Melanoma is one of the most common cancers in pregnancy¹ and approximately one third of melanomas in women occur during child-bearing years,^{2, 3} yet there is debate regarding the impact of pregnancy on melanoma prognosis. Initial reports suggested that pregnancy promotes malignant transformation, growth, and metastatic potential of melanoma.^3–5 Since then, various studies have shown mixed results on the characteristics and prognosis of pregnancy-associated melanoma (PAM) defined as melanoma diagnosed during antepartum and postpartum periods, with a limited number of large population-based studies showing no evidence of worsened prognosis of PAM.^{3, 6–14}

The clinical management of women with PAM may also pose challenges.¹⁵ As pregnancy may influence timing of surgery or lymph node procedures,¹⁶ and delays in excision impact survival,¹⁷ it is prudent to better understand the impact of pregnancy on management of melanoma.

Recent population-based studies on PAM are lacking from the United States and data on diverse patient populations are limited.¹⁰ Additionally, investigations in the management of PAM such as timing of surgery are scarce. Therefore, we conducted a population-based, retrospective cohort study to investigate the clinical, tumor and management characteristics of PAM and the impact of pregnancy on the survival of women with PAM by studying a racially/ethnically diverse population in California using the population-based California Cancer Registry (CCR) data.

There were 13995 women aged 15 to 44 years, who were diagnosed with first primary melanoma in 1994–2015 in California. Our final study population that met inclusion criteria included 13108 women with 1406 diagnosed with PAM (463 women were diagnosed with PAM during antepartum period and 943 within the first year postpartum).

Melanoma is one of the most common malignancies in women during reproductive years and in pregnancy ¹⁸, yet the impact of melanoma diagnosed during pregnancy continues to be a controversial topic. Prior case-control studies have shown variable results and population-based studies are limited, especially from the United States ^{6, 8, 12}. The results of our population-based study show that melanomas diagnosed during the postpartum period were thicker. However, pregnancy status did not otherwise affect clinical, histological or management characteristics of melanoma or impact survival, suggesting that the evaluation of women with suspected or confirmed PAM should be similar to women with non-PAM. In addition, our study identified survival disparities by race/ethnicity, neighborhood SES and health insurance, highlighting the need for strategies to reduce health disparities in melanoma.

Our results showed that the survival of women with PAM is similar to that of non-PAM. Most population-based studies have reported similar findings ³. While one meta-analysis demonstrated an increased risk of death in PAM ⁶, the methods were criticized by others, who found no differences between PAM and non-PAM.¹⁹ Lens et al.⁹ compared 185 women with PAM to 5348 women with non-PAM in 1958–1999 in Sweden and found no association with survival and pregnancy status. Similarly, Johansson et al. ¹¹ detected no difference in survival in 1019 women with PAM and 5838 women with non-PAM in 1963–2009 in Sweden. In a study of all cancer types, including 160 women with PAM and 4460 women with non-PAM, Stensheim et al. ⁸ showed a slightly increased risk of death in PAM, but once tumor thickness was accounted for, no difference was found. Lastly, also utilizing the California Cancer Registry, O’Meara et al. ¹⁰ reported no differences in survival of 412 women with PAM and 2451 age-matched women with non-PAM diagnosed in 1991–1999. Combined with our data, these studies strengthen the conclusion that the risk of death is not increased in PAM compared with non-PAM.

We also investigated the time to surgery, and the frequency of lymph node examination, addressing some of the conundrums related to management of PAM. Determining if definitive surgery is delayed is particularly important because OS decreases for stage I melanoma when time to surgery exceeds 30 days ¹⁷. As time to definitive surgery of melanoma was less than 30 days in most women and we did not observe significant differences between PAM and non-PAM, our findings suggest that surgical management of primary tumors in women with PAM follows standard procedures for melanoma. We did not detect significant differences in the frequency of lymph node examination in pregnant women with PAM, despite challenges related to these procedures, including low-dose radiation or tracers used for sentinel lymph node mapping ^{20, 21}.

While the majority of studies report no differences between the characteristics of PAM vs non-PAM (reviewed in ³), two studies from Northern Europe report a higher proportion of tumors of the trunk ^{8, 11} and thicker tumors in PAM ^{12, 22}. In our study, the most common tumor location was the lower extremity, followed by the trunk, upper extremity, and head and neck, comparable to prior data ^{10, 23}. Notably, anatomic location impacts survival, whereby melanoma of the head/neck and trunk is associated with worsened survival compared with the lower extremity ²⁴, a result also detected in our study. Similar to most previously published studies (reviewed in ³), we did not observe a difference in tumor thickness between women with PAM and non-PAM. However, we did find an association with increased thickness of PAM diagnosed postpartum, suggesting that biopsy of melanocytic tumors in the antepartum period may be delayed to the postpartum period. Additionally, unknown stage was more common in PAM. Prior studies have noted that unknown stage often represents patients not connected with health care, including diagnosed near time of death or diagnosed without further work up or treatment and have similar survival rates to regional stage melanoma ^{25, 26}.

In this study, race/ethnicity, neighborhood SES, and health insurance were associated with an increased risk of death. Lower overall survival was associated with Asian, Black and Native American race/ethnicity, corresponding to the results from prior studies on melanoma ^27–29. While PAM was more frequent in Hispanic women, Hispanic women had similar survival to non-Hispanic white women in this study. Differences in birth rates among racial/ethnic groups³⁰ may contribute to the higher frequency of PAM in Hispanic women, so future studies are warranted to assess the incidence of melanoma in pregnant women stratified by race/ethnicity. The observed association of increased risk of death from melanoma and lower SES has been demonstrated in numerous studies from various countries ^{26, 29, 31–37}. Our findings of worse survival and public or lack of health insurance has also been previously reported ³⁸ and may relate to reduced access to care. Disruptions in health insurance coverage are particularly common in low-income populations and result in lower receipt of prevention, screening and treatment ³⁹. Lack of public education and skin cancer screenings likely also play a role. Furthermore, race/ethnicity and insurance status also effect management of melanoma, with patients of Black race/ethnicity and with public insurance receiving immunotherapy less frequently and with longer time to treatment ^{40, 41}. In sum, it is imperative to address the disparities seen in melanoma survival, including implementing policies and programs for education of the public and addressing disparities related to race/ethnicity, SES and other factors ^{42, 43}.

The main limitation of our population-based study was that it lacked tumor details, such as presence or absence of ulceration (prior to 2004), number of mitoses, and presence of immune infiltrates. It is also notable that discordance in interpreting melanocytic tumors, particularly thin melanomas, by pathologists is common. As this study was based on cancer registry data, the accuracy of histopathologic diagnoses could not be confirmed via secondary review. Additionally, it is possible that our measure of PAM was subject to some misclassification if patients diagnosed during antepartum died of melanoma prior to delivery or if patients had a spontaneous pregnancy loss or an abortion. In addition, data on placental and fetal metastases, which can be associated with high-risk PAM, were unavailable. The alterations of the immune system during pregnancy mirror those seen in malignancies, where regulatory T cells proliferate and Th1 immune response changes to Th2 immune response ^44–46. In a prior retrospective case-control study of 34 PAM, no differences were found in tumor thickness or other histological parameters, but interestingly, PAM showed more marked inflammation around the tumor compared with non-PAM ⁴⁷. As it is becoming standard of care to initiate immunotherapy for resected early stage melanoma ^{48, 49}, the impact of pregnancy on the immune microenvironment of melanoma warrants further study. Despite these limitations, our study addresses the current knowledge gaps by including a large, racially/ethnically diverse population and by including data from the most recent decades when melanoma incidence has been increasing ^{50, 51}. Furthermore, with a median follow up of 10 years, our study was able to make meaningful comparisons between PAM and non-PAM and prior published studies.

We report a population-based analysis of melanoma in pregnancy in California. Melanoma occurring postpartum was associated with greater tumor thickness, but pregnancy status did not otherwise affect survival or characteristics of melanoma. This suggests that the evaluation and surgical management of women with PAM should be similar to non-PAM, including during the antepartum period, to avoid delays in diagnosis. Race/ethnicity, neighborhood SES and health insurance impacted survival, underscoring the importance of reducing health care disparities in the US. Future goals include addressing these disparities by promoting skin cancer prevention and early detection strategies in racial and ethnic minorities and by improving access to care.