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Tailored neoadjuvant treatment of locally advanced rectal cancer (LARC) may improve outcomes. The aim of this study was to determine early MRI prognostic parameters with which to stratify neoadjuvant treatment in patients with LARC.All patients from a prospective, phase II, multicentre randomized study (GRECCAR4; NCT01333709) were included, and underwent rectal MRI before treatment, 4 weeks after induction chemotherapy and after completion of chemoradiotherapy (CRT). Tumour volumetry, MRI tumour regression grade (mrTRG), T and N categories, circumferential resection margin (CRM) status and extramural vascular invasion identified by MRI (mrEMVI) were evaluated.A total of 133 randomized patients were analysed. Median follow-up was 41·4 (95 per cent c.i. 36·6 to 45·2) months. Thirty-one patients (23·3 per cent) developed tumour recurrence. In univariable analysis, mrEMVI at baseline was the only prognostic factor associated with poorer outcome (P = 0·015). After induction chemotherapy, a larger tumour volume on MRI (P = 0·019), tumour volume regression of 60 per cent or less (P = 0·002), involvement of the CRM (P = 0·037), mrEMVI (P = 0·026) and a poor mrTRG (P = 0·023) were associated with poor outcome. After completion of CRT, the absence of complete response on MRI (P = 0·004), mrEMVI (P = 0·038) and a poor mrTRG (P = 0·005) were associated with shorter disease-free survival. A final multivariable model including all significant variables (baseline, after induction, after CRT) revealed that Eastern Cooperative Oncology Group performance status (P = 0·011), sphincter involvement (P = 0·009), mrEMVI at baseline (P = 0·002) and early tumour volume regression of 60 per cent or less after induction (P = 0·007) were associated with relapse.Baseline and early post-treatment MRI parameters are associated with prognosis in LARC. Future preoperative treatment should stratify treatment according to baseline mrEMVI status and early tumour volume regression.El tratamiento neoadyuvante personalizado del cáncer de recto localmente avanzado (locally advanced rectal cancer, LARC) puede mejorar los resultados. El objetivo de este estudio fue determinar factores pronósticos precoces mediante RMN para estratificar el tratamiento neoadyuvante en pacientes con LARC. MÉTODOS: Todos los pacientes de un eensayo prospectivo de fase II, multicéntrico y aleatorizado (GRECCAR4-NCT01333709) se incluyeron en este estudio y se les realizó una RMN antes del tratamiento, 4 semanas después de la quimioterapia de inducción y después de completar la quimiorradioterapia (chemoradiation, CRT). Se evaluó la volumetría tumoral, el grado de regresión tumoral mediante RMN (MRI Tumor Regression Grade, mrTRG), la estadificación T, la estadificación N, el estado del margen de resección circunferencial (circumferential resection margin, CRM) y la presencia de invasión extramural vascular en la RMN (extramural vascular invasion, mrEMVI).Se analizaron 133 pacientes aleatorizados. La mediana de seguimiento fue de 41,4 meses (i.c. del 95%: 36,6-45,2). En 31 pacientes (23%) se diagnosticó una recidiva. En el análisis univariado de la situación basal, mrEMVI fue el único factor pronóstico asociado con un peor resultado (P = 0,0152). Después de la quimioterapia de inducción, un volumen tumoral más alto en la RMN (P = 0,019), una regresión del volumen tumoral ≤ 60% (P = 0,002), la afectación del CRM (P = 0,037), mrEMVI (P = 0,026) y un grado escaso mrTRG (P = 0,023) se asociaron con un mal resultado. Después de completar la CRT, la ausencia de respuesta completa en la RMN (P = 0,004), la presencia de mrEMVI (P = 0,04) y una insuficiente mrTRG (P = 0,005) se asociaron con una supervivencia libre de enfermedad más corta. En el modelo multivariable final en el que se incluyeron todas las variables significativas (basales, postinducción, post-CRT), el estado de ECOG (P = 0,011), la afectación esfinteriana (P = 0,009), la presencia de EMVI al inicio (P = 0,002) y una regresión precoz del volumen tumoral ≤ 60% después de la inducción (P = 0,007) se asociaron con una recidiva. CONCLUSIÓN: Los parámetros basales y post-tratamiento precoces de la RMN se asocian con el pronóstico en el LARC. La estrategia terapéutica preoperatoria futura deberá estratificar el tratamiento de acuerdo con la presencia de EMVI al inicio y la regresión precoz del volumen tumoral.

Les classifications moleculaires des cancers colorectaux (CCR) ont ete significativement modifiees depuis 20 ans. Initialement repartis en trois groupes moleculaires, les CCR font maintenant l’objet d’une classification consensus (ou CMS pour consensus molecular subtype ). Seules certaines alterations moleculaires issues de ces classifications sont regulierement recherchees et utilisees en pratique clinique, principalement en situation metastatique. Les classifications concernant la reponse immune sont plus recentes et essentiellement morphologiques. Leur impact clinique est fort, mais elles n’ont pas encore penetre le domaine de la pratique quotidienne. Cet article a pour but de proposer une synthese des classifications moleculaires et immunes pertinentes et d’en souligner les applications cliniques reelles ou potentielles.

BackgroundThe prognostic value of the primary neoplasm responsible for pseudomyxoma peritonei (PMP) remains poorly studied. The aim of this study was to determine the prognosis for patients with extra-appendicular PMP (EA-PMP) treated optimally with complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).MethodsAll patients treated for PMP with CCRS and HIPEC between 1994 and 2016 were selected retrospectively from a French multicentre database. Patients with EA-PMP had pathologically confirmed non-neoplastic appendices and were matched in a 1 : 4 ratio with patients treated for appendicular PMP (A-PMP), based on a propensity score.ResultsSome 726 patients were identified, of which 61 (EA-PMP group) were matched with 244 patients (A-PMP group). The origins of primary tumours in the EA-PMP group included the ovary (45 patients), colon (4), urachus (4), small bowel (1), pancreas (1) and unknown (6). The median peritoneal carcinomatosis index was comparable in EA-PMP and A-PMP groups (15·5 versus 18 respectively; P = 0·315). In-hospital mortality (3 versus 2·9 per cent; P = 1·000) and major morbidity 26 versus 25·0 per cent; P = 0·869) were also similar between the two groups. Median follow-up was 66·9 months. The 5-year overall survival rate was 87·8 (95 per cent c.i. 83·2 to 92·5) per cent in the A-PMP group and 87 (77 to 96) per cent in the EA-PMP group. The 5-year disease-free survival rate was 66·0 (58·7 to 73·4) per cent and 70 (53 to 83) per cent respectively.ConclusionOverall and disease-free survival following treatment with CCRS and HIPEC is similar in patients with pseudomyxoma peritonei of appendicular or extra-appendicular origin.

Purpose: Diffuse malignant peritoneal mesothelioma (DMPM) is a severe disease with mainly locoregional evolution. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the reported treatment with the longest survival. The aim of this study was to evaluate the impact of perioperative systemic chemotherapy strategies on survival and postoperative outcomes in patients with DMPM treated with curative intent with CRS-HIPEC, using a multi-institutional database: the French RENAPE network. Patients and methods: From 1991 to 2014, 126 DMPM patients underwent CRS-HIPEC at 20 tertiary centres. The population was divided into four groups according to perioperative treatment: only neoadjuvant chemotherapy (NA), only adjuvant chemotherapy (ADJ), perioperative chemotherapy (PO) and no chemotherapy before or after CRS-HIPEC (NoC). Results: All groups (NA: n Z 42; ADJ: n Z 16; PO: n Z 16; NoC: n Z 48) were comparable regarding clinicopathological data and main DMPM prognostic factors. After a median follow-up of 61 months, the 5-year overall survival (OS) was 40%, 67%, 62% and 56% in NA, ADJ, PO and NoC groups, respectively (P Z 0.049). Major complications occurred for 41%, 45%, 35% and 41% of patients from NA, ADJ, PO and NoC groups, respectively (P Z 0.299). In multivariate analysis, NA was independently associated with worse OS (hazard ratio, 2.30; 95% confidence interval, 1.07e4.94; P Z 0.033). Conclusion: This retrospective study suggests that adjuvant chemotherapy may delay recurrence and improve survival and that NA may impact negatively the survival for patients with DMPM who underwent CRS-HIPEC with curative intent. Upfront CRS and HIPEC should be considered when achievable, waiting for stronger level of scientific evidence.

Background This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. Materials and methods A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. Results Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. Conclusions The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe., Highlights • Biosafety measures used in the first wave of the COVID-19 crisis were heterogeneous in 53 European pathology laboratories. • A dramatic decrease of the workload in pathology laboratories was noted. • No case of healthcare workers contaminated with SARS-CoV-2 associated with samples handling was identified.

Introduction L’identification de cancers colorectaux de stade II a haut risque est essentielle pour selectionner les patients qui pourraient beneficier d’une chimiotherapie adjuvante apres chirurgie. Dans ce cadre, les signatures d’expression multigeniques en rapport avec des cellules souches ou progenitrices sont prometteuses, mais difficiles a integrer en pratique clinique.

Le cancer colorectal (CCR) est une affection frequemment fatale, mais associee a une evolution et a une reponse au traitement variable. Afin de clarifier les classifications moleculaires des CCR, reposant sur l’expression de genes, et faciliter l’integration de celles-ci en pratique clinique, un consortium international de groupes d’experts a ete cree, avec l’objectif de partager les donnees existantes et leur analyse. Un regroupement des six classifications independantes deja existantes en quatre groupes a pu etre objective. Ces quatre groupes presentent des caracteristiques propres: CMS1, qualifie d’« immun », observe dans 14 % des cas, caracterise par une instabilite microsatellitaire, un fort taux de mutations et une forte activation immunitaire; CMS2, observe dans 37%des cas, qualifie de « canonique », avec des caracteristiques epitheliales, presentant une deregulation de la voie WNT/MYC; CMS3 denomme « metabolique », observe dans 13 % des cas, presentant une deregulation epitheliale et metabolique; CMS4 ou « mesenchymateux », observe dans 13 % des cas, caracterise par des phenomenes de transition epitheliomesenchymateuse, avec une implication du stroma, de l’angiogenese et de la voie TGFβ. Un cinquieme groupe non classe a ete identifie, representant possiblement un groupe de transition ou d’heterogeneite intratumorale. Les auteurs considerent que les groupes CMS representent la meilleure classification moleculaire actuellement disponible des CCR, avec une signification biologique forte. Ils peuvent constituer la base pour une future stratification clinique, notamment en matiere de ciblage therapeutique.

La prise en charge du cancer colorectal a change ces quinze dernieres annees. Ces changements reposent en partie sur des evolutions dans le domaine de l’anatomie pathologique, tant morphologique que moleculaire. Elles se declinent aux plans pronostique et predictif. Le but de cet article est de souligner quelques changements majeurs ayant eu lieu dans le domaine de l’anatomie pathologique des cancers colorectaux depuis le dernier millenaire.

Le compte rendu anatomopathologique du cancer colorectal (CCR) est un element essentiel pour etayer un traitement personnalise en 2014, qu’il s’agisse de cancer localise, localement avance ou metastatique. Il repose sur des criteres macroscopiques, histologiques, immunohistochimiques et moleculaires, et s’appuie sur les dernieres versions des classifications Tumor Node Metastase/Union for International Cancer Control (TNM/UICC) et Organisation mondiale de la sante (OMS). Les parametres y figurant peuvent etre pronostiques ou predictifs. Ils doivent etre lisibles et facilement interpretables pour une utilisation optimale en reunion de concertation pluridisciplinaire. Le compte rendu type peut beneficier d’une forme standardisee, a l’instar des formulaires proposes par la Societe francaise de pathologie (SFP) et l’Institut national du cancer (INCa). Cet article a pour but de presenter et d’argumenter les items structurant le compte rendu anatomopathologique type du CCR, a la lumiere des donnees de la litterature disponibles en 2014.

Le traitement des cancers du rectum localement avances (T3, T4 et/ou N+) repose sur un traitement neoadjuvant combinant radiotherapie et chimiotherapie, suivi par une chirurgie comportant une exerese totale du mesorectum. Cette strategie a pour but de reduire le volume tumoral et de permettre une exerese chirurgicale carcinologique. Elle s’est traduite par une diminution de la frequence des recidives locales. Cependant cette chirurgie est delicate, notamment pour les localisations au bas rectum (tiers moyen et tiers inferieur) et en raison des rapports etroits du rectum avec l’appareil genito-urinaire, les parois pelviennes et le sphincter anal. Dans ce cadre le role du pathologiste est important car il va fournir des elements permettant d’apprecier la qualite d’exerese du mesorectum, ainsi que des parametres histopronostiques essentiels, correspondant au stade (y) pTNM, a la determination de la marge circonferentielle (ou clairance) et a la reponse histologique [1]. Ces facteurs sont dependants d’une etapemacroscopique rigoureuse qui fait l’objet de notre article.

Resume Les principaux outils de l’evaluation en IRM de la reponse tumorale du cancer du rectum apres chimioradiotherapie et avant chirurgie sont detailles. Pour les cancers localement avances du rectum et du bas rectum, l’IRM a l’interet de permettre d’adapter la strategie therapeutique, en permettant une chirurgie conservatrice en cas de bonne reponse. Les differents types de reponse (fibreuse, desmoplastique, colloide), leurs aspects et leurs difficultes d’interpretation en IRM sont presentes. Les caracteristiques et les performances de l’IRM post-traitement neoadjuvant sont detaillees pour le staging T et N, l’evaluation de la marge circonferentielle radiale, ainsi que l’imagerie de diffusion. L’evaluation quantitative (variation de la volumetrie tumorale) et qualitative (grade de reponse tumorale) permet d’identifier en IRM les bons repondeurs des mauvais repondeurs.

But de l’etude : Le traitement du cancer colorectal (CCR) repose avant tout sur la determination du stade tumoral, determine par la classification TNM. Malgre des avancees dans la prise en charge de la maladie metastatique et de ses differentes localisations, cette classification n’a pas beneficie d’amelioration notable. Dans ce cadre, le role des depots tumoraux (DT) reste tres debattu. Nous avons etudie la relation entre la presence de DT et les localisations metastatiques des CCR, afin de determiner s’ils apportaient une information significative et nouvelle dans l’etablissement du stade TNM. Methodes : Une recherche systematique de la litterature a ete realisee, centree sur le role des DT dans le CCR. Les etudes comportant des patients ayant recu un traitement neoadjuvant n’ont pas ete retenues. Les donnees concernant le stade, les parametres histologiques et l’evolution ont ete recueillies. Les donnees de quatre cohortes importantes ont ete finalement analysees compte tenu de l’impact majeur des DT, des metastases ganglionnaires lymphatiques et des invasions veineuses extramurales sur le type de localisation metastatique et de l’evolution. Resultats : Parmi les 10 106 inclus dans cette analyse, 22 % presentaient des DT. Les DT etaient invariablement associes a une evolution defavorable. La presence de DT etait associee a la presence de metastases ganglionnaires lymphatiques et d’invasions veineuses extramurales. Dans une comparaison appariee, l’impact des DT etait plus important que celui des metastases ganglionnaires lymphatiques et des invasions veineuses extramurales. En utilisant un modele de regression logistique, les DT combines aux metastases ganglionnaires lymphatiques constituaient le facteur predictif le plus puissant concernant la presence de metastases hepatiques (odds ratio [OR] : 5,5), pulmonaires (OR : 4,3) et peritoneales (OR : 7,0). La presence d’invasions veineuses extramurales etait informative pour la presence de metastases hepatiques et pulmonaires, mais pas peritoneales. Conclusion : Nous avons montre que les DT ne sont pas equivalents aux metastases ganglionnaires lymphatiques et aux invasions veineuses extramurales, tant sur le plan biologique que clinique. L’integration des DT a la seule categorie N1c et leur prise en consideration, uniquement en l’absence de metastase ganglionnaire lymphatique conjointe, entrainent une perte d’information pronostique. Par consequent, nous proposons que le nombre de DT soit additionne au nombre de metastases ganglionnaires lymphatiques pour aboutir a un stade N final.

Le bourgeonnement tumoral est un facteur pronostique independant reconnu dans le cancer colorectal, mais qui ne beneficie pas de methode standardisee pour sa mise evidence. Le premier objectif de cette Conference internationale de consensus sur le bourgeonnement tumoral (International Tumor Budding Consensus Conference ou ITBCC) a ete de trouver un accord sur un systeme de scoring fonde sur des preuves, standardise, international et utilisable dans le cancer colorectal. Cette conference a comporte neuf sessions avec des presentations, un questionnaire preconference et un livre electronique comportant 38 publications cles sur le sujet. Les dix points suivants ont fait l’objet d’un consensus : le bourgeonnement tumoral est defini par la presence de cellules isolees ou d’amas de quatre cellules tumorales ou moins (22/22, 100 %). Le bourgeonnement tumoral est un facteur predictif independant de metastase ganglionnaire dans les cancers colorectaux de stade pT1 (23/23, 100 %). Le bourgeonnement tumoral est un facteur predictif independant de survie dans les cancers colorectaux de stade II (23/23, 100 %). Le bourgeonnement tumoral doit etre pris en consideration avec d’autres parametres cliniques et anatomopathologiques dans le cadre d’une approche multidisciplinaire (23/23, 100 %). Le bourgeonnement tumoral peut etre evalue par comptage a partir de lames colorees a l’hemalun-eosine (19/22, 85 %). Le bourgeonnement tumoral peut s’observer en situation intratumorale dans le cancer colorectal, en relation egalement avec un risque d’envahissement ganglionnaire (22/22, 100 %). Le bourgeonnement tumoral doit etre evalue sur un hot spot , dans un champ mesurant 0,785 mm2 , au front d’invasion (22/22, 100 %). Le bourgeonnement tumoral doit etre evalue selon un score a trois grades, de facon a faciliter la stratification du risque dans le cancer colorectal (23/23, 100 %). Le bourgeonnement tumoral apporte des informations differentes du grade (23/23, 100 %). Le bourgeonnement tumoral devrait faire l’objet de recommandations et de protocoles pour etre inclus dans les comptes rendus d’anatomie pathologique (23/23, 100 %). Les membres de cette conference internationale ont reussi a trouver un consensus, fonde sur des preuves, pour evaluer et reporter le bourgeonnement tumoral. Il est ainsi propose que la methode d’evaluation du bourgonnement tumoral puisse figurer dans les recommandations et les procedures concernant l’examen anatomopathologique du cancer colorectal.

L’utilisation des anticorps monoclonaux therapeutiques en oncologie a connu une expansion croissante ces quinze dernieres annees, tant dans les tumeurs solides qu’en hematologie. Ce phenomene est lie a une meilleure connaissance des processus biologiques de la progression tumorale et des cibles therapeutiques qui en emergent. Cependant, l’optimisation de ces therapeutiques ciblees depend de la determination de facteurs predictifs de sensibilite et de resistance et de l’ingenierie des anticorps, permettant de renforcer leur efficacite. Les facteurs predictifs peuvent etre lies a la tumeur et a l’hote, notamment en ce qui concerne les mecanismes qui regissent l’antibody dependent cell cytotoxicity (ADCC) ou cytotoxicite cellulaire dependante des anticorps, par l’intermediaire des polymorphismes des recepteurs FcΓ des cellules effectrices immunitaires. L’ingenierie des anticorps tente d’elaborer des anticorps dont la partie Fc pourrait renforcer l’ADCC. Cet article a pour but d’effectuer une synthese des mecanismes immuns engendres par les anticorps therapeutiques et d’en preciser les aspects pouvant s’integrer a une medecine de precision, tant dans ses aspects predictifs que mecanistiques.

Gastric and gastroesophageal junction cancers are associated to a poor prognosis especially when locally advanced and metastatic stages are diagnosed. Available treatments are represented by systemic chemotherapies for which no predictive marker has been validated for clinical use. Anti-HER2 antibody, trastuzumab, has shown efficacy in these tumors, associated with 5-FU and cisplatine. However, for an optimal efficiency, this targeted therapy should only be given when tumor displays a 3+ or 2+ amplified score. These predictive parameters are firstly determined by using immunohistochemistry and by in situ hybridization, only with 2+ score. Moreover immunohistochemistry scoring for gastric and gastro-esophageal junction cancers is different from the one used in breast cancer and takes in account incomplete and heterogeneous staining. Trastuzumab eligibility is based on these techniques and this dedicated scoring. C-met expression and amplification represent emerging predictive factors to C-met targeting in gastric cancer. The goal of this review is to describe the available and promising predictive biomarkers of efficacy of targeted therapies in esogastric junction and gastric cancers.

Supplementary methods: Flow cytometry experiments. Immunofluorescence studies. Surface plasmon resonance measurements. Cell migration assays. Apoptosis assay. (DOCX 37Â kb)

Distribution of patients with mCRC according to the tumor molecular subtype. (DOCX 33Â kb)

CLDN1 gene (222549_at.) expression. a, in 17 normal colorectal mucosa (NM), 20 primary tumor (PT) samples and 19 hepatic metastases (HM); *** = p

Introduction/ Background Among gastrointestinal (GI) tumours, pseudomyxoma peritonei (PMP) from appendiceal origin has unique clinical and morphologic features. Due to the relative paucity of patients and the absence of therapeutic consensus, evaluation and refinement of the morphologic criteria used for assessment of the disease are still difficult. As a result, a uniformly accepted classification is still lacking. In collaboration with NJ Carr, who initiated the conference consensus process, in Basingstoke, and on behalf of the French group RENA-PATH, 11 experienced GI pathologists agreed to participate to a virtual workshop, in order to assess inter-observer variability in PMP diagnosis and staging. Aims The goal of the study was to evaluate, for appendiceal and peritoneal mucinous neoplasms, the degree of concordance in the identification of diagnostic histological criteria by experienced pathologists, and to assess the degree of inter-individual variation in the application of WHO classification (2010) and TNM staging system (7th edition). Methods A single section stained with hematoxylin and eosin from 9 resected cases of mucinous neoplasms was selected by members of RENA-PATH. All digitalized at a maximum resolution (X40) using an HAMMAMATSU scanner system, to ensure that all participants evaluate exactly the same tumour areas; 1 to 16 questions were prepared for each case. On Teleslide web platform, interactive services provided by TRIBVN. All submitted cases were then reviewed by a panel of 11 pathologists with specific expertise and interest in PMP. Data were analyzed using SAS program. Results Whole slide set evaluated by all participants; no abstention or “unknown diagnosis” for any submitted case. Agreement for classification, WHO 2010: • Appendiceal mucinous neoplasms: LAMN 83 %; mucinous adenocarcinoma 92%. • Peritonei mucinous carcinoma: Low grade 91.7%; high grade 91.7%. • Disagreement on the concept of High Grade AMN defined by low power architecture of LAMN + high grade cytology. • Agreement for using pTNM classification (82%) in PMP. • Pushing Invasion (PI) and dissection by acellular mucin (DAM) in appendix wall are not reproducible criteria and need to be better defined. • Criteria need to be redefined to use HAMN according to a majority of participants. • The identification of signet ring cells is not reproducible; the lesion needs to be better defined. • Invasion of organs and pattern of invasion (broatfront invasion / classic by irregular glands or single cells with desmoplasia) are not reproducible criteria. • Improvement in staging assessment is needed Conclusion: Although histopathological features of peritoneal disease are significant prognostic factors requiring pathologists to classify mucinous carcinoma peritonei (pseudomyxoma peritonei), reproducibility in interpretation must be improved. This international collaborative project allows pathologists worldwide to share their expertise and knowledge through a dedicated interactive workshop session. It is expected an improvement in the management of mucinous neoplasms of the appendix and peritoneum., Diagnostic Pathology, Vol 1 No 8 (2016): 13. European Congress on Digital Pathology

Au cours de l’annee 2012 plusieurs avancees pouvant aboutir a une modification des pratiques ont ete presentees. Plusieurs options concernant le depistage du cancer du colon sont possibles. La cle de la reussite reste le taux de participation de la population. Le test fecal semble etre le mieux accepte en population europeenne. Le traitement par antiangiogenique dans les cancers colorectaux metastatique est efficace en deuxieme ligne meme apres progression sous une premiere ligne comportant un traitement antiangiogenique. Le traitement par anti-EGFR est inefficace en traitement adjuvant des cancers coliques sauf peut-etre pour les formes T4N2. Un inhibiteur de tyrosine kinase orale a pour la premiere fois demontre son efficacite en cas de cancer colorectal resistant a la chimiotherapie. Le traitement par chimiotherapie des patients âges doit tenir compte de parametres geriatriques. La determination du statut KRAS pourrait etre facilitee par un test plasmatique, enfin il a ete observe l’apparition de clones mutes pour KRAS en cas de traitement par anti-EGFR.

L’instabilite microsatellitaire (MSI) correspond a un defaut de reparation des mesappariements de l’ADN, qui survient dans 15%des cancers colorectaux (CCR). Deux tiers des cas de cancers avec MSI s’observent dans un cadre sporadique, le tiers restant dans un cadre hereditaire. Ce statut, qui peut etre determine par des techniques complementaires de biologie moleculaire et d’immunohistochimie, fait maintenant partie des tests couramment realises par le pathologiste implique en pathologie digestive. Le statut MSI permet de detecter des patients susceptibles d’etre porteurs d’un syndrome de Lynch, ce phenotype etant retrouve dans la quasi-totalit e des tumeurs developpees dans le cadre de ce syndrome. Dans ce contexte hereditaire, l’immunohistochimie presente l’avantage de cibler la recherche directe de la mutation deletere sur le gene correspondant a la proteine non exprimee. La distinction entre MSI survenant dans un contexte sporadique ou hereditaire peut s’appuyer sur la recherche de mutations de BRAF et de methylation du promoteur du gene MLH1, ces alterations ne s’observant pas dans les syndromes de Lynch. Par ailleurs, la mise en evidence d’une MSI dans les CCR de stade II contre-indique une chimiotherapie adjuvante a base de 5-FU, ce traitement etant deletere sur la survie globale. Pour etre optimales, les investigations « biopathologiques » concernant le statut MSI doivent s’inscrire dans une demarche d’assurance qualite.

Les tumeurs malignes des voies biliaires ou cholangiocarcinomes (CC) sont des tumeurs developpees aux depens de l’arbre biliaire normal. Ils representent la seconde tumeur maligne primitive hepatique apres le carcinome hepatocellulaire (CHC). La classification OMS 2010 distingue selon leur localisation anatomique dans l’arbre biliaire deux groupes de CC: les CC intrahepatiques ou peripheriques developpes aux depens des petites voies biliaires au-dela de la seconde segmentation et les CC extrahepatiques comprenant les tumeurs hilaires et les tumeurs developpees a partir de la voie biliaire principale et du choledoque. En 1992, une classification macroscopique pour les CC a ete elaboree par le “Liver Study Group of Japan” basee sur des criteres de croissance tumorale. Elle definit ainsi trois types: le type « nodulaire », « pericanalaire » et « endoluminal ». Le type « nodulaire » est le plus souvent represente par le CC peripherique dont les principaux diagnostics differentiels sont le CHC, les metastases d’adenocarcinomes et l’hepatocholangiocarcinome. Les CC extrahepatiques se manifestent le plus souvent par le type « pericanalaire » et se revelent cliniquement par un obstacle sur les voies biliaires. Le role principal de l’anatomopathologiste dans ce cas est d’affirmer la nature maligne de la stenose. La cytologie biliaire joue un role primordial dans ce diagnostic differentiel mais demeure une technique peu sensible avec de nombreux faux-negatifs.

Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify patients at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively parallel sequencingbased assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected postoperatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8%) of 164 patients with negative ctDNA (hazard ratio, 18; 95% confidence interval, 7.9–40; P < 0.001). In patients treated with chemotherapy, the presence of ctDNA after completion of chemotherapy was also associated with an inferior recurrence-free survival (hazard ratio, 11; 95% confidence interval, 1.8–68; P = 0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence.

Les formes hereditaires de cancers colorectaux (CCR) comportent des formes polyposiques et non polyposiques. Les techniques diagnostiques de ces cancers concernent avant tout le syndrome de Lynch. Elles sont essentielles a connaitre pour permettre une meilleure identification de ce type de cancer et eviter des retards diagnostiques, pouvant etre tres prejudiciables. La strategie diagnostique du syndrome de Lynch repose sur la recherche d’une instabilite microsatellitaire (MSI) par biologie moleculaire associee a l’etude de l’expression des proteines du systeme MMR (mismatch repair) par immunohistochimie. Ces techniques sont complementaires. Le statut MSI est presque constant dans le syndrome de Lynch et constitue un marqueur de depistage, quoique non specifique. L’immunohistochimie est tres concordante avec le statut MSI et permet, en objectivant la perte d’une proteine donnee du systeme MMR, d’orienter vers le gene mute. En dehors du syndrome de Lynch, il n’existe pas de marqueur somatique, moleculaire ou immunohistochimique des differentes polyposes survenant dans un cadre hereditaire.

Resume Objectif de l’etude Plusieurs etudes de phase II ont montre la faisabilite des protocoles de chimioradiotherapie neoadjuvante dans la prise en charge des adenocarcinomes du pancreas consideres comme resecables d’emblee. Cependant, en l’absence d’essai de phase III validant cette approche therapeutique, l’evaluation de son efficacite est toujours d’actualite. A partir des resultats matures de l’essai de phase II de la Societe francaise de radiotherapie oncologique (SFRO) et de la Federation francophone de cancerologie digestive (FFCD) 9704, nous avons analyse l’efficacite therapeutique d’une chimioradiotherapie preoperatoire a base de 5-fluoro-uracile et de cisplatine, avec un accent tout particulier sur la reponse anatomopathologique, et avons mene une revue de la litterature. Patients et methodes La chimioradiotherapie preoperatoire consistait en une irradiation de la tumeur pancreatique et des ganglions lymphatiques satellites a la dose de 50 Gy en 25 fractions et cinq semaines, et en une chimiotherapie concomitante par 300 mg/m2/jour de 5-fluoro-uracile, cinq jours par semaine, cinq semaines consecutives, et 20 mg/m2/j de cisplatine de j1 a j5 et j29 a j33. L’exerese chirurgicale etait realisee trois a six semaines plus tard en l’absence de progression locoregionale. Resultats Parmi les 41 patients inclus, 26 (63 %) ont eu une exerese chirurgicale de la tumeur, dont 21 (80,7 %) microscopiquement complete. Une reponse pathologique majeure (≥ 80 % de cellules cancereuses severement degenerees) a ete observee sur 13 des 26 pieces operatoires (50 %), dont une reponse histologique complete. Les taux de recidive locale et de survie globale a deux ans etaient, respectivement, de 4 et 32 % chez les 26 patients operes. Conclusion Nos resultats suggerent que la chimioradiotherapie preoperatoire aurait une efficacite antitumorale se traduisant par une reponse histopathologique majeure chez 50 % des patients et un taux eleve de resection R0. Une discussion particuliere, peu frequemment disponible dans la litterature, decoule des resultats anatomopathologiques relatifs a la reponse au traitement et suggere la mise en place de parametres predictifs et pronostiques de la reponse therapeutique.

Background We explored the feasibility and the histologic assessment of treatment effect of preoperative chemoradiation in patients presenting with resectable pancreatic adenocarcinoma. Patients and methods Treatment consisted of concurrent radiotherapy (50 Gy within 5 weeks) and chemotherapy with 5-fluorouracil (300 mg/m2/day, 5 days/week, weeks 1–5) and cisplatin (20 mg/m2/day, days 1–5 and 29–33), followed by surgical resection of the pancreatic tumor in patients without progression. Results In all, 41 patients were enrolled; 38 (93%) received ≥47 Gy; 30 patients (73%) received ≥75% of the prescribed doses of chemotherapy. Among 40 assessable patients, 27 (67.5%; 95% confidence interval 50.9% to 81.4%) were successfully treated (entire dose of radiation, ≥75% of the chemotherapy dose, no grade 4 non-hematologic toxicity). In all, 26 patients (63%) underwent surgical resection with curative intent and 21 (80.7%) had R0 resection. A total of 13 of 26 specimens (50%) presented a major pathologic response (≥80% of severely degenerative cancer cells), with one complete pathologic response. Operative mortality was 2.8%. The local recurrence and 2-year survival rates were 4% and 32%, respectively, for the 26 operated patients. Conclusions This proposed preoperative scheme is feasible, does not prevent successful surgery, and provides antitumoral effect associated with major histopathological response in 50% of patients and a high R0 resection rate.

L’anticorps dirige contre le recepteur de facteur de croissance epidermique (anti-EGFR: anti-epidermal growth factor receptor) cetuximab, est efficace dans le cancer colorectal metastatique. Les mecanismes moleculaires soustendant la reponse clinique a ce traitement ne sont pas connus. Les alterations genetiques des effecteurs intracellulaires de la voie de l’EGFR pourraient etre impliquees dans la reponse a cette therapie ciblee. Dans cette etude, 30 tumeurs issues de patients atteints de cancer colorectal metastatique ont fait l’objet d’une recherche de mutations des genes KRAS, BRAF, et PIK3CA et d’une determination du nombre de copies de l’EGFR par hybridation in situ chromogenique. Parmi les 30 patients, 11 (soit 37 %) ont presente une reponse au cetuximab. Les mutations de KRAS ont ete objectivees dans 13 tumeurs, soit 43 % de l’ensemble des cas et etaient significativement associees a l’absence de reponse au cetuximab (mutations KRAS chez 0 % des repondeurs versus 68,4 % des 19 non repondeurs; P = 0,0003). La survie globale etait significativement plus elevee en absence de mutations KRAS qu’en presence de ces memes mutations. (P = 0,016; mediane 16,3 versus 6,9 mois). Une augmentation de nombre de copies de l’EGFR etait presente chez 3 patients (10 %) et significativement associee a une reponse objective au cetuximab (P = 0,04). En conclusion, dans cette etude, les mutations KRAS representent un facteur predictif de resistance au cetuximab et sont associees a un plus mauvais pronostic. L’amplification de l’EGFR, dont la frequence semble moindre que celle initialement decrite, est associee a une reponse a ce traitement cible (Cancer Res 2006; 66(8): 3992–5).

Background We investigated the outcomes of postmenopausal women with hormone receptor-positive, early breast cancer with special histotypes (mucinous, tubular, or cribriform) enrolled in the monotherapy cohort of the BIG 1-98 trial. Patients and methods The intention-to-treat BIG 1-98 monotherapy cohort (5 years of therapy with tamoxifen or letrozole) included 4922 women, of whom 4091 had central pathology review. Histotype groups were defined as: mucinous (N = 100), tubular/cribriform (N = 83), ductal (N = 3257), and other (N = 651). Of 183 women with either mucinous or tubular/cribriform tumors, 96 were randomly assigned to letrozole and 87 to tamoxifen. Outcomes assessed were disease-free survival (DFS), overall survival (OS), breast cancer-free interval (BCFI), and distant recurrence-free interval (DRFI). Median follow-up in the analytic cohort was 8.1 years. Results Women with tubular/cribriform breast cancer had the best outcomes for all end points compared with the other three histotypes, and had less breast cancer recurrence (97.5% 5-year BCFI) than those with mucinous (93.5%), ductal (88.9%), or other (89.9%) histotypes. Patients with mucinous or tubular/cribriform carcinoma had better DRFI (5-year rates 97.8% and 98.8%, respectively) than those with ductal (90.9%) or other (92.1%) carcinomas. Within the subgroup of women with special histotypes, we observed a nonsignificant increase in the hazard of breast cancer recurrence with letrozole [hazard (letrozole versus tamoxifen): 3.31, 95% confidence interval 0.94–11.7; P = 0.06]. Conclusions Women with mucinous or tubular/cribriform breast cancer have better outcomes than those with other histotypes, although the observation is based on a limited number of events. In postmenopausal women with these histotypes, the magnitude of the letrozole advantage compared with tamoxifen may not be as large in patients with mucinous or tubular/cribriform disease. Clinicaltrials.gov NCT00004205.

Summary. Limited data are available concerning treatment and outcome of primary lymphoma of the breast (PLB), especially after CHOP (cyclophosphamide, hydroxydoxorubicin, vincristine, prednisone) chemotherapy. We retrospectively reviewed 20 consecutive cases of localized PLB seen at our institution over a 20 year period. All PLB were of B-cell origin: treatment was CHOP or a CHOP-like regimen in all patients. Sixteen of the 20 patients achieved complete remission (CR) and two achieved partial remission (. 75% tumour regression). Two patients had progressive disease on therapy. With a median follow-up of 54 months, six patients relapsed after 8‐66 months. Two of the relapses involved the central nervous system (CNS) (isolated in one case, associated with other sites of relapse in the other). The two patients who achieved partial remission also had progression in the CNS, 4 and 8 months after the end of CHOP chemotherapy. All four patients have died as a result of their disease 3, 6, 10 and 13 months after CNS relapse. Of the 16 centroblastic diffuse large B-cell lymphoma (DLCL), three had CNS disease at relapse. We also observed three (15%) controlateral breast relapses. Thirteen of the initial 20 patients are alive in CR, six patients have died as a result of their lymphoma and one of unrelated disease. In conclusion, we observed a high incidence of CNS relapse in this group of localized extranodal lymphoma, strongly suggesting that CNS prophylaxis should be associated with systemic chemotherapy in localized PLB.

uPA et PAI-1 ont ete valides comme des facteurs pronostiques de niveau de preuve 1 par l’ASCO, l’INCa et la SFSPM dans le cadre de la prise en charge adjuvante du cancer du sein localise (CSL) [1]. Leur elevation predit de plus un benefice augmente a une chimiotherapie adjuvante contenant des anthracyclines [2]. Leur association avec certains marqueurs pronostiques, ainsi que l’impact de leur utilisation meritent d’etre precises.

Ces dernieres annees ont confirme l’utilisation de biomarqueurs predictifs d’efficacite en oncologie digestive, en employant les techniques d’im- munohistochimie et d’hybridation in situ. Ces techniques, complementaires de celles de biologie moleculaire non morphologiques, s’integrent en 2012 aux strategies therapeutiques concernant plus particulierement les adenocarcinomes gastriques metastatiques. Leur emploi necessite cependant d’adopter une demarche qualite tant pour la mise au point que pour le suivi. D’autres biomarqueurs candidats pourraient prochainement emerger et etre appliques a cette meme localisation. L’expression et l’amplification de C-met dans les adenocarcimones gastriques en representent les exemples les plus prometteurs. Le but de ce chapitre est de preciser les specificites et les modalites de la determination du statut HER2 dans le cancer gastrique et de la jonction œso-gastrique (JOG) et d’en decrire les applications cliniques en oncologie digestive en 2012. Il est secondairement de souligner les biomarqueurs emergents dans cette meme pathologie.

Colorectal cancer is the fourth most common cancer in men and the third most common cancer in women worldwide. The partial failure of classic therapeutic options makes scientists to doubt the efficacy of systemic treatments in targeting the essential cell populations and achieving cure as a final goal. Overgrowing data suggest that cancer is a disease closely linked to stem cells (SCs). It is well known that the first identification of cancer stem-like cells in acute myeloid leukaemia was soon followed by similar results in solid malignancies, including colorectal cancer, and the classic model for colon carcinogenesis supports the development of sudden mutations that will lead to the activation or inactivation of certain oncogenes or tumor suppressors. Thus, this process may go on for years before the first symptoms and the only cells able to withstand for many years, avoid apoptosis and have a high regenerative capacity are the progenitor cells found at the lower part of colon crypts. A more profound study of the mechanisms and molecular signalling pathways that control the basic characteristics of SCs, such as asymmetrical division or self-renewal, may help comprehend the basic mechanisms of cancer genesis and progression. This will result in the development of new therapeutic agents that may target chemoresistant cell populations and improve the therapeutic results. In the current review we point out the importance of cancer stem-like cells in colorectal oncology from a pathologist's point of view, stating the obvious correlation between histology, embryology and surgical pathology.

Lymph node status at the time of diagnosis remains one of the principal indicators of prognosis in patients with rectal cancer. Involvement of loco-regional lymph nodes is relevant to surgical and clinical oncologists and continues to impact significantly upon local and systemic management strategies, in both neo-adjuvant and adjuvant settings. In this review, the clinical impact of lymph node status in the surgical management of rectal cancer is considered, with particular reference to the significance of lymphadenectomy and the potential implications for rectal tumours amenable to trans-anal excision. Current standards of care are reviewed and the extent to which the determination of lymph node status influences oncological decisions regarding neo-adjuvant and adjuvant therapies are discussed with areas of controversy highlighted.

Neoadjuvant radiochemotherapy followed by total mesorectal excision is now the standard treatment for locally advanced rectal cancer. However, tumor response to chemoradiation varies widely among individuals and cannot be determined before the final pathologic evaluation. The aim of this study was to identify germline genetic markers that could predict sensitivity or resistance to preoperative radiochemotherapy (RT-CT) in rectal cancer. We evaluated the predictive value of 128 single-nucleotide polymorphisms (SNPs) in 71 patients preoperatively treated by RT-CT. The selected SNPs were distributed over 76 genes that are involved in various cellular processes such as DNA repair, apoptosis, proliferation or immune response. The SNPs superoxide dismutase 2 (SOD2) rs4880 (P=0.005) and interleukin-13 (IL13) rs1800925 (P=0.0008) were significantly associated with tumor response to chemoradiation. These results reinforce the idea of using germline polymorphisms for personalized treatment.

The authors report a case of false-positive ultrasound-guided fine needle aspiration in the initial staging of a rectal cancer. A 46 year-old patient presented with a middle third tumor of the rectum staged T2-T3 by MRI and endorectal ultrasonography. Ultrasound-guided fine needle aspiration of mesorectal nodes showed adenocarcinomatous cells. A subtotal proctectomy was performed without neoadjuvant treatment. Histological report showed a well differentiated adenocarcinoma pT2pN0 (42 examined lymph nodes). The authors discuss the different hypothesis to explain the discordance between preoperative staging and definitive histological results.

Aims: To assess the impact of cytokeratin (CK) 5/6 and E-cadherin immunohistochemistry on diagnostic agreement of non-invasive proliferative breast lesions. Methods and results: Twenty pathologists classified 105 cases of non-invasive proliferative breast lesions into 10 diagnostic categories. One haematoxylin and eosin (H&E) slide of each case was analysed on a first round and one H&E slide with corresponding CK5/6 and E-cadherin immunohistochemistry was analysed on a second round. Interobserver reproducibility for category-specific and management-specific lesions was measured on each round. CK5/6 and E-cadherin had little impact on diagnostic agreement, which remained moderate between the first and second rounds (overall κ coefficients of 0.47 and 0.53, respectively, P = NS). Levels of agreement slightly improved for lesions with specific CK5/6 and E-cadherin immunoprofiles (usual ductal hyperplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, non-high-grade ductal carcinoma in situ), but the differences observed were not statistically significant. However, diagnostic agreement improved when lesions were grouped according to their management category (overall κ coefficients of 0.58 and 0.66 in the first and second rounds, respectively). Conclusions: CK5/6 and E-cadherin immunohistochemistry has little impact on interobserver reproducibility for non-invasive breast lesions. Diagnostic agreement can, however, be improved by grouping lesions in management categories.

International audience; There is an increasing demand for the evaluation of HER2 status in breast cancer. In this study, sections from fixed tissues and triton extracts of tissue homogenates were obtained from 163 malignant breast tumors and analyzed in parallel using immunohistochemistry combined with fluorescence in situ hybridization, as gold standard tests, and an ELISA test (c-erbB2/c-neu Rapid Format ELISA, Oncogene Research Products, USA). Tumor DNA was employed to evaluate two quantitative PCR methods: the HER2/neu DNA Quantification Kit (Roche Diagnostics GmbH, Germany), which uses the gastrin chromosome 17 reference gene, and our recently developed Oncolab qPCR assay, where both a chromosome 17 gene (somatostatin receptor type II (SSTR2)) and a non-chromosome 17 reference gene (glyceraldehyde-3-phosphate deshydrogenase (GAPDH)) were used to detect an increase in HER2 gene copy number and to evaluate the aneusomy of chromosome 17, respectively. By IHC/FISH and ELISA, HER2 was overexpressed in 27 (16.6%) and 24 (14.7%) samples, respectively. With the Roche and Oncolab qPCR assays, 29 (17.8%) samples showed a ratio of HER2/gastrin > or = 2.0 and 26 (16.0%) showed a ratio of HER2/SSTR2 > or = 2.0, respectively. In samples presenting HER2/SSTR2 or = 2.0, which was indicative of a chromosome 17 polysomy, we observed a modest increase in HER2 protein expression. Complete agreement between the four methods for HER2 status determination was obtained for 154 (94.5%) samples. Overall, these results demonstrate that quantitative PCR is a reliable method for analyzing HER2 status and chromosome 17 polysomy.

The HER2 proto-oncogene encodes a transmembrane protein, which is considered to function as a growth factor receptor. Overexpression of this protein found by immunohistochemistry in about 20% of infiltrating breast carcinomas, has a predictive value of response to treatment by trastuzumab, an anti-HER2 humanized monoclonal antibody. Search for HER2 gene amplification is necessary to adapt the immunohistochemical technique quality and also in the cases of delicate analysis or weak overexpression. It is usually carried out by Fluorescence In Situ Hybridization (FISH). A more recent hybridization technique, named CISH because of its chromogenic revelation is an alternative method, which gives highly correlated results with FISH. We present details of this technique, which may be more familiar for the pathologists than FISH, because reading analysis is similar to that of immunohistochemical staining.