Dataset for reporting of gastrointestinal stromal tumours: recommendations from the International Collaboration on Cancer Reporting (ICCR).

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).

Datasets for reporting of soft-tissue sarcoma: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: Soft-tissue tumours are rare and both accurate diagnosis and proper treatment represent a global challenge. Current treatment guidelines also recommend review by specialised pathologists. Here we report on international consensus-based datasets for the pathology reporting of biopsy and resection specimens of soft-tissue sarcomas. The datasets were produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of international pathology and cancer organisations. METHODS AND RESULTS: According to the ICCR's guidelines for dataset development, 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 subspecialised soft-tissue sarcoma experts and affiliated with tertiary referral centres. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the documents were finalised and ratified, and the datasets, which included a synoptic reporting guide, were published on the ICCR website. CONCLUSION: These first international datasets for soft-tissue sarcomas are aimed to promote high-quality, standardised pathology reporting. Their adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve patient's management.

Looking beyond workforce parity: addressing gender inequity in pathology.

While women pathologists have made up over one-third of pathologists in the Australian workforce for over 15 years and at least 50% since 2019, they are under-represented in senior leadership roles, scientific publications, grant recipients, editorial boards, key presentations, and professional awards. This is not unique to pathology and is seen in the broader medical and academic community. Barriers to gender equity and equality in pathology, medicine and academia include gender stereotypes, gender-based discrimination, structural and organisational barriers as well as broader social and cultural barriers. A diverse leadership reflective of the whole professional body and the broader community is important for optimal health outcomes. It is the responsibility and moral duty of individuals and organisations to address any gender disparities, inequities, and inequalities by monitoring, identifying, and acting on gender biases and systemic barriers that hinder appropriate levels of representation by women.

Pathological assessment of tumour regression following neoadjuvant therapy in pancreatic carcinoma.

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.

Neoadjuvant chemoradiotherapy for rectal cancer: how important is tumour regression?

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.

Tumour-infiltrating regulatory T cell density before neoadjuvant chemoradiotherapy for rectal cancer does not predict treatment response.

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.

The changing face of GIST: implications for pathologists.

Gastrointestinal stromal tumour (GIST) is now recognised as the most common primary mesenchymal tumour of the gut. A number of different parameters have been identified to aid prediction of clinical behaviour, but prognostication for an individual remains difficult. The pathologist plays a crucial role in guiding management of these tumours, but is faced with a number of challenges in so doing. This review describes the variable pathological features that may be encountered, and examines some of the issues in the pathology reporting of GIST and attempts to provide some guidance in factors that should be addressed in a comprehensive pathology report.

Personalising pancreas cancer treatment: When tissue is the issue.

The treatment of advanced pancreatic cancer has not moved much beyond single agent gemcitabine until recently when protocols such as FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) and nab-paclitaxel-gemcitabine have demonstrated some improved outcomes. Advances in technology especially in massively parallel genome sequencing has progressed our understanding of the biology of pancreatic cancer especially the candidate signalling pathways that are involved in tumourogenesis and disease course. This has allowed identification of potentially actionable mutations that may be targeted by new biological agents. The heterogeneity of pancreatic cancer makes tumour tissue collection important with the aim of being able to personalise therapies for the individual as opposed to a one size fits all approach to treatment of the condition. This paper reviews the developments in this area of translational research and the ongoing clinical studies that will attempt to move this into the everyday oncology practice.

National Working Group Meeting on ALK diagnostics in lung cancer.

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.

Is carcinoma a mesenchymal disease? The role of the stromal microenvironment in carcinogenesis.

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.

Optimising the management of soft tissue tumours.

The Royal College of Pathologists of Australasia is developing a series of protocols as an educational tool to assist pathologists in the reporting of relevant information for specific cancer specimens. The protocol for the management of soft tissue tumour resections has recently been released, and this document elaborates the relevant literature on which that protocol drew. Sarcoma is uncommon but is associated with significant morbidity and mortality, and its management is complex. Diagnostic errors are not uncommon and these can have disastrous effects on patient outcome. Sophisticated ancillary testing is often an important adjunct to diagnosis and prognostication. Referral to a specialist sarcoma unit is indicated for both adult and paediatric sarcoma.

The elaboration of a critical framework for understanding cancer: the cancer stem cell hypothesis.

The cancer stem cell hypothesis suggests that malignant tumours may arise from a limited number of specialised cells possessing the key 'stem' properties of self-renewal and the ability to produce differentiated progeny. Such cells purportedly constitute a small fraction of most tumours but have greater potential to produce new tumours than their 'non-stem' counterparts. However, they have proven difficult to identify and characterise in most malignancies. Cancer stem cells are liable to be resistant to most forms of conventional chemotherapy and radiation and so may help to explain tumour recurrence after a seemingly good response to initial therapy. This review examines the evidence for the existence of such cells, the therapeutic implications of this hypothesis, and problems posed by it, as well as outlining the concept of the stem cell niche and its possible role in tumour development and progression.

Immunohistochemical expression of EGFR in colorectal carcinoma correlates with high but not low level gene amplification, as demonstrated by CISH.

AIM: To assess and compare immunohistochemical expression of epidermal growth factor receptor (EGFR) with gene amplification as demonstrated by chromogenic in situ hybridisation (CISH), in colorectal adenocarcinoma. METHODS: Sections from 100 consecutive colorectal cancer resection specimens were stained for EGFR using immunohistochemistry and CISH. Immunohistochemical assessment was independently performed at two laboratories, using the same antibody and protocols. RESULTS: With immunohistochemistry, strong circumferential membrane staining (3+ staining) was demonstrated in only 5% of cases, and this was only focal in three of five cases. At one laboratory, weak or incomplete staining (1+ or 2+) was observed in five further cases (5%), which had been negative at the other laboratory. CISH demonstrated high level gene amplification (>10 copies/nucleus) in the same five cases which had demonstrated 3+ staining with immunohistochemistry, and in those cases where the staining was focal, the amplification was demonstrated in the same foci of the tumour. Five further cases (5%) had low level amplification (5-10 copies per nucleus); these cases did not exhibit significant positive staining with immunohistochemistry. All the cases which demonstrated gene amplification (high or low level) arose in the distal colon. There was no correlation between gene amplification status and a variety of other variables, including stage at diagnosis, mucinous differentiation, neuroendocrine differentiation, or loss of expression of mismatch repair proteins. CONCLUSIONS: Immunohistochemical expression of EGFR is variable between laboratories, even using standardised protocols. 3+ staining is predictive of high level gene amplification, but correlates very poorly with low level amplification, which may still be clinically significant. In some cases gene amplification was only focal, offering a potential explanation for poor response to targeted therapy in patients with EGFR positive tumours.