Eva Szentgyorgyi

International study group on rectal cancer regression grading : interobserver variability with commonly used regression grading systems

The aim of this study was to ascertain the level of concordance among gastrointestinal pathologists for regression grading in rectal cancers treated with neoadjuvant chemoradiation. Seventeen gastrointestinal pathologists participated using the Mandard, Dworak, and modified rectal cancer regression grading systems to grade 10 representative slides that were selected from 10 cases of rectal cancer treated with long-course neoadjuvant chemoradiation. The slides were scanned with a whole-slide scanner generating dynamic digitized images. The results showed very little concordance across the 3 grading systems, with κ values of 0.28, 0.35, and 0.38 for the Mandard, Dworak, and modified rectal cancer regression grading systems, respectively. In only 1 of 10 study cases was there unanimous grading concordance using the modified rectal cancer regression grading system. It was felt that these systems lacked precision and clarity for reproducible, accurate regression grading. The study concluded that there was a need for a simple, reproducible regression grading system with clear criteria, a cumulative or composite score taking into account all sections of the tumor bed that is sampled rather than the worst section (highest grade), and there should be a uniform method of sampling of these specimens.

A multi-centre pathologist survey on pathological processing and regression grading of colorectal cancer resection specimens treated by neoadjuvant chemoradiation

To ascertain the approach and degree of consensus of pathologists in the handling and regression grading of colorectal cancer resection specimens treated with neoadjuvant chemoradiation, a ten-part questionnaire was circulated to 18 gastrointestinal pathologists in eight countries. The questions were specific and addressed pertinent issues related to colorectal cancer with neoadjuvant chemoradiation. There is a lack of consensus on how to handle the specimen, number of sections taken, correlation with pre- and post-operative radiological imaging, and especially, regression grading schema employed. Consensus in the form of guidelines is required so that the pathological assessment of these specimens will provide clinically relevant information for patient management, irrespective of location.

Gastric Biopsies: The Gap between Evidence-Based Medicine and Daily Practice in the Management of Gastric Helicobacter pylori Infection

BACKGROUND Many consider histology to be the gold standard for Helicobacter pylori detection. Because the number and distribution of H pylori organisms vary, particularly in patients taking proton pump inhibitors (PPIs), the American Gastroenterological Association recommends discontinuing PPIs two weeks before endoscopy, and taking biopsies from both the body and antrum. OBJECTIVE To assess the influence of clinical practice on the histopathological detection of H pylori infection. METHODS Electronic patient records were evaluated for the sites of gastric sampling and PPI use at endoscopy. One hundred fifty cases with biopsies taken from both antrum and body were randomly selected for pathological re-review with special stains. The gastric regions sampled, H pylori distribution and influence of clinical factors on pathological interpretation were assessed. RESULTS Between 2005 and 2010, 10,268 biopsies were taken to detect H pylori. Only one region was sampled in 60% of patients (antrum 47%, body 13%). Re-review of biopsies taken from both antrum and body indicated that the correct regions were sampled in only 85 (57%) patients. Of these, 54 were H pylori positive and 96 were H pylori negative. H pylori was present in the antrum in only 15% of the patients and body only in 21%. Of 96 H pylori-negative patients, two were reinterpreted as positive. Forty-seven per cent of patients were taking PPIs at endoscopy, contributing to both false-negative and false-positive diagnoses. CONCLUSION Despite national and international guidelines for managing H pylori infection, the American Gastroenterological Association guidelines are infrequently adhered to, with PPIs frequently contributing to false diagnosis; sampling one region only increases the likelihood of missing active infection by at least 15%.

The Celiac Disease and Diabetes-Dietary Intervention and Evaluation Trial (CD-DIET) protocol: a randomised controlled study to evaluate treatment of asymptomatic coeliac disease in type 1 diabetes.

Introduction Coeliac disease (CD) is an autoimmune condition characterised by gluten-induced intestinal inflammation, and observed at a 5–10 fold greater prevalence in type 1 diabetes. While universal screening for CD in patients with diabetes is frequently advocated, objective data is limited as to benefits on diabetes control, bone health or quality of life related to the adoption of a gluten-free diet (GFD) in the large proportion of patients with diabetes with asymptomatic CD. The Celiac Disease and Diabetes-Dietary Intervention and Evaluation Trial (CD-DIET) study is a multicenter, randomised controlled trial to evaluate the efficacy and safety of a GFD in patients with type 1 diabetes with asymptomatic CD. Methods and analysis Children and adults (8–45 years) with type 1 diabetes will be screened for asymptomatic CD. Eligible patients with biopsy-proven CD will be randomly assigned in a 1:1 ratio to treatment with a GFD for 1 year, or continue with a gluten-containing diet. The primary outcome will evaluate the impact of the GFD on change in glycated haemoglobin. Secondary outcomes will evaluate changes in bone mineral density, blood glucose variability and health-related quality of life between GFD-treated and the regular diet group over a 1-year period. The study was initiated in 2012 and has subsequently expanded to multiple paediatric and adult centres in Ontario, Canada. Ethics and dissemination The findings from this study will provide high-quality evidence as to the impact of GFD treatment on glycaemic control and complications in asymptomatic children and adults with CD and type 1 diabetes. Trial registration number NCT01566110.

Pathological grading of regression: an International Study Group perspective

In this issue of the Journal of Clinical Pathology , MacGregor, Maughan and Sharma1 discuss the value and utility of pathological grading of regression from an oncologists point of view. Neoadjuvant chemoradiotherapy is now a well-accepted treatment for locally advanced rectal cancer (cT3/T4 or lymph node-positive rectal cancers). However, neoadjuvant therapy affects the histopathological reporting of resected specimens by virtue of the host response to treatment, which occurs in the majority of patients. Pathological complete responses ranging from 9% to 29% have been reported,2 ,3 but the clinical significance of ‘incomplete’ regression and, more importantly, its role in determining postoperative treatment, is not clear. Pathological complete response has been associated with good patient outcomes.4–7 However, tumour regression grade (although having prognostic value for survival and recurrence by univariate analyses) has not been established to be an independent prognostic value that is superior to ypTNM in predicting clinical outcome.6 ,7–13 On the contrary, Min et al 11 demonstrated that regression grading is a good prognostic factor in patients with lymph node negative locally advanced rectal cancer. Therefore, regression grading may be a useful parameter for monitoring patient response and also as a potential prognostic factor. Several grading systems have been proposed and used, the most popular one being the Mandard and Dworak systems.14 ,15. We, an ‘International …

Regression grading in neoadjuvant treated pancreatic cancer: an interobserver study

Aim Several regression grading systems have been proposed for neoadjuvant chemoradiation-treated pancreatic ductal adenocarcinoma (PDAC). This study aimed to examine the utility, reproducibility and level of concordance of three most frequently used grading systems. Methods Four gastrointestinal pathologists used the College of American Pathologists (CAP), Evans, MD Anderson Cancer Centre (MDA) regression grading systems to grade 14 selected cases (7–20 slides from each case) of neoadjuvant chemoradiation-treated PDAC. A postscoring discussion with each pathologist was conducted. The results were entered into a standardised data collection form and statistical analyses were performed. Results There was little concordance across the three systems. The Kendall coefficient of concordance agreement scores were: CAP: 2-poor, 2-fair; Evans: 1-fair, 1-moderate, 2-good; MDA: 1-poor, 2-moderate, 1-good. Interpretation in all three grades in the CAP grading system was a source of discrepancy. Furthermore, using fibrosis as a criterion to assess regression was contentious. In the Evans system, quantifying tumour destruction using arbitrary percentage cut-offs (ie, 9% vs 10%; 50% vs 51%, etc) was imprecise and subjective. Although the MDA system generated greatest concordance, this was due to ‘oversimplification’ surrounding wide, arbitrarily assigned thresholds of 5% of tumour. Conclusions All systems lacked precision and clarity for accurate regression grading. Presently the clinical utility and impact of histological regression grading in patient management is questionable. There is a need to re-evaluate regression grading in the pancreas and establish a reproducible, clinically relevant grading system.

Metastatic Thyroid Carcinoma to the Gastric Body

A 46-year-old woman had a 4-month history of progressive cough, dysphagia, and dysphonia. Laryngoscopy revealed left vocal cord paralysis, and computed tomography demonstrated a mediastinal mass arising from the thyroid and invading the trachea and esophagus (Figure 1). A biopsy of the mass revealed papillary thyroid carcinoma (PTC). The patient underwent bilateral neck dissections and total thyroidectomy with en bloc resection of the mediastinal mass with 3 cm of trachea and outer muscular layer of the esophagus. Histological examination identified PTC with regions of poorly differentiated thyroid carcinoma (PDTC) in nodal metastases and in areas of extrathyroidal extension (pT4aN1b); margins were involved. Angioinvasion was characterized by intravascular tumor cells admixed with thrombus (1). Postsurgical thyroglobulin was undetectable ( 0.9 g/L); thyroglobulin antibodies were positive (183 IU/L). Following 200 mCi of radioactive iodine, no uptake outside the neck was identified. The patient received prophylactic external beam radiotherapy to the neck and superior mediastinum. Four months after surgery, she was found to have lung metastases with increasing thyroglobulin antibodies (551 IU/L). The low-burden lung disease remained relatively stable. Sixteen months after surgery, a postcricoid esophageal stricture was diagnosed. During gastroscopy to dilate it, a 1.5-cm suspicious nodule in the proximal body of the stomach was noted and biopsied. This was metastatic PTC with areas of PDTC. Although most thyroid carcinomas encountered in visceral organs represent metastatic disease, these can also arise within teratomas and ectopic thyroid tissues (2). Anaplastic thyroid carcinoma is known to metastasize to the stomach; however, intra-abdominal metastases from PTC or PDTC are extremely uncommon (3, 4). The application of rigid criteria to diagnose vascular invasion as identified in this case provides a clinically relevant prediction of distant metastasis in patients with thyroid carcinomas (1). To the best of our knowledge, this is the first reported gastric metastasis originating from PTC with regions of PDTC.

Administration of Hypoxia-Activated Prodrug Evofosfamide after Conventional Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Preclinical Models of Colorectal Cancer

Purpose: Cancer-initiating cells (C-IC) have been described in multiple cancer types, including colorectal cancer. C-ICs are defined by their capacity to self-renew, thereby driving tumor growth. C-ICs were initially thought to be static entities; however, recent studies have determined these cells to be dynamic and influenced by microenvironmental cues such as hypoxia. If hypoxia drives the formation of C-ICs, then therapeutic targeting of hypoxia could represent a novel means to target C-ICs. Experimental Design: Patient-derived colorectal cancer xenografts were treated with evofosfamide, a hypoxia-activated prodrug (HAP), in combination with 5-fluorouracil (5-FU) or chemoradiotherapy (5-FU and radiation; CRT). Treatment groups included both concurrent and sequential dosing regimens. Effects on the colorectal cancer-initiating cell (CC-IC) fraction were assessed by serial passage in vivo limiting dilution assays. FAZA-PET imaging was utilized as a noninvasive method to assess intratumoral hypoxia. Results: Hypoxia was sufficient to drive the formation of CC-ICs and colorectal cancer cells surviving conventional therapy were more hypoxic and C-IC-like. Using a novel approach to combination therapy, we show that sequential treatment with 5-FU or CRT followed by evofosfamide not only inhibits tumor growth of xenografts compared with 5-FU or CRT alone, but also significantly decreases the CC-IC fraction. Furthermore, noninvasive FAZA-PET hypoxia imaging was predictive of a tumors response to evofosfamide. Conclusions: Our data demonstrate a novel means to target the CC-IC fraction by adding a HAP sequentially after conventional adjuvant therapy, as well as the use of FAZA-PET as a biomarker for hypoxia to identify tumors that will benefit most from this approach. Clin Cancer Res; 24(9); 2116–27. ©2018 AACR.

Gastric foveolar dysplasia: a survey of reporting habits and diagnostic criteria

This study aimed to ascertain views, incidence of reporting and diagnostic criteria for gastric foveolar dysplasia. A questionnaire, a post-questionnaire discussion and microscopic assessment of selected cases was conducted by gastrointestinal pathologists to explore the above-stated aims. Fifty-four percent of respondents never or rarely diagnosed gastric foveolar-type dysplasia. The general consensus was that round nuclei, lack of nuclear stratification, presence of inflammation/damage and surface maturation favoured reactive change; while architectural abnormalities/complexity and nuclear enlargement mainly were used to separate low-grade from high-grade foveolar dysplasia. Immunohistochemistry was rarely used to make the diagnosis of dysplasia and was thought not to be of help in routine practice. Inter-observer agreement in grading of dysplasia versus reactive, and the type of dysplasia (foveolar versus adenomatous), was substantial/almost perfect amongst 35.7% and 21.4% of participants, respectively. This reflects low reproducibility in making these diagnoses. In conclusion, foveolar dysplasia was a rarely made diagnosis among 14 gastrointestinal pathologists, there are no uniform criteria for diagnosis and there is poor inter-observer agreement in separating low-grade foveolar dysplasia from reactive gastric mucosa and low-grade adenomatous dysplasia. Greater awareness and agreed criteria will prevent misdiagnosis of low-grade foveolar dysplasia as reactive, and vice versa.