Prospective Detection of Germline Mutation of Fumarate Hydratase in Women With Uterine Smooth Muscle Tumors Using Pathology-based Screening to Trigger Genetic Counseling for Hereditary Leiomyomatosis Renal Cell Carcinoma Syndrome: A 5-Year Single Institutional Experience

Am J Surg Pathol. 2019 May;43(5):639-655. doi: 10.1097/PAS.0000000000001222.


Pathology-based screening of uterine smooth muscle tumors (uSMT) for morphology suggestive of fumarate hydratase deficiency (FH-d morphology) has been proposed as a method to identify women at increased risk for hereditary leiomyomatosis renal cell carcinoma (HLRCC) syndrome. For 5 years our clinical diagnostic practice has evaluated all women with any type of uSMT for FH-d morphology (defined, at low magnification, as staghorn shaped blood vessels and alveolar pattern edema and, at high magnification, as tumor macronucleoli surrounded by a halo and cytoplasmic eosinophilic globules) and, when present, used the pathology report to advise genetic counseling to further evaluate for HLRCC syndrome. We now report the results of this prospective screening strategy, with emphasis on the incidence and clinicopathologic features of FH-d morphology in uSMT, the rate of patient uptake of referral to genetic counseling, and the results of genetic testing for FH germline mutation. Among 2060 women with a uSMT, FH-d morphology was reported in 1.4% (30 women). Ten women elected to undergo FH genetic testing and 6 of 10 (60%) had a FH germline mutation: 5 were pathogenic mutations and 1 was a mutation variant of unknown significance. Therefore, the screening program led to a confirmed genetic diagnosis of HLRCC syndrome in 0.24% of all women with any type of uSMT. The women with a pathogenic mutation were ages 24 to 40 years. Although the majority of leiomyoma with bizarre nuclei exhibited FH-d morphology, the uSMT were conventional leiomyomas with FH-d morphology in 2 of 5 women found to have a pathogenic FH germline mutation. Relying on an abnormal FH immunostain result to trigger genetic counseling referral would have resulted in 2 of 5 (40%) cases with pathogenic FH germline mutation but normal FH immunoexpression going undetected, both of which were missense type mutations. There was no difference in the incidence of pathogenic FH germline mutation between FH-d morphology uSMT with an abnormal versus a normal FH immunostain result. Overall, this study demonstrates that prospective morphology-based screening, integrated with referral for genetic counseling, can result in the diagnosis of HLRCC syndrome in otherwise unselected women with uSMT. We conclude that this strategy should be incorporated in the routine pathologic examination of all uterine smooth muscle tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / genetics*
  • Biopsy
  • DNA Mutational Analysis*
  • Female
  • Fumarate Hydratase / genetics*
  • Genetic Counseling*
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • Heredity
  • Humans
  • Leiomyomatosis / enzymology
  • Leiomyomatosis / genetics*
  • Leiomyomatosis / pathology
  • Leiomyomatosis / therapy
  • Middle Aged
  • Neoplastic Syndromes, Hereditary / enzymology
  • Neoplastic Syndromes, Hereditary / genetics*
  • Neoplastic Syndromes, Hereditary / pathology
  • Neoplastic Syndromes, Hereditary / therapy
  • Patient Acceptance of Health Care
  • Pedigree
  • Phenotype
  • Predictive Value of Tests
  • Prognosis
  • Prospective Studies
  • Referral and Consultation
  • San Francisco
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Skin Neoplasms / therapy
  • Time Factors
  • Uterine Neoplasms / enzymology
  • Uterine Neoplasms / genetics*
  • Uterine Neoplasms / pathology
  • Uterine Neoplasms / therapy
  • Young Adult


  • Biomarkers, Tumor
  • Fumarate Hydratase

Supplementary concepts

  • Hereditary leiomyomatosis and renal cell cancer