Hereditary leiomyomatosis and renal cell cancer (HLRCC) is characterized by the presence of one or more of the following: cutaneous leiomyomas (or leiomyomata), uterine leiomyomas (fibroids) in females, and renal cell cancer (RCC). Germline pathogenic variants in the FHgene are responsible for the susceptibility to HLRCC. FH encodes fumarate hydratase, the enzyme that catalyzes the conversion of fumarate to malate in the tricarboxylic acid cycle (Krebs cycle).
Historically, the predisposition to the development of cutaneous leiomyomas was referred to as multiple cutaneous leiomyomatosis. In 1973, two kindreds were described in which multiple members over three generations exhibited cutaneous leiomyomas and uterine leiomyomas and/or leiomyosarcomas inherited in an autosomal dominant pattern.[
The FHgene consists of ten exons encompassing 22.15 kb of DNA. The gene is highly conserved across species. The human FH gene is located on chromosome 1q42.3-43.
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant syndrome; inheritance of a single variant FHallele predisposes the individual to develop manifestations of the disease.[
Renal tumors that develop in individuals who inherit a germline pathogenic variant in FH typically display a loss of heterozygosity because of a second somatic FHmutation. This finding suggests that loss of function of the fumarate hydratase protein is the basis for tumor formation in HLRCC and supports a tumor suppressor function for FH.[
Various pathogenic variants in FH have been identified in families with HLRCC. Most are missense pathogenic variants, but nonsense, frameshift, and splice-site variants have been described.[
The prevalence of HLRCC is unknown. Older estimates suggested a prevalence of 1 in 200,000 individuals.[
Penetrance ofFHPathogenic Variants
On the basis of the observation that most patients with HLRCC have at least one of the three major clinical manifestations, the penetrance of HLRCC in carriers of pathogenic FH variants appears to be very high. However, the estimated cumulative lifetime incidence of renal cell cancer (RCC) varies widely, with most estimates ranging from 15% to 30% in families with germline FH pathogenic variants, depending on ascertainment method and the imaging modalities used.[
No genotype -phenotype correlations have been described. Thus, no correlation has been observed between specific FH variants and the occurrence of cutaneous lesions, uterine leiomyomas, or RCC in HLRCC.[
Although smaller studies have suggested the presence of different variant spectra in FHD and HLRCC,[
Using bidirectional DNA sequencing methodology, pathogenic variants in FH have been detected in more than 85% of individuals with HLRCC.[
Genetically Related Disorders
Fumarate hydratase deficiency (fumaric aciduria, FHD)
FHD, resulting from the inheritance of biallelic pathogenic variants in FH, is an autosomal recessive inborn error of metabolism characterized by rapidly progressive neurologic impairment including hypotonia, seizures, and cerebral atrophy. Homozygous or compound heterozygous germline pathogenic variants in FH are found in individuals with FHD.[
Biallelic somatic loss of FH has been identified in two early-onset sporadic uterine leiomyomas and a soft tissue sarcoma of the lower limb without other associated tumor characteristics of the heritable disease.[
The mechanisms by which alterations in FH lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) are currently under investigation. Biallelic inactivation of FH has been shown to result in loss of oxidative phosphorylation and reliance on aerobic glycolysis to meet cellular energy requirements. Interruption of the Krebs cycle because of reduced or absent fumarate hydratase activity results in increased levels of intracellular fumarate. This increase inhibits the activity of hypoxia-inducible factor (HIF) prolyl hydroxylases, resulting in the accumulation of HIF-alpha.[
The clinical characteristics of hereditary leiomyomatosis and renal cell cancer (HLRCC) include cutaneous leiomyomas, uterine leiomyomas (fibroids), and renal cell cancer (RCC). Affected individuals may have multiple cutaneous leiomyomas, a single skin leiomyoma, or no cutaneous lesion; an RCC that is typically solitary, or no renal tumors; and/or uterine leiomyomas. HLRCC is phenotypically variable; disease severity shows significant intrafamilial and interfamilial variation.[
Cutaneous leiomyomas present as firm papules or nodules that appear pink or reddish-brown. These lesions usually appear on the trunk and the extremities and, occasionally, on the face. These lesions occur at a mean age of 25 years (age range, 10–47 y) and tend to increase in size and number with age. Lesions are sensitive to light touch and/or cold temperature; they can also be painful. Pain is correlated with severity of cutaneous involvement.[
The onset of uterine leiomyomas in women with HLRCC occurs at a younger age than in women in the general population. The age at diagnosis ranges from 18 to 63 years (mean age, 30 y). One series reported uterine leiomyomas in 18 of 29 women (62%) with a pathogenic or likely pathogenic variant in FH; the ages of the women ranged from 24 to 63 years.[
Renal Cell Cancers (RCCs)
The symptoms of RCC may include hematuria, lower back pain, and a palpable mass. However, a large number of individuals with RCC are asymptomatic. Furthermore, not all individuals with HLRCC present with or develop RCC. Most RCCs are unilateral and solitary; in a few individuals, they are multifocal. The exact incidence of RCC in affected individuals remains to be determined, and widely varying estimates have been provided by different groups (1%–60%).[
Figure 1. Hereditary leiomyomatosis and renal cell cancer–associated renal tumors are commonly unilateral and solitary; in a few individuals, they are multifocal. Red arrow indicates a retroperitoneal lymph node. White arrow indicates a left renal mass.
It is unclear whether women with HLRCC have a higher risk of developing uterine leiomyosarcomas than women of similar age in the general population. In the original description of HLRCC, it was reported that 2 of 11 women with uterine leiomyomas also had a uterine leiomyosarcoma, a cancer that may be clinically aggressive if not detected and treated at an early stage.[
Four FH-positive individuals with breast cancer, one case of bladder cancer, and one case of bilateral macronodular adrenocortical disease with Cushing syndrome have been reported. A series from the NCI found that 20 of 255 patients (7.8%) with HLRCC had adrenal nodules, some of which did not appear to be adenomas based on imaging characteristics. Because many of these lesions were fluorodeoxyglucose avid, resections were performed and all showed evidence of both micronodular and macronodular adrenal hyperplasia, suggesting that adrenal nodules could be an additional manifestation of HLRCC.[
Cutaneous leiomyomas are believed to arise from the arrectores pilorum muscles attached to the hair follicles. Histologically, these are dermal tumors that spare the epidermis. Morphologically, these tumors have interlacing smooth muscle fibers interspersed with collagen fibers.[
A review of the National Cancer Institute's experience with hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated uterine leiomyomas reported that most of these cases were well-circumscribed fascicular tumors with occasional cases showing increased cellularity and atypia. The hallmark feature of these cases was similar to those observed in HLRCC kidney cancer: the presence of orangeophilic, prominent nucleoli that are surrounded by a perinuclear halo. While some cases had atypical features, no cases had tumor necrosis or atypical mitosis suggestive of malignancy or leiomyosarcoma.[
The renal cell cancers (RCCs) associated with HLRCC have unique histologic features, including the presence of cells with abundant amphophilic cytoplasm and large nuclei with large inclusion-like eosinophilic nucleoli. These cytologic features were attributed to type 2 papillary tumors in the original description.[
Diagnosis and Testing
Genetic testing for the FHgene is clinically available and performed by Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. FH currently is the only gene known to be associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). Most patients with HLRCC have a germline pathogenic variant in FH.
Because the genetic analysis of HLRCC is complex, any interpretation of a variant of unknown significance result needs to be performed with consultation by clinical cancer geneticists, ideally in a center that has significant experience with this disease.
There is no current consensus on the diagnostic criteria for HLRCC.[
Some experts suggest that a clinical dermatologic diagnosis of HLRCC requires one of the following:[
More recent comprehensive criteria for diagnosis have been suggested and are often used by experts in the field. Suggested criteria include dermatologic manifestations as above or a combination of two of the following manifestations:[
Collecting duct RCC before age 40 years has been suggested as an additional criterion.[
Cutaneous leiomyomas are rare. The detection of multiple lesions is specific to HLRCC. Because leiomyomas are clinically similar to various cutaneous lesions, histologic diagnosis is required to objectively prove the nature of the lesion.
Uterine leiomyoma is the most common benign pelvic tumor in women in the general population. Most uterine leiomyomas are sporadic and nonsyndromic.[
Diagnostic clues of HLRCC may rely on the presence of several phenotypic features in different organs (cutaneous, uterine, and renal). One or more of these characteristic features may be present in the patient or in one or more of their affected biologic relatives.
Although familial RCCs are associated with rather specific renal pathology, the rarity of these syndromes results in few pathologists gaining sufficient experience to recognize their histologic features.
The differential diagnoses may include other rare familial RCC syndromes with specific renal pathology, including:
Genetic testing is used clinically for diagnostic confirmation of at-risk individuals. It is recommended that both pretest and posttest genetic counseling be offered to persons contemplating germline pathogenic variant testing.[
Genetic testing for a germline FH pathogenic variant is indicated in all individuals known to have or who are suspected of having HLRCC, regardless of family history. This includes individuals with cutaneous leiomyomas, as described in the Clinical diagnosis section of this summary, or individuals who have renal tumors with histologic characteristics consistent with HLRCC.[
Risk to family members
HLRCC is inherited in an autosomal dominant manner.[
Parents of a proband
Although some individuals diagnosed with HLRCC have an affected parent, the family history may appear to be negative because of limited family history, failure to recognize the disorder in family members, early death of the affected parent before the onset of syndrome-related symptoms, or late onset of the disease in the affected parent.[
Siblings of a proband
Testing of at-risk family members
Use of genetic testing for early identification of at-risk family members improves diagnostic certainty. It reduces the number of unnecessary costly and stressful screening procedures in at-risk members who have not inherited their family's disease-causing variant.[
Early recognition of clinical manifestations may allow timely intervention, which could, in theory, improve outcome. Therefore, clinical surveillance of asymptomatic at-risk relatives for early RCC detection is reasonable, but additional objective data regarding the impact of screening on syndrome-related mortality are needed.
Related genetic counseling issues
Predicting the phenotype in individuals who have inherited a pathogenic variant
It is not possible to predict whether HLRCC-related symptoms will occur or, if they do, what the age at onset, type, severity, or clinical characteristics will be in individuals who have a pathogenic variant. In an in-depth characterization of clinical and genetic features analyzed within 21 new families, the phenotypes displayed a wide range of clinical presentations and no apparent genotype -phenotype correlations were found.[
When neither parent of a proband with an autosomal dominant condition has the disease-causing variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, nonmedical explanations include the possibility of alternate paternity or undisclosed adoption. Genetic testing of at-risk family members is appropriate in order to identify the need for continued lifelong clinical surveillance. Interpretation of the pathogenic variant test result is most accurate when a disease-causing variant has been identified in an affected family member. Those who have a disease-causing variant are recommended to undergo lifelong periodic surveillance. Meanwhile, family members and offspring who have not inherited the pathogenic variant are thought to have RCC risks similar to those in the general population; no special management of these individuals is recommended.
Early detection of at-risk individuals affects medical management
Screening for early disease manifestations in HLRCC is an important aspect of clinical care of affected individuals. Although there are no prospective studies comparing specific renal cancer screening practices, the aggressive nature of HLRCC-associated RCC [
Uterine fibroids often cause significant symptoms related to bleeding and the presence of a large mass, but small fibroids may be asymptomatic. As HLRCC fibroids can lead to hysterectomies and loss of the ability to bear children in affected young women, the goal of screening in women interested in preserving fertility is to limit some of these irreversible complications. Although there are no specific management recommendations related to HLRCC-associated fibroids, various management strategies have proven effective in the treatment of sporadic fibroids. These strategies include use of hormonal therapies, pain medications, percutaneous and endovascular procedures, and surgical options. Early referral to a fertility specialist may be useful to assist with family planning.
It has been suggested that individuals with a suspected or confirmed diagnosis of HLRCC, individuals with heterozygous pathogenic variants in FH regardless of clinical manifestations, and at-risk family members who have not undergone genetic testing undertake the following regular surveillance, performed by physicians familiar with the clinical manifestations of HLRCC.
Any suspicious renal lesion (indeterminate, questionable, or complex cysts) at a previous examination should be closely followed with periodic imaging, preferably using the same modality to allow for comparisons. The use of renal ultrasound examination may be helpful in the characterization of cystic lesions identified on cross-sectional imaging. It should be cautioned that ultrasound examination alone is never sufficient. Renal tumors should be evaluated by a clinician familiar with HLRCC-related renal cancer.[
Because of the aggressive growth of these tumors, patients warrant regular surveillance with a low threshold for early surgical intervention for solid renal lesions. This strategy differs from that described for several other hereditary RCC syndromes, in which the tumor behavior is more indolent, and for which observation may be a viable option.[
Level of evidence (skin surveillance): 5
Level of evidence (uterine surveillance): 4
Level of evidence (renal surveillance): 4
Treatment of Manifestations
Cutaneous leiomyomas are most appropriately examined by a dermatologist. Generally, asymptomatic cutaneous leiomyomas require no treatment. Treatment of symptomatic cutaneous leiomyomas may be difficult if a patient has diffuse disease in a wide distribution. Surgical excision may be performed for a solitary painful lesion. Lesions can be treated by cryoablation and/or lasers. Several medications, including calcium channel blockers, alpha blockers, nitroglycerin, antidepressants, and antiepileptic drugs, reportedly reduce leiomyoma-related pain.[
Level of evidence: 5
Uterine leiomyomas are best evaluated by a gynecologist. HLRCC-associated leiomyomas are treated in the same manner as sporadic leiomyomas. However, because of the multiplicity, size, and potential rapid growth observed in HLRCC-related uterine leiomyomas, most women may require medical and/or surgical intervention earlier and more often than would be expected in the general population. Medical therapy (currently including gonadotropin-releasing hormone agonists, anti-hormonal medications, and pain relievers) may be used to initially treat uterine leiomyomas, both to decrease their size in preparation for surgical removal and to provide temporary relief from leiomyoma-related pain. When women desire fertility preservation, myomectomy can be used to remove leiomyomas and simultaneously preserve the uterus. Hysterectomy should be performed only when necessary.[
Level of evidence: 4
Efforts aimed at early detection of HLRCC-related RCC are prudent, given its biological aggressiveness. However, studies do not currently show that early detection is clearly associated with improved survival. Surgical excision of these malignancies at the first sign of disease is recommended, unlike management of other hereditary cancer syndromes. The propensity for lymph node involvement, even with small renal tumors, may necessitate a lymph node dissection for more appropriate staging.[
Level of evidence: 4
Therapies under investigation
It has been suggested that hypoxia-inducible factor (HIF1)-alpha overexpression is involved in HLRCC tumorigenesis.[
Loss of oxidative phosphorylation resulting from biallelic inactivation of FH renders HLRCC tumors almost entirely reliant on aerobic glycolysis for meeting cellular adenosine triphosphate and other bioenergetics requirements. Consequently, targeting aerobic glycolysis is being explored as a therapeutic strategy.[
Other investigations [
General information about clinical trials is also available from the NCI website.
Prognosis is quite good for cutaneous and uterine manifestations of hereditary leiomyomatosis and renal cell cancer (HLRCC). Local management of cutaneous manifestations, when required, and hysterectomy, where indicated, address these sites fairly effectively and with minimal long-term consequences. The incidence of uterine leiomyosarcomas is likely quite low and is unlikely to substantively affect median survival at a cohort level. Renal cell cancer (RCC) in the context of HLRCC is a considerably more ominous manifestation, and the HLRCC patients who develop RCC [
There are two major unmet needs, other than the availability of effective medical therapy for metastatic disease, in the management of patients with hereditary leiomyomatosis and renal cell cancer (HLRCC). The first is the ability to predict who will develop renal cell cancer to allow detection earlier and with a higher degree of precision. The development of diagnostic blood-based tests or imaging tools that permit cost-effective surveillance of the kidneys of patients with HLRCC would have a major positive effect on the outcomes of these individuals. The second major unmet need is for a more accurate determination of the genotype -phenotype correlations for various genetic lesions found in the FHgene. New polymorphisms in the FH gene are frequently of uncertain significance, and considerable effort needs to be expended to determine their clinical significance. Devising in silico prediction tools and linking these to robust patient databases and registries will expand our understanding of specific FH gene variants.
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