Clinicopathologic Features and Genetic Alterations in Mixed-Type Ampullary Carcinoma.

Mixed-type ampullary carcinoma is a subtype that combines intestinal-type (I-type) and pancreatobiliary-type (PB-type) lesions, but few studies have examined its clinicopathologic features and genetic alterations. The differences in genetic alterations between mixed type and other subtypes, as well as the genetic differences between I-type and PB-type lesions in the mixed type, remain unclear. In this study, we compared the clinicopathologic features and prognosis of 110 ampullary carcinomas classified by hematoxylin and eosin and immunohistochemical staining as follows: 63 PB-type, 35 I-type, and 12 mixed-type carcinomas. A comparative analysis of genetic mutations by targeted sequencing of 24 genes was also performed in 3 I-type cases, 9 PB-type cases, and I and PB-type lesions of 6 mixed-type cases. The mixed subtype had a poorer prognosis than the other subtypes, and there was also a similar tendency in the adjuvant group (n = 22). A total of 49 genetic mutations were detected in all 18 lesions for which genetic alteration was analyzed. No genetic mutations specific to the mixed type were found, and it was not possible to determine genetically whether the mixed type had originally been I or PB type. However, 5 of 6 cases had mutations common to both I and PB-type lesions, and additional mutations were found only in either I or PB-type lesions. In support of this, the mixed type more frequently exhibited genetic heterogeneity intratumorally than the other subtypes. Mixed-type tumors are histologically, immunohistochemically, and genetically heterogeneous, and this heterogeneity is associated with poor prognosis and may affect treatment resistance.

Correlation of basal cell carcinoma subtype with histologically confirmed subclinical extension during Mohs micrographic surgery: A prospective multicenter study.

BACKGROUND: Traditionally "aggressive" histologic subtypes (HSs) of basal cell carcinoma (BCC) are more likely to quantitatively exhibit subclinical extension (SCE), requiring more stages during Mohs micrographic surgery (MMS) and, therefore, larger margins upon excision. However, the tendency for SCE has never been compared between HSs of BCC in a prospective manner. OBJECTIVE: To prospectively correlate the HS of BCC with the likelihood of SCE as defined by the number of MMS stages required to clear the tumor. METHODS: In a prospective, multicenter study involving 17 Mohs surgeons in 16 different practices across the United States, data regarding 1686 cases of BCC undergoing MMS were collected. Patient demographics, tumor characteristics, number of MMS stages required for tumor clearance, and specific BCC subtypes noted on both index biopsy and the final MMS stage were recorded. RESULTS: Analysis of the average number of MMS stages for each HS required to clear tumor revealed 2 distinct degrees of SCE (P < .0001): high (higher than average) risk of SCE (1.9 stages, 1.0 SD) and low (lower than average) risk of SCE (1.6 stages, 0.9 SD). Subtypes of BCC within the high category were morpheaform (2.1), infiltrative (1.9), metatypical (1.9), mixed (1.8), and superficial (1.8). The low category included BCC subtypes of basosquamous (1.6), micronodular (1.6), nodular (1.6), and unspecified (1.5). Three hundred twenty-four cases (22.0%) manifested HS drift or a change in subtype from index biopsy to the final MMS stage. Superficial BCC was the only subtype that showed an increase in prevalence from index biopsy to the final MMS stage (from 16.0% to 25.8%; P < .0002). LIMITATIONS: HSs from index biopsy may not be representative of all HSs present, resulting in sampling bias. CONCLUSION: SCE of superficial BCC was as likely as SCE of BCC subtypes that are considered "aggressive" and are deemed "appropriate" for MMS by the appropriate use criteria. Our study also found that when HS drift occurs, the most likely subtype to extend subclinically is superficial BCC.

Does histologic subtype impact overall survival in observed T1a kidney cancers compared with competing risks? Implications for biopsy as a risk stratification tool.

OBJECTIVES: We sought to assess if adding a biopsy proven histologic subtype to a model that predicts overall survival that includes variables representing competing risks in observed, biopsy proven, T1a renal cell carcinomas, enhances the model's performance. METHODS: The National Cancer Database was assessed (years 2004-2015) for patients with observed T1a renal cell carcinoma who had undergone renal mass biopsy. Kaplan-Meier curves were utilized to estimate overall survival stratified by histologic subtype. We utilized C-index from a Cox proportional hazards model to evaluate the impact of adding histologic subtypes to a model to predict overall survival for each stage. RESULTS: Of 132 958 T1a renal masses identified, 1614 had biopsy proven histology and were managed non-operatively. Of those, 61% were clear cell, 33% papillary, and 6% chromophobe. Adjusted Kaplan-Meier curves demonstrated a difference in overall survival between histologic subtypes (P = 0.010) with greater median overall survival for patients with chromophobe (85.1 months, hazard rate 0.45, P = 0.005) compared to clear cell (64.8 months, reference group). Adding histology to a model with competing risks alone did not substantially improve model performance (C-index 0.65 vs 0.64 respectively). CONCLUSIONS: Incorporation of histologic subtype into a risk stratification model to determine prognostic overall survival did not improve modeling of overall survival compared with variables representing competing risks in patients with T1a renal cell carcinoma managed with observation. These results suggest that performing renal mass biopsy in order to obtain tumor histology may have limited utility. Future studies should further investigate the overall utility of renal mass biopsy for observed T1a kidney cancers.

Risk of epithelial ovarian cancer Type I and II after hysterectomy, salpingectomy and tubal ligation-A nationwide case-control study.

The proposed different origins and pathways to of the dualistic model of epithelial ovarian cancer (EOC) may affect and alter the potential risk reduction related to hysterectomy, salpingectomy and tubal ligation. The aim of our study was to analyze associations between hysterectomy, salpingectomy or tubal ligation and risk reduction of EOC Type I and II. In this nationwide register-based case-control study, women diagnosed with EOC, Fallopian tube or primary peritoneal cancer between 2008 and 2014 were included. Cases were classified into Type I and II according to histology and predefined criteria. The exposure variables: hysterectomy, salpingectomy and tubal ligation were identified from national registries. Conditional logistic regression analyses were performed to evaluate associations between Type I and II EOC and the exposure variables. Among 4669 registered cases, 4040 were eligible and assessed for subtyping resulting in 1033 Type I and 3007 Type II. Ten controls were randomly assigned to each case from the register of population. In regression analyses, women with previous salpingectomy had a significantly lower risk of EOC Type II (odds ratio [OR] 0.62; 95% confidence interval [95%CI] 0.45-0.85) but not Type I (OR 1.16; 95%CI 0.75-1.78). Hysterectomy was associated with a reduced risk of both EOC Type I (OR 0.71; 95%CI 0.52-0.99) and Type II (OR 0.81; 95%CI 0.68-0.96). Similar estimates were obtained for tubal ligation, although without statistical significance. The association between salpingectomy and reduced risk of EOC Type II supports the proposed theory of high-grade serous cancer originating from the tubal fimbriae.

Histologic subtype classification of non-small cell lung cancer using PET/CT images.

PURPOSES: To evaluate the capability of PET/CT images for differentiating the histologic subtypes of non-small cell lung cancer (NSCLC) and to identify the optimal model from radiomics-based machine learning/deep learning algorithms. METHODS: In this study, 867 patients with adenocarcinoma (ADC) and 552 patients with squamous cell carcinoma (SCC) were retrospectively analysed. A stratified random sample of 283 patients (20%) was used as the testing set (173 ADC and 110 SCC); the remaining data were used as the training set. A total of 688 features were extracted from each outlined tumour region. Ten feature selection techniques, ten machine learning (ML) models and the VGG16 deep learning (DL) algorithm were evaluated to construct an optimal classification model for the differential diagnosis of ADC and SCC. Tenfold cross-validation and grid search technique were employed to evaluate and optimize the model hyperparameters on the training dataset. The area under the receiver operating characteristic curve (AUROC), accuracy, precision, sensitivity and specificity was used to evaluate the performance of the models on the test dataset. RESULTS: Fifty top-ranked subset features were selected by each feature selection technique for classification. The linear discriminant analysis (LDA) (AUROC, 0.863; accuracy, 0.794) and support vector machine (SVM) (AUROC, 0.863; accuracy, 0.792) classifiers, both of which coupled with the ℓ2,1NR feature selection method, achieved optimal performance. The random forest (RF) classifier (AUROC, 0.824; accuracy, 0.775) and ℓ2,1NR feature selection method (AUROC, 0.815; accuracy, 0.764) showed excellent average performance among the classifiers and feature selection methods employed in our study, respectively. Furthermore, the VGG16 DL algorithm (AUROC, 0.903; accuracy, 0.841) outperformed all conventional machine learning methods in combination with radiomics. CONCLUSION: Employing radiomic machine learning/deep learning algorithms could help radiologists to differentiate the histologic subtypes of NSCLC via PET/CT images.

International trends in ovarian cancer incidence from 1973 to 2012.

PURPOSE: Ovarian cancer is the 7th leading cancer diagnosis and the 8th leading cause of cancer death in women worldwide. We conducted this study to investigate the incidence of ovarian cancer internationally. METHODS: The trends in ovarian cancer incidence were analyzed through the latest data of CI5 over the 40-year period from 21 populations in 4 continents using Joinpoint analysis, ASRs and proportions of different histological subtypes in those populations were also analyzed using volume XI of CI5. RESULTS: ASRs of ovarian cancer were from 7.0 to 11.6 per 100,000 in non-Asia populations during 2008-2012. In Asia, the ASR in Israel (Jews) were the highest, up to 8.1 per 100,000 in the same period. The international trends from 1973 to 2012 showed that ASRs of ovarian cancer were decreasing in 8 of 21 selected populations, whereas ASRs in Slovakia, Spain (Navarra) and China (Shanghai) were increasing. Meanwhile, there are certain differences in the main pathological classification patterns within different regions. In Asia, China (Hong Kong) and Japan both have a higher ASRs and proportions for clear cell and endometrioid carcinomas, while Japan has the highest ASRs and proportions for mucinous carcinomas. CONCLUSION: Although the reasons for those trends were not entirely clear, environmental, reproductive and genetic factors were likely to have led to these patterns. Meanwhile, more attention and further study should be given to the etiological factors of histology-specific ovarian cancer.

Can the location of the mural nodule indicate benign or malignant in branch duct-type intraductal papillary mucinous neoplasm of the pancreas?

BACKGROUND/OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are classified into main duct (MD)-type IPMNs, branch duct (BD)-type IPMNs, and mixed type IPMNs. While MD-type IPMN has a high risk of malignancy and should therefore be considered for resection if the patient is fit, BD-type IPMN needs to be carefully judged for surgical indication. The decision to resect BD-type IPMN is often based on international consensus Fukuoka guidelines 2017, but further investigation is required. In this study, we focused on whether the location of the mural nodule (MN) could be an indicator of malignancy. METHODS: We enrolled 17 cases who had been diagnosed BD-type IPMNs which were surgically resected from January 2016 to December 2019. These cases were classified into benign and malignant group. Subsequently, a clinicopathological study was conducted based on the localization of MN (MN-central type or MN-peripheral type). RESULTS: Although MN was found in 57% (4/11) in the benign group, 88% (7/8) was noted in the malignant group, indicating the presence of MN to be more common in the malignant group. Those with MN consisted of 6 cases of MN-central type and 5 cases of MN-peripheral type. All cases of central type were malignant compared to only one case of the peripheral group being confirmed on histology as cancer. CONCLUSION: BD-IPMN with central mural nodule should be considered high risk for malignancy.

Acral lentiginous melanoma: Clinicopathologic and survival differences according to tumour location.

BACKGROUND/OBJECTIVES: Acral lentiginous melanoma (ALM) is a melanoma subtype associated with atypical locations on the hands and feet and advanced disease at diagnosis. There is a limited understanding of whether the survival is similar for nail, non-nail, lower limb and upper limb ALM patients. We therefore explored clinicopathologic characteristics and melanoma-specific survival of ALM patients according to tumour location. METHODS: A prospectively collected cohort study was performed of all primary invasive cutaneous acral lentiginous melanomas with known thickness and tumour location reviewed at a tertiary referral centre over 21 years. RESULTS: A total of 101 ALM patients were reviewed from 1994 until 2016. The majority of cases (82/101) occurred on the feet. Hand ALMs were thicker and more likely to be ulcerated than feet ALMs (P = 0.05 and 0.02, respectively); however, survival was not statistically different between these two groups (univariate HR 0.48 P = 0.11, 95% CI, 0.20-1.17; multivariate HR 0.67 P = 0.40, 95% CI, 0.27-1.69, respectively). Non-nail ALM patients had longer survival when compared to nail ALM on univariate analysis (HR 0.40, 95% CI, 0.17 to 0.90) which was accounted for by Breslow thickness and ulceration (multivariate HR 0.56, 95% CI, 0.24 to 1.34). CONCLUSIONS: The reduced melanoma-specific survival in nail ALM patients was likely due to their greater thickness and ulceration. Although hand ALMs are thicker and more frequently ulcerated, this is likely due to the higher proportion of nail ALMs present in this location.

Cause-specific mortality among Medicare beneficiaries with newly diagnosed non-Hodgkin lymphoma subtypes.

BACKGROUND: As the US population ages and non-Hodgkin lymphoma (NHL)-specific mortality declines, deaths from causes other than NHL will become increasingly important in treatment decision making for older patients with NHL. The objective of the current study was to describe how the 5-year cumulative incidence of NHL-specific and other-cause mortality varies by subtype, age, comorbidity level, and time since diagnosis in older patients. METHODS: Using the Surveillance, Epidemiology, and End Results cancer registry data linked to Medicare claims, patients aged ≥66 years were identified at the time of diagnosis with a first, primary NHL diagnosis from 2004 through 2013. Death certificate data and Fine-Gray competing risks models were used to estimate the 5-year cumulative incidence of NHL-specific and other-cause mortality by NHL subtype, age, and comorbidity level. Estimates were displayed over time using stacked cumulative incidence curves. RESULTS: Among 30,666 patients with NHL, 32% died of NHL and 13% died of other causes within 5 years of diagnosis. The cumulative incidence of other-cause mortality increased with age and comorbidity level for all subtypes. Among patients with aggressive NHL subtypes, NHL-specific mortality exceeded other-cause mortality across all age groups, comorbidity levels, and number of years after diagnosis. For patients with indolent NHL subtypes, other-cause mortality was similar to or exceeded NHL-specific mortality, especially among older patients with severe comorbidity or with the indolent marginal zone, lymphoplasmacytic, and mycosis fungoides subtypes. CONCLUSIONS: The findings of the current study suggest that mortality from causes other than NHL are important for patients of an older age, with a higher comorbidity level, and with indolent disease. Evidence from the current study can guide the development of tools for estimating individual prognosis that inform treatment discussions in patients with NHL.

Differences in race, molecular and tumor characteristics among women diagnosed with invasive ductal and lobular breast carcinomas.

BACKGROUND: The dominant invasive breast cancer histologic subtype, ductal carcinoma, shows intrinsic subtype diversity. However, lobular breast cancers are predominantly Luminal A. Both histologic subtypes show distinct relationships with patient and tumor characteristics, but it is unclear if these associations remain after accounting for intrinsic subtype. METHODS: Generalized linear models were used to estimate relative frequency differences (RFDs) and 95% confidence intervals (95% CIs) for the associations between age, race, tumor characteristics, immunohistochemistry (IHC) and RNA-based intrinsic subtype, TP53 status, and histologic subtype in the Carolina Breast Cancer Study (CBCS, n = 3,182) and The Cancer Genome Atlas (TCGA, n = 808). RESULTS: Relative to ductal tumors, lobular tumors were significantly more likely to be Luminal A [CBCS RNA RFD: 44.9%, 95% CI (39.6, 50.1); TCGA: RFD: 50.5%, 95% CI (43.9, 57.1)], were less frequent among young (≤ 50 years) and black women, were larger in size, low grade, less frequently had TP53 pathway defects, and were diagnosed at later stages. These associations persisted among Luminal A tumors (n = 242). CONCLUSIONS: While histology is strongly associated with molecular characteristics, histologic associations with age, race, size, grade, and stage persisted after restricting to Luminal A subtype. Histology may continue to be clinically relevant among Luminal A breast cancers.

Outcomes of non-high grade serous carcinoma after neoadjuvant chemotherapy for advanced-stage ovarian cancer: a Korean gynecologic oncology group study (OV 1708).

BACKGROUND: Outcomes of patients with ovarian high-grade serous carcinoma (HGSC) treated with neoadjuvant chemotherapy (NAC) have been widely studied, but there is limited information on the outcomes of patients with non-HGSC. This study aimed to evaluate the outcomes of NAC in non-HGSC patients with advanced-stage ovarian cancer. METHODS: We conducted a retrospective cohort study of patients who underwent NAC for advanced stage non-HGSC between 2002 and 2017 in 17 institutions. Demographics, surgical outcomes, and survival rates were evaluated according to histological subtypes. RESULTS: A total of 154 patients were included in this study, comprising 20 cases (13.0%) of mucinous adenocarcinoma, 31 cases (20.1%) of endometrioid adenocarcinoma, 28 (18.2%) cases of clear cell carcinoma, 29 (18.8%) cases of low-grade serous carcinoma and 12 cases (7.8%) of carcinosarcoma. Complete remission/partial remission after the third cycle of NAC was achieved in 100 (64.9%) patients and optimal debulking surgery (residual disease ≤1 cm) at interval debulking surgery was achieved in 103 (66.9%) patients. The most common reason for performing NAC was high tumor burden (n = 106, 68.8%). The median progression-free survival (PFS) was 14.3 months and median overall survival (OS) was 52.9 months. In multivariate analyses, mucinous and clear cell carcinoma were negative prognostic factors for both PFS (p = 0.007 and p = 0.017, respectively) and OS (p = 0.002 and p = 0.013, respectively). CONCLUSIONS: In this study, poor survival outcomes were observed in patients with mucinous and clear cell carcinoma undergoing NAC. Different treatment strategies are urgently required to improve survival outcomes for this disease subset.

The degree of sclerosis is associated with prognosis in well-differentiated liposarcoma of the retroperitoneum.

BACKGROUND AND OBJECTIVES: Well-differentiated liposarcomas (WDL) are often partly composed of sclerotic tissue, however, the amount varies widely between tumors, and its prognostic significance is unknown. We hypothesized that tumors with more sclerosis would behave more aggressively. METHODS: Primary retroperitoneal WDL from 29 patients resected at our institution with follow-up were histologically evaluated by soft tissue pathologists blinded to outcome. Tumors with ≥ 10% sclerosis were designated "sclerotic" while tumors with < 10% sclerosis were designated as "minimally sclerotic". Cellular and dedifferentiated tumors were excluded. Clinical parameters and radiologic assessments on computed tomography (CT) were recorded. RESULTS: Histological evaluation identified 13 minimally sclerotic WDL and 16 sclerotic WDL. Median follow-up was 9 years (range, 3-20). Median recurrence-free survival (RFS) and median overall survival (OS) were 6.16 and 13.9 years, respectively. Compared with patients with sclerotic WDL, those with minimally sclerotic WDL had superior RFS (HR = 0.17 [95% CI, 0.06-0.53], P = .002) and OS (log-rank test, P = .002). Sclerotic WDL exhibited higher Houndsfield Units than minimally sclerotic WDL (26 vs 1, P = .040). CONCLUSIONS: Minimally sclerotic WDL were associated with more favorable outcome compared with sclerotic tumors. Assessment of sclerosis in WDL is likely a useful prognostic marker.

A population-based registry study on relative survival from melanoma in Germany stratified by tumor thickness for each histologic subtype.

BACKGROUND: Differences in relative survival (RS) of melanoma between histologic subtypes were discussed to be mainly caused by tumor thickness. OBJECTIVE: To investigate RS of melanoma, stratified by tumor thickness for each histologic subtype, and identify survival trends. METHODS: With use of cancer registry data on melanoma cases (International Classification of Diseases, 10th Revision, codes C43.0-C43.9) diagnosed in Germany in 1997-2013, 5- and 10-year age-standardized RS stratified by histologic subtype and stratified or standardized by T stage was estimated by standard and modeled period analyses. We restricted 10-year RS analyses to patients younger than 75 years. RESULTS: We analyzed 82,901 cases. Overall, the 5- and 10-year RS rates were 91.7% and 90.8%, respectively. Prognosis worsened with increasing T stage for all histologic subtypes, but T-stage distribution varied substantially. Survival differences by histologic subtype were strongly alleviated after adjustment for T stage but remained significant. Overall, 5-year RS increased significantly (by 3.8 percentage points) between the periods 2002-2005 and 2010-2013. This increase was no longer seen after adjustment for T stage. LIMITATIONS: Exclusion of cases on account of missing information on T stages, changes in the definition of T stages, and lack of information on screening and treatment limit our analyses. CONCLUSION: Differences in RS between histologic subtypes were strongly mediated by tumor thickness. Over time, RS of melanoma increased as a result of changes in T-stage distribution.

Histologic subtype of treatment failures after noninvasive therapy for superficial basal cell carcinoma: An observational study.

BACKGROUND: There have been concerns that recurrences after noninvasive therapy for basal cell carcinoma (BCC) transform into a "more aggressive" histologic subtype. OBJECTIVE: We sought to evaluate the proportion of patients with a nonsuperficial treatment failure after noninvasive therapy for superficial BCC. METHODS: An observational study was performed using data from a single blind, noninferiority, randomized controlled trial (March 2008-August 2010) with 5-year follow-up in patients with primary superficial BCC treated with methylaminolevulinate-photodynamic therapy, 5-fluorouracil, or imiquimod. Data were used from 166 adults with a histologically confirmed treatment failure. RESULTS: A nonsuperficial subtype was found in 64 of 166 treatment failures (38.6%). Proportions with a more aggressive subtype than the primary tumor were 51.3% (38/74) for early and 28.3% (26/92) for later treatment failures (P = .003). The proportion of more aggressive early failures was significantly lower after imiquimod (26.3%) compared with methylaminolevulinate-photodynamic therapy (54.8%, P = .086) and 5-fluorouracil (66.7%, P = .011). LIMITATIONS: There was limited information on the exact time of occurrence of treatment failures. CONCLUSION: More aggressive treatment failure recurrences after noninvasive therapy for superficial BCC occur most often within the first 3 months posttreatment, probably indicating underdiagnosis of more aggressive components in the primary tumor rather than transformation.

Birth weight and the risk of histological subtypes of ovarian and endometrial cancers: Results from the Copenhagen School Health Records Register.

BACKGROUND: Studies of birth weight associations with ovarian and endometrial cancer risks are limited with inconsistent results, and none has evaluated associations by histologic subtype. We utilized prospectively collected birth weight information to investigate the association with risk of ovarian and endometrial cancers overall and by histologic subtype. METHODS: 162,559 girls, born from 1930 to 1989, from the Copenhagen School Health Records Register (CSHRR) were followed prospectively via linkage with the Danish health registers. Ovarian (n=666) and endometrial (n=694) cancers were identified from 1978 to 2014. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Women with lower (2.0-3.25 vs. 3.26-3.75kg) and higher (3.75-5.5 vs. 3.26-3.75kg) birth weights had increased risks of ovarian cancer overall [HR (95% CI): 1.27 (1.06-1.52); 1.51 (1.21-1.87), respectively] and serous ovarian cancers [1.54 (1.19-1.98); 1.98 (1.47-2.67), respectively]. A decreased risk of Type II endometrial tumors was suggested per kilogram increase in birth weight [HR (95% CI): 0.63 (0.40-1.00)]. CONCLUSIONS: Our results suggest that both lower and higher birth weights were associated with increased ovarian cancer risk and associations were particularly strong for serous ovarian cancer, the most common subtype. Birth weight was not associated with most types of endometrial cancer.

International patterns and trends in ovarian cancer incidence, overall and by histologic subtype.

Internationally, ovarian cancer is the 7th leading cancer diagnosis and 8th leading cause of cancer mortality among women. Ovarian cancer incidence varies by region, particularly when comparing high vs. low-income countries. Temporal changes in reproductive factors coupled with shifts in diagnostic criteria may have influenced incidence trends of ovarian cancer and relative rates by histologic subtype. Accordingly, we evaluated trends in ovarian cancer incidence overall (1973-1977 to 2003-2007) and by histologic subtype (1988-1992 to 2003-2007) using volumes IV-IX of the Cancer Incidence in Five Continents database (CI5plus) and CI5X (volume X) database. Annual percent changes were calculated for ovarian cancer incidence trends, and rates of histologic subtypes for individual countries were compared to overall international incidence. Ovarian cancer incidence rates were stable across regions, although there were notable increases in Eastern/Southern Europe (e.g., Poland: Annual Percent Change (APC) 1.6%, p = 0.02) and Asia (e.g., Japan: APC 1.7%, p = 0.01) and decreases in Northern Europe (e.g., Denmark: APC -0.7%, p = 0.01) and North America (e.g., US Whites: APC -0.9%, p < 0.01). Relative proportions of histologic subtypes were similar across countries, except for Asian nations, where clear cell and endometrioid carcinomas comprised a higher proportion of the rate and serous carcinomas comprised a lower proportion of the rate than the worldwide distribution. Geographic variation in temporal trends of ovarian cancer incidence and differences in the distribution of histologic subtype may be partially explained by reproductive and genetic factors. Thus, histology-specific ovarian cancer should continue to be monitored to further understand the etiology of this neoplasm.

Reproductive and hormone-related risk factors for epithelial ovarian cancer by histologic pathways, invasiveness and histologic subtypes: Results from the EPIC cohort.

Whether risk factors for epithelial ovarian cancer (EOC) differ by subtype (i.e., dualistic pathway of carcinogenesis, histologic subtype) is not well understood; however, data to date suggest risk factor differences. We examined associations between reproductive and hormone-related risk factors for EOC by subtype in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Among 334,126 women with data on reproductive and hormone-related risk factors (follow-up: 1992-2010), 1,245 incident cases of EOC with known histology and invasiveness were identified. Data on tumor histology, grade, and invasiveness, were available from cancer registries and pathology record review. We observed significant heterogeneity by the dualistic model (i.e., type I [low grade serous or endometrioid, mucinous, clear cell, malignant Brenner] vs. type II [high grade serous or endometrioid]) for full-term pregnancy (phet = 0.02). Full-term pregnancy was more strongly inversely associated with type I than type II tumors (ever vs. never: type I: relative risk (RR) 0.47 [95% confidence interval (CI): 0.33-0.69]; type II, RR: 0.81 [0.61-1.06]). We observed no significant differences in risk in analyses by major histologic subtypes of invasive EOC (serous, mucinous, endometrioid, clear cell). None of the investigated factors were associated with borderline tumors. Established protective factors, including duration of oral contraceptive use and full term pregnancy, were consistently inversely associated with risk across histologic subtypes (e.g., ever full-term pregnancy: serous, RR: 0.73 [0.58-0.92]; mucinous, RR: 0.53 [0.30-0.95]; endometrioid, RR: 0.65 [0.40-1.06]; clear cell, RR: 0.34 [0.18-0.64]; phet = 0.16). These results suggest limited heterogeneity between reproductive and hormone-related risk factors and EOC subtypes.

Endogenous androgens and risk of epithelial invasive ovarian cancer by tumor characteristics in the European Prospective Investigation into Cancer and Nutrition.

The role of endogenous androgens and sex hormone-binding globulin (SHBG) in ovarian carcinogenesis is poorly understood. Epithelial invasive ovarian cancer (EOC) is a heterogeneous disease and there are no prospective data on endogenous androgens and EOC risk by tumor characteristics (histology, grade, stage) or the dualistic model of ovarian carcinogenesis (i.e. type I vs. type II, leading to less or more aggressive tumors). We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort evaluating androgens and SHBG and invasive EOC risk by tumor characteristics. Female participants who provided a blood sample and were not using exogenous hormones at blood donation were eligible (n = 183,257). A total of 565 eligible women developed EOC; two controls (n = 1,097) were matched per case. We used multivariable conditional logistic regression models. We observed no association between androgens, SHBG and EOC overall. A doubling of androstenedione reduced risk of serous carcinomas by 21% (odds ratio (OR)log2 = 0.79, 95% confidence interval [CI] = [0.64-0.97]). Moreover, associations differed for low-grade and high-grade carcinomas, with positive associations for low-grade and inverse associations for high-grade carcinomas (e.g. androstenedione: low grade: ORlog2 = 1.99 [0.98-4.06]; high grade: ORlog2 = 0.75 [0.61-0.93], phet ≤ 0.01), similar associations were observed for type I/II tumors. This is the first prospective study to evaluate androgens, SHBG and EOC risk by tumor characteristics and type I/II status. Our findings support a possible role of androgens in ovarian carcinogenesis. Additional studies exploring this association are needed.

Tubal ligation and salpingectomy and the risk of epithelial ovarian cancer and borderline ovarian tumors: a nationwide case-control study.

OBJECTIVE: According to the recent theories on the ovarian cancer origin, any protective effect of tubal ligation may vary with histologic subtype of ovarian cancer. Furthermore, bilateral salpingectomy may represent an opportunity for surgical prevention of serous ovarian cancer. DESIGN: Nationwide register-based case-control study. SETTING: Denmark during 1982-2011. POPULATION: Cases were all Danish women diagnosed with epithelial ovarian cancer (n = 13 241) or borderline ovarian tumor (n = 3605) in the study period. Age-matched female population controls were randomly selected by risk set sampling. We required that cases and controls have no previous cancer and that controls have no previous bilateral oophorectomy. METHODS: Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals, adjusting for potential confounders. MAIN OUTCOME MEASURES: Epithelial ovarian cancer and borderline ovarian tumors stratified according to histology. RESULTS: Tubal ligation reduced overall epithelial ovarian cancer risk (odds ratios 0.87; 95% confidence interval 0.78-0.98). We observed significant risk variation according to histology (p = 0.003) with the strongest risk reductions associated with endometrioid cancer (odds ratios 0.66; 95% confidence interval 0.47-0.93) and epithelial ovarian cancer of "other" histology (odds ratios 0.60; 95% confidence interval 0.43-0.83). Tubal ligation was not associated with risk of borderline ovarian tumors. Finally, bilateral salpingectomy reduced epithelial ovarian cancer risk by 42% (odds ratios 0.58; 95% confidence interval 0.36-0.95). CONCLUSIONS: We confirmed that tubal ligation reduces the risk of epithelial ovarian cancer and particularly endometrioid cancer. To our knowledge, this is the first observational publication to report on salpingectomy and ovarian cancer risk and our promising findings warrant further investigation.

Efficacy of avelumab maintenance therapy for advanced urothelial carcinoma with histologic subtype and divergent differentiation: a multicenter retrospective study conducted by the Uro-Oncology Group in Kyushu.

Background: The subtype of urothelial carcinoma (SUC) has been known to possess morphological diversity for histologic subtype or divergent differentiation. However, the efficacy of avelumab against SUC remains unclear. Therefore, the effect of the treatment as well as the survival results of avelumab monotherapy were evaluated as a first-line therapeutic maintenance in patients with advanced SUC. Methods: A retrospective analysis was conducted on consecutive patients from the Uro-Oncology Group in Kyushu study population with advanced lower and upper urinary tract cancer who underwent avelumab maintenance therapy without progression after first-line platinum-based chemotherapy. Patients with pure urothelial carcinoma (PUC) and SUC were comparatively analyzed based on objective response rate (ORR), disease control rate, progression-free survival (PFS), and overall survival (OS). Results: Out of 49 recorded patients, 38 and 11 had PUC and SUC, respectively. The most common subtype element was glandular differentiation (n=5), followed by squamous differentiation (n=3), micropapillary (n=1), and plasmacytoid subtypes (n=1). The SUC and PUC groups had comparable ORR (0% vs. 2.6%, P>0.99) and disease control rates (54.5% vs. 44.7%, P=0.73). These patient groups also showed no significant difference in PFS (median 3.9 vs. 3.1 months, P=0.33) or OS (median 16.7 vs. 22.1 months, P=0.47). Conclusions: The response of SUC and PUC to avelumab was comparable in patients with advanced lower and upper urinary tract cancer, indicating that avelumab maintenance therapy is also effective for SUC.