Cell origin HGSC are further distinguished from LGSC by ‘type I/II’ ovarian tumour nomenclature; type I referring to tumour types (e.g. LGSCs) where precursor lesions within the ovary have been characterised, and type II referring to tumour types (e.g. HGSCs) without association of such lesions, tumours understood to develop de novo from the tubal and/or ovarian surface epithelium. This classification has more relevance to research rather than to clinical practice. The serous membrane is a particular type of secretory epithelium which covers organs in body cavities and secretes serous fluid to reduce friction from muscle movement. Serous membrane lining the abdominopelvic cavity is called the peritoneum; that lining heart and mediastinum is the pericardium, and that lining the thoracic cavity and lungs is the pleura. Technically a ‘serous<unk> ’ can occur anywhere on these membranes, but<unk>  is generally limited to the peritoneal area. While until recently HGSC was thought to arise from simple differentiation of cortical inclusion cysts (CICs) of ovarian surface epithelium (OSE), the cell origin of HGSC is now understood to be much more complex, with evidence for other sites of origin, both intra- and extra-ovarian, having come to light. Tissue Evidence for role as HGSC cell of origin Ovary Supporting: # Metastatic HGSC arose in the ovaries of mouse triple knockouts of p53, PTEN and Dicer in which the Fallopian tubes had been removed, as well as in double murine knockouts of PTEN and p53 with intact Fallopian tubes. # The stem-cell-rich hilum region of the ovarian surface epithelium is a cancer-prone area. Opposing: # A convincing precursor of HGSC in the ovary has not yet been identified. Coelomic epithelium Supporting: 'Coelomic hypothesis' # Due to the embryological relationship between the coelomic epithelium and the Müllerian ducts, the coelomic epithelium is predisposed to differentiation via Müllerian metaplasia into the different epithelial tumour tissue types (e.g. serous, endometrioid, clear cell and mucinous). Cortical inclusion cysts of the OSE can thus undergo differentiation into neoplasms. # This hypothesis can account for primary peritoneal<unk> s by implying that extra-ovarian coelomic epithelium can similarly undergo Müllerian metaplasia. Opposing: # There has so far been an absence of precursor lesions of ovarian<unk> s on the OSE despite extensive histopathology. Fallopian tube Supporting: # Precursor lesions (serous tubal intraepithelial<unk> s or ‘STICs’) found on the fimbrial ends of the Fallopian tube of BRCA 1/2 women. # There is physical contact between the fimbriae and the ovary during ovulation (supports ‘incessant ovulation’ hypothesis). # The fringes of the fimbriae come into contact with the pro-inflammatory follicular fluid. # Identical TP53 mutations in STIC and concurrent HGSC were reported, suggesting a clonal relationship. # In the triple p53-PTEN-Dicer knockout mice earlier mentioned, where the Fallopian tubes were intact, HGSC arose from the tubes 100% of the time, eclipsing the tumourgenicity of the ovary. Identical findings were found from PTEN-Dicer knockouts. # A 2012 clinical trial of a screening technique found that 7 out of 9 identified HGSC cases arose from the Fallopian tube fimbriae # Transfer of transformed serous Fallopian tube secretory epithelium into the peritoneum of severe combined immunodeficiency (SCID) mice induced tumours which resemble human HGSC. # Reliable HGSC precursors were found on the Fallopian tubes in the form of abnormal TP53 expression patterns. # Serous fimbrial cells are less able to correct DNA damage and reverse mutations than their ciliated counterparts, indicating how they might be particularly vulnerable to the mutagenicity of the follicular fluid at ovulation. Opposing: # A 2013 study shows that STICs only advance to form HGSC in the presence of a BRCA mutation, remaining uninvasive in models without such mutations – suggesting that HGSCs may arise from Fallopian tube tissue in individuals with BRCA mutations, but not generally. Extra-uterine Müllerian epithelium (EUME) All epithelia of the female genital tract – Fallopian tubes, endometrium, endocervix, ectocervix, upper vagina - are derived from the embryonal Müllerian ducts. Extra-uterine Müllerian epithelium includes the distal end of the Fallopian tubes (the fimbriae), and instances of endosalpingiosis, endometriosis and endocervicosis. Supporting: #<unk><unk>  serous extra-uterine<unk> s have been reported. # Intraovarian Müllerian cysts can be explained as examples of endosalpingiosis within the ovary, rather than as results of Müllerian metaplasia in pre-existing cortical inclusion cysts as per the coelomic hypothesis. # This hypothesis can also account for primary peritoneal<unk> s, as EUME can be found far away enough from the ovary and fimbriae to give rise to tumors without input from those organs. # The extensiveness of EUME can also explain the presence of paratubal and paraovarian tumours. # Endosalpingiosis - a condition where Fallopian tube epithelium is found outside the Fallopian tube - supports the likelihood of HGSC arising in the wider peritoneum. # Endosalpingiosis is associated with<unk>  incidence of borderline serous<unk>  (38%) and HGSC (18%). # A central role of EUME in HGS carcinogenesis would account for cases of HGSC that do not involve precursor STICs. Opposing: # This is a relatively new hypothesis and requires further research using appropriate models before conclusions can be drawn. Border between ovary and Fallopian tube (transition zone) Supporting: # Transition zones in other epithelia are frequent sites of stem cells. # Such an epithelial transition zone may have more ambiguous stem cell fate signalling, and thus may be vulnerable to carcinogenesis. # A number of epithelial transition zones, e.g. ectocervix junction, gastro-duodenal junction, are implicated in the development of different epithelial cancers. Opposing: # This is a relatively new hypothesis and requires further research using appropriate models before conclusions can be drawn. The common Müllerian origin of the Fallopian tubes, uterus, cervix, and upper vagina has resulted in the proposal that peritoneal<unk>  is a spectrum of a single disease. Relevant animal models of HGSC can only be developed when the cell origin is properly understood. However, as HGSC tends to have the same clinical behaviour, regardless of its primary cell origin, determining cell origin is less important for clinical treatment, but may be of relevance when looking for biomarkers. The specific process by which a HGSC arises may be related to the BRCA mutation status of the individual, as well as the p53 mutation status. A 2007 paper describes the process of determining cell of origin as “Tumour origin is typically assigned to the organ presenting with the dominant tumour mass. The one exception is the peritoneum, which is classified as a primary site only if a candidate origin is not found in the endometrium, tube or ovary”. It is recognised that HGSC can have variable and complex primary origins, but understanding and determining this will give insight into its pathogenesis. Diagram of HGSC theories of origin Pathogenesis Assuming a fimbrial origin, as observed in the majority of HGSC cases, the current understanding of HGSC genesis suggests a process by which STIC fimbrial cells implant into the ovary as cortical inclusion cysts through the ovulation rupture site. To account for instances where there is no STIC involvement, endosalpingiosis or de novo metaplasia of ovarian surface epithelium inclusions are also possible. A much rarer occurrence is the differentiation of HGSC from LGSC.
High-grade serous carcinoma
Endometrial stromal sarcoma
Adenomyomatosis
Uterine clear-cell carcinoma
Endometrial stromal tumour
Tubular carcinoma
Uterine serous carcinoma
Papillary serous cystadenocarcinoma