Kidney Tumor
Adult renal carcinoma
Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) syndrome associated renal cancer

Author: Nicole K. Andeen, M.D. and Maria Tretiakova, M.D., Ph.D. (see Authors page)

Revised: 24 May 2016, last major update May 2016

Copyright: (c) 2003-2016,, Inc.

PubMed Search: HLRCC renal cancer
Cite this page: Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) syndrome associated renal cancer . website. Accessed January 21st, 2017.
Definition / General
  • Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome associated renal cancer may be papillary, solid and infiltrative
  • It has characteristic inclusion-like nucleoli with perinucleolar clearing
  • Due to germline fumarate hydratase (FH) mutations
  • Other common clinical manifestation is non-renal leiomyomatosis
Essential Features
  • Oncogenesis driven by metabolic derangements due to defective fumarate hydratase enzyme
  • High grade, papillary, solid or infiltrative with prominent CMV inclusion-like nucleoli with perinucleolar clearing (may be only focal)
  • Immunohistochemically shows overexpression of modified cysteine (2SC) and loss of fumarate hydratase
  • May be confirmed by germline fumarate hydratase mutation
  • HLRCC syndrome has germline mutations of fumarate hydratase gene, conferring an increased risk of uterine and cutaneous leiomyomata as well as renal cancer
  • The associated renal cell carcinoma is termed HLRCC associated renal cancer
  • Kidney
  • Leiomyomas in uterus and skin in HLRCC syndrome
  • Mutations in the Fumarate Hydratase (FH) gene lead to a defective FH enzyme in the citric acid cycle, causing metabolic derangement, "pseudohypoxic" upregulation of hypoxia inducible factor 1 alpha (HIF1a) and non-enzymatic modification of cysteine residues in multiple proteins (succination), altering their function and ultimately driving oncogenesis (Am J Surg Pathol 2014;38:567, Oncogene 2014;33:2547)
Clinical Features
  • HLRCC associated renal cancer occurs in 1/3 with HLRCC germline mutation
  • Mean age of presentation with renal cancer: 36 years (Am J Surg Pathol 2014;38:627)
  • Leiomyomas of skin and uterus are the most common features (seen in 85%), usually develop in the 3rd decade
  • Uterine leiomyomas are often numerous and large, 50% of women have hysterectomy before age 30 (18 - 52 years)
Prognostic Factors
  • HLRCC has a poor prognosis, with early and widespread metastases, even with small tumors
Case Reports
Gross Description
  • Solitary, unilateral
  • Solid or cystic, 2.5 cm to 12 cm
Micro Description
  • High grade with various patterns: papillary, tubular, solid, cribriform, cystic, collecting duct carcinoma-like, sarcomatoid (Am J Surg Pathol 2014;38:627)
  • Prominent eosinophilic CMV-like nucleoli with perinucleolar halo (may be only focal)
  • May have hyalinized and edematous fibrovascular cores with micropapillary fronds but no foamy histiocytes (Am J Surg Pathol 2014;38:627)
Micro Images

Images hosted on Flickr:

Courtesy of Nicole K. Andeen, M.D. and Maria Tretiakova, M.D., Ph.D.

HLRCC with tubulopapillary
growth and eosinophilic cells

HLRCC with pale eosinophilic cytoplasm
and inclusion-like nucleoli

Uterine leiomyoma from a patient with
HLRCC, with multinucleation

Images hosted on other servers:

Findings in patient with HLRCC and RCC

HLRCC renal tumors

2SC IHC shows diffuse and strong
reactivity in HLRCC renal cancer

2SC IHC shows cytoplasmic staining
pattern in a few unclassified RCC

Clear cell RCC

Uterine leiomyomas in HLRCC

Positive Stains
Negative Stains
Molecular / Cytogenetics Description
  • Fumarate Hydratase (FH) gene is located on 1q42- 43, and consists of 10 exons
  • Autosomal dominant inheritance
  • In HLRCC, oxidative phosphorylation is impaired, and cells undergo a metabolic shift to aerobic glycolysis (Clin Cancer Res 2013;19:3345)
  • Without fumarate hydratase activity, fumarate increases and acts as an oncometabolite
  • Fumarate impairs the function of hypoxia inducible factor prolyl hydroxylase, resulting in increased levels of HIF1alpha (WHO 2016)
Molecular / Cytogenetics Images

Images hosted on other servers:

Proposed mechanisms
of tumorigenesis in HLRCC

Consequences of
elevated cellular fumarate

TCA cycle enzyme

Differential Diagnosis