Haider Mahdi

Implementation of tumor testing for lynch syndrome in endometrial cancers at a large academic medical center

OBJECTIVES Lynch syndrome (LS) is a hereditary condition that increases the risk for endometrial and other cancers. Recognizing women at risk for LS based on personal/family history is burdensome and imprecise. Tumor testing using microsatellite instability (MSI) testing and immunohistochemistry (IHC) for mismatch repair protein expression can be an effective strategy for identifying potential LS in patients presenting with colorectal or endometrial cancer. Here we describe our experience implementing a screening program for endometrial cancers. METHODS Endometrial cancers diagnosed ≤50 years or those with suspicious personal history or histopathologic features were screened with MSI/IHC, June 2009-June 2011. Criteria were later (July 2011-July 2012) expanded to patients diagnosed <60 years, or at any age with suspicious features, and finally (after August 2012) universal screening was implemented. Screening techniques began with both MSI and IHC for every tumor, and later converted to IHC for two proteins, and MLH1 promoter methylation analysis when indicated. A genetic counselor contacted patients directly to offer genetic counseling appointments. RESULTS Two hundred and forty-five endometrial cancers (average age, 57 years) were screened. Sixty-two patients (25%) had abnormal results, and 42 patients were referred for genetic counseling. Of the 42 patients, 34 underwent genetic counseling, 28 pursued genetic testing, and 11 were diagnosed with LS. When age and pathology criteria were used, 27 eligible cases were overlooked for screening and 3 cases of LS were found only because a clinician requested screening. CONCLUSIONS Universal screening of endometrial cancers for LS is practical and successfully implemented with collaboration among genetic counselors, gynecologic oncologists, and pathologists.

Predictors of surgical site infection in women undergoing hysterectomy for benign gynecologic disease: a multicenter analysis using the national surgical quality improvement program data.

STUDY OBJECTIVE To estimate the rate and predictors of surgical site infection (SSI) after hysterectomy performed for benign indications and to identify any association between SSI and other postoperative complications. DESIGN Retrospective cohort study (Canadian Task Force classification II-2). SETTING National Surgical Quality Improvement Program data. PATIENTS Women who underwent abdominal or laparoscopic hysterectomy performed for benign indications from 2005 to 2011. INTERVENTIONS Univariable and multivariable logistic regression analyses were used to identify predictors of SSI and its association with other postoperative complications. Odds ratios were adjusted for patient demographic data, comorbidities, preoperative laboratory values, and operative factors. MEASUREMENTS AND MAIN RESULTS Of 28 366 patients, 758 (3%) were diagnosed with SSI. SSI occurred more often after abdominal than laparoscopic hysterectomy (4% vs 2%; p < .001). Among patients who underwent abdominal hysterectomy, predictors of SSI included diabetes, smoking, respiratory comorbidities, overweight or obesity, American Society of Anesthesiologists class ≥ 3, perioperative blood transfusion, and operative time >180 minutes. Among those who underwent laparoscopic hysterectomy, predictors of SSI included perioperative blood transfusion, operative time >180 minutes, serum creatinine concentration ≥ 2 mg/dL, and platelet count ≥ 350 000 cells/mL(3). For patients with deep or organ/space SSI, significant predictors included perioperative blood transfusion and American Society of Anesthesiologists class ≥ 3 for abdominal hysterectomy, and non-white race, renal comorbidities, preoperative or perioperative blood transfusion, and operative time >180 minutes for laparoscopic hysterectomy. SSI was associated with longer hospital stay and higher rates of repeat operation, sepsis, renal failure, and wound dehiscence. SSI was not associated with increased 30-day mortality. CONCLUSIONS SSI occurred more often after abdominal hysterectomy than laparoscopic hysterectomy performed to treat benign gynecologic disease. SSI was associated with increased postoperative complications but not mortality. Several risk factors for SSI after each abdominal and laparoscopic hysterectomy were identified in this study.

The Impact of Obesity on the 30-Day Morbidity and Mortality After Surgery for Endometrial Cancer

STUDY OBJECTIVES To examine the effect of body mass index (BMI) on postoperative 30-day morbidity and mortality after surgery to treat endometrial cancer. DESIGN Retrospective cohort study (Canadian Task Force classification II-2). SETTING National Surgical Quality Improvement Program. PATIENTS Patients with endometrial cancer who underwent surgery from 2005 to 2011. INTERVENTIONS Women were grouped according to weight, as follows: normal weight (BMI 18 to <30), obese (BMI 30 to <40), and morbidly obese (BMI ≥ 40). Univariate and multivariable logistic regression models were analyzed. MEASUREMENTS AND MAIN RESULTS Of 3947 patients, 38% were of normal weight, 38% were obese, and 24% were morbidly obese. Of these, 48% underwent laparoscopy and 52% underwent laparotomy. Overall 30-day morbidity and mortality were 13% and 0.7%, respectively. Obesity and morbid obesity were associated with a higher American Society of Anesthesiologists class, diabetes, and hypertension. Preoperatively, elevated serum creatinine concentration, hypoalbuminemia, and leukocytosis were more common in morbidly obese women than those of normal weight. Laparoscopic surgery was performed less frequently in morbidly obese women than in those of normal weight (42.5% vs 50%; p = .001). Morbidly obese patients were more likely to develop postoperative complications (morbidly obese 16% vs normal weight 13% vs obese 11%; p = .001), in particular surgical (morbidly obese 14% vs normal weight 11% vs obese 9%; p < .001) and infectious complications (morbidly obese 10% vs normal weight 5% vs obese 5%; p = .01). After laparotomy, morbidly obese women demonstrated a higher rate of any complication (normal weight 21%, obese 18%, morbidly obese 25%; p = .002), surgical complications (normal weight 18%, obese 14%, morbidly obese 22%; p = .002) and infectious complications (normal weight 6%, obese 10%, morbidly obese 16%; p < .001). After laparoscopy there was no difference in complication rates according to BMI group. The 30-day mortality was not significantly different according to BMI. After adjusting for confounders, obesity and morbid obesity did not independently predict 30-day morbidity or mortality. CONCLUSIONS Morbidly obese patients with endometrial cancer have more preoperative morbidities and postoperative complications, in particular surgical and infectious complications, and are less likely to undergo minimally invasive surgery. However, obesity was not an independent predictor of perioperative outcomes after controlling for other confounders.

Germline PTEN, SDHB‐D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden‐like syndromes: An international, multicenter, prospective study

Endometrial cancer has been recognized only recently as a major component of Cowden syndrome (CS). Germline alterations in phosphatase and tensin homolog (PTEN; PTEN_mut+), succinate dehydrogenase B/C/D (SDHB‐D; SDHx_var+), and killin (KLLN_Me+) cause CS and Cowden syndrome–like (CSL) phenotypes. This study was aimed at identifying the prevalence and clinicopathologic predictors of germline PTEN_mut+, SDHx_var+, and KLLN_Me+ in CS/CSL patients presenting with endometrial cancer.

Recurrence patterns and survival endpoints in women with stage II uterine endometrioid carcinoma: A multi-institution study

OBJECTIVE There is paucity of data in regard to prognostic factors and outcome of women with 2009 FIGO stage II disease. The objective of this study was to investigate prognostic factors, recurrence patterns and survival endpoints in this group of patients. METHODS Data from four academic institutions were analyzed. 130 women were identified with 2009 FIGO stage II. All patients underwent hysterectomy, oophorectomy and lymph node evaluation with or without pelvic and paraaortic lymph node dissections and peritoneal cytology. The Kaplan-Meier approach and Cox regression analysis were used to estimate recurrence-free (RFS), disease-specific (DSS) and overall survival (OS). RESULTS Median follow-up was 44months. 120 patients (92%) underwent simple hysterectomy, 78% had lymph node dissection and 95% had peritoneal cytology examination. 99 patients (76%) received adjuvant radiation treatment (RT). 5-year RFS, DSS and OS were 77%, 90%, and 72%, respectively. On multivariate analysis of RFS, adjuvant RT, the presence of lymphovascular space invasion (LVSI) and high tumor grades were significant predictors. For DSS, LVSI and high tumor grades were significant predictors while older age and high tumor grade were the only predictors of OS. CONCLUSIONS In this multi-institutional study, disease-specific survival for women with FIGO stage II uterine endometrioid carcinoma is excellent. High tumor grade, lymphovascular space invasion, adjuvant radiation treatment and old age are important prognostic factors. There was no significant difference in the outcome between patients who received vaginal cuff brachytherapy compared to those who received pelvic external beam radiation treatment.

Impact of age on 30-day mortality and morbidity in patients undergoing surgery for endometrial cancer☆

OBJECTIVES To investigate the impact of age on postoperative mortality and morbidity for women undergoing surgery for endometrial cancer. METHODS Patients with endometrial cancer who had a hysterectomy were identified in the 2005-2011 National Surgical Quality Improvement Program database. Patient characteristics and outcomes were compared between age groups. Multivariable logistic regression models were used. RESULTS 4000 patients met inclusion criteria. Octogenarians (n=328) were less likely to undergo laparoscopic surgery (p<0.001) but there was no difference in surgical complexity among age groups (p=0.54). In multivariate analysis, ages 60-69 (OR 0.9, 95% CI 0.3-2.8, p=0.82), 70-79 (OR 1.4, 95% CI 0.4-4.3, p=0.60) and ≥80 years (OR 2.4, 95% CI 0.7-8.1, p=0.17) were not associated with increased mortality compared to age<60 years. Significant predictors of mortality were respiratory or renal disease, dependent functional status, and hypoalbuminemia. Octogenarians were more likely to have non-surgical complications (8% vs. 3-5%, p=0.001) but there was no difference in surgical complications (p=0.89). In multivariate analysis, ages 60-69 (OR 1.2, 95% CI 1.0-1.6, p=0.09), 70-79 (OR 1.3, 95% CI 1.0-1.8, p=0.05) and ≥80 years (OR 1.3, 95% CI 0.9-2.5, p=0.14) were not associated with increased complications compared to age<60 years. Significant predictors of complications were higher ASA class, anemia, and thrombocytosis. CONCLUSIONS Older patients should not be denied surgery for endometrial cancer based on age alone as they do not have higher rates of 30-day morbidity or mortality after adjusting for other factors. An increased effort should be made to perform minimally invasive surgery in octogenarians.

Type II endometrial cancer in Hispanic women: Tumor characteristics, treatment and survival compared to non-Hispanic white women

OBJECTIVES To compare survival of Hispanic white (HW) and non-Hispanic white (NHW) women with type II endometrial adenocarcinoma (EC). METHODS Patients with serous, clear cell or grade 3 endometrioid EC were identified from the Surveillance, Epidemiology, and End Results (SEER) program 1988-2009 and were divided into HW and NHW. HW were subdivided into natives and immigrants. RESULTS Of the 14,434 women, 13,012 (90.2%) were NHW and 1422 (9.8%) were HW. HW were younger than NHW (mean 63 vs. 68years, p<0.001). A higher proportion of HW presented with late stage disease than NHW (43.8% vs. 36.6%, p=0.04). Performing lymphadenectomy was not different but HW were more likely to have positive lymph nodes than NHW (27.6% vs. 23.1%, p=0.02). Further, HW were less likely to receive radiation than NHW (39.5% vs. 42.3%, p=0.04). No difference in clinicopathologic characteristics was found between immigrant and native HW. In multivariate models adjusting for age, stage, histology, surgical treatment, extent of lymphadenectomy, and radiation therapy, no difference in overall survival (OS) (HR 1.06, 95% CI 0.97-1.16, p=0.19) and cancer-specific survival (CSS) (HR 1.02, 95% CI 0.91-1.14, p=0.75) was found between HW and NHW. Interestingly, immigrant HW had better OS (HR 0.74, 95% CI 0.62-0.89, p<0.001) and CSS (HR 0.72, 95% CI 0.58-0.90, P=0.003) than native HW. CONCLUSIONS Although they were more likely to present with advanced stage and positive nodal disease, no difference in outcome was noted between Hispanic and non-Hispanic whites with EC. Interestingly, immigrant HW had more favorable outcome compared to native HW.

Endometrial cancer in Asian and American Indian/Alaskan Native women: Tumor characteristics, treatment and outcome compared to non-Hispanic white women

OBJECTIVE The objective of this study is to compare survival of Asian (AS), American Indian/Alaskan Native (AI/AN) and non-Hispanic white (NHW) women with endometrial adenocarcinoma (EC). METHODS Patients with EC were identified from the Surveillance, Epidemiology, and End Results program from 1988 to 2009. Kaplan-Meier survival methods and Cox proportional hazards regression were performed. RESULTS Of the 105,083 women, 97,763 (93%) were NHW, 6699 (6.4%) were AS and 621 (0.6%) were AI/AN. AS and AI/AN were younger than NHW with mean age of 57.7 and 56.5 vs. 64.3 years (p < 0.001 and 0.059). Advanced stage and high-risk histology were more prominent in AS than NHW (15.6% vs. 13.3%, p = 0.04, 10.6% vs. 9.6%, p= 0.041). Lymphadenectomy was performed more frequently in AS than NHW (56.7% vs. 48.2%, p < 0.001). Asian immigrants were younger than Asian natives (mean age 57 vs. 60.5 years, p < 0.001). In multivariate analysis, AS had better overall (OS) (HR 0.86, 95% CI 0.81-0.91, p < 0.001) and cancer-specific survival (CSS) (HR 0.92, 95% CI 0.84-1.00, p = 0.05) than NHW. Further, Asian immigrants had better OS (HR 0.83, 95% CI 0.73-0.94, p = 0.002) and CSS (HR 0.66, 95% CI 0.54-0.80, p < 0.001) than Asian natives. In contrast, AI/AN had worse OS (HR 1.35, 95% CI 1.15-1.59, p < 0.001) but no difference in CSS (HR 1.06, 95% CI 0.80-1.40, p = 0.69) than NHW. CONCLUSIONS Asians were younger at presentation, more likely to have lymphadenectomy and had an improved outcome compared to NHW. Interestingly, Asian immigrants had more favorable outcome than Asians born in the US. Further studies are warranted to find possible explanations for such a difference.

Prognostic impact of lymphadenectomy in uterine clear cell carcinoma

Objective The aim of this study was to estimate the survival impact of lymphadenectomy in patients diagnosed with uterine clear cell cancer (UCCC). Methods Patients with a diagnosis of UCCC were identified from Surveillance, Epidemiology, and End Results (SEER) program from 1988 to 2007. Only surgically treated patients were included. Statistical analysis using Student t-test, Kaplan-Meier survival methods, and Cox proportional hazard regression were performed. Results One thousand three hundred eighty-five patients met the inclusion criteria; 955 patients (68.9%) underwent lymphadenectomy. Older patients (≥65) were less likely to undergo lymphadenectomy compared with their younger cohorts (64.3% vs. 75.9%, p<0.001). The prevalence of nodal metastasis was 24.8%. Out of 724 women who had disease clinically confined to the uterus and underwent lymphadenectomy, 123 (17%) were found to have nodal metastasis. Lymphadenectomy was associated with improved survival. Patients who underwent lymphadenectomy were 39% (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.52 to 0.72; p<0.001) less likely to die than patient who did not have the procedure. Moreover, more extensive lymphadenectomy correlated positively with survival. Compared to patients with 0 nodes removed, patients with more extensive lymphadenectomy (1 to 10 and >10 nodes removed) were 32% (HR, 0.68; 95% CI, 0.56 to 0.83; p<0.001) and 47% (HR, 0.53; 95% CI, 0.43 to 0.65; p<0.001) less likely to die, respectively. Conclusion The extent of lymphadenectomy is associated with an improved survival of patients diagnosed with UCCC.

Impact of adjuvant chemotherapy and pelvic radiation on pattern of recurrence and outcome in stage I non-invasive uterine papillary serous carcinoma. A multi-institution study

OBJECTIVES To determine the impact of adjuvant chemotherapy or pelvic radiation on risk of recurrence and outcome in stage IA non-invasive uterine papillary serous carcinoma (UPSC). METHODS This is a multi-institutional retrospective study for 115 patients with stage IA non-invasive UPSC (confined to endometrium) treated between 2000 and 2012. Kaplan-Meier and multivariable Cox proportional hazards regression modeling were used. RESULTS Staging lymphadenectomy and omentectomy were performed in 84% and 57% respectively. Recurrence was seen in 26% (30/115). Sites of recurrences were vaginal in 7.8% (9/115), pelvic in 3.5% (4/115) and extra-pelvic in 14.7% (17/115). Adjuvant chemotherapy did not impact risk of recurrence (25.5% vs. 26.9%, p=0.85) even in subset of patients who underwent lymphadenectomy (20% vs. 23.5%, p=0.80). These findings were consistent for pattern of recurrence. Among those who underwent lymphadenectomy, adjuvant chemotherapy did not impact progression-free survival (p=0.34) and overall survival (p=0.12). However among patients who did not have lymphadenectomy, adjuvant chemotherapy or pelvic radiation was associated with longer progression-free survival (p=0.04) and overall survival (p=0.025). In multivariable analysis, only staging lymphadenectomy was associated with improved progression-free survival (HR 0.34, 95% CI 0.12-0.95, p=0.04) and overall survival (HR 0.35, 95% CI 0.12-1.0, p=0.05). Neither adjuvant chemotherapy nor pelvic radiation were predictors of progression-free or overall survivals. CONCLUSION In stage IA non-invasive UPSC, staging lymphadenectomy was significantly associated with recurrence and outcome and therefore, should be performed in all patients. Adjuvant chemotherapy or pelvic radiation had no impact on outcome in surgically staged patients but was associated with improved outcome in unstaged patients.