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Melanoma Research Paper

Melanoma is not the most common type of skin cancer, but it is the most serious because it often spreads. Risk factors for melanoma include overexposure to the sun.

This article explains the symptoms of melanoma, how it is diagnosed, and how it is treated. We also explain how best to prevent melanoma.

Fast facts on melanoma
  • The incidence of melanoma appears to be increasing for people under the age of 40 years, especially women.
  • Avoiding sunburn is an effective way to reduce the risk of skin cancer.
  • Self-monitoring of moles and other markings on the skin can help with early detection.

What is melanoma?


The most common cause of melanoma is excessive sun exposure.

Melanoma is a form of skin cancer that arises when pigment-producing cells—known as melanocytes—mutate and become cancerous.

Most pigment cells are found in the skin, but melanoma can also occur in the eyes (ocular melanoma) and other parts of the body, including, rarely, the intestines. It is rare in people with darker skin.

Melanoma is just one type of skin cancer. It is less common than basal cell and squamous cell skin cancers, but it can be dangerous because it is more likely to spread, or metastasize.

Melanomas can develop anywhere on the skin, but certain areas are more prone than others. In men, it is most likely to affect the chest and the back. In women, the legs are the most common site. Other common sites are the neck and face.

According to the National Cancer Institute, about 87,110 new melanomas were expected to be diagnosed in 2017, and about 9,730 people were expected to die of melanoma.

Stages

The stage at which a cancer is diagnosed will indicate how far it has already spread and what kind of treatment is suitable.

One method of staging melanoma describes the cancer in five stages, from 0 to 4.

Stage 0: The cancer is only in the outermost layer of skin and is known as melanoma in situ.

Stage 1: The cancer is up to 2 millimeters (mm) thick. It has not spread to lymph nodes or other sites, and it may or may not be ulcerated.

Stage 2: The cancer is at least 1.01 mm thick and it may be thicker than 4 mm. It may or may not be ulcerated, and it has not yet spread to lymph nodes or other sites.

Stage 3: The cancer has spread to one or more lymph nodes or nearby lymphatic channels, but not to distant sites. The original cancer may no longer be visible. If it is visible, it may be thicker than 4 mm, and it may also be ulcerated.

Stage 4: The cancer has spread to distant lymph nodes or organs, such as the brain, lungs, or liver.

Types

There are four types of melanoma.

Superficial spreading melanoma: This is the most common, and it often appears on the trunk or limbs. The cells tend to grow slowly at first, before spreading across the surface of the skin.

Nodular melanoma: It is the second most common type, appearing on the trunk, head, or neck. It tends to grow more quickly than other types, turning red—rather than black—as it grows.

Lentigo maligna melanoma: This is less common, and tends to affect older people, especially in parts of the body that have been exposed to the sun over several years. It starts as a Hutchinson's freckle, or lentigo maligna, which looks like a stain on the skin. It usually grows slowly and it less dangerous than other types.

Acral lentiginous melanoma: This is the rarest kind of melanoma. It usually appears on the palms of the hands, soles of the feet, or under the nails. It is more likely in people with darker skin and does not appear to be linked to sun exposure.

Causes

As with all cancers, research is ongoing into the causes of melanoma.

People with certain types of skin are more prone to developing melanoma, and the following factors are associated with an increased incidence of skin cancer:

  • high freckle density or tendency to develop freckles after sun exposure
  • high number of moles
  • five or more atypical moles
  • presence of actinic lentigines, small gray-brown spots, also known as liver spots, sun spots, or age spots
  • giant congenital melanocytic nevus, brown skin marks that present at birth, also called birth marks
  • pale skin that does not tan easily and burns, plus light-colored eyes
  • red or light-colored hair
  • high sun exposure, particularly if it produces blistering sunburn, and especially if sun exposure is intermittent rather than regular
  • age, as risk increases with age
  • family or personal history of melanoma
  • having an organ transplant

Of these, only high sun exposure and sunburn are avoidable.

The World Health Organization (WHO) estimates that around 60,000 early deaths occur each year worldwide because of excessive exposure to the sun's ultraviolet (UV) radiation. An estimated 48,000 of these deaths are from malignant melanoma.

Avoiding overexposure to the sun and preventing sunburn can significantly lower the risk of skin cancer. Tanning beds are also a source of damaging UV rays.

Pictures

If you can tell the difference between a normal mole or freckle and skin cancer, it may help get an early diagnosis.

Symptoms

As with other forms of cancer, the early stages of melanoma may be hard to detect, so it is important to check the skin actively for signs of change.

Alterations in the appearance of the skin are key indicators of melanoma and are used in the diagnostic process.

The Melanoma Research Foundation has produced a web page that compares pictures of melanoma with those of normal moles.

This American non-profit organization also lists the symptoms and signs that should prompt a visit to the doctor.

These are:

  • skin changes, such as a new spot or mole or a change in color, shape, or size of a current spot or mole
  • a skin sore that fails to heal
  • a spot or sore that becomes painful, itchy, or tender, or which bleeds
  • a spot or lump that looks shiny, waxy, smooth, or pale.
  • a firm red lump that bleeds or appears ulcerated or crusty
  • a flat, red spot that is rough, dry, or scaly

ABCDE examination

The ABCDE examination of skin moles is also a key way to reveal suspect lesions. It describes five simple characteristics to look out for in melanoma appearance:

Asymmetric: normal moles are often round and symmetrical, whereas one side of a cancerous mole is likely to look different from the other side - not round or symmetrical.

Border: this is likely to be irregular rather than smooth - ragged, notched, or blurred.

Color: melanomas tend not to be of one color but to contain uneven shades and colors, including varying black, brown, and tan, and even white or blue pigmentation.

Diameter: a change in the size of the mole, or a mole that is larger than a normal mole (more than a quarter inch in diameter) can indicate skin cancer.

Evolving: a change in a mole's appearance over a period of weeks or months can be a sign of skin cancer.

Treatment

The treatment of skin cancer is similar to that of other cancers, but, unlike many internal cancers, it is easier to access the cancer to remove it completely. Surgery is the most common treatment for melanoma.

Surgery involves removing the lesion and some of the normal tissue around it. A biopsy may be taken at the same time.

If melanoma covers a large area of skin, a skin graft may be necessary. If the cancer may have penetrated into the lymph nodes, a lymph node biopsy may be performed.

Other, less common treatments for skin cancer include:

  • chemotherapy
  • biological therapy, using drugs that work with the immune system

Rarely, photodynamic therapy, which uses a combination of light and drugs, and radiation are used.

Prevention


Avoiding excessive exposure to UV radiation reduces the risk of melanoma.

Avoiding excessive exposure to ultraviolet radiation can reduce the risk of skin cancer.

This can be achieved by:

  • avoiding sunburn
  • wearing clothes that protect against the sun
  • using sunscreen with a minimum sun protection factor (SPF) of 15, but preferably SPF 20-30, with 4- or 5-star UVA protection
  • liberally applying sunscreen about half an hour before going out, and applying it again after half an hour
  • reapplying every 2 hours and after swimming to maintain adequate protection
  • avoiding the highest sun intensity between 11 am and 3 pm by finding shade.
  • protecting children by keeping them in the shade, with clothing, and by applying SPF 50+ sunscreen
  • keeping infants out of direct sunlight

Wearing sunscreen is not a reason to spend longer in the sun. Sun exposure should still be limited, where possible. People who work outdoors should take precautions to minimize exposure.

Doctors recommend avoiding tanning booths, lamps, and sunbeds.

What about vitamin D?

Despite warnings against overexposure to the sun, it remains important to get a little sun exposure as this enables our bodies to produce vitamin D.

Vitamin D is an important nutrient for the prevention of diseases such as rickets and osteomalacia. As such, sensible sun exposure is advised.

The time it takes to produce sufficient vitamin D is less than the time it takes to get sunburnt. This means we can enjoy the sun safely and maintain optimal vitamin D levels without dramatically increasing the risk of skin cancer.

Diagnosis

Most cases of melanoma affect the skin. They usually produce changes in existing moles. A person to detect the early signs of melanoma themselves by regularly examining moles and other colored blemishes and freckles.

Any changes in the appearance of the skin should prompt further examination by a doctor. The back should also be checked regularly, especially as 1 in 3 melanomas in men occur on the back. A partner, family member, friend, or doctor can help check the back and other hard-to-see areas.

Cancer doctors are most concerned with lesions that "stand out from the crowd." The ABCDE checklist described above can help with this.

Clinical tests

Doctors may use microscopic or photographic tools to see a lesion in more detail.

If a doctor suspects skin cancer, the patient will be referred to a cancer specialist and a biopsy will be arranged to test the lesion. A biopsy is a procedure where a sample of the lesion is taken for examination in the laboratory.

1Unit of Medical Oncology and Innovative Therapy, Department of Melanoma, National Tumor Institute, 80131 Naples, Italy
2Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA
3Department of Transfusion Medicine, NIH Clinical Center, National Institute of Health, Bethesda, MD 20892, USA
4Institute of Biomolecular Chemistry-CNR, Trav. La Crucca, 3-Baldinca Li Punti, 07100 Sassari, Italy

Copyright © 2011 Paolo A. Ascierto et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.



The last two decades have deepened our understanding of the biology of melanoma in significant new directions. This progress has resulted in the development of therapeutics with unprecedented clinical potential. Ipilimumab and tremelimumab are anti-CTLA4 monoclonal antibodies that alter the regulatory immune network responsible for damping anticancer immune responses, and this class of agent has shown the first significant impact upon survival of metastatic melanoma. Meanwhile, agents that inhibit activating mutations that drive the oncogenic processes such as B-RAF or c-KIT have shown clear effectiveness and almost immediate responses. It remains uncertain how the current individual treatments work at the level of the tumor during treatment. Moreover, the weight that the genetic background of the host may have in relation to treatment response has yet to be explored. A lot still needs to be done to improve the durability of treatment benefits, and cure remains an elusive goal. The topics presented here are not an exhaustive representation of the field of melanoma research, but a sampling of the large and many-faceted agenda of current interest that we have the pleasure of sharing with the readers. We would like to thank the authors for their excellent contributions and patience in this venture. Finally, the fundamental work of reviewers of the papers is also very warmly acknowledged.

This special issue contains seven papers, three related to epidemiology, diagnosis, risk factors, and characteristics of melanoma. Two papers focus on specific disease treatments, one using the isolated limb infusion (ILI) and the second based on the adoptive transfer of autologous tumor-infiltrating lymphocytes (TIL) for therapy of locally or systemically advanced melanoma, respectively. Also two papers address the management of brain metastases and uveal melanoma.

In the paper entitled “The contribution of electron paramagnetic resonance to melanoma research,” Q. Godechal and B. Gallez showed how electron paramagnetic resonance (EPR), a method able to detect free radicals trapped in melanin pigments, has recently provided insight to basic features of melanoma that may improve its diagnosis. These advances may improve the diagnosis of melanoma, but the limitations of the method are also detailed.

The paper entitled “Nonsteroidal anti-inflammatory drugs and risk of melanoma” presents a pilot study of the association between NSAID usage and melanoma incidence, to determine whether epidemiologic evidence of a chemopreventive effect of these agents is compelling. On the basis of the conflicting reports in the literature, it is suggested that meta-analysis may better establish this possible association.

In the paper entitled “What is really risky in melanoma? prognostic parameters for the primary care of melanoma patients,” D. Göppner and M. Leverkus reviewed the literature data and summarized current understanding of carcinogenesis in melanoma giving a detailed overview of known morphologic and potentially future genetic prognostic parameters in malignant melanoma.

The paper entitled “Treatment of locally advanced melanoma by isolated limb infusion with cytotoxic drugs” overviews isolated limb infusion (ILI), as a less invasive technique than the classical isolated limb perfusion (ILP) which may be preferred for locally advanced melanoma confined to a limb. The minimally invasive character of ILI may replace ILP in the future as palliation for locally advanced limb tumors.

In the paper entitled “Characterization of ex vivo expanded tumor infiltrating lymphocytes from patients with malignant melanoma for clinical application,” M. H. Andersen et al. report a different method for expanding tumor infiltrating lymphocytes (TIL) to clinically relevant quantities in two steps within 8 weeks. This method may be utilized for new clinical trials, where adoptive transfer of autologous tumor infiltrating lymphocytes (TIL) has shown objective clinical responses in up to 50% of treated patients.

In the paper entitled “Management of melanoma brain metastases in the era of targeted therapy,” D. G. Shapiro and W. E. Samlowski discuss approaches for melanoma brain metastases using targeted agents combined with classical surgery and radiosurgery, along with the possibility of improving survival in at least a subset of melanoma patients with brain metastases.

In the paper entitled “Uveal melanoma,” V. M. L. Cohen and V. P. Papastefanou give a 360°C overview uveal melanoma from genetic alterations to diagnosis and treatment.

These studies span the range of etiology and regional as well as systemic therapy for melanoma, to provide a background that may be useful for readers in relation to regional and systemic metastasis, including the most ominous phase of brain metastasis, which punctuate the course of disease. The clear differences between uveal melanoma, a disease nominally included among ‘‘the melanomas’’ are now biologically recognized as diverse in histogenesis and relevant mutational oncogenic pathways. These papers are timely in this year of regulatory approvals for several new agents, and the pending likelihood that new agents will join this armamentarium for melanoma. An area not touched upon is that of adjuvant therapy, which may provide insights to further roles of therapy and ultimately, with chemoprevention, may lessen the burden of advanced disease in the future.

Paolo A. Ascierto
John M. Kirkwood
Francesco M. Marincola
Giuseppe Palmieri