Differential Expression and Copy Number Variation of Gasdermin (GSDM) Family Members, Pore-Forming Proteins in Pyroptosis, in Normal and Malignant Serous Ovarian Tissue.

Gasdermins (GSDM) are members of a family of pore-forming effector proteins which lead to membrane permeabilization and pyroptosis, a lytic cell death with pro-inflammatory characteristics. Recently, two members of the gasdermin family, gasdermin B (GSDMB) and gasdermin E (GSDME), were shown to suppress tumor growth, through the involvement of cytotoxic lymphocytes. Other studies also reported the important functions of gasdermins in various cancer types including gastric cancer, hepatocarcinoma, and cervix and breast cancer. However, gasdermins have not been previously studied in the context of serous ovarian cancer. Here, we showed that gasdermin D (GSDMD) and gasdermin C (GSDMC) expression increases in serous ovarian cancer; in contrast, the expression of GSDME and PJVK (Pejvakin, DFNB59) is downregulated, compared to healthy ovaries, in multiple independent gene expression datasets. We found that copy number gains are highly frequent (present in approximately 50% of patients) in genes encoding GSDMD and GSDMC in ovarian cancer, in line with their upregulated expression in serous ovarian cancer. Moreover, we observed that the expression of GSDMB and GSDMD, but not of GSDME, is different among several histotypes of epithelial ovarian cancer. Therefore, we propose that differential expression and copy number variations of certain gasdermins might be associated with the development of serous ovarian cancer, in which different members of the family have distinct functions; however, further research is required in in vivo models to understand how changes in gasdermin family members mechanistically contribute to serous ovarian cancer.

Expression of B7-H4 and IDO1 is associated with drug resistance and poor prognosis in high-grade serous ovarian carcinomas.

High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy. While immune checkpoint inhibitors against PD-L1 and CTLA-4 have shown significant effects in multiple tumor types, the response rate to single-agent immune checkpoint inhibitors is low in HGSC. Alternative biomarkers and targets must be identified to guide patient selection and new therapeutic strategies in HGSC. Here, we aim to investigate the clinical significance of novel immune modulators, including B7-H4, IDO1, Tim3, IL6, and IL-8, in patients with HGSC. A total of 48 patients with HGSCs, comprising 24 cases that were sensitive and 24 that were resistant to standard paclitaxel and carboplatin chemotherapy, were selected for our initial analysis. A NanoString assay including 33 immune-related genes was used to compare the expression of different immune regulatory molecules in the sensitive and resistant groups. Differentially expressed proteins were verified using multiplex immunohistochemical staining on tissue arrays of 202 patients with HGSCs who underwent primary surgery at MDACC. We analyzed the expression levels of immune checkpoints and compared expression profiles with clinicopathologic features including response, progression-free survival, and overall survival. HGSC tumors resistant to therapy expressed higher levels of B7-H4 (69.3%), IDO1 (71.8%), Tim3 (89.1%), and inflammatory factors IL-6 and IL-8, and expressed higher Tim3 in stromal components. High expression of B7-H4 and IDO1 was associated with significantly lower overall survival and progression-free survival. B7-H4 and IDO1 were co-expressed in 49.1% of studied cases. A panel of immunomodulatory proteins including B7-H4, IDO1, Tim3, IL-6, and IL-8 are expressed at high levels in HGSCs. These modulators represent novel targets to enhance immunotherapy in patients with HGSCs.

Fertility-sparing treatment in advanced-stage serous borderline ovarian tumors. An analysis from the MITO14 study database.

OBJECTIVES: To evaluate oncological and reproductive outcomes of women undergoing fertility-sparing surgery (FSS) for stage II-III serous borderline ovarian tumors (BOTs). METHODS: A multi-institutional retrospective study was conducted within the MITO Group. RESULTS: A total of 91 patients were recruited. The median follow-up time from primary cytoreduction was 127 months (IQR range 91-179). Forty-nine patients (53.8%) experienced at least one recurrence (median time to first relapse 22 months, IQR range 9.5-57). At univariable analysis, significant predictors of relapse were: size of largest extra-ovarian lesion, peritoneal cancer index, completeness of cytoreduction, type of implants. After multivariable analysis, the size of extra-ovarian lesions and the presence of invasive implants resulted as the only independent predictors of recurrence. Median disease-free survival (DFS) was 96 months (95% CI, 24.6-167.3), while median disease-specific survival (DSS) was not reached. Twenty-nine patients (31.8%) attempted to conceive: 20 (68.9%) achieved at least one pregnancy and 18 (62%) gave birth to a healthy child. At the end of the observation period, 88 patients (96.7%) showed no evidence of disease, 2 (2.2%) were alive with disease, and 1 patient (1.1%) died from BOT. CONCLUSIONS: Despite the recurrence high rate, FSS provides good chances of reproductive success with no impact on DSS. The presence of invasive peritoneal implants affects the DFS but not DSS nor reproductive outcome. The risk of recurrence would not seem to be related to the ovarian preservation per se, but to the natural history of the initial peritoneal spread.

High grade, advanced, serous ovarian cancer with low serum CA125 levels.

This study compares characteristics of advanced stage, high grade serous ovarian cancer, presenting with high or low serum CA125 level. This was a retrospective cohort of 118 patients with high grade serous ovarian, fallopian tube or primary peritoneal cancer, stages IIIC-IV diagnosed from January 1 1997 through January 9 2017. Patient demographics, tumour characteristics, surgical findings, chemotherapy protocols and clinical outcomes were collected. Three groups were evaluated: group A: 21 patients with CA125 serum level ≤152 U/ml, group B: 97 patients with CA125 serum level >152 U/ml, group C: 43 patients from group B with CA125 serum level >500 U/ml and <1000 U/ml. No significant difference was found between groups regarding age, stage at diagnosis, extent of residual disease or disease volume. More group A patients had surgery as primary treatment compared to groups B and C (p=.003, p=.022, respectively). CA125 level at recurrence was lower in group A as compared to the other groups (162.2 vs. 851.7 and 603.4, p=.003, p=.006). Overall survival and progression-free survival did not differ based on CA125 levels. We conclude that patients with advanced stage, high grade, serous ovarian cancer with low CA125 serum levels had the same clinical outcome as patients with higher levels.Impact StatementWhat is already known on this subject? It is known that CA125 level is a prognostic and predictive factor for epithelial ovarian cancer (EOC) outcome. It is elevated in 80% of the patients and within normal range in only 10% of women with advanced stage EOC. Various studies had addressed the patients with advanced stage serous EOC who had high serum CA125 levels at time of diagnosis. But, no study has addressed the 10% of patients with advanced stage who had low serum CA125 levels at time of diagnosis.What the results of this study add? To the best of our knowledge, this is the first study addressing patients with advanced stage EOC who had low serum CA125 levels at time of diagnosis. According to the results of this study, patients with advanced stage, high grade serous EOC presenting with low serum CA125 levels have similar clinical outcomes as do patients with high serum CA125 levels.What the implications are of these findings for clinical practice and/or further research? Further translational research is encouraged for this group of tumours to identify specific molecular markers that might lead to better understanding and treatment for the disease.

Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses.

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.

Expression of the cancer stem cell marker SSEA1 is associated with poor survival in metastatic high-grade serous carcinoma.

The objective of the present study was to perform a quantitative analysis of cancer stem cell (CSC) marker expression in ovarian carcinoma effusions. The clinical role of SSEA1 in metastatic high-grade serous carcinoma (HGSC) was additionally analyzed. CD133, Nanog, SOX2, Oct3/4, SSEA1, and SSEA4 protein expressions were quantitatively analyzed using flow cytometry (FCM) in 24 effusions. SSEA1 expression by immunohistochemistry was analyzed in 384 HGSC effusions. Highly variable expression of CSC markers by FCM was observed, ranging from 0 to 78% of Ber-EP4-positive cells in the case of CD133, with the largest number of negative specimens seen for SSEA4. SSEA1 expression by immunohistochemistry was found in HGSC cells in 336/384 (89%) effusions, most commonly focally (< 5% of cells). SSEA1 was overexpressed in post-chemotherapy disease recurrence specimens compared with chemo-naïve HGSC effusions tapped at diagnosis (p = 0.029). In univariate survival analysis, higher SSEA1 expression was significantly associated with poor overall survival (p = 0.047) and progression-free survival (p = 0.018), though it failed to retain its prognostic role in Cox multivariate survival analysis in which it was analyzed with clinical parameters (p = 0.059 and p = 0.111 for overall and progression-free survival, respectively). In conclusion, CSC markers are variably expressed in ovarian carcinoma effusions. SSEA1 expression is associated with disease progression and poor survival in metastatic HGSC. Silencing this molecule may have therapeutic relevance in this cancer.

Combined CCNE1 high-level amplification and overexpression is associated with unfavourable outcome in tubo-ovarian high-grade serous carcinoma.

CCNE1 amplification is a recurrent alteration associated with unfavourable outcome in tubo-ovarian high-grade serous carcinoma (HGSC). We aimed to investigate whether immunohistochemistry (IHC) can be used to identify CCNE1 amplification status and to validate whether CCNE1 high-level amplification and overexpression are prognostic in HGSC. A testing set of 528 HGSC samples stained with two optimised IHC assays (clones EP126 and HE12) was subjected to digital image analysis and visual scoring. DNA and RNA chromogenic in situ hybridisation for CCNE1 were performed. IHC cut-off was determined by receiver operating characteristics (ROC). Survival analyses (endpoint ovarian cancer specific survival) were performed and validated in an independent validation set of 764 HGSC. Finally, combined amplification/expression status was evaluated in cases with complete data (n = 1114). CCNE1 high-level amplification was present in 11.2% of patients in the testing set and 10.2% in the combined cohort. The optimal cut-off for IHC to predict CCNE1 high-level amplification was 60% positive tumour cells with at least 5% strong staining cells (sensitivity 81.6%, specificity 77.4%). CCNE1 high-level amplification and overexpression were associated with survival in the testing and validation set. Combined CCNE1 high-level amplification and overexpression was present in 8.3% of patients, mutually exclusive to germline BRCA1/2 mutation and significantly associated with a higher risk of death in multivariate analysis adjusted for age, stage and cohort (hazard ratio = 1.78, 95 CI% 1.38-2.26, p < 0.0001). CCNE1 high-level amplification combined with overexpression identifies patients with a sufficiently poor prognosis that treatment alternatives are urgently needed. Given that this combination is mutually exclusive to BRCA1/2 germline mutations, a predictive marker for PARP inhibition, CCNE1 high-level amplification combined with overexpression may serve as a negative predictive test for sensitivity to PARP inhibitors.

PD-L1 Expression and CD8+ Tumor-infiltrating Lymphocytes in Different Types of Tubo-ovarian Carcinoma and Their Prognostic Value in High-grade Serous Carcinoma.

The prevalence and significance of programmed death-1 ligand (PD-L1) expression in different types of tubo-ovarian carcinoma have not been well defined. We evaluated PD-L1 expression and CD8 tumor-infiltrating lymphocyte (TIL) density in whole tissue sections of 189 cases of tubo-ovarian carcinoma, including high-grade serous carcinoma (HGSC, n=100), clear cell carcinoma (CCC, n=24), endometrioid carcinoma (EmC, n=40), and mucinous carcinomas (MC, n=25). Using the tumor proportion score (TPS) with a 1% cutoff, PD-L1 expression was present in 21% of HGSC, 16.7% of CCC, 2.5% of EmC, and 4% of MC. Using the combined positive score (CPS) with a cutoff of 1, PD-L1 expression was present in 48% of HGSC, 25% of CCC, 20% of EmC, and 24% of MC. HGSC demonstrated significantly higher CD8 TIL density than CCC (P=0.013238), EmC (P=0.01341), or MC (P=0.004556). In HGSC, CD8 TIL density was directly correlated with PD-L1 positivity using either TPS (P=0.0008) or CPS (P=0.00011). Survival analysis of patients with high stage (stage III to IV) HGSC revealed PD-L1 positivity by TPS to be associated with improved progression-free survival (adjusted hazard ratio: 0.4912 vs. 2.036, P=0.0378). Although not statistically significant, a similar trend was observed in overall survival (adjusted hazard ratio: 0.3387 vs. 2.953, P=0.0548). In contrast, with CPS, no significant difference was identified between PD-L1-positive and negative groups in either progression-free survival (P=0.5086) or overall survival (P=0.7823). Neoadjuvant chemotherapy was associated with higher PD-L1 expression by TPS (P=0.00407) but not CPS. No significant difference in PD-L1 expression was detected in tumors from patients with germline BRCA1/2 mutations compared with germline mutation-negative tumors by either TPS or CPS. In conclusion, the prevalence of PD-L1 expression is variable in different types of tubo-ovarian carcinoma and is highest in HGSC. In high-stage HGSC, PD-L1 positivity in tumor cells is associated with an increased immune response and improved survival.

The effect of the peritoneal tumor microenvironment on invasion of peritoneal metastases of high-grade serous ovarian cancer and the impact of NEOADJUVANT chemotherapy.

Peritoneal metastases of high-grade serous ovarian cancer (HGSOC) are small-sized deposits with superficial growth toward the peritoneal cavity. It is unknown whether integrity of the peritoneal elastic lamina (PEL) correlates with the peritoneal tumor microenvironment (pTME) and whether neoadjuvant chemotherapy (NACT) affects the pTME. We explored integrity of PEL, composition of pTME, effects of NACT, and the prognostic implications in patients with extensive peritoneal metastases of HGSOC. Peritoneal samples (n = 69) were collected during cytoreductive surgery between 2003 and 2016. Clinical data were collected from medical charts. Integrity of PEL was evaluated with elastic stains. T cell (CD3, CD8) and M2-macrophage markers (CD163) were scored using algorithms created in definiens tissue studio. Patients with a disrupted PEL (n = 39; 57%), more often had residual disease after surgery (p = 0.050), compared to intact PEL. An intact PEL was associated with increased intraepithelial (ie) CD8+ cells (p = 0.032), but was not correlated with improved survival. After NACT, increased ieCD3+ cells were shown, compared to no-NACT (p = 0.044). Abundance of total CD3+ and CD8+ cells were associated with PFS (multivariate HR 0.40; 95%CI 0.23-0.69 and HR 0.49; 95%CI 0.29-0.83) and OS (HR 0.33; 95%CI 0.18-0.62 and HR 0.36; 95%CI 0.20-0.64). M2-macrophage infiltration was not correlated with survival. NACT increases abundance of ieCD3+ cells in peritoneal metastases of HGSOC. Increase of CD3+ and CD8+ cells is associated with improved PFS and OS. This suggests that CD3+ and CD8+ cells may function as prognostic biomarkers. Their role as predictive biomarker for chemotherapy or immunotherapy response in HGSOC warrants further research.

Solid pseudopapillary neoplasms of the pancreas: Case series with a review of the literature.

BACKGROUND/AIMS: The solid pseudopapillary neoplasms are quite rare tumors of the pancreas, comprising roughly 1-2% of all pancreatic neoplasms. It has a low malignant potential and usually affects young females. Despite increasing number of articles in the last decade, there is still debate on the pathogenesis, malignant potential and optimal surgical strategy for the solid pseudopapillary neoplasms. MATERIALS AND METHODS: Medical recordings of 326 patients who were operated due to pancreatic mass were retrospectively analyzed. Patient demographics, presenting symptoms, surgical and pathologic characteristics of the tumor, postsurgical course, long-term survival, and other relevant data were extracted from patients' charts. RESULTS: Majority of the patients were female in consistency with the classic data in the literature. All the patients underwent curative intent resections. Tumors were commonly localized in the tail of the pancreas making distal pancreatectomy the most commonly performed surgical procedure. Mean tumor diameter was 5.8 centimeters with tumor sizes ranging from 1 to 19 cm. CONCLUSION: The solid pseudopapillary neoplasms of the pancreas is a rare tumor with low malignant potential, which is more common in females of reproductive age, with abdominal pain being their most common presentation. The short-term outcomes in patients following surgical R0 resection are excellent. However, proximal placement of the tumor and female gender may have slightly worse prognosis. We hope that our findings from a series of patients represent a contribution to the existing literature on SPN, and authors declare their willingness to provide further details for future meta-analyses.

Surveillance of Low-Grade Appendiceal Mucinous Neoplasms With Peritoneal Metastases After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Are 5 Years Enough? A Multisite Experience.

BACKGROUND: Low-grade appendiceal mucinous neoplasms (LAMNs) are tumors that often present with widespread mucin in the peritoneal cavity (pseudomyxoma peritonei [PMP]). Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are effective treatment, but no published recommendations exist regarding surveillance. METHODS: Data from prospective databases of patients who underwent CRS-HIPEC from 2001 to 2017 at two high-volume institutions were retrospectively analyzed. Patients who underwent complete CRS-HIPEC for PMP secondary to LAMN were included in the analysis. Pathologic examination confirmed the diagnosis of LAMN. Cases of mucinous adenocarcinomas and neuroendocrine tumors (goblet cell carcinoids) were excluded. RESULTS: The study enrolled 156 patients. The median peritoneal cancer index (PCI) was 18 (interquartile range IQR1-3, 12-23), and 125 patients (80.1%) had a CC0 cytoreduction. According to American Joint Committee on Cancer (AJCC) grading, 152 patients (97.4%) presented with acellular mucin or G1 implants, 2 patients (1.3%) presented with G2 disease, and 2 patients (1.3%) presented with G3 disease. During the follow-up period (median, 45 months; IQR1-3 23-76 months), 23 patients (14.7%) experienced recurrence. All the recurrences were peritoneal and occurred within 5 years. The 1-, 3-, and 5-year disease-free survival (DFS) rates were respectively 95.5%, 83.4%, and 78.3%. Univariate Cox regression analysis showed that higher PCI scores (p < 0.001), a CC1 cytoreduction (p = 0.005), and higher preoperative levels of carcinoembryonic antigen (CEA) (p = 0.012) and CA-125 (p = 0.032) correlated with a shorter DFS. Only higher PCI scores independently predicted earlier recurrences (p < 0.001). CONCLUSION: Most patients had recurrence within 3 years after CRS-HIPEC, and none after 5 years. High PCI was the only independently significant variable. The study findings support intensive surveillance (every 3-6 months) with tumor markers and imaging methods during the first 3 years, and annual surveillance thereafter, with follow-up assessment after 5 years yielding limited benefit.

"Trivial" Cysts Redefine the Risk of Cancer in Presumed Branch-Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas: A Potential Target for Follow-Up Discontinuation?

OBJECTIVES: The management of small and incidental branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) still is of concern. The aim is assessing the safety of a surveillance protocol through the evaluation of their progression to malignancy. METHODS: All presumed BD-IPMNs observed from 2000 to 2016 were included. Only patients presenting without worrisome features (WFs) and high-risk stigmata (HRS) at diagnosis were included. Development of WF, HRS, pancreatic cancer (PC), and survival were analyzed. BD-IPMNs were defined as trivial in the continuing absence of WF/HRS after 5 years of surveillance. The age-specific standardized incidence ratio of PC in the general population was used for comparison. RESULTS: A total of 1,036 BD-IPMNs without WF/HRS at diagnosis were included, 4.2% developed WF or HRS, and 1.1% developed PC after a median of 62 months. The median cyst growth rate was 0 mm/yr. A growth rate ≥2.5 mm/yr and the development of WF resulted independent predictors of PC. The standardized incidence ratio of PC for trivial BD-IPMN (n = 378) was 22.45 (95% confidence interval 8.19-48.86), but considering only patients aged >65 years (n = 198), it decreased to 3.84 (95% confidence interval 0.77-11.20). DISCUSSION: Surveillance of the vast majority of presumed BD-IPMNs is safe, as the risk of PC is comparable to postoperative mortality of pancreatic surgery. A growth rate ≥2.5 mm/yr is the main predictor of PC, reinforcing the role of repeated observations. A trivial BD-IPMN in patients aged >65 years might not increase the risk of developing PC compared with general population, identifying potential targets for follow-up discontinuation.

Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: A systematic review and meta-analysis of individual patient data.

OBJECTIVE: There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT. METHODS: We established an international collaboration to conduct a systematic review and meta-analysis, pooling individual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3-4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS). RESULTS: 877 patients were included from published and unpublished studies. Median PFS and OS were 15 months (IQR 5-65) and 28 months (IQR 7-92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0·55 (95% CI, 0·45-0·66; P < 0·001) and 0·65 (95% CI 0·50-0·85, P = 0·002) respectively; no heterogeneity was identified (PFS: Q = 6·42, P = 0·698, I2 = 0·0%; OS: Q = 6·89, P = 0·648, I2 = 0·0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (n = 80) were more likely to achieve CRS3 (P = 0·027). CONCLUSIONS: CRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical trial design.

Natural History and Treatment Trends in Pancreatic Cancer Subtypes.

BACKGROUND: While pancreatic ductal adenocarcinoma is the most common form of pancreatic cancer, many other histologic forms of pancreatic cancer are also recognized. These histologic variants portray unique characteristics in terms of patient demographics, tumor behavior, survival, and responsiveness to treatments. MATERIALS AND METHODS: Patients who underwent surgical resection of the pancreas for non-metastatic, invasive pancreatic cancer between 2004 and 2014 were selected from the National Cancer Data Base and categorized by histologic variant according to WHO classification guidelines. Patient demographics, tumor variables, treatment characteristics, and survival were compared between histologic groups and subgroups. RESULTS: A total of 57,804 patients met inclusion and exclusion criteria and were grouped into eight major histologic categories. Survival analysis by the histologic group showed median overall survival of 20.2 months for ductal adenocarcinoma, 20.5 months for squamous cell carcinoma, 26.8 months for mixed acinar-neuroendocrine carcinomas, 52.6 months for cystic mucinous neoplasms with an associated invasive carcinoma, 67.5 months for acinar cell carcinoma, and 69.3 months for mesenchymal tumors. Median survival was not reached for neuroendocrine tumors and solid-pseudopapillary neoplasms, with 5-year overall survival rates of 84% and 97% respectively. CONCLUSIONS: Rare subtypes of pancreatic cancer present unique clinicopathologic characteristics and display distinct tumor biologies. This study presents data on demographic, prognostic, treatment, and survival outcomes between rare forms of pancreatic neoplasms in order to aid understanding of the natural history and behavior of these neoplasms, with the hope of serving as a reference in clinical decision-making and ability to provide accurate prognostic information to patients.

Age-related risks of complications after distal pancreatectomy for neuroendocrine and cystic neoplasms.

BACKGROUND: Distal pancreatic neuroendocrine tumors (PNET) and pancreatic cystic neoplasms (PCN) are often incidentally found in older adults, requiring careful consideration between operative management and watchful waiting. This study analyzes the short-term complications associated with distal pancreatectomy (DP) for PNET and PCN in older adults to inform clinical decision-making. METHODS: Patients undergoing DP for PNET and PCN were analyzed using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database and the pancreatectomy procedure-targeted dataset. Associations between decade of age and 30-day outcomes were evaluated. RESULTS: 1626 patients were analyzed from 2014 to 2015. 692 (42.6%) were younger than 60 years, 507 (31.2%) were sexagenarians, 342 (21.0%) were septuagenarians, and 85 (5.2%) were octogenarians. Minimally invasive approaches were used in 62.7%. While septuagenarians and octogenarians constituted 26.3% of the cohort, they were affected by 55.6% of reintubations, 66.7% of failures to wean, 82.4% of myocardial infarctions, and 57.1% of septic shock. Septuagenarians and octogenarians had longer hospital stays, as compared to those younger than 60 years. CONCLUSION: Septuagenarians and octogenarians are disproportionately affected by perioperative complications after DP for PNET and PCN. Careful patient selection and thorough counseling should be provided when surgery is considered.

HtrA1 expression and the prognosis of high-grade serous ovarian carcinoma: a cohort study using digital analysis.

BACKGROUND: The expression of high temperature requirement factor A1 (Htra1) has been reported to be decreased in ovarian carcinoma, but its prognostic effect remains undetermined. METHODS: We evaluated the impact of HtrA1 downregulation in tumoral tissues on cancer progression and death in women with serous ovarian carcinoma. HtrA1 staining was performed on tissue microarrays (TMA) comprised of tumor samples from a cohort of 106 women who were diagnosed with primary high-grade serous ovarian carcinoma and receiving standard treatment at the Québec University Hospital between 1993 and 2006. HtrA1 expression was assessed visually (percentage of positive nuclei) and by digital image analysis (percentage of positive area). Cox regression multivariate models included standard prognostic factors and were used to estimate adjusted hazard ratios (aHR) for progression or death in the cohort. RESULTS: By visual analysis, a low percentage of HtrA1-positive nuclei (< 10% vs ≥10%) tend to be associated with a lower risk of progression (aHR = 0.71; 95% Confidence interval (CI) = 0.46-1.09; P = 0.11) and mortality (aHR = 0.65; 95% CI = 0.41-1.04; P = 0.07). Low nuclear HtrA1 expression assessed by digital image analysis (< median % vs ≥ median %) showed a significant association with lower risk of progression (aHR = 0.62; 95% CI = 0.40-0.95; p = 0.03) and death (aHR = 0.60; 95% CI = 0.38-0.95; p = 0.03). CONCLUSION: Altogether, our results demonstrate that nuclear downregulation of HtrA1 is associated with a better prognosis in women with high grade serous ovarian carcinoma.

Cytogenetic and immunohistochemical study of 42 pigmented microcystic chromophobe renal cell carcinoma (PMChRCC).

Pigmented microcystic chromophobe renal cell carcinoma (PMChRCC) is a recently described morphologic variant of ChRCC. We have identified 42 cases in 40 patients in the last 24 years. We have investigated their clinical, morphologic, immunohistochemical, and cytogenetic features. Chromosomal abnormalities of chromosomes 7 and 17 were evaluated by automated dual-color silver-enhanced in situ hybridization on paraffin-embedded tissue. Chromosomal imbalance was defined on the basis of changes in both chromosomal index and signal distribution. The main age was 60.20 years, being 34 males and 6 women. The mean tumor diameter was 4.84 cm, with 39 intrarenal tumors. Grossly, the tumors were solid with a brown dark colored. Microscopically, tumors consisted of pale and eosinophilic cells arranged in microcysts or microalveolar in a cribriform pattern; there were microcalcifications and a dark brown pigment, mostly extracellular. One case showed sarcomatoid transformation. All tumors were positive for epithelial membrane antigen (EMA), Claudin 7, and E-cadherin. Monosomy of 7 and 17 chromosomes was present in 1/36 cases and 2/37 cases, respectively. Polysomy of chromosome 7 and 17 was found in 26/36 cases and in 4/37, respectively. With a median follow-up of 74.05 months, 37 patients were alive without disease and two were alive with disease progression. PMChRCCs expand the morphologic spectrum of the ChRCC with an unusual immunohistochemical profile. Cytogenetically, they showed monosomy to chromosome (CHR) 17 as other ChRCCs and polysomy of CHR 7 infrequent to ChRCCs. We present the probably largest series of PMCRCC, confirming their low aggressive behavior, with exceptional sarcomatoid transformation and distant metastases.

Predominantly cystic clear cell renal cell carcinoma and multilocular cystic renal neoplasm of low malignant potential form a low-grade spectrum.

Multilocular cystic renal cell carcinoma has been recently excluded from clear cell renal cell carcinoma (CCRCC) category and re-designated as multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) due to its uniformly good outcomes. While strict distinction between MCRNLMP from predominantly cystic CCRCC (pc-CCRCC) is being emphasized, the significance of extensive true cystic component in CCRCC has not been investigated. Herein, we analyzed 57 MCRNLMP, 69 pc-CCRCC, and 46 non-cystic CCRCC. There were no statistically significant differences between the three subtypes in age, gender, and laterality. ISUP grades were 1 (73%) or 2 (27%) for MCRNLMP; for pc-CCRCC were 1 (31%), 2 (60%), and 3 (9%); and for non-cystic CCRCC were 1 (9%), 2 (52%), 3 (26%), and 4 (13%). MCRNLMP were either pT stage 1 (91%) or 2 (9%), pT stages for pc-CCRCC were 1 (92.5%), 2 (1.5%), and 3 (6%) and for non-cystic CCRCC were 1 (58.7%), 2 (6.5%), and 3 (34.8%). None of MCRNLMP patients developed recurrences or metastases, and only 1 contralateral kidney tumor and 1 metastasis developed in pc-CCRCC. In contrast, 19 patients with non-cystic CCRCC developed metastases (5-year PFS 58%, CI 38.3-73.5%), and 1 patient died of disease. Monosomy 3 was common in both MCRNLMP (3/3) and pc-CCRCC (6/7). This large series of MCRNLMP confirms its indolent behavior, shows that pc-CCRCC has significantly better prognosis than non-cystic CCRCC and may define the lower grade spectrum of CCRCC. We recommend that the presence and extent of CCRCC cystic component should be documented in the pathology report.

Significance of T1a and T1b Carcinoma Arising in Mucinous Cystic Neoplasm of Pancreas.

Mucinous cystic neoplasm (MCN) of pancreas is one of the precursor lesions of pancreatic ductal adenocarcinoma. The 5-year disease-specific survival for noninvasive MCNs was 100% and 20% to 60% for those with pancreatic ductal adenocarcinoma arising in a MCN. However, the significance of T1a (≤0.5 cm) and T1b (>0.5 and <1.0 cm) carcinoma arising in MCN as defined by the upcoming American Joint Committee on Cancer, eighth edition is unclear. In this study, we examined 3 cases of MCN with T1a or T1b carcinoma and compared their clinicopathologic characteristics and survival to 46 cases of MCN with low-grade dysplasia (MCN-LGD), 7 cases of MCN with high-grade dysplasia (MCN-HGD), and 7 cases of MCN with advanced invasive carcinoma (T2 or higher T stage). The tumors from all 3 cases were submitted in their entirety in 123, 296, and 200 blocks, respectively. All 3 patients were alive with no recurrence during the follow-up of 20.0, 113.8, and 137.2 months, respectively. Similarly, none of the patients who had MCN with either LGD or HGD had recurrence or died of disease. In contrast, 5 of 7 patients who had MCN with advanced invasive carcinoma had recurrence and later died of disease with a median survival of 22.9 months (P<0.001). Our study showed that MCN with T1a and T1b carcinoma had an excellent prognosis similar to MCNs with LGD or HGD after complete tumor sampling for histologic examination. Our results along with the previous studies suggest that close follow-up, rather than aggressive systemic therapy, may be a better approach for these patients.

Racial disparities in young women with endometrial cancer.

OBJECTIVE: Although racial disparities in treatment and outcome for endometrial cancer are well recognized, little work has explored disparities in young women. We performed a population-based analysis to compare survival between black and white women with endometrial cancer at <50years of age. METHODS: We used the National Cancer Data Base to identify women <50years of age with endometrial cancer from 1998 to 2012. Clinical and demographic characteristics were compared between black and white women and survival by race analyzed using Kaplan-Meier curves and multivariable Cox proportional hazards models. RESULTS: We identified a total of 35,850 women <50years of age including 31,947 (89.1%) white and 3903 (10.9%) black patients. Black women were more likely to have advanced stage, poorly differentiated, and non-endometrioid histology neoplasms (P<0.05 for all). In a multivariable model, survival was 19% worse for black patients than white patients (HR=1.19; 95% CI, 1.08-1.32). A similar effect was seen when limited to women with early-stage tumors (HR=1.24; 95% CI, 1.04-1.49), while among patients with advanced stage tumors, no association between race and survival was seen (HR=1.12; 95% CI, 0.89-1.41). Five-year survival rates were 90.6% (95% CI, 88.6-92.3%) for white and 81.5% (95% CI, 73.0-87.5%) for black women with stage IB tumors, and 75.1% (95% CI, 72.5-77.5%) and 63.3% (95% CI, 54.1-71.2%) for white and black women with stage III tumors, respectively. CONCLUSIONS: Young black women are more likely to present with pathologically aggressive, advanced stage tumors. Even after adjusting for these pathologic differences, young black women with endometrial cancer have higher mortality than white women.