Multiple Cutaneous and Uterine Leiomyomatosis Syndrome: A Review

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Sonal Choudhary, MD; Michael McLeod, MS; Daniele Torchia, MD; Paolo Romanelli, MD
Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida

Disclosure: The authors report no relevant conflicts of interest.

Abstract
Multiple cutaneous and uterine leiomyomatosis is an autosomal dominant disease characterized by leiomyomas of the skin and uterus. A small proportion of patients affected by multiple cutaneous and uterine leiomyomatosis will develop renal cell carcinoma and this condition is known as hereditary leiomyomatosis and renal cell carcinoma. Diagnosis usually occurs during histological analysis of a cutaneous biopsy. Management should involve a multidisciplinary team along with periodical radiological studies to closely monitor tumor size in the uterus and kidneys. Gonadotropin-releasing hormone analogues are helpful in reducing the size of uterine fibroids.  (J Clin Aesthet Dermatol. 2013;6(4):16–21.)

Formerly known as Reed’s syndrome, multiple cutaneous and uterine leiomyomatosis (MCUL) (OMIM 150800) is an autosomal dominant disease characterized by leiomyomas of the skin and uterine leiomyomas. When MCUL is associated with different forms of renal cancer, it is referred to as hereditary leiomyomatosis and renal cell cancer (HLRCC) (OMIM 605839). MCUL was first described in 1973 by Reed et al[1] who emphasized an association between cutaneous leiomyomas (CLs) and uterine leiomyomas. In 2001, Launonen et al[2] were the first to report the occurrence of renal cell carcinomas (RCC) in a small proportion of families with MCUL. Both MCUL and HLRCC were demonstrated to result from heterozygous germline mutations in the fumarate hydratase (FH) gene that is believed to function in its normal state as a tumor suppressor gene.[3]

The prevalence of MCUL and HLRCC is unknown. Similarly, neither of the sexes is known to have a higher prevalence. Despite the rare occurrence of this condition, it is vital to recognize it due to its potential to be associated with aggressive renal cell carcinomas and debilitating uterine fibroids.

Presentation
Patients with MCUL/HLRCC can present with a variety of clinical features. Cutaneous leiomyomas are often the earliest lesions of MCUL; therefore, dermatologists are often the first physicians to see affected individuals. In 1854, Virchow described CLs for the first time as rare, slow-growing, benign, smooth muscle tumors of the skin.[4] CLs typically present in the second and fourth decades of life as skin-colored to brown-reddish grouped papules or nodules on the trunk and limbs (Figure 1). Different patterns and distribution of multiple leiomyoma have been observed, such as bilateral, symmetrical, clustered, linear, zosteriform or dermatomal-like arrangements (Figure 1).[5,6] The patients may often complain of pain in these lesions in response to pressure and low temperature; the cause for which remains undetermined, but has often been attributed to pressure on the nerve fibers within the tumor, contraction of smooth muscle fibers developing in leiomyomas, or an increased number of nerve elements within the tumor.[5,7–9] Older lesions may increase in size and newer lesions may emerge. They can be classified into the following three types depending on their site of origin: piloleiomyomas—CLs derived from the arrector pili muscle of the hair follicles; angioleiomyomas—CLs derived from vascular smooth muscles; and dartotic leiomyomas—CLs arising from the smooth muscle of genital skin.

The piloleiomyoma is the most common of the CLs, presenting as multiple tumors (leiomyomatosis) that may be symmetrically distributed either in a diffuse or segmental pattern. The band-like or segmental distribution generally indicates mosaicism.[10–15] Happle[12] had postulated that whenever segmental skin lesions exhibit the same degree of severity as seen in the nonmosaic trait, with the absence of a germline mutation, it can be classified as a type 1 segmental involvement. On the other hand, if the severity of cutaneous involvement observed in the segmentally affected skin is more pronounced, it could be explained by the loss of heterozygosity (LOH) at the same locus that caused the phenotypically less severe and diffuse involvement and should be referred to as type 2 segmental involvement.[12] This postulate of Happle was confirmed on a molecular and cellular level in the condition Hailey Hailey[16]; however, the postulate has not yet been confirmed in hereditary cutaneous leiomyomatosis.

Microscopic Analysis
Histologically, cutaneous leiomyomas present as poorly circumscribed lesions of interlacing bundles of smooth muscle fibers and varying amounts of collagen bundles, primarily in the dermis, which may encroach into the subcutaneous tissue (Figure 2).[5] The cytoplasm of the smooth muscle cells is eosinophilic and the nuclei are “cigar shaped.” Positive staining with anti-desmin and anti-? smooth muscle actin is seen on immunohistochemistry.[5] The cutaneous leiomyosarcoma also shows a similar histological picture as the cutaneous leiomyoma; however, mitotic figures and atypical cells are present. Additionally, unlike uterine leiomyomas, cutaneous leiomyomas do not demonstrate estrogen and progesterone receptors upon immunohistochemistry.[17]

Ninety percent of women with MCUL develop uterine leiomyomas. As uterine fibroids are a common occurrence in the general population, the diagnosis of MCUL is easy to miss. The symptoms of patients with or without MCUL and uterine fibroids are quite similar, including menorrhagia, pelvic pressure or pain, and possibly anemia and subfertility. These symptoms should prompt suspicion for MCUL if the patient’s symptoms are severe enough to lead to a hysterectomy before 30 years of age and/or are associated with cutaneous lesions.[18] A small number of MCUL/HLRCC patients may develop uterine leiomyosarcoma, which is a highly aggressive malignant tumor, before 30 years of age; a finding so far only observed in the Finnish population.[19,20] Histologically, uterine leiomyomas are characterized by whirled bundles of closely packed elongated smooth muscle cells, with elongated and uniform nuclei.[21] Uterine leiomyosarcomas demonstrate a similar picture, but show high mitotic activity, nuclear atypia, and tumor necrosis.[22] There has been a report of familial cutaneous leiomyoma in association with a symplastic uterine leiomyoma, wherein the patient presented with a uterine tumor that had some degree of nuclear atypia, low mitotic activity, and no myxoid change or coagulative necrosis.[23] The symplastic uterine leiomyoma is therefore also known as bizarre/atypical/ pleomorphic leiomyoma.

Clinical Features of HLRCC
A proportion of patients with MCUL may develop renal cell cancer (RCC), which is approximately 15.6 percent of FH-mutation-positive individuals.[24] The mean age at detection of RCC is 44 years.[24] The symptoms of RCC include hematuria, lower back pain, a palpable mass, or diverse symptoms associated with metastasis, such as inferior vena cava syndrome. The renal tumors associated with HLRCC are usually solitary and unilateral. Few cases of bilateral RCC in HLRCC have been reported.[25,26] The most common type of RCC seen in HLRCC is type II papillary RCC (PRCC II) followed by collecting duct cancer (CDC). Oncocytoma, or clear cell cancer, and Wilms tumor have also been described.[25,27] Metastases occur in 50 percent of the patients with RCC in MCUL, a disproportionately high percentage in comparison to the size and number of primary tumor or tumors. Microscopically, PRCC II generally shows large cells with abundant cytoplasm, a high Fuhrman nuclear grade, and large and prominent “owl-eye” nuclei outlining thick lengthened papillae.[28,29] Besides this, tubular, tubulopapillary, and cystic growth patterns may be seen in HLRCC-related RCC. According to the observations made by Merino et al[25] in their study of 40 RCCs from HLRCC patients, they concluded that a majority of the tumor cells had characteristic eosinophilic nucleoli with a clear perinuclear halo, irrespective of the histological pattern.[25] Furthermore, using immunohistochemistry, absence of cytokeratin 7 (CK7), and Ulex europaeus agglutinin (UEA-1) could help to reach the diagnosis of HLRCC-associated renal tumor.[25] FH-specific antibodies could also point toward HLRCC-associated malignant tumors.

Genetics
The gene for MCUL and HLRCC encoding FH enzyme has been linked to the chromosome 1q42.3–q43.30 The FH enzyme is responsible for catalyzing the conversion of fumarate to malate in the Kreb’s cycle. Heretozygous germline mutations in the FH gene, found in MCUL and HLRCC, indicate that these disorders are allelic.[31] FH is believed to be a tumor suppressor gene such that when it loses its wild-type allele, it can lead to the development of tumors, as demonstrated through cutaneous and uterine tumor biopsies of MCUL and HLRCC patients.[32–34] Several mutations spread over the FH gene have been identified to date, including missense (58%), frameshift (27%), nonsense (9%), and whole gene deletions (7%), amounting to 73 different mutations and counting.[33,35] However, there is no clear evidence of a genotype-phenotype correlation for MCUL.[3,31] The most frequent germline mutation demonstrated is N64T.[36] Due to the possibility, but low frequency of RCC in MCUL, it is believed by some that a heterozygous germline mutation alone is most likely not sufficient to cause RCC, and there may be an important role of additional genetic inactivation, such as loss of heterozygosity or a second hit mutation, that leads to the development of renal cancers.[36]

Etiology
In a study by Badeloe et al,[37] the investigators explored the molecular basis of diffuse and segmental cutaneous leiomyomatosis in six unrelated patients of Dutch and Spanish origin. By using polymerase chain reaction (PCR) technique, they identified six novel mutations and also indicated that in cutaneous leiomyomatosis, segmental manifestation patterns are encountered more often than in other autosomal dominantly inherited diseases.[37] The steps that take place from an FH mutation to development of tumors in MCUL are not clearly understood, but recent studies suggest the possible role of a pseudohypoxic drive.[38,39] It has been suggested that the loss of mitochondrial FH could lead to accumulation of fumarate intracellularly, which in turn could be a factor to stabilize transcription factors, such as hypoxia-inducible factors 1? and 2? (HIF 1? and 2?).[39] HIF regulates transcription of anti-apoptotic factors and proliferative genes, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), endothelial growth factor receptor (EGFR), glucose transporter protein 1 (Glut-1), and transforming growth factor-? (TGF-?). Overexpression of these gene products is associated with pseudohypoxia (improved vascularity, autocrine stimulation, uncontrolled growth, and survival of the cell); all factors conducive for tumor development.[40,41] This theory receives further support from recent studies—first, demonstrated by increased expression of HIF 1? and 2? and Glut-1 in RCC from HLRCC patients and second, where enhanced expression of VEGF was seen in leiomyomas of HLRCC patients.[38,39]

Alam et al[36] reviewed in depth the possible association between FH mutations and MCUL and HLCC. They studied four cohorts of patients; 2 from North America (Toro et al[31] and Martinez-Mir et al[42]), one from United Kingdom, and one from Finland.[3,31,33,36,42] Of the 89 MCUL probands investigated, germline FH mutations were found in 76 (85%). Table 1 represents some important findings of the review by Alam et al. They found that truncating, particularly frameshift, mutations appeared to be significantly associated with renal cancer. Hormonal factors could also play a role as animal studies suggest that prolonged estrogen administration could predispose to RCC.[43] It was demonstrated in Alam et al’s review that of 20 MCUL/HLRCC patients whose sex was known, 16 (80%) were females.

Management
Based on their review, Alam et al also weighed the advantages and disadvantages of screening patients with MCUL for RCC. Although RCC in MCUL is associated with a high mortality, the low overall risk of RCC, the adverse effects of radiation exposure through radiological investigations, the associated anxiety for the patient and the requirement for resources, makes screening controversial. PRCC II is also the most common histological subtype of RCC found in MCUL/HLRCC, and this subtype is often isoechoic on ultrasound making if difficult to distinguish from normal surrounding tissue; therefore, the modality of choice to image these tumors is computerized tomography (CT) scan or magnetic resonance imaging (MRI).[31] Thus, it is advised that prospective radiological screening could possibly be limited to individuals, especially females, from families with previous cases of renal cancer and/or families with truncating mutations.[31]

Besides screening, the management of MCUL requires a multidisciplinary approach due to the presence of multiple and diverse conditions. Genetic counseling is very important in patients with a family history of this condition. It can help to establish a diagnosis at an asymptomatic stage, and women can plan early pregnancies to avoid any infertility issues related to their uterine fibroids, which tend to appear in the third or fourth decade of life.

The cutaneous leiomyomas and leiomyosarcomas are not only a cosmetic problem, but also often cause discomfort and pain that can disturb the patient’s daily activities. Solitary leiomyomas can be managed by surgical excision; however, multiple lesions extending over larger surfaces of the skin may be difficult to excise. Furthermore, 50 percent of cases may recur. Pain relief can be achieved by medications, such as nifedipine, gabapentin, doxasozine, phenoxybenzamine, hyoscine, hydrobromide, and nitroglycerine.[9,44–51] Modalities such as electrocoagulation, cryotherapy, and CO2 laser ablation can possibly replace extensive surgeries in certain cases.[5,52] A combination therapy may prove to be useful.

The uterine leiomyomas in MCUL patients are generally multiple and very symptomatic. Myomectomy (surgical removal of fibroids) can be performed for the leiomyomas; however, the recurrence and large numbers of these tumors, may not warrant permanent relief. In case of suspicion or diagnosis of leiomyosarcoma, the treatment of choice is hysterectomy with peritoneal washings and omentectomy. Myomectomy can be considered for patients with low-stage leiomyosarcoma who strongly desire fertility.[53] Pharamacological agents, such as gonadotropin-releasing hormone analogues, are valuable options to reduce/treat uterine leiomyoma, as these agents act on progesterone and/or estrogen receptors to suppress the growth of fibroids.

The aggressive nature of the RCC in HLRCC suggests that nephrectomy may actually be beneficial in the early stages, although no standard of treatment is known in HLRCC for renal tumors. The advancement in knowledge of the molecular pathways in the pathogenesis of RCC has led to development of targeted therapies in hereditary malignant kidney tumors.[54,55]

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