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 August 2018, last major update May 2016

Copyright: (c) 2003-2018,, Inc.

PubMed Search: HLRCC renal cancer
Cite this page: Andeen, N. K. and Tretiakova, M. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome associated renal cancer. website. Accessed November 15th, 2018.
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 nonrenal 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 nonenzymatic 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)
Diagrams / tables

Images hosted on other servers:

Proposed mechanisms
of tumorigenesis in HLRCC

Consequences of
elevated cellular fumarate

TCA cycle enzyme

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
Microscopic (histologic) 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)
Microscopic (histologic) images

Images hosted on Flickr:

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

HLRCC with
growth and
eosinophilic cells

HLRCC with pale
eosinophilic cyto-
plasm and inclu-
sion-like nucleoli

Uterine leiomyoma
from a patient
with HLRCC, with

Images hosted on other servers:

Findings in patient with HLRCC and RCC

HLRCC renal tumors

Clear cell RCC

Uterine leiomyomas in HLRCC

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

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