High-Grade Serous Carcinomas of the Ovary, Fallopian Tube, and Peritoneum

David E. Cohn and Ronald D. Alvarez

Epithelial ovarian, fallopian tube, and primary peritoneal cancers remain the most lethal of all the gynecologic malignancies. In 2010, approximately 21,880 women will be diagnosed with ovarian cancer in the United States; of these, 13,850 will be expected to die from this disease.¹ Cancers arising from the fallopian tube and peritoneum are significantly less common that those arising from the ovarian epithelium, but share several similarities in their epidemiology, diagnosis, treatment, and associated outcomes. Because the vast majority of fallopian tube and primary peritoneal cancers exhibit a high-grade papillary serous histology, comparisons to similar disease in primary ovarian cancers suggest common molecular pathways that may promote carcinogenesis within the serous classification of these tumors. Several recent hypotheses also propose a fallopian tube origin for metastatic disease that would traditionally be considered as primary ovarian or peritoneal. Given the recent advances surrounding these diseases, this chapter considers this subset of high-grade serous reproductive cancers as a group, with specific differences highlighted.

EPIDEMIOLOGY

Key Points

1. Women with an inherited ovarian cancer syndrome, particularly those with mutations in the BRCA1 and BRCA2 genes, have the highest lifetime risk of developing high-grade, papillary serous epithelial ovarian, primary peritoneal, and fallopian tube cancer.

2. For ovarian cancer, epidemiologic factors that are associated with an increase in lifetime ovulatory cycles confer an increased risk.

3. Bilateral salpingo-oophorectomy, oral contraceptives, tubal ligation, and hysterectomy are all well established risk modifiers of epithelial ovarian, fallopian tube, and primary peritoneal cancer.

Epidemiologic data indicate that ovarian cancer is the ninth most common malignancy affecting women in the United States, with 21,880 cases predicted for 2010; unfortunately, it is the fifth most common cause of cancer-related deaths, with 13,850 women estimated to die of this disease in the same time period.¹ The incidence of ovarian cancer increases with age and is most prevalent in the eighth decade of life, with a rate of 57 per 100,000 women. The median age at diagnosis is 63 years, and 70% of patients present with advanced disease.²

The true incidence of fallopian tube and primary peritoneal malignancies is more difficult to quantify. Despite criteria established by the Gynecologic Oncology Group to define primary peritoneal cancers, uniform application by pathologists remains unclear, which clouds identification of the true incidence of this disease. High-grade serous carcinomas of the fallopian tube are rare entities, with 3479 new cases expected to be diagnosed yearly.³ However, incomplete pathologic sectioning and evaluation of the tubes in women with presumed metastatic ovarian cancer may preclude identification of a true tubal origin. Recent evidence suggests that nearly 60% of all high-grade, non-uterine serous cancers initially classified as primary ovarian or peritoneal in origin demonstrate serous tubal intraepithelial carcinoma (STIC), suggesting that the fallopian tube may be the organ of origin.^4,5

One of the strongest risk factors for the development of serous gynecologic cancers is the presence of a genetic predisposition to the disease. The majority of patients with a genetic predisposition to ovarian cancer have mutations in the BRCA1 or BRCA2 genes. As such, a personal or family history of premenopausal breast cancer or any ovarian cancer suggests that the presence of a BRCA gene mutation is more probable and thus increases the risk of these diseases (Table 12-1).

Table 12-1 Risk Factors for Ovarian Cancer

Epithelial ovarian cancer is, however, a disease that occurs most commonly as a result of sporadic (noninherited) acquisition. The median age of patients diagnosed with epithelial ovarian cancer is in the early seventh decade. Epidemiologic studies have established several specific risk modifiers that are associated with an increased risk for the development of ovarian cancer, including increased lifetime exposure to ovulation. These factors include a longer duration of menstruation (early menarche, late menopause), nulliparity, and lack of breast feeding.⁶ Although it would intuitively make sense that medications that induce ovulations (such as those used for the treatment of infertility) would increase the risk for ovarian cancer, this has only been suggested but not proven. Ovarian cancer occurs more frequently in industrialized countries, where obesity and a high-fat diet are more common. The hormonal basis of ovarian cancer is less certain, with some studies associating menopausal estrogen replacement with an increased risk and others with a decreased or no impact on the disease.⁷

Protection against ovarian cancer may be provided through several interventions. Factors that decrease ovulation, such as oral contraceptives, decrease the risk of the disease both in patients with and without a genetic predisposition to developing ovarian cancer. Removal of the ovaries will in large part guarantee the prevention of ovarian cancer, although rare cases of adenocarcinoma of the peritoneal cavity (primary peritoneal cancer) can occur in high-risk women. Likely due to the disruption of the ovarian blood supply, hysterectomy also decreases the risk for developing ovarian cancer. Given the relationship between peritoneal and iatrogenic irritants (possibly such as talc) and ovarian cancer, tubal ligation has been proven to decrease the risk of the disease as well.

High-grade papillary serous epithelial malignancies can arise from numerous anatomic locations in the gynecologic system, including the ovaries, peritoneum, uterus, and cervix. This chapter focuses on the most common sites of epithelial serous malignancies: the ovaries, fallopian tubes, and peritoneum. Epithelial ovarian and peritoneal cancers are predominantly of serous histology (85%) and histologically recapitulate the appearance of the fallopian tubal epithelium. The remaining histologies of epithelial ovarian cancers (endometrioid, mucinous, clear cell, and Brenner tumor) are discussed in Chapter 13.

Serous adenocarcinomas of the ovary, peritoneum, or fallopian tubes can be cytologically low grade or high grade, with high-grade adenocarcinomas comprising more than 80% of all serous cancers. The clinical importance of segregating invasive ovarian neoplasms by cytology relates to the strong influence of grade on the biologic behavior of these. Comparisons of low-grade with high-grade serous ovarian cancers show differences in genetics, response to chemotherapy, and survival. The “2-tier” system has been shown to be both reproducible and biologically relevant. High-grade serous cancers are generally diagnosed at advanced stages and are responsive to taxane and platinum chemotherapy. Low-grade serous cancers are considered to be chemotherapy resistant and may not respond as robustly to the adjuvant chemotherapy generally administered to patients with ovarian cancer.⁸ In fact, genetic profiling of low-grade serous cancers demonstrates distinct fingerprints from high-grade tumors, with segregation closer to the profile of borderline cancers.⁹ These studies have been invaluable in providing insight into potential molecular targets for the treatment of low-grade serous cancers.

Recently, increasing attention has been paid to the biology and pathogenesis of ovarian cancer. Whereas historically, high-grade serous ovarian cancer was thought to develop from precursor lesions of the ovarian surface epithelium (mesothelium), with metaplastic changes leading to transformation into malignancy, increasing scrutiny has challenged this long-held theory. It is now hypothesized that the majority of epithelial ovarian and primary peritoneal cancers arise from the fallopian tubes, either from high-grade intraepithelial neoplasia of the tubal epithelium or from the ciliated columnar epithelium residing in the para-tubal and para-ovarian tissues.¹⁰ Although this recent shift in the description of the origin of ovarian cancer is conceptually attractive, it is by no means definitive, and substantial research will need to be completed before its universal adoption.

Screening for Ovarian Cancer

Ovarian cancer is a rare disease, with a woman’s lifetime risk of being diagnosed approaching 1 in 75 (1.5%) in the general population. The prevalence of the disease is approximately 1 in 2500 in postmenopausal women. This rate, in contrast with a woman’s lifetime risk of being diagnosed with breast cancer (1 in 9, or 11%), is responsible for the challenges of ovarian cancer screening in the general population. In women with an increased risk of developing ovarian cancer as a result of a hereditary predisposition, screening becomes more feasible, as the tests required to detect the disease do not require as high a sensitivity and specificity as with detection of a more rare disease. Given that more than 90% of women diagnosed with ovarian cancer have sporadic disease, accurate screening remains a challenge. As such, fewer than 30% of patients with ovarian cancer are diagnosed with stage I disease (when the 5-year survival rates can exceed 90%).

Currently used modalities attempting to identify early-stage ovarian cancer (and thus improve survival) have mainly focused on transvaginal pelvic ultrasonography and serum CA-125 testing. Although novel serum markers and other imaging technologies are in evaluation, previous and current clinical protocols evaluating the role of ovarian cancer screening have tested pelvic ultrasound and CA-125. To date, there has been no evidence in the general population that routine screening for ovarian cancer reduces mortality related to this disease.¹¹ However, 2 ongoing clinical trials are continuing to gather information to assess the value of screening in the general population. The PLCO (Prostate, Lung, Colorectal, Ovary) screening trial randomized more than 34,000 postmenopausal women without oophorectomy to both annual CA-125 and pelvic ultrasounds for 4 years versus routine care. The most recent results from the screening arm demonstrated that 60 of 89 invasive ovarian or peritoneal cancers were detected by screening, although 72% of the screen-detected cases were diagnosed at an advanced stage.¹² The primary objective of the study, the impact of screening on mortality, has yet to be reported.

In the United Kingdom, the UKCTOCS (Collaborative Trial of Ovarian Cancer Screening) randomized more than 100,000 postmenopausal women to routine care, versus more than 50,000 postmenopausal women to screening with both pelvic ultrasound and CA-125, versus more than 50,000 to pelvic ultrasound alone. Although the data regarding ovarian cancer mortality are not yet mature, preliminary results suggest that the use of multimodality screening with CA-125 and ultrasound is superior to ultrasound alone or routine care in the detection of ovarian cancer.¹³ Recently, a single arm multi-institutional study describing the use of the Risk of Ovarian Cancer Algorithm (ROCA) interpretation of the trend of multiple CA-125 levels followed by ultrasound for a positive ROCA screen in a general population cohort of 3251 postmenopausal women over 9 years demonstrated that of the 5 women diagnosed with ovarian cancer, 3 (60%) had early-stage disease, and most had a normal (but increasing by ROCA) level of CA-125 that would have gone without detection by standard CA-125 screening. The ROCA triage strategy was associated with a positive predictive value of 37% and a specificity of 99.9%.¹⁴ Together, these trials suggest that screening of ovarian cancer may be feasible, but data regarding its impact on mortality are imperative for the widespread introduction of this technique into the general population.

DIAGNOSIS

Key Points

1. Women with ovarian cancer often experience symptoms that may include bloating, pelvic or abdominal pain, difficulty eating, early satiety, or urinary symptoms (urgency or frequency).

2. The evaluation of a patient with such symptoms or suspected ovarian cancer should include a thorough abdominal and pelvic examination, selective imaging studies, and selective tumor markers.

Until recently, many providers have described ovarian, fallopian tube, and peritoneal cancers as a “silent” disease, with the thought that there are no classic symptoms until metastases have developed. There is evidence now to suggest that most women with these cancers, including those with early-stage disease, often experience distinct clinical features and symptoms for several months before their initial diagnosis. A national survey of 1500 women, before their diagnosis of ovarian cancer, identified common signs that included abdominal, gastrointestinal, pain, constitutional, urinary, or pelvic symptoms in nature.¹⁵ In a landmark prospective case-control study, Goff et al¹⁶ identified 4 symptoms more likely to occur in women with ovarian cancer than in the general population of women presenting to primary clinics. These symptoms included an increase in abdominal size, bloating, urinary urgency, and pain. Symptoms in women with malignant ovarian masses were likely to be more recent in onset, more frequent, and higher in severity than those experienced by women without an ovarian malignancy. The results of this study and others led to the development of an Ovarian Cancer Symptoms Consensus Statement (Table 12-2).¹⁷

Table 12-2 Symptoms Likely to Occur More Commonly in Women With Ovarian Cancer Than in the General Population

Fallopian tube cancer may present with similar symptoms. A specific clinical entity, hydrops tubae profluens, is also considered classic for this disease, but is typically not identified in women diagnosed with tubal cancer. This cluster of symptoms includes cramping lower abdominal pain, which resolves after passage of a profuse, watery, and/or yellow vaginal discharge.

The importance of both the patient and the clinician recognizing the symptoms suggestive of epithelial ovarian, fallopian tube, or primary peritoneal cancer cannot be understated. Studies have demonstrated that even 80% to 90% of patients with early-stage disease are symptomatic.¹⁵ Given the lack of effective screening strategies, early recognition of symptoms associated with ovarian cancer may facilitate diagnosis of ovarian cancer at an earlier stage where outcome is improved. Several efforts are underway to develop algorithms that direct the evaluation and management of women who present with symptoms of ovarian cancer that include physical examination by a gynecologist and appropriate imaging and laboratory assessment.

Patients with symptoms such as those previously described should undergo a thorough physical assessment, which should include an abdominal and pelvic examination. Physical examination findings are often based on the stage of disease. Patients with early-stage disease may be found to have an adnexal mass appreciated on abdominal or pelvic examination.¹⁸ Patients with a malignant ovarian neoplasm may have a mass of various dimensions but typically such masses are solid, irregular, or fixed. However, pelvic examination has limited sensitivity in the detection of adnexal masses; thus many patients with early- or late-stage ovarian cancer have a normal pelvic examination.¹⁹ The adnexal mass may be tender to the patient on palpation, but rarely do patients have significant guarding or rebound tenderness. Patients with more advanced-stage disease are often found to have, along with a pelvic mass, abdominal distension or a fluid wave indicating the presence of ascites. These patients are often noted to have an upper abdominal mass suggestive of omental metastasis.

Physical examination should also include evaluation of the supraclavicular and inguinal lymph nodes to assess for nodal metastasis and evaluation of the breasts and rectum to assess for cancers originating in these organs. Other aspects of the physical examination should focus on evaluation of the other major organ systems to appropriately assess for comorbidi-ties that may affect management decisions.

Various imaging studies can be selectively used to further evaluate a patient with a pelvic mass or with symptoms suggestive of ovarian cancer.^20,21 Pelvic and/or transvaginal ultrasound remains the modality of choice to evaluate a patient with an adnexal mass due to its ease of use and relatively less expense. Pelvic ultrasound can most often distinguish uterine from ovarian pathology, and certain features noted on sonography can raise or lower suspicion for malignant disease. Findings most suggestive of malignancy in the postmenopausal woman with an ovarian mass include the presence of excrescences or papillary structures within a cyst, size greater than 10 cm, a solid or mixed solid and cystic mass, thickened septa, and color or Doppler demonstration of blood flow in the mass.^20,21 Recent studies have confirmed the ability of such ultrasound findings alone and in combination with selective tumor markers (CA-125) to be predictive in discriminating between benign and malignant adnexal masses.^22,23

Abdominal/pelvic computed tomography (CT) is also a very useful imaging modality, particularly in those patients with nonspecific symptoms suggestive of a malignant ovarian neoplasm or clinical evidence of potential metastatic disease.^20,21 Although not as accurate as ultrasound in characterizing the components of an ovarian mass, abdominal/pelvic CT is able to accurately determine the presence of ascites or metastases to the omentum, peritoneal surfaces, retroperitoneal lymph nodes, or intraparenchymal organs such as the liver and spleen. In addition, valuable information can be ascertained regarding other intraperitoneal organ sites that may be contributing to clinical symptoms and findings or that may be secondarily involved with a malignant ovarian process.

Magnetic resonance imaging (MRI) or positron emission tomography (PET) imaging rarely adds to the assessment of a patient with a pelvic mass or evidence of metastases over that which can be achieved with pelvic ultrasound or abdominal/pelvic CT.^20,21 MRI may be useful in the setting in which there is a sonographically indeterminate or complex pelvic mass and there is uncertainty about the ovary as an origin of the mass. Fluorodeoxyglucose (FDG) PET alone or combined with CT has improved sensitivity over CT in the evaluation of an adnexal mass; however, low specificity and false-positive physiologic signals are not infrequently noted, and rarely does FDG-PET imaging enhance the ability of a clinician to make a management decision over what can be decided with ultrasound or CT imaging.

Serum CA-125 may also be very useful in guiding clinical management decisions in patients with symptoms or physical examination findings suggestive of an ovarian neoplasm, particularly in the postmenopausal woman.^24,25 An elevated CA-125 in the presence of an adnexal mass in a postmenopausal woman is highly predictive of a malignant ovarian neoplasm. Care must be exercised in interpreting a normal serum CA-125 level in a patient with an ovarian mass as an indication that the patient may not harbor a malignant ovarian mass. Serum CA-125 may not be elevated in patients with nonserous (eg, mucinous) ovarian neoplasms and is only elevated in approximately 50% of patients with early-stage ovarian cancer. OVA1 (Vermillion) is a laboratory test recently approved by the US Food and Drug Administration (FDA) that assesses 5 serum biomarkers including CA-125, prealbumin, transferrin, β2 microglobulin, and apolipoprotein A1.^26,27 OVA1 is reported to improve the ability of physicians to predict whether an ovarian mass is malignant when used in combination with clinical and radiographic imaging as compared with when physicians use clinical and radiographic imaging alone. Continued investigation of this multiplex test, as well as others, is needed before its establishment as a routine investigation in women with ovarian cancer or as a screening tool.²⁸

The American Congress of Obstetricians/Gynecologists and the Society of Gynecologic Oncologists have issued guidelines applicable to all primary care physicians that provide recommendations to obstetrician/gynecologists for the evaluation and management of patients with a pelvic or ovarian mass.^29,30 The differential diagnosis in a patient with a pelvic mass should take into consideration problems that can arise from all organ systems located within the pelvis (Table 12-3).

Table 12-3 Differential Diagnosis of Pelvic Mass

The primary care physician must first have a high index of suspicion for a malignant ovarian neoplasm in patients who present with any of the previously described symptoms or signs commonly experienced in patients with a malignant ovarian mass. A thorough history and physical examination, including an abdominal and pelvic examination, are paramount. Primary care physicians should obtain selective imaging and laboratory studies to evaluate for a possible ovarian neoplasm in women with symptoms or physical examination findings suggestive of an ovarian neoplasm. A pelvic ultrasound can provide useful information about an adnexal mass that can guide clinical management decisions. An abdominal/pelvic CT may be helpful in evaluating whether symptoms may be attributable to other organ systems or, if an adnexal mass is present, whether metastases are present. A serum CA-125 is most useful in determining whether an adnexal mass may be malignant, particularly in the postmenopausal patient. An OVA1 study may also be useful in situations in which a serum CA-125 is normal, characteristics of an adnexal mass are not definitive, and concern persists for the possibility of an ovarian malignancy. It is important that primary care physicians take into consideration all clinical, radiographic, and laboratory findings to guide management decisions, in particular those findings that may determine the need for surgical evaluation or subspecialty referral.

PATHOLOGY

Key Points

1. Metastatic ovarian and primary peritoneal cancer may arise from an abnormal focus in the fallopian tube epithelium.

2. The majority of malignant epithelial ovarian, primary peritoneal, and fallopian tube neoplasms are serous cancers.

3. Staging of gynecologic cancers reflects the distribution of disease, but does not take into consideration other important prognostic factors, such as the volume of disease remaining after surgical resection.

High-grade papillary serous cancers of the ovarian, fallopian tube, and peritoneum share similar histologic characteristics that frequently do not permit determination of the organ of origin. These malignancies are characterized by clusters of atypical cells arranged in papillary patterns with irregular underlying stroma or may appear as sheets of malignant cells with marked atypia without underlying stroma (Figure 12-1). As with all grade 3 malignancies, the nuclear-to-cytoplasmic ratio is high, and observation of atypical mitoses is common. Psammoma bodies are more common in low-grade serous malignancies; they are rarely seen in grade 3 disease.

FIGURE 12-1. Photomicrograph of histologic specimen of grade 3 serous adenocarcinoma. (Reproduced, with permission, from Shorge JO, Schaffer JI, Halvorson LM, et al, eds. Williams’ Gynecology. New York, NY: McGraw-Hill; 2008.)

Spread of serous ovarian, tubal, and peritoneal cancer can be through a number of mechanisms, including direct tumor dissemination into the peritoneal cavity, lymphatic spread, and hematogenous spread (into solid organs and bone). The vast majority of patients with advanced serous cancers have peritoneal metastases. For epithelial ovarian cancer, disease most commonly spreads to the surface of the peritoneal cavity, the serosa of the large or small intestines, the omentum, and the surface of the liver or diaphragm (Figure 12-2). Although peritoneal spread of advanced ovarian cancer is quite common, it is estimated that at least 50% of these patients have concurrent or isolated retroperitoneal (pelvic, aortic, celiac) lymph node metastasis.³¹ The rate of solid organ involvement in newly diagnosed ovarian cancer is quite low,³² although involvement of solid organs in the context of recurrent disease has been increasing as patients are experiencing increased disease-free survival in the primary and recurrent settings, thus allowing for the manifestations of solid organ metastasis before death from peritoneal spread of ovarian cancer. The pattern of spread of peritoneal cancers is similar to that of ovarian cancers, with common dissemination throughout the peritoneal cavity and spread to the peritoneal surface of the pelvis, intestines, diaphragm, and omentum. Although generally the behavior of these malignancies is similar to those of the ovary and peritoneal cavity, fallopian tube cancers are different in that the rate of disease metastasis to the retroperitoneal lymph nodes exceeds that of the other high-grade serous gynecologic cancers; specifically, in tumors clinically confined to the fallopian tube, more than one-third have pathologic involvement of the retroperitoneal lymph nodes.³³

FIGURE 12-2. Omental caking caused by tumor invasion. (Reproduced, with permission, from Shorge JO, Schaffer JI, Halvorson LM, et al, eds. Williams’ Gynecology. New York, NY: McGraw-Hill; 2008.)

The staging system for ovarian cancer was established to provide a common language for the communication of results regarding diagnosis and treatment of the disease. The International Federation of Gynecology and Obstetrics (FIGO) 2009 staging system is shown in Table 12-4. Although stage clearly is an important prognostic factor in patients with ovarian cancer overall, what is not conveyed in the FIGO staging system is the description of the volume of residual disease after primary cytoreduction in women with advanced ovarian cancer, which has been shown to be the most important prognostic factor in women with metastatic disease. It is important to consider that although distant metastasis (to the upper abdomen or lymph nodes) is generally associated with stage IV disease in most other solid tumors, it is considered stage III in ovarian cancer, with stage IV cases reserved for those with parenchymal liver involvement, cytologically positive pleural effusions, or other extra-abdominal metastasis.

Table 12-4 FIGO Staging of Ovarian (and Peritoneal) Cancer

Although the treatment of fallopian tube cancer is identical to that of ovarian cancer, fallopian tube cancers are staged by a separate system (Table 12-5). In order for an adnexal malignancy to be designated a high-grade serous fallopian tube (and not ovarian) cancer, specific pathologic criteria must be met. Specifically, all or most of the adnexal malignancy must arise in the fallopian tube, and a transition from benign to invasive neoplasm must be identified in the fallopian tube.^34,35 In the absence of these criteria, and adnexal malignancy is classified as an ovarian cancer. Primary peritoneal cancers are staged similarly to epithelial ovarian malignancies. The Gynecologic Oncology Group established pathologic definitions of primary peritoneal cancer in 1993: (1) The ovaries are normal in size or enlarged by a benign process; (2) the involvement in the extraovarian sites must be greater than the involvement on the surface of either ovary; (3) microscopically, the ovaries are not involved with the tumor or exhibited only serosal or cortical implants less than 5 × 5 mm; (4) the histopathologic and cytologic characteristics of the tumor are predominantly of the serous type.³⁶

Table 12-5 FIGO Staging of Fallopian Tube Cancer

TREATMENT

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