More than one shade of pink as a marker of early amelanotic/hypomelanotic melanoma

Amelanotic/hypomelanotic melanoma (AHM) may be difficult to diagnose because of a lack of pigmentation. To evaluate whether dermoscopy can be useful for the diagnosis of early AHM, 133 digital dermoscopic images of lesions histopathologically diagnosed as amelanotic/hypomelanotic superficial spreading melanoma with ≤1 mm thickness (AHSSMs) (n = 27), amelanotic/hypomelanotic non‐melanocytic lesions (AHNMLs) (e.g., seborrhoeic keratosis and basal cell carcinoma) (n = 79), and amelanotic/hypomelanotic benign melanocytic lesions (AHBMLs) (e.g., compound and dermal nevi) (n = 27), were dermoscopically assessed by three blinded dermatologists. Using multivariate analysis, we found a significantly increased risk of diagnosing AHSSM versus AHNML and AHBML when the lesion was characterized by the presence of more than one shade of pink (odds ratio [OR] 37.11), irregular dots/globules (OR 23.73), asymmetric pigmentation (OR 8.85), and structureless pattern (OR 7.33). In conclusion, dermoscopy may improve early AHM detection, discriminating AHSSM from amelanotic/hypomelanotic non melanoma lesions.

Amelanotic/hypomelanotic melanoma (AHM) is a subtype of melanoma that includes both hypomelanotic (partially pigmented and light colored) and amelanotic melanoma (AM) with no melanin pigmentation. 1e diagnosis of AHM may be very difficult because of the absence of pigmentation and presence of symmetry. 22][3] In this retrospective study, 133 amelanotic/hypomelanotic skin lesions were evaluated dermoscopically to identify predictive features of amelanotic/hypomelanotic superficial spreading melanoma (AHSSM) of ≤1 mm thickness.

| PATIENTS AND ME THODS
We collected 133 cases of histopathologically confirmed AHSSMs, amelanotic/hypomelanotic benign melanocytic lesions (AHBMLs) (e.g., compound and dermal nevus), and amelanotic/hypomelanotic non-melanocytic lesions (AHNMLs) (e.g.seborrhoeic keratosis and basal cell carcinoma) from eight participating centers between January 2007 and December 2011.This series was partially derived from our previous study. 2 this study only amelanotic/hypomelanotic lesions were considered, including amelanotic, having no melanin pigmentation (i.e., tan, dark brown, blue, gray, or black) and hypomelanotic melanomas.The latter comprise both partially pigmented lesions with a melanin pigmentation area ≤25% and light-colored melanoma with a faint brown or light gray-blue pigmentation. 1All cases were examined to assess the presence or absence of specific criteria by a panel of three blinded observers.The evaluation of the dermoscopic criteria was made when 3/3 or 2/3 observers agreed.
To identify the relevant factors associated with the diagnosis of AHSMM versus AHBML plus AHNML, univariate and multivariate analyses were used to compute odds ratios (ORs) and their corresponding 95% confidence intervals (CIs).Statistical significance was claimed for p values of ≤0.05 (two-sided).structureless pattern.More than one shade of pink, also known as pink veil or milky red areas, probably correspond to areas with increased vascular volume. 1 Neoangiogenesis is a dynamic process occurring during the rapid proliferation of melanocytes that determine an increase of oxygen and nutrient demands leading to hypoxia. 4 Neoangiogenesis following the initial disarranged melanoma growth could satisfy increased requirements, playing an essential role in melanoma development. 4In fact, melanoma seems to contain more blood vessels than dysplastic nevi and these latter contain more blood vessels than common nevi. 5Moreover, a high density vascular network seems to be associated with the evolution of atypical intraepidermal melanocytic to melanoma in situ. 6In our study, AHSSM showed a significantly greater frequency of more than one shade of pink and this vascular-related feature could be considered a marker of early AHM (Figures 1b,d and 2b).In fact, milky red areas were significantly associated with an augmented risk of amelanotic/hypomelanotic lentigo maligna. 7 In our study, a structureless or non-specific pattern was significantly associated with AHSSM.This pattern, correlated with absence or reduced amounts of the features seen in AHM (Figures 1d and 2b), has already been significantly associated with melanoma in situ. 8 agreement with our previous study, AHSSM showed a significantly greater frequency of irregular dots/globules and asymmetric pigmentation, (Figure 1b). 3 Histopathologically, globules correspond to nests of melanocytes at the dermo-epidermal junction or dermis, and dots with aggregates of melanocytes or melanin granules in the dermis. 9The pigmentation correlates aggregates of melanin in one or more layers of the epidermis and upper dermis. 9 Although AM show no melanin pigmentation to the naked eye, melanosomes in various stages of melanization and melanin granules can be found on histopathological examination. 10Dermoscopy, thanks to visualization of criteria reflecting pigmentation not visible to the naked eye, improves the diagnosis of AHM, (Figure 1b).

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DISCUSS IONMany features, such as atypical network, multicomponent pattern, irregular blotches, irregular streaks, irregular depigmentation, regression structures, shiny white structures, asymmetric shape, and peripheral light brown structureless areas, were significantly more frequent in AHSSM compared with AHBML plus AHNML in the univariate analysis.The most striking results of our study were that the only significant features discriminating AHSSM from AHBML plus AHNML in the multivariable analysis were more than one shade of pink, irregular dots/globules, asymmetric pigmentation, and aF I G U R E 1 (a, b) Clinical and dermoscopic image of hypomelanotic melanoma in situ on the neck of an 80 year old man.(a) In the clinical image a pink-brownish asymmetrical macule with irregular borders can be observed.(b) Dermoscopically, the melanoma reveals a structureless pattern, more than one shade of pink (square) and a peripheral light brown pigmentation (blue arrow) with foci of irregular brown dots/globules, (black arrow).(c, d) Clinical and dermoscopic images of amelanotic superficial spreading melanoma with a Breslow thickness of 0.2 mm on the neck of a 61-year-old man.(c) In the clinical image a pink reddish macule with irregular borders surrounded by a white asymmetric halo can be seen.(d) The dermoscopic image of the same lesion shows a structureless pattern, ill-defined areas of a milky red color with more than one shade of pink throughout the lesion, without clearly visible vascularity (squares), (original magnification 10×).
The dermoscopic diagnosis for melanoma completely devoid of pigment, relies on the analysis of vascular related features and vascular structures.The morphology of vessels depends on the thickness of the melanoma.Early AHM is characterized by predominant dotted vessels, often orderly arranged within ill-defined areas of milky red background, presenting more than one shade of pink. 11The combination of dotted and linear irregular vessels may be an indicator for intermediate thickness (1-2 mm) while thick AHM F I G U R E 2 (a, b) Clinical and dermoscopic image of amelanotic melanoma in situ on the back of a 50 year-old man.(a) Magnified detail (arrow) of a pink macule, surrounded by whitish irregular halo, on the back of a patient having multiple pink lesions, can be seen.(b) The dermoscopic image shows an overall structureless pattern consisting of ill-defined areas of milky red background presenting more than one shade of pink throughout the lesion (squares), that allows the identification of the "little red riding hood sign"; the more innocent lesion could clinically look benign from a distance but not when seen close up with dermoscopy.(c, d) Clinical and dermoscopic images of a compound nevus on the back of a 40-year-old man.(c) In the clinical image a pink symmetric papule can be observed.(d) The dermoscopic image of the same nevus shows a pink colored center surrounded by a peripheral light brown pigmentation not visible to the naked eye (original magnification 10×).The presence of more than one shade of pink throughout the lesion can help in discriminating early amelanotic melanoma from pink melanocytic nevus in which the pink color is located more frequently in the center, and the silhouette of the lesion can be discerned the at edge.

Positive features AHSSM (n = 27) AHBML+ AHNML (n = 106) OR (95% CI) Univariate Multivariate a n (%) n (%)
The approval by the Board of Ethics is waived for retrospective studies in accordance with the Italian research regulations (D.Lgs.101/2018,art.8), as the patients give their consent to the use of clinical data for research purposes, including publication of photographic material, at hospitalization.Table1shows the dermoscopic features that were significantly associated with the diagnosis of AHSSM versus AHBML/ AHNML in the univariate analysis.Among them, at the multivariable analysis, four dermoscopic features were significantly and independently associated with AHSSM, namely more than one shade of pink (OR 37.11, 95% CI 6.98-197.37),irregular dots/ p = 0.0452Abbreviations: AHBML, amelanotic/hypomelanotic benign melanocytic lesions; AHNML, amelanotic/hypomelanotic nonmelanocytic lesions; AHSSM, amelanotic/hypomelanotic superficial spreading melanoma with ≤1 mm thickness; CI, confidence interval; OR, odds ratio.aEstimatedfrom stepwise unconditional logistic regression model including all significant features in the univariate analysis.TA B L E 1 Univariate and multivariate analyses of positive dermoscopic features of AHSSM versus AHBML+AHNML.The study comprised 65 males and 68 females with a median age of 57 years (range, 24-84 years).No differences by sex emerged across the study groups, however, AHBML patients were younger than AHSSM and AHNML patients (median age 39 years vs 61 years and 63 years respectively).The back was the most frequent lesion localization area in all study groups.