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Management of low-grade, serous carcinomas of the ovary

Management of low-grade, serous carcinomas of the ovary
Authors:
David M Gershenson, MD
Michael J Birrer, MD, PhD
Section Editors:
Barbara Goff, MD
Don S Dizon, MD, FACP
Deputy Editor:
Sadhna R Vora, MD
Literature review current through: Jun 2022. | This topic last updated: Feb 15, 2022.

INTRODUCTION — Ovarian cancer is the second most common gynecologic malignancy and the most common cause of gynecologic cancer death in the United States. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Incidence and risk factors", section on 'Incidence'.)

The most common epithelial ovarian cancer histologic subtype is serous. Approximately 90 percent of serous carcinomas are high-grade, and 10 percent are low-grade. Low-grade, serous carcinoma of the ovary or peritoneum appears to exist on a continuum with serous borderline tumors, which are likely precursor lesions, and has a distinct pathology, clinical behavior, and prognosis compared with high-grade, serous carcinoma. Thus, a diagnosis of low-grade serous carcinoma may be made de novo or following an original diagnosis of serous borderline tumor.

The pathogenesis, clinical presentation, diagnosis, and treatment of low-grade, serous carcinoma will be reviewed here. Aspects of the management of ovarian and peritoneal carcinomas (of higher grade) as well as borderline ovarian tumors are discussed elsewhere.

(See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum".)

(See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging".)

(See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis".)

(See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer".)

(See "Patient selection and approach to neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer".)

(See "Borderline ovarian tumors".)

PATHOGENESIS — Based upon pathologic, clinical, and molecular evidence from multiple groups, it is now accepted that low-grade serous tumors of the ovary are a separate disease from high-grade, serous tumors.

Pathologic assessment has demonstrated the presence of a serous borderline tumor, non-invasive or invasive implants, and a low-grade cancer in the same patient. Approximately 60 percent of low-grade, serous carcinomas are associated with a serous borderline tumor at diagnosis [1]. The continuum between these pathologic entities strongly supports a developmental relationship [2]. In addition, clinical studies of the natural history of patients with low-grade serous cancer show that conversion to high-grade cancers essentially never occurs.

Furthermore, molecular studies have also supported that low-grade tumors are distinct from high-grade tumors and have a unique developmental pathway.

Whole genome gene expression profiling shows that borderline tumors are indistinguishable from low-grade tumors and are more similar to normal surface epithelia cells than to high-grade cancers [3]. DNA copy number changes in low-grade serous tumors may be important events in the transition from borderline tumors [4].

Multiple investigators have demonstrated that Kirsten rat sarcoma viral oncogene homolog (KRAS) and B-Raf proto-oncogene (BRAF) mutations are frequent in low-grade tumors and exceptionally rare in high-grade cancers [5-8]. Of interest, RAS mutations (but not BRAF) have been associated with recurrence [9].

Mutations in tumor protein p53 (TP53), a hallmark of high-grade, serous ovarian cancer, are not found in low-grade cancers.

These molecular features support a potential model of disease progression from benign cysts (inclusion cysts) to borderline tumors and then to invasive low-grade serous cancers. Early events (in borderline tumors) would include mutations in RAS (n, K, and H) and BRAF that are mutually exclusive, and are likely activators of the MAP kinase pathway.

CLINICAL PRESENTATION — The clinical presentation of low-grade, serous carcinoma of the ovary or peritoneum is similar to that of other epithelial cancers of the ovary or peritoneum (see "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis", section on 'Clinical presentation'). However, on average, women with low-grade, serous carcinoma are younger than those with ovarian cancer of all types. Early reports indicate that the median age at diagnosis is 43 to 46.5 years of age [10,11].

Approximately 90 percent of low-grade, serous carcinoma present with disseminated disease (International Federation of Gynecology and Obstetrics [FIGO] stage II to IV). The clinical presentation may range from an asymptomatic adnexal mass to significant symptomatology consisting of bloating, early satiety, urinary urgency, and abdominal or pelvic pain. In more advanced cases, women may also present with a pleural effusion or bowel obstruction.

DIAGNOSIS — The diagnosis of low-grade, serous carcinoma is based on histologic evaluation. This evaluation is performed following removal of the ovary(ies) and/or biopsies of the peritoneum. In cases in which primary cytoreductive surgery is deemed inappropriate due to extensive disease or patient comorbidities, the diagnosis is performed following image-guided fine needle aspiration/core biopsy or laparoscopic biopsies.

The binary grading system for serous carcinoma was initially proposed in 2004 [1]. In this system, low-grade, serous carcinoma is characterized by mild to moderate nuclear atypia as a primary feature and up to 12 mitoses per 10 high powered fields (HPF) as a secondary feature. By comparison, high-grade, serous carcinoma is characterized by marked nuclear atypia and >12 mitoses per 10 HPF.

Prior to this report, serous carcinomas were most widely graded using a three-tier system; either the Shimizu-Silverberg system, or the system of the International Federation of Gynecology and Obstetrics (FIGO) [12,13]. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Histopathology", section on 'Low-grade serous carcinoma'.)

Since the introduction of the binary grading system for serous carcinoma, it has been demonstrated to be more prognostic than the three-tier systems. It has been widely accepted into clinical practice and incorporated into the 2014 World Health Organization classification [14,15]. In addition, serous borderline tumors with concomitant invasive peritoneal implants have been reclassified as low-grade, serous carcinomas.

In most cases, low-grade, serous carcinoma is characterized by low Ki-67 proliferative rates, wild-type p53 expression, and estrogen receptor (ER) expression. However, ER expression is not pathognomonic for low-grade tumors and should not be used to make the diagnosis.

TREATMENT

Preoperative management — The preoperative management of low-grade, serous carcinoma is essentially identical to that for all types of epithelial carcinoma of the ovary or peritoneum. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging".)

In the process of the preoperative evaluation, based on findings, a determination should be made as to whether the patient is a candidate for surgery. These include several factors, including age, comorbidities, and extent of disease based on imaging. For the rare patient in whom comprehensive surgical staging is not an option (eg, due to unresectable abdominal disease or the presence of extra-abdominal metastases), neoadjuvant chemotherapy is utilized with the goal of proceeding with interval cytoreduction at a later date. (See 'Those in whom primary resection is not feasible' below.)

Importantly, if neoadjuvant chemotherapy is being considered, then a histologic diagnosis of serous carcinoma should be confirmed by either image-guided fine needle aspiration/core biopsy or laparoscopic evaluation and biopsies.

Imaging — Women suspected of having ovarian/peritoneal cancers should be evaluated with imaging studies of the chest, abdomen, and pelvis. Generally, computed tomography (CT) is the most commonly recommended type of imaging study.

Tumor markers — A baseline serum cancer antigen (CA) 125 should be drawn prior to surgery. Approximately 85 percent of women with low-grade, serous carcinoma have an elevated serum CA 125 preoperatively [16].

Genetic testing for hereditary cancer syndromes — Guidelines from the National Comprehensive Cancer Network (NCCN) recommend genetic testing for familial ovarian cancer syndromes in all women with epithelial ovarian carcinoma [17]. (See "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes", section on 'Criteria for genetic risk evaluation'.)

However, germline BRCA mutations are very infrequently associated with low-grade, serous carcinoma. In a study of 1915 women with epithelial ovarian cancer, only 4 of 70 (5.7 percent) women with low-grade, serous carcinoma carried a BRCA1 or BRCA2 germline mutation [18]. Since the frequency of germline BRCA1 or 2 mutations in patients with low-grade serous ovarian cancer is low, the authors of the study recommended that women with newly diagnosed low-grade serous tumor should undergo genetic testing.

Surgery — With rare exceptions, primary surgery is the recommended approach for the optimal treatment of low-grade, serous carcinoma. There are no distinguishing factors between low-grade, serous carcinoma and other histologic subtypes of epithelial ovarian cancer in terms of surgical management. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging".)

For patients with apparent stage I disease, comprehensive surgical staging is recommended. In selected young patients with unilateral ovarian involvement, fertility-sparing surgery may be feasible. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging", section on 'Staging in patients who desire fertility preservation'.)

For those patients with stage II to IV, low-grade, serous carcinoma, maximum cytoreductive surgery to achieve minimal residual disease (ideally no gross residual disease) is the standard. In an ancillary analysis of Gynecologic Oncology Group (GOG) 182, 189 women with grade 1 (low-grade), serous carcinoma were accrued. Those women whose primary cytoreductive surgery resulted in microscopic residual disease had a significantly superior progression-free survival (PFS) and overall survival (OS) compared with women with any gross residual disease [19]. Among 145 women with stage IIIB to IV low-grade, serous carcinoma treated with primary cytoreductive surgery, those with microscopic residual disease experienced a better PFS and OS (median, 97 versus 35 months) compared with women with residual disease >1 cm [20].

The cytoreductive procedure may occur as primary cytoreductive surgery or as interval cytoreductive surgery following neoadjuvant chemotherapy. (See 'Those in whom primary resection is not feasible' below.)

Adjuvant treatment — For those undergoing surgery, the approach to adjuvant treatment depends on the stage of the disease.

Stage IA, IB, and IC — Because stage I, low-grade, serous carcinoma is extremely rare (approximately 2 to 6 percent of all low-grade serous tumors [1,11,21]), no definitive information exists regarding standard adjuvant therapy. As per the NCCN Ovarian Cancer Guidelines, surveillance is generally recommended for stage IA and IB disease [22]. For stage IC, there is no widely accepted standard approach. The NCCN guidelines list a series of options, including observation, taxane/platinum chemotherapy for three to six cycles, or endocrine therapy. The UpToDate authors and editors feel that each of these represents an appropriate option depending on patient and provider preferences, and decisions should be individualized. (See 'Stage II to IV' below.)

Stage II to IV — Following surgery for more advanced disease, adjuvant systemic therapy consisting of a taxane/platinum regimen is often administered, typically for six cycles. While the NCCN guidelines include alternative options, such as endocrine monotherapy, for most patients we continue to suggest adjuvant chemotherapy, followed by endocrine maintenance therapy. Unlike treatment of higher-grade ovarian cancer, there are no known benefits to intraperitoneal chemotherapy or dose-dense paclitaxel/carboplatin chemotherapy over standard chemotherapy, as trials have not provided enough information specifically for low-grade, serous carcinoma to support these approaches in this subtype.

Despite the widespread use of adjuvant chemotherapy for these patients, essentially all of the reports of taxane/platinum chemotherapy in women with newly diagnosed, stage II to IV, low-grade, serous carcinoma have noted the relative chemoresistance of this subtype compared with high-grade, serous carcinoma [10,11,20,22-25]. These findings have underscored the need for more effective therapy for the first-line treatment of low-grade, serous carcinoma. (See 'Recurrent or metastatic disease' below.)

For patients treated with adjuvant chemotherapy, there may be a benefit to maintenance endocrine therapy, though prospective data are needed. In a retrospective single-institution study of women with stage II to IV, low-grade, serous carcinoma, those who received endocrine maintenance therapy following completion of primary chemotherapy had an improved PFS compared with women who underwent observation (65 versus 26 months) [26]. There was a trend towards improved OS that did not reach statistical significance (116 versus 103 months, respectively).

Yet another strategy under investigation is adjuvant endocrine therapy in place of adjuvant chemotherapy. In a second retrospective study, 27 women were treated with cytoreductive surgery followed by endocrine monotherapy (no adjuvant chemotherapy) [27]. Optimal cytoreduction to no gross residual disease was achieved in 85.2 percent of patients. Following a median follow-up of 41 months, only six patients had relapsed, and two patients had died due to tumor. The three-year PFS and OS rates were 79.0 and 92.6 percent, respectively.

Based on the findings of these two studies, an NRG Oncology phase III international clinical trial, NRG-GY-019 (NCT04095364), comparing platinum/taxane chemotherapy followed by letrozole maintenance therapy with letrozole monotherapy in women with stage II to IV, low-grade, serous carcinoma following primary cytoreductive surgery, is actively recruiting.

Those in whom primary resection is not feasible — For patients in whom initial surgical resection is not appropriate (eg, multiple hepatic or other visceral metastases), an attempt with primary systemic therapy is appropriate. In such cases, we re-image after three cycles to identify patients who can proceed with interval cytoreductive surgery. The approach following surgery mirrors that for patients with higher-grade ovarian cancer undergoing neoadjuvant chemotherapy. (See "Patient selection and approach to neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer".)

Women who undergo neoadjuvant chemotherapy appear to have a significantly worse outcome than those who undergo primary surgery followed by chemotherapy, though this a likely consequence of their more extensive disease rather than the sequence of treatments. In a retrospective report of 24 evaluable women treated with neoadjuvant chemotherapy, the response rate was only 4 percent (one patient had a complete response), with 88 percent having stable disease and 8 percent having disease progression [23]. Furthermore, the median OS for this cohort was only 56.1 months (versus over 100 months for those who undergo surgery and adjuvant therapy, seen in other studies [26]). In an updated series from this group, 36 women with low-grade serous carcinoma received neoadjuvant chemotherapy; the response rate was 11 percent compared with 75 percent for a matched group of 36 women with high-grade serous carcinoma [28]. Median OS for the women with low-grade serous carcinoma was only 47 months, likely representing the extensive nature of their initial tumor burden.

Recurrent or metastatic disease — Several options exist for women with recurrent, low-grade, serous carcinoma of the ovary or peritoneum. These include possible secondary cytoreductive surgery, chemotherapy (using standard definitions for either platinum-sensitive or platinum-resistant disease), endocrine therapies, or targeted agents such as angiogenesis inhibitors, or others available on clinical trial. (See "Cancer of the ovary, fallopian tube, and peritoneum: Surgical options for recurrent cancer".)

Secondary cytoreductive surgery – Secondary cytoreductive surgery is considered selectively for a subset of women with relapsed, low-grade, serous carcinoma. For ovarian cancer of all subtypes, there are no strict criteria for recommending this procedure. In general, ideal patients for such an operative procedure are those with platinum-sensitive disease and a limited number of metastatic sites. In a retrospective study of 41 women with recurrent, low-grade, serous carcinoma, no gross residual disease was achieved in only 22 percent [29]. Patients who had no gross residual disease following secondary cytoreductive surgery had a significantly better median PFS and OS from the time of secondary surgery compared with women with gross residual disease (60.3 versus 10.7 months, respectively; and 93.6 versus 45.8 months, respectively). Despite the low rate of achievement of no gross residual disease, some gynecologic oncologists may consider secondary cytoreductive surgery with more enthusiasm for low-grade ovarian carcinomas owing to its relative chemoresistance.

Chemotherapy – As in the neoadjuvant chemotherapy setting, the reported response rates to conventional chemotherapy in the relapsed setting are low. In a study of 58 evaluable women who received a total of 108 separate chemotherapy regimens, the overall response rate was <4 percent [30]. The response rate was 4.9 percent in the platinum-sensitive cohort and 2.1 percent in the platinum-resistant cohort. However, stable disease was observed in over 60 percent of the treatment regimens. In addition, the median PFS was 29 weeks, and 58 percent of women were progression-free at six months. Patients in this study were generally heavily pretreated. It is possible that a cohort of women who have had a more limited number of prior regimens may demonstrate a higher response rate. In two subsequent prospective randomized trials of a MEK inhibitor versus standard of care drugs in the relapsed setting (see below), the response rate to chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, and topotecan) was 13 percent in the MILO/ENGOT-ov11 trial but only 3 percent in GOG 281 [31,32]. The obvious difference in response rates between the two trials is most likely attributable to the fact that GOG 281 included a much more heavily pretreated cohort.

Endocrine therapy – Endocrine therapy also is an option for women with recurrent, low-grade, serous carcinoma. Evidence indicates that a very high proportion of these tumors express the estrogen receptor (ER) [33-35]. A wide variety of anti-estrogen agents, many of which are commonly used to treat ER-positive breast cancer, appear to be active in low-grade, serous carcinoma. These include the aromatase inhibitors, tamoxifen, fulvestrant, and leuprolide acetate. In a single-institution study, 64 patients with recurrent, low-grade, serous carcinoma received 89 different endocrine therapy regimens [34]. The objective response rate (ORR) was 9 percent, and the stable disease rate was 61.8 percent, for a clinical benefit rate of 70.8 percent. The ORR to aromatase inhibitors in this study was 13.0 percent compared with only 5.9 percent for tamoxifen. Similarly, in a phase II study of 36 patients with hormone receptor-positive, low-grade ovarian cancers (34 low-grade serous carcinomas and two low-grade endometrioid carcinomas), the ORR was 14 percent, and the clinical benefit rate at six months with anastrozole was 61 percent, with a median duration of clinical benefit of 9.5 months [36].

Based on the experience in ER-positive breast cancer, there are two ongoing clinical trials combining endocrine therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor for women with low-grade serous carcinoma. GOG 3026 (NCT03673124) is a phase II trial of letrozole plus ribociclib for women with recurrent low-grade serous ovarian cancer, and NCT03531645 is a pilot study of neoadjuvant fulvestrant plus abemaciclib in women with extensive, newly diagnosed, advanced low-grade serous carcinoma.

MEK inhibition – The MEK inhibitor trametinib is a novel treatment strategy for recurrent low-grade, serous carcinoma of the ovary, having shown improvement in PFS and response rates relative to standard treatment in a randomized trial in patients (GOG 281) [31]. Although it does not have regulatory approval for this indication, it is commercially available and is used in other disease settings. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Dabrafenib plus trametinib'.)

In GOG 281, 260 patients with a mean of 2.9 previous lines of systemic therapy were assigned to trametinib versus standard therapy, which consisted of one of the following: letrozole, tamoxifen, pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan [31]. The median PFS for the trametinib versus the standard treatment group was 13.0 versus 7.2 months, respectively (hazard ratio [HR] 0.48, 95% CI 0.36-0.64), and the ORRs were 26 versus 6 percent. The presence of mutations in KRAS, BRAF, and NRAS was not predictive of PFS; although there appeared to be a larger magnitude of improvement in ORRs with trametinib over standard treatment in mutation-positive patients compared with mutation-negative patients, this did not reach statistical significance.

Median OS was 38 months in the trametinib group and 29 months in the standard treatment group (HR 0.76, 95% CI 0.51–1·12). This OS analysis includes the effect of 68 percent in the standard care group crossing over to trametinib following disease progression.

The most frequent grade 3 to 4 adverse events with trametinib were skin rash and anemia (13 percent each), hypertension (12 percent), diarrhea (10 percent), nausea (9 percent), and fatigue (8 percent). Trametinib was added to the NCCN ovarian guidelines based on the results of this trial.

Other MEK inhibitors have also been evaluated, including selumetinib, which was associated with a 15 percent response rate in a phase II study in 52 women with recurrent, low-grade serous ovarian carcinoma; another 65 percent had stable disease [37]. In a separate trial (MILO/ENGOT-ov11) of a cohort with less prior systemic therapy than in the GOG 281 trial, the median PFS for those randomly assigned to binimetinib was similar to the clinician's choice of chemotherapy group, resulting in early study closure for futility [32]. Post hoc analysis suggested a possible association between the presence of a KRAS mutation and response to binimetinib. These agents require further investigation prior to use in this setting.

Avoidance of hormone replacement therapy — Although epidemiologic or trial data are lacking, we avoid hormone replacement therapy for women with low-grade, serous carcinoma, based on the high frequency of ER positivity and activity of anti-estrogen endocrine therapy. Clearly, more studies are needed to define the role of hormonal agents in the management of low-grade, serous carcinoma and to also understand the correlation between ER expression and response to therapy.

Is there a role for angiogenesis inhibitors? — There are no data to support the use of bevacizumab with chemotherapy as part of a first-line treatment paradigm in this population. This was shown in the ICON7 trial, which compared standard chemotherapy with or without bevacizumab [38]. Among women with low-grade, serous carcinoma, there was no benefit from the addition of bevacizumab to standard chemotherapy. Importantly, this trial did not include a central pathology review, and it is unlikely that the trial was powered to show a difference in the outcome for this rare ovarian cancer subset.

For patients who require second- or later-line treatment, however, several studies have reported the effectiveness of anti-angiogenic agents in the treatment of low-grade, serous carcinoma. One study reported a 39 percent response rate and 62 percent clinical benefit rate in 17 patients who received bevacizumab-containing regimens [39]. In an update to this study, of 45 women who received bevacizumab alone or in combination for recurrent, low-grade, serous carcinoma, the response rate was 48 percent [40]. Other small retrospective reports have described response rates ranging between 11 percent in a heterogeneous cohort to as high as 55 percent [41,42].

PROGNOSIS — Women with low-grade, serous carcinoma have a substantially prolonged overall survival (OS) time compared with women with high-grade, serous carcinoma.

For women with stage I, low-grade, serous carcinoma, very little information is available in terms of prognosis. In a review of the Surveillance, Epidemiology, and End Results (SEER) data set, the mean OS for patients with stage I disease was 123 months; the median OS had not yet been reached [21].

For women with stage II to IV, low-grade, serous carcinoma of the ovary or peritoneum, the prognosis is clearly superior to that of high-grade, serous carcinoma; clear cell carcinoma; or mucinous carcinoma. In a review of the MD Anderson Low-Grade Serous Tumor Database, of 287 women treated with primary surgery and platinum-based chemotherapy for stage II to IV, low-grade, serous carcinoma, the median progression-free survival was 25.3 months, and the median OS was 97.8 months [11]. This compares favorably relative to OS in women with higher-grade carcinomas. For example in Gynecologic Oncology Group (GOG) 218, women with stage III to IV disease experienced an OS of approximately 39 months [43].

In a multivariable analysis of the MD Anderson database study, factors significantly associated with lower risk of progression were age (age >35 years compared with age <35 years), primary site (peritoneal compared with ovarian), and disease status at completion of chemotherapy (no disease compared with persistent disease). Factors associated with a better OS were site (peritoneal compared with ovarian), disease status at completion of chemotherapy (no disease compared with persistent disease), and age (>35 years compared with <35 years). In addition, preliminary evidence suggests that women with low-grade, serous carcinoma whose tumors have a mutation in the MAP kinase pathway have a better prognosis than those whose tumors have no mutations [44].

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

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

SUMMARY AND RECOMMENDATIONS

Ovarian cancer is the second most common gynecologic malignancy and the most common cause of gynecologic cancer death in the United States. The most common epithelial ovarian cancer histologic subtype is serous. Approximately 90 percent of serous carcinomas are high grade, and 10 percent are low-grade. (See 'Introduction' above.)

On average, women with low-grade, serous carcinoma are younger than those with ovarian cancer of all types, with a median age at diagnosis of 43 to 46.5 years of age. Approximately 90 percent of low-grade, serous carcinoma present with disseminated disease (International Federation of Gynecology and Obstetrics [FIGO] stage II to IV). (See 'Clinical presentation' above.)

The diagnosis of low-grade, serous carcinoma is based on histologic evaluation of the ovary(ies) and/or biopsies of the peritoneum. Low-grade, serous carcinoma is characterized by mild to moderate nuclear atypia as a primary feature and up to 12 mitoses per 10 high powered fields (HPF) as a secondary feature. By comparison, high-grade, serous carcinoma is characterized by marked nuclear atypia and >12 mitoses per 10 HPF. (See 'Diagnosis' above.)

The preoperative management of low-grade, serous carcinoma is essentially identical to that for all types of epithelial carcinoma of the ovary or peritoneum. In the process of the preoperative evaluation, based on findings, a determination should be made as to whether to recommend primary surgery or neoadjuvant chemotherapy based on several factors, including age, comorbidities, serum cancer antigen (CA) 125 level, and extent of disease based on imaging. (See 'Preoperative management' above.)

With rare exceptions, primary surgery is the recommended approach for the optimal treatment of low-grade, serous carcinoma. There are no distinguishing factors between low-grade, serous carcinoma and other histologic subtypes of epithelial ovarian cancer in terms of surgical management. (See 'Surgery' above.)

For patients in whom initial surgical resection is not appropriate (eg, multiple hepatic or other visceral metastases, or comorbidities), an attempt with primary systemic therapy is appropriate. In such cases, we re-image after three cycles to identify patients who can proceed with interval cytoreductive surgery.

For those undergoing surgery, the approach to adjuvant treatment depends on the stage of the disease. (See 'Adjuvant treatment' above.)

For those with stage II to IV disease who have undergone surgery, we suggest adjuvant systemic therapy with a taxane/platinum regimen, typically for six cycles, rather than observation or other regimens (Grade 2C). For stage IC disease, there is no widely accepted standard approach. The National Comprehensive Cancer Network guidelines list a series of options, including observation, taxane/platinum chemotherapy for three to six cycles, or endocrine therapy. Decisions should be individualized based on patient and provider preferences. (See 'Stage IA, IB, and IC' above.)

For those with stage II to IV disease who have undergone surgery, we suggest adjuvant systemic therapy with a taxane/platinum regimen (Grade 2C), typically for six cycles. Following adjuvant chemotherapy, we suggest endocrine maintenance therapy (Grade 2C). An alternative to these steps would be endocrine monotherapy in place of chemotherapy.

Unlike treatment of higher-grade ovarian cancer, there are no known benefits to intraperitoneal chemotherapy or dose-dense paclitaxel/carboplatin chemotherapy over standard chemotherapy, as trials have not provided enough information specifically for low-grade, serous carcinoma to support these approaches. (See 'Stage II to IV' above.)

Several options exist for women with recurrent, low-grade, serous carcinoma of the ovary or peritoneum. These include possible secondary cytoreductive surgery, chemotherapy (using standard definitions for either platinum-sensitive or platinum-resistant disease), endocrine therapies, or targeted agents (eg, trametinib or bevacizumab). (See 'Recurrent or metastatic disease' above.)

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