Hiroko Machida

Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma

BACKGROUND To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma. PATIENTS AND METHODS A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes. RESULTS Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P < 0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P < 0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P < 0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P > 0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P < 0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P < 0.001). CONCLUSION Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.

Significance of monocyte counts on tumor characteristics and survival outcome of women with endometrial cancer

OBJECTIVE Tumor-associated macrophages are known to be associated with decreased survival of patients with endometrial cancer. Given the physiological link of circulating monocytes as a progenitor of tumor-associated macrophages, monocyte counts were examined for tumor characteristics and survival in endometrial cancer. METHODS A retrospective study was conducted to examine consecutive patients with endometrial cancer with all histologic types who underwent hysterectomy-based surgical staging between 2003 and 2013 (n=541). Preoperative monocyte counts were correlated to patient demographics, pathological findings, complete blood count results, and survival outcomes. RESULTS Median monocyte counts were 0.5×10(9)/L. Monocyte counts significantly correlated with all other complete blood count components, with neutrophil counts having the most significant association (r=0.52, p<0.001). Elevated monocyte counts (defined as >0.7×10(9)/L) when compared to lower counts were significantly associated with an increased risk of >50% myometrial tumor invasion (29.2% versus 22.0%, odds ratio [OR] 1.59, 95% confidence interval [CI] 1.01-2.45, p=0.045), pelvic lymph node metastasis (39.0% versus 18.8%, OR 2.76, 95%CI 1.35-5.62, p=0.007), and advanced-stage (stage I through IV, 18.5%, 24.6%, 32.5%, and 41.5%, p=0.001). In survival analysis, elevated monocyte counts were associated with decreased disease-free survival (5-year rates, 71.0% versus 84.5%, p=0.001) and overall survival (77.2% versus 89.3%, p<0.001). In multivariate analysis, elevated monocyte counts remained an independent prognostic factor for decreased disease-free (hazard ratio [HR] 1.74, 95% CI 1.02-2.96, p=0.041) and overall (HR 2.63, 95% CI 1.37-5.05, p=0.004) survival. CONCLUSIONS Elevated monocyte counts were associated with aggressive tumor features and poor survival outcomes of patients with endometrial cancer.

Impact of depth and extent of lymphovascular space invasion on lymph node metastasis and recurrence patterns in endometrial cancer

To determine the significance of depth and extent of lymphovascular space invasion (LVSI) on lymph node metastasis and recurrence in endometrial cancer.

Association of Low-Dose Aspirin and Survival of Women With Endometrial Cancer.

OBJECTIVE: To examine the survival outcomes in women with endometrial cancer who were taking low-dose aspirin (81–100 mg/d). METHODS: A multicenter retrospective study was conducted examining patients with stage I–IV endometrial cancer who underwent hysterectomy-based surgical staging between January 2000 and December 2013 (N=1,687). Patient demographics, medical comorbidities, medication types, tumor characteristics, and treatment patterns were correlated to survival outcomes. A Cox proportional hazard regression model was used to estimate adjusted hazard ratio for disease-free and disease-specific overall survival. RESULTS: One hundred fifty-eight patients (9.4%, 95% confidence interval [CI] 8.8–11.9) were taking low-dose aspirin. Median follow-up time for the study cohort was 31.5 months. One hundred twenty-seven patients (7.5%) died of endometrial cancer. Low-dose aspirin use was significantly correlated with concurrent obesity, hypertension, diabetes mellitus, and hypercholesterolemia (all P<.001). Low-dose aspirin users were more likely to take other antihypertensive, antiglycemic, and anticholesterol agents (all P<.05). Low-dose aspirin use was not associated with histologic subtype, tumor grade, nodal metastasis, or cancer stage (all P>.05). On multivariable analysis, low-dose aspirin use remained an independent prognostic factor associated with an improved 5-year disease-free survival rate (90.6% compared with 80.9%, adjusted hazard ratio 0.46, 95% CI 0.25–0.86, P=.014) and disease-specific overall survival rate (96.4% compared with 87.3%, adjusted hazard ratio 0.23, 95% CI 0.08–0.64, P=.005). The increased survival effect noted with low-dose aspirin use was greatest in patients whose age was younger than 60 years (5-year disease-free survival rates, 93.9% compared with 84.0%, P=.013), body mass index was 30 or greater (92.2% compared with 81.4%, P=.027), who had type I cancer (96.5% compared with 88.6%, P=.029), and who received postoperative whole pelvic radiotherapy (88.2% compared with 61.5%, P=.014). These four factors remained significant for disease-specific overall survival (all P<.05). CONCLUSION: Our results suggest that low-dose aspirin use is associated with improved survival outcomes in women with endometrial cancer, especially in those who are young, obese, with low-grade disease, and who receive postoperative radiotherapy.

Ovarian Conservation and Overall Survival in Young Women With Early-Stage Low-Grade Endometrial Cancer.

OBJECTIVE: To characterize contributing factors for ovarian conservation during surgical treatment for endometrial cancer and to examine the association of ovarian conservation on survival of young women with early-stage, low-grade tumors. METHODS: This was a population-based study using the Surveillance, Epidemiology, and End Results program to identify surgically treated stage I type I (grade 1–2 endometrioid histology) endometrial cancer cases diagnosed between 1983 and 2012 (N=86,005). Multivariable models were used to identify independent factors for ovarian conservation. Survival outcomes and cause of death were examined for women aged younger than 50 with stage I type I endometrial cancer who underwent ovarian conservation (1,242 among 12,860 women [9.7%]). RESULTS: On multivariable analysis, age younger than 50 years, grade 1 endometrioid histology, and tumor size 2.0 cm or less were noted to be independent factors for ovarian conservation (all, P<.001). For 9,110 women aged younger than 50 years with stage I grade 1 tumors, cause-specific survival was similar between ovarian conservation and oophorectomy cases (20-year rates 98.9% compared with 97.7%, P=.31), whereas overall survival was significantly higher in ovarian conservation cases than oophorectomy cases (88.8% compared with 82.0%, P=.011). On multivariable analysis, ovarian conservation remained an independent prognostic factor for improved overall survival (adjusted hazard ratio 0.73, 95% confidence interval [CI] 0.54–0.98, P=.036) and was independently associated with a lower cumulative risk of death resulting from cardiovascular disease compared with oophorectomy (20-year rates, 2.3% compared with 3.7%, adjusted hazard ratio 0.40, 95% CI 0.17–0.91, P=.029). Contrary, cause-specific survival (20-year rates 94.6% compared with 96.1%, P=.68) and overall survival (81.0% compared with 80.6%, P=.91) were similar between ovarian conservation and oophorectomy among 3,750 women aged younger than 50 years with stage I grade 2 tumors. CONCLUSION: Ovarian conservation is performed in less than 10% of young women with stage I type I endometrial cancer. Ovarian conservation is associated with decreased mortality in young women with stage I grade 1 tumors.

Impact of adjuvant therapy on recurrence patterns in stage I uterine carcinosarcoma

BACKGROUND To examine recurrence patterns in women with stage I uterine carcinosarcoma (UCS) stratified by adjuvant therapy pattern. METHODS We examined 443 cases of stage I UCS derived from a retrospective cohort of 1192 UCS cases from 26 institutions. Adjuvant therapy patterns after primary hysterectomy-based surgery were correlated to recurrence patterns. RESULTS The most common adjuvant therapy was chemotherapy alone (41.5%) followed by chemotherapy/radiotherapy (15.8%) and radiotherapy alone (8.4%). Distant-recurrence was the most common recurrence pattern (5-year cumulative rate, 28.1%) followed by local-recurrence (13.3%). On multivariate analysis, chemotherapy but not radiotherapy remained an independent prognostic factor for decreased risk of local-recurrence (5-year cumulative rates 8.7% versus 19.8%, adjusted-hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.25-0.83, P=0.01) and distant-recurrence (21.2% versus 38.0%, adjusted-HR 0.41, 95%CI 0.27-0.62, P<0.001). The chemotherapy/radiotherapy group had a lower 5-year cumulative local-recurrence rate compared to the chemotherapy alone group but it did not reach statistical significance (5.1% versus 10.1%, adjusted-HR 0.46, 95%CI 0.13-1.58, P=0.22). Radiotherapy significantly decreased local-recurrence when tumors had high-grade carcinoma, sarcoma component dominance, and deep myometrial tumor invasion (all, P<0.05); and combining radiotherapy with chemotherapy was significantly associated with decreased local-recurrence compared to chemotherapy alone in the presence of multiple risk factors (5-year cumulative rates, 2.5% versus 21.8%, HR 0.12, 95%CI 0.02-0.90; P=0.013) but not in none/single factor (P=0.36). CONCLUSION Adjuvant chemotherapy appears to be effective to control both local- and distant-recurrences in stage I UCS; adding radiotherapy to chemotherapy may be effective to control local-recurrence when the tumor exhibits multiple risk factors.

Ovarian Conservation and Overall Survival in Young Women With Early-stage Cervical Cancer

OBJECTIVE To identify predictors of ovarian conservation at hysterectomy and to examine the association of ovarian conservation and survival of young women with early-stage cervical cancer. METHODS This is a retrospective cohort study using the Surveillance, Epidemiology, and End Results Program to identify hysterectomy-based surgically treated patients with stage I cervical cancer diagnosed between 1983 and 2012 (N=16,511). Multivariable models were used to identify independent factors associated with ovarian conservation. Among the subgroup of 9,419 women younger than 50 years of age with stage I disease, survival outcomes and causes of death were examined for 3,908 (41.5%) women who underwent ovarian conservation at hysterectomy without radiotherapy. RESULTS On multivariable analysis, age younger than 50 years, stage IA disease, and squamous histology were independent factors associated with ovarian conservation (all, P<.001). Among 5,526 women younger than 50 years of age with stage IA disease who underwent hysterectomy without radiotherapy, overall survival was significantly higher in patients undergoing ovarian conservation than in those undergoing oophorectomy (20-year rate, 93.5% compared with 86.8%, P<.001); cervical cancer-specific survival was similar between the patients who underwent ovarian conservation and those who underwent oophorectomy (98.8% compared with 97.8%, P=.12). On multivariable analysis, ovarian conservation remained an independent prognostic factor for improved overall survival (adjusted hazard ratio 0.63, 95% confidence interval [CI] 0.49-0.82, P=.001) and was independently associated with lower cumulative risks of death resulting from cardiovascular disease (20-year cumulative rate, 1.2% compared with 3.3%, adjusted hazard ratio 0.47, 95% CI 0.26-0.86, P=.014) and other chronic disease (0.5% compared with 1.4%, adjusted hazard ratio 0.24, 95% CI 0.09-0.65, P=.005) compared with oophorectomy. Both cervical cancer-specific survival (20-year rate, 93.1% compared with 92.0%, P=.37) and overall survival (86.7% compared with 84.6%, P=.12) were similar between ovarian conservation and oophorectomy among 3,893 women younger than 50 years of age with stage IB disease who underwent hysterectomy without radiotherapy. CONCLUSION Among young women with stage IA cervical cancer, ovarian conservation at hysterectomy is associated with decreased all-cause mortality including death resulting from cardiovascular disease and other chronic diseases.

Tumor characteristics and survival outcomes of women with tamoxifen-related uterine carcinosarcoma

OBJECTIVE To examine tumor characteristics and survival outcome of women with uterine carcinosarcoma who had a history of tamoxifen use. METHODS This is a multicenter retrospective study examining stage I-IV uterine carcinosarcoma cases based on history of tamoxifen use. Patient demographics, tumor characteristics, treatment pattern, and survival outcomes were compared between tamoxifen users and non-users. RESULTS Sixty-six cases of tamoxifen-related uterine carcinosarcoma were compared to 1009 cases with no history of tamoxifen use. Tamoxifen users were more likely to be older (mean age, 69 versus 64, P<0.001) and had a past history of malignancy (100% versus 12.7%, P<0.001). Tamoxifen-related uterine carcinosarcoma was significantly associated with a higher proportion of stage IA disease (48.4% versus 29.9%) and a lower risk of stage IVB disease (7.8% versus 16.0%) compared to tamoxifen-unrelated carcinosarcoma (P=0.034). Deep myometrial tumor invasion was less common in uterine carcinosarcoma related to tamoxifen use (28.3% versus 48.8%, P=0.002). On univariate analysis, tamoxifen use was not associated with progression-free survival (5-year rates 44.5% versus 46.8%, P=0.48) and disease-specific survival (64.0% versus 59.1%, P=0.39). After adjusting for age, past history of malignancy, stage, residual disease status at surgery, and postoperative treatment patterns, tamoxifen use was not associated with progression-free survival (adjusted-hazard ratio 0.86, 95% confidence interval 0.50 to 1.50, P=0.60) and disease-specific survival (adjusted-hazard ratio 0.68, 95% confidence interval 0.36 to 1.29, P=0.24). CONCLUSION Our study suggests that tamoxifen-related uterine carcinosarcoma may have favorable tumor characteristics but have comparable stage-specific survival outcomes compared to tamoxifen-unrelated uterine carcinosarcoma.

Trends of uterine carcinosarcoma in the United States

Objective Uterine carcinosarcoma (UCS) is a rare type of high-grade endometrial cancer (EC) that has been understudied with population-based statistics due to its rarity. This study examined temporal trends in the proportion of UCS among women with EC. Methods This is a retrospective observational study examining The Surveillance, Epidemiology, and End Results program between 1973–2013. Primary EC cases were eligible for analysis, and a time-specific proportion of UCS was examined during the study period. Results UCS was seen in 11,000 (4.7%) women among 235,849 primary EC cases. Mean age at UCS diagnosis increased from 65.9 to 71.7 years between 1973–1989 and then decreased from 71.7 to 67.0 years between 1989–2013 (both, p<0.001). Proportion of Black women significantly increased during the study period (11.9%–20.0%, p<0.001), whereas the proportion of White women decreased from 86.0% to 60.5% between 1987–2013 (p<0.001). There was a significant increase in the proportion of UCS among primary EC from 1.7% to 5.6% between 1973–2013 (p<0.001). Among type II ECs (n=76,118), the proportion of UCS also increased significantly from 6.0% to 17.5% between 1973–2013 (p<0.001). An increasing proportion of UCS was seen in both young and older women but the magnitude of interval increase was larger in the older age group between 1973–2013 (<60 years, from 1.3% to 3.3%. p<0.001; and ≥60 years, from 2.6% to 7.0%, p<0.001). Conclusion Our study demonstrated that the proportion of UCS has significantly increased among EC, accounting for more than 5% in recent years.

Survival outcome of women with stage IV uterine carcinosarcoma who received neoadjuvant chemotherapy followed by surgery

To examine survival of women with stage IV uterine carcinosarcoma (UCS) who received neoadjuvant chemotherapy followed by hysterectomy.