Clinical significance of urothelial carcinoma ambiguous for muscularis propria invasion on initial transurethral resection of bladder tumor.

PURPOSE: To evaluate the clinical significance of invasive urothelial carcinoma that is ambiguous for muscularis propria invasion on initial transurethral resection of bladder tumor (TURBT). METHODS: All consecutive in-house TURBTs with invasive urothelial carcinoma from 1999 to 2017 that underwent radical cystectomy (RC) were grouped as follows: invasion of the lamina propria (INLP; n = 102; 24%), invasion of muscularis propria (INMP; n = 296; 69%) and ambiguous for muscularis propria invasion (AMP; n = 30; 7%). AMP was defined as extensive invasive carcinoma displaying thin muscle bundles where it is difficult to determine with certainty if those muscle bundles represent muscularis mucosae or muscularis propria (detrusor). Cases with any amount of small cell carcinoma or prior therapy were excluded. RESULTS: The average age was 66 years in INLP, 67 years in INMP, and 65 years in AMP. RC showed invasive carcinoma stage pT2 or above in 50/102 (49%) of INLP vs. 255/296 (86%) of INMP (P ≤ 001) vs. 25/30 (83.33%) of AMP (P = 0.002). Lymph nodes showed metastatic carcinoma in 18/98 (18.36%) of INLP vs. 96/272 (35.29%) of INMP (P = 0.002), and 6/25 (24%) in AMP (P = 0.729). The average follow-up was 48 months (range 0-192). Survival of AMP patients was similar to INLP and both were significantly better than INMP (P = 0.002 and P = 0.016). CONCLUSION: The great majority of patients with AMP on initial TURBT have advanced disease on RC and emphasizes the need for early repeat TURBT or even consideration of early cystectomy to lower the risk of worse pathological findings and to prolong survival.

Expression of PD-L1, indoleamine 2,3-dioxygenase and the immune microenvironment in gastric adenocarcinoma.

AIMS: The tumour microenvironment is increasingly important in several tumours. We studied the relationship of key players of immune microenvironment with clinicopathological parameters in gastric adenocarcinomas. METHODS AND RESULTS: Tissue microarrays were constructed from gastrectomy specimens, 2004-13. Immunohistochemistry was performed for programmed cell death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), tryptophanyl-tRNA synthetase (WARS), guanylate-binding protein 5 (GBP5), tumour-infiltrating lymphocytes (TIL) expressing CD3/CD8/FoxP3/PD1 and mismatch repair proteins (MMRs) MLH1, PMS2, MSH2 and MSH6. Clinicopathological parameters and clinical follow-up were recorded. The study included 86 patients; median follow-up was 34 months (0-148). Tumour types were 45% tubular, 38% diffuse, 17% mixed. PD-L1 was positive in 70%, epithelial IDO in 58%, stromal IDO in 91%, epithelial WARS in 67%, stromal WARS in 100%, epithelial GBP5 in 53% and stromal GBP5 in 71%. MMR-deficiency was found in 22%. There was no difference in biomarker expression by histological subtype, with the exception of fewer diffuse-type being MMR-deficient. Low stromal IDO was associated with decreased progression-free, overall and disease-specific survival. PD-L1-positive tumours were larger with MMR-deficiency and with increasing TILs, and had significantly higher FoxP3TILs. CONCLUSIONS: PD-L1 is expressed in a large proportion of gastric carcinomas, suggesting that therapy targeting this pathway could be relevant to many patients. PD-L1 expression and MMR-deficiency are associated with increased TILs and larger tumour size, emphasising their role in tumour biology. Higher stromal IDO expression is associated with better prognosis. Finally, we observed that immune modulators WARS and GBP5 are expressed highly in gastric adenocarcinomas, suggesting an important role in tumour pathobiology.

Clinicopathologic and gene expression analysis of initial biopsies from patients with eosinophilic esophagitis refractory to therapy.

Some patients with eosinophilic esophagitis (EoE) do not respond to therapy. The clinicopathologic characteristics and gene expression profile at time of presentation could help predict response to therapy. Refractory EoE was defined as persistence of symptoms and biopsies with histologic features of EoE after 6 months of therapy with proton pump inhibitors and topical corticosteroids. Initial biopsies from refractory EoE patients (n=21), responder to therapy (n=8), patients who relapsed (n=6), and reflux controls (n=24) were studied. RNA was isolated from a subset of cases, and gene expression analysis of 285 genes involved in inflammation was performed using NanoString technology. There was no difference in the presenting symptoms among groups. The number of eosinophils/high-power field among nonresponders was higher (66±15) than responders (39±8; P<.0001) and similar to patients who relapsed (62±11). Six genes were expressed by at least 4-fold compared with reflux at a false discovery rate < 0.05, including overexpression of ALOX15, CCL26, FCER2, RTNLB, and RNASE2, and underexpression of DSG1. EoE patients refractory to therapy or who relapsed showed a trend toward higher ALOX15 expression compared with patients with good response to therapy (364.4- and 425-fold change, P=.097 and P=.07). RTNLB was significantly overexpressed in patients who were refractory to therapy versus those who responded favorably (10-fold versus 3-fold; P<.01). In conclusion, the number of eosinophils/high-power field in the initial biopsy inversely correlates with therapy response. Overexpression of RTNLB in refractory-to-therapy patients and overexpression of ALOX15 and CCL26 suggest that they are critical in the EoE pathogenesis.