Rare Epithelial Ovarian Cancers: Low Grade Serous and Mucinous Carcinomas

for all LGSCs is cytoreductive surgery, possibly in combination with platinum-based chemotherapeutics; the type of chemotherapy administered is dependent on tumor stage. Patients with tumors that have recurred or progressed may receive a second round of cytoreductive surgery in conjunction with chemotherapeutics. Hor- mone therapy may be administered to patients with estrogen/progesterone receptor-positive (ER/PR-positive) tumors; patient tumors can also be sequenced to identify targetable mutations or pathway alterations, after which more personalized treatment strategies can be used. O. Craig et al. 10 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190 www .perspectivesinmedicine.org on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from (>1 cm) (97 mo vs. 35 mo, respectively) (Gra- bowski et al. 2016). Indeed, LGSC patients with macroscopic disease post-debulking exhib- ited similar progression-free and overall survival to HGSC patients with macroscopic disease (13 mo and 30 mo, respectively, for LGSC vs. 10 mo and 28 mo for HGSC [Chen et al. 2014]). In the relapse setting, a second round of cytoreduction has been proposed to be of a greater bene fit (especially if no gross residual disease can be achieved) to patients with LGSC than for those with HGSC, in part due to the chemoresistant nature of LGSC (Moujaber et al. 2021). In combination with surgery, platinum- based monotherapy is administered to patients with LGSC (Ledermann et al. 2013). However, with increased genetic stability and a lower proliferation rate than their high-grade counter- part, LGSCs are typically more resistant to stan- dard chemotherapeutics (Gershenson et al. 2006, 2009). A study analyzing the ef ficacy of nonplatinum monotherapy in platinum-resis- tant HGSCs found the objective response rate (ORR) to treatment to be 19.7% (Gordon et al. 2001). By contrast, in a study of 58 LGSC pa- tients with either platinum-sensitive or resistant tumors, who were treated with varying chemo- therapy regimens (including hormonal thera- py), ORRs were just 4.9% and 2.1%, respectively (Gershenson et al. 2009). The ef ficacy of neo- adjuvant chemotherapy is equally low; in a study of 24 patients who underwent combined taxane and platinum-based therapy, only one had a complete response, with 21 patients experienc- ing stable disease and two patients progressing (Schmeler et al. 2008). Furthermore, a study of 36 LGSC patients found that only 11% had a partial response to neoadjuvant platinum-based chemotherapy; in sharp contrast, 75% of HGSC patients analyzed in the same study had a partial response to treatment (Cobb et al. 2020). LGSC has a high recurrence rate; more than 80% of patients will experience relapse (Ger- shenson 2016). For some patients, second- round cytoreductive surgery may be advised. Again, the ef ficacy of surgery depends on the presence of macroscopic residual tumor postop- eration. When no gross residual disease was present, patients experienced a roughly sixfold better progression-free survival than those that had macroscopic disease postsurgery for recur- rent disease (Crane et al. 2015). LGSC can exhibit a high expression of estro- gen and progesterone receptors (ERs and PRs, respectively) (Sieh et al. 2013). Furthermore, pa- tients with LGSC are diagnosed at a younger age and are likely to be premenopausal, thus impli- cating hormonal involvement in cancer progres- sion. However, a study conducted by Sieh et al. (2013) found that there was no statistically sig- nificant correlation between ER/PR status and survival in LGSC patients. Retrospective studies by Gershenson et al. analyzed the ef ficacy of hormonal treatment regimens for LGSC pa- tients with recurrent or stage II –IV disease. Clinical bene fit from various hormonal thera- pies was observed in the recurrent population (Gershenson et al. 2012), and hormonal main- tenance therapy was associated with improved progression-free survival (Gershenson et al. 2017). Almost all patients in these studies car- ried ER + tumors, and there was no difference in survival for ER +/PR+ cases compared to ER +/ PR− in the maintenance setting, although num- bers were small. Hormonal therapies are now an active area of clinical trial research, with at least two active trials listed evaluating combinations with letrozole in LGSC (NCT03673124 [clini- caltrials.gov/ct2/show/NCT03673124] with ri- bociclib and NCT04095364 [clinicaltrials.gov/ ct2/show/NCT04095364] with/without carbo- platin/paclitaxel). Another trial is underway to assess the ef ficacy of the antiprogesterone drug onapristone in treated patients with PR + LGSC (NCT03909152), and two others are evaluating fulvestrant either alone (NCT03926936 [clini- caltrials.gov/ct2/show/NCT03926936]) or in combination with the CDK4/6 inhibitor abema- ciclib (NCT03531645). TARGETED THERAPIES TO IMPROVE OUTCOMES OF RARE GYNECOLOGICAL CANCER SUBTYPES For rare cancers such as MOC and LGSC, large clinical trial data sets are not available to direct clinical management strategies. As a result, treatment paradigms for rare cancers are under- Rare Epithelial Ovarian Cancers Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190 11 www .perspectivesinmedicine.org on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from going a shift toward identifying and developing novel targeted therapy strategies for individu- al patients using multiomic sequencing ap- proaches. Targeted therapies, aimed at aberrant genes/proteins detected by sequencing can then be tested for their ef ficacy, especially as combination therapies. As mutations in the MAPK/ERK pathway are common in MOC and LGSC, inhibitors of mitogen-activated protein kinase (MEK inhibi- tors) are a potential therapy option for these patients (Miller et al. 2014). Indeed, at the cell line level, EOC cell growth was markedly re- duced using the MEK inhibitor CI-1040. Re- cently, LGSC-speci fic cell lines have also been used to investigate various MEK inhibitors (Fer- nandez et al. 2016, 2019), with responses noted particularly in KRAS-mutated cell lines. A clin- ical trial testing the MEK inhibitor binimetinib was attempted in LGSC patients, but due to the small sample size no statistically signi ficant ef- fect on progression-free survival compared to chemotherapy was observed (Grisham et al. 2019). Nonetheless, individual durable re- sponses were noted, particularly in patients with KRAS mutations. One case study reported a patient on this trial with recurrent, chemore- sistant, and hormone therapy –resistant LGSC with a KRAS mutation who demonstrated par- tial response to MEKi, with an 81% reduction in tumor size during treatment (Han et al. 2018). While MOC patients were not included in this trial, given the high rate of KRAS mutations in this tumor subtype, there is also a strong ratio- nale for binimetinib use in these patients. An- other MEK inhibitor, selumetinib, has been test- ed on 52 LGSC patients (Farley et al. 2013; Miller et al. 2014). At the conclusion of this small trial, more than half of the patients had stable disease, while approximately 15% experienced complete or partial response to treatment. Median overall survival was 32.4 months. Patients were not se- lected for RAS/RAF mutations, and response was not related to the presence of such a muta- tion, with the caveat of a small sample size. Other current clinical trials of MEK inhibitors in- clude evaluation of trametinib (NCT02101788 [clinicaltrials.gov/ct2/show/NCT02101788]), with preliminary outcomes reported suggesting im- proved progression-free survival and an objec- tive tumor response rate of 26% (Gershenson et al. 2022). A recent phase I clinical study using the RAF/ MEK inhibitor VS-6766 and the FAK inhibitor defactinib to treat 25 patients with LGSC report- ed promising preliminary results; the ORR for all patients was 46%, increasing to 64% for patients with KRAS mutations (NCT03875820). Mutations in BRAF, and in particular BRAFV600E, are a relatively common occur- rence in LGSC and MOC (Moujaber et al. 2018). BRAF inhibitors are now successfully used in the treatment of metastatic melanoma (Hauschild et al. 2012). The ef ficacy of such treatment for MOC and LGSC has yet to be determined, although there are case reports of positive results from treatment. For example, a patient who had chemoresistant, recurrent LGSC underwent treatment with the BRAF in- hibitor dabrafenib in combination with the MEK1/2 inhibitor trametinib; CA-125 levels de- clined over a 6-month treatment period (Men- divil et al. 2018). Similarly, a report by Stover et al. (2018) highlights the bene fits of using tar- geted sequencing on two LGSC patients; for one patient with BRAFV600E, the BRAF inhibitor vemurafenib had considerable ef ficacy, marked by a decrease in CA-125 levels. Interestingly, the second patient who had progressive LGSC un- derwent hormonal therapy and responded to treatment, although a recurrent lesion harbored a mutation in ESR1, conferring resistance to an- tiestrogen therapy. Bevacizumab, a monoclonal antibody that inhibits vascular endothelial growth factor, has been successfully implemented in colorectal car- cin oma (Macedo et al. 2012). Subsequent studies have shown the benefit of Bevacizumab in EOC phase 3 trials, but limited MOC patient partici- pation hindered collection of speci fic data for this subtype (Xu et al. 2016). The GOG241 trial also tested Bevacizumab in combination with carboplatin-paclitaxel or oxaliplatin-capecita- bine, and showed no bene fit from the addition of Bevacizumab, although only 18 confi rmed MOC cases were available for analysis (Gore et al. 2019). Despite this, individual case reports have reported success with Bevacizumab mono- O. Craig et al. 12 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190 www .perspectivesinmedicine.org on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from therapy (Winer and Buckanovich 2010). Beva- cizumab has also been tested in a small number of patients with LGSC with considerably greater success. In retrospective studies, Bevacizumab showed efficacy in patients for recurrent LGSC with response rates of 40% –47.5% and clinical benefit of 73% –78% (Grisham et al. 2014; Dal- ton et al. 2017). Bevacizumab was used alongside chemotherapy as a primary treatment strategy for patients in several randomized trials. Meta- analyses showed limited progression-free (but not overall) survival bene fit, although LGSCs were not assessed separately from all serous or all low-grade carcinomas (Rossi et al. 2017). Targeting of other growth factor receptors has been similarly considered although with much fewer samples. In cases of ERBB2 ampli- fication, anti-HER2 therapy using targeted anti- bodies or tyrosine kinase inhibitors has been successful in other cancers such as gastric and breast cancer. Given the relative frequency of HER2 overexpression in MOC, it is hoped such efforts might translate to this subtype. Ev- idence of ef ficacy has been provided by case studies of a few individual patients (McAlpine et al. 2009; Jain et al. 2012), but more robust data on larger sample sizes are lacking. The EGFR inhibitor cetuximab could be useful in treating KRAS wild-type MOC. Ef ficacy has been dem- onstrated successfully by Sato et al. (2012) in KRAS wild-type MOC cell lines and mice; again, however, there are currently no clinical data sup- porting its use. Recently, other less frequent genetic events that occur in MOC patients were identi fied as having potential clinical utility, including RNF43, ARID1A, and PIK3CA/PTEN mutations (Gorringe et al. 2020). These events may be ac- tionable using targeted agents currently used or being tested in other cancer types, potentially giving otherwise untreatable patients therapeu- tic options. Additionally, approximately 11% of MOC patients may be ER + and thus could ben- efit from hormonal therapy. By the same preci- sion oncology paradigm, PARPi and immuno- therapies were deemed unlikely to be useful in MOC treatment due to the rarity of homologous recombination deficiency (HRD) and mismatch repair de ficiency (MRD). In LGSC, ∼27% of cases recently analyzed had a genetic event that was predictive of benefit with an agent already in the clinic for another cancer type (Cheasley et al. 2021). FUTURE DIRECTIONS Overall, the major limitation of most clinical trials discussed above is their restricted sample size; due to the rarity of these diseases, recruiting patients with the given histotype as well as the specific mutation(s) being targeted is challeng- ing. A further challenge is the paucity of patient- derived models to establish preclinical evidence for drug efficacy. Only a handful of cell lines and patient-derived xenografts are available for ei- ther MOC or LGSC (Table 1), and very recently a few novel tumor organoid models have been developed (Kopper et al. 2019). Older cell lines are relatively untrustworthy for studies as the subtype (especially LGSC) was often not record- ed. Despite recent efforts to identify the origins of such cell lines using mutations and gene-ex- pression data (Domcke et al. 2013; Barnes et al. 2021), it would generally be advisable to work with more recently derived models (Nelson et al. 2020; Shrestha et al. 2021). In synergy with identifying appropriate tar- geted therapies, research should also focus on establishing markers of treatment response and resistance for MOC and LGSC. For example, Shrestha et al. (2021) combined genomic, tran- scriptomic, and proteomic methods to discover potential predictive markers of MEKi treatment response and new therapy combinations. Such studies can aid clinical trials in selecting patients who will likely have a better response to treat- ment. Sequencing approaches can also reveal novel driver mutations (either standalone or co-occurring), aiding in the identi fication of new treatment targets. USP9X and EIF1AX are two genes that have been recently identi fied as recurring mutations that may play a role in LGSC development (Hunter et al. 2015; Ete- madmoghadam et al. 2017). In particular, the group of LGSC patients lacking the known RAS/RAF drivers remain to be fully explored for genetic drivers. Rare Epithelial Ovarian Cancers Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190 13 www .perspectivesinmedicine.org on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from Table 1. Cell lines for use in mucinous ovarian carcinoma (MOC) and low-grade serous ovarian carcinoma (LGSC) research Cell line Original histological type Likely histological type Known mutationsa References Plausible MOC cell lines MCAS MOC MOC KRAS, TP53 Kidera et al. 1985; Anglesio et al. 2013b RMUG-S MOC MOC TP53 Sakayori et al. 1990 JHOM1 MOC MOC (seromucinous?) TP53, CDKN2A, PTEN RIKEN cell bank COV644 MOC MOC CDKN2A, MDM2 ampli fication van den Berg-Bakker et al. 1993 Previous MOC cell lines that are likely to be non-MOC SW626 NK Colorectal cancer (CK20 +) APC, KRAS, TP53 Furlong et al. 1999 EFO27 MOC Endometrioid/ endometrial ARID1A, MSH2 (dMMR), PIK3CA, PTEN, TP53 Simon et al. 1983 JHOM2B MOC Colorectal cancer TP53, BRAF, SMAD4 RIKEN cell bank OMC-3 MOC Pancreatic? BRCA2, SMAD4, CDKN2A Yamada et al. 1991; KL Gorringe, unpubl. LGSC cell lines iOvCa241 LGSC LGSC KRAS Shrestha et al. 2021 VOA-1312 LGSC LGSC KRAS Shrestha et al. 2021 VOA-1056/VOA-3993 LGSC LGSC NRAS Shrestha et al. 2021 VOA-3448/VOA-3723 LGSC LGSC Shrestha et al. 2021 VOA-4627/VOA-4698 LGSC LGSC TP53 Shrestha et al. 2021 VOA-6406 LGSC LGSC NRAS Shrestha et al. 2021 VOA-8862 LGSC LGSC KRAS Shrestha et al. 2021 VOA-9164 LGSC LGSC KRAS Shrestha et al. 2021 CAISMOV24 LGSC LGSC KRAS da Silva et al. 2017 PM-LGSC-01 LGSC LGSC KRAS De Thaye et al. 2020 HeyA8 Moderately differentiated papillary cystadenocarcinoma LGSCb KRAS Buick et al. 1985; Barnes et al. 2021 OVCAR8 NK LGSC/HGSCb TP53, KRAS, CTNNB1, ERBB2 Schilder et al. 1990; Barnes et al. 2021 TYK-nu Undifferentiated LGSC/HGSC c NRAS, TP53 Yoshiya 1986; Barnes et al. 2021 OV7 Mixed LGSC/HGSCc KRAS, TP53 Boocock et al. 1995; Barnes et al. 2021 aFrom the Cancer Cell Line Encyclopedia unless otherwise stated (Ghandi et al. 2019). bOriginal histology was nonspeci fic, the LGSC call is based on gene expression and mutations and therefore may be incorrect (Barnes et al. 2021). cDescribed as poorly differentiated or undifferentiated. Do carry characteristic LGSC drivers, so potential progression to HGSC from an LGSC precursor. O. Craig et al. 14 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190 www .perspectivesinmedicine.org on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from Another application of a multiomics ap- proach is to assist in elucidating the cell of origin for these rare cancers, which is still contentious for both histotypes. Using a combination of ge- nomic, transcriptomic, methylation, and chro- matin sequencing studies, further evidence can be obtained to either confi rm or disprove the various theories (Li et al. 2011; Hao et al. 2017). Inducible animal model systems and lin- eage-tracing analysis could also be used to iden- tify the correct cell type. CONCLUDING REMARKS Although MOC and LGSC are distinct from each other and the other ovarian histotypes, there are certain similarities, summarized in Ta- Table 2. Characteristics of mucinous ovarian carcinoma (MOC) and low-grade serous ovarian carcinoma (LGSC) MOC LGSC References Incidence 0.6/100,000 0.5/100,000 Howlader et al. 2017; Leary et al. 2017 Risk factors Smoking Number of children; age at menopause; endometriosis; oral contraceptive use; menopausal hormone therapy Collaborative Group on Epidemiological Studies of Ovarian Cancer et al. 2012; Wentzensen et al. 2016 Cell of origin Unknown —potentially ovarian surface epithelium, transitional cells of peritoneal junction, Brenner tumors, fallopian tube epithelium via endosalpingiosis, primordial germ cells Unknown, possibly fallopian tube secretory cells or ovarian surface epithelium Seidman and Khedmati 2008; Kurman et al. 2011; Chen et al. 2013; Qiu et al. 2017; Elias et al. 2018; Park et al. 2018; Wang et al. 2019b Precursor tumors Commonly, mucinous benign and borderline tumors; rarely, Brenner tumors, teratomas Serous benign and borderline Hunter et al. 2011, 2012; Emmanuel et al. 2014; Wang et al. 2015a,b; Cheasley et al. 2019 Stage distribution Localized 48.2% Regional 25% Distant 26.7% Localized 20.3% Regional 26.3% Distant 53.4% Peres et al. 2019 Key genetic features (>25%) KRAS (40%–65%), TP53 (30%–64%), ERRB2 (20%–35%), CDK2NA (20%–45%) NRAS (25%), BRAF (14%), KRAS (20%), EIF1AX (13%), USP9X (13%) McAlpine et al. 2009; Hunter et al. 2015; Mackenzie et al. 2015; Etemadmoghadam et al. 2017; Meagher et al. 2018; Moujaber et al. 2018; Mueller et al. 2018; Cheasley et al. 2019 IHC markers CK7 +, CK20−, SATB2− WT1+, p53wt, p16 −/patchy McCluggage 2012; Köbel et al. 2014; Sallum et al. 2018; Meagher et al. 2019 Response to platinum- based therapies (%) 26.3%–60% 4% –5% Hess et al. 2004; Pectasides et al. 2005; Gershenson et al. 2006, 2009; Pignata et al. 2008; Schmeler et al. 2008; Alexandre et al. 2010 5-Year overall survival Localized 83% Regional 70% Distant 14% Localized 93% Regional 83% Distant 54% Peres et al. 2019 Rare Epithelial Ovarian Cancers Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190 15 www .perspectivesinmedicine.org on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from ble 2. The most notable similarity between these histotypes is not related to their biology, but simply their rarity, which confers profound clin- ical and research challenges. Both diseases are relatively chemoresistant, yet such rarity means that performing well-powered clinical trials in either subgroup is dif ficult. Hence, targeted agents for MOC and LGSC may best be test- ed using novel approaches such as registry trials, n = 1 trials, and basket trials in concert with oth- er solid tumor types with similar genetic fea- tures. In addition, directed efforts must be made toward establishing relevant preclinical models to test the ef ficacy of targeted agents and combinations. ACKNOWLEDGMENTS K.G. is supported by a Victorian Cancer Agency Mid-Career Fellowship and the Peter MacCal- lum Foundation. A.N. is supported by a Uni- versity of Melbourne International Research Scholarship. O.C. is supported by a University of Melbourne Graduate Research Scholarship. G.V.D. is supported by a Victorian Cancer Agency Early Career Fellowship.

Aarestrup J, Trabert B, Ulrich LG, Wentzensen N, Sørensen TIA, Baker JL. 2019. Childhood overweight, tallness, and growth increase risks of ovarian cancer.Cancer Epidemiol Biomarkers Prev 28: 183–188. doi:10.1158/1055-9965 .EPI-18-0024 Alexandre J, Ray-Coquard I, Selle F, Floquet A, Cottu P, Weber B, Falandry C, Lebrun D, Pujade-Lauraine E; GINECO. 2010. Mucinous advanced epithelial ovarian carcinoma: clinical presentation and sensitivity to plati- num-paclitaxel-based chemotherapy, the GINECO expe- rience. Ann Oncol 21: 2377–2381. doi:10.1093/annonc/ mdq257 Anglesio MS, Kommoss S, Tolcher MC, Clarke B, Galletta L, Porter H, Damaraju S, Fereday S, Winterhoff BJ, Kalloger SE, et al. 2013a. Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas. J Pathol 229: 111–120. doi:10.1002/path.4088 Anglesio MS, Wiegand KC, Melnyk N, Chow C, Salamanca C, Prentice LM, Senz J, Yang W, Spillman MA, Cochrane DR, et al. 2013b. Type-speci fic cell line models for type- specific ovarian cancer research. PLoS ONE 8: e72162. doi:10.1371/journal.pone.0072162 Barnes BM, Nelson L, Tighe A, Burghel GJ, Lin IH, Desai S, McGrail JC, Morgan RD, Taylor SS. 2021. Distinct tran- scriptional programs stratify ovarian cancer cell lines into the five major histological subtypes.Genome Med 13: 140. doi:10.1186/s13073-021-00952-5 Bell DA. 2005. Origins and molecular pathology of ovarian cancer. Mod Pathol 18 (Suppl 2): S19–S32. doi:10.1016/ S0893-3952(22)04456-8 Bonome T, Lee JY, Park DC, Radonovich M, Pise-Masison C, Brady J, Gardner GJ, Hao K, Wong WH, Barrett JC, et al. 2005. Expression pro filing of serous low malignant po- tential, low-grade, and high-grade tumors of the ovary. Cancer Res 65: 10602–10612. doi:10.1158/0008-5472 .CAN-05-2240 Boocock CA, Charnock-Jones DS, Sharkey AM, McLaren J, Barker PJ, Wright KA, Twentyman PR, Smith SK. 1995. Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma.J Natl Cancer Inst 87: 506–516. doi:10.1093/jnci/87.7.506 Buick RN, Pullano R, Trent JM. 1985. Comparative proper- ties of five human ovarian adenocarcinoma cell lines. Cancer Res 45: 3668–3676. Cancer Genome Atlas Research Network (CGARN). 2011. Integrated genomic analyses of ovarian carcinoma. Na- ture 474: 609–615. doi:10.1038/nature10166 Chang KL, Lee MY, Chao WR, Han CP. 2016. The status of Her2 amplification and Kras mutations in mucinous ovarian carcinoma. Hum Genomics 10: 40. doi:10.1186/ s40246-016-0096-9 Cheasley D, Wake field MJ, Ryland GL, Allan PE, Alsop K, Amarasinghe KC, Ananda S, Anglesio MS, Au-Yeung G, Böhm M, et al. 2019. The molecular origin and taxonomy of mucinous ovarian carcinoma. Nat Commun 10: 3935. doi:10.1038/s41467-019-11862-x Cheasley D, Nigam A, Zethoven M, Hunter S, Etemadmog- hadam D, Semple T, Allan P, Carey MS, Fernandez ML, Dawson A, et al. 2021. Genomic analysis of low-grade serous ovarian carcinoma to identify key drivers and ther- apeutic vulnerabilities. J Pathol 253: 41–54. doi:10.1002/ path.5545 Chen C, Li J, Yao G, Chambers SK, Zheng W. 2013. Tubal origin of ovarian low-grade serous carcinoma. Am J Clin Exp Obstet Gynecol 1: 13–36. Chen M, Jin Y, Bi Y, Yin J, Wang Y, Pan L. 2014. A survival analysis comparing women with ovarian low-grade se- rous carcinoma to those with high-grade histology. Onco Targets Ther 7: 1891–1899. doi:10.2147/OTT.S67 812 Chui MH, Ryan P, Radigan J, Ferguson SE, Pollett A, Aron- son M, Semotiuk K, Holter S, Sy K, Kwon JS, et al. 2014. The histomorphology of Lynch syndrome-associated ovarian carcinomas: toward a subtype-speci fic screening strategy. Am J Surg Patho 38: 1173–1181. doi:10.1097/ PAS.0000000000000298 Cobb LP, Sun CC, Iyer R, Nick AM, Fleming ND, Westin SN, Sood AK, Wong KK, Silva EG, Gershenson DM. 2020. The role of neoadjuvant chemotherapy in the manage- ment of low-grade serous carcinoma of the ovary and peritoneum: further evidence of relative chemoresistance. Gynecol Oncol 158: 653–658. doi:10.1016/j.ygyno.2020 .06.498 Collaborative Group on Epidemiological Studies of Ovarian Cancer; Beral V, Gaitskell K, Hermon C, Moser K, Reeves G, Peto R. 2012. Ovarian cancer and smoking: individual O. Craig et al. 16 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190 www .perspectivesinmedicine.org on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from participant meta-analysis including 28,114 women with ovarian cancer from 51 epidemiological studies. Lancet Oncol 13: 946–956. doi:10.1016/S1470-2045(12)70322-4 Crane EK, Sun CC, Ramirez PT, Schmeler KM, Malpica A, Gershenson DM. 2015. The role of secondary cytoreduc- tion in low-grade serous ovarian cancer or peritoneal cancer. Gynecol Oncol 136: 25–29. doi:10.1016/j.ygyno .2014.11.005 Dalton HJ, Fleming ND, Sun CC, Bhosale P, Schmeler KM, Gershenson DM. 2017. Activity of Bevacizumab-contain- ing regimens in recurrent low-grade serous ovarian or peritoneal cancer: a single institution experience. Gynecol Oncol 145: 37–40. doi:10.1016/j.ygyno.2017.01.027 da Silva RF, Cardozo DM, Rodrigues GOL, Souza-Araujo CN, Migita NA, Andrade L, Derchain S, Yunes JA, Gui- marães F. 2017. CAISMOV24, a new human low-grade serous ovarian carcinoma cell line. BMC Cancer 17: 756. doi:10.1186/s12885-017-3716-4 De Thaye E, Van de Vijver K, Van der Meulen J, Taminau J, Wagemans G, Denys H, Van Dorpe J, Berx G, Ceelen W, Van Bocxlaer J, et al. 2020. Establishment and character- ization of a cell line and patient-derived xenograft (PDX) from peritoneal metastasis of low-grade serous ovarian carcinoma. Sci Rep 10: 6688. doi:10.1038/s41598-020- 63738-6 Domcke S, Sinha R, Levine DA, Sander C, Schultz N. 2013. Evaluating cell lines as tumour models by comparison of genomic pro files. Nat Commun 4: 2126. doi:10.1038/ ncomms3126 du Bois A, Ewald-Riegler N, de Gregorio N, Reuss A, Mahner S, Fotopoulou C, Kommoss F, Schmalfeldt B, Hilpert F, Fehm T, et al. 2013. Borderline tumours of the ovary: a cohort study of the Arbeitsgmeinschaft Gynakologische Onkologie (AGO) study group. Eur J Cancer 49: 1905– 1914. doi:10.1016/j.ejca.2013.01.035 Elias KM, Tsantoulis P, Tille JC, Vitonis A, Doyle LA, Hor- nick JL, Kaya G, Barnes L, Cramer DW, Puppa G, et al. 2018. Primordial germ cells as a potential shared cell of origin for mucinous cystic neoplasms of the pancreas and mucinous ovarian tumors. J Pathol 246: 459–469. doi:10 .1002/path.5161 Emmanuel C, Chiew YE, George J, Etemadmoghadam D, Anglesio MS, Sharma R, Russell P, Kennedy C, Fereday S, Hung J, et al. 2014. Genomic classification of serous ovar- ian cancer with adjacent borderline differentiates RAS pathway and TP53-mutant tumors and identi fies NRAS as an oncogenic driver. Clin Cancer Res 20: 6618–6630. doi:10.1158/1078-0432.CCR-14-1292 Etemadmoghadam D, Azar WJ, Lei Y, Moujaber T, Garsed DW, Kennedy CJ, Fereday S, Mitchell C, Chiew YE, Hendley J, et al. 2017. EIF1AX and NRAS mutations co- occur and cooperate in low-grade serous ovarian carcino- mas. Cancer Res 77: 4268–4278. doi:10.1158/0008-5472 .CAN-16-2224 Fader AN, Java J, Krivak TC, Bristow RE, Tergas AI, Book- man MA, Armstrong DK, Tanner EJ, Gershenson DM. 2014. The prognostic signi ficance of pre- and post-treat- ment CA-125 in grade 1 serous ovarian carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 132: 560–565. doi:10.1016/j.ygyno.2013.11.016 Farley J, Brady WE, Vathipadiekal V, Lankes HA, Coleman R, Morgan MA, Mannel R, Yamada SD, Mutch D, Rod- gers WH, et al. 2013. Selumetinib in women with recur- rent low-grade serous carcinoma of the ovary or perito- neum: an open-label, single-arm, phase 2 study. Lancet Oncol 14: 134–140. doi:10.1016/S1470-2045(12)70572-7 Fathalla MF. 1971. Incessant ovulation —a factor in ovarian neoplasia? Lancet 2: 163. doi:10.1016/S0140-6736(71) 92335-X Fernandez ML, DiMattia GE, Dawson A, Bamford S, Ander- son S, Hennessy BT, Anglesio MS, Shepherd TG, Sala- manca C, Hoenisch J, et al. 2016. Differences in MEK inhibitor efficacy in molecularly characterized low-grade serous ovarian cancer cell lines. Am J Cancer Res 6: 2235– 2251. Fernandez ML, Dawson A, Hoenisch J, Kim H, Bamford S, Salamanca C, DiMattia G, Shepherd T, Cremona M, Hen- nessy B, et al. 2019. Markers of MEK inhibitor resistance in low-grade serous ovarian cancer: EGFR is a potential therapeutic target. Cancer Cell Int 19: 10. doi:10.1186/ s12935-019-0725-1 Furlong MT, Hough CD, Sherman-Baust CA, Pizer ES, Morin PJ. 1999. Evidence for the colonic origin of ovarian cancer cell line SW626. J Natl Cancer Inst 91: 1327–1328. doi:10.1093/jnci/91.15.1327 Gates MA, Rosner BA, Hecht JL, Tworoger SS. 2010. Risk factors for epithelial ovarian cancer by histologic subtype. Am J Epidemiol 171: 45–53. doi:10.1093/aje/kwp314 Gershenson DM. 2016. Low-grade serous carcinoma of the ovary or peritoneum. Ann Oncol 27 (Suppl 1): i45–i49. doi:10.1093/annonc/mdw085 Gershenson DM, Sun CC, Lu KH, Coleman RL, Sood AK, Malpica A, Deavers MT, Silva EG, Bodurka DC. 2006. Clinical behavior of stage II-IV low-grade serous carcino- ma of the ovary. Obstet Gynecol 108: 361–368. doi:10 .1097/01.AOG.0000227787.24587.d1 Gershenson DM, Sun CC, Bodurka D, Coleman RL, Lu KH, Sood AK, Deavers M, Malpica AL, Kavanagh JJ. 2009. Recurrent low-grade serous ovarian carcinoma is relative- ly chemoresistant. Gynecol Oncol 114: 48–52. doi:10 .1016/j.ygyno.2009.03.001 Gershenson DM, Sun CC, Iyer RB, Malpica AL, Kavanagh JJ, Bodurka DC, Schmeler K, Deavers M. 2012. Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum.Gynecol Oncol 125: 661–666. doi:10 .1016/j.ygyno.2012.02.037 Gershenson DM, Bodurka DC, Lu KH, Nathan LC, Milo- jevic L, Wong KK, Malpica A, Sun CC. 2015. Impact of age and primary disease site on outcome in women with low-grade serous carcinoma of the ovary or peritoneum:

of a large single-institution registry of a rare tumor. J Clin Oncol 33: 2675–2682. doi:10.1200/JCO.2015.61 .0873 Gershenson DM, Bodurka DC, Coleman RL, Lu KH, Mal- pica A, Sun CC. 2017. Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum. J Clin Oncol 35: 1103–1111. doi:10.1200/ JCO.2016.71.0632 Gershenson DM, Miller A, Brady WE, Paul J, Carty K, Rodgers W, Millan D, Coleman RL, Moore KN, Banerjee S, et al. 2022. Trametinib versus standard of care in pa- tients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open- Rare Epithelial Ovarian Cancers Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190 17 www .perspectivesinmedicine.org on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from label, multicentre, phase 2/3 trial. Lancet 399: 541–553. doi:10.1016/S0140-6736(21)02175-9 Ghandi M, Huang FW, Jané-Valbuena J, Kryukov GV, Lo CC, McDonald ER, Barretina J, Gelfand ET, Bielski CM, Li H, et al. 2019. Next-generation characterization of the Cancer Cell Line Encyclopedia . Nature 569: 503–508. doi:10.1038/s41586-019-1186-3 Gockley A, Melamed A, Bregar AJ, Clemmer JT, Birrer M, Schorge JO, Del Carmen MG, Rauh-Hain JA. 2017. Out- comes of women with high-grade and low-grade ad- vanced-stage serous epithelial ovarian cancer. Obstet Gynecol 129: 439–447. doi:10.1097/AOG.000000000000 1867 Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. 2001. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal dox- orubicin versus topotecan. J Clin Oncol 19: 3312–3322. doi:10.1200/JCO.2001.19.14.3312 Gore M, Hackshaw A, Brady WE, Penson RT, Zaino R, McCluggage WG, Ganesan R, Wilkinson N, Perren T, Montes A, et al. 2019. An international, phase III ran- domized trial in patients with mucinous epithelial ovar- ian cancer (mEOC/GOG 0241) with long-term follow- up: and experience of conducting a clinical trial in a rare gynecological tumor. Gynecol Oncol 153: 541–548. doi:10.1016/j.ygyno.2019.03.256 Gorringe KL, Cheasley D, Wake field MJ, Ryland GL, Allan PE, Alsop K, Amarasinghe KC, Ananda S, Bowtell DDL, Christie M, et al. 2020. Therapeutic options for mucinous ovarian carcinoma. Gynecol Oncol 156: 552–560. doi:10 .1016/j.ygyno.2019.12.015 Grabowski JP, Harter P, Heitz F, Pujade-Lauraine E, Reuss A, Kristensen G, Ray-Coquard I, Heitz J, Traut A, Pfisterer J, et al. 2016. Operability and chemotherapy responsiveness in advanced low-grade serous ovarian cancer. An analysis of the AGO Study Group metadatabase. Gynecol Oncol 140: 457–462. doi:10.1016/j.ygyno.2016.01.022 Grisham RN, Iyer G, Sala E, Zhou Q, Iasonos A, DeLair D, Hyman DM, Aghajanian C. 2014. Bevacizumab shows activity in patients with low-grade serous ovarian and primary peritoneal cancer. Int J Gynecol Cancer 24: 1010–1014. doi:10.1097/IGC.0000000000000190 Grisham R, Monk JB, Banerjee S, Coleman LR, Oza MA, Oehler KM, Kalbacher E, Mirza Raza M, del Campo MJ, Marth C, et al. 2019. 1 MILO/ENGOT-OV11: phase-3 study of binimetinib versus physician ’s choice chemotherapy (PCC) in recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum. Int J Gynecol Cancer 29: A1. doi:10.1136/ ijgc-2019-IGCS.1 Hamed EO, Ahmed H, Sedeek OB, Mohammed AM, Abd- Alla AA, Abdel Ghaffar HM. 2013. Signi ficance of HE4 estimation in comparison with CA125 in diagnosis of ovarian cancer and assessment of treatment response. Diagn Pathol 8: 11. doi:10.1186/1746-1596-8-11 Han C, Bellone S, Zammataro L, Schwartz PE, Santin AD. 2018. Binimetinib (MEK162) in recurrent low-grade se- rous ovarian cancer resistant to chemotherapy and hor- monal treatment. Gynecol Oncol Rep 25: 41–44. doi:10 .1016/j.gore.2018.05.011 Hao D, Li J, Jia S, Meng Y, Zhang C, Wang L, Di LJ. 2017. Integrated analysis reveals tubal- and ovarian-originated serous ovarian cancer and predicts differential therapeu- tic responses. Clin Cancer Res 23: 7400–7411. doi:10 .1158/1078-0432.CCR-17-0638 Hauptmann S, Friedrich K, Redline R, Avril S. 2017. Ovarian borderline tumors in the 2014 WHO classification: evolv- ing concepts and diagnostic criteria. Virchows Arch 470: 125–142. doi:10.1007/s00428-016-2040-8 Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH, Kaemp- gen E, et al. 2012. Dabrafenib in BRAF-mutated metastat- ic melanoma: a multicentre, open-label, phase 3 random- ised controlled trial. Lancet 380: 358–365. doi:10.1016/ S0140-6736(12)60868-X Heinzelmann-Schwarz V A, Gardiner-Garden M, Henshall SM, Scurry JP, Scolyer RA, Smith AN, Bali A, Vanden Bergh P, Baron-Hay S, Scott C, et al. 2006. A distinct molecular pro file associated with mucinous epithelial ovarian cancer. Br J Cancer 94: 904–913. doi:10.1038/sj .bjc.6603003 Hess V, A’Hern R, Nasiri N, King DM, Blake PR, Barton DP, Shepherd JH, Ind T, Bridges J, Harrington K, et al. 2004. Mucinous epithelial ovarian cancer: a separate entity re- quiring speci fic treatment. J Clin Oncol 22: 1040–1044. doi:10.1200/JCO.2004.08.078 Howlader N, Noone A, Krapcho M, Miller D, Bishop K, Kosary C, Yu M, Ruhl J, Tatalovich Z, Mariotto A, et al. 2017. SEER cancer statistics review 1975 –2014. National Cancer Institute, Bethesda, MD. Hunter SM, Anglesio MS, Sharma R, Gilks CB, Melnyk N, Chiew YE, deFazio A, Longacre TA, Huntsman DG, Gor- ringe KL, et al. 2011. Copy number aberrations in benign serous ovarian tumors: a case for reclassi fication? Clin Cancer Res 17: 7273–7282. doi:10.1158/1078-0432 .CCR-11-2080 Hunter SM, Gorringe KL, Christie M, Rowley SM, Bowtell DD, Australian Ovarian Cancer Study G, Campbell IG. 2012. Pre-invasive ovarian mucinous tumors are charac- terized by CDKN2A and RAS pathway aberrations. Clin Cancer Res 18: 5267–5277. doi:10.1158/1078-0432.CCR- 12-1103 Hunter SM, Anglesio MS, Ryland GL, Sharma R, Chiew YE, R owley SM, Doyle MA, Li J, Gilks CB, Moss P, et al. 2015. Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes. Oncotarget 6: 37663–37677. doi:10.18632/oncotarget.5438 Jain A, Ryan PD, Seiden MV. 2012. Metastatic mucinous ovarian cancer and treatment decisions based on histol- ogy and molecular markers rather than the primary loca- tion. J Natl Compr Canc Netw 10: 1076–1080. doi:10 .6004/jnccn.2012.0113 Kang EY, Cheasley D, LePage C, Wake field MJ, da Cunha Torres M, Rowley S, Salazar C, Xing Z, Allan P, Bowtell DDL, et al. 2021. Refined cut-off for TP53 immunohisto- chemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses. Mod Pathol 34: 194–206. doi:10.1038/s41379- 020-0618-9 Kehoe S, Hook J, Nankivell M, Jayson GC, Kitchener H, Lopes T, Luesley D, Perren T, Bannoo S, Mascarenhas M, et al. 2015. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, O. Craig et al. 18 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190 www .perspectivesinmedicine.org on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from non-inferiority trial. Lancet 386: 249–257. doi:10.1016/ S0140-6736(14)62223-6 Kelemen LE, Lawrenson K, Tyrer J, Li Q, Lee JM, Seo JH, Phelan CM, Beesley J, Chen X, Spindler TJ, et al. 2015. Genome-wide significant risk associations for mucinous ovarian carcinoma. Nat Genet 47: 888–897. doi:10.1038/ ng.3336 Kidera Y, Yoshimura T, Ohkuma Y, Iwasaka T, Sugimori H. 1985. Establishment and characterization of a cell line derived from mucinous cystadenocarcinoma of human ovary. Nippon Sanka Fujinka Gakkai Zasshi 37: 1820– 1824. Köbel M, Bak J, Bertelsen BI, Carpen O, Grove A, Hansen ES, Levin Jakobsen AM, Lidang M, Masback A, Tolf A, et al. 2014. Ovarian carcinoma histotype determination is highly reproducible, and is improved through the use of immunohistochemistry. Histopathology 64: 1004–1013. doi:10.1111/his.12349 Kommoss FKF, Cheasley D, Wakefield MJ, Scott CL, Camp- bell IG, Gilks CB, Gorringe K. 2021. Primary mucinous ovarian neoplasms rarely show germ cell histogenesis. Histopathology 78: 640–642. doi:10.1111/his.14297 Kopper O, de Witte CJ, Lohmussaar K, Valle-Inclan JE, Hami N, Kester L, Balgobind A V, Korving J, Proost N, Begthel H, et al. 2019. An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity.Nat Med 25: 838–849. doi:10.1038/s41591-019-0422-6 Kuchenbaecker KB, Ramus SJ, Tyrer J, Lee A, Shen HC, Beesley J, Lawrenson K, McGuffog L, Healey S, Lee JM, et al. 2015. Identification of six new susceptibility loci for invasive epithelial ovarian cancer.Nat Genet 47: 164–171. doi:10.1038/ng.3185 Kurman RJ, Vang R, Junge J, Hannibal CG, Kjaer SK, Shih Ie M. 2011. Papillary tubal hyperplasia: the putative precur- sor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis. Am J Surg Pathol 35: 1605–1614. doi:10.1097/PAS.0b 013e318229449f Kurman RJ, Carcangiu ML, Herrington CS, Young RH. 2014. WHO classification of tumours of female reproduc- tive organs. IARC, Lyon, France. Kurnit KC, Sinno AK, Fellman BM, Varghese A, Stone R, Sood AK, Gershenson DM, Schmeler KM, Malpica A, Fader AN, et al. 2019. Effects of gastrointestinal-type che- motherapy in women with ovarian mucinous carcinoma. Obstet Gynecol 134: 1253–1259. doi:10.1097/AOG.0000 000000003579 Leary AF, Quinn M, Fujiwara K, Coleman RL, Kohn E, Su- giyama T, Glasspool R, Ray-Coquard I, Colombo N, Ba- con M, et al. 2017. Fifth Ovarian Cancer Consensus Con- ference of the Gynecologic Cancer Intergroup (GCIG): clinical trial design for rare ovarian tumours. Ann Oncol 28: 718–726. doi:10.1093/annonc/mdw662 Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C; ESMO Guidelines Working Group. 2013. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diag- nosis, treatment and follow-up. Ann Oncol 24 (Suppl 6): vi24–vi32. doi:10.1093/annonc/mdt333 Ledermann JA, Luvero D, Shafer A, O’Connor D, Mangili G, Friedlander M, Pfis terer J, Mirza MR, Kim JW, Alexandre J, et al. 2014. Gynecologic Cancer Intergroup (GCIG) consensus review for mucinous ovarian carcinoma. Int J Gynecol Cancer 24: S14–S19. doi:10.1097/IGC.0000 000000000296 Lee KR, Scully RE. 2000. Mucinous tumors of the ovary: a clinicopathologic study of 196 borderline tumors (of in- testinal type) and carcinomas, including an evaluation of 11 cases with “pseudomyxoma peritonei. ” Am J Surg Pathol 24: 1447–1464. doi:10.1097/00000478-20001 1000-00001 Lee KR, Young RH. 2003. The distinction between primary and metastatic mucinous carcinomas of the ovary: gross and histologic findings in 50 cases. Am J Surg Pathol 27: 281–292. doi:10.1097/00000478-200303000-00001 Lee JY, Jo YR, Kim TH, Kim HS, Kim MA, Kim JW, Park NH, Song YS. 2015. Safety of fertility-sparing surgery in primary mucinous carcinoma of the ovary. Cancer Res Treat 47: 290–297. doi:10.4143/crt.2014.004 Lertkhachonsuk AA, Buranawongtrakoon S, Lekskul N, Rermluk N, Wee-Stekly WW, Charakorn C. 2020. Serum CA19-9, CA-125 and CEA as tumor markers for mucin- ous ovarian tumors. J Obstet Gynaecol Res46: 2287–2291. doi:10.1111/jog.14427 Li J, Abushahin N, Pang S, Xiang L, Chambers SK, Fadare O, Kong B, Zheng W. 2011. Tubal origin of “ovarian” low- grade serous carcinoma. Mod Pathol 24: 1488–1499. doi:10.1038/modpathol.2011.106 Lin W, Cao D, Shen K. 2018. Prognostic signi ficance of preoperative serum CEA in primary mucinous ovarian carcinoma: a retrospective cohort study. Cancer Manag Res 10: 6913–6920. doi:10.2147/CMAR.S186258 Longacre TA. 2011. Benign and low grade serous epithelial tumors: recent developments and diagnostic problems. Surg Pathol Clin 4: 331–373. doi:10.1016/j.path.2010.12 .011 Macedo LT, da Costa Lima AB, Sasse AD. 2012. Addition of Bevacizumab to first-line chemotherapy in advanced co- lorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups.BMC Cancer 12: 89. doi:10.1186/1471-2407-12-89 Mackenzie R, Kommoss S, Winterhoff BJ, Kipp BR, Garcia JJ, Voss J, Halling K, Karnezis A, Senz J, Yang W, et al. 2015. Targeted deep sequencing of mucinous ovarian tu- mors reveals multiple overlapping RAS-pathway activat- ing mutations in borderline and cancerous neoplasms. BMC Cancer 15: 415. doi:10.1186/s12885-015-1421-8 McAlpine JN, Wiegand KC, Vang R, Ronnett BM, Adamiak A, Köbel M, Kalloger SE, Swenerton KD, Huntsman DG, Gilks CB, et al. 2009. HER2 overexpression and ampli fi- cation is present in a subset of ovarian mucinous carci- nomas and can be targeted with trastuzumab therapy. BMC Cancer 9: 433. doi:10.1186/1471-2407-9-433 McCluggage WG. 2012. Immunohistochemistry in the dis- tinction between primary and metastatic ovarian mucin- ous neoplasms. J Clin Pathol65: 596–600. doi:10.1136/jcp .2010.085688 Meagher NS, Schuster K, Voss A, Budden T, Pang CNI, deFazio A, Ramus SJ, Friedlander ML. 2018. Does the primary site really matter? Pro filing mucinous ovarian cancers of uncertain primary origin (MO-CUP) to per- sonalise treatment and inform the design of clinical trials. Gynecol Oncol 150: 527–533. doi:10.1016/j.ygyno.2018 .07.013 Rare Epithelial Ovarian Cancers Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190 19 www .perspectivesinmedicine.org on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from Meagher NS, Wang L, Rambau PF, Intermaggio MP, Hunts- man DG, Wilkens LR, El-Bahrawy MA, Ness RB, Odunsi K, Steed H, et al. 2019. A combination of the immuno- histochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases. Mod Pathol 32: 1834–1846. doi:10.1038/s41379-019-0302-0 Mendivil AA, Tung PK, Bohart R, Bechtol K, Goldstein BH. 2018. Dramatic clinical response following dabrafenib and trametinib therapy in a heavily pretreated low grade serous ovarian carcinoma patient with a BRAF V600E mutation. Gynecol Oncol Rep 26: 41–44. doi:10.1016/j .gore.2018.09.002 Miller CR, Oliver KE, Farley JH. 2014. MEK1/2 inhibitors in the treatment of gynecologic malignancies.Gynecol Oncol 133: 128–137. doi:10.1016/j.ygyno.2014.01.008 Moujaber T, Etemadmoghadam D, Kennedy CJ, Chiew YE, Balleine RL, Saunders C, Wain GV, Gao B, Hogg R, Sri- rangan S, et al. 2018.BRAF mutations in low-grade serous ovarian cancer and response to BRAF inhibition. JCO Precis Oncol 1–14. doi:10.1200/PO.17.00221 Moujaber T, Balleine RL, Gao B, Madsen I, Harnett PR, DeFazio A. 2021. New therapeutic opportunities for women with low-grade serous ovarian cancer. Endocr Relat Cancer 29: R1–R16. doi:10.1530/ERC-21-0191 Mueller JJ, Schlappe BA, Kumar R, Olvera N, Dao F, Abu- Rustum N, Aghajanian C, DeLair D, Hussein YR, Soslow RA, et al. 2018. Massively parallel sequencing analysis of mucinous ovarian carcinomas: genomic profiling and dif- ferential diagnoses. Gynecol Oncol 150: 127–135. doi:10 .1016/j.ygyno.2018.05.008 Muyldermans K, Moerman P, Amant F, Leunen K, Neven P, Vergote I. 2013. Primary invasive mucinous ovarian car- cinoma of the intestinal type: importance of the expansile versus infiltrative type in predicting recurrence and lymph node metastases. Eur J Cancer 49: 1600–1608. doi:10.1016/j.ejca.2012.12.004 Nasioudis D, Albright BB, Ko EM, Haggerty AF, Giuntoli RL II, Burger RA, Morgan MA, Latif NA. 2020. Advanced stage primary mucinous ovarian carcinoma. Where do we stand? Arch Gynecol Obstet 301: 1047–1054. doi:10.1007/ s00404-020-05489-3 Nelson L, Tighe A, Golder A, Littler S, Bakker B, Moralli D, Murtuza Baker S, Donaldson IJ, Spierings DCJ, Warde- naar R, et al. 2020. A living biobank of ovarian cancer ex vivo models reveals profound mitotic heterogeneity. Nat Commun 11: 822. doi:10.1038/s41467-020-14551-2 Park KJ, Patel P, Linkov I, Jotwani A, Kauff N, Pike MC. 2018. Observations on the origin of ovarian cortical inclusion cysts in women undergoing risk-reducing salpingo-oophorectomy. Histopathology 72: 766–776. doi:10.1111/his.13444 Park JY, Lee SH, Kim KR, Kim YT, Nam JH. 2019. Accuracy of frozen section diagnosis and factors associated with final pathological diagnosis upgrade of mucinous ovarian tumors. J Gynecol Oncol 30: e95. doi:10.3802/jgo.2019.30 .e95 Pectasides D, Fountzilas G, Aravantinos G, Kalofonos HP, Efstathiou E, Salamalekis E, Farmakis D, Skarlos D, Bria- soulis E, Economopoulos T, et al. 2005. Advanced stage mucinous epithelial ovarian cancer: The Hellenic Coop- erative Oncology Group experience. Gynecol Oncol 97: 436–441. doi:10.1016/j.ygyno.2004.12.056 Peres LC, Cushing-Haugen KL, Köbel M, Harris HR, Ber- chuck A, Rossing MA, Schildkraut JM, Doherty JA. 2019. Invasive epithelial ovarian cancer survival by histotype and disease stage. J Natl Cancer Inst 111: 60–68. doi:10 .1093/jnci/djy071 Perren TJ. 2016. Mucinous epithelial ovarian carcinoma. Ann Oncol 27: i53–i57. doi:10.1093/annonc/mdw087 Phelan CM, Kuchenbaecker KB, Tyrer JP, Kar SP, Lawren- son K, Winham SJ, Dennis J, Pirie A, Riggan MJ, Chor- nokur G, et al. 2017. Identi fication of 12 new susceptibil- ity loci for different histotypes of epithelial ovarian cancer. Nat Genet 49: 680–691. doi:10.1038/ng.3826 Pignata S, Ferrandina G, Scarfone G, Scollo P, Odicino F, Cormio G, Katsaros D, Villa A, Mereu L, Ghezzi F, et al. 2008. Activity of chemotherapy in mucinous ovarian can- cer with a recurrence free interval of more than 6 months:

from the SOCRATES retrospective study. BMC Cancer 8: 252. doi:10.1186/1471-2407-8-252 Pisano C, Greggi S, Tambaro R, Losito S, Iodice F, Di Maio M, Ferrari E, Falanga M, Formato R, Iaffaioli VR, et al. 2005. Activity of chemotherapy in mucinous epithelial ovarian cancer: a retrospective study. Anticancer Res 25: 3501–3505. Qiu C, Lu N, Wang X, Zhang Q, Yuan C, Yan S, Dongol S, Li Y, Sun X, Sun C, et al. 2017. Gene expression pro files of ovarian low-grade serous carcinoma resemble those of fallopian tube epithelium. Gynecol Oncol 147: 634–641. doi:10.1016/j.ygyno.2017.09.029 Rambau PF, Duggan MA, Ghatage P, Warfa K, Steed H, Perrier R, Kelemen LE, Köbel M. 2016. Signi ficant fre- quency of MSH2/MSH6 abnormality in ovarian endome- trioid carcinoma supports histotype-speci fic Lynch syn- drome screening in ovarian carcinomas. Histopathology 69: 288–297. doi:10.1111/his.12934 Rechsteiner M, Zimmermann AK, Wild PJ, Caduff R, von Teichman A, Fink D, Moch H, Noske A. 2013. TP53 mutations are common in all subtypes of epithelial ovarian cancer and occur concomitantly with KRAS mu- tations in the mucinous type. Exp Mol Pathol 95: 235– 241. doi:10.1016/j.yexmp.2013.08.004 Reid BM, Permuth JB, Sellers TA. 2017. Epidemiology of ovarian cancer: A review. Cancer Biol Med 14: 9–32. doi:10.2089 2/j.issn.2095-3941.2016.0084 Ricciardi E, Baert T, Ataseven B, Heitz F, Prader S, Bommert M, Schneider S, du Bois A, Harter P. 2018. Low-grade serous ovarian carcinoma. Geburtshilfe Frauenheilkd 78: 972–976. doi:10.1055/a-0717-5411 Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, Tang J, Li S, Zhang S, Shaw PA, et al. 2006. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98: 1694–1706. doi:10.1093/jnci/djj465 Rossi L, Verrico M, Zaccarelli E, Papa A, Colonna M, Strudel M, Vici P, Bianco V, Tomao F. 2017. Bevacizumab in ovarian cancer: a critical review of phase III studies. On- cotarget 8: 12389–12405. doi:10.18632/oncotarget.13310 Ryan NAJ, Evans DG, Green K, Crosbie EJ. 2017. Patholog- ical features and clinical behavior of Lynch syndrome- associated ovarian cancer. Gynecol Oncol 144: 491–495. doi:10.1016/j.ygyno.2017.01.005 O. Craig et al. 20 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190 www .perspectivesinmedicine.org on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from Ryland GL, Hunter SM, Doyle MA, Caramia F, Li J, Rowley SM, Christie M, Allan PE, Stephens AN, Bowtell DD, et al. 2015. Mutational landscape of mucinous ovarian carci- noma and its neoplastic precursors. Genome Med 7: 87. doi:10.1186/s13073-015-0210-y Sakayori M, Nozawa S, Udagawa Y, Chin K, Lee SG, Sakuma T, Iizuka R, Wada Y, Yoshida S, Takeda Y. 1990. Biological properties of two newly established cell lines (RMUG-S, RMUG-L) from a human ovarian mucinous cystadeno- carcinoma. Hum Cell 3: 52–56. Sallum LF, Andrade L, Ramalho S, Ferracini AC, de Andrade Natal R, Brito ABC, Sarian LO, Derchain S. 2018. WT1, p53 and p16 expression in the diagnosis of low- and high- grade serous ovarian carcinomas and their relation to prognosis. Oncotarget 9: 15818–15827. doi:10.18632/on cotarget.24530 Santucci C, Bosetti C, Peveri G, Liu X, Bagnardi V, Specchia C, Gallus S, Lugo A. 2019. Dose-risk relationships be- tween cigarette smoking and ovarian cancer histotypes: a comprehensive meta-analysis. Cancer Causes Control 30: 1023–1032. doi:10.1007/s10552-019-01198-8 Sato S, Itamochi H, Kigawa J, Oishi T, Shimada M, Naniwa J, Uegaki K, Nonaka M, Terakawa N. 2009. Combination chemotherapy of oxaliplatin and 5-fluorouracil may be an effective regimen for mucinous adenocarcinoma of the ovary: a potential treatment strategy. Cancer Sci 100: 546–551. doi:10.1111/j.1349-7006.2008.01065.x Sato N, Saga Y, Mizukami H, Wang D, Fujiwara H, Takei Y, Machida S, Ozawa K, Suzuki M. 2012. Cetuximab inhibits the growth of mucinous ovarian carcinoma tumor cells lacking KRAS gene mutations. Oncol Rep 27: 1336–1340. doi:10.3892/or.2012.1626 Schiavone MB, Herzog TJ, Lewin SN, Deutsch I, Sun X, Burke WM, Wright JD. 2011. Natural history and out- come of mucinous carcinoma of the ovary. Am J Obstet Gynecol 205: 480 e481 –488. doi:10.1016/j.ajog.2011.06 .049 Schilder RJ, Hall L, Monks A, Handel LM, Fornace AJ Jr, Ozols RF, Fojo AT, Hamilton TC. 1990. Metallothionein gene expression and resistance to cisplatin in human ovarian cancer. Int J Cancer 45: 416–422. doi:10.1002/ ijc.2910450306 Schmeler KM, Sun CC, Bodurka DC, Deavers MT, Malpica A, Coleman RL, Ramirez PT, Gershenson DM. 2008. Neoadjuvant chemotherapy for low-grade serous carci- noma of the ovary or peritoneum. Gynecol Oncol 108: 510–514. doi:10.1016/j.ygyno.2007.11.013 Seidman JD, Khedmati F. 2008. Exploring the histogenesis of ovarian mucinous and transitional cell (Brenner) neo- plasms and their relationship with Walthard cell nests: a study of 120 tumors. Arch Pathol Lab Med 132: 1753– 1760. doi:10.5858/132.11.1753 Seidman JD, Kurman RJ, Ronnett BM. 2003. Primary and metastatic mucinous adenocarcinomas in the ovaries: in- cidence in routine practice with a new approach to im- prove intraoperative diagnosis.Am J Surg Pathol 27: 985– 993. doi:10.1097/00000478-200307000-00014 Seidman JD, Yemelyanova A, Zaino RJ, Kurman RJ. 2011. The fallopian tube-peritoneal junction: a potential site of carcinogenesis. Int J Gynecol Pathol 30: 4–11. doi:10 .1097/PGP.0b013e3181f29d2a Shimada M, Kigawa J, Ohishi Y, Yasuda M, Suzuki M, Hiura M, Nishimura R, Tabata T, Sugiyama T, Kaku T. 2009. Clinicopathological characteristics of mucinous adeno- carcinoma of the ovary. Gynecol Oncol 113: 331–334. doi:10.1016/j.ygyno.2009.02.010 Shimizu Y, Nagata H, Kikuchi Y, Umezawa S, Hasumi K, Yokokura T. 1998. Cytotoxic agents active against mucin- ous adenocarcinoma of the ovary. Oncol Rep 5: 99–101. doi:10.3892/or.5.1.99 Shrestha R, Llaurado Fernandez M, Dawson A, Hoenisch J, Volik S, Lin YY, Anderson S, Kim H, Haegert AM, Col- borne S, et al. 2021. Multiomics characterization of low- grade serous ovarian carcinoma identi fies potential bio- markers of MEK inhibitor sensitivity and therapeutic vul- nerability. Cancer Res 81: 1681–1694. doi:10.1158/0008- 5472.CAN-20-2222 Sieh W, Köbel M, Longacre TA, Bowtell DD, deFazio A, Goodman MT, Hogdall E, Deen S, Wentzensen N, Moy- sich KB, et al. 2013. Hormone-receptor expression and ovarian cancer survival: An Ovarian Tumor Tissue Anal- ysis consortium study. Lancet Oncol 14: 853–862. doi:10 .1016/S1470-2045(13)70253-5 Simon WE, Albrecht M, Hansel M, Dietel M, Holzel F. 1983. Cell lines derived from human ovarian carcinomas: growth stimulation by gonadotropic and steroid hor- mones. J Natl Cancer Inst 70: 839–845. Simons M, Simmer F, Bulten J, Ligtenberg MJ, Hollema H, van Vliet S, de Voer RM, Kamping EJ, van Essen DF, Ylstra B, et al. 2020. Two types of primary mucinous ovarian tumors can be distinguished based on their ori- gin. Mod Pathol 33: 722–733. doi:10.1038/s41379-019- 0401-y Song T, Lee DH, Jung YW, Yun BS, Seong SJ, Choi CH, Lee JW, Bae DS, Kim BG. 2018. Elevated preoperative CA125 or CA19-9 in borderline ovarian tumors: could it be sug- gestive of advanced stage or a poor prognosis? Gynecol Obstet Invest 83: 45–51. doi:10.1159/000475817 Stover EH, Feltmate C, Berkowitz RS, Lindeman NI, Matu- lonis UA, Konstantinopoulos PA. 2018. Targeted next- generation sequencing reveals clinically actionable BRAF and ESR1 mutations in low-grade serous ovarian carci- noma. JCO Precis Oncol 2018: PO.18.00135. doi:10.1200/ PO.18.00135 van den Berg-Bakker CA, Hagemeijer A, Franken-Postma EM, Smit VT, Kuppen PJ, van Ravenswaay Claasen HH, Cornelisse CJ, Schrier PI. 1993. Establishment and char- acterization of 7 ovarian carcinoma cell lines and one granulosa tumor cell line: growth features and cytogenet- ics. Int J Cancer 53: 613–620. doi:10.1002/ijc.2910530415 Vang R, Gown AM, Barry TS, Wheeler DT, Yemelyanova A, Seidman JD, Ronnett BM. 2006. Cytokeratins 7 and 20 in primary and secondary mucinous tumors of the ovary: analysis of coordinate immunohistochemical expression profiles and staining distribution in 179 cases. Am J Surg Pathol 30: 1130–1139. doi:10.1097/01.pas.0000213281 .43036.bb Vang R, Shih Ie M, Kurman RJ. 2009. Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopath- ologic and molecular biologic features, and diagnostic problems. Adv Anat Pathol 16: 267–282. doi:10.1097/ PAP.0b013e3181b4fffa Rare Epithelial Ovarian Cancers Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190 21 www .perspectivesinmedicine.org on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N, Verheijen RH, van der Burg ME, Lacave AJ, Panici PB, et al. 2010. Neoadjuvant chemotherapy or pri- mary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 363: 943–953. doi:10.1056/NEJMoa0908806 Vici P, Sergi D, Pizzuti L, Mariani L, Arena MG, Barba M, Maugeri-Sacca M, Vincenzoni C, Vizza E, Corrado G, et al. 2013. Gemcitabine-oxaliplatin (GEMOX) as salvage treatment in pretreated epithelial ovarian cancer patients.J Exp Clin Cancer Res 32: 49. doi:10.1186/1756-9966-32-49 Wang Y, Schwartz LE, Anderson D, Lin MT, Haley L, Wu RC, Vang R, Shih Ie M, Kurman RJ. 2015a. Molecular analysis of ovarian mucinous carcinoma reveals different cell of origins. Oncotarget 6: 22949–22958. doi:10.18632/ oncotarget.5146 Wang Y, Wu RC, Shwartz LE, Haley L, Lin MT, Shih Ie M, Kurman RJ. 2015b. Clonality analysis of combined Bren- ner and mucinous tumours of the ovary reveals their monoclonal origin. J Pathol 237: 146–151. doi:10.1002/ path.4572 Wang Y, Hong S, Mu J, Wang Y, Lea J, Kong B, Zheng W. 2019a. Tubal origin of “ovarian” low-grade serous carci- noma: a gene expression pro file study. J Oncol 2019: 8659754. doi:10.1155/2019/8659754 Wang Y, Sessine MS, Zhai Y, Tipton C, McCool K, Kuick R, Connolly DC, Fearon ER, Cho KR. 2019b. Lineage tracing suggests that ovarian endosalpingiosis does not result from escape of oviductal epithelium. J Pathol 249: 206– 214. doi:10.1002/path.5308 Wentzensen N, Poole EM, Trabert B, White E, Arslan AA, Patel A V, Setiawan VW, Visvanathan K, Weiderpass E, Adami HO, et al. 2016. Ovarian cancer risk factors by histologic subtype: an analysis from the Ovarian Cancer Cohort Consortium. J Clin Oncol 34: 2888–2898. doi:10 .1200/JCO.2016.66.8178 Winer I, Buckanovich RJ. 2010. A case of progressive mu- cinous ovarian cancer of low malignant potential respon- sive to biologic therapy with Bevacizumab.Gynecol Oncol 116: 578–579. doi:10.1016/j.ygyno.2009.10.068 Wong AK, Seidman JD, Barbuto DA, McPhaul LW, Silva EG. 2011. Mucinous metaplasia of the fallopian tube: a diagnostic pitfall mimicking metastasis. Int J Gynecol Pathol 30: 36–40. doi:10.1097/PGP.0b013e3181f45f28 Xu W, Rush J, Rickett K, Coward JI. 2016. Mucinous ovarian cancer: a therapeutic review.Crit Rev Oncol Hematol 102: 26–36. doi:10.1016/j.critrevonc.2016.03.015 Yamada T, Ueda M, Otsuki Y, Ueki M, Sugimoto O. 1991. Establishment and characterization of a cell line (OMC-3) originating from a human mucinous cystadenocarcinoma of the ovary. Gynecol Oncol 40: 118–128. doi:10.1016/ 0090-8258(91)90102-B Yoshida H, Tanaka H, Tsukada T, Abeto N, Kobayashi-Kato M, Tanase Y, Uno M, Ishikawa M, Kato T. 2021. Diag- nostic discordance in intraoperative frozen section diag- nosis of ovarian tumors: a literature review and analysis of 871 cases treated at a Japanese cancer center. Int J Surg Pathol 29: 30–38. doi:10.1177/1066896920960518 Yoshihara M, Kajiyama H, Tamauchi S, Iyoshi S, Yokoi A, Suzuki S, Kawai M, Nagasaka T, Takahashi K, Matsui S, et al. 2020. Impact of uterus-preserving surgery on stage I primary mucinous epithelial ovarian carcinoma: a multi- institutional study with propensity score-weighted anal- ysis. Int J Gynaecol Obstet 150: 177–183. doi:10.1002/ijgo .13244 Yoshiya N. 1986. Establishment of a cell line from human ovarian cancer (undifferentiated carcinoma of FIGO clas- sification) and analysis of its cell-biological characteristics and sensitivity to anticancer drugs.Nippon Sanka Fujinka Gakkai Zasshi 38: 1747–1753. Yuan SF, Zhang LP, Zhu LJ, Chen WJ, Zheng WE, Xiong JP. 2013. Phase II clinical study on the GEMOX regimen as second-line therapy for advanced ovarian cancer. Asian Pac J Cancer Prev 14: 3949–3953. doi:10.7314/APJCP .2013.14.6.3949 Zaino RJ, Brady MF, Lele SM, Michael H, Greer B, Bookman MA. 2011. Advanced stage mucinous adenocarcinoma of the ovary is both rare and highly lethal: a gynecologic oncology group study. Cancer 117: 554–562. doi:10 .1002/cncr.25460 Zhang Y, Li C, Luo S, Su Y, Gang X, Chu P, Zhang J, Wu H, Liu G. 2020. Retrospective study of the epidemiology, pathology, and therapeutic management in patients with mucinous ovarian tumors. Technol Cancer Res Treat 19: 1533033820946423. doi:10.1177/1533033820946423 Zorn KK, Tian C, McGuire WP, Hoskins WJ, Markman M, Muggia FM, Rose PG, Ozols RF, Spriggs D, Armstrong DK. 2009. The prognostic value of pretreatment CA 125 in patients with advanced ovarian carcinoma: a gyneco- logic oncology group study. Cancer 115: 1028–1035. doi:10.1002/cncr.24084 O. Craig et al. 22 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190 www .perspectivesinmedicine.org on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from June 5, 2023 2023; doi: 10.1101/cshperspect.a038190 originally published onlineCold Spring Harb Perspect Med    Olivia Craig, Abhimanyu Nigam, Genevieve V. Dall and Kylie Gorringe   Carcinomas Rare Epithelial Ovarian Cancers: Low Grade Serous and Mucinous Subject Collection Ovarian Cancer Models of High-Grade Serous Ovarian Carcinoma Oscar J. Pundel and Benjamin G. Neel Ovarian Cancer Therapy Porter Diana Miao, Ursula A. Matulonis and Rebecca L. Therapeutic Challenges Endometriosis-Associated Cancer with Ovarian Clear Cell Carcinoma: An Ruby Yun-Ju Huang and Jimmy Jin-Che Lin Cancer Harnessing Antitumor Immunity in Ovarian Katherine C. Kurnit and Kunle Odunsi Early Detection of Ovarian Cancer Naoko Sasamoto and Kevin M. Elias Ovarian Cancer Tumor Microenvironment in High-Grade Serous The Emerging Role of the Single-Cell and Spatial Anniina Färkkilä Inga-Maria Launonen, Anna Vähärautio and Serous and Mucinous Carcinomas Rare Epithelial Ovarian Cancers: Low Grade et al. Olivia Craig, Abhimanyu Nigam, Genevieve V. Dall, Prevention of Epithelial Ovarian Cancer Hathaway, et al. Thomas A. Sellers, Lauren C. Peres, Cassandra A. 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