C Blake Gilks

University of British Columbia - Vancouver, Vancouver, British Columbia, Canada

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Publications (217)1205.6 Total impact

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    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.
    Oncotarget 10/2015; DOI:10.18632/oncotarget.5438 · 6.36 Impact Factor
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    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).
    The American journal of surgical pathology 10/2015; DOI:10.1097/PAS.0000000000000536 · 5.15 Impact Factor
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    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. Conclusions: 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.
    Histopathology 09/2015; DOI:10.1111/his.12878 · 3.45 Impact Factor
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    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.
    The Journal of Pathology 09/2015; DOI:10.1002/path.4633 · 7.43 Impact Factor
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    ABSTRACT: Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3,194 cases and 7,060 controls) and a large ovarian cancer dataset genotyped on the customised iCOGS arrays (10,065 cases and 21,663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI=0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI=0.07-0.89 and 0.40, 95% CI=0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI=0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Molecular Genetics 07/2015; 24(20). DOI:10.1093/hmg/ddv306 · 6.39 Impact Factor
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    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/.
    Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 07/2015; DOI:10.1097/PAI.0000000000000249 · 2.01 Impact Factor
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    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.
    International Journal of Gynecological Cancer 07/2015; 25(7). DOI:10.1097/IGC.0000000000000492 · 1.95 Impact Factor
  • Raeda Al-Bannai · Dianne Miller · Leslie Sadownik · C. Blake Gilks ·
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    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
    International Journal of Gynecological Pathology 07/2015; 34(4). DOI:10.1097/PGP.0000000000000182 · 1.67 Impact Factor
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    ABSTRACT: To develop and validate a histopathologic scoring system for measuring response to neoadjuvant chemotherapy in interval debulking surgery specimens of stage IIIC to IV tubo-ovarian high-grade serous carcinoma. A six-tier histopathologic scoring system was proposed and applied to a test cohort (TC) of 62 patients treated with neoadjuvant chemotherapy and interval debulking surgery. Adnexal and omental sections were independently scored by three pathologists. On the basis of TC results, a three-tier chemotherapy response score (CRS) system was developed and applied to an independent validation cohort of 71 patients. The initial system showed moderate interobserver reproducibility and prognostic stratification of TC patients when applied to the omentum but not to the adnexa. Condensed to a three-tier score, the system was highly reproducible (kappa, 0.75). When adjusted for age, stage, and debulking status, the score predicted progression-free survival (PFS; score 2 v 3; median PFS, 11.3 v 32.1 months; adjusted hazard ratio, 6.13; 95% CI, 2.13 to 17.68; P < .001). The three-tier CRS system applied to omental samples from the validation cohort showed high reproducibility (kappa, 0.67) and predicted PFS (CRS 1 and 2 v 3: median, 12 v 18 months; adjusted hazard ratio, 3.60; 95% CI, 1.69 to 7.66; P < .001). CRS 3 also predicted sensitivity to first-line platinum therapy (94.3% negative predictive value for progression < 6 months). A Web site was established to train pathologists to use the CRS system. The CRS system is reproducible and shows prognostic significance for high-grade serous carcinoma. Implementation in international pathology reporting has been proposed by the International Collaboration on Cancer Reporting, and the system could potentially have an impact on patient care and research. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 06/2015; 33(22). DOI:10.1200/JCO.2014.60.5212 · 18.43 Impact Factor
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    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.
    Pathology 06/2015; 47(5). DOI:10.1097/PAT.0000000000000291 · 2.19 Impact Factor
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    ABSTRACT: A comprehensive pathological report is essential for optimal patient management, cancer staging and prognostication. In many countries, proforma reports are used but these vary in their content. The International Collaboration on Cancer Reporting (ICCR) is an alliance formed by the Royal College of Pathologists of Australasia, the Royal College of Pathologists of the United Kingdom, the College of American Pathologists, the Canadian Partnership Against Cancer and the European Society of Pathology, with the aim of developing an evidence-based reporting data set for each cancer site. This will reduce the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish and maintain standardised cancer reporting data sets. The resultant standardisation of cancer reporting will benefit not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets. We describe the development of a cancer data set by the ICCR expert panel for the reporting of primary ovarian, fallopian tube and peritoneal carcinoma and present the 'required' and 'recommended' elements to be included in the report with an explanatory commentary. This data set encompasses the recent International Federation of Obstetricians and Gynaecologists staging system for these neoplasms and the updated World Health Organisation Classification of Tumours of the Female Reproductive Organs. The data set also addresses issues about site assignment of the primary tumour in high-grade serous carcinomas and proposes a scoring system for the assessment of tumour response to neoadjuvant chemotherapy. The widespread implementation of this data set will facilitate consistent and accurate data collection, comparison of epidemiological and pathological parameters between different populations, facilitate research and hopefully will result in improved patient management.
    Modern Pathology 06/2015; 28(8). DOI:10.1038/modpathol.2015.77 · 6.19 Impact Factor
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    ABSTRACT: Growing insights into the biological features and molecular underpinnings of ovarian cancer has prompted a shift toward histotype-specific treatments and clinical trials. As a result, the preoperative diagnosis of ovarian carcinomas based on small tissue sampling is rapidly gaining importance. The data on the accuracy of ovarian carcinoma histotype-specific diagnosis based on small tissue samples, however, remains very limited in the literature. Herein, we describe a prospective series of 30 ovarian tumors diagnosed using cytology, frozen section, core needle biopsy, and immunohistochemistry (p53, p16, WT1, HNF-1β, ARID1A, TFF3, vimentin, and PR). The accuracy of histotype diagnosis using each of these modalities was 52%, 81%, 85%, and 84% respectively, using the final pathology report as the reference standard. The accuracy of histotype diagnosis using the Calculator for Ovarian Subtype Prediction (COSP), which evaluates immunohistochemical stains independent of histopathologic features, was 85%. Diagnostic accuracy varied across histotype and was lowest for endometrioid carcinoma across all diagnostic modalities (54%). High-grade serous carcinomas were the most overdiagnosed on core needle biopsy (accounting for 45% of misdiagnoses) and clear cell carcinomas the most overdiagnosed on frozen section (accounting for 36% of misdiagnoses). On core needle biopsy, 2/30 (7%) cases had a higher grade lesion missed due to sampling limitations. In this study, we identify several challenges in the diagnosis of ovarian tumors based on limited tissue sampling. Recognition of these scenarios can help improve diagnostic accuracy as we move forward with histotype-specific therapeutic strategies.
    International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 06/2015; 34(6). DOI:10.1097/PGP.0000000000000199 · 1.67 Impact Factor
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    ABSTRACT: Epithelial ovarian cancer (EOC) consists of 5 major histotypes: high-grade serous carcinoma (HGSC), endometrioid carcinoma (EC), clear cell carcinoma (CCC), mucinous carcinoma (MC), and low-grade serous carcinoma (LGSC). Each can have a broad spectrum of morphologic appearances, and 1 histotype can closely mimic histopathologic features more typical of another. Historically, there has been a relatively high frequency of mixed, defined by 2 or more distinct histotypes present on the basis of routine histopathologic assessment, histotype carcinoma diagnoses (3% to 11%); however, recent immunohistochemical (IHC) studies identifying histotype-specific markers and allowing more refined histotype diagnoses suggest a much lower incidence. We reviewed hematoxylin and eosin-stained slides from 871 cases of EOC and found the frequency of mixed carcinomas to be 1.7% when modern diagnostic criteria are applied. Through international collaboration, we established a cohort totaling 22 mixed EOCs, consisting of 9 EC/CCC, 4 EC/LGSC, 3 HGSC/CCC, 2 CCC/MC, and 4 other combinations. We interrogated the molecular differences between the different components of each case using IHC, gene expression, and hotspot sequencing analyses. IHC data alone suggested that 9 of the 22 cases were not mixed tumors, as they presented a uniform immuno-phenotype throughout, and these cases most probably represent morphologic mimicry and variation within tumors of a single histotype. Synthesis of molecular data further reduces the incidence of mixed carcinomas. On the basis of these results, true mixed carcinomas with both morphologic and molecular support for the presence of >1 histotype within a given tumor represent <1% of EOCs.
    The American journal of surgical pathology 05/2015; 39(11). DOI:10.1097/PAS.0000000000000476 · 5.15 Impact Factor
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    ABSTRACT: Endometrial cancer (EC) is the most common gynecologic malignancy with known risk factors including excess estrogen and hereditary syndromes. The objective of this study was to determine the proportion of young women with EC that could be attributed to these factors and if, as we suspected, there is a third population of young women in which neither factor is identifiable. We were interested in comparing clinicopathologic characteristics and outcomes across subgroups in order to better inform treatment recommendations. We performed a retrospective chart review of women age 15-49 diagnosed with EC or complex atypical hyperplasia. Demographic, clinicopathologic, treatment, fertility, and outcome parameters were analyzed. Of 719 women identified, 327 were fully evaluable. 57.5% fit the "High Estrogen" risk criteria. 8.25% met criteria for suspected Lynch syndrome. 34.25% classified as "Neither" had no classical risk factors identified. There were no statistical differences in age, gravidity, tumor grade, treatment selection and response to hormonal therapy. Age of menarche, stage, histology, and synchronous ovarian cancer differed significantly. Prevalence of synchronous ovarian cancer was 21.0% of "Neither", 23.1% of "Lynch", and 6.6% of "High Estrogen". For women who attempted pregnancy, 2/27 of "High Estrogen", 0/3 of "Lynch", and 2/16 of "Neither" achieved a live birth. This study confirmed that a third population of young women with EC exist that lack classical risk factors and have distinct clinicopathologic parameters. No difference in success of conservative treatment or live births was noted in the small cohort in whom this treatment approach was attempted. Copyright © 2015. Published by Elsevier Inc.
    Gynecologic Oncology 04/2015; 138(1). DOI:10.1016/j.ygyno.2015.02.028 · 3.77 Impact Factor
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    ABSTRACT: •Conventional definitions of STIC do not capture all lesions associated with serous neoplasia and the presence of abnormal p53 expression may be helpful diagnostically.•The management of STICs and tubal atypias remain uncertain.•The POINT Project is a registry set up to address this critical gap in knowledge.
    03/2015; 35. DOI:10.1016/j.gore.2015.03.007
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    ABSTRACT: Most nonuterine high-grade serous carcinomas (HGSCs) in women with hereditary breast and ovarian cancer syndrome, due to germline BRCA1/2 mutation, arise in the fimbria of the fallopian tube. However, the site of origin of sporadic HGSC, which is usually widely disseminated at presentation, is not well established. We sought to characterize cases of HGSC discovered incidentally in patients not known to be at high risk, in order to determine the site distribution and possible origin of sporadic HGSC. Incidental microscopic, non-mass-forming cases of serous tubal intraepithelial carcinoma or HGSC in salpingo-oophorectomy specimens in which the tubes and ovaries had been extensively examined were identified. No patients were known or suspected BRCA1/2 mutation carriers. Twenty-one cases were identified (mean age: 57 y). Surgery was for benign disease (n = 15), uterine endometrioid adenocarcinoma or atypical hyperplasia (n = 3), bladder carcinoma (n = 1), or ovarian serous borderline tumor (n = 2). In 16 of 21 cases, the lesion was confined to the fallopian tube (unilateral in 14 cases, bilateral in 2). There was serous tubal intraepithelial carcinoma in all cases and invasive HGSC into the underlying lamina propria in 8 of these 16 cases; the invasive focus measured 1.3 cm or less in every case. In the remaining 5 cases, there was fallopian tube mucosal and ovarian involvement; in 2 of these cases, there was also microscopic peritoneal involvement. Sporadic cases of nonuterine HGSC arise in the fallopian tube fimbria in a large majority of cases, providing further evidence for the tubal origin of these neoplasms.
    American Journal of Surgical Pathology 03/2015; 39(3):357-364. · 5.15 Impact Factor
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    ABSTRACT: AimsEvidence indicates that most non-uterine high-grade serous carcinomas (HGSC) arise from the fallopian tube, but approaches to primary site assignment have not evolved to reflect this. This study aimed to assess application of recently proposed criteria for site assignment.Methods and Results151 HGSCs from four centres were reviewed retrospectively. 63/80 (79%) chemo-naïve (CN) and 45/71 (68%) post-neoadjuvant chemotherapy (NACT) cases were assigned as fallopian tube (FT) primaries with the new criteria, while 58/80 (73%) and 45/71 (63%) were considered ovarian primaries using traditional criteria (p<0.0001). In 111 prospectively collected HGSC's, with consistent detailed fimbrial examination, 44/53 (83%) CN and 44/58 (76%) NACT cases were assigned as FT primaries. Reproducibility of site assignment was tested in a subset of 50 cases: 4/4 reviewing pathologists agreed on primary site in 48/50 (96%), and 3/4 in 49/50 (98%) cases. Of the 53 prospectively studied CN cases, bilateral ovarian involvement (62%) was significantly more frequent than bilateral tubal involvement (12%, p<0.0001), further supporting tubal origin and ovarian metastasis in most cases.Conclusions With currently accepted protocols, the proposed guidelines are easy to apply and result in consistent site assignment in non-uterine HGSC. Most cases of non-uterine HGSC were considered primary FT neoplasms.This article is protected by copyright. All rights reserved.
    Histopathology 01/2015; 67(3). DOI:10.1111/his.12651 · 3.45 Impact Factor
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    ABSTRACT: Uterine tumors resembling ovarian sex cord tumors (UTROSCTs) are rare uterine neoplasms characterized by pure or predominant epithelial-like patterns that share morphologic, immunohistochemical, and ultrastructural features with ovarian sex cord tumors. FOXL2 immunoexpression has recently been found in sex cord stromal tumors of the ovary, including granulosa cell tumors, Sertoli-Leydig cell tumors, thecomas, and fibromas, but mutations have been identified mostly in adult granulosa cell tumors. In this study, we investigated FOXL2 mutation status and protein expression in UTROSCTs. Mutational analysis using a TaqMan real-time polymerase chain reaction-based allelic discrimination assay was performed on formalin-fixed, paraffin-embedded tissue from 15 UTROSCTs. FOXL2 mutation was absent in all tumors. FOXL2 immunoexpression was tested in all 15 tumors. Intensity of staining was scored as weak, moderate, or strong. Percentage of tumor cells with nuclear staining was recorded as follows: 0 (negative); 1+ (1% to 25%); 2+ (26% to 50%); 3+ (51% to 75%); and 4+ (76% to 100%). Nuclear expression of FOXL2 was present in 6 of 15 (40%) UTROSCTs. One tumor demonstrated strong 4+ staining. Moderate expression was seen in 3 cases, including 2 and 1 showing 2+ and 1+ staining, respectively. Weak expression was observed in 2 tumors demonstrating 3+ and 1+ staining. Although UTROSCTs show overlapping morphologic, immunohistochemical, and ultrastructural features with sex cord stromal tumors of the ovary, they do not harbor FOXL2 mutation despite focal immunoreactivity in a subset of these tumors.
    American Journal of Surgical Pathology 01/2015; 39(5). DOI:10.1097/PAS.0000000000000367 · 5.15 Impact Factor
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    ABSTRACT: To conduct a cost-effectiveness analysis of opportunistic salpingectomy (elective salpingectomy at hysterectomy or instead of tubal ligation). A Markov Monte Carlo simulation model estimated the costs and benefits of opportunistic salpingectomy in a hypothetical cohort of women undergoing hysterectomy for benign gynecologic conditions or surgical sterilization. The primary outcome measure was the incremental cost-effectiveness ratio. Effectiveness was measured in terms of life expectancy gain. Sensitivity analyses accounted for uncertainty around various parameters. Monte Carlo simulation estimated the number of ovarian cancer cases associated with each strategy in the Canadian population. Salpingectomy with hysterectomy was less costly ($11,044.32±$1.56) than hysterectomy alone ($11,206.52±$29.81) or with bilateral salpingo-oophorectomy ($12,626.84±$13.11) but more effective at 21.12±0.02 years compared with 21.10±0.03 and 20.94±0.03 years, representing average gains of 1 week and 2 months, respectively. For surgical sterilization, salpingectomy was more costly ($9,719.52±$3.74) than tubal ligation ($9,339.48±$26.74) but more effective at 22.45±0.02 years compared with 22.43±0.02 years (average gain of 1 week) with an incremental cost-effectiveness ratio of $27,278 per year of life gained. Our results were stable over a wide range of costs and risk estimates. Monte Carlo simulation predicted that salpingectomy would reduce ovarian cancer risk by 38.1% (95% confidence interval [CI] 36.5-41.3%) and 29.2% (95% CI 28.0-31.4%) compared with hysterectomy alone or tubal ligation, respectively. Salpingectomy with hysterectomy for benign conditions will reduce ovarian cancer risk at acceptable cost and is a cost-effective alternative to tubal ligation for sterilization. Opportunistic salpingectomy should be considered for all women undergoing these surgical procedures.
    Obstetrics and Gynecology 01/2015; 70(5). DOI:10.1097/AOG.0000000000000630 · 5.18 Impact Factor
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    ABSTRACT: Sprouty (SPRY) proteins are well-characterized factors that inhibit receptor tyrosine kinase signaling. Our Human Exonic Evidence-Based Oligonucleotide (HEEBO) microarray results showed that the mRNA levels of SPRY2, but not of SPRY1 or SPRY4, are down-regulated in high-grade serous ovarian carcinoma (HGSC) tissues and epithelial ovarian cancer (EOC) cell lines. Molecular inversion probe (MIP) copy number analysis showed the deletion of the SPRY2 locus in HGSC. Overexpression of SPRY2 reduced EGF-induced cell invasion by attenuating EGF-induced E-cadherin down-regulation. Moreover, a positive correlation between SPRY2 and E-cadherin protein levels was observed in HGSC tissues. This study reveals the loss of SPRY2 in HGSC and indicates an important tumor-suppressive role for SPRY2 in mediating the stimulatory effect of EGF on human EOC progression. Copyright © 2014. Published by Elsevier B.V.
    FEBS Letters 12/2014; 589(3). DOI:10.1016/j.febslet.2014.12.012 · 3.17 Impact Factor

Publication Stats

9k Citations
1,205.60 Total Impact Points


  • 1994-2015
    • University of British Columbia - Vancouver
      • • Department of Pathology and Laboratory Medicine
      • • Genetic Pathology Evaluation Center (GPEC)
      Vancouver, British Columbia, Canada
  • 1989-2015
    • Vancouver General Hospital
      • Department of Pathology and Laboratory Medicine (UBC)
      Vancouver, British Columbia, Canada
  • 2011
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
    • The University of Calgary
      • Department of Pathology and Laboratory Medicine
      Calgary, Alberta, Canada
  • 2008-2011
    • Vancouver Coastal Health
      Vancouver, British Columbia, Canada
    • BC Cancer Agency
      Vancouver, British Columbia, Canada
  • 2002-2011
    • Stanford University
      • • Department of Biochemistry
      • • Department of Pathology
      Stanford, California, United States
  • 2004
    • Stanford Medicine
      Stanford, California, United States
  • 2003
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States