Predictive and prognostic biomarkers in gastrointestinal tract tumours.

Tumours of the gastrointestinal tract represent nearly a quarter of all newly diagnosed tumours diagnosed in 2019. Various treatment modalities for gastrointestinal cancers exist, some of which may be guided by biomarkers. Biomarkers act as gauges of either normal or pathogenic processes or responses to an exposure or intervention. They come in many forms. This review explores established and potential molecular/immunohistochemical (IHC) predictive and prognostic biomarkers of the gastrointestinal tract.

Gene of the month: PALB2.

The partner and localiser of BRCA2 (PALB2) gene, located on chromosome 16, functions as a tumour suppressor that plays a critical role in homologous recombination repair after DNA double-strand breaks. It encodes proteins involved in the BRCA2 and BRCA1, and RAD51 pathways. Heterozygous germline mutations in PALB2 have been implicated in the development of breast, pancreatic and ovarian cancers. Whereas biallelic mutations of PALB2 have been associated with Fanconi anaaemia. Currently, 604 distinct PALB2 variants have been discovered. However, only 140 variants are thought to be pathogenic and approximately 400 are variants of unknown significance. Further studies are needed before the presence of PLAB2 mutations can be implemented as a routine clinical biomarker.

Clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma.

OBJECTIVE: To describe the clinical, pathological and genomic characteristics of pancreatic cancer with DNA mismatch repair deficiency (MMRD) and proficiency (MMRP). DESIGN: We identified patients with MMRD and MMRP pancreatic cancer in a clinical cohort (N=1213, 519 with genetic testing, 53 with immunohistochemistry (IHC)) and a genomic cohort (N=288 with whole-genome sequencing (WGS)). RESULTS: 12 out of 1213 (1.0%) in the clinical cohort were MMRD by IHC or WGS. Of the 14 patients with Lynch syndrome, 3 (21.4%) had an MMRP pancreatic cancer by IHC, and 4 (28.6%) were excluded because tissue was unavailable for testing. MMRD cancers had longer overall survival after surgery (weighted HR after coarsened exact matching 0.11, 95% CI 0.02 to 0.78, p=0.001). One patient with an unresectable MMRD cancer has an ongoing partial response 3 years after starting treatment with PD-L1/CTLA-4 inhibition. This tumour showed none of the classical histopathological features of MMRD. 9 out of 288 (3.1%) tumours with WGS were MMRD. Despite markedly higher tumour mutational burden and neoantigen loads, MMRD cancers were significantly less likely to have mutations in usual pancreatic cancer driver genes like KRAS and SMAD4, but more likely to have mutations in genes that drive cancers with microsatellite instability like ACV2RA and JAK1. MMRD tumours were significantly more likely to have a basal-like transcriptional programme and elevated transcriptional markers of immunogenicity. CONCLUSIONS: MMRD pancreatic cancers have distinct clinical, pathological and genomic profiles. Patients with MMRD pancreatic cancer should be considered for basket trials targeting enhanced immunogenicity or the unique genomic drivers in these malignancies.

SWI/SNF-deficient cancers of the Gastroenteropancreatic tract: an in-depth review of the literature and pathology.

The SWItch Sucrose non-fermentable (SWI/SNF) complex is a large, multi-subunit ATP-dependent nucleosome remodeling complex that acts as a tumor suppressor by modulating transcription. Mutations of SWI/SNF subunits have been described in relation to developmental disorders, hereditary SWI/SNF deficiency syndromes, as well as malignancies. In this review we summarize the current literature in regards to SWI/SNF-deficient tumors of the luminal gastrointestinal tract (GIT) and pancreas. As a group they range from moderately to undifferentiated tumors composed of monotonous anaplastic cells, prominent macronucleoli and a variable rhabdoid cell component. Deficiency of a SWI/SNF subunit is typified by complete loss of nuclear staining by immunohistochemistry for respective subunit.

Review of pathology and cost benefit analysis of hernia sacs processed over a 19-year period.

AIM: Hernia sacs with pathological evaluation over a 19-year period were analysed with regards to pathological diagnoses, full costing and the impact on patient management. MATERIALS AND METHODS: The database of the Department of Pathology were searched over the study period (2001 to 2019 inclusive) for hernia sacs. The total cost of complete pathology examination was calculated on average numbers and rates of pay that existed over the study period. RESULTS: A total of 3619 hernia sacs from the abdominal, hiatus/diaphragmatic, inguinal and femoral hernias were retrieved. Of these 3592 cases (99.25%) had sections taken for histological evaluation. A total of 3437 cases representing 95.7% of all hernia sacs did not show any pathological abnormality. If non-neoplastic clinically insignificant lesions seen in hernia sacs is included, then 3552 of 3592 (98.9%) hernia sacs underwent full pathological evaluation for no patient benefit.On average two blocks or tissue sections per case were processed incurring a technical cost of $53 175.00. The total pathologist cost in reporting the 3592 cases was approximately $39 870.00 and rose to $40 410.00 when interpretation of ancillary tests was factored in. $95 328.90 (average $26.90 per specimen with a yearly average total cost of $5 017.31) was spent over the 19-year period in full pathological examination of 3592 hernia sacs. CONCLUSION: Given the low return on investment and the difficult to quantify time savings and reallocation, we do not advocate the routine sampling of hernia sacs. Gross examination will suffice in 99% of the cases. Selective cases may be sampled if clinically indicated.