Stanford School of Medicine

Surgical Pathology Criteria

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Hereditary / Familal Renal Cell Carcinoma


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

Diagnostic Criteria

Syndrome Genetic Abnormality Extra-renal Renal Carcinoma
von Hippel Lindau


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


None Multiple clear cell RCC
Succinate dehydrogenase

usually B
may be recessive

Pheochromocytomas, head & neck paragangliomas and gastric GIST Bubbly, flocculent 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
      • Mean age 37 years
    • Various patterns reported, including oncocytoid and papillary tumors
    • SDH subtype IPOX staining can detect deficiencies but not widely used
      • Keratins frequently negative
      • CD117 negative
      • May be focally positive for PAX8 and EMA
    • Recent reports describes distinctive features (Gill 2011, 2014)
      • Circumscribed but not encapsulated
        • Not infiltrative but may surround occasional normal elements
      • Numerous clear to pale cytoplasmic inclusions imparting a bubbly, flocculent appearance to cytoplasm
        • Inclusions are actually giant mitochondria
      • Frequently cystic and multifocal, bilateral
      • Very good behavior unless sarcomatoid areas (high grade nuclei or coagulative tumor necrosis)
        • Irregular nuclei 2x size of usual bland nuclei, prominent nucleoli, coarse chromatiin

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

Last update: 12/30/16

Classification / Lists

Renal epithelial neoplasms


  • 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.
  • Gill AJ, Hes O, Papathomas T, Sedivcov√° M, Tan PH, Agaimy A, Andresen PA, Kedziora A, Clarkson A, Toon CW, Sioson L, Watson N, Chou A, Paik J, Clifton-Bligh RJ, Robinson BG, Benn DE, Hills K, Maclean F, Niemeijer ND, Vlatkovic L, Hartmann A, Corssmit EP, van Leenders GJ, Przybycin C, McKenney JK,¬† Magi-Galluzzi C, Yilmaz A, Yu D, Nicoll KD, Yong JL, Sibony M, Yakirevich E, Fleming S, Chow CW, Miettinen M, Michal M, Trpkov K. Succinate Dehydrogenase (SDH)-deficient Renal Carcinoma: A Morphologically Distinct Entity: A Clinicopathologic Series of 36 Tumors From 27 Patients. Am J Surg Pathol. 2014 Dec;38(12):1588-602. PubMed Central PMCID: PMC4229399.
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