Antigen Processing Machinery Alterations in Bladder Carcinoma: A Tissue Microarray Study of 167 Cases
HP Cathro, ME Smolkin, D Theodoresceau, VY Jo, S Ferrone, HF Frierson. University of Virgina, Charlottesville; University of Pittsburgh, Pittsburgh
Background: T-lymphocytes may be important in controlling the growth of many carcinomas including bladder carcinoma. Tumors may avoid detection and destruction by down-regulating antigen processing machinery (APM) proteins. The aim of this study is to investigate defects in APM using a comprehensive panel of monoclonal antibodies.
Design: Paraffin blocks from 167 cystectomies for primary bladder carcinoma were used to create a tissue microarray. Immunohistochemistry was performed for 15 APM components, (2-microglobulin, calnexin, calreticulin, Delta, Z, MB1, LMP2, LMP7, MICA, LMP10, HLA Class I, tapasin, TAP1, TAP2 and ERp57). Full sections of normal urothelium from 6 subjects were also examined. Most tumors were urothelial carcinoma (n=152); the remainder were mixed urothelial or other types of bladder carcinoma. 58 tumors were Stage I/II and 105 were Stage III/IV. Survival data were available for 128 patients with pure urothelial carcinoma; of these 28 were Grade 1/2, 83 were Grade 3 and 17 were Grade 4.
Results: Delta, MB1, Z, LMP2 and LMP7 had high staining scores in superficial and deeper layers of normal urothelium, with calreticulin high in superficial urothelium alone. All APM components except MB1, LMP2 and TAP2, had significantly lower staining in urothelial carcinoma than in either superficial or deeper urothelium, or both. No significant differences were found in APM staining between different grades of urothelial carcinoma. Squamous cell carcinoma had the highest APM scores, with urothelial carcinoma intermediate and other types of bladder carcinoma lowest. High-stage urothelial carcinoma demonstrated significantly lower staining for calnexin, LMP2, LMP7 and LMP10. On average 3.6 year follow-up, significant survival differences were associated with the Delta score in urothelial carcinoma (p=0.0369) and the calreticulin score in all tumor types (p=0.0267).
Conclusions: With a few exceptions, both superficial and deep normal urothelial layers have relatively low APM component staining. High-stage urothelial carcinomas have lower scores for APM immunoproteasome components compared with low-stage urothelial carcinomas. Delta and calreticulin staining scores are associated with survival differences in urothelial carcinoma and in all types of bladder carcinoma respectively. These findings delineate specific defects in APM proteins and may provide insight to guide future immunotherapeutic approaches for controlling bladder malignancies.
Category: Genitourinary (including renal tumors)
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 147, Tuesday Afternoon