1.Department of Pathology,, Human Oncology, Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA (RM); Tissue Pathology, Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown NSW, Australia (RAS); Departments of Dermatology, Pathology,, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, USA (BCB)
, 1. Desmoplastic Spitz Tumor with HRAS mutations , HRAS-mutant ASTs show distinctive histopathologic and cytogenetic features. They are larger lesions with a predominantly intradermal distribution of melanocytes in horizontal rather than vertical orientation, have marked desmoplasia, characteristic cytologic features with epithelioid melanocytes scattering between thickened collagen bundles, giving them an infiltrating growth pattern. Proliferation rates in the majority of these cases are low. The majority shows a distinctive cytogenetic abnormality comprised of a high-level copy number increase of the entire short arm of chromosome 11 (Bastian et al., 2000; van Engen-van Grunsven et al., 2010).
, 2. Nodular Spitz Tumor with BRAF and BAP1 mutations , Recently, it was shown that a significant subset of atypical Spitz tumors is characterized by the concomitant presence of BRAFV600E mutation and loss of BAP1 expression, the latter being the result of inactivating BAP1 mutation and/or deletions (Wiesner et al., 2012). These BRAFV600E/BAP1-negative tumors show distinctive features. They are non-pigmented, dermal tumors composed of epithelioid melanocytes with abundant amphophilic cytoplasm, well-defined cytoplasmic borders, and vesicular, pleomorphic nuclei with prominent nucleoli. The cells are arranged in large cohesive nests or nodular aggregates. The overlying epidermis is thinned (rather than thickened as in Spitz nevi), and the rete ridges are effaced. They are often associated with moderate to large numbers of tumor-infiltrating lymphocytes (Wiesner et al., 2012). Loss of nuclear BAP1 expression by immunohistochemistry is a reliable feature to recognize these lesions.
, These ASTs have also been observed in a newly described syndrome caused by monoallelic BAP1 germline mutations. Individuals with this condition can have increased numbers of the ASTs described above, and have an increased risk of cutaneous and uveal melanoma (Wiesner et al., 2012). Hereditary BAP1 mutations have also been described in mesothelioma (Testa et al., 2011). The appearance of multiple ASTs with the features described above thus raises the suspicion of germline mutations in the BAP1 tumor suppressor gene and should prompt a careful family history and physical examination and genetic counseling should be considered. , Immunohistochemically, HMB-45 tends to show heterogeneous staining in the invasive component of spitzoid melanomas, including in the deep portion of the tumor; in contrast, HMB-45 is usually negative in the deeper dermal component of Spitz nevi (Bergman et al., 1995). The Ki-67 index in spitzoid melanomas is higher (often >10% in the dermal component) than that in Spitz nevi (Bergman et al., 2001). However, there is considerable overlap in these patterns in Spitz nevi and spitzoid melanomas, and individual features/characteristics cannot be used in isolation to distinguish these tumors. Use of cytogenetic techniques such as fluorescence in situ hybridization (Gerami et al., 2009) or comparative genomic hybridization (Bastian et al., 1999) might be more useful adjuncts for this distinction.
Rajmohan Murali ; Richard A Scolyer ; Boris C Bastian
Skin: Spitz tumors
Atlas Genet Cytogenet Oncol Haematol. 2012-07-01
Online version: http://atlasgeneticsoncology.org/solid-tumor/6241/skin-spitz-tumors