{"paper_id":"c5e2bbab-942b-4c7a-9938-62e9f9fe3d79","body_text":"Rare Epithelial Ovarian Cancers: Low Grade\nSerous and Mucinous Carcinomas\nOlivia Craig,1,2,4 Abhimanyu Nigam,1,2,4 Genevieve V. Dall,3 and Kylie Gorringe 1,2\n1Department of Laboratory Research, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia\n2The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia\n3University of Melbourne, Parkville, VIC 3010, Australia\nCorrespondence: kylie.gorringe@petermac.org\nThe ovarian epithelial cancer histotypes can be divided into common and rare types.\nCommon types include high-grade serous ovarian carcinomas and the endometriosis-\nassociated cancers, endometrioid and clear-cell carcinomas. The less common histotypes\nare mucinous and low-grade serous, each comprising less than 10% of all epithelial carci-\nnomas. Although histologically and epidemiologically distinct from each other, these histo-\ntypes share some genetic and natural history features that distinguish them from the more\ncommon types. In this review, we will consider the similarities and differences of these rare\nhistological types, and the clinical challenges they pose.\nE\npithelial ovarian cancer (EOC) has long been\nrecognized to comprise different histological\nsubtypes. Currently, these are high-grade and\nlow-grade serous, clear-cell, endometrioid, and\nmucinous carcinomas (Reid et al. 2017). Recent\nexploration of their biology has led to an in-\ncreased understanding of the genetic, cellular,\nand epidemiological differences that underpin\ntheir histopathology, and subsequently in-\nformed more targeted clinical approaches. In\nthis review, we focus on the two least common\nof these histotypes, mucinous ovarian carcino-\nma (MOC) and low-grade serous ovarian carci-\nnoma (LGSC), comprising 3% and 5% –8%\nof all EOCs, respectively (Reid et al. 2017).\nWe will consider their epidemiological risk\nfactors, how these relate to putative cells of ori-\ngin, their natural history via precursor tumors,\nand their pathological, genetic, and clinical\nfeatures.\nMUCINOUS OV ARIAN CARCINOMA\nMOC is characterized by the formation of\nlarge, mucin-containing tumors. Recent ad-\nvances have revealed MOC is molecularly\ndistinct from the more common epithelial ma-\nlignancies, and should thus be recognized as a\nunique and separate entity.\nEpidemiology\nMOC is more likely to be diagnosed in younger\nwomen compared to other EOCs, with more\nthan half aged under 55 at first presentation\n(Peres et al. 2019). In general, MOC does not\n4These authors contributed equally to this work.\nEditors: James D. Brenton and Benjamin G. Neel\nAdditional Perspectives on Ovarian Cancer available at www.perspectivesinmedicine.org\nCopyright © 2023 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a038190\nCite this article as Cold Spring Harb Perspect Med 2023;13:a038190\n1\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nshare risk factors with other EOC, highlighting\nthe need to regard it as an independent disease.\nIn particular, hormonal factors known to in flu-\nence the more common high-grade serous ovar-\nian carcinoma (HGSC) are absent in MOC\n(Gates et al. 2010). Furthermore, there is a two-\nfold increase in MOC development associated\nwith a history of smoking (Collaborative Group\non Epidemiological Studies of Ovarian Cancer\net al. 2012; Santucci et al. 2019), a characteristic\nunique to this subtype of EOC. Recently, being\noverweight in childhood was shown to be asso-\nciated with a higher risk of developing MOC\n(Aarestrup et al. 2019).\nThere is no association between family his-\ntory and risk of MOC, and the BRCA1 and\nBRCA2 gene variants that are known to predis-\npose to HGSC are not relevant for MOC (Risch\net al. 2006). Large-scale genome-wide associa-\ntion studies show MOC to be genetically distinct\nfrom other EOCs. In 2015, Kelemen et al. (2015)\nfound three single-nucleotide polymorphisms\n(SNPs) associated with MOC risk (2q13, 2q31,\nand 19q13). A later study added two further\nSNPs (3q22 and 9q31), additionally demon-\nstrating that these were also shared by mucinous\nborderline tumors (Phelan et al. 2017). At\npresent, only three loci have been identi fied\nshowing a risk shared with other EOCs (9q34,\n22q12, 2q13) (Kuchenbaecker et al. 2015). Al-\nthough not always straightforward to identify\nthe associated causative gene, functional studies\nsupported PAX8 (2q13) and HOXD9 (2q31) as\nstrong candidates (Kelemen et al. 2015).\nClinicopathological Features and Diagnosis\nMucinous ovarian tumors can be classi fied as\nbenign, borderline, or malignant. According to\nthe World Health Organization (WHO) diag-\nnostic criteria, benign tumors usually present\nas cystadenomas comprising multinodal cysts\nand glands, with some cellular atypia but no\nstromal invasion. Borderline lesions also lack\ninvasion, but demonstrate stratified gastrointes-\ntinal-type mucinous epithelium with papillae\nor pseudopapillae infoldings, mild-to-moderate\nnuclear atypia, and proliferation of >10% of the\nepithelial volume. Carcinoma is diagnosed\nwhen stromal invasion of >5 mm or >10 mm\n2\nis observed (Ledermann et al. 2014).\nIn 2014, the WHO introduced a new diag-\nnostic classi fication, further segregating MOC\ninto expansile or in filtrative subtypes (Kurman\net al. 2014). Expansile carcinoma is de fined by\na confl uent glandular growth pattern with\nabsence of intervening normal ovarian paren-\nchyma. This subtype is almost always found in\nearly-stage disease, with 95% of expansile tu-\nmors identi fied at stage 1. As such, expansile\nMOC is associated with lower metastatic poten-\ntial and overall better prognosis than in filtrative\ndisease (Muyldermans et al. 2013). The latter is\ndefined by small glands, nests, or individual cells\ninfiltrating the stroma.\nMOC is characterized by the development of\nvery large tumors, commonly presenting as a\nmultiloculated mucin-containing cystic mass\nexceeding 10 cm in size. MOC is unilateral in\n79% of cases (Lee and Scully 2000) and is most\noften diagnosed at an early stage, with >80% of\ncases still con fined to the ovary (Perren 2016).\nPatients typically present when symptoms arise\ndue to the expansion of the large tumor mass\nand resultant pressure exerted on surrounding\norgans, with tumor presence con firmed by ul-\ntrasound, MRI, or PET/CT scans. However, this\ndetection course is problematic, as until the tu-\nmor reaches such a size there are usually mini-\nmal symptoms, making early diagnosis difficult.\nThe most commonly used serum marker for\novarian cancer, CA-125, is elevated in <70% of\nadvanced-stage MOC (Zorn et al. 2009) and\neven less frequently in borderline tumors\n(Song et al. 2018). CEA and CA19-9 have also\nlong been used for detection and prediction of\nmalignancy (Lin et al. 2018; Lertkhachonsuk\net al. 2020), and, recently, HE4 has emerged as\na more ovarian cancer –specific alternative to\nCA-125 (Hamed et al. 2013); however, none of\nthese biomarkers are MOC-speci fic. Thus, final\ndiagnosis and whether a neoplasm is benign,\nborderline, or malignant is determined by his-\ntological analysis of tissue removed at surgical\nexploration or debulking.\nAlthough now reported to comprise ∼3% of\nall EOC diagnoses (Reid et al. 2017), the preva-\nlence of MOC was initially thought to be as high\nO. Craig et al.\n2 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nas 12% (Seidman et al. 2003). This overestimate\nhas since proven to be an artifact of the challenge\nin distinguishing primary MOC from misdiag-\nnosed metastases of other sites of origin. The\nfrequency of such an occurrence was demon-\nstrated by Zaino et al. (2011), who found 61%\nof MOC patients in their study (n = 44) had me-\ntastases misdiagnosed as primary MOC. The\nmost common origins for metastases confused\nwith primary MOC are the stomach and gastro-\nintestinal tract, pancreas, cervix, breast, and\nuterus (Seidman et al. 2003), with metastases\nfrom the appendix and biliary tract also seen\n(Lee and Scully 2000; Lee and Young 2003).\nThorough investigation is therefore necessary\nto confidently diagnose a lesion as true primary\nMOC.\nThe knowledge that MOC typically presents\nas larger, predominantly unilateral tumors com-\npared with metastases can aid in diagnosis. This\nwas demonstrated by Seidman et al. (2003), who\nconstructed an algorithm based on size and lat-\nerality to predict primary or metastatic origin\nwith a signi ficant success rate. Other factors\nthat distinguish primary MOC from metastases\nare expansile patterns of invasion and presence\nof “other ovarian pathology, ” like mural nod-\nules, Brenner tumors, or teratomas (Lee and\nYoung 2003). The coexistence of benign and\nborderline areas within a single invasive tumor\nfavors a diagnosis of primary MOC over one of\nmetastatic origin. Such coexistence can also hin-\nder classi fication, as dispersion of benign and\ninvasive areas within such a large mass can\nmake it diffi cult to accurately assess the malig-\nnancy of a tumor without sampling widely, as\ndemonstrated by the reported rates of discord-\nance between perioperative frozen and final\npathological diagnosis (Park et al. 2019; Yoshida\net al. 2021).\nImmunohistochemistry analysis is another\nuseful tool for distinguishing primary MOC\nfrom metastasis. Cytokeratin 7 (CK7) and cyto-\nkeratin 20 (CK20) are the most commonly used\nbiomarkers in clinical practice (Vang et al.\n2006). In particular, CK7 stains positively in\nMOC and negatively in metastatic colorectal\ncancer (McCluggage 2012). The utility of novel\nmarker SATB2 in identifying primary MOC\nversus colorectal or appendiceal metastasis\nwas recently demonstrated (Meagher et al.\n2019). Promisingly, this study found combining\nSATB2 with CK7 distinguished gastrointestinal\nfrom primary ovarian tumors with >95% accu-\nracy. Pathologists may also investigate estab-\nlished biomarkers known to be associated with\ncertain metastatic sites to sequentially rule out\npotential extraovarian origins. Such pathologi-\ncal analysis can prompt further imaging or clin-\nical investigations to identify metastatic origins.\nHowever, assessment based on these criteria is\nnot infallible, and thus in the clinical context,\ndiagnosis of metastatic versus primary origin\ncan sometimes only be understood in retrospect,\nfollowing patient outcomes. Thus, going for-\nward, improved biomarkers are needed for ear-\nlier and more reliable diagnosis.\nNatural History and Genetics\nCurrently, the cell of origin in MOC is unknown\n(Fig. 1). However, the prevalent theory suggests\nthis disease may develop from the ovarian sur-\nface epithelium (OSE) through a continuum of\nprogression from benign cystadenoma to malig-\nnancy, as areas of carcinoma are commonly\nfound adjacent to or mixed with benign and\nborderline epithelium (Bell 2005). This mor-\nphological progression has been supported by\ngenetic studies revealing shared key molecular\nevents (Hunter et al. 2012; Cheasley et al. 2019).\nAn alternative mechanism suggests the origin of\nMOC may lie in transitional cells or metaplasia\nof the fallopian tube –peritoneal junction (Seid-\nman et al. 2011; Wong et al. 2011). Rarely, MOC\ncan coexist with Brenner tumors or teratomas,\nand these have also been hypothesized to be\nprecursor lesions to MOC (Seidman and Khed-\nmati 2008). Recent genetic evidence supports a\nclonal relationship between primary MOC and\nnearby Brenner tumors (Simons et al. 2020).\nHowever, most primary MOCs do not have\nsuch associated tumors, and very few have hap-\nloid genomes suggestive of a germ cell origin\n(Kommoss et al. 2021).\nMolecularly, MOC differs from that of other\nEOCs, exhibiting distinct genetic and gene-ex-\npression pro files (Heinzelmann-Schwarz et al.\nRare Epithelial Ovarian Cancers\nCite this article as Cold Spring Harb Perspect Med 2023;13:a038190 3\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nFallopian tube Fallopian tube\nPeritoneumPeritoneum\nOvary\n= Mucin\n= Mucin-producing\n   columnar cell\n= Driver mutations,\n= Secretory cell of \n   fallopian tube\n= Ciliated cell of\n   fallopian tube\nCarcinomaCarcinoma\nTeratoma\nBrenner\ntumor\nCystadenoma\nCystadenoma\nOvary\n3\n2\n2\n1\n1\nA MucinousBLow-grade serous\nFigure 1. (See following page for legend. )\nO. Craig et al.\n4 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\n2006). KRAS is the most common and charac-\nteristic mutation of MOC, and is believed to\nrepresent an early founder event (Hunter et al.\n2012; Mackenzie et al. 2015; Chang et al. 2016)\nwith an incidence of 40% –65%. The most com-\nmon mutation type is G12D (39%), followed by\nG12V (34%) (Cheasley et al. 2019). TP53 muta-\ntions and ERBB2 amplification can develop later\nin disease progression in 30% –64% and 20% –\n35% of cases, respectively (Anglesio et al. 2013a;\nRechsteiner et al. 2013; Mackenzie et al. 2015;\nCheasley et al. 2019). The presence of a TP53\nmutation in mucinous borderline tumors has\nbeen associated with an increased risk of recur-\nrence with invasive carcinoma, supporting the\nrole of this gene in driving invasive progression\n(Kang et al. 2021). The incidence of ERBB2\namplification differs from that of other EOCs,\nas does TP53, which is much more frequently\nmutated in HGSC than MOC, but only rarely\nin endometrioid or clear-cell ovarian cancer\n(CCOC).\nRegularly associated with MOC are homo-\nzygous deletions or mutations in CDKN2A/B,\nwith aberrations reported in 20% –45% of cases\n(Mackenzie et al. 2015; Ryland et al. 2015;\nCheasley et al. 2019). Less commonly, mutations\nare seen in PI3KCA (9%–13% incidence) and a\ncollection of other genes including RNF43,\nPTEN, ARID1A, and BRAF at a frequency of\n>5% (Ryland et al. 2015; Meagher et al. 2018;\nMueller et al. 2018; Cheasley et al. 2019). Al-\nthough in the past microsatellite instability had\nbeen reported, recent studies with rigorous\npathology review to exclude metastases have\nfound few MOCs with microsatellite instability\n(Cheasley et al. 2019) or associated with Lynch\nsyndrome (Chui et al. 2014; Rambau et al. 2016;\nRyan et al. 2017). Additionally, MOC demon-\nstrates a somatic mutational spectrum distinct\nfrom colorectal, appendiceal, gastric, and endo-\nmetrial carcinomas (Cheasley et al. 2019).\nCurrent Clinical Approach and Outcomes\nDebulking surgery with the aim of complete\nresection is the principal approach for early-\nand late-stage MOC (Fig. 2). This typically con-\nsists of total hysterectomy and bilateral sal-\npingo-oophorectomy, with appendectomy and\nlymphadenectomy often conducted in high-\ngrade MOC. In instances of early-stage disease\nin which the tumor is con fined to one ovary,\nunilateral salpingo-oophorectomy with uterus\nconservation is often preferred as a fertility pres-\nervation procedure for younger patients (Lee\net al. 2015) with no detrimental effect on sur-\nvival (Yoshihara et al. 2020).\nIn circumstances where MOC is diagnosed\nat early stages, the prognosis is better than that\nof other EOC types with a 5-year survival rate of\n>80% (Peres et al. 2019). Conversely, in the case\nof advanced MOC, the prognosis is poor and\nconsiderably worse compared to other EOCs,\npredominantly due to chemotherapy resistance.\nHence, late-stage MOC exhibits a lower overall\nFigure 1. Current theories of cell of origin and disease genesis in rare ovarian cancers. (A) Developmental models\nfor low-grade serous ovarian carcinoma (LGSC). (1) The “incessant ovulation hypothesis.” Frequent damage to\nthe ovarian surface epithelium during ovulation results in the formation of ovarian epithelial neoplasms. During\novulation, the surface epithelium becomes enveloped by the stroma, forming an epithelial cell-inclusion cysts\n(EICs). EICs undergo rapid cell turnover, develop mutations, and form cystadenomas and cystadeno fibromas,\nwhich then progress to serous borderline tumors (SBTs) and LGSCs. (2) The fallopian tube epithelium is the\nsource of EICs. The fallopian tube mucosa consists of ciliated and secretory cells. As the EIC progresses toward an\nSBT and LGSC, the ratio of ciliated to secretory cells shifts toward a largely secretory mucosa (for SBT) or almost\nentirely secretory (LGSC). (B) Developmental models for mucinous ovarian carcinoma (MOC). (1) Metaplastic\ncells of the peritoneal –fallopian tube junction (or elsewhere in the Müllerian tract) with a mucin-producing\ncellular phenotype are incorporated into ovarian inclusion cysts. Over time, these cells gain driver mutations and\ncontribute to the formation of a mucinous cystadenoma, which eventually progresses to carcinoma. (2) Brenner\ntumors and/or teratomas progress to a mucinous carcinoma. (3) Ovarian surface epithelium is incorporated into\novarian inclusion cysts, where a metaplastic change leads to a mucin-producing phenotype. The aberrant cell\naccumulates genetic changes facilitating neoplastic evolution. Over time, these cells contribute to the formation\nof a mucinous cystadenoma, which eventually progresses to carcinoma.\nRare Epithelial Ovarian Cancers\nCite this article as Cold Spring Harb Perspect Med 2023;13:a038190 5\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nsurvival, with median survival currently at 12–\n14 months for stage III or IV MOC (Hess et al.\n2004; Zaino et al. 2011; Peres et al. 2019) com-\npared with 37–42 months for HGSC.\nHistorically, chemotherapy treatment of\nMOC has been similar to other EOC types de-\nspite low representation of MOC in EOC clinical\ntrials. The gold standard chemotherapy drugs\nfor HGSC are still used for MOC despite docu-\nmented differences in response patterns to plat-\ninum-based chemotherapy (Pectasides et al.\n2005; Pisano et al. 2005; Shimada et al. 2009;\nTypical clinical management of MOCs\nAll stages\nStage lb/c\nProgressive or recurrent disease\nStage II–IV\nSurgical debulking\nObservation/optional\nadjuvant chemotherapy\nSurgical debulking where\npossible\nChemotherapy\nMolecular\nprofile\nMatched\ntherapy/clinical\ntrial\nMolecular characterization of\nprimary and/or recurrent tumor\nvia targeted sequencing\nObservation Adjuvant\nchemotherapy\nHER2\namplification\nor mutation\nRAS\npathway\nalteration\nERRB3\nmutation\nBRAF\nmutation\nPIK3CA or\nPTEN\nmutation\nTP53\nmissense\nmutation\nRNF43\nmutation\nER-\npositive\nARID1A\nmutation\nHER2-\ndirected\nantibody\nor TKI\nMEK/RAS/\nRAF\ninhibitor\nERRB3-\ndirected\nantibody\nor TKI\nBRAF\ninhibitor\nAKT/PI3K/\nMTOR\ninhibitor\np53\nreactivator\nPORCN\nor FZD\ninhibitor\nHormone\ntherapy\nATR inhibitor\nor\nepigenetic\ntherapy\nStage la*\nFigure 2. Typical clinical management of mucinous ovarian carcinomas (MOCs). Primary treatment for all stages\ninvolves surgical debulking of tumors. Further treatment is usually not necessary in stage 1a patients (adjuvant\nchemotherapy may be administered in high-grade cases). Adjuvant chemotherapy is offered to stage Ib and Ic\npatients, depending on grade, while it is routinely administered for stage II to IV cases. Upon disease progression\nor recurrence, second-round surgical debulking is performed when physically possible, usually combined with\nadjuvant chemotherapy. The increasing accessibility of tumor sequencing has recently yielded the use of tumor-\nspecific management, in which therapies can be chosen to target distinct molecular pro files. (ER) Estrogen\nreceptor, (MEK) mitogen-activated protein kinase, (FZD) frizzled.\nO. Craig et al.\n6 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nAlexandre et al. 2010; Schiavone et al. 2011).\nMOC cell lines exhibit platinum therapy resis-\ntance (Shimizu et al. 1998), re flecting the infe-\nrior response shown in patients. There have also\nbeen attempts to try neoadjuvant chemothera-\npy, but mucinous patient enrollment was insuf-\nficient to generate signi ficant findings (Vergote\net al. 2010; Kehoe et al. 2015). There are current-\nly no de finitive guidelines for chemotherapy in\nadvanced primary MOC.\nFor recurrent MOC, data showing the ef fi-\ncacy of chemotherapy has proved even more\narduous to obtain due to the rarity of these pa-\ntients. Thus, most information has come from\npooled trial data or retrospective reviews of cases\n(Ledermann et al. 2014). Currently, the sole\npublished work investigating recurrent disease\ndemonstrated that MOC had statistically signif-\nicant lower response to second-line chemother-\napy and shorter progression-free and overall\nsurvival than other ovarian cancer histotypes\n(Pignata et al. 2008).\nWith ineffective standard platinum-based\nchemotherapies, some clinicians administer\ntherapeutics designed for gastrointestinal can-\ncers; however, there is limited evidence to sup-\nport their use (Ledermann et al. 2014). 5FU in\ncombination with oxaliplatin (known as FOL-\nFOX) had shown some promise in vitro and in\nvivo (Sato et al. 2009). Attempts such as the\nmEOC/GOG241 trial have been made to assess\nthe ef ficacy of oxaliplatin and capecitabine for\nMOC (Gore et al. 2019). However, a nonsignif-\nicant benefit was reported in the oxaliplatin/ca-\npecitabine arm (hazard ratio [HR] 0.35, 95%\nconfidence interval [CI] 0.08 = 1.41) and the tri-\nal was closed prematurely due to slow recruit-\nment. A small 2019 retrospective study found\nadjuvant gastrointestinal-type chemotherapy\nimproved survival in MOC patients; however,\nit is dif ficult to draw conclusions from such a\nlimited sample size (Kurnit et al. 2019). There is\nalso hope for combination gemcitabine and ox-\naliplatin (GEMOX), which has been tested in\nplatinum-resistant pretreated patients but not\nMOC speci fically (Vici et al. 2013; Yuan et al.\n2013). Furthermore, some studies have shown\npromising results for irinotecan as MOC treat-\nment (for review, see Xu et al. 2016). A recent\nretrospective analysis tried to investigate wheth-\ner late-stage MOC patients bene fited from re-\nceiving any chemotherapy regimens over those\ntreated with surgery alone, and found a modest\nsurvival bene fit. However, data were not avail-\nable on which drugs were included, and pathol-\nogy review was not performed, so it is likely that\nthese results were skewed by inclusion of extra-\novarian metastases (Nasioudis et al. 2020).\nHyperthermic intraperitoneal chemothera-\npy (HIPEC) is an emerging treatment that has\nshown to be effective in other cancers such as\ncolorectal and appendiceal, and the limited re-\nsearch on its bene fit in MOC patients shows\nsome promise (Zhang et al. 2020). However,\nthese data are once again retrospective and in-\nvolved only 54 participants. More clinical stud-\nies are needed to elucidate its true value.\nLOW-GRADE SEROUS OV ARIAN\nCARCINOMA\nOf the EOC histotypes, serous ovarian carcino-\nmas (SOCs) are the most common (Peres et al.\n2019). Historically, SOC was thought to be a\nhomogenous disease, but several clinicopatho-\nlogical, molecular, and genetic studies analyzing\nepithelial SOCs have generated a large body of\nevidence indicating that SOCs can be divided\ninto high-grade (HGSC) and the rarer low-grade\n(LGSC) (Vang et al. 2009). This classi fication\nmodel, introduced in 2004, distinguishes\nHGSC and LGSC according to levels of nuclear\natypia and mitotic count (Gershenson 2016).\nLGSCs now account for 5%–10% of patients di-\nagnosed with ovarian, fallopian, and peritoneal\ncarcinomas.\nEpidemiology\nMost epidemiological studies do not distinguish\nHGSC from LGSC; however, a recent analysis\nconcluded that the majority of risk factors are\nshared between these histotypes (Wentzensen\net al. 2016). These factors include age at meno-\npause and use of hormone replacement therapy\n(HRT), where increased duration of ovulation or\nhormonal exposure is associated with a higher\nrisk of disease. Disparity emerges with endome-\nRare Epithelial Ovarian Cancers\nCite this article as Cold Spring Harb Perspect Med 2023;13:a038190 7\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\ntriosis (not signi ficant for HGSC) and body\nmass index, parity, and oral contraceptive use,\nwhich were reported as weaker risk factors for\nLGSC. However, the study featured few cases of\nconfirmed LGSC, limiting the power to detect\nthe subtle hazard ratios observed in HGSC.\nLGSC is consistently diagnosed at a younger\nage than HGSC, and thus correlates with greater\npotential years of life lost (Chen et al. 2014;\nGockley et al. 2017). Additionally, a particularly\nyoung age at diagnosis (<35) is a poor prognos-\ntic indicator for LGSC (Gershenson et al. 2015).\nLGSC is not commonly associated with a\nfamily history or high-penetrance mutations in\nknown ovarian cancer genes such as BRCA1 or\nBRCA2. Several low-penetrance SNPs have been\nidentified, including LGSC/serous borderline\ntumor (SBT)-speci fic loci on 3q28, 4q32.3,\n8q21.11, 10q24.33, 18q11.2, and loci shared\nwith HGSC such as 22q12, 2q13, 8q24.21, and\n12q24.31 (Phelan et al. 2017). Associated\ngenes include PAX8 (2q13), PVT1 and MYC\n(8q24.21), HNF1A (12q24.31), and OBFC1\n(10q24.33).\nClinicopathological Features and Diagnosis\nLGSC tumors have histological features distinct\nfrom HGSC, and commonly demonstrate a clus-\ntered, micropapillary pattern of neoplastic cells\ninvading the stroma (Vang et al. 2009). The mi-\ntotic index of LGSC is relatively low, and the\ncells tend to be uniform in size, with minimal\nnuclear atypia. Multiple microscopic bodies of\ncalcium, known as psammoma bodies, are a fre-\nquent occurrence in LGSC (Vang et al. 2009).\nLGSCs are thought to develop from nonin-\nvasive serous tumors. Benign serous ovarian tu-\nmors are comprised of cystadenomas, cystade-\nnofibromas, and adeno fibromas, which are\nmostly restricted to the ovaries (Longacre\n2011). Cystadenomas have a smooth lining or\nprotrusions and contain clear fluid that have\nsimilar viscosity to that of a mucinous tumor.\nCystadenofibromas have similar features to the\ncystadenomas but contain fibrous stroma, while\nadenofibromas are more solid,firm, and typical-\nly contain more psammoma bodies than the\nother two subtypes (Longacre 2011).\nSBTs are intermediate between benign tu-\nmors and malignant carcinomas (Hauptmann\net al. 2017), with increased cellular proliferation\ncompared with benign tumors and mild nuclear\natypia without stromal invasion. SBTs present as\nsingle- or multicavity cystic tumors composed\nof ciliated epithelial cells (Hauptmann et al.\n2017). Approximately 22% of SBT cases present\nwith peritoneal implants featuring proliferating\nepithelial cells either on the surface of the peri-\ntoneum or in peritoneal invaginations, lacking\nsubperitoneal invasion (du Bois et al. 2013).\nLGSC patients suffer from rather diffuse\nsymptoms akin to HGSC, rendering early diagno-\nsis a challenge. As a result, more than half of LGSC\npatients are diagnosed at a late stage (stage III–IV)\n( R i c c i a r d ie ta l .2 0 1 8 ) .C o m m o ns y m p t o m si n -\nclude abdominal pain and bowel impairment\n(Ricciardi et al. 2018), with diagnosis usually\nmade on the basis of body imaging and physical\nexamination along with serum biomarker assess-\nment. CA-125 levels are high in only half of early-\nstage SOC cases, compared to >85% in patients\nwith advanced stage disease (Fader et al. 2014).\nHowever, the clinical use of CA-125 has not\nbeen specifically assessed for LGSC.\nNatural History and Genetics\nHistorically, “the incessant ovulation hypothe-\nsis” (Fathalla 1971) proposed that repeated\ndamage to OSE cells during ovulation resulted\nin the generation of ovarian epithelial neo-\nplasms. This model had support from the epi-\ndemiological risk factors seen in LGSC, as it\nsuggested that the OSE was enveloped by the\novarian stroma during ovulation, generating ep-\nithelial cell-inclusion cysts (EICs; Fig. 1). These\ninclusion cysts were then thought to form be-\nnign cystadenomas or cystadeno fibromas that\nsubsequently progress to borderline and inva-\nsive LGSCs. This hypothesis was supported by\nan early gene-expression analysis (Bonome et al.\n2005) that appeared to show SBTs and LGSCs\nclustering with the OSE rather than HGSC.\nHowever, the differences were mostly driven\nby proliferation and DNA damage gene sets.\nMore recent immunotyping of EIC cells sug-\ngests that the fallopian tube epithelium (FTE),\nO. Craig et al.\n8 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nrather than the OSE, might be the source of EIC\nvia endosalpingiosis (Li et al. 2011). There are\ntwo types of epithelial cells that form the fallopi-\nan tube mucosa: ciliated and secretory. Both cil-\niated ( α-tubulin\n+) and secretory cells (PAX8 +)\nare present in EICs and serous cystadenomas,\nwhich have similar secretory cell/ciliated cell ra-\ntios. This ratio skews toward a greater abundance\nof secretory cells when the EIC progresses to an\nSBT and further to LGSCs, which are almost\nentirely composed of secretory cells. Analysis\nof 11 LGSC samples found that LGSC and FTE\nhave very similar gene-expression pro files; fur-\nthermore, the gene-expression pro files of EIC,\nbenign tumors, and SBT are more similar to\nthat of the fallopian tube than the OSE (Qiu\net al. 2017; Wang et al. 2019a). However, a study\nin mice expressing yellow fluorescent protein\nfrom an inducible oviductal (fallopian tube\nequivalent) promoter (OVGP1) showed inclu-\nsion cysts in mice before the onset of ovulation,\nwhich did not increase with age or number of\novulatory cycles (Wang et al. 2019b). This find-\ning provides evidence against an ovulatory endo-\nsalpingiosis mechanism. Further support for a\nnon-FTE origin of EIC comes from immuno-\nphenotyping, demonstrating that EIC is positive\nfor both PAX8 and calretinin (a mesothelial cell\nmarker), suggesting metaplasia of mesothelial\ncells (Park et al. 2018), although the inverse ar-\ngument could also be made.\nThese contrasting studies highlight the chal-\nlenges in determining cell of origin using gene-\nexpression profiles alone. Regardless of the cell\nof origin, multiple studies have indicated a step-\nwise model for LGSC development, from benign\ncystadenoma/cystadenofibromas, through to\nSBT and eventually to LGSC (Li et al. 2011).\nKey evidence for this model is the early acquisi-\ntion of shared key driver mutations in genes\nsuch as BRAF and KRAS (Hunter et al. 2011;\nEmmanuel et al. 2014).\nThe mutational profile of LGSC is also quite\ndistinct from HGSC. The genomic landscape of\nHGSC includes mutations in TP53, BRCA1, and\nBRCA2 (Cancer Genome Atlas Research Net-\nwork [CGARN] 2011). Significantly fewer geno-\nmic studies have been conducted on LGSCs;\nhowever, mutations in the RAS/RAF signaling\npathway (mostly KRAS [usually G12D and\nG12V], NRAS [Q61R and K61K], and BRAF\n[almost always V600E]) are found in approxi-\nmately half of LGSC tumors and are largely mu-\ntually exclusive (Cheasley et al. 2021). Mutations\nin TP53 are considerably rarer (Emmanuel et al.\n2014; Hunter et al. 2015; Cheasley et al. 2021).\nFurthermore, a genetic study by Etemadmogha-\ndam et al. (2017) identi fied frameshift muta-\ntions in NF1, encoding a negative regulator of\nthe RAS pathway, in 9% of cases. Missense mu-\ntations in EIF1AX (5.6%–13%) and frameshift\nmutations in USP9X (11.3%–13%) are also ob-\nserved in LGSC, with most EIF1AX mutations\nco-occurring with NRAS mutations (Hunter\net al. 2015; Etemadmoghadam et al. 2017;\nCheasley et al. 2021). USP9X appears to be a\ntumor suppressor gene that does not require a\nsecond\nhit, with frameshift mutations showing\ncomplete loss of protein despite retaining a nor-\nmal copy and escaping silencing through X\nchromosome inactivation (Cheasley et al. 2021).\nCompared to SBTs, LGSCs exhibit higher\nnumbers of copy number aberrations, although\nthey are more genetically stable than their high-\ngrade counterparts (Hunter et al. 2015). The\nmost common copy number events are loss of\nchromosomes 1p, 9, 16p, 18, 22, and X, and\ngains of 1q, 7, 8, and 12 (Hunter et al. 2015;\nCheasley et al. 2021). In comparison to SBTs,\nloss of chromosomes 1p, 9q, 18q, and X were\nmore common in LGSCs, while no loss of chro-\nmosome 22 or gain of 13 was observed in SBTs\n(n = 57) (Hunter et al. 2015). Nevertheless, in a\nstudy of paired borderline and invasive samples,\ncopy number pro files were nearly identical,\nwhich provides evidence for a clonal relation-\nship (Emmanuel et al. 2014). This study also\nfound NRAS mutations to be associated with\nLGSCs but rare in SBTs lacking progression to\ninvasion.\nCurrent Clinical Approach and Outcomes\nCytoreductive surgery is standard for patients\nwith primary LGSC (Fig. 3). It has been shown\nthat patients with postoperative microscopic re-\nsidual disease had signi ficantly better overall\nsurvival than those with macroscopic disease\nRare Epithelial Ovarian Cancers\nCite this article as Cold Spring Harb Perspect Med 2023;13:a038190 9\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nAll primary LGSCs\nStages I–II\nRecurrent or metastatic disease\nStages III–IV\nCytoreductive surgery with/without\nwith/without\nwith/without\nCarboplatin\nmonotherapy\nPlatinum-based\nchemotherapy Hormone therapy Molecular characterization of\nLGSC tumor via sequencing\nCarboplatin and\npaclitaxel\nAnti-angiogenics\n(e.g., Bevacizumab)\nAnti-angiogenics\n(e.g., Bevacizumab)\nMolecular\nprofile\nMatched\ntherapy/clinical\ntrial\nMAPK/ERK\npathway\nalterations\nMEK inhibitors\n(e.g.,\nbinimetinib,\nselumetinib)\nBRAF\n inhibitors\n(e.g.,\ndabrafenib,\nvemurafenib)\nHormone\ntherapy (e.g.,\ntamoxifen,\nonapristone)\nBRAF\n mutations\nER/PR\nstatus\nPlatinum-based\nchemotherapy\nSecond-round\ncytoreduction\nTypical clinical management of LGSCs\nFigure 3. Typical clinical management of low-grade serous ovarian carcinomas (LGSCs). The primary treatment\nmethod for all LGSCs is cytoreductive surgery, possibly in combination with platinum-based chemotherapeutics;\nthe type of chemotherapy administered is dependent on tumor stage. Patients with tumors that have recurred or\nprogressed may receive a second round of cytoreductive surgery in conjunction with chemotherapeutics. Hor-\nmone therapy may be administered to patients with estrogen/progesterone receptor-positive (ER/PR-positive)\ntumors; patient tumors can also be sequenced to identify targetable mutations or pathway alterations, after which\nmore personalized treatment strategies can be used.\nO. Craig et al.\n10 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\n(>1 cm) (97 mo vs. 35 mo, respectively) (Gra-\nbowski et al. 2016). Indeed, LGSC patients\nwith macroscopic disease post-debulking exhib-\nited similar progression-free and overall survival\nto HGSC patients with macroscopic disease (13\nmo and 30 mo, respectively, for LGSC vs. 10 mo\nand 28 mo for HGSC [Chen et al. 2014]). In the\nrelapse setting, a second round of cytoreduction\nhas been proposed to be of a greater bene fit\n(especially if no gross residual disease can be\nachieved) to patients with LGSC than for those\nwith HGSC, in part due to the chemoresistant\nnature of LGSC (Moujaber et al. 2021).\nIn combination with surgery, platinum-\nbased monotherapy is administered to patients\nwith LGSC (Ledermann et al. 2013). However,\nwith increased genetic stability and a lower\nproliferation rate than their high-grade counter-\npart, LGSCs are typically more resistant to stan-\ndard chemotherapeutics (Gershenson et al.\n2006, 2009). A study analyzing the ef ficacy of\nnonplatinum monotherapy in platinum-resis-\ntant HGSCs found the objective response rate\n(ORR) to treatment to be 19.7% (Gordon et al.\n2001). By contrast, in a study of 58 LGSC pa-\ntients with either platinum-sensitive or resistant\ntumors, who were treated with varying chemo-\ntherapy regimens (including hormonal thera-\npy), ORRs were just 4.9% and 2.1%, respectively\n(Gershenson et al. 2009). The ef ficacy of neo-\nadjuvant chemotherapy is equally low; in a study\nof 24 patients who underwent combined taxane\nand platinum-based therapy, only one had a\ncomplete response, with 21 patients experienc-\ning stable disease and two patients progressing\n(Schmeler et al. 2008). Furthermore, a study of\n36 LGSC patients found that only 11% had a\npartial response to neoadjuvant platinum-based\nchemotherapy; in sharp contrast, 75% of HGSC\npatients analyzed in the same study had a partial\nresponse to treatment (Cobb et al. 2020).\nLGSC has a high recurrence rate; more than\n80% of patients will experience relapse (Ger-\nshenson 2016). For some patients, second-\nround cytoreductive surgery may be advised.\nAgain, the ef ficacy of surgery depends on the\npresence of macroscopic residual tumor postop-\neration. When no gross residual disease was\npresent, patients experienced a roughly sixfold\nbetter progression-free survival than those that\nhad macroscopic disease postsurgery for recur-\nrent disease (Crane et al. 2015).\nLGSC can exhibit a high expression of estro-\ngen and progesterone receptors (ERs and PRs,\nrespectively) (Sieh et al. 2013). Furthermore, pa-\ntients with LGSC are diagnosed at a younger age\nand are likely to be premenopausal, thus impli-\ncating hormonal involvement in cancer progres-\nsion. However, a study conducted by Sieh et al.\n(2013) found that there was no statistically sig-\nnificant correlation between ER/PR status and\nsurvival in LGSC patients. Retrospective studies\nby Gershenson et al. analyzed the ef ficacy of\nhormonal treatment regimens for LGSC pa-\ntients with recurrent or stage II –IV disease.\nClinical bene fit from various hormonal thera-\npies was observed in the recurrent population\n(Gershenson et al. 2012), and hormonal main-\ntenance therapy was associated with improved\nprogression-free survival (Gershenson et al.\n2017). Almost all patients in these studies car-\nried ER\n+ tumors, and there was no difference in\nsurvival for ER +/PR+ cases compared to ER +/\nPR− in the maintenance setting, although num-\nbers were small. Hormonal therapies are now an\nactive area of clinical trial research, with at least\ntwo active trials listed evaluating combinations\nwith letrozole in LGSC (NCT03673124 [clini-\ncaltrials.gov/ct2/show/NCT03673124] with ri-\nbociclib and NCT04095364 [clinicaltrials.gov/\nct2/show/NCT04095364] with/without carbo-\nplatin/paclitaxel). Another trial is underway to\nassess the ef ficacy of the antiprogesterone drug\nonapristone in treated patients with PR\n+ LGSC\n(NCT03909152), and two others are evaluating\nfulvestrant either alone (NCT03926936 [clini-\ncaltrials.gov/ct2/show/NCT03926936]) or in\ncombination with the CDK4/6 inhibitor abema-\nciclib (NCT03531645).\nTARGETED THERAPIES TO IMPROVE\nOUTCOMES OF RARE GYNECOLOGICAL\nCANCER SUBTYPES\nFor rare cancers such as MOC and LGSC, large\nclinical trial data sets are not available to direct\nclinical management strategies. As a result,\ntreatment paradigms for rare cancers are under-\nRare Epithelial Ovarian Cancers\nCite this article as Cold Spring Harb Perspect Med 2023;13:a038190 11\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\ngoing a shift toward identifying and developing\nnovel targeted therapy strategies for individu-\nal patients using multiomic sequencing ap-\nproaches. Targeted therapies, aimed at aberrant\ngenes/proteins detected by sequencing can\nthen be tested for their ef ficacy, especially as\ncombination therapies.\nAs mutations in the MAPK/ERK pathway\nare common in MOC and LGSC, inhibitors of\nmitogen-activated protein kinase (MEK inhibi-\ntors) are a potential therapy option for these\npatients (Miller et al. 2014). Indeed, at the cell\nline level, EOC cell growth was markedly re-\nduced using the MEK inhibitor CI-1040. Re-\ncently, LGSC-speci fic cell lines have also been\nused to investigate various MEK inhibitors (Fer-\nnandez et al. 2016, 2019), with responses noted\nparticularly in KRAS-mutated cell lines. A clin-\nical trial testing the MEK inhibitor binimetinib\nwas attempted in LGSC patients, but due to the\nsmall sample size no statistically signi ficant ef-\nfect on progression-free survival compared to\nchemotherapy was observed (Grisham et al.\n2019). Nonetheless, individual durable re-\nsponses were noted, particularly in patients\nwith KRAS mutations. One case study reported\na patient on this trial with recurrent, chemore-\nsistant, and hormone therapy –resistant LGSC\nwith a KRAS mutation who demonstrated par-\ntial response to MEKi, with an 81% reduction in\ntumor size during treatment (Han et al. 2018).\nWhile MOC patients were not included in this\ntrial, given the high rate of KRAS mutations in\nthis tumor subtype, there is also a strong ratio-\nnale for binimetinib use in these patients. An-\nother MEK inhibitor, selumetinib, has been test-\ned on 52 LGSC patients (Farley et al. 2013; Miller\net al. 2014). At the conclusion of this small trial,\nmore than half of the patients had stable disease,\nwhile approximately 15% experienced complete\nor partial response to treatment. Median overall\nsurvival was 32.4 months. Patients were not se-\nlected for RAS/RAF mutations, and response\nwas not related to the presence of such a muta-\ntion, with the caveat of a small sample size. Other\ncurrent clinical trials of MEK inhibitors in-\nclude evaluation of trametinib (NCT02101788\n[clinicaltrials.gov/ct2/show/NCT02101788]), with\npreliminary outcomes reported suggesting im-\nproved progression-free survival and an objec-\ntive tumor response rate of 26% (Gershenson\net al. 2022).\nA recent phase I clinical study using the RAF/\nMEK inhibitor VS-6766 and the FAK inhibitor\ndefactinib to treat 25 patients with LGSC report-\ned promising preliminary results; the ORR for all\npatients was 46%, increasing to 64% for patients\nwith KRAS mutations (NCT03875820).\nMutations in BRAF, and in particular\nBRAFV600E, are a relatively common occur-\nrence in LGSC and MOC (Moujaber et al.\n2018). BRAF inhibitors are now successfully\nused in the treatment of metastatic melanoma\n(Hauschild et al. 2012). The ef ficacy of such\ntreatment for MOC and LGSC has yet to be\ndetermined, although there are case reports of\npositive results from treatment. For example, a\npatient who had chemoresistant, recurrent\nLGSC underwent treatment with the BRAF in-\nhibitor dabrafenib in combination with the\nMEK1/2 inhibitor trametinib; CA-125 levels de-\nclined over a 6-month treatment period (Men-\ndivil et al. 2018). Similarly, a report by Stover\net al. (2018) highlights the bene fits of using tar-\ngeted sequencing on two LGSC patients; for one\npatient with BRAFV600E, the BRAF inhibitor\nvemurafenib had considerable ef ficacy, marked\nby a decrease in CA-125 levels. Interestingly, the\nsecond patient who had progressive LGSC un-\nderwent hormonal therapy and responded to\ntreatment, although a recurrent lesion harbored\na mutation in ESR1, conferring resistance to an-\ntiestrogen therapy.\nBevacizumab, a monoclonal antibody that\ninhibits vascular endothelial growth factor, has\nbeen successfully implemented in colorectal car-\ncin\noma (Macedo et al. 2012). Subsequent studies\nhave shown the benefit of Bevacizumab in EOC\nphase 3 trials, but limited MOC patient partici-\npation hindered collection of speci fic data for\nthis subtype (Xu et al. 2016). The GOG241 trial\nalso tested Bevacizumab in combination with\ncarboplatin-paclitaxel or oxaliplatin-capecita-\nbine, and showed no bene fit from the addition\nof Bevacizumab, although only 18 confi rmed\nMOC cases were available for analysis (Gore\net al. 2019). Despite this, individual case reports\nhave reported success with Bevacizumab mono-\nO. Craig et al.\n12 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\ntherapy (Winer and Buckanovich 2010). Beva-\ncizumab has also been tested in a small number\nof patients with LGSC with considerably greater\nsuccess. In retrospective studies, Bevacizumab\nshowed efficacy in patients for recurrent LGSC\nwith response rates of 40% –47.5% and clinical\nbenefit of 73% –78% (Grisham et al. 2014; Dal-\nton et al. 2017). Bevacizumab was used alongside\nchemotherapy as a primary treatment strategy\nfor patients in several randomized trials. Meta-\nanalyses showed limited progression-free (but\nnot overall) survival bene fit, although LGSCs\nwere not assessed separately from all serous or\nall low-grade carcinomas (Rossi et al. 2017).\nTargeting of other growth factor receptors\nhas been similarly considered although with\nmuch fewer samples. In cases of ERBB2 ampli-\nfication, anti-HER2 therapy using targeted anti-\nbodies or tyrosine kinase inhibitors has been\nsuccessful in other cancers such as gastric and\nbreast cancer. Given the relative frequency of\nHER2 overexpression in MOC, it is hoped\nsuch efforts might translate to this subtype. Ev-\nidence of ef ficacy has been provided by case\nstudies of a few individual patients (McAlpine\net al. 2009; Jain et al. 2012), but more robust data\non larger sample sizes are lacking. The EGFR\ninhibitor cetuximab could be useful in treating\nKRAS wild-type MOC. Ef ficacy has been dem-\nonstrated successfully by Sato et al. (2012) in\nKRAS wild-type MOC cell lines and mice; again,\nhowever, there are currently no clinical data sup-\nporting its use.\nRecently, other less frequent genetic events\nthat occur in MOC patients were identi fied\nas having potential clinical utility, including\nRNF43, ARID1A, and PIK3CA/PTEN mutations\n(Gorringe et al. 2020). These events may be ac-\ntionable using targeted agents currently used or\nbeing tested in other cancer types, potentially\ngiving otherwise untreatable patients therapeu-\ntic options. Additionally, approximately 11% of\nMOC patients may be ER\n+ and thus could ben-\nefit from hormonal therapy. By the same preci-\nsion oncology paradigm, PARPi and immuno-\ntherapies were deemed unlikely to be useful in\nMOC treatment due to the rarity of homologous\nrecombination deficiency (HRD) and mismatch\nrepair de ficiency (MRD). In LGSC, ∼27% of\ncases recently analyzed had a genetic event that\nwas predictive of benefit with an agent already in\nthe clinic for another cancer type (Cheasley et al.\n2021).\nFUTURE DIRECTIONS\nOverall, the major limitation of most clinical\ntrials discussed above is their restricted sample\nsize; due to the rarity of these diseases, recruiting\npatients with the given histotype as well as the\nspecific mutation(s) being targeted is challeng-\ning. A further challenge is the paucity of patient-\nderived models to establish preclinical evidence\nfor drug efficacy. Only a handful of cell lines and\npatient-derived xenografts are available for ei-\nther MOC or LGSC (Table 1), and very recently\na few novel tumor organoid models have been\ndeveloped (Kopper et al. 2019). Older cell lines\nare relatively untrustworthy for studies as the\nsubtype (especially LGSC) was often not record-\ned. Despite recent efforts to identify the origins\nof such cell lines using mutations and gene-ex-\npression data (Domcke et al. 2013; Barnes et al.\n2021), it would generally be advisable to work\nwith more recently derived models (Nelson et al.\n2020; Shrestha et al. 2021).\nIn synergy with identifying appropriate tar-\ngeted therapies, research should also focus on\nestablishing markers of treatment response and\nresistance for MOC and LGSC. For example,\nShrestha et al. (2021) combined genomic, tran-\nscriptomic, and proteomic methods to discover\npotential predictive markers of MEKi treatment\nresponse and new therapy combinations. Such\nstudies can aid clinical trials in selecting patients\nwho will likely have a better response to treat-\nment. Sequencing approaches can also reveal\nnovel driver mutations (either standalone or\nco-occurring), aiding in the identi fication of\nnew treatment targets. USP9X and EIF1AX are\ntwo genes that have been recently identi fied as\nrecurring mutations that may play a role in\nLGSC development (Hunter et al. 2015; Ete-\nmadmoghadam et al. 2017). In particular, the\ngroup of LGSC patients lacking the known\nRAS/RAF drivers remain to be fully explored\nfor genetic drivers.\nRare Epithelial Ovarian Cancers\nCite this article as Cold Spring Harb Perspect Med 2023;13:a038190 13\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nTable 1. Cell lines for use in mucinous ovarian carcinoma (MOC) and low-grade serous ovarian carcinoma (LGSC) research\nCell line\nOriginal histological\ntype Likely histological type Known mutationsa References\nPlausible MOC cell lines\nMCAS MOC MOC KRAS, TP53 Kidera et al. 1985; Anglesio et al. 2013b\nRMUG-S MOC MOC TP53 Sakayori et al. 1990\nJHOM1 MOC MOC (seromucinous?) TP53, CDKN2A, PTEN RIKEN cell bank\nCOV644 MOC MOC CDKN2A, MDM2 ampli fication van den Berg-Bakker et al. 1993\nPrevious MOC cell lines that are likely to be non-MOC\nSW626 NK Colorectal cancer (CK20\n+) APC, KRAS, TP53 Furlong et al. 1999\nEFO27 MOC Endometrioid/\nendometrial\nARID1A, MSH2 (dMMR), PIK3CA, PTEN,\nTP53\nSimon et al. 1983\nJHOM2B MOC Colorectal cancer TP53, BRAF, SMAD4 RIKEN cell bank\nOMC-3 MOC Pancreatic? BRCA2, SMAD4, CDKN2A Yamada et al. 1991; KL Gorringe, unpubl.\nLGSC cell lines\niOvCa241 LGSC LGSC KRAS Shrestha et al. 2021\nVOA-1312 LGSC LGSC KRAS Shrestha et al. 2021\nVOA-1056/VOA-3993 LGSC LGSC NRAS Shrestha et al. 2021\nVOA-3448/VOA-3723 LGSC LGSC Shrestha et al. 2021\nVOA-4627/VOA-4698 LGSC LGSC TP53 Shrestha et al. 2021\nVOA-6406 LGSC LGSC NRAS Shrestha et al. 2021\nVOA-8862 LGSC LGSC KRAS Shrestha et al. 2021\nVOA-9164 LGSC LGSC KRAS Shrestha et al. 2021\nCAISMOV24 LGSC LGSC KRAS da Silva et al. 2017\nPM-LGSC-01 LGSC LGSC KRAS De Thaye et al. 2020\nHeyA8 Moderately\ndifferentiated papillary\ncystadenocarcinoma\nLGSCb KRAS Buick et al. 1985; Barnes et al. 2021\nOVCAR8 NK LGSC/HGSCb TP53, KRAS, CTNNB1, ERBB2 Schilder et al. 1990; Barnes et al. 2021\nTYK-nu Undifferentiated LGSC/HGSC c NRAS, TP53 Yoshiya 1986; Barnes et al. 2021\nOV7 Mixed LGSC/HGSCc KRAS, TP53 Boocock et al. 1995; Barnes et al. 2021\naFrom the Cancer Cell Line Encyclopedia unless otherwise stated (Ghandi et al. 2019).\nbOriginal histology was nonspeci fic, the LGSC call is based on gene expression and mutations and therefore may be incorrect\n(Barnes et al. 2021).\ncDescribed as poorly differentiated or undifferentiated. Do carry characteristic LGSC drivers, so potential progression to HGSC from\nan LGSC precursor.\nO. Craig et al.\n14 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nAnother application of a multiomics ap-\nproach is to assist in elucidating the cell of origin\nfor these rare cancers, which is still contentious\nfor both histotypes. Using a combination of ge-\nnomic, transcriptomic, methylation, and chro-\nmatin sequencing studies, further evidence can\nbe obtained to either confi rm or disprove the\nvarious theories (Li et al. 2011; Hao et al.\n2017). Inducible animal model systems and lin-\neage-tracing analysis could also be used to iden-\ntify the correct cell type.\nCONCLUDING REMARKS\nAlthough MOC and LGSC are distinct from\neach other and the other ovarian histotypes,\nthere are certain similarities, summarized in Ta-\nTable 2. Characteristics of mucinous ovarian carcinoma (MOC) and low-grade serous ovarian carcinoma (LGSC)\nMOC LGSC References\nIncidence 0.6/100,000 0.5/100,000 Howlader et al. 2017; Leary et al.\n2017\nRisk factors Smoking Number of children; age at\nmenopause;\nendometriosis; oral\ncontraceptive use;\nmenopausal hormone\ntherapy\nCollaborative Group on\nEpidemiological Studies of\nOvarian Cancer et al. 2012;\nWentzensen et al. 2016\nCell of origin Unknown —potentially ovarian\nsurface epithelium,\ntransitional cells of peritoneal\njunction, Brenner tumors,\nfallopian tube epithelium via\nendosalpingiosis, primordial\ngerm cells\nUnknown, possibly\nfallopian tube secretory\ncells or ovarian surface\nepithelium\nSeidman and Khedmati 2008;\nKurman et al. 2011; Chen\net al. 2013; Qiu et al. 2017;\nElias et al. 2018; Park et al.\n2018; Wang et al. 2019b\nPrecursor\ntumors\nCommonly, mucinous benign\nand borderline tumors; rarely,\nBrenner tumors, teratomas\nSerous benign and\nborderline\nHunter et al. 2011, 2012;\nEmmanuel et al. 2014; Wang\net al. 2015a,b; Cheasley et al.\n2019\nStage\ndistribution\nLocalized 48.2%\nRegional 25%\nDistant 26.7%\nLocalized 20.3%\nRegional 26.3%\nDistant 53.4%\nPeres et al. 2019\nKey genetic\nfeatures\n(>25%)\nKRAS (40%–65%),\nTP53 (30%–64%),\nERRB2 (20%–35%), CDK2NA\n(20%–45%)\nNRAS (25%), BRAF (14%),\nKRAS (20%), EIF1AX\n(13%), USP9X (13%)\nMcAlpine et al. 2009; Hunter\net al. 2015; Mackenzie et al.\n2015; Etemadmoghadam et al.\n2017; Meagher et al. 2018;\nMoujaber et al. 2018; Mueller\net al. 2018; Cheasley et al. 2019\nIHC markers CK7\n+, CK20−, SATB2− WT1+, p53wt, p16 −/patchy McCluggage 2012; Köbel et al.\n2014; Sallum et al. 2018;\nMeagher et al. 2019\nResponse to\nplatinum-\nbased\ntherapies (%)\n26.3%–60% 4% –5% Hess et al. 2004; Pectasides et al.\n2005; Gershenson et al. 2006,\n2009; Pignata et al. 2008;\nSchmeler et al. 2008;\nAlexandre et al. 2010\n5-Year overall\nsurvival\nLocalized 83%\nRegional 70%\nDistant 14%\nLocalized 93%\nRegional 83%\nDistant 54%\nPeres et al. 2019\nRare Epithelial Ovarian Cancers\nCite this article as Cold Spring Harb Perspect Med 2023;13:a038190 15\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nble 2. The most notable similarity between these\nhistotypes is not related to their biology, but\nsimply their rarity, which confers profound clin-\nical and research challenges. Both diseases are\nrelatively chemoresistant, yet such rarity means\nthat performing well-powered clinical trials in\neither subgroup is dif ficult. Hence, targeted\nagents for MOC and LGSC may best be test-\ned using novel approaches such as registry trials,\nn = 1 trials, and basket trials in concert with oth-\ner solid tumor types with similar genetic fea-\ntures. In addition, directed efforts must be\nmade toward establishing relevant preclinical\nmodels to test the ef ficacy of targeted agents\nand combinations.\nACKNOWLEDGMENTS\nK.G. is supported by a Victorian Cancer Agency\nMid-Career Fellowship and the Peter MacCal-\nlum Foundation. A.N. is supported by a Uni-\nversity of Melbourne International Research\nScholarship. 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Craig et al.\n22 Cite this article as Cold Spring Harb Perspect Med 2023;13:a038190\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nJune 5, 2023\n2023; doi: 10.1101/cshperspect.a038190 originally published onlineCold Spring Harb Perspect Med \n \nOlivia Craig, Abhimanyu Nigam, Genevieve V. Dall and Kylie Gorringe\n \nCarcinomas\nRare Epithelial Ovarian Cancers: Low Grade Serous and Mucinous\nSubject Collection  Ovarian Cancer\nModels of High-Grade Serous Ovarian Carcinoma\nOscar J. Pundel and Benjamin G. Neel\nOvarian Cancer Therapy\nPorter\nDiana Miao, Ursula A. Matulonis and Rebecca L.\nTherapeutic Challenges\nEndometriosis-Associated Cancer with \nOvarian Clear Cell Carcinoma: An\nRuby Yun-Ju Huang and Jimmy Jin-Che Lin\nCancer\nHarnessing Antitumor Immunity in Ovarian\nKatherine C. Kurnit and Kunle Odunsi\nEarly Detection of Ovarian Cancer\nNaoko Sasamoto and Kevin M. Elias\nOvarian Cancer\nTumor Microenvironment in High-Grade Serous \nThe Emerging Role of the Single-Cell and Spatial\nAnniina Färkkilä\nInga-Maria Launonen, Anna Vähärautio and\nSerous and Mucinous Carcinomas\nRare Epithelial Ovarian Cancers: Low Grade\net al.\nOlivia Craig, Abhimanyu Nigam, Genevieve V. Dall,\nPrevention of Epithelial Ovarian Cancer\nHathaway, et al.\nThomas A. Sellers, Lauren C. Peres, Cassandra A.\nTract\nEpithelial Cancers of the Female Reproductive \nEmbryological Insights into the Origin of\nTheresa Austria and Louis Dubeau\nhttp://perspectivesinmedicine.cshlp.org/cgi/collection/ For additional articles in this collection, see \nCopyright © 2023 Cold Spring Harbor Laboratory Press; all rights reserved\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from","source_license":"public-domain-us","license_restricted":false}