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Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract and are among the most frequent sarcomas. Accurate diagnosis, classification, and reporting are critical for prognostication and patient management, including selection of appropriate targeted therapy. Here we report on international consensus-based datasets for the pathology reporting of biopsy and resection specimens of GIST. The datasets were produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major international pathology and cancer organizations. An international expert panel consisting of pathologists, a surgical oncologist, and a medical oncologist produced a set of core and noncore data items for biopsy and resection specimens based on a critical review and discussion of current evidence. All professionals involved were subspecialized soft tissue tumour experts and affiliated with tertiary referral centres. Commentary was provided for each data item to explain its clinical relevance and the rationale for selection as a core or noncore element. Following international public consultation, the datasets, which include synoptic reporting guides, were finalized and ratified, and published on the ICCR website. These first international datasets for GIST are intended to promote high-quality, standardised pathology reporting. Their widespread adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will ultimately help to improve the management of patients with GIST. All the ICCR datasets, including these on GIST, are freely available worldwide on the ICCR website (www.iccr-cancer.org/datasets).

Pancreatic carcinoma is a relatively common malignancy with an overall poor prognosis which is somewhat improved in those patients for whom resection and adjuvant therapy is feasible. In recent years there has been a trend to administering neoadjuvant therapy (combination chemotherapy and/or chemoradiotherapy), followed by resection in patients who remain surgical candidates at the completion of this treatment. Advantages of a neoadjuvant approach may include greater likelihood of achieving complete resection with negative surgical margins, reduced treatment toxicity and greater cost effectiveness, as well as potentially sparing patients with rapidly progressive disease from major surgery. To gauge the tumour's response to preoperative therapy, and to compare the efficacy of different regimens, there is a need for a robust and reproducible system of assessing tumour regression in resection specimens. Several such systems have been proposed, but there is generally a lack of consensus as to which system is the 'best'. This review describes the evolution of a number of tumour regression grading systems which have been proposed, and discusses the relative merits and shortfalls of several of the most frequently applied schemata. Some problems common to many of these include poorly defined criteria, low interobserver reproducibility and a reliance on fibrosis as a surrogate for tumour kill, which may not be valid. Despite that, recent evidence suggests that the Dworak grading system (first developed for rectal cancer) may be useful in terms of both interobserver concordance and correlation with survival.

// Melanie J. McCoy 1, 4 , Chris Hemmings 2, 3 , Chidozie C. Anyaegbu 1 , Stephanie J. Austin 1, 3 , Tracey F. Lee-Pullen 1, 3 , Timothy J. Miller 1, 3 , Max K. Bulsara 5 , Nikolajs Zeps 1, 3 , Anna K. Nowak 4, 6 , Richard A. Lake 4 , Cameron F. Platell 1, 3 1 Colorectal Research Unit, St John of God Subiaco Hospital, Subiaco, WA, 6008, Australia 2 Department of Anatomic Pathology, St John of God Pathology, Wembley, WA, 6014, Australia 3 School of Surgery, University of Western Australia, Crawley, WA, 6009, Australia 4 School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, 6009, Australia 5 Institute for Health Research, University of Notre Dame, Fremantle, WA, 6959, Australia 6 Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia Correspondence to: Melanie McCoy, email: melanie.mccoy@uwa.edu.au Keywords: rectal cancer, regulatory T cells, radiotherapy, chemotherapy, treatment response Received: September 13, 2016 Accepted: January 07, 2017 Published: February 03, 2017 ABSTRACT Neoadjuvant (preoperative) chemoradiotherapy (CRT) decreases the risk of rectal cancer recurrence and reduces tumour volume prior to surgery. However, response to CRT varies considerably between individuals and factors associated with response are poorly understood. Foxp3 + regulatory T cells (Tregs) inhibit anti-tumour immunity and may limit any response to chemotherapy and radiotherapy. We have previously reported that a low density of Tregs in the tumour stroma following neoadjuvant CRT for rectal cancer is associated with improved tumour regression. Here we have examined the association between Treg density in pre-treatment diagnostic biopsy specimens and treatment response, in this same patient cohort. We aimed to determine whether pre-treatment tumour-infiltrating Treg density predicts subsequent response to neoadjuvant CRT. Foxp3 + , CD8 + and CD3 + cell densities in biopsy samples from 106 patients were assessed by standard immunohistochemistry (IHC) and evaluated for their association with tumour regression grade and survival. We found no association between the density of any T cell subset pre-treatment and clinical outcome, indicating that tumour-infiltrating Treg density does not predict response to neoadjuvant CRT in rectal cancer. Taken together with the findings of the previous study, these data suggest that in the context of neoadjuvant CRT for rectal cancer, the impact of chemotherapy and/or radiotherapy on anti-tumour immunity may be more important than the state of the pre-existing local immune response.

Background Pathological complete response following neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer is associated with reduced local recurrence and improved long-term outcome. However, the prognostic value of a partial response, or of tumour regression in patients with metastatic disease, is less clear. Methods We present a single-centre cohort study of 205 patients with stage II–IV rectal cancer treated with surgery and neoadjuvant CRT between 2006 and 2013. Tumour regression was assessed using the Dworak system. Results The probability of 3-year recurrence-free survival (RFS) was 95% for Dworak grade 4, 82% for grade 3, 64% for grade 2 and 53% for grade 1 (P = 0.0005). In univariate regression analysis, Dworak grade was associated with RFS (hazard ratio (HR) 0.51, P < 0.0001; trend analysis) and cancer-specific survival (HR 0.52, P = 0.002). In multivariate analysis, Dworak grade remained an independent predictor of RFS (HR 0.62, P = 0.012), along with clinical metastases stage, resection margin status, the presence or absence of extramural venous invasion and type of surgical procedure. Conclusions Tumour regression grade after neoadjuvant CRT was an independent prognostic factor for RFS, highlighting the importance of the degree of local response to CRT.

Cancer stem-like cells are highly tumourigenic cells that can repopulate entire tumours after apparent successful treatment. Recent evidence suggests they interact with other cells in the tumour microenvironment, including immune cell subsets, to enhance their survival. The aim of this study was to determine whether the expression of immune cell markers in primary colon cancer impacts the prognostic significance of cancer stem-like cell marker expression. Immunohistochemistry was used to assess the expression of putative stem cell markers (ALDH1, CD44v6, CD133, Lgr5, SOX2) and immune cell related markers (CD3, CD8, FoxP3, PD-L1) in 104 patients with stage III colon cancer. Associations of marker expression with overall and cancer-specific survival were determined using Kaplan-Meier analysis. High SOX2 expression in the central tumour area was found to be an independent factor for poor cancer-specific survival [hazard ratio (HR) 6.19; 95% confidence interval (CI) 2.24-17.14; p=0.001]. When immune-related factors were taken into account, patients categorised as SOX2low/FoxP3high had good outcome (HR 0.164; 95%CI 0.066-0.406; p

The global landscape of molecular testing is rapidly changing, with the recent publication of the International Association for the Study of Lung Cancer (IASLC)/College of American Pathologists (CAP) guidelines and the ALK Atlas. The IASLC/CAP guidelines recommend that tumors from patients with non-small cell lung cancer (NSCLC) be tested for ALK rearrangements in addition to epidermal growth factor receptor (EGFR) mutations. The spur for this recommendation is the availability of novel therapies that target these rearrangements. This article is based on coverage of a Pfizer-sponsored National Working Group Meeting on ALK Diagnostics in Lung Cancer, held around the 15th World Lung Cancer Conference, in Sydney on October 31, 2013. It is based on the presentations given by the authors at the meeting and the discussion that ensued. The content for this article was discussed and agreed on by the authors.

Pathological complete response following neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer is associated with reduced local recurrence and improved long-term outcome. However, the prognostic value of a partial response, or of tumour regression in patients with metastatic disease, is less clear.We present a single-centre cohort study of 205 patients with stage II-IV rectal cancer treated with surgery and neoadjuvant CRT between 2006 and 2013. Tumour regression was assessed using the Dworak system.The probability of 3-year recurrence-free survival (RFS) was 95% for Dworak grade 4, 82% for grade 3, 64% for grade 2 and 53% for grade 1 (P = 0.0005). In univariate regression analysis, Dworak grade was associated with RFS (hazard ratio (HR) 0.51, P0.0001; trend analysis) and cancer-specific survival (HR 0.52, P = 0.002). In multivariate analysis, Dworak grade remained an independent predictor of RFS (HR 0.62, P = 0.012), along with clinical metastases stage, resection margin status, the presence or absence of extramural venous invasion and type of surgical procedure.Tumour regression grade after neoadjuvant CRT was an independent prognostic factor for RFS, highlighting the importance of the degree of local response to CRT.

The global landscape of molecular testing is rapidly changing, with the recent publication of the International Association for the Study of Lung Cancer (IASLC)/College of American Pathologists (CAP) guidelines and the ALK Atlas. The IASLC/CAP guidelines recommend that tumors from patients with non-small cell lung cancer (NSCLC) be tested for ALK rearrangements in addition to epidermal growth factor receptor (EGFR) mutations. The spur for this recommendation is the availability of novel therapies that target these rearrangements. This article is based on coverage of a Pfizer-sponsored National Working Group Meeting on ALK Diagnostics in Lung Cancer, held around the 15th World Lung Cancer Conference, in Sydney on October 31, 2013. It is based on the presentations given by the authors at the meeting and the discussion that ensued. The content for this article was discussed and agreed on by the authors.

A woman presenting with recurrent purpura fulminans was eventually found to have inflammatory bowel disease. We suggest the inflammatory state resulted in a deficiency of functional protein C.

Most research into the biology of carcinoma has focused on the epithelial cells therein; the inherent assumption has been that the tumour arises from epithelial cells 'gone bad', and that the surrounding stroma is simply an 'innocent bystander'. However, there is increasing evidence that there is a complex interplay between tumour cells and their surrounding microenvironment, and that the latter may be just as important in determining the development and clinical behaviour of a given tumour. Similarly, traditional oncological practice has been predominantly aimed at a perceived ideal goal of killing all the tumour epithelial cells, with only a few recently developed therapies seeking to affect other components (such as tumour vasculature); but identifying stromal factors involved in tumour growth and survival may well lead to the development of novel therapies. This review examines current understanding of the interplay between tumour epithelial cells and their microenvironment, and enumerates various stromal factors which appear to play a role in tumour progression and/or metastasis.

Gastrointestinal stromal tumour (GiST) is now recognised as the most common mesenchymal malignancy of the gut. With a little experience most cases are fairly easy to diagnose, although some unusual morphological variants exist. But whereas diagnosis is generally quite straightforward, prognostication is more difficult. A variety of risk stratification schemata have been developed, but none is infallible and the pathologist is left with a number of imperfect options for predicting how a particular tumour will behave. The better known of these will be canvassed and some guidance offered as to what information should be included in a comprehensive pathology report. Some other, less common mesenchymal tumours which may at times enter the differential diagnosis of GiST will also be considered.

Neuroendocrine tumours are a diverse group of neoplasms which may arise in many organs and which display variable clinical behaviour. Multiple systems of nomenclature, classification, grading and staging have been proposed for these tumours, leading to confusion and inconsistency in their pathological assessment. In particular, predicting how a given tumour will behave can be difficult; however with increasing options for clinical management, pathologists are coming under increasing pressure to do so. This talk will canvas various proposals for classification and grading of gastroenteropancreatic neuroendocrine tumours (GEP-NETs) and outline some of the issues and challenges raised by these systems, as well as attempt to offer some practical advice on pathological reporting of GEP-NETs.

Introduction Menetrier’s disease (MD) is an uncommon entity characterised by massive foveolar hyperplasia of the gastric mucosa, typically confined to the gastric body and associated with hypoalbuminaemia, and carrying an increased risk of malignancy. Nevertheless, no diagnostic criteria for the disease have been established since Menetrier’s description in 1888, and its aetiology remains unclear. Aims and Methods Gastrectomy specimens from three recent cases of MD with differing clinical presentations were studied and their histopathological and clinical features reviewed. Discussion All three cases showed Menetrier-like features, with florid foveolar hyperplasia, cystic dilation of underlying glands and paucity of inflammation, sometimes including the antrum. No Helicobacter were identified in any of the cases. One patient had intramucosal adenocarcinoma, and another had a long history of ulcerative colitis. Recently, transforming growth factor (TGF) α has been implicated in the genesis of MD. As TGFα shares a receptor with epidermal growth factor, a trial of the EGFR inhibitor cetuximab was attempted in one patient, with limited clinical benefit. Current knowledge of MD will be reviewed, using the three cases to highlight diagnostic and clinical features of this rare disease.