Published online March 1, 2005
PEDIATRICS Vol. 115 No. 3 March 2005, pp. 649-654 (doi:10.1542/peds.2004-0471)
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Does Melanoma Behave Differently in Younger Children Than in Adults? A Retrospective Study of 33 Cases of Childhood Melanoma From a Single Institution

Andrea Ferrari, MD*, Aldo Bono, MD§, Marzia Baldi, MD§, Paola Collini, MD{ddagger}, Michela Casanova, MD*, Elisabetta Pennacchioli, MD§, Monica Terenziani, MD*, Ilaria Marcon, MD*, Mario Santinami, MD§ and Cesare Bartoli, MD§

* Pediatric Oncology Unit
{ddagger} Pathology Department
§ Melanoma and Sarcoma Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective.To ascertain whether childhood melanoma presents any peculiar clinical features or differences in prognosis with respect to adults, we retrospectively analyzed the data from 33 patients who were up to 14 years of age and treated for cutaneous melanoma at the Istituto Nazionale Tumori, Milan, over a 25-year period.

Methods.Primary lesions were amelanotic in half of the cases and raised in 73%. Lower extremities were the most common primary sites. Histologically, 9 cases were classified as nodular type, and median thickness was 2.5 mm. Nine children had nodal involvement at diagnosis, 2 in-transit metastases, and 1 distant spread. Surgery was the mainstay of treatment; 9 patients underwent lymph node dissection, 3 received chemotherapy, and 2 received radiotherapy.

Results.With a median follow-up of 122 months, 5-year event-free survival and overall survival were 60% and 70%, respectively. Age seemed to correlate with survival, event-free survival being 90% in children under 10 and 47% in older patients, although the initial microstaging seemed worse in the former.

Conclusion.By comparison with adult cases, childhood melanoma can have a higher percentage of atypical clinical features (amelanotic and raised lesions), nodular histotype, and thick lesions. Although we have no data to support any suggestion of biological differences between young children and adolescents or adults, our findings give the impression that melanoma behaves differently in the younger age group.

Key Words: age • children • cutaneous melanoma • pediatric rare tumors • prognostic factors

Abbreviations: AJCC, American Joint Committee on Cancer • EFS, event-free survival • OS, overall survival

Melanoma is very rare in children, accounting for only 1% to 3% of the malignant tumors in this age group: ~2% of all reported melanomas have occurred in patients younger than 20 years, but only 0.3% to 0.4% of them have developed in prepubertal children, with an estimated annual incidence of 0.8 per million in the first decade of life.1–6 Because of this rarity, little information is available on clinical and biological features of childhood melanoma, so treatment strategies are generally extrapolated from experience with adults.7–11 The misdiagnosis of pigmented lesions is common in pediatric age (it has been reported in up to 40% of cases)12 and often leads to therapeutic delay. In an attempt to ascertain whether childhood melanoma presents any peculiar clinical features or differences in prognosis with respect to adults, we analyzed retrospectively the clinical findings, treatment, and outcome of 33 cutaneous melanoma patients who were up to 14 years of age and treated at our institution over a 25-year time span.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
All patients who were up to 14 years of age and had a diagnosis of cutaneous melanoma, observed from 1975 to 2001 at the Istituto Nazionale dei Tumori in Milan, were considered for the study. The incidence of cases observed over the years did not change substantially in the study period.

The histologic slides were reviewed. Of the 35 patients identified in all, 2 were histologically reinterpreted as Spitz nevi and thereafter were excluded. The remaining 33 children form the object of this analysis. The histologic slides of the primitive tumors were unavailable in 5 cases (the pigmented lesions having been treated elsewhere using cryosurgery or resection without any histologic evaluation), and the histologic diagnosis of melanoma was made when the disease relapsed. Some of these cases have been included in a previous study.13

All 33 patients were white, and age at diagnosis ranged from 3 to 14 years, with a median of 11. Ten patients were <10 years of age. Eighteen were male, and 15 were female. None of the patients reportedly had a family history of melanoma. One child had oculocutaneous albinism.14

Staging investigations at diagnosis included physical examination, chest radiograph, and abdominal ultrasound for all patients. The regional lymph nodes assessment was clinical and/or radiologic (ultrasound) in all cases. The last 4 patients underwent sentinel node biopsy.

Patients were classified according to Clark level15 and Breslow thickness16 and according to the original 3-stage system17 and the revised American Joint Committee on Cancer (AJCC) Staging System.18,19 In the original 3-stage system, stage I refers to localized melanoma, stage II refers to cases with regional metastases, and stage III refers to patients with distant metastases.17 The AJCC Staging System also considers melanoma thickness and ulceration (T category), the number of lymph nodes involved and the tumor burden in nodes (N category), and the site of distant metastases and the level of serum lactate dehydrogenase (M category): using the TNM categories, staging goes from 0 (melanoma in situ) to I A and B; II A, B, and C (localized disease); III (nodal involvement); and IV (distant metastases).18,19

During the period considered, patients were treated with a relatively consistent approach, ie, surgical excision represented the mainstay of treatment, whereas adjuvant therapies were used in only a few cases.

Event-free survival (EFS) and overall survival (OS) were estimated according to the Kaplan-Meier method.20 Patients were evaluated from the time of histologic diagnosis up to latest uneventful follow-up or disease progression, relapse, or death for any cause (for EFS) and until death (for OS). The log-rank test21 was used to compare the survival curves in patient subgroups using univariate analysis to ascertain the potential value of prognostic factors. Patient follow-up, as of December 2003, ranged from 28 to 210 months (median: 122 months).


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients characteristics are detailed in Table 1. Melanoma arose from congenital nevi in 7 cases (none of the giant type) and from an acquired nevus in 2. The remaining 24 (73%) cases appeared de novo. The most common primary sites of origin were the extremities. No correlation was found between gender and site.


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  		TABLE 1. Patient Characteristics

 
Table 2 shows the clinical features of the primary lesions. Half of the children (14 of 28 with available data) had clinically amelanotic lesions (9 pink or pink-white, 5 red), and the shape of the tumor was raised in the majority of patients, clinically resembling pyogenic granuloma.


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  		TABLE 2. Clinical Features and Histology

 
On histologic evaluation, 9 cases were classified as nodular type. The median thickness according to Breslow was 2.5 mm (range: 0.52–9). Most cases were Clark level IV to V.

According to the 3-stage system, 21 patients were stage I, 9 were stage II because of lymph node involvement, and 3 were stage III (2 had in-transit metastases and 1 had lung and bone metastases at diagnosis). According to the AJCC system, 4 patients were stage IA, 3 were stage IB, 11 were stage IIA, 3 were stage IIB, 11 were stage III, and 1 was stage IV. Data on the degree of nodal involvement were not available for most patients (ie, micro- or macrometastases, number of involved nodes).

All but 5 patients underwent adequate excision of the primary lesion (in 20 cases through a resurgery to obtain adequate margins). Among the remaining 5 cases (initially treated elsewhere) 2 were treated with cryosurgery and 3 with excision without any histologic evaluation, so the diagnosis of melanoma was obtained at the relapse.

Nine patients had lymph node dissection, ie, for clinically evident node involvement in 5 cases, and 2 had selective lymphadenectomy after positive sentinel node biopsy and 2 were treated as a prophylactic measure (in the 80s; neither of them showed clinical signs of nodal involvement, but tumor was detected at histology). Sentinel node biopsy was performed in 4 patients, and 2 were found to have nodal microdissemination.

Five patients received adjuvant therapies. Chemotherapy was given to 3 patients with positive node (1 had dacarbazine; 2 had dacarbazine, vincristine, and lomustine). Two children had external radiotherapy, 1 on the involved nodal field after incomplete dissection (45 Gy), the other on the primary site (40 Gy) after marginal resection of a thick lesion of the face.

With a median follow-up of 122 months, 21 patients were alive in first CR. OS and EFS rates were 70.1% (SE: 8.5) and 60.3% (SE: 9.1) at 5 years and 65.7% (SE: 9.1) and 56.2% (SE: 9.4) at 10 years. Thirteen patients experienced relapse, from 2 to 52 months after diagnosis (median: 14 months). Site of recurrence was lymph nodes in 3 cases, lymph nodes and distant sites in 3, and distant sites alone in 7. The sites of metastatic relapses were soft tissue in 5 cases; liver, lung, bones, and bone marrow in 1 case each; and systemically in 1. Among relapsing patients, 10 died of disease, 2 were alive in second CR 10 and 130 months after relapsing, and 1 was in third CR 30 months after the latest relapse.

Table 3 shows the univariate analysis for the different prognostic variables; although the very small numbers involved severely limit the value of the analysis, the P value was significant for AJCC stages (Fig 1) and for age (Fig 2). The prognostic role of age seemed particularly interesting, because the outcome in children who were younger than 10 years was statistically better (5-year EFS: 90% vs 47%) even when the presenting clinical features seemed worse (median thickness: 3.4 mm; 4 of 10 patients were AJCC stage III) than in the older patients (median thickness: 2 mm; 7 of 23 patients were AJCC stage III and 1 was stage IV). Among the 10 children who were younger than 10 years, only 1 recurrence (and subsequently 1 death) was observed.


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  		TABLE 3. Univariate Analysis: 5-Year EFS According to Prognostic Variables

 

Figure 1
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  		Fig 1. OS according to the revised AJCC Staging System: 5-year OS was 85.7% for stage I patients, 83.6% for stage II, 49.9% for stage III, and 0% for stage IV.

 

Figure 2
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  		Fig 2. EFS according to age: EFS was significantly better for children who were younger than 10 years (5-year EFS: 90.0%) than for older patients (5-year EFS: 46.7%).

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This retrospective, single-institution study analyzed 33 pediatric patients who were up to 14 years of age. The rarity of melanoma in this age group makes this small series one of the largest extent. Although no data are available to support any biological or histologic differences between melanoma arising in children and melanoma of adolescents and adults, our findings suggest a better outcome for melanoma in children and some differences in the natural history.

It is well known that melanoma is exceedingly infrequent in childhood despite the increasing incidence of this tumor type.1–11 In the United States, childhood and adolescent cases account for 1.3% of all cases of melanoma, with a higher proportion of female and nonwhite patients when compared with adults.22 An increase in the incidence of melanoma in pediatric ages was observed recently in Sweden23 and particularly in Australia,24 where the overall incidence of melanoma is >5 times that in Europe. In particular, melanoma in Queensland accounts for 6% of all pediatric tumors and is the seventh most frequent malignancies in children: incidence rates rise from 1 per million in the 0 to 4 age group to 30 per million in the 10 to 14 age group.24 These data are undoubtedly related to ultraviolet exposure, latitude, and skin type and pigmentation (fair-skinned individuals with red hair are more likely to develop melanoma than darkly pigmented individuals), even if it is generally accepted that the cause of melanoma is complex and includes family history of melanoma and well-recognized melanoma susceptibility genes (CDKN2A and CDK4).25–27 Epidemiologic studies suggest that the penetrance of these genes is altered by other factors, either genetic or environmental25,27; besides, it is of note that germline mutations are rare in childhood melanoma cases, thus not accounting for the cause of the disease.25,28

According to our single-institution series, the incidence of melanoma in childhood seems the same over the past 20 years. In our cohort, none of the patients reportedly had a family history of melanoma. The tumor arose from congenital nevi in 21% of cases (the majority appearing de novo). All of our cases can be defined as "childhood melanoma" according to the definitions of Richardson et al,29 who divided prepubertal melanoma into the following categories: 1, congenital (diagnosed in utero to birth); 2, infantile (from birth to 1 year); and 3, childhood (1 year to puberty).29 Congenital and infantile melanomas are very rare and have a poor outcome,29 as well as the reported cases of maternally derived (via the placenta) melanoma metastases of the fetus.30

The pediatric oncologist is faced with a paucity of data on the management of melanoma: its rarity prevents prospective trials, and retrospective reports include very few patients by comparison with adult studies.1–11,22,31–45 In published pediatric series, moreover, the majority of patients are adolescents,6,9,22,38,45 and the various reports often reach different conclusions. The clinical behavior and overall outcome of melanoma in childhood are generally held to be the same as in adults,6,9 although some data support an adverse prognostic role of younger age38 and others suggest a better survival in children.1,5,22,34,45

Similarly, controversy exists concerning clinical presentation and surgical approach. Various authors have noted a tendency for thicker lesion and later stages in pediatric melanoma,7,11,33 probably as a result of a delay in diagnosis (because of a reluctance to perform biopsies in children)7,33 or very rapid growth.11

Ceballos et al7 strongly recommended that suspicious pigmented lesions undergo excisional biopsy whenever possible, to ensure early diagnosis and prompt surgery. In response, our group reported on 656 skin lesions that were surgically removed over a period of 16 years, in which only 2 cases of histologically confirmed cutaneous melanoma emerged. Excision is warranted only in cases of well-founded clinical suspicion of malignancy to reduce the number of operations and the worry for children and parents.8 This does not mean underestimating pigmental lesions in children but referring the evaluation to expert physicians who are professionally dedicated to melanoma. An ample clinical experience is needed for clinicians and surgeons who see children with skin lesions not only to avoid delay in melanoma diagnosis (which remains the main concern) but also to avoid surgical overtreatment.8

There is a better consensus on the clinical and histologic difficulties of diagnosis in children as opposed to adults. As reported by Saenz et al,6 misdiagnosis is common: in that series, nearly one half of the children who died of melanoma initially had received a misdiagnosis, thus receiving delayed or inadequate treatment. Melanoma is a challenge even for clinicians who see pigmented skin lesions in children on a daily basis: benign lesions can have alarming melanoma-like features, whereas melanomas often have an atypical presentation as nodular, pedunculated, or amelanotic lesions, sometimes simulating pyogenic granulomas.7,10,11,32,33,40,43 Our series is a good example of this fact, 50% of the lesions being amelanotic and 73% raised. Our clinical experience suggests that the ABCD clinical rule (asymmetry, border irregularity, color variability, diameter >6 mm) may be useless and even misleading in childhood melanoma. Size, for instance, deserves particular consideration and seems to be of little value (benign nevi normally grow up to relatively large size as the child grows, whereas melanomas may be detected at a very small size).7,11,46

Another factor that can make it clinically difficult to recognize a melanoma in children is its development in a congenital nevus. The risk for developing melanoma in congenital nevi has been estimated to be between 2% and 20%, being higher for the giant forms and lower (0%–5%) for the small lesions.1,7,9,47 Dysplastic nevi should also be considered potential precursors of melanoma.7,26,39

Pathologists can likewise have a greater difficulty in diagnosing childhood melanoma than adult cases: various benign lesions that are typical of pediatric age may mimic melanoma, particularly Spitz nevus.11,30,33,34 Although a histopathologic review and discussion of the biology and natural history of Spitz nevi is beyond the scope of this report, it is worth mentioning the multicenter European study reported by Spatz et al12: among 102 lesions that were originally diagnosed as melanoma, only 60 were confirmed as malignancies at histologic review, and 42 were reclassified as benign.

Although our series is too small to draw any definitive conclusions, our findings prompt a few suggestions. Overall, our series is consistent with other reports,6,9,11,40,43 suggesting that certain clinical findings are more frequent in pediatric age. By comparison with adult melanoma, our series revealed (1) a higher frequency of atypical features (amelanotic or verrucoid lesions, features simulating pyogenic granulomas), (2) thicker lesions at diagnosis, (3) a higher proportion of the nodular histotype, and (4) a higher frequency of particular sites (eg, lower limbs).

Considering our series as a whole, no major differences in outcome were found between childhood and adult melanoma. The most interesting suggestion deriving from our study, however, concerns the strong influence of age on outcome: survival was significantly better in children who were younger than 10 years than in the older patients, whose results seemed consistent with adult series. Although the small number of patients clearly prevents any definitive conclusion, this point seems relevant (considering that the difference was statistically significant and the median thickness (usually the most important predictor of outcome) was higher in the younger patients). Younger age might well be a favorable prognostic factor. Similar results emerged from the Boston Children’s Hospital experience, which described 2 deaths among 11 children up to 10 years of age and 6 among the 12 older children.34 Others have also reported slightly better survival rates in children than in adults.1,5,22,45

We are unable to speculate on possible explanations for this finding: in our series, it is probably not attributable to early diagnosis, given the higher median thickness of the younger cases. It is generally assumed that childhood melanoma behaves biologically like its adult counterpart,6,9 but our results make us wonder whether this is really so. Larger cooperative studies are needed to study this aspect further.

Our data allow no conclusions regarding treatment. We believe that the therapeutic recommendations for childhood melanoma should remain the same as for adults. Surgery is the mainstay and the only effective therapy for primary lesions and for positive lymph nodes. The sentinel node biopsy technique is now generally accepted as being a safe and accurate method for staging regional lymph nodes and establishing any need for elective nodal dissection.48–50 As in adult patients, this technique should be recommended in children with primary melanomas >0.75 to 1 mm in thickness.48–50 Medical treatment may be useful in the case of disseminated disease, and pediatric patients could be included in adult therapeutic trails (eg, immunotherapy, immunochemotherapy, vaccinotherapy).51–54

In conclusion, our report adds to the clinical information currently available on a very uncommon tumor of childhood. Although cutaneous melanoma is very rare in children, it is imperative for clinicians to be aware that it does occur. Early diagnosis is crucial to outcome, given the close correlation between depth of invasion and prognosis and that surgery remains the only effective treatment. International cooperation between pediatric oncologists who deal with rare tumors is imperative and therefore should be encouraged, also reinforcing collaboration with dermatologists and surgeons who are dedicated to adult melanoma.


   ACKNOWLEDGMENTS
 
We thank Alberto Pappo (Hospital for Sick Children, Toronto, Ontario, Canada) and Juan Rosai (Pathology Department, Istituto Nazionale Tumori, Milan, Italy) for precious suggestions. We thank all of the colleagues who helped in collecting slides: Dr A. Bellomi (Ospedale Carlo Poma, Mantova), Dr E. Pezzica (Ospedale Treviglio), Dr M. Bonetti (Spedali Civili, Brescia), Dr M. Piazza (Datamedica Padova), Dr G. De Rosa (Università Federico II, Napoli), Dr R.M. Bona (Ospedale Milulli, Acquaviva delle Fonti, Bari), Dr A. Boscaino (Ospedale Cardarelli, Napoli), Dr C.D. Inchingolo (Ospedale Bonomo, Andria), and Dr A. Angelone (AUSL Pescara).


   FOOTNOTES
 
Accepted Aug 25, 2004.

Address correspondence to Andrea Ferrari, MD, Pediatric Oncology Unit, Istituto Nazionale Tumori, Via G. Venezian, 1-20133 Milano, Italy. E-mail: andrea.ferrari{at}istitutotumori.mi.it

No conflict of interest declared.


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 RESULTS
 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics

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