TERT Promoter Mutations Are Predictive of Aggressive Clinical Behavior in Patients with Spitzoid Melanocytic Neoplasms.

Seungjae Lee,Alberto Pappo,Jianrong Wu,Raymond L Barnhill,James Dalton,Armita Bahrami,Reinhard Dummer

doi:10.1038/srep11200

Abstract

Spitzoid neoplasms constitute a morphologically distinct category of melanocytic tumors, encompassing Spitz nevus (benign), atypical Spitz tumor (intermediate malignant potential), and spitzoid melanoma (fully malignant). Currently, no reliable histopathological criteria or molecular marker is known to distinguish borderline from overtly malignant neoplasms. Because TERT promoter (TERT-p) mutations are common in inherently aggressive cutaneous conventional melanoma, we sought to evaluate their prognostic significance in spitzoid neoplasms. We analyzed tumors labeled as atypical Spitz tumor or spitzoid melanoma from 56 patients with available follow-up data for the association of TERT-p mutations, biallelic CDKN2A deletion, biallelic PTEN deletion, kinase fusions, BRAF/NRAS mutations, nodal status, and histopathological parameters with risk of hematogenous metastasis. Four patients died of disseminated disease and 52 patients were alive and disease free without extranodal metastasis (median follow-up, 32.5 months). We found TERT-p mutations in samples from the 4 patients who developed hematogenous metastasis but in none of tumors from patients who had favorable outcomes. Presence of TERT-p mutations was the most significant predictor of haematogenous dissemination (P < 0.0001) among variables analyzed. We conclude that TERT-p mutations identify a clinically high-risk subset of patients with spitzoid tumors. Application of TERT-p mutational assays for risk stratification in the clinic requires large-scale validation.

Highlights

Spitzoid neoplasms are melanocytic tumors with distinct histologic characteristics that more commonly develop during the first 2 decades of life
telomerase reverse transcriptase (TERT) promoter (TERT-p) mutations have been found in 22%–71% of cutaneous melanoma in adult series[14,15,16,17,18,19] and in the majority of conventional pediatric melanoma in a study from our group[20], suggesting that they contribute to TERT regulation in melanoma
Lallas et al conducted a systemic review of the literature and found that having positive sentinel lymph nodes did not predict a worse outcome in patients with AST9

Summary

Introduction

Spitzoid neoplasms are melanocytic tumors with distinct histologic characteristics that more commonly develop during the first 2 decades of life. Since their initial description by Sophie Spitz in19481, the histologic diagnosis and appropriate management of spitzoid tumors have been controversial[2,3,4,5,6,7,8]. In our original series of pediatric melanoma, we found a hot-spot TERT-p mutation in the single patient with SM who died of disease but in no other patients with spitzoid tumors who had favorable outcomes[20]. We investigated the presence of TERT-p mutations in 56 patients with histopathologically well-characterized atypical spitzoid neoplasms for whom follow-up information was available

Methods

Results

Conclusion