New Directions in Melanoma Management
The incidence of melanoma, one of the most lethal forms of skin cancer, is increasing more quickly than that of any other cancer (except lung cancer in women), particularly among the young.¹ Although men are 1.5 times more likely than women to develop melanoma during their lifetime, the situation is reversed in the young, with increased incidence in young women double that in young men (from the 1970s to the 2000s, incidence increased 8-fold in women vs 4-fold in men),¹ perhaps as a result of young women being far more likely to use tanning beds.
In 2013, there will be an estimated 76,690 new cases of invasive melanoma and 9,480 deaths in the United States.² Many dermatologists think that new cases of melanoma are underreported and that the incidence rate is even higher than these already alarming numbers reflect.
South Carolina saw an increase from 320 new cases in 2000 to an average annual count of 1054 new cases from 2005 to 2009.³ The incidence of melanoma in South Carolina is significantly higher than the national average (age-adjusted incidence rate of 22.4 per 100,000 for South Carolina during the years 2005-2009, vs 19.2 per 100,000 for the United States as a whole),³ making it an issue of special concern in our state.
MUSC’s Hollings Cancer Center, one of 66 National Cancer Institute–designated cancer centers in the nation and the only one in South Carolina, offers state-of-the-art multidisciplinary care for patients with melanoma. Designated a Melanoma Center of Excellence in 2008, the Jenny Sullivan Sanford Melanoma & Skin Cancer Program, named after the state’s former first lady who made a generous donation to the program, offers multidisciplinary care by specialists in dermatologic surgery, surgical oncology, head and neck surgery, medical oncology, radiation oncology, and pathology. New patients are reviewed by the Melanoma Tumor Board, the members of which include specialists from each of these fields who also have broad experience in the diagnosis and management of melanoma. The tumor board reaches a consensus as to the best treatment plan for the patient and evaluates whether he or she may be eligible for participation in a clinical trial.
Risk Factors for Melanoma
The key risk factors for melanoma include a family history of the disease, a fair complexion, sun exposure, tanning bed use, a high number of moles (common melanocytic nevi), irregular or asymmetrical moles, and a suppressed immune status. The worst damage from sun exposure may be done in the first couple of decades of life, with studies showing that sunburn in childhood is linked to higher mole counts and thus a higher risk of subsequent melanoma.⁴ However, sunscreen and protective clothing are recommended for all ages to protect against melanoma. According to a recent meta-analysis, those exposed to tanning beds before age 35 were 1.75 times more likely to develop melanoma than those who did not engage in indoor tanning,⁵ and yet use of such tanning beds by adolescent females is growing (according to the American Academy of Dermatology [AAD], 32% of young women used a tanning bed within the past year, 25% of whom visited a tanning bed weekly).
Although survival is high when melanoma is caught early (>90% in localized melanomas [stage 0, 1, and 2]), it is halved when diagnosed after lymph node involvement (stage 3) and less than 20% when diagnosed as metastatic disease (stage 4). Early detection is therefore crucial to reducing melanoma mortality.
To encourage early detection, the AAD has designated the first Monday in May as Melanoma Monday (this year, May 6), also known as National Skin Examination Day. This day kicks off a wide variety of activities, including free screenings, throughout the month of May to raise awareness about melanoma, reminding people of the importance of regular self-examination and advising the public about the dangers of excess sun exposure and use of tanning beds.
Physicians should encourage all patients, but in particular those at high risk for melanoma, to engage in self-examination, to look for the ABCDEs (asymmetry, border irregularities, color variegation [ie, different colors within the same region], diameter greater than 6 mm, enlargement or evolution of color change, shape, or symptoms), and to consult a dermatologist if a suspect lesion is found. Those at highest risk (a family history, white men over 50 years [46% of all US melanoma deaths occur in men older than 50 years], individuals with a history of significant sunburn, or multiple nevi) should undergo regular examination by a dermatologist. For all patients, primary care physicians should be alert to any changes in exposed skin when conducting an examination for another purpose and refer patients with such changes to a dermatologist for evaluation.
Despite the importance of early detection, universal screening for melanoma by clinicians in asymptomatic patients has not been proven definitively to decrease mortality. A randomized controlled trial at the power needed to establish such a link would require the enrollment of hundreds of thousands of melanoma patients, unlikely given the relative low incidence of the disease. In the absence of such definitive data, national guidelines differ in their screening recommendations, with the United States Preventive Services Task Force finding insufficient evidence to recommend for universal screening while the American Cancer Society advises skin examination as part of periodic broader cancer-related checkups. A large German observational study showed that, after institution of a screening program in Schleswig-Holstein in 2008, mortality from melanoma dropped by 50% compared with other German cities in that year, prompting Germany to institute biannual screening in adults aged 35 and older.⁶ Data regarding the impact of that nationwide program on melanoma-specific mortality are being collected and may help provide the definitive evidence needed to settle the question about the efficacy of universal screening in reducing mortality due to melanoma.
Staging and Prognosis
Correct staging is crucial to predicting prognosis and providing appropriate treatment for melanoma. The TNM system (primary tumor, regional lymph nodes, distant metastasis) is used to stage primary melanoma. Stage 0 is melanoma in situ (ie, cancer cells restricted to the epidermis) or lentigo maligna (a subtype of melanoma in situ that typically develops on sun-damaged skin). Stage 1 and 2 cancers are localized with no regional lymph node involvement. Stage-3 cancers have lymph node involvement, and stage-4 tumors have distant metastases. Breslow’s depth, the measure of how deeply cancer cells have invaded the skin, is among the best predictors of prognosis and is used, along with other factors, to further subclassify and stage primary melanomas.
An important tool for staging higher-risk, localized (stage 1 and 2) melanomas is sentinel lymph node biopsy (SLNB), a minimally invasive procedure in which a blue dye and nuclear medicine tracer are injected into the lesion (Figure). The drainage from that lesion into the lymph node basin can then be traced with a probe, and the specific lymph node(s) draining the site of the cancer can be identified. This node is then biopsied and undergoes pathological examination. If no cancer cells are found, the patient has been spared surgery to remove all of the lymph nodes in the drainage basin. If cancer cells are found, further surgery to remove more lymph nodes will likely be necessary. According to E. Ramsay Camp, M.D., Director of the Jenny Sullivan Sanford Melanoma & Skin Cancer Program at MUSC, SLNB is “the most effective staging procedure for melanoma and also has high prognostic value, allowing us to identify lymph node metastatic disease early and discern who would benefit from removing all lymph nodes.” Although the Multicenter Selective Lymphadenectomy Trial (n=1269) showed that overall 5-year melanoma-specific mortality did not differ significantly among patients with intermediate-thickness melanomas (1.2–3.5 mm) who underwent SLNB vs regional lymph node observation after wide excision, SLNB followed by complete lymphadenectomy provided a 20% survival advantage over observation in the subgroup of patients with nodal metastases.⁷ To achieve the full promise of SLNB, it should be performed by a clinician specially trained and experienced with the procedure.
The National Comprehensive Cancer Network (NCCN) publishes guidelines on the treatment of melanoma and is the single best source of information on the disease (available at http://www.nccn.org/clinical.asp).
Stage 0: Melanoma In Situ/Lentigo Maligna
For patients with lentigo maligna or melanoma in situ, shallow forms of melanoma often characterized by ambiguous margins (subclinical extension beyond the visible margins), the NCCN lists Mohs micrographic surgery, more commonly used for basal and squamous cell carcinomas, as an option with proven efficacy. This recommendation stems in part from the advent of new immunostains (eg, MART-1 [melanoma-associated antigen recognized by T cells]) that improve the visualization of melanocytes. Mohs for melanoma is technically demanding and best performed in a highly capable laboratory with fellowship-trained surgeons who can obtain adequately thin sections for evaluation. Instead of excising to a predetermined margin and awaiting external biopsy results, Mohs surgeons, like MUSC’s Joel Cook, M.D., Director of the Division of Dermatologic Surgery, and Brian C. Leach, M.D., Assistant Professor of Dermatology, both fellowship-trained in Mohs micrographic surgery, remove the visible melanoma and, while the patient waits, examine all excised tissue under the microscope after it has been frozen, stained, and sliced to monitor for cancer cells. If cancerous cells are observed, more tissue is removed from the problematic area and likewise examined. The process continues until no more cancerous cells can be discerned. The aim of Mohs is to remove all cancerous cells while taking no more margin than necessary.
The most common treatment for early-stage primary melanoma is wide local excision. The margin to be excised depends on the Breslow’s depth of the lesion (Table 1). Excised tissue then undergoes pathological examination so that a treatment approach can be planned. For stage 1B and stage 2 melanomas, SLNB may be recommended. According to Dr. Camp, surgery to remove the lesion and the appropriate margin is likely sufficient to cure early-stage melanoma. However, positive findings on SLNB in patients initially classified as having stage 1B or stage 2 melanoma will result in their being reclassified as stage 3 and identify patients who may benefit from a complete lymphadenectomy to remove all of the involved lymph nodes.
TABLE 1. Recommended Excision Margins for Primary Melanoma
Recommended margins in the United States
Newly Approved Treatments
Until recently, few treatments were available for advanced melanoma. The approval in 2011 of two new agents by the US Food and Drug Administration—ipilimumab, a monoclonal antibody that activates the immune system, and vemurafenib, a BRAF inhibitor—has considerably expanded the treatment options available for patients with advanced disease. Mutations of the BRAF gene are common in a number of cancers but particularly frequent in melanoma, leading to increased BRAF protein activity (increased cellular signaling) that fosters proliferation of cancer cells. Ipilimumab begins to show effect only after several months of treatment and can lead to adverse immunological effects (particularly affecting the gastrointestinal tract), but, for those patients who show a response, the response is stable and long-lasting. Results are usually quicker with vemurafenib, but the effects are not as durable; adverse side effects include skin complications and the development of basal and squamous cell carcinomas. It is thought that resistance is developed to BRAF inhibitors when the function of the blocked BRAF pathway is assumed by a redundant pathway (the MEK pathway), allowing continued spread of the cancer.
Clinical Trials at MUSC’s Hollings Cancer Center
Patients referred to MUSC’s Hollings Cancer Center can not only take advantage of the newly approved agents but also choose to participate in clinical trials of experimental therapies. Two trials at MUSC are currently recruiting patients (Table 2). One is a pharmaceutical company–sponsored phase 3 trial seeking to determine whether the development of resistance to BRAF inhibitors could be reduced by using a combination therapy with both a BRAF inhibitor and a MEK inhibitor, which would block the redundant MEK pathway associated with resistance. The second is a MUSC-sponsored phase 1 trial testing the feasibility and safety of using Poly-IC as an adjuvant for a dendritic cell vaccine. As discussed in more detail in the January/February 2013 issue of Progressnotes, dendritic cells present antigen to T cells, thereby activating them and making them into killer cells that seek out and destroy cancer cells. Dendritic cell vaccines make it more likely that T cell recognition will occur by studding the dendritic cell with more melanoma-relevant targets. The MUSC trial is testing whether Poly-IC could safely and effectively enhance the effects of such a dendritic cell vaccine.
TABLE 2. Melanoma Trials at MUSC’s Hollings Cancer Center
Description of Study
BRAF-positive advanced or metastatic melanoma
Keisuke Shirai, M.D.
Metastatic and/or unresectable melanoma
Keisuke Shirai, M.D.
Description of Study
Ipilimumab-refractory advanced melanoma
Keisuke Shirai, M.D.
Surgically resected cutaneous BRAF-mutant melanoma at high risk for recurrence
Keisuke Shirai, M.D.
The focused multidisciplinary melanoma team at MUSC’s Jenny Sullivan Sanford Melanoma & Skin Cancer Program recognizes the importance of developing individualized plans for patients with melanoma and of optimizing those treatment plans by offering comprehensive care that encompasses screening, state-of-the-art staging, as well as definitive treatment of melanoma at any stage. For those who have exhausted other options, the clinical trials at Hollings Cancer Center provide access to promising investigational medications that are not available elsewhere in South Carolina.
¹ Reed KB, Brewer JD, Lohse CM, et al. Increasing incidence of melanoma among young adults: an epidemiological study in Olmsted County, Minnesota. Mayo Clinic Proc 2012;87(4):328-334.
² Siegel R, Naishadham D, Jemal A. Cancer Statistics, 2013. CA: A Cancer Journal for Clinicians 2013;63(1):11-30. Available at http://dx.doi.org/10.3322/caac.21166
³ State Cancer Registry and the CDC’s National Program of Cancer Registries Cancer Surveillance System (NPCR-CSS) January 2012 data submission. State rates include rates from metropolitan areas funded by SEER. National Cancer Institute State Cancer Profiles available at http://statecancerprofiles.cancer.gov/cgi-bin/quickprofiles/profile.pl?45&053
⁴ de Maleissye MF, Beauchet A, Aegerter P, et al. Parents’ attitudes related to melanocytic nevus count in children. Eur J Cancer Prev 2010 Nov;19(6):472-477. Available at http://dx.doi.org/10.1097/CEJ.0b013e32833eba4f.
⁵ The International Agency for Research on Cancer Working Group on artificial ultraviolet (UV) light and skin cancer. The association of use of sunbeds with cutaneous malignant melanoma and other skin cancers: a systematic review. Int. J. Cancer 2007;120:1116-1122. Available at http://dx.doi.org/10.1002/ijc.22453
⁶ Waldmann A, Nolte S, Weinstock MA, et al. Skin cancer screening participation and impact on melanoma incidence in Germany--an observational study on incidence trends in regions with and without population-based screening. Br J Cancer 2012;106(5):970-974. Available at http://dx.doi.org/10.1038/bjc.2012.22.
⁷ Morton DL, Thompson JF, Cochran AJ, et al; for the MSLT Group. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355(13):1307-17.