Role of Immunohistochemistry in Suspected Pancreatic Ductal Adenocarcinoma: A Prospective Study on Fine Needle Aspiration Biopsies.

OBJECTIVES: Differential diagnosis between pancreatic ductal adenocarcinoma (PDAC) and benign mimickers can be very difficult on small histological samples, such as fine needle aspiration biopsies (FNAB). We aimed to investigate the diagnostic value of immunostaining for IMP3, Maspin, S100A4, S100P, TFF2, and TFF3 in FNAB pancreatic lesions. METHODS: We prospectively enrolled 20 consecutive patients with suspected PDAC, collecting FNABs at our department between 2019 and 2021. RESULTS: Three of the 20 enrolled patients resulted negative for all immunohistochemical markers, while all the others were positive for Maspin. All other immunohistochemistry (IHC) markers had sensitivity and accuracy of less than 100%. On the basis of the IHC, the preoperative diagnosis on FNAB was nonmalignant lesions in the IHC negative cases and PDAC in the others. All patients subsequently underwent surgery for the pancreatic solid mass demonstrated by imaging techniques. The concordance between the preoperative and postoperative diagnosis was 100%; all IHC negative samples were diagnosed on surgical specimens as chronic pancreatitis and Maspin-positive samples as PDAC. CONCLUSIONS: Our results demonstrate that even in the presence of little histological material, such as FNAB, the use of Maspin alone is sufficient to discriminate between PDAC and nonmalignant pancreatic lesions, with 100% accuracy.

RAS-expanded Mutations and HER2 Expression in Metastatic Colorectal Cancer: A New Step of Precision Medicine.

Cetuximab and panitumumab monoclonal antibodies are a milestone in the history of treatment of metastatic colorectal cancer (mCRC) and point toward future directions for personalized treatment. Recent studies have shown that broader RAS testing is needed to select patients for targeted therapy. The objectives of our study were to identify the prevalence of RAS mutations and evaluate human epidermal growth factor receptor 2 (HER2) expression in KRAS exon 2 wild-type (WT) mCRC patients, correlating the findings with objective response rate, progression-free survival, and overall survival. In total, 29 mCRC patients undergoing treatment with cetuximab therapy were enrolled in this study. By pyrosequencing, mutations were found in 17% of nonresponder patients, in KRAS codon 146 and NRAS codon 12. HER2 positivity was limited to only 1 responder carcinoma specimen. There was no correlation between RAS mutation, HER2/neu expression, and clinicopathologic findings. We highlighted significantly the differences between objective response rate and RAS gene status. The overall survival and progression-free survival of RAS WT patients were higher compared with those with RAS-mutated disease. Clinical response to cetuximab therapy is impaired in the presence of RAS-expanded mutations. In fact, our finding of 5 mutations in RAS-expanded genes allowed us to understand the resistance to cetuximab in 33% of KRAS WT exon 2 nonresponder patients. HER2 does not seem to be a potential biomarker for cetuximab-targeted therapy. These analyses suggest that the assessment of other biomarkers is needed to determine the best treatment for patients with mCRC, to maximize benefit and minimize harm.

Characterization of a rare variant (c.2635-2A>G) of the MSH2 gene in a family with Lynch syndrome.

INTRODUCTION: Lynch syndrome is caused by germline mutations in one of the mismatch repair genes ( MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. Lynch syndrome is defined on the basis of clinical, pathological, and genetic findings. Accordingly, the identification of predisposing genes allows for accurate risk assessment and tailored screening protocols. CASE DESCRIPTION: Here, we report a family case with three family members manifesting the Lynch syndrome phenotype, all of which harbor the rare variant c.2635-2A>G affecting the splice site consensus sequence of intron 15 of the MSH2 gene. This mutation was previously described only in one family with Lynch syndrome, in which mismatch repair protein expression in tumor tissues was not assessed. In this study, we report for the first time the molecular characterization of the MSH2 c.2635-2A>G variant through in silico prediction analysis, microsatellite instability, and mismatch repair protein expression experiments on tumor tissues of Lynch syndrome patients. The potential effect of the splice site variant was revealed by three splicing prediction bioinformatics tools, which suggested the generation of a new cryptic splicing site. The potential pathogenic role of this variant was also revealed by the presence of microsatellite instability and the absence of MSH2/MSH6 heterodimer protein expression in the tumor cells of cancer tissues of the affected family members. CONCLUSIONS: We provide compelling evidence in favor of the pathogenic role of the MSH2 variant c.2635-2A>G, which could induce an alteration of the canonical splice site and consequently an aberrant form of the protein product (MSH2).