Melanoma

• 1. Introduction

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  Melanoma is the most dangerous type of skin cancer, and its origins lie in a cell that was built to protect you. Melanocytes are the cells responsible for producing melanin, the pigment that gives skin its color and offers a layer of defense against ultraviolet radiation. When those very cells turn against the body and begin multiplying without control, the result is melanoma. In 2015, roughly 3.1 million people worldwide were living with active melanoma. By 2022, there were 331,722 new cases globally in a single year, and projections suggest that number will climb past 510,000 by 2040. Australia and New Zealand carry the highest rates on earth, but the disease has been rising for decades across every region settled primarily by people of European descent. What makes melanoma so dangerous is not just how it begins, but how it moves. Once it reaches the lymph nodes, survival odds drop sharply. Once it reaches distant organs, they fall further still. Yet the past decade has brought a wave of treatments that are genuinely changing those odds. The question this documentary examines is how a cancer so closely tied to sunlight became one of the most intensively researched diseases in modern oncology, and what it took to understand it well enough to fight it.

• 2. A Disease With Deep Roots

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  In the 1960s, researchers examining nine Peruvian mummies estimated to be approximately 2,400 years old found what appeared to be melanotic masses in the skin and diffuse metastases in the bones. It was one of the earliest documented traces of melanoma in human history. The disease, however, went unnamed for centuries more. John Hunter is recorded as the first surgeon to operate on metastatic melanoma, in 1787, though he did not know what he was cutting away. He described the tumor as a "cancerous fungous excrescence." The specimen was preserved at the Hunterian Museum of the Royal College of Surgeons of England, and it was not until 1968 that microscopic examination confirmed it as metastatic melanoma. The first physician to identify melanoma as a distinct disease entity was the French doctor Rene Laennec, who presented his report in a lecture for the Faculte de Medecine de Paris in 1804 and published it as a bulletin in 1806. The first English-language report came from William Norris, a general practitioner from Stourbridge, in 1820. In his later work published in 1857, Norris noted a familial tendency toward melanoma and drew connections between the disease and environmental exposures. He observed that most of his patients had pale complexions. He also described amelanotic melanomas, tumors with little or no pigmentation, and traced how the disease could spread to other organs. By 1840, Samuel Cooper made the bleak declaration that the only chance of a cure rested on early removal. More than a century and a half later, the word melanoma itself still carries that original Greek weight: melano from the word for dark, and oma for a tissue mass or neoplasm.

• 3. Sun, Skin, and Ultraviolet Light

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  UVB light, which reaches the skin at wavelengths between 280 and 315 nm, is absorbed directly by DNA in skin cells, creating damage known as cyclobutane pyrimidine dimers. These are structural faults in the DNA strand formed when two adjacent pyrimidine bases bond together under radiation. UVA light, which operates at longer wavelengths between 315 and 400 nm, also damages DNA, but at efficiencies roughly 1/100 to 1/1000 of UVB. Together, these two wavelengths drive what researchers describe as UV fingerprint mutations: cytosine to thymine transitions, abbreviated as C to T, that are found frequently in sun-exposed skin but rarely in internal organs. When researchers sequenced the entire genomes of 25 melanomas, they found on average about 80,000 mutated bases per melanoma genome, most of them C to T transitions, along with about 100 structural rearrangements. That is far more genetic disruption than the roughly 70 mutations that occur naturally across a generation. Tanning devices compound the problem significantly. The International Agency for Research on Cancer classifies tanning beds as carcinogenic to humans. People who begin using tanning devices before the age of thirty are 75% more likely to develop melanoma. Even UV nail lamps, common in nail salons, carry some risk, though at lower levels, and using fingerless gloves or applying SPF 30 or higher sunscreen to the hands before use is recommended. The relationship between sun exposure and melanoma is not straightforward, however. The risk appears more strongly associated with occasional intense exposures that lead to sunburn than with sustained outdoor work. Melanoma is actually more common in professional and administrative workers than in people with outdoor unskilled jobs, a pattern researchers attribute to socioeconomic factors. Childhood exposures carry particular weight: migration studies in Australia have shown that exposure to intense sunlight in childhood is a more significant risk factor than adult exposure.

• 4. Written in the Genome

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  Between 5 and 12 percent of melanoma cases are hereditary, and having a first-degree relative with the disease raises a person's risk by 1.74 times. Having a personal history of melanoma raises the risk of developing a future melanoma by an estimated 8.40 times. The gene most frequently implicated in familial melanoma is CDKN2A. One mutation in this gene destabilizes p53, a transcription factor involved in apoptosis that is disrupted in roughly 50 percent of all human cancers. A second mutation in the same gene disables an inhibitor of CDK4, a protein that promotes cell division. Familial melanoma linked to CDKN2A also brings a 38-fold increased risk of pancreatic cancer, and people with the associated syndrome called FAMMM, or familial atypical multiple mole-melanoma, face a 30 percent lifetime risk of developing melanoma. The gene called MC1R, which is linked to red hair, also elevates risk. People with mutations in MC1R are two to 2.7-3.6 times more likely to develop melanoma than those carrying two typical copies of the gene. The Cancer Genome Atlas study established four subtypes of cutaneous melanoma based on somatic mutations: BRAF mutant, RAS mutant, NF1 mutant, and triple wild-type. The most common single mutation occurs at the 600th codon of the BRAF gene, present in roughly 50 percent of cases. This mutation locks BRAF into a permanently active state, driving uncontrolled tumor growth independent of normal regulation. RAS genes, including NRAS, HRAS, and KRAS, carry mutations in 30 percent of cases. These genetic subtypes matter clinically because BRAF, RAS, and NF1 mutations tend not to overlap in the same patient, a pattern of mutual exclusivity that allows doctors to match targeted therapies to the specific mutation driving a given tumor.

• 5. From Mole to Metastasis

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  Approximately 30 percent of melanomas develop from existing moles, and the ABCDE mnemonic was built to help people and clinicians catch the warning signs: Asymmetry, irregular Borders, variegated Color, Diameter greater than 6 mm (roughly the size of a pencil eraser), and Evolution over time. A separate classification applies to nodular melanoma, the second most common type at 15-20 percent of cases, which tends to grow more in depth than width and is identified by being elevated above the skin surface, firm to the touch, and actively growing. Superficial spreading melanoma is the most common type overall, accounting for 70 percent of diagnoses. Lentigo maligna melanoma makes up 5-10 percent, and acral lentiginous melanoma, which appears on the soles of the feet and palms of the hands, accounts for 7-10 percent of cases. Acral melanomas present a particular diagnostic challenge: 30-40 percent of them are amelanotic, meaning they produce little to no pigment, which makes visual detection significantly harder. At the cellular level, melanoma progresses through defined phases. In the earliest radial growth phase, the tumor is less than 1 mm thick and spreads at the level of the basal epidermis. Cancer cells have not yet reached the blood vessels deeper in the skin, so spread is very unlikely. Once the tumor enters the vertical growth phase, it pushes into the papillary dermis and deeper layers, gaining access to blood and lymph vessels. At this point, metastasis becomes possible. Research by Sarna's team found that heavily pigmented melanoma cells have a Young's modulus of about 4.93, while non-pigmented cells measured only 0.98. Stiffer pigmented cells are actually less prone to spreading, while softer non-pigmented tumor cells prove easier to dislodge and metastasize. The brain, liver, bone, and lungs are common sites of distant metastasis.

• 6. Treating a Moving Target

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  In August 2011, the FDA approved vemurafenib for late-stage melanoma, the first BRAF inhibitor to reach patients. In May 2013, the FDA approved dabrafenib as a single-agent treatment for BRAF V600E mutation-positive advanced melanoma. The combination of dabrafenib and trametinib, a MEK inhibitor, received FDA approval in January 2014 for BRAF V600E/K-mutant metastatic melanoma. In a clinical trial comparing the combination against dabrafenib alone, progression-free survival improved from 9 percent to 41 percent, and the median progression-free survival extended from 5.8 months to 9.4 months. The challenge is that tumors develop resistance. The therapy combination of dabrafenib and trametinib carries a 3-year progression-free survival of 23 percent and a 5-year progression-free survival of 13 percent. A cell surface protein called EphA2 is now under investigation as a possible driver of that resistance. Immunotherapy opened a different front. At a clinical oncology conference in June 2010, the pharmaceutical company Bristol Myers Squibb reported that ipilimumab, a monoclonal antibody, increased median survival from 6.4 months to 10 months in patients with advanced melanoma compared to an experimental vaccine. Ipilimumab received FDA approval in March 2011. When combined with dacarbazine in a June 2011 trial, median survival for late-stage patients reached 11 months rather than the usual 9 months. A course of ipilimumab, sold under the brand name Yervoy, costs $120,000. Anti-PD-1 antibodies such as pembrolizumab and nivolumab proved more effective still, with less systemic toxicity than anti-CTLA4 antibodies. The five-year progression-free survival for pembrolizumab immunotherapy is 21 percent. Lifileucel, a tumor-derived autologous T-cell immunotherapy sold under the name Amtagvi, received FDA approval in February 2024. In the United States, annual mortality from melanoma decreased 6.1 percent annually between 2013 and 2017, and 1.4 percent annually from 2017 to 2022, a decline that researchers attribute directly to these treatment advances.

• 7. Where the Numbers Land

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  In the United States, melanoma is diagnosed in men about 1.6 times more often than in women. The average age at diagnosis is 63. Melanoma occurs more than 20 times more frequently in white Americans than in African Americans. The lifetime risk for white Americans is about 2.5 percent, or roughly 1 in 40. For African Americans it is 0.1 percent, or 1 in 1,000. For Mexican Americans it is 0.5 percent, or 1 in 200. In 2024, the United States recorded 100,640 invasive cases and 8,290 deaths. There were also 107,240 cases of melanoma in situ, confined to the epidermis. The five-year survival rate for localized disease in the United States is 100 percent. When the disease has spread to regional lymph nodes, that figure drops to 76 percent. For distant metastatic disease, it was 34.6 percent among people diagnosed between 2015 and 2021, a figure that has been rising. Australia, which in 2012 recorded more than 12,000 diagnoses at a rate of 59.6 new cases per 100,000 population per year, stands as a case study in how geography and migration interact with skin cancer risk. Australian melanoma incidence increased by more than 30 percent between 1991 and 2009. As of 2008, age-standardized incidence rates in Australia were at least 12 times higher than the global average. The explanation traces back to the population: settlers of European descent arrived in a country with intense direct sunlight to which their skin was not adapted, and childhood exposure established a cumulative burden that played out over generations. The SUNMEL trial is now evaluating high-resolution ultrasound scanning as a way to monitor metastatic spread to sentinel lymph nodes without invasive surgery, offering a potential path to earlier intervention before the numbers turn against the patient.