Paul Nathan and Oliver Bassett
Case history
A 52-year-old white man presented to a plastic surgeon concerned about a mole on his back which had changed in pigmentation. He reported to be fit and well, had no significant past medical history, and took no medications. Examination was otherwise unremarkable. He underwent excision biopsy of the lesion and histopathology showed: ‘a centrally situated area of nodular malignant melanoma 6mm in maximum diameter, and an area of adjacent radial growth phase component of superficial spreading type. It appears to have arisen from pre-existing melanocytic naevus. There is focal invasion into the reticular dermis (Breslow thickness 1.6mm). The overlying dermis is thin but not ulcerated. There is no evidence of vascular invasion. The minimum clearances in the lateral plane of section are 11mm (vertical) and 8mm (radial)’.
Questions
1. What is the patient’s stage/prognosis and which feature not included in this pathology report can provide important prognostic information in thin melanomas?
2. Is further surgery recommended at this stage? What further procedure should be considered at this time?
Answers
1. What is this patient’s stage/prognosis and which feature not included in this pathology report can provide important prognostic information in thin melanomas?
The AJCC published a revised staging system for cutaneous melanoma in 2009. The database used contained prospective data from more than 27,000 patients with stage I and II melanoma. Primary tumour (Breslow) thickness remained the most valuable independent prognostic indicator. Increasing tumour thickness (<1mm, >1mm, >2mm, and >4mm) showed a significant association with reduced 5- and 10-year survival rates. The presence of ulceration and mitotic rate were other important independent prognostic factors on multivariant analysis. Thin melanomas are rarely ulcerated; however, the presence of pathological ulceration in melanoma of any thickness upstages the tumour. The presence of one or more mitotic figure(s)/mm2 in a thin melanoma (<1mm Breslow thickness) upstages the tumour from AJCC stage Ia to Ib with an associated reduction in the 10-year survival rate from 95% to 88% (P < 0.0001). The presence of ulceration or mitotic rate is now used to differentiate stage T1a and T1b. The level of invasion (Clark’s level) is no longer used. The tumour under discussion was an AJCC stage IIa lesion with an associated 10-year survival of >80%.
2. Is further surgery recommended at this stage? What further procedure should be considered at this time?
The British Association of Dermatologists, the British Association of Plastic and Reconstructive and Aesthetic Surgeons, and the Melanoma Study Group UK published revised guidelines for the management of cutaneous melanoma in 2010 (Marsden et al. 2010). Surgery remains the only potentially curative treatment for primary melanoma. Current recommendations are for initial biopsy to be followed up with wide local excision to ensure removal of primary lesion and any local micrometastasis. A Cochrane Review (Sladden et al. 2011) showed that although there appeared to be a small survival advantage favouring wide excision it was not statistically significant, and current evidence is insufficient to define optimal excision margins. Current consensus is for lateral margins of 1cm for a tumour thickness of <1mm, 2cm for tumour thickness of >1mm, and 3cm for tumours >4mm. The guidance states that the final decision will be made depending on anatomical site, MDT discussion, and patient choice. Sentinel lymph node biopsy (SLNB) has become an established part of staging in melanomas >1mm thick of which approximately 20% will have a positive SLNB. The majority of patients with a positive node will go on to have completion lymphadenectomy, where 20% will show involved nodes in addition to the sentinel node.
Eight months after a normal clinical review the patient presented with discomfort in the right axilla. Examination revealed a palpable axillary mass of approximately 6cm × 7cm. CT scan confirmed a right axillary lymph node mass and the patient went on to have an axillary clearance which showed melanoma metastases in 29 out of 30 lymph nodes, including the apical node. There was evidence of extranodal spread and lymphovascular invasion. While awaiting adjuvant axillary radiotherapy the patient developed a palpable supraclavicular node.
Questions
3. Should further surgery be considered?
4. Is further imaging necessary?
Answers
3. Should further surgery be considered?
Despite limited evidence of survival benefit, the majority of clinicians would recommend metastatectomy in patients with oligometastatic disease. Early relapse, however, is a poor prognostic marker and heralds a high likelihood of the future appearance of further metastases. The majority of published data are from retrospective single-institution studies, which have a clear potential for selection bias. Morton (2007) presented results of a randomized phase III trial comparing an allogenic melanoma vaccine with a placebo in patients who had all undergone complete resection of metastasis to regional or distant sites. The study was stopped after an interim analysis due to no evidence of improved survival in the vaccine arm. However, the study showed an excellent survival for the whole study cohort, with 5-year survival of 42.3% in the stage IV patients. Sosman et al. (2011) published results of the Southwest Oncology Group trial which prospectively followed patients with stage IV disease who underwent complete resection. Four-year OS was 31%. It should be noted that all published studies were conducted before recent advances in treatment for metastatic melanoma when systemic therapeutic options were limited and response rates were notoriously poor. Simultaneously, PET/CT has become established in the assessment of metastatic spread in patients with melanoma prior to potential metastatectomy.
4. Is further imaging necessary?
This patient needs imaging with PET/CT prior to consideration for surgery.
The patient underwent a PET/CT scan prior to consideration for further surgery. This is shown in Fig. 21.1.
Fig. 21.1 (See also colour plate section)
Question
5. What does the scan in Fig. 21.1 show?
Answer
5. What does the scan in Fig. 21.1 show?
The PET scan shows tracer uptake over the right axillary apical, infraclavicular, and supraclaviular lymph nodes.
The PET scan also shows unresectable loco-regional disease involving the skin and multiple regional lymph nodes as well as external iliac nodal disease.
Questions
6. What are the further treatment options?
7. What needs to be established before treatment options can be offered?
Answers
6. What are the further treatment options?
Further treatment options are systemic treatment using dacarbazine (DTIC; an alkylating agent), enrolment in an appropriate clinical trial, or vemurafenib (if BRAF mutation positive). Ipilimumab is a second-line treatment after chemotherapy.
Until recently the standard therapeutic agent available outside a clinical trial for metastatic melanoma was DTIC or its derivative temozolomide. In use since the 1970s, it has formed the mainstay of treatment for nearly 40 years. Published response rates are 5–15%, with the majority demonstrating only a short-lived partial response and no evidence of an increase in OS. Multiple trials comparing additional chemotherapy agents, immunotherapy, or biological modulating agents have shown no significant increase in survival when compared with DTIC alone.
Treatment options in metastatic melanoma have recently been revolutionized by the development of two new strategies now proven to increase OS. The first drug to be licensed was ipilimumab, a humanized monoclonal antibody that binds to an immune checkpoint molecule CTLA-4. Ipilimumab inhibits a negative regulatory pathway in T-lymphocyte activation, and therefore increases T-cell mediated immune killing. The first phase III trial recruited patients who had already progressed on therapy for systemic disease. They were randomly assigned to receive either a gp100 peptide vaccine, ipilimumab, or both treatments. Median OS in the ipilimumab treatment arms was 10.0 months compared with 6.4 in the gp100 vaccine arm. The most significant activity, however, appeared to be that a group of patients experienced durable long-term remission. Ipilimumab is given as a 3-weekly infusion, usually for a total of four doses. Grade 3 and 4 immune reactions occurred in 10–15% of patients, most commonly diarrhoea and skin reactions. Life-threatening colitis can occur and physicians should be particular vigilant for symptoms so prompt diagnosis can be made and steroid treatment commenced.
The second approach is with antagonists of oncogenic BRAF. Vemurafenib, an oral BRAF inhibitor, has been shown to increase OS in patients with stage IIIC and IV disease compared with DTIC. A phase III study (Chapman et al. 2011) showed a median PFS of 5.3 versus 1.6 months and OS at 6 months of 84% versus 64%. Several other similar drugs are currently in development and have shown promising early results.
7. What needs to be established before treatment options can be offered?
The BRAF mutation status needs to be established before deciding on further treatment.
Vemurafenib is a treatment option only in those patients whose tumours contain an acquired activating mutation in the BRAF oncogene. BRAF is a protein kinase which forms part of the RAS-RAS-MEK-ERK intracellular signalling pathway. The pathway is involved in cell proliferation, differentiation, and apoptosis. Approximately 50% of patients with melanoma will have a BRAF mutant tumour, of which the majority (90%) will be the single-point mutation V600E. Vemurafenib potently and specifically inhibits mutant BRAF, therefore the BRAF mutation status of a patient’s tumour needs to be established before treatment options can be discussed. Mutation testing can be performed on the original tissue sample or on a biopsy of a metastatic lesion if the original sample is unavailable or insufficient. BRAFmutation testing should be considered in patients with high-risk primary melanoma and regional (stage III) disease and is the standard of care in stage IV disease. Treatment options for patients with wild-type (non-mutant) BRAF melanoma are still limited to chemotherapy or enrolment into a clinical trial.
The patient’s tumour was found to be positive for the BRAF mutation and he entered into a clinical trial comparing DTIC with vemurafenib.
Question
8. How is vemurafenib administered and how should it be monitored?
Answer
8. How is vemurafenib administered and how should it be monitored?
Vemurafenib is administered in tablet form. The original study found a dose of 960mg twice daily to be the maximum tolerated dose. During the phase II trial 45% of patients required a dose reduction due to drug toxicities. Common side-effects include arthralgia, skin toxicity, and photosensitivity. Approximately 20% of patients develop skin lesions consistent with keratoacanthoma or squamous cell carcinoma thought to be due to signalling of braf/craf heterodimers in the presence of an upstream ras mutation. Therefore, regular skin examinations should be performed and surgical excision may be required. Patients should be advised to wear high-factor sun protection because severe sunburn can occur even in cloudy conditions. Median time to confirmed radiological response in the phase III trial was 1.45 months; however, a clinical improvement can be seen in as little as 2 weeks, and the drug can rapidly palliate patients suffering severe tumour-related symptoms.
Treatment and follow-up
The patient was initially randomized to DTIC within the clinical trial but showed progression of disease after 14 weeks. He crossed over to the vemurafenib arm where he has shown an ongoing prolonged response to treatment lasting >18 months.
Further reading
Balch CM, Morton DL, Gershenwald JE, et al. Sentinel node biopsy and standard of care for melanoma. Journal of the American Academy of Dermatology 2009; 60: 872–875.
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New England Journal of Medicine 2011; 364: 2507–2516.
Eigentler TK, Caroli UM, Radny P, Garbe C. Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomised clinical trials. Lancet Oncology 2003; 4: 748–759.
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine 2010; 363: 711–723.
Marsden JR, Newton-Bishop JA, Burrows L, et al. Revised UK guidelines for the management of cutaneous melanoma 2010. Journal of Plastic, Reconstructive and Aesthetic Surgery 2010; 63: 1401–1419.
Morton DL, Mozzillo N, Thompson JF, et al. An international, randomized, phase III trial of bacillus Calmette–Guerin (BGC) plus allogenic melanoma vaccine or placebo after complete resection of melanoma metastatic to regional or distant sites. Journal of Clinical Oncology 2007; 25 (18s): abstract 8508.
Sladden MJ, Balch C, Barzilai DA, et al. Surgical excision margins for primary cutaneous melanoma: a summarised Cochrane review. Clinical and Experimental Dermatology 2011; 36: 334–335.
Sosman JA, Moon J, Tuthill RJ, et al. A phase 2 trial of complete resection for stage IV melanoma: results of Southwest Oncology Group Clinical Trial S9430. Cancer 2011; 117: 4740–4746.
Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600–mutant advanced melanoma treated with vemurafenib. New England Journal of Medicine 2012; 366: 707–714.