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.

EPIDEMIOLOGY

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 TANK, PARP1, 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, KRAS mutations 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.

DIAGNOSIS

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.

PATHOLOGY

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 13-5, 13-8, 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.

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