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Jeremy P. Segal - One of the best experts on this subject based on the ideXlab platform.
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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, 2019Co-Authors: David B. Chapel, Sushant A. Patil, Andrei Plagov, Rutika Puranik, Anastasiya Mendybaeva, George Steinhardt, Pankhuri Wanjari, Ricardo R. Lastra, Sabah Kadri, Jeremy P. SegalAbstract: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, 2019Co-Authors: David B. Chapel, Sushant A. Patil, Andrei Plagov, Rutika Puranik, Anastasiya Mendybaeva, George Steinhardt, Pankhuri Wanjari, Ricardo R. Lastra, Sabah Kadri, Jeremy P. SegalAbstract: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.
Begüm Özel - One of the best experts on this subject based on the ideXlab platform.
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progestin therapy for obese women with complex Atypical Hyperplasia levonorgestrel releasing intrauterine device vs systemic therapy
American Journal of Obstetrics and Gynecology, 2020Co-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 ÖzelAbstract: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, 2019Co-Authors: Marcia A. Ciccone, Stephanie A. Whitman, Charlotte L. Conturie, Niquelle Brown, Christina E. Dancz, Begüm Özel, Koji MatsuoAbstract: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.
Lynn C Hartmann - One of the best experts on this subject based on the ideXlab platform.
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Atypical Hyperplasia of the breast risk assessment and management options
The New England Journal of Medicine, 2015Co-Authors: Lynn C Hartmann, Amy C Degnim, Richard J Santen, William D Dupont, Karthik GhoshAbstract: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, 2015Co-Authors: Lynn C Hartmann, Amy C Degnim, Richard J Santen, William D Dupont, Karthik GhoshAbstract: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, 2014Co-Authors: Lynn C Hartmann, Richard J Santen, Karthik Ghosh, Marlene H Frost, Robert A Vierkant, Daniel W Visscher, Derek C Radisky, Lorelle L Benetti, Yaman Tarabishy, Amy C DegnimAbstract: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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ki67 a time varying biomarker of risk of breast cancer in Atypical Hyperplasia
Breast Cancer Research and Treatment, 2010Co-Authors: Marta Santisteban, Amy C Degnim, Carol Reynolds, Emily Barr G Fritcher, Marlene H Frost, Robert A Vierkant, Stephanie Anderson, Daniel W Visscher, Shane V Pankratz, Lynn C HartmannAbstract:Uncontrolled proliferation is a defining feature of the malignant phenotype. Ki67 is a marker for proliferating cells and is overexpressed in many breast cancers. Atypical Hyperplasia is a premalignant lesion of the breast (relative risk ~ 4.0). Here, we asked if Ki67 expression could stratify risk in women with atypia. Ki67 expression was assessed immunohistochemically by digital image analysis in archival sections from 192 women with atypia diagnosed at the Mayo Clinic 1/1/67–12/31/91. Risk factor and follow-up data were obtained via study questionnaire and medical records. Observed breast cancer events were compared to population expected rates (Iowa SEER) using standardized incidence ratios (SIRs). We examined two endpoints: risk of breast cancer within 10 years and after 10 years of atypia biopsy. Thirty-two (16.7%) of the 192 women developed breast cancer over a median of 14.6 years. Thirty percent (58) of the atypias had ≥2% cells staining for Ki67. In these women, the risk of breast cancer within 10 years after atypia was increased (SIR 4.42 [2.21–8.84]) but not in those with <2% staining. Specifically, the cumulative incidence for breast cancer at 10 years was 14% in the high Ki67 vs. 3% in the low Ki67 group. Conversely, after 10 years, risk in the low Ki67 group rose significantly (SIR 5.69 [3.63–8.92]) vs. no further increased risk in the high Ki67 group (SIR 0.78 [0.11–5.55]). Ki67 appears to be a time-varying biomarker of risk of breast cancer in women with Atypical Hyperplasia.
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Refining risk assessment in women with Atypical Hyperplasia
Current Breast Cancer Reports, 2009Co-Authors: Amy C Degnim, Lynn C HartmannAbstract:Atypical Hyperplasia (AH) is associated with an approximate fourfold increase in breast cancer risk. Although this increase in risk is significant, the majority of women with AH will not develop breast cancer. Current breast cancer risk prediction models are unable to provide accurate risk estimates for individuals with AH. Tamoxifen offers a substantive risk reduction for women with AH, but its profile of risks and side effects limits its acceptance and widespread use. Therefore, additional differentiation of breast cancer risk among women with AH is desirable. In addition to clinical factors (ie, age at AH diagnosis), recently investigated histologic features and molecular markers of an individual’s breast tissue show promise as features that further differentiate breast cancer risk in women with AH.
David B. Chapel - One of the best experts on this subject based on the ideXlab platform.
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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, 2019Co-Authors: David B. Chapel, Sushant A. Patil, Andrei Plagov, Rutika Puranik, Anastasiya Mendybaeva, George Steinhardt, Pankhuri Wanjari, Ricardo R. Lastra, Sabah Kadri, Jeremy P. SegalAbstract: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, 2019Co-Authors: David B. Chapel, Sushant A. Patil, Andrei Plagov, Rutika Puranik, Anastasiya Mendybaeva, George Steinhardt, Pankhuri Wanjari, Ricardo R. Lastra, Sabah Kadri, Jeremy P. SegalAbstract: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.
Lois M Ramondetta - One of the best experts on this subject based on the ideXlab platform.
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Prospective Phase II Trial of Levonorgestrel Intrauterine Device: Non-Surgical Approach for Complex Atypical Hyperplasia and Early Endometrial Cancer
American Journal of Obstetrics and Gynecology, 2020Co-Authors: Shannon N. Westin, Russell Broaddus, Diana L Urbauer, Kathleen M Schmeler, Lois M Ramondetta, Bryan Fellman, Charlotte C. Sun, Misty L. Woodall, Navdeep Pal, Pamela T SolimanAbstract:Abstract Background The incidence of complex Atypical Hyperplasia and early stage endometrioid endometrial cancer is increasing, in part due to the epidemic of obesity, a risk factor tightly linked to development of endometrial Hyperplasia and cancer. The standard upfront treatment for complex Atypical Hyperplasia and early stage endometrial cancer is hysterectomy. However, non-surgical treatment of early endometrial neoplasia may be necessary due to medical co-morbidities precluding surgery or desired future fertility. Objective We sought to evaluate efficacy of the Levonorgestrel Intrauterine Device to treat complex Atypical Hyperplasia and grade 1 endometrioid endometrial carcinoma. Study Design A single-institution, single-arm, phase II study of the Levonorgestrel Intrauterine Device (52 mg levonorgestrel, Mirena®) was conducted in patients with complex Atypical Hyperplasia or grade 1 endometrioid endometrial cancer. The primary endpoint was pathologic response rate at 12 months, including complete or partial response. Quality of life and toxicity were assessed. Molecular analyses for proliferation markers, hormone-regulated genes, and WNT pathway activation were performed at baseline and 3 months. Results Fifty-seven patients were treated (21 endometrial cancer, 36 complex Atypical Hyperplasia). Median age was 48.0 years, median body mass index was 45.5 kg/m2. Of 47 evaluable patients, 12-month response rate was 83% (90%CrI 72.7, 90.3); 37 complete responders (8 endometrial cancer; 29 complex Atypical Hyperplasia), 2 partial responders (2 endometrial cancer), 3 stable disease (2 endometrial cancer, 1 complex Atypical Hyperplasia), 5 progressive disease (3 endometrial cancer; 2 complex Atypical Hyperplasia). After stratification for histology, response rate was 90.6% for complex Atypical Hyperplasia and 66.7% for grade 1 endometrioid endometrial cancer. Four patients (9.5%) had relapse after initial response. Adverse events were mild, primarily irregular bleeding and cramping. Quality of life was not negatively impacted. At 3 months, exogenous progesterone effect was present in 96.9% of responders (31/32) versus 25% (2/8) of non-responders (p=0.001). Non-responders had higher baseline proliferation (Ki67) and lower DKK3 gene expression compared to responders (p=.023 and p=0.030). Non-responders had significantly different changes in sFRP1, FZD8, and RALDH2 compared to responders. Conclusion The Levonorgestrel Intrauterine Device has substantial activity in complex Atypical Hyperplasia and grade 1 endometrioid endometrial cancer, with a modest proportion demonstrating upfront progesterone resistance. Potential biomarkers were identified that may correlate with resistance to therapy, further exploration is warranted.
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treatment of low risk endometrial cancer and complex Atypical Hyperplasia with the levonorgestrel releasing intrauterine device
Obstetrics & Gynecology, 2017Co-Authors: Russell Broaddus, Diana L Urbauer, Nyla Balakrishnan, Andrea Milbourne, Kathleen M Schmeler, Larissa A Meyer, Pamela T Soliman, Karen H Lu, Pedro Tomas Ramirez, Lois M RamondettaAbstract:OBJECTIVE: To assess efficacy of the levonorgestrel-releasing intrauterine device (LNG-IUD) for treatment of complex Atypical Hyperplasia or low-grade endometrial cancer. METHODS: This retrospective case series included all patients treated with the LNG-IUD for complex Atypical Hyperplasia or early-grade endometrial cancer from January 2003 to June 2013. Response rates were calculated and the association of response with clinicopathologic factors, including age, body mass index, and uterine size, was determined. RESULTS: Forty-six patients diagnosed with complex Atypical Hyperplasia or early-grade endometrial cancer were treated with the LNG-IUD. Of 32 evaluable patients at the 6-month time point, 15 had complex Atypical Hyperplasia (47%), nine had G1 endometrial cancer (28%), and eight had grade 2 endometrial cancer (25%). Overall response rate was 75% (95% CI 57-89) at 6 months; 80% (95% CI 52-96) in complex Atypical Hyperplasia, 67% (95% CI 30-93) in grade 1 endometrial cancer, and 75% (CI 35-97) in grade 2 endometrial cancer. Of the clinicopathologic features evaluated, there was a trend toward the association of lack of exogenous progesterone effect in the pathology specimen with nonresponse to the IUD (P=.05). Median uterine diameter was 1.3 cm larger in women who did not respond to the IUD (P=.04). CONCLUSION: Levonorgestrel-releasing IUD therapy for the conservative treatment of complex Atypical Hyperplasia or early-grade endometrial cancer resulted in return to normal histology in a majority of patients.
