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The four TCGA-based molecular prognostic groups of endometrial carcinoma (EC), i.e., POLE-mutant, mismatch repair (MMR)-deficient, p53-abnormal, and “no specific molecular profile” (NSMP), have recently been integrated into ESGO-ESTRO-ESP guidelines. The POLE-mutant and MMR-deficient groups are associated with high mutational load, morphological heterogeneity, and inflammatory infiltration. These groups are frequent in high-grade endometrioid, undifferentiated/dedifferentiated, and mixed histotypes. POLE-mutant ECs show good prognosis and do not require adjuvant treatment, although the management of cases at stage >II is still undefined. MMR-deficient ECs show intermediate prognosis and are currently substratified based on clinicopathological variables, some of which might not have prognostic value. These groups may benefit from immunotherapy. P53-mutant ECs are typically high-grade and often morphologically ambiguous, accounting for virtually all serous ECs, most carcinosarcomas and mixed ECs, and half of clear-cell ECs. They show poor prognosis and are treated with chemoradiotherapy; a subset may benefit from HER2 inhibitors or PARP inhibitors. The NSMP group is the most frequent TCGA group; its prognosis is highly variable and affected by clinicopathological/molecular factors, most of which are still under evaluation. In conclusion, the TCGA classification has improved diagnosis, risk stratification, and management of EC. Further studies are needed to resolve the points of uncertainty that still exist.

ObjectiveAlthough ovarian cancer is a deadly disease, approximately a third of women survive ≥9years after diagnosis. The factors associated with achieving long-term survival are not well understood. In this study, data from the Surveillance, Epidemiology, and End Results (SEER) program were used to determine predictors of survival trajectories among women with epithelial ovarian cancer and across histotype (high-grade serous carcinoma (HGSC) and non-HGSC).MethodsData on 35,868 women diagnosed with epithelial ovarian cancer in 2004-2016 were extracted from SEER. Extended Cox proportional hazards regression was used to estimate overall and histotype-specific associations between patient and tumor characteristics and all-cause mortality within each survival time (t) interval (t70years at diagnosis, where a high risk of mortality was observed in both the t&nbsp

Background Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer. Patients and Methods In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability. Results We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status. Conclusions Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy. Graphic Abstract

According to the 2019 WHO classification of breast tumors, neuroendocrine neoplasms (NENs) are classified into well-differentiated NE tumors (NET) and poorly differentiated NE carcinomas (NEC), while other breast cancers (BCs) of special and no special type with neuroendocrine (NE) features are not incorporated in this scheme anymore. We aimed to assess whether INSM1, a novel NE marker, could have a role in breast NEN subtyping. We selected 63 BCs operated from 2003 to 2018, classified as BCs with NE features, with available clinico-pathological data. Following 2019 WHO criteria, this cohort was reclassified into 37 NETs/NECs, the remaining 26 tumors representing solid-papillary (7), mucinous (7), and mixed type (12) carcinomas with NE differentiation. Chromogranin A (CGA) and synaptophysin (SYN) immunostains were reviewed, and INSM1 was tested by immunohistochemistry. Thirty CGA- and SYN-negative no special type BCs served as negative control. INSM1 was expressed in 52/63 cases of the whole cohort (82.54%). INSM1 positive and negative cases had no significantly different clinico-pathological characteristics. INSM1 expression was not significantly different between the newly reclassified NET/NEC group and other BCs with NE features. No immunoexpression was observed in control BCs. The sensitivity and specificity of INSM1 for the NE phenotype was 82.5% and 100%, respectively, compared to 61.9% and 100% for CGA, and 95.2 and 100% for SYN. In conclusion, INSM1 is as accurate as traditional NE biomarkers to identify NE differentiation in BC. In analogy to standard NE markers, INSM1 could not distinguish NET and NEC from the other BC histotypes with NE differentiation. Supplementary Information The online version contains supplementary material available at 10.1007/s12022-021-09682-1.

Background The addition of human epididymis protein 4 (HE4) to carbohydrate antigen 125 (CA125) in ovarian cancer (OC) assessment has been proposed. We compared the clinical value of biomarker changes in a prospective series of patients undergoing OC monitoring. Methods We studied 43 patients (79% post-menopausal), followed for 3.5 ± 3.1 years. Serous OC was prevalent (53.5%), with 81.4% of patients diagnosed at late stages. Both cut-offs and reference change values (RCV) were used for assessing significant marker changes. Results The use of cut-offs for CA125 and HE4 interpretation appeared equally fitting the evaluation of disease progression defined according to running guidelines, performing better than RCV criterion. However, both markers were simultaneously over cut-offs only in 46% of samples and changed in agreement in 35% of cases. The inspection of individual longitudinal trends indicated as main causes of disagreement the influence of renal impairment on HE4 concentrations and the more significant rate of decrease of CA125 vs. HE4 concentrations early after treatment. CA125 and HE4 changes according to RCV were not predictive of OC progression. Conclusions CA125 appears the most reliable biomarker for OC monitoring, whereas HE4 contributes additional information only in a minority of cases.

Background: Ovarian carcinoma is the most lethal gynecological malignancy due to early dissemination and acquired resistance to platinum-based chemotherapy. Reliable markers that are independent and complementary to clinical parameters are needed to improve the management of patients with this disease. The Canadian Ovarian Experimental Unified Resource (COEUR) provides researchers with biological material and associated clinical data to conduct biomarker validation studies. Using standards defined by the Canadian Tissue Repository Network (CTRNet), we have previously demonstrated the quality of the biological material from this resource. Here we describe the clinical characteristics of the COEUR cohort. Methods: With support from 12 Canadian ovarian cancer biobanks in Canada, we created a central retrospective cohort comprised of more than 2000 patient tissue samples with associated clinical data, including 1246 high-grade serous, 102 low-grade serous, 295 endometrioid, 259 clear cell and 89 mucinous carcinoma histotypes. A two-step reclassification process was applied to assure contemporary histological classification (histotyping). For each histotypes individually, we evaluated the association between the known clinico-pathological parameters (stage, cytoreduction, chemotherapy treatment, BRCA1 and BRCA2 mutation) and patient outcome by using Kaplan-Meier and Cox proportional hazard regression analyses. Results: The median follow-up time of the cohort was 45 months and the 5-year survival rate for patients with high-grade serous carcinomas was 34%, in contrast to endometrioid carcinomas with 80% at 5 years. Survival profiles differed by histotype when stratified by stage or cytoreduction. Women with mucinous or clear cell carcinomas at advanced stage or with non-optimally debulked disease had the worst outcomes. In high-grade serous carcinoma, we observed significant association with longer survival in women harboring BRCA1 or BRCA2 mutation as compared to patients without detectable mutation. Conclusions: Our results show the expected survival rates, as compared with current literature, in each histotype suggesting that the cohort is an unbiased representation of the five major histotypes. COEUR, a one stop comprehensive biorepository, has collected mature outcome data and relevant clinical data in a comprehensive manner allowing stratified analysis.

BACKGROUND: To investigate the role of Kodama PenA subtype in influencing survival in patients with early gastric cancer (EGC). METHODS: All patients surgically treated for EGC at 7 Italian centers (Forlì, Varese, Siena, Verona, Milan, Rome and Perugia) belonging to the Italian Research Group for Gastric Cancer (GIRCG) from January 1982 and December 2009 were included. RESULTS: PenA patients were 230 (21.5%) while other types were 839 (78.5%). Nodal metastases were more common in PenA (30.7%) than non-PenA (10.4%) EGCs. Among preoperative variables, only age (OR 1.02; 95% CI 1.00-1.03, p = 0.009) and macrotype III (OR 1.95; 95% CI 1.39-2.75, p = 0.0001) were significantly associated with Pen A type. Survival analysis performed on N0 patients demonstrated that only size >2 cm (HR 1.85; 95% CI 1.12-3.05, p = 0.017) and age (HR 1.06; 95% CI 1.03-1.08, p < 0.0001) were independent poor prognostic factor. Among N+ patients age (HR 1.04; 95% CI 1.00-1.07, p = 0.048), number of positive lymph nodes (HR 1.13; 95% CI 1.05-1.20, p = 0.0002) and PenA (HR 4.23; 95% CI 1.70-10.55, p = 0.002) were significantly correlated with poor prognosis at multivariate analysis. CONCLUSIONS: Kodama PenA subtype was the most powerful independent prognostic factor in patients with nodal metastases. Its status should always be investigated in EGCs patients.

Endometrial carcinoma (EC) is the fourth most common cancer in women in the developed world. Classification of ECs by histomorphologic criteria has limited reproducibility and better tools are needed to distinguish these tumors and enable a subtype-specific approach to research and clinical care. Based on the Cancer Genome Atlas, two research teams have developed pragmatic molecular classifiers that identify four prognostically distinct molecular subgroups. These methods can be applied to diagnostic specimens (e.g., endometrial biopsy) with the potential to completely change the current risk stratification systems and enable earlier informed decision making. The evolution of genomic classification in ECs is shared herein, as well as potential applications and discussion of the essential research still needed in order to optimally integrate molecular classification in to current standard of care.

Background: Until recently ovarian carcinoma was considered to be a single disease, and treatment decisions were based solely on grade and pre- and postoperative tumour burden. New insights into molecular features, treatment response, and patient demographics led the scientific community to conclude that ovarian carcinoma histotypes are different disease entities. Methods: In 2002, the pathology specimens from patients in a clinical trial were reviewed by an experienced gynaecopathologist (pathologist A) for translational research purposes. All cases were typed according to what were then current criteria. The identical cohort was now reassessed by the same expert pathologist and independently reviewed by another gynaecopathologist (pathologist B) applying WHO 2014 diagnostic criteria. Survival analyses were done based on the original as well as the new diagnoses, and historical biomarker study results were recalculated. Results: Upon re-review, pathologist A rendered the same histotype diagnosis in only 54% of cases. In contrast, pathologists A and B independently rendered the same diagnosis in 98% of cases. Histotype was of prognostic significance when 2014 diagnoses were used, but was not prognostic using the original (2002) histotype diagnoses. Conclusions: Our study demonstrates a marked shift in ovarian carcinoma histotype diagnosis over the past 15 years. The new criteria are associated with a very high degree of interobserver reproducibility, allowing for treatment decisions based on histotype. Finally, biomarkers of putative prognostic significance were revealed to be primarily histotype-specific markers, confirming the critical importance of obtaining up-to-date diagnoses rather than accepting archival histotype data in clinical research.

Objectives To evaluate concordance, using the kappa statistic, between tumour histotypes assigned at initial diagnosis and those after slide revision, and to assess the independent predictive value of reviewed tumour histotype. Materials and methods We analysed records of 491 patients who had undergone partial or radical nephrectomy for renal cell carcinoma (RCC) in our department from 1986 to 2000. Pathologic slides were reviewed by one uropathologist blinded to original diagnoses and follow-up data, who reassigned histologic subtype and nuclear grades. Results Concordance between original and reviewed histotypes was substantial (kappa=0.52). Data were affected by the year of initial diagnosis: Concordance was moderate (kappa=0.43) in patients treated from 1986 to 1997 and substantial (kappa=0.73) in those observed thereafter. The original histotype did not stratify the cancer-related outcome. According to the reviewed histotypes, the 5-year cancer-specific survival probabilities of conventional, papillary and chromophobe RCC patients were 81.3%, 90.1% and 100%, respectively ( p =0.009). Patients with conventional RCC showed significantly lower cancer-specific survival than those with papillary or chromophobe RCC, even in the cases with locally advanced ( p =0.04) or high-grade ( p =0.02) neoplasms. The reviewed histologic subtype was not an independent prediction of cancer-specific survival on multivariate analysis. Conclusion Concordance between histologic subtype assigned before 1997 and after slide revision was only moderate. In univariate analysis, reviewed tumour histotype stratified cancer-related outcome, but the data of multivariate analysis were strongly influenced by the prevalent number of conventional RCC.