Kidney Diseases: Environmental and Genetic Factors

The spectrum of hereditary (autosomal dominant) renal cancer syndrome is widening with time. Von Hippel-Lindau (VHL) disease was first to be identified. Attention has been focused on novel localizations of VHL disease (in addition to central nervous system and retinal involvement, bilateral and multifocal renal cell carcinoma [RCC], and pheochromocytoma), such as pancreas cysts and tumors and, more recently, endolymphatic sac tumors, causing irreversible sensorineural hearing loss as a result of intralabyrinthine hemorrhage (1). Then, the Birt-Hogg-Dube (BHD) syndrome, first described in 1977, was better recognized, and its molecular basis was identified in recent years. This syndrome comprises skin fibrofolliculomas, kidney neoplasms (chromophobe carcinoma, oncocytoma, or mixed tumors), lung cysts, and spontaneous pneumothorax. The BHD gene is located at chromosome 17p, and its product has been called folliculin. Two recent studies stressed the frequency of lung involvement (2,3). Among 198 patients from 89 families with BHD syndrome, 25% had a history of pneumothorax (2). The BHD syndrome can occur as an isolated phenotype with pulmonary involvement (3). The risk for subsequent development of renal neoplasms should be remembered. In the more recently described (in 2001) hereditary cancer syndrome, affected individuals are at risk for cutaneous and uterine leiomyomas and kidney cancer (hereditary leiomyomatosis and RCC [HLRCC]). These individuals are characterized by heterozygous mutations of the fumarate hydratase gene, located at 1q. Fifty-six families have been studied in North America by Grubb et al. in National Institutes of Health laboratories. Skin lesions appear as firm, flesh-colored to light red/brown papules or nodules, with onset typically in the third decade of life. Grubb et al. underline the aggressive nature of the renal tumors. These tumors may be isoechoic by ultrasonography and may therefore be missed. Overall, nine (47%) of 19 patients presented with nodal or distant metastases. At a median follow-up of 34 mo, 10 (53%) of these 19 patients had died of kidney cancer or had advanced disease. Parenchymal-sparing surgery, often advocated in other hereditary renal cancer syndromes, may not be appropriate for patients with HLRCC syndrome. Among 40 renal tumors resected from 38 patients (from 17 to 75 yr of age) belonging to families with HLRCC, papillary carcinomas predominated (25 cases), followed by tubulopapillary, tubular, and mixed patterns. The histologic hallmark of these tumors is the presence of a characteristic large nucleus with very prominent inclusion such as orangiophilic or eosinophilic nucleolus, surrounded by a clear halo. Proper diagnosis of these tumors by the pathologist may assist in early detection of HLRCC syndrome (4). Adequate diagnosis of these hereditary renal cancer syndromes is of great importance for at-risk individuals in these affected families. Genetic testing allows identification of carriers of the mutation and establishment of appropriate follow-up and early diagnosis of renal cancer.