Pathology of anal canal cancers

Même si les cancers de l’anus ne sont pas les tumeurs les plus fréquentes du tube digestif, ils posent des problèmes diagnostiques et thérapeutiques spécifiques. Il s’agit dans la grande majorité des cas de tumeurs malpighiennes, dans le développement desquelles l’infection anale à HPV (Human PapillomaVirus) joue un rôle central. On distingue classiquement, en fonction de l’origine et de la localisation tumorale, les cancers du canal anal et les cancers de la marge anale. Cette distinction repose généralement sur des données purement cliniques puisque l’aspect histologique ne permet pas de faire la différence entre ces 2 types tumoraux, notamment en cas d’étude de prélèvement biopsiques. La classification histologique distingue : i) les lésions bénignes correspondant aux condylomes acuminés ; ii) les lésions précancéreuses, nommées AIN (pour Anal Intraepithelial Neoplasia), de bas grade ou de haut grade, généralement planes, mais parfois végétantes ; et iii) les cancers. La classification des cancers a été simplifiée, la distinction du sous-type « cloacogénique » ne figurant plus dans la récente classification de l’OMS. Par ailleurs, le carcinome verruqueux est désormais assimilé au condylome acuminé géant ou tumeur de Buschke-Lowenstein et le carcinome indifférencié correspond au seul sous-type histologique classé à part au sein des carcinomes épidermoïdes invasifs.Anal cancers are relatively rare, but they raise specific diagnostic and therapeutic issues. The large majority of tumours develop from the squamous epithelium, and are related to anal HPV (human papilloma virus) infection. They are classically classified in two categories upon their location in the anal canal or the anal margin. This distinction is based on clinical features, as the histological aspect does not allow distinguishing between the two locations, especially on small bioptic samples. The histological lassification comprises : i) benign lesions or condylomata acuminatum ; ii) precancerous lesions (AIN for Anal Intraepithelial Neoplasia) either low grade or high grade, and iii) cancers. The histological classification of squamous cell carcinoma has been simplified, as the “cloacogenic” subtype does not appear as a separate entity in the last WHO categories. Moreover, verrucous carcinoma is now considered as the same lesion as giant condylomata acuminatum or tumour of Buschke Lowenstein and undifferentiated carcinoma is the only histological sub-type of invasive squamous carcinomas of the anal canal

Tumor budding in colorectal cancers

Le « tumor budding » est défini comme la présence, au niveau du front d’invasion de la tumeur, de cellules isolées ou groupées en petits amas de 5 cellules tumorales au maximum se détachant du reste de la tumeur. On peut traduire en français ce terme par celui de bourgeonnement tumoral, mais nous emploierons dans cette mise au point le terme anglais consacré dans la littérature. Cette caractéristique morphologique, qui s’observe dans un grand nombre de cancers colorectaux (CCR), est considérée comme la traduction morphologique du phénomène de transition épithéliomésenchymateuse (TEM), étape-clé dans le processus d’invasion tumorale et dans la dissémination métastatique. Au cours de ces dernières années, le « tumor budding » est clairement apparu comme un facteur pronostique péjoratif dans le CCR, en particulier le CCR de stade II (i.e. sans métastase ganglionnaire), raison pour laquelle l’Union Internationale Contre le Cancer (UICC), dans sa dernière version, a proposé d’inclure ce critère pour porter l’indication d’un traitement adjuvant. Cependant, il apparaît que les méthodes de détermination et de quantification du « tumor budding » varient considérablement d’une étude l’autre. C’est pourquoi un effort important doit être fait dans ce sens, de la part des pathologistes, avant d’inclure ce critère dans la décision thérapeutique pour les malades atteints de CCR.“Tumor budding” is defined by the presence, at the invasive tumor front, of isolated neoplastic cells or clusters of up to 5 neoplastic cells, detaching from the rest of the tumor. The term “tumor budding” is also used in French. This morphological feature, which is observed in a large number of colorectal cancers (CRC), is closely related to the epithelial-mesenchymal transition (EMT), a key component of the tumoral invasion process and of metastatic scattering. During the past years, strong, consistent evidence shows that “tumor budding” is an adverse prognostic factor, mostly in stage II CRC (i.e. without lymph node metastasis). That is why the International Union against Cancer (UICC) in its last version suggested to include this criteria for the management of adjuvant chemotherapy. Nevertheless, the scoring systems of “tumor budding” are still lacking standardization and inter-observer reproducibility. Consensus has to be reached by pathologists before this feature can be implemented as part of the therapeutic decisionmaking

MiRNA Genes Constitute New Targets for Microsatellite Instability in Colorectal Cancer

Mismatch repair-deficient colorectal cancers (CRC) display widespread instability at DNA microsatellite sequences (MSI). Although MSI has been reported to commonly occur at coding repeats, leading to alterations in the function of a number of genes encoding cancer-related proteins, nothing is known about the putative impact of this process on non-coding microRNAs. In miRbase V15, we identified very few human microRNA genes with mono- or di-nucleotide repeats (n = 27). A mutational analysis of these sequences in a large series of MSI CRC cell lines and primary tumors underscored instability in 15 of the 24 microRNA genes successfully studied at variable frequencies ranging from 2.5% to 100%. Following a maximum likelihood statistical method, microRNA genes were separated into two groups that differed significantly in their mutation frequencies and in their tendency to represent mutations that may or may not be under selective pressures during MSI tumoral progression. The first group included 21 genes that displayed no or few mutations in CRC. The second group contained three genes, i.e., hsa-mir-1273c, hsa-mir-1303 and hsa-mir-567, with frequent (≥80%) and sometimes bi-allelic mutations in MSI tumors. For the only one expressed in colonic tissues, hsa-mir-1303, no direct link was found between the presence or not of mono- or bi-allelic alterations and the levels of mature miR expression in MSI cell lines, as determined by sequencing and quantitative PCR respectively. Overall, our results provide evidence that DNA repeats contained in human miRNA genes are relatively rare and preserved from mutations due to MSI in MMR-deficient cancer cells. Functional studies are now required to conclude whether mutated miRNAs, and especially the miR-1303, might have a role in MSI tumorigenesis

Nonsense-Mediated mRNA Decay Impacts MSI-Driven Carcinogenesis and Anti-Tumor Immunity in Colorectal Cancers

Nonsense-mediated mRNA Decay (NMD) degrades mutant mRNAs containing premature termination codon (PTC-mRNAs). Here we evaluate the consequence of NMD activity in colorectal cancers (CRCs) showing microsatellite instability (MSI) whose progression is associated with the accumulation of PTC-mRNAs encoding immunogenic proteins due to frameshift mutations in coding repeat sequences. Inhibition of UPF1, one of the major NMD factors, was achieved by siRNA in the HCT116 MSI CRC cell line and the resulting changes in gene expression were studied using expression microarrays. The impact of NMD activity was also investigated in primary MSI CRCs by quantifying the expression of several mRNAs relative to their mutational status and to endogenous UPF1 and UPF2 expression. Host immunity developed against MSI cancer cells was appreciated by quantifying the number of CD3ε-positive tumor-infiltrating lymphocytes (TILs). UPF1 silencing led to the up-regulation of 1251 genes in HCT116, among which a proportion of them (i.e. 38%) significantly higher than expected by chance contained a coding microsatellite (P<2×10−16). In MSI primary CRCs, UPF1 was significantly over-expressed compared to normal adjacent mucosa (P<0.002). Our data provided evidence for differential decay of PTC-mRNAs compared to wild-type that was positively correlated to UPF1 endogenous expression level (P = 0.02). A negative effect of UPF1 and UPF2 expression on the host's anti-tumor response was observed (P<0.01). Overall, our results show that NMD deeply influences MSI-driven tumorigenesis at the molecular level and indicate a functional negative impact of this system on anti-tumor immunity whose intensity has been recurrently shown to be an independent factor of favorable outcome in CRCs

Human equilibrative nucleoside transporter 1 testing in pancreatic ductal adenocarcinoma: A comparison between murine and rabbit antibodies

Aims: The human equilibrative nucleoside transporter 1 (hENT1) expression level in pancreatic ductal adenocarcinoma (PDAC) may predict survival in gemcitabine-treated patients after resection. These results have been obtained with a murine anti-hENT1 antibody (10D7G2) that is not commercially available. Another antibody, which is rabbit-derived (SP120), appears to have no predictive value in local, advanced or metastatic PDAC. We aimed to study whether the two antibodies are equivalent. Methods and results: We compared hENT1 expression with both antibodies in resected PDAC. The results were correlated with overall survival (OS) following gemcitabine treatment. Tissues from two sets of patients (n = 147 each) were stained with SP120 by the use of different equipment, with an amplification technique being used for set 2. The rate of 'hENT1 high' cases was lower with SP120 (set 1, 7% versus 48%; set 2, 11% versus 38%). With the amplification technique, the rate of hENT1 high cases was globally similar between both antibodies. However, concordance between the antibodies was found in only 50% of cases. High hENT1 expression was predictive of OS only with 10D7G2 (hazard ratio 0.49; 95% confidence interval 0.24-0.98; P = 0.045). Conclusions: The two antibodies are not equivalent. Further prospective studies seem to be warranted before hENT1 testing for PDAC is used in daily practise.SCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe

L’autopsie de Napoléon Bonaparte. Mise au point anatomo-pathologique pour le bicentenaire de la mort de Napoléon Ier sur l’île de Sainte-Hélène en 1821

International audienceNapoleon 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.Napoléon Bonaparte est mort le 5 mai 1821 sur l’île de Sainte-Hélène après presque six années d’exil. Le lendemain, le docteur Francesco Antommarchi, médecin corse choisi par la famille Bonaparte pour soigner l’empereur exilé, procéda à l’autopsie en présence de seize personnes, dont sept médecins britanniques. Deux cents ans après cet événement du 6 mai 1821, des mystères entourent encore la cause de la mort de Napoléon. Différentes hypothèses, telle qu’une intoxication à l’arsenic, une arythmie cardiaque ou, plus récemment, une anémie causée par une hémorragie gastro-intestinale associée à une gastrite chronique, ont été avancées dans la littérature médico-historique. Les principales raisons de tous ces débats et malentendus sont la présence de plusieurs rapports d’autopsie, de leur interprétation souvent peu scientifique, de même qu’un certain goût pour le mystère. Toutefois, d’un point de vue scientifique, la question de savoir si les rapports d’autopsie permettent vraiment de conclure quant à la cause réelle du décès se pose. Ainsi, à l’occasion du bicentenaire de la mort de Napoléon 1er à Sainte Hélène, un groupe international d’anatomo-pathologistes spécialisés en pathologie digestive s’est donné pour objectif d’analyser les rapports d’autopsie de Napoléon 1er selon leur niveau d’évidence médicale (élevé, modéré et faible). Les rapports d’autopsie de 1821 sont en faveur de l’hypothèse d’une néoplasie maligne avancée de l’estomac associée à une hémorragie gastrique comme cause immédiate de la mort de Napoléon Ier le 5 mai 1821

Hepatocellular adenoma displaying a HNF1alpha inactivation in a patient with familial adenomatous polyposis coli.

Patients with familial adenomatous polyposis coli (FAP) may rarely develop hepatocellular adenoma. Here we report the case of a 37-year-old FAP woman presenting a hepatocellular adenoma after oestroprogestative oral contraception use. In this steatotic adenoma, we identified an inactivating biallelic mutation of HNF1alpha. In addition to the known germline APC mutation Q1062fs, we did not find an inactivation of the second APC allele nor an activation of the beta-catenin target genes GLUL and GPR49. Our findings contrast with two hepatocellular adenoma cases related to FAP, for which a biallelic inactivation of the APC gene was previously described. Altogether, these results suggest that benign hepatocellular carcinogenesis may be dependent on or independent of the Wnt/beta-catenin pathway in patients with FAP

The gastric disease of Napoleon Bonaparte: brief report for the bicentenary of Napoleon’s death on St. Helena in 1821

Item does not contain fulltextAfter 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

Robotic-assisted abdominoperineal resection: technique, feasibility, and short-term outcomes

Aim: The use of robotic-assisted laparoscopy seems fully adapted to pelvic surgery. However, few studies focus on robotic-assisted abdominoperineal resection (RAAPR). The aim of this study was to assess the feasibility, short-term postoperative outcomes, and pathological results of RAAPR. In addition, we provide a detailed description of the operative procedure and a brief review of the current literature.Methods: Between January 2013 and April 2018, we performed a total of 428 robotic surgeries, including 294 colorectal resections (68.7%). Data were prospectively collected and included demographics, intraoperative findings, postoperative outcomes, and pathological data. For this study, we included the first 20 consecutive RAAPRs performed with the four-arm da Vinci Si surgical system (Intuitive Surgical Inc., Sunnyvale, CA, USA).Results: Twenty patients (nine men) with a mean age of 68 years and a mean BMI of 24.5 ± 5.0 kg/m2 underwent RAAPR for low rectal adenocarcinoma (80%) or squamous cell carcinoma of the anal canal. Sixteen (80%) patients underwent preoperative pelvic radiotherapy and eight (40%) had a history of previous abdominal surgery. Mean operative duration was 218 ± 52 min. There was no conversion to open surgery. Mortality, reoperation, and morbidity rate were 5%, 25%, and 60%, respectively. Three (15%) patients presented perineal complications. Mean length of hospital stay was 20 days. Three (15%) patients had pT4 tumor. Mesorectal excision was considered complete in 90%. On average, 16.5 ± 7.2 lymph nodes were retrieved.Conclusion: RAAPR is feasible, with acceptable pathologic and short-term outcomes. The current literature does not demonstrate significant differences between robotic and laparoscopic APR. Indeed, we cannot justify its use in routine on the basis on the available evidence