Clinical Follow-up of Atypical Spitzoid Tumors Analyzed by Fluorescence In Situ Hybridization

Abstract

Many neoplasms with spitzoid features remain enigmatic, especially those with intermediate grade features or "atypical spitzoid tumors" (ASTs). Fluorescence in situ hybridization (FISH) has emerged as a complementary technique to conventional microscopy, with certain chromosomal patterns conveying diagnostic information. In this study, we examined 36 ASTs analyzed by FISH for specific abnormalities in chromosomes 6, 9, and 11. Aberrations were detected in 11 cases, 7 of which met FISH criteria for spitzoid melanoma. These had homozygous deletion of 9p21, partial deletion of 11q13, gain of 6p25, and gain of 11q13. All 3 patients with positive sentinel lymph nodes, including one with progression beyond the sentinel lymph node, had homozygous deletion of chromosome 9p21, but there were no deaths in an average of 28 months of follow-up of these cases. Other aberrations in the chromosomal pattern of ASTs were heterozygous deletion of 9p21, partial deletion of 6p23, and tetraploidy. We found that ASTs, including those eventually diagnosed as spitzoid melanoma, had a more indolent course in our cohort than conventional malignant melanoma. Moreover, the addition of FISH results led to a more definitive diagnosis in 7 cases, 4 of which had abnormalities on FISH consistent with spitzoid melanoma.

Diagnostic Distinction of Malignant Melanoma and Benign Nevi by a Gene Expression Signature and Correlation to Clinical Outcomes

“…This includes the limited proportion of melanoma patients who develop distant metastases, the large number of patients who are lost to follow-up before a benign diagnosis can be definitively confirmed, and the difficulties encountered in acquiring corresponding clinical outcome data and primary biopsy tissue from multiple separate institutions. For these reasons, most reports validating molecular diagnostic tests against clinical outcomes for melanocytic lesions have been small subset analyses of larger studies that use histopathology as the reference standard (9,(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

“…To date, evaluation of adjunctive melanoma diagnostic methods against clinical outcomes has been limited to relatively small samples sizes (9,(16)(17)(18)(19)(20)(21)(22)(23)(24), and previously published validations of the 23-gene signature have been based on histopathologic diagnosis. However, validation against a large, clinical cohort is necessary to accurately assess the performance of a diagnostic test for clinical use.…”

An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi

“…The original 4‐probe FISH assay targeting 6p25 (RREB1), 6q23 (MYB), Cep6 (centromere 6), and 11q13 (CCND1) was reported to discriminate between histologically unequivocal melanomas and benign nevi with a sensitivity of 86.7% and a specificity of 95.4% 24. However, the sensitivity was subsequently found to be only 70% for melanomas with a Spitzoid morphology 25, 26, 29, 30, 31, 32…”

“…24 However, the sensitivity was subsequently found to be only 70% for melanomas with a Spitzoid morphology. 25,26,[29][30][31][32] The gene signature assessed here is intended to provide adjunctive information for the diagnosis of melanoma in ambiguous and difficult-to-diagnose lesions. The prospective cohort used in this study included numerous melanoma and nevus subtypes, including some types known to present significant diagnostic challenges in the clinical setting.…”

Clinical Use of a Diagnostic Gene Expression Signature for Melanocytic Neoplasms

“…Not surprisingly, studies documenting clinical outcomes of patients with ambiguous melanocytic neoplasms tested prospectively with diagnostic adjuncts are scarce, and this study's sample size and clinical follow-up compare favorably with the few that exist. 17,18 Although most melanomas declare themselves through recurrence or metastasis within several years of initial biopsy, 1,19 some are clinically dormant for as long as 10 years after initial detection. 20,21 This may be particularly true for the small or early-stage lesions that now comprise the majority of biopsied neoplasms, and such events would go undetected by this study and many others.…”