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Summary Hepatoid tumors (HT) are rare neoplasms morphologically resembling hepatocellular carcinoma, which arise in several organs other than the liver. A comprehensive molecular profile of this group of neoplasms is still lacking. Genomic characterization of 19 HTs from different organs (three colon HTs, four esophagogastric HTs, four biliary HTs, six genitourinary HTs, two lung HTs) was performed using a multigene next-generation sequencing panel. NGS unraveled a composite molecular profile of HT. Their genetic alterations were clearly clustered by tumor site: (i) colorectal HT displayed microsatellite instability, high tumor mutational burden, mutations in ARID1A/B genes and NCOA4-RET gene fusion (2/3 cases); (ii) gastric HT had TP53 mutations (2/4); (iii) biliary HT displayed loss of CDKN2A (3/4) and loss of chromosome 18 (2/4); (iv) genital HT showed gain of chromosome 12 (3/6); (v) lung HT had STK11 somatic mutations (2/2). The only commonly mutated gene occurring in HT of different sites was TP53 (8/19 cases: colon 2, esophagogastric 2, biliary 2, genital 1, lungs 1). This study shows that most genetic alterations of HT were clustered by site, indicating that context matters. The novel potential targets for HT precision oncology are also clustered based on the anatomic origin. This study shed light on the biology of these rare cancers and may have important consequences for treatment decisions and clinical trial selection for HT patients.

The objective of the present study was to investigate the association between angiotensin-converting enzyme (ACE) inhibitor use and cancer incidence (overall, and breast, prostate, and colorectal cancers specifically) in a large representative sample of US adults. Cross-sectional data on cancer diagnosis, timing of cancer diagnosis, ACE inhibitor use, and other characteristics were extracted from 49 512 adults aged ≥ 20years participating in the National Health and Nutrition Examination Survey (1999–2016). Multivariable-logistic and propensity score matching (PSM) regressions examined the relationship between pre-diagnosis use of ACE inhibitors and diagnosis of all cancers, and breast, prostate, and colorectal cancers specifically. Overall, we observed an increased likelihood of cancer diagnosis [odds ratio (OR) 1.269, 95% confidence interval (CI) 1.088–1.480] among those who used ACE inhibitors compared to non-ACE inhibitor use, and for prostate cancer diagnosis (OR 1.438, 95% CI 1.090–1.897), after adjusting for age, sex, body mass index, race/ethnicity, educational attainment, physical activity, alcohol drinking status, smoking status, and high blood pressure. PSM regression retrieved more conservative estimates such that the increased likelihood of cancer diagnosis was only observed when comparing ACE inhibitor users with non-drug users (OR 1.022, 95% CI 1.016–1.027). Compared with non-ACE inhibitor use, ACE inhibitor use was associated with an increased risk of prostate cancer. In conclusion, in this large representative sample of US adults, it was found that ACE inhibitor use may have a marginal influence on some cancers. © 2020, Springer Nature Switzerland AG.

Ki-67 assessment is a key step in the diagnosis of neuroendocrine neoplasms (NENs) from all anatomic locations. Several challenges exist related to quantifying the Ki-67 proliferation index due to lack of method standardization and inter-reader variability. The application of digital pathology coupled with machine learning has been shown to be highly accurate and reproducible for the evaluation of Ki-67 in NENs. We systematically reviewed all published studies on the subject of Ki-67 assessment in pancreatic NENs (PanNENs) employing digital image analysis (DIA). The most common advantages of DIA were improvement in the standardization and reliability of Ki-67 evaluation, as well as its speed and practicality, compared to the current gold standard approach of manual counts from captured images, which is cumbersome and time consuming. The main limitations were attributed to higher costs, lack of widespread availability (as of yet), operator qualification and training issues (if it is not done by pathologists), and most importantly, the drawback of image algorithms counting contaminating non-neoplastic cells and other signals like hemosiderin. However, solutions are rapidly developing for all of these challenging issues. A comparative meta-analysis for DIA versus manual counting shows very high concordance (global coefficient of concordance: 0.94, 95% CI: 0.83–0.98) between these two modalities. These findings support the widespread adoption of validated DIA methods for Ki-67 assessment in PanNENs, provided that measures are in place to ensure counting of only tumor cells either by software modifications or education of non-pathologist operators, as well as selection of standard regions of interest for analysis. NENs, being cellular and monotonous neoplasms, are naturally more amenable to Ki-67 assessment. However, lessons of this review may be applicable to other neoplasms where proliferation activity has become an integral part of theranostic evaluation including breast, brain, and hematolymphoid neoplasms. © 2022, The Author(s).

In the last two decades, there has been marked development in virtual slide technology as well as its application in various subspecialties of pathology. In particular, there have been several studies examining the utility of whole slide imaging (WSI) in breast and gynecological pathology. The aim of this systematic review is to analyse published evidence regarding validation studies of WSI applied specifically to the female genital tract and breast pathology.A systematic search was carried out in Pubmed and Embase databases and studies dealing with the validation of a WSI system for breast and gynaecological pathology. The topics evaluated concerned expertise of engaged pathologists, varied specimens, scanners, washout period, experience viewing WSI, and diagnostic concordance of WSI to traditional light microscopic diagnoses.Of 1467 publications retrieved, 23 studies were included. Most of these studies concerned breast pathology. Validation guidelines recommended by the College of American Pathologists pertaining to a dataset of at least 60 cases, washout period, and recording intra-observer variability were followed by most studies. Major challenges encountered with WSI included difficulty identifying high-grade nuclear atypia and mitotic count for borderline ovarian tumors, interpretation of squamous intraepithelial lesions in liquid-based cervical cytology, and grading breast cancer.Published data demonstrates the value of utilizing WSI in breast and gynecological pathology. Key issues reported with WSI systems were problems related to focus, resolution and the contrast and brightness of immunohistochemical staining patterns. Grading breast cancer and mitotic count remained challenging in WSI as in conventional microscopy.

Juvenile polyposis (JP) is a rare familial syndrome characterized by the development of numerous hamartomatous polyps of the gastrointestinal tract and by an increased risk of developing gastrointestinal cancers. It follows a pattern of autosomal dominant inheritance and is associated with germline variants of SMAD4 or BMPR1A genes. Differential diagnosis may be difficult based on histology alone, due to morphological similarities to other familial syndromes. Here we report a case of familial JP diagnosed in a 50-years woman with a familial history positive for gastrointestinal cancers and other tumor types. The patient presented with severe iron deficiency anemia and showed numerous polyps in the stomach and jejunum according to endoscopy and imaging. She underwent an intra-gastric laparoscopic removal of the major gastric polyp, followed by jejunal exploration and resection of a segment with multiple neoformations. Histological examination revealed the presence of hamartomatous polyposis. Gastric and intestinal samples were analyzed with next-generation sequencing. Molecular analysis showed that the patient harbored a germline splicing site variant of SMAD4, c.1139 + 3A > G, which was complemented by different somatic variants of the same gene in the different polyps. Immunohistochemistry for SMAD4 confirmed loss of protein expression in the polyps, with regular expression in normal cells. cDNA sequencing further confirmed the findings. We thus definitively diagnosed the woman as having JP thanks to an integrated approach based on histology, immunohistochemistry and molecular analysis. The identified variants, all previously reported as variants of unknown significance, were classified as pathogenic as they complemented each other leading to SMAD4 loss.

Contains fulltext : 215605.pdf (Publisher’s version ) (Closed access) BACKGROUND: Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined as having microsatellite instability (MSI). Therefore, MSI is a marker of dMMR. MSI/dMMR can be identified using immunohistochemistry to detect loss of MMR proteins and/or molecular tests to show microsatellite alterations. Together with tumour mutational burden (TMB) and PD-1/PD-L1 expression, it plays a role as a predictive biomarker for immunotherapy. METHODS: To define best practices to implement the detection of dMMR tumours in clinical practice, the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project, based on a systematic review-approach, to generate consensus recommendations on the: (i) definitions related to the concept of MSI/dMMR; (ii) methods of MSI/dMMR testing and (iii) relationships between MSI, TMB and PD-1/PD-L1 expression. RESULTS: The MSI-related definitions, for which a consensus frame-work was used to establish definitions, included: 'microsatellites', 'MSI', 'DNA mismatch repair' and 'features of MSI tumour'. This consensus also provides recommendations on MSI testing; immunohistochemistry for the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 represents the first action to assess MSI/dMMR (consensus with strong agreement); the second method of MSI/dMMR testing is represented by polymerase chain reaction (PCR)-based assessment of microsatellite alterations using five microsatellite markers including at least BAT-25 and BAT-26 (strong agreement). Next-generation sequencing, coupling MSI and TMB analysis, may represent a decisive tool for selecting patients for immunotherapy, for common or rare cancers not belonging to the spectrum of Lynch syndrome (very strong agreement). The relationships between MSI, TMB and PD-1/PD-L1 expression are complex, and differ according to tumour types. CONCLUSIONS: This ESMO initiative is a response to the urgent questions raised by the growing success of immunotherapy and provides also important insights on the relationships between MSI, TMB and PD-1/PD-L1.

Objective Ampulla of Vater carcinoma (AVC) has a broad spectrum of different prognoses. As such, new moderators of survival are urgently needed. We aimed at clarifying the prognostic role of perineural invasion in AVC. Methods Using PubMed and SCOPUS databases, we conducted the first systematic review and meta-analysis on this topic. Results Analyzing 29 articles for a total of 2379 patients, we found that the presence of perineural invasion increased the risk of all-cause mortality more than 2 times (relative risk [RR], 2.07; 95% confidence interval [CI], 1.78-2.42 [P < 0.0001]; hazard ratio [HR], 2.72; 95% CI, 1.86-3.97 [P < 0.0001]), of cancer-specific mortality more than 6 times (RR, 6.12; 95% CI, 3.25-11.54 [P < 0.0001]; HR, 6.59; 95% CI, 2.29-3.49 [P < 0.0001]), and of recurrence more than 2 times (RR, 2.63; 95% CI, 1.89-3.67 [P < 0.0001]; HR, 2.54; 95% CI, 1.24-5.21 [P = 0.01]). Conclusions Perineural invasion is strongly associated with a poorer prognosis in AVC, influencing both survival and risk of recurrence. It should be reported in the final pathology report and should be taken into account by future oncologic staging systems, identifying a group of AVC with a more malignant biological behavior. © Wolters Kluwer Health, Inc. All rights reserved.

Systematic reviews and meta-analyses pool data from individual studies to generate a higher level of evidence to be evaluated by guidelines. These reviews ultimately guide clinicians and stakeholders in health-related decisions. However, the informativeness and quality of evidence synthesis inherently depend on the quality of what has been pooled into meta-research projects. Moreover, beyond the quality of included individual studies, only a methodologically correct process, in relation to systematic reviews and meta-analyses themselves, can produce a reliable and valid evidence synthesis. Hence, quality of meta-research projects also affects evidence synthesis reliability. In this overview, the authors provide a synthesis of advantages and disadvantages and main characteristics of some of the most frequently used tools to assess quality of individual studies, systematic reviews, and meta-analyses. Specifically, the tools considered in this work are the Newcastle-Ottawa scale (NOS) and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) for observational studies, the Consolidated Standards of Reporting Trials (CONSORT), the Jadad scale, the Cochrane risk of bias tool 2 (RoB2) for randomized controlled trials, the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) and the Assessment of Multiple Systematic Reviews 2 (AMSTAR2), and AMSTAR-PLUS for meta-analyses. What is already known?: The informativeness and quality of evidence synthesis inherently depend on the quality of what has been pooled into meta-research projects. Beyond the quality of included individual studies, only a methodologically correct process, in relation to systematic reviews and meta-analyses themselves, can produce a reliable and valid evidence synthesis. What is new?: In this overview, the authors provide a synthesis of advantages and disadvantages and main characteristics of some of the most frequently used tools to assess quality of individual studies, systematic reviews, and meta-analyses. Potential impact: This overview serves as a starting point and a brief guide to identify and understand the main and most frequently used tools for assessing the quality of studies included in meta-research. The authors here share their experience in publishing several meta-research-related articles covering different areas of medical sciences. © 2020 John Wiley & Sons Ltd

Introduction High fidelity between non–small cell lung cancer (NSCLC) primary tumours and patient-derived tumour xenografts (PDTXs) is of paramount relevance to spur their application. Extensive proteomic and kinomic analysis of these preclinical models are missing and may inform about their functional status, in terms of phosphopeptides and hyperactive signalling pathways. Methods We investigated tumour xenografts derived from patients with NSCLC to identify hyperactive signalling pathways. Fresh tumour fragments from 81 NSCLC surgical samples were implanted in Nod/Scid/Gamma mice, and engrafted tumours were compared with primary specimens by morphology, immunohistochemistry, gene mutation analyses, and kinase activity profiling. Four different tyrosine and serine/threonine kinase inhibitors were tested against primary tumour and PDTX lysates using the PamGene peptide microarray platform. Results The engraftment rate was 33%, with successful engraftment being more associated with poor clinical outcomes. Genomic profiles led to the recognition of hotspot mutations, some of which were initially undetected in donor samples. Kinomic analyses showed that characteristics of primary tumours were retained in PDTXs, and tyrosine kinase inhibitors (TKIs) responses of individual PDTX lines were either expected, based on the genetic status, or alternatively defined suitable targets unpredictable by single-genome fingerprints. Conclusions Collectively, PDTXs mostly resembled their parental NSCLC. Combining genomic and kinomic analyses of tumour xenografts derived from patients with NSCLC, we identified patients' specific targetable pathways, confirming PDTXs as a preclinical tool for biomarker identification and therapeutic algorithm'' improvement.

To assess efficacy and safety of trastuzumab biosimilars in comparison to the reference drug through a systematic review and meta-analysis of randomized controlled trials (RCTs). A comprehensive search was conducted using PubMed, Web of Science, Cochrane library, Open Grey and ClinicalTrials.gov databases. Dichotomous data for efficacy and safety outcomes were pooled to obtain the relative risk (RR) and 95% confidence intervals (CIs). Meta-analysis was performed with the Mantel–Haenszel method using Revman 5.3 software. Eight phase III RCTs including a total of 3913 patients with HER2 + breast cancer were identified that met the inclusion criteria. The pooled results for the comparison of trastuzumab biosimilars to the reference drug showed no differences of objective response rate (ORR) (RR 1.05, 95% CI 0.98–1.12, P = 0.20) or overall survival (RR 0.82, 95% CI 0.61–1.09, P = 0.17) in the intention-to-treat population, as well as no difference of ORR (RR 1.03, 95% CI 0.97–1.10, P = 0.30) in the per-protocol population. Similarly, no significant difference was detected in any type of adverse event reported in at least three RCTs, including any serious treatment-emergent adverse effects (RR 0.97, 95% CI 0.76–1.25, P = 0.83), heart failure (RR 1.47, 95% CI 0.69–3.14, P = 0.32), neutropenia (RR 1.05, 95% CI 0.96–1.15, P = 0.26), and infusion-related reaction (RR 1.10, 95% CI 0.89–1.36, P = 0.38). This meta-analysis provides compelling evidence of clinical comparability between trastuzumab biosimilars and the originator product in terms of both efficacy and safety for the treatment of HER2 + breast cancer.

Strong prognostic markers able to stratify lung adenocarcinoma (ADC) patients are lacking. We evaluated whether a six-immunohistochemical markers panel (TTF1, SP-A, Napsin A, MUC5AC, CDX2 and CK5), defining the putative neoplastic “cell of origin,” allows to identify prognostic subgroups among lung ADC. We screened a large cohort of ADC specimens (2003–2013) from Torino Institutional Repository identifying: (i) marker positivity by immunohistochemistry, (ii) main morphological appearance by light microscopy, (iii) presence of “hotspot” mutations of candidate genes by Sequenom technology. To evaluate possible predictors of survival and time to recurrence, uni- and multivariable-adjusted comparisons were performed. We identified 4 different subgroups: “alveolar,” “bronchiolar,” “mixed” and “null type." Alveolar-differentiated ADC were more common in young (P =.065), female (P =.083) patients, frequently harboring EGFR-mutated (P =.003) tumors with acinar pattern (P

Background Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by a broad range of neoplasms to maintain telomere length, permitting uncontrolled replication during their progression. ALT has been described in different types of sarcoma, but a comprehensive analysis of its clinical significance is still lacking. Therefore, we provide here the first meta-analysis on this topic. Methods We searched SCOPUS and PubMed through July 2018 to identify all studies that investigated the prognostic role of ALT in sarcomas. We considered the risk of death (risk ratio, RR) calculated as the number of death vs. total participants during follow-up in ALT+ versus ALT- patients as the primary outcome. The secondary outcome was the hazard ratio (HR), adjusted for the maximum number of covariates available, using ALT- patients as reference. Results Eight articles comprising a total of 551 patients with sarcomas (226 ALT+ and 325 ALT-) were selected. The ALT+ group showed a higher mitotic count and a higher tumor grade compared with the ALT- group (p

CD200 has been recently indicated as a robust marker of well-differentiated neuroendocrine neoplasms. Here, we evaluate its role in differential diagnosis of solid pancreatic neoplasms. We immunostained for CD200 22 solid pseudopapillary neoplasms (SPNs), 8 acinar carcinomas (ACs), 2 pancreatoblastomas (PBs), 138 neuroendocrine tumors (PanNETs), and 48 ductal adenocarcinomas. All SPNs showed strong cytoplasmic and membranous staining for CD200, while only one case of AC had focal positivity. The two PBs showed focal CD200 positivity, mainly located in squamoid nests. The vast majority of PanNETs (96%) showed strong cytoplasmic and membranous staining for CD200, whereas all PDACs were negative. As both PanNETs and SPNs express CD200, it has no role in the differential diagnosis between these two entities.

The aim of the present study was to map and grade evidence for the relationships between telomere length with a diverse range of health outcomes, using an umbrella review of systematic reviews with meta-analyses. We searched for meta-analyses of observational studies reporting on the association of telomere length with any health outcome (clinical disease outcomes and intermediate traits). For each association, random-effects summary effect size, 95% confidence interval (CI), and 95% prediction interval were calculated. To evaluate the credibility of the identified evidence, we assessed also heterogeneity, evidence for small-study effect and evidence for excess significance bias. Twenty-one relevant meta-analyses were identified reporting on 50 different outcomes and including a total of 326 observational studies. The level of evidence was high only for the association of short telomeres with higher risk of gastric cancer in the general population (relative risk, RR=1.95, 95%CI: 1.68-2.26), and moderate for the association of shorter telomeres with diabetes or with Alzheimer’s disease, even if limited to meta-analyses of case-control studies. There was weak evidence for twenty outcomes and not significant association for 27 health outcomes. The present umbrella review demonstrates that shorter telomere length may have an important role in incidence gastric cancer and, probably, diabetes and Alzheimer’s disease. At the same time, conversely to general assumptions, it does not find strong evidence supporting the notion that shorter telomere length plays an important role in many health outcomes that have been studied thus far.

Invasive breast cancer is the most common malignancy in women. Its most common site of metastasis is represented by the lymph nodes of axilla, and the sentinel lymph node (SLN) is the first station of nodal metastasis. Axillary SLN biopsy accurately predicts axillary lymph node status and has been accepted as standard of care for nodal staging in breast cancer. To date, the morphologic aspects of SLN metastasis have not been considered by the oncologic staging system. Extranodal extension (ENE) of nodal metastasis, defined as extension of neoplastic cells through the nodal capsule into the peri-nodal adipose tissue, has recently emerged as an important prognostic factor in several types of malignancies. It has also been considered as a possible predictor of non-sentinel node tumor burden in SLN-positive breast cancer patients. We sought out to clarify the prognostic role of ENE in SLN-positive breast cancer patients in terms of overall and disease-free survival by conducting a systematic review and meta-analysis. Among 172 screened articles, 5 were eligible for the meta-analysis; they globally include 624 patients (163 ENE+ and 461 ENE−) with a median follow-up of 58 months. ENE was associated with a higher risk of both mortality (RR=2.51; 95% CI: 1.66–3.79, p&nbsp

Recent studies highlighted the role of mitochondrial dysregulation in cancer, suggesting that the different mitochondrial haplogroups might play a role in tumorigenesis and risk of cancer development. Our aim is to investigate whether any mitochondrial haplogroups carried a significant higher risk of cancer development in a large prospective cohort of North American people. The haplogroup assignment was performed by a combination of sequencing and PCR-RFLP techniques. Our specific outcome of interest was the incidence of any cancer during follow-up period. Overall, 3222 participants were included in the analysis. Women having I, J, K haplogroup reported a significant higher incidence of cancer compared to people with other haplogroups (p

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), a variant of pancreatic ductal adenocarcinoma (PDAC), has a striking genetic similarity to PDAC but a significantly improved overall survival. We hypothesize that this difference could be due to the immune response to the tumor, and as such, we investigated the expression of PD-1, PD-L1, and CD163 in a series of UCOGC. To this aim, 27 pancreatic UCOGCs (11 pure and 16 PDAC-associated), 5 extrapancreatic tumors with osteoclast-like giant cells and 10 pancreatic anaplastic carcinomas were immunostained using antibodies against PD-1, PD-L1, and CD163. In pancreatic UCOGCs, PD-L1 was expressed in neoplastic cells of 17 (63%) of 27 cases, more often in cases with an associated PDAC (P =.04). Expression of PD-L1 was associated with poor prognosis, confirmed by multivariate analysis: patients with PD-L1–positive UCOGCs had a risk of all-cause mortality that was 3 times higher than did patients with PD-L1–negative UCOGCs (hazard ratio, 3.397; 95% confidence interval, 1.023-18.375; P =.034). PD-L1 expression on tumor cells was also associated with aberrant P53 expression (P =.035). PD-1 was expressed on rare lymphocytes in 12 UCOGCs (44.4%), mainly located at the tumor periphery. CD163 was expressed on histiocytes, with a diffuse and strong staining pattern in all UCOGCs. Extrapancreatic tumors with osteoclast-like giant cells showed very similar staining patterns for the same proteins. Anaplastic carcinomas have some similarities to UCOGCs, but PD-L1 has no prognostic roles. Our results may have important implications for immunotherapeutic strategies in UCOGCs; these tumors may also represent a model for future therapeutic approaches against PDAC. © 2018 Elsevier Inc.

The extranodal extension (ENE) of nodal metastasis involves the extension of neoplastic cells through the lymph node capsule into the perinodal adipose tissue. This morphological feature has recently been indicated as an important prognostic factor in various cancer types, but its role in prostate cancer is still unclear. We aimed to clarify it, performing the first meta-analysis on this issue, comparing prognostic parameters in surgically treated, node-positive prostate cancer patients with (ENE+) vs. without (ENE−) ENE. Data were summarized using risk ratios (RRs) for number of deaths/recurrences and hazard ratios (HRs), with 95% confidence intervals (CI), for the time-dependent risk related to ENE positivity. Six studies followed-up 1,113 patients with N1 prostate cancer (658 ENE+ vs. 455 ENE−) for a median of 83 months. The presence of ENE was associated with a significantly higher risk of biochemical recurrence (RR = 1.15; 95%CI: 1.03–1.28; I2 = 0%; HR = 1.40, 95%CI: 1.12–1.74; I2 = 0%) and “global” (biochemical recurrence and distant metastasis) recurrence (RR = 1.15; 95%CI: 1.04–1.28; I2 = 0%; HR = 1.41, 95%CI: 1.14–1.74; I2 = 0%). ENE emerged as a potential prognostic moderator, earmarking a subgroup of patients at higher risk of recurrence. It may be considered for the prognostic stratification of metastatic patients. New possible therapeutic approaches may explore more in depth this prognostic parameter.

Aims: Somatic mutations in genes encoding chromatin remodellers have been reported recently in several cancer types, including approximately half of cholangiocarcinomas. One of the most commonly mutated chromatin remodellers in cholangiocarcinoma is the Polybromo-1 (PBRM1) gene located on chromosome 3p21, which encodes a subunit of the SWI/SNF complex. The aim of this study was to determine the timing of PBRM1 mutations in biliary carcinogenesis. Methods and results: In order to accomplish this goal, we used immunohistochemistry to assess PBRM1 protein expression in a series of precursor lesions andinvasive biliary carcinomas. Previous studies havecorrelated loss of protein expression on immunohistochemistry with inactivating mutations in this tumour suppressor gene. We found that PBRM1 loss occurred in approximately 26% of invasive cancers, but PBRM1 expression was retained in all biliary intra-epithelial neoplasia (BilIN) specimens, including 25 intrahepatic BilINs and 19 gallbladder BilINs. Conclusions: These findings indicate that PBRM1 mutation (and resultant loss of expression) is a late event during biliary carcinogenesis. In addition, we confirm a lack of prognostic significance of PBRM1 status in invasive intrahepatic cholangiocarcinoma. This study provides important insights into the basic mechanisms of chromatin remodelling genes in carcinogenesis. © 2017 John Wiley & Sons Ltd

Recent studies have definitively established that chromatin remodeling is a crucial epigenetic mechanism not only in physiological conditions but also in influencing cancer biology. It is a dynamic process in which the chromatin, the functional entity of DNA, can undergo specific modifications by obtaining transcriptional activation or transcriptional silencing. One of the most important recent discoveries in cancer genetics and genomics is that the genes involved in the establishment of chromatin structure, the so called chromatin remodelers, are frequently mutated in different types of human cancer. This review aims to summarize the main novelties related to this topic, describing also the contribution of such genes during oncogenesis. Particularly, we focus on the switch/sucrose non-fermentable complexes and on three of the most important chromatin remodeling genes in biliary and pancreatic cancer: ARID1A, PBRM1, and BAP1.

Aims: The association between lung cancer and idiopathic pulmonary fibrosis (IPF) is well known, but the significance of this association is poorly understood. Bronchiolar honeycomb cysts have been proposed as possible precursors for the development of carcinoma, but limited evidence in support of this hypothesis is available. The aim of this study was to investigate this hypothesis analysing a series of carcinomas arising in IPF by immunohistochemistry. Methods and results: Thirty-three lung carcinomas arising in patients with IPF were analysed with a panel of immunohistochemical markers. The antibodies included those against pneumocyte markers [thyroid transcription factor 1 (TTF1), napsin-A, and surfactant protein A], the goblet cell marker mucin 5AC, markers of basal/squamous cell differentiation [cytokeratin (CK) 5/6 and ΔN-p63] , and markers related to enteric differentiation (CDX2, mucin 2, CK20, and villin). A series of 100 consecutive lung adenocarcinomas arising in smokers without IPF were investigated as controls. All carcinomas arising in IPF patients were peripherally located on imaging analysis. The diagnoses were: eight squamous cell carcinomas, 20 adenocarcinomas, three small-cell carcinomas (including one composite small-cell carcinoma and adenocarcinoma), and two large-cell carcinomas. Among adenocarcinomas, a 'pneumocyte' profile (TTF1/napsin-A/SPA1-triple-positive) was observed in seven of 20 (35% versus 84% in non-IPF controls, P = 0.0001). The remaining 13 adenocarcinomas (65%) showed rare histotypes: four invasive mucinous adenocarcinomas (20% in IPF patients versus 1% in non-IPF controls, P = 0.002), seven tumours (35%) that were characterized by variable expression of markers of enteric differentiation, and two tumours (10%) that showed a peculiar basaloid component. Conclusions: The immunohistochemical characterization of carcinomas arising in IPF patients shows striking divergence from that in non-IPF smokers. The prevalence of rare entities showing bronchiole-related markers is in line with the hypothesis that these tumours arise from transformed small airways in honeycomb lung areas where abnormal bronchiolar proliferation takes place. © 2017 John Wiley & Sons Ltd.

BACKGROUND Gains of a gene due to DNA polyploidy versus amplification of the specific locus are distinct molecular alterations in tumors. OBJECTIVE We quantified copy number gains of ALK gene due to unspecific polyploidy versus amplifications of the specific locus in a series of non-small cell lung cancers. METHODS The locus specific ALK copy (LSI) number status was evaluated in 205 cases by FISH. Ratio LSI ALK copy number corrected for control probes CEP2, CEP3 and CEP17 (CEPs) was scored. Amplification of the specific ALK locus was defined when ratio set to ≥ 2 while polyploidy was interpreted when the increase in gene copy resulted < 2 in ratio (LSI/control CEPs). RESULTS Twenty one cases (10.2%) showed ≥ 8 ALK signals, 68 cases (33.2%) 3-7 signals and 116 cases (56.6%) a mean of 2 signals. Only 2/21 cases of the cohort harboring ≥ 8 signals showed a ratio ≥ 2 after CEPs correction interpretable as amplified, showing numerous doubled fluorescent spots. All the remaining cases showed a mirrored number of fluorescent spots per each CEPs, interpretable as polyploidy. CONCLUSION We detected a high prevalence of ALK gene copy number usually due to polyploidy rather than ALK locus amplification, the latter visible prevalently as double minutes.

Aberrant function of Smad2, a crucial member of transforming growth factor beta (TGF-β) signaling, is associated with the development of malignancies, particularly in the gastrointestinal district. However, little is known about its possible prognostic role in such tumor types. With the first meta-analysis on this topic, we demonstrated that the lack of the activated form of Smad2 (phosphor-Smad2 or pSmad2), which was meant to be the C-terminally phosphorylated form, showed a statistically significant association with an increased risk of all-cause mortality in patients with gastrointestinal cancers (RR, 1.58; 95% CI, 1.05–2.37, p = 0.029, I2 = 84%), also after having adjusted for potential confounders (RR, 1.65; 95% CI, 1.24–2.18; p < 0.001; I2 = 4%). This finding highlights the importance of the TGF-β signaling in this type of cancer. In this line, further studies are needed to explore more in depth this important molecular pathway, focusing also on potential therapeutic strategies based on its effectors or molecular targets. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Background Pulmonary Adenocarcinoma with Enteric Differentiation (PAED) is a rare subtype of adenocarcinoma of emerging interest, recently introduced in the 2015 WHO classification. However, little is known about major molecular signatures of this class of adenocarcinomas and information about new biomarkers totally lack. Methods We examined the NRAS, PIK3CA, EGFR, KRAS and BRAF status through mass spectrometry sequencing and ALK rearrangement by FISH in a series of 8 PAEDs. Results 1/8 (12.5%) case had a simultaneous PIK3CA mutation (E545K) and an EML4-ALK translocation. KRAS gene showed a mutation in the codon 12 in 4/8 of PAED (50%), NRAS, BRAF and EGFR genes were wild type in all tumor samples. Conclusions We concluded that PIK3CA mutations and ALK rearrangement occur also in PAEDs, while NRAS mutations might be a very rare event similarly to pulmonary adenocarcinomas of conventional type. KRAS is the prevailing gene mutated in this class of adenocarcinoma.

Introduction: The extranodal extension (ENE) of nodal metastases (the extension of neoplastic cells through the nodal capsule into the perinodal soft tissue) is a histological feature that has been considered a prognostic factor in several cancers, but the role in gastric cancer was not yet investigated. We aimed to investigate the prognostic role of ENE in patients affected by gastric cancer through a systematic review and meta-analysis. Material and Methods: Two independent authors searched major databases until 09/30/2015 to identify studies providing data on gastric cancer patients’ prognostic parameters and comparing patients with ENE (ENE+) vs intra-nodal extension (ENE−). The data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) with 95% confidence intervals (CI), adjusted for potential confounders. Results: Nine studies followed up 3250 patients with gastric cancer (1064 ENE+ and 2186 ENE−). ENE+ was associated with a significantly higher risk of all-cause mortality (RR = 1.70; 95% CI: 1.43–2.03, I2 = 66%; HR = 2.14; 95% CI: 1.66–2.75, I2 = 0%), cancer-specific mortality (RR = 1.59; 95% CI: 1.42–1.79; HR = 1.52; 95% CI: 1.19–1.96), and disease recurrence (RR = 3.43, 95% CI: 1.80–6.54, I2 = 0%). Discussion: Judging from our results, ENE in gastric cancer patients should be considered for prognostic purposes from the gross sample to the pathology report. © 2016, The Society for Surgery of the Alimentary Tract.

Squamous cell carcinoma (SCC) of the vulva is the fourth most common gynecological cancer, usually staged with the TNM or FIGO systems. Since 2009, FIGO staging has taken the extranodal extension (ENE) of lymph node metastases into account. ENE is defined as the spread of a lymph node metastasis into surrounding soft tissue. Although the TNM and FIGO systems acknowledge the importance of ENE in SCC, no comprehensive studies have analyzed the prognostic impact of this parameter. We therefore queried the PubMed and SCOPUS databases from their inception up until 04/01/2015, adopting no language restrictions: all prospective studies reporting on prognostic parameters in patients with vulvar SCC, and comparing participants with and without ENE were eligible for our analysis. Data were summarized using risk ratios (RR) for the number of deaths/recurrences and hazard ratios (HR) for the time-dependent risk related to ENE positivity, adjusting for potential confounders. Among 859 hits, 13 studies were found eligible and were included in our meta-analysis. Compared with ENE-negative (ENE-) cases, the ENE-positive (ENE+) patients had significantly higher rates of all-cause mortality (6 studies: RR = 3.18; 95%CI: 2.02-5.00, p < 0.0001, I2 = 56%), cancer-specific mortality (3 studies: RR = 2.03; 95%CI: 1.12-3.69, p = 0.02, I2 = 80%), and recurrence (4 studies: RR = 2.69, 95%CI: 1.61-3.76, p < 0.0001, I2 = 57%). Using HRs after adjusting for potential confounders, ENE + carried a significantly higher risk of all-cause mortality (6 studies: HR = 3.08, 95%CI: 1.73-5.48, p < 0.0001, I2 = 66%), and recurrence (5 studies: HR = 3.93, 95%CI: 2.33-6.62, p < 0.0001, I2 = 28%). Our meta-analysis clarifies the prognostic significance of ENE in vulvar SCC, also pointing to its implications for gross sampling, histology and oncological staging. © 2015 Elsevier Ltd.All rights reserved.

Background. The role of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is still an issue for clinical research. Toward this end, a sensitivity analysis of neoadjuvant and adjuvant randomized clinical trials was performed according to disease subtypes. Methods. Pathological complete responses (pCRs) after neoadjuvant treatment according to the presence or absence of lymphocyte-predominant BC (LPBC) were extracted and cumulated as odds ratios (ORs) by adopting a random-effects model by subtype. Overall survival hazard ratios as a function of 10% incremental values of stromal TILs (sTILs) in adjuvant trials were extracted. The interaction test was adopted to determine the differential effect according to the subtype. Results. Eight trials (5,514 patients) were identified. With regard to neoadjuvant setting (4 studies), a significant interaction (p < .0001) according to LPBC was found. The presence of LPBC was associated with a 29.5% increase in pCR rate compared with non-LPBC (p < .0001). The pCR rate was significantly higher in patients with LPBC in triple-negative BC (TNBC) and HER2-positive BC settings, with an absolute difference of 15.7% (95% confidence interval [CI], 4.9%–26.2%) and 33.3% (95% CI, 23.6%–42.7%), respectively. With respect to the adjuvant setting (4 studies), a significant interaction (p < .0001) according to sTILs was found. A survival benefit was more likely to be determined for HER2-positive BC (p = .025) and TNBC (p < .0001), with no statistically significant difference for estrogen receptor-positive/HER2-negative disease. Conclusion. Despite the retrospective nature of this analysis, the presence of TILs may represent a robust predictive and prognostic marker for BC, particularly for TNBC and HER2-positive disease.

Pulmonary adenocarcinoma with enteric differentiation (PAED) is a rare subtype of lung adenocarcinoma recently recognized in the WHO classification. It is defined as an adenocarcinoma in which the enteric component exceeds 50% and have to show the expression of at least 1 immunohistochemical marker of enteric differentiation. Although the definition of this tumor type is very important, above all in the differential diagnosis between a primary lung tumor and a metastasis of colorectal adenocarcinoma, this cancer still lacks a distinctive immunohistochemical and molecular signature. We recruited the largest series in the literature of PAEDs according to the morphology and the positivity for intestinal markers. Then, we evaluated the immunohistochemical and molecular profile of these adenocarcinomas. In our series, CDX-2 and CK7 were the immunohistochemical markers mostly expressed by PAEDs. There was an inverse relationship between the expression of pnuemocytes markers, such as TTF-1, and intestinal markers. Molecular analysis revealed KRAS as the most frequently mutated gene (>60% of cases), with very few cases harboring abnormalities affecting EGFR, BRAF, and ALK genes. PAEDs are morphologically very heterogenous. The immunohistochemical profile based on CDX-2 and CK7 positivity of PAEDs appears very robust to support this diagnosis, and it is applicable also on small biopsies. KRAS appears as the most important mutated gene in such tumors. © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Introduction The epithelial to mesenchymal transition, a well-known and re-emerging model in pathology, has not been completely investigated in the field of gestational pathology. This study aims at improving the comprehension of this process in molar disease, even looking for new possible immunohistochemical markers. Materials and methods We have analysed the immunohistochemical expression of Twist1 and Snai2, two of the most important transcription factors involved in epithelial to mesenchymal transition, in formalin-fixed paraffin-embedded samples of 23 spontaneous abortive pregnancies, 22 molar pregnancies (10 partial and 12 complete) and 7 term placentas. Results Twist1 and Snai2 were highly expressed in stromal villi cells of molar disease. Particularly, Twist1 was highly expressed in complete moles compared to both abortive pregnancies (p < 0.001) and partial moles (p < 0.05). Also Snai2 was more expressed by complete moles, differentiating them from non-molar abortions (p < 0.05). Discussion On the basis of the known cadherins and claudins expression in these pathologies, our new findings reinforce the hypothesis of the involvement of epithelial to mesenchymal transition in early molar pregnancies and above all in complete moles. Furthermore, we highlighted that in molar disease not only the trophoblast, but even the villi stromal cells, are involved. Thanks to their specificity, furthermore, these Twist1 and Snai2 could be used as additional immunohistochemical tool in the diagnosis of complete molar disease, with Twist1 as the first choice. © 2015 Elsevier Ltd. All rights reserved.

Transferrin receptor/CD71 is a membrane protein expressed on nucleated red blood cells (NRBCs) and trophoblasts. Here, we propose the first study to evaluate the usefulness of CD71 immunolabeling in the main fields of gestational pathology. To this aim, formalin-fixed, paraffin-embedded samples of 45 orthotopic (23 spontaneous abortive and 22 molar pregnancies) and 11 ectopic pregnancies were immunostained for CD71. NRBCs were morphologically evident in 23 cases: 12/23 abortive, 4/11 ectopic, and 7/10 partial molar pregnancies. CD71 immunolabeling detected NRBCs in all 23 previous cases and in 8 new cases: 2 partial moles and 6 spontaneous abortive pregnancies. No NRBCs were detected in complete moles by means of either morphology or immunohistochemistry (IHC). In 4 cases with extensive necrotic changes, CD71 marked NRBCs and a few ghost villi, which were not certainly identifiable with standard histological evaluation. Furthermore, there was an inversely proportional relationship between total percentage of CD71-positive NRBCs and gestational age (R=0.69; P

Introduction: The report of cases of lung squamous cell cancers harboring anaplastic lymphoma kinase ( ALK ) gene rearrangements raises the question whether this histologic subtype should be also evaluated for such molecular predictive test. Methods: A consecutive series of 40 lung pure squamous cell carcinomas were analyzed for ALK gene status by fluorescence in situ hybridization. Squamous differentiation was validated using an immunohistochemical panel including n-p63 (p40), cytokeratin (CK) 5/6, sex-determining region Y (SRY)-Box2 (SOX2), thyroid transcription factor 1, CK7, and Napsin-A. Results: Squamous differentiation was confirmed in all tumors as they stained positive for n-p63 and CK5/6 and negative for thyroid transcription factor 1 and Napsin-A. One of 40 cases (2.5%) showed an ALK rearrangement on fluorescence in situ hybridization analysis. Conclusions: ALK translocation may be found in lung pure squamous cell carcinomas. Our data suggest the opportunity to test ALK rearrangements on biopsy samples harboring squamous cell cancer differentiation.

Squamous lung carcinoma lacks specific “ad hoc” therapies. Amplification of chromosome 3q is the most common genomic aberration and this region harbours genes having role as novel targets for therapeutics. There is no standard definition on how to score and report 3q amplification. False versus true 3q chromosomal amplification in squamous cell lung carcinoma may have tremendous impact on trials involving drugs which target DNA zones mapping on 3q. Forty squamous lung carcinomas were analyzed by FISH to assess chromosome 3q amplification. aCGH was performed as gold-standard to avoid false positive amplifications. Three clustered patterns of fluorescent signals were observed. Eight cases out of 40 (20%) showed ≥8 3q signals. Twenty out of 40 (50%) showed from 3 to 7 signals. The remaining showed two fluorescent signals (30%). When corrected by whole chromosome 3 signals, only cases with ≥8 signals maintained a LSI 3q/CEP3 ratio >2. Only the cases showing 3q amplification by aCGH (+3q25.3−3q27.3) showed ≥8 fluorescent signals at FISH evidencing a 3q/3 ratio >2. The remaining cases showed flat genomic portrait at aCGH on chromosome 3. We concluded that: 1) absolute copy number of 3q chromosomal region may harbour false positive interpretation of 3q amplification in squamous cell carcinoma; 2) a case results truly “amplified for chromosome 3q” when showing ≥8 fluorescent 3q signals; 3) trials involving drugs targeting loci on chromosome 3q in squamous lung carcinoma therapy have to consider false versus true 3q chromosomal amplification.

The extranodal extension (ENE) of nodal metastasis (i.e. the extension of tumor cells through the nodal capsule into the perinodal adipose tissue) has recently emerged as an important prognostic factor in different types of malignancies. However, the tumor-node-metastasis (TNM) staging system for colorectal cancer does not consider it as a prognostic parameter. Therefore, we conducted a systematic review and meta-analysis to determine the prognostic role of ENE in patients with lymph node-positive colorectal cancer.Two independent authors searched PubMed and SCOPUS until 7 January 2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with colorectal cancer, comparing participants with the presence of ENE (ENE+) versus only intranodal extension (ENE-) were eligible. Data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) together with 95% confidence intervals (CIs) for time-dependent risk related to ENE+, adjusted for potential confounders.Thirteen studies including 1336 patients were identified with a median follow-up of 4.7 years. ENE was associated with a higher T stage and tumor grading. In addition, ENE was associated with a significantly increased risk of all-cause mortality (RR = 1.75; 95% CI 1.42-2.16, P0.0001, I(2) = 60%; HR = 1.69, 95% CI 1.32-2.17, P0.0001, I(2) = 46%) and of recurrence of disease (RR = 2.07, 95% CI 1.65-2.61, P0.0001, I(2) = 47%; HR = 2.31, 95% CI 1.54-3.44, P0.0001, I(2) = 48%).Based of these results, in colorectal cancer, ENE should be considered from the gross sampling to the pathology report, as well as in future oncologic staging systems.

Background Lobular breast carcinoma usually shows poor responsiveness to chemotherapies and often lacks targeted therapies. Since FGFR1 expression has been shown to play pivotal roles in primary breast cancer tumorigenesis, we sought to analyze the status of FGFR1 gene in a metastatic setting of lobular breast carcinoma, since promising FGFR1 inhibitors has been recently developed. Methods Fifteen tissue metastases from lobular breast carcinomas with matched primary infiltrative lobular breast carcinoma were recruited. Eleven cases showed loco-regional lymph-nodal and four haematogenous metastases. FGFR-1 gene (8p12) amplification was evaluated by chromogenic in situ hybridization (CISH) analysis. Her-2/neu and topoisomerase-IIα gene status was assessed. E-cadherin and Hercept Test were also performed. We distinguished amplification (>6 or cluster of signals) versus gains (3–6 signals) of the locus specific FGFR-1 gene. Results Three (20%) primary lobular breast carcinomas showed >6 or cluster of FGFR1 signals (amplification), six cases (40%) had a mean of three (range 3–6) chromogenic signals (gains) whereas in 6 (40%) was not observed any abnormality. Three of 15 metastasis (20%) were amplified, 2/15 (13,4%) did not. The ten remaining cases (66,6%) showed three chromogenic signals. The three cases with FGFR-1 amplification matched with those primary breast carcinomas showing FGFR-1 amplification. The six cases showing FGFR-1 gains in the primary tumour again showed FGFR-1 gains in the metastases. Four cases showed gains of FGFR-1 gene signals in the metastases and not in the primary tumours. Her-2/neu gene amplification was not observed in all cases but one (6%) case. Topoisomerase-IIα was not amplified in all cases. Conclusions 1) a subset of metastatic lobular breast carcinoma harbors FGFR-1 gene amplification or gains of chromogenic signals; 2) a minor heterogeneity has been observed after matching primary and metastatic carcinomas; 3) in the era of tailored therapies, patients affected by the lobular subtype of breast carcinoma with FGFR1 amplification could be approached to the new target biological therapy such as emerging FGFR-1 inhibitors.