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ABSTRACT

ABSTRACT
Melanoma is the deadliest form of skin cancer. In the early stages, melanoma can be treated successfully with surgery alone and survival rates are high, but after metastasis survival rates drop significantly. Therefore, early and correct diagnosis is key for ensuring patients have the best possible prognosis. Melanoma misdiagnosis accounts for more pathology and dermatology malpractice claims than any cancer other than breast cancer, as an early misdiagnosis can significantly reduce a patient's chances of survival. As far as treatment for metastatic melanoma goes, there have been several new drugs developed over the last 10 years that have greatly improved the prognosis of patients with metastatic melanoma, however, a majority of patients do not show a lasting response to these treatments. Thus, new biomarkers and drug targets are needed to improve the accuracy of melanoma diagnosis and treatment. This article will discuss the major advancements of melanoma diagnosis and treatment from antiquity to the present day.

Introduction

At the basal level of the epidermis sit the melanocytes, which produce the UV absorbing pigment melanin. Melanocytes make up a minority cell population in the epidermis, with only 1500 melanocytes per square millimeter, and divide infrequently, less than twice per year. In response to UV radiation keratinocytes produce α-melanocyte stimulating hormone (α-MSH), which binds to the melanocortin 1 receptor (MC1R) on melanocytes signaling to induce melanin synthesis.1 The melanocytes then transfer the melanin to surrounding keratinocytes through finger-like projections that reach out into the surrounding cells.2 Sun-exposed keratinocytes accumulate melanin, which shields their nuclei from the mutagenic effects of UV radiation. As the keratinocytes mature, they undergo keratinization, anucleate and die. Thus, the outer layer of the skin is protected by both melanin pigment in keratinocytes and a layer of dead keratinocytes that act as a barrier to protect the living cells beneath.

There are two forms of melanin produced by melanocytes: the black/brown pigment eumelanin, and a red/yellow pigment pheomelanin. The ratio of eumelanin to pheomelanin in the skin determines skin color rather than the number of melanocytes, which is relatively constant in all skin types. The darker eumelanin is a better UV shield, and consequently people with darker skin have a lower skin cancer risk. Pheomelanin not only offers less protection against UV radiation, but the production of pheomelanin produces carcinogens. Pheomelanin has been shown to produce more ultraviolet-A-induced reactive oxidative species (ROS) leading to greater DNA damage in response to UV radiation. It has long been known that melanoma risk was tied to skin, hair and eye coloration: people who have light skin that does not tan, blond or red hair, and light eyes have a much higher risk of having melanoma compared to the population as a whole.

Coloration of the skin, hair and eyes is controlled, in part, by MC1R. Polymorphisms in the MC1R gene determine the activity level of MC1R. Variants of the MC1R gene that lead to reduced MC1R function result in the production of predominantly the red/yellow pheomelanin pigment and fair skin that does not tan, and light eyes and hair.1,4,11 Fully functional MC1R stimulates production of the black/brown eumelanin.1 People harboring less functional variants of MC1R accumulate more mutations due to increased exposure of the nuclei to UV damage. If mutations accumulate in sensitive regions of the genome, then skin cancers can arise.

Melanoma, a malignant tumor arising from melanocytes, is a rare disease, affecting only 22.1 out of 100,000 people in the US (Cancer statistics from the Center for Disease Control and Prevention). However, it is also a very deadly disease accounting for 75% of skin cancer deaths though it only accounts for 4% of skin cancer cases. In 2019, it is expected that 96,480 new cases of melanoma will be diagnosed, and 7,230 people will die in the US alone (American Cancer Society). This review will go over a brief history of melanoma, the major molecular defects that lead to melanoma progression, the major methods for diagnosing and determining patient prognosis and melanoma treatment options.

History of melanoma

Melanoma is generally thought of as a modern disease exacerbated by migration of fair skinned people to areas nearer the equator and by modern sun-seeking behavior. However, although melanoma incidence rates have certainly skyrocketed in modern times, melanoma is an ancient disease that has been documented throughout history. The first documented case of melanoma was recorded in the 5th century by Hippocrates of Cos, but earlier physical evidence of melanoma has been found in the bones of pre-Columbian mummies thought to be ~2400 years old.12 The first recorded cases of melanoma in Western medical literature are found in the 1651 writings of Drs. Highmore and Bonet, and in the 1757 writings of Henrici and Nothnagel, which all describe fatal black tumors spread throughout the bodies of their patients.12

The first surgical removal of a melanoma tumor was recorded in 1787 by the Scottish surgeon John Hunter, who believed, as most (if not all) doctors did at the time, that melanoma was a fungal growth; it would not be until much later that the exact nature of the disease would be discovered. He successfully removed a recurring tumor from the jaw of a 35 year-old man, and from this point surgical resection became routine for the treatment of melanoma.

In the 1820s Dr. William Norris described a patient who had 'fungoid disease' and noted that the man's father had also died of a similar disease and postulated that the disease could, in certain cases, be heritable. Norris observed that melanomas arose from moles, and that individuals from families with hereditary melanoma often had a large number of moles. Norris was the first to recommend surgical removal of melanoma lesions with wide excision margins, noting that if the margins were not wide enough, the disease tended to recur, and that surgical excision was ineffective if the disease had already disseminated. Norris' observations were remarkable for the time, as melanoma was so little understood, and as they were made some 50 years before Mendel's work on inheritance.

Molecular defects

When melanoma was first recognized as a disease in the 1800s it was classified based on where the tumor arose. In the 1960s melanomas began to be classified based on histologic patterns. While histology is still important for melanoma diagnosis, one of the most influential shifts in the understanding of cancer progression was the realization that cancer arises due to the accumulation of genetic mutations, leading to misregulation of cellular pathways.12 Since the 1980s there has been a concerted effort to identify individual mutations that commonly occur in cancers such as melanoma, and to develop targeted therapies to treat each patient in a more personalized way based on the mutations they carry.

Approximately 5-12% of melanomas are hereditary, and hereditary melanomas tend to have different mutation profiles to non-hereditary melanomas.12 CDKN2A is a mutation commonly found in familial melanoma syndromes, though somatic CDKN2A mutations also occur in sporadic melanomas.15 Families that carry CDKN2A mutations tend to have high numbers of clinically atypical (but benign) nevi and a family history of melanoma.12 Of familial melanomas, up to 40% contain CDKN2A mutations, which lead to defects in the proteins p14 ARF and p16 INK4A. These proteins are important tumor suppressors that regulate the G1 checkpoint and stabilize p53 expression. P16 binds to CDK4 leading to cell cycle arrest, while mutations in p16 prevent its binding to CDK4 thus disrupting cell cycle arrest.15 Though p14 ARF and p16 INK4A are not druggable targets, therapeutic targeting of other related proteins, such as CDK4, is being explored.15

A less common but far more virulent group of germline mutations that increase the risk of developing melanoma, are mutations in nucleotide excision repair (NER) pathways. UV radiation creates bulky DNA lesions that must be removed and repaired by repair mechanisms such as NER; if these pathways are disrupted, mutational events will be propagated. The disease xeroderma pigmentosum (XP) is caused by hereditary mutations in one of eight NER genes; XPA, XPB, XPD, XPE, XPF, XPG, or XP-V. Though mutations in any of these eight nucleases result in XP, XPA and XPC are the most commonly mutated and account for half the cases of XP. The lack of functional NER pathways results in the accumulation of UV or chemically induced mutations in the skin and a heightened risk of skin malignancies. Patients with XP show extreme sensitivity to UV radiation; often they develop some form of skin cancer before the age of 10 and have a far greater risk of developing cutaneous melanoma on sun exposed skin than the population as a whole. This disease highlights the importance of nucleotide excision repair in melanoma prevention.

Not all variants of melanoma have the same mutational frequencies, however, there are recurrent somatic mutations that appear frequently in all types of melanoma. Driving mutations in melanoma tend to be in signaling pathways that regulate proliferation ( BRAF, NRAS, and NF1),14 growth and metabolism ( PTEN and KIT),14 resistance to apoptosis ( TP53),14 replicative lifespan ( TERT), cell identity ( ARID2),14 and cell cycle control ( CDKN2A) ( Figure 1).

Though a handful of mutations involved in melanoma development may be inherited, the majority of melanomas arise from somatic mutations acquired later in life. One of the most commonly mutated pathways in melanoma, and one that has garnered a lot of interest for targeted therapeutic purposes, is the MAP kinase signaling pathway. Mutations in BRAF and other MAPK mutational events are thought to be early oncogenic events. Nearly 80% of benign nevi have BRAF mutations, indicating that a BRAF mutation alone is insufficient for a malignant phenotype and that more than one mutation is needed to transform normal melanocytes into a malignant tumor. It is estimated that 70% of melanomas contain mutations in the MAPK signaling pathway;14 ~50% of melanomas contain activating BRAF mutations, the most common of which is the V600E mutation (>85% of BRAF mutations), which lead to constitutive activity of downstream MAPK signaling. This mutation is seen more commonly in melanomas arising from intermittent (rather than chronic) sun exposure and with a superficial spreading melanoma (SSM) phenotype.4,7,9,12,14,19 Another 15-20% of melanomas have NRAS mutations, 2% have CKIT mutations (common in mucosal melanomas),14 and 50% of uveal melanomas have GNAQ mutations.20 The MAPK pathway is involved in controlling proliferation and survival in response to growth factors, so when mutations cause constitutive activity, cells grow unchecked. Therefore, this is a particularly important oncogenic pathway making it a prime target for therapeutic intervention. BRAF is an attractive target in this pathway as it is mutated in approximately half of melanoma patients, it is easy to target and it is not active in healthy cells.14

UV radiation also directly stimulates MAPK signaling and has been shown to be a major pathway involved in UV-induced carcinogenesis.21 ERK, JNK and p38 kinases have all been shown to be activated in response to UV radiation through phosphorylation of threonine and tyrosine in the T-X-Y motif of the activation loop.21 Activation of these proteins results in their translocation into the nucleus where they in turn phosphorylate transcription factors leading to the expression of target genes that control cellular pathways such as proliferation, differentiation, development and cell death.21 UV-induced activation of this pathway is an area of interest for melanoma research, as understanding the mechanism by which UV-induced carcinogenesis occurs may result in the development of drugs to target these pathways, which may lead to new treatment options for skin cancers such as melanoma.

Diagnosis and prognosis of melanoma

The early classification of melanoma was based on where the tumor arose from (existing nevus, acquired melanocytic lesion, blemish free skin), but in the 1960s a prominent dermatologist, Wallace Clark, suggested that melanoma ought to be classified based on histological features instead, thus revolutionizing the way melanoma was diagnosed. He initially described three histological variants of melanoma, superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM) and nodular melanoma (NM), and while several new variants such as acral lentiginous melanoma, mucosal melanoma, desmoplastic melanoma and nevoid melanoma have since been described, SSM, LLM and NM are still variants recognized today.14 This was important work as melanoma was once thought of a homogenous disease; Clark was the first to recognize that it is actually a heterogenous disease, to show that the variants behaved differently, had differences in prognosis and that not all melanomas should be treated in the same way.

Level 1: melanoma cells are confined to the epidermis (melanoma in situ)

Level 2: invasion of single cells or very small nests of melanoma into the papillary dermis

Level 3: melanoma cells "fill and expand" the papillary dermis

Level 4: invasion into the reticular dermis

Level 5: invasion into the subcutaneous fat.

The Clark levels still remain a standardized way to convey information related to risk of disease aggressiveness and are reported in melanoma reports by some pathologists, however in 1970 Alexander Breslow independently devised a more accurate method for classifying melanoma based on a measured depth of invasion that captured the thickness of the tumor.12-14,22 Breslow's classification system, known as Breslow's depth, was based on the depth of invasion in millimeters rather than the depth by anatomic compartments, which vary in thickness at different anatomic sites.22 Breslow also initially divided melanoma into five stages:

Stage I: less than or equal to 0.75 mm

Stage II: 0.76 − 1.5 mm

Stage III: 1.51-2.25 mm

Stage IV: 2.26-3.0 mm

Stage V: greater than 3.0 mm. ²²

He showed that patients with thinner melanomas (stages I and II) had a much better chance of survival and a lower risk of regional and distant metastasis.14 This observation allowed for smaller resections than were commonly performed at the time and, like Clark's method, allowed physicians to assess the risk of the melanoma having spread to the lymph nodes and to determine whether lymph node removal was necessary (patients with a Breslow thickness of 1.5 mm or greater were more likely to benefit from prophylactic lymph node dissection). Eventually, modification of measurement cut-offs would be made and incorporated into the staging systems that are still used today to guide treatment and predict prognosis; Breslow depth remains one of the best independent predictors of patient outcome.23

In the 1980s it became clear that using the Clark level and Breslow thickness for prognostic purposes resulted in variation in the predicted outcome and therapeutic recommendations between pathologists, and that new consensus guidelines for reporting melanoma were needed. Over the next 40 years, as data on melanoma patient treatment and survival accumulated and statistical methods improved, new staging systems were created. The American Joint Committee on Cancer (AJCC) has been instrumental in the creation of the TNM (tumor, node, metastasis) staging system. Most major tumor types have their own TNM staging system and melanoma is no exception; multiple committees and taskforces have worked to analyze the every-growing mountain of data on melanoma patient treatment and prognosis and have put together an internationally recognized melanoma database, which is assessed and updated regularly. This database is continually analyzed and used to update the AJCC melanoma TNM staging system. The AJCC staging system provides pathologists and clinicians a guideline for staging patients diagnosed with melanoma. By combining histologic attributes of the primary tumor (T), the presence and extent of regional lymph node disease (N), and the presence and extent of distant metastasis (M), clinicians are able to assign patients a stage grouping that is strongly linked to survival and prognosis. In addition to Breslow depth, attributes of the primary tumor such as ulceration, mitotic rate, tumor-associated inflammation, and regression27 have all been correlated with outcome and therefore incorporated into the AJCC staging system for melanoma.

The most recent revision of the AJCC staging manual (8th edition) was released in 2016 and implemented in 2018.28 Highlights of the evidence-based changes now reflected in current staging criteria include refinements in measurements of tumor thickness, removal of mitotic activity as a reason to upstage a thin melanoma, expansion of the regional lymph node (N) categories based on number of positive regional lymph nodes, expansion of metastasis (M) categories based on location of metastasis, and expanded stage groupings in stage III disease to better stratify long term prognosis.28

Staging is vitally important as it gives clinicians the tools to assess patient prognosis and put together a treatment regimen that will give the patient the best possible chance for recovery or prolonged survival. However, it has long been observed that, though there is an international staging system, the diagnosis of melanoma remains a difficult one to render accurately and consistently. Multiple studies show surprisingly high inter- and intra- observer variability between pathologists in the diagnosis of melanocytic neoplasms, particularly those with ambiguous histologic features.14,15,19,21-23 Much of the variability in diagnosis and prognosis for melanoma is due to the somewhat subjective visual observations used for melanoma diagnosis and prognosis, therefore, research into new, (****)) more objective methods to improve the accuracy and reproducibility in the field of melanoma diagnosis is ongoing.33

To improve detection and diagnosis of melanoma (as well as other cancers), non-invasive imaging technology pre-biopsy and more quantitative techniques post-biopsy, such as fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), sequencing, mass spectrometry (MS) and IHC are being used more frequently.

Non-invasive imaging for melanoma detection

Recent technological advancements have resulted in the emergence of non-invasive imaging technology to detect melanoma. Several smartphone applications, such as SkinVision, UMSkinCheck, and MoleScope, have been developed with purported goals of wide-spread accessibility, cost-effective screening, and ultimately increased early detection for patients. However, multiple studies have shown that these applications are often inaccurate: one study found that 3 out of 4 applications incorrectly classified upwards of 30% of melanomas as low-risk lesions.37 These applications could be a very useful tool for melanoma diagnosis if accuracy could be improved and if strict regulatory oversight was ensured, however, experts caution that reliance on these applications as they are currently available has the potential to harm patients through a false sense of security, potentially resulting in delayed diagnosis. As the technology evolves and becomes more reliable, these applications may become very effective tools for melanoma diagnosis, but at present users should chose applications judiciously to ensure that they are effective.

Other imaging technologies have been developed for use by clinicians as an adjunct to visual screening alone. These devices aim to help clinicians decide whether biopsies are needed for ambiguous lesions. Two devices, MelaFind and SIAscope (Spectrophotometric Intracutaneous Analysis), use visible and near infrared light (~400 nm to ~1000 nm) to visualize lesions and give information to help clinicians decide whether a biopsy is necessary. MelaFind is a fully automatic diagnostic system that was developed in 2010.39 It uses light to visualize skin lesions up to 2.5 mm deep, and provides information on morphologic disorganization of cells in a lesion that can help clinicians decide whether a lesion needs to be biopsied to rule out melanoma.39 Studies have shown that the use of MelaFind results in more accurate biopsy decisions. A study was conducted in 2017 in which 160 board certified dermatologists analyzed 25 melanomas and 25 benign nevi with or without multi-spectral digital skin lesion analysis performed with MelaFind: researchers found that evaluation with MelaFind increased biopsy sensitivity from 76% after clinical evaluation alone to 92%, increased specificity from 52% to 79% and increased overall biopsy accuracy from 64% to 86%.39 Though these results are encouraging, many insurance companies will not cover MelaFind use as they consider it to be experimental, and so patients must pay for the procedure out of pocket, which may dissuade patients from agreeing to its use. As multi-spectral imaging technology becomes more refined and if it continues to provide evidence of cost-savings through more directed biopsy practice, it may find its way into routine clinical use.

SIAscope, a device similar to MelaFind, was developed in 2002. It is capable of measuring collagen, blood and melanin.43 The device shows whether melanin is confined to the epidermis and images the vascular network and pigment composition of a lesion. Early versions of the device had some sensitivity issues with a sensitivity 82.7% and specificity 80.1%, which is similar to sensitivity and specificity of dermatoscopy (visual examination of a pigmented lesion with a handheld magnifier) performed by experienced dermatopathologists. As such, some clinicians have questioned whether it provides enough of a benefit to warrant its use for detecting and diagnosing melanoma.43 However, the device may be useful for improving diagnosis of pigmented lesions by primary care physicians, particularly those practicing in more rural environments without easy access to specialized dermatology care.40

Immunohistochemistry use in melanoma diagnosis

Treatment

Surgical resection

Surgical removal of the tumor and surrounding healthy tissue is the primary treatment for localized melanoma, and sentinel lymph node biopsy is performed in patients whose tumors are greater than 0.8 mm thick or are thinner than this but ulcerated (stage pT1b or greater).13 If melanoma cells are found in the sentinel lymph nodes, then the remaining lymph nodes in the area are sometimes removed. In some situations, metastatic tumors can be surgically removed as well, but surgical treatment in the setting of known metastatic disease is not meant to be curative and will require other treatment options as well.

Chemotherapy

For patients with metastatic disease, surgical treatment alone will not be curative and drug therapies are the next line of defense. Until recently, the only treatment options for patients with metastatic melanoma was chemotherapy. The idea of developing chemical treatments for cancer, or chemotherapies, was first explored in the early 20th century by the German chemistry Paul Ehrlich.12,13,97-99 Ehrlich theorized that chemical agents could target defined sub-populations of cells, and to this end he developed the first primitive alkylating agents.12,13,97-99 Ehrlich, incidentally, was also the first to suggest that immune cells were involved in eliminating transformed cells, though immune-based therapies would not be developed until the end of the 20th century.98

In 1910 George Clowes developed the first transplantable tumor system in rodents, which led to the development of model systems leading to a major breakthrough that allowed researchers and clinicians to screen prospective chemotherapeutic agents in a living organism.97 The early chemotherapy agents developed by Ehrlich and others were largely ineffectual, and it was not until the 1940s that progress was made in the development of chemical agents that were effective for treating cancer.

The use of mustard gas during WWI led to the observation that exposure to these compounds resulted in depletion of the bone marrow and lymph nodes.97 In the 1940s two pharmacologists from Yale, Alfred Gilman and Louis Goodman, were asked by the US Office of Scientific Research and Development, to explore therapeutic uses for these chemicals. Gilman and Goodman found that one mustard compound, nitrogen mustard, effectively treated mice with transplanted lymphoid tumors; nitrogen mustard was then administered to lymphoma patients and a marked regression was observed, however, the regressions did not last and side effects were severe. Regardless, the development of chemotherapeutics made it possible to treat metastatic cancers for the first time in history.

In 1968, the first chemotherapy clinical trials in metastatic melanoma were conducted using the drug 1-phenylalanine mustard, commonly known as melphalan, however, it was not effective and had extremely high toxicity. The first and only chemotherapeutic drug to be approved by the FDA for the treatment of melanoma was dacarbazine in 1975. Until more recently, dacarbazine remained the standard of care for metastatic melanoma, though the response is partial at best, with median survival from 5-11 months and a 1 year survival rate of only 27%. Yet no other chemotherapeutic developed for melanoma treatment since has been more effective or less toxic. Thus, early detection of melanoma was vital for improving patient prognosis, and in the 1960s doctors began to focus on public education about the disease and to stress the importance of regular skin cancer screening, especially for at-risk populations.12

More recent drug discoveries have greatly improved the prognosis for patients with metastatic melanoma, and as targeted therapies and immunotherapies are being used more, chemotherapy is being used much less frequently.

Targeted therapies

Multiple targeted therapies have been developed to combat molecular defects present in melanoma. The most promising of these include the BRAF inhibitors, vemurafenib and dabrafenib, that were approved for the treatment of metastatic and unresectable BRAF-mutated melanomas in 2011 and 2013 respectively. However, though these drugs are highly effective for approximately half of patients with BRAF mutated melanomas, a majority of patients develop secondary resistance within a relatively short amount of time. Some of the mechanisms by which this secondary resistance develops have been discovered, and researchers have been working to develop new drugs and new drug combinations to try to achieve a more lasting effect.12

Immune response in melanoma and immunotherapies

While early and correct diagnosis gives patients their best chance for survival, some melanoma cases will not be diagnosed until the late stages, and so developing new therapies for melanoma treatment is still a priority, and in the last 30 years there have been major breakthroughs in immunotherapy treatments for metastatic melanoma.

The human immune system has the difficult job of distinguishing between self and non-self. To communicate to the cells of the immune system that a somatic cell is a healthy self-cell, all nucleated cells have major histocompatibility complex (MHC) class I proteins on their surfaces. These complexes display epitopes that come from proteins that were expressed and then degraded within the cell. These proteins can either be self-proteins or non-self-proteins. If the epitopes displayed on the MHC class I proteins are non-self, the immune system is alerted that there is a pathogen present within the cell, and the cell needs to be neutralized. Cancer cells are essentially self-cells, but they are highly mutagenic, and the epitopes displayed by MHC proteins on their surfaces can be recognized by immune cells as aberrant, signaling that the cells are diseased and need to be neutralized.71 Melanoma has the highest rate of mutations of any cancer,102 and as a result, they produce a wide range of tumor antigens that are recognized by the immune system and are highly immunogenic. Tumor antigens are classed into two groups; tumor associated antigens (TAA), which are mostly found in tumor cells though are expressed in normal cells as well, and tumor specific antigens (TSA), which are solely expressed in tumor cells.71 Melanoma tumors also have a group of antigens specific to melanoma cells; these antigens are involved in melanoma differentiation and are called melanoma differentiation antigens (MDA). TAAs, TSAs and MDAs are all proteins that are displayed on MHC class I proteins on melanoma cell surfaces, which can alert the immune system that the cells are diseased.

The antigens displayed on the MHC class I proteins are recognized by T-cell receptors (TCR) found on CD8+ cytotoxic T lymphocytes (CTL), which can kill cells that are non-self or diseased self-cells. MHC class II proteins are present on the surface of antigen presenting cells (APCs) such as macrophages and dendritic cells. APCs take up extracellular proteins from the environment and display them to CD4 + T helper (Th) cells, which then activates an immune response to specific antigens.

Once the immune system has been alerted to the presence of non-self or diseased self-cells, lymphocytes invade the tissue and begin to kill the aberrant cells. These lymphocytes, when histologically visualized in the microscope in the evaluation of a tumor, are called tumor infiltrating lymphocytes (TILs), and the number of TILs present in a tumor is a prognostic indicator in some tumors, including melanomas.71 If there are no TILs present in a tumor, this is a sign that the tumor has successfully evaded the immune system and correlates with a worse prognosis. The battle between the immune system and malignant tumors, therefore, comes down to a tumor's ability to evolve mechanisms to escape immune detection before the immune system can destroy the tumor. This process is known as immune editing.

There are three phases of immune editing: elimination, equilibrium and evasion.103 During the elimination phase, natural killer (NK), dendritic cells (DC), CTLs and B cells enter the tumor microenvironment or peripheral tissue and begin killing cancer cells faster than they can grow.103 In the equilibrium phase the cancer cells are constantly growing but are suppressed by the immune cells, therefore, the growth and expansion of cancer cells is counterbalanced by the immune system.103 Finally, if tumors enter the evasion phase of immune editing, tumor cells are able to develop strategies to neutralize the immune response enabling them to grow unchecked.

Due to the highly mutagenic nature of melanoma cells, they quickly develop mechanisms to evade the immune response. Particularly virulent melanoma tumors have even been shown to have reduced levels of MHC class I proteins on the cell surfaces, thereby reducing antigen presentation. It has been shown that some melanomas downregulate TAAs and MDAs, which inhibits recognition and clearance of tumor cells by CTLs. Melanomas have also been shown to secrete immune inhibitory molecules like transformation growth factor beta (TGF-β), prostaglandin E2 (PGE2) and immune suppressive cytokines.26,51,71,105

Another common way that melanoma cells avoid immune detection is through manipulation of immune checkpoints. On the surface of T-cells there is a protein called the programed cell death protein 1 (PD-1).103 When an immune cell recognizes the PD-1 ligand (PD-L1/2) on the surface of somatic cells, this further communicates to the immune cells that the cell is a self-cell leading to inhibition of the immune system, promoting self-tolerance and preventing autoimmunity.103 The PD-1 immune checkpoint normally regulates the immune system by inducing apoptosis of maturing T-cells that recognize self-antigens in the lymph nodes.103 PD-1 also prevents apoptosis of regulatory T-cells, which are anti-inflammatory cells that repress the immune response to self-cells.103 This mechanism normally protects tissue from damage during anti-microbial immune responses, however, PD-L1/2 is commonly overexpressed in cancers, including melanoma, enabling tumor cells to effectively "turn off" the immune response and evade immune destruction.

As knowledge of the immune system's response to cancer, and the mechanisms by which cancer cells evade the immune system has grown, new therapies have been developed to try to redirect the immune system and stimulate an anti-tumor response. There are three main types of immune treatments for cancer: cancer vaccines, adoptive cell therapies and immunomodulatory strategies.

One of the first immune therapies developed for metastatic melanoma was an interleukein-2 (IL2) treatment that was approved for use in 1992. IL-2 is a pro-proliferative cytokine, which promotes expansion of melanoma specific T-cells. IL-2 treatments elicited a response in a small percent of patients, with 6% showing a complete response.12,98,104,107-109 At the time, even such a small response was considered promising, but IL-2 treatment proved to be highly toxic, and more recent treatments have shown to be less toxic and more effective.

In the 1990's researchers also started developing cancer vaccines. Cancer vaccines, unlike prophylactic vaccines that are administered to healthy people to prevent disease, are therapeutic vaccines administered to patients in the late stages of cancer to try to sensitize the immune system to cancer antigens. Creating effective therapeutic cancer vaccines is challenging, however, due to the adaptations that allow cancer cells to hide from the immune system. Several melanoma vaccines were developed and tested in the 1990s and early 2000s, however, none of the early vaccines developed were effective and no melanoma vaccines have been approved for clinical use.

The most effective treatments for metastatic melanoma to date are the immune checkpoint inhibitors, the first of which was approved for clinical use in 2011. Melanoma manipulation of immune checkpoints can be overcome by treatment with antibodies against PD1, PD-L1/2 and CTLA-4 ( Figure 2). Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is another immune checkpoint receptor that acts in a comparable way to PD-1. CTLA-4 is constitutively expressed on T-reg cells and recognizes B7-1/2 receptor on APCs. CTLA-4 competes with CD28 on T-cells for binding to B7-1/2; when CD28 binds B7-1/2 an immune response is activated while CTLA-4 binding represses the immune response. Treatment with antibodies to PD-1, PD-L1/2 and CTLA-4 effectively block binding to the respective ligands and the corresponding signal that causes tolerance, allowing for stimulation of an immune response.71,98,106,114,115

There are three immune checkpoint inhibitor drugs that have been approved for use in melanoma treatment: the anti-CTLA-4 antibody ipilimumab and two anti-PD-1 antibodies nivolumab and pembrolizumab.106 There are also several PD-L1/2 antibody drugs currently in clinical trials, and a few that have been approved for clinical use, though not for melanoma.106

Treatment with iplimumab showed durable survival of up to 10 years in 20% of cases; compared to the median survival rate of less than one year in stage IV melanoma patients, this is a great advancement. Pembrolizumab has a response rate of ~37-38% in patients with metastatic melanoma, and an overall survival of 74% at 12 months.118 Treatment with nivolumab showed a ~40% response rate with a 12 month overall survival rate of 73% compared to 43% of patients treated with dacarbazine.109 Ipilimumab combined with nivolumab treatment has resulted in a ~57% response rate and 11.5 months of progression free survival.

While checkpoint inhibiters are promising, there are necessarily complications involved in inhibiting mechanisms that promote tolerance of self-cells. Therefore, the side-effects of checkpoint inhibiters can be severe. The side effects are typically immune-related inflammatory conditions of the skin, GI system, and endocrine organs. Recognizing and managing side effects of the these treatments is important, and though the toxicity of these drugs can be offset in some cases by treatment with corticosteroids, some patients cannot tolerate the side-effects and treatment must be terminated.120

Though immune checkpoint inhibitors have been a breakthrough for cancer therapeutics and have revolutionized the treatment of metastatic melanoma, a significant subset of patients still does not respond to these drugs, and many patients who do respond develop a secondary resistance. Research into why some patients respond and other do not is ongoing. As treatments are expensive and side effects can be severe, there is great interest in finding biomarkers that can predict whether a patient will respond to treatment or not. Research into other drug targets is also a priority as it is clear that there is no "magic bullet" for melanoma, and a more personalized medicine approach is needed.

Conclusion

Melanoma is an incredibly virulent disease. It is a heterogenous and complex disease, which can make it difficult to diagnose and treat. Understanding the mechanisms that lead to melanomagenesis and allow melanomas to evade the immune system will give us new strategies for diagnosis and treating the disease. Furthermore, new technologies that can provide more objective methods for diagnosing and prognosticating melanoma are being developed, which will improve patient outcomes.

Over the last 20 years the use of IHC as an ancillary test in the diagnosis of melanoma has increased. The development of robust sensitive and specific cancer biomarkers in the field of tissue immunohistochemistry remains a focus of research. Though it can be a useful tool for diagnostic (and possibly prognostic) purposes, this technique has its shortcomings. IHC scoring can be subjective, and thus developing diagnostic systems using multiple biomarkers will require coincident development of strict interpretation criteria and standardization procedures to ensure reproducibility from laboratory to laboratory and between pathologists. Though IHC is a useful method for biomarker recognition, newer, more objective and repeatable methods are currently being developed and could potentially revolutionize the way cancers like melanoma are diagnosed.

The treatment of metastatic melanoma has greatly improved in recent years with the introduction of treatments such as BRAF, CTLA4 and PD1 inhibitors. Some of the mechanism by which secondary resistance develops have been discovered, and researchers have been working to develop new drugs and new drug combinations to try to achieve a more lasting effect.12 Research into how and why these treatments succeed or fail is ongoing. Biomarker discovery for the prediction of patients who will or will not respond is a priority with the hope that eventually clinicians will be able to stratify patients and develop more personalized treatments based on mutational and biomarker profiles. Developing a more personalized approach to treating melanoma patients will not only improve prognosis, it will also cut down on the cost of treatment . Drugs that will not help a patient will not be administered, and it will also reduce patient suffering due to side effects of treatments that will be ineffective for them.

Metastatic melanoma has long been one of the most virulent and deadly diseases, which has, until recently, evaded all attempts at treatment. However, we are beginning to understand the underlying genetic and mechanistic causes of the disease, allowing for the development of more effective therapies and giving hope that one day, a cure may be within reach.

Acknowledgments

We acknowledge support from NIH grant P20GM121293 (AJT), the Scharlau Family Endowed Chair in Cancer Research to AJT, and the UAMS Experimental Pathology Core.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Additional information

Funding

This work was supported by the National Institutes of Health [P20GM121293].

References

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Moncrieff M . Use of a spectrophotometric intracutaneous analysis device in the real-time diagnosis of melanoma. 2008; doi:10.1111/j.1365-2133.2007.08325.x.

Kaufmann SHE . Paul Ehrlich: founder of chemotherapy. Nat Rev Drug Discovery. 2008;7:373. doi:10.1038/nrd2582.

Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US, White DE, Levy CL, Rosenberg SA, Phan GQ. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res. 2012;18(7):2039-2047. doi:10.1158/1078-0432.CCR-11-1823.

Fellner C . Ipilimumab (yervoy) prolongs survival in advanced melanoma: serious side effects and a hefty price tag may limit its use. P & T. 2012;37(9):503-530.

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Current state of melanoma diagnosis and treatment

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ABSTRACT ABSTRACT Melanoma is the deadliest form of skin cancer. In the early stages, melanoma can be treated successfully with surgery alone and survival rates are high, but after metastasis survival rates drop significantly. Therefore, early and correct diagnosis is key for ensuring patients have the best possible prognosis.

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Doctors' Circle - World's Largest Health Platform

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Difference between Melanoma and other skin pigmentations - Dr. Rajdeep Mysore

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Melanoma is a specific kind of skin cancer. It begins in skin cells called melanocytes. Melanocytes produce melanin, the substance that gives your skin color.

Only about of skin cancers are melanomas. Melanoma is also called malignant melanoma or cutaneous melanoma.

When melanoma is diagnosed in the early stages, most people respond well to treatment. But when not caught early, it spreads easily to other parts of the body.

Early signs and symptoms of melanoma are:

changes to an existing mole

the development of a new, unusual growth on your skin

If melanoma cells are still making melanin, the tumors tend to be brown or black. Some melanomas don't make melanin, so those tumors can be tan, pink, or white.

Clues that a mole might be melanoma are:

irregular shape

irregular border

multicolored or uneven coloring

larger than a quarter of an inch

changes in size, shape, or color

itchiness or bleeding

Melanoma can start anywhere on your skin. The most likely areas, though, are:

This may be because these areas have more exposure to the sun than other parts of the body. Melanoma can form in areas that don't receive much sun, such as the soles of your feet, palms of your hands, and fingernail beds.

Sometimes, the skin will appear normal even though melanoma has begun to develop.

The most common type of melanoma is superficial spreading melanoma. It tends to spread across the surface of the skin, has uneven borders, and varies in color from brown to black, pink, or red.

Nodular melanoma is another type that grows down into deeper layers of the skin and may appear as a raised bump or growth.

Lentigo maligna melanoma tends to appear on parts of the body that get more sun, especially the face, and it often affects older people. It looks like a large, uneven dark patch on the surface of the skin.

Metastatic melanoma occurs when the cancer spreads, or metastasizes, to other parts of the body, possibly including the lymph nodes, organs, or bones.

Other rare types of melanoma also exist, and while it most commonly affects the skin, some affect internal tissues, as well as the eyes.

Mucosal melanoma can develop in the mucous membranes that line the:

Eye melanoma, also known as ocular melanoma, can occur underneath the white of the eye.

Ultraviolet light

It's not entirely clear what causes melanoma, but exposure to the sun and other sources of ultraviolet light, like tanning beds, is a very important risk factor.

Race

The American Cancer Society states that the lifetime risk of developing melanoma is about:

2.6% for white people

0.1% for Black people

0.6% for Hispanic people

Melanoma is reportedly 20 times more common in white people than Black people. Keep in mind that this data may be due to inequities in healthcare and other contributing factors.

Besides skin with less pigment, having many moles may also be a risk factor.

Genetics/family history

If a parent or sibling has had melanoma in the past, you may have a higher chance of developing melanoma.

Age

The risk of melanoma grows as you age. The average age at diagnosis is 65, even though it's one of the most common cancers among young adults.

Cancer staging tells you how far cancer has grown from where it originated. Cancer can spread to other parts of the body through tissue, the lymph system, and the bloodstream.

Melanoma is staged as follows:

Stage 0

You have abnormal melanocytes, but only on the outermost layer of skin (epidermis). This is also called melanoma in situ.

Stage 1

1A: You have a cancerous tumor, but it's less than 1 millimeter (mm) thick. It has no ulceration.

1B: The tumor is less than 1 mm thick, but it has ulceration. Or, it's between 1-2 mm thick with no ulceration.

Stage 2

2A: The tumor is between 1-2 mm thick with ulceration. Or, it's between 2-4 mm thick without ulceration.

2B: The tumor is between 2-4 mm and is ulcerated. Or it's thicker than 4 mm without ulceration.

2C: The tumor is over 4 mm thick and is ulcerated.

Stage 3

You have a tumor of any size that may or may not be ulcerated. At least one of these is also true:

cancer has been found in at least one lymph node

lymph nodes are joined together

cancer has been found in a lymph vessel between the tumor and the closest lymph nodes

cancer cells have been found more than 2 centimeters (cm) from the primary tumor

other tiny tumors have been discovered on or under your skin within 2 cm of the primary tumor

Stage 4

Cancer has spread to distant sites. This can include soft tissue, bone, and organs.

Treatment depends on the stage of melanoma.

Stage 0

Stage 0 melanoma only involves the top layer of skin. It's possible to completely remove the suspicious tissue during a biopsy. If not, your surgeon can remove it, along with a border of normal skin.

You may not need further treatment.

Stage 1 and 2

Very thin melanomas can be completely removed during biopsy. If not, they can be surgically removed later. This involves removing the cancer along with a margin of healthy skin and a layer of tissue underneath the skin.

Early-stage melanoma doesn't necessarily require additional treatment.

Stage 3 and 4

Stage 3 melanoma has spread away from the primary tumor or into nearby lymph nodes. Wide-excision surgery is used to remove the tumor and affected lymph nodes.

In stage 4 melanoma, cancer has spread to distant sites. The skin tumors and some enlarged lymph nodes can be surgically removed. You can also have surgery to remove tumors on internal organs. But your surgical options depend on the number, size, and location of tumors.

Stages 3 and 4 generally require some additional treatments, which may involve:

Immunotherapy drugs. These may include interferon or interleukin-2 or checkpoint inhibitors, such as ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda).

Targeted therapy for those cancers related to mutations in the BRAF gene. These may include cobimetinib (Cotellic), dabrafenib (Tafinlar), trametinib (Mekinist), and vemurafenib (Zelboraf).

Targeted therapy for melanoma related to mutations in the C-KIT gene. These may include imatinib (Gleevec) and nilotinib (Tasigna).

Vaccines. These may include Bacille Calmette-Guerin (BCG) and T-VEC (Imlygic).

Radiation therapy. This can be used to shrink tumors and to kill cancer cells that may have been missed during surgery. Radiation can also help relieve symptoms of cancer that has metastasized.

Isolated limb perfusion. This involves infusing only the affected arm or leg with a heated solution of chemotherapy.

Systemic chemotherapy. This may include dacarbazine (DTIC) and temozolomide (Temodar), which may be used to kill cancer cells throughout your body.

Immunotherapy and targeted therapies haven't been shown to cure melanoma, but they can increase life expectancy. Chemotherapy for melanoma can shrink tumors, but they can recur within a few months.

Each type of therapy comes with its own set of side effects, some of which can be serious. It's important to discuss these with your doctor so you can make an informed choice.

Clinical trials can help you get innovative therapies not yet approved for general use. If you're interested in a clinical trial, talk to your doctor.

Normally, healthy new skin cells nudge older skin cells toward the surface, where they die.

DNA damage within the melanocytes can cause new skin cells to grow out of control. As the skin cells build up, they form a tumor.

It's not entirely clear why DNA in skin cells gets damaged. It may be a combination of genetic and environmental factors.

The leading cause may be exposure to ultraviolet (UV) radiation. UV radiation can come from such sources as natural sunlight, tanning beds, and tanning lamps.

Physical examination

First, you'll need a thorough examination of your skin. Most of us have between 10 and 40 moles as adults.

A normal mole usually has a uniform color and a clear border. They can be round or oval, and are generally less than a quarter of an inch in diameter.

A good skin examination will involve looking in less obvious places, such as:

between the buttocks

genitals

palms and under your fingernails

scalp

soles of your feet, between your toes, and under your toenails

Blood chemistry studies

Your doctor can check your blood for lactate dehydrogenase (LDH). Levels of this enzyme can be higher than normal when you have melanoma.

LDH levels may not be checked for early stage disease.

Skin biopsy

A skin biopsy is the only way to confirm melanoma. For a biopsy, a sample of the skin is removed. If at all possible, the entire suspected area should be removed. Then, the tissue is sent to a lab for examination under a microscope.

The pathology report will be sent to your doctor who will explain the results.

If there's a diagnosis of melanoma, it's important to determine the stage. This will provide information on your overall outlook and help guide treatment.

The first part of staging is to find out how thick the tumor is. This can be done by measuring the melanoma under a microscope.

Lymph node biopsy

If you have a diagnosis, your doctor may need to find out if cancer cells have spread, though they won't do this for melanoma in situ. The first step is to perform a sentinel node biopsy.

For the surgery, a dye will be injected into the area where the tumor was. This dye will naturally flow to the nearest lymph nodes. The surgeon will remove the lymph nodes to test them for cancer.

If no cancer is found in the sentinel nodes, the cancer probably hasn't spread outside the area that was originally tested. If cancer is found, the next set of nodes may be tested.

Imaging tests

Imaging tests are used to see if cancer has spread beyond the skin to other parts of the body.

CT scan. Before the scan, you'll have a dye injected into a vein. A series of X-rays will be taken at different angles. The dye will help highlight organs and tissues.

MRI. For this test, a substance called gadolinium is injected into a vein. The scanner uses magnet and radio waves to take pictures, and the gadolinium causes cancer cells to brighten.

PET scan. This test requires a small amount of radioactive glucose to be injected into a vein. Then, the scanner will rotate around your body. Cancer cells use more glucose, so they're highlighted on the screen.

It's natural to want to research survival rates, but it's important to understand that they're generalizations. Your circumstances are unique to you, so speak to your doctor about your own prognosis.

Based on data from 2010 to 2016, the 5-year relative survival rates for melanoma of the skin in the United States are 92.7 percent overall, and:

99% for localized melanoma

66.3% for regional spread

27.3% for distant metastasis

About 83 percent of the time, melanoma is diagnosed at the local stage.

While you can't completely eliminate risk, here are a few ways to help prevent melanoma and other skin cancers from developing:

Avoid exposing your skin to the midday sun whenever possible. Remember, the sun still affects your skin on cloudy days and in winter.

Use sunscreen. Use a broad-spectrum sunscreen with an SPF of at least 30. Reapply every 2 hours or more often if you perspire a lot or go in the water. Do this regardless of the season.

Cover up. When spending time outdoors, keep your arms and legs covered. Wear a broad-brimmed hat to protect your head, ears, and face.

Wear sunglasses that protect from UVA and UVB rays.

Don't use tanning beds or tanning lamps.

When it comes to your own outlook, survival rates are only rough estimates. Your doctor can offer you a more individualized assessment.

Some factors that can affect your outlook are:

Age. Older people tend to have shorter survival times.

General health. You may not do as well with treatment if you have a weakened immune system or other underlying health problems.

As you can see from the relative survival rates above, many people survive melanoma. Later-stage melanoma is harder to treat, but it's possible to survive many years after diagnosis.

Every year in the United States, 22 out of every 100,000 people receive a diagnosis of melanoma. The sooner it's diagnosed and treated, the better your outlook.

Your chances of early diagnosis may be greater if you:

Check your body regularly for new growths. Note size, shape, and color changes to existing moles, freckles, and birthmarks. Don't forget to check the bottoms of your feet, between your toes, and nail beds. Use a mirror to check hard-to-see areas such as genitals and between your buttocks. Take photos to make it easier to spot changes. And report any suspicious findings to your doctor right away.

See your primary care physician every year for a complete physical. If your doctor doesn't check your skin, request it. Or, ask for a referral to a dermatologist.

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Everything You Need to Know About Melanoma

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Melanoma is a specific kind of skin cancer. It begins in skin cells called melanocytes. Melanocytes produce melanin, the substance that gives your skin color. Only about of skin cancers are melanomas. Melanoma is also called malignant melanoma or cutaneous melanoma. When melanoma is diagnosed in the early stages, most people respond well to treatment.

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Skin Cancer Signs: The ABCDEs of Melanoma

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If you've been diagnosed with melanoma, your cancer care team will discuss your treatment options with you. It's important to weigh the benefits of each treatment option against the possible risks and side effects.

How is melanoma skin cancer treated?

Who treats melanoma skin cancer?

Depending on your options, you may have different types of doctors on your treatment team. These doctors may include:

A dermatologist: a doctor who treats diseases of the skin

A surgical oncologist (or oncologic surgeon): a doctor who uses surgery to treat cancer

A medical oncologist: a doctor who treats cancer with medicines such as chemotherapy, immunotherapy, or targeted therapy

A radiation oncologist: a doctor who treats cancer with radiation therapy

Many other specialists may be involved in your care as well, including  physician assistants (PAs), nurse practitioners (NPs), nurses, psychologists, social workers, rehabilitation specialists, and other health professionals.

Health Professionals Associated with Cancer Care

Making treatment decisions

It’s important to discuss all of your treatment options as well as their possible side effects with your treatment team to help make the decision that best fits your needs. Some important things to consider include:

Your age and overall health

The stage (extent) of your cancer

The likelihood that treatment will cure your cancer or help in some other way

The possible side effects from treatment

You may feel that you need to make a decision quickly, but it’s important to give yourself time to absorb the information you have just learned. Ask questions if there is anything you’re not sure about.

If time permits, it is often a good idea to seek a second opinion. A second opinion can give you more information and help you feel more confident about the treatment plan you choose.

Questions to Ask About Melanoma Skin Cancer

Seeking a Second Opinion

Thinking about taking part in a clinical trial

Clinical trials are carefully controlled research studies that are done to get a closer look at promising new treatments or procedures. Clinical trials are one way to get state-of-the art cancer treatment. In some cases they may be the only way to get access to newer treatments. They are also the best way for doctors to learn better methods to treat cancer. Still, they're not right for everyone.

If you would like to learn more about clinical trials that might be right for you, start by asking your doctor if your clinic or hospital conducts clinical trials.

Clinical Trials

Considering complementary and alternative methods

You may hear about alternative or complementary methods that your doctor hasn’t mentioned to treat your cancer or relieve symptoms. These methods can include vitamins, herbs, and special diets, or other methods such as acupuncture or massage, to name a few.

Complementary methods refer to treatments that are used along with your regular medical care. Alternative treatments are used instead of a doctor’s medical treatment. Although some of these methods might be helpful in relieving symptoms or helping you feel better, many have not been proven to work. Some might even be harmful.

Be sure to talk to your cancer care team about any method you are thinking about using. They can help you learn what is known (or not known) about the method, which can help you make an informed decision.

Complementary and Integrative Medicine

Help getting through cancer treatment

People with cancer need support and information, no matter what stage of illness they may be in. Knowing all of your options and finding the resources you need will help you make informed decisions about your care.

Whether you are thinking about treatment, getting treatment, or not being treated at all,  you can still get supportive care to help with pain or other symptoms. Communicating with your cancer care team is important so you understand your diagnosis, what treatment is recommended, and ways to maintain or improve your quality of life.

Different types of programs and support services may be helpful, and can be an important part of your care. These might include nursing or social work services, financial aid, nutritional advice, rehab, or spiritual help.

The American Cancer Society also has programs and services – including rides to treatment, lodging, and more – to help you get through treatment. Call our National Cancer Information Center at 1-800-227-2345 and speak with one of our trained specialists.

Palliative Care

Programs & Services

Choosing to stop treatment or choosing no treatment at all

For some people, when treatments have been tried and are no longer controlling the cancer, it could be time to weigh the benefits and risks of continuing to try new treatments. Whether or not you continue treatment, there are still things you can do to help maintain or improve your quality of life.

Some people, especially if the cancer is advanced, might not want to be treated at all. There are many reasons you might decide not to get cancer treatment, but it’s important to talk to your doctors and you make that decision. Remember that even if you choose not to treat the cancer, you can still get supportive care to help with pain or other symptoms.

If Cancer Treatments Stop Working

The treatment information given here is not official policy of the American Cancer Society and is not intended as medical advice to replace the expertise and judgment of your cancer care team. It is intended to help you and your family make informed decisions, together with your doctor. Your doctor may have reasons for suggesting a treatment plan different from these general treatment options. Don't hesitate to ask your cancer care team any questions you may have about your treatment options.

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Treating Melanoma Skin Cancer | How Is Melanoma Treated?

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If you have been diagnosed with melanoma, learn about the different types of melanoma treatment options including surgery, immunotherapy and targeted therapy.

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Types

There are four different types of melanoma cancer. Three of them begin 'in situ', which means they occupy and spread in the top layer of the skin and can become invasive. The fourth type is invasive from the start.

Superficial spreading melanoma is the most common of the melanomas. It is seen mostly in young people and accounts for 70% of all cases. It grows along the top layer of the skin for quite a long time before penetrating deeper layers. The first sign of this cancer is usually a flat or slightly raised discolored patch with irregular borders and asymmetrical shape. It can form anywhere on the body. It is most often found on the trunk in men and on the legs in women or on the upper back in both.

Superficial spreading melanoma

Lentigo maligna remains on the skin's surface for quite a long time before it spreads to the deeper layers. It also appears as a flat or slightly elevated discoloration that is usually tan, brown, or dark brown. It is most commonly found in the elderly on the face, ears, arms and upper trunk.

Acral lentiginous melanoma, like the two types discussed previously, spreads superficially before it penetrates deeper. However, it usually appears as a black or brown discoloration on the soles of the feet or palms of the hands. It can also appear under the nails on hands and feet. This type of melanoma is most common in African-Americans and Asians and least common in Caucasians.

Nodular melanoma is usually invasive at the time of diagnosis. It is recognized when it becomes a bump or lump. It is most frequently found on the trunk, legs, arms, and scalp in men. It is more common in elderly people. It usually appears as black but can also be blue, gray, white, brown, tan, red or skin tone. It is the most aggressive of the melanoma and accounts for 10 to 15% of all cases.

Nodular melanoma showing changes over time

Stages

Once the diagnosis of melanoma has been made, the next step is to classify the disease on its level of severity. Classifications for melanomas and other cancers are called stages. The stage of cancer refers to the thickness, depth of penetration, and local of metastasis if present. Stages range from 0, which means localized and has not spread, to IV, which means it has metastasized to other parts of the body.

Stages 0 and I are early melanomas and are the most easily treated. They are localized and 'in situ', which means they have not penetrated to deeper layers of the skin. Stage I tumors have invaded the skin, but are small and growing at a slow rate.

Stage II tumors are still localized but are larger, usually over 1 mm thick. They are considered intermediate melanomas; meaning not advanced but not early stage either.

Stages III and IV and advanced melanomas and have spread, or metastasized, either to deeper layers of the skin or to other parts of the body.

Symptoms

There are many symptoms of melanoma. Most people need yearly skin checks to check for these symptoms, but groups at higher risk may need checks more frequently. It is also important for people to regularly examine their own skin, including moles. The following symptoms are the ABCDE's of melanoma:

A - asymmetry. If a line is drawn through the center of a mole, each half should look the same as the other. If this is not the case, then the mole is asymmetrical and needs to be looked at by a doctor.

B - border. The border of melanoma tends to be uneven. The edges may be raised or notched.

C - color. The color of a mole should be uniform throughout. If a mole has darker areas than others or the color seems to be changing in any way, then it needs to be looked at by a doctor.

D - diameter. Melanomas are usually larger than the eraser on a pencil (1/4 in. or 6mm.).

E - evolving. Any change in a mole or other area of skin is a symptom or warning sign of melanoma. Changes in size, shape, color, or elevation need to be addressed. Also, other symptoms include bleeding, itching, or crusting.

Pictures of melanomas on the left vs. normal moles on the right

Treatment

Treatment options depend on the type of melanoma and the stage of disease. The following are different treatments used to treat melanoma:

Surgery

With this treatment, an excision of the tumor will be made to remove it. The doctor will excise a small amount of healthy tissue on all sides of the excision to make sure all the melanoma tissue is removed.

Sometimes further surgery is necessary, especially in cases where the melanoma has spread. This may include deeper excisions or removal of nearby lymph nodes. If cancer has spread beyond the lymph nodes to other organs, it is unlikely that surgery can cure the cancer. Doctors may still perform surgery if tumors are painful or interfering with quality of life.

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Rates of melanoma, the deadliest form of skin cancer, have been rising for at least the last three decades, and this increase has been largely blamed on exposure to ultraviolet (UV) light from the sun.

However, research published in the British Journal of Dermatology shows that the sun is likely nothing more than a scapegoat in the development of melanoma, and the sharp increase may actually be "an artifact caused by diagnostic drift."

Melanoma Increases Due to Benign Disease, Not Sunlight

Diagnostic drift, according to the study, refers to a hefty increase in disease that is being fueled by non-cancerous lesions.

In fact, during the study period from 1991 to 2004, there were nearly 4,000 cases of melanoma included in the report, with an annual increase of 9.39 to 13.91 cases per 100,000 per year.

The researchers revealed that, rather than being fueled by increasing exposure to sunlight as is commonly suggested, the increased incidence was almost entirely due to minimal, stage 1 disease.

They noted:
"There was no change in the combined incidence of the other stages of the disease, and the overall mortality only increased from 2.16 to 2.54 cases per 100,000 per year ... We therefore conclude that the large increase in reported incidence is likely to be due to diagnostic drift, which classifies benign lesions as stage 1 melanoma."
In other words, people are being diagnosed with melanoma skin cancer even when they have only a minimal, non-cancerous lesion, and these diagnoses appear to be skewing disease rates significantly. Further, adding even more credence to the growing body of evidence showing sun exposure is not the primary cause of melanoma, the researchers noted that the distribution of the lesions reported did not correspond to the sites of lesions caused by sun exposure.

They concluded:
"These findings should lead to a reconsideration of the treatment of 'early' lesions, a search for better diagnostic methods to distinguish them from truly malignant melanomas, re-evaluation of the role of ultraviolet radiation and recommendations for protection from it, as well as the need for a new direction in the search for the cause of melanoma."
Is Lack of Sunlight a More Likely Culprit?

Despite all the bad press linking sun exposure to skin cancer, there's almost no evidence at all to support it. There is, however, plenty of evidence to the contrary. Over the years, several studies have confirmed that appropriate sun exposure actually helps prevent skin cancer. In fact, melanoma occurrence has been found to decrease with greater sun exposure, and can be increased by sunscreens.

One of the most important facts you should know is that an epidemic of the disease has in fact broken out among indoor workers. These workers get three to nine times LESS solar UV exposure than outdoor workers get, yet only indoor workers have increasing rates of melanoma - and the rates have been increasing since before 1940.

There are two major factors that help explain this, and the first has to do with the type of UV exposure.

There are two primary types of UV rays from sunlight, the vitamin-D-producing UVB rays and the skin-damaging UVA light. Both UVA and UVB can cause tanning and burning, although UVB does so far more rapidly. UVA, however, penetrates your skin more deeply than UVB, and may be a much more important factor in photoaging, wrinkles and skin cancers.

A study in Medical Hypotheses suggested that indoor workers may have increased rates of melanoma because they're exposed to sunlight through windows, and only UVA light, unlike UVB, can pass through window glass. At the same time, these indoor workers are missing out on exposure to the beneficial UVB rays, and have lower levels of vitamin D.

Researchers wrote:
"We hypothesize that one factor involves indoor exposures to UVA (321-400nm) passing through windows, which can cause mutations and can break down vitamin D3 formed after outdoor UVB (290-320nm) exposure, and the other factor involves low levels of cutaneous vitamin D3. After vitamin D3 forms, melanoma cells can convert it to the hormone, 1,25-dihydroxyvitamin D3, or calcitriol, which causes growth inhibition and apoptotic cell death in vitro and in vivo. ... We agree that intense, intermittent outdoor UV overexposures and sunburns initiate CMM [cutaneous malignant melanoma]; we now propose that increased UVA exposures and inadequately maintained cutaneous levels of vitamin D3 promotes CMM."
To put it simply, UVB appears to be protective against melanoma - or rather, the vitamin D your body produces in response to UVB radiation is protective.

As written in The Lancet:
"Paradoxically, outdoor workers have a decreased risk of melanoma compared with indoor workers, suggesting that chronic sunlight exposure can have a protective effect."
Vitamin D Helps Protect You Against Cancer

Vitamin D is a steroid hormone that influences virtually every cell in your body, and is easily one of nature's most potent cancer fighters. So I want to stress again that if you are shunning all sun exposure, you are missing out on this natural cancer protection.

Your organs can convert the vitamin D in your bloodstream into calcitriol, which is the hormonal or activated version of vitamin D. Your organs then use it to repair damage, including damage from cancer cells and tumors. Vitamin D's protective effect against cancer works in multiple ways, including:

Increasing the self-destruction of mutated cells (which, if allowed to replicate, could lead to cancer)

Reducing the spread and reproduction of cancer cells

Causing cells to become differentiated (cancer cells often lack differentiation)

Reducing the growth of new blood vessels from pre-existing ones, which is a step in the transition of dormant tumors turning cancerous

This applies not only to skin cancer but other types of cancer as well. Theories linking vitamin D to certain cancers have been tested and confirmed in more than 200 epidemiological studies, and understanding of its physiological basis stems from more than 2,500 laboratory studies, according to epidemiologist Cedric Garland, DrPH, professor of family and preventive medicine at the UC San Diego School of Medicine.

Here are just a few highlights into some of the most noteworthy findings:

Some 600,000 cases of breast and colorectal cancers could be prevented each year if vitamin D levels among populations worldwide were increased, according to previous research by Dr. Garland and colleagues.

Optimizing your vitamin D levels could help you to prevent at least 16 different types of cancer including pancreatic, lung, ovarian, prostate, and skin cancers.

A large-scale, randomized, placebo-controlled study on vitamin D and cancer showed that vitamin D can cut overall cancer risk by as much as 60 percent. This was such groundbreaking news that the Canadian Cancer Society has actually begun endorsing the vitamin as a cancer-prevention therapy.

Light-skinned women who had high amounts of long-term sun exposure had half the risk of developing advanced breast cancer (cancer that spreads beyond your breast) as women with lower amounts of regular sun exposure, according to a study in the American Journal of Epidemiology.

A study by Dr. William Grant, Ph.D., internationally recognized research scientist and vitamin D expert, found that about 30 percent of cancer deaths - which amounts to 2 million worldwide and 200,000 in the United States - could be prevented each year with higher levels of vitamin D.

When Using the Sun to Fight Cancer, the Dose is What Matters

When I recommend using the sun therapeutically, this means getting the proper dosage to optimize your vitamin D levels. This typically means exposing enough of your unclothed skin surface to get a slight pink color on your skin. Your exact time will vary radically depending on many variables, such as you skin color, time of day, season, clouds, altitude and age. The key principle is to never get burned, while still spending as much time as you can in the sun during the peak hours, as it is virtually impossible to overdose as long as you don't get burned.

A common myth is that occasional exposure of your face and hands to sunlight is "sufficient" for vitamin D nutrition. For most of us, this is an absolutely inadequate exposure to move vitamin D levels to the healthy range. Further, if you use sunscreen, you will block your body's ability to produce vitamin D!

And, contrary to popular belief, the best time to be in the sun for vitamin D production is actually as near to solar noon as possible which is 1 PM in the summer for most (due to Daylight Saving Time).. The more damaging UVA rays are quite constant during ALL hours of daylight, throughout the entire year - unlike UVB, which are low in morning and evening and high at midday.

When using the sun to maximize your vitamin D production and minimize your risk of malignant melanoma, the middle of the day (roughly between 10:00 a.m. and 1:00 p.m.) is the best and safest time. During this time you need the shortest exposure time to produce vitamin D because UVB rays are most intense at this time. Plus, when the sun goes down toward the horizon, the UVB is filtered out much more than the dangerous UVA.

Once you reach this point your body will peak at about 10,000-40,000 units of vitamin D. Any additional exposure will only cause harm and damage to your skin. Most people with fair skin will max out their vitamin D production in just 10-20 minutes, or, again, when your skin starts turning the lightest shade of pink. Some will need less, others more. The darker your skin, the longer exposure you will need to optimize your vitamin D production.

Why Not Just Take Vitamin D from a Supplement?

You can get vitamin D3 in supplement form, and if sunlight or a safe tanning bed is not an option, this is a better choice than getting no vitamin D at all. If you do use a supplement, it now appears as though most adults need about 8,000 IU's of vitamin D a day in order to get their serum levels above 40 ng/ml.

However, sunlight is really the superior source for vitamin D, as when you expose your skin to sunshine, your skin synthesizes vitamin D3 sulfate. This form of vitamin D is water soluble, unlike oral vitamin D3 supplements, which is unsulfated. The water-soluble form can travel freely in your bloodstream, whereas the unsulfated form needs LDL (the so-called "bad" cholesterol) as a vehicle of transport.

The oral non-sulfated form of vitamin D may not provide all of the same benefits as the vitamin D created in your skin from sun exposure, because it cannot be converted to vitamin D sulfate.

I believe this is a very compelling reason to really make a concerted effort to get your vitamin D requirements from exposure to sunshine, or by using a safe tanning bed (one with electronic ballasts rather than magnetic ballasts, to avoid unnecessary exposure to EMF fields). Safe tanning beds also have less of the dangerous UVA than sunlight, while unsafe ones have more UVA than sunlight. If neither of these are feasible options, then you should take an oral vitamin D3 supplement.

What Should Your Vitamin D Levels be for Cancer Protection?

In 2007 the recommended level was between 40 to 60 nanograms per milliliter (ng/ml). Since then, the optimal vitamin D level has been raised to 50-70 ng/ml, and when treating cancer or heart disease, as high as 70-100 ng/ml.

I recommend you have your levels tested and regularly monitored to make sure they are in the therapeutic range. Your physician can do this for you, or another alternative is to join the D*Action study. D*Action is a worldwide public health campaign aiming to solve the vitamin D deficiency epidemic through focus on testing, education, and grassroots word of mouth.

When you join D*action, you agree to test your vitamin D levels twice a year during a five-year program, and share your health status to demonstrate the public health impact of this nutrient. There is a $60 fee each 6 months ($120/year) for your sponsorship of the project, which includes a complete new test kit to be used at home, and electronic reports on your ongoing progress.

Natural Treatment for Non-Melanoma Skin Cancer

Melanoma skin cancer is the deadliest form, but far more common are non-melanoma skin cancers, which impact millions of Americans every year.

If you or someone you love is affected, a cream containing eggplant extract, known as BEC and BEC5, appears to cure and eliminate most non-melanoma skin cancers in several weeks time. Unlike conventional skin-cancer treatment, which is often surgery, the eggplant-extract cream leaves no scarring and no visible sign a tumor or lesion was ever present. The eggplant extract appears to be exceptionally safe and only kills cancerous cells, leaving healthy cells untouched, and causes only minor side effects, such as itching and burning.

The leading researcher in this area today is Dr. Bill E. Cham, who reported as early as 1991 in Cancer Letters that:
"A cream formulation containing high concentrations (10%) of a standard mixture of solasodine glycosides (BEC) has been shown to be effective in the treatment of malignant and benign human skin tumors. We now report that a preparation ... which contains very low concentrations of BEC (0.005%) is effective in the treatment of keratoses, basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) of the skin of humans. In an open study, clinical and histological observations indicated that all lesions (56 keratoses, 39 BCCs and 29 SCCs) treated with [the preparation] had regressed."
Dr. Cham's latest study was published in the International Journal of Clinical Medicine this year. The paper includes two impressive case reports of 60-something men who were suffering from large basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), which had plagued them for years. The results upon treatment with a cream formulation of BEC (eggplant extract) twice a day are astounding, and you can view the pictures here.

Unfortunately, simply eating eggplant, tomatoes, peppers or similar veggies, while beneficial for many reasons, will not induce this same effect because the active components are not able to effectively penetrate your cells. This requires the addition of glycosides, molecules with various simple sugars attached to them that can latch on to receptors found on skin cancer cells.

Simple Skin Cancer Prevention Strategies

What's even better than an inexpensive, safe and natural cure for skin cancer is, of course, preventing it in the first place. Your body is made to be in the sun, and, when done properly, sun exposure will be one of the best ways you can help reduce your risk of skin, and many other forms of, cancer. Along with optimizing your vitamin D levels, the carotenoid astaxanthin has also piqued the interest of researchers due to its ability to reduce signs of aging by helping protect your skin from sun damage. I personally take 8 mg every day to help limit any potential damage from sun exposure as most of the year I am able to spend one to two hours a day in the sun.

Consuming a healthy diet full of natural antioxidants is another useful strategy to avoid sun damage to your skin, as fresh, raw, unprocessed foods deliver the nutrients that your body needs to maintain a healthy balance of omega-6 and omega-3 oils in your skin, which is your first line of defense against sunburn.

Fresh, raw vegetables also provide your body with an abundance of powerful antioxidants that will help you fight the free radicals caused by sun damage that can lead to burns and cancer.

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The Surprising Cause of Melanoma (And No, It's Not Too Much Sun)

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Rates of melanoma, the deadliest form of skin cancer, have been rising for at least the last three decades, and this increase has been largely blamed on exposure to ultraviolet (UV) light from the sun.