Hereditary Leiomyomatosis and Renal Cell Cancer: A Case Report of Pilar Leiomyomatosis with History of Kidney Cancer and Review of the Literature

Cutaneous leiomyomas are benign smooth muscle tumors and can be classified into 3 types: pilar leiomyoma (synonym: piloleiomyoma), solitary genital leiomyoma which is further subclassified into dartoic, vulvar, nipple, and areolar type, and angioleiomyoma. Among them, pilar leiomyoma is the most common type in Caucasians, whereas angioleiomyoma is the most common subtype in Koreans1. Pilar leiomyomas arise from the arrector pili muscle attached to the hair follicle. Development of multiple pilar leiomyomas during adolescence in the setting of combined cutaneous leiomyomatosis and visceral tumors such as uterine leiomyoma or renal cell carcinoma (RCC) strongly indicates a genetic predisposition, a germline mutation in the fumarate hydratase (FH) gene.

Hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM #150800) is an autosomal-dominant hereditary disorder resulting from germline mutations in the FH gene that encodes an enzyme comprising the tricarboxylic acid cycle. HLRCC patients might develop multiple cutaneous leiomyomas, uterine leiomyoma especially in women resulting in early hysterectomies, and papillary subtype of RCC which metastasizes easily2. Uterine leiomyoma usually develops at an early age (median 28~32 years) with multiple lesions with a size of 1.5 to 10 cm2, 3. Renal tumors also tend to develop at an early age (10~44 years) with characteristic histopathology of type 2 papillary RCC4. To date only 11 cases of HLRCC confirmed by genetic test have been reported in Korea, and skin manifestations in each case were poorly described. Here we describe another confirmed case of HLRCC.

A 55-year-old male presented with reddish-brown papulonodules on the left cheek, neck, and upper back (Fig. 1). In the third decade, he first noticed tiny acneiform lesions on the face and upper back, which continuously increased in size and number and became hardened. Episodes of sharp pain accompanied the facial lesions, and usually occurred in response to touch and cold temperature. The patient had a history of hypertension and RCC. At the age of 46 years, he underwent a computed tomography scan of the abdomen that detected a 5 to 7 cm size tumor in the upper pole of the left kidney, for which he underwent partial nephrectomy (Fig. 2). The excised tumor was pathologically reported as type 2 papillary RCC. He had a family history of skin leiomyomatosis affecting his brother and uterine myoma affecting his sister. The physical examination revealed multiple indurated firm nodules with variation in size from 0.7 to 1.8 cm, segmentally distributed on the face and back. Histologic examination of the skin lesion showed non-encapsulated tumor bundles of smooth muscle fibers within the dermis and interlacing fascicles of spindle cells (Fig. 3A, B). There was no cellular atypia or mitotic activity. Dermoscopic examination showed multiple whitish yellow dots and globules, white scar-like patch, milky red structureless area, and irregular vasculature with telangiectasia (Fig. 3C).

Fig. 1
(A) Multiple reddish-brown firm papulonodules on the left cheek. The sizes of the papules and nodules vary from 0.7 cm to 1.8 cm. (B) Segmentally distributed numerous red to brown firm papulonodules on the mid upper back.

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Fig. 2
Images of contrast enhanced computed tomography scan. (A) Axial view shows 5 cm×7 cm sized renal cell carcinoma with a hypovascular region and ill-defined margins at the upper pole of the left kidney (arrow). (B) Coronal view demonstrates renal cell carcinoma with infiltrative margins and discrete foci of calcification (arrow), which are characteristic radiologic features of type 2 papillary morphology.

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Fig. 3
(A) Histologic examination shows non-encapsulated bundles of smooth muscle irregularly mixed with the surrounding collagen fibers (H&E, ×100). (B) High-power examination demonstrates interlacing fascicles of spindle cells with blunt ended nuclei (H&E, ×400). (C) On dermoscopic examination, multiple whitish yellow dots and globules, white scar like patch, milky red structureless area, and irregular vasculature with telangiectasia were observed.

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These characteristic features were compatible with pilar leiomyoma. Based on the clinical and histopathologic findings, the patient satisfied all the major and minor criteria of HLRCC5 and was strongly suspected to have HLRCC. For a definitive diagnosis, which can be made by the FH mutation test, we performed whole exome sequencing (WES) from a peripheral blood sample obtained from the patient after receiving informed consent. WES analysis identified a novel point mutation in the FH gene (c.739G>A, p.Glu247Lys, heterozygous). The mutation was initially categorized as a variant of uncertain significance. However, after consultation with a pediatric geneticist, it was interpreted as a likely pathogenic variant according to The American College of Medical Genetics and Genomics standards and guidelines, as the clinical features of the patient corresponded with the phenotypic profiles of HLRCC. We received the patient’s signed consent for publishing the clinical photos, radiological images, and sequencing data from the genetic study.

Cutaneous leiomyomas are relatively uncommon benign neoplasms of the smooth muscle, with an incidence of 0.04% from a 10-year observational study6. In contrast to the solitary form, multiple lesions of cutaneous leiomyoma require special attention, since they might be accompanied by tumors of the internal organs.

Recent evidence suggests that most patients presenting with multiple cutaneous leiomyomas are at an increased risk of developing visceral tumors such as uterine leiomyoma or renal cancer4, 7. The association between multiple cutaneous leiomyomas and uterine leiomyoma was observed in female patients with Reed’s syndrome, a genetic disorder also known as multiple cutaneous and uterine leiomyomatosis. Additional studies found that subsets of patients with Reed’s syndrome were associated with early onset renal cancer, which was later proved to be HLRCC4. Two genodermatoses are now thought to share the same etiology and pathophysiological mechanism.

HLRCC is an autosomal dominant hereditary disorder characterized by skin lesions of leiomyomatosis and a predisposition to develop internal tumors such as uterine leiomyoma or renal cancer. HLRCC is caused by a germline loss of function mutation in the FH gene, located on chromosome 1q42.3-43, which encodes an enzyme participating in the tricarboxylic acid cycle by converting fumarate to malate7. According to previous cohort studies examining HLRCC patients, mutational “hot spot” in FH gene was observed at Arg190 (Arg190His, Arg190Leu, Arg190Cys)5. In the present case, a novel point mutation was observed at Glu247 (Glu247Lys), which is located at the exon 5. To the best of our knowledge, this is the first case of HLRCC with a point mutation at the exon 5 of FH gene.

The correlation between FH mutation and development of cancer is not completely understood. In the FH deficient cell, fumarate accumulates in a high concentration and acts as an oncometabolite, which leads to a series of aberrant biochemical reactions. First, excessive accumulation of fumarate might stabilize the hypoxia-inducible factor 1 alpha (HIF1-a), which promotes the expression of genes related to angiogenesis and glucose transport in the tumor tissue. Second, it might also cause the pathological activation of nuclear factor erythroid 2 related factor 2 (NFR2) pathway, which has been found in several types of cancer. Further investigations are required to elucidate the complex mechanism of the oncogenic properties of FH deficiency8.

Renal cancer developing in the setting of HLRCC is usually type II papillary RCC, which easily metastasizes even when small. The renal cancer in our case was also proved to be type II papillary RCC and distant metastasis to the lung was detected 6 years after nephrectomy, which reflects the typical features and prognosis of renal cancer occurring in HLRCC. Due to the aggressive behavior of papillary type II RCC, active surveillance is warranted for early diagnosis of RCC in HLRCC patients. There are no specific guidelines for HLRCC, and annual MRI surveillance is recommended in patients with family members who test positive for germline FH mutation9.

Cutaneous leiomyomas are a common manifestation of HLRCC, which occur in 76% to 100% of the cases4. Among them, pilar leiomyoma is a subtype highly associated with HLRCC, whereas angioleiomyoma has been rarely reported in association with kidney or uterine tumors. Pilar leiomyomas are benign tumors arising from the arrector pili muscle, and usually appear as red-brown papules or plaques accompanied by sharp pain in response to compression or cold10, 11. The skin lesions of our patient exhibited typical features of pilar leiomyoma with red-brown papules and plaque mainly distributed on the face and trunk, accompanied by episodes of sharp pain.

In the research of dermatology in Korea, more than 20 cases of pilar leiomyomas have been pathologically confirmed till date (Table 1)1, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19. Seven out of 14 cases except those without a clear description of the cutaneous lesions, developed multiple lesions as in our case. Among them only one case had a history of developing uterine myoma at less than 40 years of age, which was highly suspicious for HLRCC11. Korean journals in urology or oncology reported 11 cases of definitive HLRCC confirmed by PCR based sequencing for the FH gene. Among them, 9 cases had papillary RCC, and 10 patients had pathologically confirmed cutaneous leiomyomas9, 20.

Table 1
Review of previous cases with pilar leiomyoma or HLRCC

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Our patient was another rare case of genetically confirmed HLRCC in Korea with clear manifestations including multiple pilar leiomyomas on the skin, family history of cutaneous or uterine leiomyoma, and history of RCC with type 2 papillary morphology. Dermatologists should consider HLRCC in the differential diagnosis when encountering patients with multiple pilar leiomyomas, which requires interdisciplinary approach and active surveillance for the early detection of uterine or renal tumors.