Risk factors and outcomes of cutaneous melanoma in women less than 50 years of age

ORIGINAL

ARTICLE

Risk factors and outcomes of cutaneous melanoma in women less than 50 years of age Alejandra Tellez, MD,b Steven Rueda, MD,a Ruzica Z. Conic, MD,b Kristin Powers, BS,c Izabela Galdyn, MD,d Natasha Atanaskova Mesinkovska, MD, PhD,b and Brian Gastman, MDa Cleveland, Ohio; Washington, District of Columbia; and Loma Linda, California Background: Melanoma is the fifth most common cancer in the United States, with recent reports indicating increasing incidence among young women. Objective: This study sought to investigate histopathology, staging, risk factors, and outcomes of cutaneous melanoma in women younger than 50 years. Methods: All female patients aged up to 49 years with biopsy-proven diagnosis of melanoma between 1988 and 2012 were included. Patients with a follow-up of less than 2 years were excluded. Results: A total of 462 patients were identified, with mean age of 34.7 years. Invasive melanoma was less common in women 19 years of age or younger (P \ .0008). Positive sentinel node status (P \ .008), recurrence rates, metastatic disease (P \.001), and death rates (P \.008) were higher for women ages 40 to 49 years. The 41 patients with a pregnancy-associated melanoma had a significantly worse prognosis in comparison with a control group of nonpregnant patients, with a 9-fold increase in recurrence (P \ .001), 7-fold increase in metastasis (P = .03) and 5-fold increase in mortality (P = .06). Limitations: This was a retrospective study. Conclusion: The increasing incidence of melanoma for women younger than 50 years suggests that regular skin checks and self-examinations are warranted. In addition, in women given the diagnosis of melanoma during or within 1 year after childbirth, regular follow-up and monitoring for recurrence are recommended. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2015.11.014.) Key words: melanoma; pregnancy; pregnancy-associated melanoma; outcomes; sentinel node; survival; young.

T

he incidence of malignant melanoma (MM) has been increasing at a rapid pace in the last few decades.1 Surveillance, Epidemiology, and End Results showed an increase in female MM incidence rates by year from 7.44 cases per 100,000 in 1975 to 18.35 cases per 100,000 in 2011.2,3 Recent epidemiologic studies showed that the incidence of melanoma is rapidly increasing in women between 20 and 40 years of age.4 Although pregnancy-associated melanoma (PAMM) is considered a rare occurrence, the number

of cases may be expected to rise given the corresponding increase of melanoma among women of childbearing age. In fact, a recent population-based

From the Departments of Plastic Surgerya and Dermatology,b Cleveland Clinic; Georgetown University School of Medicine, Washingtonc; and Department of Plastic Surgery, Loma Linda University.d Funding sources: None. Conflicts of interest: None declared. Accepted for publication November 12, 2015.

Reprint requests: Brian Gastman, MD, Department of Plastic Surgery, A60, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected]. Published online January 12, 2016. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.11.014

Abbreviations used: AJCC: MM: PAMM:

American Joint Committee on Cancer malignant melanoma pregnancy-associated malignant melanoma

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study conducted in Sweden identified melanoma as 1 year of diagnosis. Patients with miscarriages and the most common malignancy diagnosed during pregnancy terminations were included. Patients pregnancy, followed by breast and cervical cancer.5 were categorized in 4 age groups (0-19, 20-29, Whether pregnancy itself has an adverse effect on 30-39, and 40-49 years) for categorical data analyses. the prognosis of MM is still unclear and remains a matter of debate. Statistical analysis In this single-center retrospective case-control Statistical analysis was performed using software study, a large clinical data(Stata 11.0, StataCorp LP, base was used to collect College Station, TX). MannCAPSULE SUMMARY detailed data of cutaneous Whitney or Student t tests melanomas developing in were used for continuous Incidence of malignant melanoma women aged 49 years or variables as deemed approamong women younger than 50 years is younger. The odds of melapriate. The x 2 or Fisher exact increasing, with highly variable reported noma mortality, recurrence, tests were used for categorioutcomes among pregnant women. and metastasis in women cal variables; Fisher was the This study found higher rates of with MM diagnosed during test of choice for variables recurrence, metastasis, and mortality in or within 1 year after pregwith frequency limited to 5 or women with pregnancy-associated nancy were analyzed. fewer occurrences per submelanoma. group. Post hoc analysis was METHODS Women younger than 50 years, performed for variables with This study was approved particularly those who are pregnant and multiple nominal categories by the Cleveland Clinic at higher risk of developing melanoma, and x2 with P less than .05 Institutional Board Review. should be vigilant in monitoring considered significant. To Patient population was obchanging skin lesions and maintain avoid high type 1 error, tained from the institutional diligent dermatologic follow-up. Bonferroni correction was diagnosis database. Data for applied when indicated. all female patients up to Multivariate analysis was 49 years of age who had a biopsy-proven diagnosis performed using logistic regression to determine if of cutaneous MM from 1988 to 2012 were reviewed. history of pregnancy, stage, location, and age group Patients with less than 2 years of follow-up were independently associated with melanoma after diagnosis were excluded from the study. death, metastasis, and recurrence. Detailed data were extracted from patients’ electronic medical records and included patient RESULTS demographics, tumor characteristics, sentinel lymph After applying exclusion criteria, the study node biopsy, and histopathologic data. Multiple cohort comprised 462 patients (Table I). The mean manual searches for terms ‘‘child,’’ ‘‘children,’’ ‘‘pregage at the time of melanoma diagnosis was 34.7 years. nancy,’’ ‘‘pregnant,’’ ‘‘delivery,’’ ‘‘delivered,’’ ‘‘birth,’’ The mean length of follow-up was 91 months. The ‘‘gravida,’’ ‘‘gestation,’’ ‘‘miscarriage,’’ and ‘‘abortion’’ majority of the patients in the study were aged 30 to were used in the electronic medical record system to 39 years (42.5%). The mean Breslow level identify all patients with melanoma that developed was 1.14 mm. Breslow level was available for 92% during pregnancy or within 1 year of childbirth. of the patients. The most common anatomic Cutaneous melanoma stage was assigned based on location was the trunk (38%), followed by lower the 7th edition of the American Joint Committee on 6 extremities (33%) and upper extremities (20%). All Cancer (AJCC) staging system. patients included in the study had information on Melanoma outcomes included all-cause MM6 AJCC stage. specific mortality, recurrence, metastasis rate, and need for immunotherapy, chemotherapy, and radiotherapy. Length of follow-up was defined as Study population the last office visit recorded in the electronic medical The most common pathologic stages across all record. PAMM was arbitrarily defined as MM age groups were stage 0 and I. Stage I was the most diagnosed during pregnancy or within 1 year after frequent in women presenting at 20 to 49 years of delivery. age, with approximately half of the cases (P \ .001 PAMM data were compared with a control group vs. other subgroups). In addition, a higher defined as the remaining study population with proportion of patients in the youngest age group no evidence of pregnancy or childbirth within (#19 years) had a stage 0 melanoma (P \.0008). d

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Table I. Characteristics of young women with melanoma Characteristic

Average age, y Age group, y \19 20-29 30-39 40-49 Location Trunk Lower extremity Upper extremity Head Breslow thickness, mm Stage 0 I II III IV SLNB performed SLNB positive Recurrence Metastasis Mortality

34.7 3.46% 29% 43.07% 24.46% 38% 33% 20% 9% 1.14 35.4% 48.9% 6.2% 7.6% 1.9% 21.9% 28.71% 2.4% 13.7% 17.1%

SLNB, Sentinel lymph node biopsy.

Only a minority of women across all age groups developed metastatic disease (Fig 1, B). Rates of melanoma metastases were unevenly distributed between subgroups (P \.001), with higher proportion noted in women in the age groups of 20 to 29 and 40 to 49 years (14.1% and 27.8%, respectively). Recurrence rates were low across age groups with notable variability. Again, higher recurrence rates were observed in age groups 20 to 29 and 40 to 49 years (3.7% and 5.2%, respectively) (Fig 1, C ). Patients presenting at age # 19 years and 30 to 39 years had no recurrence documented. Rates of melanoma mortality varied across age groups (P \ .001) (Fig 1, D). The highest rate was observed in women who presented at 40 to 49 years of age. Post hoc analysis revealed higher rates of melanoma-related death in patients in the oldest age group (40-49 years) compared with those presenting at younger than 39 years (P \.008). There was a trend toward higher frequency of sentinel node biopsy in older age groups. No sentinel node biopsies were performed in women in the youngest age group (Fig 2, A). Patients presenting at 40 to 49 years of age had the highest biopsy rate at 32.2%. Sentinel node biopsy rate was independent from age group.

Patients presenting at 40 to 49 years of age had the highest incidence of positive sentinel nodes with a rate of 45.9% (P \ .008 vs other groups) (Fig 2, B). This rate was nearly twice and 3 times as high as those presenting at 20 to 29 and at 30 to 39 years of age, with rates estimated at 23.1% and 17.1%, respectively (P = .02). Pregnancy and recent childbirth associated with MM There were 41 patients with MM diagnosed during or within 1 year after pregnancy. A total of 19 patients (46%) were given the diagnosis of MM during pregnancy. Among the cases diagnosed during pregnancy, there were 2 cases that resulted either in spontaneous abortion or elective termination of pregnancy. The mean age at the time of melanoma diagnosis in the PAMM group was 32.6 6 years and 34.7 years for the control group (P = .04). The mean Breslow level was 1.18 mm for the PAMM group and 1.14 mm for the control group (P = .57). The affected anatomic location differed between groups; the lower extremity was the most common site for the PAMM group (39.6%) whereas in the control group it was the trunk (36.6%) (Table II). In women with PAMM, 38 patients had melanoma stage II or less at diagnosis. A total of 2 women presented with stage III, both of whom were given a diagnosis within 1 year after delivery. A single patient presented with stage IV during pregnancy and underwent elective abortion before receiving immunotherapy and chemotherapy. History of pregnancy 1 year before diagnosis was similar across stages (P = .45) (Fig 3, A). There was a trend toward higher incidence of melanoma mortality in patients with PAMM compared with nonpregnant control subjects, with rates of 20% and 10.3%, respectively (P = .06) (Fig 3, B). Post hoc analysis demonstrated patients with stage II disease did not have significantly higher rates of mitoses or ulceration (P = .62 and 0.19, respectively) compared with the stage III group. There was higher incidence of melanoma recurrence in patients with PAMM diagnosis compared with nonpregnant control subjects, with rates of 12.5% and 1.4%, respectively (P \ .001) (Fig 3, C ). Similar to mortality and recurrence, there was higher incidence of melanoma metastasis in patients with PAMM compared with nonpregnant control subjects, with rates of 25% and 12.7%, respectively (P = .03) (Fig 3, D).

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Fig 1. Young women with diagnosis of melanoma; the relationship between age groups and: pathologic stage (A), rates of metastatic melanoma (B), recurrence rates (C), and rate of melanoma mortality (D).

Fig 2. Young women with diagnosis of melanoma; the relationship between age groups and: rates of sentinel lymph node biopsy (A) and sentinel lymph node biopsy results (B).

Multivariate analysis of melanoma mortality, metastasis, and recurrence Patients with PAMM had 5.1 increased odds of death from melanoma compared with control subjects independent of stage, age, and melanoma location (P = .03) (Table III). Stage IV disease had a higher associated mortality, followed by stage II and stage III. In this study, stage IIA to IIC melanoma was found to have higher mortality than stage III disease. This finding could be a result of 60% of stage III cases being subclassified into IIIA, which is in line with the findings by Balch et al6 showing patients with stage IIIA disease faring better than those with stage II. An additional possible cause of this observation is the sample size. Difference in age at diagnosis and location of tumor at diagnosis were not significant (P [.05). Patients with PAMM had 6.7 increased odds of developing distant melanoma metastasis independent of stage, age, and location (P = .01). Stage

IV was not included in analysis because by definition these patients present with distant metastatic disease. Stages II and III were associated with increased odds of distant melanoma metastasis with 47.4 and 23.7, respectively (P = .01). Patients between 40-49 years of age had a higher risk of metastasis when compared to those younger than 29 years old (P = .01). Tumor location was not significant (Table IV). Recurrences were limited to 11 observations across the entire study population. Despite the small number of observations, patients with PAMM had 9.2 greater odds of local recurrence when compared with the control group (P = .01). Stage, age group, and location were not significant (Table V).

DISCUSSION Inconsistent results are reported in relation to pregnancy and melanoma prognosis.7-24 While most investigations have defined PAMM as a melanoma

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Table II. Characteristics of pregnancy-associated malignant melanoma and control groups Average age, y Age group, y \19 20-29 30-39 40-49 Location Trunk Lower extremity Upper extremity Head Breslow thickness, mm Staging I II III IV SLNB performed SLNB positive Recurrence Metastasis Mortality

PAMM

Control

P value

32.6

34.7

.04

5% 37.5% 42.5% 15%

3.3% 28.3% 43.2% 25.2%

.23

30.1% 39.6% 18% 10.7% 1.18

36.6% 32.6% 20% 7.8% 1.14

.74 .57

50% 2.8% 8.3% 5.6% 22.5% 33.3% 12.5% 25% 20%

48.8% 6.5% 7.5% 1.6% 21.9% 28.3% 1.4% 12.7% 10.3%

.44 .67 .94 .001 .03 .06

PAMM, Pregnancy-associated malignant melanoma; SLNB, sentinel lymph node biopsy.

diagnosed during pregnancy,9,11-13,17,19-21,24,25 few previous studies have defined PAMM as a melanoma diagnosed either during pregnancy or within the postpartum period.10,14,15,22 Furthermore, variability in completeness of melanoma prognostic information represents a common limiting factor in the aforementioned published data.7 Such methodological differences make it difficult to draw definitive conclusions. The current study aimed to further elucidate this long-debated controversy. After adjusting for stage, age, and location, this study showed an overwhelming 5-fold, 7-fold, and 9-fold increase in mortality, metastasis, and recurrence, respectively, in women given the diagnosis of MM during or within 1 year after pregnancy. The findings of this study do not support the current consensus of no adverse effect of PAMM on the prognosis of MM.26 However, the great majority of previous investigations have focused on women given the diagnosis of melanoma during pregnancy thus have not included women given the diagnosis during the postpartum period.11-13,16,17,21 To date, only 4 studies have looked specifically at the outcomes in women given the diagnosis of melanoma during pregnancy and within 1 year after pregnancy. For instance, Moller et al14 reported a 2-fold mortality for patients with melanoma given the diagnosis

within a year after childbirth. In contrast to the current study, adjustment for tumor location was not available in this large population-based study. Another retrospective study published by Travers et al22 showed improved survival in women with PAMM diagnosed during pregnancy and up to 1 year postpartum; this study included women with stage I melanoma and had a mean follow-up time of 5 years. Two large population-based studies looking at the prognosis of women given the diagnosis of melanoma during and within 1 year after pregnancy concluded that it does not negatively affect survival.10,15 These aforementioned studies may have been limited by well-known drawbacks of data obtained from population-based registries including potential inaccuracy, incompleteness, reporting delays, and erroneous entries.27 In addition, population studies might fail to include miscarriages or terminated pregnancies given data are generally extracted from live birth registries. To our knowledge this is the first study that shows a decrease in survival for PAMM despite adjusting for age, tumor location, and AJCC stage. In addition, in contrast to other studies, 100% of the patients included in this study had information on AJCC staging. Furthermore, our data set began in 1988 in contrast to other studies that evaluated patients from earlier decades; given the rising rates of melanoma and its changing biology, PAMM may also be changing with time. In comparison with other register-based studies, this study’s patient population included women whose pregnancy did not result in a live birth. Compared with nonaggregate data from varied institutions using large databases, a manual electronic medical records review allowed us to capture important information on clinical history and melanoma characteristics (ie, stage and Breslow level at diagnosis), possibly accounting for this study’s findings. There were some limitations to the current study. Data were garnered through a retrospective singlecenter hospital-based review within a predominantly US population. Furthermore, the institution of origin represents both a primary and tertiary referral center thus may be biased toward more complex cases. There are several possible explanations for the poorer outcomes recorded in women with PAMM in this study, including a well-known issue of a possible delay in diagnosis.22,26 Most importantly, a biologic mechanism may be responsible for a more invasive potential. Several authors have hypothesized the adverse effects of high estrogen levels during pregnancy, yet strong evidence is lacking. The fact that tamoxifen therapy has not showed improved survival suggests that the role of estrogen may not be

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Fig 3. Pregnancy-associated malignant melanoma and: distribution for stage of disease (A), mortality (B), recurrence rate (C), and rate of metastatic disease (D).

Table III. Multivariate logistic regression for melanoma mortality Variable

Pregnancy Stage I II III IV Age category, y 30-39 40-49 Location Head and neck

Odds ratio

P value

Table IV. Multivariate logistic regression for melanoma metastasis SE

Variable

5.10

.03

3.8

3.00 59.40 37.30 539.40

.32 .01 .01 .01

3.3 66.9 41.3 730.2

0.46 2.55

.26 .14

0.32 1.6

Pregnancy Stage I II III Age category, y 30-39 40-49 Location Head and neck

0.61

.60

0.6

Regression adjusted for pregnancy, stage, age, and location of tumor. Odds ratio for each stage is that compared with melanoma in situ. Odds ratio reported for age is that compared with patients age 0-29 years. Odds ratio for location is head and neck compared with rest of the body.

very significant.28,29 This statement is supported by several studies showing no increased risk of melanoma after assisted reproductive technology.30-33 Another explanation for our results could be related to pregnancy and its natural state of immunosuppression, aimed at preventing fetal rejection.34 The reports of association of immunosuppression with excess melanoma mortality support this statement.35,36 Based on recent evidence, intratumoral lymphangiogenesis may a play an even more important role in PAMM.37-39 Khosrotehrani et al37 showed a 2-fold increase in the intratumoral lymphatic area in pregnant women

Odds ratio

P value

SE

6.70

.01

4.4

2.90 47.40 23.70

.19 .01 .01

3.3 66.9 41.3

1.00 5.50

.99 .01

0.32 1.6

3.40

.08

0.6

Regression adjusted for pregnancy, stage, age, and location of tumor. Odds ratio for each stage is that compared with melanoma in situ. Odds ratio reported for age is that compared with patients age 0-29 years. Odds ratio for location is head and neck compared with rest of the body.

when compared with nonpregnant control subjects. Moreover, a recent study showed that development of microscopic or macroscopic lymph node invasion depends on the level of lymphangiogenesis of the primary melanoma.38 These data are consistent with reported increased lymphangiogenic activity seen in sentinel lymph nodes among PAMM.39 This in turn may explain why PAMM seems to display a more ‘‘inflamed’’ tumor phenotype, a phenomenon clearly associated with tumor aggressiveness.40-42 This study provides good evidence of worse outcomes among patients with PAMM, thus highlights the importance of optimizing management

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Table V. Multivariate logistic regression for melanoma recurrence Variable

Pregnancy Stage I and II III and IV Age category, y 30-39 Location Head and neck

Odds ratio

P value

SE

9.30

.01

5.9

0.50 2.70

.31 .22

0.4 2.1

0.70

.56

0.4

1.30

.80

1.4

Regression adjusted for pregnancy, stage, age, and location of tumor. Odds ratio for each stage range is that compared with melanoma in situ. Odds ratio reported for age is that compared with patients age 0-29 years. Odds ratio for location is head and neck compared with rest of the body.

approaches to this challenging clinical scenario. Future prospective, multi-institutional studies will ultimately be required to determine the true impact of PAMM on a woman’s prognosis, and how to design best practices of surveillance and treatment. A better explanation of the underlying mechanisms for the worse survival in women with PAMM may prompt new opportunities for prevention and treatment. On the basis of our data, it may be recommended for women with PAMM to be made aware of the importance of vigilant monthly self-skin examinations.43 For physicians of patients with PAMM we suggest instructing patients to seek timely evaluation of any changing or new lesions noted during or immediately after pregnancy. In summary, the current study creates a need to reexamine the potential dangers of PAMM. REFERENCES 1. Mayer JE, Swetter SM, Fu T, Geller AC. Screening, early detection, education, and trends for melanoma: current status (2007-2013) and future directions: part I, epidemiology, high-risk groups, clinical strategies, and diagnostic technology. J Am Acad Dermatol. 2014;71(4):599.e1-599.e12. quiz 610, 599.e12. 2. Howlader N, Noone AM, Krapcho M, et al, eds. SEER cancer statistics review, 1975-2012. Bethesda, MD: National Cancer Institute; April 2015. http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER web site. 3. Purdue MP, Freeman LE, Anderson WF, Tucker MA. Recent trends in incidence of cutaneous melanoma among US Caucasian young adults. J Invest Dermatol. 2008;128(12): 2905-2908. 4. Bleyer A, O’Leary M, Barr R, Ries LAG, eds. Cancer epidemiology in older adolescents and young adults 15 to 29 years of age, including SEER incidence and survival: 1975-2000. Bethesda, MD: National Cancer Institute, NIH Pub. No. 06-5767; 2006.

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