Hensin Tsao, MD, PhD
Philip LeBoit, MD
Keith Flaherty, MD
A forty year-old woman presents to her PCP with a lesion that she had removed near her left knee (cryotherapy) about one year ago. She thinks something is returning. “It is a tiny miniscule nodule that appears to be a scar.” This appears to be a dermatological issue and “she wants to see her old dermatologist to have it rechecked.” What is an appropriate next step for the physician?
- Refer and document
- Refer and follow-up with phone call in 1 m
- Refer and call the local dermatologist
- Refer and follow up with letters until lesion is removed
If you have a general concern, three certified letters can be a good approach. It is extremely important to follow-through and maintain good communication so that you are not held liable.
Seven months later, the patient returns to the PCP with her parents. She was diagnosed with an invasive melanoma. She didn’t see the dermatologist, whom she was supposed to see last spring, until just recently. The patient was referred to Massachusetts General Hospital.
Melanoma on the left knee showed NMM; 7.5mm thick, ulceration 0.4mm, 12 mits/mm2; no microsatellites. She underwent wide resection and sentinel lymph node biopsy (0/8). One year after the diagnosis, she returns for a follow-up and informs you that she wants to become pregnant. She is now 41 years old and she had a miscarriage several years ago. This scenario is not uncommon and Dr Tsao has had referrals regarding this situation.
What do you tell a 41 year-old woman with a stage IIc (life expectancy 30-50%) melanoma about pregnancy?
- Fine to become pregnant
- Wait at least 2 years
- Wait at least 5 years
- Wait at least 10 years
Dr Flaherty comments that the fundamental question that we don’t have a great answer to is whether or not every instance of microscopic metastatic disease would ultimately manifest as overt metastatic disease with time. Or, are there patients who can live chronically, i.e., forever with microscopic disease? We do know of late relapses with melanoma. Dr Flaherty tends to tell patients the suggestion that microscopic metastatic disease will convert to macroscopic metastatic disease and the worst that could happen, in the pregnancy setting, is that you could influence the conversion, in other words, it could happen sooner. It is also important to discuss where patients are on the risk curve. The risk of occurrence falls with time.
The risk of relapse after 10 years is actually not clear because high-risk lesions should have relapsed by then while thin relapses continue to emerge. There are differences in the kinetics of relapse between a thin melanoma and a thick melanoma. The bigger the tumor, the more aggressive it is. If the patient survives to year five or ten, it is less likely that something will happen. In fact, there might be a cross over point, probably around year 10, whereby if you had a thick tumor and you’re still alive, the likelihood of it recurring is quite low.
Pregnancy and Melanoma
There are many case control series of melanoma during pregnancy versus not during pregnancy. A 2008 study found no evidence that pregnancy worsens the prognosis. (Cancer Causes Control. 2008;5:437) Some studies suggest that melanoma during pregnancy may be slightly thicker but survival is not altered that much.
The patient visits with a high-risk obstetrician who clears her to become pregnant. Three months later, she finds out that she is pregnant. How do you follow a pregnant person with a history of melanoma?
- Routine post-melanoma surveillance
- Routine surveillance with total body photography
- Increased surveillance every three months
- Increased surveillance with total body photography
Total body photography could be a viable option. There is really no literature on dermoscopy in pregnancy. These patients should be followed very carefully. Regarding post-melanoma surveillance, you don’t need to necessarily change your practice because of pregnancy. There are no great studies that convincingly demonstrate a higher risk of relapse during pregnancy. This is highly anecdotal, yet it is very compelling and memorable when it happens.
At week 17 of her pregnancy, she noticed a small, firm nodule within her melanoma scar. Wedge biopsy showed recurrence of melanoma with neurotropism. Wide resection cleared recurrence and a skin graft was placed.
Management of Melanoma Recurrence During Pregnancy
There are treatment options; however, there are no data for metastatic disease during pregnancy. With regards to immunotherapy, high-dose IL-2, which is a physiologic stress, poses a theoretical risk of abruption (in the setting of hypotension). Ipilimumab is likely the first-line choice. Looking at targeted therapy, BRAF inhibitors showed no risk of teratogenicity in limited preclinical studies and MEK inhibitors are theoretically of greater concern; however, that may not be the case in combination with BRAF inhibitors. Chemotherapy is rarely an attractive first-line option in any case.
- Pregnancy Category D
- Vemurafenib can cause fetal harm when administered to a pregnant woman based on its mechanism of action
- Pregnancy Category C
- Use ipilimumab during pregnancy only if the potential benefit justifies the potential risk to the fetus.
The patient received XRT to the left knee graft area with shielding of the fetus to prevent radiation crossover. At 36 weeks, she underwent a Caesarian section. A histological examination of the placenta did not reveal melanoma. (There have been reports of metastases to the placenta or fetus) One month after delivery she noticed two subcutaneous nodules in the mid-calf distal to the scar site. A biopsy showed metastatic melanoma consistent with in-transit disease. PET/CT showed multiple left lower leg FDG avid nodules, but no visceral metastases. Both radiologically and clinically, she’s beginning to develop at a faster pace.
What would you recommend now?
- Isolated limb perfusion
- Targeted removal of individual lesions
- Genotyping with anti-BRAF agent if BRAF+
- Systemic treatment with IL-2 or immune checkpoint antibody
We lack high-level evidence for the optimal approach in this case. According to the NCCN guidelines, enrollment in a clinical trial is the preferred approach. Options for local therapy include complete surgical excision, intralesional injection (BCG, IFN, IL-2), local ablation therapy, topical imiquimod for superficial dermal lesions, and consideration of palliative XRT for unresectable disease. Isolated limb infusions/perfusions with melphalan could be considered as a regional therapy option as well as the use of systemic therapy. Systemic used to be considered as bottom of the list; however, it is being utilized more and more.
The issue with regional therapy is that it has no impact on disease elsewhere. With regards to intralesional therapy, Weide and colleagues found a high response rate after intratumoral treatment with IL-2 in a phase two study of 51 patients with metastatic melanoma. The 2-year survival rate was 77 percent for patients with stage IIIB/IIIC disease. Efficacy and survival did not differ between patients who had greater than or equal to 20 lesions and patients who had less than 20 lesions. (Weide B, et al. Cancer. 2010;116(17):4139-4146.)
Alexander and colleagues analyzed factors that influenced the outcome in patients with in-transit malignant melanoma undergoing isolated limb perfusion using modern treatment parameters. Between May 1992 and February 2005, 91 patients underwent a 90-minute hyperthermic ILP. There were 62 complete responses (69%) and 23 partial responses (26%) in 90 assessable patients.
The patient underwent isolated limb perfusion with melphalan but unfortunately continued to progress. She continued to progress through multiple experimental treatments over the ensuing year and she expired six years after her initial diagnosis.
Pregnancy and Melanoma-Take Home Points
- Pregnancy does not appear to compromise survival
- “Wait time” considerations include:
- Potential treatment complications during pregnancy
- Age of patient and desire for children
- Personal outlook (e.g. religion, “abandoning” children)
- Availability of oocyte cryopreservation
- Risk extinction is more obvious for thicker tumors
- “Wait time” considerations include:
- Bottom line (not scientifically based)
- For patients with multiple DN- watch q3m’s during pregnancy
- For MIS and thin melanomas- OK to start (need discussion)
- For melanomas >1mm- wait 2 yrs unless age is major concern
- Discussion (Push/pull model)
- Push information-
- There is the chance of relapse and death (estimate prognosis)
- Come to an agreement on a course of action
- There is a tiny chance of transplacental metastasis
- Pregnancy per se does not appear to influence outcome- gestation cannot be an instrument of guilt or regret
- Need partnership with high-risk OB and possibly early consult with medical oncology
- Patients should probably be monitored more frequently
- Inform patient about possibility of additional biopsies during pregnancy
- Inform patient about oocyte cryopreservation
- Pull information (warning: takes time and may be difficult emotionally)-
- Does the patient understand the implications of relapse during pregnancy (including the possibility of termination)?
- What are the plans should baby survive but mother does not?
- Discussion becomes more concrete and intense as relapse risk increases
- Wait time is meant to clarify this risk a bit
- May need social work to help through these conversations
MauiDerm News Editor-Judy Seraphine