Managing Cancer during Pregnancy

11. Managing Melanoma During Pregnancy

Stergios Boussios¹ and George Pentheroudakis¹

(1)

Department of Medical Oncology, Ioannina University Hospital, Stavros Niarchou Avenue, Ioannina, 45 110, Greece

Stergios Boussios (Corresponding author)

Email: stergiosboussios@gmail.com

George Pentheroudakis

Email: gpenther@otenet.gr

Keywords

MelanomaPregnancyTreatmentPlacentaMetastasis

Introduction

Malignant melanoma is on the second place in terms of the incidence among the population between 20 and 39 years of age. Although the disease is more frequent in men, its incidence during the reproductive period is higher among women. The impact of pregnancy to the course of melanoma does not appear to be related to the patients’ survival.

In this chapter, data are reviewed, and key aspects of the immunohistochemical expression of hormone receptors, use of SLNB, therapeutic management, and transplacental metastasis are presented.

The treatment of melanoma in pregnant women is similar to that in the general population, and the therapy is based upon stage. Surgical excision remains the only effective treatment. With modern surgical and anesthesia techniques, the maternal death rate is negligible and surgery during the first trimester does not appear to increase the incidence of major birth defects. When indicated, an SLNB can be performed. Interferon alpha 2b (IFNα2b) has been implemented safely in pregnancy in terms of treatment of hepatitis, myeloproliferative disorders, and multiple myeloma. The toxicity of high-dose regimen, indicated for the treatment of metastatic disease, was not estimated throughout the course of pregnancy. The knowledge concerning the use of dacarbazine in pregnant women is sparse, based on isolated clinical cases or small series, and in the majority of cases, dacarbazine was administered as part of poly-chemotherapy. The recent development of novel agents has revolutionized the field of melanoma treatment, but given the lack of experience on treating women during pregnancy, treatment should be avoided and postponed until postpartum when possible.

Melanoma is the most common malignancy to metastasize to the placenta. Very rarely, fetal metastasis is seen. Following delivery, the placenta should be examined both grossly and histologically for signs of metastatic melanoma including appropriate immunohistochemical staining.

Hormonal Regulation of Melanoma

The consideration of dismal prognosis for maternal melanoma in the 1970s and 1980s was based on the aggressive phenotype of this hormonally stimulated malignancy in women with high levels of hormones, which is the case in pregnancy.

Increased systemic estrogen levels have been related to hyperpigmentation and nevus enlargement found during pregnancy. Estrogen receptor-β (ERβ) protein is frequently expressed in melanoma. Immunohistochemical and real-time polymerase chain reaction analyses showed that expression of ERβ is reversely proportional to Breslow’s thickness. Progesterone has been shown to inhibit the proliferation of human melanocytes and has been either detected in the cytoplasm and nucleus of melanocytes by immunohistochemistry.

Hormone replacement therapy does not seem to be a risk factor for melanoma. The use of oral contraceptives does also not affect the incidence of the disease. High-dose hormones, such as in the case of protocols for in vitro fertilization or intrauterine insemination, have not yet been evaluated in this context.

Sentinel Lymph Node Procedure and Pregnancy

The approach for the treatment of melanoma begins with the identification of a suspicious lesion followed by biopsy and should not be deferred due to the pregnancy. The currently known factors determining outcome are mostly the Breslow thickness, ulceration status, dermal mitotic rate, and deep and peripheral margins [1]. Invasive lesions with Breslow’s thickness ≤1.0 mm are overall associated with a favorable prognosis [1], and wide surgical excision is the treatment of choice even during pregnancy. If the primary cutaneous melanoma has Breslow’s depth greater than 1.0 mm and there are no clinically palpable lymph nodes, an SLNB should be considered [2].

In general, this is a staging process of melanoma, developed to identify patients with subclinical nodal involvement who could be candidates for complete lymph node dissection and adjuvant therapy. Overall, it is a minimally invasive, low-morbidity procedure performed with the use of blue dye and radiolabeled colloids. Nevertheless, some studies conclude that the use of blue dye can be avoided if SLNB is imaged on lymphoscintigraphy due to the possibility of anaphylactic allergic reactions [2]. Apart from the primary arguments, SLNB appears feasible in pregnant women, exposing the fetus under the 50 mGy threshold and hence to minimum risk. Most of the data concerning SLNB and pregnancy is retrieved by patients with breast cancer. In terms of the experience in this population, the procedure appears to be safe and accurate using either methylene blue or technetium 99-Tc. Gropper et al. reported recently that in pregnant women with breast cancer who underwent SLNB, 25 infants were born alive, of whom only 1 had cleft palate in the maternal risk factors [3]. Nevertheless, given the anatomical distance, the radioactive exposure of the fetus from the 99-Tc should be lower in patients undergoing axillary SLNB as compared to groin SLNB; this difference should be minimal since all radioactivity is cleared by the kidney and excreted through the bladder. Although safe during pregnancy, there is still controversy in terms of the appropriate timing of the procedure. Interestingly enough, Broer et al. [4] proposed the option of resecting the primary tumor under local anesthesia and postponing the SLNB postpartum in pregnant melanoma patients. On the other hand, Gziri et al. [5] argue against deferring SLNB basing their position on the fetal outcome of 12,000 cases of non-obstetric surgical interventions [6].

Treatment of Melanoma During Pregnancy

The management of melanoma during pregnancy involves careful consideration of the disease stage, treatment options, and fetal risks such as treatment-related teratogenicity, all of which are dependent upon the gestational age of the pregnancy. We will expose below the feasibility of the different therapeutic approaches usually used which include surgery, immunotherapy, chemotherapy, and radiotherapy.

Surgery

Multiple studies have evaluated the risk of general anesthesia for both mother and child during pregnancy. A literature review by Cohen-Kerem et al. [6], with consideration of more than 12,000 patients, evaluated that the complication rates following surgery with general anesthesia during pregnancy resulted in a miscarriage rate of 5.8 %, induction of premature labor in 3.5 %, fetal loss in 2.5 %, prematurity rate of 8.2 %, and major birth defects in 3.9 %. Nevertheless, these adverse events were not statistically higher as compared to the control population; they designate the clear risk of the fetus. Overall, in cases that the delay of surgery would put at a higher risk the mother and the fetus, then the potential risk of general anesthesia does not outweigh the risk of surgical delay.

The primary treatment for melanoma today remains to be wide surgical excision including the full thickness of the skin and subcutaneous fat tissue around the tumor site with 1–3 cm margins, according to the thickness of the primary lesion. Lateral or posterolateral neck dissection and axillary dissection including level III can easily be performed during pregnancy. Although inguinal lymphadenectomy has historically been the standard treatment for metastatic melanoma in the inguinal lymph node basin, multiple studies have reported significant morbidity following the procedure. At that regard, the deep part of the groin dissection could be delayed until after delivery; nevertheless with SLNB techniques, it could be feasible at the time of the primary tumor wide excision. The patients with melanoma at low risk for nodal involvement (T1b to T2b) can undergo resection of the primary lesion under local anesthesia and delay the SLNB to the postpartum period. If the relevant risk is higher, such as in Breslow’s depth greater than 2.0 mm, resection of the primary melanoma can be performed under local anesthesia, and either delaying the SLNB until after the delivery or proceeding to SLNB under local anesthesia is reasonable. Patients with metastatic melanoma identified in their SLNB should undergo completion lymphadenectomy under general anesthesia. If a positive SLNB is detected under local anesthesia during the gestation, postponement of completion lymphadenectomy until postpartum could be an option.

In the select group of patients with isolated single or a limited number of metastases, surgical resection should be strongly considered and performed without deferment as it is safe in pregnant patients. However, there are no studies comparing surgical with conservative treatment of single metastasis. Cryosurgery or laser ablation for small lesions is also an option for the treatment of locoregional metastases. Certain studies demonstrated successful treatment with isolated extremity perfusion by melphalan and tumor necrosis factor-α. However, there is no experience in this procedure during pregnancy. The termination of pregnancy will not alter the maternal prognosis in this cohort of patients.

Adjuvant Therapy

The use of adjuvant IFNα2b in patients with high-risk melanoma is controversial. The results of various studies are conflicting. An updated meta-analysis published by the Cochrane group of a total of 10,499 participants found that adjuvant IFNα2b was associated with a significant improvement in disease-free survival but improved overall survival only in a subset of patients with ulcerated primary melanoma and microscopic SLNB involvement [7]. Nevertheless, there are insufficient data on IFNα2b safety in pregnant patients with melanoma; some reports regarding its use in some other indications are available. Among 41 pregnant patients, IFNα2b was administered to treat 33 diagnosed with chronic myeloid leukemia (CML), 2 with hairy cell leukemia, 4 with melanoma, and 1 patient with Hodgkin lymphoma and multiple myeloma respectively [8]. A total of 43 infants were born, including 2 sets of twins. From the available data, 19 patients commenced treatment during the first trimester and 20 in the second and third trimester. Only 2 patients received the agent as polytherapy. Major malformations attributable to in utero exposure to IFNα2b were observed in only 1 out of the 43 live-born infants (2 %) who was yet exposed to imatinib in the first trimester. As a point of reference, the prevalence of major malformations in the general population of the USA is 3 %. Similarly, Azim et al. [9] described 26 CML patients exposed to IFNα2b during the course of pregnancy without reported congenital abnormalities. Nevertheless, IFNα2b can be safely administered throughout the course of pregnancy; this is a subject of controversy due to the absence of a clear benefit in survival. Careful consideration should be made in each patient in order to balance potential maternal benefits with possible fetal risks. The adjuvant treatment in metastatic setting requires higher doses of IFNα2b which is not evaluated in pregnant patients and such therapy should be implemented postpartum.

Systemic Therapy for Metastatic Disease

The use of chemotherapy in a pregnant woman affected with metastatic melanoma is a much more challenging situation, widely considered as palliative and not associated with increase in overall survival. The use of the alkylating agents fotemustine and dacarbazine in pregnant women has been the subject of only a few publications in the literature. Since the 1960s, 36 cases of administration of dacarbazine to pregnant women have been reported [10]. Congenital abnormalities were observed during the first trimester exposure in two cases. Among the infants exposed in utero to dacarbazine in the second and third trimesters of pregnancy, one fetus died and nearly 50 % were born prematurely. In all these cases, dacarbazine had been applied in association with other cytotoxic agents. However, the follow-up of children exposed in utero to chemotherapy is often too short, and therefore, the risk of secondary malignant disease is likely to be underestimated. In conclusion, the use of dacarbazine in pregnant women is sparse, based on isolated clinical cases or small series, and in the majority of cases, dacarbazine was administered as part of poly-chemotherapy.

Intensive research in metastatic melanoma treatment achieved significant results in the past few years. Several new drugs proved to be more effective than standard dacarbazine therapy, and it is required to properly understand whether these compounds are safe in the subset of pregnant patients without jeopardizing fetal outcome. Approximately 50 % of malignant melanoma carries an activating mutation of the proto-oncogene BRAF. The BRAF inhibitor vemurafenib demonstrated improved progression-free and overall survival over dacarbazine in patients with previously untreated advanced melanoma with BRAF V600E mutation. In terms of safety, vemurafenib has not been associated with teratogenesis in animal studies [11]. In 2013, Maleka et al. [11] described a 37-year-old woman diagnosed with metastatic melanoma and treated with vemurafenib during gestation. The patient had a 3-month progression-free survival, which enabled the delivery of a healthy baby at week 30 with low birth weight but no evidence of metastatic disease. Interestingly enough, the pharmacological study indicated placental transfer of the drug, 10.9 μg/mL in the umbilical cord as compared to 24.3 μg/mL in the mother [11]. Given the lack of experience on treating pregnant patients, this type of therapy should be avoided and postponed until postpartum when possible.

Ipilimumab, a monoclonal antibody which binds to cytotoxic T-lymphocyte-associated antigen (CTLA4), causes autoimmunity which may be expressed through a syndrome, similar to lupus or antiphospholipid syndrome. This may be fatal both for the fetus and the mother. Finally, although the experience is limited in the subset of pregnant patients with CML, a disturbing cluster of rare teratogenic effect has prevented imatinib, a tyrosine-kinase inhibitor, from being recommended safely during the pregnancy.

Radiation Therapy

Nevertheless, the efficacy of radiotherapy is poor in melanoma; the palliation of the relevant symptoms in the setting of recurrent or metastatic disease could be an indication for this approach. Furthermore, for a few brain metastases, patients can be treated by neurosurgical resection or stereotactic radiosurgery (SRS). In most of cases, brain melanoma metastases are multifocal, and in this context, the correct risk/benefit balance for the use of radiotherapy would be steroid-resistant symptomatic metastasis. Irradiation of brain lesions to high dose during pregnancy may result in fetal exposure < 0.10 Gy, without other harmful effects to the fetus after the fourth week of gestation. Phantom thermoluminescent dosimeter measurements estimate fetal dose with precision for energies <10 MV and should be adopted for each pregnant patient considered for treatment to confirm and record acceptable dosage. There are two reported cases of radiotherapy during pregnancy for cerebral metastases of melanoma [10]. In the first case, whole-brain radiotherapy (WBRT) was associated with the administration of fotemustine during the second and third trimesters; in the second case, brain gamma knife SRS was performed as a single treatment at 23 weeks of gestation for cerebral metastases. The fetal dose was estimated in the second case to be between 0.02 and 0.04 Gy for a maximum tumor dose of 20 Gy which was below the deterministic threshold value of 0.10 Gy. No morphological abnormalities were observed in the two infants.

There is no clear consensus on the effect that gamma knife treatment for melanoma cerebral metastases may have on the outcome of the newborns and its implementation would not be recommended during gestation. Given that SRS is associated with a higher risk of distant brain failure resulting in a higher likelihood of retreatment during the pregnancy, WBRT alone is presented as the safest and most conservative management. Some reported cases in the literature of healthy neonates following WBRT emphasize the importance of discussing the risk/benefit ratio of therapy with respect to the patients’ desires regarding their pregnancies.

In addition, a possible irradiation of some distant regions postoperatively, due to positive margins, could be considered. Sinusal melanoma irradiation was proven useful and it is safe for the fetus. On the other hand, adjuvant radiotherapy after lymphadenectomy demonstrated no benefit and should be avoided during pregnancy.

Transplacental Melanoma Metastasis

Vertical transmission of malignant cells to the placenta or fetus is uncommon. Placentofetal malignant seeding takes place via hematogenous spread and less often via lymphatic spread or contiguous invasion. Melanoma is known as the malignancy with the propensity to metastasize to the products of conception (Fig. 11.1).

Fig. 11.1

Sections of placenta show multiple aggregates of atypical epithelioid cells in the intervillous space (With permission of Boussios S. from the 20th Congress of the Hellenic Society of Medical Oncology [HeSMO], 2014). The yellow arrows indicate areas with atypical epithelioid cells in the intervillous space.

A literature review from 1866 to 2002 by Alexander et al. [12] identified 87 cases of placental or fetal metastases with melanoma accounting for 27 cases (31 %). Eighteen out of the 27 patient cases (67 %) resulted in healthy, unaffected infants, nevertheless the median follow-up was only 14.2 months. The involvement of the fetus was identified in 6 of the 27 patients with placental metastases from melanoma (22 %). Five out of the six infants died. The mean age at the time of metastatic presentation was 4.6 months (range, 0–8 months). In terms of the factors indicating unfavorable fetal or infant outcome, male gender seems to be at higher risk for development of metastasis of maternal melanoma and composed 80 % of all infants with metastasis of melanoma. At that regard, male fetuses are probably more immunotolerant than female. On the other hand, it is unlikely for tumor burden to be a prognostic indicator, taking into consideration that only three placentas of the six patients with fetal melanoma metastasis demonstrated evidence of the disease. In addition, gross placental involvement was identified in six patients without fetal melanoma metastasis. The placenta is a site of production for many growth factors including placental growth factor, hepatocyte growth factor, and vascular endothelial growth factor. It is highly possible that these factors promote adhesion, survival, and invasion of melanoma cells. This relative tendency of melanoma for placental metastasis, growth, and invasion may increase the risk of fetal metastasis. There is no difference in the timing of maternal metastasis of melanoma between placental and fetal metastasis. Fetal metastasis may arise before the immune system is well developed, whereby the fetus develops tolerance toward the tumor and is subsequently unable to eliminate it. Morbidity for the fetus in patients with placental disease is unclear. Prematurity was a common complication in infants born with placental disease, with a mean gestational age of 34 weeks, but the mortality rate secondary to prematurity was low. Maternally derived metastases consisted mostly of subcutaneous nodules, abdominal masses, and liver metastases. These infants have poor outcome, with death typically occurring within 3 months of diagnosis. Neonates delivered with concomitant placental involvement without clinical evidence of the disease should be considered at high risk. They should be periodically evaluated for development of melanoma for at least 24 months postpartum. Evaluation should include a baseline chest X-ray and liver enzymes, including lactate dehydrogenase, abdominal ultrasound, skin inspection, and screening for melanocytic proteins in urine which may be repeated every 6 months. Adjuvant treatment of infants born to women with placental metastasis of melanoma has not been reported.

The placenta should be closely evaluated by gross and microscopic examination for evidence of metastases in any patients with a history of melanoma. Immunohistochemical staining for melanoma antigens should be performed on histologic sections, using S-100, HMB-45, or other appropriate markers. Research tests that may be of value include examination of cord blood buffy coat for the presence of tumor cells using immunohistochemical staining or reverse transcriptase polymerase chain reaction (Fig. 11.2, Tables 11.1 and 11.2).

Fig. 11.2

Proposed algorithm for surgery in maternal melanoma

Table 11.1

Controlled studies evaluating the maternal survival rates since 1989

Author and year of publication	Number of patients diagnosed with maternal melanoma (group 1)	Number of patients within nonpregnant group (group 2)	Breslow’s thickness (mm) group 1/group 2	Survival rates between groups	Follow-up time (months)
Broer et al. (2012) [4]	5	3657	1.52/NA	NS	8–120
Lens et al. (2004) [13]	185	5348	1.28/1.07	NS	139.2 (median)
Wong et al. (1989) [14]	66	619	1.24/1.28	NS	NR
MacKie et al. (1991) [15]	92	143	2.38/1.96	NS	NA
O’Meara et al. (2005) [16]	149	2451	0.77/0.81	NS	24–120
Stensheim et al. (2009) [17]	160	4460	NA	NS	142.8 (median)
McManamny et al. (1989) [18]	23	243	1.62/1.72	NS	2–240
Slingluff et al. (1990) [19]	100	86	2.17/1.52	NS	72 (median)
Travers et al. (1995) [20]	45	420	2.28/1.22	NS	NA
Daryanani et al. (2003) [21]	46	368	2/1.70	NS	106 (median)
Silipo et al. (2006) [22]	10	30	NA	NS	60 (median)
Miller et al. (2009) [23]	11	65	4.28/1.69	NS	NA
Khosrotehrani et al. (2011) [24]	14	26	1.4/1.3	NA	NA
Zhou et al. (2014) [25]	18	18	1.63/2	NS	15.8 (median)

Abbreviations: NA not available, NS statistically nonsignificant difference in survival rates between groups

Table 11.2

Reviewed information summary about maternal malignant melanoma

Frequency in pregnancy	1:1000–10,000 gestations
Diagnosis	The same index of suspicion for melanoma as compared to the general population. A, B, C, D danger signs of melanoma:  Asymmetry (A)  Borderline irregularity (B)  Color variations from one area to another (C)  Diameter larger than 6 mm (D)
Staging	Assessment of Breslow’s thickness, ulceration status, dermal mitotic rate, deep and peripheral margins Ultrasound Fine-needle aspiration biopsy SLNB (eventually postpartum for stage T1 and T2 disease) MRI (gadolinium should only be used if absolutely necessary)
Histology	Superficial spreading melanomas most common (41 %)
Treatment	Similar to that for nonpregnant women, but with specific considerations associated to pregnancy Stage T1b to T2b  Resection of the primary lesion under local anesthesia Stage T3 to T4  Resection of the primary lesion under local anesthesia and either   Delay of SLNB until after the delivery   Proceeding to SLNB under local anesthesia Metastatic disease  Completion of lymphadenectomy under general anesthesia Adjuvant treatment  IFNα2b in high dose should be implemented postpartum Systemic treatment  Dacarbazine (lack of evidence of in utero exposure)  BRAF inhibitors (lack of experience)  Anti-CTLA-4 antibody (to be avoided during gestation) Oral contraceptives and melanoma  No increased risk of melanoma Hormone replacement therapy  No increased risk of melanoma
Metastases to products of conception	It is the most frequent cancer that metastasizes to the placenta or fetus, accounting for 31 % of reported cases The placenta and the fetus of women with suspected metastatic melanoma during pregnancy should be closely evaluated by gross and microscopic examination
Prognosis	When matched for age, anatomic site, and stage, most studies have not demonstrated a difference in survival between pregnant and nonpregnant women
Pregnancy after treatment of melanoma	Pregnancy after melanoma diagnosis and treatment is safe Decreased risk of cause-specific deaths for women who had subsequent pregnancies in a study

Conclusion

The ability to diagnose and treat melanoma with local surgery allows for prompt diagnosis and treatment despite the pregnant state, maximizing patients’ survival. The arrival of innovatory therapies in the area of advanced melanoma, such as immunotherapy with anti-CTLA4 antibodies or targeted therapies, constitutes a breakthrough in the care of these patients and raises hopes in terms of prognosis. Dealing with these drugs during pregnancy will be a challenge.

Pregnancy was not identified as an independent prognostic factor for recurrence or survival. Fetal morbidity or mortality does not significantly increase either, in comparison to the general population. Large cohort studies with long-term follow-up are needed to evaluate the entire spectrum of adverse effects of melanoma or melanoma treatment on offspring of the patients.

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