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hereditary leiomyomatosis and renal cell cancer syndrome


Wednesday 24 September 2003

HLRCC syndrome; FH-associated RCC; FH-deficient RCC

Definition: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cell carcinoma. The mutation of this condition has been identified in the fumarate hydratase (FH, 1q42.3-q43) gene.

Mutations in the fumarate hydratase (FH) gene underlie HLRCC, a rare syndrome involving cutaneous and uterine leiomyomata and aggressive kidney tumors.

Loss of heterozygosity at the wild-type FH gene locus results in profound cellular metabolic derangement, "pseudohypoxic" upregulation of hypoxia-inducible factor 1α (HIF-1α)-dependent transcription, and aberrant protein succination; these molecular changes drive oncogenesis of kidney tumors in HLRCC patients.

The current index patient had a high-grade RCC with classic morphologic features of HLRCC, including large nuclei with prominent eosinophilic nucleoli and perinucleolar clearing.

In addition, FH patient’s RCC can demonstrate extensive sarcomatoid and rhabdoid features-morphologies not previously well described in HLRCC-associated kidney tumors.

Tumor cells strongly express PAX8, vimentin, CD10, and the HIF target GLUT1 and showed increased nuclear p53 accumulation; the expression of other RCC markers is negative.

Microscopic tubular epithelial changes in the grossly uninvolved ipsilateral renal parenchyma have been described and demonstrate sporadic, aberrant upregulation of the HIF targets GLUT1 and CAIX in dysplastic peritumoral tubules.


- renal cell carcinoma (17895761)

  • mostly unilateral
  • size of the tumors between 2.3 and 20 cm
  • no laterality preference
  • architectural patterns
    • papillary
    • tubulo-papillary
    • tubular
    • solid
    • mixed patterns
  • characteristic large nucleus with a very prominent inclusion like orangiophilic or eosinophilic nucleolus, surrounded by a clear halo
  • loss of heterozygosity: 1q32 LOH and 1q42-44 LOH
  • poor prognosis
  • frequent spread to regional lymph nodes

- uterine leiomyomas (21753700)


- mutations in the fumarate hydratase gene (FH) (MIM.136850) cause hereditary leiomyomatosis and renal cell cancer in families in North America (12772087)

Open references

- Hereditary leiomyomatosis and renal cell carcinoma (HLRCC): a rapid autopsy report of metastatic renal cell carcinoma. Udager AM, Alva A, Chen YB, Siddiqui J, Lagstein A, Tickoo SK, Reuter VE, Chinnaiyian AM, Mehra R. Am J Surg Pathol. 2014 Apr;38(4):567-77. doi : 10.1097/PAS 0000000000000127 PMID: 24625422 (Free)


- Kiuru M, Launonen V. Hereditary leiomyomatosis and renal cell cancer (HLRCC). Curr Mol Med. 2004 Dec;4(8):869-75. PMID: 15579034

- Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma. Gardie B, Remenieras A, Kattygnarath D, Bombled J, Lefèvre S, Perrier-Trudova V, Rustin P, Barrois M, Slama A, Avril MF, Bessis D, Caron O, Caux F, Collignon P, Coupier I, Cremin C, Dollfus H, Dugast C, Escudier B, Faivre L, Field M, Gilbert-Dussardier B, Janin N, Leport Y, Leroux D, Lipsker D, Malthieu F, McGilliwray B, Maugard C, Méjean A, Mortemousque I, Plessis G, Poppe B, Pruvost-Balland C, Rooker S, Roume J, Soufir N, Steinraths M, Tan MH, Théodore C, Thomas L, Vabres P, Van Glabeke E, Meric JB, Verkarre V, Lenoir G, Joulin V, Deveaux S, Cusin V, Feunteun J, Teh BT, Bressac-de Paillerets B, Richard S; French National Cancer Institute "Inherited predisposition to kidney cancer" network. J Med Genet. 2011 Apr;48(4):226-34. Epub 2011 Mar 12. Erratum in: J Med Genet. 2011 Aug;48(8):576. PMID: 21398687

- Morphologic features of uterine leiomyomas associated with hereditary leiomyomatosis and renal cell carcinoma syndrome: a case report. Garg K, Tickoo SK, Soslow RA, Reuter VE. Am J Surg Pathol. 2011 Aug;35(8):1235-7. PMID: 21753700

- Merino MJ, Torres-Cabala C, Pinto P, Marston Linehan W. The Morphologic Spectrum of Kidney Tumors in Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) Syndrome. Am J Surg Pathol. 2007 Oct;31(10):1578-1585. PMID: 17895761