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Melanoma pp 239-252 | Cite as

Melanoma in Pregnancy

  • Joanna L. Walker
  • Annie Wang
  • George Kroumpouzos
  • Martin A. Weinstock
Chapter

Abstract

Pregnancy may transiently alter clinical features of benign melanocytic nevi (BMN) but does not increase the rate of malignant transformation. Changes in size and/or pigment network are minor, infrequent, and typically associated with anatomic sites prone to skin stretching in pregnancy. Females with dysplastic nevus syndrome (DNS) may have elevated risk of malignant transformation and should be monitored closely during pregnancy. Approximately 8% of malignant melanoma (MM) cases occur during pregnancy; therefore, screening, evaluation, and biopsy of suspicious lesions are paramount to avoid delayed diagnosis of MM during pregnancy. It is unclear whether pregnancy worsens outcome or survival for MM; translational and clinical studies show complex and conflicting trends. Two recent meta-analyses report a 17–56% elevated risk of mortality for pregnancy-associated malignant melanoma (PAMM); however, controversy still exists among experts as data is limited and analysis methods have been criticized. Early-stage PAMM does not cause poor fetal or maternal pregnancy outcomes, but metastatic MM is the most common cancer to spread to the placenta and fetus. PAMM should be treated according to standard guidelines for MM whenever possible, with expeditious surgery the main treatment modality for localized MM. The safety of systemic targeted and immunotherapy for MM in pregnancy is unknown; expert multidisciplinary teams should manage advanced-stage PAMM. Pregnancy following diagnosis and treatment of MM does not have any fetal or maternal adverse effects, but counseling should be individualized based on stage of disease and maternal preferences in cases with high risk for recurrence or metastasis.

Keywords

Malignant melanoma Pregnancy Pregnancy-associated melanoma Melanocytic nevi Management Prognosis Review 

Melanocytic Nevi in Pregnancy

Melanocytic nevi should be monitored during pregnancy, and a biopsy performed for significant change or features of malignant melanoma (MM) [1]. Historically, change in BMN pigmentation during pregnancy was once considered to be a normal hormonally driven phenomenon. This hypothesis was derived from other pregnancy-induced pigmentary disorders, such as melasma and linea nigra, whereby sex hormone signaling increases pigment production. However, no correlation between sex hormone signaling and pigmentation has been proven with BMN in pregnancy.

Melanocytic nevus enlargement and/or darkening can occur during pregnancy, but the rate of malignant transformation of BMN is not increased according to histologic and clinical data [2]. While the natural course of BMN is not altered by pregnancy, dysplastic nevi (DN) in patients with dysplastic nevus syndrome (DNS) may have an increased risk for malignant change [3].

Evidence for pregnancy’s effect on DN comes from Ellis et al., examining 17 females with DNS where nevi were photographed and prospectively followed. The rate of change in nevi increased 3.9-fold in pregnancy compared to the nonpregnant state, with the risk of change in DN found to be 1.6 times higher [3]. One patient in the study developed MM during pregnancy [3]. Altered estrogen receptor (ER) expression in changing DN is a plausible mechanism for elevated rate of change during pregnancy. ERβ expression is higher in DN compared with BMN and expression correlates with the grade of atypia [2]. The ERβ receptor is upregulated in BMN, but not DN during pregnancy, and it appears to have protective antitumoral effects [2]. Interpretation of this data is difficult as ER signaling is complex, the effects of endogenous estrogen binding to ERβ on DN are unknown, and the newly identified G protein-coupled ER (GPER) has not been studied in DN. Further studies are needed to clarify the significance of ER expression in melanocytic lesions and the natural course of DN in pregnancy.

Mild histologic changes in melanocytic nevi may occur in pregnancy. A histopathologic review reported a slight increase in atypical histologic features in nevi of pregnant patients, compared with those of non-pregnant controls. The atypical findings were not of a sufficient degree to result in diagnostic confusion in distinguishing between benign nevus and MM [4]. Interestingly, the histologic features were no different compared with male controls [4]. A smaller histologic study by Chan et al. documented more mitotic figures and higher mitotic rates in nevi from pregnant patients compared with non-pregnant controls, supporting a theory of higher “activation” of cells during pregnancy. They also described a distinctive morphologic pattern of clustered epithelioid melanocytes in the superficial dermis that was more common in BMN from pregnant cases (81% vs. 27% of controls) [5] (Fig. 14.1).
Fig. 14.1

Nevus on the left breast that enlarged, became lighter, and more raised during pregnancy. Pathology showed moderate melanocytic atypia with expansile dermal nest and elevated Ki67 expression (5%) on dermal melanocytes. No atypia or signs of proliferation were present on the residual lesion that was excised 9 months post-partum

Studies evaluating clinical and dermoscopic changes in nevi during pregnancy report either no change [6] or changes in size, pigment network, and/or vascular structures that return to normal within approximately 12 months postpartum [7, 8, 9]. Physical stretching of the skin, increased vascularity, and behavioral modifications such as reduced exposure to sunlight are postulated to contribute to pregnancy-associated changes in nevi [9]. BMN on the breasts and abdomen are more likely to change as tissue expands in these regions [7, 10, 11]. Growth in diameter is less common on areas such as the back, occurring in 0–9.5% of BMN between the first and third trimester [12, 13].

Pregnancy-associated dermoscopic changes include lightening or darkening of pigment, reduced thickness and prominence of pigment network, peripheral pigment globules, and increased vascularity (increased dotted or comma-shaped vascular structures) [6, 7, 8, 9, 11, 12]. A dermoscopic scoring system for BMN change during pregnancy has documented minimal, but statistically significant, change occurring in ~10–19% of nevi [7, 8, 12] (Table 14.1.).
Table 14.1.

Pregnancy-associated dermoscopic changes in melanocytic nevi

Lightened or darkened pigment

Reduced pigment network prominence

Peripheral pigment globules

Increased vascular structures

Traditional dermoscopic criteria for dysplasia such as asymmetry, irregular pigment network, and blue-white veil should not be attributed to physiologic gestational changes [9]. Clinically suspicious lesions should always warrant a biopsy to obtain a pathologic diagnosis, performed in the same manner as a non-pregnant patient. Excision of a dysplastic nevus with severe cytologic atypia may be safely postponed until postpartum. However, there may be certain circumstances whereby an immediate re-excision may be considered [14] (Fig. 14.2).
Fig. 14.2

Pregnancy-associated MM

MM in Pregnancy

Introduction

MM is the most common malignancy in pregnancy, accounting for 24–33% of all malignancies diagnosed during pregnancy in Swedish, Norwegian, and Australian population studies [15, 16, 17, 18]. One-third of MMs affecting women occur during childbearing age [15, 16] and 3.3–11.8% of cases in this group are associated with pregnancy [18, 19]. Approximately 8% of all MM diagnoses occur during pregnancy [20]. PAMM incidence is rising due to the increasing incidence of MM in younger females and trends in the delay in childbearing [18, 21, 22, 23]. The incidence of PAMM in Australia increased from 37.1 to 51.84 per 100,000 maternities between 1994 and 2008, with maternal age accounting for the difference in cases [24].

The conventional definition of pregnancy-associated cancer is a diagnosis occurring during pregnancy through 1-year postpartum. While the definition of PAMM in the literature varies from inclusion of pregnancy only and/or 1–5 years postpartum, the definition of PAMM here includes the diagnosis during pregnancy and up to 1 year after delivery.

Pathophysiology

Pregnancy-induced changes in the immune milieu, hormone levels, metabolic activity, lymphangiogenesis, and fetal cell microchimerism underlie theories for altered tumor and host behavior in PAMM. Evidence of poorer outcome in pregnant mice with MM stimulates efforts to identify potential pathogenic mechanisms [25]. The interplay of various pregnancy-specific changes is complex, with some factors having a seemingly protective role against MM and others associated with increased risk (Table 14.2).
Table 14.2

Potential factors in pathophysiology and outcome in PAMMa

Protective

Increased peri-tumoral inflammation

Unclear/mixed effect on outcome

Female hormone levels

Estrogen receptor expression on tumor cells

Fetal cell microchimerism

Unfavorable

Increased lymphangiogenesis

Reduced cellular immunity/increased tumor tolerance

Increased metabolic activity

aFurther research is needed to clarify the role of these factors in PAMM

The immune milieu in pregnancy shifts toward a T-helper cell 2 (Th2)-dominant phenotype with increased cellular tolerance and relative immunosuppression. Cancer cells and fetal trophoblast cells survive through biologic mechanisms that promote “immune escape” via natural killer and regulatory T cells [26]. Human leukocyte antigen (HLA)-G expression suppresses immune surveillance via dampened response against tumor antigens and sustains immune tolerance by inducing CD4+ lymphocyte differentiation into regulatory T cells (Tregs). Tregs and trophoblast expression of HLA-G prevent maternal rejection of the semi-allogeneic fetus. In a similar manner, cancer cells alter the local immune response through these pathways to allow tumor progression [27]. In fact, increased Treg cells correlate with a worse outcome in metastatic MM [28]. It is unknown whether the trophoblast alteration in Tregs affects surveillance and response to MM and evidence of suppressed immune response to PAMM is lacking. In fact, increased peri-tumoral lymphocytic infiltrates are seen in PAMM compared with non-PAMM tumors [29]. The prognostic implications of the inflammatory reaction in this setting are unknown.

The effects of sex hormones on the development and outcome of MM are varied and poorly understood. Female gender and multiparity are associated with improved MM survival and MM outcomes in some studies [24, 29, 30, 31]. An Australian population-based study reported a 40% decreased risk of PAMM in females with at least three prior pregnancies compared with nulliparous females [24]. However, the association between parity and decreased MM risk has been shown for both male and female genders, suggesting environmental over hormonal or biologic factors [32].

MM cells have estrogen receptors [33, 34] but it is unclear whether it is a “hormone-responsive” tumor. Some theorize that elevated estrogen levels have a detrimental effect on MM outcome, but recent data suggests that estrogen signaling on tumor cells is more complex than initially thought, and possibly could even have favorable effects. Additionally, treatment of metastatic MM with the antiestrogen drug, tamoxifen, does not seem to affect outcome [35, 36].

Estrogen receptors are expressed differently in PAMM. There is higher expression of G protein-coupled estrogen receptor (GPER) in PAMM compared with non-PAMM (78% vs. 28%) and in most of these cases ERβ is co-expressed [34]. GPER and ERβ co-expression correlates with favorable pathologic prognostic features such as lower Breslow’s depth, fewer mitoses, increased peri-tumoral lymphocytic infiltrates, and a decreased risk of metastasis [34]. Loss of ERβ expression promotes tumorigenesis [34, 37].

Pregnancy is well known to represent a state of increased metabolic activity, with some studies showing an increased mitotic activity in tumors associated with pregnancy [5]. However, several studies analyzing mitotic rate and immunohistochemical markers for PAMM tumors do not show increased tumor proliferation rates [29, 38]. Pregnancy-associated plasma protein-A (PAPPA) is a metalloproteinase that influences insulin growth factor and tumor transition from the epidermis to the mesenchyme. The serum levels of PAPPA are increased in pregnancy, suggesting that increased levels can correlate with increased MM cell migration and worse survival, particularly for advanced-stage MM [39].

The most compelling data on pregnancy’s role in the pathogenesis of MM relates to recent data on the increased lymphangiogenesis and fetal microchimeric cells. Pregnant mice with MM were shown to have larger tumors, increased metastases, and poorer survival as well as increased lymphatic vessels compared with nonpregnant controls [25, 40, 44]. Increased lymphatic vessel size and lymphatic intra-tumoral area were also documented in MMs from human pregnant individuals, with no increase in blood vessel angiogenesis [25, 40]. Prior studies increased MM tumor lymphangiogenesis with an increased risk for lymph node invasion and a higher hazards ratio of 5.5 of finding a sentinel lymph node with metastatic disease [41, 42]. While the mouse model showing increased lymphangiogenesis is more representative of advanced MM, the potential correlation between poorer outcomes associated with pregnancy requires further exploration.

A study evaluating fetal cell microchimerism (FCM) provided a potential mechanism for MM tumor lymphatic formation unique to pregnancy. FCM is the phenomenon whereby fetal cells enter the maternal circulation, persist, and act as progenitor cells that may differentiate into other cell lines, particularly in the setting of damaged tissue. The role of FCM in cancer is quite complex and in many studies they appear to have a protective effect for the mother [43]. In the case of MM, such cells are found in the majority of tumors in pregnant mice and humans, often expressing endothelial cell markers. In fact, they were found to cluster in the form of vessels in some instances, leading the authors to hypothesize that fetal-derived lymphatic progenitor cells acquired during gestation lead to increased MM-associated lymphatics [44]. Further studies are required to explore these concepts further and evaluate potential clinical impact for these findings.

Outcomes and Prognosis

Maternal Risks

There is insufficient evidence to determine if pregnancy affects MM prognosis and an overall consensus is lacking. Historically, the prevailing view was that PAMM portended worse outcomes based on several case series in the 1950s–1990s [45, 46, 47, 48]. Subsequently, some controlled studies have disproven this belief, while others continue to show poorer outcomes in this population. Variability in the definition of PAMM complicates the interpretation of results, as studies include MM cases ranging from diagnosis 1 year prior to pregnancy, and during pregnancy only, to inclusion of diagnosis 2 or more years following pregnancy. Further analysis of several studies has shown a wide variation in applied statistical methods, as well as a lack of other confounding factors such as staging, tumor thickness, and anatomic location. Table 14.3 summarizes research findings on PAMM’s influence on prognosis.
Table 14.3

Studies on prognosis of melanoma arising in pregnancya

First author, publication year

Study design and country: pregnant cases (stage)

Findings

Pregnancy has no effect on prognosis

Jones et al. 2017 [20]

Prospective hospital-based cohort

No difference in stage, recurrence, disease-free interval, melanoma-specific survival, or overall survival

United States

156 cases (stages 0–III)

Complete dataset, controlled analyses

Johansson et al. 2014 [57] (extension of Lens et al. 2004 [55])

Retrospective population-based cohort

No difference in MSS or OS between cases and controls (HR 1.05 CI 0.81–1.36)

Sweden

1019 cases (include pregnancy and 2 years postpartum; 247 during pregnancy) staging data available in 59%, mostly early stage

Sub-analysis with non-significant ↓ mortality in pregnant cases (HR 0.79, CI 0.44–1.41)

O’Meara et al. 2005 [56]

Retrospective population-based cohort

No difference in stage, tumor thickness, or prognosis (HR for death 0.79, p = .57)

United States

412 cases; MM diagnosed during or within 1 year of pregnancy (all stages, but survival analysis limited to localized disease)

Daryanani et al. 2003 [60]

Retrospective clinic-based cohort

Pregnancy does not affect survival

The Netherlands

Non-significant ↑ tumor thickness in pregnancy

46 cases (stage I/II)

Travers et al. 1995 [61]

Retrospective clinic-based cohort

Trend toward better survival in pregnant MM pts (p = .08)

United States

↑ thickness in tumors in PAMM

45 cases in pregnancy or 1 year postpartum (stage “clinically localized”)

MacKie et al. 1991b [92]

Retrospective clinic-based cohort

No effect on DFI or survival after correcting for tumor thickness

United Kingdom

92 cases (stage I/II MM)

Wong et al. 1989 [62]

Retrospective clinic-based cohort

No differences in tumor location, histologic features, and 5-year survival between groups

United States

66 cases (stage I MM)

Adverse effect of pregnancy on prognosis

Kyrgidis et al. 2017 [49]

Meta-analysis

↑ Risk of mortality (HR 1.17 CI 1.03–1.33), ↓ OS

Pooled data from 14 studies

↓ DFS (HR 1.50 CI 1.19–1.90)

Byrom et al. 2015 [51]

Meta-analysis

↑ Risk of melanoma death (HR 1.56 CI 1.23–1.99)

Pooled data from 4 studies (Lens, Mackie, Stensheim, Moller)

Addition of Tellez study increases HR to 1.64 (53)

Repeat analysis with exclusion of Moller and other adjustments show HR non-significantly elevated [52]

Tellez et al. 2015 [63]

Retrospective hospital-based cohort

5.1 ↑ odds of death (p = .03), 6.7 ↑ odds of metastasis (p = .01), 9.2 ↑ odds of local recurrence (p = .01)

Discrepancies in staging, criticism for methods [65, 66]

United States

41 cases (all stages, mostly stage I/II) during or within 1 year of preg (19 during preg)

Moller et al. 2013 [58]

Retrospective population-based cohort

↑ risk of death (HR 1.92 CI 1.42–3.01)

Study design

United Kingdom

 

306 cases (all stages) diagnosis during 1 year postpartum only (no cases during pregnancy); stage available for 72%

examined the effect of recent childbirth on outcome, did not examine MM during pregnancy

Stensheim et al.2008 [16]

Retrospective population-based cohort

↑ risk of cause-specific death (HR 1.52, CI 1.01–2.31); no longer significant when adjusted for tumor location. No difference in survival

Norway

160 cases (stage not stated; Breslow’s depth available for 55%)

Slingluff et al. 1989 [48] (extension of Reintgen et al. 1985 [70])

Retrospective clinic-based cohort

Thicker MMs (p = .05), ↑ metastatic disease (p = .008) but no difference in OS between groups (Slingluff)

United States

100 cases (all stages, but 98% with stage I/II)

↓ DFI in pts compared to controls (p = .04); no difference in OS (Reintgen)

Trapeznikov et al. 1989 [64]

Russia

↓ 10-year survival in pts compared to controls (p < .05)

102 cases (all stages)

HR hazard ratio, DFI disease-free interval, DFS disease-free survival, MSS melanoma-specific survival, OS overall survival, MM malignant melanoma, pts patients, preg pregnancy, ↑ increased, and ↓ decreased

Table is substantially modified from Tierney E, Krounpouzos G, Rogers G. Skin Tumors. In: Kroumpouzos G, editor. Text Atlas of Obstretric Dermatology. Philadelphia: Lippincott Williams & Wilkins Publishers. 2013; 141–151

aTable includes only studies of ≥40 patients

b143 completed pregnancy before MM; 85 diagnosed/treated before pregnancy; 68 diagnosed between pregnancies

Recent meta-analyses suggest increased mortality for PAMM, but the results are controversial based on differences in inclusion criteria, methods of statistical analyses, and poor quality of evidence in included studies such as retrospective case–control study design, incomplete data that lacks confounding factors, and inconsistent definition and analysis of outcomes [49, 50, 51, 52, 53, 54]. Mortality is increased by 17% and recurrence by 50% in PAMM according to a meta-analysis by Kyrgidis et al. Sensitivity analyses addressed the heterogeneity in case definition, study design, and ability to control for stage and tumor depth, and the effect of PAMM on mortality remained. However, the overall grade for the quality of evidence was too low to have confidence in the estimate according to the author’s analysis [49].

A meta-analysis by Byrom et al. showed a 56% increase in the mortality risk for PAMM and a hazards ratio of 1.64 [51, 53]. The study design and analysis were criticized for selection bias and improperly utilized statistical methods that included the pooling of the hazard ratio outcomes. In addition, the study with the greatest weight in the analysis included cases during post-partum only, evaluating the effect of recent childbirth on MM outcome as opposed to the other studies evaluating MM during pregnancy. When the results are recalculated according to alternative definitions and inclusion criteria, the adverse survival outcome is no longer found to be statistically significant [52, 54].

Population-based cohort studies are the highest level of evidence available for PAMM. Most of the available evidence shows no worsened survival for PAMM, but some results are conflicting and pertinent confounding factors, such as staging data, are missing in some of the larger studies [55, 56, 57, 58]. In addition to the population-based cohort studies with largely negative results, several single-institution cohort and case–control studies on localized PAMM fail to show that pregnancy has any adverse influence on outcomes [20, 38, 59, 60, 61, 62]. Conversely, others demonstrate poorer survival and outcomes for PAMM [63, 64], but again the utilized methods and statistical analyses have been questioned [65, 66]. Increased gravity at diagnosis was associated with worse survival in early-stage PAMM in one study [20]. This finding was not noted in stage III disease, and overall pregnancy did not portend worse outcome or survival in that study [20].

The effect of pregnancy on stage III and IV malignant melanoma is unclear, as controlled studies lack adequate numbers of advanced MMs in pregnancy. Two retrospective case series summarize outcomes for a total of 52 stage III and IV PAMMs, but interpretation is difficult without a comparison group [67, 68]. Theoretically, several behavioral and biologic mechanisms negatively affect late-stage PAMM outcomes. With the advent of effective systemic therapies that lack safety data in pregnancy, there is the risk for sub-standard and delayed care in late-stage PAMM [48, 56]. Additionally, the mechanisms of increased lymphangiogenesis during pregnancy are more likely to be impactful with invasive tumors.

Delay in diagnosis during pregnancy can cause an increase in postpartum MM diagnoses, i.e., a “rebound effect” in incidence, later stage disease, and poorer outcome [15, 17]. Diagnostic delay likely explains the increased tumor thickness of PAMM compared with controls in some studies [24, 48, 61, 69, 70] and accounts for some trends showing decreased survival in PAMM. Alternatively, increased tumor depth in PAMM could be interpreted as more aggressive disease associated with pregnancy, but the majority of studies do not find pregnancy as an adverse prognostic factor in MM when tumor depth and stage are controlled. In fact, PAMM cases were actually diagnosed at an earlier stage in a study involving patients under close surveillance in a pigmented lesion clinic [38].

Several adverse maternal effects have been reported for pregnancy-associated cancers including increased hospitalizations, cesarean section delivery, sepsis, thromboembolic events, and severe maternal morbidity [17]. However, studies with separate analyses for PAMM indicate that the incidence of thromboembolic events is not increased [71], and the risk of hospitalization is lower in MM compared with that of other pregnancy-associated cancers [72]. Potential PAMM complications and maternal risks include those relevant to MM treatment, late-stage disease, and emotional stress.

Fetal Risks

While the majority of research focuses on maternal health risks for PAMM, few studies analyze potential adverse fetal effects. The risk for cesarean delivery and planned preterm birth are elevated in pregnancy-associated cancers and PAMM [17]. Prematurity is the most common fetal adverse outcome associated with PAMM, typically iatrogenic, and much more common in advanced-stage MM (occurring in 56% of stage III/IV cases) [67, 68]. Whether MM diagnosis during pregnancy affects infant birth weight is unclear. PAMM was associated with large-for-gestational age (LGA) newborns in one study [17] and lower mean birth weight in another [73], and two population studies showed no influence on birth weight [56, 74].

Adverse fetal effects are more likely to occur from the diagnostic and therapeutic interventions, particularly in stage III and IV MM. A recent report included cases treated with surgery, lymph node biopsy (11 cases), lymph node dissections (10 cases), radiation (3 cases), and chemotherapy (1 case) during pregnancy, showing uneventful adverse newborn outcomes [68]. In a retrospective review of 22 stage III and IV PAMM cases at a single institution, there were no neonatal deformities or severe fetal complications noted, except for one spontaneous abortion occurring after a lymph node dissection in the first trimester [67].

The fetal risk is most clearly defined for advanced-stage MM when there is a substantial risk for placental and fetal metastasis; fortunately, this is a rare occurrence. MM is the most common type of pregnancy-related cancer that also metastasizes to the placenta and fetus. Forty to 58% of all metastatic cancers to the fetus are due to MM [75, 76, 77]. One review highlighted that in all cases of fetal metastasis, microscopic evidence of metastatic MM was found in all placentas, and all mothers had visceral metastases (stage IV) [75]. In a separate study, 87 cases of maternal MM were reviewed, of which 17% (15 of 87 patients) had placental involvement, but only 40% of those (6 of the 15 patients) were found to have fetal metastasis [77]. On average, cases of metastatic MM presented in the fetus around 4.5 months post-partum (range : 0 to 20 months). The most common sites of metastasis were the liver and subcutaneous tissues [77].

Management

There are no NCCN guidelines for MM in pregnancy. The current standard of care is to manage melanocytic lesions in pregnant females just as one would in nonpregnant females. Once a histopathologic confirmation of MM is made, staging and prognostication, including evaluation of maternal and fetal risks from diagnostic procedures, surgery and systemic chemotherapy, targeted therapy, and immunotherapy, should be performed. When imaging is required for staging, modalities using ionizing radiation should be avoided whenever possible. Magnetic resonance imaging (MRI) is a diagnostic tool to be used when other nonionizing diagnostic procedures such as ultrasound are deemed inadequate. MRI is safe for both mother and fetus in the second and third trimesters, but its use in the first trimester is typically reserved for clinically imperative cases [78] (Fig. 14.3).
Fig. 14.3

Pregnancy-associated melanocytic nevi

Treatment

The surgical management of MM is the same for pregnant women as it is for nonpregnant women. Biopsies of suspicious lesions should not be delayed. Local anesthesia, with the minimum necessary amount of lidocaine 1% (pregnancy category B), for shave, punch, or excisional biopsy, ensures prompt diagnosis and carries minimal risks to mother and fetus. Subsequent re-excision of MM lesions with appropriate wide margins based on tumor Breslow’s depth is recommended for all localized MM and should not be postponed.

In thicker lesions (>0.8 mm Breslow’s thickness) and tumor stage ≥T1b, the sentinel lymph node biopsy (SLNB) is a powerful prognostic test [77], which is useful for staging but has no impact on MM survival. There is no evidence-based guidance regarding the role and timing of SLNB in pregnancy, and therefore SLNB should be discussed on an individual basis, ideally within the confines of a comprehensive cancer center that specializes in the multidisciplinary management of melanoma. Radiopharmaceuticals with a short half-life, such as preoperative intradermal technetium-99 m-sulfur colloid, deliver <5 mGy of radiation and have not been associated with any maternal or fetal adverse effects [79]. The use of radiocolloid alone for SLNB, without blue dye, is recommended to prevent potential complications, such as anaphylactic reactions [14, 80]. Some authors suggest postponing SLNB until after delivery for pregnant patients with a perceived low risk for nodal involvement (stage T1b to T2b) [81]. For patients without advance disease, premature delivery should be avoided [68].

For stage III/IV disease, the benefits versus potential maternal and fetal risks of staging and treatment should be weighed [82]. Indications for complete lymph node or therapeutic lymph node dissection in regional metastatic MM (stage III) are the same as for a nonpregnant patient. If advanced-stage MM is diagnosed in the first trimester, termination of pregnancy may be offered. However, there is no specific guideline for this since it is unknown if pregnancy affects the outcome of MM in the mother [82], and the risk for fetal metastasis is very low.

The need for imaging and systemic therapies that pose fetal risk must also be considered. For the patients needing systemic therapy or radiation, premature induction of delivery at 34 weeks prior to the initiation of therapy can be considered [83]. However, this decision will depend on several factors, including the specific therapy’s risk for fetal harm compared with the dangers of delayed treatment of MM.

There is scarce safety data for adjuvant and newer targeted or immunomodulatory therapy (such as interferon-α, BRAF inhibitors, MEK inhibitors, anti-CTLA-4 monoclonal antibodies, or PD1 inhibitors) during pregnancy. One report of vemurafenib use in pregnancy resulted in premature cesarean delivery for fetal distress but, fortunately, did not result in any fetal malformations [84]. Ipilimumab, an anti-CTLA-4 antibody, is known to cross the placenta and has been associated with urogenital tract malformations, miscarriages, stillbirths, premature births, and neonatal death in monkeys [85]. The anti-PD1 antibodies (nivolumab and pembrolizumab) have resulted in fetal loss, but no increase in birth defects in animal studies [86]. There is no safety data in human pregnancy; therefore, the use of such medications should be restricted to experienced practitioners after extensive discussion and evaluation of the potential risks and benefits on a case-by-case basis [87].

Fetal Metastasis

Since melanoma may metastasize to the placenta and the fetus [75, 76, 77], gross and microscopic evaluation of the placenta postpartum is recommended. This is performed with immunohistochemical staining for MM antigens in all stage IV metastatic melanoma patients [77]. In neonates without metastases at birth, careful evaluation and monitoring for the next 24 months are recommended, including periodic evaluation at wellness checks with full body examination of the skin. Baseline chest X-ray and liver enzymes, including lactate dehydrogenase, every 6 months, are also advocated by some experts [77].

Counseling

Preconception counseling for women with a history of MM and a desire to conceive can be a difficult discussion for healthcare providers. There are no evidence-based guidelines regarding pregnancy after a diagnosis of MM [87]. Discussion points include patient prognosis and maternal/fetal risks should recurrence occur during pregnancy. If chemotherapy or immunotherapy were used, their potential effects on fertility should be acknowledged. Overall, fertility and pregnancy rates are decreased in cancer survivors.

However, MM may be an exception, as post-cancer pregnancy rates do not appear to be adversely affected in women with a prior MM [88]. Additionally, fetal adverse outcomes such as congenital abnormalities, stillbirth, low birth weight, and preterm birth are not increased for gestations occurring after a diagnosis of MM [73, 74]. There is no evidence to suggest that a post-cancer pregnancy worsens outcomes or prognosis in females with treated MM [16, 30, 89, 90]. Several reviews have failed to show an increase in MM recurrence, or a decrease in survival, associated with pregnancy after a diagnosis of MM. This data is predominantly derived from patients with stage I/II MM and a detrimental effect for those with a higher stage MM diagnosis cannot be ruled out [89, 90, 91].

Tumor thickness remains the single most important predictor of recurrence. MacKie et al. documented a <10% 5-year MM recurrence rate in tumors <1.5 mm thickness, as compared with a 30% 5-year mortality risk for tumors 1.5–3.5 mm in Breslow’s depth [92]. Tumors thicker than 3.5 mm had >50% mortality [92]. The same authors also showed that 83% of recurrence in stage II occurred within 2 years of the initial treatment [92]. Based on this data, the authors proposed waiting 2 years after surgery before becoming pregnant.

Schwartz et al. supported the 2-year wait for thinner MMs, and also recommended waiting 3–5 years for thicker lesions [14]. In a retrospective review of 22 cases of stage III and IV PAMM, the median time between primary melanoma and regional or distant disease occurring during pregnancy was 16 months, with a range of 0–10 years [67]. In general, however, a waiting period prior to becoming pregnant is not shown to alter outcomes. Recommendations should be made on a case-by-case basis after weighing the risks and benefits of recurrence risk with the age of the patient and eagerness to conceive.

It is worth noting that there is no evidence that oral contraceptives or hormone replacement therapies have any role in the natural history of MM. The decision to use either of the above should be based on a thorough evaluation of health and familial risk factors beyond that of a MM history [93, 94, 95, 96].

Conclusions

Controversy remains regarding the effect of pregnancy on MM outcomes, especially for stage III and IV, but it is clear that early diagnosis and treatment are imperative to improve outcomes. This requires countering former assumptions regarding the normalcy of changing pigmented lesions during pregnancy, with prompt biopsy of changing or worrisome lesions. Future studies are necessary to clarify the role of pregnancy in MM prognostication. In general, treatment for PAMM should be according to standard guidelines, but in some cases consideration for fetal and maternal health may individualize the timing and course of staging and therapy.

References

  1. 1.
    Walker JL, Wang AR, Kroumpouzos G, Weinstock MA. Cutaneous tumors in pregnancy. Clin Dermatol. 2016;34(3):359–67.CrossRefPubMedGoogle Scholar
  2. 2.
    Nading MA, Nanney LB, Boyd AS, Ellis DL. Estrogen receptor beta expression in nevi during pregnancy. Exp Dermatol. 2008;17(6):489–97.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ellis DL. Pregnancy and sex steroid hormone effects on nevi of patients with the dysplastic nevus syndrome. J Am Acad Dermatol. 1991;25(3):467–82.CrossRefPubMedGoogle Scholar
  4. 4.
    Foucar E, Bentley TJ, Laube DW, Rosai J. A histopathologic evaluation of nevocellular nevi in pregnancy. Arch Dermatol. 1985;121(3):350–4.CrossRefPubMedGoogle Scholar
  5. 5.
    Chan MP, Chan MM, Tahan SR. Melanocytic nevi in pregnancy: histologic features and Ki-67 proliferation index. J Cutan Pathol. 2010;37(8):843–51.CrossRefPubMedGoogle Scholar
  6. 6.
    Wyon Y, Synnerstad I, Fredrikson M, Rosdahl I. Spectrophotometric analysis of melanocytic naevi during pregnancy. Acta Derm Venereol. 2007;87(3):231–7.PubMedGoogle Scholar
  7. 7.
    Akturk AS, Bilen N, Bayramgurler D, Demirsoy EO, Erdogan S, Kiran R. Dermoscopy is a suitable method for the observation of the pregnancy-related changes in melanocytic nevi. J Eur Acad Dermatol Venereol. 2007;21(8):1086–90.CrossRefPubMedGoogle Scholar
  8. 8.
    Rubegni P, Sbano P, Burroni M, Cevenini G, Bocchi C, Severi FM, et al. Melanocytic skin lesions and pregnancy: digital dermoscopy analysis. Skin Res Technol. 2007;13(2):143–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Zampino MR, Corazza M, Costantino D, Mollica G, Virgili A. Are melanocytic nevi influenced by pregnancy? A dermoscopic evaluation. Dermatol Surg. 2006;32(12):1497–504.PubMedGoogle Scholar
  10. 10.
    Sanchez JL, Figueroa LD, Rodriguez E. Behavior of melanocytic nevi during pregnancy. Am J Dermatopathol. 1984;6(Suppl):89–91.PubMedGoogle Scholar
  11. 11.
    Strumia R. Digital epiluminescence microscopy in nevi during pregnancy. Dermatology. 2002;205(2):186–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Gunduz K, Koltan S, Sahin MT, EF E. Analysis of melanocytic naevi by dermoscopy during pregnancy. J Eur Acad Dermatol Venereol. 2003;17(3):349–51.CrossRefPubMedGoogle Scholar
  13. 13.
    Pennoyer JW, Grin CM, Driscoll MS, Dry SM, Walsh SJ, Gelineau JP, et al. Changes in size of melanocytic nevi during pregnancy. J Am Acad Dermatol. 1997;36(3 Pt 1):378–82.CrossRefPubMedGoogle Scholar
  14. 14.
    Tierney EKG, Tumors RGS. In: Kroumpouzos G, editor. Text atlas of obstretric dermatology. Philadelphia: Lippincott Williams & Wilkins Publishers; 2013. p. 141–51.Google Scholar
  15. 15.
    Andersson TM, Johansson AL, Fredriksson I, Lambe M. Cancer during pregnancy and the postpartum period: a population-based study. Cancer. 2015;121(12):2072–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Stensheim H, Moller B, van Dijk T, Fossa SD. Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. J Clin Oncol. 2009;27(1):45–51.CrossRefPubMedGoogle Scholar
  17. 17.
    Lee YY, Roberts CL, Dobbins T, Stavrou E, Black K, Morris J, et al. Incidence and outcomes of pregnancy-associated cancer in Australia, 1994–2008: a population-based linkage study. BJOG. 2012;119(13):1572–82.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Eibye S, Kjaer SK, Mellemkjaer L. Incidence of pregnancy-associated cancer in Denmark, 1977–2006. Obstet Gynecol. 2013;122(3):608–17.CrossRefPubMedGoogle Scholar
  19. 19.
    Lens M, Rosdahl I, Newton-Bishop J. Cutaneous melanoma during pregnancy: is the controversy over? J Clin Oncol. 2009;27(19):e11–2; author reply e3–4CrossRefPubMedGoogle Scholar
  20. 20.
    Jones MS, Lee J, Stern SL, Faries MBI. Pregnancy-associated melanoma associated with adverse outcomes? J Am Coll Surg. 2017;225(1):149–58.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Peccatori FA, Azim HA Jr, Orecchia R, Hoekstra HJ, Pavlidis N, Kesic V, et al. Cancer, pregnancy and fertility: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl 6):vi160–70.CrossRefPubMedGoogle Scholar
  22. 22.
    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):2905–8.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Bleyer WA. Cancer in older adolescents and young adults: epidemiology, diagnosis, treatment, survival, and importance of clinical trials. Med Pediatr Oncol. 2002;38(1):1–10.CrossRefPubMedGoogle Scholar
  24. 24.
    Bannister-Tyrrell M, Roberts CL, Hasovits C, Nippita T, Ford JB. Incidence and outcomes of pregnancy-associated melanoma in New South Wales 1994–2008. Aust N Z J Obstet Gynaecol. 2015;55(2):116–22.CrossRefPubMedGoogle Scholar
  25. 25.
    Khosrotehrani K, Nguyen Huu S, Prignon A, Avril MF, Boitier F, Oster M, et al. Pregnancy promotes melanoma metastasis through enhanced lymphangiogenesis. Am J Pathol. 2011;178(4):1870–80.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Cristiani CM, Palella E, Sottile R, Tallerico R, Garofalo C, Carbone E. Human NK cell subsets in pregnancy and disease: Toward a new biological complexity. Front Immunol. 2016;7:656.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Johansen LL, Lock-Andersen J, Hviid TV. The pathophysiological impact of HLA class Ia and HLA-G expression and regulatory T cells in malignant melanoma: a review. J Immunol Res. 2016;2016:6829283.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Baumgartner JM, Gonzalez R, Lewis KD, Robinson WA, Richter DA, Palmer BE, et al. Increased survival from stage IV melanoma associated with fewer regulatory T cells. J Surg Res. 2009;154(1):13–20.CrossRefPubMedGoogle Scholar
  29. 29.
    Fabian M, Toth V, Somlai B, Harsing J, Kuroli E, Rencz F, et al. Retrospective analysis of clinicopathological characteristics of pregnancy associated melanoma. Pathol Oncol Res. 2015;21(4):1265–71.CrossRefPubMedGoogle Scholar
  30. 30.
    Vihinen P, Vainio-Kaila M, Talve L, Koskivuo I, Syrjanen K, Pyrhonen S. Previous pregnancy is a favourable prognostic factor in women with localised cutaneous melanoma. Acta Oncol. 2012;51(5):662–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Roh MR, Eliades P, Gupta S, Tsao H. Cutaneous melanoma in women. Int J Womens Dermatol. 2015;1(1):21–5.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kaae J, Andersen A, Boyd HA, Wohlfahrt J, Melbye M. Reproductive history and cutaneous malignant melanoma: a comparison between women and men. Am J Epidemiol. 2007;165(11):1265–70.CrossRefPubMedGoogle Scholar
  33. 33.
    Zhou JH, Kim KB, Myers JN, Fox PS, Ning J, Bassett RL, et al. Immunohistochemical expression of hormone receptors in melanoma of pregnant women, nonpregnant women, and men. Am J Dermatopathol. 2014;36(1):74–9.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Fabian M, Rencz F, Krenacs T, Brodszky V, Harsing J, Nemeth K, et al. Expression of G protein-coupled estrogen receptor, GPER in melanoma and in pregnancy-associated melanoma. J Eur Acad Dermatol Venereol. 2017;31(9):1453–61.CrossRefPubMedGoogle Scholar
  35. 35.
    Beguerie JR, Xingzhong J, Valdez RP. Tamoxifen vs. non-tamoxifen treatment for advanced melanoma: a meta-analysis. Int J Dermatol. 2010;49(10):1194–202.CrossRefPubMedGoogle Scholar
  36. 36.
    Lens MB, Reiman T, Husain AF. Use of tamoxifen in the treatment of malignant melanoma. Cancer. 2003;98(7):1355–61.CrossRefPubMedGoogle Scholar
  37. 37.
    Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P. Loss of ERbeta expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer. 2004;11(3):537–51.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Merkel EA, Martini MC, Amin SM, Yelamos O, Lee CY, Sholl LM, et al. A comparative study of proliferative activity and tumor stage of pregnancy-associated melanoma (PAM) and non-PAM in gestational age women. J Am Acad Dermatol. 2016;74(1):88–93.CrossRefPubMedGoogle Scholar
  39. 39.
    Prithviraj P, Anaka M, McKeown SJ, Permezel M, Walkiewicz M, Cebon J, et al. Pregnancy associated plasma protein-A links pregnancy and melanoma progression by promoting cellular migration and invasion. Oncotarget. 2015;6(18):15953–65.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Rodero MP, Prignon A, Avril MF, Boitier F, Aractingi S, Khosrotehrani K. Increase lymphangiogenesis in melanoma during pregnancy: correlation with the prolactin signalling pathway. J Eur Acad Dermatol Venereol. 2013;27(1):e144–5.CrossRefPubMedGoogle Scholar
  41. 41.
    Dadras SS, Lange-Asschenfeldt B, Velasco P, Nguyen L, Vora A, Muzikansky A, et al. Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod Pathol. 2005;18(9):1232–42.CrossRefGoogle Scholar
  42. 42.
    Massi D, Puig S, Franchi A, Malvehy J, Vidal-Sicart S, Gonzalez-Cao M, et al. Tumour lymphangiogenesis is a possible predictor of sentinel lymph node status in cutaneous melanoma: a case-control study. J Clin Pathol. 2006;59(2):166–73.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Cirello V, Fugazzola L. Novel insights into the link between fetal cell microchimerism and maternal cancers. J Cancer Res Clin Oncol. 2016;142(8):1697–704.CrossRefPubMedGoogle Scholar
  44. 44.
    Nguyen Huu S, Oster M, Avril MF, Boitier F, Mortier L, Richard MA, et al. Fetal microchimeric cells participate in tumour angiogenesis in melanomas occurring during pregnancy. Am J Pathol. 2009;174(2):630–7.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Conybeare RC. Malignant melanoma and pregnancy: report of 3 cases. Obstet Gynecol. 1964;24:451–4.CrossRefPubMedGoogle Scholar
  46. 46.
    Riberti C, Marola G, Bertani A. Malignant melanoma: the adverse effect of pregnancy. Br J Plast Surg. 1981;34(3):338–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Pack GT, Scharnagel IM. The prognosis for malignant melanoma in the pregnant woman. Cancer. 1951;4(2):324–34.CrossRefPubMedGoogle Scholar
  48. 48.
    Slingluff CL Jr, Reintgen DS, Vollmer RT, Seigler HF. Malignant melanoma arising during pregnancy. A study of 100 patients. Ann Surg. 1990;211(5):552–7. discussion 8-9CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Kyrgidis A, Lallas A, Moscarella E, Longo C, Alfano R, Argenziano G. Does pregnancy influence melanoma prognosis? A meta-analysis. Melanoma Res. 2017;27(4):289–99.CrossRefPubMedGoogle Scholar
  50. 50.
    Mendizabal E, De Leon-Luis J, Gomez-Hidalgo NR, Joigneau L, Pintado P, Rincon P, et al. Maternal and perinatal outcomes in pregnancy-associated melanoma. Report of two cases and a systematic literature review. Eur J Obstet Gynecol Reprod Biol. 2017;214:131–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Byrom L, Olsen C, Knight L, Khosrotehrani K, Green AC. Increased mortality for pregnancy-associated melanoma: systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2015;29(8):1457–66.CrossRefPubMedGoogle Scholar
  52. 52.
    Martires KJ, Stein JA, Grant-Kels JM, Driscoll MS. Meta-analysis concerning mortality for pregnancy-associated melanoma. J Eur Acad Dermatol Venereol. 2016;30(10):e107-e8.CrossRefGoogle Scholar
  53. 53.
    Khosrotehrani K, Olsen CM, Byrom L, Green AC. Melanoma during pregnancy: level of evidence and principles of precaution. J Am Acad Dermatol. 2017;76(1):e29–e30.CrossRefPubMedGoogle Scholar
  54. 54.
    Kyrgidis A, Argenziano G, Moscarella E, Longo C, Alfano R, Lallas A. Increased mortality for pregnancy-associated melanoma: different outcomes pooled together, selection and publication biases. J Eur Acad Dermatol Venereol. 2016;30(9):1618.CrossRefPubMedGoogle Scholar
  55. 55.
    Lens MB, Rosdahl I, Ahlbom A, Farahmand BY, Synnerstad I, Boeryd B, et al. Effect of pregnancy on survival in women with cutaneous malignant melanoma. J Clin Oncol. 2004;22(21):4369–75.CrossRefPubMedGoogle Scholar
  56. 56.
    O'Meara AT, Cress R, Xing G, Danielsen B, Smith LH. Malignant melanoma in pregnancy. A population-based evaluation. Cancer. 2005;103(6):1217–26.CrossRefPubMedGoogle Scholar
  57. 57.
    Johansson AL, Andersson TM, Plym A, Ullenhag GJ, Moller H, Lambe M. Mortality in women with pregnancy-associated malignant melanoma. J Am Acad Dermatol. 2014;71(6):1093–101.CrossRefPubMedGoogle Scholar
  58. 58.
    Moller H, Purushotham A, Linklater KM, Garmo H, Holmberg L, Lambe M, et al. Recent childbirth is an adverse prognostic factor in breast cancer and melanoma, but not in Hodgkin lymphoma. Eur J Cancer. 2013;49(17):3686–93.CrossRefPubMedGoogle Scholar
  59. 59.
    Silipo V, De Simone P, Mariani G, Buccini P, Ferrari A, Catricala C. Malignant melanoma and pregnancy. Melanoma Res. 2006;16(6):497–500.CrossRefPubMedGoogle Scholar
  60. 60.
    Daryanani D, Plukker JT, De Hullu JA, Kuiper H, Nap RE, Hoekstra HJ. Pregnancy and early-stage melanoma. Cancer. 2003;97(9):2248–53.CrossRefPubMedGoogle Scholar
  61. 61.
    Travers RL, Sober AJ, Berwick M, Mihm MC Jr, Barnhill RL, Duncan LM. Increased thickness of pregnancy-associated melanoma. Br J Dermatol. 1995;132(6):876–83.CrossRefPubMedGoogle Scholar
  62. 62.
    Wong JH, Sterns EE, Kopald KH, Nizze JA, Morton DL. Prognostic significance of pregnancy in stage I melanoma. Arch Surg. 1989;124(10):1227–30; discussion 30–1CrossRefPubMedGoogle Scholar
  63. 63.
    Tellez A, Rueda S, Conic RZ, Powers K, Galdyn I, Mesinkovska NA, et al. Risk factors and outcomes of cutaneous melanoma in women less than 50 years of age. J Am Acad Dermatol. 2016;74(4):731–8.CrossRefPubMedGoogle Scholar
  64. 64.
    Trapeznikov NN, Khasanov Sh R, Iavorskii VV. Melanoma of the skin and pregnancy. Vopr Onkologii. 1987;33(6):40–6.Google Scholar
  65. 65.
    Driscoll MS, Martires K, Bieber AK, Pomeranz MK, Grant-Kels JM, Stein JA. Pregnancy and melanoma. J Am Acad Dermatol. 2016;75(4):669–78.CrossRefPubMedGoogle Scholar
  66. 66.
    Martires KJ, Pomeranz MK, Stein JA, Grant-Kels JM, Driscoll MS. Pregnancy-associated melanoma (PAMM): is there truly a worse prognosis? Would not sound alarm bells just yet. J Am Acad Dermatol. 2016;75(2):e77.CrossRefPubMedGoogle Scholar
  67. 67.
    Pages C, Robert C, Thomas L, Maubec E, Sassolas B, Granel-Brocard F, et al. Management and outcome of metastatic melanoma during pregnancy. Br J Dermatol. 2010;162(2):274–81.CrossRefPubMedGoogle Scholar
  68. 68.
    de Haan J, Lok CA, de Groot CJ, Crijns MB, Van Calsteren K, Dahl Steffensen K, et al. Melanoma during pregnancy: a report of 60 pregnancies complicated by melanoma. Melanoma Res. 2017;27(3):218–23.CrossRefPubMedGoogle Scholar
  69. 69.
    Miller E, Barnea Y, Gur E, Leshem D, Karin E, Weiss J, et al. Malignant melanoma and pregnancy: Second thoughts. J Plast Reconstr Aesthet Surg. 2010;63(7):1163–8.CrossRefPubMedGoogle Scholar
  70. 70.
    Reintgen DS, McCarty KS Jr, Vollmer R, Cox E, Seigler HF. Malignant melanoma and pregnancy. Cancer. 1985;55(6):1340–4.CrossRefPubMedGoogle Scholar
  71. 71.
    Bleau N, Patenaude V, Abenhaim HA. Risk of venous thrombo-embolic events in pregnant patients with cancer. J Matern Fetal Neonatal Med. 2016;29(3):380–4.PubMedGoogle Scholar
  72. 72.
    Lee YY, Roberts CL, Young J, Dobbins T. Using hospital discharge data to identify incident pregnancy-associated cancers: a validation study. BMC Pregnancy Childbirth. 2013;13:37.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Langagergaard V. Birth outcome in women with breast cancer, cutaneous malignant melanoma, or Hodgkin’s disease: a review. Clin Epidemiol. 2010;3:7–19.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Langagergaard V, Puho EH, Lash TL, Norgard B, Sorensen HT. Birth outcome in Danish women with cutaneous malignant melanoma. Melanoma Res. 2007;17(1):31–6.CrossRefPubMedGoogle Scholar
  75. 75.
    Dildy GA III, Moise KJ, Carpenter RJ Jr, et al. Maternal malignancy metastatic to the products of conception: a review. Obstet Gynecol Surv. 1989;44:5.CrossRefGoogle Scholar
  76. 76.
    Eltorky MKV, Osborne P, et al. Placental metastasis from maternal carcinoma: a report of three cases. J Reprod Med. 1995;40:4.Google Scholar
  77. 77.
    Alexander A, Samlowski WE, Grossman D, Bruggers CS, Harris RM, Zone JJ, et al. Metastatic melanoma in pregnancy: risk of transplacental metastases in the infant. J Clin Oncol. 2003;21(11):2179–86.CrossRefPubMedGoogle Scholar
  78. 78.
    Patenaude Y, Pugash D, Lim K, Morin L, Diagnostic Imaging C, Lim K, et al. The use of magnetic resonance imaging in the obstetric patient. J Obstet Gynaecol Can. 2014;36(4):349–63.CrossRefPubMedGoogle Scholar
  79. 79.
    Andtbacka RH, Donaldson MR, Bowles TL, Bowen GM, Grossmann K, Khong H, et al. Sentinel lymph node biopsy for melanoma in pregnant women. Ann Surg Oncol. 2013;20(2):689–96.CrossRefPubMedGoogle Scholar
  80. 80.
    Hu Y, Melmer PD, Slingluff CL Jr. Localization of the sentinel lymph node in melanoma without blue dye. Ann Surg. 2016;263(3):588–92.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Broer N, Buonocore S, Goldberg C, Truini C, Faries MB, Narayan D, et al. A proposal for the timing of management of patients with melanoma presenting during pregnancy. J Surg Oncol. 2012;106(1):36–40.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Leachman SA, Jackson R, Eliason MJ, Larson AA, Bolognia JL. Management of melanoma during pregnancy. Dermatol Nurs. 2007;19(2):145–52. 61PubMedGoogle Scholar
  83. 83.
    Beyeler M, Hafner J, Beinder E, Fauchere JC, Stoeckli SJ, Fehr M, et al. Special considerations for stage IV melanoma during pregnancy. Arch Dermatol. 2005;141(9):1077–9.CrossRefPubMedGoogle Scholar
  84. 84.
    Maleka A, Enblad G, Sjors G, Lindqvist A, Ullenhag GJ. Treatment of metastatic malignant melanoma with vemurafenib during pregnancy. J Clin Oncol. 2013;31(11):e192–3.CrossRefPubMedGoogle Scholar
  85. 85.
    Grunewald S, Jank A. New systemic agents in dermatology with respect to fertility, pregnancy, and lactation. J Dtsch Dermatol Ges. 2015;13:277.PubMedGoogle Scholar
  86. 86.
    Wang SCLY, Piao HL, Hong XW, Zhang D, Xu YY, et al. PD-1 and Tim-3 pathways are associated with regulatory CD8+ T cell function in decidua and maintenance of normal pregnancy. Cell Death Dis. 2015;6:e1738.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Ribero S, Longo C, Dika E, Fortes C, Pasquali S, Nagore E, et al. Pregnancy and melanoma: A European-wide survey to assess current management and a critical literature overview. J Eur Acad Dermatol Venereol. 2017;31(1):65–9.CrossRefPubMedGoogle Scholar
  88. 88.
    Stensheim H, Cvancarova M, Moller B, Fossa SD. Pregnancy after adolescent and adult cancer: a population-based matched cohort study. Int J Cancer. 2011;129(5):1225–36.CrossRefPubMedGoogle Scholar
  89. 89.
    Byrom L, Olsen CM, Knight L, Khosrotehrani K, Green AC. Does pregnancy after a diagnosis of melanoma affect prognosis? Systematic review and meta-analysis. Dermatol Surg. 2015;41(8):875–82.CrossRefPubMedGoogle Scholar
  90. 90.
    Brady MS, Noce NS. Pregnancy is not detrimental to the melanoma patient with clinically localized disease. J Clin Aesthet Dermatol. 2010;3(3):22–8.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Albersen M, Westerling VI, van Leeuwen PA. The influence of pregnancy on the recurrence of cutaneous malignant melanoma in women. Dermatol Res Pract. 2010;2010Google Scholar
  92. 92.
    MacKie RM, Bufalino R, Morabito A, Sutherland C, Cascinelli N. Lack of effect of pregnancy on outcome of melanoma. For the World Health Organisation Melanoma Programme. Lancet. 1991;337(8742):653–5.CrossRefPubMedGoogle Scholar
  93. 93.
    Karagas MR, Zens MS, Stukel TA, Swerdlow AJ, Rosso S, Osterlind A, et al. Pregnancy history and incidence of melanoma in women: a pooled analysis. Cancer Causes Control. 2006;17(1):11–9.CrossRefPubMedGoogle Scholar
  94. 94.
    Naldi LAA, Imberti GL, Giordano L, Gallus S, La Vecchia C. Oncology Study Group of the Italian Group for Epidemiologic Research in Dermatology (GISED). Cutaneous malignant melanoma in women. Phenotypic characteristics, sun exposure, and hormonal factors: a case-control study from Italy. Ann Epidemiol. 2005;15:5.CrossRefGoogle Scholar
  95. 95.
    Lea CSHE, Hartge P, et al. Reproductive risk factors for cutaneous melanoma in women: a case-control study. Am J Epidemiol. 2007;165:8.Google Scholar
  96. 96.
    Mackie RM, Bray CA. Hormone replacement therapy after surgery for stage I or II cutaneous melanoma. Br J Cancer. 2004;90:2.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Joanna L. Walker
    • 1
    • 2
  • Annie Wang
    • 3
  • George Kroumpouzos
    • 1
    • 4
    • 2
  • Martin A. Weinstock
    • 1
    • 2
  1. 1.Department of DermatologyThe Warren Alpert Medical School of Brown UniversityProvidenceUSA
  2. 2.Division of DermatologyVeterans Affairs Medical CenterProvidenceUSA
  3. 3.Department of DermatologyHawaii Permanente Medical GroupHonoluluUSA
  4. 4.Department of DermatologyMedical School of JundiaiSao PauloBrazil

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