The correct answer is D: Papillary renal cell carcinoma.
Discussion: Given the patient's clinically proven skin and uterine leiomyomas, and a relatively strong family history for similar lesions, she is a rather classic example of the autosomal dominant disorder known as Reed syndrome. This hereditary condition is also known as multiple cutaneous and uterine leiomyomatosis (MCUL) or leiomyomatosis cutis et uteri. Aside from the hallmark smooth muscle tumors, a strong predisposition exists for the development of papillary type 2 renal cell carcinoma. Because cutaneous leiomyomata are not very common, their presence, either singly or multiply, should raise the suspicion for associated and underlying uterine fibroids and the potential for concurrent or future renal cell carcinoma.
The genetic findings in this disorder have now been well established. The predisposition to Reed syndrome has been localized to chromosome 1q42.3-q43, namely the locus of the gene encoding for fumarate hydratase.[4,5] This enzyme operates in the mitochondrial citric acid(Drug information on citric acid) cycle (Krebs cycle) and is thus involved in cellular energy metabolism. While genetic mutations leading to the loss of fumarate hydratase function appear to be the basis for tumor formation in Reed syndrome, the precise etiopathologic mechanism for this relationship remains uncertain. Cells lacking adequate fumarate hydratase will demonstrate a defective Krebs cycle; thus, it has been hypothesized that cellular pseudohypoxia may drive cellular transformation and tumorigenesis. Another possibility is that a fully functional fumarate hydratase gene also acts as a tumor-suppressor gene, and that various mutations of this locus lead to disinhibition of cellular proliferation.
Leiomyomas of the skin typically present as firm, skin-colored to pink or pink-brown plaques, papules, or nodules of no more than 2 cm in largest diameter. Leiomyomas are both spontaneously painful and tender to palpation. The complete list of painful/tender skin tumors must be considered in the differential diagnosis. In addition to leiomyoma, other such skin lesions include: angiolipoma, dermatofibroma, eccrine spiradenoma, endometrioma, glomus tumor, granular cell tumor, neurilemmoma, and neuroma. The exact diagnosis is easily established by skin biopsy. Leiomyomas are most common on the upper portion of the trunk or upper extremities, but they may be linear, dermatomal (zosteriform), or disseminated in distribution. Leiomyomas have no proclivity for spontaneous resolution, and the treatment of choice is complete surgical excision. Electrodesiccation, cryosurgery, and laser ablation may be employed for small lesions but often lead to scarring and recurrence. When the number of lesions is so large as to preclude surgical removal, then medical management can be entertained in order to relieve associated discomfort. Oral gabapentin(Drug information on gabapentin), topical capsaicin, and topical analgesics (eg, lidocaine(Drug information on lidocaine)) may be utilized. A relatively new and promising technique involves injection of botulinum toxin to inhibit release of pain-inducing neurotransmitters.[10,11]
It should be noted that the National Institute of Health recommends screening and periodic reassessment of all patients with cutaneous leiomyomatosis for the presence of an occult renal malignancy. At a minimum, this evaluation should include a nephrology referral, urinalysis, and renal ultrasound. Obviously, awareness of the connection between cutaneous leiomyomatosis and renal cell carcinoma can lead to life-saving early diagnosis of an otherwise undetected malignancy, thereby facilitating timely cancer management.
1. Reed WB, Walker R, Horowitz R. Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol. 1973;53:409-416.
2. Kiuru M, Launonen V. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Curr Mol Med. 2004;4:869-875.
3. Garcia-Muret MP, Pujol RM, Amomar A, et al. Familial leiomyomatosis cutis et uteri (Reed's syndrome). Arch Dermatol Res. 1988;280:829-832.
4. Alam NA, Bevan S, Churchman M, et al. Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43. Am J Hum Genet. 2001;68:1264-1269.
5. Alam NA, Olpin S, Leigh IM. Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas, and renal cancer. Br J Dermatol. 2005;153:11-17.
6. Toro JR, Nickerson ML, Wei MH, et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell carcinoma in families in North America. Am J Hum Genet. 2003;73:95-106.
7. Sudarshan S, Pinto PA, Neckers L, et al. Mechanisms of disease: hereditary leiomyomatosis and renal cell carcinoma: A distinct form of hereditary kidney cancer. Nat Clin Pract Urol. 2007;4:104-110.
8. Alam NA, Roawn AJ, Wortham NC, et al. Genetic and functional analysis of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet. 2003;12:1242-1252.
9. Holst VA, Junkins-Hopkins JM, Elenitsas R. Cutaneous smooth muscle neoplasms: clinical features, histologic findings, and treatment options. J Am Acad Dermatol. 2002;46:477-490.
10. Onder M, Adeflin E. A new indication of botulinum toxin: leiomyoma-related pain. J Am Acad Dermatol. 2009;60:325-328.
11. Sifaki MK, Kreuger-Krasagakis S, Koutsopoulos A, et al. Botulinum toxin type A-treatment of a patient with multiple cutaneous piloleiomyomas. Dermatology. 2009;218:44-47.