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The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named ‘Immunoscore’ has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune). © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Pancreas cancer (PC), a highly aggressive tumour type with uniformly poor prognosis, is an exemplar of the classical view of cancer development based on stepwise progression1. The current progression model, based on analyses of precursor lesions termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: 1) PC develops through a particular sequence of genetic alterations2–5 (KRAS > CDKN2A > TP53/SMAD4); and 2) the evolutionary trajectory of PC progression is gradual because each alteration is acquired independently. One shortcoming of this nearly two decade old contention is that clonally expanded precursor lesions have been identified that do not always belong to the tumour lineage2,5–9, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing view of tumourigenesis has contributed to the clinical notion that PC evolves slowly and presents at a late stage10. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes despite efforts aimed at early detection11, argue that PC progression is anything but gradual. By tracking DNA copy number changes and their associated rearrangements from tumour-enriched genomes using novel informatics tools, we found that PC tumourigenesis neither is gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory12. In a subset of cases, the consequence of such errors was the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that likely set-off invasive cancer growth. These findings challenge the current model of PC tumourigenesis and provide novel insights into the mutational processes giving rise to these aggressive tumours.

Graphical Abstract Highlights d Higher cell cycle progression in PDAC metastases; increases with driver gene loss d Half of PDACs are hypoxic and are associated with subtypes and treatment response d Paired tumors show molecular conservation and Halstedian progression d Multiple PDACs arising in the same pancreas are intraparenchymal metastases In Brief Connor et al. molecularly characterize primary and metastatic PDAC and show conserved alterations between primary and metastatic lesions. Clinical features outperform molecular alterations in survival analyses, but cell cycle progression and hypoxia signatures may inform clinical practice. SUMMARYWe integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Paired tumor heterogeneity showed cancer cell migration by Halstedian progression. Multiple PDACs arising synchronously and metachronously in the same pancreas were actually intra-parenchymal metastases, not independent primary tumors. Established clinical co-variates dominated survival analyses, although CCP and hypoxia may inform clinical practice. SignificancePancreatic ductal adenocarcinoma has dismal prognosis due to rapid metastatic dissemination. This rigorous study of paired and unpaired tumors informs both progression mechanisms and therapy. First, there was no evidence of discrete metastases enabling genes. Second, greater CCP in metastases may explain aggressive behavior and correspond to treatment response. Third, hypoxia signature was associated with chemotherapy resistance. Fourth, comparing mutations in paired samples revealed sequential progression from primary to lymph node to distant metastases, and sequencing synchronous and metachronous lesions distinguished these as recurrences rather than separate primaries, resolving this clinical conundrum. Finally, clinical features outperformed and were independent of molecular alterations in survival analyses, implying greater insight is needed before molecular profiling broadly informs therapy.