Anne Jouret-Mourin

Vascular Reconstruction During Pancreatoduodenectomy for Ductal Adenocarcinoma of the Pancreas Improves Resectability but does not Achieve Cure

ObjectiveCombined vascular and pancreatic resection improves long-term survival of patients suffering from ductal adenocarcinoma of the pancreatic head. This study was designed to compare the results of surgical resection in patients with pancreatic cancer with or without vascular resection. Late 10-year disease-free survival was considered as an indicator of patients’ disease cure.MethodsA total of 149 consecutive patients have undergone pancreatoduodenectomy without vascular resection (group 1: 82 patients), with isolated venous resection (group B: 67 patients), or with arterial and/or venous resection (group C: 8 patients).ResultsThe duration of surgery and blood losses were significantly more important in groups B and C compared with group A; however, postoperative morbidity and mortality rates were similar. R1 resection was significantly more frequent in groups B (42%) and C (50%) compared with group A (13%; pxa0=xa00.0002), but there were more advanced tumors in these groups, as demonstrated by a lower Karnowsky index, higher Ca 19-9 plasmatic level, greater tumor size, more advanced stage in the AJCC classification, and more tumor location in the uncinate process of the pancreas. Ten-year overall and disease-free survivals were significantly better in group A (19 and 20%) compared with group B (2.8 and 0%) and group C (0% and 0%). Multivariate analysis proved vascular resection and metastatic nodal status as being independent predictive factors of disease-free survival.ConclusionsVascular resection combined to pancreatoduodenectomy for pancreatic cancer increases local resectability without increasing mortality and morbidity rates but does not improve patients’ disease cure rate.

Liver transplantation and neuroendocrine tumors: lessons from a single centre experience and from the literature review.

Neuroendocrine tumor (NET) metastases represent at this moment the only accepted indication of liver transplantation (LT) for liver secondaries. Between 1984–2007, nine (1.1%) of 824 adult LTs were performed because of NET. There were five well differentiated functioning NETs (four carcinoids and one gastrinoma), three well differentiated non functioning NETs and one poorly differentiated NET. Indications for LT were an invalidating unresectable tumor (4×), and/or a diffuse tumor localization (3×) and/or a refractory hormonal syndrome (5×). Median post‐LT patient survival is 60.9u2003months (range 4.8–119). One‐, 3‐ and 5‐year actuarial survival rates are 88%, 77% and 33%; 1, 3 and 5u2003years disease free survival rates are 67%, 33% and 11%. Due to a more rigorous selection procedure, results improved since 2000; three out of five patients are alive disease‐free at 78, 84 and 96u2003months. Review of these series together with a review of the literature reveals that results of LT for this oncological condition can be improved using better selection criteria, adapted immunosuppression and neo‐ and adjuvant surgical as well as medical tretament. LT should be considered earlier in the therapeutic algorithm of selected NET patients as it is the only therapy that can offer a cure.

International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study

BACKGROUNDnThe estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer.nnnMETHODSnAn international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrells C-statistics was used to assess model performance.nnnFINDINGSnTissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system.nnnINTERPRETATIONnThe Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer.nnnFUNDINGnFrench National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.

Comprehensive Intrametastatic Immune Quantification and Major Impact of Immunoscore on Survival.

BackgroundnThis study assesses how the metastatic immune landscape is impacting the response to treatment and the outcome of colorectal cancer (CRC) patients.nnnMethodsnComplete curative resection of metastases (nu2009=u2009441) was performed for two patient cohorts (nu2009=u2009153). Immune densities were quantified in the center and invasive margin of all metastases. Immunoscore and T and B cell (TB) score were analyzed in relation to radiological and pathological responses and patients disease-free (DFS) and overall survival (OS) using multivariable Cox proportional hazards models. All statistical tests were two-sided.nnnResultsnThe spatial distribution of immune cells within metastases was nonuniform. Patients, as well as metastases of the same patient, had variable immune infiltrates and response to therapy. A beneficial response was statistically significantly associated with increased immune densities. Among all metastases, Immunoscore (I) and TB score evaluated in the least immune-infiltrated metastases were the strongest predictors for DFS and OS (five-year follow-up, Immunoscore: I 3-4: DFS rate = 27.9%, 95% CIu2009=u200915.2 to 51.3; vs I 0-1-2: DFS rate = 12.3%, 95% CIu2009=u20094.9 to 30.6; HRu2009=u20090.45, 95% CIu2009=u20090.28 to 0.70, P = .02; I 3-4: OS rate = 64.6%, 95% CIu2009=u200946.6 to 89.6; vs I 0-1-2: OS rate = 32.5%, 95% CIu2009=u200917.2 to 61.4; HRu2009=u20090.32, 95% CIu2009=u20090.15 to 0.66, P = .001, C-index = 65.9%; five-year follow-up, TB score: TB 3-4: DFS rate = 25.7%, 95% CIu2009=u200914.2 to 46.6; vs TB 0-1-2: DFS rate = 5.0%, 95% CIu2009=u20090.8 to 32.4; HRu2009=u20090.36, 95% CIu2009=u20090.22 to 0.57, P < .001; TB 3-4: OS rate = 63.7%, 95% CIu2009=u200946.4 to 87.5; vs TB 0-1-2: OS rate: 21.4%, 95% CIu2009=u20099.2 to 49.8; HRu2009=u20090.25, 95% CIu2009=u20090.12 to 0.51, P < .001, C-index = 67.8%). High TB score and Immunoscore patients had a median survival of 70.5u2009months, while low patients survived only 25.1 to 38.3u2009months. Nonresponding patients with high-immune infiltrates had prolonged DFS (HRu2009=u20090.28, 95% CIu2009=u20090.15 to 0.52, P = .001) and OS (HRu2009=u20090.25, 95% CIu2009=u20090.1 to 0.62, P = .001). The immune parameters remained the only statistically significant prognostic factor associated with DFS and OS in multivariable analysis (P < .001), while response to treatment was not.nnnConclusionsnResponse to treatment and prolonged survival of metastatic CRC patients were statistically significantly associated with high-immune densities quantified into the least immune-infiltrated metastasis.

Endoscopic submucosal dissection specimens in early colorectal cancer: lateral margins, macroscopic techniques, and possible pitfalls

Endoscopic submucosal dissection (ESD) allows en-bloc resection of superficial gastrointestinal tumors, providing specimens on which lateral margin analysis can be performed reliably. Positive lateral margins have been linked to higher rates of recurrence/residual tumor. There are no guidelines for macroscopic processing of lateral margins. Currently, most institutions use parallel lateral sections, which are difficult to interpret. We use perpendicular lateral sections, hypothesizing that it decreases potential artifactually positive lateral margins. We analyzed positive lateral margin rates in colorectal ESD specimens according to sectioning method. We also looked at morphological factors associated with margin positivity as a function of technique used. We studied 166 ESD specimens, on which parallel sectioning practiced from 2006 to 2011 (nxa0=xa075). Perpendicular sectioning was used from 2010 to 2015 (nxa0=xa091). We recorded the number of positive margins, along with grade of dysplasia/carcinoma. Other information such as histopathological type, specimen size, lesion location, and patient follow-up was also recorded for evaluation. Forty of seventy-five (63%) margins were positive for parallel sections. In contrast, perpendicularly cut margins were significantly less frequently positive: 22/91 (24%) (pxa0=xa00.0001). Positive margins were found significantly more frequently in tubulo-villous lesions compared to tubular lesions in both the parallel and perpendicular groups (pxa0=xa00.03 and pxa0=xa00.02, respectively). Specimen size was not significantly associated with positive margins. Using perpendicular sectioning of colorectal ESD specimens, the proportion of cases with a positive lateral margin was significantly lower than when parallel sectioning was used. We suggest perpendicular sectioning to improve accuracy in histopathological analysis. This method is particularly important to use in future studies, as it may prevent authors from making conjectures based on overestimation of positive lateral margins.

The Normal Biopsy: Colonic and Ileal Mucosa and Submucosa

The digestive tract is a hollow tube consisting throughout of three coats or layers. The first layer, the mucosa, is made up of an epithelial lining which borders on the lumen of the bowel and rests upon a basement membrane, the lamina propria and the muscularis mucosae. The mucosa of the colon has a smooth surface and is composed of tubular parallel crypts embedded in a loosely arranged stroma. The mucosa of the ileum is composed of fingerlike villi and displays a number of specific features including the shorter villi and more epithelial goblet cells on the surface than the proximal small intestine and the presence of Peyer’s patches. The second coat is the submucosa. The muscularis propria, the third layer, is composed of two layers of smooth muscle separated by a thin layer of connective tissue in which the ganglionated myenteric plexus (Auerbach’s) can be observed. The subserosa is composed of loose areolar tissue covered by mesothelium where the tract borders on the body cavity (serosa). Endoscopic biopsies are limited to the mucosa and upper part of the submucosa. A good understanding of the normal histology of the mucosa and submucosa is essential for analysis of endoscopic biopsies of the ileum and the colon.

Mucosal Prolapse Syndrome

Prolapse of the large intestinal mucosa occurs in various situations including at the margin of a colostomy, the apex of hemorrhoids protruding outside the anus, and in the context of diverticular disease. However the best known sites of mucosal prolapse are the anterior wall of the rectum where it gives rise to the solitary ulcer syndrome and the anorectal junction resulting in a peculiar polyp called “cloacogenic polyp.” These are both benign conditions. Common clinical symptoms are constipation and/or red blood loss per annum. The endoscopy of the solitary ulcer can show a variable picture of erythema, a shallow ulcer, or even a polypoid lesion. The histology is characteristic. The mucosa around the solitary ulcer shows crypt distortion, reactive epithelial cells, and typical fibromuscular obliteration of the lamina propria. Inflammation is usually mild. A “cloacogenic polyp” appears as a villiform tumor mass at the anorectal junction and has a great potential to be confused with other polyps such as adenomas or even carcinoma. It is important to recognize these lesions in order to avoid the morbidity and mortality associated with major surgery (misdiagnosis of neoplasia) or the side effects of long-term medical treatment.

The Endoscopic Biopsy: How to Proceed and How to Look at a Biopsy

Pathology is one of the tools for reaching a diagnosis. Like all procedures in medicine, the analysis of biopsies has some limitations. The diagnostic yield can be increased by using good quality samples, by optimizing the number of samples and sections, by optimal preparation of the samples and by confronting the findings with appropriate clinical information. Numbers of samples needed depend on the indication for the endoscopic procedures. When reading a biopsy, analysis can be improved with a systematic approach. This implies a proper knowledge of the normal histology and of potential artifacts. The pathologists should take note of the origin, the number, and the size of the samples and subsequently evaluate the architecture and cytological aspects of the specimen. The analysis can be improved by using a checklist or pro forma report.

Drug-Induced Colon Injury

Drug-induced injury of the colon is a relatively frequent though underestimated event. The histological manifestations are very variable and frequently mimic other disease entities with different etiologies. The pathologist should try to give to the clinician indications concerning a possible drug-related etiology of the injury, with a specification of the drug involved, if feasible. Careful clinicopathological confrontation is important to distinguish drug-related injury from other diseases of the colon. The following section provides an overview of the different patterns that can be encountered in drug-induced colon injury, their relation to specific medications, and the possible differential diagnosis.

Evaluation of the correlation between KRAS mutated allele frequency and pathologist tumorous nuclei percentage assessment in colorectal cancer suggests a role for zygosity status

Evaluation of molecular tumour heterogeneity relies on the tumorous nuclei percentage (TNP) assessment by a pathologist, which has been criticised for being inaccurate and suffering from interobserver variability. Based on the ‘Big Bang theory’ which states that KRAS mutation in colorectal cancer is mostly homogeneous, we investigated this issue by performing a critical analysis of the correlation of the KRAS mutant allele fraction with the TNP in 99 colorectal tumour samples with a positive KRAS mutation status as determined by next-generation sequencing. Our results yield indirect evidence that the KRAS zygosity status influences the correlation between these parameters and we show that a well-trained pathologist is indeed capable of accurately assessing TNP. Our findings indicate that tumour zygosity, a feature which has largely been neglected until now, should be taken into account in future studies on (colorectal) molecular tumour heterogeneity.