent ovarian carcinoma is an area of active investigation.

Approximately 50 to 80 percent of HGSCs, regardless of BRCA germline status, also have mutations in tumor protein p53 gene (TP53) [28-31]. Loss of function TP53 mutations have been identified in up to 80 percent of HGSC and have also been identified in the putative precursor lesion of many HGSCs, serous intraepithelial neoplasia/carcinoma. Relatively few other specific genetic mutations have been identified in HGSC, although widespread chromosomal instability and DNA copy number changes are consistently found in HGSC. Mutations in PTEN and PI3CA have also been reported, but their mutation frequency is generally low (<10 percent) [32-34].

LOW-GRADE SEROUS CARCINOMA

Prevalence and disease characteristics — In contrast to high-grade serous carcinoma (HGSC), low-grade serous ovarian carcinoma (LGSC) is uncommon and accounts for fewer than 5 percent of all cases of ovarian carcinoma [35].

Like HGSC, LGSC is typically diagnosed at an advanced stage, and consequently the long-term prognosis is poor. However, these neoplasms are biologically distinct from HGSC and are slow-growing, indolent neoplasms with relative insensitivity to platinum-based chemotherapy [36,37].

LGSC is often found along with a noninvasive serous borderline component. Borderline serous neoplasms are more common than LGSC, and LGSC most likely represents progression of a serous borderline neoplasm. (See 'Serous borderline neoplasm' below.)

Gross pathology — LGSC is often grossly indistinguishable from HGSC or serous borderline neoplasms. LGSC can be solid and cystic and may have numerous friable papillary excrescences either within the cysts or on the surface. Compared with HGSC, there is often less prominent hemorrhage and necrosis, although this is not a reliable gross feature. Extra-ovarian implants are typically firm and gritty due to stromal reaction and abundant psammoma body formation.

Microscopic pathology — Histologically, LGSC is an invasive carcinoma that is distinguished from serous borderline neoplasms by the presence of destructive stromal invasion. The three main patterns of invasion include:

Infiltration of the stroma by single cells and small clusters of cells

Infiltration of the stromal by small nests of epithelial cells (micropapillary pattern)

Infiltration of the stroma by large papillae with a broad central fibrovascular core lined by neoplastic cells (macropapillary pattern)

A desmoplastic stromal response is often present.

LGSC is differentiated from HGSC by cytologic features. LGSC is composed of small papillae lined by neoplastic cells that exhibit uniform nuclei with less than threefold variability in size. This uniformity of nuclear size is one of the features that distinguishes LGSC from HGSC; this has been shown to be highly reproducible [38,39]. The other distinguishing feature of LGSC is that it has a much lower mitotic activity than that observed in HGSC, with <12 mitoses present per 10 high-powered fields (HPF) as the defined threshold. However, LGSC may demonstrate an even lower mitotic rate than the 11 per 10 HPF and this feature is very helpful in differentiating it from HGSC.

Another distinct feature that may be found in LGSC is a hyalinized stroma with numerous psammoma bodies (picture 3).

In addition, any peritoneal involvement by the neoplasm that may have been previously classified as an "invasive implant" is now classified as a metastasis from a LGSC. These metastases invade into peritoneal tissue, organs, and/or omental fat and show destruction of the normal organ architecture. If a serous "borderline" neoplasm has "invasive implants," the ovarian neoplasm is classified as a LGSC and the implants are metastases [40]. (See 'Microscopic pathology' below.)

Immunophenotype — LGSC has an immunophenotype similar to both serous borderline neoplasms and HGSC, but with two important differences. LGSC typically have low Ki67 proliferative rates (corresponding to the lower mitotic rate) and weak or wild-type p53 expression. However, p53 expression by immunohistochemistry has been shown to not be statistically significant in predicting p53 mutational analysis, so aberrant p53 staining in either LGSC or HGSC should not override the histologic impression [7]. LGSC express WT-1, estrogen receptor, progesterone receptor, and are negative for HNF-1 beta and calretinin.

Molecular biology — Molecular studies have demonstrated that both LGSC and serous borderline neoplasms frequently have mutations in BRAF and KRAS, rather than in p53 or BRCA1/2, as in HGSC [6]. In addition, LGSC and serous borderline neoplasms do not demonstrate the prominent chromosomal instability or widespread DNA copy alterations seen in HGSC [41,42].

These findings have led to the proposal of two pathways of serous carcinogenesis. One pathway is typical for HGSC, in which mutations in p53 play an important role, and the second pathway is typical of low-grade serous neoplasms, in which KRAS and BRAF play a prominent role. These studies have further implicated serous borderline neoplasms as the precursor lesion to LGSC and support the hypothesis that LGSCs do not progress into HGSCs [43]. These molecular differences may lead to important treatment decisions in the future as new agents are utilized to target the KRAS and BRAF pathways in low-grade serous neoplasms, which are otherwise relatively resistant to platinum-based chemotherapy.

ENDOMETRIOID CARCINOMA

Prevalence and disease characteristics — Endometrioid carcinoma of the ovary accounts for approximately 10 percent of all ovarian carcinomas. Endometrioid carcinoma presents most frequently in female patients in their 40s and 50s, with a mean patient age of 56 years [44,45].

Endometrioid carcinomas are most often identified at an early stage (unlike serous carcinomas), consequently these patients have a much better prognosis [46]. Endometrioid carcinomas tend to be relatively chemosensitive (unlike low-grade serous or clear cell carcinoma), which also contributes to the better prognosis relative to other subtypes of ovarian carcinoma. (See 'Clear cell carcinoma' below.)

Primary ovarian endometrioid adenocarcinoma is typically low-grade. However, high-grade endometrioid carcinomas are morphologically and molecularly indistinguishable from high-grade serous carcinoma (HGSC), with immunophenotypic and gene profiling studies suggesting that high-grade endometrioid carcinoma is not a distinct tumor type, but rather a subtype of HGSC [47].

Ovarian endometrioid carcinoma is often associated with and believed to arise from endometriosis (up to 42 percent of patients have evidence of ovarian or pelvic endometriosis) [3,46,48,49]. (See "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact", section on 'Ovarian cancer risk'.)

Endometrioid ovarian carcinoma is associated with carcinoma of the endometrium in 15 to 20 percent of cases [5]. Endometrioid carcinoma of the ovary also closely resembles the uterine counterparts histologically. In the setting of a concurrent endometrial carcinoma, the likelihood that the ovarian neoplasm is a metastasis is quite high, although other possibilities are metastasis from the ovary to the endometrium and concurrent ovarian and endometrial primaries. Characteristics that help to determine the primary site of the neoplasm are shown in the table (table 2).

Gross pathology — Grossly, endometrioid carcinoma can have a variable appearance. It may be cystic or solid. Residual foci of endometriosis can often be identified with the typical "chocolate cyst" appearance of an endometrioma. The outer surfaces are generally smooth. It is usually confined to one ovary (bilaterality favors metastasis from endometrium).

The papillary excrescences seen in serous carcinomas are not present, although the neoplasm can be quite friable and areas of hemorrhage and necrosis can be present. Grossly identifiable areas of endometrioid adenofibroma with cysts separated by prominent firm fibromatous stroma are often seen in association with both endometrioid carcinoma and endometrioid borderline neoplasm. (See 'Endometrioid borderline neoplasm' below.)

Microscopic pathology — Histologically, endometrioid carcinoma of the ovary resembles low-grade endometrioid endometrial carcinoma. The majority of ovarian endometrioid carcinomas have a complex glandular, cribriform, and/or villoglandular architectural pattern with back-to-back growth or elongated or round glands with smooth luminal contours (picture 4). The glands are typically lined by stratified columnar cells with scant eosinophilic cytoplasm and low- to intermediate-grade nuclei. Mitotic figures are frequently seen. Squamous morules containing bland, immature-appearing squamous cells are often present within the neoplasm. Foci of cells with typical secretory changes are commonly identified and believed to be due to endogenous or exogenous progestin effect, although they may occur in the absence of hormonal stimulation.

If a sheet-like pattern of growth or cells with high nuclear grade are identified, a diagnosis of HGSC should be considered.

Endometriosis with endometrial epithelium and stroma is frequently present and it is not uncommon to see a spectrum of lesions ranging from endometriosis to atypical endometriosis, endometrioid borderline neoplasm, and endometrioid carcinoma. (See 'Endometrioid borderline neoplasm' below.)

Immunophenotype — Immunophenotypically, low-grade endometrioid adenocarcinomas express markers similar to endometrioid endometrial carcinoma. The neoplasm express vimentin, ER, PR, PAX-8, and cancer antigen 125; are negative or focally express p16 and p53; and are negative for WT-1, calretinin, and inhibin. High-grade endometrioid carcinomas have similar profiles to HGSC, with diffuse and strong expression of p53, p16, and WT-1, supporting the hypothesis that high-grade endometrioid carcinoma is simply a subtype of HGSC, although this remains controversial.

Molecular biology — Various gene mutations have been identified in ovarian endometrioid carcinoma. Somatic mutation in CTNNB-1 (beta-catenin) and PTEN genes are the most common genetic abnormalities identified in ovarian endometrioid carcinomas [50-52]. Mutations in PIK3CA and ARID1A, a component of a large multi-protein complex that behaves as a tumor suppressor gene, are commonly seen [52-58]. In addition, high levels of microsatellite instability have been noted in endometrioid carcinomas of the ovary, and this histopathologic subtype is the most common ovarian carcinoma associated with Lynch syndrome [54,59]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and prevention of endometrial and ovarian cancer".)

CLEAR CELL CARCINOMA

Prevalence and disease characteristics — Clear cell carcinoma accounts for approximately 5 to 10 percent of all ovarian carcinomas in North America and presents most commonly in perimenopausal patients in their late 40s or 50s [1,2]. Clear cell carcinoma constitutes a larger percentage of ovarian cancers in East Asia, although it is unclear whether this is due to genetic or environmental factors [60].

Like endometrioid carcinoma, ovarian clear cell carcinoma often presents at an early stage (stage I or II) and has a relatively good prognosis due to the absence of distant metastases. However, when clear cell carcinoma presents at an advanced stage, it has a worse prognosis than serous or endometrioid carcinoma. This is because clear cell carcinoma is not as sensitive to platinum-based chemotherapy as the other histologic subtypes [61,62]. Clear cell carcinoma is also associated with an increased risk of vascular thrombotic events and paraneoplastic hypercalcemia [63,64].

Similar to endometrioid carcinoma, clear cell ovarian carcinoma is often associated with, and likely arises from, endometriosis [61,63,65]. In fact, tubal ligation has been shown to be protective against the development of ovarian clear cell carcinoma. The mechanism of this may be that occlusion of the tubes prevents retrograde menstruation and the subsequent development of endometriosis [66]. (See "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact", section on 'Ovarian cancer risk'.)

In addition to the association of clear cell carcinoma with endometriosis, clear cell carcinomas are often diagnosed adjacent to, and appear to arise from, clear cell adenofibromas [67-69]. Approximately 15 to 20 percent of clear cell carcinomas have a predominant adenofibromatous component and may constitute a subgroup with distinct clinicopathologic characteristics.

Gross pathology — Ovarian clear cell carcinoma often presents as a large mass with an average size of 15 cm. The tumor usually consists of a thick-walled uni- or multilocular cyst with yellowish, fleshy nodules protruding into the lumen of the cyst(s), and watery or mucinous fluid within the cyst(s). However, the neoplasm may also be solid or have a honeycomb-cut surface, especially those arising in conjunction with a clear cell adenofibroma or clear cell borderline neoplasm. Neoplasms arising in endometriosis often have features of an endometriotic cyst, with chocolate-brown fluid and a thickened, nodular area in the wall representing the area of malignant transformation.

Microscopic pathology — Clear cell carcinomas display an array of different histologic patterns that often occur together within the same neoplasm (picture 5) [44,70]. The most common patterns are solid, tubulocystic, and papillary. Sheets of polyhedral cells with clear cytoplasm separated by fibrous stroma characterize the solid pattern. The tubulocystic pattern contains multiple complex tubules and cysts that may be intermixed with the other patterns. The papillary pattern is formed by fibrous papillae of varying complexity lined by the neoplastic cells. In both the tubulocystic and papillary patterns, the neoplastic cells often assume a hobnail appearance with the nucleus protruding into the cyst or lumen and from the papillae.

Regardless of the overall architectural pattern, clear cell carcinomas often contain a prominent hyalinized stroma. The neoplastic cells often have distinct cell borders with nuclei of varying sizes and shapes. There may be a wide range of nuclear atypia, although there are almost always areas with marked cytologic atypia. However, the epithelium lining the glands and cyst can be flattened, creating a deceptively bland appearance. Mitotic activity can be prominent, but is often variable and lower than that seen in other epithelial ovarian carcinomas.

Immunophenotype — Clear cell carcinomas have a unique immunophenotype among the epithelial ovarian carcinomas, lacking expression of both estrogen receptors and WT-1. They can have some p53 expression, although the strong and diffuse expression noted in HGSC is not typically identified. Ovarian clear cell carcinomas typically express napsin-A, hypoxia-inducible factor 1 alpha (HIF-1 alpha), glypican-3, and hepatocyte nuclear factor 1-beta (HNF-1 beta) [71-73]. HNF-1 beta appears to be a sensitive and specific marker of clear cell carcinoma of the ovary with reports of 82 to 100 percent of ovarian clear cell carcinoma expressing this protein, with only rare reports of expression in the other epithelial ovarian carcinomas [73-75].

Molecular biology — Mutations in KRAS, PTEN, and PIK3CA have been reported in ovarian clear cell carcinoma [55,76,77]. Additionally, similar to endometrioid carcinoma of the ovary, high levels of microsatellite instability have been noted in ovarian clear cell carcinoma, and this neoplasm is also associated with Lynch syndrome [59,78,79]. Studies have also identified mutations in ARID1A, similar to those seen in endometrioid carcinoma [80]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and prevention of endometrial and ovarian cancer".)

MUCINOUS CARCINOMA

Prevalence and disease characteristics — Mucinous carcinoma accounts for 3 to 4 percent of primary ovarian cancers [81-83]. These neoplasms most often present in perimenopausal patients in their late 40s to early 50s, although they have been reported in patients as young as 14 and old as 87 [84]. Nearly all mucinous carcinomas of the ovary present with early stage disease, usually stage I.

When including all types of mucinous neoplasms, they account for 10 to 15 percent of all ovarian neoplasms. Approximately 80 percent are benign mucinous cystadenomas, and the majority of the rest are mucinous borderline neoplasms [81,85-87]. In addition, most mucinous carcinomas within the ovary are metastases, frequently from the gastrointestinal tract [82].

Primary ovarian mucinous carcinoma and borderline neoplasms are often seen together in the same tumor. In addition, it is not unusual to see a mucinous borderline neoplasm with high-grade intraepithelial neoplasia adjacent to invasive mucinous carcinoma. Consequently, primary ovarian mucinous carcinomas are thought to arise from mucinous borderline neoplasms [81,84,86].

Gross pathology — Primary ovarian mucinous carcinoma range size from 8 to 20 cm, but can be much larger [83]. It is typically cystic or solid, unilateral, and confined to the ovary. The external surface is usually smooth without surface involvement [81]. Mucinous neoplasms of the ovary that are bilateral with surface involvement and not confined to the ovary are almost always metastases, usually from the gastrointestinal tract [88,89].

Primary ovarian mucinous carcinomas do not present with gross pseudomyxoma peritonei. Although pseudomyxoma peritonei historically was believed to result from rupture of primary ovarian mucinous neoplasm, it is now accepted that pseudomyxoma peritonei almost always results from metastasis to the ovary, often from an appendiceal primary. The primary site should be sought in these cases. Rarely, mucinous neoplasms arising from primary ovarian teratomas lead to pseudomyxoma peritonei, but this is the exception rather than the rule [84,90,91]. (See "Well-differentiated neuroendocrine tumors of the appendix".)

Microscopic pathology — The cells of ovarian mucinous carcinomas can resemble those of the intestine, endocervix, or gastric pylorus, although the vast majority of these neoplasms have gastrointestinal differentiation (picture 6). The same histology is seen in mucinous borderline neoplasms. The primary distinction between a mucinous carcinoma and a mucinous borderline neoplasm is the presence of invasion.

The neoplasms generally display complex glandular arrangements with areas of stromal invasion greater than 10 mm2 or 3 mm in linear extent [84,92]. Two patterns of "invasion" of mucinous carcinomas have been described: infiltrative invasion and expansile growth pattern. The infiltrative type of invasion has obvious destructive stromal invasion in the form of glands, cell clusters, or individual cells haphazardly infiltrating the stroma, often with an accompanying desmoplastic stromal reaction. The infiltrative pattern of invasion meets the standard definition of invasive carcinoma with destructive stromal invasion and has a corresponding worse prognosis.

By contrast, the expansile growth pattern does not demonstrate obvious stromal invasion, but has complex architecture with back-to-back glands and minimal to no intervening stroma. The expansile pattern of growth has been referred to as "noninvasive carcinoma" by some experts and mucinous carcinoma with expansile growth that is tantamount to invasion by others [83]. In our institution, we prefer to classify this as mucinous ovarian neoplasms with complex architectural growth pattern with no definite invasion, since destructive stromal invasion is not identified. The expansile pattern of mucinous neoplasm has also been associated with a more favorable prognosis, further supporting the idea that these neoplasms are not truly invasive carcinomas.

Immunophenotype — Ovarian mucinous carcinoma of the ovary often expresses gastrointestinal markers, including CK20 and CDX2, in addition to expression of CK7 [93-95]. There can be patchy expression of p16 and generally no expression of ER, PR, WT-1, and cancer antigen 125 [96-98]. Therefore, immunohistochemistry is often not helpful in determining if a mucinous neoplasm in the ovary is a primary ovarian neoplasm or metastatic lesion.

Molecular biology — Over 75 percent of ovarian mucinous carcinomas have a KRAS mutation [99-101]. Identical KRAS mutations are also seen in mucinous cystadenomas and mucinous borderline neoplasms, giving further support to the model of tumor progression from mucinous cystadenoma to borderline neoplasm to carcinoma [41,102,103]. In addition, ovarian mucinous carcinomas express several mucin genes (MUC2, MUC3, and MUC17) that are characteristic of mucinous carcinomas regardless of their tissue of origin [103]. The frequency of genomic alterations in mucinous carcinomas in one study were HER2 amplification (20 to 38 percent), c-MYC (65 percent), and TP53 mutations (50 to 75 percent). Less frequent alterations were CDKN2A/B (25 percent); PI3KCA (13 percent); and PTEN, BRAF, FGFR, KIT, or STK11 (2 to 5 percent).

OTHER HISTOLOGIC SUBTYPES

Transitional cell carcinoma — Historically, the definition of transitional cell carcinoma of the ovary has been a neoplasm composed of epithelial elements histologically resembling urothelium that lack a component of a benign or borderline Brenner tumor [104,105]. It was believed that transitional cell carcinomas were examples of malignant Brenner tumors in which the benign component had been overgrown. However, molecular and immunohistochemical data have demonstrated that the neoplasms previously classified as transitional cell carcinomas express the same immunophenotype and genetic mutations as high-grade serous carcinoma (HGSC) [104,106,107]. Thus, most experts believe that transitional cell carcinoma is simply a subset of HGSC in which the epithelium is morphologically similar to malignant urothelium. As a result, it should be diagnosed as HGSC, not transitional cell carcinoma.

Carcinosarcoma — Carcinosarcoma, also referred to as a malignant mixed müllerian tumor (MMMT), comprises between 2 to 7.5 percent of ovarian carcinomas with a mean age of presentation of 75 years [44]. These tumors are typically large at presentation with abundant hemorrhage and necrosis, and present at an advance stage. The characteristic histologic feature of these neoplasms is the intimate admixture of malignant epithelial and stromal elements. The malignant epithelial component most commonly resembles HGSC, although other subtypes have been reported, and the malignant stromal component usually contains hyperchromatic rounded to spindled cells with marked nuclear atypia and a high mitotic index. Heterologous elements such as cartilage, osteoid, and rhabdomyoblasts are also frequently observed. The stromal components are often positive, at least focally, for epithelial markers and like endometrial carcinosarcomas, the majority of ovarian carcinosarcomas are monoclonal, suggesting they are metaplastic carcinomas [108]. These neoplasms are highly aggressive and behave similarly to HGSC, both in the pattern of spread, response to platinum-based chemotherapy, and prognosis [109].

Undifferentiated/dedifferentiated carcinoma — The World Health Organization defines undifferentiated ovarian carcinoma as a primary ovarian carcinoma with little to no differentiation and dedifferentiated carcinoma as a carcinoma with an undifferentiated and a differentiated component (a lower grade endometrioid component, or less often, a serous component) [5]. These neoplasms are rare and similar to those seen in the uterine corpus. Inactivation of ARID1A/B and SMARCA4/A2/B1 is thought to be important in the transition to the undifferentiated state. In addition, DNA mismatch repair abnormalities are common.

Histologically, undifferentiated carcinomas and the undifferentiated component of dedifferentiated carcinomas display sheet-like growth of monotonous and discohesive round cells with minimal cytoplasm. Rhabdoid and spindled areas may also be seen, and necrosis is not uncommon. Mitotic activity is typically high, and tumor-infiltrating lymphocytes are common. In dedifferentiated carcinomas, the proportions of the differentiated and undifferentiated component can be variable, and the transition is often very abrupt, which can impart a biphasic appearance. Cytokeratin staining in the undifferentiated areas is often only focal or patchy and loss of SMARCA4 (BRG1) protein expression is seen in a subset of these. The differential diagnosis includes lymphoma, small cell carcinoma of the ovary of hypercalcemic type, small cell neuroendocrine carcinoma, high-grade endometrial stromal sarcoma, and rhabdomyosarcoma. Prognostically, these are highly aggressive neoplasms, and patients usually present with high stage with poor overall survival [5,110].

OVERVIEW OF BORDERLINE NEOPLASMS — In the early 1970s, the histologic category of borderline ovarian epithelial neoplasms was introduced to describe a group of neoplasms that did not display overt malignant features (invasion), but that occasionally had intraperitoneal spread [44]. This group of neoplasms seemed to have behavior that was intermediate between benign cystadenomas and invasive carcinomas.

Since this category was created, many terms have been used to describe this group of noninvasive epithelial ovarian neoplasms: borderline, atypical proliferative, and tumors of low malignant potential [111,112]. Borderline neoplasm is the most widely used designation by pathologists, gynecologists, and oncologists, and has been adopted into the World Health Organization classification [5].

Initially, a borderline category was recognized only in serous neoplasms, but it has since been established that mucinous, endometrioid, and clear cell neoplasms also exist. Serous, mucinous, and endometrioid borderline neoplasms are covered below. Clear cell borderline neoplasms are rare and usually associated with clear cell carcinoma.

Borderline neoplasms account for an estimated 14 to 15 percent of all primary ovarian neoplasms [113] and 15 to 20 percent of ovarian serous neoplasms [114].

SEROUS BORDERLINE NEOPLASM

Prevalence and disease characteristics — Serous borderline neoplasm is the most common histologic subtype and accounts for approximately 65 percent of borderline ovarian neoplasms [115]. The mean age of presentation is 35 to 40 years of age, although this can range widely [114].

This type of neoplasm is frequently confined to the ovary and is slow-growing with an indolent clinical course. The 10-year survival rate is 95 to 100 percent, although late recurrences are not uncommon [111]. Prognosis is still excellent despite presence of peritoneal implants and regional lymph node involvement in up to 35 percent of patients [116,117]. Although it is presumed that these implants originate from detachment of the serous borderline neoplasm with subsequent implantation, the precise origin of these implants is not known, and they may in fact be involved in the pathogenesis of serous borderline neoplasms [118]. However, patients with peritoneal spread or lymph node involvement are at increased risk of recurrence and progression to low-grade invasive serous carcinoma (LGSC), particularly in those with invasive implants [111]. (See 'Low-grade serous carcinoma' above.)

Serous borderline neoplasms are associated with peritoneal endosalpingiosis or benign glandular inclusions of the ovary in 40 percent of cases, although it is unclear if there is a causal relationship between the two.

Gross pathology — Serous borderline neoplasms tend to arise within a cyst, but have fine, friable, and exuberant papillary projections (picture 7). The papillae are nearly always present on the internal surface of the cyst, but can be on the exterior surface of the cyst in many cases. The excrescences can often be easily disrupted grossly, in contrast to the solid, firm papillae of an adenofibroma. If peritoneal implants are present, these are often firm and fibrotic and may resemble metastatic serous carcinoma grossly, although are often less bulky and more calcified. Thorough sampling of the neoplasm is required to rule out an invasive component (LGSC).

Microscopic pathology — The key microscopic feature of serous borderline neoplasms is a serous epithelial proliferation consisting of epithelial stratification and tufting, with hierarchical branching of successively smaller papillae arising from larger, more centrally located papillae (picture 8). Such epithelial proliferation and stratification must be present in at least 10 percent of the tumor to warrant a diagnosis of serous borderline neoplasm. In cysts with less than 10 percent serous budding and tufting, the diagnosis should be serous cystadenoma with focal borderline change.

Occasionally, the epithelial tufting and stratification can become more complex, leading to a cribriform pattern, or the neoplasm can assume a nonhierarchical branching pattern comprised of elongated micropapillae arising directly from a central large papillae. If the cribriform or micropapillary architecture constitutes greater than 10 percent of the neoplasm or 5 mm of confluent area, some experts designate the neoplasm as micropapillary serous carcinoma. There is controversy if these neoplasms carry a worse prognosis and tend to behave more like LGSC in the absence of definite invasion. In our institution, we prefer to designate these as serous borderline neoplasm with cribriform and/or micropapillary architecture to alert the clinician to a potentially worse prognosis, while at the same time differentiating these neoplasms from those that truly have destructive stromal invasion (carcinoma).

In addition to more complex architectural patterns, approximately 10 percent of serous borderline neoplasms can have areas of microinvasion. Microinvasion is defined as isolated cells, cell clusters, or haphazard nests of cells measuring less than 5 mm that are invading into the stromal core of the papillae or cyst wall. The invasive cells often have abundant eosinophilic cytoplasm, and so a definite desmoplastic stromal response can be difficult to identify. In other cases, the invasive nests elicit a prominent stromal response and resemble that seen in LGSC. By definition, the microinvasive focus must be smaller than 5 mm, although there can be several foci of microinvasion throughout the tumor. If the invasive component measures greater than 5 mm, the neoplasm should be classified as a LGSC arising in a borderline neoplasm.

Peritoneal implants on the serosal and omental surfaces are found in association with serous borderline neoplasm in approximately 35 percent of patients at the time of surgery [114]. There is a high correlation between the presence of exophytic neoplasm on the surface of the ovary and the presence of implants. Peritoneal implants were previously classified as "invasive" or "noninvasive" based on the presence of destructive stromal invasion at the site of implantation. However, if the patient has invasive implants, these are now designated as LGSC rather than invasive implants from a serous borderline neoplasm (see 'Microscopic pathology' above). By contrast, noninvasive implants can result from a serous borderline neoplasm and are classified either as epithelial or desmoplastic noninvasive implants. Epithelial implants often resemble endosalpingiosis.

Desmoplastic implants, also with a "plastered on" appearance, elicit a prominent fibrous or desmoplastic response that consists of cellular fibrous tissue with epithelial nests embedded within the reactive stroma. Importantly, noninvasive desmoplastic implants do not appear to invade and destroy below the surface upon which they have implanted.

Immunophenotype — Serous borderline neoplasms have an immunophenotype similar to LGSCs, with a low Ki67 proliferative rate; weak or wild-type p53 expression; and nuclear expression of WT-1, estrogen receptor, and progesterone receptor. HNF-1 beta and calretinin are not expressed by serous borderline neoplasms [31].

Molecular biology — Molecular studies have demonstrated that LGSC and serous borderline neoplasms frequently have similar mutations, supporting the hypothesis that LGSC arises from serous borderline neoplasms. Mutations in BRAF and KRAS without significant chromosomal instability are characteristic of both serous borderline neoplasms and LGSCs [6,7,31].

MUCINOUS BORDERLINE NEOPLASM

Prevalence and disease characteristics — Borderline mucinous neoplasms are nearly always confined to the ovary, unlike serous borderline neoplasms [82,84].

Gross pathology — Mucinous borderline neoplasm is most commonly a large, unilateral, multilocular cyst with a smooth, white capsule. The locules of the cyst are usually filled with mucinous material, and friable papillary excrescences may be present. A small subset of mucinous borderline neoplasms may be associated with an endometriotic cyst, in which case the gross appearance may have areas characteristic of a typical chocolate cyst. Solid areas should be carefully sampled to rule out invasive carcinoma.

Microscopic pathology — Mucinous borderline neoplasm, like all borderline neoplasms, is comprised of cysts and glands that are lined by a proliferative and stratified epithelium that may exhibit tufting and a villoglandular or cribriform growth pattern, but without an invasive component (picture 9). Mucinous borderline neoplasm is classified based upon the histologic appearance of the epithelial lining with two general types: the gastrointestinal type and the endocervical, or seromucinous, type.

Most mucinous borderline neoplasms are of the gastrointestinal type, in which the proliferating mucinous cells have a gastrointestinal-type appearance, most commonly that of goblet cells [82,84]. However, a subset have a similar overall architecture, but are lined by cells with an endocervical and/or ciliated appearance [119]. The epithelial lining of both the gastrointestinal type and the endocervical type have only mild to moderate cytologic atypia and no invasive carcinoma is identified. If a mucinous borderline neoplasm exhibits marked nuclear atypia but lacks invasion, it is considered a mucinous borderline neoplasm with high-grade intraepithelial neoplasia. Some experts refer to these as having intraepithelial carcinoma, although in our institution we prefer the term high-grade intraepithelial neoplasia, given the lack of stromal invasion.

Like serous borderline neoplasms, approximately 10 to 20 percent of mucinous borderline neoplasms exhibit microinvasion. This is defined as single cells, clusters, or haphazard nests of cells that invade and destroy the underlying stroma with a size less than 5 mm. If definite stromal invasion greater than 5 mm is identified, the neoplasm should be classified as an invasive carcinoma. Unlike serous borderline neoplasms, peritoneal implants have not been associated with mucinous borderline neoplasms [120]. If peritoneal mucinous lesions are present, the primary neoplasm is most likely extraovarian carcinoma in origin and other primary sites should be sought.

Immunophenotype — Ovarian mucinous neoplasms of the gastrointestinal type, whether a cystadenoma, borderline neoplasm, or invasive carcinoma, are characterized by CK7, CK20, and CDX2 expression and lack of estrogen receptor, progesterone receptor, and WT-1. Mucinous borderline neoplasms of the endocervical type express CK7, ER, and PR, and lack CK20, CDX2, and WT1 [95].

Molecular biology — Mucinous borderline neoplasms have been shown to harbor the identical KRAS mutations, as those seen in mucinous cystadenomas and in mucinous carcinomas. These molecular data further support the morphological impression of a continuum of tumor progression in ovarian mucinous neoplasia from cystadenoma to borderline neoplasm to invasive carcinoma [103]. Furthermore, the pattern of gene expression of mucinous neoplasms of the ovary have also been determined to be distinct from that seen in serous, endometrioid, and clear cell carcinomas of the ovary, lending support to the idea that the epithelial ovarian neoplasms are indeed distinct entities.

ENDOMETRIOID BORDERLINE NEOPLASM

Prevalence and disease characteristics — As with serous and mucinous neoplasms, a neoplasm with a biologic potential between cystadenomas/adenofibromas and invasive endometrioid adenocarcinoma of the ovary with an endometrioid morphology has been reported [121]. These endometrioid borderline neoplasms are uncommon (2 to 10 percent of all borderline neoplasms) and occur most commonly in postmenopausal patients. The majority of endometrioid borderline neoplasms are unilateral and present with early-stage disease, and the prognosis is excellent [122].

Gross pathology — Grossly, endometrioid borderline neoplasms are similar to benign endometrioid cystadenomas and adenofibromas. The neoplasm is generally firm with a smooth surface, and multiple small cysts with clear or hemorrhagic fluid are often identified. Areas of necrosis should not be present, and if identified, should raise concern for carcinoma.

Microscopic pathology — Histologically, most endometrioid borderline neoplasm have an adenofibromatous pattern with a nodular architecture. However, unlike adenofibromas, the epithelial component is more proliferative and often has an appearance similar to that seen in complex atypical hyperplasia of the endometrium (picture 10). Squamous morules are common and can make it challenging to differentiate between borderline endometrioid neoplasm and invasive endometrioid carcinoma. The criteria for making this designation are the same as those to distinguish between complex atypical hyperplasia and well-differentiated endometrioid adenocarcinoma of the endometrium: extensive gland fusion without intervening stroma, gland cribriforming, extensive papillary/villoglandular architecture, and maze-like lumens are considered surrogate markers of invasion [123,124]. Microinvasion in endometrioid borderline neoplasms can also be encountered and is defined by destructive stromal invasion less than 5 mm in size. Similarly, high-grade intraepithelial neoplasia has been described with high-grade cytologic features, but with the expected borderline architectural features.

Immunophenotype and molecular biology — As in the other histologic subtypes of borderline neoplasms, the immunophenotype and molecular biology are similar to that seen in endometrioid adenocarcinomas of the ovary, including PTEN, CTNN-B1, PI3CA, and ARID1A mutations, and high levels of microsatellite instability [50,54,55,125]. These immunohistochemical and genetic data lend further support to the notion that there is a continuum in tumor progression from endometrioid cystadenoma to endometrioid borderline neoplasm to endometrioid adenocarcinoma.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian, fallopian tube, and peritoneal cancer".)

SUMMARY

Epithelial carcinoma is the most common histologic types of malignant neoplasm of the ovary, fallopian tube, and peritoneum, accounting for 90 percent of all ovarian cancers. Noninvasive or borderline neoplastic counterparts exist for some subtypes. (See 'Introduction' above.)

The five main subtypes of epithelial ovarian, fallopian tube, and peritoneal carcinomas and their relative proportions are: high-grade serous carcinoma (HGSC; 70 percent); endometrioid carcinoma (10 percent); clear cell carcinoma (10 percent); low-grade serous carcinoma (LGSC; <5 percent); and mucinous carcinoma (3 percent). (See 'Overview' above.)

HGSC is the most common type of cancer of the ovary, fallopian tube, and peritoneum. Most HGSC is stage III or IV at diagnosis and has a poor prognosis. Molecular evidence supports that transitional cell carcinoma is a subset of HGSC in which the epithelium is morphologically similar to malignant urothelium. (See 'High-grade serous carcinoma' above and 'Transitional cell carcinoma' above.)

LGSC is typically diagnosed at an advanced stage. However, these neoplasms are biologically distinct from HGSC and are slow-growing, indolent neoplasms with relative insensitivity to platinum-based chemotherapy. LGSC is often found along with a noninvasive serous borderline component. Borderline serous neoplasms are more common than LGSC, and LGSC most likely represents progression of a serous borderline neoplasm. (See 'Low-grade serous carcinoma' above and 'Serous borderline neoplasm' above.)

Endometrioid carcinomas are typically low-grade and most often identified at an early stage. They are relatively sensitive to platinum chemotherapy. These factors contribute to a better prognosis, in general, than for serous carcinomas. However, high-grade endometrioid carcinoma is likely not a distinct neoplasm, but rather a subtype of HGSC. (See 'Endometrioid carcinoma' above.)

Endometrioid ovarian carcinoma is associated with carcinoma of the endometrium in 15 to 20 percent of cases. In such cases, it must be determined whether the primary site is the ovary or the uterus, or whether there are synchronous neoplasms at both sites (table 2). (See 'Endometrioid carcinoma' above.)

Both ovarian endometrioid carcinoma and clear cell carcinoma are associated with endometriosis and adenofibromas of the ovary. (See 'Endometrioid carcinoma' above and 'Clear cell carcinoma' above.)

Primary mucinous carcinoma of the ovary is uncommon. It is usually unilateral, presents at an early stage, and does not cause pseudomyxoma peritonei. However, other mucinous neoplasms of the ovary account for 10 to 15 percent of all ovarian neoplasms. These include: benign mucinous cystadenomas, mucinous borderline neoplasms, and metastases, most frequently from the gastrointestinal tract. (See 'Mucinous carcinoma' above.)

Borderline neoplasms of the ovary have variably proliferative epithelium and a biologic potential between that of a benign cystadenoma and invasive carcinoma. Borderline neoplasms can display numerous histologic subtypes, including serous borderline neoplasm (most common), mucinous borderline neoplasm, and endometrioid borderline neoplasm. (See 'Overview of borderline neoplasms' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Lee-may Chen, MD and Jonathan S Berek, MD, MMS, who contributed to earlier versions of this topic review.

  1. Heintz AP, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. J Epidemiol Biostat 2001; 6:107.
  2. Banks E. The epidemiology of ovarian cancer. Methods Mol Med 2001; 39:3.
  3. Lee K, Tavassoli FA, Prat J, et al. Tumors of the ovary and peritoneum. In: World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Breast and Female Genital Organs, IARC Press, Lyon, France 2003. p.117.
  4. Cannistra SA. Cancer of the ovary. N Engl J Med 2004; 351:2519.
  5. WHO Classification of Tumours Editorial Board. Female Genital Tumours, 5th ed, IARC, 2020. Vol 4.
  6. Singer G, Oldt R 3rd, Cohen Y, et al. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 2003; 95:484.
  7. Singer G, Stöhr R, Cope L, et al. Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation. Am J Surg Pathol 2005; 29:218.
  8. Folkins AK, Jarboe EA, Saleemuddin A, et al. A candidate precursor to pelvic serous cancer (p53 signature) and its prevalence in ovaries and fallopian tubes from women with BRCA mutations. Gynecol Oncol 2008; 109:168.
  9. Jarboe E, Folkins A, Nucci MR, et al. Serous carcinogenesis in the fallopian tube: a descriptive classification. Int J Gynecol Pathol 2008; 27:1.
  10. Jarboe EA, Folkins AK, Drapkin R, et al. Tubal and ovarian pathways to pelvic epithelial cancer: a pathological perspective. Histopathology 2009; 55:619.
  11. Kindelberger DW, Lee Y, Miron A, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol 2007; 31:161.
  12. Laury AR, Ning G, Quick CM, et al. Fallopian tube correlates of ovarian serous borderline tumors. Am J Surg Pathol 2011; 35:1759.
  13. Lee Y, Miron A, Drapkin R, et al. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol 2007; 211:26.
  14. Medeiros F, Muto MG, Lee Y, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 2006; 30:230.
  15. Kurman RJ, Vang R, Junge J, et al. Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis. Am J Surg Pathol 2011; 35:1605.
  16. Prat J, FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet 2014; 124:1.
  17. Köbel M, Kalloger SE, Huntsman DG, et al. Differences in tumor type in low-stage versus high-stage ovarian carcinomas. Int J Gynecol Pathol 2010; 29:203.
  18. Kurman RJ. Origin and molecular pathogenesis of ovarian high-grade serous carcinoma. Ann Oncol 2013; 24 Suppl 10:x16.
  19. Blaustein's Pathology of the Female Genital Tract, 6th ed, Kurman RJ, Ellenson LH, Ronnett RM (Eds), Springer, New York 2011.
  20. Li J, Fadare O, Xiang L, et al. Ovarian serous carcinoma: recent concepts on its origin and carcinogenesis. J Hematol Oncol 2012; 5:8.
  21. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361:123.
  22. Ford D, Easton DF, Bishop DT, et al. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 1994; 343:692.
  23. Hennessy BT, Timms KM, Carey MS, et al. Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol 2010; 28:3570.
  24. King MC, Marks JH, Mandell JB, New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003; 302:643.
  25. Pal T, Permuth-Wey J, Betts JA, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer 2005; 104:2807.
  26. Risch HA, McLaughlin JR, Cole DE, et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 2006; 98:1694.
  27. Norquist BM, Garcia RL, Allison KH, et al. The molecular pathogenesis of hereditary ovarian carcinoma: alterations in the tubal epithelium of women with BRCA1 and BRCA2 mutations. Cancer 2010; 116:5261.
  28. Ahmed AA, Etemadmoghadam D, Temple J, et al. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J Pathol 2010; 221:49.
  29. Herrington CS, McCluggage WG. The emerging role of the distal Fallopian tube and p53 in pelvic serous carcinogenesis. J Pathol 2010; 220:5.
  30. Kurman RJ, Shih IeM. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 2010; 34:433.
  31. Vang R, Shih IeM, Kurman RJ. Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Adv Anat Pathol 2009; 16:267.
  32. Merajver SD, Pham TM, Caduff RF, et al. Somatic mutations in the BRCA1 gene in sporadic ovarian tumours. Nat Genet 1995; 9:439.
  33. Willner J, Wurz K, Allison KH, et al. Alternate molecular genetic pathways in ovarian carcinomas of common histological types. Hum Pathol 2007; 38:607.
  34. Nakayama K, Nakayama N, Kurman RJ, et al. Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms. Cancer Biol Ther 2006; 5:779.
  35. Gershenson DM, Sun CC, Lu KH, et al. Clinical behavior of stage II-IV low-grade serous carcinoma of the ovary. Obstet Gynecol 2006; 108:361.
  36. Gershenson DM, Sun CC, Bodurka D, et al. Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecol Oncol 2009; 114:48.
  37. Schmeler KM, Sun CC, Malpica A, et al. Low-grade serous primary peritoneal carcinoma. Gynecol Oncol 2011; 121:482.
  38. Malpica A, Deavers MT, Lu K, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol 2004; 28:496.
  39. Malpica A, Deavers MT, Tornos C, et al. Interobserver and intraobserver variability of a two-tier system for grading ovarian serous carcinoma. Am J Surg Pathol 2007; 31:1168.
  40. McKenney JK, Gilks CB, Kalloger S, Longacre TA. Classification of Extraovarian Implants in Patients With Ovarian Serous Borderline Tumors (Tumors of Low Malignant Potential) Based on Clinical Outcome. Am J Surg Pathol 2016; 40:1155.
  41. Kuo KT, Guan B, Feng Y, et al. Analysis of DNA copy number alterations in ovarian serous tumors identifies new molecular genetic changes in low-grade and high-grade carcinomas. Cancer Res 2009; 69:4036.
  42. Bonome T, Lee JY, Park DC, et al. Expression profiling of serous low malignant potential, low-grade, and high-grade tumors of the ovary. Cancer Res 2005; 65:10602.
  43. Bodurka DC, Deavers MT, Tian C, et al. Reclassification of serous ovarian carcinoma by a 2-tier system: a Gynecologic Oncology Group Study. Cancer 2012; 118:3087.
  44. Seidman JD, Kurman RJ. Pathology of ovarian carcinoma. Hematol Oncol Clin North Am 2003; 17:909.
  45. Seidman JD, Horkayne-Szakaly I, Haiba M, et al. The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin. Int J Gynecol Pathol 2004; 23:41.
  46. Prat J. (Saunders, Philadelphia, 2004).
  47. Tothill RW, Tinker AV, George J, et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res 2008; 14:5198.
  48. Bell DA, Weinstock MA, Scully RE. Peritoneal implants of ovarian serous borderline tumors. Histologic features and prognosis. Cancer 1988; 62:2212.
  49. Diagnostic pathology of ovarian tumors, Soslow RA, Tornos C (Eds), Springer Science, New York 2011.
  50. Catasús L, Bussaglia E, Rodrguez I, et al. Molecular genetic alterations in endometrioid carcinomas of the ovary: similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations than in uterine endometrioid carcinomas. Hum Pathol 2004; 35:1360.
  51. Obata K, Morland SJ, Watson RH, et al. Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Res 1998; 58:2095.
  52. Palacios J, Gamallo C. Mutations in the beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas. Cancer Res 1998; 58:1344.
  53. Irving JA, Catasús L, Gallardo A, et al. Synchronous endometrioid carcinomas of the uterine corpus and ovary: alterations in the beta-catenin (CTNNB1) pathway are associated with independent primary tumors and favorable prognosis. Hum Pathol 2005; 36:605.
  54. Moreno-Bueno G, Gamallo C, Pérez-Gallego L, et al. beta-Catenin expression pattern, beta-catenin gene mutations, and microsatellite instability in endometrioid ovarian carcinomas and synchronous endometrial carcinomas. Diagn Mol Pathol 2001; 10:116.
  55. Sato N, Tsunoda H, Nishida M, et al. Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res 2000; 60:7052.
  56. Wu R, Zhai Y, Fearon ER, Cho KR. Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas. Cancer Res 2001; 61:8247.
  57. Wu R, Hendrix-Lucas N, Kuick R, et al. Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/beta-catenin and PI3K/Pten signaling pathways. Cancer Cell 2007; 11:321.
  58. Lemon B, Inouye C, King DS, Tjian R. Selectivity of chromatin-remodelling cofactors for ligand-activated transcription. Nature 2001; 414:924.
  59. Gras E, Catasus L, Argüelles R, et al. Microsatellite instability, MLH-1 promoter hypermethylation, and frameshift mutations at coding mononucleotide repeat microsatellites in ovarian tumors. Cancer 2001; 92:2829.
  60. Sugiyama T, Kamura T, Kigawa J, et al. Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy. Cancer 2000; 88:2584.
  61. Goff BA, Sainz de la Cuesta R, Muntz HG, et al. Clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy in stage III disease. Gynecol Oncol 1996; 60:412.
  62. Chan JK, Teoh D, Hu JM, et al. Do clear cell ovarian carcinomas have poorer prognosis compared to other epithelial cell types? A study of 1411 clear cell ovarian cancers. Gynecol Oncol 2008; 109:370.
  63. Tan DS, Kaye S. Ovarian clear cell adenocarcinoma: a continuing enigma. J Clin Pathol 2007; 60:355.
  64. Jenison EL, Montag AG, Griffiths CT, et al. Clear cell adenocarcinoma of the ovary: a clinical analysis and comparison with serous carcinoma. Gynecol Oncol 1989; 32:65.
  65. del Carmen MG, Birrer M, Schorge JO. Clear cell carcinoma of the ovary: a review of the literature. Gynecol Oncol 2012; 126:481.
  66. Kurian AW, Balise RR, McGuire V, Whittemore AS. Histologic types of epithelial ovarian cancer: have they different risk factors? Gynecol Oncol 2005; 96:520.
  67. Veras E, Mao TL, Ayhan A, et al. Cystic and adenofibromatous clear cell carcinomas of the ovary: distinctive tumors that differ in their pathogenesis and behavior: a clinicopathologic analysis of 122 cases. Am J Surg Pathol 2009; 33:844.
  68. Yamamoto S, Tsuda H, Takano M, et al. Clear-cell adenofibroma can be a clonal precursor for clear-cell adenocarcinoma of the ovary: a possible alternative ovarian clear-cell carcinogenic pathway. J Pathol 2008; 216:103.
  69. Yamamoto S, Tsuda H, Takano M, et al. Expression of platelet-derived growth factors and their receptors in ovarian clear-cell carcinoma and its putative precursors. Mod Pathol 2008; 21:115.
  70. Czernobilsky B, Silverman BB, Enterline HT. Clear-cell carcinoma of the ovary. A clinicopathologic analysis of pure and mixed forms and comparison with endometrioid carcinoma. Cancer 1970; 25:762.
  71. Lee S, Garner EI, Welch WR, et al. Over-expression of hypoxia-inducible factor 1 alpha in ovarian clear cell carcinoma. Gynecol Oncol 2007; 106:311.
  72. Stadlmann S, Gueth U, Baumhoer D, et al. Glypican-3 expression in primary and recurrent ovarian carcinomas. Int J Gynecol Pathol 2007; 26:341.
  73. Kato N, Sasou S, Motoyama T. Expression of hepatocyte nuclear factor-1beta (HNF-1beta) in clear cell tumors and endometriosis of the ovary. Mod Pathol 2006; 19:83.
  74. Kalloger SE, Köbel M, Leung S, et al. Calculator for ovarian carcinoma subtype prediction. Mod Pathol 2011; 24:512.
  75. Köbel M, Kalloger SE, Carrick J, et al. A limited panel of immunomarkers can reliably distinguish between clear cell and high-grade serous carcinoma of the ovary. Am J Surg Pathol 2009; 33:14.
  76. Amemiya S, Sekizawa A, Otsuka J, et al. Malignant transformation of endometriosis and genetic alterations of K-ras and microsatellite instability. Int J Gynaecol Obstet 2004; 86:371.
  77. Kuo KT, Mao TL, Jones S, et al. Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. Am J Pathol 2009; 174:1597.
  78. Jensen KC, Mariappan MR, Putcha GV, et al. Microsatellite instability and mismatch repair protein defects in ovarian epithelial neoplasms in patients 50 years of age and younger. Am J Surg Pathol 2008; 32:1029.
  79. Cai KQ, Albarracin C, Rosen D, et al. Microsatellite instability and alteration of the expression of hMLH1 and hMSH2 in ovarian clear cell carcinoma. Hum Pathol 2004; 35:552.
  80. Wiegand KC, Shah SP, Al-Agha OM, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 2010; 363:1532.
  81. Hart WR, Norris HJ. Borderline and malignant mucinous tumors of the ovary. Histologic criteria and clinical behavior. Cancer 1973; 31:1031.
  82. Riopel MA, Ronnett BM, Kurman RJ. Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors: atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinomas. Am J Surg Pathol 1999; 23:617.
  83. Hoerl HD, Hart WR. Primary ovarian mucinous cystadenocarcinomas: a clinicopathologic study of 49 cases with long-term follow-up. Am J Surg Pathol 1998; 22:1449.
  84. Lee KR, Scully RE. Mucinous tumors of the ovary: a clinicopathologic study of 196 borderline tumors (of intestinal type) and carcinomas, including an evaluation of 11 cases with 'pseudomyxoma peritonei'. Am J Surg Pathol 2000; 24:1447.
  85. Bladt O, De Man R, Aerts R. Mucinous cystadenoma of the ovary. JBR-BTR 2004; 87:118.
  86. de Nictolis M, Montironi R, Tommasoni S, et al. Benign, borderline, and well-differentiated malignant intestinal mucinous tumors of the ovary: a clinicopathologic, histochemical, immunohistochemical, and nuclear quantitative study of 57 cases. Int J Gynecol Pathol 1994; 13:10.
  87. Hart WR. Mucinous tumors of the ovary: a review. Int J Gynecol Pathol 2005; 24:4.
  88. Prayson RA, Hart WR, Petras RE. Pseudomyxoma peritonei. A clinicopathologic study of 19 cases with emphasis on site of origin and nature of associated ovarian tumors. Am J Surg Pathol 1994; 18:591.
  89. Young RH, Gilks CB, Scully RE. Mucinous tumors of the appendix associated with mucinous tumors of the ovary and pseudomyxoma peritonei. A clinicopathological analysis of 22 cases supporting an origin in the appendix. Am J Surg Pathol 1991; 15:415.
  90. McKenney JK, Soslow RA, Longacre TA. Ovarian mature teratomas with mucinous epithelial neoplasms: morphologic heterogeneity and association with pseudomyxoma peritonei. Am J Surg Pathol 2008; 32:645.
  91. Ronnett BM, Seidman JD. Mucinous tumors arising in ovarian mature cystic teratomas: relationship to the clinical syndrome of pseudomyxoma peritonei. Am J Surg Pathol 2003; 27:650.
  92. Rodríguez IM, Prat J. Mucinous tumors of the ovary: a clinicopathologic analysis of 75 borderline tumors (of intestinal type) and carcinomas. Am J Surg Pathol 2002; 26:139.
  93. Vang R, Gown AM, Barry TS, et al. Cytokeratins 7 and 20 in primary and secondary mucinous tumors of the ovary: analysis of coordinate immunohistochemical expression profiles and staining distribution in 179 cases. Am J Surg Pathol 2006; 30:1130.
  94. Baker PM, Oliva E. Immunohistochemistry as a tool in the differential diagnosis of ovarian tumors: an update. Int J Gynecol Pathol 2005; 24:39.
  95. McCluggage WG. Immunohistochemical and functional biomarkers of value in female genital tract lesions. Int J Gynecol Pathol 2006; 25:101.
  96. Vang R, Gown AM, Wu LS, et al. Immunohistochemical expression of CDX2 in primary ovarian mucinous tumors and metastatic mucinous carcinomas involving the ovary: comparison with CK20 and correlation with coordinate expression of CK7. Mod Pathol 2006; 19:1421.
  97. Vang R, Gown AM, Barry TS, et al. Immunohistochemistry for estrogen and progesterone receptors in the distinction of primary and metastatic mucinous tumors in the ovary: an analysis of 124 cases. Mod Pathol 2006; 19:97.
  98. Vang R, Gown AM, Farinola M, et al. p16 expression in primary ovarian mucinous and endometrioid tumors and metastatic adenocarcinomas in the ovary: utility for identification of metastatic HPV-related endocervical adenocarcinomas. Am J Surg Pathol 2007; 31:653.
  99. Gemignani ML, Schlaerth AC, Bogomolniy F, et al. Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma. Gynecol Oncol 2003; 90:378.
  100. Mayr D, Hirschmann A, Löhrs U, Diebold J. KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants. Gynecol Oncol 2006; 103:883.
  101. Cuatrecasas M, Villanueva A, Matias-Guiu X, Prat J. K-ras mutations in mucinous ovarian tumors: a clinicopathologic and molecular study of 95 cases. Cancer 1997; 79:1581.
  102. Shi H, Wang MX, Caldwell CW. CpG islands: their potential as biomarkers for cancer. Expert Rev Mol Diagn 2007; 7:519.
  103. Kurman RJ, Shih IeM. Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications. Int J Gynecol Pathol 2008; 27:151.
  104. Ali RH, Seidman JD, Luk M, et al. Transitional cell carcinoma of the ovary is related to high-grade serous carcinoma and is distinct from malignant brenner tumor. Int J Gynecol Pathol 2012; 31:499.
  105. Cuatrecasas M, Catasus L, Palacios J, Prat J. Transitional cell tumors of the ovary: a comparative clinicopathologic, immunohistochemical, and molecular genetic analysis of Brenner tumors and transitional cell carcinomas. Am J Surg Pathol 2009; 33:556.
  106. Logani S, Oliva E, Amin MB, et al. Immunoprofile of ovarian tumors with putative transitional cell (urothelial) differentiation using novel urothelial markers: histogenetic and diagnostic implications. Am J Surg Pathol 2003; 27:1434.
  107. Riedel I, Czernobilsky B, Lifschitz-Mercer B, et al. Brenner tumors but not transitional cell carcinomas of the ovary show urothelial differentiation: immunohistochemical staining of urothelial markers, including cytokeratins and uroplakins. Virchows Arch 2001; 438:181.
  108. Silasi DA, Illuzzi JL, Kelly MG, et al. Carcinosarcoma of the ovary. Int J Gynecol Cancer 2008; 18:22.
  109. Mano MS, Rosa DD, Azambuja E, et al. Current management of ovarian carcinosarcoma. Int J Gynecol Cancer 2007; 17:316.
  110. Shih IeM, Kurman RJ. Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol 2004; 164:1511.
  111. Segal GH, Hart WR. Ovarian serous tumors of low malignant potential (serous borderline tumors). The relationship of exophytic surface tumor to peritoneal "implants". Am J Surg Pathol 1992; 16:577.
  112. Seidman JD, Kurman RJ. Ovarian serous borderline tumors: a critical review of the literature with emphasis on prognostic indicators. Hum Pathol 2000; 31:539.
  113. Skírnisdóttir I, Garmo H, Wilander E, Holmberg L. Borderline ovarian tumors in Sweden 1960-2005: trends in incidence and age at diagnosis compared to ovarian cancer. Int J Cancer 2008; 123:1897.
  114. Hart WR. Borderline epithelial tumors of the ovary. Mod Pathol 2005; 18 Suppl 2:S33.
  115. Jones MB. Borderline ovarian tumors: current concepts for prognostic factors and clinical management. Clin Obstet Gynecol 2006; 49:517.
  116. Longacre TA, McKenney JK, Tazelaar HD, et al. Ovarian serous tumors of low malignant potential (borderline tumors): outcome-based study of 276 patients with long-term (> or =5-year) follow-up. Am J Surg Pathol 2005; 29:707.
  117. Kaern J, Tropé CG, Abeler VM. A retrospective study of 370 borderline tumors of the ovary treated at the Norwegian Radium Hospital from 1970 to 1982. A review of clinicopathologic features and treatment modalities. Cancer 1993; 71:1810.
  118. Sherman ME, Berman J, Birrer MJ, et al. Current challenges and opportunities for research on borderline ovarian tumors. Hum Pathol 2004; 35:961.
  119. Lee KR, Nucci MR. Ovarian mucinous and mixed epithelial carcinomas of mullerian (endocervical-like) type: a clinicopathologic analysis of four cases of an uncommon variant associated with endometriosis. Int J Gynecol Pathol 2003; 22:42.
  120. Ronnett BM, Kajdacsy-Balla A, Gilks CB, et al. Mucinous borderline ovarian tumors: points of general agreement and persistent controversies regarding nomenclature, diagnostic criteria, and behavior. Hum Pathol 2004; 35:949.
  121. Norris HJ. Proliferative endometrioid tumors and endometrioid tumors of low malignant potential of the ovary. Int J Gynecol Pathol 1993; 12:134.
  122. Bell KA, Kurman RJ. A clinicopathologic analysis of atypical proliferative (borderline) tumors and well-differentiated endometrioid adenocarcinomas of the ovary. Am J Surg Pathol 2000; 24:1465.
  123. Chen S, Leitao MM, Tornos C, Soslow RA. Invasion patterns in stage I endometrioid and mucinous ovarian carcinomas: a clinicopathologic analysis emphasizing favorable outcomes in carcinomas without destructive stromal invasion and the occasional malignant course of carcinomas with limited destructive stromal invasion. Mod Pathol 2005; 18:903.
  124. Roth LM, Emerson RE, Ulbright TM. Ovarian endometrioid tumors of low malignant potential: a clinicopathologic study of 30 cases with comparison to well-differentiated endometrioid adenocarcinoma. Am J Surg Pathol 2003; 27:1253.
  125. Oliva E, Sarrió D, Brachtel EF, et al. High frequency of beta-catenin mutations in borderline endometrioid tumours of the ovary. J Pathol 2006; 208:708.
Topic 3241 Version 37.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟