Malignant diseases of the ovary, fallopian tube, and peritoneum

Evaluation of the adnexal mass

Ultrasound has helped define criteria to allow conservative follow-up and the risk of malignancy of some adnexal masses. Goldstein and associates studied 42 postmenopausal patients whose ultrasound scans showed unilocular cysts smaller than 5 cm in diameter; 28 were explored, none had malignancy, and 14 were followed for as long as 6 years with no change in ultrasound appearance. Finkler and colleagues noted that the addition of a CA-125 serum assay to their ultrasound criteria in postmenopausal women increases the accuracy of preoperative evaluation. In a study to evaluate the performance of the Society of Radiologists in Ultrasound consensus guidelines for risk stratification of adnexal masses, Maturen and colleagues evaluated adnexal cysts in 500 women. Of 219 with simple unilocular cysts, only one was malignant. In contrast, malignancy rates were 12.5% (12 of 84) for complex cysts and all four predominantly solid masses were malignant. Among the 132 cysts in postmenopausal women, 14 (10.6%) were malignant. Conversely, among 438 cysts in premenopausal women, 4 (0.9%) were malignant. In an ultrasound study of cystic ovarian masses in women older than 50 years, Bailey and coworkers noted that unilocular cysts smaller than 10 cm in diameter are rarely malignant, whereas complex cysts or those with solid areas are at high risk of malignancy.

Several scoring systems have been proposed to try to determine the risk of an ovarian mass being malignant. They usually include the following:

• 1.

  Is the finding a simple (unilocular) or complex (multicystic or multilocular with solid components) cyst?

• 2.

  Are there papillary projections?

• 3.

  Are the cystic walls or septa regular and smooth?

• 4.

  What is the echogenicity (tissue characterization)?

These terms, definitions, and measurements have been standardized under a consensus opinion from the International Ovarian Tumor Analysis (IOTA) group and help refine the likelihood of malignancy. Shalev and coworkers combined transvaginal ultrasonography and normal CA-125 values in 55 postmenopausal women with simple cystic or septate cystic ovarian masses; all 55 had benign disease. Although this was a small study, it suggests the potential of applying stringent ultrasound criteria with CA-125 evaluation of ovarian masses in postmenopausal women.

Others have advocated using transvaginal pulsed Doppler color-enhanced flow studies to differentiate benign from malignant masses. The resistance index, which measures resistance to flow in the vessels, has been used and presumably is low in the presence of the neovascularization that is seen with malignant tumors. The vessels of neoangiogenesis are abnormal in their distribution, with disorganized branching and a loss of the muscularis layer, all of which contribute to the decreased resistance to flow. A resistance of 0.40 or less was found useful by Kurjak and coworkers in a study of 254 women. In contrast, Bromley and colleagues, in a study of 33 postmenopausal women, used a cutoff of 0.6, which did not greatly add to their specificities; they relied on morphologic criteria (e.g., solid elements, papillary projections) to diagnose malignancy.

Valentin and associates evaluated the characteristics of 1066 adnexal masses; 266 were malignant (55 borderline ovarian tumors, 144 primary invasive epithelial cancers, 25 nonepithelial ovarian cancers, 42 metastatic cancers). A scoring system was used as well as information from color Doppler studies. They reported that borderline and stage I ovarian cancers shared similar morphology but had different characteristics from more advanced-stage tumors. They were larger, contained more papillary projections, and were more often multilocular, without solid components, but were less often purely solid and less likely to be associated with ascites. Significant variation was noted, however. Similarly, Twickler and colleagues described a scoring model to create an ovarian tumor index for women with adnexal disease. Of 244 women with follow-up, 214 had nonmalignant findings and 30 had cancer. In addition to age, TVUS variables, including ovarian volume, the Sassone morphology scale, and Doppler determination of angle-corrected systole, diastole, and time-averaged velocity, were evaluated. An ovarian tumor index was created from discriminant variables (continuous and weighted) correctly classifying the two cohorts. The area under the receiver operator characteristic curve (AUC) was highly significant (AUC, 0.91). Unfortunately, scoring systems such as these, developed from data produced by highly skilled and proficient sonographers, are difficult to generalize and, although promising, are highly operator dependent. The IOTA group has temporally and externally validated the diagnostic performance of two logistic regression models containing clinical and ultrasound variables for malignancy identification. In this study the prevalence of invasive cancer was 3%. The likelihood of cancer from a positive screen exceeded 6 for both models; a negative likelihood ratio was less than 0.1, suggesting that the criteria may be of use for evaluating women with an adnexal masses.

It should be noted that there is a difference in using ultrasonography to screen for ovarian cancer compared with using different modalities of ultrasonography to characterize an ovarian mass as benign or malignant. For example, the addition of color Doppler sonography, which measures blood flow and direction of flow, and power Doppler sonography, which can detect slow flow in small vessels, can add useful information. These permit visualization of flow location (peripheral, central, or within a septum). Most malignant tumors have a central flow (75% to 100%) compared with only 5% to 40% of benign ovarian tumors. Schelling and colleagues studied transvaginal B-mode and color Doppler sonography for the diagnosis of malignancy in 257 adnexal masses with unclear malignant status. They achieved 92% sensitivity and 94% specificity. The development of three-dimensional (3D) ultrasonography may allow more accurate volume assessments. In addition, color Doppler with 3D ultrasonography may permit better detection of vessel irregularity, coiling, and branching. Another possibility is the use of contrast media to quantify and permit earlier detection of abnormal angiogenesis, as noted by Abramowicz. Contrast-enhanced (microbubble) power 3D Doppler sonography has been investigated to evaluate the efficacy of antiangiogenic biologic agents in serial scanning.

Ovarian cancer screening

Although ovarian cancer is characterized by advanced-stage disease at diagnosis and high mortality, early-stage disease is often curable. The greatest impact on these statistics, other than prevention, would be screening to identify early-stage disease. Four modalities, used individually or in combination, have been the common theme of this effort: physical examination, biomarkers (e.g., CA-125), proteomics-genomics (experimental), and sonography. For a disease to be amenable to screening, it should be sufficiently severe (high mortality); it should have a natural history that is well characterized from latency to overt disease; and there should be a successful outcome if early disease is treated. The screening modality should have high positive and negative predictive values; have high sensitivity and specificity; and be acceptable to the population, cost-effective, and widely available. The screening population should be identifiable, and effective therapy should be available for those in whom early disease is identified. Although ovarian cancer satisfies many of these mandates, it is rare in the general population (1/2500 postmenopausal women) and not readily characterized by an identifiable precursor, thus producing a high bar for any modality.

Of the three most commonly used modalities, the least sensitive and specific is physical examination. It is estimated that just one early ovarian cancer will be identified in 10,000 physical examinations. Although the easiest to implement, poor sensitivity limits this intervention as an effective strategy.

Biomarkers such as CA-125 are of great interest because they are easy to obtain and serial evaluation can be tracked. CA-125 has been used most consistently since being discovered as a reliable biomarker to monitor epithelial nonmucinous ovarian cancer, particularly during treatment; however, large, population-based studies highlighted its limitation as a sole strategy for ovarian cancer screening. Einhorn and associates screened 5550 women and in 1992 reported that only two stage I cancers in 175 women with elevated CA-125 values were identified. As noted, a differential effect would be expected between pre- and postmenopausal women. Using the modality in women with a pelvic mass (in whom prevalence is increased) has substantial effects on assay performance but overlooks the obvious need for cancer identification before gross ovarian enlargement. This has led to the development of combined evaluation (sonography) as described here.

Ultrasonography as an isolated modality has also been advocated for screening. Although more expensive and less amenable to population-wide screening, it has become increasingly accurate in identifying early changes within the ovary, as noted. Campbell and coworkers screened 5479 patients and obtained 338 abnormal scans. Five early-stage ovarian cancers were identified. The positive predictive value was only 1.5%. Similarly, van Nagell screened 1300 patients and obtained 33 abnormal scans. Two early-stage ovarian cancers were identified. As with single-modality testing, sonography is too insensitive to be widely used for screening.

Population-based ovarian cancer screening programs have been difficult to recommend and implement because poor sensitivity and positive predictive value characteristics accompany expensive and inefficient testing methodology and triage algorithms. Menon and colleagues approached this problem by evaluating a prospectively based algorithm in a population-based screening program in the United Kingdom. The population cohort used to evaluate this screening strategy involved 13,582 menopausal women 50 years or older with at least one ovary, of whom 6532 randomly allocated women completed a first screen; the remainder served as controls. The screening strategy was a staged process in which each CA-125 sample drawn underwent a calculation using the Risk of Ovarian Cancer Algorithm (ROCA) based on the woman’s age and CA-125 value relative to her personal baseline. In this trial an estimated risk of less than 1 in 2000 was considered normal, whereas a risk of more than 1 in 500 was considered increased; those in between were considered intermediate and required repeat testing. Those not considered normal were referred for a second stage of screening that incorporated a TVUS scan and repeat CA-125 testing. A TVUS scan was considered normal, abnormal, or equivocal based on ovarian volume and morphology. From the combination of CA-125 risk estimation and transvaginal ultrasound scan, a follow-up recommendation was made that could be a gynecologic oncology referral, repeat CA-125 testing, or TVUS scan or annual screening. In the screened group, almost 80% continued with annual screening; 91 (1.4%) were considered at increased risk. Among the intermediate group, repeat testing was normal in 92%, leaving 188 (2.9% of the initial population) to undergo second-stage evaluation. Of the 144 who stayed in the program, 95 were returned to annual screening based on CA-125 and TVUS scan findings; 6 were found to have nongynecologic malignancies; and 43 were referred to a gynecologic oncologist, of whom 27 women were returned to annual screening and 16 underwent surgery. From this group, 5 cases of ovarian cancer were identified (4 malignant epithelial and 1 borderline); the 11 remaining women had benign ovarian neoplasms. Compared with the authors’ previous algorithm based on flat CA-125 values (normal = 30 U/mL), the new process referred less than 50% to secondary screening. It was concluded that this algorithm increased screening precision.

Two other prospective trials of general population screening deserve mention: the Prostate, Lung, Colorectal and Ovarian (PLCO) study and the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) ( ; ). The primary objective of the PLCO study is to evaluate the impact of annual screening with TVUS and CA-125 on ovarian cancer mortality. The study is prospectively following a cohort of more than 78,000 largely postmenopausal women with intact ovaries using an algorithm indicating that an abnormal CA-125 level (≥35 U/mL) or an abnormality on TVUS is considered a positive screen. Follow-up procedures for a positive screen are not prespecified but have been tracked, along with any surgical interventions resulting from these findings. Depending on when patients joined the study, between four and six rounds of screening could be experienced. Compliance of screening decreased slightly over the 6 years of postbaseline evaluation but remained greater than 75%; in years 5 and 6 TVUS was not administered. CA-125 screen positives ranged from 1.4% to 1.8% during six screening rounds and from 2.9% to 4.6% during the four screening rounds with TVUS. Ovarian cancer was diagnosed in 212 women in the intervention group and 176 in the usual care, control group. The relative risk (RR) for incident disease was 1.21 (95% CI, 0.99 to 1.48). Accordingly, 118 and 100 deaths were recorded in the intervention and usual care groups, respectively, over a median follow-up of 12.4 years. The RR for ovarian cancer mortality was 1.18 (95% CI, 0.82 to 1.71). In addition, of the cases diagnosed, no stage migration was experienced. Collectively, this suggests that annual screening with combined CA-125 and TVUS is insufficiently sensitive to affect ovarian cancer natural history.

The UKCTOCS was designed to definitively assess the effect of ovarian cancer screening on mortality, as well as comprehensively address the cost, acceptance, physical and psychosocial morbidity, and performance characteristics of multimodal screening and ultrasound-based screening. Between 2001 and 2005, a total of 202,638 postmenopausal women 50 to 74 years of age were randomly assigned to control (no screening), annual CA-125 screening (based on the ROCA), and second-line ultrasound testing (multimodal screening [MMS]) or annual TVUS screening (USS) alone in a 2:1:1 ratio. In the prevalence screen, 50,078 women (98.9%) underwent MMS and 48,230 (95.2%) underwent USS. Overall, 9% of the MMS cohort and 12% of the USS cohort required repeat testing. Surgery was undertaken in a small proportion of both cohorts but was significantly more likely after USS. Ovarian neoplasms, benign and malignant, were identified in both screening cohorts. The proportion of stage I and II cases was 48.3% and was balanced between the two screening algorithms; however, specificity was significantly higher for the MMS cohort (99.8%) relative to USS (98.2%). The primary endpoint was reported in 2016 with 50,639 patients randomly allocated to USS and 50,640 patients to MMS (with 101,359 controls). Over a median follow-up of 11 years, 1282 women were diagnosed with ovarian cancer: 338 in the MMS group, 314 in the USS group, and 630 in the control group. The percentage of screened patients dying from ovarian cancer was 0.29%, 0.30%, and 0.34% for the MMS, USS, and control groups, respectively. The reduction in mortality relative to control over years 0 to 14 was 15% (95% CI, −3 to 30; P = .10) with MMS and 11% (−7 to 27; P = .21) with USS. In detailed analysis of time-dependent risk reduction, the strongest effect was late in the screening interval (years 7 to 14). In a sensitivity analysis, removing the prevalent cases of ovarian cancer (those diagnosed in the first year of screening) raised the hypothesis that MMS could, in fact, reduce mortality (averaging 20% over 14 years of screening). These two studies establish the feasibility of screening; determining efficacy will required further work to firmly establish a change in clinical practice ( Table 33.5 ).

One strategy to improve the predictive index is to address a population in which prevalence is increased. A number of studies have been undertaken using transvaginal ultrasonography to screen for ovarian malignancy in higher-risk women. Bourne and colleagues screened 775 women who had at least one first-degree (n = 677) or second-degree (n = 98) relative with ovarian cancer. Overall, 43 women were referred for surgery with abnormal-appearing ovaries and 39 underwent surgery, with three stage IA ovarian carcinomas discovered (3.9 of 1000 screened); one of these was a borderline tumor. One screened patient was found to have peritoneal carcinomatosis 11 months after a normal screening study. The remainder had nonmalignant findings. The UK Familial Ovarian Cancer Screening Study (UKCTOCS) evaluated the Bayesian ROCA every 4 months with annual TVUS, if normal; if ROCA values were elevated, TVUS was to be performed within 2 months. A total of 4348 women were enrolled and followed for a median 4.8 years; 19 cases of ovarian or fallopian tube cancer were diagnosed, with 10 (52.6%) at stage I/II. Mortality data are immature. Similarly, Skates and colleagues evaluated ROCA screening with every 3 months of CA-125 testing in 3692 high-risk women. At the time of the report approximately half of incident cancers were stage I/II.

Given the potential value of an effective screening algorithm, investigation into more sensitive modalities continue. For instance, based on a deeper understanding of tissue and bloodborne factors associated with ovarian cancer, molecular-based and enhanced standard imaging are entering the clinical domain. In addition, multiomic assays, such as proteomics, microRNAs, circulating tumor DNA, exosomes, and TP53 autoantibodies, are under investigation ( ).

Diagnosis, staging, spread, preoperative evaluation, and prognostic factors

Ovarian carcinomas are usually diagnosed by detection of an adnexal mass on pelvic or abdominal examination. Occasionally the diagnosis is made from a radiographic survey carried out for the evaluation of nonspecific gastrointestinal symptoms. Unfortunately, the diagnosis is commonly made only after the disease has spread beyond the ovary, as noted earlier when we described the de novo origin of these tumors. Scully has estimated that the risk of malignancy in a primary ovarian tumor increases to approximately 33% in a woman older than 45, whereas it is less than 1 in 15 for women aged 20 to 45. In general, more than 50% of ovarian carcinomas occur in women older than 50. In a hospital-based study of ovarian neoplasms in 861 women, Koonings and associates noted that the risk of malignancy was 13% in premenopausal women but rose to 45% in postmenopausal women. More than 90% of women diagnosed with ovarian cancer report symptoms before diagnosis. Unfortunately, these symptoms are vague and not specific for early-stage disease or even ovarian cancer. Goff and colleagues conducted a prospective survey of women seeking medical care. The case patients were those about to undergo surgery for a known or suspected pelvic or ovarian mass; the controls were women presenting to one of two primary care clinics, in which approximately two-thirds were being seen for a specific problem. The voluntary questionnaire instrument administered to both cohorts asked the respondents to score the severity, frequency, and duration of 20 symptoms generally reported by ovarian cancer patients. In both groups, recurring symptoms were common and nonspecific. Symptoms in control patients were related to the purpose of their visit (general checkup vs. specific complaint), underlying disease comorbidities, and menopausal status. Not surprisingly, women with the final diagnosis of ovarian cancer generally reported numerically more symptoms and symptoms of greater severity but of shorter duration of onset compared with the clinic controls and patients with benign ovarian tumors. Patients with ovarian cancer were also statistically more likely to report increased abdominal size, bloating, urinary urgency, and pelvic pain. Because the combination of increased abdominal size, bloating, and urinary urgency was reported five times more often and had greater severity in cancer patients than in controls, the authors recommended further clinical investigation when identified. The diagnosis is established by histologic examination of tumor tissue removed at operation, although occasionally the initial diagnosis is suggested by malignant cells found in ascitic or pleural fluid obtained at paracentesis or thoracentesis, respectively.

On abdominal pelvic examination, patients may present with a suspicious or palpable pelvic mass, ascites, abdominal distention, and/or other symptoms that may not indicate an obvious source of malignancy. These may include bloating, pelvic or abdominal pain, difficulty eating or feeling full quickly, and urinary symptoms such as urgency or frequency. The initial workup for such patients, as suggested by the 2019 National Comprehensive Cancer Network (NCCN) guidelines, should include an abdominal/pelvic examination, an ultrasound, and/or abdominal/pelvic computed tomography (CT) or magnetic resonance imaging (MRI) as indicated. A chest CT is generally obtained when an ovarian malignancy is suspected. Tumor markers such as CA-125 should be obtained; other tumor markers may include inhibin, beta human chorionic gonadotropin (β-HCG), alpha-fetoprotein (α-fetoprotein), lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), and CA-19-9. A thorough family history assessment should be performed; if the patient is not being evaluated by a gynecologic oncologist, when findings are indicative of a primary ovarian malignancy, a referral to a gynecologic oncologist should be made ( ).

The staging of ovarian cancer ( Table 33.6 ) is designed according to the criteria of the International Federation of Gynecology and Obstetrics (FIGO), which are based on the results of operative exploration. Involvement of certain sites in the abdominal or pelvic cavity would lead to disease being considered inoperable to achieve an optimal cytoreduction (no gross residual disease). These include retroperitoneal suprarenal lymph node enlargement, mesenteric disease, portal hepatis disease, and bilateral parenchymal liver metastases.

Radiologic imaging has an important role in the management of ovarian cancer. Ultrasonography may be used to confirm the presence of an ovarian mass and to help distinguish between a benign or malignant lesion. CT is more commonly used to determine extent of disease and treatment response, although one of the limitations of such imaging is that it may not detect small tumor implants (<2 cm). ¹⁸ F-2-fluoro-2-deoxy-D-glucose positron emission tomography/CT (FDG-PET/CT) is a hybrid metabolic and anatomic imaging technique. In the setting of ovarian cancer, it is not routinely performed in the initial evaluation but rather more so in patients with suspected recurrence based on elevated serum CA-125 or when findings on traditional CT scans are nonspecific ( ).

Occasionally, a diatrizoate (Gastrografin) enema or colonoscopy is performed to evaluate pelvic or gastrointestinal symptoms. Consideration of gastrointestinal pathologic changes is of importance for the potential of a primary colon carcinoma, which may present initially as an adnexal mass in the older woman. Approximately 4% of colon cancers have metastatic involvement of the ovary at diagnosis. Determination of the serum CEA level may be useful in this setting and is recommended as part of the preoperative evaluation of a pelvic mass when there is suspicion of metastatic disease to the ovary. An endoscopic or gastrointestinal radiographic examination is performed if there is evidence of gastrointestinal bleeding or the suggestion of any gastrointestinal pathologic condition.

Preoperatively the use of routine bowel preparation before major abdominal surgery for advanced ovarian cancer is no longer considered the standard of care. In a Cochrane review of 260 trials including 43,451 participants with colorectal cancer, the authors aimed to determine whether rates of postoperative surgical wound infection were affected by prophylactic antibiotics compared with no treatment. The main findings from that study were that antibiotics delivered orally or intravenously before elective colorectal surgery reduced the risk of surgical wound infection. The risk of postoperative surgical wound infection was reduced by as much as 75%. ( ). In another study by Koller et al., the investigators aimed to determine the relationship between bowel preparation and surgical site infection. The analysis included 32,359 patients who underwent elective colorectal resections in the American College of Surgeons National Surgery Quality Improvement Program. Mechanical bowel preparation was not associated with decreased risk of surgical site infection compared with no bowel preparation. In contrast, both oral antibiotics or oral antibiotics and mechanical bowel preparation were associated with decreased risk of any surgical site infection compared with no bowel preparation. Venous thromboembolism prophylaxis is of particular importance in patients with ovarian cancer because a large tumor burden is associated with venous stasis and prolonged operation times. Treatment with variable-compression leg support stockings and heparin (fractionated and unfractionated) appears to reduce the risk of thromboembolism in gynecologic oncology patients undergoing surgical tumor extirpation.

Ovarian carcinomas infiltrate the peritoneal surfaces of the parietal and intestinal areas, as well as the undersurface of the diaphragm, particularly on the right side ( Fig. 33.7 ). This is particularly important because tumors that at operation appear to be confined to the ovary may have small areas of diaphragmatic involvement as the sole site of extraovarian spread. As noted earlier, most ovarian carcinomas, particularly the serous type, appear to arise from microscopic ovarian sites and do not become clinically evident until there is widespread metastatic disease. Lymphatic dissemination is also a prominent part of disease spread ( Fig. 33.8 ), and it is particularly important to note that the paraaortic nodes are at risk through lymphatics that run parallel to the ovarian vessels. In a study of 180 patients, Burghardt and coworkers observed that the proportion of positive nodes increases with higher-stage tumors: 24% in stage I, 50% in stage II, and 73.5% in stages III and IV. A study conducted by Schmeler and colleagues has evaluated the prevalence of lymph node involvement in women with primary mucinous ovarian carcinomas. A total of 107 patients were identified. Of the patients with tumor grossly confined to the ovary at surgical exploration who underwent lymphadenectomy, none had metastatic disease to the pelvic or paraaortic lymph nodes. In addition, the authors found no significant differences in progression-free survival or overall survival between patients who underwent lymphadenectomy and those who did not.

The prognosis for patients with ovarian carcinoma is related to tumor stage, tumor grade, cell type, and amount of residual tumor after resection. Information from the SEER database is presented in Table 33.7 .

Cell type has been reported to be an important factor in prognosis, as shown in Fig. 33.9 , which summarizes the 10-year survival rate of a group of patients. The most common invasive epithelial cancers, serous carcinomas, have the worst prognosis; prognosis may be better for mucinous and endometrioid tumors. A variant of papillary serous carcinoma termed transitional cell carcinoma is thought by some to be a rare but more chemosensitive tumor; however, this has not been established in multiinstitutional studies. Endometrioid carcinoma may be associated with endometriosis; such cases more commonly occur in younger women and have a better prognosis than typical endometrioid carcinomas of the ovary. Clear cell cancers have a worse prognosis, but Kennedy and associates noted that mitotic activity and tumor stage are important prognostic features of this tumor in their series. Serous tumors tend to be more poorly differentiated and discovered at a higher stage than mucinous tumors.

In addition to stage, the grade of the tumor is a major determinant of patient prognosis. Fig. 33.10 demonstrates the survival of 442 patients with ovarian carcinoma by grade, with a markedly worse prognosis for poorly differentiated tumors (grade 3). The relationship between grade and survival also exists when the results are examined separately for each stage of disease.

The development of gene expression profiling has enabled a more precise evaluation of clinical behavior in some tumors. Bonome and coworkers studied the gene expression of low malignant potential (LMP) serous neoplasms and invasive low-grade and high-grade serous tumors. A distinct and separate clustering was observed between LMP tumors and high-grade cancers. Low-grade serous tumors generally clustered with LMP neoplasms. High-grade tumors differentially expressed genes linked to cell proliferation, chromosomal instability, and epigenetic silencing. Based on these findings, high-grade epithelial cancers appear to have a distinct profile relative to LMP neoplasms. Low-grade serous tumors are remarkably similar to LMP serous neoplasms. These observations have ushered in the reclassifying invasive malignant cancers into two categories, low grade and high grade.

Treatment

Borderline ovarian tumors: Ovarian carcinomas of low malignant potential

Approximately 20% of ovarian epithelial cancers are tumors of LMP and usually have an excellent prognosis, regardless of stage. Most studies have been confined to borderline tumors of the serous (see Fig. 33.2 , B ) and mucinous (see Fig. 33.3 , B ) varieties, which are the most common histologic types; however, other epithelial types (see Table 33.3 ) can occur. Serous borderline tumors include two patterns—atypical proliferating tumor and micropapillary/cribriform (also known as noninvasive low-grade serous carcinoma) ( Fig. 33.11 ). The cells of these epithelial tumors do not invade the stroma of the ovary. It is extremely important that the ovarian tumor be thoroughly sampled by the pathologist to ensure that a borderline tumor is not mixed with invasive elements. Numerous studies have confirmed that borderline tumors have a slower growth rate than invasive ovarian carcinomas, manifested by prolonged survival

Surgery is the primary treatment for women with borderline ovarian tumors. The principal objectives of surgery are as follows: (1) diagnosis, (2) fertility-sparing surgery for patients who have not completed childbearing or who are young and have only unilateral ovarian involvement, (3) surgical staging for apparent early-stage disease, and (4) cytoreductive surgery for the minority of patients who have obvious advanced-stage disease.

The typical scenario is surgery for an adnexal mass of unknown type. One of the initial considerations in planning surgery for a pelvic mass is the surgical approach—minimally invasive or open technique. Factors to be considered in the selection of minimally invasive surgery (laparoscopic or robotic) include size of the ovarian mass(es), extent of tumor metastasis, number and type of previous operations, and body habitus. Several reports have documented the feasibility and safety of the minimally invasive approach when appropriately used ( ; ).

Once the mass is excised, frozen-section examination is a key element in ensuring appropriate decision making. If the frozen section suggests a borderline ovarian tumor, considerations for fertility-sparing surgery include the woman’s age, her desire for future childbearing, and the degree of involvement of the ovaries—unilateral versus bilateral disease. Options for fertility-sparing surgery include ovarian cystectomy and unilateral adnexectomy. Even with bilateral borderline ovarian tumors, bilateral ovarian cystectomies or ovarian cystectomy plus unilateral adnexectomy may be performed, depending on the extent of ovarian disease. Lim-Tan and associates reported on 33 cases of stage I serous borderline tumors initially treated by cystectomy. Only 3 of 33 patients undergoing cystectomy had recurrence or persistence of borderline tumor, and these patients had positive resection margins or multiple cysts present in the ovary, emphasizing the effectiveness of conservative operation; however, for most stage IA cases, unilateral adnexectomy is performed and, if the opposite ovary looks normal, no biopsy or wedge resection is done.

Surgical staging for borderline ovarian tumors remains somewhat controversial. The most compelling reason for surgical staging in a woman with borderline tumor on frozen-section examination is the risk of invasive carcinoma on final pathologic diagnosis. For women with pathologically confirmed borderline tumors, the incidence of lymph node involvement is only approximately 5%. Therefore most investigators have recommended against routine pelvic and paraaortic lymphadenectomy; however, omental and peritoneal biopsies are recommended because peritoneal implants are usually small or microscopic ( ).

As noted earlier, there are two types of serous borderline tumors: atypical proliferating tumor and micropapillary pattern. The former is more common, and the latter is more often associated with relapse. For stage I serous borderline tumors, surgery alone is the standard of care because the cure rate associated with this treatment approaches 100%. On the other hand, approximately 30% of women will have peritoneal implants, which are classified as noninvasive (see Fig. 33.11 ) or invasive (now classified as invasive low-grade serous carcinoma based on the 2014 WHO classification) ( Fig. 33.12 ). For these women, the recurrence rate associated with noninvasive implants is 20% to 50% and the recurrence rate with invasive implants ( Fig. 33.13 ) (invasive low-grade serous carcinoma) is 50% to 70%. No studies to date have convincingly demonstrated any benefit to postoperative therapy for women with stages II to IV disease with noninvasive implants; however, for women with invasive implants (invasive low-grade serous carcinoma), postoperative treatment—paclitaxel-carboplatin chemotherapy or hormonal therapy—is recommended.

Outcomes are influenced by pathologic, clinical, and other factors. Pathologic factors that may be associated with an increased risk of relapse include the presence of the micropapillary/cribriform pattern or microinvasion in the primary ovarian serous LMP tumor and the presence of peritoneal implants ( ). Clinical factors include age at diagnosis, baseline serum CA-125, conservative surgery, and residual disease.

Mucinous borderline tumors also are associated with an excellent prognosis. Hart and Norris reviewed 97 patients aged 9 to 70 years (median, 35 years) with stage I tumors. More than 10% of the tumors were discovered during pregnancy or in the immediate postpartum period. Follow-up data were available on 87 of the patients, and there were only three tumor-related deaths during the 5- to 10-year follow-up. The actuarial survival was 98% at 5 years and 96% at 10 years. This was also noted by Bostwick and colleagues, who reported on 109 borderline tumors, 33 of which were mucinous and all of which were stage I, contributing to the good prognosis.

Mucinous borderline tumors include two distinct subtypes, gastrointestinal and seromucinous or endocervical. In the seromucinous type, the association of endometriosis is high (40%). They also may have associated microinvasion and lymph node involvement. The prognosis associated with the seromucinous type is excellent. Conversely, the gastrointestinal type may rarely be associated with the condition known as pseudomyxoma peritonei, consisting of widespread growth of mucin-producing cells in the peritoneum. The result may be the accumulation of large amounts of mucinous material, which is sometimes associated with recurrent episodes of bowel obstruction. Studies by Young and coworkers suggested that pseudomyxoma peritonei usually arises in the appendix. The review of Ronnett and coworkers supports a primary appendiceal origin for these tumors and suggest that therefore appendectomy may be indicated for women with an intraoperative diagnosis of a mucinous ovarian tumor. On the other hand, more recent studies have recommended appendectomy only if the appendix appears abnormal ( ). The disease tends to recur and is commonly characterized by repeated laparotomy to relieve bowel obstruction. Chemotherapy and mucolytic agents have been tried but are usually not successful.