Epstein-Barr virus positivity (EBV(+)) and high-microsatellite instability (MSI-H) have been identified as molecular subgroups in gastric carcinoma. The aim of our study was to determine the prognostic and predictive relevance of these subgroups in the context of platinum/5-fluorouracil (5-FU) based preoperative chemotherapy (CTx). Additionally, we investigated the clinical relevance of the low-MSI (MSI-L) phenotype. We analysed 760 adenocarcinomas of the stomach or the gastro-oesophageal junction encompassing 143 biopsies before CTx and 617 resected tumours (291 without and 326 after CTx). EBV was determined by PCR and in situ hybridisation for selected cases. MSI was analysed by PCR using five microsatellite markers and classified as MSI-H and MSI-L. Frequencies of EBV(+), MSI-H and MSI-L in the biopsies before CTx were 4.2, 10.5 and 4.9% respectively. EBV(+) or MSI-H did not correlate with response, but MSI-L was associated with better response (p = 0.011). In the resected tumours, frequencies of EBV(+), MSI-H and MSI-L were 3.9, 9.6 and 4.5% respectively. Overall survival (OS) was significantly different in the non-CTx group (p = 0.014). Patients with EBV(+) tumours showed the best OS, followed by MSI-H. MSI-L was significantly associated with worse OS (hazard ratio [HR], 2.21; 95% confidence interval [CI], 1.21-4.04, p = 0.01). In the resected tumours after CTx, MSI-H was also associated with increased OS (HR, 0.54; 95% CI, 0.26-1.09, p = 0.085). In multivariable analysis, molecular classification was an independent prognostic factor in the completely resected (R0) non-CTx group (p = 0.035).In conclusion, MSI-H and EBV(+) are not predictive of response to neoadjuvant platinum/5-FU based CTx, but they are indicative of a good prognosis. In particular, MSI-H indicates a favourable prognosis irrespective of treatment with CTx. MSI-L predicts good response to CTx and its negative prognostic effect for patients treated with surgery alone suggests that MSI-L might help to identify patients with potentially high-benefit from preoperative CTx.

Background:Recently, histopathological tumour regression, prevalence of signet ring cells, and localisation were reported as prognostic factors in neoadjuvantly treated oesophagogastric (junctional and gastric) cancer. This exploratory retrospective study analyses independent prognostic factors within a large patient cohort after preoperative chemotherapy including clinical and histopathological factors.Methods:In all, 850 patients presenting with oesophagogastric cancer staged cT3/4 Nany cM0/x were treated with neoadjuvant chemotherapy followed by resection in two academic centres. Patient data were documented in a prospective database and retrospectively analysed.Results:Of all factors prognostic on univariate analysis, only clinical response, complications, ypTNM stage, and R category were independently prognostic (P<0.01) on multivariate analysis. Tumour localisation and signet ring cells were independently prognostic only when investigator-dependent clinical response evaluation was excluded from the multivariate model. Histopathological tumour regression correlates with tumour grading, Laurén classification, clinical response, ypT, ypN, and R categories but was not identified as an independent prognostic factor. Within R0-resected patients only surgical complications and ypTNM stage were independent prognostic factors.Conclusions:Only established prognostic factors like ypTNM stage, R category, and complications were identified as independent prognostic factors in resected patients after neoadjuvant chemotherapy. In contrast, histopathological tumour regression was not found as an independent prognostic marker.

No abstract

Recently, we discovered the recurrent genomic rearrangement [t(4;9)(q13;q31)] enabling upregulation of the transcription factor Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) through enhancer hijacking as the oncogenic driver event in acinic cell carcinoma (AciCC) of the salivary glands. In the current study, we evaluated the usefulness of NR4A3 immunostaining and NR4A3 fluorescence in situ hybridization (FISH) in the differential diagnosis of AciCC, comparing a total of 64 AciCCs including 17% cases with high-grade transformation, 29 secretory (mammary analog) carcinomas (MASC), and 70 other salivary gland carcinomas. Nuclear NR4A3 immunostaining was a highly specific (100%) and sensitive (98%) marker for AciCC with only 1 negative case, whereas NR4A3 FISH was less sensitive (84%). None of the MASCs or other salivary gland carcinomas displayed any nuclear NR4A3 immunostaining. The recently described HTN3-MSANTD3 gene fusion was observed in 4 of 49 (8%) evaluable AciCCs, all with nuclear NR4A3 immunostaining. In summary, NR4A3 immunostaining is a highly specific and sensitive marker for AciCC, which may be especially valuable in cases with high-grade transformation and in “zymogen granule”-poor examples within the differential diagnostic spectrum of AciCC and MASC.