What changes occur in melanocytic naevi during pregnancy?
Melanocytic naevi (moles) may change during pregnancy, and some of these changes are considered normal and benign. More than 10% of women notice darkening and/or enlargement of melanocytic naevi during pregnancy. It is common for naevi on the breasts and abdomen to enlarge due to stretching of the skin. Whereas naevi on the back and limbs show no significant change in size during pregnancy. Clinical changes in naevi often develop during pregnancy in women with FAMMM syndrome (dysplastic naevus syndrome) [see Atypical melanocytic naevus].
Transient changes in the dermoscopic appearance of moles have been identified during pregnancy: new dot formation, thickening of the pigment network, darkening of globules, and increasing numbers of vessels have been described as the pregnancy-related naevus pattern. These changes are subtle and not suggestive of melanoma.
Dermoscopic change in a melanocytic naevus during pregnancy
Reactivated naevus occurs occasionally in pregnancy as a focal change in a long-standing naevus with increased mitotic figures on histology. Superficial micronodules of pregnancy (SMOP) are nests of heavily pigmented upper dermal melanocytes which contrast with the usual non-pigmented dermal melanocytes.
What changes in a melanocytic naevus should raise concern for melanoma in pregnancy?
Any clinical, dermoscopic, or histologic features suggestive of melanoma should be viewed with suspicion and not attributed to pregnancy. New, changing, or unusual-looking pigmented lesions should be assessed and investigated as per usual protocols.
What is pregnancy-associated melanoma and who gets it?
Pregnancy-associated melanoma is defined as a melanoma diagnosed during pregnancy or within 12 months of delivery.
The global incidence of pregnancy-associated melanoma is reported to be 10–26 per 100,000 pregnancies, and 5–8% of pregnancy-associated cancers. In Australia, however, melanoma accounts for one-third of malignancies diagnosed in pregnancy, with a reported incidence of 52 per 100,000. This may be due to an increase in maternal age.
Metastatic pregnancy-associated melanoma (MPAM) may present following a previous melanoma excision. Recurrent melanoma is most common in the first two to five years after diagnosis. Current evidence does not suggest pregnancy affects recurrence-free or overall survival related to a previously treated melanoma.
How is melanoma in pregnancy diagnosed?
Prompt complete excisional biopsy with histological examination should be performed on any concerning skin lesion. Minor cutaneous surgery using local anaesthetic can be performed safely during pregnancy and should not be delayed until after delivery if there is any suspicion of melanoma.
What is the treatment for melanoma in pregnancy?
Following initial complete excisional biopsy and confirmation of melanoma on histology, wide local excision around the initial surgical site is performed as usual. If surgery requires general anaesthesia and cannot be deferred, the second trimester is the safest time to perform it. Anaesthetic agents should be avoided in the first trimester if possible.
Staging should be performed as necessary with ultrasound and magnetic resonance imaging (MRI) considered the safest techniques during pregnancy. Computerised tomography (CT) could be considered if the benefits clearly outweigh the risks.
Sentinel lymph node biopsy provides prognostic information only and is difficult to justify during pregnancy. If considered essential for treatment planning, technetium radioactive tracer alone (without the blue dye) should be used as a marker.
Immune checkpoint inhibitors target PD-1 and/or CTLA4 pathways, and protein kinase inhibitors target BRAF and MEK. Immune checkpoint inhibitors can reduce maternal tolerance for the fetus, increasing the risk of spontaneous abortion (miscarriage).
Systemic treatment for advanced melanoma during pregnancy:
- BRAF inhibitors
- Vemurafenib — crosses the placenta with no associated teratogenic effects or adverse pregnancy outcomes in animal studies, however it has not been widely used in pregnancy and fetal effects in humans are unknown.
- Dabrafenib — teratogenic. (Pregnancy Category D/positive evidence of human fetal risk)
- MEK inhibitors
- Ipilimumab — good outcomes without apparent harm to the newborn have been reported. However, increased fetal loss has been reported in animal studies including miscarriage, stillbirth, preterm birth, and neonatal death. (Pregnancy Category C/human fetal risk not ruled out)
- Trametinib — can harm the fetus. (Pregnancy Category D/positive evidence of human fetal risk)
- Cobimetinib — based on animal studies and its mechanism of action, cobimetinib can cause fetal harm. (Pregnancy Category D)
- PD-1 pathway immune checkpoint inhibitors
- Nivolumab — animal studies report stillbirth and miscarriage. Use in pregnancy is therefore not recommended. (Pregnancy category D)
- Pembrolizumab — crosses the placenta and may increase the risk of autoimmune-mediated disorders. Animal studies report increased risk of premature fetal death and spontaneous abortion. (Pregnancy Category D/positive evidence of human fetal risk)
How may the baby be affected by maternal melanoma in pregnancy?
Metastatic pregnancy-associated melanoma
- Careful examination of the placenta after delivery including macroscopic, histological, and immunostaining:
- If there is no placental involvement, fetal metastasis can be reasonably excluded
- Evidence of placental involvement requires thorough examination of the neonate including skin inspection, chest x-ray, abdominal ultrasound, blood tests for liver enzymes and lactate dehydrogenase, as approximately 22% can show clinical evidence of melanoma.
- Healthy neonate delivered with associated placental metastasis has a high risk of developing melanoma and should be followed-up for at least 24 months.
Treatment of melanoma during pregnancy
- Termination or early delivery of pregnancy may need to be considered if the mother has advanced disease requiring systemic treatment
- Effects of melanoma treatments on the fetus (see above)
What is the outcome for melanoma in pregnancy?
Early reports suggesting a worse prognosis for pregnancy-associated melanoma have not been supported by recent large studies, but this remains controversial. This may reflect the tendency in the past to misattribute changes in a mole to normal changes of pregnancy, with subsequent delay in diagnosis and treatment.
While the effects of oestrogen and progesterone on melanoma are under investigation, it is now generally accepted that oral contraceptive use is not contraindicated after a diagnosis of melanoma in pregnancy. Subsequent pregnancy should be delayed for two to three years after a diagnosis of a high-risk melanoma to allow for adjuvant therapies if required. The decision regarding further pregnancies will need to be considered on an individual basis.
Metastatic pregnancy-associated melanoma (MPAM) has a very poor outcome for the mother. Involvement of the placenta and fetus is rare but can occur.