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Cancer in Pregnancy: Malignant Melanoma and Pregnancy

Introduction
Malignant melanoma is a serious health problem worldwide and is increasing at a rate that exceeds all other solid tumors 1. The increasing incidence is accompanied by an associated decrease in age at presentation. Malignant melanoma during pregnancy has an estimated incidence between 0.14 to 2.8 cases per 1000 births2 and represents 8% of malignancies diagnosed during pregnancy 3. Aprroximately 10,000 melanomas occur in the United States each year in women ages 20 to 40, the peak years of reproduction4. Estrogen receptors have not been identified in melanoma 5,6.

Diagnosis
The signs and symptoms of melanoma are similar to the nonpregnant population and the anatomic location of the primary tumor does not differ between pregnant and non-pregnant women. Changes in size, colour and configuration of any pigmented lesion suggest a malignant change and the need for further investigation. Two-thirds of melanomas occur in pre-exisiting nevi. However, some degree of hyper pigmentation during pregnancy is experienced by most women. 8 It has been suggested that this hyper-pigmentation may lead to a delay in diagnosis of the disease 9. A growing number of reports suggest minimal changes in size occur during pregnancy10,11.Bleeding and ulceration are more ominous signs and require immediate attention.

Excisional biopsy is the recommended procedure for any suspicious lesions.

Staging
Clinical staging traditionally has included assessment of the local tumor site and adjacent skin, regional lymph node areas and distant organs that are frequently the site of metastatic disease. The decision to perform radiological investigations in the pregnant patient should be based on the presence of symptoms, the stage of the pregnancy, the specific test needed and the estimated dose of ionizing radiation and risks associated with that dose. Intensive radiologic investigation(s) is not required for patients with early disease. Routine elective lymph node dissection is controversial and has not been shown to have a consistent impact on survival 6-10. The use of blue dye or a radio-labelled tracer injected at the primary tumor site to identify the draining or 'sentinal lymph node' has been shown to be accurate with little morbidity and high accuracy 11, 12 . During pregnancy, the radio-labeled technique should be avoided due to the risk of radiation exposure of the fetus.

Therapeutic Abortion and Contraception
There is no conclusive evidence that regression of melanoma occurs after therapeutic abortion19,20,21. Since the influence of pregnancy or hormones on melanoma has not been observed, the general consensus is that oral contraceptives are not contraindicated in patients with a prior history of melanoma 22, regardless of the duration of their use 23.

Pathology and Biology
The effect of pregnancy on melanocytic nevi is unclear. Previous studies have suggested that patients may overestimate changes in melanocytic nevi24,25. A recent prospective study of 22 patients using photographs and objective measurements failed to demonstrate any significant change in size of nevi from the first to the third trimester10. Another area of controversy exists regarding the effect of pregnancy on site of presentation. Some studies have suggested an increased risk in pregnancy of lesions in areas associated with a worse prognosis such as the head and neck and truncal regions 9,26-28 while others have not found this association29,30. Similarly, there is debate as to whether or not pregnancy is associated with increased tumor thickness 7,9,19,20,29,31-33. Stage of the disease at diagnosis and not pregnancy is the only consistent factor influencing the prognosis in terms of survival and disease-free interval.

Treatment

Early disease
Surgical removal of the melanoma with adequate margins remains the standard primary therapy for early melanoma. For thin melanomas (<1mm thick) a 1 cm margin is considered adequate; for a Breslow intermediate thickness (1mm > x < 4mm) a 2cm margin is used. The standard surgical margin for thick melanoma remains undefined 34-39. But a margin of at least 2 cm appears to be justified. Elective lymph node dissection is not recommmended 40. Sentinel node biopsy appears to be a promising method to detect occult metastases in the regional lymph nodes 40. For most patients, this procedure can be done with a local anaesthetic with little risk to the fetus. Locally advanced disease requiring more extensive surgery or regional node dissection should be performed with a general anaesthetic when needed.

Node positive disease
The use of adjuvant interferon alpha - 2b in patients with melanoma is controversial and remains experimental40. Recent evidence demonstrating that adjuvant interferon increased overall survival for patients with node positive disease 1 was not confirmed in a follow-up study 18.

The existing literature on use of INF during pregnancy is restricted to case reports involving patients treated for various conditions such as hepatitis, myeloproliferative disorders (essential thrombocytemia and chronic myelogenous leukemia) and multiple myeloma. To date, there is no evidence of teratogenic or adverse effect on the fetus, regardless of timing of treatment during pregnancy. Doses used in the case reports have generally been in the range of 0.5 - 6.5 million units of interferon sc/day, significantly less than the recommended doses for the adjuvant treatment of melanoma41-54. Lack of fetoplacental passage of interferon alpha has been shown in one study of two patients prior to abortion 50. Treatment with interferon does not appear to affect fertility43,47,49.

No information regarding the safety of use of the much higher doses may be used in the treatment of melanoma exists (i.e. 20 million units/m2 intravenous for 4 weeks followed by 10 million units/m2 subcutaneous for 48 weeks). Toxicity of this therapy in the non-pregnant patient is significant. Nearly all patients experience flu like symptoms to a moderate or severe degree. Other significant sideeffects include depression, cognitive changes, bone marrow suppression and liver toxicity. Delay of therapy until the post partum period has been suggested55. The use of altered dosing of interferon in the adjuvant setting is under investigation 56.

Advanced or recurrent disease
Metastatic disease to lymph nodes, as well as isolated metastases to areas such as lung, breast, gastrointestinal tract and brain may be palliated by surgical removal with a potential for long term survival57,58. There is no contraindication to surgery during pregnancy provided that the physiologic changes of pregnancy are understood.

In the non-pregnant patient, chemotherapy and/or radiotherapy remain valid options for treatment of metastatic disease. Agents used in treatment include dacarbazine, the nitrosoureas - carmustine and lomustine, vinca alkaloids, platinum compounds, taxanes and biologic agents such as interferon and interleukin. Use of dacarbazine in pregnancy for malignant melanoma is limited to a case report in which a critically ill woman was treated in the third trimester. Spontaneous labour and a normal delivery occurred at 38 weeks gestation with no abnormalities reported in the offspring. The patient died 8 weeks postpartum after a dramatic response to therapy 59.

Chemotherapy
Cancer chemotherapeutic drugs are very potent teratogens. Currently, there is very little information on the effect of cancer chemotherapy on the fetus 60. The risk of malformations when chemotherapy is administered in the first trimester has been estimated to be around 10% for single agent chemotherapy61 and 25% for combination chemotherapy 62. It is generally suggested that chemotherapy be avoided during first trimester, when cells are actively dividing. Use of these agents in the second and third trimesters has been associated with an increased risk of stillbirth, intrauterine growth retardation and low birth weight60,63,64. When chemotherapy is administered during pregnancy, timing of delivery of the infant should take into account the expected bone marrow depression and potential problems such as bleeding or infections. Self limiting fetal haematopoetic depression has been described and the neonate should be monitored for complications of this65. Long term neurodevelopmental complications of in utero chemotherapy exposure have not been extensively studied. Limited data exists to suggest that this may be normal in the offspring of patients with haematologic malignancies treated during various stages of the pregnancy66.

Irradiation
The essentially palliative nature of therapy for advanced melanoma and the limited success rate(s) seen with existing therapies suggests that delay in therapy until the later stages of gestation or after delivery and aggressive use of supportive therapy during pregnancy (i.e. analgesics, steroids, oxygen) are reasonable options.

Prognosis
The effect of pregnancy on prognosis of melanoma has been a focus of interest in the medical literature for years. When matched for age, anatomic site and stage, most studies have not demonstrated a difference in survival9,20,27,29-31. However, some studies have demonstrated a shorter disease free interval in pregnant patients compared to controls26,30,31. It has been suggested that small patient numbers and variable follow-up time in these studies may have limited the ability to detect pregnancy related changes in outcome67,68. Also, there is no sufficient data to establish the role of adjuvant chemotherapy or biological therapy during pregnancy 69.

Fetal outcome
Metastases to the placenta and fetus are rare but have been documented with hematologic as well as solid tumors. Malignant melanoma is the tumor that most frequently metastasizes to the placenta or fetus. Therefore, the placenta should be thoroughly examined for metastasis. If present, the infant should be monitored for development of malignant disease 70. Of the 17 reported cases, only 4 have resulted in fetal death71-73.

Since the majority of recurrences occur in the first 3 years, some authors suggest delaying pregnancy for a few years after initial diagnosis and treatment3,9,74.

Fertility
There is no evidence that a diagnosis of melanoma adversely affects fertility.

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