Distinct Clinicopathological and Prognostic Features of Thin Nodular Primary Melanomas

An International Study From 17 Centers

Clio Dessinioti; Niki Dimou; Alan C. Geller; Aravella Stergiopoulou; Serigne Lo; Ulrike Keim; Jeffrey E. Gershenwald; Lauren E. Haydu; Simone Ribero; Pietro Quaglino; Susana Puig; Josep Malvehy; Lidija Kandolf-Sekulovic; Tatjana Radevic; Roland Kaufmann; Laura Meister; Eduardo Nagore; Victor Traves; Grigorios G. Champsas; Mihaela Plaka; Brigitte Dreno; Emilie Varey; David Moreno Ramirez; Reinhard Dummer; Joanna Mangana; Axel Hauschild; Friederike Egberts; Ketty Peris; Laura del Regno; Ana-Maria Forsea; Sabina A. Zurac; Ricardo Vieira; Ana Brinca; Iris Zalaudek; Teresa Deinlein; Eleni Linos; Evangelos Evangelou; John F. Thompson; Richard A. Scolyer; Claus Garbe; Alexander J. Stratigos


J Natl Cancer Inst. 2019;111(12):1314-1322. 

In This Article

Abstract and Introduction


Background: Nodular melanoma (NM) is more likely to be fatal compared with other melanoma subtypes, an effect attributed to its greater Breslow thickness.

Methods: Clinicopathological features of NM and superficial spreading melanoma (SSM) diagnosed in 17 centers in Europe (n = 15), the United States, and Australia between 2006 and 2015, were analyzed by multivariable logistic regression analysis, with emphasis on thin (T1 ≤ 1.0 mm) melanomas. Cox analysis assessed melanoma-specific survival. All statistical tests were two sided.

Results: In all, 20 132 melanomas (NM: 5062, SSM: 15 070) were included. Compared with T1 SSM, T1 NM was less likely to have regression (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.29 to 0.72) or nevus remnants histologically (OR = 0.60, 95% CI = 0.42 to 0.85), and more likely to have mitoses (OR = 1.97, 95% CI = 1.33 to 2.93) and regional metastasis (OR = 1.77, 95% CI = 1.02 to 3.05). T1 NM had a higher mitotic rate than T1 SSM (adjusted geometric mean = 2.2, 95% CI = 1.9 to 2.5 vs 1.6, 95% CI = 1.5 to 1.7 per mm2, P < .001). Cox multivariable analysis showed a higher risk for melanoma-specific death for NM compared with SSM for T1 (HR = 2.10, 95% CI = 1.24 to 3.56) and T2 melanomas (HR = 1.30, 95% CI = 1.01 to 1.68), and after accounting for center heterogeneity, the difference was statistically significant only for T1 (HR = 2.20, 95% CI = 1.28 to 3.78). The NM subtype did not confer increased risk within each stratum (among localized tumors or cases with regional metastasis).

Conclusions: T1 NM (compared with T1 SSM) was associated with a constellation of aggressive characteristics that may confer a worse prognosis. Our results indicate NM is a high-risk melanoma subtype that should be considered for inclusion in future prognostic classifications of melanoma.


The incidence of cutaneous melanoma is increasing worldwide in white populations, with projected continuous increases in cases for the next several decades.[1] Melanoma incidence is highest in Queensland, Australia, with a rate of 72 per 100 000 per year (2010–2014).[2] In the United States, Surveillance, Epidemiology, and End Results (SEER)-9 registry data (1989–2009) indicated increasing incidence (from 13.94 to 21.87 per 100 000 person-years) across melanomas of all thicknesses.[3] A similar increase in incidence of invasive melanoma was observed in European cancer registry data (1995–2012), mostly attributed to the increasing incidence of thin tumors (≤1 mm).[4]

Melanoma is a heterogeneous tumor that can be classified into four major subtypes: superficial spreading melanoma (SSM, frequency 41–57%), nodular melanoma (NM, 14–17%), lentigo maligna melanoma (6–14%), and acral lentiginous melanoma (1–7%).[5–8] NM represents a considerable proportion of thicker and ultimately fatal melanomas[9] and exhibits aggressive clinicopathological features considered as proxies of increased Breslow thickness, such as ulceration, rapid growth rate, and increased mitotic rate (MR).[6,10–12]

Although patients with thin melanomas have high survival rates overall, the number of patients with fatal T1 melanomas is greater than the number with fatal T4 melanomas because the vast majority of melanoma patients present with early-stage disease.[13] There is growing interest in the predictors of aggressive thin (T1) melanomas, but there are limited data on thin NMs (≤1 mm). It has been proposed that patients with thin melanomas should be evaluated by more refined criteria to determine their individual prognosis.[14] Characteristics that may determine the prognosis of thin melanoma include ulceration, location on the head and neck,[15] higher MR,[16] and NM subtype.[17,18] We conducted a large international collaborative study to investigate the clinical, histological, and prognostic parameters of T1 NM vs T1 SSM, and provide evidence of whether NM represents a melanoma subtype affecting patient survival independent of Breslow thickness.