The content of these case studies, ideal to review during peer study groups, was developed by Julia Schwartz, MD and Thomas Lee, MD under the guidance of dermatologist Adam Friedman, MD, FAAD, Associate Professor of Dermatology, Residency Program Director, Director of Translational Research, Department of Dermatology GW University.
Julia Schwartz, MDGW School of Medicine and Health Sciences, Department of Dermatology
Thomas Lee, MDGW School of Medicine and Health Sciences, Department of Dermatology
1) The correct answer is D: There is a defect in an enzyme involved in the citric acid cycle.The histologic findings are most consistent with cutaneous leiomyoma. Given the family history and multiple lesions on physical exam, hereditary leiomyomatosis with renal cell cancer syndrome (HLRCC) should be at the top of the differential diagnosis.Patients with HLRCC present with multiple cutaneous leiomyomas. Clinically they may present as skin colored to erythematous papules on the face, neck, trunk and extensor surfaces. Tumors arising from the arrector pili muscles or vascular smooth muscle are often tender, while those derived from genital or mammary smooth muscles are often asymptomatic. Physical contact or rubbing of the lesions may lead to a transient elevation of the papules and nodules, which is also known as the Pseudo-Darier sign. Biopsies of lesions will show interlacing fascicles of spindle-shaped cells with blunt, cigar shaped nuclei with clear, perinuclear vacuoles composed of glycogen. Immunohistochemical staining for smooth muscle markers such as smooth muscle actin and desmin will be positive. Stains for S100 will be negative, differentiating this from other nerve tissue derived neoplasms with a similar spindle-shaped cell morphology. Female patients may also present with uterine leiomyomas, on average, 10 years before the general population. Patients with HLRCC are at high risk of papillary renal cell carcinoma, which can be found in 20-34% of affected families. There is a 70% mortality rate due to metastatic disease within 5 years of diagnosis. Annual screening with MRI is recommended.HLRCC is an autosomal dominant genetic disease due to a mutation in fumarate hydratase, an enzyme in the citric acid cycle, also known as the Kreb’s cycle. While the exact mechanism is unclear, it is thought that the impairment of oxidative phosphorylation leads to a hypoxic state with upregulation of vascular endothelial growth factors, cellular proliferation, and prevention of apoptosis, which may give rise to tumors. Genetic testing is required for definitive diagnosis.Brooke-Spiegler syndrome arises from a mutation in CYLD, characterized by eccrine spiradenomas, cylindromas, and trichoepitheliomas. While spiradenomas may be tender clinically, the histopathology would show well circumscribed dermal tumors with basophilic cells, lymphocyte-like cells, and eosinophilic hyaline droplets within the tumor nodules. Glomus tumors and glomangiomas are derived from the cells of glomus bodies, also known as Suquet-Hoyer canals, which are modified smooth muscle cells involved in thermoregulation. While they may be tender clinically and also stain positive for smooth muscle markers, histological examination will show blood vessels lined by rows of round basophilic cells with dark nuclei and minimal cytoplasm, which has been described as a “string of black pearls.”Muir-Torre syndrome arises from mutations in MSH2 or MLH1 leading to defects in DNA mismatch repair. It is characterized by sebaceous neoplasms, keratoacanthomas, and internal malignancies, most notably colorectal cancer. References1. Patel VM, Handler MZ, Schwartz RA, Lambert WC. Hereditary leiomyomatosis and renal cell cancer syndrome: An update and review. J Am Acad Dermatol. 2017 Jul;77(1):149-158.2. Menko FH, Maher E, Schmidt LS, et al. Hereditary leiomyomatosis and renal cell cancer (HLRCC). Renal cancer risk, surveillance and treatment. Familial cancer. 2014;13(4):637-644.