Clear cell renal cell carcinoma: validation of World Health Organization/International Society of Urological Pathology grading

The prognostic significance of morphologic parameters was evaluated in 103 patients with renal cell carcinoma diagnosed during 1961--1974. Pathologic material was classified as to pathologic stage, tumor size, cell arrangement, cell type and nuclear grade. Four nuclear grades (1--4) were defined in order of increasing nuclear size, irregularity and nucleolar prominence. Nuclear grade was more effective than each of the other parameters in predicting development of distant metastasis following nephrectomy. Among 45 patients who presented in Stage I, tumors classified as nuclear grade 1 did not metastasize for at least 5 years, whereas 50% of the higher grade tumors did so. Moreover, among Stage I tumors there was a significant difference in subsequent metastatic rate between nuclear grades 1 and 2. There was an apparent positive relationship between cell type and metastatic rate; clear cell tumors were less aggressive than predominantly granular cell tumors (metastatic rate 38% versus 71%). This relationship in part a function of the nuclear grade: only 5% of grade 3 and 4 tumors consisted of clear cells, whereas such high grades were seen in 57% of granular cell tumors. The size of the primary correlated well with the stage at the time of surgery. However, with the exception of extremely large and small tumors, the size was not useful in predicting the subsequent course of patients treated for Stage I tumors. Nuclear grade was the most significant prognostic criterion for the outcome of Stage I renal cell carcinoma.

The importance of nucleolar changes in cancer cells is underestimated in tumour pathology. There is evidence that the nucleolus is the mirror of a series of metabolic changes that characterize cancer cells. Cell entry into the cell cycle is always associated with up-regulation of the nucleolar function and increased nucleolar size, which are also directly dependent on the rapidity of cell cycle progression. Furthermore, alterations of the major tumour suppressor retinoblastoma (Rb) and p53 pathways also contribute to the stimulation of nucleolar function and to nucleolar enlargement. High cell growth fraction, high cell growth rate and disruption of the Rb and p53 pathways are responsible for greater aggressiveness of cancer tissues. Therefore, the evaluation of nucleolar size allows one to obtain reliable information on the clinical outcome of the cancer: the greater the nucleolar size, the worse the tumour prognosis. Indeed, a series of studies carried out on numerous human tumours has shown that nucleolar hypertrophy (prominent nucleolus) was an independent predictive and prognostic parameter of a fatal clinical outcome.