Chapter 45 Malignant melanoma
2. How common is malignant melanoma in the United States?
In terms of incidence, melanoma is the most rapidly increasing form of cancer in the United States. Its incidence has increased more than 15-fold over the past 40 years. In 2005, the age-adjusted incidence was 24.6 per 100,000 for men and 15.6 per 100,000 for women. More than 59,000 cases of invasive melanoma and approximately 46,000 new cases of melanoma in situ were diagnosed in the United States in 2005. Malignant melanoma is the fifth and sixth most common form of cancer in men and women, respectively. It is now the most common cancer in young women aged 25 to 29 years. The lifetime risk of developing melanoma has increased from 1 in 1500 for someone born in the early 1900s to 1 in 100 for people born in 1990 to an estimated 1 in 41 to 61 for persons born in the year 2007. Incidence rates differ between genders, ages, ethnic groups, and regions. In this regard, before the age of 40, the incidence of melanoma is higher in young women; subsequently the incidence of melanoma increases rapidly in men, but the rate of increase slows in women.
DevCan: Probability of developing or dying of cancer software, version 6.2.1, Statistical Research and Applications Branch, NCI, 2007. Available at: http://srab.cancer.gov/devcan. Accessed July 28, 2010.
Tucker MA: Melanoma epidemiology, Hematol Oncol Clin North Am 23:383–395, 2009.
3. What causes melanoma?
At present the causes of melanoma are not known with certainty, but epidemiologic studies suggest that brief, intense exposure to ultraviolet A (long-wave UVA radiation) contributes to the development of melanoma. Current evidence suggests that long-wave UV radiation (UVA) is more important than short-wave radiation (UVB). Other potential causes include mutations in, or loss of, tumor suppressor genes.
4. What groups have a genetic predisposition to familial melanoma?
Germline genetic mutations and polymorphisms can predispose to melanoma. The major high-penetrance melanoma susceptibility gene locus associated with familial melanoma is CDKN2A, which encodes p16 and p14ARF; p16 and p14ARF regulate retinoblastoma (Rb) nd p53 pathways, respectively. Germline CDKN2A mutations are observed in 25% of familial melanoma.
Meyle KD, Guldberg P: Genetic risk factors for melanoma, Hum Genet 126:499–510, 2009.
5. List the risk factors for melanoma.
Risk factors for malignant melanoma may be divided into genetic factors, environmental factors, and the interaction between the two.
Genetic factors include past medical history of melanoma, familial medical history of melanoma in a first-degree relative, Fitzpatrick type I or II skin, large congential nevi, the presence of dysplastic (atypical) nevi, >50 benign nevi (>2 mm in size), xeroderma pigmentosum, and familial dysplastic mole syndrome (FDMS). In FDMS, which is defined as occurring in families with atypical nevi and two or more blood relatives with melanoma, the estimated prevalence of melanoma approaches 85% by age 48. It is noteworthy that variations in the melanocortin receptor 1 (MCR1) gene, which is a component of pigment diversity, also confer an increased risk of melanoma. Variants differ in their associations with melanoma and nonmelanoma skin cancer, but both red hair and non–red hair variants confer increased risk.
6. List the high-risk groups for developing melanoma.
• Persons with a past medical history of melanoma or a family history of melanoma in a first-degree relative
7. Do all melanomas develop from atypical nevi?
In the past, the development of melanoma has been modeled as a stepwise process from a cutaneous melanocyte through nevus through atypical nevus stages to melanoma in situ and eventually invasive melanoma. However, around 40% to 75% of melanomas develop in normal skin de novo, and, of those melanomas that develop in association with a preexisting nevus, <50% of the nevi are atypical. At present it is difficult to determine whether an atypical nevus is any more likely to become a melanoma than any other nevus or isolated melanocyte. Moreover, it is now clear that a preexisting nevus is not required for a melanoma to develop. It is thought that the discrepancy between melanomas arising in preexisting nevi and de novo melanomas can best be explained by the cancer stem cell theory. In this regard, the risk of melanoma associated with nevi may be due to the potential for secondary mutations within nevi, as well as due to the inherent properties of the stem cell population in individuals with numerous moles. Therefore, although there is a clear association between nevi and melanoma risk, only a portion of this risk may be related to the acquisition of genetic mutations within the nevi. The majority of the risk may be associated with the inherent properties of melanocyte stem cell populations in individuals with numerous nevi.
Friedman RJ, Farber MJ, Warycha MA, et al: The “dysplastic” nevus. Clin Dermatol 27:103–115, 2009.
Elder, DE: Dysplastic nevi: an update, Histopathology 56:112–120, 2010.
8. What are cancer stem cells?
In recent years, there has been increasing evidence demonstrating that melanoma, as well as other solid tumors, contain a subpopulation of cancer stem cells (CSCs). CSCs are rare cells within tumors with the ability to self-renew, drive tumorigenesis, and give rise to a phenotypically diverse tumor cell population. They are considered the source of the primary tumor mass and are thought to be responsible for drug resistance and cancer recurrence. Experimental evidence supports the existence of CSCs in leukemia and melanoma, as well as in breast, brain, colon, pancreatic, and ovarian cancer. Although controversy exists regarding the location of melanoma stem cells in the skin, it has been hypothesized that most melanomas arise from mutations that accumulate in a common precursor CSC, which subsequently drives the establishment of primary and metastatic lesions. This CSC-like precursor is thought to be responsible for the metastatic process, while the less stable progeny are unable to spread locally or distantly. Although definitive markers are still lacking for melanoma CSC, CD133, ABCB5, and ABCG2 have been identified as potential markers.
La Porta C: Cancer stem cells: lessons from melanoma, Stem Cell Rev 5(1):61–65, 2009.
9. Is melanoma a single disease?
No. Melanoma has historically been divided into major subsets based on the clinical and histologic appearance and varied associations with skin color, sun exposure, and anatomic site. However, recent molecular investigations have demonstrated biologically distinct subsets of the disease that vary in their relationship to anatomic site, sun exposure, nevus phenotype, and mutational analysis.
Key Points: Diagnosis of Malignant Melanoma
1. Melanoma, the most aggressive malignant neoplasm arising in the skin, has one of the most rapidly increasing incidence rates of all human malignancies.
3. High-risk patients include those with FDMS, CDKN2A mutations, atypical nevi, >50 benign nevi, large congential nevi, a past medical history of melanoma or a family history of melanoma in a first-degree relative, and xeroderma pigmentosum.
10. What are the molecular pathways in melanoma?
Major molecular pathways that have been implicated in melanoma include p16 (25% to 50%) and p14ARF (25% to 50%), microphthalmia-associated transcription factor (MITF) (50% to 75%), B-Raf (50% to 60%), and PTEN (15% to 25%). Furthermore, the antiapoptotic factor Bcl-2 is often overexpressed in melanoma. It should be stressed, that as noted above, not all melanomas are the same. In this regard, those melanomas that develop in younger patients on intermittently sun-exposed skin demonstrate a greater percentage of B-Raf mutations (>60%) than those melanomas that develop on chronically sun-exposed skin in older patients (<15%). In contrast, those melanomas that develop on chronically sun-exposed skin in older patients demonstrate a greater percentage of N-Ras mutations (20% to 40%). Along the same lines, melanomas that develop on acral and mucosal sites more demonstrate a greater percentage of c-Kit mutations (∼40%) compared to non–sun-exposed (0%) and sun-exposed (30%) melanomas. Further, acral and mucosal melanomas demonstrate a lower percentage of B-Raf mutations (∼20% and ∼10%, respectively).
Bauer J, Bastian B: Genomic analysis of melanocytic neoplasia, Adv Dermatol 21:81–99, 2005.
Miller AJ, Mihm MC: Melanoma, N Engl J Med 355:51–65, 2006.
11. Is there a host immune response to melanoma?
Yes. Observations such as incomplete or complete regression of melanoma, occurrence of vitiligo and halo nevi in patients, as well as increased rates of melanoma in immune suppressed patients indicate that immunologic events appear to play a role in the clinical course of the melanoma and may occasionally cause clinical regressions. Tumor antigen (TA)–specific T cells have been shown to play an active role in eliminating tumors and metastases, as well as in inducing TA-specific T-cell memory responses in a wide range of animal tumor models. Similarly, in vitro studies employing human peripheral blood lymphocytes (PBL) isolated from patients with melanoma have been reported to contain TA-specific CD8+ and CD4+ T-cell precursors, as well as natural killer (NK) cells and macrophages that are capable of killing tumor cell targets after appropriate in vitro activation. CD8+ T cells are believed to play a major role in control of melanoma growth. It is thought that this immunosurveillance of melanoma often fails in patients. This has been the rationale for the development of immunotherapy of melanoma.
12. Describe the clinical appearance of melanoma.
Cutaneous melanoma can have a number of different appearances. Malignant melanomas can begin in a preexisting melanocytic nevus; however, as noted above, the exact percentage of malignant melanomas arising in preexisting nevi versus those arising de novo is controversial. When malignant melanoma arises in a preexisting nevus, the nevus usually demonstrates a change in appearance, such as an increase in size or change in shape, or it may bleed easily when traumatized. A changing nevus is the most important risk factor for melanoma. The development of a new pigmented nevus in any patient over 35 years of age should be evaluated. Classically, early melanoma lesions are characterized by containing different colors, such as different hues of brown, black, red, and blue. Melanoma may also appear as a brown or black discoloration of the nail or as a skin ulcer that does not heal.
13. What are the ABCDEs of melanoma?
The development of a new or changing pigmented lesion is the classic initial presentation of melanoma. A lesion that demonstrates a noticeable increase in size over a period of weeks to months or development of pigment irregularity (black, hues of brown, red, blue, or white) should be evaluated by a physician and biopsied. The ABCDEs of melanoma (Fig. 45-1) are a helpful guideline for determining which moles could be suspicious for melanoma:
• Border and bleeding. The border of any melanocytic nevus should be relatively smooth, with a clear demarcation between the nevus and surrounding normal skin. Nevi that develop irregular or ill-defined borders should be evaluated. B is also for bleeding, and any mole that bleeds needs careful evaluation.
• Color. Most moles have a homogeneous tan or brown color. Moles that develop pigment variegation within an otherwise homogeneous background should be evaluated.
• Diameter. Most melanomas are 0.6 mm in diameter, but an otherwise suspicious lesion that is small might also be malignant.
14. What is dermoscopy?
Dermoscopy, also known as skin surface microscopy, or epiluminescence microscopy, is a noninvasive tool to assist in the diagnosis of melanocytic and nonmelanocytic tumors. A number of dermoscopy algorithms have been developed to aid in the diagnosis of melanocytic tumors. However, these algorithms cannot be applied to lesions located on the face, acral and mucosal surfaces, and the nails. The sensitivity of dermoscopy in the diagnosis of melanoma ranges from 70% to 95%, compared to clinical investigation with the unaided eye, which ranges from 60% to 90%. It is noteworthy that the success of dermoscopy depends critically on appropriate training.
Campos-do-Carmo G, Ramos-e-Silva M: Dermoscopy: basic concepts, Int J Dermatol 47:712–719, 2008.
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