Naevus and melanoma: the essentials

Naevi and melanomas are neoplasms, that is to say, consist of a population of cells that has emerged as a result of mutations that result in increased cell proliferation and/or decreased cell death.

Oncogenic mutations in naevi identified so far are few in number. Most common acquired naevi contain an activating BRAF mutation (usually BRAFV600E); NRAS mutations occur in some congential naevi, HRAS mutations are encountered in some Spitz naevi, and a variety of other mutations, such as GNA11 in some blue naevi, have been identified in less common naevus subtypes. Apart from such isolated mutations, the genome of naevus cells appears to be normal.

Melanomas contain similar mutations but in addition have many more (typically numbering in the tens of thousands), as a result of genetic instability that leads to the constant emergence of new subclones with additional mutations (point mutations, duplications, amplifications, deletions, translocations &c). Viable subclones grow out and, since they differ from each other - since genetic differences translate into phenotypic differences - melanomas tend to display variatiability 'from within', resulting in asymmetry, irregular contours, differences in amount or distribution of pigment, flat versus raised contours, induction of an inflammatory response, etcetera. The microscopist can assess this variability of melanomas better than the clinician, who is limited to naked eye inspection and dermatoscopy. In fact, histological investigation is highly effective in distinguishing melanomas from naevi.

However, the sensitivity and specificity of the histological diagnosis of melanoma are not 100%. There is a small group of lesions that defies classification as melanoma or naevus. When confronted with such a lesion, the histopathologist is well advised to seek help from an expert with special interest and expertise in this field. But even the expert may be unsure about the correct diagnosis. This results in a verdict of MELTUMP (melanocytic tumour of uncertain malignant potential). Not uncommonly, the differential diagnosis is: Spitz naevus versus melanoma resembling Spitz naevus ('spitzoid melanoma'): such lesions are commonly called STUMP (Spitz tumour of uncertain malignant potential). It will be clear that STUMP constitutes a subset of MELTUMP. Finally, if the lesion is of uncertain malignant potential and limuted to a very superficial part of the skin, the term SAMPUS (superficial atypical melanocytic proliferation of uncertain significance) has been proposed, since the clinical consequences of such a lesion are subtly different from those of a thicker MELTUMP.

Surgery remains the mainstay of curative care in melanoma. Chances of cure are high in case of a thin primary melanoma with no signs of disease elsewhere, but prognosis progressively decreases with increased melanoma thickness, presence of ulceration and intradermal mitotic activity, and especially the presence of regional lymph nodes metastases and/or satellites or in-transit metastases (superficial melatases limited to the body region of the primary tumour, and presumably reslting from lymphatic spread only). Surgery cannot be curative in case of distant, hematogenic metastasis (stage IV melanoma), but in selected cases remains an important option for prolonging life and increasing quality of life. Radiotherapy, chemotherapy and, in some situations, selective mutated BRAF inhibition and immunotherapy, are of proven value in stage IV melanoma. In this website, we shall not discuss this further. A quick impression of prognosis in individual cases can be gleaned from the large follow-up data set of melanoma patients (over 28,000 in number) treated in melanoma centers that forms the basis of a dedicated website www. melanomaprognosis.org.