RESUMO
BACKGROUND: Microsatellite instability (MSI) due to mismatch repair deficiency (dMMR) is common in colorectal cancer (CRC). These cancers are associated with somatic coding events, but the noncoding pathophysiological impact of this genomic instability is yet poorly understood. Here, we perform an analysis of coding and noncoding MSI events at the different steps of colorectal tumorigenesis using whole exome sequencing and search for associated splicing events via RNA sequencing at the bulk-tumor and single-cell levels. RESULTS: Our results demonstrate that MSI leads to hundreds of noncoding DNA mutations, notably at polypyrimidine U2AF RNA-binding sites which are endowed with cis-activity in splicing, while higher frequency of exon skipping events are observed in the mRNAs of MSI compared to non-MSI CRC. At the DNA level, these noncoding MSI mutations occur very early prior to cell transformation in the dMMR colonic crypt, accounting for only a fraction of the exon skipping in MSI CRC. At the RNA level, the aberrant exon skipping signature is likely to impair colonic cell differentiation in MSI CRC affecting the expression of alternative exons encoding protein isoforms governing cell fate, while also targeting constitutive exons, making dMMR cells immunogenic in early stage before the onset of coding mutations. This signature is characterized by its similarity to the oncogenic U2AF1-S34F splicing mutation observed in several other non-MSI cancer. CONCLUSIONS: Overall, these findings provide evidence that a very early RNA splicing signature partly driven by MSI impairs cell differentiation and promotes MSI CRC initiation, far before coding mutations which accumulate later during MSI tumorigenesis.
Assuntos
Processamento Alternativo , Neoplasias Colorretais , Instabilidade de Microssatélites , Fator de Processamento U2AF , Neoplasias Colorretais/genética , Humanos , Fator de Processamento U2AF/genética , Fator de Processamento U2AF/metabolismo , Mutação , Sítios de Ligação , ÉxonsRESUMO
The dysplasia grading of Barrett's esophagus (BE), based on the histomorphological assessment of formalin-fixed, paraffin-embedded (FFPE) tissue, suffers from high interobserver variability leading to an unsatisfactory prediction of cancer risk. Thus, pre-analytic preservation of biological molecules, which could improve risk prediction in BE enabling molecular and genetic analysis, is needed. We aimed to evaluate such a molecular pre-analytic fixation tool, PAXgene-fixed paraffin-embedded (PFPE) biopsies, and their suitability for histomorphological BE diagnostics in comparison to FFPE. In a ring trial, 9 GI pathologists evaluated 116 digital BE slides of non-dysplastic BE (NDBE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and esophageal adenocarcinomas (EAC) using virtual microscopy. Overall quality, cytological and histomorphological parameters, dysplasia criteria, and diagnosis were analyzed. PFPE showed better preservation of nuclear details as chromatin and nucleoli, whereas overall quality and histomorphologic parameters as visibility of basal lamina, goblet cells, and presence of artifacts were scored as equal to FFPE. The interobserver reproducibility with regard to the diagnosis was best for NDBE and EAC (κF = 0.72-0.75) and poor for LGD and HGD (κF = 0.13-0.3) in both. In conclusion, our data suggest that PFPE allows equally confident histomorphological diagnosis of BE and EAC, introducing a novel tool for molecular analysis and parallel histomorphological evaluation.
Assuntos
Adenocarcinoma , Esôfago de Barrett , Neoplasias Esofágicas , Lesões Pré-Cancerosas , Humanos , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Esôfago de Barrett/diagnóstico , Esôfago de Barrett/patologia , Progressão da Doença , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patologia , Hiperplasia , Lesões Pré-Cancerosas/patologia , Reprodutibilidade dos Testes , Fixação de TecidosRESUMO
OBJECTIVE: The aim of this study to describe a new international dataset for pathology reporting of colorectal cancer surgical specimens, produced under the auspices of the International Collaboration on Cancer Reporting (ICCR). BACKGROUND: Quality of pathology reporting and mutual understanding between colorectal surgeon, pathologist and oncologist are vital to patient management. Some pathology parameters are prone to variable interpretation, resulting in differing positions adopted by existing national datasets. METHODS: The ICCR, a global alliance of major pathology institutions with links to international cancer organizations, has developed and ratified a rigorous and efficient process for the development of evidence-based, structured datasets for pathology reporting of common cancers. Here we describe the production of a dataset for colorectal cancer resection specimens by a multidisciplinary panel of internationally recognized experts. RESULTS: The agreed dataset comprises eighteen core (essential) and seven non-core (recommended) elements identified from a review of current evidence. Areas of contention are addressed, some highly relevant to surgical practice, with the aim of standardizing multidisciplinary discussion. The summation of all core elements is considered to be the minimum reporting standard for individual cases. Commentary is provided, explaining each element's clinical relevance, definitions to be applied where appropriate for the agreed list of value options and the rationale for considering the element as core or non-core. CONCLUSIONS: This first internationally agreed dataset for colorectal cancer pathology reporting promotes standardization of pathology reporting and enhanced clinicopathological communication. Widespread adoption will facilitate international comparisons, multinational clinical trials and help to improve the management of colorectal cancer globally.
Assuntos
Neoplasias Colorretais/patologia , Conjuntos de Dados como Assunto/normas , Projetos de Pesquisa , HumanosRESUMO
Perioperative chemotherapy is increasingly used in combination with surgery for the treatment of patients with locally advanced, resectable gastric cancer. Histologic tumor regression grade (TRG) has emerged as an important prognostic factor; however, a common standard for its evaluation is lacking. Moreover, the clinical significance of regressive changes in metastatic lymph nodes (LNs) remains unclear. We conducted an international study to examine the interobserver agreement of a TRG system that is based on the Becker system for the primary tumors and additionally incorporates regression grading in LNs. Twenty observers at different levels of experience evaluated the TRG in 60 histologic slides (30 primary tumors and 30 LNs) based on the following criteria: for primary tumors, grade 1 represented complete response (no residual tumor), grade 2 represented <10%, grade 3 represented 10-50%, and grade 4 represented >50% residual tumor, as described by Becker et al. For LNs, grade "a" represented complete, grade "b" represented partial, and grade "c" represented no regression. The interobserver agreement was estimated using the Kendall's coefficient of concordance (W). Regarding primary tumors, agreement was good irrespective of the level of experience, reaching a W-value of 0.70 overall, 0.71 among subspecialized, and 0.71 among nonsubspecialized observers. Regarding LNs, interobserver agreement was moderate to good, with W-values of 0.52 overall, 0.64 among subspecialized, and 0.45 among nonsubspecialized observers. These findings indicate that the combination of the Becker TRG system with a three-tiered grading of regression in LNs generates a system that is reproducible. Future studies should investigate whether the additional information of TRG in LNs adds to the prognostic value of histologic regression grading in gastric cancer specimens.
Assuntos
Adenocarcinoma/patologia , Metástase Linfática/patologia , Gradação de Tumores/métodos , Variações Dependentes do Observador , Neoplasias Gástricas/patologia , Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Humanos , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Metástase Linfática/tratamento farmacológico , Terapia Neoadjuvante , Indução de Remissão , Neoplasias Gástricas/tratamento farmacológicoRESUMO
Glomus tumors (GTs) are perivascular tumors mostly occurring in the distal extremities. Rare cases arise in the digestive tract and may be misdiagnosed with neuroendocrine or gastrointestinal stromal tumors. We aimed to specify the features of GT of the upper digestive tract. Clinical, histological, phenotypic, and molecular features of 16 digestive GTs were analyzed, of whom two underwent whole exome and RNA sequencing to search for gene alterations. RNA-sequencing disclosed a t(1:5)(p13;q32) translocation, which resulted in the fusion of CARMN and NOTCH2 in two GTs. The fusion gene encoded a protein sequence corresponding to the NOTCH2 intracellular domain that functions as transcription factor. These finding was supported by high expression of genes targeted by NOTCH. The CARMN-NOTCH2 translocation was detected in 14 out of 16 (88%) GTs of the upper digestive tract; but in only in two out of six cutaneous GTs (33%). Most digestive GT arose from the stomach (n = 13), and the others from duodenal (2) or oesophagous (1). Nuclear expression of NOTCH2 was detected in the 14 cases containing the fusion transcripts. The CARMN-NOTCH2 fusion transcript may contribute to activation of the NOTCH2 pathway in GT and drive tumor development. The high frequency of this translocation in GT of the upper digestive track suggest that detection of nuclear NOTCH2 expression may be useful diagnostic biomarker of these tumors.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Gastrointestinais/genética , Fusão Gênica , Tumor Glômico/genética , MicroRNAs/genética , Receptor Notch2/genética , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Tumor Glômico/metabolismo , Tumor Glômico/patologia , HumanosRESUMO
Napoleon Bonaparte died on 5 May 1821 on the island of St Helena after almost six years of exile. The next day, Dr Francesco Antommarchi, a Corsican doctor chosen by the Bonaparte family to treat the exiled emperor, performed the autopsy in the presence of sixteen people, including seven British doctors. Two hundred years after the event of 6 May 1821, the cause of Napoleon's death is still a mystery. Various hypotheses, such as arsenic intoxication, cardiac arrhythmia or, more recently, anaemia caused by gastrointestinal haemorrhage associated with chronic gastritis, have been put forward in the medical-historical literature. The main reasons for all these debates and misunderstandings are the presence of several autopsy reports, their often unscientific interpretation, as well as a certain taste for mystery. However, from a scientific point of view, the question arises as to whether autopsy reports are really conclusive as to the real cause of death. Thus, on the occasion of the bicentenary of Napoleon I's death in St. Helena, an international group of anatomo-pathologists specialising in digestive pathology set themselves the goal of analysing Napoleon I's autopsy reports according to their level of medical evidence (high, moderate and low). The autopsy reports of 1821 support the hypothesis of advanced malignant neoplasia of the stomach associated with gastric haemorrhage as the immediate cause of Napoleon I's death on 5 May 1821.
Assuntos
Pessoas Famosas , Neoplasias Gástricas , Ilhas Atlânticas , Autopsia , Hemorragia Gastrointestinal , História do Século XIX , HumanosRESUMO
BACKGROUND & AIMS: Next-generation sequencing (NGS) was recently approved by the United States Food and Drug Administration to detect microsatellite instability (MSI) arising from defective mismatch repair (dMMR) in patients with metastatic colorectal cancer (mCRC) before treatment with immune checkpoint inhibitors (ICI). In this study, we aimed to evaluate and improve the performance of NGS to identify MSI in CRC, especially dMMR mCRC treated with ICI. METHODS: CRC samples used in this post hoc study were reassessed centrally for MSI and dMMR status using the reference methods of pentaplex polymerase chain reaction and immunohistochemistry. Whole-exome sequencing (WES) was used to evaluate MSISensor, the Food and Drug Administration-approved and NGS-based method for assessment of MSI. This was performed in (1) a prospective, multicenter cohort of 102 patients with mCRC (C1; 25 dMMR/MSI, 24 treated with ICI) from clinical trials NCT02840604 and NCT033501260, (2) an independent retrospective, multicenter cohort of 113 patients (C2; 25 mCRC, 88 non-mCRC, all dMMR/MSI untreated with ICI), and (3) a publicly available series of 118 patients with CRC from The Cancer Genome Atlas (C3; 51 dMMR/MSI). A new NGS-based algorithm, namely MSICare, was developed. Its performance for assessment of MSI was compared with MSISensor in C1, C2, and C3 at the exome level or after downsampling sequencing data to the MSK-IMPACT gene panel. MSICare was validated in an additional retrospective, multicenter cohort (C4) of 152 patients with new CRC (137 dMMR/MSI) enriched in tumors deficient in MSH6 (n = 35) and PMS2 (n = 9) after targeted sequencing of samples with an optimized set of microsatellite markers (MSIDIAG). RESULTS: At the exome level, MSISensor was highly specific but failed to diagnose MSI in 16% of MSI/dMMR mCRC from C1 (4 of 25; sensitivity, 84%; 95% confidence interval [CI], 63.9%-95.5%), 32% of mCRC (8 of 25; sensitivity, 68%; 95% CI, 46.5%-85.1%), and 9.1% of non-mCRC from C2 (8 of 88; sensitivity, 90.9%; 95% CI, 82.9%-96%), and 9.8% of CRC from C3 (5 of 51; sensitivity, 90.2%; 95% CI, 78.6%-96.7%). Misdiagnosis included 4 mCRCs treated with ICI, of which 3 showed an overall response rate without progression at this date. At the exome level, reevaluation of the MSI genomic signal using MSICare detected 100% of cases with true MSI status among C1 and C2. Further validation of MSICare was obtained in CRC tumors from C3, with 96.1% concordance for MSI status. Whereas misdiagnosis with MSISensor even increased when analyzing downsampled WES data from C1 and C2 with microsatellite markers restricted to the MSK-IMPACT gene panel (sensitivity, 72.5%; 95% CI, 64.2%-79.7%), particularly in the MSH6-deficient setting, MSICare sensitivity and specificity remained optimal (100%). Similar results were obtained with MSICare after targeted NGS of tumors from C4 with the optimized microsatellite panel MSIDIAG (sensitivity, 99.3%; 95% CI, 96%-100%; specificity, 100%). CONCLUSIONS: In contrast to MSISensor, the new MSICare test we propose performs at least as efficiently as the reference method, MSI polymerase chain reaction, to detect MSI in CRC regardless of the defective MMR protein under both WES and targeted NGS conditions. We suggest MSICare may rapidly become a reference method for NGS-based testing of MSI in CRC, especially in mCRC, where accurate MSI status is required before the prescription of ICI.
Assuntos
Algoritmos , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Sequenciamento do Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Instabilidade de Microssatélites , Tomada de Decisão Clínica , Ensaios Clínicos como Assunto , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Bases de Dados Genéticas , França , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imuno-Histoquímica , Reação em Cadeia da Polimerase Multiplex , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Shwachman-Diamond syndrome with Shwachman-Bodian-Diamond syndrome (SBDS) biallelic variants is a rare disorder that predisposes the carrier to malignant hemopathies but solid-cancer predisposition is poorly known. Among 155 cases entered in the French Registry for Severe Chronic Neutropenia, three were identified with malignant solid tumors (ovary, breast, and esophagus). All cancers occurred during the fifth decade and, despite being localized at diagnosis, were rapidly fatal thereafter. No cancer was observed post transplantation in the 14 HSCT survivors. Based on the literature and our patient data, we can merely advance that this complication is predominantly diagnosed in adults.
Assuntos
Neoplasias , Neutropenia , Síndrome de Shwachman-Diamond , Feminino , Humanos , Neoplasias/complicações , Neoplasias/epidemiologia , Neoplasias/genética , Neutropenia/epidemiologia , Neutropenia/etiologia , Neutropenia/genética , Sistema de Registros , Síndrome de Shwachman-Diamond/complicaçõesRESUMO
BACKGROUND AND AIMS: Histological scoring plays a key role in the assessment of disease activity in ulcerative colitis [UC] and is also important in Crohn´s disease [CD]. Currently, there is no common scoring available for UC and CD. We aimed to validate the Inflammatory Bowel Disease [IBD]-Distribution [D], Chronicity [C], Activity [A] score [IBD-DCA score] for histological disease activity assessment in IBD. METHODS: Inter- and intra-rater reliability were assessed by 16 observers on biopsy specimens from 59 patients with UC and 25 patients with CD. Construct validity and responsiveness to treatment were retrospectively evaluated in a second cohort of 30 patients. RESULTS: Inter-rater reliability was moderate to good for the UC cohort (intraclass correlation coefficients [ICCs]â =â 0.645, 0.623, 0.767 for D, C, and A, respectively) and at best moderate for the CD cohort [ICCâ =â 0.690, 0.303, 0.733 for D, C, and A, respectively]. Intra-rater agreement ranged from good to excellent in both cohorts. Correlation with the Nancy Histological Index [NHI] was moderate and strong with the Simplified Geboes Score [SGS] and a Visual Analogue Scale [VAS], respectively. Large effect sizes were obtained for all three parameters. External responsiveness analysis revealed correlated changes between IBD-DCA score and NHI, SGS and VAS. CONCLUSIONS: The IBD-DCA score is a simple histological activity score for UC and CD, agreed and validated by a large group of IBD specialists. It provides reliable information on treatment response. Therefore, it has potential value for use in routine diagnostics as well as clinical studies.
Assuntos
Colite Ulcerativa/patologia , Doença de Crohn/patologia , Índice de Gravidade de Doença , Biópsia , Humanos , Mucosa Intestinal/patologia , Reprodutibilidade dos TestesRESUMO
Tumor budding is a long-established independent adverse prognostic marker in colorectal cancer, yet methods for its assessment have varied widely. In an effort to standardize its reporting, a group of experts met in Bern, Switzerland, in 2016 to reach consensus on a single, international, evidence-based method for tumor budding assessment and reporting (International Tumor Budding Consensus Conference [ITBCC]). Tumor budding assessment using the ITBCC criteria has been validated in large cohorts of cancer patients and incorporated into several international colorectal cancer pathology and clinical guidelines. With the wider reporting of tumor budding, new issues have emerged that require further clarification. To better inform researchers and health-care professionals on these issues, an international group of experts in gastrointestinal pathology participated in a modified Delphi process to generate consensus and highlight areas requiring further research. This effort serves to re-affirm the importance of tumor budding in colorectal cancer and support its continued use in routine clinical practice.
Assuntos
Carcinoma/patologia , Movimento Celular , Pólipos do Colo/patologia , Neoplasias Colorretais/patologia , Patologia Clínica/normas , Biópsia , Diferenciação Celular , Consenso , Técnica Delphi , Humanos , Invasividade Neoplásica , Estadiamento de Neoplasias , Valor Preditivo dos TestesRESUMO
After the defeat at the battle of Waterloo on June 18, 1815, Napoleon Bonaparte was sent into exile to the Island of St. Helena where he died 6 years later on May 5, 1821. One day after his death, Napoleon's personal physician, Dr. Francesco Antommarchi, performed the autopsy in the presence of Napoleon's exile companions and the British medical doctors. Two hundred years later, mysteries still surround the cause of his death and different hypotheses have been postulated in the medical and historical literature. The main reasons seem to be the presence of several autopsy reports, their interpretation and perhaps the greed for thrill and mystery. Therefore, for the bicentenary of Napoleon's death, an international consortium of gastrointestinal pathologists assembled to analyse Napoleon's autopsy reports based on the level of medical evidence and to investigate if the autopsy reports really do not allow a final statement.
Assuntos
Hemorragia Gastrointestinal/história , Neoplasias Gástricas/história , Aniversários e Eventos Especiais , Autopsia/história , Causas de Morte , Pessoas Famosas , Hemorragia Gastrointestinal/patologia , História do Século XIX , Humanos , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Human papillomavirus (HPV) infection is more frequent in men having sex with men (MSM) who are living with human immunodeficiency virus (HIV) than in MSM without HIV. There are currently no data regarding HPV infections in preexposure prophylaxis (PrEP)-using MSM. METHODS: MSM living without HIV who were enrolled in the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales "Intervention Préventive de l'Exposition aux Risques avec et pour les hommes Gays" PrEP study were prospectively enrolled. Anal, penile, and oral samples were collected at baseline and every 6 months for HPV detection and genotyping. Anal swabs for cytology were obtained at baseline and at 24 months. RESULTS: We enrolled 162 participants. The prevalences of any HPV genotypes at baseline were 92%, 32%, and 12% at the anal, penile, and oral sites, respectively. High-risk (HR) HPV genotypes were observed in 84%, 25%, and 10% of anal, penile, and oral baseline samples, respectively. Nonavalent HPV vaccine genotypes were observed in 77%, 22%, and 6% of anal, penile, and oral baseline samples, respectively. Multiple infections were observed in 76%, 17%, and 3% of cases at the anal, penile, and oral sites, respectively. The most frequent HR genotypes were HPV 53, 51, and 16 in anal samples; HPV 33, 39, and 73 in penile samples; and HPV 66 in oral samples. The incidence of any HPV genotype at the anal site was 86.2/1000 person-months and the incidence of HR-HPV genotypes was 72.3/1000 person-months. The baseline cytology was normal in 32% of cases and was classified as atypical squamous cells of undetermined significance, low-grade squamous intra-epithelial lesion, high-grade squamous intra-epithelial lesion (HSIL), and atypical squamous cells that cannot exclude HSIL in 23%, 40%, 5%, and 1% of cases, respectively. CONCLUSIONS: PrEP users have a similar risk of HPV infection as MSM living with HIV and the risk is much higher than that previously reported in MSM living without HIV.
Assuntos
Infecções por HIV , Infecções por Papillomavirus , Profilaxia Pré-Exposição , Minorias Sexuais e de Gênero , Canal Anal , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Homossexualidade Masculina , Humanos , Incidência , Masculino , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/prevenção & controle , PrevalênciaRESUMO
A serrated polyposis syndrome was diagnosed in a 26-year-old female presenting with gastrointestinal symptoms. Screening for other lesions of the gastrointestinal tract showed a serpiginous looking papilla, described as possibly dysplastic. Histological analysis of biopsies showed a serrated lesion. This case describes the first known association between a duodenal serrated lesion and serrated polyposis syndrome. Upper GI screening is probably of little interest in this setting. In patients with upper GI serrated lesions, we recommend screening colonoscopy.
Assuntos
Pólipos do Colo , Colonoscopia , Adulto , Biópsia , Colo , Pólipos do Colo/diagnóstico , Duodeno , Feminino , HumanosAssuntos
Esofagite/diagnóstico , Esôfago/imunologia , Doença Relacionada a Imunoglobulina G4/diagnóstico , Imunoglobulina G/análise , Plasmócitos/imunologia , Idoso de 80 Anos ou mais , Biópsia , Esofagite/tratamento farmacológico , Esofagite/imunologia , Esofagite/patologia , Esofagoscopia , Esôfago/patologia , Humanos , Doença Relacionada a Imunoglobulina G4/tratamento farmacológico , Doença Relacionada a Imunoglobulina G4/imunologia , Doença Relacionada a Imunoglobulina G4/patologia , Imuno-Histoquímica , MasculinoAssuntos
Colite Ulcerativa/patologia , Doença de Crohn/patologia , Técnicas de Apoio para a Decisão , Intestinos/patologia , Biópsia , Tomada de Decisão Clínica , Colite Ulcerativa/terapia , Consenso , Doença de Crohn/terapia , Técnica Delphi , Humanos , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos TestesRESUMO
Biliary tract carcinomas are divided into intrahepatic, perihilar, distal extrahepatic cholangiocarcinomas, and gallbladder adenocarcinomas. Therapies targeting ROS1, ALK, MET, and HER2 alterations are currently evaluated in clinical trials. We assessed ROS1 and ALK translocations/amplifications as well as MET and HER2 amplifications for each tumor subtype by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) in 73 intrahepatic, 40 perihilar bile duct, 36 distal extrahepatic cholangiocarcinomas, and 45 gallbladder adenocarcinomas (n = 194). By FISH, we detected targetable alterations in 5.2% of cases (n = 10): HER2 and MET amplifications were found in 4.1% (n = 8) and 1.0% (n = 2), respectively. The HER2-amplified cases were mostly gallbladder adenocarcinomas (n = 5). The MET- and HER2-amplified cases were all positive by IHC. Fourteen cases without MET amplification were positive by IHC, whereas HER2 over-expression was detected by IHC only in HER2-amplified cases. We detected no ALK or ROS1 translocation or amplification. Several alterations were consistent with aneuploidy: 24 cases showed only one copy of ROS1 gene, 4 cases displayed a profile of chromosomal instability, and an over-representation of centromeric alpha-satellite sequences was found in five cases. We confirm a relatively high rate of HER2 amplifications in gallbladder adenocarcinomas and the efficacy of IHC to screen these cases. Our results also suggest the value of IHC to screen MET amplification. Contrary to initial publications, ROS1 rearrangements seem to be very rare in biliary tract adenocarcinomas. We confirm a relatively high frequency of aneuploidy and chromosomal instability and reveal the over-representation of centromeric alpha-satellite sequences in intrahepatic cholangiocarcinomas.
Assuntos
Adenocarcinoma/genética , Rearranjo Gênico/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptor ErbB-2/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Quinase do Linfoma Anaplásico/genética , Sistema Biliar/patologia , Humanos , Hibridização in Situ Fluorescente/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-met/genéticaRESUMO
OBJECTIVE: Anal high-grade squamous intraepithelial lesion (HSIL) may precede invasive cancer and can be detected clinically or during high-resolution anoscopy (HRA). The aims of this study were to compare the characteristics of HSIL discovered by HRA or in a surgical specimen without clinically visible lesion when diagnosed versus macroscopic HSIL when first diagnosed and then to compare their progression to invasive cancer. PATIENTS AND METHODS: Clinical records of all patients with at least one HSIL lesion confirmed by histology and evaluated by HRA in a single center between September 1, 2009, and April 30, 2017, were retrospectively reviewed. The center's histological anal cancer data base was questioned in December 2017 to identify all cases. RESULTS: During a median (interquartile range) follow-up of 19.1 (5.6-40.2) months, 12 (2.9%) anal cancers were diagnosed in patients with a diagnosis of HSIL. Period of time between the first diagnosis of anal lesion and the cancer was 28.8 months (interquartile range = 15.4-65.6), and 11 (92%) of 12 were diagnosed as superficially invasive squamous cell carcinoma or T1N0M0. The rate of progression to anal cancer differed significantly between patients with macroscopic HSIL at diagnosis (5.4%) and patients with microscopic HSIL diagnosed during HRA (0.9%) (p = .01). CONCLUSIONS: Patients with macroscopic histologically proven HSIL at first diagnosis of anal intraepithelial lesion have a significantly higher risk of anal cancer compared with patients with microscopic lesions diagnosed during HRA, but the duration between the first diagnosis of HSIL and cancer does not differ between the 2 groups.
Assuntos
Neoplasias do Ânus/diagnóstico , Gerenciamento Clínico , Progressão da Doença , Diagnóstico Precoce , Lesões Intraepiteliais Escamosas/diagnóstico , Adolescente , Adulto , Idoso , Endoscopia , Feminino , Histocitoquímica , Humanos , Masculino , Microscopia , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE: The aim of this study was to investigate the association between expression of insulin-like growth factor-1 receptor (IGF1R) and its ligand, IGF-II, and disease-free survival (DFS) in patients with stage III colon cancer (CC). METHODS: In this retrospective study we included consecutive patients who underwent curative surgery for stage III CC. IGF1R and IGF-II/IGF2 status were evaluated in tumour samples by immunohistochemistry and quantitative real-time PCR (qRT-PCR). Associations of markers with DFS were analysed using Cox proportional hazards models. RESULTS: Hundred and fifty-one CC patients were included (median age, 66.6 years; female, 54.3%). Low levels of IGF1R and IGF-II protein expression were observed in 16.1% and 10.7% of the cases, respectively. No significant differences in clinicopathological characteristics between patients with tumours expressing low IGF1R or IGF-II protein levels and those with high levels were observed. A low IGF1R protein expression was found to be significantly associated with a shorter DFS (HR 3.32; 95% CI, 1.7-6.31; p = 0.0003), while no association was observed between IGF-II protein expression and DFS (HR 0.91; 95% CI, 0.28-2.96; p = 0.87). In a multivariate analysis, IGF1R protein status remained an independent prognostic factor for DFS (HR 2.73; 95% CI, 1.40-5.31; p = 0.003). Furthermore, we found that neither IGF1R nor IGF2 mRNA expression levels as measured by qRT-PCR correlated with the respective protein expression levels as assessed by immunohistochemistry. Neither of the mRNA expression levels was significantly associated with DFS. CONCLUSIONS: From our data we conclude that low IGF1R protein expression represents a poor prognostic biomarker in stage III colon cancer.
Assuntos
Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , RNA Mensageiro/genética , Receptor IGF Tipo 1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Mensageiro/metabolismo , Receptor IGF Tipo 1/biossíntese , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND AND AIMS: Different types of histologic lesions at the ileal margin, detected by histology, have been associated with increased rates of recurrence after ileocaecal surgery in patients with Crohn's disease (CD). We aimed to characterize histologic features of the ileal margin and to evaluate their association with disease recurrence. METHODS: We collected histologic data from 211 patients with ileal or ileocolonic CD who underwent ileocolonic resections at hospitals in France from September 2010 through December 2016. Ileal margins were analyzed. Early endoscopic recurrence was defined by a Rutgeerts score of i2 or more, 6 months after surgery. We also collected data from 10 adults with healthy ileum who underwent ileocecal resection for colonic tumors (controls). Clinical relapse was defined by CD-related symptoms confirmed by imaging, endoscopy, therapy intensification, CD-related complication, or subsequent surgery. RESULTS: Six months after surgery, 49% of patients had endoscopic recurrence; 5 years after surgery, 57% of patients had clinical relapse. Ileal margins were macroscopically affected in 20.9% of patients. CD transmural lesions at the margin (defined by mucosal ulceration or cryptitis, submucosal fibrosis and lymphoplasmacytic infiltrate of the subserosa) were observed in 13.6% of patients. Endoscopic recurrence was observed in 75% of patients with CD transmural lesions vs 46% of patients without (P =.005). In multivariate analysis, CD transmural lesions at the margin were independently associated with early endoscopic recurrence (OR, 3.83; 95% CI, 1.47-11.05; P =.008) and clinical recurrence (OR 2.04; 95% CI, 1.09-3.99; P =.026). CONCLUSION: In patients with CD, transmural lesions at the ileal margin were associated with an increased risk of post-operative recurrence. Histologic features of the ileal margin should be included in making decisions about post-operative therapy.
Assuntos
Doença de Crohn/patologia , Doença de Crohn/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Íleo , Margens de Excisão , Adulto , Anastomose Cirúrgica/efeitos adversos , Colectomia/efeitos adversos , Colectomia/métodos , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Feminino , Humanos , Íleo/patologia , Íleo/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RecidivaRESUMO
BACKGROUND & AIMS: The degree of histologic and endoscopic disease activity has been associated with an increased risk of colorectal neoplasia (CRN) in patients with inflammatory bowel diseases (IBDs), but no histologic scoring systems have been validated for determining risk of CRN. We investigated the association between histologic and endoscopic disease activity and risk of first CRN in patients with IBD who had negative findings from a surveillance colonoscopy. METHODS: We performed a retrospective analysis of consecutive patients who underwent at least 2 colonoscopies at Saint Antoine Hospital in France from January 1, 1996, through March 1, 2015, and whose first procedure was a surveillance colonoscopy. Histologic IBD activity was assessed by the Nancy histologic index. Patients were followed up for a mean 5.7 ± 3.3 years. Logistic regression and generalized estimating equations were used to identify clinical, endoscopic, and histologic factors associated with detection of neoplasia in the inflamed colon mucosa. RESULTS: Among 398 patients who underwent 1277 colonoscopies, we identified 45 patients with CRN. Factors associated with CRN were primary sclerosing cholangitis (odds ratio [OR], 2.65; 95% CI, 1.06-6.61; P = .04), age (OR per 1-year increase, 1.04; 95% CI, 1.01-1.07; P = .003), and mean Nancy histologic index during follow-up evaluation (per 1-unit increase, OR, 1.69; 95% CI, 1.29-2.21; P < .001). After adjustment for established factors, chronic disease activity defined as detection of ulcerations at more than 50% of colonoscopies was not associated with an increased risk of CRN (OR, 1.24; 95% CI, 0.53-2.91; P = .62). CONCLUSIONS: In addition to established risk factors, we associated Nancy histologic index scores with development of CRN. Histologic findings based on the Nancy histologic index therefore should be included in determining the risk of colonic neoplasia in patients with IBD.