Melanoma 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

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

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).

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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].