contents
17.1 introduction. . . . 272
17.2 epidemiology. . . . 272
. 17 2 1. Incidence.Trends . . . . 272
. 17 2 2. Race/Ethnic.Differences.in.Incidence.. . 274
. 17 2 3. Gender.Differences.in.Incidence.. . . . . 274
. 17 2 4. Incidence.by.Anatomic.Location. . . . . 274
. 17 2 5. Incidence.Trends.by.Anatomic . . Location .. . . . 275
. 17 2 6. Stage.and.Thickness.Trends.in . . Incidence. . . . 275
17.3 etiology and risk Factors .. .. .. .. .. .. .. .. .. .. .. .. .. .. 276
. 17 3 1. Xeroderma.Pigmentosum.. . . . 276
. 17 3 2. Immunosuppression. . . . 276
. 17 3 3. Familial.Melanoma. . . . 277
. 17 3 4. .Nevus.Phenotype.and.Environmental. Factors .. . . . 278
. 17 3 5. The.Sun.and.Other.Ultraviolet . . Exposures .. . . . 279
17.4 clinical Presentation .. . . . 279
17.5 Pathology .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 279
. 17 5 1. Primary.Skin.Tumor.. . . . 279
. 17 5 2. Sentinel.Node. . . . 281
. 17 5 3. Lymph.Node.Dissection .. .. .. .. .. .. .. .. .. .. 281
17.6 Surgery . . . . 281
. 17 6 1. Treatment.of.the.Primary.Tumor . . . . . 282
. 17 6 2. Lymph.Node.Mapping.. . . . 282
. 17 6 3. Lymph.Node.Dissection .. .. .. .. .. .. .. .. .. .. 283
. 17 6 4. Surgical.Treatment.of.Spitz.Nevus . . . . 283
17.7 Staging.. . . . 283
. 17 7 1. Blood.Tests. . . . 284
. 17 7 2. Imaging.Studies .. . . . 284
. 17 7 2 1. Ultrasound. . . . 284
. 17 7 2 2. Computed.Tomography .. . . 284
. 17 7 2 3. Magnetic.Resonance . . Imaging. . . . 284
. 17 7 2 4. Positron.Emission . . Tomography. . . . 285
17.8 non-surgical therapy. . . . 285
. 17 8 1. Adjuvant.Therapy. . . . 285
. 17 8 1 1. Interferon .. .. .. .. .. .. .. .. .. .. .. .. 285
. 17 8 1 2. Radiotherapy.. . . . 286
. 17 8 2.. Treatment.of.Measurable . . Disease . . . . 286
. 17 8 2 1. Biotherapy. . . . 286
. 17 8 2 2. Bio-chemotherapy. . . . 286
. 17 8 2 3. Chemotherapy.. . . . 286
. 17 8 2 4. Vaccine.Therapy .. . . . 286
17.9 Prognosis. . . . 286
17.10 conclusions.. . . . 287
references . . . .287
Malignant Melanoma
Cynthia.E .Herzog.•.Archie.Bleyer.•..
Alberto.S .Pappo
.
17.1 introduction
Malignant melanoma is one of the most common can- cers in young adults and its incidence has increased dramatically over the past decade in fair-skinned indi- viduals. Despite its relatively good prognosis, the in- creased health-care burden and the fact that it is large- ly preventable render melanoma one of the most important malignances in the age group. As with most cancers that are considered preventable, the most ef- fective preventive strategies are those that are applied early in life. As such, melanoma has a special role in pediatric and young adult oncology. This chapter will examine the epidemiology, etiologies, risk factors, clinical presentations, diagnostic and staging evalua- tion, treatment, and late effects of the disease and its therapies, with special emphasis on incidence trends and early detection.
17.2 epidemiology 17.2.1 incidence trends
The incidence of melanoma has increased steadily in the United States (Figs. 17.1 and 17.2) and in many other countries with a predominantly white popula- tion. For the period 1975–2000, the incidence rate
among 15- to 29-year-olds increased at a statistically significant average annual rate of 1.3% for females (Fig. 17.1), or more than triple in the last quarter cen- tury [1]. The increase in young men was slower, but for men and women over the same interval, 20- to 25- year-olds had a peak increase of >1.2% per year (Fig. 17.2), also a tripling. The current rates for whites are 18.3 per 100,000 for males, and 13 per 100,000 for females [2]. In New Zealand and Australia, the two countries with the highest incidence of melanoma in the world, the age-standardized rates for melanoma are 562 and 289 per year per million, respectively [1].
The age-standardized incidence of melanoma in Scot- land for men and women rose from 35 and 70 per year per million, respectively, in 1979, to 106 and 131 per year per million, respectively, in 1998. This translates to an increase of 303% for men and 187% for women over a 19-year period [4].
In the United States, melanoma has become the fifth most common cancer among men, and the sixth most common cancer in women, accounting for 3.5%
of all malignancies [5]. Furthermore, melanoma is the ninth most commonly diagnosed cancer among 15- to 19-year-olds, the fourth most common among 20- to 24-year-olds, and the most common cancer in females aged 25–29 years.
Melanoma preferentially affects white individuals in the third and fourth decade of life, and its incidence
Average.annual.percent.change.(AAPC).in.incidence.
of.malignant.melanoma.by.gender,.United.States.
SEER.1975–2000.[1]
Figure 17.1
Average.annual.percent.change.(AAPC).in.incidence.
melanoma,.1975–2000,.by.5-year.age.intervals.from.
15.to.44,.United.States.SEER.1975–2000.[1]
Figure 17.2
is linked closely to geographical location (higher rates are seen in countries whose latitudes are closer to the equator), pigmentary traits, and sun exposure pat- terns. The incidence rates for melanoma appear to be stabilizing or even decreasing in many countries, including the United States. This trend is most notice- able among the birth cohort of males and females born in the United States between 1945 and 1950 (Fig. 17.1) [5]. Despite this trend, the Surveillance Epidemiology, and End Results (SEER) section of the National Can- cer Institute (NCI) estimates that in the United States
there were 54,200 cases of melanoma and 7,600 deaths from melanoma in 2003, and it is likely that an increased trend will continue for several years. Based on these findings, melanoma must continue to be viewed as a threat to public health.
Melanoma is rare during the first two decades of life, particularly among pre-pubertal patients. As described in Fig. 17.3 and Table 17.1, the incidence of melanoma increases rapidly with age, with a nearly 100-fold incidence difference between children younger than 5 years of age and young adults aged table 17.1 Incidence,.incidence.trends.and.number.of.cases.of.malignant.melanoma.in.the.United.States.by.age.up.to.
30.years.(Surveillance,.Epidemiology,.and.End.Results,.SEER) .na.Not.available
age at diagnosis (years) <5 5–9 10–14 15–19 20–24 25–29
United.States.population,.year.
2000.census 19,175,798 20,549,505 20,528,072 20,219,890 18,964,001 19,381,336 Average.incidence,.1975–2000,.
per.million 0 7 0 9 2 8 14 0 38 9 69 4
Average.annual.increase,.1975–
2000,.SEER na na na 0 87 1 23 0 58
Estimated.incidence,.year.2000,.
per.million na na 4 0 15 5 44 4 73 8
Number.of.persons.diagnosed.
with.malignant.melanoma,.year.
2000,.United.States 13 19 81 314 841 1,431
Incidence.of.malignant.melanoma,.United.States.
SEER.1975–2000.[1]
Figure 17.3
Incidence.of.malignant.melanoma.ba.race/ethnicity,.
1975–2000,.United.States.SEER.1975–2000.[1]
Figure 17.4
25–29 years. When the incidence of melanoma relative to the incidence of all cancers is compared by age, mel- anoma accounts for less than 1% of malignancies in patients under the age of 10 years, while it accounts for 7.1% of cancers in the 15–19 year age group and for more than 12% of cancers in those 20–29 years of age.
Approximately 427 new cases of melanoma were pre- dicted to be diagnosed in 2000 in the United States in patients under 20 years of age; 74% of these cases were predicted to be in patients 15–19 years of age. These findings are of significant importance since the adoles- cent and young adult population has been grossly under-represented in NCI-sponsored clinical trials. In a linkage study of consolidated files of invasive cancer between 1992 and 1997, the age-specific and age- adjusted registration rates for patients aged 15–19 years was only 24% when compared to 74.3% for patients younger than 5 years of age. Furthermore, the registra- tion rates for carcinomas (melanoma is coded under carcinomas in the SEER registries) for 15- to 19-year- olds was only 6.3% [6].
17.2.2 race/ethnic differences in incidence Melanoma affects predominantly white, non-Hispanic persons, as a fair-skinned population, including those of adolescent and young adult age (Fig. 17.4). Hispan- ics/Latinos have the second highest rates among ado- lescents and young adults, albeit their rates are a dis-
tant second. African Americans/blacks are essentially unaffected by this cancer, at least among those aged below 30 years.
17.2.3 gender differences in incidence Overall, in the United States, males have higher inci- dence rates of melanoma than females [4]. As shown in Fig. 17.5, melanoma in adolescents and young adults has a female predominance, in contrast to the male predominance seen after age 45 years. The male:female ratio (Fig. 17.6) varies more for this cancer than for any other.
17.2.4 incidence by anatomic location In the United States, age-adjusted rates for invasive melanoma have increased for the trunk as well as lower and upper limbs in men and for the trunk and lower limbs in females [4]. The incidence of melanoma tends to be higher in anatomic areas that have been intermit- tently exposed to sun (trunk and limbs) in patients younger than 50 years of age, whereas chronically sun- exposed areas such as the head and neck predominate in older patients [4]. Figure 17.7 demonstrates that in the 15- to 29-year age group, females have a higher inci- dence than males of melanoma of both the lower and upper limbs and trunk. Only the incidence of head and neck melanoma is higher in males in this age group.
Incidence.of.malignant.melanoma.by.gender,.
United.States.SEER.1975–2000.[1]
Figure 17.5
Female:male.ratio.of.malignant.melanoma.as.
function.of.age.at.diagnosis,.United.States.SEER.
1975–2000.[1]
Figure 17.6
17.2.5 incidence trends by anatomic location
The rising incidence of melanoma over time has been well established (Figs. 17.1 and 17.2); however, as shown in Fig. 17.8, this increase has been slowing in age groups younger than 45 years. Although the over- all incidence trend in younger patients appears unchanged during the past decade (Fig. 17.8), the inci- dence of melanoma for 15- to 29-year-old females had been increasing in all age groups at all of the anatomic locations evaluated except the upper extremity
(Fig. 17.9). In males younger than age 30 years, there has been no statistically significant change in the inci- dence of melanoma during the past quarter century at any of the anatomic sites evaluated (Fig. 17.10). Some of the increase in melanoma at specific anatomic sites may be explained by better reporting.
17.2.6 Stage and thickness trends in incidence
The majority of invasive melanomas (86.4%) in the United States are localized and only 4% have distant Incidence.of.melanoma.by.gender.and.site,..
.United.States.SEER.1975–2000.[1]
Figure 17.7
Change.in.incidence.of.malignant.melanoma.by.era,.
United.States.SEER.1975–2000.[1]
Figure 17.8
Average.annual.percent.change.(AAPC).in.
.malignant.melanoma.in.males.by.site,.United.
States.SEER.1975–2000.[1]
Figure 17.10
Average.annual.percent.change.(AAPC).in.
.malignant.melanoma.in.females.by.site,.
.United.States.SEER.1975–2000.[1]
Figure 17.9
metastases at the time of initial diagnosis. Over the last 15 years there has been a shift toward an increased number of in situ melanomas, with the percentage increasing from 3.6% in 1973 to 35.3% in 1998. In the United States, between 1973 and 1997, the rate of mel- anoma for each stage, as well as the estimated annual percentage change in each tumor stage was higher for males than for females [7]. During the same time period, rates for patients under age 40 years decreased for each tumor stage in males, while in females only rates for metastatic disease decreased. However, the rates increased statistically for regional disease among females. For patients aged 40–59 years, the rates for localized disease increased only among males and for those 60 years of age or older, statistically significant upward trends were evident for localized and regional disease among males and for localized disease among females.
17.3 etiology and risk Factors
Pre-pubertal melanoma is rare, accounting for less than 1% of cases of melanoma and for 0.9% of all malignan- cies in patients younger than 15 years of age. Richard- son et al. have defined pre-pubertal melanoma as a melanoma that has been diagnosed unequivocally by histologic examination before sexual maturity [8]. The authors have further divided this entity into three cat- egories based on the age at which melanoma was diag- nosed: congenital (in utero to birth), infantile (birth to 1 year), and childhood (1 year to puberty). Among 23 cases of infantile and congenital melanoma identified in the literature by the authors, 11 were present at birth and 12 developed during the 1st year of life. The dis- ease arose from intermediate and large-sized nevi in 57% of cases, and from smaller cutaneous nevi in 26%
of cases. Only one child had a true de novo malignancy and three had transplacentally acquired disease. The latter phenomenon has been reviewed recently [9]. In this report, 6 of 15 cases of transplacentally acquired fetal malignancy were due to melanoma (40%), and prematurity was a common presenting feature. Five of the affected infants died within the first 10.5 months of life and the disease became evident in the affected infant anywhere from 11 days of life to 8 months of life.
The authors recommend that placentas of all women with suspected metastatic melanoma during pregnancy should be closely evaluated by gross and microscopic examination including immunohistochemical staining for melanoma, and that unaffected newborns be fol- lowed for up to 24 months postpartum.
17.3.1 Xeroderma Pigmentosum
Xeroderma pigmentosum is a rare autosomal recessive disorder characterized by increased cutaneous light sensitivity and a greater than a 1,000-fold increase in the frequency of sunlight-induced cancers. Neurologi- cal abnormalities are present in approximately 20–30%
of these patients. In patients with xeroderma pigmen- tosum, the median age at diagnosis of skin tumors is approximately 8 years; however, the median age at diagnosis of melanoma, which occurs in 5% of these patients, is 19 years. Melanomas in this population more commonly affect the head and neck. Avoiding sun exposure is the mainstay of prevention, but admin- istration of retinoids has been found to decrease the incidence of cutaneous neoplasms [10, 11].
17.3.2 immunosuppression
Patients with inherited immune deficiencies have an increased risk of developing melanoma [12]. Organ transplant recipients have a 1.6- to 4-fold increased risk of developing melanoma when compared to the general population. In this population, melanomas tend to affect patients with a light complexion, a ten- dency to freckle, and light eyes and hair. Melanoma accounts for 6.2% of cancers after organ transplanta- tion in adults and for 15% in children [13].
A five-fold increased risk of melanoma has been described following the use of conditioning regimens that incorporate total body radiation prior to allogenic bone marrow transplantation. The relative risk of developing melanoma is 8.2 after higher doses of total- body irradiation (>10 Gy per single dose, or >13 Gy for fractionated dosing) and a relative risk of 4.5 was described for patients who received T-cell-depleted donor marrows [14].
More recently, the administration of local radiother- apy at doses of >15 Gy and the administration of alkyl-
ating agents and spindle cell inhibitors have also been reported to increase the risk of melanoma. Interest- ingly, children treated for gonadal tumors had an increased risk of developing melanoma [15]. The latter observation has recently been confirmed by Avril et al.
[16], suggesting that the relationship between germ-cell tumors and melanoma needs to be explored further.
There have been a variety of reports documenting the association between melanoma and an increased number of nevi that measure less than 5 mm in patients who are affected with human immunodeficiency virus [17–19]. Survivors of childhood leukemia are also at increased risk for developing melanoma. These chil- dren have been shown to have higher counts of nevi, higher nevus densities, and a large number of melano- cytic nevi more than 6 mm in size when compared to the general population [20, 21]. These findings empha- size the importance of host immunity in the develop- mental of melanoma and should reinforce the need for cautious follow up of these patients.
17.3.3 Familial Melanoma
A family history of melanoma in first- or second- degree relatives of patients with melanoma can be elic- ited in up to 10% of cases. Germ-line inactivating mutations of the CDKN2A gene have been docu- mented in 25–40% of families with three or more affected individuals, and in up to 15% of individuals with multiple primary melanomas [22, 23]. CDKN2A encodes two tumor-suppressor proteins: p16 and ARF, which are known to negatively regulate the retinoblas- toma and p53 pathways, respectively. Their loss has been documented to predispose to the development of melanoma. Mutations of the CDKN2A gene that affect p16 are much more common than those that affect the p14 gene. The estimated frequency of a mutated p16 gene in the general population is 0.01%, and the inci- dence of mutations in sporadic melanoma cases is only 0.2% [22, 24]. Similarly, the incidence of germ-line CDKN2A mutations in patients with early-onset dis- ease, a population that would resemble a familial can- cer syndrome, is also exceedingly low (1.6%) [25].
It is estimated that in patients with germ-line CDKN2A mutations, the overall cumulative risk of developing melanoma by age 50 years is 0.3, and by
age 80 years is 0.67 [26]. However, the penetrance of the gene can be modified by the geographical location and the degree of ultraviolet exposure of the popula- tion. For example, by age 80 years, the age-specific penetrance estimate in Europe was 0.58, whereas the estimates for patients in the United States and Austra- lia were 0.76 and 0.91, respectively [26]. Among sub- sets of families with germ-line CDKN2A mutations there also appears to be an increased risk for the devel- opment of pancreatic cancer and oral squamous cell carcinomas [5, 22]. Further collaborative efforts from the Melanoma Genetics Consortium are underway to help clarify these complex cancer associations. ARF mutations, although very rare, have also recently been demonstrated to predispose to the development of melanoma, as well as nervous system tumors [22].
Activating mutations of the CDK4 gene, which neg- atively regulates the pRb pathway, have been described in three families. All mutations have been clustered within codon 24 and the clinical characteristics of these patients are similar to those seen in patients with CDKN2A mutations [22, 27].
The melanocortin receptor 1 gene (MC1R) is a key determinant of the pigmentary process. In humans, three variants of the MC1R gene have been associated with the red hair phenotype (RHC), which includes red hair, fair complexion, inability to tan, and a ten- dency to freckle [28]. Patients with one or more of the variants of the MC1R gene have a compromised capa- bility of inducing the switch from pheomelanin to eumelanin and therefore have a compromised ability to respond to damage by ultraviolet light. The presence of one or more MC1R variants has been associated with the red hair phenotype and an increased pene- trance of mutations in CDKN2A-melanoma-prone families [29, 30].
Other recently described low-penetrance genes that are associated with increased melanoma risk include the rare alleles at the C500G and C540T polymor- phisms of the CDKN2A gene, and null GSTM1 (gluta- thione S-tranferase gene) phenotype [22, 31, 32].
Finally, activating somatic BRAF mutations have been identified in approximately two-thirds of malig- nant melanomas and in common benign and dysplas- tic nevi. However, germ-line BRAF mutations are extremely rare (0.29%), suggesting that the BRAF gene
is an important initiating factor in the transformation of melanocytic neoplasia, but that it does not contrib- ute significantly to melanoma susceptibility [33, 34].
17.3.4 nevus Phenotype and environmental Factors
The potential for malignant transformation of small congenital nevi, which affect up to 1% of all newborn infants, continues be a source of debate. A study by Mackie et al. revealed that melanoma develops in a small nevus that was present either at birth or during early childhood, in 44% of patients under the age of 30 years [35]. However, two recent studies do not sup- port the view of an increased risk of melanoma in patients with small or medium-sized congenital nevi [36, 37].
Patients with large congenital melanocytic nevi (defined as those that exceed 20 cm in diameter during adulthood) have approximately a 5–15% lifetime risk of developing melanoma, and the risk is greatest in the first decade of life [38]. The risk of cutaneous melanoma in these patients appears to be confined to those with axial lesions, and an equal risk of extra-cutaneous involve- ment has recently been documented [39]. Patients with symptomatic neuro-cutaneous melanosis have an increased risk of developing melanoma. Most of these patients have large congenital nevi in the scalp or poste- rior axial location, and the prognosis is poor [40, 41].
The non-symptomatic form of neuro-cutaneous mela- nosis has recently been described and is characterized by the presence of focal magnetic resonance imaging signal abnormalities in the brain in up to 25% of patients with large congenital nevi, and the large majority of these patients have not developed melanoma [42].
A two- to fourfold increased risk of melanoma has been consistently documented with increasing number of acquired nevi [43]. Given the close association between the presence of acquired nevi and melanoma, multiple epidemiologic studies have been performed examining the association between environmental and constitutional factors and the development of nevi and melanoma in various populations. In a study of over 3,000 Italian school children age 13–14 years, patients who burned easily following their first sun exposure and those with an ability to tan had an increased num-
ber of nevi. The nevus density was directly related to recurrent episodes of sunburn, and large nevi size was closely associated with the presence of a lighter pig- mentary trait and a propensity to sunburn easily. In another study from Queensland, 111 schoolchildren aged 13–14 years who were followed for up to 5 years, the degree of shoulder freckling and habitual sun expo- sure were the most important determinant of melano- cytic nevi in adolescents in a area of high sun exposure [44]. In another study of 61 children from Queensland diagnosed with melanoma at 13 and 14 years of age, the presence of multiple large nevi, sun-sensitive phe- notype, and inability to tan strongly, predicted the risk of melanoma development in this population [45]. In this study, a family history of melanoma was present in nearly one-third of cases and was associated with an increased risk of developing melanoma, suggesting that heredity plays an important role in the predisposi- tion to childhood melanoma. In a study of 250 eligible cases of melanoma in patients aged 15–19 years, the strongest predictor of melanoma development was the presence of more than 100 nevi 2 mm or more in diam- eter. Other risk factors included pigmentary traits that are commonly associated with the development of melanoma, such as, red hair, blue eyes, inability to tan after prolonged exposure, heavy facial freckling, and a family history of melanoma. Only 2 of 147 cases tested had a CDKN2A mutation. A slightly higher number of cases reported more than ten episodes of peeling sun- burn, and a statistically significant increased risk of melanoma was documented with increasing number of peeling or blistering sunburns [46].
Dysplastic nevi or clinically atypical moles affect approximately 5% of the United States population and are known to confer an increased risk of melanoma. In 1 study of 716 patients with melanoma, the presence of 1 dysplastic nevus was associated with a 2-fold risk of melanoma, whereas 10 or more nevi conferred a 12- fold risk [43]. In a study of 33 families with two or more members with invasive melanoma, comprising a total of 844 subjects, the authors identified 86 cases of melanoma in 37 individuals over a follow-up period of 2–25 years. Of these melanomas, 51 were found to have a precursor lesion and 32 met the criteria for dys- plastic nevi. In an earlier study, 37% of children in melanoma-prone families had dysplastic nevi, and
cases of pediatric melanoma only occurred in those individuals with these nevi [47].
17.3.5 the Sun and Other Ultraviolet exposures
The sun and other ultraviolet exposures are a major risk factor for the development of melanoma. Analyses of 29 case control studies demonstrated a positive association between intermittent sun exposure and melanoma with an odds ratio of developing melanoma of 1.71. In this study there was also a twofold increase of melanoma following sunburns at any age [48]. The current data are consistent with cumulative exposure being important whether acquired as a adult or as a child, and ultraviolet exposure is important in all stages of melanoma development.
Whether sunscreens protect or enhance the risk of developing melanoma continues to be a source of debate.
A meta-analysis of 20 studies of sunscreen use and mel- anoma in humans did not support a positive association between the use of sunscreen and melanoma develop- ment [49]. Among adolescents in Australia, the lack or rare use of sunscreen under the age of 5 years doubled the risk of melanoma [46]. In another trial the use of sunscreen decreased the number of new nevi in children [5]. This could indicate that sunscreens might protect against melanoma, since the number of nevi is directly correlated with the risk of developing melanoma.
The use of tanning beds has been popular only since the 1970s, thus there is limited information regarding its effects on the risk of developing melanoma. How- ever, in the United States the use of tanning devices has been associated with an increased risk for squamous- and basal-cell carcinomas. In a population study from Sweden, a significantly increased risk was found for developing melanoma with regular exposure to sun beds after adjusting for hair color, race, nevi, skin type, and number of sunburns [4].
17.4 clinical Presentation
An increased risk of melanoma at an early age is known to occur in the setting of large congenital nevus, xero- derma pigmentosum, and dysplastic nevi. However
the majority of melanomas in adolescent and young adult patients occur in patients with none of these risk factors. The patient often does not consider the possi- bility of melanoma and presents late. More often the physician fails to consider the diagnosis of melanoma in younger patients, and therefore delays removal of the lesion. Failure to consider the possibility of mela- noma in the adolescent and young adult population can delay the diagnosis. In two reports on melanoma in pediatric and adolescent patients, delays in diagno- sis were reported in about half of the patients [50, 51].
In the SEER data, 6,112 cases of cutaneous mela- noma have been reported in patients age 15–29 years.
Melanoma in this population has a female predomi- nance, in contrast to the male predominance seen with older adults (male to female ratio of 1:1.7) [52]. The most common primary site was the trunk, followed by the upper and lower limbs. The lowest incidence was in head and neck tumors, and this is the only site where there was a slight male predominance.
As in older adults, changes in the appearance of a pig- mented lesion should alert the physician to the possibil- ity of melanoma in younger patients. The most common clinical presentation includes increasing size, color change, bleeding, itching, or palpable adenopathy. The initial approach for a suspected melanoma is a biopsy procedure. This can be a punch or excisional biopsy, to confirm the diagnosis and determine pathologic criteria that will then dictate further surgical management.
17.5 Pathology
Melanomas in adolescents and young adults are patho- logically similar to those in older adults. However, this age group has a higher incidence of Spitz nevus, which must be distinguished from melanoma.
17.5.1 Primary Skin tumor
All suspicious skin lesions should be removed and sent for pathologic review. The revised American Joint Committee on Cancer (AJCC) melanoma staging cri- teria [53] provides a reproducible model that reflects the natural history of melanoma and incorporates important prognostic variables that are predictive of
table 17.3 Tumor.staging
clinical staging Pathologic staging
0 Tis N0 M0 0 Tis N0 M0
1A T1a N0 M0 1A T1a N0 M0
1B T1b
T2a N0 M0 1B T1b
T2a N0 M0
IIA T2b
T3a N0 M0 IIA T2b
T3a N0 M0
IIB T3b
T4a N0 M0 IIB T3b
T4a N0 M0
IIC T4b N0 M0 IIC T4b N0 M0
III Any N+ Mo IIIA T1–4a
T1–4a N1a
N2a M0
IIIB T1–4b
T1–4b T1–4a T1–4a T1–4a
N1aN2a N1bN2b N2c
M0
IIIC T1–4b
T1–4b T1–4b Any.T
N1bN2b N2cN3
M0
IV Any Any Any IV Any Any Any
table 17.2 Tumor-Nodes-Metastasis.(TNM).classification
tumor thickness Ulceration
T1 ≤1 0.mm a:.no.ulceration,.II/III
b:.ulceration.or.IV/V
T2 1 01–2 0 a:.no.ulceration
b:.ulceration
T3 2 01–4 0 a:.no.ulceration
b:.ulceration
T4 >4 0 a:.no.ulceration
b:.ulceration nodes number of positive nodes Ulceration
N1 1 a:.micro
b:.macro
N2 2–3 a:.micro
b:.macro
c:.in.transit,.satellite.with.negative.nodes N3 ≥4,.or.matted,.or.in.transit,.satellite.with.
positive.nodes
clinical outcome (Tables 17.2 and 17.3). The pathology report for primary cutaneous melanoma should incor- porate these prognostic variables, including tumor thickness, level of invasion, presence of ulceration, presence of perineural, venous or lymphatic invasion, presence of lymphocytes, presence of regression, and mitotic index [54]. In the revised AJCC melanoma staging criteria, the most important prognostic factors for the primary tumor were thickness and ulceration.
Level of invasion was only of prognostic value in mela- nomas <1 mm in thickness [53].
The distinction between Spitz nevus and melanoma, particularly among younger patients, can be controver- sial and difficult. Some authors advocate the term atypi- cal Spitz tumor to describe controversial melanocytic lesions that resemble Spitz nevi, but raise the diagnostic possibility of melanoma [55]. Furthermore, these lesions may be classified as being at “high risk” for aggressive behavior based on presence of ulceration, large size, asymmetry, deep extension, hypercellularity, cytologic atypia, and prominent and atypical mitosis [55].
17.5.2 Sentinel node
Sentinel-node biopsy allows for the careful pathologic assessment of a limited number of lymph nodes. The analysis of the sentinel node(s) has evolved over time.
Initial analyses consisted of routine hematoxylin and eosin (H&E) staining of the bisected node. This method has been shown to under-estimate the presence of dis- ease. Serial sections and immunohistochemistry (IHC) increases the sensitivity for detecting microscopic lymph node metastases. Retrospective evaluation of lymph nodes using serial sections and IHC has been performed for patients with a false-negative sentinel lymph node (SLN) biopsy. These patients had nodal recurrences in the lymph node basin for which the SLN was initially reported to be negative. More detailed analysis of the SLN has revealed the presence of senti- nel-node tumor in 80% [56] and 31% [57]. IHC stain- ing can be performed with a variety of melanoma-spe- cific antibodies, including those for detection of S100, tyrosinase, gp100 (HMB-45), and melan-A (melanoma antigen recognized by T cells-1, MART-1).
More recently reverse transcriptase-polymerase chain reaction (RT-PCR) has been evaluated as a tool
for the detection of occult metastases in SLNs and found to further increase the percentage of positive nodes detected [58]. Kuo et al. have shown that RT- PCR can be done using archival tissue, thus eliminat- ing the need for additional, immediate processing to obtain fresh tissue for RT-PCR [59]. Using four mark- ers (tyrosinase, MART-1, and tyrosinase-related pro- tein 1 and 2, TRP-1 and TRP-2, respectively) to evalu- ate paraffin-embedded specimens, they were able to upstage 25% of negative SLNs based on two or more positive markers by RT-PCR. Of the ten patients whose disease was upstaged by RT-PCR, eight developed recurrence, while two have not.
Although RT-PCR increases the percentage of posi- tive nodes, part of this increase may be due to false positives. Cook et al. reported a 7.2% false-positive rate due to the detection of capsular or trabecular nevus cells by RT-PCR [60]. Based on these findings, the European Organization for Research and Treat- ment of Cancer has adopted a protocol for evaluating SLNs using serial sectioning and IHC, without the use of RT-PCR.
17.5.3 lymph node dissection
When patients undergo lymph node dissection (LND), all lymph nodes should be submitted in their entirety with each node evaluated. The total number of nodes evaluated, as well as the number that are positive for tumor should be reported. The involvement of more than one node is predictive of a worse outcome [61].
17.6 Surgery
Early detection and surgical removal of any suspicious pigmented lesion is the mainstay of therapy for mela- noma. The extent of surgery is determined by clinical and pathologic findings. The patient should be evalu- ated clinically for evidence of regional disease, includ- ing satellite lesions, in transit lesions, or lymph node metastasis. Patients should also be evaluated clinically for evidence of distant metastases. With thicker mela- nomas or evidence of regional or distant metastases, patients should be evaluated for metastases using imaging studies.
17.6.1 treatment of the Primary tumor There are no specific guidelines for the surgical treat- ment of melanoma in adolescent and young adult patients. Thus, recommended guidelines for resection of primary melanomas in adolescent and young adult patients should follow the same principles as those published for adult melanoma. The margins of exci- sion are determined by the thickness and site of the primary tumor. Generally, the margins employed are 0.5 cm for in situ lesions, 1 cm for lesions less than 1 mm [62, 63], and 2 cm for lesions 2–4 mm [64]. The margins of excision for tumors 1–2 mm are more con- troversial, with recommendation for margins of 1–
2 cm [62, 64]. For lesions greater than 4 mm, a margin of at least 2 cm is recommended, but there have been no prospective trials. More conservative margins are often employed in anatomically restricted areas such as the face.
17.6.2 lymph node Mapping
SLN biopsy has become a standard staging procedure in adult melanoma and should be incorporated into the surgical management of younger patients. Prior to the introduction of SLN biopsy, the alternative for patients with intermediate-thickness melanoma, who were at risk of developing regional disease, was either an elective LND (ELND) or observation. ELND was an unappealing alternative due to the facts that only 15–20% of patients were ultimately found to have evi- dence of lymph node involvement and ELND is asso- ciated with a high incidence of morbidity, including seroma formation, infection, and edema. Morton et al.
reported the first use of SLN biopsy in melanoma in 1992 [65]. An SLN was identified in 82% of patients, with tumor identified by H&E in 12% of the nodes, and by IHC in 9% of the nodes. Subsequent evaluation of the remainder of the lymph nodes, after a complete LND revealed only 1% of the non-sentinel nodes were positive for tumor.
As with the pathologic evaluation of the SLN, the technique used for identification of the SLN(s) has evolved over time. In the initial study, isosulfan blue or patent blue-V was injected around the primary mela- noma to enable identification of a blue sentinel node in
82% of patients [65]. Subsequent use of intra-operative lymphoscintigraphy with intra-dermal injection of
99mTc-sulfur colloid or 99mTc-human serum albumin improved the identification of the SLN. The intra- operative use of both isosulfan blue and 99mTc-sulfur colloid with the use of a hand-held gamma counter results in the identification of a SLN in almost 100% of cases [56, 58]. The false negative rate, that is patients who are reported to have a negative SLN but subse- quently relapse in the nodal region from which the SLN was taken, is less than 10% with experienced sur- geons [56, 66].
Lymphoscintigraphy can identify the lymph node basin(s) at risk in cases where the primary melanoma is located on the trunk or in the head and neck area where one or more of several lymph node basins can be involved. Lymphoscintigraphy also allows for detec- tion of abnormal lymph node drainage sites in 5–7% of patients [67–70]. However, use of the hand-held gamma counter intra-operatively appears to be more sensitive for the detection of 99mTc-sulfur colloid in unusual locations. SLNs were identified in unusual sites in 7–12% of melanomas on the trunk, 0–6% of head and neck melanomas, and 4–7% and 1–2% of melanomas of the upper or lower limbs, respectively.
The unusual site may be the only site of lymph nodes identified as harboring occult disease.
The morbidity of SLN biopsy is low. A report from the Sunbelt Melanoma Trial gave a 4.6% incidence of complications after SLN biopsy, in comparison to an incidence of 23.2% after SLN biopsy and complete LNDs. Complications for both procedures were more common in the groin than in the axilla [71].
A positive SLN is the single most important prog- nostic factor in patients that have clinical stage I or II melanomas. Because of this prognostic significance, as well as the fact SLN biopsy sampling is both sensitive and specific, and has a low morbidity, the recently revised AJCC Staging for Cutaneous Melanoma rec- ommends SLN biopsy for patients with melanomas
>1 mm in thickness without evidence of regional or distant metastases on exam (T2-4N0M0) [53].
The indication for lymph node mapping and SLN biopsy in patient with thin melanomas (<1 mm thick) needs further evaluation. Using the new AJCC staging, patients with thin melanomas, but with ulceration or
level IV or V invasion (T1b) have a worse outcome than patients with thin melanomas without these fea- tures [61]. At the MD Anderson Cancer Center, patients with T1b melanomas routinely undergo SLN biopsy. A positive SLN has been found in 4.7 % of these cases [72]. Bleicher et al. identified a positive SLN in 1.7% of 118 patients with melanoma ≤0.75 mm in thickness, in 3.9% of 154 patients with 0.76–1 mm tumors, and 7.1% of 240 patients with 1.01–1.5 mm tumors [73]. There was evidence in the Bleicher study that the incidence of SLN involvement in thin melano- mas was higher in patients under age 44 years.
Although lymph node mapping and SLN biopsy is not routinely recommended in older adults with thin mel- anomas, it should be considered in adolescent and young adult patients.
17.6.3 lymph node dissection
When melanoma is detected clinically or microscopi- cally in any lymph nodes, further treatment with LND is recommended. Whether selective LND (SLND) improves survival is not yet documented [66, 74]. In a retrospective study of stage III patients, when survival was measured from the time of the LND procedure, those who had SLND did better than those who had clinical LND. However, no benefit was seen for SLND in comparison to clinical LND when survival was measured from the time of primary tumor resection [75]. This suggests that while SLND may be of prog- nostic value, it does not impact ultimate outcome.
17.6.4 Surgical treatment of Spitz nevus Spitz nevi can be difficult to distinguish from mela- noma histologically, and are more likely to occur in adolescent and young adult patients than in older adults. In cases where melanoma cannot be ruled out as a possibility, the patient should undergo both wide local excision and SLN biopsy. In a survey of derma- tologists in the United States, over 90% of the respond- ing dermatologists stated that they would biopsy sam- ple a lesion suspected of being a Spitz nevus, and 43%
favored a complete excision. Most respondents selected a 1- to 2-mm margin of excision and 69% recom- mended complete reexcision in cases where the lesion
was initially incompletely excised. In this survey, only 8% of respondents recalled ever seeing cases of meta- static melanoma arising from lesions designated as Spitz nevus [76].
The role of SLN biopsy sampling in controversial melanocytic lesions such as Spitz nevus remains to be established. Involvement of the SLN in these cases can further suggest a diagnosis of melanoma; however, iso- lated regional-node metastases have been reported in patients with Spitz nevus with no subsequent distant metastases. Nevertheless, the “benign” nature of Spitz nevus with regional metastases is questionable [77].
Two studies have been reported on the evaluation of SLN in patients with atypical Spitz nevi in which a diagnosis of malignant melanoma could not be defini- tively excluded [78, 79]. In the first report, five out of ten patients had a positive SLN. All are without evi- dence of disease at a mean follow-up of 34 months [79]. In the second report, 8 out of 18 patients (44%) had a positive SLN and all were without evidence of disease at a mean follow-up of 12 months [78]. It is clear that further evaluation is needed to determine the natural history of these controversial melanocytic lesions.
17.7 Staging
The revised staging system developed by the AJCC [53] incorporates pathological and clinical factors that are predictive of clinical outcome. For localized dis- ease, there are new thresholds for melanoma thickness and recognition that the presence of ulceration is an important predictor of outcome. The results of SLN biopsy have also been incorporated to account for the reported differences in outcomes between pathologi- cally and clinically involved nodes. For patients with nodal spread, the new system recognizes the impor- tance of the number of lymph nodes involved, as well as the prognostic significance of ulceration and in- transit or satellite metastases. For patients with meta- static disease, the new staging system incorporates a description of sites of metastases and the diagnostic value of serum lactic dehydrogenase (LDH). It is vital that trials for melanoma in adolescent and young adult patients incorporate this staging system in order to
facilitate the interpretation of results from different institutions and patient populations.
Given the scarce literature describing the use of SNL biopsy for pediatric melanoma [80, 81] and the suggestion that younger patients have a higher inci- dence of positive SLN biopsy specimens with thin melanoma [73], future trials must mandate the routine use of SLN biopsy sampling in order to determine the prognostic and therapeutic value of this procedure in adolescent and young adult patients and to compare these results with those in the older adults.
For patients with localized disease, a complete blood count, serum chemistries including liver func- tion tests, and a chest radiograph are sufficient to screen for metastatic disease. For patients with thicker melanomas or evidence of regional or distant metasta- ses, further workup with cross-sectional imaging is indicated.
17.7.1 Blood tests
There is no good blood test to screen melanoma patients for metastatic disease, although LDH and alkaline phosphatase have long been used. Recently, several markers have been evaluated for their ability to improve staging and prediction for outcome in patients with melanoma. Tyrosinase, an enzyme involved in melanin synthesis, has been one of the most widely studied. Other markers include S-100β, melanoma- inhibiting activity (MIA), and MART-1.
Elevated LDH is included in the new AJCC staging criteria as a variable for staging patients with meta- static disease [53]. Patients with stage IV disease and elevated LDH levels have been shown to have a worse outcome, with no additional prognostic information added by the evaluation of S-100β or MIA in these patients [82].
The value of serum markers in stage I–III disease is less clear. Detection of circulating melanoma cells by multimarker RT-PCR at the time of diagnosis did not increase the ability to predict progression-free survival when evaluated by multivariant analysis including stage [83]. Others have suggested that monitoring serum markers in patients with melanoma allows for the earlier detection of recurrence [84, 85]. Prospec- tive studies are needed to determine the role of tumor
marker analysis in the follow-up of melanoma patients.
17.7.2 imaging Studies
A baseline chest x-ray to evaluate for metastases is indicated for all patients except those with thin mela- noma. Data regarding which patients need further imaging studies and, indeed, the most appropriate imaging studies continues to evolve.
17.7.2.1 Ultrasound
Ultrasound is useful for the evaluation of clinically suspicious lymph nodes and can be used to guide fine- needle aspiration for the pathologic evaluation of sus- picious nodes. It can also be used to evaluate liver metastases, but is not as sensitive as computed tomog- raphy (CT) or magnetic resonance imaging (MRI).
17.7.2.2 computed tomography
Buzaid et al. [86] looked at 89 patients with locore- gional disease who were asymptomatic and had a nor- mal LDH and chest x-ray. Further imaging revealed true positive findings in 6 cases and false positives in 20 cases. They therefore recommended only chest x- ray and CT scan of the abdomen as baseline exams.
For patients with recurrence below the waist, a CT of the abdomen is recommended, and, with recurrence in the head and neck region, a CT of the neck. How- ever, a study at St. Jude Children’s Hospital identified clinically undetectable metastases in 25% of pediatric patients with thick localized melanomas or melano- mas arising at an unknown primary site [87], suggest- ing that younger patients have a higher risk of clini- cally undetectable metastases. This should be further evaluated in pediatric, and adolescent and young adult patients.
17.7.2.3 Magnetic resonance imaging
MRI, rather than CT, should be done to look for brain metastases. However, in the absence of symptoms, the routine use of MRI to assess the brain is not recom- mended.
17.7.2.4 Positron emission tomography Positron emission tomography (PET) scanning has been approved for the evaluation of melanoma. PET is not as sensitive as SLN biopsy sampling in detecting subclinical regional lymph node involvement [88], but is more sensitive than CT in detecting distant metasta- ses, except for pulmonary metastases [89] In patients with known recurrence of melanoma, PET imaging can identify additional unsuspected sites of disease in up to 20% of cases when compared to CT scanning [90, 91].
Pediatric patients frequently have reactive lymph nodes that raise concerns about metastatic disease. In these cases, PET may be helpful in differentiating reac- tive nodes from metastatic nodes. To date, there are no published studies using PET imaging to stage pediatric melanoma.
17.8 non-surgical therapy 17.8.1 adjuvant therapy 17.8.1.1 interferon
The role of interferon in the treatment of melanoma remains under study. The Eastern Cooperative Oncol- ogy Group (ECOG) has performed several trials with interferon. In the first trial (1684) patients were ran- domized to either observation or high-dose interferon (HDI) [92]. HDI consisted of interferon α-2b 20 MU/
m2/day given intravenously 5 days a week for 4 weeks, followed by 10 MU/m2/day given subcutaneously 3 days a week for 48 weeks. The first trial enrolled 287 patients with melanomas >4 mm or with regional lymph node involvement. At a median follow-up of 7 years, a significant improvement in relapse-free sur- vival (RFS) and overall survival (OS) was seen in patients who received HDI. The benefit of HDI was most marked in patients with clinically detectable lymph node metastases.
A subsequent trial (1690) compared HDI, low-dose interferon (LDI), and observation [93]. In an attempt to lower the rate of interferon-associated toxicity, LDI was given at a dose of 3 MU/m2/day given subcutane-
ously 3 days a week for 2 years. With 608 patients enrolled and a median follow up of 52 months, a sig- nificant improvement in RFS was observed with HDI, but there was no significant difference in OS. Several differences between these two trials may account for the differences in outcome. There was higher propor- tion of patients on 1684 with lymph node involvement and a higher proportion with regional recurrence. The outcome on the later trial was better in comparison to the former trial for both the observation arm and the HDI arm, suggesting an impact of improvement of surgical staging and treatment. In addition, a substan- tial number of patients on the observation arm who relapsed were treated with salvage HDI therapy, thus potentially prolonging the OS in this group.
A third trial (1694) compared HDI to GM2-KLH/
QS-21 vaccine therapy [94]. A total of 880 patients were randomized, prior to early termination of the trial due to a significantly better RFS and OS with HDI.
The greatest difference was seen in node-negative patients. There was no observation arm in this study, but vaccine therapy did not appear to negatively impact outcome and may have provided some benefit.
The Sunbelt melanoma trial [95] is currently ongo- ing. This is a prospective, randomized trial that was designed to evaluate the role of interferon in patients with lymph node metastases detected only by histol- ogy, IHC, or RT-PCR.
Despite the evidence that adjuvant HDI is effective in patients with high-risk melanoma, the use of HDI is associated with significant toxicity, including anorexia and weight loss, neuro-psychiatric symptoms, myelo- suppression, and hepatotoxicity [92–94]. There are limited data on the use of this interferon regimen in patients under age 18 years. At the MD Anderson Cancer Center, 11 patients under aged 18 years have been treated with HDI, 1 patient was lost to follow-up after completion of the IV interferon (age 4 years), 6 completed the regimen with no problems (ages 9–
16 years), and 4 had therapy discontinued early due to toxicity, 2 liver (age 6 and 11 years), 1 each neuro-cog- nitive (age 5 years) and pancreatic (age 2 years). At St.
Jude Children’s Hospital, 11 patients have been treated with HDI. It was well tolerated during induction, with only two grade 4 hematologic events and one grade 4 liver event (WL Furman, personal communication).
Adolescent and young adult patients without mea- surable disease, but with higher-stage disease, and therefore at increased risk of recurrence, should be considered for adjuvant therapy. Since interferon can be associated with significant toxicity, it is best to use it in the setting of a clinical trial. Although melanoma trials have in the past excluded patients under the age of 18 years, ECOG studies have recently opened to include younger patients with melanoma. This should allow for evaluation of the benefit and toxicity of the HDI regimen in younger patients.
17.8.1.2 radiotherapy
Radiotherapy should be considered in patients with high-risk head and neck melanomas, defined as cervi- cal lymph nodes, with any of the following: (1) extra- capsular extension, (2) node greater than or equal to 3 cm, (3) involvement of four or more lymph nodes, or (4) recurrence. Ballo et al. reported on 160 adult patients with cervical lymph node metastases, all but 43 of whom had at least 1 of these high-risk features [96]. These patients, who were at high risk for recur- rence, had a 10-year regional control rate of 94% when treated with radiation at a median dose of 30 Gy given at 6 Gy twice weekly.
17.8.2 treatment of Measurable disease The majority of adolescent and young adult patients present with localized or local regional disease that will be treated with surgery and, possibly, adjuvant treatment. However, for patients with metastatic dis- ease either at presentation or subsequently, effective treatment options are limited.
17.8.2.1 Biotherapy
Interleukin-2 (IL-2) has been used extensively in adult melanoma with response rates of approximately 17%
[97].
17.8.2.2 Bio-chemotherapy
The use of bio-chemotherapy has been shown to have response rates of 40–60% in patients with measurable
disease [86, 98]. Although the exact regimen varies between studies, bio-chemotherapy generally consists of cisplatin-based chemotherapy in combination with interferon and IL-2. The activity of chemotherapy is augmented by the addition of biologic response modi- fiers [99]. The response rate, complete response rate, and median time to progression were 48%, 6%, and 4.9 months, respectively, for bio-chemotherapy, as compared to 25%, 2%, and 2.4 months, respectively, for chemotherapy alone. This increase in activity is at the cost of significant increase in toxicity. Atkins et al.
reported a randomized phase III study comparing che- motherapy to bio-chemotherapy performed in patients with metastatic disease [100]. Biochemotherapy was associated with higher response rate and higher toxic- ity, but no difference was seen in OS.
17.8.2.3 chemotherapy
Recently, temozolomide has shown promise in the treatment of melanoma [101, 102]. Danson et al. eval- uated 181 patients with metastatic melanoma [101].
Treatment with temozolomide alone resulted in response or stabilization in 20%, with a median sur- vival of 5.3 months. In combination with interferon, the results were 26% and 7.7 months, respectively, while combination with thalidomide resulted in 24%
disease response or stabilization and a median survival of 7.3 months. Hwu et al. reported a 32% response rate with temozolomide and thalidomide [102].
17.8.2.4 accine therapy
Numerous vaccine approaches have been attempted in melanoma [103], including cell-based, peptides, recombinant viruses, DNA, and dendritic cell vaccines.
To date, this approach has not had a significant impact on patients with melanoma. Vaccine trials have gener- ally not been open to patients under 18 years of age.
17.9 Prognosis
Most adolescent and young adult patients with mela- noma have an excellent prognosis due to the high inci- dence of lower-stage disease in these patients. Exami-
nation of SEER data shows that adolescent and young adult patients have a 5-year OS rate of about 90%, sim- ilar to that seen in the 30- to 44-year age group. Both age groups have a better outcome than patients older than age 44 years. In all age groups, females have a bet- ter outcome than males. Despite the higher incidence of melanoma in adolescent and young adult females, the mortality from melanoma is higher in adolescent and young adult males (16% vs 6%) [52].
Prognosis is based on clinicopathologic staging.
There is very little data on the stage, treatment, and outcome of patients under age 18 years. SEER data from 1988–1999 include 431 patients <20 years of age and 2,823 age 20–29 years. In the <20 years age group, 23% had in situ lesions, 73% had localized disease, and 4% had regional disease. Stage at diagnosis was similar for 20- to 29-year-olds, 19% in situ lesions, 75% local- ized disease, 5% regional disease, and 1% with metas- tases. Survival rates were also similar for both age groups, 99–100% for in situ lesions, 96–97% for local- ized disease and 60–62% for regional disease.
Balch et al. [61] looked at survival for stage I and II patients and showed 5-year and 10-year survival rates of 85–87% and 75–81%, respectively, for each age decade between 10 and 50 years. After age 50 years survival decreased with increasing age. For all ages survival for stage I and II disease decreased with increasing tumor thickness and the presence of ulcer- ation. The outcome for patients with stage III disease is impacted by the number of involved nodes and whether the nodes were microscopically or macro- scopically involved; 5-year survival was 61% with a single microscopic nodule, but decreased to 35% with four or more microscopic nodes, and to 46% with a single macroscopic node. The presence of four or more macroscopically involved nodes was associated with a 24% 5-year survival. Ulceration was also associated with a worse outcome.
For patients with stage IV disease, the outcome is very poor. Patients with skin, subcutaneous, or distant lymph node metastases have a better survival than patients with visceral metastases, with a 5-year sur- vival of 19% and 10%, respectively [53]. Patients with lung metastases have a better short-term survival than those with involvement of other visceral sites, but the survival at 2 years is the same [53, 61].
17.10 conclusions
Melanoma makes up a significant proportion of the cancer seen in the adolescent and young adult popula- tion, and sun exposure appears to be leading to increased incidence. There are no data to indicate that melanoma in this age group is biologically different than melanoma in older patients. Therefore, adoles- cent and young adult patients with melanoma should be treated according to the guidelines established for older adults. The mainstay of treatment is surgical, including wide local excision of the primary tumor with lymph node mapping, and if indicated by nodal disease, LND. Patients with stage IIIB or greater dis- ease should be offered systemic therapy, consisting of immunotherapy and/or chemotherapy.
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