Hereditary leiomyomatosis and renal cell cancer (HLRCC)

INTRODUCTION — Cutaneous leiomyomas, also called piloleiomyomas, are uncommon benign smooth muscle tumors derived from the arrector pili muscle, which is responsible for piloerection of hair follicles. Piloerection, commonly known as "goose bumps," is an involuntary process that may occur upon cold exposure as well as a variety of emotional states (eg, fear, pleasure).

Cutaneous leiomyomas may occur sporadically or in multiple numbers as part of an autosomal dominant cancer syndrome called hereditary leiomyomatosis and renal cell cancer (HLRCC; MIM #150800) [1,2]. The discovery in 2001 of the association between cutaneous leiomyomas, uterine leiomyomas in women, and an aggressive form of renal cell cancer (RCC) underscores the importance of accurate dermatologic diagnosis of CL so that appropriate cancer screening and counseling of patients and at-risk relatives can be instituted [3].

This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and management of HLRCC. The treatment of RCC is discussed separately. Other hereditary renal cancer syndromes and uterine leiomyomatosis are also discussed separately.

●(See "Overview of the treatment of renal cell carcinoma".)

●(See "Hereditary kidney cancer syndromes".)

●(See "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history".)

●(See "Uterine fibroids (leiomyomas): Variants and smooth muscle tumors of uncertain malignant potential", section on 'Fumarate hydratase deficiency'.)

TERMINOLOGY — Prior to the discovery of the association with renal cell cancer (RCC), the co-occurrence of uterine leiomyoma and cutaneous leiomyomas was known under several different eponyms, including Reed syndrome, multiple cutaneous leiomyomas (MCL), and multiple cutaneous and uterine leiomyomatosis syndrome (MCUL1), leading to potential confusion regarding the associated cancer risk [4]. It is now well established that all of these syndromes are associated with variants in the fumarate hydratase gene (FH). (See 'Pathogenesis' below.)

EPIDEMIOLOGY — The incidence of hereditary leiomyomatosis and renal cell cancer (HLRCC) is unknown. Worldwide, approximately 200 families have been identified. The overall penetrance of HLRCC in affected families has been reported to be 90 to 100 percent [5]. A population-based genome study reported an overall frequency of fumarate hydratase gene (FH) alterations of 1 in 1000 individuals, suggesting a potentially higher asymptomatic carrier frequency [6]. Cutaneous leiomyomas and uterine leiomyomas are much more penetrant (76 to 100 percent and 80 to 90 percent, respectively) than renal cell cancer (15 to 20 percent) [4,5,7,8].

PATHOGENESIS — Hereditary leiomyomatosis and renal cell cancer (HLRCC) is caused by autosomal dominantly inherited germline heterozygous variants in the fumarate hydratase gene (FH) on chromosome 1q42.2, encoding the Krebs cycle enzyme responsible for the conversion of fumarate to malate [9]. This disorder must be differentiated from fumarase deficiency (MIM #606812), an autosomal recessive condition that is lethal in the neonatal period due to neurologic disease and is associated with homozygous or compound heterozygous germline FH hydratase variants. Specific germline FH variants have also been identified in malignant pheochromocytomas and paragangliomas, although affected patients do not appear to manifest the skin or internal manifestations characteristic of HLRCC [10].

Germline FH heterozygous variants have been identified in 76 to 100 percent of families with clinical features suggestive of HLRCC [4]. Inactivating FH variants are thought to lead to tumorigenesis via activation of the hypoxia inducible factor 1 (HIF-1) pathway. Impairment of oxidative phosphorylation leads to oxidative stress, inhibiting HIF prolyl hydroxylase, which in turn stabilizes HIF-1-alpha, resulting in transcription of genes integral for tumor vascularity, such as vascular endothelial growth factor (VEGF) [11].

PATHOLOGY — Histologically, cutaneous leiomyomas (CL) are characterized by interlacing bundles of smooth muscle cells in the upper dermis (picture 1). Increased nerve density has been described within CL lesions compared with the surrounding dermis [12].

Uterine leiomyomas in the hereditary leiomyomatosis and renal cell cancer (HLRCC) setting are often multiple, large (1 to 8.5 cm), and histologically show characteristic inclusion-like nucleoli. Occasional mitosis is also a feature of HLRCC-associated uterine leiomyomas, but tumor cell necrosis and atypical mitosis suggestive of leiomyosarcoma are not typically seen. Indeed, one study reported that HLRCC uterine leiomyomas demonstrate increased cellularity, atypia, and occasional mitoses, as compared with sporadic leiomyomas, but do not fulfill criteria for malignancy [13].

Renal cell carcinoma in HLRCC demonstrates a unique papillary histology distinct from the classic papillary type I pattern associated with hereditary papillary renal cell carcinoma (MIM #605074) [4]. Cells in the renal cancers associated with HLRCC have a characteristic large nucleus with prominent orangeophilic or eosinophilic nucleolus surrounded by a clear halo [14]. These tumors, previously called type II papillary renal cell cancer (RCC) and subsequently reclassified as "HLRCC-associated RCC" [15], are highly aggressive and frequently metastasize when the primary tumor is still quite small (<1 cm) [4].

Abnormal succination of cellular proteins has been demonstrated by immunohistochemical detection of S-(2-succino)-cysteine (2SC) in renal tumors in affected patients [16]. Similarly, the immunohistochemical detection of 2SC in cutaneous leiomyomas improves the diagnostic accuracy of HLRCC, compared with the loss of fumarate hydratase staining alone [17].

CLINICAL MANIFESTATIONS

Cutaneous leiomyomas — Cutaneous leiomyomas typically present as firm, red or reddish-brown nodules, ranging in size from 3 mm to 1 cm (picture 2A-B). Small lesions may appear as fine, slightly raised papules, whereas larger nodules may be quite exophytic and protrude significantly from other surrounding lesions (picture 2G). Rarely, isolated leiomyomas may develop from specialized smooth muscle of the scrotum (dartos muscle), vulva, or nipple (areolar smooth muscle). In contrast to piloleiomyoma, leiomyomas derived from genital skin are usually asymptomatic.

In individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC), multiple cutaneous leiomyomas develop in early adulthood (mean age 25 years) as discrete or agminated pink to tan nodules, most frequently on the trunk, particularly the upper back, as well as the upper and lower extremities (picture 2A-G). Three patterns have been described: scattered (picture 2D), segmental (picture 2C), and disseminated (picture 2E) [5]. Multiple patterns may occur in the same patient.

Although patients with HLRCC usually have multiple cutaneous leiomyomas, there are several reports of patients with a family history of renal cell cancer (RCC) and germline fumarate hydratase (FH) variants who have small numbers of leiomyomas, a single cutaneous leiomyoma, or lack any cutaneous manifestations of the disease [7,18].

The hallmark clinical symptom of cutaneous leiomyomas is pain, reported in approximately 90 percent of patients. Pain may be provoked by ambient cold or ice provocation, light touch, pressure, or incidental contact and may be sharp, shooting discomfort, or may have an aching quality. Pain contributes to moderate to severe impairment in quality of life in approximately 20 percent of patients [5].

Although pain is a consistent feature of most cutaneous leiomyomas, the intensity is highly variable among patients, and patients may not volunteer this symptom if pain is infrequent or relatively mild. A history of episodic pain upon cold exposure, rubbing, or pressure is a classic sign associated with cutaneous leiomyomas. The mechanism of pain associated with cutaneous leiomyomas is poorly understood, but may be related to neuropeptide release, pressure on nerve fibers within lesions, or contraction of the arrector pili muscle.

Uterine leiomyomas — Uterine leiomyomas are common in the general population, but are, in most cases, small and asymptomatic [19-21]. In the HLRCC setting, uterine leiomyomas develop at an earlier age than in the general population, tend to be large and multiple, and are symptomatic in the majority of cases. (See "Uterine fibroids (leiomyomas): Variants and smooth muscle tumors of uncertain malignant potential", section on 'Fumarate hydratase deficiency'.)

Symptoms may include irregular menses, menorrhagia, and pain. In one review of 67 women with FH variants, 76 percent were diagnosed with uterine leiomyomas at a median age of 30 years (range 19 to 47 years) [5]. Ninety percent of the women with uterine fibroids were symptomatic and 65 percent underwent hysterectomy at a median age of 34 years (range 27 to 47 years). In another study of 75 women with FH variants, 85 percent had uterine fibroids diagnosed at a median age of 28 years, and approximately 50 percent underwent hysterectomy before the age of 43 [22].

Risk of renal cell cancer — The lifetime renal cancer risk in HLRCC is approximately 15 percent and the median age at diagnosis is 42 to 44 years [8,23]. However, an 11-year-old patient with RCC has been described in the literature [24]. Because genotypic correlation between specific FH variants and RCC risk and phenotypic correlation between cutaneous or uterine leiomyoma burden and RCC risk are not possible, all individuals known to have an FH variant and those suspected to have an FH variant (eg, individuals with multiple cutaneous leiomyomas or early-onset uterine leiomyomas) should be screened for RCC.

HLRCC-associated renal tumors are typically solitary, unilateral, and are among the most aggressive of heritable renal cancers. Frequent screening is recommended to detect small tumors for which early surgical intervention may decrease the potential for metastatic disease. (See 'Surveillance for renal cancer' below and "Hereditary kidney cancer syndromes".)

DIAGNOSIS

Clinical diagnosis — The diagnosis of cutaneous leiomyoma is suspected in a patient presenting with single or multiple papules or nodules located on the trunk or extremities that are typically tender to the touch. A history of episodic pain upon cold exposure, rubbing, or pressure is characteristic.

The presence of multiple cutaneous leiomyomas should raise suspicion for hereditary leiomyomatosis and renal cell cancer (HLRCC). Proposed criteria for the clinical diagnosis of HLRCC include [1,25]:

●Major criterion

•Multiple cutaneous leiomyomas, with at least one histologically confirmed lesion.

●Minor criteria

•Solitary cutaneous leiomyoma and family history of HLRCC.

•In women, onset of severely symptomatic uterine fibroids before age 40.

•Type II papillary renal cell cancer before age 40.

•First-degree family member who meets one of the above-mentioned criteria. The occurrence of severely symptomatic uterine leiomyomas before the age of 40 years in second-degree paternal family members may also be relevant.

The presence of multiple cutaneous leiomyomas indicates a high likelihood of HLRCC. The diagnosis of HLRCC is suspected if ≥2 minor criteria are present.

Biopsy — A skin biopsy is necessary to confirm the diagnosis of cutaneous leiomyoma (see 'Pathology' above). A punch biopsy usually provides sufficient dermal tissue for pathologic diagnosis.

Patients with a histologic diagnosis of cutaneous leiomyoma should receive a complete skin examination by a dermatologist to detect subtle additional lesions. A thorough personal and family history for possible cutaneous leiomyomas, uterine leiomyomas, and/or renal cell cancer should be elicited.

Genetic testing — The definitive diagnosis of HLRCC is based upon the demonstration of a germline variant in the FH gene. Thus, genetic testing should be offered to individuals who present with clinical manifestations of HLRCC or have a family history of HLRCC.

Most experts suggest that deoxyribonucleic acid (DNA) testing be offered starting at the age of 8 to 10 years [8]. However, given the small risk of renal cell cancer before age 20 and the potential drawbacks of screening, the timing of genetic testing should be evaluated on a patient-by-patient basis. (See "Evidence-based approach to prevention", section on 'Unintended consequences of screening'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of isolated cutaneous leiomyomas includes other painful skin tumors such as angiolipoma (picture 3), neurilemmoma, glomus tumor, neuroma, granular cell tumor, and eccrine spiradenoma (picture 4). (See "Overview of benign lesions of the skin".)

Isolated lesions may be mistaken for dermal nevi (picture 5) or small epidermoid cysts (picture 6). Segmental cutaneous leiomyomas may resemble cutaneous neurofibromas (picture 7) as seen in segmental type I neurofibromatosis. However, cutaneous neurofibromas tend to be softer and are not associated with pain provoked by contact or cold exposure.

MANAGEMENT — The management of patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) requires a multidisciplinary approach involving dermatologists, gynecologists, and urologic oncologists [1,8]. Important aspects of management include:

●Control of pain in patients with multiple painful cutaneous leiomyomas

●Regular gynecologic consultation to assess the presence and severity of uterine leiomyomas

●Surveillance for renal cancer

Genetic counseling is extremely important for patients with a family history of HLRCC to identify asymptomatic at-risk family members and initiate surveillance for renal cell cancer (RCC) at an early age.

Treatment of cutaneous leiomyomas

Isolated lesions — Surgical excision is the treatment of choice for cutaneous leiomyomas that are isolated or limited in number. Local anesthesia should be administered with care as pain is often exacerbated by intralesional injection. (See "Subcutaneous infiltration of local anesthetics", section on 'Methods to decrease injection pain'.)

In the HLRCC setting, complete excision of segmental or other large areas of cutaneous leiomyoma involvement may result in large surgical scars that may be cosmetically unacceptable. In addition, a recurrence rate of 50 percent has been reported in patients with multiple lesions [26].

Multiple clustered or diffuse lesions — For patients with numerous symptomatic cutaneous leiomyomas for whom surgery is not a viable option due to location, burden of disease, or cosmetic outcome, several alternative ablative, topical, or systemic treatments have been attempted. However, evidence on their efficacy is limited to single case reports and one small, randomized trial.

Successful treatment of cutaneous leiomyomas has been reported with carbon dioxide laser [27]; intralesional corticosteroids [28]; calcium channel blockers (nifedipine 10 mg three to four times daily) [29,30]; non-selective alpha antagonists (phenoxybenzamine 20 to 60 mg daily); selective alpha-1 antagonists (doxazosin 1 mg daily) [31,32]; nitroglycerin [33]; narcotic and non-narcotic analgesic agents [34,35]; neuroactive agents such as gabapentin or pregabalin and duloxetine (100 to 300 mg three times daily) [36-38]; and botulinum toxin [39-41].

One small randomized clinical trial including 18 patients evaluated the efficacy of intralesional botulinum toxin to ameliorate leiomyoma-associated pain [42]. Compared with placebo, treatment with botulinum toxin was associated with increased skin-related quality of life, but no change in average lesional pain or pain after ice provocation.

Surveillance for renal cancer — Appropriate screening for RCC and long-term follow-up surveillance imaging is the most important aspect of HLRCC management. Genetic testing, if available, should be offered prior to renal cancer surveillance in order to avoid unnecessary imaging in individuals lacking a fumarate hydratase (FH) variant [8]. Although DNA testing of late-onset hereditary cancer syndromes is generally recommended at age 16 to 18 when the individual can provide informed consent, there is a small but definite risk of RCC prior to this age, suggesting that genetic screening should be considered at an earlier age [8]. (See 'Genetic testing' above.)

Contrast-enhanced magnetic resonance imaging (MRI) with 1 to 3 mm slices through the kidneys is recommended every 6 to 12 months by most groups [8]. Ultrasound may not detect small tumors and is not recommended unless no other modality is available. Prompt surgical intervention with wide surgical margins and consideration of retroperitoneal lymph node dissection are recommended even for small tumors, given the aggressive metastatic potential of HLRCC-associated RCC [8]. (See "Definitive surgical management of renal cell carcinoma".)

PROGNOSIS — The lifetime renal cancer risk for fumarate hydratase (FH) variant carriers is 15 to 20 percent [7,8]. The risk of renal cell cancer (RCC) between ages 10 and 20 in FH carriers is approximately 1 to 2 percent and continues to increase through adulthood [8]. These renal tumors tend to be aggressive, with rapid nodal and distant dissemination even if the primary tumor is relatively small [43].

Early-onset symptomatic uterine leiomyomas may result in myomectomy or hysterectomy during childbearing years. A small number of uterine leiomyosarcoma cases have been reported in the hereditary leiomyomatosis and renal cell cancer (HLRCC) setting [44]. However, in a Finnish cohort of HLRCC families, reevaluation of pathology specimens according to current World Health Organization diagnostic criteria led to the reclassification of several uterine leiomyosarcomas as atypical leiomyomas [4].

Although cutaneous leiomyosarcoma has been reported in association with HLRCC, including in one member of the family originally described by Reed [45], the risk of this cutaneous malignancy appears to be very low. In our experience, cutaneous leiomyomas are frequently interpreted as having atypical histopathologic features concerning for leiomyosarcoma but are more correctly classified as benign [46]. Clinicopathologic correlation with a pathologist experienced in HLRCC may be helpful.

SUMMARY AND RECOMMENDATIONS

●Definition – Cutaneous leiomyomas are uncommon benign smooth muscle tumors derived from the arrector pili muscle. They may occur sporadically or in multiple numbers as part of an autosomal dominant cancer syndrome called hereditary leiomyomatosis and renal cell cancer (HLRCC), which is characterized by multiple cutaneous and uterine leiomyomas and an increased risk of renal cell cancer. (See 'Introduction' above.)

●Pathogenesis – HLRCC is caused by autosomal dominantly inherited germline heterozygous variants in the fumarate hydratase gene (FH), encoding the Krebs cycle enzyme responsible for the conversion of fumarate to malate. (See 'Pathogenesis' above.)

●Clinical presentation – Individuals with HLRCC develop multiple cutaneous leiomyomas in early adulthood, most frequently on the trunk and extremities (picture 2A-G). Most affected women develop multiple symptomatic uterine leiomyomas at a median age of 28 to 30 years. (See 'Clinical manifestations' above.)

●Risk of renal cancer – The lifetime renal cancer risk in HLRCC is approximately 15 percent and the median age at diagnosis is 42 to 44 years [8,23]. HLRCC-associated renal tumors are typically solitary, unilateral, and are among the most aggressive of heritable renal cancers. (See 'Risk of renal cell cancer' above.)

●Diagnosis – The diagnosis of HLRCC is suspected in patients presenting with multiple cutaneous leiomyomas or in patients with solitary cutaneous leiomyoma and family history of HLRCC. The definitive diagnosis of HLRCC is based upon the demonstration of a germline variant in the FH gene. (See 'Diagnosis' above.)

●Management – The management of patients with HLRCC requires a multidisciplinary approach involving dermatologists, gynecologists, and urologic oncologists. Appropriate screening for renal cell cancer and long-term follow-up surveillance imaging is the most important aspect of HLRCC management. (See 'Management' above and 'Surveillance for renal cancer' above.)

ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the National Institutes of Health or the United States Government or its components.