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Am J Pathol. 1996 Oct; 149(4): 1201–1208.
PMCID: PMC1865172

Tuberous sclerosis-associated renal cell carcinoma. Clinical, pathological, and genetic features.


The tuberous sclerosis complex (TSC) is a multisystem autosomal dominant disorder characterized by seizures, mental retardation, and hamartomas. Patients with TSC have been reported to develop renal cell carcinomas (RCC) with increased frequency, an observation that is supported by the Eker rat model. To address the role of the tuberous sclerosis tumor suppressor genes in the pathogenesis of RCC, we studied six TSC-associated RCCs. Our findings suggest that some TSC-associated RCCs have clinical, pathological, or genetic features distinguishing them from sporadic RCC. Clinically, the TSC-associated tumors occurred at a younger age (mean, 36 years) than sporadic tumors and occurred primarily in women. Four of the six patients died of metastatic disease. Pathologically, five tumors displayed clear cell morphology. Of those five, two had high-grade spindle cell areas and one had granular cell histology in addition to the clear cell areas. A sixth tumor was anaplastic throughout. Four of the six tumors immunostained positively for a melanocyte-associated marker, HMB-45. HMB-45 positivity has been seen in two other TSC lesions: renal angiomyolipomas and pulmonary lymphangiomyomatosis. Five tumors were analyzed for loss of heterozygosity. Two had loss of heterozygosity on chromosome 9q34 and one had loss of heterozygosity on chromosome 16p13. We conclude that TSC-associated RCCs occur at an earlier age than sporadic RCCs, that some TSC-associated renal carcinomas have a different immunophenotype than sporadic RCCs, and that the TSC tumor suppressor genes may play a specific pathogenic role in these tumors.

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  • Povey S, Armour J, Farndon P, Haines JL, Knowles M, Olopade F, Pilz A, White JA, Kwiatkowski DJ. Report and abstracts of the Third International Workshop on Chromosome 9. Cambridge, United Kingdom, 9-11 April, 1994. Ann Hum Genet. 1994 Jul;58(Pt 3):177–250. [PubMed]
  • Henske EP, Ozelius L, Gusella JF, Haines JL, Kwiatkowski DJ. A high-resolution linkage map of human 9q34.1. Genomics. 1993 Sep;17(3):587–591. [PubMed]
  • Henske EP, Kwiatkowski DJ. A 5.4-Mb continuous pulsed-field gel electrophoresis map of human 9q34.1 between ABL and D9S114, including the tuberous sclerosis (TSC1) region. Genomics. 1995 Jul 1;28(1):105–108. [PubMed]
  • Green AJ, Smith M, Yates JR. Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nat Genet. 1994 Feb;6(2):193–196. [PubMed]
  • Henske EP, Neumann HP, Scheithauer BW, Herbst EW, Short MP, Kwiatkowski DJ. Loss of heterozygosity in the tuberous sclerosis (TSC2) region of chromosome band 16p13 occurs in sporadic as well as TSC-associated renal angiomyolipomas. Genes Chromosomes Cancer. 1995 Aug;13(4):295–298. [PubMed]
  • Green AJ, Johnson PH, Yates JR. The tuberous sclerosis gene on chromosome 9q34 acts as a growth suppressor. Hum Mol Genet. 1994 Oct;3(10):1833–1834. [PubMed]
  • Carbonara C, Longa L, Grosso E, Borrone C, Garrè MG, Brisigotti M, Migone N. 9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene. Hum Mol Genet. 1994 Oct;3(10):1829–1832. [PubMed]
  • Knudson AG., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. [PMC free article] [PubMed]
  • Ahuja S, Loffler W, Wegener OH, Ernst H. Tuberous sclerosis with angiomyolipoma and metastasized hypernephroma. Urology. 1986 Nov;28(5):413–419. [PubMed]
  • Graves N, Barnes WF. Renal cell carcinoma and angiomyolipoma in tuberous sclerosis: case report. J Urol. 1986 Jan;135(1):122–123. [PubMed]
  • Ilgren EB, Westmoreland D. Tuberous sclerosis: unusual associations in four cases. J Clin Pathol. 1984 Mar;37(3):272–278. [PMC free article] [PubMed]
  • Kobayashi T, Hirayama Y, Kobayashi E, Kubo Y, Hino O. A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer. Nat Genet. 1995 Jan;9(1):70–74. [PubMed]
  • Yeung RS, Xiao GH, Jin F, Lee WC, Testa JR, Knudson AG. Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11413–11416. [PMC free article] [PubMed]
  • EKER R. Familial renal adenomas in Wistar rats; a preliminary report. Acta Pathol Microbiol Scand. 1954;34(6):554–562. [PubMed]
  • Cairns P, Tokino K, Eby Y, Sidransky D. Localization of tumor suppressor loci on chromosome 9 in primary human renal cell carcinomas. Cancer Res. 1995 Jan 15;55(2):224–227. [PubMed]
  • Kwiatkowski DJ, Henske EP, Weimer K, Ozelius L, Gusella JF, Haines J. Construction of a GT polymorphism map of human 9q. Genomics. 1992 Feb;12(2):229–240. [PubMed]
  • Shen Y, Kozman HM, Thompson A, Phillips HA, Holman K, Nancarrow J, Lane S, Chen LZ, Apostolou S, Doggett NA, et al. A PCR-based genetic linkage map of human chromosome 16. Genomics. 1994 Jul 1;22(1):68–76. [PubMed]
  • Kwiatkowski DJ, Diaz MO. Dinucleotide repeat polymorphism at the IFNA locus (9p22). Hum Mol Genet. 1992 Nov;1(8):658–658. [PubMed]
  • Weissenbach J, Gyapay G, Dib C, Vignal A, Morissette J, Millasseau P, Vaysseix G, Lathrop M. A second-generation linkage map of the human genome. Nature. 1992 Oct 29;359(6398):794–801. [PubMed]
  • Naylor SL, Buys CH, Carritt B. Report and abstracts of the Fourth International Workshop on Human Chromosome 3 Mapping. Cytogenet Cell Genet. 1994;65(1-2):2–50. [PubMed]
  • Gyapay G, Morissette J, Vignal A, Dib C, Fizames C, Millasseau P, Marc S, Bernardi G, Lathrop M, Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. [PubMed]
  • RAVAULT PP, GIRARD PF, ALEX R, TRILLET M. [Tuberculous myositis of atypical development and paratuberculous polymyositis]. Lyon Med. 1960 Jul 17;92:105–118. [PubMed]
  • Washecka R, Hanna M. Malignant renal tumors in tuberous sclerosis. Urology. 1991 Apr;37(4):340–343. [PubMed]
  • Farrow GM, Harrison EG, Jr, Utz DC. Sarcomas and sarcomatoid and mixed malignant tumors of the kidney in adults. 3. Cancer. 1968 Sep;22(3):556–563. [PubMed]
  • Kapur RP, Bigler SA, Skelly M, Gown AM. Anti-melanoma monoclonal antibody HMB45 identifies an oncofetal glycoconjugate associated with immature melanosomes. J Histochem Cytochem. 1992 Feb;40(2):207–212. [PubMed]
  • Morita R, Saito S, Ishikawa J, Ogawa O, Yoshida O, Yamakawa K, Nakamura Y. Common regions of deletion on chromosomes 5q, 6q, and 10q in renal cell carcinoma. Cancer Res. 1991 Nov 1;51(21):5817–5820. [PubMed]
  • Kovacs G, Frisch S. Clonal chromosome abnormalities in tumor cells from patients with sporadic renal cell carcinomas. Cancer Res. 1989 Feb 1;49(3):651–659. [PubMed]
  • Thrash-Bingham CA, Greenberg RE, Howard S, Bruzel A, Bremer M, Goll A, Salazar H, Freed JJ, Tartof KD. Comprehensive allelotyping of human renal cell carcinomas using microsatellite DNA probes. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2854–2858. [PMC free article] [PubMed]
  • Foster K, Prowse A, van den Berg A, Fleming S, Hulsbeek MM, Crossey PA, Richards FM, Cairns P, Affara NA, Ferguson-Smith MA, et al. Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet. 1994 Dec;3(12):2169–2173. [PubMed]
  • Shuin T, Kondo K, Torigoe S, Kishida T, Kubota Y, Hosaka M, Nagashima Y, Kitamura H, Latif F, Zbar B, et al. Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res. 1994 Jun 1;54(11):2852–2855. [PubMed]
  • Foster K, Crossey PA, Cairns P, Hetherington JW, Richards FM, Jones MH, Bentley E, Affara NA, Ferguson-Smith MA, Maher ER. Molecular genetic investigation of sporadic renal cell carcinoma: analysis of allele loss on chromosomes 3p, 5q, 11p, 17 and 22. Br J Cancer. 1994 Feb;69(2):230–234. [PMC free article] [PubMed]
  • Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. [PubMed]

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