Risk factors affecting the first metastasis of acral melanoma: Low- pigmentation independently predicts a first lung metastasis

To the Editor: In cutaneous melanomas, the coloration or degree of pigmentation of the melanoma is variable and may be associated with histologic features and prognosis.1Thomas N.E. Weston A.K. Waxweiler W.T. et al.Comparison of clinicopathologic features and survival of histopathologically amelanotic and pigmented melanomas: a population-based study.JAMA Dermatol. 2014; 150: 1306-1314Crossref PubMed Scopus (85) Google Scholar, 2Phan A. Touzet S. Dalle S. Ronger-Savle S. Balme B. Thomas L. Acral lentiginous melanoma: histopathological prognostic features of 121 cases.Br J Dermatol. 2007; 157: 311-318Crossref PubMed Scopus (84) Google Scholar, 3Phan A. Touzet S. Dalle S. Ronger-Savle S. Balme B. Thomas L. Acral lentiginous melanoma: a clinicoprognostic study of 126 cases.Br J Dermatol. 2006; 155: 561-569Crossref PubMed Scopus (178) Google Scholar The effect of the degree of pigmentation on the occurrence and site of first metastasis is unknown. We investigated the prognostic factors for acral melanomas and whether the degree of pigmentation of acral melanoma was correlated with the first metastasis site. The study enrolled 178 patients with acral melanoma who were diagnosed at the Chonnam National University Hospital from January 1992 to September 2019. Patients were divided into subgroups according to the metastatic patterns of their melanoma: melanoma in situ (group 1), invasive melanoma without metastasis (group 2), invasive melanoma with a first lymph node metastasis (group 3), and invasive melanoma with a first distant metastasis (group 4). The degree of pigmentation was evaluated by 2 dermatologists blinded as to outcome, using clinical and dermoscopic photographs. Pigmentation was divided into amelanotic and mild, moderate, severe, and heavy pigmentation; we made a representative typical clinical photo of each category (Fig 1). In addition, low-pigmentation (amelanotic and mild) and high-pigmentation (moderate, severe, and heavy) groups were established to minimize subjective bias. Patients in the low-pigmentation group had a mean age of 68.3 years, and those in the high-pigmentation group had a mean age of 61.9 years; the difference was statistically significant (P = .003) (Table I). In the low-pigmentation group, the tendencies toward a deeper T stage, the presence of ulceration, higher mitotic rate (P < .001), and positive sentinel lymph node biopsy (SLNB) status (P =.003) were significantly higher . Patients in the low-pigmentation group had a significantly higher risk of a first metastasis to a lymph node, the skin (in transit, distant), or a lung than patients in the high-pigmentation group (P < .001). In the multivariate analysis, low pigmentation was independently associated with a first lung metastasis (odds ratio, 4.15; 95% confidence interval, 1.25-13.82; P = .02). Low pigmentation was identified as an independently significant prognostic factor for melanoma-specific mortality (hazard ratio, 2.62; 95% confidence interval, 1.45-4.73; P = .001).Table IComparison between the 2 pigmentation groups∗Percentages have been rounded and may not add up to 100%.VariableLow-pigmentation groupHigh-pigmentation groupP value†Statistically significant at P < .05.AmelanoticMildModerateSevereHeavyN (%)43 (24.2)135 (75.8)Age, y, mean (SD)68.3 (12.1)61.9 (12.3).003Sex, n (%).374 Male23 (53.5)67 (49.6).659 Female20 (46.5)68 (50.4)Site of lesion, n (%).439 Sole29 (67.4)95 (70.4) Palm0 (0)6 (4.4) Fingernail8 (18.6)21 (15.6) Toenail6 (14.0)13 (9.6)Disease duration, months, mean (SD)4.7 (7.8)35.3 (83.7).018Group,‡Group 1, melanoma in situ. Group 2, invasive melanoma without metastasis. Group 3, invasive melanoma with first lymph node metastasis. Group 4, invasive melanoma with first distant metastasis. n (%)<.001 11 (2.3)44 (32.6) 22 (4.7)26 (19.3) 334 (79.1)57 (42.2) 46 (14.0)8 (5.9)T stage, n (%)<.001 Tis (melanoma in situ)1 (2.3)44 (32.6) T11 (2.3)15 (11.1) T25 (11.6)20 (14.8) T317 (39.5)26 (19.3) T419 (44.2)30 (22.2)Ulceration, n (%)<.001 Present33 (76.7)43 (31.9) Absent10 (23.3)92 (68.1)Mitotic rate, mm2, n (%)<.001 05 (11.6)64 (47.4) 1-614 (32.6)45 (33.3) ≥724 (55.8)26 (19.3)SLN biopsy, n (%).003 Positive9 (90.0)17 (38.6) Negative1 (10.0)27 (61.4)First metastasis site, n (%) Lymph node<.001Present26 (60.5)40 (29.6)Absent17 (39.5)95 (70.4) Skin (in transit)<.001Present17 (39.5)14 (10.4)Absent26 (60.5)121 (89.6) Skin (distant)<.001Present3 (7.0)0 (0.0)Absent40 (93.0)135 (100) Lung.001Present9 (20.9)6 (4.4)Absent34 (79.1)129 (95.6) Brain.593Present2 (4.7)4 (3.0)Absent41 (95.3)131 (97.0) Liver.222Present2 (4.7)2 (1.5)Absent41 (95.3)133 (98.5)Survival, n (%).001 Lived18 (41.9)94 (69.6) Died25 (58.1)41 (30.4)Time to death, months, mean (SD)36.5 (37.5)72.6 (50.7)<.001SD, Standard deviation; SLN, sentinel lymph node.∗ Percentages have been rounded and may not add up to 100%.† Statistically significant at P < .05.‡ Group 1, melanoma in situ. Group 2, invasive melanoma without metastasis. Group 3, invasive melanoma with first lymph node metastasis. Group 4, invasive melanoma with first distant metastasis. Open table in a new tab SD, Standard deviation; SLN, sentinel lymph node. In our study, deeper invasion, ulceration, higher mitotic rate, and much higher mortality were more often seen in the low- than in the high-pigmentation group and indicated a poor prognosis. The low-pigmentation group was more likely to have a positive SLNB and to have the lymph node, skin, or lung as a first metastasis site. A first metastasis to distant organs was also associated with melanoma pigmentation. Interestingly, the multivariate analysis showed that a first lung metastasis was strongly associated with low- pigmentation. Patients with low-pigmentation acral melanoma may have a greater tendency to develop metastasis through the vascular system, but further studies are warranted to explain why lung involvement was more frequent than liver and brain involvement in these patients. In conclusion, low-pigmentation acral melanomas were significantly associated with advanced T stage, the presence of ulceration, a higher mitotic rate, SLNB positivity, and a higher risk of metastasis. Furthermore, low-pigmentation was independently associated with a first lung metastasis.