Not All Melanomas are Created Equal: A Review and Call for More Research Into Nodular Melanoma

C. Dessinioti; A.C. Geller; D.C. Whiteman; C. Garbe; J.J. Grob; J.W. Kelly; R.A. Scolyer; R.V. Rawson; A. Lallas; G. Pellacani; A.J. Stratigos


The British Journal of Dermatology. 2021;185(4):700-710. 

In This Article

Abstract and Introduction


Among the histogenic subtypes of melanoma, nodular melanoma (NM) is the major contributor for thicker and fatal melanomas and it has been associated with melanoma-specific death in thin tumours, highlighting an important subgroup of 'aggressive thin' melanomas. This review provides a synthesis of the distinct characteristics of NM, with respect to epidemiology and risk factors, clinical presentation, histopathology, molecular and dermoscopic aspects, and screening practices. The real challenges are to find better biomarkers of aggressiveness and to know whether the control of such aggressive melanomas can be influenced by targeted interventions such as early detection, drug interventions and preventive strategies.


Cutaneous melanoma (CM) accounts for approximately 10% of skin cancers in light-skinned populations, but causes the most skin cancer-related deaths.[1] Melanoma is a heterogenous tumour comprised of biologically distinct subtypes based on their cell of origin, role of ultraviolet radiation exposure, pattern of somatic mutations and precursor lesion.[2] The four major subtypes of invasive melanoma distinguished by clinical and histopathological features are: superficial spreading melanoma (SSM) (approximately 41–56%), followed by nodular melanoma (NM) (16%[3] to 25·6%[4]), lentigo maligna melanoma (LMM) (2·7–14%) and acral lentiginous melanoma (ALM) (1–5% in non-Hispanic white populations and higher proportions but similar absolute incidence in Asian and African American populations).[5] When 'melanoma not otherwise specified' is included in the reported subtypes, the rates of NM range from 7% to 16·5%.[3,6–12]

The NM subtype is the main contributor for thicker and fatal melanomas,[9,11] thus a persistent burden on public health.[9,12,13] The median Breslow thickness of NM has increased over time, while it decreased for SSM, as reported in a Surveillance, Epidemiology and End Results (SEER)-9 registry study (1989–2009).[9] The greater Breslow thickness associated with NM may be attributed in part to obstacles that reduce the likelihood of early detection as well as inherent biological characteristics, such as a faster growth rate,[14,15] and points to distinct clinical and biological characteristics from its outset compared with other melanoma subtypes.

This review presents a comprehensive synthesis of the current knowledge of characteristics of NM that underlie its distinctive aggressive nature. In this context, the evidence for NM available in the literature was reviewed, with regard to epidemiology and survival, risk factors, clinical presentation, histopathology, molecular differences, characteristics with dermoscopy and reflectance confocal microscopy, and screening practices.