Changing pathology with changing drugs: tumors of the gastrointestinal tract

Gastrointestinal cancer treatment is being based more and more on pathology that yields integrated information leading to targeted therapy, i.e. morphological identification of the histological type of the tumor and its context, staging of the tumor, and identification of various targets. This provides a realistic appraisal of the tumor and allows surgeons and oncologists to choose the best treatment from an increased range of drug options. An accurate diagnosis remains the major determinant of treatment, but new drugs and new insights into molecular pathways acting in carcinogenesis enhance molecular diagnosis in cancer. In most adenocarcinomas, therapy is only organ orientated and staging dependent, and not patient targeted. Currently, the identification and validation of new targets as well as molecular classification of the tumors are inducing the incorporation of new tests into the daily practice of surgical pathology. These new tests require appropriate tissue preservation and selection of the tissue to be analyzed and harmonized to morphological criteria. In colorectal adenocarcinoma, which is the second most common malignant tumor in both genders, the biomarkers that are relevant at the present time are the genetic instability status of the tumor, the KRAS mutation status as a negative predictive marker for the overall rate of response to anti-EGFR treatment in patients with metastatic cancer, and BRAF mutation as an unfavorable prognostic marker. In gastric adenocarcinoma, HER2 overexpression is correlated with poor outcomes and more aggressive disease in a subset of cases with clinical response to trastuzumab. Met mutations have also been evidenced. Hepatocellular carcinoma is a highly chemoresistant tumor with several genetic alterations. Pancreatic adenocarcinoma is a leading cause of cancer death with frequent KRAS mutations. No biomarker has been clearly identified in either of these tumors. Gastrointestinal stromal tumors that constitute less than 3% of all gastrointestinal malignancies have been individualized since 1988. They express the KIT protein, a membrane receptor, and respond to imatinib which is a tyrosine kinase receptor inhibitor, depending on the mutational status of the tumor.