Diagnosis and management of atypical melanocytic lesions

Discriminating between benign and malignant melanocytic tumours is essential, yet the diagnosis can sometimes be equivocal. To address this, a new intermediate category, called melanocytoma, has been added to the classification system, also acknowledging that pathologists may encounter atypical melanocytic lesions that are difficult to classify. How should we deal with these lesions?

Histologically, melanocytic lesions can be categorised into benign lesions, such as Spitz nevi, inflamed nevi, and special site nevi, intermediate lesions known as melanocytomas, malignant lesions (melanoma), and a residual category for difficult-to-classify lesions. Dr Willeke Blokx (University Medical Center Utrecht, the Netherlands) explained that discovering BRAF mutations and other genetic abnormalities in melanocytic lesions has improved understanding of melanocytic tumour biology [1]. “The molecular data showed us that nevi are diverse, with various underlying genetic causes,” she said.

These developments have been incorporated into the latest WHO classification of melanocytic tumours, which now comprises 9 molecular pathways of melanocytic lesions, all with different progression stages [2]. The pathways include conventional nevi, lentigo malignant spectrum, Spitz lesions, acral lesions, mucosal lesions, congenital lesions, blue nevi, and eye lesions. Within each pathway, lesions may exist across a spectrum from benign nevi, through intermediate melanocytomas, to malignant melanoma. For example, conventional nevi may lead to the most frequently observed type of melanoma, namely, superficially spreading melanoma or nodular melanoma. Dr Blokx outlined the factors that were taken into account for the development of this classification system. Some lesions, including conventional nevi, lentigo maligna spectrum, and desmoplastic melanoma, are associated with long-term sun exposure. Acral and eye lesions are anatomically based categories, and congenital lesions have an obvious developmental context. The classification of Spitz lesions relies heavily on morphological features. “However, the most important factor within this system is the integration of molecular pathology,” according to Dr Blokx. For example, melanomas arising from the conventional nevi pathway are usually associated with BRAFV600E or NRAS mutations, whereas Spitz melanoma may be associated with HRAS mutations and various genetic fusions (see Figure). “These genetic abnormalities help us to discriminate between tumours but also provide us with important prognostic information,” explained Dr Blokx. “We know now that patients who have Spitz tumours with MAP3K8 fusions have a worse prognosis than others within the same category.”

Figure: Genetic drivers of melanoma per pathway [1]



The typical progression of melanocytic tumours starts with a melanocyte, which turns into a nevus, subsequently into a melanocytoma, and finally into a melanoma. “However, a melanocyte can also skip the nevus and melanocytoma stages and turn directly into a melanoma,” mentioned Dr Blokx. Generally, the initial transformation into a nevus involves a single-driver mutation, while additional mutations and chromosomal aberrations are responsible for further progression into melanocytoma or melanoma.

For the majority of melanocytic lesions, diagnosis may be determined by histology. In approximately 95% of the lesions, haematoxylin and eosin staining is sufficient. Immunohistochemistry may be performed when atypical features, such as mitotic activity, are observed. Several markers can be utilised to further determine the nature of a lesion, such as SOX10, HMB45, BAP1, and melan A. If there is still unclarity after immunohistochemistry, molecular pathology may be employed to clarify the nature of the lesion. “In clinical practice, however, this is only needed in about 1–2% of the cases,” added Dr Blokx.

Dr Blokx highlighted that the group of melanocytomas, or intermediate tumours, has only been officially recognised by the WHO since 2023. These lesions are characterised by the presence of >1 genetic abnormality, for example, 2 mutations or 1–2 copy number variations. Melanocytomas are typically considered low-risk tumours, with growth generally limited to locoregional areas, and are rarely associated with distant metastases. “Risk stratification within the group of melanocytic tumours is still evolving,” according to Dr Blokx. BAP1-inactivated and WNT-activated melanocytomas are usually classified as low-risk, whereas pigmented epithelioid melanocytoma (PEM) is defined as a higher-risk tumour. “It would not be surprising if the PEM classification is revised in the next edition of the WHO tumour classification system,” she added. In Europe, recommendations suggest excising low-risk lesions with a 2 mm margin and higher-risk lesions with a 5–10 mm margin. Finally, there remains a residual category of lesions that cannot be identified even after molecular testing. This latter category encompasses lesions named superficial atypical melanocytic proliferation of uncertain significance (SAMPUS), melanocytic tumour of uncertain malignant potential (MELTUMP), and Spitz tumour of uncertain malignant potential (STUMP). Dr Blokx highlighted that the risk of metastasis is essentially negligible in SAMPUS lesions and less than 1% in MELTUMP and STUMP cases.

A Dutch guideline is currently being developed for the management of atypical melanocytic lesions. This guideline will recommend an initial diagnostic excision with a 2 mm margin. In cases where the diagnosis remains unclear, a second pathologist should be consulted, and an expert panel may be requested if the 2 pathologists do not reach a diagnostic consensus. Immunohistochemistry and molecular diagnostics are indicated when histologic analysis cannot exclude the presence of melanoma. “However, no true evidence-based guidelines are available concerning excision margins and the follow-up of atypical melanocytic lesions,” Dr Blokx concluded. “For now, it is believed that radical excision is sufficient in low-risk melanocytoma, and re-excision with a 2 mm margin should be performed if the initial excision was not complete. For higher-risk melanocytomas, MELTUMP, and STUMP lesions, a re-excision with a 5 mm margin is recommended. In case of high suspicion of malignancy, the follow-up protocols should be similar to those used for melanoma.”

1. Blokx W. Atypical melanocytic lesions. Dermatologendagen 2025, 10–11 April, Apeldoorn, the Netherlands.
2. WHO classification of skin tumours (2022). International Agency for Research on Cancer.

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Posted on 5 June 20255 June 2025