Histologic Grading of Noninvasive Papillary Urothelial Tumors
Histologic Grading of Noninvasive Papillary Urothelial Tumors
Cytokeratin (CK) 20, Ki-67, and p53 were applied to 84 noninvasive papillary urothelial tumors graded by the 1973 World Health Organization (WHO) and 1998 WHO/International Society of Urological Pathology (ISUP) systems. In the WHO/ISUP classification, all benign lesions showed normal CK20 staining and all carcinomas showed abnormal staining. The Ki-67 index was significantly different between benign and malignant lesions (P < .05) and between low- and high-grade carcinomas (P < .001). p53 was negative in all benign lesions, with a significant difference between low- and high-grade carcinomas (P < .001). Tumor recurrence was significantly different between low- and high-grade carcinomas (no recurrences among the papillary urothelial neoplasms of low malignant potential). By the 1973 WHO classification, normal CK20 staining was present both in benign lesions and in carcinomas. Ki-67 staining did not distinguish between grade 2 and grade 3 carcinomas (P > .05), and there was no difference in p53 staining in grades 1 and 2 carcinomas (P > .05). Recurrences were not different between grades 1, 2, and 3 carcinomas. All biologic markers studied and tumor recurrences were significantly different among papillary lesions classified by the WHO/ISUP system but not by the 1973 WHO system, validating the predictive value of the WHO/ISUP system and providing objective markers for the grading of papillary urothelial tumors.
Tumor stage is the best predictor of clinical outcome in urothelial neoplasms; however, the prognosis of patients with noninvasive papillary urothelial tumors is influenced largely by the pathologic grade of the initial tumor. Grading systems proposed for papillary carcinomas of the bladder include 2-, 3-, 4-, and 5-tiered systems. Complex systems can provide the most data but might be less reproducible and difficult to implement in routine practice. Simple systems with fewer categories are the easiest to learn and use but convey less information. The best grading system should be not only easy to apply but also able to divide tumors into groups with different biologic characteristics that correlate with different clinical outcomes.
A number of classification systems for the grading of papillary urothelial neoplasms of the bladder have been introduced, but despite the absence of detailed defining criteria, the 1973 World Health Organization (WHO) classification has remained widely used ( Table 1 ). In 1998, the WHO/International Society of Urological Pathology (ISUP) consensus classification was developed in an effort to reach a universally acceptable system. Noninvasive papillary urothelial tumors essentially were divided into 4 groups, namely, papilloma, papillary urothelial neoplasm of low malignant potential (LMP), low-grade carcinoma (LGC), and high-grade (HGC) carcinoma ( Table 1 ). However, several authors have argued that the prognostic value of this classification is limited, reproducibility is worse than the widely used 1973 WHO system, and the new entity, LMP, showed increased risk of local recurrence, progression, and death due to the tumor.
One method used by pathologists to test the validity of a classification system is to compare tumor recurrence and progression or survival of patients between the different prognostic groups. Papillary urothelial tumors tend to recur. Some tumors recur within a short period, and others recur after a long period. Recurrences of papilloma have been reported in as many as 50% of cases if follow-up is long enough. As such, long-term follow-up for recurrences does not actually differentiate different prognostic groups. It would be predictable for high-grade tumors mostly to recur early and low-grade tumors to recur late. In the present study, we adopted this premise and set the cutoff at 36 months for comparison of recurrent rates between the different tumor grades.
In normal urothelium, the expression of cytokeratin (CK) 20 is related to differentiation and is limited to superficial and occasional intermediate cells. Abnormalities of urothelial differentiation are accompanied by loss of this restriction so that the immunoexpression of CK20 is seen in deeper cell layers or in all layers. Tumors with normal CK20 staining have shown no recurrences, whereas those with abnormal staining developed recurrences, suggesting that changes in CK20 expression might be useful for predicting behavior.
Ki-67 is a nuclear protein that is present during the G1, S, G2, and M phases of cycling cells. Previous studies have demonstrated a significant correlation between the Ki-67 index and tumor grade and stage of urinary bladder cancer.
Mutations of the p53 gene have been found in a wide variety of malignant neoplasms, including urothelial carcinomas, and have been shown to be an independent predictor of survival, progression, and development of metastasis in bladder cancer.
In the present study, we correlated the immunoexpression of these biologic markers with recurrence of noninvasive papillary urothelial tumors graded by the 1973 WHO and the 1998 WHO/ISUP systems to identify which of the systems was a better predictor of tumor behavior and whether immunophenotyping can aid grading.
Cytokeratin (CK) 20, Ki-67, and p53 were applied to 84 noninvasive papillary urothelial tumors graded by the 1973 World Health Organization (WHO) and 1998 WHO/International Society of Urological Pathology (ISUP) systems. In the WHO/ISUP classification, all benign lesions showed normal CK20 staining and all carcinomas showed abnormal staining. The Ki-67 index was significantly different between benign and malignant lesions (P < .05) and between low- and high-grade carcinomas (P < .001). p53 was negative in all benign lesions, with a significant difference between low- and high-grade carcinomas (P < .001). Tumor recurrence was significantly different between low- and high-grade carcinomas (no recurrences among the papillary urothelial neoplasms of low malignant potential). By the 1973 WHO classification, normal CK20 staining was present both in benign lesions and in carcinomas. Ki-67 staining did not distinguish between grade 2 and grade 3 carcinomas (P > .05), and there was no difference in p53 staining in grades 1 and 2 carcinomas (P > .05). Recurrences were not different between grades 1, 2, and 3 carcinomas. All biologic markers studied and tumor recurrences were significantly different among papillary lesions classified by the WHO/ISUP system but not by the 1973 WHO system, validating the predictive value of the WHO/ISUP system and providing objective markers for the grading of papillary urothelial tumors.
Tumor stage is the best predictor of clinical outcome in urothelial neoplasms; however, the prognosis of patients with noninvasive papillary urothelial tumors is influenced largely by the pathologic grade of the initial tumor. Grading systems proposed for papillary carcinomas of the bladder include 2-, 3-, 4-, and 5-tiered systems. Complex systems can provide the most data but might be less reproducible and difficult to implement in routine practice. Simple systems with fewer categories are the easiest to learn and use but convey less information. The best grading system should be not only easy to apply but also able to divide tumors into groups with different biologic characteristics that correlate with different clinical outcomes.
A number of classification systems for the grading of papillary urothelial neoplasms of the bladder have been introduced, but despite the absence of detailed defining criteria, the 1973 World Health Organization (WHO) classification has remained widely used ( Table 1 ). In 1998, the WHO/International Society of Urological Pathology (ISUP) consensus classification was developed in an effort to reach a universally acceptable system. Noninvasive papillary urothelial tumors essentially were divided into 4 groups, namely, papilloma, papillary urothelial neoplasm of low malignant potential (LMP), low-grade carcinoma (LGC), and high-grade (HGC) carcinoma ( Table 1 ). However, several authors have argued that the prognostic value of this classification is limited, reproducibility is worse than the widely used 1973 WHO system, and the new entity, LMP, showed increased risk of local recurrence, progression, and death due to the tumor.
One method used by pathologists to test the validity of a classification system is to compare tumor recurrence and progression or survival of patients between the different prognostic groups. Papillary urothelial tumors tend to recur. Some tumors recur within a short period, and others recur after a long period. Recurrences of papilloma have been reported in as many as 50% of cases if follow-up is long enough. As such, long-term follow-up for recurrences does not actually differentiate different prognostic groups. It would be predictable for high-grade tumors mostly to recur early and low-grade tumors to recur late. In the present study, we adopted this premise and set the cutoff at 36 months for comparison of recurrent rates between the different tumor grades.
In normal urothelium, the expression of cytokeratin (CK) 20 is related to differentiation and is limited to superficial and occasional intermediate cells. Abnormalities of urothelial differentiation are accompanied by loss of this restriction so that the immunoexpression of CK20 is seen in deeper cell layers or in all layers. Tumors with normal CK20 staining have shown no recurrences, whereas those with abnormal staining developed recurrences, suggesting that changes in CK20 expression might be useful for predicting behavior.
Ki-67 is a nuclear protein that is present during the G1, S, G2, and M phases of cycling cells. Previous studies have demonstrated a significant correlation between the Ki-67 index and tumor grade and stage of urinary bladder cancer.
Mutations of the p53 gene have been found in a wide variety of malignant neoplasms, including urothelial carcinomas, and have been shown to be an independent predictor of survival, progression, and development of metastasis in bladder cancer.
In the present study, we correlated the immunoexpression of these biologic markers with recurrence of noninvasive papillary urothelial tumors graded by the 1973 WHO and the 1998 WHO/ISUP systems to identify which of the systems was a better predictor of tumor behavior and whether immunophenotyping can aid grading.
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