Gynecologic Oncology: Clinical Practice and Surgical Atlas, 1st Ed.

Epithelial Ovarian Cancers: Low Malignant Potential and Non-Serous Ovarian Histologies

Gregory P. Sfakianos, Angeles Alvarez Secord, and Ie-Ming Shih

Epithelial ovarian cancer is the leading cause of death from gynecologic cancers and the fifth leading cause of all cancer-related deaths among women. The American Cancer Society estimates that 21,880 new cases of ovarian cancer will be diagnosed and 13,850 women will die of the disease in the United States in 2010.1 Approximately 90% of epithelial ovarian cancers are derived from coelomic epithelium of the ovary, fallopian tube, or peritoneum. Epithelial ovarian cancers are heterogeneous and comprise a group of neoplasms that differ based on their histopathologic and molecular features, as well as their clinical behavior.2,3 These include low malignancy potential (LMP) tumors and frankly invasive malignant neoplasms. Malignant ovarian cancers can be further subdivided into 2 distinct groups based on their morphologic and molecular genetics features. Type I tumors include low-grade serous, mucinous, low-grade endometrioid, clear cell, and transitional (Brenner) carcinomas. Conversely, type II tumors include high-grade serous carcinoma, high-grade endometrioid carcinoma, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas.4 Type II tumors are characterized as highly aggressive, evolving rapidly, and uniformly having poor outcomes. In contrast, LMP and type I tumors tend to be diagnosed at an earlier stage, behave in an indolent fashion, and have a better prognosis.


Key Points

1. Women with mucinous, endometrioid, clear cell, and low-grade serous ovarian cancers present at a younger age than women with high-grade serous ovarian, tubal, and peritoneal cancers.

2. Mucinous, endometrioid, clear cell, and low-grade serous cancers progress in a stepwise manner from precursor lesions to invasive disease.

3. Type I and type II ovarian cancers may be distinguished by specific and distinct genetic alterations.

Approximately 15% to 20% of all epithelial neoplasms are LMP (also referred to as borderline) tumors, and type I tumors account for 25% of malignant epithelial ovarian cancers (Figure 13-1).4-6 High-grade serous ovarian, primary peritoneal, and tubal carcinomas are treated in a similar fashion and are discussed in Chapter 12. The histologic subsets of both type I and II tumors comprise 42% serous, including 2% to 10% low-grade serous carcinomas, 7% to 20% endometrioid, 17% undifferentiated, 3% to 12% clear cell carcinoma, and 3.5% to 12% mucinous (Figure 13-2).6-13 Transitional-cell tumors consist of both Brenner tumors and transitional-cell carcinomas and are exceedingly rare. Only 2% of all epithelial ovarian cancers are Brenner tumors.


FIGURE 13-1. Representative examples of type I epithelial ovarian tumors. A. Low-grade serous carcinoma. B. Clear cell carcinoma. C. Mucinous carcinoma. D. Low-grade endometrioid carcinoma. (Images contributed by Sonam Loghavi, MD and Denise Barbuto, MD, PhD.)


FIGURE 13-2. Histologic subsets for type I and II tumors.6-13

Risk factors for type I epithelial ovarian cancers are similar to those with type II disease (see Chapter 12). However, there are differences with regard to certain risk factors between the 2 subtypes. Age is the strongest patient-related risk factor for ovarian cancer and is a prime example of differences between type I and II tumors. In general, epithelial ovarian cancer is a disease of postmenopausal women, with the median age of diagnosis at 63 years. However, women with type I cancers tend to be younger as compared with those women with type II disease.14-16 Specifically, the mean age in women with mucinous ovarian cancer is 52 years; endometrioid, 57 to 60 years; clear cell, 53 years; and low-grade serous carcinomas, 55 years.8,12,15-18 Similarly, patients with LMP tumors are relatively young, with a mean age of 38 years (range, 17-77 years).19

Although the differences between LMP tumors and malignant epithelial ovarian cancers are well recognized, the distinction between type I from type II disease is more recent. The stratification of types I and II tumors is based on mounting evidence that demonstrates that the pathogenesis, molecular biology, and clinical behavior of these cancers are not similar.20 Type I tumors progress in a stepwise manner from well-defined precursor lesions (benign and LMP tumors) to malignant cancer.21 This stepwise histopathologic progression is often accompanied by an accumulation of genetic mutations that result in the deregulation of critical pathways involved in cellular growth and proliferation and ultimately lead to carcinogenesis. The stepwise sequence from a benign lesion to an LMP tumor to a type I ovarian cancer parallels the widely accepted and recognized sequence seen in colorectal cancers, where an adenomatous lesion can evolve into a carcinoma after a series of genetic alterations.21 Specifically, low-grade serous carcinomas often arise from cystadenomas and cystadenofibromas, which may transform to serous LMP tumors and micropapillary serous carcinomas. In contrast, although the precursor lesion of high-grade serous carcinomas is largely unknown, recent evidence implicates tubal intraepithelial carcinoma as the originating lesion (Figure 13-3).22-37 It may be that both low-grade and high-grade serous carcinomas are of tubal origin and the ovary is secondarily involved (Figure 13-4). Kurman and Shih5 have proposed that tubal epithelium may be directly implanted into the ovary to form an inclusion cyst and can develop into either a low-grade or high-grade serous cancer, depending on the type of genetic alteration incurred.


FIGURE 13-3. The dualistic pathways in the development of high-grade and low-grade serous carcinoma. Schematic illustration of type I and type II ovarian serous carcinoma pathogenesis. Development of ovarian high-grade (HGSC) and low-grade serous carcinomas (LGSC) involves 2 distinct pathways. LGSCs arise from serous low malignant potential tumors, which in turn develop from serous cystadenomas. This stepwise tumor progression in the low-grade pathway contrasts with the rapid progression pathway of high-grade (type II) carcinomas, for which precursor lesions are not well recognized. APST, atypical proliferative serous tumor; CIN, chromosomal instability; LOH, loss of heterozygosity; MPSC, micropapillary serous carcinoma. (Images contributed by Sonam Loghavi, MD and Denise Barbuto, MD, PhD.)


FIGURE 13-4. Proposed development of low-grade serous carcinoma (LGSC) and high-grade serious carcinoma (HGSC). One mechanism involves normal tubal epithelium from the fimbria, which implants on the ovary to form an inclusion cyst. Depending on whether there is a mutation of KRAS/BRAF/Her2/neu or TP53, an LGSC or HGSC develops, respectively. LGSC often develops from a serous low malignant potential tumors, which in turn arises from a serous cystadenoma. Another mechanism involves exfoliation of malignant cells from a serous tubal intraepithelial carcinoma (STIC) that implants on the ovarian surface, resulting in the development of an HGSC.

Endometrioid and clear cell ovarian cancers also develop from a stepwise histopathologic progression from endometriosis to benign endometrioid neoplasm to well-differentiated carcinoma (Figure 13-5).38 Endometrioid and clear cell cancers most likely originate from endometrial tissue and/or endometriotic implants that via retrograde menstruation become implanted on the ovary or peritoneum (Figure 13-6).21 The ovarian endometrioid adenoma-carcinoma model of progression may be accompanied by a progressive molecular deregulation of the Wnt/β-catenin/Tcf and PI3KCA/AKT/PTEN pathways for low-grade tumors (Figure 13-7).


FIGURE 13-5. Low-grade endometrioid carcinomas often arise from endometrioid borderline tumors, which in turn may arise from endometriosis. This stepwise histopathologic progression is often accompanied by accumulation of mutations predicted to deregulate canonical Wnt/β-catenin/Tcf (Wnt) signaling (usually CTNNB1) and/or PI3KCA/AKT/PTEN signaling (PTEN, PIK3CA). (Reproduced, with permission, from Cho and Shih.3)


FIGURE 13-6. Schematic representation of the proposed development of clear cell and low-grade endometrioid carcinoma. Endometrial tissue, by a process of retrograde menstruation, implants on the ovarian surface to form an endometriotic cyst, from which a clear cell and low-grade endometrioid carcinoma can develop. CCC, clear cell carcinoma of the ovary; EMC, endometrioid carcinoma of the ovary.


FIGURE 13-7. Activating mutations of PIK3CA or inactivating mutations of PTEN result in activation of AKT-mediated signaling to downstream effectors that affect protein synthesis. mTOR, mammalian target of rapamycin; PDK1, 3-phosphoinositide-dependent kinase 1; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PI3K, phosphoinositide-3-kinase; PIK3CA, phosphoinositide-3-kinase (PI3K), catalytic, alpha polypeptide; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase.

Furthermore, mucinous neoplasms have striking histopathologic and molecular similarities between benign and malignant mucinous tumors, supporting a model of progression from benign to LMP tumors to malignant mucinous ovarian cancer (Figure 13-8). KRAS mutations are the most common mutation in mucinous ovarian carcinomas and can also be present in benign-appearing areas of mucinous tumors, adjacent to frank mucinous carcinoma, suggesting that they are an early event during carcinogenesis.39 In contrast to serous, endometrioid, and clear cell tumors, the origin of mucinous and transitional-cell (Brenner) tumors is perplexing because they do not have mullerian features.21 These tumors may develop from cortical inclusion cysts or Walthard cell nests that are composed of benign transitional-type epithelium that are frequently found in paraovarian and paratubal locations.21 In contrast, a precursor lesion for transitional-cell carcinomas has not been as clearly identified.


FIGURE 13-8. Mucinous carcinomas often arise from mucinous low malignant potential (LMP) tumors, which in turn may arise from benign mucinous cystadenomas. This stepwise histopathologic progression is accompanied by accumulation of mutations involving KRAS and BRAF. (Images contributed by Sonam Loghavi, MD and Denise Barbuto, MD, PhD.)

The histopathologic differences between LMP, type I, and type II tumors are mirrored by differences in their molecular genetic features.3,38 Although the underlying molecular biology of epithelial ovarian cancers has yet to be completely elucidated, current genomic data clearly demonstrates that LMP, type I, and type II disease are very distinct entities (See Chapter 2). LMP and type I tumors are genetically more stable than type II tumors and display specific mutations in the different histologic cell types.40 Mutations that characterize most type I tumors include Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog (BRAF), human epidermal growth factor receptor 2 (HER-2/neu [erythroblastic leukemia viral oncogene homolog 2 (ERBB2]), phosphatase and tensin homolog (PTEN), beta-catenin (CTNNB1), and phosphoinositide-3-kinase, catalytic, alpha polypeptide (PI3K-CA) mutations38 (Tables 13-1 and 13-2). In contrast, high-grade serous carcinoma, the prototypic type II tumor, is characterized by greater genetic instability, tumor protein 53 (TP53) mutations, and endcoding cyclin E1 (CCNE1) amplification (Table 13-1).38,41

Table 13-1 Genetic Features of Type I and Type II Ovarian Tumors


Table 13-2 Common Precursor Lesions and Molecular Features of Type I Carcinomas


Molecular derangements of the mitogen-activated protein kinase (MAPK) (Ras-Raf-MEK-MAPK) pathway are common in LMP, low-grade serous carcinomas, and mucinous tumors.42 The Ras-Raf-MEK-MAPK pathway plays an important role in cellular proliferation, transformation, and survival (Figure 13-9).43 Mutations of either KRAS or BRAF lead to constitutive activation of MAPK signaling. Mutations in KRAS or BRAF mutations are present in more than 50%, 68%, and 80% of serous LMP tumors, low-grade serous cancer, and mucinous LMP tumors, respectively.38,42,44 In addition, mutations of HER-2/neu (ERBB2), which activates an upstream regulator of KRAS, have also been found in 9% of LMP tumors.38 Overall, more than 70% to 80% LMP tumors express activated components of the MAPK (Ras-Raf-MEK-MAPK) pathway.


FIGURE 13-9. Schematic illustration of the Ras-Raf-MEK-ERK (mitogen-activated protein kinase [MAPK]) signaling pathway. This cell signaling pathway plays a role in cellular proliferation, transformation, and survival in response to a variety of growth and differentiation factors. Aberration of this pathway in low malignant potential tumors and low-grade serous carcinomas is mainly due to activating mutations of KRAS and BRAF, which result in constitutive activation of MAPK-mediated signaling in these tumors. Activated MAPK signaling alters expression of downstream target genes, including upregulation of cyclin D1. SBT, serous borderline tumors; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; MEK, MAPK/ERK kinase; ERK, extracellular signal-regulated kinase. (Reproduced, with permission, from Cho and Shih.3)

Other members of the MAPK pathway, including TRAF family-member-associated NF-kappa-B-activator (TANK), poly [ADP-ribose] polymerase 1 (PARP1), cell division protein kinase 2 (CDK2) and astrocytic phosphoprotein (PEA15), have been evaluated in serous LMP, micropapillary serous carcinomas, and low-grade serous tumors. Using real-time quantitative polymerase chain reaction, the differential expression of the 4 genes was not significantly different between these clinical entities, but TANKPARP1, and PEA15 were higher in the low-grade serous tumors. Significantly more intense protein expression was present for TANK and CDK2 in the low-grade serous tumors, whereas PARP1 expression was lowest in the LMP tumors.37 KRAS mutations are also the most common genetic alteration in mucinous carcinomas and are present up to 50% of these malignancies.45,46 Interestingly, KRASmutations are present in 50% of colorectal cancers.47 In contrast, KRAS or BRAF mutations are uncommon in endometrioid (7%) and clear cell cancers (6.3%) and absent in high-grade serous disease.9,48

High-grade endometrioid ovarian cancers have a similar gene expression profile to serous carcinomas, are more likely to contain TP53 mutations (> 80%),41,49 and lack alterations of the Wnt/β-catenin(CTNNB1)/Tcf or PI3K-CA/AKT/PTEN pathways.50 In contrast, the low-grade (grade 1) endometrioid tumors typically lack TP53 mutations and have mutations involving the Wnt/CTNNB1/Tcf and PIK3CA/AKT/PTEN pathways.50-53 CTNNB1 mutations are present in 38% to 58% of cases, PTEN mutations in 14% to 21% of cases, and PIK3CA mutations in 20% of endometrioid ovarian cancers. Defects in these 2 signaling pathways appear to be characteristic of low-grade endometrioid disease. Endometrioid carcinomas of the ovary are sometimes associated with hereditary nonpolyposis colon cancer syndrome in patients with germline mutations in a gene encoding a DNA mismatch repair. Microsatellite instability is present in 13% to 20% of endometrioid ovarian cancer and is typically associated with loss of hMLH1 or hMSH2 expression.3

Very recent genomic analyses of ovarian clear cell carcinoma have revealed somatic inactivating mutations of a newly identified tumor suppressor, ARID1A, in approximately half of the cases, making ARID1A mutation the molecular genetic signature in ovarian clear cell carcinoma.54,55 Similar to low-grade endometrioid carcinoma, mutations involving the PI3K-CA/AKT/PTEN signaling are common in clear cell carcinomas. PIK3CA mutations have been found in 20% to 25% to nearly 50% of clear cell tumors,3,56,57 whereas PTEN mutations have been reported in 8% of clear cell lesions.3 Interestingly, although the gene expression profiles of clear cell ovarian cancers are distinct from other type I cancers, they are remarkably similar to renal clear cell carcinomas.58 Similar to renal clear cell cancer, 50% of primary and 43% of metastatic clear cell ovarian cancers demonstrated loss of Von Hippel-Lindau (VHL) tumor suppressor gene.59 Loss of VHL function results in a marked increase in hypoxia-inducible factor-1α (HIF-1α) activity.60 HIF-1α upregulates vascular endothelial growth factor (VEGF) and fms-like tyrosine kinase-1 (Flt-1) transcription and induces increased tumor vascularity.

BRCA mutations and TP53 mutations do not seem to play a significant role in mucinous, low-grade serous, or clear cell cancers.61-63 TP53 alterations are present in only 8.3% of clear cell tumors. BRCA mutations are not common in endometrioid cancers. Neither clear cell nor low-grade serous disease have significant chromosomal instability.64 Low-grade serous cancers are usually diploid or near diploid and do not show the complex genetic abnormalities seen in HGSC.65 Serous ovarian cancers, whether low grade or high grade, have been noted to have higher protein expression of Wilms tumor protein 1 (WT1) as compared with endometrioid, clear cell, and mucinous epithelial ovarian cancer.3 The molecular changes in transitional-cell carcinomas of the ovary remain largely unknown.


Key Points

1. The majority of women with LMP and type I ovarian cancers present with earlier-stage disease.

2. The initial evaluation should include a comprehensive history and physical examination, as well as preoperative imaging and serum tumor marker testing.

3. General gynecologists should consider referral to a gynecologic oncologist when malignancy is suspected.

Approximately 70% to 80% of women with type II epithelial ovarian cancers present with advanced-stage disease at the time of diagnosis, including large-volume intra-abdominal tumor, ascites, and in some cases malignant pleural effusions. Before diagnosis, women with ovarian cancer frequently have vague, nonspecific symptoms. The most common symptoms include abdominal bloating, early satiety, heartburn, constipation, and nausea, as well as genitourinary symptoms including urinary frequency, urgency, or incontinence.66 In contrast, women with low malignant potential and type I epithelial ovarian cancers are often diagnosed with earlier-stage disease. They may have physical examination findings consistent with a large pelvic-abdominal mass, but typically do not have extensive upper abdominal disease or tense ascites.67 Nevertheless, symptoms in women with early and advanced disease are strikingly similar. Those with early disease tend to have a decreased frequency of diarrhea and lower use of antidiarrheal medications as compared with those with advanced-stage disease.68 The general gynecologist and primary care physician should have a heightened awareness regarding ovarian cancer symptoms and conduct a thorough evaluation and refer the patient to a gynecologic oncologist if warranted.

The initial evaluation and differential diagnosis is similar to those with type II epithelial ovarian cancer (see Chapter 12) and include a comprehensive history, physical examination including a pelvic and rectal evaluation, laboratory parameters, and imaging studies if needed. Tumor markers, including CA-125, carcinoembryonic antigen, and CA–19–9 may be useful. Imaging studies such as computed tomography and/or ultrasound imaging can be obtained to determine the extent of the disease and allow preparation for more radical debulking procedures such as hepatic resection and splenectomy. However, preoperative radiographic evaluation is limited in predicting a surgeon’s ability to achieve optimal cytoreduction (residual tumor < 1 cm) of metastatic ovarian neoplasms. The diagnosis of LMP tumors and type I epithelial ovarian cancer is typically made via surgical exploration. Other options for diagnosis include fine-needle aspiration and core biopsy or cytologic evaluation of pleural or ascitic fluid.

Because these diseases may present with pelvic masses and the absence of obvious metastatic disease, many women with LMP and type I ovarian cancers may be managed initially by a general gynecologist. Surgical staging can be critical in prescribing appropriate adjuvant therapy, and as such referral to a gynecologic oncologist is recommended for those patients with clinical features suggestive of malignant disease. Chapter 11 reviews the management of a pelvic mass.


Key Points

1. LMP tumors are characterized by a degree of cellular proliferation and nuclear atypia in the absence of obvious stromal invasion.

2. Low-grade serous cancers can also be reproducibly distinguished from their high-grade counterparts based primarily on their very uniform nuclei, using low-mitotic rate as a secondary diagnostic criterion.

3. Mucinous ovarian cancers typically present with unilateral, large adnexal masses (up to 30 cm in size).

4. A strong association exists between endometrioid and clear cell ovarian cancers and endometriosis.

The pathologic appearance of type I tumors vary depending on their histologic subtype (Figure 13-1). The histopathologic characteristics are detailed for each tumor type separately in their respective sections. In contrast to type I tumors, type II tumors tend to exhibit papillary, glandular, and solid patterns (Figure 13-10 and 13-11). The metastatic spread patterns for LMP and type I tumors are similar to those of type II ovarian cancers, and staging is performed using the International Federation of Gynecology and Obstetrics (FIGO) classification (see Chapter 12).


FIGURE 13-10. Low- and high-grade endometrioid epithelial ovarian cancer. (Images contributed by Sonam Loghavi, MD and Denise Barbuto, MD, PhD.)


FIGURE 13-11. Low- and high-grade serous epithelial ovarian cancer. (Images contributed by Sonam Loghavi, MD and Denise Barbuto, MD, PhD.)

Classically, epithelial ovarian cancers are graded on a 3-tier grading scheme based on architecture (glandular, papillary, or solid), degree of nuclear atypia, and mitotic index.69 Tumors are graded according to their degree of differentiation. Grade 1 tumors are well-differentiated and maintain their glandular appearance. Grade 2, or moderately differentiated tumors, have both glandular features and sheets of cells. Grade 3, or poorly differentiated tumors, are generally sheets of cells, with little to no architecture. All clear cell carcinomas are considered grade 3. Grade is an important independent predictor of prognosis. In 2004, a 2-tier grading system based on nuclear atypia and mitotic rate was proposed for serous carcinomas, in which tumors are subdivided into low grade and high grade.70 There is very good correlation between the new 2-tiered system and the established International FIGO and the 3-tiered systems.71 Furthermore, the distinct epidemiology, biology, and clinical behavior of low-grade serous and low-grade endometrioid carcinomas compared with high-grade serous and endometrioid carcinomas supports the 2-tiered system.

Low Malignant Potential Tumors

In 1929, Howard Taylor72 first described LMP tumors as a “semi-malignant” disease with histologic features and biologic behavior between a benign neoplasm and invasive carcinoma. Histologically, LMP tumors are characterized by a degree of cellular proliferation and nuclear atypia in the absence of obvious stromal invasion (Figures 13-513-8, and 13-12). LMP tumors of every surface epithelial cell type (serous, mucinous, endometrioid, clear cell, transitional cell and mixed epithelial cell) have been reported. Serous and mucinous neoplasms constitute the majority of LMP tumors and occur mostly in women of reproductive age (Figure 13-12).73 According to the 2003 World Health Organization classification schema, LMP ovarian tumors are classified on the basis of histopathology and histogenesis into serous, mucinous, endometrioid, clear cell, and transitional (Brenner) subtypes. The histology of LMP tumors is characterized by the following features: epithelial multilayering of more than 4 cell layers, mitoses ≤ 4 per 10 high-power field, mild nuclear atypia, increase in nuclear-to-cytoplasmic ratio, slight-to-complex branching of epithelial papillae and pseudopapillae, epithelial budding and cell detachment into the lumen, architecturally complex glands, and no destructive stromal invasion.


FIGURE 13-12. Representative sections of serous and mucinous low malignant potential tumors. (Images contributed by Sonam Loghavi, MD and Denise Barbuto, MD, PhD.)

Low-Grade Serous Carcinoma

The separation of serous carcinomas into low-grade and high-grade types is a recent development and was first described by Singer et al9 followed by other investigators.2,10 Similar to high-grade serous cancers, most women with low-grade serous disease present with advanced-stage disease and have bilateral tumors. These tumors are characterized by micropapillae and small, round nests of cells that infiltrate the stroma and are frequently surrounded by a clear space (Figures 13-1 and 13-13). They are often associated with a serous adenofibroma, atypical proliferative serous tumor, or noninvasive micropapillary serious carcinoma. Psammoma bodies are common. The nuclei are uniform, small, and round to oval. The chromatin is even, and mitotic features are infrequent. The nuclear-to-cytoplasmic ratio may be high. However, only mild variation in size and shape of nuclei are allowed for a diagnosis of low-grade serous carcinoma. Serous tumors with cells showing ≥ 3:1 variation in nuclear size and shape are classified as high-grade disease.74 Low-grade serous cancers can also be reproducibly distinguished from their high-grade counterparts, based primarily on their very uniform nuclei, using low-mitotic rate as a secondary diagnostic criterion.10,17 Low-grade serous tumors are also almost invariably positive for hormone receptor expression (estrogen and/or progesterone receptors).65 Only rarely do these tumors progress to higher-grade tumors.75


FIGURE 13-13. Progression-free and overall survival in epithelial ovarian cancer. A retrospective review was conducted on 1895 patients with stage III epithelial ovarian cancer (EOC) who had undergone primary surgery followed by 6 cycles of intravenous platinum/paclitaxel on Gynecologic Oncology Group protocols. A. The estimated progression-free survival (PFS) in 4 subtypes of EOC revealed that women with endometrioid cancers had a decreased risk of progression of 0.76 (95% CI, 0.64-0.92; P = .004) compared with those with serous cancers. Those with clear cell and mucinous cell type had a significantly increased risk of disease progression (1.37 [95% CI, 1.01-1.85; images] and 2.18 [95% CI, 1.48-3.22; images], respectively) compared with women with serous cancers. Women with the mucinous cell type had a marginally increased risk for disease progression compared with those with clear cell type (1.59 [95% CI, 0.98-2.59; images). B. Similar findings were noted for overall survival (OS). The OS probability adjusted relative risk of death for endometrioid, clear cell, and mucinous cell type as compared with serous cell type was 0.79 (95% CI, 0.65-0.97; images), 1.74 (95% CI, 1.26-2.41; P < .001), and 4.14 (95% CI, 2.77-6.19; P < .001), respectively. Women with mucinous versus clear cell type cancer had a 2.4-fold increased risk of death (2.38 [95% CI, 1.43-3.95; P < .001]). (Reproduced, with permission, from Winter et al.117)

Mucinous Carcinoma

Mucinous cancers of the ovary comprise approximately 15% of all ovarian epithelial tumors. The majority of mucinous ovarian tumors are benign, with 15% being LMP and only 3.5% being malignant.7 Clinically, mucinous tumors may grow quite large, reaching 30 cm in size and weighing as much as 40 kg.76 Although malignant mucinous tumors may be bilateral in 10% to 20% of cases,7 benign tumors are rarely bilateral. Eighty-three percent of mucinous ovarian carcinomas but only 4% of serous ovarian carcinomas are stage I at diagnosis.77

Microscopically, mucinous tumors are often compared with mucinous cells of the endocervix or colon.77 However, the mucinous epithelium that characterizes type I epithelial ovarian cancer more closely resembles gastrointestinal mucosa than the endocervix.21 Mucinous adenocarcinomas also demonstrate gland formation, similar to endometrioid ovarian cancers, but the tumor cell cytoplasm is mucin rich (Figure 13-1). Microscopic features that favor the diagnosis of primary ovarian mucinous carcinoma include the coexistence of LMP and benign mucinous components, an expansile (confluent) pattern of invasion, and a coexisting ovarian teratoma, Brenner tumor, or mural nodule. Mucinous adenocarcinomas often contain areas indistinguishable from mucinous cyst-adenomas and mucinous LMP tumors. To be classified as an LMP mucinous tumor, the epithelium lining the papillae should generally not exceed 3 cell layers in thickness and lack the following: a marked overgrowth of atypical cells; solid, cellular masses devoid of connective tissue support; severely anaplastic nuclear features; and destructive stromal invasion (Figures 13-6and 13-11).77 In contrast, the following microscopic features favor the diagnosis of metastatic adenocarcinoma to the ovary: prominent desmoplastic response, nodular pattern of invasion (ie, tumor nodules among structures indigenous to the ovarian parenchyma), small clusters of tumor cells within corpora lutea or albicantia, numerous pools of mucin dissecting the ovarian stroma (ie, pseudomyxoma ovarii) in the absence of a coexistent ovarian teratoma, an extensive signet-ring cell pattern, ovarian surface involvement, vascular invasion, hilar involvement, and an extensive infiltrative pattern of invasion (Figure 13-10).78,79 Pseudomyxoma peritonei is a rare condition that is characterized by copious mucin and clusters of well-differentiated mucinous cells throughout the abdomen.76 Mucinous tumors can be associated with appendiceal tumors, and appendiceal involvement is frequently observed when pseudomyxoma peritonei is encountered.44,80

Of significant concern is the finding that only 23% of invasive mucinous carcinomas of the ovary are actually primary ovarian cancers.81 Making the distinction between primary and metastatic gastrointestinal cancers to the ovary can be difficult. Immunohistochemistry may assist in determining the primary site of a mucinous carcinoma. Primary ovarian mucinous carcinomas tend to be positive for CK7 and CK20 with a predominance of CK7 expression, whereas colorectal primaries tend to express CK20 only.82,83

Endometrioid Carcinoma

Endometrioid ovarian cancer has morphologic features similar to the endometrioid endometrial cancers and has varying amounts of gland formation, sometimes accompanied by squamous differentiation. It appears that endometrioid ovarian cancer, similar to serous cancer, may be stratified into 2 distinct entities based on grade (Figures 13-1 and 13-11). These cancers are frequently associated with endometriosis,84 benign endometrioid neoplasms such as endometrioid adenofibroma, endometrioid LMP tumors, and well-differentiated endometrioid carcinoma. On gross examination these tumors vary in size from 12 to 25 cm.63,85 They are often fleshy in character and more cystic than serous tumors.76 Microscopically they resemble endometrioid adenocarcinomas of the endometrium. A concomitant endometrial primary may occur in 10% to 25% of cases.86-89

In 1985, Ulbright and Roth90 developed pathologic criteria to help distinguish metastatic disease from synchronous primary tumors. More recently, Scully et al91 described a similar but more extensive list of clinicopathologic features used to differentiate endometrial disease with metastasis to the ovary, ovarian disease with metastasis to the endometrium, and independent primary cancers.

Clear Cell Carcinoma

Similar to endometrioid ovarian cancers, a strong association exists between clear cell carcinoma and endometriosis in more than 50% of cases.12,92 Clear cell cancers present predominantly as a large pelvic mass measuring 3 to 20 cm12 and are bilateral in 12% of cases.93 Grossly, clear cell carcinomas resemble endometrioid tumors and cannot be distinguished from serous disease. They may be predominantly solid or cystic and contain white, yellow, or pale brown polypoid masses protruding into the lumen of cysts.94 Nearly one-third of clear cell ovarian cancers are stage I at diagnosis.7

Clear cell carcinoma of the ovary is morphologically similar to the clear cell carcinoma of the endometrium and the clear cell vaginal and cervical cancers seen in young women exposed to diethylstilbestrol.95 Microscopically, the tumors are composed of clear cells and hobnail cells. The clear cell appearance is due to the presence of copious cytoplasmic glycogen (Figure 13-1). The hobnail cells are when the nuclei, instead of being basal, appear to stand on a narrow stalk of cytoplasm, resembling a large-headed hobnail, and protrude into the lumen. The tumor cell may be arranged in solid, tubulocystic, or papillary patterns. Clear cell carcinomas have relatively low-mitotic rates, and it is therefore not surprising that responses to agents targeting dividing cells are poor.64,96

It is uncertain whether clear cell epithelial ovarian cancer should be classified into type I and type II subsets, similar to serous and endometrioid tumors. Clear cell carcinomas are typically considered high grade by definition.97Currently, most clear cell epithelial ovarian cancers are thought to behave similar to other type I tumors. However, it is obvious that some clear cell cancers behave in a more aggressive fashion, as manifested by an increased risk of recurrence and worse survival.

Transitional-Cell Tumors

Brenner tumors are almost always benign, and rarely are these tumors of LMP or frankly malignant. There are 2 variants of malignant tumors: malignant Brenner tumors and transitional-cell carcinomas. Benign Brenner tumors are predominantly small (< 5 cm), solid, and often associated with mucinous tumors. In contrast, Brenner LMP tumors usually are large cysts, and the malignant tumors contain both solid and cystic areas. Both benign and malignant Brenner tumors have areas of stromal calcification. Brenner tumors have 2 important distinguishing features: epithelial cords with coffee-bean shaped cells and a dense, fibrous, and abundant stroma. Transitional-cell carcinomas have a urothelial-like appearance but, unlike bladder, epithelium will demonstrate cytokeratin-7–positive staining.

The transitional-cell carcinomas tend to present at higher stages and be associated with a greater risk for recurrence compared with malignant Brenner tumors. However, DNA content studies on Brenner tumors have shown that diploid tumors tend to be benign and nonaggressive, whereas those with aneuploid features are typically aggressive and have a worse prognosis.98,99


Key Points

1. LMP tumors diagnosed by frozen section at the time of surgery should undergo staging, as invasive ovarian cancer may be found on final pathologic analysis. Adjuvant therapy may be considered for advanced disease or invasive implants, but remains controversial.

2. Women with stage IA or IB disease with grade 1 or 2 histology are unlikely to benefit from chemotherapy and may undergo close surveillance.

3. Women with advanced-stage type I ovarian cancers should be treated with platinum- and taxane-based regimens until further evidence confirms the use of alternative chemotherapeutic agents in non–high-grade serous disease.

Low Malignant Potential Tumors

Intraoperative management of LMP is similar to that for invasive ovarian cancers and may include systematic staging and abdominal exploration. The primary treatment modality is surgical resection of gross disease. There is considerable debate regarding the extent of surgery as well as the role of lymphadenectomy. Patients with advanced-stage disease who have completed childbearing should undergo a hysterectomy, bilateral salpingo-oophorectomy, omentectomy, complete peritoneal resection of macroscopic lesions, multiple peritoneal biopsies if indicated, and peritoneal washings and may also undergo pelvic and para-aortic lymph-adenectomy. For premenopausal women with early-stage disease and/or those who strongly desire future fertility, conservative fertility-sparing surgery with unilateral salpingo-oophorectomy or ovarian cystectomy combined with surgical staging can be performed.100Although the conservative approach is associated with a higher recurrence rate, overall survival is likely not compromised.100

The role of lymphadenectomy is controversial and has not been shown to confer a reduction in recurrence or a survival benefit.100,101 However, these tumors can be large, and a definitive diagnosis excluding invasive ovarian cancer based on intraoperative frozen section evaluation is limited. Specifically, 11% to 28% of invasive carcinomas were underdiagnosed in LMP tumors at the time of frozen section.102-104 In a meta-analysis, Tempfer et al104 found that intraoperative frozen section analysis had an overall sensitivity of 71.1% and an overall positive predictive value of 84.3%. Thus, given the inaccuracy of frozen sections and risk of nodal recurrence, it is reasonable to perform a pelvic and para-aortic lymphadenectomy in patients with LMP tumors identified on frozen section at the time of surgery.

Treatment recommendations for women with LMP tumors are determined based on the presence or absence of invasive implants. For patients who have no microscopically demonstrable invasive implants, adjuvant chemotherapy has not been shown to be beneficial. The use of chemotherapy even in those women with advanced-stage disease and invasive implants is controversial, with many studies showing no benefit, most likely due to the relative chemoresistant nature of these tumors.73,100,101 Thus, in women with invasive implants, treatment options may include observation or treatment with adjuvant chemotherapy regimens similar to those used in epithelial ovarian cancer.99

Type I Tumors

In general, women with type I and type II epithelial ovarian cancers are treated in a similar fashion with regard to surgical management, adjuvant therapy, and surveillance. Mucinous LMP tumors and epithelial ovarian cancer are frequently associated with appendiceal neoplasms, especially when pseudomyxoma peritonei is encountered. Therefore, appendectomy is recommended at the time of surgical resection of mucinous ovarian tumors. Although high-grade serous cancers tend to be chemo-responsive, mucinous, clear cell, and low-grade serous disease do not have as high as a response rate to the traditional platinum- and taxane-based chemotherapy regimens.

Women with stage IA or 1B, grade 1 or 2 disease are unlikely to benefit from adjuvant chemotherapy and may undergo close surveillance. Women with 1B, grade 2 disease may also be offered chemotherapy with intravenous (IV) taxane and carboplatin chemotherapy for 3 to 6 cycles. For those with stage 1A, 1B clear cell or grade 3 disease or 1C, grade 1, 2, or 3 disease, intravenous taxane and carboplatin chemotherapy for 3 to 6 cycles is recommended. Patients with stage II, III, and IV disease should be counseled regarding combination intraperitoneal/intravenous chemotherapy versus intravenous chemotherapy alone for a total of 6 to 8 cycles.99 Neoadjuvant chemotherapy followed by interval debulking is an option for select patients and does not appear to negatively impact survival compared with primary debulking surgery in a large European study.99,105 Typically, neoadjuvant therapy is reserved for individuals who have significant malnutrition, a poor performance status, and tense ascites, or extensive disease that would not be amendable to optimal resection (mediastinal adenopathy, unresectable liver disease). Neoadjuvant therapy may be less beneficial in women with certain type I tumors, as they are less likely to respond to taxane and platinum-based chemotherapy compared with high-grade serous cancers.106-110 Participation in clinical trials, if they are available, should be encouraged.

Many of the landmark studies that have guided the management of epithelial ovarian cancers have included mostly women with high-grade serous disease. Patients with mucinous, endometrioid, clear cell, and low-grade serous cancer typically comprise only a fraction, if any, of these patient populations. A retrospective analysis of a large Gynecologic Oncology Group (GOG) trial in women with early-stage disease was conducted to explore histologic subsets of patients who may benefit from 6 versus 3 cycles of chemotherapy. Thirty percent of the patient population had clear cell carcinoma, whereas 25% had endometrioid, 23% had serous, 7% had mucinous, and 15% had other cell types. The risk of recurrent disease was significantly lower in women with serous cancers who were treated with 6 versus 3 cycles of chemotherapy (hazard ratio images; confidence interval imagesimages). In contrast, there was no difference in recurrence risk between the 2 chemotherapy groups in women with non-serous cancers (imagesimages).111 This study did not distinguish between low-grade and high-grade serous disease, and most women in the trial had grade 3 tumors. However, the authors did conduct additional subgroup analyses and did not detect any differences with regard to grade in women with serous cancers.111

Alternative chemotherapeutic regimens are under evaluation in women with type I ovarian cancers. Collaborative groups in the United States, Europe, and Japan are currently undertaking prospective studies with chemotherapy and biologically targeted therapies in patients with advanced or recurrent mucinous ovarian cancer. Given the morphologic and molecular similarities between mucinous ovarian cancer and colorectal cancers, it is reasonable to treat these diseases with a similar chemotherapeutic regimen. The GOG has developed a phase 3 clinical trial comparing paclitaxel and carboplatin to capecitabine and oxaliplatin (a regimen commonly used in colorectal cancers) with and without bevacizumab. Given the frequent alterations involving components of the Ras-Raf-MEK-MAPK pathway, agents that inhibit this cascade are of interest in the treatment of mucinous epithelial ovarian cancer.


Key Points

1. Type I ovarian cancers have improved survival in comparison with type II disease, in part due to the earlier stage at presentation and lower grade.

2. Clear cell and mucinous ovarian cancers have worse prognosis than low-grade serous and endometrioid disease, potentially resulting from relative chemoresistance.

The survival and prognosis for LMP tumors are significantly better compared with those of type I and II epithelial ovarian cancers. LMP tumors are usually confined to the ovary, occur predominantly in premenopausal women, and are associated with good outcomes. Approximately 75% of LMP tumors are stage I at the time of diagnosis. The majority of patients presents at an early stage and have excellent 5-year survival rates approaching 100%.112 The recurrence and the overall survival rates of LMP tumors with noninvasive implants is time dependent,113 but for patients with peritoneal implants, the 10-year survival rate is between 70% and 95%, caused by late recurrence.114,115However, a lower 5-year survival rate of 69.3% was reported for mucinous LMP in one study. The 5-year survival for stage I and stage II/III disease was 93% and 15%, respectively. The lower than expected survival rate may have been secondary to the inclusion of women with pseudomyxoma peritonei, which tends to have a worse prognosis.116

There has been considerable controversy regarding serous LMP tumors and the “noninvasive” variant, micropapillary serous carcinomas. Some studies have indicated that the latter are more likely to have invasive implants, advanced disease, increased risk of tumor recurrence, and worse clinical outcome than serous LMP. In 2010, May and colleagues37 reported their results regarding gene expression profiling in serous LMP, serous LMP-micropapillary serous carcinoma, and invasive low-grade serous cancers. The gene expression profile of micropapillary serous carcinomas was similar to low-grade malignancies and distinct from serous LMP tumors.37 Given these findings, micropapillary serous carcinomas may require more extensive surgical staging and cytoreductive surgery as well as more frequent surveillance.

Type I ovarian cancers for the most part are considered to be indolent cancers, and the survival for women with type I tumors is overall better than that for type II disease (see Chapter 12). The improved survival probably is in part a reflection of stage and grade, as most of the type I cancers are diagnosed at earlier stages compared with their more aggressive counterpart and are well-differentiated tumors. Women with stage I disease, with appropriate surgical staging, have a 5-year survival rate of 90% when treated with surgery alone. Those with stage II, III, and IV disease have 5-year survival rates of 74%, 15% to 37%, and 5% to 25%, respectively.98,99 Similar to type II tumors, survival is also associated with the amount of residual tumor (see Chapter 12).

There is also evidence that the clinical behavior of type I histologic subtypes are distinct even from each other with regard to prognosis and survival. For example, women with clear cell carcinoma of the ovary have a worse prognosis than those with serous and endometrioid ovarian cancers.117,118 The 5-year survival for women with stage I clear cell cancers was 60%, compared with 12% for other stages.98 Similarly, most women with mucinous carcinomas are diagnosed with early-stage disease, and the overall prognosis for women with primary mucinous ovarian cancer is better than for those with high-grade serous disease. However, those with advanced-stage mucinous carcinomas of the ovary have a worse prognosis, as manifested by a worse progression-free and overall survival than those with advanced-stage serous, endometrioid, and clear cell carcinomas (Figure 13-13).117 The relative risk of death for women with mucinous cancers was increased 4.1-fold compared with those with serous cancer images.117 The worse prognosis noted for advanced clear cell and mucinous type I tumors may be due to resistance to traditional chemotherapy regimens often used for type II tumors.5 Another explanation for the poor prognosis and lack of response for advanced mucinous ovarian cancers is that some of these malignancies represent metastatic disease rather than primary ovarian cancers.

Conversely, women with endometrioid cancer are more likely to undergo optimal cytoreduction, have a better prognosis, and have longer progression-free and overall survival compared with those with serous, mucinous, or clear cell cancer.16,117 Patients with concurrent endometrioid ovarian and endometrial malignancies had a survival advantage compared with those with ovarian carcinoma alone.16 Soliman et al89 reported a median survival approaching 10 years for women with concurrent endometrioid tumors of the endometrium and ovary.

Women with low-grade serous cancers have a better prognosis than those with high-grade disease and were found to have a longer median survival (median not reached) compared with those with high-grade disease (median, 39 months).17 Although low-grade serous cancers typically have a relatively indolent course, they tend to be chemoresistant, and treatment can be challenging.14,119


Key Points

1. Surgical resection of recurrent disease remains the cornerstone for women with LMP tumors; chemotherapy may be considered with the presence of invasive metastases.

2. Secondary cytoreductive surgery may be considered for women with recurrent low-grade serous, endometrioid, or mucinous cancers, but attention to the treatment-free interval is critical given the relative chemoresistance of these malignancies.

3. Chemotherapeutic agents active in type II ovarian, tubal, and peritoneal disease may also be effective in recurrent type I ovarian cancer.

Patients with LMP tumors should be monitored with a careful review of symptoms and clinical examinations every 3 to 6 months for up to 5 years and then annually. Ultrasounds are indicated for women who underwent fertility-sparing surgery. After completion of child-bearing, patients who underwent fertility-sparing surgery should be counseled regarding completion surgery.99 CA-125 tumor marker assessment can be performed at the discretion of the treating physician. Radiographic studies may be obtained as needed to investigate new symptoms or findings on examination.

The treatment of recurrent disease for women with LMP tumors is typically surgery, but depends on the patient’s comorbidities and disease characteristics. The use of adjuvant therapy in the recurrent setting is based on the presence of invasive disease. Those with noninvasive disease can be observed, whereas those with invasive disease may be considered for treatment with chemotherapy.99 Given the relative chemoresistance of LMP tumors,114alternative therapies are needed. Agents targeting the Ras-Raf-MEK-MAPK pathway would be of interest given the high frequency of aberrations in LMP tumors.

Currently the surveillance, management of recurrent disease, and palliative care for type I epithelial ovarian cancers is the same as type II cancers (see Chapter 12). The role of secondary cytoreductive surgery, which is considered in women who have at least a treatment-free interval of 6 months before relapse, may have an even more prominent part in the management of type I ovarian cancers given their relative chemoresistant nature as compared with type II cancers. There are several chemotherapy options available, and current US Food and Drug Administration–approved drugs for the treatment of ovarian cancer include carboplatin, cisplatin, paclitaxel, liposomal doxorubicin, topotecan, and gemcitabine in combination with carboplatin. The type of relapse therapy used depends of the treatment-free interval, prior toxicities, the patient’s comorbidities, convenience, quality of life, and the goals of therapy. The treatment-free interval is an important prognostic factor, and women are treated differently based on whether they have platinum-resistant or sensitive disease (see Chapter 12).

The preferred chemotherapy regimens for women for platinum-sensitive disease include platinum monotherapy or platinum doublets combined with either paclitaxel, docetaxel, gemcitabine, or liposomal doxorubicin.99 For women with platinum-resistant disease, single-agent non-platinum therapy is preferred with the following agents; docetaxel, etoposide, gemcitabine, liposomal doxorubicin, weekly paclitaxel, or topotecan. Additional therapies include altretamine, capecitabine, cyclophosphamide, ifosfamide, irinotecan, melphalan, oxaliplatin, conventional dose paclitaxel, nab-paclitaxel, pemetrexed, and vinorelbine.99 Biologic therapies are also being used in the recurrent setting. Bevacizumab, a monoclonal antibody that binds to VEGF has been shown to have activity in ovarian cancer. Antitumor activity has also been demonstrated for other antiangiogenic therapies, as well as mammalian target of rapamycin (mTOR) and PARP1 inhibitors.

A specific concern for type I ovarian cancers is their chemoresistant nature,120 and there is an acute need for effective systemic therapy. Given the poor responses of low-grade serous carcinomas to traditional chemotherapy and strong association with alterations of the MAPK pathway, the GOG evaluated AZD6244, a biologic agent that inhibits the MAPK, MEK-1/2, in women with recurrent ovarian and peritoneal low-grade serous disease. The trial is closed to enrollment, and data are not yet available but are eagerly awaited. The GOG has also activated a phase 2 trial of sunitinib, a tyrosine kinase inhibitor that inhibits VEGF and platelet-derived growth factor receptors in women with persistent and recurrent clear cell epithelial ovarian cancer. Clear cell cancers have poor response rates ranging from 15% to 45%. Given the molecular similarities between clear cell epithelial ovarian cancer and renal carcinomas, there is interest in evaluating biologic therapies, such as sunitinib, that are active in renal cell cancers in women with clear cell ovarian cancer.

Other agents to consider include mTOR, PIK3, and AKT inhibitors in clear cell and mucinous cancers, as they have frequent alterations in the PIK3-CA/AKT/PTEN pathway. This pathway is very complex, activated by numerous factors, and plays a pivotal role in cellular transformation (Figure 13-7). AKT is the major known effector of the PI3K-CA/AKT/PTEN pathway and phosphorylates multiple downstream proteins, including mTOR. mTOR is involved in protein synthesis and regulates cellular proliferation, growth, and survival. A strategy of combining multiple agents that inhibit different pathways such as PARP1 and MAPK may be of particular interest in select cancers such as low-grade serous disease that exhibit aberrations in both these pathways.

Hormonal therapies in ovarian cancer have a response rate of approximately 10% in previously treated patients. A correlation may exist between the presence of hormone receptors and a response to therapy. A variety of agents have been used, including progestational agents such as megestrol acetate, gonadotropic-releasing analogs (leuprolide acetate), selective estrogen receptor modulators (tamoxifen), anti-androgen agents, and aromatase inhibitors (anastrozole and letrozole).98,99 Given the presence of hormone receptors on low-grade serous and endometrioid cancers, hormonal agents should also be evaluated.


As we continue to recognize the varying clinical behavior and molecular biology of patients with LMP tumors and type I epithelial ovarian cancers, the management of these distinct histologic subtypes may change dramatically in the future. Paradigms for screening, recommended prophylactic procedures, surgery, treatment, and surveillance may all be altered. Biologic therapies that target the underlying molecular biology of these ovarian cancer subtypes may be exceedingly important, as most of these tumors are resistant to traditional chemotherapeutic regimens used in type II disease. Translational research objectives should be incorporated in the design of clinical trials to correlate specific mutational status or pathway activation to clinical response and survival outcomes. This will enhance the ability to identify patients who are most likely benefit from these therapies and provide guidance regarding future implementation of adjuvant and relapse therapy. These unique tumors represent an exceptional and exciting opportunity to develop individually tailored cancer therapy based on molecular alterations and potentially improve outcome for women with type I ovarian cancer.


1. Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277-300.

2. Shih IeM, Kurman RJ. Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol. 2004;164(5):1511-1518.

3. Cho KR, Shih IeM. Ovarian cancer. Annu Rev Pathol. 2009; 4:287-313.

4. Chu CS, Rubin SC. Epidemiology, staging, and clinical characteristics. In: RE Bristow, BY Karlan, eds. Surgery for Ovarian Cancer: Principles and Practices. Boca Raton, FL: Taylor and Francis; 2007:13-15.

5. Kurman RJ, Shih IeM. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol. 2010;34(3):433-443.

6. 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 [Erratum in: Cancer Res. 2009;69(12):5267]. Cancer Res. 2009; 69(9):4036-4042.

7. Robboy SJ, Duggan M, Kurman RJ. The female reproductive system. In: Rubin E, Farber J, eds. Pathology. 2nd ed. Philadelphia, PA: JB Lippincott; 1988.

8. Gilks CB. Molecular abnormalities in ovarian cancer subtypes other than high-grade serous carcinoma. J Oncol. 2010;2010: 740968.

9. Singer G, Kurman RJ, Chang HW, et al. Diverse tumorigenic pathways in ovarian serous carcinoma. Am J Pathol. 2002; 160(4):1223-1228.

10. Seidman JD, Horkayne-Szakaly I, Cosin JA, et al. Testing of two binary grading systems for FIGO stage III serous carcinoma of the ovary and peritoneum. Gynecol Oncol. 2006;103(2): 703-708.

11. Stern RC, Dash R, Bentley RC, et al. Malignancy in endometriosis: frequency and comparison of ovarian and extraovarian types. Int J Gynecol Pathol. 2001;20(2):133-139.

12. Behbakht K, Randall TC, Benjamin I, et al. Clinical characteristics of clear cell carcinoma of the ovary. Gynecol Oncol. 1998;70(2):255-258.

13. Disaia PJ, Creasman WT. Germ cell, stromal and other ovarian tumors. In: DiSaia PJ, Creasman WT, eds. Clinical Gynecologic Oncology. 5th ed. St Louis, MO: Mosby Year Book; 1997, Chapter 11.

14. 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(2):361-368.

15. Schmeler KM, Gershenson DM. Low-grade serous ovarian cancer: a unique disease. Curr Oncol Rep. 2008;10(6):519-523.

16. Storey DJ, Rush R, Stewart M, et al. Endometrioid epithelial ovarian cancer: 20 years of prospectively collected data from a single center. Cancer. 2008;112(10):2211-2220.

17. Plaxe SC. Epidemiology of low-grade serous ovarian cancer. Am J Obstet Gynecol. 2008;198(4):459.e1-e8; discussion 459.e8-e9.

18. Kennedy AW, Hart WR. Ovarian papillary serous tumors of low malignant potential (serous borderline tumors). A long-term follow-up study, including patients with microinvasion, lymph node metastasis, and transformation to invasive serous carcinoma. Cancer. 1996;78(2):278-286.

19. Kaern J, Tropé CG, Kristensen GB, et al. DNA ploidy; the most important prognostic factor in patients with borderline tumors of the ovary. Int J Gynecol Cancer. 1993;3(6):349-358.

20. Riman T, Dickman PW, Nilsson S, et al. Risk factors for invasive epithelial ovarian cancer: results from a Swedish case-control study. Am J Epidemiol. 2002;156(4):363-373.

21. Heintz AP, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006; 95(suppl 1): S161-S192.

22. Callahan MJ, Crum CP, Medeiros F, et al. Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction. J Clin Oncol. 2007; 25(25):3985-3990.

23. Carcangiu ML, Radice P, Manoukian S, et al. Atypical epithelial proliferation in fallopian tubes in prophylactic salpingo-oophorectomy specimens from BRCA1 and BRCA2 germline mutation carriers. Int J Gynecol Pathol.2004;23(1):35-40.

24. Carlson JW, Jarboe EA, Kindelberger D, et al. Serous tubal intraepithelial carcinoma: diagnostic reproducibility and its implications. Int J Gynecol Pathol. 2010;29(4):310-314.

25. Finch A, Shaw P, Rosen B, et al. Clinical and pathologic findings of prophylactic salpingo-oophorectomies in 159 BRCA1 and BRCA2 carriers. Gynecol Oncol. 2006;100(1):58-64.

26. Folkins AK, Jarboe EA, Roh MH, et al. Precursors to pelvic serous carcinoma and their clinical implications. Gynecol Oncol. 2009;113(3):391-396.

27. 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(2):168-173.

28. Kuhn E, Meeker A, Wang TL, et al. Shortened telomeres in serous tubal intraepithelial carcinoma: an early event in ovarian high-grade serous carcinogenesis. Am J Surg Pathol. 2010;34(6):829-836.

29. Paley PJ, Swisher EM, Garcia RL, et al. Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis. Gynecol Oncol.2001;80(2):176-180.

30. Piek JM, van Diest PJ, Zweemer RP, et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol. 2001;195(4): 451-456.

31. Piek JM, van Diest PJ, Zweemer RP, et al. Tubal ligation and risk of ovarian cancer. Lancet. 2001;358(9284):844.

32. Piek JM, Verheijen RH, Kenemans P, et al. BRCA1/2-related ovarian cancers are of tubal origin: a hypothesis. Gynecol Oncol. 2003;90(2):491.

33. Przybycin CG, Kurman RJ, Ronnett BM, et al. Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol. 2010;34(10):1407-1416.

34. Sehdev AS, Kurman RJ, Kuhn E, et al. Serous tubal intraepithelial carcinoma upregulates markers associated with high-grade serous carcinomas including Rsf-1 (HBXAP), cyclin E and fatty acid synthase. Mod Pathol.2010;23(6):844-855.

35. Shaw TJ, Senterman MK, Dawson K, et al. Characterization of intraperitoneal, orthotopic, and metastatic xenograft models of human ovarian cancer. Mol Ther. 2004;10(6):1032-1042.

36. Shih IeM. Ovarian serous low malignant potential (borderline) tumor—does “micropapillary” matter? Gynecol Oncol. 2010; 117(1):1-3.

37. May T, Virtanen C, Sharma M, et al. Low malignant potential tumors with micropapillary features are molecularly similar to low-grade serous carcinoma of the ovary. Gynecol Oncol. 2010;117(1):9-17.

38. Modugno F, Ness RB, Allen GO, et al. Oral contraceptive use, reproductive history, and risk of epithelial ovarian cancer in women with and without endometriosis. Am J Obstet Gynecol. 2004;191(3):733-740.

39. Cuatrecasas M, Villanueva A, Matias-Guiu X, et al. K-ras mutations in mucinous ovarian tumors: a clinicopathologic and molecular study of 95 cases. Cancer. 1997;79(8):1581-1586.

40. Hankinson SE, Colditz GA, Hunter DJ, et al. A quantitative assessment of oral contraceptive use and risk of ovarian cancer. Obstet Gynecol. 1992;80(4):708-714.

41. 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(1):49-56.

42. 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(8):1168-1174.

43. Bonni A, Brunet A, West AE, et al. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science. 1999;286(5443):1358-1362.

44. Ronnett BM, Zahn CM, Kurman RJ, et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinoma-tosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei”. Am J Surg Pathol. 1995;19(12):1390-1408.

45. Gemignani ML, Schlaerth AC, Bogomolniy F, et al. Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma. Gynecol Oncol. 2003;90(2):378-381.

46. Mok SC, Bell DA, Knapp RC, et al. Mutation of K-ras protooncogene in human ovarian epithelial tumors of borderline malignancy. Cancer Res. 1993;53(7):1489-1492.

47. Williams AC, Browne SJ, Yeudal WA, et al. Molecular events including p53 and k-ras alterations in the in vitro progression of a human colorectal adenoma cell line to an adenocarcinoma. Oncogene. 1993;8(11):3063-3072.

48. 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(6):484-486.

49. Salani R, Kurman RJ, Giuntoli R 2nd, et al. Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance. Int J Gynecol Cancer. 2008;18(3):487-491.

50. 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(4):321-333.

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(10):2095-2097.

52. Palacios J, Gamallo C. Mutations in the beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas. Cancer Res. 1998;58(7):1344-1347.

53. 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(11):1360-1368.

54. Jones S, Wang TL, Shih IeM, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science. 2010;330(6001):228-231.

55. Wiegand KC, Shah SP, Al-Agha OM, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 2010;363(16):1532-1543.

56. 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(7):779-785.

57. Kuo KT, Mao TL, Jones S, et al. Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. Am J Pathol. 2009;174(5):1597-1601.

58. Zorn KK, Bonome T, Gangi L, et al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res. 2005;11(18):6422-6430.

59. Simsir A, Palacios D, Linehan WM, et al. Detection of loss of heterozygosity at chromosome 3p25-26 in primary and metastatic ovarian clear-cell carcinoma: utilization of microdissection and polymerase chain reaction in archival tissues. Diagn Cytopathol. 2001;24(5):328-332.

60. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003t;3(10):721-732.

61. Evans DG, Young K, Bulman M, Shenton A, Wallace A, Lalloo F. Probability of BRCA1/2 mutation varies with ovarian histology: results from screening 442 ovarian cancer families. Clin Genet. 2008;73(4):338-345.

62. Schuijer M, Berns EM. TP53 and ovarian cancer. Hum Mutat. 2003;21(3):285-291.

63. Schueller EF, Kirol PM. Prognosis in endometrioid carcinoma of the ovary. Obstet Gynecol. 1966;27(6):850-858.

64. Press JZ, De Luca A, Boyd N, et al. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer. 2008;8:17.

65. Pradhan M, Davidson B, Tropé CG, et al. Gross genomic alterations differ between serous borderline tumors and serous adenocarcinomas—an image cytometric DNA ploidy analysis of 307 cases with histogenetic implications. Virchows Arch. 2009;454(6):677-683.

66. Goff BA, Mandel L, Muntz HG, Melancon CH. Ovarian carcinoma diagnosis. Cancer. 2000;89(10):2068-2075.

67. Goff BA, Mandel LS, Drescher CW, et al. Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer. 2007;109(2):221-227.

68. Olson SH, Mignone L, Nakraseive C, et al. Symptoms of ovarian cancer. Obstet Gynecol. 2001;98(2):212-217.

69. Shimizu Y, Kamoi S, Amada S, et al. Toward the development of a universal grading system for ovarian epithelial carcinoma: testing of a proposed system in a series of 461 patients with uniform treatment and follow-up. Cancer.1998;82(5):893-901.

70. Malpica A, Deavers MT, Lu K, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol. 2004; 28(4):496-504.

71. Shimizu Y, Kamoi S, Amada S, et al. Toward the development of a universal grading system for ovarian epithelial carcinoma. I. Prognostic significance of histopathologic features—problems involved in the architectural grading system. Gynecol Oncol. 1998;70(1):2-12.

72. Taylor HC Jr. Malignant and semi-malignant tumors of the ovary. Surg Gynecol Obstet. 1929;48:204-230.

73. Acs G. Serous and mucinous borderline (low malignant potential) tumors of the ovary. Am J Clin Pathol. 2005; 123 (suppl): S13-S57.

74. 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(5):267-282.

75. Dehari R, Kurman RJ, Logani S, Shih IeM. The development of high-grade serous carcinoma from atypical proliferative (borderline) serous tumors and low-grade micropapillary serous carcinoma: a morphologic and molecular genetic analysis. Am J Surg Pathol. 2007;31(7):1007-1012.

76. Ozols RF, Rubin SC, Thomas GM, et al. Epithelial ovarian cancer. In: Hoskins WJ, Perez CA, Young RC, Barakat RR, Markman M, Randall ME, eds. Principles and Practice of Gynecologic Oncology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:910-911.

77. Seidman JD, Horkayne-Szakaly I, Haiba M, et al. The histo-logic type and stage distribution of ovarian carcinomas of surface epithelial origin. Int J Gynecol Pathol. 2004;23(1):41-44.

78. Hart WR. Mucinous tumors of the ovary: a review. Int J Gynecol Pathol. 2005;24(1):4-25.

79. Lee KR, Young RH. The distinction between primary and metastatic mucinous carcinomas of the ovary: gross and histologic findings in 50 cases. Am J Surg Pathol. 2003;27(3):281-292.

80. 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(6):591-603.

81. Seidman JD, Kurman RJ, Ronnett BM. Primary and meta-static mucinous adenocarcinomas in the ovaries: incidence in routine practice with a new approach to improve intraoperative diagnosis. Am J Surg Pathol. 2003; 27(7):985-993.

82. Frumovitz M, Schmeler KM, Malpica A, Sood AK, Gershenson DM. Unmasking the complexities of mucinous ovarian carcinoma. Gynecol Oncol. 2010;117(3):491-496.

83. Rekhi B, George S, Madur B, Chinoy RF, Dikshit R, Maheshwari A. Clinicopathological features and the value of differential Cytokeratin 7 and 20 expression in resolving diagnostic dilemmas of ovarian involvement by colorectal adenocarcinoma and vice-versa. Diagn Pathol. 2008;3:39.

84. Stern RC, Dash R, Bentley RC, Snyder MJ, Haney AF, Robboy SJ. Malignancy in endometriosis: frequency and comparison of ovarian and extraovarian types. Int J Gynecol Pathol. 2001;20(2):133-139.

85. Long ME, Taylor HC Jr. Endometrioid carcinoma of the ovary. Am J Obstet Gynecol. 1964;90:936-950.

86. Kline RC, Wharton JT, Atkinson EN, Burke TW, Gershenson DM, Edwards CL. Endometrioid carcinoma of the ovary: retrospective review of 145 cases. Gynecol Oncol. 1990;39(3): 337-346.

87. Czernobilsky B, Silverman BB, Mikuta JJ. Endometrioid carcinoma of the ovary. A clinicopathologic study of 75 cases. Cancer. 1970;26(5):1141-1152.

88. Tidy J, Mason WP. Endometrioid carcinoma of the ovary: a retrospective study. Br J Obstet Gynaecol. 1988;95(11):1165-1169.

89. Soliman PT, Slomovitz BM, Broaddus RR, et al. Synchronous primary cancers of the endometrium and ovary: a single institution review of 84 cases. Gynecol Oncol. 2004;94(2):456-462.

90. Ulbright TM, Roth LM. Metastatic and independent cancers of the endometrium and ovary: a clinicopathologic study of 34 cases. Hum Pathol. 1985;16(1):28-34.

91. Scully RE, Young RH, Clement PB. Tumors of the ovary, mal-developed gonads, fallopian tube, and broad ligament. In: Atlas of Tumor Pathology. Bethesda, MD: Armed Forces Institute of Pathology; 1998.

92. Brescia RJ, Dubin N, Demopoulos RI. Endometrioid and clear cell carcinoma of the ovary. Factors affecting survival. Int J Gynecol Pathol. 1989;8(2):132-138.

93. Scully RE, Young RH, Clement PB. Tumors of the ovary, maldeveloped gonads, fallopian tube, and broad ligament. In: Atlas of Tumor Pathology. Third series, Fascicle 23. Washington, DC: Armed Forces Institute of Pathology; 1999.

94. Eastwood J. Mesonephroid (clear cell) carcinoma of the ovary and endometrium: a comparative prospective clinico-pathological study and review of literature. Cancer. 1978;41(5):1911-1928.

95. Toki T, Fujii S, Silverberg S. A clinicopathologic study on the association of endometriosis and carcinoma of the ovary using a scoring system. Int J Gynecol Cancer. 1996;6:68-75.

96. Köbel M, Kalloger SE, Boyd N, et al. Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med. 2008;5(12):e232.

97. Tavassoli FA, Devilee P, eds. World Health Organization Classification of Tumors: Pathology and Genetics. Tumours of the Breast and Female Genital Organs. Lyon, France: IARC Press; 2003.

98. Ozols RF, Rubin SC, Thomas GM, et al. Epithelial ovarian cancer. In: Hoskins WJ, Perez CA, Young RC, Barakat RR, Markman M, Randall ME, eds. Principles and Practice of Gynecologic Oncology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

99. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer. V.1.2008. Accessed March 13, 2008.

100. Cadron I, Leunen K, Van Gorp T, et al. Management of borderline ovarian neoplasms. J Clin Oncol. 2007;25(20):2928-2937.

101. Leake JF, Rader JS, Woodruff JD, et al. Retroperitoneal lymphatic involvement with epithelial ovarian tumors of low malignant potential. Gynecol Oncol. 1991;42(2):124-130.

102. Houck K, Nikrui N, Duska L, et al. Borderline tumors of the ovary: correlation of frozen and permanent histopathologic diagnosis. Obstet Gynecol. 2000;95(6 pt 1):839-843.

103. Menzin AW, Rubin SC, Noumoff JS, et al. The accuracy of a frozen section diagnosis of borderline ovarian malignancy. Gynecol Oncol. 1995;59(2):183-185.

104. Tempfer CB, Polterauer S, Bentz EK, et al. Accuracy of intra-operative frozen section analysis in borderline tumors of the ovary: a retrospective analysis of 96 cases and review of the literature. Gynecol Oncol.2007;107(2):248-252.

105. Vergote I, Tropé CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943-953.

106. 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(3):412-417.

107. Pectasides D, Fountzilas G, Aravantinos G, et al. Advanced stage clear-cell epithelial ovarian cancer: the Hellenic Cooperative Oncology Group experience. Gynecol Oncol. 2006;102(2): 285-291.

108. Itamochi H, Kigawa J, Sugiyama T, et al. Low proliferation activity may be associated with chemoresistance in clear cell carcinoma of the ovary. Obstet Gynecol. 2002;100(2): 281-287.

109. 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(11):2584-2589.

110. Crotzer DR, Sun CC, Coleman RL, Wolf JK, Levenback CF, Gershenson DM. Lack of effective systemic therapy for recurrent clear cell carcinoma of the ovary. Gynecol Oncol. 2007;105(2):404-408.

111. Chan JK, Tian C, Fleming GF, et al. The potential benefit of 6 vs. 3 cycles of chemotherapy in subsets of women with early-stage high-risk epithelial ovarian cancer: an exploratory analysis of a Gynecologic Oncology Group study. Gynecol Oncol. 2010;116(3):301-306.

112. Barnhill DR, Kurman RJ, Brady MF, et al. Preliminary analysis of the behavior of stage I ovarian serous tumors of low malignant potential: a Gynecologic Oncology Group study. J Clin Oncol. 1995;13(11):2752-2756.

113. Silva EG, Gershenson DM, Malpica A, et al. The recurrence and the overall survival rates of ovarian serous borderline neoplasms with noninvasive implants is time dependent. Am J Surg Pathol. 2006;30(11):1367-1371.

114. Kane A, Uzan C, Rey A, et al. Prognostic factors in patients with ovarian serous low malignant potential (borderline) tumors with peritoneal implants. Oncologist. 2009;14(6): 591-600.

115. Tropé C, Davidson B, Paulsen T, et al. Diagnosis and treatment of borderline ovarian neoplasms “the state of the art”. Eur J Gynaecol Oncol. 2009;30(5):471-482.

116. Nakashima N, Nagasaka T, Oiwa N, et al. Ovarian epithelial tumors of borderline malignancy in Japan. Gynecol Oncol. 1990;38(1):90-98.

117. Winter WE 3rd, Maxwell GL, Tian C, et al. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25(24):3621-3627.

118. Montag AG, Jenison EL, Griffiths CT, et al. Ovarian clear cell carcinoma. A clinicopathologic analysis of 44 cases. Int J Gynecol Pathol. 1989;8(2):85-96.

119. Schmeler KM, Sun CC, Bodurka DC, et al. Neoadjuvant chemotherapy for low-grade serous carcinoma of the ovary or peritoneum. Gynecol Oncol. 2008;108(3):510-514.

120. Gershenson DM, Sun CC, Bodurka D, et al. Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecol Oncol. 2009;114(1):48-52.

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