May 2021 Case
A male patient in his 30s presented initially for multiple firm, red or reddish-brown cutaneous nodules, ranging from 3 mm to 2 cm, on his legs, arms and chest. Multiple excisional biopsies were performed.
Histology showed multiple dermal nodules; some originated from the arrector pili muscles, composed of interlacing smooth muscle bundles, with bland, blunt-ended spindle cell nuclei and abundant fibrillary eosinophilic cytoplasm.
Clinical presentation and histology raised the possibility of hereditary leiomyomatosis and renal cell carcinoma (HLRCC). HLRCCs are mostly associated with germline mutations and loss of function in fumarate hydratase (FH) gene. Loss of FH confirmed by immunohistochemistry on a selected nodule.
Cutaneous leiomyomas (CL), or so-called piloleiomyomas, are rare, benign smooth muscle tumors derived from the arrector pili muscle. Arrector pili muscles are responsible for piloerection (commonly known as "goosebumps") of hair follicles.
Piloleiomyomas may occur sporadically or as part of an autosomal dominant cancer syndrome called hereditary leiomyomatosis and renal cell carcinoma, present as multiple cutaneous nodules.
The association between cutaneous leiomyomas, uterine leiomyomas in women, and an aggressive form of renal cell carcinoma (RCC) was discovered in 2001. That emphasizes the importance of accurate dermatologic/dermatopathologic diagnosis of CL that can institute appropriate cancer screening and counseling of patients and at-risk relatives.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by autosomal dominantly inherited germline heterozygous mutations in the fumarate hydratase gene (FH) on chromosome 1q42.2. This mutation may lead to tumorigenesis via activation of the hypoxia inducible factor 1 (HIF-1) pathway.
Uterine leiomyomas in the HLRCC setting are usually multiple, large, and histologically show characteristic inclusion-like nucleoli. Occasional mitosis is also seen, but without necrosis and atypical mitosis, suggestive of leiomyosarcoma.
Renal cell carcinoma in HLRCC demonstrates a unique papillary histology, with large nucleus and prominent eosinophilic nucleolus surrounded by a clear halo. These tumors are highly aggressive and frequently metastasize when the primary tumor is still quite small (<1 cm).
The lifetime renal cancer risk in HLRCC is approximately 15 percent and the median age at diagnosis is 42 to 44 years. All individuals known to have an FH mutation and those suspected to have an FH mutation (eg, individuals with multiple cutaneous leiomyomas or early onset uterine leiomyomas) should be screened for RCC to detect small tumors. Early detection and surgical intervention may decrease the potential of metastatic disease.
The definitive diagnosis of HLRCC is based upon the demonstration of a germline mutation 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.
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