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Hereditary / Familal Renal Cell Carcinoma

Definition

  • Several clinico-pathologic syndromes exist, defined by distinct genetic abnormalities

Diagnostic Criteria

Syndrome Genetic Abnormality Extra-renal Renal Carcinoma
von Hippel Lindau

VHL
3p25
dominant

 Retinal and CNS hemangioblastomas, pancreatic and other cystadenomas, pheochromocytomas Multiple clear cell carcinomas
Birt Hogg Dubé FLEN
17p11.2
dominant		 Cutaneous fibrofolliculomas, trichodiscomas, skin tags, lung cysts & pneumothorax Multiple hybrid chromophobe-oncocytomas
Hereditaary leiomyomatosis and renal cell carcinoma FH
1q42-43
dominant		 Cutaneous and uterine leiomyomas, rare kindreds with uterine leiomyosarcoma Aggressive papillary RCC
Hereditary papillary RCC MET
7q31
dominant		 None Multiple type 1 papillary RCC
Constitutional chromosome 3 translocation

Various
dominant

 None Multiple clear cell RCC
Succinate dehydrogenase B SDHB
1p36
may be recessive		 Pheochromocytomas, head & neck paragangliomas Bubbly pale to clear cytoplasm

 

  • von Hippel Lindau
    • Most common renal carcinoma syndrome
      • Prevalence 1:35,000
    • Multifocal clear cell carcinomas
    • Surrounding kidney parenchyma frequently has innumerable microscopic foci of clear cells
    • Renal cysts frequent
  • Birt Hogg Dubé
    • Various types of renal cell carcinomas may occur (Pavlovich 2002)
      • Most (84%) are chromophobe or hybrid chromophobe-oncocytoma
        • Very low incidence of aggressive behavior
        • Hybrid tumors have also been reported in non-syndromic cases (Petersson)
      • Most others are clear cell carcinomas
        • Frequently high grade
        • Behavior same as non-syndromic cases
    • Frequent microscopic foci of oncocytosis
      • Clusters of cells with eosinophilic cytoplasm, sharp cell borders and large nuclei
      • Not restricted to kidneys with chromophobe or hybrid tumors
        • May be seen even in BHD syndrome kidneys with clear cell carcinomas
  • Hereditary leiomyomatosis and renal cell carcinoma
    • Usually solitary tumors
    • Papillary or tubulopapillary pattern lined by tall cells with abundant eosinophilic cytoplasm (Merino)
      • Large pleomorphic nuclei
        • Large inclusion-like eosinophilic nucleoli
    • May have focal clear cells
    • In the past, some cases reported as type 2 papillary carcinoma or as collecting duct carcinoma
    • Negative for mucin, ulex lectin binding, CK7, CD10
    • Clinically aggressive
  • Hereditary papillary renal cell carcinoma
  • Constitutional chromosome 3 translocation carcinomas
    • Very rare
    • Multiple clear cell carcinomas
  • Succinate dehydrogenase mutation carcinomas
    • Very rare
    • Various patterns reported, including oncocytoid tumors
    • Most recent report describes distinctive features (Gill 2011)
      • Circumscribed but not encapsulated
        • Not infiltrative but may surround occasional normal elements
      • Numerous clear to pale cytoplasmic inclusions imparting a bubbly appearance to cytoplasm
        • Inclusions are actually giant mitochondria
      • Frequently cystic
      • Good behavior unless sarcomatoid (1 of 4 cases)


Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates:: 2/24/11, 11/11/11

Classification / Lists

Renal epithelial neoplasms

Bibliography

  • Eble JN, Sauter G, Epstein JI, Sesterhenn IA eds. World Health Organization Classification of Tumors. Pathology and genetics of tumors of the Urinary System and Male Genital Organs. IARC Press: Lyon 2004.
  • Maher ER. Genetics of familial renal cancers. Nephron Exp Nephrol. 2011;118(1):e21-6.
  • Pavlovich CP, Schmidt LS, Phillips JL. The genetic basis of renal cell carcinoma. Urol Clin North Am. 2003 Aug;30(3):437-54, vii.
  • Coleman JA, Russo P. Hereditary and familial kidney cancer. Curr Opin Urol. 2009 Sep;19(5):478-85
  • Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, Linehan WM, Merino MJ. Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol. 2002 Dec;26(12):1542-52.
  • Adley BP, Smith ND, Nayar R, Yang XJ. Birt-Hogg-Dubé syndrome: clinicopathologic findings and genetic alterations. Arch Pathol Lab Med. 2006 Dec;130(12):1865-70.
  • Petersson F, Gatalica Z, Grossmann P, Perez Montiel MD, Alvarado Cabrero I, Bulimbasic S, Swatek A, Straka L, Tichy T, Hora M, Kuroda N, Legendre B, Michal M, Hes O. Sporadic hybrid oncocytic/chromophobe tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular cytogenetic study of 14 cases. Virchows Arch. 2010 Apr;456(4):355-65.
  • Merino MJ, Torres-Cabala C, Pinto P, Linehan WM. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol. 2007 Oct;31(10):1578-85.
  • Schmidt LS, Nickerson ML, Angeloni D, Glenn GM, Walther MM, Albert PS, Warren MB, Choyke PL, Torres-Cabala CA, Merino MJ, Brunet J, Bérez V, Borràs J, Sesia G, Middelton L, Phillips JL, Stolle C, Zbar B, Pautler SE, Linehan WM. Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene. J Urol. 2004 Oct;172(4 Pt 1):1256-61.
  • Housley SL, Lindsay RS, Young B, McConachie M, Mechan D, Baty D, Christie L, Rahilly M, Qureshi K, Fleming S. Renal carcinoma with giant mitochondria associated with germ-line mutation and somatic loss of the succinate dehydrogenase B gene. Histopathology. 2010 Feb;56(3):405-8.
  • Gill AJ, Pachter NS, Chou A, Young B, Clarkson A, Tucker KM, Winship IM, Earls
    P, Benn DE, Robinson BG, Fleming S, Clifton-Bligh RJ. Renal tumors associated
    with germline SDHB mutation show distinctive morphology. Am J Surg Pathol. 2011
    Oct;35(10):1578-85.
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