ABCD syndrome

The incidence of melanoma has increased dramatically in the United States over the past several decades, and it continues to rise.1 From 1992-2000 it had the highest annual percent increase of any malignancy in the over 65 age group, and was near the top of the list for those less than 65.2 Melanoma is the sixth most common cancer in men and seventh most common in women according to the most recent data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute.2 Overall age adjusted incidence rate was 17.4 per 100,000 in 1999 compared to 11.1 in 1981. The annual percent increase in incidence during that time was slower, however, compared to 1973-1981. The SEER program also stratifies data by sex, race, and age.2 From 1996-2000, there were approximately 21.8 cases per 100,000 in males compared to 14.5 m women. Melanoma is much more common in the white population versus the black population (20.6 cases per 100,000 compared with 1.1 cases). There is a clear stepwise increase in incidence with increasing age." The number of cases per 100,000 for the age group 20-54 was approximately 15.1, for 55-64 was 36.0, for 65-74 was 50.0, and for those older than 75 was 56.0.2

Overall ten-year survival rates have improved from 77% in 1981 to 84% in 1989, according to seeR data.2 The rate of increase in mortality has not been as high as for incidence, as the age-adjusted mortality rate was 2.4 per 100,000 in 1981 and rose only slightly to 2.5-2.6 between 1995-1999.2 The mortality rate in Rhode Island from 1996-2000 was approximately the same as in the United States as a whole.2 Mortality trends are also changing. Not only has the increase in age-adjusted mortality been slowing down, but there actually has been a recent decline in mortality in the youngest age groups.3 Furthermore, mortality is no longer increasing in women overall.2

Finally, the incidence of melanoma at different body sites has been changing. Melanoma is most likely to occur on the trunk for men and the lower leg for women, but the largest increase has been on the trunk for both groups.1

Many factors are known to be associated with an increased risk of developing melanoma. A person's nevus status, or number and type of moles, is the most important factor in assessing the risk of melanoma according to most studies.4,5 An increased number of melanocytic nevi or atypical nevi are risk factors for melanoma development. Patients with congenital nevi are also at increased risk.6 Approximately 30-50% of melanoma lesions develop in existing nevi. Those at highest risk are patients with the "B-K mole" syndrome who have dysplastic nevi and a family history of two or more relatives with melanoma.4

A family history of melanoma is another major risk factor linked to developing melanoma.3-6 Mutations of the CDKN2A or p16 gene on chromosome 9 are associated with an increased susceptibility to melanoma.5 It is estimated that of all the melanoma patients, 5 percent have a first degree affected relative, and of those, 25 percent possess the associated mutation. The majority of people who develop melanoma, however, do not possess this gene. Additionally, certain polymorphisms in the MClR gene on chromosome 16q24.3 are associated with increased risk of melanoma.''

A personal history of melanoma has also been established as a major risk factor.1 Those with a history of a non-melanoma skin cancer are also at somewhat increased risk.6

A fair complexion is the last major risk factor for developing melanoma.1,4,6 As noted, the incidence of melanoma in the white population is at least 10 times that in the black population.6 While blue eyes and red or blonde hair are indicators of risk, they are not as strongly linked as skin color.

Additionally, excessive sun exposure, a major avoidable risk factor, is estimated to be responsible for more than half of all melanoma cases worldwide.3 Incidence rates increase at latitudes closer to the equator where individuals are subjected to increased intensity of sunlight.1 Individuals with a history of sunburns have been shown to be at increased risk.4,6 Childhood exposure is a more important risk factor for melanoma than exposure later in life.4 In temperate climates the development of most melanomas correlates more closely with intermittent intense sun exposure than with chronic exposure-an individual who works indoors and goes to the beach every weekend is more likely to develop melanoma than an outdoor worker.4 The use of tanning beds has also been linked to increased melanoma risk.4,6

Finally, immunosuppressed patients have also been shown to be at increased risk of developing melanoma.3,4,6

EARLY DETECTION

Tumors with a depth or = 4 mm with ulceration have a 32% tenyear survival rate, while metastatic lesions have only a 2.5-16% survival rate depending on the location of the metastasis.7 These data emphasize the importance of early detection.

Prompt physician evaluation of new or changing lesions is the first step toward enhanced early detection.8 Although data suggest that monthly self-skin examination can reduce mortality and that most melanomas are detected first by the patient or a spouse, the reported frequency of thorough skin examinations is low.9 This highlights the need for health care providers not only to recommend monthly skin examinations, but also to teach self-examination procedures and proper recognition of early melanoma warning signs.

Complete skin exams need to be performed not only by dermatologists, but by primary care providers as well.4 A Basic Skin Cancer Triage curriculum has been developed to assist primary care providers, and evidence suggests that it can improve detection skills.4

Many organizations recommend routine screening only for high-risk groups, which has been associated with positive results. There is no randomized controlled trial to support an increased benefit of population-based screening, but the American Academy of Dermatology, the National Institutes of Health Consensus Conference on Early Melanoma, and the American Cancer Society favor screening the entire population.8 The U.S. Preventive Services Task Force (USPSTF) "concludes that the evidence is insufficient to recommend for or against routine screening."10 A randomized trial of population-based early detection has been initiated in Australia.3

Once a patient presents for evaluation, it is the role of the physician to determine which lesions need a biopsy based on the history and appearance of the lesion, and risk factors which provide an initial level of suspicion. The "ABCD" rule is most often used to evaluate the likelihood of melanoma. Moles more likely to be melanoma are those that have asymmetry, irregular borders, multiple colors, and a diameter greater than 6mm.6

Unfortunately, the accuracy of the clinical diagnosis of melanoma based on the ABCD rule may be as low as 60%.11 This is due in part to the facts that melanomas of less than 6mm occur, and that melanomas such as the nodular type may achieve a substantial depth without asymmetry, irregular borders, multiple colors, or large diameter.12 The rule is most useful for the superficial spreading subtype. Recently there has been movement away from solely utilizing the ABCD rules. Pruritus, bleeding, and ulceration may be symptoms of advanced melanoma development.6 A new growth, a sore that doesn't heal, or a change in the size, shape, or color of an existing lesion are also warning signs. Utilizing these other criteria will help detect lesions early, possibly even before they develop ABCD signs.

Dermoscopy utilizes a magnifier with incident light and oil immersion to examine lesions.11 The same effect can be obtained with magnification and cross-polarized light. This technique has been shown to improve accuracy of diagnosis for experienced examiners, but not for the untrained.11 Consensus groups are working on standardizing and simplifying diagnostic criteria, which in the future may make dermoscopy more feasible for the nonspecialist. Additionally, computer assisted analysis of images is also under study, and comparison of dermatoscopic images with a large database may in the future improve diagnostic accuracy.13

Regular and digital photography can also aid in early detection. One study found that a change in appearance from baseline images was the only clue to melanoma development in some cases.14

DIAGNOSIS

For a definitive diagnosis, an excisional biopsy is performed to remove the suspicious lesion with a margin of normal tissue.15 A punch excision 1-1.5mm greater in diameter than the lesion usually ensures a full thickness complete specimen with an acceptable scar. Larger lesions, or those in areas such as the head or neck, may be excised with an elliptical cut to provide better cosmetic results.15

Histopathological analysis is best performed by a dermatopathologist due to the difficulty of accurate interpretation of these specimens. A complete pathology report makes note of Breslow's measurement (tumor thickness), Clark's level (level of invasion), the radial and vertical growth phase, margin status, ulceration, mitoses, lymphoid response, pigmentation, regressive changes, microscopic satellites, and vascular invasion. This will then guide further surgery or adjunctive treatment.6

Additionally, patients with melanoma on biopsy require a thorough history to ascertain symptoms of possible metastases, a careful physical examination including palpation for lymph nodes, and other appropriate studies, including a chest radiograph. Further studies may be obtained based on symptoms, signs, and risk of metastases.

TREATMENT, STAGE I-III

Once melanoma is confirmed histologically, treatment depends on the stage of the disease. Melanoma is staged according to the 2002 American Joint Commission on Cancer TNM Staging System (Table 1,2),7 which better reflects the prognostic factors most important in predicting survival-tumor thickness, ulceration, number of metastatic lymph nodes, and in stage IV disease, site of distant metastases and lactate dehydrogenase (LDH) level.7

Surgery is the treatment of choice for melanoma confined to the skin which extends no farther than regional lymph nodes, and can be curative for most early stage lesions.16 While margins of 4-5cm around the tumor or biopsy site were utilized in the past, randomized trials have indicated that narrower margins are acceptable.17 For lesions less than 1 mm in depth, a 1 cm margin of excision is adequate. For lesions 1 mm-2mm thick, a 2cm margin is preferred, but a 1 cm margin is adequate if anatomic constraints are present. For 2-4mm lesions, a 2cm margin is recommended. Finally, for those lesions with depth greater than 4mm, a 2cm margin is the current recommendation, but to date there are no randomized prospective trials evaluating this directly.17

The approach to evaluation and therapy of lymph node involvement has also changed. Clinically positive nodes necessitate removal, but elective lymph node dissection (ELND) in those with clinically negative nodes is no longer recommended.18 A recent systematic review of randomized trials showed no significant improvement in survival of ELND in stage I and II malignant melanoma.19 Sentinel lymph node dissection (SLND) has provided an alternative to ELND, and is now widely used.17,19 This technique uses blue dye or a radioactive tracer injected at the tumor site to identify the first or "sentinel" draining lymph nodes at the time of the wide excision. Those with nodal metastases can be identified and assessed for complete dissection and adjuvant therapy, while those who show no evidence of metastases can avoid the potential additional morbidity. In centers experienced in SLND, fewer than 5% of patients with negative sentinel lymph nodes will relapse. While this procedure may be beneficial to those with a significant chance of lymph node metastases, there are currently no randomized controlled studies demonstrating survival benefit.19

The cytokine Interferon alpha is FDA approved for adjuvant treatment in some stage lib and in stage III melanoma patients on the basis of the ECOG trial.16 That and other randomized controlled trials suggested a modest improvement in survival of adjuvant Interferon therapy.20 Based on these data, it is reasonable to consider high dose interferon off-study for selected patients with stage IIB or III disease.20 High dose interferon is associated with high toxicity, however, and lower doses have not demonstrated improved survival.16

The use of melanoma vaccines to stimulate a patient's immune system against the melanoma cells is still investigational.16,21 A number of vaccines have low reported toxicity and appear effective based on comparisons with historic controls and other small trials.21 One recent prospective study utilizing the Mclacine vaccine found improved relapse free survival in patients with two or more of five specific HLA class I antigens (HLA-A2, HLA-A28, HLA-B44, HLA-B45, HLA-C3), helping confirm research suggesting the association between HLA expression and vaccine response.22 Vaccines are thought to have the most potential benefit as adjuvant therapy for those patients with melanoma that has been completely resected but are at high risk of recurrence.21 In those with stage IV disease the vaccines are thought to be less effective.

Isolated limb perfusion (ILP) is a technique in which chemotherapy is administered only to the local area surrounding the tumor through the use of an extracorporeal circuit and a proximal tourniquet.23 A recent trial found that although ILP produced some benefit, it had no impact on survival and therefore is not recommended as a standard adjunct to surgery.17

TREATMENT, STAGE IV

Chemotherapy for melanoma has been disappointing.16,23 Dacarhazine (DTIC) is approved by the FDA and has been shown to have response rates ranging from 10-20%.23 Temozolomide, a precursor of DTIC, and cisplatin have also demonstrated activity similar to DTIC.24 To date, multidrug regimens have not demonstrated a survival advantage in randomized trials over DTIC alone.16,23

Interleukin-2 (IL-2) has shown reproducible antimelanoma activity, but its high toxicity has limited its use.16 Further studies are needed to determine its optimal role in melanoma treatment.

Biochemotherapy has shown some promise, and cisplatin-based regimens including immunologic agents such as Interferon and IL-2 have had the highest response rates.24 One regimen included the combination of cisplatin, vinblastin, and DTIC with IL-2 and Interferon, and had an overall response rate of approximately 60% and approximately 20% complete responses.24 However, the preliminary results of randomized phase III trials comparing multi-agent chemotherapy with or without II,-2 based immunotherapy to date have not shown consistent benefit for biochemotherapy.

Current trials are evaluating the effectiveness of gene therapy in patients with metastatic disease, which is designed to change the malignant phenotype of the tumor or to cause its destruction.16

In the past, melanoma has been considered to be radioresistant, but it now appears that radiosensitivity is in fact variable.16 23 In general, smaller melanoma lesions with shorter doubling time respond better to radiothetapy. Primary tumors are not often treated with radiation, with the exception of lentigo maligna melanoma.23 Radiation has most often been utilized for brain metastases, and may also be useful to reduce the rate of local lymph node recurrence in certain populations, treat soft tissue metastases, of as a palliative tteatment for pain associated with bone metastases.16'23

PREVENTION

Ultraviolet radiation is the most important avoidable cause of melanoma, but it should be recognized that not all melanomas are due to excessive ultraviolet radiation exposure, and some melanomas occur on areas of the body that have seen relatively little sun.3 The evidence linking exposure to tanning lamps with melanoma risk is strong, but the case is not yet completely proven. Furthermote, there are no randomized trials demonstrating the efficacy of any modality for preventing melanoma.

Since intense, intermittent ultraviolet exposure has been most closely linked to melanoma, however, minimizing sun exposure and tanning booth use has been the focus of public health messages. The American Cancer Society has adopted the slogan (originally publicized in Australia) "Slip!Slop!Slap!", which advocates Slip on a shirt, Slop on the sunscreen, and Slap on a hat.4 Clothing is most protective when the weave of the cloth is tight, and one can purchase laundry additives that increase the ultraviolet protection afforded by clothing. Recommended sunscreens are SPF 30 or greater, should be applied before going out in the sun, and reapplied a half hour later and every two hours thereafter while the sun is high in the sky. Shade from hats, trees, or other structures can offer some protection that depends on its density and the proportion of the sky that is blocked.

The glorification of the tan has contributed to the dramatic increase in melanoma rates over the past several decades.3 Public health messages should now reflect our understanding that the healthiest color for your skin is the color you were born with, and efforts to change that color with radiation are unwise.

RESOURCES

The American Cancer Society (www.cancer.org, 1-800-ACS-2345) and the American Academy of Dermatology (www.aad.org) have information about melanoma for the general public. Mole mapping for people with many moles at high risk for melanoma is available from the Pigmented Lesion Unit of University Dermatology in Providence (444-7959). An Interdisciplinary Melanoma Program (444-8852) is available at Rhode Island Hospital where a team typically including a dermatologist, medical oncologist, and melanoma surgeon evaluate patients and make recommendations to the patient and referring physician to guide future therapy and follow-up.

ACKNOWLEDGEMENT

We thank Dr. Neal Ready for his comments on this manuscript.

REFERENCES

1. Bevona C, Sober AJ. Dermatol Clinics 2002;20:589-95,vii

2. seeR Melanoma Statistics, http:// seet.cancer.gov. Verified 7/26/03.

3. Weinstock MA. Hematol/Oncol Clinics NAm 1998; 12:681-98.

4. Weinstock MA. Med & Health/RI 2001:84:234-6.

5. MacKie RM. Dermatol Clinics 2002;20:597-600.

6. Goldstein B, Goldstein A. Am Fam Physician 2001 ;63:1359-68,1374.

7. Balch CM, Buzaid AC, Soong SJ, et al. J Clin Oncol 2001:19:3635-48.

8. Edman RL, Wolfe JT. Am Fam Physician 2000:62:2277-85.

9. Weinstock MA, Martin RA, Risica PM, et al. Am J Prev Med 1999;17:169-75.

10. Screening for Skin Cancer: Recommendations and Rationale. Article originally in Am J Prev MeJ 2001;20(3S):44-6. Agency for Healthcare Research and Quality, Rockville, MD. http://wvvw.ahrq.gov/ clinic/ajpmsuppl/skcarr.htm

11. Kittler H, Pehamerger H, WoIfF K, Binder M. Lancet Oncol 2002;3:159-65.

12. Weinstock MA, Goldstein MG, Dube CE, Rhodes AR. Lettter to the editor. JAMA 1998;280:881-2.

13. Rigel DS, Carucci JA. CA Cancer J Clin 2000:50:215-36.

14. Kelly JW, Yeatman JM, Regalia C, et al. MedJAust 1997:167:191-4.

15. Swanson NA, Lee KK, Gorman A, Lee HN. Dermatol Clinics 2002:20:677-80.

16. Bonaccorsi P, Ansel JC, Armstrong CA. Dermatol Clinics 2001; 19:727-35.

17. Bedrosian I, Gershenwald JE. Surg Clinics NAm 2003; 83:385-403.

18. Piepkorn M, Weinstock MA, Barnhill RL. Arch Dermatol 1 997; 133:995-1002.

19. Ready N, Weinstock MA. Arch Dermatol 2003; 139:in press

20. Ready N, Weinstock MA. Arch Dermatol 2003; 139:in press

21. Bystryn JC. Dermatol Clin 2002;20: 717-25.

22. SosmanJA, UngerJM, Li u PY, et al. Clin Oncol 2002:20:2067-75.

23. Pitts JM, Maloney ME. Dermatol Clinics 2000; 18:157-67.

24. Buzaid AC. Critical Reviews Oncolv/ Hematol2002;44:103-8.

JOHN C. KAWAOKA, MD, AND MARTIN A. WEINSTOCK, MD, PHD

Martin A. Weinstock MD, PhD, is Professor of Dermatology and Community Health, Brown Medical School; Chief of Dermatology, VA Medical Center Providence; Director, Pigrnented Lesion unit; and Chair, Skin Cancer Advisory Group, American Cancer Society.

John C. Kawaoka,, MD, graduated from Brown Medical School, '04.

CORRESPONDENCE:

Martin A. Weinstock, MD, PhD

Dermatoepidcmiology Unit

V A Medical Center - 111D

830 Chalkstonc Avenue

Providence, RI 02908

Phone: (401)457-3333

Fax: (401)457-3332

e-mail: maw@brown.edu

Copyright Rhode Island Medical Society May 2004
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