Dermoscopic features of melanocyte-derived tumors in mucosal sites: a case control study

Background: Mucosal melanoma (MM) is a rare tumor characterized by aggressive behavior and a poor prognosis. Typically, its diagnosis occurs at the onset of symptoms in advanced lesions, often leading to adverse effects. Dermoscopy signi�cantly enhances the diagnostic accuracy of malignant melanoma, making it valuable for adjunctive diagnosis. OBJECTIVE: This study was aimed to investigate the imaging features of cutaneous melanocytic lesions in mucosal areas. METHODS: Dermoscopic images of melanocytic-derived tumors in mucosal sites up until December 2021 were searched in the International Cooperative Skin Imaging Database. Duplicate and pathologically undiagnosed images were excluded. The diagnostic e�cacy of various microscopic modalities were calculated and the impact of age on these features was examined. Results: Based on our data, the main signs in the skin images of mucosal melanoma were blue-grey dots accompanied by 2 colored structureless areas, both displaying a �gure of 93.3% and a speci�city of 66.7%. The prevalence of small blue-grey dot structures in MM was signi�cantly higher in comparison to the younger age group (OR 7, 95% CI 5-9, P<0.001). Conclusion: Blue-grey dots are the most sensitive and speci�c characteristics associated with diagnosis of MM. Moreover, the presence of blue-grey dots in the elderly population further suggests the likelihood of MM.


Introduction
Cutaneous malignant melanoma is a malignant tumor originating from neural crest melanocytes.
Mucosal melanoma (MM), on the other hand, is a rare yet aggressive cancer primarily affecting the mucosal surface of the head and neck.The clinical presentation of these malignancies is often nonspeci c, characterized by high malignancy and a propensity for metastasis.Consequently, delayed diagnosis is common, leading to a poor prognosis.The 5-year survival rate for MM is merely 25%. 1 In the context of early melanoma signs and symptoms, which remain crucial for accurate diagnosis, calculations similar to the ABCDE principle have been made to distinguish MM from nevi using asymmetry (A), irregular borders (B), mottled color (C), diameter greater than 6 mm (D), and evolving lesion size, shape, or color (E).However, there is an urgent need for a simpler visual examination technique to detect more subtle melanomas compared to the current cumbersome steps.
Dermoscopy plays a signi cant role in the adjunctive diagnosis of malignant melanoma.It greatly enhances diagnostic accuracy and was one of the earliest indications for dermoscopy.As a result, various diagnostic analysis modalities have been developed over an extended period of clinical application.The dermatoscopic ABCD method, proposed by Nachbar et al. 2 , was the rst approach used to differentiate benign and malignant melanocytogenic lesions through dermoscopy.Due to the speci c anatomical location of mucosal sites and the lack of early visible signs and symptoms, MM typically exhibits a microscopic pattern distinct from the skin.Diagnosis of this condition is often made at a late Stage. 2 Clinically, cutaneous malignant melanoma commonly manifests as an isolated, brown-to-black spot that is challenging to distinguish frommelanosis, the most frequent cause of hyperpigmentation in the mucosa. 3Moreover, approximately one-fth of MMs are estimated to be non-pigmented, further complicating diagnosis.4 The aim of this study was to analyze the structure of dermoscopic features in melanocytic lesions (malignant melanomas versus pigmented nevi) at mucosal sites.Additionally, the validity of these features in relation to the seven-point list method was assessed.

Methods
Dermoscopic images up to December 2021 were searched in the International Cooperative Dermatologic Imaging Database (www.isic-archive.com) using the terms "mucosa, pigmented nevus, malignant melanoma," excluding duplicates and images with undiagnosed pathology.Three dermatologists with specialized training in dermoscopy were selected as investigators to determine the presence or absence of impact structures.A structure was considered present if it was identi ed by at least two out of the three investigators.Subsequently, we calculated the diagnostic e cacy of various microscopic modalities and evaluated mucosal malignant melanoma and pigmented nevi using a seven-pointscale.
In the dataset of mucosal malignant melanoma images, the top three most sensitive indicators were bluegrey dots (93.3%), twocolored structureless areas (93.3%), and polymorphic vessels (66.7%).However, polymorphic vessels exhibited low speci city of 16.7% compared to 66.7% for the top two indicators.
Furthermore, statistical analysis revealed a signi cant difference in blue-grey dots between the observation groups (p<0.05)(Figure 1).Structureless areas containing three or more colors were observed in 46.7% of patients with malignant melanoma in mucosal areas.The frequency of pink areas, eccentric stains, degenerate areas, and irregular stripes in mucosal malignant melanoma was 66.7%, 60.0%, 53.3%, and 60.0% respectively.However, these patterns were also present in mucosal pigmented nevi, with frequencies of 60.0%, 40.0%, 60.0%, and 60.0% respectively (Table 2).
Patients with malignant melanoma were categorized into two subgroups based on age (>60 years and <60 years).Blue-grey dots (OR 7, 95% CI 5-9, p<0.001) were more prevalent in both subgroups (90.0% and 80.0% respectively) compared to other imaging structures (OR 7, 95% CI 5-9, p<0.001), while polymorphic vessels (OR 5, 95% CI 2-8, p<0.001) were the second most frequent indicator after blue-grey dots, occurring in 80.0% of the older age group (Table 3).Additionally, multiple structureless regions (OR 3.5, 95% CI 1-6, p<0.001) and degenerate regions (OR 4, 95% CI 3-5, p<0.001) were more prevalent in the older age group compared to the younger age group and exhibited statistical signi cance.However, no signi cant association was found between irregular stripes and age (p=0.075)(Figure 2).Among the cases that met the diagnostic requirements based on the seven-point list method assessment criteria, there were 14 cases of malignant melanoma and four pigmentednevi.When all imaging structures except pseudopods were considered as diagnostic indicators, the sensitivity of the model was 100%.

Discussion
There is limited data on dermoscopic imaging of melanoma in mucosal sites.Previous studies have primarily focused on structureless areas, and the literature reports signi cant variation in the diagnostic models and e cacy of dermoscopy.Lin et al. 5 performed the rst dermoscopic study of MM in eight cases and found that melanoma predominantly exhibited a multicomponent pattern (75%) and a homogeneous pattern (25%).A multicenter study examining the dermoscopic appearance of mucosal lesions demonstrated that the presence of blue, grey, or white structureless areas contributed to the diagnosis of malignant lesions. 6Diagnostic sensitivity was highest when only considering blue, grey or white. 7Similar results were obtained from a multicenter retrospective observational study 6 conducted by the International Dermoscopy Society (IDS), which showed that the combination of blue, grey, or white with structured areas was the strongest indicator for distinguishing mucosal malignant melanoma from other lesions.According to our data, using only two colors of the structureless region as a differential diagnostic element is equally sensitive and speci c as blue-grey dots, making it the most effective screening indicator for MM.
Surprisingly, in this study, multiple-colored structureless areas showed lower diagnostic sensitivity compared to blue-grey dots and polymorphic vessels.Particularly, blue-grey dots also exhibited the highest speci city.However, it should be noted that this imaging structure is commonly observed in pigmented nodular basal cell carcinoma (BCC), possibly due to smaller tumor masses with dermal pigmentationSince the proportion of dermoscopic features of melanocytic lesions present in BCC increases linearly with the degree of pigmentation contained in the lesion 8 , heavily pigmented BCC is di cult to differentiate from MM.When considering multifactorial indicators, the sensitivity of the diagnostic model in combination with other microscopic structures can reach up to 100% after excluding pseudopods.The presence of multiple blood vessels suggests the possibility of malignancy, particularly melanoma. 9This structure was more frequently observed in senior MM patients in our study, indicating that its presence is more alarming when diagnosing malignant melanoma in mucosal sites among older individuals.Longo et al. 10 suggested thatnested melanoma should be considered as the primary diagnosis when at, large pigmented lesions with an irregular globular pattern are found in people over the age of sixty.These ndings suggest that age is also a factor in dermoscopic ndings.
In the case of degenerative super cial diffuse malignant melanoma, two main characteristic manifestations of dermoscopy are observed.In the early and middle stages of degenerative changes, multiple blue-grey dots, also known as blue-grey peppercorn dots, are visible microscopically.In the later stages, they tend to show scar-like depigmentation, predominantly appearing white due to brosis and melanisation of the dermal papillae.The blue-grey granules represent aggregated melanophages and melanin granules in the dermis.Another common pattern in super cially diffuse malignant melanomas is the irregular stripe, which usually suggests radial growth of the melanoma.We found this structure in nine cases of MM but not in mucosal pigmented nevi.Notably, the presence of the radial stripe does not appear to be related to the age of the patients.
The seven-point list method is a pattern recognition-based algorithm 11 that quanti es the score of the entire lesion by identifying a limited number of structures.Using this method allowed for correct diagnosis of 82% of MM cases.Based on these results, Lin et al. 5 rst proposed to apply the algorithm to skin pigmented lesions at the skin-mucosal junction and on the mucosa.According to our ndings, 93.3% of mucosal malignant melanomas couldbe accurately diagnosed, indicating that this assessment method is equally applicable to speci c sites.Unfortunately, most malignant melanoma skin imagesin this study exhibited a multicomponent pattern, including structural asymmetry, multiple shades, blue-grey dots, pleomorphic vessels, and irregular stripes.These characteristics may be associated with advanced melanoma, while structureless areas and grey areas were commonly observed in early MM.The main limitation of this study was the small sample size.A multicenter, large cohort study is required to further con rm these ndings and identify more characteristic imaging structures in future.

Conclusions
In preliminary study, dermoscopy with the seven-point list method mightbe useful in the differential diagnosis of mucosal melanotic lesions.Blue-grey dots appeared to be the most effective differential diagnostic indicator for melanotic lesions in mucosal areas.The presences of blue-grey dots, multiple structureless areas, polymorphic vessels, and degenerated areas in the skin of mucosal areas among senior individuals were highly suggestive of malignancy.

Declarations
Funding: This research received by Climbing Scienti c Peak Project for Talents, the Second A liated Hospital of Wannan Medical College (No. DFJH2022015).
Con icts of interest The author declare no con ict of interest Figure 2

Figure 1 Box
Figure 1

Table 2 .
Structural characteristics of all patients

Table 3 .
Structural characteristics of mucosal according to age