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Hereditary leiomyomatosis and renal cell carcinoma syndrome: A case report

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Hereditary leiomyomatosis and renal cell carcinoma syndrome: A case report
Hayedeh Ghaninejad MD1, Fatemeh Moeineddin MD1, Ahmadreza Rajaee MD1, Masoud Asgari MD2, Ahmad Salimzadeh3
Dermatology Online Journal 14 (1): 16

1. Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran
2. Department of Pathology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran
3. Department of Rheumatology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran


The simultaneous occurrence of multiple cutaneous leiomyomas, uterine leiomyoimatosis, and renal cancer is described as a cancer syndrome with an autosomal dominant pattern of inheritance. We report a 79-year-old man who presented with multiple hyperkeratotic, erythematous nodules on his right leg with a histological diagnosis of pilar leiomyoma. In a review of systems, gross hematuria, weight loss, and bone pain were noted. His pathologic diagnosis was determined to be metastatic papillary renal cell carcinoma. A family history revealed that his sister had a hysterectomy for uterine leiomyomas. The findings in this case can be attributed to hereditary leiomyomatosis and renal cell carcinoma syndrome.

Cutaneous leiomyomas are benign tumors originating generally from the smooth muscles located at various sites of the body. They are categorized according to the tissue origin as follows: pilar leiomyoma, angioleiomyoma, and genital leiomyoma. Leiomyomas may present in grouped, linear, or dermatomal patterns of firm, red, brown or skin-colored dermal nodules. They involve the extensor surfaces of the extremities, trunk, face, or neck [1, 2].

Pilar leiomyomas are the most common type; they present in two forms, solitary and multiple. The solitary type develops sporadically. The multiple type is thought to have a specific genetic pattern [2].

Multiple cutaneous leiomyomas, uterine leiomyoimatosis, and renal cell cancer make up a cancer syndrome with an autosomal dominant pattern of inheritance. Recent studies indicate the same genetic basis for these manifestations.

Clinical synopsis

Figure 1
Multiple asymptomatic, hyperkeratotic nodules on right leg

A 79-year-old man presented to our dermatology clinic with multiple nodular skin lesions of the lateral side of his right leg that developed over the last year. Upon review of systems, the patient complained of odinophagia, dysphagia, hematuria, and dysuria for 6 months. In addition, he complained of 2 years of severe pain and restricted range of motion involving his right knee and hip joints. Over the last 2 months he noted a weight loss of nearly 30 kg. His family history included a sister who underwent hysterectomy for uterine leiomyomatosis.

Examination of the skin revealed multiple erythematous nodules (measuring 1-1.5 cm) with hyperkeratotic surfaces. No pruritus, flushing, or tenderness to palpation was noted.

The laboratory investigations revealed an erythrocyte sedimentation rate greater than 100 and a hypochromic microcytic anemia. The urinalysis revealed gross hematuria and moderate proteinuria. An ultrasound examination of the kidneys showed that the corticomedullary junction of the right kidney had four cysts with average diameter of 1-1.2 cm. No hepatosplenomegaly or lymphadenopathy was noted. Abdominal CT scan demonstrated several hypodense lesions in the right kidney. A whole body bone scan detected complete destruction of the femoral head, suggesting the differential diagnosis of severe degenerative joint disease or metastasis.

A skin biopsy revealed an intradermal nodular neoplasm composed of proliferating cellular elements with elongated blunt-end nuclei and fibrillar cytoplasm. The cells were arranged in interlacing bundles with a whorl-like appearance. The neoplastic cells were uniform and lacked mitotic figures. The pathologic diagnosis was leiomyoma arising from the erectores pilorum (piloleiomyoma).

Figure 2Figure 3
Figure 2. Intradermal nodular neoplasm with proliferated cellular elements having elongated blunt-end nuclei and fibrillar cytoplasm
Figure 3. Interlacing bundles with whorled appearance of uniform neoplastic cells

Figure 4Figure 5
Figure 4. Uniform neoplastic cells with absence of mitotic figures
Figure 5. Trichrome staining showed proliferative smooth muscle cells with blue color collagen fibers.

Histopathology of the renal cyst revealed a mixture of papillary cells, tubulo- papillary elements and mitotic figures suggestive of papillary renal cell carcinoma. The final diagnosis was hereditary leiomyomatosis and renal cell carcinoma.


Several studies indicate an autosomal dominant basis for multiple cutaneous leiomyomatosis and associated conditions. The gene associated with developing multiple cutaneous leiomyomatosis has been localized to the 1q42.3-q43 region [5]. Klopfer in 1958 reported multiple cutaneous leiomyomatosis as a inheritable cancer syndrome [3]. Reed syndrome, the association of uterine and cutaneous leiomyomas [4], has been linked to mutations in one tumor suppressor gene in chromosome 7q22 [6]. Toro et al. found that patients with Reed syndrome demonstrated cutaneous lesions before developing clinical features of uterine leiomyomas (p=0/48) [7]. Nevertheless, other reports not revealed this timing [8,9].

Another finding associated with this cancer syndrome is renal cell carcinoma [9,11]. The syndrome of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) results from a germline mutation in the gene encoding fumarate hydratase (FH). Fumarate hydratase is an active enzyme in the Krebs cycle that converts fumarate to malate [10, 12]. Recent investigations have documented the that mutation in 55-83 percent of cases with cutaneous and uterine leiomyomas [13]. Fumarate hydratase mutation consisting of missense and frame shift patterns, as well as whole gene deletions have been described in HLRCC syndrome [14]. The incidence of renal cell carcinoma in a person with FH mutation is unclear but seems to be less than uterine and cutaneous leiomyomatosis. Reports have shown this to be less than 1-2 percent [7, 13].

In association with leiomyomatosis, renal cell carcinoma occurs in the third to fourth decade of life; its histopathology demonstrates cysts of papillary cell carcinoma. The disease generally follows an aggressive course with metastasis usually being found rapidly after diagnosis.Variable genotype and phenotype are noted in this syndrome [14].

Considering the spectrum of presentations within this autosomal dominant syndrome, including uterine leiomyomatosis, multiple cutaneous leiomyomas, and renal cell carcinoma, recent studies recommend screening protocols and testing to allow early diagnosis and identification of tumors. Abdominal ultrasonography or CT scan in patients with a suspicious history or symptoms are advised and family members should be screened and offered genetic counseling.

The most important goal of this screening is prevention of rapid and diffuse growth of tumors and identification of renal cell carcinoma in an earlier, treatable stage.


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