Increased melanoma recurrence in patients with multiple primary invasive melanomas.

To the Editor: Primary melanoma patients have an increased risk of developing other primary melanomas over time, but the influence of multiple primary melanomas on recurrence rates is unknown. Survival was formerly believed to be better in those with multiple primary melanomas,1Kricker A. Armstrong B.K. Goumas C. et al.Survival for patients with single and multiple primary melanomas: the genes, environment, and melanoma study.JAMA Dermatol. 2013; 149: 921-927Crossref PubMed Scopus (27) Google Scholar but it is now known to be worse with increased melanoma mortality.2Peek G. Olsen C.M. Baade P. et al.Survival in patients with multiple primary melanomas: systematic review and metaanalysis.J Am Acad Dermatol. 2020; 83: 1406-1414Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar We prospectively assessed the recurrence rates in patients 5 years after the diagnosis of high-risk primary melanoma, comparing patients in whom other primary melanomas developed before or since their index primary melanoma with patients with only the index melanoma. Adults with melanoma tumor stage 1b-4b were recruited from public hospitals, private practices, and pathology laboratories in Queensland, from 2010 to 2014, with approval from the respective ethics committees.3Von Schuckmann L.A. Hughes M.C. Ghiasvand R. et al.Risk of melanoma recurrence after diagnosis of a high-risk primary tumor.JAMA Dermatol. 2019; 155: 688-693Crossref PubMed Scopus (35) Google Scholar At baseline, the participants completed a questionnaire about age, sex, serious comorbidities, previous diagnosis of primary melanoma (confirmatory histology obtained), and family history. The histologic details of index melanomas (site, thickness, ulceration, mitoses, and subtype) and results of sentinel lymph node biopsies (SLNBs) were recorded. All the participants were followed up for ≥5 years. Self-reported new primary melanomas were verified against clinical records, as were recurrences (with histologic or radiologic evidence of a secondary melanoma ≥1 month after the index primary melanoma).3Von Schuckmann L.A. Hughes M.C. Ghiasvand R. et al.Risk of melanoma recurrence after diagnosis of a high-risk primary tumor.JAMA Dermatol. 2019; 155: 688-693Crossref PubMed Scopus (35) Google Scholar The Queensland Cancer Registry and hospital records were searched regularly for any new patients with primary or metastatic melanoma or deaths. Recurrence sites were categorized as local, regional, or distant.3Von Schuckmann L.A. Hughes M.C. Ghiasvand R. et al.Risk of melanoma recurrence after diagnosis of a high-risk primary tumor.JAMA Dermatol. 2019; 155: 688-693Crossref PubMed Scopus (35) Google Scholar Multiple recurrences within 30 days were counted once, classified based on the most distant site. We used Cox proportional hazard regression model to compare the recurrence (melanoma-related death) rates in those with multiple melanomas versus those with a single melanoma, adjusting for age, sex, the thickest melanoma, any ulceration, and applied Firth bias correction.4Heinze G. Schemper M. A solution to the problem of monotone likelihood in Cox regression.Biometrics. 2001; 57: 114-119Crossref PubMed Scopus (221) Google Scholar All-cause and cause-specific (or disease-free) survival time accumulated from the time of the first primary diagnosis to the time of death (or first recurrence), the time of loss to follow up, or 5 years from study entry, whichever occurred first. Patients who died recurrence-free or those still alive at 5 years were censored. Survival times were left-truncated (“delayed entry”) at the time of second primary diagnosis.5Youlden D.R. Baade P.D. Soyer H.P. et al.Ten-year survival after multiple invasive melanomas is worse than after a single melanoma: a population-based study.J Invest Dermatol. 2016; 136: 2270-2276Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Of 700 patients with T1b-T4b melanomas,3Von Schuckmann L.A. Hughes M.C. Ghiasvand R. et al.Risk of melanoma recurrence after diagnosis of a high-risk primary tumor.JAMA Dermatol. 2019; 155: 688-693Crossref PubMed Scopus (35) Google Scholar 64 (9%) had experienced at least 2 invasive melanomas before any recurrence. Within 5 years, 160 (23%) experienced recurrence; the associated factors (P ≤ .001) were male sex, head/neck primary melanoma, increasing tumor thickness and mitotic rate, tumor ulceration, and SLNB positivity (Table I). Excluding 38 patients with positive SLNB results, 82 (13%) of 662 patients died, of whom 49 (8% of 662 patients) died from melanoma), while 8 (1%) were lost to follow up (Table II).Table IPatient and tumor characteristics at baseline by any 5-year melanoma recurrenceCharacteristicsTotalNo recurrenceRecurrenceP value‡From χ2 test.n = 700 (%)n = 540 (%)∗Includes n = 27 patients who died without recurrence and n = 9 patients who were lost to follow up before recurrence.n = 160 (%)†Of n = 160, 66 subsequently died (59 melanoma-specific and 7 non-melanoma cause of death).Patient characteristics Age at baseline (years)<55189 (27)157 (29)32 (20)55-70286 (41)215 (40)71 (45)>70225 (32)168 (31)57 (35).075 SexMale410 (59)299 (55)111 (69)Female290 (41)241 (45)49 (31).002 Previous melanoma at baselineNo563 (80)439 (81)124 (78)Noninvasive102 (15)78 (14)24 (15)Invasive35 (5)23 (4)12 (7).24 First-degree relative with melanomaNo504 (73)382 (71)122 (77)Yes189 (27)153 (29)36 (23).149 Comorbidity§Defined as ever diagnosis of heart disease, diabetes, hypertension/stroke, or cancers other than skin cancers.No362 (52)289 (54)73 (46)Yes338 (48)251 (46)87 (54).079 SLNBNo442 (63)333 (62)109 (68)Yes258 (37)207 (38)51 (32).137 SLNB positive resultNo220 (85)194 (94)26 (51)Yes38 (15)13 (6)25 (49)<.0001Baseline tumor characteristics SiteTrunk247 (35)193 (36)54 (34)Head/neck154 (22)93 (17)61 (38)Upper limbs143 (20)129 (24)14 (9)Lower limbs156 (22)125 (23)31 (19)<.0001 Thickness (mm)≤1121 (17)111 (21)10 (6)>1-2312 (45)257 (48)55 (34)>2-4178 (25)119 (22)59 (37)>489 (13)53 (10)36 (23)<.0001 UlcerationAbsent504 (72)415 (77)89 (56)Present196 (28)125 (23)71 (44)<.0001 Mitotic rate (per mm)‖Missing mitotic rate data for n = 16.<1†Of n = 160, 66 subsequently died (59 melanoma-specific and 7 non-melanoma cause of death).88 (13)79 (15)9 (6)1-3296 (43)254 (48)42 (27)>3300 (44)196 (37)104 (67)<.0001 SubtypeSSM278 (40)233 (43)45 (28)Nodular172 (25)119 (22)53 (33)Other¶Other includes lentigo maligna (9%), desmoplastic (19%), nevoid (10%), spitzoid (2%), lentiginous (1%) acral lentiginous (3%), mixed (5%), unable to classify (8%), not stated (44%), and other (0.4%).250 (36)188 (35)62 (39).001SLNB, Sentinel lymph node biopsy; SSM, superficial spreading melanoma.∗ Includes n = 27 patients who died without recurrence and n = 9 patients who were lost to follow up before recurrence.† Of n = 160, 66 subsequently died (59 melanoma-specific and 7 non-melanoma cause of death).‡ From χ2 test.§ Defined as ever diagnosis of heart disease, diabetes, hypertension/stroke, or cancers other than skin cancers.‖ Missing mitotic rate data for n = 16.¶ Other includes lentigo maligna (9%), desmoplastic (19%), nevoid (10%), spitzoid (2%), lentiginous (1%) acral lentiginous (3%), mixed (5%), unable to classify (8%), not stated (44%), and other (0.4%). Open table in a new tab Table II5-year outcomes by multiplicity of invasive primary melanomas before the first recurrence in 662 patients without a positive SLNB result5-year outcomeTotal (n = 662) n (%)Multiplicity of invasive primary melanoma before recurrenceUnadjusted HR (95% CI)Adjusted∗Adjusted for age, sex, thickness category of the thickest melanoma, and the presence of ulceration in any melanoma. HR (95% CI)Single (n = 600) n (%)Multiple (n = 62) n (%)Recurrence Alive, no recurrence493 (74)454 (76)39 (63)1.00†Referent category includes all patients with no recurrence (including those who died without recurrence or those who were lost to follow up before recurrence).1.00†Referent category includes all patients with no recurrence (including those who died without recurrence or those who were lost to follow up before recurrence). Lost to follow up8 (1)8 (1)0 (0) Died, no recurrence26 (4)23 (4)3 (5) Recurrence135 (20)115 (19)20 (32)3.49 (1.89, 5.95)2.82 (1.51, 4.85)Mortality Alive580 (87)529 (87)51 (82)1.00‡Referent category includes all patients who were alive, regardless of recurrence status.1.00‡Referent category includes all patients who were alive, regardless of recurrence status.With recurrence79 (14)67 (13)12 (19)No recurrence501 (73)462 (74)39 (63) All-cause82 (13)§Includes n = 7 (n = 6 with single primary and n = 1 with multiple primary invasive melanoma) with recurrence prior to death, but the cause of death does not include metastatic melanoma; thus, of the 135 with recurrence, 56 subsequently died (49 melanoma-specific and 7 non-melanoma cause of death).71 (13)11 (18)2.06 (0.89, 4.11)1.65 (0.71, 3.34)Melanoma49 (8)42 (8)7 (11)1.67 (0.46, 4.36)1.42 (0.38, 3.78)Non-melanoma33 (5)§Includes n = 7 (n = 6 with single primary and n = 1 with multiple primary invasive melanoma) with recurrence prior to death, but the cause of death does not include metastatic melanoma; thus, of the 135 with recurrence, 56 subsequently died (49 melanoma-specific and 7 non-melanoma cause of death).29 (5)4 (6)2.87 (0.91, 7.04)2.16 (0.68, 5.44)CI, Confidence interval; HR, hazard ratio.∗ Adjusted for age, sex, thickness category of the thickest melanoma, and the presence of ulceration in any melanoma.† Referent category includes all patients with no recurrence (including those who died without recurrence or those who were lost to follow up before recurrence).‡ Referent category includes all patients who were alive, regardless of recurrence status.§ Includes n = 7 (n = 6 with single primary and n = 1 with multiple primary invasive melanoma) with recurrence prior to death, but the cause of death does not include metastatic melanoma; thus, of the 135 with recurrence, 56 subsequently died (49 melanoma-specific and 7 non-melanoma cause of death). Open table in a new tab SLNB, Sentinel lymph node biopsy; SSM, superficial spreading melanoma. CI, Confidence interval; HR, hazard ratio. Of 600 patients with single primary melanomas and no positive SLNB result, 115 (19%) had recurrent disease compared with 20 (32%) of 62 with multiple melanomas (adjusted hazard ratio, 2.82; 95% confidence interval, 1.51-4.85; Table II). The results were similar after further adjusting for mitotic rate and head/neck primary melanoma (adjusted hazard ratio, 2.45; 95% confidence interval, 1.28-4.31) and after accounting for competing risk of death. Patients with multiple melanomas compared with those with a single melanoma, had a 64% increase in distant melanoma recurrence (n = 59; 44% of patients with recurrence) (adjusted prevalence ratio, 1.64; 95% confidence interval, 1.03-2.60, calculated using log binomial regression) versus combined regional (n = 65; 48% of patients with recurrence) or local (n = 11; 8%) melanoma recurrence. We conclude that patients with multiple invasive primary melanomas carry significantly higher risk of recurrent disease, including distant metastases (and, thus, not an artifact of increased surveillance), than those with a single primary melanoma. None disclosed.