What Is Spitzoid Melanoma

Introduction

Spitzoid melanoma (SM) is a rare subtype of malignant skin cancer, bearing significant similarities to the benign Spitz nevi. It typically manifests as moles of asymmetrical shape and varying pigmentation, ranging from pinkish or unpigmented to brown or black, and are commonly found on the face, arms or legs of affected individuals.

Melanoma, a type of skin cancer, is often associated with ultraviolet (UV) radiation exposure and represents one of the most rapidly growing and dangerous types of neoplasms (abnormal masses of tissue), especially when late or misdiagnosed. Melanomas belong to melanocytic skin tumours, as they involve melanocytes, the cells responsible for producing melanin; the protein responsible for determining skin colour.¹

The term 'Spitzoid' first appeared in Sophie Spitz’s scientific paper in 1948, marking the initial step to further differentiating melanocytic tumours.² Nowadays, a more extensive evaluation and classification has defined specific characteristics of SM, allowing for its distinguishment. Spitzoid tumours belong to the spectrum of melanocytic tumours. Melanocytic tumours themselves are further categorised into Spitz nevus, which is benign; SM, which is malignant; and other atypical Spitz tumours.³

SM is a rare variant of melanoma holding similar histological and clinical features to Spitz nevi. It can appear newly formed or develop from a pre-existing Spitz nevus. Its aetiology remains largely unknown. Typically presented as an amelanotic (lacks pigmentation) growing nodule that is usually asymmetrical in shape, it is commonly found on the face or extremities of patients. Due to the similarities observed not only to the naked eye but also microscopically with Spitz nevi, diagnosing SM remains remarkably challenging. It predominantly affects people of younger ages (typically less than 20 years of age), who exhibit better survival rates compared to older patients with SM.⁴

Characteristics and features of spitzoid melanoma

Clinical presentation

SM lacks a distinct clinical profile, often leading to late diagnosis, even after the onset of metastasis. It is most commonly found on the face, neck, legs and arms of patients of different ages. It appears as a cutaneous lesion, nodule, or papule of varying sizes, frequently exceeding 1 cm in diameter. SMs usually lack symmetry, with an undefined shape and no clear circumscribed margins, and they mostly appear amelanotic or pink, but can also be darker-coloured. Advanced stages of SM may also display ulceration and crust formation.⁴

Histopathological findings

Histological observations (examinations of diseased tissues) are decisive for distinguishing SM from similar cutaneous abnormalities. Microscopic analysis of a SM lesion revealed:

• Deep dermal invasion, indicating both epidermal and dermal involvement
• Poor or absent melanocyte maturation (decrease in melanocyte size) with dermal depth
• The absence of Kamino bodies, also known as eosinophilic globules, that are otherwise typical of Spitzoid nevi
• A high degree of cytologic atypia, signifying the presence of cells that are abnormal in size, shape and/or organisation
• Significant mitotic activity, showing the prognostic count of cells entering mitosis, and hence counting the rate at which cells are dividing and potentially be metastasised
• The presence of numerous epithelioid or spindle-shaped melanocytes
• Despite the apparent specificity of these findings, there remains the possibility of deviation from expected results, along with notable similarities to other cutaneous pathologies, such as Spitz nevus, haemangioma, pyogenic granuloma, xanthogranuloma and basal cell carcinoma.^5,6

Genetic profile

On a molecular level, SM has been subject to targeted analysis in specific cases. Its molecular profile remains ambiguous due to multiple discrepancies across studies, which further complicate the classification of Spitzoid tumours, specifically the classification of SM. However, common characteristics have been stated. For instance, according to the World Health Organisation’s (WHO) 2018 guidelines, Spitz melanoma is classified as a distinct subtype of SM, with the term 'Spitz' correlated with at least one genetic aberration, while 'Spitzoid' is used for lesions resembling Spitz nevi.⁷

Further identification of specific genetic alterations in patients aids in accurate diagnosis. For example, mutations on the protooncogene HRAS are associated with Spitz nevi but not Spitz melanoma, while translocations on the protooncogene ROS1 are also linked to Spitz nevi and atypical Spitz tumours. BRAF gene mutations are typically absent in most Spitz tumours. Conversely, MET gene translocations and MAP3K8 alterations, often associated with lymph node metastasis, have demonstrated oncogenic activity and are affiliated with Spitzoid tumours, including SM, though without confirming a distinct diagnosis as of yet.⁷

Table of differences

An overview of the differences between the various Spitz tumours is demonstrated in the table below:^6,7

Diagnosis of spitzoid melanoma

The WHO has established comprehensive guidelines for melanoma diagnosis, serving as key references for the identification and classification of various types of melanomas, including Spitz tumours. However, the challenging diagnostic process is exacerbated by the considerable variabilities and similarities within this subgroup, rendering further distinction more than necessary. Common diagnostic tools include:

• Dermatoscopy

This technique involves the use of a dermatoscope (a handheld instrument used for closely examining skin lesions and other characteristics) and computer software for mole mapping. After careful examination of the morphology of legions, dermatologists have identified various dermatoscopic patterns. Patterns such as:^6,7

• Pinkish or white pigmentation
• Asymmetry and multicoloured pigmentation
• Reticular depigmentation, with a white line network
• Shiny white lines
• Heterogeneous vascular patterns,

are connected to potential SM manifestation but are not sufficient for a precise diagnosis.

• Histopathological features

A skin biopsy, along with consideration of histopathologic and genetic profiles, is vital for excluding other cutaneous melanomas and confirming the presence of SM.

• Immunohistochemistry (IHC)

This tool involves the assessment of proteins involved in the cell cycle and apoptosis (programmed cell death) using immunohistochemistry markers. Results related to the expression of the proteins Ki67, p16, and HMB45 offer significant distinctions between SM and other Spitzoid tumours, although this idea is not universally supported. Notably, a positive result of Ki67 and a negative result of p16 are associated with the presence of SM.⁸

• Fluorescence in situ hybridisation (FISH)

This technique aids in SM diagnosis by detecting multiple chromosomal alterations.⁹

• Next-generation sequencing (NGS)

NGS is another necessary diagnostic tool that identifies variants of specific genes associated with melanomas. By comparing the presence or absence of mutations in these genes, the malignancy of a tumour can be assessed, facilitating the accurate classification of the lesion.¹⁰

Management and treatment of spitzoid melanoma

Given the absence of specific guidelines for treating SM, several therapeutic approaches align with the established treatment regimen recommended for patients with melanoma:

1. Initial biopsy: Performing a biopsy is crucial to distinguish SM from other types of melanoma. This step is essential in evaluating the malignancy of the tumour and preventing unnecessary and potentially harmful interventions.
2. Lesion excision: Following the biopsy, lesion excision is typically performed to minimise the risk of recurrence. Subsequent excision of the lesion’s margins is often recommended as well.
3. Sentinel lymph node biopsy: This procedure is performed to determine the presence of tumour metastasis.
4. Immunotherapy and targeted therapies: When feasible, the use of specific medications such as ipilimumab, imatinib, sunitinib, and others is recommended. Ongoing clinical trials offer promising prospects for introducing novel, efficacious drugs.
5. Relapse management: Generally, relapse of SM and Spitz melanoma is limited in comparison to that of melanomas. As a result, a less aggressive therapeutic regimen, accompanied by regular dermatological visits, could also be beneficial.^11,12

Prognosis

The enigmatic nature of Spitzoid tumours contributes to further uncertainty regarding the prognosis of certain lesions. If the lesion is not initially identified, prognosis cannot be provided accurately since the benign or malignant character of the mole remains unknown. Regular clinical follow-ups are crucial for definitive identification, categorisation, and the exclusion of adverse outcomes.¹³

Overall, when malignant SM was reported, it demonstrated a more favourable prognosis compared to other types of melanomas, particularly in paediatric patients. Recurrence, metastasis, and morbidity were significantly lower than in conventional melanomas. SM in younger patients also appears to yield more positive outcomes compared to adults.^4,13 Furthermore, specific gene mutations, such as TERT mutations, have been linked to worsened outcomes of SM.¹³

Conclusion

In summary, SM is an uncommon form of skin cancer sharing numerous resemblances with Spitz nevi. It is typically found on the face or extremities of patients, appearing as an asymmetrical lesion of 1 cm or more, with varying colours. Challenges persist in accurately diagnosing, classifying and predicting the outcomes of SM, due to its indistinct histopathological profile and complex genetic analysis.  

The data and findings presented herein provide a simplified overview of the majority of cases. The extensive variability, especially in the context of cancerous events and the peculiar nature of SM, underscores the limits of our current understanding. Future studies are required to profoundly comprehend the attributes and functions of all Spitz tumours.

Educating individuals about the risks of extensive sun exposure and promoting self-examination can significantly contribute to early detection and improved prognostic rates. Additionally, raising awareness and providing psychosocial support play pivotal roles in enhancing patient outcomes. If in doubt, seek an appointment with a dermatologist. Skin mapping is completely painless and can prove to be lifesaving.