Publications by authors named "Bojana Djordjevic"

56 Publications

Hot Seat Diagnosis: Competency-Based Tool Is Superior to Time-Based Tool for the Formative In-Service Assessment of Pathology Trainees.

Arch Pathol Lab Med 2021 Jun 16. Epub 2021 Jun 16.

From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (Han, Keith, Slodkowska, Nofech-Mozes, Djordjevic, Shachar, Mirkovic, Sherman, Lu).

Context.—: Competency-based medical education relies on frequent formative in-service assessments to ascertain trainee progression. Currently at our institution, trainees receive a summative end-of-rotation In-Training Evaluation Report based on feedback collected from staff pathologists. There is no method of simulating report sign-out.

Objective.—: To develop a formative in-service assessment tool that is able to simulate report sign-out and provide case-by-case feedback to trainees. Further, to compare time- versus competency-based assessment models.

Design.—: Twenty-one pathology trainees were assessed for 20 months. Hot Seat Diagnosis by trainees and trainee assessment by pathologists were recorded in the Laboratory Information System. In the first iteration, trainees were assessed by using a time-based assessment scale on their ability to diagnose, report, use ancillary testings, comment on clinical implications, provide intraoperative consultation and/or gross cases. The second iteration used a competency-based assessment scale. Trainees and pathologists completed surveys on the effectiveness of the In-Training Evaluation Report versus the Hot Seat Diagnosis tool.

Results.—: Scores from both iterations correlated significantly with other assessment tools including the Resident In-Service Examination (r = 0.93, P = .04 and r = 0.87, P = .03). The competency-based model was better able to demonstrate improvement over time and stratify junior versus senior trainees than the time-based model. Trainees and pathologists rated Hot Seat Diagnosis as significantly more objective, detailed, and timely than the In-Training Evaluation Report, and effective at simulating report sign-out.

Conclusions.—: Hot Seat Diagnosis is an effective tool for the formative in-service assessment of pathology trainees and simulation of report sign-out, with the competency-based model outperforming the time-based model.
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http://dx.doi.org/10.5858/arpa.2020-0702-EPDOI Listing
June 2021

Maximizing cancer prevention through genetic navigation for Lynch syndrome detection in women with newly diagnosed endometrial and nonserous/nonmucinous epithelial ovarian cancer.

Cancer 2021 May 13. Epub 2021 May 13.

Division of Gynecologic Oncology, Princess Margaret Cancer Centre/University Health Network/Sinai Health Systems, Toronto, Ontario, Canada.

Background: Despite recommendations for reflex immunohistochemistry (IHC) for mismatch repair (MMR) proteins to identify Lynch syndrome (LS), the uptake of genetic assessment by those who meet referral criteria is low. The authors implemented a comprehensive genetic navigation program to increase the uptake of genetic testing for LS in patients with endometrial cancer (EC) or nonserous/nonmucinous ovarian cancer (OC).

Methods: Participants with newly diagnosed EC or OC were prospectively recruited from 3 cancer centers in Ontario, Canada. Family history questionnaires were used to assess LS-specific family history. Reflex IHC for MMR proteins was performed with the inclusion of clinical directives in pathology reports. A trained genetic navigator initiated a genetic referral on behalf of the treating physician and facilitated genetic referrals to the closest genetics center.

Results: A total of 841 participants (642 with EC, 172 with OC, and 27 with synchronous EC/OC) consented to the study; 194 (23%) were MMR-deficient by IHC. Overall, 170 women (20%) were eligible for a genetic assessment for LS: 35 on the basis of their family history alone, 24 on the basis of their family history and IHC, 82 on the basis of IHC alone, and 29 on the basis of clinical discretion. After adjustments for participants who died (n = 6), 149 of 164 patients (91%) completed a genetic assessment, and 111 were offered and completed genetic testing. Thirty-four women (4.0% of the total cohort and 30.6% of those with genetic testing) were diagnosed with LS: 5 with mutL homolog 1 (MLH1), 9 with mutS homolog 2 (MSH2), 15 with mutS homolog 6 (MSH6), and 5 with PMS2.

Conclusions: The introduction of a navigated genetic program resulted in a high rate of genetic assessment (>90%) in patients with gynecologic cancer at risk for LS.
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http://dx.doi.org/10.1002/cncr.33625DOI Listing
May 2021

Understanding the clinical implication of mismatch repair deficiency in endometrioid endometrial cancer through a prospective study.

Gynecol Oncol 2021 Apr 19;161(1):221-227. Epub 2021 Jan 19.

Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network/Sinai Health Systems, Toronto, Ontario, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada; Zane Cohen Centre for Digestive Diseases, Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, Ontario, Canada. Electronic address:

Objectives: Findings on impact of mismatch repair deficiency (MMRd) on patient outcomes in endometrial cancer (EC) have been inconsistent to date. The objective of this study was to compare the oncologic outcomes and recurrence patterns between MMRd and MMR-intact (MMRi) endometrioid EC (EEC).

Methods: Between 2015 and 2018, we prospectively recruited 492 EEC cases from three cancer centers in Ontario, Canada. Tumors were reflexively assessed for MMR protein expression by immunohistochemistry (IHC). Clinicopathological, survival and recurrence patterns were compared between MMRd and MMRi cases.

Results: Of 492 EEC, 348 were MMRi (71%) and 144 were MMRd (29%) with median follow-up of 16.8 months (0-69.6). MMRd tumors tended to be grade 2 or 3 (56% vs. 29%, p < 0.001), with propensity for lymphovascular space invasion (28% vs. 18%, p = 0.024), lymph node involvement (7% vs. 5%, p < 0.001) and received more adjuvant treatment (46% vs. 33%, p = 0.027). This group also had significantly lower 3-year recurrence-free survival (78% vs. 90%, p = 0.014) although there was no difference in OS (p = 0.603). MMRd cases were more likely to recur in retroperitoneal lymph nodes (p = 0.045). Upon subgroup analysis, MLH1 methylated tumors had the worst prognostic features and survival outcomes.

Conclusions: MLH1 methylated EECs exhibit more aggressive features compared to other MMRd and MMRi EECs. This may indicate an inherent difference in tumor biology, suggesting the importance of individualized management based on EC molecular phenotype.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.002DOI Listing
April 2021

Tumor site discordance in mismatch repair deficiency in synchronous endometrial and ovarian cancers.

Int J Gynecol Cancer 2020 12 20;30(12):1951-1958. Epub 2020 Oct 20.

Gynecologic Oncology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada

Objectives: For synchronous endometrial and ovarian cancers, most centers rely on mismatch repair testing of the endometrial cancer to identify Lynch syndrome, and neglect the ovarian tumor site completely. We examined the mismatch repair immunohistochemistry and microsatellite instability results from the endometrium and ovary to assess discordance between the tumor sites and between tests.

Methods: 30 women with newly diagnosed synchronous endometrial and ovarian cancer were prospectively recruited from three cancer centers in Ontario, Canada. Both tumor sites were assessed for mismatch repair deficiency by immunohistochemistry and microsatellite instability test; discordance in results between tumor sites and discordance between test results at each site was examined. Cases with discordant results had tumors sequenced with a targeted panel in order to reconcile the findings. All women underwent mismatch repair gene germline testing.

Results: Of 30 patients, 11 (37%) were mismatch repair deficient or microsatellite instable at either tumor site, with 5 (17%) testing positive for Lynch syndrome. Mismatch repair immunohistochemistry expression was discordant between endometrial and ovarian tumor sites in 2 of 27 patients (7%) while microsatellite instability results were discordant in 2 of 25 patients (8%). Relying on immunohistochemistry or microsatellite instability alone on the endometrial tumor would have missed one and three cases of Lynch syndrome, respectively. One patient with Lynch syndrome with a pathogenic variant was not detected by either immunohistochemistry or microsatellite instability testing. The rate of discordance between immunohistochemistry and microsatellite instability test was 3.8% in the ovary and 12% in the endometrium.

Conclusions: There was discordance in immunohistochemistry and microsatellite instability results between tumor sites and between tests within each site. Endometrial tumor testing with mismatch repair immunohistochemistry performed well, but missed one case of Lynch syndrome. Given the high incidence of Lynch syndrome (17%), consideration may be given to germline testing in all patients with synchronous endometrial and ovarian cancers.
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http://dx.doi.org/10.1136/ijgc-2020-001927DOI Listing
December 2020

Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer.

Cancer 2020 11 18;126(22):4886-4894. Epub 2020 Aug 18.

Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network, Sinai Health Systems, Toronto, Ontario, Canada.

Background: For women with ovarian cancer (OC), the optimal screening strategy to identify Lynch syndrome (LS) has not been determined. In the current study, the authors compared the performance characteristics of various strategies combining mismatch repair (MMR) immunohistochemistry (IHC), microsatellite instability testing (MSI), and family history for the detection of LS.

Methods: Women with nonserous and/or nonmucinous ovarian cancer were recruited prospectively from 3 cancer centers in Ontario, Canada. All underwent germline testing for LS and completed a family history assessment. Tumors were assessed using MMR IHC and MSI. The sensitivity, specificity, and positive and negative predictive values of screening strategies were compared with the gold standard of a germline result.

Results: Of 215 women, germline data were available for 189 (88%); 13 women (7%) had pathogenic germline variants with 7 women with mutS homolog 6 (MSH6); 3 women with mutL homolog 1 (MLH1); 2 women with PMS1 homolog 2, mismatch repair system component (PMS2); and 1 woman with mutS homolog 2 (MSH2). A total of 28 women had MMR-deficient tumors (13%); of these, 11 had pathogenic variants (39%). Sequential IHC (with MLH1 promoter methylation analysis on MLH1-deficient tumors) followed by MSI for nonmethylated and/or MMR-intact patients was the most sensitive (92.3%; 95% confidence interval, 64%-99.8%) and specific (97.7%; 95% confidence interval, 94.2%-99.4%) approach, missing 1 case of LS. IHC with MLH1 promoter methylation analysis missed 2 patients of LS. Family history was found to have the lowest sensitivity at 55%.

Conclusions: Sequential IHC (with MLH1 promoter methylation analysis) followed by MSI was found to be most sensitive. However, IHC with MLH1 promoter methylation analysis also performed well and is likely more cost-effective and efficient in the clinical setting. The pretest probability of LS is high in patients with MMR deficiency and warrants universal screening for LS.
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http://dx.doi.org/10.1002/cncr.33144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693219PMC
November 2020

CTNNB1 Mutations and Aberrant β-Catenin Expression in Ovarian Endometrioid Carcinoma: Correlation With Patient Outcome.

Am J Surg Pathol 2021 01;45(1):68-76

Department of Laboratory Medicine and Pathobiology, University of Toronto.

CTNNB1 mutations and aberrant β-catenin expression have adverse prognosis in endometrial endometrioid carcinoma, and recent evidence suggests a prognostic role of β-catenin in ovarian endometrioid carcinoma. Thus, we aimed to determine the prognostic value of the CTNNB1 mutational status, and its correlation with β-catenin expression, in a well-annotated cohort of 51 ovarian endometrioid carcinomas. We performed immunohistochemistry for β-catenin and developed an 11-gene next-generation sequencing panel that included whole exome sequencing of CTNNB1 and TP53. Results were correlated with clinicopathologic variables including disease-free and disease-specific survival. Tumor recurrence was documented in 14 patients (27%), and cancer-related death in 8 patients (16%). CTNNB1 mutations were found in 22 cases (43%), and nuclear β-catenin in 26 cases (51%). CTNNB1 mutation highly correlated with nuclear β-catenin (P<0.05). Mutated CTNNB1 status was statistically associated with better disease-free survival (P=0.04, log-rank test) and approached significance for better disease-specific survival (P=0.07). It also correlated with earlier International Federation of Gynecology and Obstetrics stage (P<0.05). Nuclear β-catenin, TP53 mutations, age, ProMisE group, surface involvement, tumor grade and stage also correlated with disease-free survival. There was no association between membranous β-catenin expression and disease-free or disease-specific survival. CTNNB1 mutations and nuclear β-catenin expression are associated with better progression-free survival in patients with OEC. This relationship may be in part due to a trend of CTNNB1-mutated tumors to present at early stage. β-catenin immunohistochemistry may serve as a prognostic biomarker and a surrogate for CTNN1B mutations in the evaluation of patients with ovarian endometrioid neoplasia, particularly those in reproductive-age or found incidentally without upfront staging surgery.
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http://dx.doi.org/10.1097/PAS.0000000000001553DOI Listing
January 2021

Undifferentiated endometrial carcinoma arising in the background of high-grade endometrial carcinoma - Expanding the definition of dedifferentiated endometrial carcinoma.

Histopathology 2020 Nov 27;77(5):769-780. Epub 2020 Sep 27.

Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Science Center, Toronto, Canada.

Dedifferentiated endometrial adenocarcinoma (DEC) is defined by the coexistence of undifferentiated carcinoma with low-grade (FIGO grade 1 or 2) endometrioid carcinoma. Few cases of DEC arising in the background of high-grade carcinoma (DEC-HG) have been reported, however, this phenomenon is poorly characterized. In this study we describe the morphologic, immunohistochemical and clinico-pathologic characteristics of DEC-HG. 18 DECs were diagnosed at our institution between 2008-2019, and in 11 (61%), the undifferentiated component was associated with high-grade carcinoma (8 endometrioid FIGO grade 3, 2 with ambiguous features, 1 serous). The remaining 7 (39%) represented DEC-LG (3 FIGO grade 1 and 4 FIGO grade 2). 7/11 (64%) patients with DEC-HG presented with advanced stage (FIGO stage III/IV), whereas most with DEC-LG (6/7, 86%) were stage I. On follow up, 2 patients in the DEC-HG group died of disease and 2 had progressive disease within 2 months of surgery. There was only one recurrence in the DEC-LG, 6 months post-surgery. The DEC component in both groups showed similar morphology and immunophenotype, with predominantly focal or complete loss of expression of pan-keratin, EMA, E-cadherin, CK8/18, PAX8 and ER. The DEC component in the DEC-HG group had wild-type p53 expression in 8/11 (73%) cases, loss of MLH1 and PMS2 in 6/11 (55%) and loss of SMARCA4 in 3/9 (33%). Although numbers are small, we show that DEC-HG is a previously under-recognized phenomenon, with morphologic and immunophenotypic similarities to DEC-LG, which supports expanding the definition of DEC to include DEC-HG. DEC-HG may be more aggressive than DEC-LG.
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http://dx.doi.org/10.1111/his.14186DOI Listing
November 2020

The prognostic role of horizontal and circumferential tumor extent in cervical cancer: Implications for the 2019 FIGO staging system.

Gynecol Oncol 2020 08 26;158(2):266-272. Epub 2020 May 26.

Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. Electronic address:

Objective: The FIGO 2019 update on cervical cancer staging removed horizontal tumor extent (HZTE) as a staging variable. Evidence is needed to substantiate this change. The prognostic significance of HZTE and a related variable, circumferential tumor extent (%CTE), is similarly unknown. We aimed to investigate the association of HZTE and %CTE with survival outcomes in cervical cancer patients.

Methods: We identified patients treated with primary surgery for stage I cervical cancer in a single institution during a 9-year period. HZTE and, when available, %CTE were obtained from pathology records. Cases were staged using 2019 FIGO staging. Correlations between HZTE, %CTE and FIGO stage with recurrence-free (RFS) and disease-specific survival (DSS) were determined using univariable and multivariable analyses.

Results: 285 patients were included with a median follow-up of 48 (range 7-123) months. HZTE was statistically associated with RFS and DSS on univariate and multivariate analysis. None of the 168 stage IA patients in our series had tumor recurrence or death during follow-up, including 42 with HZTE ≥7 mm. None of the patients with a tumor horizontal extent <7 mm experienced recurrence or death. %CTE correlated only with RFS on univariate analysis. 2019 FIGO stage did not independently correlate with RFS or DSS in our sample.

Conclusions: HZTE is an independent predictor of survival in cervical carcinoma. In stage IA tumors, however, HZTE does not offer superior prognostic value, supporting the 2019 FIGO recommendations to remove this variable from staging in these cases. HZTE may be useful in larger tumors in which staging depends on maximum tumor size. %CTE is not an independent prognostic variable in cervical cancer, and we advise against its use.
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http://dx.doi.org/10.1016/j.ygyno.2020.05.016DOI Listing
August 2020

NTRK-rearranged Cervical Sarcoma: Expanding the Clinicopathologic Spectrum.

Int J Gynecol Pathol 2021 Jan;40(1):73-77

The NTRK genes (NTRK1, NTRK2, and NTRK3) encode for TrkA, TrkB, and TrkC, neurotrophic tyrosine receptor kinases which serve a variety of functions including in the regulation of pathways involved in carcinogenesis. A number of reports have described NTRK gene fusions in a variety of adult and pediatric tumor types from various organ systems including the central nervous system, thyroid gland, breast, and soft tissue. NTRK-rearranged uterine sarcomas are a recently described group of tumors which occur in both the uterine corpus and cervix, tend to morphologically resemble fibrosarcoma, and may behave aggressively, although data is limited given the newly recognized nature and thus relative rarity of these tumors. Herein, we present the case of a cervical sarcoma with SPECC1L-NTRK3 fusion (detected with Illumina RNA Fusion Panel), prospectively diagnosed at the time of cervical biopsy and subsequently treated with hysterectomy. The clinical presentation, radiologic findings, morphologic features, and immunohistochemical profile of this case will be reviewed and compared with the body of existing literature to date. Identification of NTRK-rearranged neoplasms is important as targeted therapy in the form of NTRK inhibitors has recently become widely available.
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http://dx.doi.org/10.1097/PGP.0000000000000669DOI Listing
January 2021

Histological grading of ovarian mucinous carcinoma - an outcome-based analysis of traditional and novel systems.

Histopathology 2020 Jul 29;77(1):26-34. Epub 2020 May 29.

Department of Laboratory Medicine, Sunnybrook Health Science Centre and University of Toronto, Toronto, ON, Canada.

Aims: Grading of primary ovarian mucinous carcinoma (OMC) is inconsistent among practices. The International Collaboration on Cancer Reporting recommends grading OMC using the International Federation of Gynecology and Obstetrics (FIGO) system for endometrial endometrioid carcinoma, when needed. The growth pattern (expansile versus infiltrative), a known prognostic variable in OMC, is not considered in any grading system. We herein analysed the prognostic value of various grading methods in a well-annotated cohort of OMC.

Methods And Results: Institutional OMCs underwent review and grading by the Silverberg and FIGO schemes and a novel system, growth-based grading (GBG), defined as G1 (expansile growth or infiltrative invasion in ≤10%) and G2 (infiltrative growth >10% of tumour). Of 46 OMCs included, 80% were FIGO stage I, 11% stage II and 9% stage III. On follow-up (mean = 52 months, range = 1-190), five patients (11%) had adverse events (three recurrences and four deaths). On univariate analysis, stage (P = 0.01, Cox proportional analysis), Silverberg grade (P = 0.01), GBG grade (P = 0.001) and percentage of infiltrative growth (P < 0.001), but not FIGO grade, correlated with disease-free survival. Log-rank analysis showed increased survival in patients with Silverberg grade 1 versus 2 (P < 0.001) and those with GBG G1 versus G2 (P < 0.001). None of the parameters evaluated was significant on multivariate analysis (restricted due to the low number of adverse events).

Conclusions: Silverberg and the new GBG system appear to be prognostically significant in OMC. Pattern-based grading allows for a binary stratification into low- and high-grade categories, which may be more appropriate for patient risk stratification. Despite current practices and recommendations to utilise FIGO grading in OMC, our study shows no prognostic significance of this system and we advise against its use.
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http://dx.doi.org/10.1111/his.14039DOI Listing
July 2020

and are required for the maintenance of multipotency in the Müllerian duct mesenchyme.

Development 2019 10 18;146(20). Epub 2019 Oct 18.

Département de Biomédecine Vétérinaire, Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, Québec, J2S 7C6, Canada

WNT signaling plays essential roles in the development and function of the female reproductive tract. Although crosstalk with the Hippo pathway is a key regulator of WNT signaling, whether Hippo itself plays a role in female reproductive biology remains largely unknown. Here, we show that conditional deletion of the key Hippo kinases and in mouse Müllerian duct mesenchyme cells caused them to adopt the myofibroblast cell fate, resulting in profound reproductive tract developmental defects and sterility. Myofibroblast differentiation was attributed to increased YAP and TAZ expression (but not to altered WNT signaling), leading to the direct transcriptional upregulation of and the activation of the myofibroblast genetic program. Müllerian duct mesenchyme cells also became myofibroblasts in male mutant embryos, which impeded the development of the male reproductive tract and resulted in cryptorchidism. The inactivation of in differentiated uterine stromal cells did not compromise their ability to decidualize, suggesting that Hippo is dispensable during implantation. We conclude that Hippo signaling is required to suppress the myofibroblast genetic program and maintain multipotency in Müllerian mesenchyme cells.
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http://dx.doi.org/10.1242/dev.180430DOI Listing
October 2019

Myxoid smooth muscle neoplasia of the uterus: comprehensive analysis by next-generation sequencing and nucleic acid hybridization.

Mod Pathol 2019 11 12;32(11):1688-1697. Epub 2019 Jun 12.

Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada.

Uterine myxoid smooth muscle tumors, including myxoid leiomyosarcoma, are rare and their genomic profile has not been fully characterized. With the discovery of uterine sarcomas with ZC3H7B-BCOR fusion and BCOR internal tandem duplications, the differential diagnosis of myxoid smooth muscle lesions is expanding to include molecularly-defined tumors. Thus, we aimed to explore the genomic landscape of myxoid smooth muscle tumor using comprehensive tools. We performed whole exome next-generation sequencing and a pan-sarcoma RNA fusion assay in tumoral paraffin-embedded tissue from nine well-characterized uterine myxoid smooth muscle tumors (seven myxoid leiomyosarcomas and two myxoid smooth muscle tumors of unknown malignant potential). By immunohistochemistry, all tumors were strongly positive for smooth muscle markers and negative for BCOR staining; 4/6 expressed PLAG1. None of the tumors harbored known fusions including ZC3H7B-BCOR, TRPS1-PLAG1, and RAD51B-PLAG1. None harbored exon 15 BCOR internal tandem duplications; however, four tumors contained BCOR internal tandem duplications of unknown significance (mostly intronic). Mutational burden was low (median 3.8 mutations/megabase). DNA damage repair pathway gene mutations, including TP53 and BRCA2, were found. Copy number variation load, inferred from sequencing data, was variable with genomic indexes ranging from 2.2 to 74.7 (median 25.7), with higher indexes in myxoid leiomyosarcomas than myxoid smooth muscle tumors of unknown malignant potential. The absence of clear driver mutations suggests myxoid smooth muscle tumors to be genetically heterogeneous group of tumours and that other genetic (eg., undiscovered translocation) or epigenetic events drive the pathogenesis of uterine myxoid smooth muscle neoplasia.
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http://dx.doi.org/10.1038/s41379-019-0299-4DOI Listing
November 2019

GREB1 is an estrogen receptor-regulated tumour promoter that is frequently expressed in ovarian cancer.

Oncogene 2018 11 4;37(44):5873-5886. Epub 2018 Jul 4.

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.

Estrogenic hormone replacement therapy increases the risk of developing ovarian cancer, and estrogen promotes tumour initiation and growth in mouse models of this disease. GREB1 (Growth regulation by estrogen in breast cancer 1) is an ESR1 (estrogen receptor 1)-upregulated protein which may mediate estrogen action. GREB1 knockdown prevents hormone-driven proliferation of several breast and prostate cancer cell lines and prolongs survival of mice engrafted with ovarian cancer cells, but its mechanism of action remains unclear. In this study, we explored GREB1 function in ovarian cancer. GREB1 overexpression in ovarian cancer cell lines increased cell proliferation and migration and promoted a mesenchymal morphology associated with increased Col1a2, which encodes a collagen I subunit. GREB1 knockdown inhibited proliferation and promoted an epithelial morphology associated with decreased Col1a2. In human tissues, GREB1 was expressed in all ESR1-expressing tissues throughout the normal female reproductive tract, in addition to several tissues that did not show ESR1 expression. In a TMA of ovarian cancer cases, GREB1 was expressed in 75-85% of serous, endometrioid, mucinous, and clear cell carcinomas. Serous, endometrioid, and mucinous ovarian cancers were almost always positive for either ESR1 or GREB1, suggesting a possible reliance on signalling through ESR1 and/or GREB1. Targeting GREB1 may inhibit tumour-promoting pathways both downstream and independent of ESR1 and is therefore a possible treatment strategy worthy of further investigation.
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http://dx.doi.org/10.1038/s41388-018-0377-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212416PMC
November 2018

International Endocervical Adenocarcinoma Criteria and Classification: Validation and Interobserver Reproducibility.

Am J Surg Pathol 2019 01;43(1):75-83

Department of Laboratory Medicine and Pathobiology, University of Toronto.

The current World Health Organization (WHO) classification for endocervical adenocarcinoma (EA) is based on descriptive morphologic characteristics; however, it does not fully reflect our current knowledge of the diverse pathogenesis of cervical glandular neoplasia. A novel classification system, the International Endocervical Adenocarcinoma Criteria and Classification (IECC), which incorporates etiology and biological behavior into the morphologic scheme, has been recently proposed. We aimed to validate the IECC by assessing its interobserver reproducibility in comparison to the WHO system. A cohort of 75 EAs was reviewed independently by 7 gynecologic pathologists and categorized following IECC and WHO criteria based on hematoxylin and eosin material alone and after immunohistochemistry results for p16, PR, p53, Napsin-A, vimentin, CDX2, and GATA3 were provided. Human papillomavirus (HPV) in situ hybridization and polymerase chain reaction results were compared with consensus diagnoses. IECC was superior to WHO in terms of interobserver agreement with κ=0.46 versus 0.3, respectively, on hematoxylin and eosin review and κ=0.51 versus 0.33, respectively, with immunohistochemistry. Under the IECC, 73 (97%) of EAs had majority agreement (≥4 reviewers in agreement) whereas 42 (56%) had perfect agreement (7/7 reviewers in agreement). Conversely, WHO showed majority agreement in 56 (75%) and perfect agreement in only 7 (10%) EAs. Reproducibility was poor in HPV-related WHO types (usual κ=0.36, mucinous not otherwise specified κ=0.13, intestinal κ=0.31, villoglandular κ=0.21) and good in major HPV-unrelated categories (gastric type κ=0.63, clear cell κ=0.81, mesonephric κ=0.5). Classification as per the IECC had excellent correlation with HPV status (by RNA in situ hybridization or polymerase chain reaction). We have shown that the IECC has superior interobserver agreement compared with the WHO classification system, and that distinction between HPV-related and HPV-unrelated EA can be made with good reproducibility and excellent prediction of HPV status. WHO morphologic variants of HPV-related EA are poorly reproducible. Conversely, agreement is high among important high-risk HPV-unrelated subtypes. Thus, our results further support replacing the current WHO classification with the IECC.
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http://dx.doi.org/10.1097/PAS.0000000000001095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281796PMC
January 2019

Nuclear β-catenin localization and mutation of the CTNNB1 gene: a context-dependent association.

Mod Pathol 2018 10 24;31(10):1553-1559. Epub 2018 May 24.

Department of Pathology, Unit 85, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Although the majority of low-grade, early-stage endometrial cancer patients have good survival with surgery alone, patients who recur tend to do poorly. Identification of patients at high risk of recurrence who would benefit from adjuvant treatment or more extensive surgical staging would help optimize individualized care of endometrial cancer patients. CTNNB1 (encodes β-catenin) mutations identify a subset of low-grade, early-stage endometrial cancer patients at high risk of recurrence. Mutation of CTNNB1 exon 3 is classically associated with translocation of the β-catenin protein from the membrane to the nucleus and activation of Wnt/β-catenin signaling. Given the clinical utility of identifying endometrial carcinomas with CTNNB1 mutation, the purpose of this study was to determine if immunohistochemistry could act as a surrogate for CTNNB1 gene sequencing. Next-generation sequencing was performed on 345 endometrial carcinomas. Immunohistochemical localization of β-catenin was determined for 53/63 CTNNB1 exon 3 mutant tumors for which tissue was available and a subset of wild-type tumors. Nuclear localization of β-catenin had 100% specificity in distinguishing CTNNB1 mutant from wild type, but sensitivity was lower (84.9%). Nearly half of CTNNB1 mutant cases had only 5-10% of tumor cells with β-catenin nuclear localization. The concordance between pathologists blinded to mutation status in assessing nuclear localization was 100%. The extent of β-catenin nuclear localization was not associated with specific CTNNB1 gene mutation, tumor grade, presence of non-endometrioid component, or specific concurrent gene mutations in the tumor. For comparison, nuclear localization of β-catenin was more diffuse in desmoid fibromatosis, a tumor also associated with CTNNB1 mutation. Thus, nuclear localization of β-catenin assessed by immunohistochemistry does not detect all endometrial cancers with CTNNB1 gene mutation. The extent of nuclear localization may be tumor type dependent. For endometrial cancer, immunohistochemistry could be an initial screen, with CTNNB1 sequencing employed when nuclear localization of β-catenin is absent.
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http://dx.doi.org/10.1038/s41379-018-0080-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168348PMC
October 2018

Cervical Adenocarcinoma: A Comparison of the Reproducibility of the World Health Organization 2003 and 2014 Classifications.

J Low Genit Tract Dis 2018 Apr;22(2):132-138

Department of Pathology, Lion's Gate Hospital, Vancouver, British Columbia, Canada.

Objective: The aim of the study was to compare the reproducibility of malignant glandular tumors of the uterine cervix classified per World Health Organization (WHO) 2003 and 2014.

Materials And Methods: Two pathologists reviewed 228 cases composed of adenocarcinoma in situ and 22 adenocarcinoma histotypes and selected 405 representative hematoxylin and eosin slides, which were digitally scanned. Six other pathologists (3 gynecological and 3 anatomical) independently reviewed and classified the images per both WHO classifications. One year later, they classified a random sample of 25 cases. Inter- (inter-OR) and intra-observer (intra-OR) reproducibility of the 6 pathologists and separately for gynecological compared with anatomical pathologists was tested using κ statistics.

Results: Both classifications were collapsed into 6 categories as benign, adenocarcinoma in situ, and mucinous, endometrioid, rare, and adenosquamous-miscellaneous carcinomas. WHO 2014 had an additional category: endocervical adenocarcinoma, usual type. Inter-observer κ values were more reliable than the intra-OR results based on 95% CIs. The average inter-OR κ values with both classifications were moderate between the 6 pathologists and between the 3 anatomical pathologists. In contrast, they were substantial between the 3 gynecological pathologists. With both classifications, the average intra-OR κ values of the 6 pathologists and both pathologist groups trended toward substantial.

Conclusions: Reproducibility among 6 pathologists is unaffected by changes in the WHO 2014 classification and averages moderate between different and trends toward substantial between the same pathologist. Reproducibility between different pathologists can improve to substantial when they have expertise in gynecological pathology.
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http://dx.doi.org/10.1097/LGT.0000000000000380DOI Listing
April 2018

Canadian Consensus-based and Evidence-based Guidelines for Benign Endometrial Pathology Reporting in Biopsy Material.

Int J Gynecol Pathol 2019 Mar;38(2):119-127

Department of Laboratory Medicine and Pathobiology, University of Toronto and Sunnybrook Health Sciences Centre (C.P.-H., M.C., B.D.) Department of Laboratory Medicine and Pathobiology, University of Toronto and Trillium Health Partners (A.P.), Toronto, ON Department of Pathology, University Hospital of Quebec (Centre Hospitalier Universitaire de Quebec), Quebec, QC (K.G.) Department of Pathology and Laboratory Medicine, University of Saskatchewan and Saskatoon City Hospital, Saskatoon, SK (M.K.) Department of Pathology and Laboratory Medicine, University of Calgary and Arnie Charbonneau Cancer Institute, Calgary, AB (M.K.) Department of Laboratory Medicine, Memorial University, St John's, NL (A.P.) Department of Pathology, University of British Columbia and Vancouver General Hospital, Vancouver, BC, Canada (C.B.G.).

Standardized terminology has proven benefits in cancer reporting; in contrast, reporting of benign diagnoses in endometrial biopsy currently lacks such standardization. Unification and update on the lexicon can provide the structure and consistency needed for optimal patient care and quality assurance purposes. The Special Interest Group in Gynecologic Pathology of the Canadian Association of Pathologists-Association Canadienne des Pathologistes (CAP-ACP) embarked in an initiative to address the current need for consensus terminology in benign endometrial biopsy pathology reporting. Nine members of the Special Interest Group developed a guideline for structured diagnosis of benign endometrial pathology through critical appraisal of the available peer-reviewed literature and joint discussions. The first version of the document was circulated for feedback to a group of professionals in akin fields, the CAP-ACP Executive Committee and the CAP-ACP general membership. The final 1-page document included 17 diagnostic terms comprising the most common benign endometrial entities, as well as explanatory notes for pathologists. The proposed terminology was implemented in the practice of 5 pathologists from the group, who applied the guideline to all benign endometrial biopsies over a 2-wk period. A total of 212 benign endometrial biopsies were evaluated in this implementation step; the recommended terminology adequately covered the diagnosis in 203 cases (95.8%). A list of terminology for benign endometrial biopsy reporting, based on expert consensus and critical appraisal of the available literature, is presented. On the basis of our results of implementation at multiple centers, the proposed guideline can successfully cover the large majority of diagnostic scenarios. The document has the potential to positively impact patient care, promote quality assurance, and facilitate research initiatives aimed at improving histopathologic assessment of benign endometrium.
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http://dx.doi.org/10.1097/PGP.0000000000000481DOI Listing
March 2019

High-grade Müllerian Adenosarcoma: Genomic and Clinicopathologic Characterization of a Distinct Neoplasm With Prevalent TP53 Pathway Alterations and Aggressive Behavior.

Am J Surg Pathol 2017 Nov;41(11):1513-1522

Department of Anatomic Pathology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

Müllerian adenosarcoma harbors low malignant potential, except in cases with myometrial invasion or sarcomatous overgrowth. The presence of a high-grade stromal component has been proposed as an important pathologic predictor of outcome. We hypothesized that high-grade adenosarcoma has distinct clinical and molecular features, distinct from low-grade adenosarcoma. We analyzed the clinicopathologic features and follow-up of 9 high-grade adenosarcomas and a control group of 9 low-grade adenosarcomas. Comprehensive genomic analysis of the high-grade group was performed targeting exons of 409 oncogenes and tumor suppressor genes. In 1 case, the high-grade and low-grade components were separately sequenced. High-grade and low-grade adenosarcomas were comparable in patient age, myometrial invasion, and stage at presentation. Sarcomatous overgrowth was observed in 2/9 (22%) low-grade and 8/9 (89%) high-grade adenosarcomas. Six of 9 (67%) patients with high-grade adenosarcoma developed rapid recurrence; 1 died of her disease. Conversely, no low-grade tumors recurred or metastasized. Sequencing of high-grade adenosarcomas revealed frequent TP53 pathway alterations, identified in 7/9 (78%) cases. p53 expression by immunohistochemistry highly correlated with mutation status. Copy number variations occurred at a mean of 28.8 per tumor; most frequently involved genes included CDK4, MDM2, GNAS, SGK1, and DICER1. High-grade adenosarcoma is an aggressive neoplasm with propensity for short-interval recurrence and metastasis. The proportion of copy number alterations is similar to that reported for adenosarcoma with sarcomatous overgrowth. However, the high frequency of TP53 abnormalities is a novel finding, indicating that high-grade adenosarcoma is a distinct subset with driver TP53 pathway alterations. p53 immunohistochemistry can be used to confirm the presence of a high-grade component. Given its aggressive potential, the presence of any high-grade component in an adenosarcoma should be reported, even in the absence of sarcomatous overgrowth.
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http://dx.doi.org/10.1097/PAS.0000000000000907DOI Listing
November 2017

Genomic abnormalities in invasive endocervical adenocarcinoma correlate with pattern of invasion: biologic and clinical implications.

Mod Pathol 2017 11 21;30(11):1633-1641. Epub 2017 Jul 21.

Department of Pathology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

The pattern-based classification system for HPV-related endocervical adenocarcinoma, which classifies tumors based on the destructiveness of stromal invasion, is predictive of the risk of nodal metastases and adverse outcome. Previous studies have demonstrated clinically important molecular alterations in endocervical adenocarcinoma, including KRAS and PIK3CA mutations; however, correlation between the molecular landscape and pathological variables including pattern of invasion has not been thoroughly explored. In this study, 20 endocervical adenocarcinomas were classified using the pattern-based classification system and were subjected to targeted sequencing using the Ion AmpliSeq Cancer Hotspot Panel v2 (ThermoFisher Scientific, Waltham, MA, USA) that surveys hotspot regions of 50 oncogenes and tumor suppressor genes. Single-nucleotide polymorphisms were correlated with clinical and pathologic variables including pattern of invasion. Five (25%), six (30%), and nine (45%) cases were classified as patterns A, B, and C respectively. Lymph node metastases, advanced stage at presentation and mortality from disease were exclusively seen in destructively invasive tumors (patterns B or C). Prevalent mutations in the cohort involved PIK3CA (30%), KRAS (30%), MET (15%), and RB1 (10%). Most (94%) relevant genomic alterations were present in destructively invasive tumors with PIK3CA, KRAS, and RB1 mutations seen exclusively in pattern B or C subgroups. KRAS mutations correlated with advanced stage at presentation (FIGO stage II or higher). Our findings indicate that the pattern of stromal invasion correlates with genomic abnormalities detected by next-generation sequencing, suggesting that tumors without destructive growth (pattern A) are biologically distinct from those with destructive invasion (patterns B and C), and that pattern B endocervical adenocarcinoma is more closely related to its pattern C counterpart. The pattern-based classification may be used as a triage tool when considering molecular testing for prognostic or therapeutic purposes.
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http://dx.doi.org/10.1038/modpathol.2017.80DOI Listing
November 2017

Architectural overlap between benign endocervix and pattern-A endocervical adenocarcinoma: Are all pattern-A tumors invasive?

Pathol Res Pract 2017 Jul 8;213(7):799-803. Epub 2017 Mar 8.

Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada. Electronic address:

Studies on the pattern-based classification for invasive endocervical adenocarcinoma showed that tumors with nondestructive invasion (pattern-A) have a 0% rate of nodal metastases. Our understanding of pattern-A tumors and their distinction from in-situ adenocarcinoma requires further study. Thirteen sections diagnosed independently as pattern-A adenocarcinoma by three gynecologic pathologists, and 14 sections of benign endocervix were selected. Three additional pathologists (reviewers) evaluated a digital image from each section and classified it as pattern-A or benign based on architecture only. To blind the interpretation to cytologic features, nuclei and cytoplasm were obscured using morphometric software (Zen 2011, Carl Zeiss Microscopy, Germany). 13/27 cases (48%; 8 pattern-A, 5 benign) were correctly classified by all reviewers; 19/27 (70%; 10 pattern-A, 9 benign) were correctly classified by ≥2 reviewers. 3/13 pattern-A cases (23%) were interpreted as benign by ≥2 reviewers. Conversely, 5/14 benign cervices (36%) were misinterpreted as pattern-A by ≥2 reviewers. The number of glands per 20× field was higher in pattern-A cases with high reviewer agreement (p=0.004). An abnormal architecture is seen in many pattern-A adenocarcinomas in support of their invasive nature; some, however, have architecture that overlaps with that of benign endocervix thus may actually represent in-situ lesions. Likewise, normal cervix can be architecturally complex and mirror patterns that pathologists would classify as pattern-A if malignant cytologic features were present. Based on this overlap and the nil risk of nodal spread, an emphasis on the non-destructive, rather than the invasive, nature of pattern-A adenocarcinoma is recommended.
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http://dx.doi.org/10.1016/j.prp.2017.03.008DOI Listing
July 2017

Clear Cell Urothelial Carcinoma.

Int J Surg Pathol 2017 Feb 28;25(1):18-25. Epub 2016 Jul 28.

1 The Ottawa Hospital, Ottawa, Ontario, Canada.

Clear cell urothelial carcinoma (CCUC) is a rare variant of urothelial carcinoma (UC) and its clinical significance has not been well elucidated. Consecutive cases of UC over a period of 5 years were reviewed. Histopathological tumor parameters, including the proportion of tumor cells with clear cell change, and patient outcomes were recorded. Expression of the following immunohistochemical markers was investigated: CK7, CK20, CK5, CD44, and PAX8. We also conducted a review of the literature for case reports/series of CCUC. Ten CCUCs were identified out of a total of 872 cases of UC. The clear cell component was characterized by prominent cytoplasmic membranes and voluminous clear cytoplasm, and accounted for 30% to 90% of the invasive tumor component. Of all the non-CCUC cases reviewed, at least 50% (noninvasive or invasive UC) showed focal areas of clear cell change that accounted for less than 5% of the neoplastic cells. Immunohistochemically, CCUC exhibited positive reactivity for CK5/CD44 (n = 9); CK20 (n = 5), PAX8 (very focal to extensive) (n = 6), and GATA3/CK7 (n = 10). Eight of 10 CCUC were of advanced clinical stage (pT3/pT4) and 6 of 10 experienced tumor recurrence and/or death due to disease. In conclusion, CCUC can be distinguished from non-CCUC by the extensive clear cell change in more than 30% of cells. This variant is associated with rapid progression to muscle invasion and metastasis, with an aggressive clinical course. Expression of CK5/CD44 may represent basal cell features in most CCUC cases, while PAX8 expression is suggestive of mesonephric derivation.
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http://dx.doi.org/10.1177/1066896916660195DOI Listing
February 2017

Laboratory Assays in Evaluation of Lynch Syndrome in Patients with Endometrial Carcinoma.

Surg Pathol Clin 2016 Jun 11;9(2):289-99. Epub 2016 Apr 11.

Department of Pathology, Unit 85, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.

This article reviews the main tissue testing modalities for Lynch Syndrome in the pathology laboratory, such as immunohistochemistry and PCR based analyses, and discusses their routine application, interpretation pitfalls, and troubleshooting of common technical performance issues. Discrepancies between laboratory and genetic testing may arise, and are examined in the context of the complexity of molecular abnormalities associated with Lynch Syndrome. The merits of targeted versus universal screening in a changing healthcare climate are addressed. In the absence of comprehensive screening programs, specific tumor topography and histological features that may prompt pathologist-initiated molecular tumor testing are outlined.
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http://dx.doi.org/10.1016/j.path.2016.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548190PMC
June 2016

Pattern-based classification of invasive endocervical adenocarcinoma, depth of invasion measurement and distinction from adenocarcinoma in situ: interobserver variation among gynecologic pathologists.

Mod Pathol 2016 08 13;29(8):879-92. Epub 2016 May 13.

Department of Pathology, Women's and Perinatal Pathology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

A pattern-based classification for invasive endocervical adenocarcinoma has been proposed as predictive of the risk of nodal metastases. We aimed to determine the reproducibility of such classification in the context of common diagnostic challenges: distinction between in situ and invasive adenocarcinoma and depth of invasion measurement. Nine gynecologic pathologists independently reviewed 96 cases of endocervical adenocarcinoma (two slides per case). They diagnosed each case as in situ or invasive carcinoma classifying the latter following the pattern-based classification as pattern A (non-destructive), B (focally destructive) or C (diffusely destructive). Depth of invasion, when applicable, was measured (mm). Overall, diagnostic reproducibility of pattern diagnosis was good (κ=0.65). Perfect agreement (9/9 reviewers) was seen in only 11 cases (11%), all destructively invasive (10 pattern C and 1 pattern B). In all, ≥5/9 reviewer concordance was achieved in 82/96 cases (85%). Distinction between in situ and invasive carcinoma, regardless of the pattern, showed only slight agreement (κ=0.37). Likewise, distinction restricted to in situ versus pattern A was poor (κ=0.23). Distinction between non-destructive (in situ+pattern A) and destructive (patterns B+C) carcinoma showed significantly higher agreement (κ=0.62). Estimation of depth of invasion showed excellent reproducibility (ICC=0.82). However, different measurements resulting in differing FIGO stages were common (from at least 1 reviewer in 79% cases). On the basis of interobserver agreement, the pattern-based classification is best at diagnosing destructive invasion, which carries a risk for nodal metastases. Agreement in diagnosing in situ versus invasive carcinoma, including pattern A, was poor. Given the nil risk of nodal spread in in situ and pattern A lesions, the term 'endocervical adenocarcinoma with non-destructive growth' can be considered when the distinction is difficult, after excluding destructive invasion. Depth of invasion measurement was highly reproducible among pathologists; thus, the pattern-based approach can complement, but should not replace, the depth of invasion metric.
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http://dx.doi.org/10.1038/modpathol.2016.86DOI Listing
August 2016

IFITM1 Is Superior to CD10 as a Marker of Endometrial Stroma in the Evaluation of Myometrial Invasion by Endometrioid Adenocarcinoma.

Am J Clin Pathol 2016 Apr 21;145(4):486-96. Epub 2016 Mar 21.

From the Department of Pathology and Laboratory Medicine, University of Ottawa, the Ottawa Hospital and Eastern Ontario Regional Laboratory Association, Ottawa, Canada.

Background: Distinguishing myometrial invasion from adenomyosis involvement is important for staging of endometrial endometrioid adenocarcinoma. We aimed to compare CD10, which has limited value in this scenario, with interferon-induced transmembrane protein 1 (IFITM1), a recently described sensitive and specific marker of endometrial stroma.

Methods: We reviewed 25 hysterectomies containing endometrial endometrioid adenocarcinoma and adenomyosis. Tumor areas were classified as unequivocally myoinvasive or unequivocally noninvasive. Foci equivocal for invasion were also recorded. Immunohistochemistry for IFITM1 and CD10 was performed and scored in terms of intensity and distribution and classified as negative or positive.

Results: Unlike CD10, IFITM1 staining showed significant differences in mean intensity (P < .0001) and distribution (P < .0001) between invasive vs noninvasive areas. Sixteen (84.2%) invasive and 34 (97.1%) noninvasive areas were positive for CD10 (P = .22). In contrast, none of the invasive vs 25 (71.4%) noninvasive areas were positive for IFITM1 (P < .0001). IFITM1 had 71.4% sensitivity and 100% specificity in detecting stroma surrounding endometrioid adenocarcinoma, hence excluding myoinvasion. Eleven (45.8%) of 24 foci designated as equivocal stained with IFITM1.

Conclusions: Compared with CD10, IFITM1 has superior performance distinguishing endometrial stroma of adenomyosis from mesenchyma surrounding invasive endometrial adenocarcinoma. IFITM1 expression is highly predictive of the absence of invasion and may be valuable in cases in which determining myoinvasion has staging implications.
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http://dx.doi.org/10.1093/ajcp/aqw021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109682PMC
April 2016

Loss of switch/sucrose non-fermenting complex protein expression is associated with dedifferentiation in endometrial carcinomas.

Mod Pathol 2016 Mar 8;29(3):302-14. Epub 2016 Jan 8.

Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital and University of Alberta, Edmonton, AB, Canada.

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.
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http://dx.doi.org/10.1038/modpathol.2015.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980656PMC
March 2016

Application of a Pattern-based Classification System for Invasive Endocervical Adenocarcinoma in Cervical Biopsy, Cone and Loop Electrosurgical Excision (LEEP) Material: Pattern on Cone and LEEP is Predictive of Pattern in the Overall Tumor.

Int J Gynecol Pathol 2016 Sep;35(5):456-66

Department of Pathology and Laboratory Medicine, University of Ottawa, The Ottawa Hospital, Ottawa, ON, Canada.

A pattern-based classification system has been recently proposed for invasive endocervical adenocarcinoma, which is predictive of the risk of nodal metastases. Identifying cases at risk of nodal involvement is most relevant at the time of biopsy and loop electrosurgical excision procedure (LEEP) to allow for optimal surgical planning, and, most importantly, consideration of lymphadenectomy. This study aims to determine the topography of patterns of stromal invasion in invasive endocervical adenocarcinoma with emphasis on patterns in biopsy, cone, and LEEP. Invasive pattern was assessed following the pattern-based classification (Patterns A, B, and C) in 47 invasive endocervical adenocarcinomas treated with hysterectomy or trachelectomy and correlated with pattern of invasion at the tumor surface (2 mm of tumor depth) and on preoperative biopsy and cone/LEEP. Patterns A, B, and C were present in 21.3%, 36.2%, and 42.5% of cases, respectively. Most pattern A cases were Stage IA (90%), whereas most Pattern B and C cases were Stage IB (76.5% and 80%, respectively). Horizontal spread was on average larger in Pattern C (24.1 mm) than in Patterns A and B (7.7 and 12.3 mm, respectively). Pattern at the tumor surface correlated with the overall pattern in 95.7% of cases. Concordance between patterns at cone/LEEP and hysterectomy was 92.8%; the only discrepant case was upgraded from Pattern A on LEEP to C on final excision. Agreement between patterns in biopsy and the overall tumor, however, was only 37.5%. In all discrepant cases, biopsy failed to reveal destructive invasion, which was evident on excision. All discrepant biopsies with pattern A showed glandular complexity resembling exophytic papillary growth but did not meet criteria for destructive invasion. On excision, marked gland confluence with papillary architecture was evident. We conclude that the pattern of invasion on cone/LEEP is a good predictor of pattern of invasion on hysterectomy, particularly if there is destructive invasion (B or C). Thus, pattern-based classification can be successfully applied in these samples to guide definitive surgical treatment. Prediction of the overall pattern based on biopsy material alone appears to be suboptimal. However, glandular confluence and complexity on biopsy, regardless of its size, appears to be associated with destructive invasion in the overall tumor.
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http://dx.doi.org/10.1097/PGP.0000000000000264DOI Listing
September 2016

Histopathology of Placenta Creta: Chorionic Villi Intrusion into Myometrial Vascular Spaces and Extravillous Trophoblast Proliferation are Frequent and Specific Findings With Implications for Diagnosis and Pathogenesis.

Int J Gynecol Pathol 2016 Nov;35(6):497-508

Department of Pathology and Laboratory Medicine, The Ottawa Hospital and Eastern Ontario Regional Laboratory Association, University of Ottawa, Ottawa, ON, Canada.

Placenta creta is characterized by invasion of placental villi into the myometrium in the setting of a dysfunctional or absent decidua. Histopathologic diagnosis of placenta creta is important, particularly in cases of hysterectomy because of unanticipated intractable postpartum hemorrhage. Previous studies have documented a higher amount and depth of myometrial infiltration by the implantation site intermediate trophoblast compared with controls. In addition, we have anecdotally observed chorionic villi in myometrial vascular spaces in specimens with placenta creta. The aim of this study was to explore the prevalence and specificity of these features. Sixty-one postpartum hysterectomies, 44 with placenta creta and 17 without were reviewed. Villous intrusion into vascular spaces was recorded. Using immunohistochemistry for GATA3, the amount of intermediate trophoblast (number of positive cells in five 40× fields) and depth of trophoblast myometrial infiltration were assessed. Mean gestational ages of the creta group (34.4 yr; range, 20-43 yr) and control group (35 yr; range, 25-51 yr) were comparable. Presence of chorionic villi in myometrial vascular spaces was frequent in placenta creta: 31/44 versus 1/17 controls (70.4% vs. 5.8%, P<0.0001). This finding was more common in the percreta (87.5%) and increta (84%) than in the accreta (27.2%, P=0.0008). Mean depth of trophoblast myometrial invasion was greater in cretas (47.9%) than in controls (14.5%, P=0.004). Likewise, mean distance of deepest trophoblast to serosa was shorter in the cretas (7.3 mm) than in controls (23.8 mm, P<0.0001). These differences were, however, attributable to placentas increta and percreta. When only accretas and controls were compared, the myometrial depth of trophoblast was similar. The mean intermediate trophoblast cell count in the placental bed was greater in cretas (664) than in controls (288, P<0.0001). Such difference was seen in all creta cases despite the type (accreta 639, increta 676, percreta 661). A trophoblast count of ≥100 cells/high-power field was seen in 75.8% of cretas and 11.1% of controls (P=0.0009). For the first time, we document the finding of chorionic villi intrusion into myometrial vascular spaces, which is highly specific of placenta creta. In addition, assessment of the amount of intermediate trophoblast using GATA3 immunohistochemistry can assist in the diagnosis. We hypothesize that placental invasion in placenta creta is due, at least partially, to transformation of low-resistance myometrial vessels leading to subsequent protrusion of villi into their lumens, in the context of absent decidua.
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http://dx.doi.org/10.1097/PGP.0000000000000250DOI Listing
November 2016

Immunohistochemistry in the Diagnosis of Mucinous Neoplasms Involving the Ovary: The Added Value of SATB2 and Biomarker Discovery Through Protein Expression Database Mining.

Int J Gynecol Pathol 2016 May;35(3):191-208

Department of Pathology and Laboratory Medicine (S.C., J.K.W., A.G., B.D., C.P.H.), University of OttawaThe Ottawa Hospital and Eastern Ontario Regional Laboratory Association (S.C., J.K.W., B.D., C.P.H.), Ottawa, ON, Canada.

Immunohistochemistry is frequently used to identify ovarian mucinous neoplasms as primary or metastatic; however, there is significant overlap in expression patterns. We compared traditional markers (CK7, CK20, CDX2, PAX8, estrogen receptor, β-catenin, MUC1, MUC2, and MUC5AC) to 2 novel proteins identified through mining of the Human Protein Atlas expression database: SATB2 and POF1B. The study cohort included 49 primary gastrointestinal (GI) mucinous adenocarcinomas (19 colorectal, 15 gastric, 15 pancreatobiliary), 60 primary ovarian mucinous neoplasms (19 cystadenomas, 21 borderline tumors, 20 adenocarcinomas), and 19 metastatic carcinomas to the ovary (14 lower and 5 upper GI primaries). Immunohistochemistry was performed on tissue microarrays, scored and interpreted as negative (absent or focal/weak) or positive. Metastatic tumors were frequently unilateral (42.8% of tumors from lower and 40% of tumors from upper tract) and ≥10 cm (85.7% of tumors from lower and 80% of tumors from upper tract). CK7 was positive in 88.5% upper GI and 88.3% primary ovarian compared with 24.3% lower GI neoplasms. CK20 and CDX2 were positive in 84.8% and 100% of lower GI tumors, respectively; however, expression was also common in upper GI (CK20 42.8%, CDX2 50%) and primary ovarian neoplasms (CK20 65.7%, CDX2 38.3%). Conversely, SATB2 was more specific for lower GI origin, being positive in 78.8% lower GI but only 11.5% upper GI and 1.7% primary ovarian neoplasms. PAX8 expression was common in primary ovarian neoplasms (75% of all neoplasms, 65% of carcinomas); only 1 (1.5%) GI tumor was positive. MUC2 and β-catenin were frequently positive in lower GI tumors (96.9% and 51.5%, respectively). Estrogen receptor expression was only seen in primary ovarian neoplasms (13.3%). Nuclear premature ovarian failure 1B (POF1B) expression was seen in malignant tumors regardless of their origin. A panel including CK7, SATB2, and PAX8 separated primary from secondary GI neoplasms with up to 77.1% sensitivity and 99% specificity, outperforming tumor laterality and size. Second-line markers such as CDX2, MUC2, estrogen receptor, MUC1, and β-catenin increased the sensitivity of immunohistochemistry in excluding lower GI origin. Biomarker search using proteomic databases has a value in diagnostic pathology, as shown with SATB2; however, as seen with POF1B, expression profiles in these databases are not always reproduced in larger cohorts.
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http://dx.doi.org/10.1097/PGP.0000000000000238DOI Listing
May 2016

Risk factor analysis of recurrence in low-grade endometrial adenocarcinoma.

Hum Pathol 2015 Oct 30;46(10):1529-39. Epub 2015 Jun 30.

Department of Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, 77030; Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048.

Prognosis of endometrial adenocarcinoma is favorable; however, the risk of recurrence ranges from 7% to 13%. Recurrence has been related to age, tumor type, International Federation of Gynecology and Obstetrics grade, depth of invasion, and lymphovascular invasion (LVI); however, morphologic features that would predict the site of recurrence have not been established. In this multi-institutional study, we reviewed 589 patients with International Federation of Gynecology and Obstetrics grades 1 or 2 endometrial adenocarcinoma, endometrioid type. Cox proportional hazard analysis was used to identify univariate and multivariate risk factors for recurrence and survival. Univariate analysis revealed features of tumors that recurred only in the vagina: low nuclear grade; superficial myoinvasion; minimal to no LVI; and minimal myoinvasion with microcystic, elongated, and fragmented (MELF) pattern; low nuclear grade and superficial myoinvasion persisted on multivariate analysis. Features of tumors that recurred at other sites included large size, deep myoinvasion, tumor necrosis, 1 or more LVI foci, LVI foci distant/deeper than invasive tumor front, MELF myoinvasion pattern, lower uterine segment and cervical stromal involvement, pelvic and/or paraaortic lymph node metastases at presentation, and higher grade of tumor in the metastatic foci, whereas increased percentage of solid component and lower percentage of mucinous features were marginally associated. Tumors with recurrences only in vagina had different features than tumors that recurred at other sites. The presence of tumor necrosis, MELF foci at the invasive tumor front, and the percentage of solid component and mucinous features could be helpful in grading endometrioid adenocarcinomas, if a 2-tier rather than a 3-tier grading system is accepted in the future.
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http://dx.doi.org/10.1016/j.humpath.2015.06.015DOI Listing
October 2015

Intact PTEN Expression by Immunohistochemistry is Associated With Decreased Survival in Advanced Stage Ovarian/Primary Peritoneal High-grade Serous Carcinoma.

Int J Gynecol Pathol 2015 Nov;34(6):497-506

Departments of Pathology (R.B., S.-S.X., K.V., R.R.B.) Biostatistics (D.L.U.), University of Texas MD Anderson Cancer Center, Houston, Texas Eastern Ontario Regional Laboratory (B.D.), Department of Pathology and Laboratory Medicine, University of Ottawa, The Ottawa Hospital, Ottawa, ON, Canada.

Ovarian high-grade serous carcinoma is an aggressive malignancy with poor prognosis. Optimal surgical debulking and tumor sensitivity to platinum-based chemotherapy are 2 well-established prognostics for this tumor type. Molecular markers that identify more clinically aggressive tumors would potentially allow for the development of individualized treatment options. PTEN is a key negative regulator of the PI3K signaling pathway. Loss of PTEN expression in endometrial carcinoma is associated with endometrioid histology; women with endometrioid tumors have a better prognosis than those with nonendometrioid tumors. The prognostic and predictive value for PTEN has not been effectively explored in ovarian/peritoneal high-grade serous carcinoma. PTEN immunohistochemistry was assessed in 126 women with Stage III, high-grade serous carcinoma of the ovary/peritoneum treated with surgery and then a platinum-based regimen. Compared with PTEN-negative or PTEN-reduced tumors, positive PTEN immunohistochemistry, detected in 58% of tumors, was associated with decreased pS6 and increased PTEN mRNA levels. Positive PTEN expression was independent of surgical debulking status or platinum sensitivity. PTEN-positive tumors were associated with significantly decreased recurrence-free survival. Importantly, the devised PTEN immunohistochemistry scoring system was reproducible among pathologists.
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http://dx.doi.org/10.1097/PGP.0000000000000205DOI Listing
November 2015