Publications by authors named "Gulisa Turashvili"

80 Publications

Lynch syndrome screening of women with endometrial cancer: feasibility and outcomes in a community program.

J Obstet Gynaecol Can 2021 Oct 14. Epub 2021 Oct 14.

LifeLabs.

Objective: Universal screening of endometrial cancer for underlying Lynch syndrome (LS) using DNA mismatch repair immunohistochemistry (MMR IHC) has been recommended. The objective of this study was to assess the feasibility and outcomes of using office endometrial samplings in a community LS screening program.

Methods: A community laboratory adopted Cancer Care Ontario's LS screening recommendations. All new endometrial cancers in women aged <70 years were screened for LS using MMR IHC and MLH1 promoter methylation testing cascade for MLH1/PMS2-deficient cases. This retrospective validation study analyzes the first year's results.

Results: Of 693 new endometrial cancers, 467 (67.4%) were eligible for LS screening. Both MMR IHC and MLH1 promoter methylation testing were conclusive in >98% of cases. MMR deficiency (MMRd), which includes LS screen positive cases, was identified in 25.9% of patients (121/467). LS screen positive tumours comprised 5.9% (27/467) of all cases.

Conclusion: Endometrial samplings from community practice are suitable for pre-operative LS screening. This testing can identify MMRd endometrial cancers with significant prognostic implications. Approximately 1 in 20 Ontario women <70 years with endometrial cancer screen positive for LS. Pre-operative and/or operative assessment for co-existent colonic neoplasms needs to be considered in this high-risk group. In addition, these women should be referred to genetic counselling.
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http://dx.doi.org/10.1016/j.jogc.2021.08.014DOI Listing
October 2021

What's new in gynecologic pathology 2021: ovary and fallopian tube.

J Pathol Transl Med 2021 Sep 15;55(5):366-367. Epub 2021 Sep 15.

Department of Pathology, University of Chicago Medical Center, Chicago, IL, USA.

The 5th edition of the World Health Organization (WHO) Classification of Female Genital Tumors was published in 2020. Although the classification of ovarian and fallopian tube neoplasms is largely unchanged from the prior (4th) edition, this newsletter compiles the most important refinements in these organ sites, including serous and non-serous epithelial tumors, and sex cord-stromal tumors.
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http://dx.doi.org/10.4132/jptm.2021.07.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476317PMC
September 2021

BCOR Internal Tandem Duplication Associated Uterine Sarcoma: Expanding the Clinicopathologic Spectrum.

Int J Gynecol Pathol 2021 Aug 30. Epub 2021 Aug 30.

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto (S.A.T., J.L.-E., G.T.) The Centre for Applied Genomics, The Hospital for Sick Children (T.A.P.) Advanced Molecular Diagnostics, Mount Sinai Hospital (A.W., D.Y., E.A., J.M., J.L.-E.), Toronto Department of Pathology and Laboratory Medicine, London Health Sciences Centre and Western University (H.E., E.A.G.) Department of Obstetrics & Gynecology, London Health Sciences Centre (M.P.), London, ON, Canada.

The diagnosis of high-grade endometrial stromal sarcoma has become more refined following molecular characterization of these tumors. Recently BCOR internal tandem duplications (ITD) have been identified in a small number of high-grade endometrial stromal sarcoma. Here we present an additional case of this rare entity in a young woman in her late teens. She presented with menorrhagia and underwent resection of 2 uterine lesions. The tumor was a spindle cell neoplasm composed of long fascicles with low to moderate cellularity, mild to moderate cytologic atypia, and up to 2 mitotic figures per 10 high power fields. Necrosis was not identified. Immunohistochemical stains showed the tumor to be positive for cyclin D1 in >50% of tumor cells, focally positive for CD10, and negative for SMA, desmin, h-caldesmon, and ALK1. BCOR ITD was confirmed by polymerase chain reaction with subsequent Sanger sequencing. Clues to the diagnosis of BCOR ITD uterine sarcoma include young patient age, uniform nuclear features, and diffuse positivity for cyclin D1. These features should prompt further molecular interrogation for definitive diagnosis, which is important for prognostication.
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http://dx.doi.org/10.1097/PGP.0000000000000822DOI Listing
August 2021

Solid Papillary Carcinoma and Encapsulated Papillary Carcinoma of the Breast: Clinical-Pathologic Features and Basement Membrane Studies of 50 Cases.

Pathobiology 2021 15;88(5):359-373. Epub 2021 Jul 15.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Introduction: Solid papillary carcinoma (SPC) and encapsulated papillary carcinoma (EPC) of the breast are usually considered in situ lesions due to favorable prognosis, despite the variable presence of myoepithelial cells. We aimed to describe clinical-pathologic features including basement membrane (BM) studies in these tumors.

Methods: Patients diagnosed with SPC and EPC in 2000-2019 were retrospectively identified. Microscopic slides and clinical history were reviewed. Immunohistochemical stains for BM and myoepithelial markers were performed.

Results: Of 23 SPCs and 27 EPCs, there were 5/23 (21.7%) pure SPCs and 9/27 (33.3%) pure EPCs, while 4/23 (17.4%) and 12/27 (44.5%) were associated with ductal carcinoma in situ (DCIS), and 6/23 (26.1%) and 6/27 (22.2%) with invasive carcinoma, respectively; 8/23 (34.8%) SPCs were considered invasive. The median tumor size was 1.7 cm (range 0.1-16). All tumors were positive for hormone receptors and negative for HER2. Myoepithelial cells were absent in 20 tumors (40%) and focally present in 30 (60%). Collagen IV and laminin were negative in most invasive lesions, but they were expressed in 21/21 (100%) and 18/21 (85.7%) of EPCs without invasion, and 16/17 (94.1%) and 10/17 (58.8%) SPCs, including invasive SPCs, respectively. Lymph node involvement was identified in 3/26 (11.5%) patients, including micrometastasis in 1 EPC associated with DCIS, macrometastasis in 1 EPC associated with invasive carcinoma, and isolated tumor cells in 1 invasive SPC. Of 31 patients with outcome data (median follow-up 35 months, range 1-85), 2 (6.5%; 1 SPC, 1 EPC) developed local recurrence, both associated with invasive carcinoma. No distant recurrences or deaths were observed.

Conclusions: Our study confirms favorable prognosis of SPCs and EPCs, with 2 local recurrences occurring in the presence of invasion. SPCs are more commonly associated with invasive carcinoma or considered invasive compared to EPCs (60.9 vs. 22.2%). The presence of BM material and lack of lymph node involvement in most cases indicates that the majority of these tumors may represent in situ lesions; however, some may behave as low-grade invasive malignancy with metastatic potential even in the absence of conventional invasion.
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http://dx.doi.org/10.1159/000517189DOI Listing
July 2021

PLAG1-rearrangment in a uterine leiomyosarcoma with myxoid stroma and heterologous differentiation.

Genes Chromosomes Cancer 2021 Oct 8;60(10):713-717. Epub 2021 Jul 8.

Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.

A variety of molecular alterations have been reported in uterine leiomyosarcomas, but most are considered nondiagnostic. There are, however, rare exceptions including PLAG1 rearrangement which has recently been identified in a subset of myxoid leiomyosarcomas. A 41-year-old woman presented with symptoms of a fibroid. She underwent a myomectomy which revealed a high-grade uterine sarcoma with areas of myxoid stroma and heterologous elements. The tumor expressed desmin, smooth muscle actin, H-caldesmon, and estrogen and progesterone receptors. RNA sequencing revealed a novel TRIM13-PLAG1 fusion gene which was subsequently independently confirmed by fluorescence in situ hybridization. On further evaluation the patient was found to have multiple pulmonary metastases and died due to disease progression shortly after diagnosis. This report describes a novel fusion partner of PLAG1 in a uterine leiomyosarcoma with myxoid leiomyosarcoma and heterologous elements, thereby broadening the spectrum of morphologic and genetic findings within this rare group of neoplasms.
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http://dx.doi.org/10.1002/gcc.22980DOI Listing
October 2021

MLH1 epimutation is a rare mechanism for Lynch syndrome: A case report and review of the literature.

Genes Chromosomes Cancer 2021 Sep 15;60(9):635-639. Epub 2021 May 15.

Department of Pathology and Laboratory Medicine, Sinai Health System and University of Toronto, Toronto, Ontario, Canada.

Endometrial carcinoma is one of the prototypical malignancies associated with Lynch syndrome, an inherited cancer syndrome most commonly caused by germline mutations in DNA mismatch repair (MMR) genes, although rare alternative mechanisms also exist. In this report, we describe a patient first diagnosed with colorectal cancer at age 33, then vulvar squamous cell carcinoma, facial sebaceous adenoma/sebaceoma, and finally endometrial carcinoma at age 52. All tumors were MLH1/PMS2-deficient by immunohistochemistry, and MLH1 promoter methylation was identified in the endometrial cancer. Germline MLH1 testing was negative for pathogenic variants, but she was subsequently diagnosed with Lynch syndrome secondary to a germline monoallelic constitutional epimutation of the MLH1 promoter. Identification of patients displaying a Lynch syndrome phenotype but lacking germline MMR mutations is important to avoid delays in the diagnosis of Lynch syndrome as well as the initiation of appropriate cancer screening and genetic counseling.
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http://dx.doi.org/10.1002/gcc.22957DOI Listing
September 2021

SATB2 Expression in Uterine Sarcoma: A Multicenter Retrospective Study.

Int J Gynecol Pathol 2021 Sep;40(5):487-494

Uterine sarcomas represent a clinical challenge because of their difficult diagnosis and the poor prognosis of certain subtypes. The aim of this study was to evaluate the expression of the special AT-rich sequence-binding protein 2 (SATB2) in endometrial stromal sarcoma (ESS) and other types of uterine sarcoma by immunohistochemistry. We studied the expression of SATB2 on 71 full tissue sections of endometrial stromal nodule, low-grade ESS, uterine leiomyomas and leiomyosarcoma, undifferentiated uterine sarcoma, adenosarcoma, and carcinosarcoma samples. Nuclear SATB2 expression was then evaluated in an extended sample set using a tissue microarray, including 78 additional uterine tumor samples. Overall, with a cut-off of ≥10% of tumor cell staining as positive, the nuclear SATB2 score was negative in all endometrial stromal nodule samples (n=10) and positive in 83% of low-grade ESS samples (n=29/35), 40% of undifferentiated uterine sarcoma (n=4/10), 13% of leiomyosarcoma (n=2/16), 14% of adenosarcoma (n=3/22), and 8% carcinosarcoma (n=2/25) samples. Furthermore, in ESS patients, direct comparison of nuclear SATB2 scores with clinicopathologic parameters and other reported biomarkers such as progesterone receptor and estrogen receptor showed that nuclear SATB2 was associated with PR expression and a decreased risk of disease-specific death (odds ratio=0.06, 95% confidence interval=0.04-0.81, P=0.04). Our data suggest that SATB2 could be a marker with relative sensitivity (83%) for distinguishing between endometrial stromal nodule and ESS with potential prognostic value.
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http://dx.doi.org/10.1097/PGP.0000000000000730DOI Listing
September 2021

HER2 fluorescent in situ hybridization signal degradation: a 10-year retrospective study.

Breast Cancer Res Treat 2021 Feb 3;186(1):99-105. Epub 2021 Jan 3.

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.

Context: Fluorescence in situ hybridization (FISH) analysis is recommended for invasive breast carcinomas with equivocal (2+) immunohistochemical expression of human epidermal growth factor receptor 2 (HER2). However, existing guidelines for the retention and storage requirements for HER2 FISH slides vary widely among countries and laboratories.

Objective: To determine the degradation rate of HER2 FISH signals, and the optimal retention time and storage conditions for HER2 FISH slides.

Design: Dual-probe HER2 FISH slides from March 2009 to June 2019 were retrieved from the archive to assess the presence, intensity and quantity of the green chromosome enumeration probe 17 (CEP 17) and orange HER2 signals. Per the institutional policy, FISH slides are placed in slide boxes and stored in - 80 °C freezers for up to 4 years, whereas older slides are stored at room temperature.

Results: After excluding HER2 FISH slides that were deemed uninterpretable due to technical issues, a total of 6255 slides were assessed. Slides from 2009 to 2014 were stored at room temperature, while slides from 2015 to 2019 were stored in - 80 °C freezers. Slides stored in freezers showed retention of both the green and the orange signals. Slide stored at room temperature demonstrated significant decrease in the signal retention rate and the loss of signal did not progress in a linear fashion. The CEP17 signal was quenched much faster than the HER2 signal.

Conclusion: Our study is the first to demonstrate HER2 FISH signal degradation with time and slide storage conditions. Storing HER2 FISH slides in a -80 °C freezer allows for retention of both HER2 and CEP17 signals. At room temperature, the signals start to degrade with CEP17 signals lost at a faster rate. The results of the study may be used in official guidelines for storage conditions and retention time for HER2 FISH slides.
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http://dx.doi.org/10.1007/s10549-020-06048-9DOI Listing
February 2021

A Survey of Breast Pathologists' Practice in Staging Multiple Foci of Invasive Carcinoma.

Clin Breast Cancer 2021 Oct 5;21(5):e506-e511. Epub 2020 Dec 5.

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: The American Joint Committee on Cancer (AJCC) staging system is the reference standard for describing the extent of neoplastic disease on the basis of the size of primary tumor (T), and the presence of regional lymph node (N) involvement and distant metastasis (M). Multiple foci of invasive breast carcinoma may pose staging challenges to the reporting pathologist. We set out to evaluate the practice of local breast pathologists with regard to staging of multiple foci of invasive carcinoma.

Patients And Methods: Breast pathologists were surveyed at a Community of Interest in Breast Pathology meeting. The live voting survey contained 6 case-based scenarios of multiple foci of invasive mammary carcinoma of the same or different histologic type and with unilateral or bilateral involvement. A supporting illustration was provided for each case.

Results: There was poor interobserver agreement with no consensus reached among the respondents in any of the cases. Staging choices varied from staging tumors together irrespective of histology or procedure type to staging tumors of the same histologic type together, or staging each tumor focus separately. Confusion was particularly evident when tumor foci with different histologic types were present.

Conclusion: Inconsistencies exist in the reporting of AJCC pathologic TNM stage for multiple foci of invasive carcinoma. The results serve as a reminder that education and strict adherence to the AJCC guidelines is essential for establishing standard practice in order to provide accurate cancer staging and ensure optimal clinical management.
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http://dx.doi.org/10.1016/j.clbc.2020.11.018DOI Listing
October 2021

Editorial: Hereditary Breast and Ovarian Cancer: Current Concepts of Prevention and Treatment.

Front Oncol 2020 2;10:618369. Epub 2020 Dec 2.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Mount Sinai Hospital, Toronto, ON, Canada.

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http://dx.doi.org/10.3389/fonc.2020.618369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738629PMC
December 2020

Pathology of IgG4-related sclerosing mastitis.

J Clin Pathol 2021 Aug 16;74(8):475-482. Epub 2020 Dec 16.

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

Immunoglobulin G4-related sclerosing mastitis (IgG4-RM) is a recently recognised member of the IgG4-related disease (IgG4-RD) family, a multisystem fibroinflammatory condition that can affect any organ system. IgG4-RM is rare and predominantly occurs in middle-aged women. It may present with painless palpable mass and/or lymphadenopathy thereby mimicking breast cancer. Although there is an abundance of literature describing the clinicopathological characteristics of IgG4-RD in a variety of organs, data on IgG4-RM are limited due to its rarity. This review describes the manifestation of the disease in the breast based on reported cases, emphasising the clinicopathological features, pathophysiology, differential diagnosis, treatment and prognosis.
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http://dx.doi.org/10.1136/jclinpath-2020-207029DOI Listing
August 2021

Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue Requirements.

Cancers (Basel) 2020 Nov 21;12(11). Epub 2020 Nov 21.

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON M5G 1X5, Canada.

Background: Approximately 25% of women diagnosed with tubo-ovarian high-grade serous carcinoma have germline deleterious mutations in or , characteristic of hereditary breast and ovarian cancer syndrome, while somatic mutations have been detected in 3-7%. We set out to determine the BRCA mutation rates and optimal tissue requirements for tumor BRCA testing in patients diagnosed with tubo-ovarian high-grade serous carcinoma.

Methods: Sequencing was performed using a multiplexed polymerase chain reaction-based approach on 291 tissue samples, with a minimum sequencing depth of 500X and an allele frequency of >5%.

Results: There were 253 surgical samples (87%), 35 biopsies (12%) and 3 cytology cell blocks (1%). The initial failure rate was 9% (25/291), including 9 cases (3%) with insufficient tumor, and 16 (6%) with non-amplifiable DNA. Sequencing was successful in 78% (228/291) and deemed indeterminate due to failed exons or variants below the limit of detection in 13% (38/291). Repeat testing was successful in 67% (28/42) of retested samples, with an overall success rate of 86% (251/291). Clinically significant (pathogenic, likely pathogenic) variants were identified in 17% (48/276) of complete and indeterminate cases. Successful sequencing was dependent on sample type, tumor cellularity and size ( ≤ 0.001) but not on neoadjuvant chemotherapy or age of blocks ( > 0.05).

Conclusions: Our study shows a 17% tumor BRCA mutation rate, with an overall success rate of 86%. Biopsy and cytology samples and post-chemotherapy specimens can be used for tumor testing, and optimal tumors measure ≥5 mm in size with at least 20% cellularity.
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http://dx.doi.org/10.3390/cancers12113468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700467PMC
November 2020

Assessment of Sentinel Lymph Node Biopsy vs Lymphadenectomy for Intermediate- and High-Grade Endometrial Cancer Staging.

JAMA Surg 2021 Feb;156(2):157-164

Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada.

Importance: Whether sentinel lymph node biopsy (SLNB) can replace lymphadenectomy for surgical staging in patients with high-grade endometrial cancer (EC) is unclear.

Objective: To examine the diagnostic accuracy of, performance characteristics of, and morbidity associated with SLNB using indocyanine green in patients with intermediate- and high-grade EC.

Design, Setting, And Participants: In this prospective, multicenter cohort study (Sentinel Lymph Node Biopsy vs Lymphadenectomy for Intermediate- and High-Grade Endometrial Cancer Staging [SENTOR] study), accrual occurred from July 1, 2015, to June 30, 2019, with early stoppage because of prespecified accuracy criteria. The study included patients with clinical stage I grade 2 endometrioid or high-grade EC scheduled to undergo laparoscopic or robotic hysterectomy with an intent to complete staging at 3 designated cancer centers in Toronto, Ontario, Canada.

Exposures: All patients underwent SLNB followed by lymphadenectomy as the reference standard. Patients with grade 2 endometrioid EC underwent pelvic lymphadenectomy (PLND) alone, and patients with high-grade EC underwent PLND and para-aortic lymphadenectomy (PALND).

Main Outcomes And Measures: The primary outcome was sensitivity of the SLNB algorithm. Secondary outcomes were additional measures of diagnostic accuracy, sentinel lymph node detection rates, and adverse events.

Results: The study enrolled 156 patients (median age, 65.5 years; range, 40-86 years; median body mass index [calculated as weight in kilograms divided by height in meters squared], 27.5; range, 17.6-49.3), including 126 with high-grade EC. All patients underwent SLNB and PLND, and 101 patients (80%) with high-grade EC also underwent PALND. Sentinel lymph node detection rates were 97.4% per patient (95% CI, 93.6%-99.3%), 87.5% per hemipelvis (95% CI, 83.3%-91.0%), and 77.6% bilaterally (95% CI, 70.2%-83.8%). Of 27 patients (17%) with nodal metastases, 26 patients were correctly identified by the SLNB algorithm, yielding a sensitivity of 96% (95% CI, 81%-100%), a false-negative rate of 4% (95% CI, 0%-19%), and a negative predictive value of 99% (95% CI, 96%-100%). Only 1 patient (0.6%) was misclassified by the SLNB algorithm. Seven of 27 patients with node-positive cancer (26%) were identified outside traditional PLND boundaries or required immunohistochemistry for diagnosis.

Conclusions And Relevance: In this prospective cohort study, SLNB had acceptable diagnostic accuracy for patients with high-grade EC at increased risk of nodal metastases and improved the detection of node-positive cases compared with lymphadenectomy. The findings suggest that SLNB is a viable option for the surgical staging of EC.
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http://dx.doi.org/10.1001/jamasurg.2020.5060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658802PMC
February 2021

p53 immunohistochemical analysis of fusion-positive uterine sarcomas.

Histopathology 2021 May 14;78(6):805-813. Epub 2021 Feb 14.

Department of Pathology and Laboratory Medicine, BC Cancer, Vancouver, BC, Canada.

Aims: Uterine sarcomas can be grouped into tumours with pathognomonic genetic fusions such as low-grade endometrial stromal sarcoma (LGESS), high-grade endometrial stromal sarcoma (HGESS), and inflammatory myofibroblastic tumour (IMT), and tumours lacking genetic fusions such as leiomyosarcoma (LMS) and undifferentiated uterine sarcoma (UUS). Members of the latter group frequently harbour TP53 mutations. The aim of this study was to evaluate TP53 mutations by the use of immunohistochemistry in fusion-positive uterine sarcomas.

Methods And Results: We performed p53 immunohistochemical staining on 124 uterine sarcomas harbouring genetic fusions and 38 fusion-negative LMSs and UUSs. These included 41 HGESSs with YWHAE, BCOR and BCORL1 fusions/rearrangements, 13 IMTs with ALK fusion, 12 sarcomas with NTRK1/3 fusion, three sarcomas with PDGFB fusion, and 55 LGESSs with JAZF1, SUZ12 and PHF1 fusions/rearrangements. All HGESSs, LGESSs, IMTs and sarcomas with PDGFB fusion showed wild-type p53 expression. Among NTRK1/3-positive sarcomas, a TPR-NTRK1-positive sarcoma with nuclear pleomorphism showed mutation-type p53 expression. The remaining 11 NTRK1/3-positive sarcomas showed wild-type p53 expression, except for the subclonal p53 mutation-type staining in a minor pleomorphic focus of an NTRK3-positive sarcoma. Twenty-one of 27 (78%) LMSs and six of nine (67%) UUSs showed mutation-type p53 expression.

Conclusion: p53 immunohistochemistry may be considered in the initial work-up of a uterine sarcoma, as mutation-type staining would make a fusion-positive sarcoma very unlikely. Mutation-type p53 expression, however, can be seen in a small subset of NTRK1/3-positive sarcomas showing pleomorphic round/ovoid cell histology, which may represent a mechanism of progression in these tumours.
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http://dx.doi.org/10.1111/his.14292DOI Listing
May 2021

Pathology of Hereditary Breast and Ovarian Cancer.

Front Oncol 2020 29;10:531790. Epub 2020 Sep 29.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

Hereditary breast and ovarian cancer (HBOC) syndrome is most commonly characterized by deleterious germline mutations in and . HBOC patients are prone to the development of malignant neoplasms in multiple organs including the breast, ovary, and fallopian tube. From a pathological perspective, a number of morphological features have been described in -associated breast and tubo-ovarian cancers. For example, breast cancers diagnosed in -mutation carriers are frequently of a high Nottingham grade and display medullary morphology and a triple-negative and/or a basal-like immunophenotype. In contrast, breast cancers in -mutation carriers are similar to sporadic luminal-type tumors that are positive for hormone receptors and lack expression of human epidermal growth factor receptor 2. Cancers arising in the fallopian tube and ovary are almost exclusively of a high-grade serous histotype with frequent Solid, pseudo-Endometrioid, and Transitional cell carcinoma-like morphology ("SET features"), marked nuclear atypia, high mitotic index, abundant tumor infiltrating lymphocytes, and necrosis. In addition, pushing or infiltrative micropapillary patterns of invasion have been described in -associated metastases of tubo-ovarian high-grade serous carcinomas. Besides and mutations, alterations in a number of other homologous recombination genes with moderate penetrance, including , and others, have also been described in HBOC patients with varying frequency; however, distinct morphological characteristics of these tumors have not been well characterized to date. In this review, the above pathological features are discussed in detail and a focus is placed on how accurate pathologic interpretation plays an important role in allowing HBOC patients to receive the best possible management.
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http://dx.doi.org/10.3389/fonc.2020.531790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550871PMC
September 2020

Androgenetic/Biparental Mosaic/Chimeric Conceptions With a Molar Component: A Diagnostic and Clinical Challenge.

Int J Gynecol Pathol 2021 Sep;40(5):510-517

Hydatidiform moles (HM) are gestational trophoblastic diseases which arise due to an imbalance in genetic material and which are morphologically characterized by enlarged and irregular chorionic villi and trophoblastic hyperplasia, among other features. The morphologic differential diagnosis for HM encompasses a number of entities including androgenetic/biparental mosaic/chimeric (ABMC) conceptions, an interesting duo of lesions with a nonmolar form (placental mesenchymal dysplasia) and a molar form (typically with a complete HM component). ABMC conceptions contain a mixture of 2 cell populations (1 androgenetic and 1 biparental) and arise as a result of mosaicism (mitotic error in a zygote) or chimerism (fusion of 2 zygotes). Because of their unique molecular underpinnings, these rare lesions show a number of findings including the presence of multiple villous populations, discordant p57 immunostaining, and mixed genotypes. ABMC conceptions are important to accurately diagnose as the molar form in particular carries a risk for persistent gestational trophoblastic diseases and thus requires appropriate treatment and follow-up. In this report, we provide detailed characterizations of 2 such cases of ABMC conceptions with a molar component. Both patients (ages 34 and 31) were in the first trimester of pregnancy and had ultrasound findings concerning for HM. Increased comprehension of the pathogenesis and morphology of ABMC conceptions, combined with ancillary techniques including p57 immunohistochemistry, fluorescence in situ hybridization, and molar genotyping, has allowed us to accurately and efficiently identify these lesions. However, a number of pitfalls exist which may lead to misdiagnosis.
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http://dx.doi.org/10.1097/PGP.0000000000000719DOI Listing
September 2021

Secondary Involvement of the Uterine Cervix by Nongynecologic Neoplasms: A Detailed Clinicopathologic Analysis.

Am J Surg Pathol 2020 12;44(12):1699-1711

Institute of Pathology, University Hospital of Leipzig, Germany.

Secondary involvement of the uterine cervix by nongynecologic neoplasms is rare accounting for <2% of metastases to the gynecologic tract. This study aimed to analyze the clinicopathologic features of cervical involvement by nongynecologic malignancies. A total of 47 cases were identified including 39 (83%) carcinomas, 6 lymphomas (12.8%), and 2 (4.2%) cutaneous malignant melanomas. The most common primary site of origin among carcinomas was the gastrointestinal tract (27, 69.2%), followed by breast and urothelium (5 each, 12.8%), gallbladder, and lung (1 each, 2.6%). The gynecologic tract was involved at the presentation in 16 patients (34%), including 5 (10.6%) with the cervix being the first site, 7 (14.9%) with synchronous involvement of the cervix and other gynecologic sites, and 4 (8.5%) with the involvement of other gynecologic sites before the cervical presentation. Patients with lymphoma were younger compared with those with carcinoma (43.7 vs. >50.5) (P=0.01). Mean time to identification of cervical metastases was <1 year for gallbladder carcinoma, melanomas, and gastrointestinal signet ring cell carcinomas (P=0.03). Features that varied with different types of metastatic tumor included lymphovascular space invasion, depth of stromal invasion, growth pattern (glands lacking architectural complexity, cribriforming, solid), presence of goblet cells, and signet ring cells, degree of cytologic atypia, and overall findings mimicking a benign/noninvasive process (P≤0.027). Six tumors (12.8%) were initially misdiagnosed as cervical primary. Metastatic nongynecologic tumors can mimic primary in situ or invasive neoplasms in both ectocervix and endocervix. In patients with a known prior malignancy, the clinical history with ancillary studies and a high level of suspicion are crucial to ensure accurate diagnosis.
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http://dx.doi.org/10.1097/PAS.0000000000001578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657974PMC
December 2020

Gene fusions characterize a subset of uterine cellular leiomyomas.

Genes Chromosomes Cancer 2020 Jul 17. Epub 2020 Jul 17.

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.

Uterine leiomyomas are the most common benign tumor of the female genital tract. Previous studies have shown that conventional leiomyomas often harbor-specific alterations including rearrangements involving HMGA2. Cellular leiomyomas are a variant of uterine leiomyoma that are less well-studied from a genomic point of view. Morphologically and immunohistochemically, cellular leiomyomas may be confused with low-grade endometrial stromal neoplasms, a group of tumors which frequently harbor a number of recurrent gene fusions. Ancillary molecular testing may be used to investigate tumors where low-grade endometrial stromal neoplasms enter into the differential diagnosis. At our institution, we identified a uterine cellular leiomyoma harboring a HMGA2-TRAF3IP2 fusion. After a retrospective review 11 additional tumors were identified. All included cases were reviewed and evaluated for immunohistochemical expression of smooth muscle actin, desmin, h-caldesmon, CD10, estrogen receptor, and progesterone receptor. RNA sequencing using the TruSight RNA Fusion Panel was performed on formalin-fixed paraffin-embedded tissue samples. In addition to the index case, two other cases harbored fusions: HMGA2-NAA11 and TPCN2-YAP1, of which the latter is novel and was confirmed with reverse transcriptase-polymerase chain reaction. In conclusion, a subset of cellular leiomyomas harbor rearrangements involving HMGA2, suggesting molecular kinship with conventional uterine leiomyomas. In addition, the prevalence of the novel TPCN2-YAP1 gene fusion in cellular leiomyomas requires further study. The fusions reported here, when identified, may be useful when the diagnosis of cellular leiomyoma is in question.
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http://dx.doi.org/10.1002/gcc.22888DOI Listing
July 2020

Multigene testing in breast cancer: What have we learned from the 21-gene recurrence score assay?

Breast J 2020 06 26;26(6):1199-1207. Epub 2020 May 26.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Most invasive breast cancers express hormone receptors (HR) and typically have a favorable prognosis following endocrine therapy. Patients at a higher risk of recurrence can be identified by multigene prognostic classifiers such as the 21-gene recurrence score (RS) assay, 70-gene prognostic signature, PAM-50, 12-gene molecular score, and others. The 21-gene RS assay (Oncotype Dx™, Genomic Health, Redwood City, CA) has level I clinical evidence and is the most widely used multigene assay in North America. The RS assay is based on reverse transcriptase polymerase chain reaction that can be performed on the RNA isolated from formalin-fixed paraffin-embedded tissue. It evaluates the expression of 16 cancer-related genes developed based on a multi-step approach. Due to its ability to assess recurrence risk and predict potential benefit from chemotherapy, the assay is recommended for patients with node-negative, HR-positive, and human epidermal growth factor receptor 2 (HER2)-negative breast cancer by the American Society of Clinical Oncology, National Comprehensive Cancer Network clinical practice guidelines in oncology, European Society for Medical Oncology clinical practice guidelines, and St. Gallen consensus panel guidelines. The RS assay has also been incorporated in the prognostic stage groups in the 8th edition of the American Joint Commission of Cancer staging manual in order to provide essential genomic information for optimal treatment decisions. This review will focus on the utility of the RS assay in HR-positive and HER2-negative breast cancer patients, including risk of distant and locoregional recurrence in node-negative and node-positive tumors, association with radiotherapy, special subtypes of breast cancer, practical issues related to selecting tumors for testing, and overview of the recently published TailorX (Trial Assigning IndividuaLized Options for treatment [Rx]) results.
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http://dx.doi.org/10.1111/tbj.13859DOI Listing
June 2020

High-grade transformation of low-grade endometrial stromal sarcomas lacking YWHAE and BCOR genetic abnormalities.

Mod Pathol 2020 09 21;33(9):1861-1870. Epub 2020 Apr 21.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

High-grade histologic transformation of low-grade endometrial stromal sarcoma (LGESS) is rare. Here, we describe the clinicopathologic features and gene fusion status of 12 cases (11 primary uterine corpus and 1 primary vaginal), 11 diagnosed prospectively from 2016, and 1 retrospectively collected. Targeted RNA sequencing and/or fluorescence in situ hybridization was employed in all cases. High-grade transformation was seen at the time of initial diagnosis in eight patients and at the time of recurrence in four patients, 4-11 years after initial diagnosis of LGESS. High-grade morphology consisted of generally uniform population of round to epithelioid cells with enlarged nuclei one to two times larger than a lymphocyte, visible nucleoli, and increased mitotic index (range, 6-30; median, 16 per 10 high-power fields); there was often an associated sclerotic and/or myxoid stroma. Estrogen receptor, progesterone receptor, and CD10 expression was absent or significantly decreased (compared with the low-grade component) in the high-grade foci of five tumors. One tumor demonstrated positive (diffuse and strong) cyclin D1 and BCOR staining. p53 staining was wild type in both components of all eight tumors tested. JAZF1-SUZ12 (n = 6), JAZF1-PHF1 (n = 3), EPC1-PHF1, (n = 1), or BRD8-PHF1 (n = 1) fusions were detected in 11 tumors; no fusions were found in one by targeted RNA sequencing. Patients presented with FIGO stages I (n = 4), II (n = 4), III (n = 1), and IV disease (n = 2). Median overall survival calculated from the time of histologic transformation was 22 months (range, 8 months to 8 years) with five patients who died of disease 8-18 months after transformation. High-grade transformation may occur in LGESS with JAZF1 and PHF1 rearrangements at the time of or years after initial diagnosis. Such high-grade transformation is characterized by nuclear enlargement, prominent nucleoli, and increased mitotic index compared with typical LGESS. Histologic high-grade transformation may herald aggressive behavior.
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http://dx.doi.org/10.1038/s41379-020-0535-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288077PMC
September 2020

Classic IgG4-related sclerosing mastitis is not so classic.

Breast J 2020 06 20;26(6):1245-1248. Epub 2020 Apr 20.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

IgG4-related sclerosing mastitis (IgG4-RM) is a rare, benign, mass-forming fibroinflammatory disease of the breast that can mimic a neoplastic process and pose a diagnostic challenge to clinicians and pathologists. We present a case of IgG4-RM in an 84-year-old woman and highlight the characteristic morphologic findings that should allow the pathologist to raise the possibility of this entity. We also briefly discuss pathophysiology and differential diagnosis. Awareness of clinical and morphologic features suggestive of this rare condition and its variable presentation in the breast can prevent unnecessary surgeries as well as undue patient anxiety.
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http://dx.doi.org/10.1111/tbj.13846DOI Listing
June 2020

Cystic neutrophilic granulomatous mastitis: an update.

J Clin Pathol 2020 Aug 24;73(8):445-453. Epub 2020 Feb 24.

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

Cystic neutrophilic granulomatous mastitis (CNGM) is a rare subtype of granulomatous mastitis with a highly distinct histological pattern often associated with species. CNGM is characterised by suppurative lipogranulomas that are composed of central lipid vacuoles rimmed by neutrophils and an outer cuff of epithelioid histiocytes. Some of the lipid vacuoles may contain sparse, rod-shaped, gram-positive bacilli that can be easily missed or dismissed. The surrounding mixed inflammatory infiltrate contains Langhans-type giant cells, lymphocytes and neutrophils. CNGM occurs in reproductive age women with a history of pregnancy and typically presents as a palpable mass that can be painful. CNGM has many mimickers, most significantly breast carcinoma. In many cases, CNGM has significant pathological and clinical overlap with other forms of granulomatous mastitis. Given the association with species, early diagnosis of CNGM is essential in offering patients the most appropriate treatment. Prolonged antibiotic therapy specifically directed to corynebacteria is required, sometimes even beyond resolution of clinical symptoms. This comprehensive review of the existing literature on CNGM describes clinical-pathological features, microbiological findings, challenges associated with the microscopic differential diagnosis, clinical implications of this diagnosis and emerging treatment options. Morphological criteria and suggested comments to convey the degree of diagnostic certainty are also proposed for standard pathology reporting.
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http://dx.doi.org/10.1136/jclinpath-2019-206180DOI 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

ADNP (Activity Dependent Neuroprotector Homeobox): A novel oncogene driving poor prognosis in high-grade serous carcinoma.

EBioMedicine 2020 Jan 2;51:102589. Epub 2020 Jan 2.

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, 600 University Avenue, Toronto, ON M5G 1X5, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2019.11.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940605PMC
January 2020

Wilms Tumor of the Ovary: Review of the Literature and Report of 2 Cases.

Int J Gynecol Pathol 2020 Jan;39(1):72-78

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Primary extrarenal Wilms tumor of the gynecologic tract is extremely rare with scattered case reports occurring in the ovary, uterine corpus and cervix. Only 9 cases of primary ovarian Wilms tumor have been reported to date. Here, we provide an extensive literature review and describe 2 patients with ovarian Wilms tumor: a 36-yr-old female (patient 1) and a 16-yr-old female (patient 2), both presenting with abdominal pain and suspected ovarian torsion. They were each found to have unilateral ovarian masses measuring >15 cm in size which were removed by unilateral salpingo-oophorectomy. Microscopically, the tumors exhibited the typical triphasic histology of Wilms tumor. In addition, the tumor from patient 1 contained elements of mature cystic teratoma, while an extensive rhabdomyosarcomatous component was identified in patient 2. Both tumors were diffusely and strongly positive for WT1 with variable staining for other biomarkers. The cases were diagnostically challenging and referred to our center for an expert opinion. Teratoid Wilms tumor in patient 1 is the second reported case of ovarian Wilms tumor arising in association with teratoma. Recognition of primary ovarian Wilms tumor requires a high index of suspicion and exclusion of other entities based on tumor morphology and immunohistochemical studies.
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http://dx.doi.org/10.1097/PGP.0000000000000565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546561PMC
January 2020

Cervical Glandular Neoplasia: Classification and Staging.

Surg Pathol Clin 2019 Jun;12(2):281-313

Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address:

Endocervical adenocarcinomas (EAs) account for 25% of all primary cervical carcinomas. Approximately 85% of EAs are driven by high-risk human papillomavirus (HPV) infection, the most common of which is the so-called usual type endocervical adenocarcinomas. Non-HPV-driven subtypes harbor distinct clinicopathologic features and prognosis and have been increasingly recognized in recent years, which has led to efforts to improve classification of EA based on clinically relevant and reproducible criteria. This review discusses a recently proposed classification system, the International Endocervical Adenocarcinoma Criteria and Classification, which uniquely integrates morphology, cause/pathogenesis, and biological behavior of HPV and non-HPV-driven subtypes of EA.
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http://dx.doi.org/10.1016/j.path.2019.01.002DOI Listing
June 2019

PGR Gene Fusions Identify a Molecular Subset of Uterine Epithelioid Leiomyosarcoma With Rhabdoid Features.

Am J Surg Pathol 2019 06;43(6):810-818

Departments of Pathology.

Genetic aberrations among uterine epithelioid leiomyosarcomas are unknown. Following identification of an index case with NR4A3-PGR fusion demonstrating monomorphic morphologic features, we interrogated additional uterine tumors demonstrating similar histology and sought to describe the morphologic and immunohistochemical characteristics of PGR-rearranged sarcomas. Targeted next-generation RNA sequencing was performed on RNA extracted from formalin-fixed paraffin-embedded tissue of the index case. Fluorescence in situ hybridization using custom probes flanking PGR and NR4A3 genes was applied to 17 epithelioid leiomyosarcomas, 6 endometrial stromal tumors, and 3 perivascular epithelioid cell tumors. NR4A3-PGR fusion (n=4) and PGR rearrangement (n=2) were detected in 6 (35%) epithelioid leiomyosarcomas. Median patient age was 45 years, and all presented with FIGO stage I or II tumors, 2 being alive with disease at 75 and 180 months. All tumors were centered in the cervical stroma or myometrium and consisted of cells with abundant eosinophilic cytoplasm (epithelioid), including many displaying dense intracytoplasmic inclusions (rhabdoid). Myxoid matrix and hydropic change imparted a microcystic growth pattern in 4 tumors. Five also showed a minor spindle cell component which was low-grade in 3, consisting of bland spindle cells with low mitotic activity. High-grade spindle cell morphology was seen in 2 tumors, exhibiting a storiform pattern of atypical spindle cells associated with brisk mitotic activity. Desmin, estrogen receptor, and progesterone receptor were positive in all 6 tumors, while CD10 and HMB45 were negative. PGR rearrangements define a genetic subset of epithelioid leiomyosarcomas with often biphasic morphology consisting of epithelioid and rhabdoid as well as spindle cell components.
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http://dx.doi.org/10.1097/PAS.0000000000001239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520111PMC
June 2019

Intravital imaging reveals systemic ezrin inhibition impedes cancer cell migration and lymph node metastasis in breast cancer.

Breast Cancer Res 2019 01 24;21(1):12. Epub 2019 Jan 24.

Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada.

Background: Limited understanding of the cancer biology of metastatic sites is a major factor contributing to poor outcomes in cancer patients. The regional lymph nodes are the most common site of metastasis in most solid cancers and their involvement is a strong predictor of relapse in breast cancer (BC). We have previously shown that ezrin, a cytoskeletal-membrane linker protein, is associated with lymphovascular invasion and promotes metastatic progression in BC. However, the efficacy of pharmacological inhibition of ezrin in blocking cancer cell migration and metastasis remains unexplored in BC.

Methods: We quantified ezrin expression in a BC tissue microarray (n = 347) to assess its correlation with risk of relapse. Next, we developed a quantitative intravital microscopy (qIVM) approach, using a syngeneic lymphatic reporter mouse tumor model, to investigate the effect of systemic ezrin inhibition on cancer cell migration and metastasis.

Results: We show that ezrin is expressed at significantly higher levels in lymph node metastases compared to matched primary tumors, and that a high tumor ezrin level is associated with increased risk of relapse in BC patients with regional disease. Using qIVM, we observe a subset of cancer cells that retain their invasive and migratory phenotype at the tumor-draining lymph node. We further show that systemic inhibition of ezrin, using a small molecule compound (NSC668394), impedes the migration of cancer cells in vivo. Furthermore, systemic ezrin inhibition leads to reductions in metastatic burden at the distal axillary lymph node and lungs.

Conclusions: Our findings demonstrate that the tumor ezrin level act as an independent biomarker in predicting relapse and provide a rationale for therapeutic targeting of ezrin to reduce the metastatic capacity of cancer cells in high-risk BC patients with elevated ezrin expression.
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http://dx.doi.org/10.1186/s13058-018-1079-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345049PMC
January 2019

Risk-based stratification of carcinomas concurrently involving the endometrium and ovary.

Gynecol Oncol 2019 01 6;152(1):38-45. Epub 2018 Nov 6.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Objective: Determining whether carcinomas concurrently involving endometrium and ovary are independent primary tumors (IPTs) or endometrial carcinomas with ovarian metastases (at least stage IIIA endometrial cancers, IIIA-EC) using clinicopathologic criteria is often challenging. Recent genomic studies showed that most such tumors are clonally related. We sought to identify clinicopathologic features associated with clinical outcomes, and to separate women with these tumors into clinically low-risk and high-risk groups.

Methods: We reviewed clinical and pathologic data from 74 women who, between 1993 and 2014, underwent primary surgery for endometrial cancer and had concurrent ovarian involvement.

Results: The endometrial carcinomas were endometrioid (EECs, n = 41) or non-endometrioid (ENECs, n = 33). Nineteen (26%) cases were originally classified as IPTs using clinicopathologic criteria. Multivariate analysis revealed that lymph node involvement (hazard ratio (HR) = 2.38, 95% CI 1.13-5.02, p = 0.023) and non-endometrioid endometrial tumor histology (HR = 6.27, 95% CI 2.6-15.13, p < 0.001) were associated with poorer progression-free survival (PFS). Multivariate analysis of 65 women with known lymph node status revealed two prognostically distinct groups: a high-risk group comprising ENECs with ≥50% myometrial invasion irrespective of lymph node status (n = 21; median PFS 12.7 months, 95% CI, 9.24-19.8); and a low-risk group consisting of all EECs, as well as lymph node-negative ENECs with <50% myometrial invasion (n = 44, median PFS not reached). The risk-based classification was superior to the original classification of endometrial cancers as IPTs vs. IIIA-EC for predicting PFS (log-rank test, p < 0.001 vs. p = 0.07).

Conclusion: Our proposed risk-based stratification enables categorization of women with concurrent endometrial and ovarian tumors according to their likely clinical outcomes.
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http://dx.doi.org/10.1016/j.ygyno.2018.10.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321787PMC
January 2019

Next-generation sequencing based detection of germline and somatic alterations in a patient with four metachronous primary tumors.

Gynecol Oncol Rep 2018 May 18;24:94-98. Epub 2018 Apr 18.

Gynecologic Medical Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Introduction: Multiple primary tumors (MPTs) are defined as two or more separate synchronous or metachronous neoplasms occurring in different sites in the same individual. These tumors differ in histology, as well as primary sites from which they arise. Risk factors associated with the occurrence of MPTs include germline alterations, exposure to prior cancer therapies, occupational hazards, and lifestyle and behavioral influences.

Case Report: We present a case of a patient who was diagnosed with four metachronous primary tumors. In 2013, she was diagnosed with serous proliferations associated with psammomatous bodies of primary peritoneal origin (pT3NxM0). This was followed by invasive ductal carcinoma of the breast (stage pT2N0Mx, histological grade III/III) in 2014, melanoma (stage pT2bNxMx) in 2016 that further advanced to the lung and brain in 2017, and a low-grade lung carcinoid in 2017. To better understand the biology of this patient's MPTs, we performed next-generation sequencing (NGS) to assess for both somatic and germline alterations. The treatment course for this patient aims to target the tumor with the strongest prognostic value, namely her malignant melanoma, and has contributed favorably to the overall survival of this patient.

Conclusion: We report the clinical and genomic landscape of a patient with MPTs who had no identifiable unique somatic or germline mutations to explain her predilection to cancer. The treatment course and overall prognosis for this patient is important for understanding future cases with unrelated, metachronous MPTs, the occurrence of which cannot always be explained by underlying genetic mechanisms.
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http://dx.doi.org/10.1016/j.gore.2018.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003430PMC
May 2018
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