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An Uncommon but Often Lethal Skin Cancer Could Be That Individual Melanoma Patients Cancers Can Be Assessed by Gene Expression to Answer These Questions

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An Uncommon but Often Lethal Skin Cancer Could Be That Individual Melanoma Patients Cancers Can Be Assessed by Gene Expression to Answer These Questions HEALTH in the US and Australia are successfully actions of vitamin D, genetic alterations CONCLUSION treated by early surgery. However, 10 in the gene that controls the vitamin D At this point, the role of genetics in percent of melanomas have been highly receptor or related genes might reasonably melanoma is still unclear. While intense, recalcitrant to treatment. In the quest for be associated with poorer survival from intermittent sun exposure is clearly better understanding, multiple investiga- melanoma. It may be that individuals who important in the etiology of melanoma, tors are evaluating the role of genetic factors have aggressive melanoma have a different its importance for survival is not known. in survival. While excessive, intermittent set of genetic mutations from those com- Therefore, one cannot reliably say whether sun exposure is an important risk factor mon in more indolent melanomas. nature or nurture (i.e., behavior) is more Merkel Cell Carcinoma: for melanoma, it does not appear to be as- The genetic factors associated with important in either the etiology or the sociated with poorer melanoma survival. melanoma progression and survival are progression of melanoma. Hopefully, this Thus, genetic factors may be the culprit; it still being explored. While genetics in other uncertainty will continue to spur research An Uncommon But Often Lethal Skin Cancer could be that individual melanoma patients cancers can be assessed by gene expression to answer these questions. JAYASRI IYER, MD, AND PAUL NGHIEM, MD, PHD with a particular constellation of inherited analyses from fresh tumor tissue, this is ex- genetic mutations are those who have tremely difficult in melanoma, as primary DR. BERWICK is professor and chief of the increased mortality from the disease. Lem- melanomas are so small, and pathologists Division of Epidemiology and Biostatistics at ish, et al observed that survival increased need all of the lesion in order to diagnose the University of New Mexico’s Department of The number of reported cases of Merkel MELANOMA AND NONMELANOMA with increasing melanoma incidence across the disease correctly. Another alternative Internal Medicine and associate director of cell carcinoma (MCC), a relatively rare but SKIN CANCER VS. MCC MCC and a Newly several populations12 and suggested that is to measure single nucleotide polymor- the Population Science Program, UNM Cancer dangerous skin cancer, has tripled in the Melanoma and nonmelanoma (basal and Discovered Polyomavirus melanoma occurring in association with phisms (SNPs) — either in germline DNA Center, Albuquerque. She has co-authored over last 20 years to approximately 1500 new squamous cell carcinoma) skin cancers are t %JTDPWFSFEJOFBSMZ high ambient sun exposure might be bio- (that which is inherited) or in tumor DNA 100 peer-reviewed publications and is a member cases annually in the US. There are several the most common cancers in the US, with t 1SFTFOUJO_QFSDFOUPG.$$ logically “more benign.” Reinforcing this using the DNA from paraffin-embedded of the Society for Melanoma Research’s Steering reasons for the increase. MCC was not rou- over a million cases of nonmelanoma skin tumors but very rare in other notion, solar elastosis (changes in the skin tumors. However, these studies are still few Committee and the National Cancer Institute’s tinely recognized by pathologists until the cancer and approximately 62,480 cases of skin cancers due to sun exposure) has also been linked in number and have usually been performed Subcommittee-A. 1990s, when a highly effective microscopic melanoma reported each year. While MCC t 7JSBM%/"JTJOUFHSBUFEJOUP cancer cells early in MCC devel- to greater melanoma survival. on small numbers of patients that are not stain (“CK20”), differentiating it from other is 30 times rarer than melanoma, it is twice opment Given the role of sun exposure in usually representative of the general popula- References available on p.112. cancers, was developed. In addition to bet- as lethal: MCC kills approximately one in ter recognition of MCC tumors, the reported three patients compared to a one in six t 1FPQMFBSFMJLFMZFYQPTFEUPUIJT the synthesis of vitamin D and the tion of melanoma patients. Therefore, they virus early in life incidence has grown due to true increases mortality for melanoma. anti-proliferative and anti-carcinogenic are difficult to interpret so far. t 'FXFSUIBOJOWJSVT in its known risk factors, which include infected people will develop MCC solar ultraviolet (UV) exposure, immune THE NEWLY DISCOVERED VIRUS suppression and age over 50 years. Scientists at the University of Pittsburgh Variant Gene Is Linked MCC arises most often on sun-exposed recently discovered a “Merkel cell KEY RISK FACTORS To Melanoma In Young Women areas in fair-skinned individuals over age polyomavirus” — a human virus that is Age over 50, light skin color, sun/ultraviolet 50. It derives its name from the similarity present in approximately 80 percent of MCC exposure, and immune suppression are A new study from New York University Medical Center of these cancer cells to normal Merkel cells tumors but in fewer than 10 percent of all significant risk factors for MCC. We shows that women with a certain gene variation have in the skin that are thought to be associated melanomas and other skin cancers. People have created an acronym, “AEIOU”, to a four times greater risk of developing melanoma when with touch sensation (Figure 1). Normal are generally exposed to polyomaviruses help recognize factors associated with they are under age 50 than women in whom the gene Merkel cells were first described over 100 (members of a family of double-stranded MCC diagnosis. is normal. Lead author David Polsky, MD, PhD, says years ago by Friedrich Sigmund Merkel. DNA viruses) prior to age 20. When the the higher risk may be related to estrogen activity. Merkel cell carcinoma usually appears Merkel polyomavirus infects a cell, it AEIOU Features of MCC LEICA CM1510S CRYOSTAT as a firm, painless lesion on a sun-exposed produces proteins that may cause cells to Estrogen binds more strongly to the abnormal version A Asymptomatic/lack of tenderness area (Figure 2a, 2b). These tumors are grow (divide) inappropriately, promoting of the MDM2 gene, switching on greater production E Expanding rapidly typically red, blue or skin-colored and cancer. The fact that about 20 percent of of the MDM2 protein, which can lead to uncontrolled I Immune suppression vary greatly in size. The average size at MCC tumors do not have this virus clearly (cancerous) growth. Women with the genetic varia- O Older than 50 years presentation is about the diameter of a indicates that the virus (or its continued tion who also have high estrogen levels might be at U Ultraviolet-exposed/fair skin especially high risk. dime (1.7 cm). presence) is not required in all cases of MCC. Melanoma, the deadliest form of skin cancer, is more common among women than men under the age of 40, and the new findings suggest that abnormal versions of the MDM2 gene may be a reason. The gene varia- MOHS tion was found in 40 percent of the female melanoma Figure 1: Normal Merkel cells in the skin: In this illustration of a cross-section of skin, normal Merkel SURGERY patients under age 50 who were studied. Median age cells are shown in red and connect to nerves shown LABORATORY at diagnosis was 13 years earlier for women with this in yellow. The structures drawn include the epidermis gene variation. (upper third), dermis (middle), and deeper adipose layer containing the fatty tissue. Arteries are depicted as The hope, says Dr. Polsky, would be to develop a red and veins are blue. Figure Copyright © by Paul FOR MORE genetic test to help identify women at risk of developing Nghiem & Quade Medical Group. INFORMATION CALL melanoma young, so that they would be committed to Merkel cells Figure 2a, 2b: Merkel cell carcinoma on the arm of a (800) 783-9424 sun protection and regular skin checkups. 68-year-old man (left), and on the eyelid of an 85-year- ! ! ! old woman (right). 59 HEALTH Of all of these factors, the two most important are extensive SUMMARY UV exposure and profound immune suppression. Extensive UV MCC is a skin cancer that typically arises on sun-exposed areas exposure not only damages the skin, increasing skin cancer risk, of fair-skinned individuals over the age of 50. Significant prog- but also helps to deplete the immune system, reducing its ability ress has been made in recent years in improving diagnosis and to fight off skin cancers and other diseases. The immune system therapeutic management as well as in our understanding of this helps the body recognize and eliminate cancers of the skin and cancer’s causes — in particular the new Merkel cell polyomavirus. other organs. People with profoundly weakened immune systems Because survival after diagnosis is highly dependent on stage at are 10–20 times more likely to develop MCC. Relevant forms presentation, it is critical to identify and treat this cancer early. of immune deficiency include immune suppression by viruses An annual total-body skin examination is advisable. (people with HIV); transplant medications (solid organ transplant To help educate patients and physicians about MCC, we have recipients); or malignancies (those with chronic lymphocytic created an extensive website (www.merkelcell.org) focused on leukemia or lymphomas). Patients with these types of immune this often lethal disease. Our website highlights the key findings suppression are twice as likely to die of MCC as immune-competent from the literature as well as treatment guidelines. individuals. This suggests that the immune system is involved in blocking the spread of MCC cancer cells as well as preventing their development. Despite the increased risk posed by immune SENTINEL LYMPH NODE BIOPSY TECHNIQUE suppression, 90 percent of MCC cases occur in patients who do not have known immune system defects.
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