GENES, CHROMOSOMES & CANCER 4967-248 (1992)
BRIEF COMMUNICATION
Low Chromosome Number in Chromophobe Renal Cell Carcinomas Angela Kovacs and Gyula Kovacs
Institute of Pathology,Albert-Ludwigs-Univerrity,Freiburg, Federal Republic of Germany (A.K.);Biological Carcinogenesis and Development Program, Program Resources, Inc/DynCorp, National Cancer Institute-FCRDC, Frederick, Maryland (G.K.)
Cytogenetic analysis revealed low chromosome number, telomeric association, and pulverisation of chromosomes in three chrornophobe renal cell carcinomas. One fully karyotyped and a previously published case showed the common loss of Published I992 by Wiley-Liss. Inc. chromosomes I, 2, 6, 10, 13, 17, and 2 I. Genes Chrom Cancer 4:267-268 ( 1 992). @
Comparative histologic, cytogenetic, and restriction fragment length polymorphism (RFLP) studies have distinguished three types of renal cell tumors with specific genetic changes: (1) papillary renal cell tumors (adenomas and carcinomas) with trisomies of chromosomes 7,16, and 17 and loss of the Y chromosome; (2)nonpapillary, clear cell renal cell carcinomas with constant loss of the chromosome 3p13-pter segment and frequent duplication of the 5q22-qter segment; and (3) renal oncocytomas without recurrent or gross karyotype changes but with alteration of the mitochondria1DNA (for review, see Kovacs, 1990). In experimentally induced renal cell carcinomas (RCC) of the rat, Bannasch et al. (1974) described a new chromophobe cell type of tumor. In 1985, Thoenes et al. recognized this unique phenotype among human renal cell tumors. The cut surface of the chromophobe RCC has a brown-beige color. A positive reaction with Hale’s acid iron colloid is pathognomic for chromophobe RCCs in light microscopic studies. Electron microscopic analysis of tumor cells shows characteristic microvesicles in the cytoplasm. These data have been confumed by Bonsib and Lager (1990). Only one case has been published dealing with the cytogenetic changes occurring in chromophobe RCCs (Kovacs et al., 1988; Kovacs and Frisch, 1989).Chromosome analysis of tumor cells cultured for five days revealed a near haploid karyotype, with 34 chromosomes in 15 of the 27 G-banded metaphases: 34,XY, -1,-2,-3,-6, -7,-9,-10,-12, -13,-17,-18, - 21. Five near haploid cells showed random losses of chromosomes;seven metaphase cells had a double set (68 chromosomes) of the stemline karyotype. Most of the metaphase cells showed telomeric association of the chromosomes. We have now analyzed the chromosomal pattern of two additional cases of chromophobe RCCs. One of the newly analyzed cases was a 58-year-oldmale patient with a 4.5 cm tumor in the right kidney. The cut PUBLISHED 1992 BY WILEY-LISS, INC.
surface of the tumor had a beige-brown color. Histological examination revealed a chromophobe RCC consisting of sheets of Hale’s positive cells. Tumor cells grew slowly in culture, and repeated chromosome preparation within S 5 days of cultivation yielded a few metaphase cells of low quality. Only eight G-banded metaphase cells were suitable for karyotyping, each showing the same chromosome aberrations: 37,X, - Y, - 1, - 2, - 6, - 10, - 13,- 15, - 17,- 21. Two of them showed early centromere divisions, and telomeric association was found in two metaphase cells. Three other metaphase cells showed pulverisation of chromosomes. The third case was a 24-year-oldfemale patient with a 3.5 cm tumor in the left kidney. Histological analysis showed a chromophobe RCC. Chromosome preparations between days 3 and 5 of cultivation yielded a low number of metaphase cells. Nearly all of the 17 metaphase cells showed pulverisation of different chromosomes, preventing accurate karyotyping. The modal chromosome number was estimated to be around %40. The loss (e.g. the pulverisation) of chromosomes varied from cell to cell. However, none of the cells showed deletion of 3p or trisomy 17. In our hands, cells of chromophobe RCC have grown very slowly in comparison to all other types of renal cell tumors, and therefore, we obtained only few metaphase cells of low quality. Telomeric association as well as pulverisation of the chromosomes each occurred in two cases. The modal chromosome number varied between 34 and 38, which is significantly lower than in papillary renal cell tumors, nonpapillary, clear cell carcinomas, or in oncocytomas. The data presented here suggest that chromophobe RCCs are characterized by substantial loss of chromosomes. Received May 6, 1991; revision accepted October 15, 1991. Address reprint requests to Dr. Gyula Kovacs, National Cancer Center Research Institute, Genetics Division, Tsukiji 5-chome, Chuo-ku, Tokyo, Japan.
268
KOVACS AND KOVACS
It is noteworthy that, in the two cases karyotyped, loss of chromosomes 1,2,6,10,13,17,and 21 occurred in both. Whether there is random loss of chromosomes and the common loss of chromosomes in the two cases is an incidental finding, or whether the karyotype changes result from the selection of cells with loss of chromosomes marking the development of chromophobe RCCs, is not yet known. Additional cytogenetic studies as well as RFLP and flow cytometric analysis of chromophobe renal cell tumors are necessary to learn about the genetics of this unique type of kidney cancer. ACKNOWLEDGMENTS
We wish to thank Drs. W. Thoenes and S. Storkel for calling our attention to the genetic changes in chromophobe RCCs and confirming our histological diagnosis. This project was funded in part with federal funds from the U.S. Department of Health and Human Services under contract number N01-CO-74102with Pro-
gram Resources, Inc./DynCorp and by a grant of the German Research Council. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. REFERENCES Bannasch P, Schlacht U, Storch E (1974) Morphogenese und Mikromorphologie epithelialer Nierentumoren bei Nitrosomorpholin-vergifteten Ratten. I. Induktion und Histologie der Tumoren. Z. Krebsforsch 81:311-331. Bonsib SM, Lager DJ (1990) Chromophobe cell carcinoma: Analysis of five cases. Am J Surg Pathol 1426C267. Kovacs G (1990) Application of molecular cytogenetic techniques to the evaluation of renal parenchymal tumors. J Cancer Res Clin Oncol 116:31&323. Kovacs G, Frisch S (1989) Clonal chromosome abnormalities in tumor cells from patients with sporadic renal cell carcinomas. Cancer Res 49:651659. Kovacs G, Soudah B. Hoene E (1988)Binucleated cells in a human renal cell carcinoma with 34 chromosomes. Cancer Genet Cytogenet 31:211-215. Thoenes W, Storkel S, Rumpelt HJ (1985) Human chromophobe renal cell carcinoma. Virchows Arch B (Cell Pathol) 48:207-217.
BRIEF COMMUNICATION
Low Chromosome Number in Chromophobe Renal Cell Carcinomas Angela Kovacs and Gyula Kovacs
Institute of Pathology,Albert-Ludwigs-Univerrity,Freiburg, Federal Republic of Germany (A.K.);Biological Carcinogenesis and Development Program, Program Resources, Inc/DynCorp, National Cancer Institute-FCRDC, Frederick, Maryland (G.K.)
Cytogenetic analysis revealed low chromosome number, telomeric association, and pulverisation of chromosomes in three chrornophobe renal cell carcinomas. One fully karyotyped and a previously published case showed the common loss of Published I992 by Wiley-Liss. Inc. chromosomes I, 2, 6, 10, 13, 17, and 2 I. Genes Chrom Cancer 4:267-268 ( 1 992). @
Comparative histologic, cytogenetic, and restriction fragment length polymorphism (RFLP) studies have distinguished three types of renal cell tumors with specific genetic changes: (1) papillary renal cell tumors (adenomas and carcinomas) with trisomies of chromosomes 7,16, and 17 and loss of the Y chromosome; (2)nonpapillary, clear cell renal cell carcinomas with constant loss of the chromosome 3p13-pter segment and frequent duplication of the 5q22-qter segment; and (3) renal oncocytomas without recurrent or gross karyotype changes but with alteration of the mitochondria1DNA (for review, see Kovacs, 1990). In experimentally induced renal cell carcinomas (RCC) of the rat, Bannasch et al. (1974) described a new chromophobe cell type of tumor. In 1985, Thoenes et al. recognized this unique phenotype among human renal cell tumors. The cut surface of the chromophobe RCC has a brown-beige color. A positive reaction with Hale’s acid iron colloid is pathognomic for chromophobe RCCs in light microscopic studies. Electron microscopic analysis of tumor cells shows characteristic microvesicles in the cytoplasm. These data have been confumed by Bonsib and Lager (1990). Only one case has been published dealing with the cytogenetic changes occurring in chromophobe RCCs (Kovacs et al., 1988; Kovacs and Frisch, 1989).Chromosome analysis of tumor cells cultured for five days revealed a near haploid karyotype, with 34 chromosomes in 15 of the 27 G-banded metaphases: 34,XY, -1,-2,-3,-6, -7,-9,-10,-12, -13,-17,-18, - 21. Five near haploid cells showed random losses of chromosomes;seven metaphase cells had a double set (68 chromosomes) of the stemline karyotype. Most of the metaphase cells showed telomeric association of the chromosomes. We have now analyzed the chromosomal pattern of two additional cases of chromophobe RCCs. One of the newly analyzed cases was a 58-year-oldmale patient with a 4.5 cm tumor in the right kidney. The cut PUBLISHED 1992 BY WILEY-LISS, INC.
surface of the tumor had a beige-brown color. Histological examination revealed a chromophobe RCC consisting of sheets of Hale’s positive cells. Tumor cells grew slowly in culture, and repeated chromosome preparation within S 5 days of cultivation yielded a few metaphase cells of low quality. Only eight G-banded metaphase cells were suitable for karyotyping, each showing the same chromosome aberrations: 37,X, - Y, - 1, - 2, - 6, - 10, - 13,- 15, - 17,- 21. Two of them showed early centromere divisions, and telomeric association was found in two metaphase cells. Three other metaphase cells showed pulverisation of chromosomes. The third case was a 24-year-oldfemale patient with a 3.5 cm tumor in the left kidney. Histological analysis showed a chromophobe RCC. Chromosome preparations between days 3 and 5 of cultivation yielded a low number of metaphase cells. Nearly all of the 17 metaphase cells showed pulverisation of different chromosomes, preventing accurate karyotyping. The modal chromosome number was estimated to be around %40. The loss (e.g. the pulverisation) of chromosomes varied from cell to cell. However, none of the cells showed deletion of 3p or trisomy 17. In our hands, cells of chromophobe RCC have grown very slowly in comparison to all other types of renal cell tumors, and therefore, we obtained only few metaphase cells of low quality. Telomeric association as well as pulverisation of the chromosomes each occurred in two cases. The modal chromosome number varied between 34 and 38, which is significantly lower than in papillary renal cell tumors, nonpapillary, clear cell carcinomas, or in oncocytomas. The data presented here suggest that chromophobe RCCs are characterized by substantial loss of chromosomes. Received May 6, 1991; revision accepted October 15, 1991. Address reprint requests to Dr. Gyula Kovacs, National Cancer Center Research Institute, Genetics Division, Tsukiji 5-chome, Chuo-ku, Tokyo, Japan.
268
KOVACS AND KOVACS
It is noteworthy that, in the two cases karyotyped, loss of chromosomes 1,2,6,10,13,17,and 21 occurred in both. Whether there is random loss of chromosomes and the common loss of chromosomes in the two cases is an incidental finding, or whether the karyotype changes result from the selection of cells with loss of chromosomes marking the development of chromophobe RCCs, is not yet known. Additional cytogenetic studies as well as RFLP and flow cytometric analysis of chromophobe renal cell tumors are necessary to learn about the genetics of this unique type of kidney cancer. ACKNOWLEDGMENTS
We wish to thank Drs. W. Thoenes and S. Storkel for calling our attention to the genetic changes in chromophobe RCCs and confirming our histological diagnosis. This project was funded in part with federal funds from the U.S. Department of Health and Human Services under contract number N01-CO-74102with Pro-
gram Resources, Inc./DynCorp and by a grant of the German Research Council. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. REFERENCES Bannasch P, Schlacht U, Storch E (1974) Morphogenese und Mikromorphologie epithelialer Nierentumoren bei Nitrosomorpholin-vergifteten Ratten. I. Induktion und Histologie der Tumoren. Z. Krebsforsch 81:311-331. Bonsib SM, Lager DJ (1990) Chromophobe cell carcinoma: Analysis of five cases. Am J Surg Pathol 1426C267. Kovacs G (1990) Application of molecular cytogenetic techniques to the evaluation of renal parenchymal tumors. J Cancer Res Clin Oncol 116:31&323. Kovacs G, Frisch S (1989) Clonal chromosome abnormalities in tumor cells from patients with sporadic renal cell carcinomas. Cancer Res 49:651659. Kovacs G, Soudah B. Hoene E (1988)Binucleated cells in a human renal cell carcinoma with 34 chromosomes. Cancer Genet Cytogenet 31:211-215. Thoenes W, Storkel S, Rumpelt HJ (1985) Human chromophobe renal cell carcinoma. Virchows Arch B (Cell Pathol) 48:207-217.
