ABSTRACT
Upper tract urothelial carcinoma (UTUC) presents diagnostic challenges due to small biopsy specimen size, poor orientation, and technical obstacles that can yield equivocal diagnoses. This uncertainty often mandates repeated biopsies to evaluate the necessity of nephroureterectomy. Prior studies have suggested cytokeratin 17 (CK17) immunostain as an adjunctive tool for diagnosing bladder urothelial neoplasia in both urine cytology and tissue biopsy specimens. We evaluated the utility of CK17 in differentiating UTUC from benign urothelium and its ability to stratify low-grade from high-grade neoplasia. Our study involved a cohort of previously diagnosed cytology (n = 29) and tissue specimens from biopsies and resections (n = 85). We evaluated CK17 staining percentage in cytology and tissue samples and localization patterns in biopsy/resection samples. Our findings showed a statistically significant distinction (p < 0.05) between UTUC and benign tissue specimens based on full thickness localization pattern (odds ratio 8.8 [95% CI 1.53-67.4]). The percentage of CK17 staining failed to significantly differentiate neoplastic from non-neoplastic cases in cytology or tissue samples. Additionally, based on prior research showing the efficacy of CK20/CD44/p53 triple panel in bladder urothelial neoplasia, we utilized tissue microarrays to evaluate if these markers could distinguish UTUC from benign urothelium. We found that CK20/CD44/p53, individually or in combination, could not distinguish urothelial neoplasia from non-neoplasia. Full thickness CK17 urothelial localization by immunohistochemistry was highly reproducible with excellent interobserver agreement and may play a supplementary role in distinguishing upper tract urothelial neoplasia from benign urothelium.
Subject(s)
Biomarkers, Tumor , Hyaluronan Receptors , Immunohistochemistry , Keratin-17 , Keratin-20 , Tumor Suppressor Protein p53 , Urothelium , Humans , Biomarkers, Tumor/analysis , Biopsy , Carcinoma, Transitional Cell/diagnosis , Carcinoma, Transitional Cell/pathology , Carcinoma, Transitional Cell/metabolism , Diagnosis, Differential , Hyaluronan Receptors/analysis , Hyaluronan Receptors/metabolism , Keratin-17/analysis , Keratin-20/analysis , Keratin-20/metabolism , Neoplasm Grading , Predictive Value of Tests , Reproducibility of Results , Tumor Suppressor Protein p53/analysis , Urinary Bladder Neoplasms/diagnosis , Urinary Bladder Neoplasms/pathology , Urologic Neoplasms/diagnosis , Urologic Neoplasms/pathology , Urothelium/pathology , Urothelium/chemistryABSTRACT
Multicancer early detection tests are precipitating a reexamination of potential short-term endpoints for cancer screening trials. A reduction in advanced stage incidence is a prime candidate, and stage-shift models that substitute early-stage for late-stage survival have been used to predict mortality reduction due to screening. However, standard stage-shift models often ignore prognostic subtypes, effectively implying that cancers detected early also have an associated subtype shift. To illustrate the differences between mortality predictions from stage-shift models that ignore versus preserve prognostic subtype, we use ovarian cancer partitioned by histologic subtype and prostate cancer partitioned by grade. We infer general conditions under which stage-shift models that preserve prognostic subtype are likely to predict mortality reductions that differ from those that ignore subtype and examine the implications for short-term endpoints based on stage in cancer screening trials.
Subject(s)
Ovarian Neoplasms , Prostatic Neoplasms , Male , Female , Humans , Early Detection of Cancer , Prognosis , Ovarian Neoplasms/pathology , Prostatic Neoplasms/diagnosis , IncidenceABSTRACT
BACKGROUND: Disease-specific mortality is a consensus endpoint in cancer screening trials. New liquid biopsy-based screening tests, including multi-cancer early detection (MCED) tests, are creating a need to reduce the typically lengthy screening trial process. Endpoints based on the reduction in late-stage disease (stage shift) have been proposed but it is unclear how well they predict the impact of screening on disease-specific mortality across a variety of cancers potentially detectable by MCED tests. METHODS: We develop a mathematical formulation relating the reduction in late-stage cancer to the expected reduction in disease-specific mortality if cases diagnosed early via screening receive a corresponding shift in mortality. We investigate the similarity between the expected mortality reduction and the observed mortality reduction in published trials of screening for breast, lung, ovarian, and prostate cancer. RESULTS: The expected mortality reduction for a given stage shift varies significantly depending on cancer- and stage-specific survival distributions, with some cancer types showing little possibility for mortality improvement even under substantial stage shift. The expected mortality reduction fails to consistently match the mortality outcomes of published trials. CONCLUSIONS: In MCED, any mortality benefit is likely to vary substantially across target cancers. Stage shift does not appear to be a reliable basis for inference about mortality reduction across cancers potentially detectable by MCED tests. IMPACT: Stage shift may be an appealing endpoint for evaluation of cancer screening tests but it appears to be an unreliable predictor of mortality benefit; furthermore, the same stage shift can mean different things for different cancers.
