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Atypical Hyperplasia

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Jeremy P. Segal – One of the best experts on this subject based on the ideXlab platform.

  • Quantitative next-generation sequencing-based analysis indicates progressive accumulation of microsatellite instability between Atypical Hyperplasia/endometrial intraepithelial neoplasia and paired endometrioid endometrial carcinoma
    Modern Pathology, 2019
    Co-Authors: David B. Chapel, Sushant A. Patil, Andrei Plagov, Rutika Puranik, Anastasiya Mendybaeva, George Steinhardt, Pankhuri Wanjari, Ricardo R. Lastra, Sabah Kadri, Jeremy P. Segal

    Abstract:

    Atypical Hyperplasia/endometrial intraepithelial neoplasia is an accepted precursor to endometrioid-type endometrial carcinoma. Mismatch repair-deficient endometrial carcinomas are also known to be a biologically and clinically distinct subset of tumors. However, the development of microsatellite instability in endometrial carcinogenesis has not yet been evaluated by novel next-generation sequencing-based methods. We examined 17 mismatch repair-deficient endometrioid endometrial carcinomas and their paired Atypical Hyperplasia/endometrial intraepithelial neoplasia precursors using a next-generation sequencing panel with quantitative microsatellite instability detection at 336 loci. Findings were compared to histological features, polymerase chain reaction-based microsatellite instability testing, immunohistochemical expression of mismatch repair proteins, and tumor mutational burden calculations. All 17 endometrial carcinomas and 8/17 Atypical Hyperplasia/endometrial intraepithelial neoplasia showed microsatellite instability by next-generation sequencing-based testing. Endometrial carcinoma specimens showed significantly more unstable microsatellite loci than paired Atypical Hyperplasia/endometrial intraepithelial neoplasia (mean: 40.0% vs 19.9 unstable loci, respectively). Out of nine microsatellite-stable Atypical Hyperplasia/endometrial intraepithelial neoplasia specimens, four showed mismatch repair loss by immunohistochemistry. All Atypical Hyperplasia/endometrial intraepithelial neoplasia and endometrial carcinoma specimens with microsatellite instability were also mismatch repair-deficient by immunohistochemistry. Tumor mutational burden was significantly greater in endometrial carcinoma than in paired Atypical Hyperplasia/endometrial intraepithelial neoplasia specimens, and tumor mutational burden was significantly correlated with percent unstable microsatellite loci. Paired Atypical Hyperplasia/endometrial intraepithelial neoplasia and endometrial carcinoma specimens show progressive accumulation of unstable microsatellite loci following loss of mismatch repair protein expression. Comprehensive next-generation sequencing-based testing of endometrial carcinomas offers new insights into endometrial carcinogenesis and opportunities for improved tumor surveillance, diagnosis, and management.

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  • quantitative next generation sequencing based analysis indicates progressive accumulation of microsatellite instability between Atypical Hyperplasia endometrial intraepithelial neoplasia and paired endometrioid endometrial carcinoma
    Modern Pathology, 2019
    Co-Authors: David B. Chapel, Sushant A. Patil, Andrei Plagov, Rutika Puranik, Anastasiya Mendybaeva, George Steinhardt, Pankhuri Wanjari, Ricardo R. Lastra, Sabah Kadri, Jeremy P. Segal

    Abstract:

    Atypical Hyperplasia/endometrial intraepithelial neoplasia is an accepted precursor to endometrioid-type endometrial carcinoma. Mismatch repair-deficient endometrial carcinomas are also known to be a biologically and clinically distinct subset of tumors. However, the development of microsatellite instability in endometrial carcinogenesis has not yet been evaluated by novel next-generation sequencing-based methods. We examined 17 mismatch repair-deficient endometrioid endometrial carcinomas and their paired Atypical Hyperplasia/endometrial intraepithelial neoplasia precursors using a next-generation sequencing panel with quantitative microsatellite instability detection at 336 loci. Findings were compared to histological features, polymerase chain reaction-based microsatellite instability testing, immunohistochemical expression of mismatch repair proteins, and tumor mutational burden calculations. All 17 endometrial carcinomas and 8/17 Atypical Hyperplasia/endometrial intraepithelial neoplasia showed microsatellite instability by next-generation sequencing-based testing. Endometrial carcinoma specimens showed significantly more unstable microsatellite loci than paired Atypical Hyperplasia/endometrial intraepithelial neoplasia (mean: 40.0% vs 19.9 unstable loci, respectively). Out of nine microsatellite-stable Atypical Hyperplasia/endometrial intraepithelial neoplasia specimens, four showed mismatch repair loss by immunohistochemistry. All Atypical Hyperplasia/endometrial intraepithelial neoplasia and endometrial carcinoma specimens with microsatellite instability were also mismatch repair-deficient by immunohistochemistry. Tumor mutational burden was significantly greater in endometrial carcinoma than in paired Atypical Hyperplasia/endometrial intraepithelial neoplasia specimens, and tumor mutational burden was significantly correlated with percent unstable microsatellite loci. Paired Atypical Hyperplasia/endometrial intraepithelial neoplasia and endometrial carcinoma specimens show progressive accumulation of unstable microsatellite loci following loss of mismatch repair protein expression. Comprehensive next-generation sequencing-based testing of endometrial carcinomas offers new insights into endometrial carcinogenesis and opportunities for improved tumor surveillance, diagnosis, and management.

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Begüm Özel – One of the best experts on this subject based on the ideXlab platform.

  • progestin therapy for obese women with complex Atypical Hyperplasia levonorgestrel releasing intrauterine device vs systemic therapy
    American Journal of Obstetrics and Gynecology, 2020
    Co-Authors: Rachel S Mandelbaum, Marcia A. Ciccone, Christina E. Dancz, David J Nusbaum, Mahdi Khoshchehreh, Heena Purswani, Elise B Morocco, Meghan B Smith, Shinya Matsuzaki, Begüm Özel

    Abstract:

    Background Though hysterectomy remains the standard treatment for complex Atypical Hyperplasia, patients who desire fertility or who are poor surgical candidates may opt for progestin therapy. However, the effectiveness of the levonorgestrel-releasing intrauterine device compared to systemic therapy in the treatment of complex Atypical Hyperplasia has not been well studied. Objective We sought to examine differences in treatment response between local progestin therapy with the levonorgestrel-releasing intrauterine device and systemic progestin therapy in women with complex Atypical Hyperplasia. Methods This single-institution retrospective study examined women with complex Atypical Hyperplasia who received progestin therapy between 2003 and 2018. Treatment response was assessed by histopathology on subsequent biopsies. Time-dependent analyses of complete response and progression to cancer were performed comparing the levonorgestrel-releasing intrauterine device and systemic therapy. A propensity score inverse probability of treatment weighting model was used to create a weighted cohort that differed based on treatment type but was similar with respect to other characteristics. An interaction-term analysis was performed to examine the impact of body habitus on treatment response, and an interrupted time-series analysis was employed to assess if changes in treatment patterns correlated with outcomes over time. Results A total of 245 women with complex Atypical Hyperplasia received progestin therapy (levonorgestrel-releasing intrauterine device n = 69 and systemic therapy n = 176). The mean age and body mass index were 36.9 years and 40.0 kg/m2, respectively. In the patient-level analysis, women who received the levonorgestrel-releasing intrauterine device had higher rates of complete response (78.7% vs 46.7%; adjusted hazard ratio, 3.32; 95% confidence interval, 2.39–4.62) and a lower likelihood of progression to cancer (4.5% vs 15.7%; adjusted hazard ratio, 0.28; 95% confidence interval, 0.11–0.73) compared to those who received systemic therapy. In particular, women with class III obesity derived a higher relative benefit from levonorgestrel-releasing intrauterine device therapy in achieving complete response compared to systemic therapy: class III obesity, adjusted hazard ratio 4.72, 95% confidence interval 2.83–7.89; class I–II obesity, adjusted hazard ratio 1.83, 95% confidence interval 1.09–3.09; and nonobese, adjusted hazard ratio 1.26, 95% confidence interval 0.40–3.95. In the cohort-level analysis, the obesity rate increased during the study period (77.8% to 88.2%, 13.4% relative increase, P = .033) and levonorgestrel-releasing intrauterine device use significantly increased after 2007 (6.3% to 82.7%, 13.2-fold increase, P Conclusion Our study suggests that local therapy with the levonorgestrel-releasing intrauterine device may be more effective than systemic therapy for women with complex Atypical Hyperplasia who opt for nonsurgical treatment, particularly in morbidly obese women. Shifts in treatment paradigm during the study period toward increased levonorgestrel-releasing intrauterine device use also led to improved complete response rates despite increasing rates of obesity.

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  • Effectiveness of progestin-based therapy for morbidly obese women with complex Atypical Hyperplasia.
    Archives of Gynecology and Obstetrics, 2019
    Co-Authors: Marcia A. Ciccone, Stephanie A. Whitman, Charlotte L. Conturie, Niquelle Brown, Christina E. Dancz, Begüm Özel, Koji Matsuo

    Abstract:

    Objective
    While progestins can effectively treat women with complex Atypical Hyperplasia (CAH), the impact of body habitus on treatment outcome is not well studied. We examine the association between body mass index (BMI) and progestin treatment outcomes.

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Lynn C Hartmann – One of the best experts on this subject based on the ideXlab platform.

  • Atypical Hyperplasia of the breast risk assessment and management options
    The New England Journal of Medicine, 2015
    Co-Authors: Lynn C Hartmann, Amy C Degnim, Richard J Santen, William D Dupont, Karthik Ghosh

    Abstract:

    Some benign breast lesions have a greatly increased risk of becoming invasive cancers. Atypical Hyperplasia is a common high-risk benign lesion, and measures to prevent its progression to cancer are available but underutilized.

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  • Atypical Hyperplasia of the Breast — Risk Assessment and Management Options
    New England Journal of Medicine, 2015
    Co-Authors: Lynn C Hartmann, Amy C Degnim, Richard J Santen, William D Dupont, Karthik Ghosh

    Abstract:

    Some benign breast lesions have a greatly increased risk of becoming invasive cancers. Atypical Hyperplasia is a common high-risk benign lesion, and measures to prevent its progression to cancer are available but underutilized.

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  • understanding the premalignant potential of Atypical Hyperplasia through its natural history a longitudinal cohort study
    Cancer Prevention Research, 2014
    Co-Authors: Lynn C Hartmann, Karthik Ghosh, Richard J Santen, Marlene H Frost, Robert A Vierkant, Daniel W Visscher, Derek C Radisky, Lorelle L Benetti, Yaman Tarabishy, Amy C Degnim

    Abstract:

    Atypical Hyperplasia is a high-risk premalignant lesion of the breast, but its biology is poorly understood. Many believe that Atypical ductal Hyperplasia (ADH) is a direct precursor for low-grade ductal breast cancer, whereas Atypical lobular Hyperplasia (ALH) serves as a risk indicator. These assumptions underlie current clinical recommendations. We tested these assumptions by studying the characteristics of the breast cancers that develop in women with ADH or ALH. Using the Mayo Benign Breast Disease Cohort, we identified all women with ADH or ALH from 1967 to 2001 and followed them for later breast cancers, characterizing side of breast cancer versus side of atypia; time to breast cancer; type, histology, and grade of breast cancer, looking for patterns consistent with precursors versus risk indicators. A total of 698 women with Atypical Hyperplasia were followed a mean of 12.5 years; 143 developed breast cancer. For both ADH and ALH, there is a 2:1 ratio of ipsilateral to contralateral breast cancer. The ipsilateral predominance is marked in the first 5 years, consistent with a precursor phenotype for both ADH and ALH. For both, there is a predominance of invasive ductal cancers with 69% of moderate or high grade. Twenty-five percent are node positive. Both ADH and ALH portend risk for ductal carcinoma in situ and invasive breast cancers, predominantly ductal, with two thirds moderate or high grade. The ipsilateral breast is at especially high risk for breast cancer in the first 5 years after atypia, with risk remaining elevated in both breasts long term. ADH and ALH behave similarly in terms of later breast cancer endpoints. Cancer Prev Res; 7(2); 211–7. ©2014 AACR .

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