“Although we have refined the common wisdom that excess sun exposure is always associated with increased risk of skin cancer, the take-home message for the public is still the same – limit sun exposure and use a sunscreen that blocks both UVA and UVB rays,” says the study’s lead investigator, Qingyi Wei, M.D., Ph.D., professor in the Department of Epidemiology.

In trying to learn more about skin cancer, researchers analyzed the ability of UVB radiation to damage a cell’s chromosomes. Previous studies at M. D. Anderson have shown that melanoma patients often have a reduced capacity to repair the DNA damage from UVB exposure.

In the latest study, researchers gathered white blood cells from 469 M. D. Anderson skin cancer patients and 329 cancer-free control subjects. Of the skin cancer patients, 238 were diagnosed with melanoma and 231 were diagnosed with basal and squamous cell carcinoma. All of the cells were then exposed to excessive UVB rays.

Researchers found that nonmalignant cancers had:

Greater UVB damage – UVB radiation affects cell chromosomes more severely in patients with basal and squamous cell carcinoma than those in melanoma patients.

Higher numbers of UVB chromosome breaks – The frequency of UVB-induced chromosome breaks was higher in nonmalignant skin cancer patients than in the control group, but was the same in melanoma patients and the control group. In fact, a higher frequency of chromosomal breaks was associated with a more than twofold-increased risk for both basal cell and squamous cell carcinoma.

Squamous skin cells lie near the top of the skin’s layers, while basal skin cells lie near the bottom layers. In both cases, these cells actively reproduce. When their chromosomes are damaged by sunlight, the cells often die or form a simple kind of cancer at the surface that is nonmalignant.

Because melanoma cell chromosomes resist damage from UVB radiation, they may stay intact long enough to continually amass genetic damage from both UVA and UVB radiation. “This allows the cells to hang in there longer, potentially passing on genetic mutations to daughter cells that can result in a cancer that is not sensitive to treatment,” Wei says.

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 Malignant melanoma is one of the most serious types of skin cancer, because advanced malignant melanomas have the ability to spread to other parts of the body. When malignant melanoma starts in the skin, the disease is called cutaneous malignant melanoma. It can also develop in the eye (called intraocular malignant melanoma) or in other parts of the body where pigment cells are found. In rare cases, malignant melanoma may arise in the meninges, the digestive tract, lymph nodes, or other areas where melanocytes are found. Malignant melanomas that begin in areas other than the skin are not discussed in this article.

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The Sydney Melanoma Unit, Camperdown, Australia

To the Editor:

The clinical and biologic behavior of desmoplastic melanoma (DM) is a subject of great relevance to those involved in the management of melanoma patients. We therefore read with interest the article by Livestro et al¹ on this subject. However, we have concerns about the validity of some of the conclusions that were drawn, particularly the claim that DM patients have survival rates similar to non-DM patients of equivalent tumor thickness. The authors based their conclusions “solely on the basis of the difference in histology.” Accordingly, they compared 89 DM patients with 178 non-DM patients matched for thickness, age, sex, and year of diagnosis. However, it is evident from their Table 1 that there were marked disproportions between key prognostic factors in their DM and non-DM groups, most importantly stage of disease at first presentation. Almost four times as many non-DM as DM patients first presented with advanced disease, mainly due to a much lower rate of sentinel node (SN) positivity in DM patients. Since stage of disease at first presentation is the major determinant of ultimate survival, this must cast considerable doubt on the comparative survival outcomes reported for the two groups. As well, there were major and potentially important differences in other prognostic characteristics between the groups, particularly in tumor mitotic rate^2,3 and primary melanoma anatomic site.⁴

Several additional comparisons from Table 1 deserve mention. The large amount of incomplete data for both tumor mitotic rate and especially neurotropism was overlooked, resulting in artifactually exaggerated differences in significance for these factors. Multiple primary melanomas, more common in DM than non-DM patients, were included in their survival analyses, a crucial factor possibly influencing outcome. Comment was made on the significant excess of DM compared with non-DM patients who had other skin cancers, but this would seem an unremarkable finding considering that most DM patients had their primary melanomas in the head and neck region—a common skin cancer site.

The Sydney Melanoma Unit (SMU) has treated 922 patients with DM since 1971, when Conley et al⁵ first described this entity. In SMU patients with localized disease, the 5-year survival rate in 280 DM patients (90%)⁶ was significantly higher than in all 7,767 cutaneous melanoma patients incorporated into the American Joint Cancer Committee on Cancer staging database (82%),⁴ despite the fact that median tumor thickness in the former group was considerably greater than in the latter (2.5 mm v 1.6 mm, respectively) group. More recently reported⁷ was another subgroup of 186 DM patients who underwent SN biopsy since 1993; 12 (6.5%) had at least one positive SN (primary tumor thickness range, 1.4 to 6.7 mm). This rate of positivity was considerably lower than the 32% rate of SN positivity in SMU patients with non-DMs of equivalent thickness undergoing SN biopsy. Three of these 12 DMs displayed neurotropism (thicknesses, 1.8, 6.2, and 6.5 mm). Thus our findings, in accord with those of Livestro et al, show a lower rate of SN positivity in DM than in non-DM patients, but neurotropism was not as closely associated with SN positivity as in their study.

It has become clear that DM differs in several major respects from other forms of cutaneous melanoma. However, most series reported to date have been small, and care must be taken to avoid drawing bold conclusions or making important management decisions (such as to withhold SN biopsy) on the basis of incomplete or inappropriate analysis of limited data.

Authors’ Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

—      Livestro DP, Muzikansky A, Kaine EM, et al: Biology of desmoplastic melanoma: A case-control comparison with other melanomas. J Clin Oncol 23:6739-6746, 2005[Abstract/Free Full Text]

—      Azzola MF, Shaw HM, Thompson JF, et al: Tumor mitotic rate is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma. Cancer 97:1488-1498, 2003[CrossRef][Medline]

—      Francken AB, Shaw HM, Thompson JF, et al: The prognostic importance of tumor mitotic rate confirmed in 1317 patients with primary cutaneous melanoma and long follow-up. Ann Surg Oncol 11:426-433, 2004[Abstract/Free Full Text]

—      Balch CM, Soong SJ, Gershenwald JE, et al: Prognostic factors analysis of 17,600 melanoma patients: Validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19:3622-3634, 2001[Abstract/Free Full Text]

—      Conley J, Lattes R, Orr W: Desmoplastic melanoma (a rare variant of spindle cell melanoma). Cancer 28:914-936, 1971[CrossRef][Medline]

—      Quinn MJ, Crotty KA, Thompson JF, et al: Desmoplastic and desmoplastic neurotropic melanoma. Cancer 83:1129-1135, 1998

—      Scolyer RA, Thompson JF, Quinn MJ: Desmoplastic melanoma and sentinel node biopsy. Presented at the Royal Australasian College of Surgeons Annual Scientific Meeting, Perth, Australia, May, 2005

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—      Basal cell carcinoma develops from abnormal growth of the cells in the lowest layer of the epidermis and is the most common type of skin cancer.

—      Squamous cell carcinoma involves changes in the squamous cells, found in the middle layer of the epidermis.

—      Melanoma occurs in the melanocytes (cells that produce pigment) and is less common than squamous or basal cell carcinoma — but more dangerous. It is the leading cause of death from skin disease.

Skin cancers are sometimes classified as either melanoma or nonmelanoma. Basal cell carcinoma and squamous cell carcinoma are the most common nonmelanoma skin cancers. Other nonmelanoma skin cancers are Kaposi’s sarcoma, Merkel cell carcinoma, and cutaneous lymphoma.

Skin cancer is the most common form of cancer in the Unites States. Known risk factors for skin cancer include the following:

—      Complexion - Skin cancers are more common in people with light-colored skin, hair, and eyes.

—      Genetics - Having a family history of melanoma increases the risk of developing this cancer.

—      Age - Nonmelanoma skin cancers are more common after age 40.

—      Sun exposure and sunburn - Most skin cancers occur on areas of the skin that are regularly exposed to sunlight or other ultraviolet radiation. This is considered the primary cause of all skin cancers.

Skin cancer can develop in anyone, not only people with these risk factors. Young, healthy people — even those with with dark skin, hair, and eyes — can develop skin cancer.

Symptoms   

Skin cancers may have many different appearances. They can be small, shiny, or waxy, scaly and rough, firm and red, crusty or bleeding, or have other features. Therefore, anything suspicious should be looked at by a physician. See the individual articles on specific skin cancers for more information.

Here are some features to look for:

—      Asymmetry: one half of the abnormal skin area is different than the other half

—      Borders: irregular borders

—      Color: varies from one area to another with shades of tan, brown, or black (sometimes white, red, blue)

—      Diameter: usually (but not always) larger than 6 mm in size (diameter of a pencil eraser)

Use a mirror or have someone help you look on your back, shoulders, and other hard-to-see areas.

Treatment   

Different types of skin cancer require different treatment approaches. See the specific type of skin cancer for information:

—      Basal cell carcinoma

—      Squamous cell carcinoma

—      Melanoma

Support Groups   

For additional resources, see cancer support group.

Outlook (Prognosis)   

The outlook depends on a number of factors, including the type of cancer and how quickly it was diagnosed. See the specific skin cancer articles for additional information.

When to Contact a Medical Professional   

Any suspicious mole, sore, or skin growth should be looked at by a physician immediately. Take any changes in a mole or sudden growth of a skin lesion seriously.

Prevention   

Minimizing sun exposure is the best way to prevent skin damage, including many types of skin cancer:

—      Protect your skin from the sun when you can — wear protective clothing such as hats, long-sleeved shirts, long skirts, or pants.

—      Try to avoid exposure during midday, when the sun is most intense.

—      Use sunscreen with an SPF of at least 15. Apply sunscreen at least one-half hour before sun exposure, and reapply frequently.

—      Apply sunscreen during winter months as well.

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Each year over a million people in the United States alone will be diagnosed with skin cancer. Of these, approximately 80,000 will be afflicted with melanoma. The incidence or the number of new cases of melanoma per year continues to rise. One in seventy-one persons born in the year 2001 will develop melanoma over their lifetime. Although it is not the most common skin cancer, melanoma is the most aggressive and has the ability to spread to other parts of the body.

Melanoma is a malignant tumor that is made up of abnormal melanocytes. Normal melanocytes, which reside in everybody’s skin, are cells that produce a brown pigment called melanin. Melanin is the major determinant of a person’s skin color and also serves as the body’s own natural sunscreen. A melanoma develops when certain melanocytes are no longer able to control their own growth and continue to multiply at a fast rate. This phenomenon occurs when melanocytes undergo significant damage. Too much exposure to sunlight, especially enough to cause blistering or peeling sunburns during childhood, can result in enough cellular injury to cause a melanoma as well as other skin cancers. In addition, there are other factors that make a person more susceptible to developing a melanoma. These include:

—      Blond or red hair, blue eyes, or fair skin

—      More than 100 normal moles or many unusual moles

—      Previous history of a melanoma

—      Blood relative(s) with a melanoma

You can’t change the way you look or your relatives. However, you can reduce your risk of melanoma by wearing plenty of sunscreen that protects against both ultraviolet A and B rays, avoiding sun exposure between the hours of 10 AM to 4 PM when the sun is brightest, seeking shade, and covering yourself up with clothing.

In general, early detection of any cancer including melanoma increases the likelihood of a complete cure. The most likely person to detect an early skin cancer is you! We do not expect you to be able to diagnosis skin cancer but simply being aware of changes occurring on your skin may save your life. There are three main points that you need to know in order to properly perform a self-skin-examination:

—      · Point #1: Melanoma can occur anywhere on the body from head to toe, although it is most common on sun-exposed skin. Therefore, you should examine your skin everywhere, including the palms of your hands and soles of your feet. Mirrors may be used to inspect areas that you are unable to directly visualize.

—      Point #2: “Know your ABCD’s.” These are different than the ones we all learned in Kindergarten. The “ABCD’s” are comprised of four descriptive features, which many melanomas have. Keep in mind that the “ABCD’s” are not perfect criteria and are meant to be used as a general guide for you to examine your skin. The bottom line is for you to remember to check your skin. If any spots on your body have a change in size, shape, or color or make you uncomfortable, the best action is to undergo a formal examination by a trained and experienced healthcare professional.

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The “MCW Melanoma Cocktail” reveals with much higher accuracy than conventional methods whether cancer cells of melanoma have spread to the “sentinel” lymph node, the first lymph node to be affected. The test is conducted during the interval between two standard surgeries performed on melanoma patients, the sentinel lymph node biopsy and the wide excision of the biopsy site to remove the melanoma.

“The MCW Melanoma Cocktail was developed about four years ago and it has been used as a routine protocol since then,” said Vinod Shidham, MD, FIAC, MRCPath, Medical College Associate Professor of Pathology. “Before that we were using other immunomarker antibodies, and those were not giving good results.” Dr. Shidham is Executive Editor and Editor-in-Chief of the online research publication Cytojournal and Director of Fine Needle Aspiration Biopsy Service and Cytopathology Fellowship Training Program at Froedtert and Medical College

Antibodies are used in biopsies to stain certain cells so that they stand out under the microscope. The antibodies change the color of the cells so that cancer cells can be identified in the vast sea of normal cells, and the MCW Melanoma Cocktail has shown good results in staining just the melanoma cells and providing a very clean picture for the interpreting pathologist and accurate results for the surgeon.

Accuracy and Speed

“At many places people are still using the other markers, but those are difficult to read and result in problems interpreting some cases, said Dr. Shidham. “That’s the reason we came up with this alternative. The cocktail has three components, what we call MART-1, Melan-A and tyrosinase. To perform all three individually is more expensive, takes more time, and makes reading results more challenging.”

“So what I did was combine them and make a ‘cocktail’ of them in a standardized pattern. “We get the lymph node when the patient is still on the operating table, we make a smear from that lymph node, and we stain that with the MCW Melanoma Cocktail. Melanoma has its own marker, and we add on antibodies that combine with that marker. Wherever those antibodies go there is a molecule that generates a color. If it is a melanoma cell, it will look brown.”

Incidence of melanoma in the US has more than doubled in the past 20 years. It is the most deadly of skin cancers, and according to the American Cancer Society more than 55,000 new cases of melanoma will develop in 2004, with nearly 8,000 deaths.

Patients evaluated by routine protocol must wait 24 to 48 hours or longer for results of sentinel lymph node biopsy to come back from a lab. If the test shows that cancer has spread to the sentinel lymph node, an additional operation is performed at a later date to remove the regional nodes to which the melanoma drains. The MCW Melanoma Cocktail gives results in about 30 minutes after the initial sentinel lymph node biopsy operation.

Study Results Promising

A Medical College study evaluated MCW Melanoma Cocktail biopsies from patients at Froedtert Hospital and revealed a high degree of accuracy. The study’s co-investigators were Associate Professor of Plastic Surgery William W. Dzwierzynski, MD, and Associate Professor of Dermatology Marcelle Neuburg, MD. “We decided that if we could tell during the first operation, then the surgeon can go ahead with the removal of the patient’s regional lymph nodes during the same anesthesia, so the patient doesn’t have to go through a second round of anesthesia, pain and complications,” said Dr. Shidham. “It saves a lot of time and money, too. All those things are beneficial.

“If the cells are there, the physician goes ahead with the second operation during the same surgery,” said Dr. Shidham. “Usually the surgeon has already explained to the patient that if something is there they will proceed with the operation.”

Dr. Shidham stressed that early detection is still the key to treatment of melanoma. The disease originates in pigment producing cells of the skin, and unlike other skin cancers it spreads very rapidly through the lymph nodes.

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People who cannot undergo surgery may be treated by external radiation therapy. Radiation therapy is the use of a small beam of radiation targeted at the skin lesion. The radiation kills the abnormal cells and destroys the lesion. Radiation therapy can cause irritation or burning of the surrounding normal skin. It can also cause fatigue. These side effects are temporary. In addition, a topical cream has recently been approved for the treatment of certain low-risk nonmelanoma skin cancers.

In advanced cases, immune therapies, vaccines, or chemotherapy may be used. These treatments are typically offered as clinical trials. Clinical trials are studies of new therapies to see if they can be tolerated and work better than existing therapies.

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Methods We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and N-RAS in 126 melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal melanomas.

Results We found significant differences in the frequencies of regional changes in the number of copies of DNA and mutation frequencies in BRAF among the four groups of melanomas. Samples could be correctly classified into the four groups with 70 percent accuracy on the basis of the changes in the number of copies of genomic DNA. In two-way comparisons, melanomas arising on skin with signs of chronic sun-induced damage and skin without such signs could be correctly classified with 84 percent accuracy. Acral melanoma could be distinguished from mucosal melanoma with 89 percent accuracy. Eighty-one percent of melanomas on skin without chronic sun-induced damage had mutations in BRAF or N-RAS; the majority of melanomas in the other groups had mutations in neither gene. Melanomas with wild-type BRAF or N-RAS frequently had increases in the number of copies of the genes for cyclin-dependent kinase 4 (CDK4) and cyclin D1 (CCND1), downstream components of the RAS–BRAF pathway.

Conclusions The genetic alterations identified in melanomas at different sites and with different levels of sun exposure indicate that there are distinct genetic pathways in the development of melanoma and implicate CDK4 and CCND1 as independent oncogenes in melanomas without mutations in BRAF or N-RAS.

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Nathan Seppa

Efforts to enlist the immune system in the fight against cancer have generally yielded disappointing results. Scientists have yet to create a so-called cancer vaccine that reliably primes the immune system to recognize malignant cells and target them for destruction.

Having taken an unusual approach in their experiments on mice, researchers now report that destroying perfectly good skin cells can incite the immune system to kill the cancerous versions of these cells—with only modest side effects.

The potential treatment targets melanocytes, the cells that give skin its pigmentation. When malignant, these cells become melanoma, the deadliest form of skin cancer.

Although the experimental therapy would be a treatment for existing disease, the researchers refer to it as a cancer vaccine since it enlists the immune system to kill malignant cells, says study coauthor Gregory A. Daniels, a medical oncologist at the Mayo Clinic in Rochester, Minn.

This vaccine, administered to the mice in a series of injections, contains DNA plus an antiviral drug. In response to the treatment, the mice lost not only melanoma cells but also many healthy melanocytes, leaving the black mice with white splotches of hair that lasted for months. The findings appear in the September Nature Biotechnology.

For the experiment, Daniels and his colleagues implanted melanoma tumors in the mice. Starting 3 days later and continuing over the next 2 weeks, the scientists injected the animals with two types of DNA and an antiviral drug called ganciclovir. One of the DNAs encodes a protein known to boost immune reactions; the other DNA encodes a viral enzyme.

“It’s fortuitous that melanocytes seem to take up the DNA,” Daniels says.

The mouse melanocytes then start making the viral enzyme and the immune-boosting protein, says Daniels. Ganciclovir latches onto the enzyme and kills the melanocytes.

The dying melanocytes “spill their contents,” says Daniels, which include the immune-boosting protein and various other stress factors. These compounds set off a response by immune cells, which then zero in on and destroy other melanocytes and melanoma cells.

The mice remained free of tumors for at least 100 days after receiving the vaccine. Notably, the treatment destroyed tumors in areas away from the injection site. However, when the team implanted new tumors in the mice 100 days after the first batch of tumors had been eradicated, the protection had waned and the mice succumbed to melanoma.

The researchers traced the immune onslaught to shock troops known as CD8 T cells. The cancer vaccine didn’t work in mice lacking such cells.

Other immune cells eventually suppress CD8 T cells, so the treatment isn’t expected to continue to attack healthy melanocytes and, in that way, cause autoimmune disease.

These experiments are “very exciting,” says cell biologist Mark E. Dudley of the National Cancer Institute in Bethesda, Md. “They indicate that the immune system is capable of seeing tumors and eliminating them under the appropriate conditions.”

“The success rate of [previously tested] vaccines is less than 5 percent of treated patients,” Dudley says. “New treatments are desperately needed.” The incidence of melanoma is growing faster than any other cancer, with some estimates suggesting that 1 in 100 people in the United States can expect to develop melanoma at some time.

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