Melanoma
Tara C. Gangadhar, Leslie A. Fecher, Chris J. Miller, Giorgos Karakousis, Robert Vonderheide, George Xu and Lynn M. Schuchter
Summary of Key Points
Incidence
• The incidence of melanoma has increased dramatically during the past few decades.
• Approximately 76,250 new cases of invasive melanoma are diagnosed each year in the United States, and it is estimated that 1 in 36 men and 1 in 55 women in the United States will be diagnosed with melanoma in their lifetime.
Biologic Characteristics
• The risk of melanoma is strongly related to exposure to ultraviolet irradiation; people with fair hair and skin, a tendency to burn, and numerous benign or atypical nevi are also at increased risk.
• Approximately 50% of melanomas have a somatic activating mutation in BRAF.
• The important pathologic features of the primary lesion are thickness (in millimeters), the presence or absence of histologic ulceration, and the mitotic rate, all of which have prognostic value.
Staging Evaluation
• A full-thickness biopsy should be performed for any suspicious, new, or changing lesion; an excisional biopsied is preferred.
• The current American Joint Committee on Cancer staging system includes the thickness and presence or absence of ulceration of the primary tumor, the number of positive nodes, whether the nodes are microscopically or macroscopically positive, and whether distant disease is present.
• The extent of radiologic staging evaluation depends on the risk of recurrence. In general, computed tomography or positron emission tomography/computed tomography imaging can be considered for patients with stage III melanoma.
Primary Therapy
• Surgery is the primary treatment for melanoma. All primary melanomas require a wide local excision for local control.
• The margins of wide excision are determined by the thickness of the primary lesion.
• Sentinel lymph node mapping is a useful staging procedure for melanoma and provides prognostic information.
• A sentinel lymph node biopsy should be offered to patients with melanomas >1 mm in thickness or melanomas ≤1 mm that are associated with either ulceration or a mitotic rate >1 mitosis/mm2 and can be considered for patients with other high-risk features (e.g., size >0.75 mm, lymphovascular invasion, or Clark level IV).
• The current standard of care is to offer patients with known nodal involvement a regional completion lymph node dissection.
Treatment of Metastatic Disease
• The median survival for patients with melanoma after distant metastatic disease has been identified is approximately 9 to 12 months.
• Treatment options include molecularly targeted therapy, immune therapy, cytotoxic chemotherapy, and participation in clinical trials.
• All patients with advanced melanoma should have their tumor tissue assessed for the presence or absence of the BRAF V600 E mutation. The presence of the mutation is predictive of response to targeted therapy with BRAF inhibitors.
• Immune therapy options include CTLA-4 inhibition with ipilimumab, high-dose interleukin-2, and clinical trials.
• Cytotoxic chemotherapy options include dacarbazine-based or temozolomide-based therapy.
• Additional supportive and palliative care options should be considered for all patients; brain metastases are managed with surgery and/or radiation therapy, depending on the size and number of lesions.
1. A 33-year-old man with stage III melanoma is receiving high-dose interferon (IFN) therapy. He has completed the 4 weeks of daily intravenous (IV) therapy and is now in the fifth month of maintenance subcutaneous therapy with IFN. Laboratory studies from yesterday revealed a normal complete blood cell count (CBC) and differential count, but the serum bilirubin level was 1.9 mg/dL, the aspartate aminotransferase level was 510 units/mL, and the alanine aminotransferase level was 420 units/mL. The patient feels well at this time except for fatigue. Physical examination last week was within normal limits. Which of the following options should you recommend regarding therapy?
A Continue with the current treatment plan
B Discontinue IFN therapy permanently
C Continue IFN but reduce the dose by 50%
D Discontinue IFN and start interleukin (IL)-2
E Withhold IFN until liver function test results normalize and then restart IFN at a 50% dose reduction
2. A 65-year-old woman was recently diagnosed with a 0.87-mm-thick melanoma. No ulceration was present, it was determined to be Clark level III, and the mitotic count was zero. The melanoma arose from her right posterior calf. In addition to blood work (CBC, chemistry panel, and lactate dehydrogenase), which of the following evaluations for staging are appropriate for this patient?
B Magnetic resonance imaging (MRI) of the brain, computed tomography (CT) scan of the chest/abdomen/pelvis
3. A 44-year-old man was recently diagnosed with stage IV melanoma. Staging workup showed multiple liver metastases and lung metastases. Symptoms at this time include mild shortness of breath, cough, and fatigue with a 15-lb weight loss. Mutation testing for BRAF confirmed V600E BRAF mutation. What treatment would you recommend now?
4. You are treating a 58-year-old woman who has stage IV melanoma with lung metastases. Treatment with ipilimumab was begun, and returns to your office today for her fourth dose of ipilimumab. She has tolerated therapy well. However, during the past few days, she has noted diarrhea. She reports four to six loose stools per day. She reports mild abdominal cramping with diarrhea. On physical examination, her pulse is 98 and regular, Her blood pressure is 110/82, and she is afebrile. Cutaneous examination shows a mild macular rash on her back. An abdominal examination shows normoactive bowel sounds and no tenderness. The remainder of the examination is normal. Blood was drawn the previous day for laboratory studies, which show a normal CBC, normal liver function tests and electrolytes, and normal thyroid-stimulating hormone. What do you recommend?
A Proceed with cycle number four of ipilimumab
B Treat today, but reduce the dose of ipilimumab by 25%
D Withhold ipilimumab and begin treatment with corticosteroids
5. A 58-year-old woman was diagnosed with malignant melanoma 2 years ago. At that time, the patient presented with a changing mole on her left arm. A biopsy was performed that revealed a superficial spreading melanoma at a depth of 1.6 mm with no ulceration. A sentinel lymph node (SLN) biopsy was performed that was negative for melanoma, and a wide excision was performed, with no residual melanoma. The patient now presents to you for a routine checkup, and physical examination reveals an enlarged 2-cm left axillary lymph node. Which of the following actions would you now advise?
A Because the sentinel node was negative, continued follow-up with close monitoring is indicated
B Arrange for lymph node biopsy or fine-needle aspiration (FNA) of the lymph node
6. You are treating a 45-year-old man with stage IV melanoma and recommend use of vemurafenib. Which of the following adverse effects are most likely?
1. Answer: E. High-dose IFN therapy is associated with significant toxicity. Patients experience flu-like symptoms such as fatigue, fever, chills, myalgias, anorexia, nausea, vomiting, and headache. Significant laboratory abnormalities include elevated hepatic transaminase levels, neutropenia, elevated triglyceride levels, thyroid dysfunction, and anemia. It is critical that patients undergoing treatment with IFN be monitored closely and that the dose of IFN be modified appropriately for toxicity. Therefore it is recommended that patients undergoing treatment with high-dose IFN have liver function tests monitored weekly during the induction phase and monthly while undergoing the maintenance phase of treatment. If the hepatic transaminase (alanine aminotransferase/serum glutamate oxaloacetate transaminase) levels rise to >5× the upper limit of normal, then IFN treatment should be temporarily discontinued until they normalize. IFN treatment should be restarted at 50% of the previous dose. Similarly, if granulocytes decrease <500/mm3, treatment should be withheld until normalization, and the IFN dose should then be reduced by 50%.
2. Answer: A. The staging evaluation of a patient with a low-risk melanoma should include a physical examination including a skin examination, chest radiograph, and blood work. The majority of patients who present with melanoma do not have a distant metastatic disease at presentation; therefore extensive evaluations with CT scans to search for distant metastases have an extremely low yield and consequently are not indicated in asymptomatic patients. More extensive staging evaluation with CT scans of the chest/abdomen/pelvis can be considered in patients with high-risk disease (i.e., a thick primary melanoma >4 mm thick or node-positive disease) for whom the risk of distant metastatic disease is higher.
3. Answer: A. In this patient with symptomatic metastatic melanoma, the most appropriate choice would be vemurafenib, a highly potent and selective BRAF inhibitor. Vemurafenib treatment is associated with an approximately 50% response rate. Clinical benefit has been seen within 72 hours of administration. Therapy with high-dose IL-2, IFN, and chemotherapy would not be appropriate next steps given the low response rate associated with these treatments. No role exists for cetuximab, which targets the epidermal growth factor receptor.
4. Answer: C. Ipilimumab is associated with significant toxicities that are immune-related adverse events. These immune-mediated reactions may involve any organ system; however, the most common immune adverse reactions are enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy. Treatment of immune-mediated toxicity requires interruption of ipilimumab and use of corticosteroids, depending on the severity of symptoms. The Food and Drug Administration (FDA) has created a Risk Evaluation and Mitigation Strategy to provide additional information regarding adverse effects and management of ipilimumab-associated adverse events. Therefore it is recommended that patients undergoing treatment with ipilimumab be monitored closely with physical examinations, review of symptoms, and blood tests including liver and thyroid function before starting and during treatment. Dose modification occurs through withholding a dose, not dose reduction.
5. Answer: B. SLN mapping has largely replaced elective lymph node dissections in patients with early-stage melanoma. This technique can identify the draining lymph node most likely to be involved with melanoma. SLN mapping may be considered in patients with melanomas >1 mm thick or in thinner lesions with worrisome histologic features such as ulceration or a Clark level of IV or V. The false-negative rate for SLN biopsy is approximately 4%. Thus in this patient, who later experiences palpable adenopathy due to melanoma, a biopsy should be performed to confirm clinical suspicions of recurrent melanoma. If the FNA or biopsy are positive for melanoma, than a therapeutic lymph node dissection should be performed, which is potentially curable. IFN therapy or enrollment in a clinical trial could be considered after the surgery is completed.
6. Answer: C. Vemurafenib, a potent and selective BRAF inhibitor, was approved by the FDA for treatment of V600E BRAF mutant melanoma, including unresectable stage III or stage IV melanoma. The most common adverse effects associated with vemurafenib are fever, arthritis, and skin changes, including rash and hyperproliferative lesions. Cutaneous squamous cell carcinomas or keratoacanthoma can occur in approximately 25% of patients treated with vemurafenib. Based on the frequent skin-associated adverse events, patients undergoing treatment with vemurafenib should be counseled to perform regular self-examination of their skin and report any new or changing skin lesions to their physicians. Additionally, patients starting therapy should be advised of sun-protective measures. Dermatologic skin examinations should be performed before the initiation of therapy and every 2 months while undergoing therapy. Arthralgias and arthritis associated with vemurafenib at times requires treatment with corticosteroids.
