[Show abstract][Hide abstract] ABSTRACT: Background: Overexpression of the transmembrane sialomucin podocalyxin, which is known to play a role in lumen formation during polarized epithelial morphogenesis, is an independent indicator of poor prognosis in a number of epithelial cancers, including those that arise in the breast. Therefore, we set out to determine if podocalyxin plays a functional role in breast tumor progression. Methods: MCF-7 breast cancer cells, which express little endogenous podocalyxin, were stably transfected with wild type podocalyxin for forced overexpression. 4T1 mammary tumor cells, which express considerable endogenous podocalyxin, were retrovirally transduced with a short hairpin ribonucleic acid (shRNA) targeting podocalyxin for stable knockdown. In vitro, the effects of podocalyxin on collective cellular migration and invasion were assessed in two-dimensional monolayer and three-dimensional basement membrane/collagen gel culture, respectively. In vivo, local invasion was assessed after orthotopic transplantation in immunocompromised mice. Results: Forced overexpression of podocalyxin caused cohesive clusters of epithelial MCF-7 breast tumor cells to bud off from the primary tumor and collectively invade the stroma of the mouse mammary gland in vivo. This budding was not associated with any obvious changes in histoarchitecture, matrix deposition or proliferation in the primary tumour. In vitro, podocalyxin overexpression induced a collective migration of MCF-7 tumor cells in two-dimensional (2-D) monolayer culture that was dependent on the activity of the actin scaffolding protein ezrin, a cytoplasmic binding partner of podocalyxin. In three-dimensional (3-D) culture, podocalyxin overexpression induced a collective budding and invasion that was dependent on actomyosin contractility. Interestingly, the collectively invasive cell aggregates often contained expanded microlumens that were also observed in vivo. Conversely, when endogenous podocalyxin was removed from highly metastatic, but cohesive, 4T1 mammary tumor cells there was a decrease in collective invasion in three-dimensional culture. Conclusions: Podocalyxin is a tumor cell-intrinsic regulator of experimental collective tumor cell invasion and tumor budding.
Preview · Article · Dec 2016 · Breast cancer research: BCR
[Show abstract][Hide abstract] ABSTRACT: The estrogen receptor (ER) is a key predictive biomarker in the treatment of breast cancer. There is uncertainty regarding the use of hormonal therapy in the setting of weakly positive ER by immunohistochemistry (IHC). We report intrinsic subtype classification on a cohort of ER weakly positive early-stage breast cancers. Consecutive cases of breast cancer treated by primary surgical resection were retrospectively identified from 4 centers that engage in routine external proficiency testing for breast biomarkers. ER-negative (Allred 0 and 2) and ER weakly positive (Allred 3-5) cases were included. Gene expression profiling was performed using qRT-PCR. Intrinsic subtype prediction was made based upon the PAM50 gene expression signature. 148 cases were included in the series: 60 cases originally diagnosed as ER weakly positive and 88 ER negative. Of the cases originally assessed as ER weakly positive, only 6 (10 %) were confirmed to be of luminal subtype by gene expression profiling; the remaining 90 % of cases were classified as basal-like or HER2-enriched subtypes. This was not significantly different than the fraction of luminal cases identified in the IHC ER-negative cohort (5 (5 %) luminal, 83(95 %) non-luminal). Recurrence-free, and overall, survival rates were similar in both groups (p = 0.4 and 0.5, respectively) despite adjuvant hormonal therapy prescribed in the majority (59 %) of weakly positive ER cases. Weak ER expression by IHC is a poor correlate of luminal subtype in invasive breast cancer. In the setting of highly sensitive and robust IHC methodology, cutoffs for ER status determination and subsequent systemic therapy should be revisited.
No preview · Article · Feb 2016 · Breast Cancer Research and Treatment
[Show abstract][Hide abstract] ABSTRACT: Rare cancers, as a collective, account for around a quarter of all cancer diagnoses and deaths. Historically, they have been divided into two groups: cancers defined by their unusual histogenesis (cell of origin or differentiation state)—including chordomas or adult granulosa cell tumours—and histologically defined subtypes of common cancers. Most tumour types in the first group are still clinically and biologically relevant, and have been disproportionately important as sources of insight into cancer biology. By contrast, most of those in the second group have been shown to have neither defining molecular features nor clinical utility. Omics-based analyses have splintered common cancers into a myriad of molecularly, rather than histologically, defined subsets of common cancers, many of which have immediate clinical relevance. Now, almost all rare cancers are either histomolecular entities, which often have pathognomonic mutations, or molecularly defined subsets of more common cancers. The presence of specific genetic variants provides rationale for the testing of targeted drugs in rare cancers. However, in addition to molecular alterations, it is crucial to consider the contributions of both mutation and cell context in the development, biology, and behaviour of these cancers. Patients with rare cancers are disadvantaged because of the challenge of leading clinical trials in this setting due to poor accrual. However, the number of patients with rare cancers will only increase as more molecular subsets of common cancers are identified, necessitating a shift in the focus of clinical trials and research into these cancer types, which, by epidemiological definitions, will become rare tumours.
No preview · Article · Feb 2016 · The Lancet Oncology
[Show abstract][Hide abstract] ABSTRACT: Objectives:
The natural history and optimal management of serous tubal intraepithelial carcinoma (STIC), regardless of BRCA status, is unknown. We report the follow-up findings of a series of incidental fallopian tube high-grade serous carcinomas (HGSCs) and STICs identified in women at low risk for hereditary breast and ovarian cancer (HBOC), undergoing surgery for other indications.
Materials and methods:
Cases of incidental STIC and HGSC were identified from 2008. Patients with known BRCA1 or BRCA2 mutations, or a family history of ovarian or breast cancer before the diagnosis of STIC or HGSC were excluded. A retrospective chart review was conducted to obtain clinical data.
Eighteen cases were identified with a median follow-up of 25 months (range, 4-88 months). Twelve of 18 patients had a diagnosis of STIC with no associated invasive HGSC and 6 had STIC associated with other invasive malignancies. Completion staging surgery was performed on 7 of the 18 patients, including 5 of 12 in which there was STIC only identified on primary surgery; 3 cases were upstaged from STIC only to HGSC based on the staging surgery. Recurrence of HGSC occurred in 2 of the 18 patients. BRCA testing was performed on 3 patients, 1 of whom tested positive for a pathogenic BRCA1 mutation.
Our study suggests that completion staging surgery for incidental STICs in non-BRCA patients may be considered. These patients should be offered hereditary testing. The Pelvic-Ovarian cancer INTerception (POINT) Project is an international registry set up to add to our understanding of STICs.
No preview · Article · Jan 2016 · International Journal of Gynecological Cancer
[Show abstract][Hide abstract] ABSTRACT: Dedifferentiated endometrial carcinoma is an aggressive type of endometrial cancer that contains a mix of low-grade endometrioid and undifferentiated carcinoma components. We performed targeted sequencing of eight dedifferentiated carcinomas and identified somatic frameshift/nonsense mutations in SMARCA4, a core ATPase of the switch/sucrose non-fermenting (SWI/SNF) complex, in the undifferentiated components of four tumors. Immunohistochemical analysis confirmed the loss of SMARCA4 in the undifferentiated component of these four SMARCA4-mutated cases, whereas the corresponding low-grade endometrioid component showed retained SMARCA4 expression. An expanded survey of other members of the SWI/SNF complex showed SMARCB1 loss in the undifferentiated component of two SMARCA4-intact tumors, and all SMARCA4- or SMARCB1-deficient tumors showed concomitant loss of expression of SMARCA2. We subsequently examined the expression of SMARCA2, SMARCA4, and SMARCB1 in an additional set of 22 centrally reviewed dedifferentiated carcinomas and 31 grade 3 endometrioid carcinomas. Combining the results from the index and the expansion set, 15 of 30 (50%) of the dedifferentiated carcinomas examined showed either concurrent SMARCA4 and SMARCA2 loss (37%) or concurrent SMARCB1 and SMARCA2 loss (13%) in the undifferentiated component. The loss of SMARCA4 or SMARCB1 was mutually exclusive. All 31 grade 3 endometrioid carcinomas showed intact expression of these core SWI/SNF proteins. The majority (73%) of the SMARCA4/SMARCA2-deficient and half of SMARCB1/SMARCA2-deficient undifferentiated component developed in a mismatch repair-deficient molecular context. The observed spatial association between SWI/SNF protein loss and histologic dedifferentiation suggests that inactivation of these core SWI/SNF proteins may contribute to the development of dedifferentiated endometrial carcinoma.Modern Pathology advance online publication, 8 January 2016; doi:10.1038/modpathol.2015.155.
No preview · Article · Jan 2016 · Modern Pathology
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to compare morphologic assessment and p16 immunohistochemistry (IHC) in the determination of human papilloma virus (HPV) status in vulvar squamous cell carcinoma (VSCC). A total of 201 invasive VSCC cases were classified as “HPV-associated” when warty/basaloid VSCC or high-grade squamous intraepithelial lesion (vulvar intraepithelial neoplasia 2/3) was observed, or “HPV-independent” in the presence of well-differentiated keratinizing invasive SCC or differentiated vulvar intraepithelial neoplasia. For p16 IHC, strong nuclear and cytoplasmic staining of all cells in at least the lowermost third of the epithelium was scored as positive. All cases with discrepant HPV predictions by hematoxylin and eosin morphology versus p16 IHC were further analyzed by polymerase chain reaction for HPV DNA. On the basis of hematoxylin and eosin morphologic assessment, 50/201 tumors showed features suggestive of HPV-associated, and 47 of those showed p16 immunoreactivity (94% concordance). Of the 146 cases considered HPV-independent based on hematoxylin and eosin, 115 (79%) showed negative p16 immunostaining. Thus 83% (162/196) concordance between morphologic assessment and p16 IHC was observed, overall. In 34 cases, where morphologic assessment and p16 IHC did not agree, HPV polymerase chain reaction agreed with p16 IHC in 32/34 (94%). The sensitivity and specificity of p16 IHC in classification of VSCC as HPV-independent or HPV-associated was 100% and 98.4%, respectively. Morphologic assessment and p16 IHC are concordant in classifying VSCC as HPV-independent or HPV-associated in a majority of cases (83%). Most of the discrepant cases are p16-positive well-differentiated keratinizing VSCC, and HPV polymerase chain reaction supports classification of a large majority of these (94%) as HPV-associated. p16 IHC is validated as an accurate surrogate marker for determination of HPV status in VSCC.
No preview · Article · Dec 2015 · International Journal of Gynecological Pathology
[Show abstract][Hide abstract] ABSTRACT: The Canadian Immunohistochemistry Quality Control provides proficiency testing for immunohistochemistry in Canadian laboratories. Canadian Immunohistochemistry Quality Control Run 42 assessed WT1, Napsin A, and p53; commonly used markers for histotyping ovarian carcinomas. A 42-core tissue microarray, which included the 5 major histotypes of ovarian carcinomas with a subset having known TP53 mutational status, was used for this Canadian Immunohistochemistry Quality Control challenge. Participants included 43 laboratories for p53, 29 for WT1, and 26 for Napsin A. p53 was scored as aberrant if the staining was strong and diffuse or absent. Napsin A and WT1 were scored positive if any tumor cells stained. The reference p53 expression pattern was inferred by TP53 mutation type when available. For WT1, Napsin A, and cases lacking mutational data, the reference staining pattern was based on the majority staining result. The error rate for p53 was 8.8%. Most errors (84%) were due to weak staining. The sensitivity and specificity of aberrant p53 expression for an underlying TP53 mutation was 91.6% and 87.9%, respectively. The error rate for WT1 was 0.76% with all errors occurring in laboratories using the 6F-h2 clone. The average errors for laboratories using 6F-h2 were 2.4 compared with 0 for WT-49. The error rate for Napsin A was 4%. The average errors for laboratories using polyclonal Napsin A were 3 compared with 1.1 for monoclonal Napsin A. Weak p53 staining increases interpretative errors, primarily due to absence of staining in tumors with wild-type TP53. p53 immunohistochemistry correlates strongly with TP53 mutational status. Polyclonal Napsin A and 6F-h2 may lack specificity in comparison to monoclonal Napsin A and WT-49. (C)2015International Society of Gynecological Pathologists
No preview · Article · Nov 2015 · International Journal of Gynecological Pathology
[Show abstract][Hide abstract] ABSTRACT: Low grade serous ovarian tumours are a rare and under-characterised histological subtype of epithelial ovarian tumours, with little known of the molecular drivers and facilitators of tumorigenesis beyond classic oncogenic RAS/RAF mutations. With a move towards targeted therapies due to the chemoresistant nature of this subtype, it is pertinent to more fully characterise the genetic events driving this tumour type, some of which may influence response to therapy and/or development of drug resistance. We performed genome-wide high-resolution genomic copy number analysis (Affymetrix SNP6.0) and mutation hotspot screening (KRAS, BRAF, NRAS, HRAS, ERBB2 and TP53) to compare a large cohort of ovarian serous borderline tumours (SBTs, n = 57) with low grade serous carcinomas (LGSCs, n = 19). Whole exome sequencing was performed for 13 SBTs, nine LGSCs and one mixed low/high grade carcinoma. Copy number aberrations were detected in 61% (35/57) of SBTs, compared to 100% (19/19) of LGSCs. Oncogenic RAS/RAF/ERBB2 mutations were detected in 82.5% (47/57) of SBTs compared to 63% (12/19) of LGSCs, with NRAS mutations detected only in LGSC. Some copy number aberrations appeared to be enriched in LGSC, most significantly loss of 9p and homozygous deletions of the CDKN2A/2B locus. Exome sequencing identified BRAF, KRAS, NRAS, USP9X and EIF1AX as the most frequently mutated genes. We have identified markers of progression from borderline to LGSC and novel drivers of LGSC. USP9X and EIF1AX have both been linked to regulation of mTOR, suggesting that mTOR inhibitors may be a key companion treatment for targeted therapy trials of MEK and RAF inhibitors.
[Show abstract][Hide abstract] ABSTRACT: Mixed endometrial carcinoma refers to a tumor that comprises 2 or more distinct histotypes. We studied 18 mixed-type endometrial carcinomas-11 mixed serous and low-grade endometrioid carcinomas (SC/EC), 5 mixed clear cell and low-grade ECs (CCC/EC), and 2 mixed CCC and SCs (CCC/SC), using targeted next-generation sequencing and immunohistochemistry to compare the molecular profiles of the different histotypes present in each case. In 16 of 18 cases there was molecular evidence that both components shared a clonal origin. Eight cases (6 EC/SC, 1 EC/CCC, and 1 SC/CCC) showed an SC molecular profile that was the same in both components. Five cases (3 CCC/EC and 2 SC/EC) showed a shared endometrioid molecular profile and identical mismatch-repair protein deficiency in both components. A single SC/EC case harbored the same POLE exonuclease domain mutation in both components. One SC/CCC and 1 EC/CCC case showed both shared and unique molecular features in the 2 histotype components, suggesting early molecular divergence from a common clonal origin. In 2 cases, there were no shared molecular features, and these appear to be biologically unrelated synchronous tumors. Overall, these results show that the different histologic components in mixed endometrial carcinomas typically share the same molecular aberrations. Mixed endometrial carcinomas most commonly occur through morphologic mimicry, whereby tumors with serous-type molecular profile show morphologic features of EC or CCC, or through underlying deficiency in DNA nucleotide repair, with resulting rapid accrual of mutations and intratumoral phenotypic heterogeneity. Less commonly, mixed endometrial carcinomas are the result of early molecular divergence from a common progenitor clone or are synchronous biologically unrelated tumors (collision tumors).
No preview · Article · Oct 2015 · The American journal of surgical pathology
[Show abstract][Hide abstract] ABSTRACT: Aims:
We characterized the histomorphological features of endometrial carcinomas (ECs) harboring polymerase epsilon (POLE) mutations.
Methods and results:
43 ECs with POLE mutations were compared to a cohort of 202 ECs. Most POLE mutated ECs were endometrioid (34/43 (79%); the remaining tumors were mixed 6/43 (14%), serous 2/43 (5%), clear cell 1/43 (2%). The endometrioid carcinomas were predominantly FIGO grade 3 (27/43, 63%). The histotype distribution did not differ from control ECs (p=0.69), but the grade of the EC was higher (p<0.0005). Both nuclear grade and mitotic index were significantly higher in the POLE mutated EC than in the comparison cohort. POLE mutated ECs were associated with peritumoral lymphocytes and numerous tumor infiltrating lymphocytes. Lymphovascular invasion was present in 20/43 tumors. Adjuvant radiotherapy and adjuvant chemotherapy would be offered in up to 80% and 40% of patients, respectively, based on stage, grade, lymphovascular invasion and histotype.
POLE mutated ECs are typically high grade, with prominent lymphocytic infiltration, but they are not sufficiently distinctive to allow accurate diagnosis based on routine H&E. Even though POLE mutated tumors are associated with an excellent prognosis, current guidelines for giving adjuvant treatment in EC result in most patients receiving adjuvant therapy. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of SCCOHT harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually-exclusive ATPases of the SWI/SNF chromatin remodelling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high-grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumour cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4-negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumours, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re-expression of SMARCA4 or SMARCA2 inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT, and that restoration of either SWI/SNF ATPase can inhibit the growth of SCCOHT cell lines.
No preview · Article · Sep 2015 · The Journal of Pathology
[Show abstract][Hide abstract] ABSTRACT: The Canadian Immunohistochemistry Quality Control program monitors clinical laboratory performance for estrogen receptor and progesterone receptor tests used in breast cancer treatment management in Canada. Current methods assess sensitivity and specificity at each time point, compared with a reference standard. We investigate alternative performance analysis methods to enhance the quality assessment. We used 3 methods of analysis: meta-analysis of sensitivity and specificity of each laboratory across all time points; sensitivity and specificity at each time point for each laboratory; and fitting models for repeated measurements to examine differences between laboratories adjusted by test and time point. Results show 88 laboratories participated in quality control at up to 13 time points using typically 37 to 54 histology samples. In meta-analysis across all time points no laboratories have sensitivity or specificity below 80%. Current methods, presenting sensitivity and specificity separately for each run, result in wide 95% confidence intervals, typically spanning 15% to 30%. Models of a single diagnostic outcome demonstrated that 82% to 100% of laboratories had no difference to reference standard for estrogen receptor and 75% to 100% for progesterone receptor, with the exception of 1 progesterone receptor run. Laboratories with significant differences to reference standard identified with Generalized Estimating Equation modeling also have reduced performance by meta-analysis across all time points. The Canadian Immunohistochemistry Quality Control program has a good design, and with this modeling approach has sufficient precision to measure performance at each time point and allow laboratories with a significantly lower performance to be targeted for advice.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0/.
No preview · Article · Jul 2015 · Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry
[Show abstract][Hide abstract] ABSTRACT: Background:
Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed.
Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared.
Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for 'copy-number' status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined 'high-risk' group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves.
Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.
Full-text · Article · Jul 2015 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Polymerase epsilon (POLE) is a DNA polymerase with a proofreading (exonuclease) domain, responsible for the recognition and excision of mispaired bases, thereby allowing high-fidelity DNA replication to occur. The Cancer Genome Atlas research network recently identified an ultramutated group of endometrial carcinomas, characterized by mutations in POLE, and exceptionally high substitution mutation rates. These POLE mutated endometrial tumors were almost exclusively of the endometrioid histotype. The prevalence and patterns of POLE mutated tumors in endometrioid carcinomas of the ovary, however, have not been studied in detail.
In this study, we investigate the frequency of POLE exonuclease domain mutations in a series of 89 ovarian endometrioid carcinomas.
We found POLE mutations in 4 of 89 (4.5%) cases, occurring in 3 of 23 (13%) International Federation of Gynecology and Obstetrics (FIGO) grade 1, 1 of 43 (2%) FIGO grade 2, and 0 of 23 (0%) FIGO grade 3 tumors. All mutations were somatic missense point mutations, occurring at the commonly reported hotspots, P286R and V411L. All 3 POLE-mutated FIGO grade 1 tumors displayed prototypical histology, and the POLE-mutated FIGO grade 2 tumor displayed morphologic heterogeneity with focally high-grade features. All 4 patients with POLE-mutated tumors followed an uneventful clinical course with no disease recurrence; however, this finding was not statistically significant (P = 0.59).
The low rate of POLE mutations in ovarian endometrioid carcinoma and their predominance within the low FIGO grade tumors are in contrast to the findings in the endometrium.
Full-text · Article · Jul 2015 · International Journal of Gynecological Cancer
[Show abstract][Hide abstract] ABSTRACT: Vulvar acanthosis with altered differentiation is an uncommon proliferation of the vulvar squamous epithelium that is typically seen in association with verrucous carcinoma, and may represent an early phase of non-HPV-related squamous neoplastic transformation. We report a case of vulvar acanthosis with altered differentiation that, over a 5-yr period, progressed first to verrucous carcinoma in association with well-differentiated invasive squamous cell carcinoma and then, after treatment with radiotherapy, to poorly differentiated carcinoma with a component of anaplastic carcinoma. This case supports the concept of vulvar acanthosis with altered differentiation as a premalignant lesion, with potential to progress to invasive carcinoma. (C)2015International Society of Gynecological Pathologists
No preview · Article · Jul 2015 · International Journal of Gynecological Pathology
[Show abstract][Hide abstract] ABSTRACT: It has long been held that most epithelial ovarian carcinomas arise from the ovarian surface epithelium. Theories on origin were based on the assumption that there was a common cell of origin for all ovarian carcinoma histotypes, and that these histotypes were closely related and frequently admixed. It is now recognised that the histotypes are distinct diseases. Recent studies on early, organ-confined, non-uterine high-grade serous carcinoma (HGSC) have led to a change in our understanding of their anatomical site of origin. These studies were initially on patients at high risk of developing HGSC but more recently have been extended to cases without family history or genetic markers of increased risk. These have shown that incidental HGSC, when detected before dissemination, is most commonly identified in the tubal fimbria. As a result, we have had to revisit theories on the cell and site of origin of HGSC. This progress in our understanding has necessitated a change in how we handle cases in clinical practice, as it impacts on primary site assignment, which in turn has implications for staging. In this review we will discuss the evolution of our understanding of the cell of origin of HGSC, the evidence for the tubal fimbria as the anatomical site of origin of most non-uterine HGSC, and the clinical implications of these recent developments.