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656 THE NEW ENGLAND JOURNAL OF MEDICINE March 9, 1995

CURRENT CONCEPTS

MELANOMA IN CHILDREN

PATRICIA I. CEBALLOS, M.D.,

RAMON RUIZ-MALDONADO, M.D.,

AND

M

ARTIN

C. M

IHM

, J

R

., M.D.

From the Department of Dermatology, Dermatopathology Section, New York

University Medical Center, New York (P.I.C.); the National Institute of Pediatrics,

Mexico City, Mexico (R.R.-M.); and the Department of Dermatology and Der-matopathology, Albany Medical College, Albany, N.Y. (M.C.M.). Address reprint

requests to Dr. Mihm at Albany Medical College, 47 New Scotland Ave., SuiteK213, Albany, NY 12208-3479.

T

O give a child the ominous diagnosis of malignantmelanoma is a very difficult decision for both clini-

cian and pathologist. Difficulties in histologic diagnosiscombined with a reluctance on the part of the clinicianmay lead to delays in diagnosis and curative surgical in-tervention. In fact, some melanomas in children aremisdiagnosed clinically as benign lesions and recog-

nized as melanomas only after excision. It is imperativeto recognize that malignant melanoma occurs in chil-dren and to appreciate its clinical characteristics andpredisposing factors.

I

NCIDENCE

AND

P

ROGNOSIS

Approximately 2 percent of melanomas occur in pa-tients under the age of 20 years, and 0.3 to 0.4 percentof melanomas occur in prepubertal children.

1

Beforethe Spitz nevus became recognized as a separate entity,the prognosis of melanoma in childhood was consid-ered to be relatively favorable.

2

Spitz nevi were fre-quently misdiagnosed as melanomas,

2

and the course

of the nevi is benign. Malignant melanoma in child-hood can metastasize and may follow an aggressivecourse. With metastatic disease, five-year survival ratesare in the range of 33 to 34 percent.

3,4

Eighty percentof children with melanoma present with stage I dis-ease.

5,6

Rates of disease-free survival in children arecomparable to those in adults with stage I or II disease:approximately 77 percent at five years.

7

The thicknessof the melanoma and the level of invasion are the mostimportant predictors of long-term survival.

8,9

Nodalmetastases develop in up to two thirds of children withdeeply invasive melanomas (Clarks levels IV and V) or

with melanomas more than 1.5 mm thick.

9,10

Converse-

ly, metastases or recurrent tumors are unusual in pa-tients with lesions less than 1.5 mm thick.

9

Twenty percent of melanomas in children and ado-lescents occur in the head and neck, the remainder be-ing distributed equally on the trunk and extremities.

6

In children, the time to recurrent disease is shorter (6.2years) than in adults (8.4 years).

6,8

Furthermore, somestudies show that melanomas in children tend to bethicker overall (

1.5 mm) than is known to be true for

adults.

6,9

The most common histologic subtypes of mel-anoma occurring in children are superficial spreadingmelanoma and nodular melanoma.

7,11

R

ISK

F

ACTORS

The risk of melanoma is increased in children with

giant congenital melanocytic nevi, dysplastic nevussyndrome, xeroderma pigmentosum, or immunodefi-ciency states. Increased numbers of benign nevi, theinability to tan, and a history of blistering sunburnsduring childhood and adolescence confer greater sus-ceptibility to the development of melanoma in adultlife.

12

However, the relevance of such factors to the de-velopment of childhood melanoma is unknown.

O

RIGIN

, S

IGNS

, AND

S

YMPTOMS

OF

M

ELANOMA

IN

C

HILDREN

Melanoma may be congenital or may develop in in-fancy either alone or in association with a preexisting

nevus, including the giant congenital melanocytic ne-vus.

13

Detecting the latter at an early stage is difficultbecause malignant transformation commonly evolvesin the deeper components of a congenital nevus, andsurface alterations are a late manifestation.

Changes in a long-standing pigmented lesion, suchas bleeding after minor trauma, inflammation, and in-creasing size or swelling, are sometimes overlooked orerroneously ascribed to other factors. Decreased sur-

vival has been attributed in up to 60 percent of cases todelays in diagnosis, most commonly due to the physi-cians hesitancy to recognize melanoma in children.

14

The clinical findings that indicate melanoma in chil-

dren are large or expanding size, irregular borders andpigment distribution, and surface changes such as ul-ceration and loss of skin markings.

5

Melanoma may beassociated with clinical symptoms such as pain or pru-ritus. Whereas Spitz nevi are usually under 1 cm in di-ameter and may resemble verrucae or small hemangi-omas, melanomas in children tend to be larger andquite striking clinically (Fig. 1A and 1B). Melanomamay also present as a subcutaneous mass beneath apigmented lesion or as regional lymphadenopathy.

C

ONGENITAL

M

ELANOMA

Melanomas that develop in utero are rare, and most

arise in melanocytic nevi.

15-17

Other congenital mela-nomas are acquired transplacentally.

14

Melanomasaccount for only 8 percent of the cancers that affectpregnant women but for 46 percent of fetal tumors ac-quired transplacentally.

18-22

Neonates with acquiredmelanoma usually have multiorgan involvement. Cuta-neous involvement takes the form of small blue-blackmacules or nodules, or large, firm, palpable masses.Microscopically, there are subepidermal aggregates ofmelanoma cells with variable epidermotropism. Al-though infants with transplacentally acquired melano-ma usually do poorly, spontaneous complete regressionhas been described.

21,22

Congenital melanoma may arise in association witha large or giant congenital nevus. It commonly develops

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Vol. 332 No. 10 CURRENT CONCEPTS 657

in the deeper aspects of the nevus and may be problem-atic histologically. Sometimes numerous cutaneous sat-ellite lesions, which may be widely disseminated, arepresent at birth (Fig. 2). Nodal metastases and visceralinvolvement should be ruled out. Primary cutaneouscongenital melanomas tend to be smaller, between

1 and 3 cm, and may grow rapidly, ulcerate, and bleed.These signs in any pigmented lesion in a newbornshould prompt excisional biopsy without delay.

The biologic behavior of congenital melanomas is es-pecially unpredictable. The presence or absence of me-tastases in regional lymph nodes does not correlateconsistently with survival.

23,24

M

ELANOMA

A

RISING

IN

C

ONGENITAL

N

EVI

Congenital nevi are often larger than nevi that ap-pear later in life (acquired melanocytic nevi).

25

Largecongenital nevi occur in 1 in 1000 to 1 in 20,000 new-borns.

26

Small congenital nevi (usually 1 or 2 cm in

greatest diameter) are much more common, with a1 percent incidence in newborn children.

27

Garment

nevi involve a very large body-surface area for ex-ample, the entire back or an extremity and occur in1 in 500,000 newborns.

At least one third of prepubertal melanomas arise inlarge congenital nevi.

3

The frequency of malignanttransformation in congenital nevi has been estimated to

be between 2 and 20 percent, although an incidence of5 percent was reported in a prospectively followed se-ries of 80 children (Fig. 1A).

26,28

Rarely, other neuroec-todermal neoplasms develop in congenital nevi (Fig. 3).Half the cases of melanoma within large congenitalnevi occur in the first decade of life.

28,29

The risk ofmelanoma arising in a large congenital nevus duringthe first year of life (8.6 per 10,000) exceeds the riskassociated with general anesthesia (1.2 per 10,000).

29

Accordingly, some authors recommend prophylacticremoval of large congenital melanocytic nevi in earlylife,

30

citing excellent cosmetic results, the removalof a potential melanoma precursor, and possible psy-

chological benefits.Because as many as two thirds of melanomas evolv-

Figure 1. Primary Malignant Melanomas in Two Children.

Shown are a primary malignant melanoma arising in a congenital nevus on the chest of a six-month-old child (Panel A; courtesy of

Dr. G. Ibarra-Duran, Mexico) and a primary nodular malignant melanoma on the back of a fair-skinned 14-year-old boy, arisingin sun-damaged skin (Panel B).

BA




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ing in large congenital nevi have nonepidermal origins,prophylactic removal of such lesions should extend tomuscle fascia, with partial excision of muscle if nevicnests remain.

27 With giant garment nevi, lifelongclinical surveillance at frequent intervals is recom-mended by most authorities.

Neurocutaneous melanosis is a rare entity associatedwith the presence of a large congenital nevus on the

scalp or upper back, with intracerebral nevic prolifera-tion, which can lead to hydrocephalus and seizures.Leptomeningeal melanoma may develop.

31,32

D

YSPLASTIC

N

EVUS

S

YNDROME

Dysplastic nevi are potential precursors of malig-nant melanoma. Cutaneous melanoma in persons withdysplastic nevi usually develops within melanocyticdysplasias, although melanoma may also arise in unaf-fected skin. In children with dysplastic nevi, melanomahas been documented as early as the age of 10 years;as in adults, it is usually the superficial spreading vari-ant.

33

In melanoma-prone kindreds in which one of the

parents has a history of melanoma but otherwise has

normal skin, offspring may manifest the dysplastic ne-vus phenotype by early adolescence.

34

An importantclue to the dysplastic nevus syndrome in children is thepresence of abundant normal-looking nevi by the ageof five or six years. During puberty the dysplastic nevusphenotype becomes fully expressed, perhaps under the

influence of such inducers as solar radiation, hor-mones, and altered host immunity.

35

Dysplastic nevi can also occur in prepubertal chil-dren.

11,33

The scalp is often the first site of involvementand must be examined. In addition, dysplastic nevicommonly affect the horse collar area of the torsoand the buttocks (Fig. 4A). An inverse pattern withpredominant involvement of the extremities is alsoknown to occur. Dysplastic nevi tend to be larger thancommon acquired nevi, with diameters between 5 and10 mm. They typically have fuzzy, indistinct bordersand are multicolored in shades of tan, brown, pink, andblack. They vary from macular forms to papules sur-

Figure 2. A 10-Day-Old Boy with a Giant Garment Congenital

Nevus and Disseminated Cutaneous Melanoma Metastases.

The patient died of metastatic melanoma.

Figure 3. Neuroblastoma Presenting as a Large Mass within a

Giant Garment Congenital Nevus.

The widely disseminated pigmented patches represent satellitemelanocytic nevi. The patient died of metastatic

neuroblastoma.

28




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rounded by a lighter macular component (Fig. 4B).The persistence of a macular component in a nevuslarger than 6 mm is strong evidence of dysplasia.

34

Theappearance of a new area of black pigmentation in adysplastic nevus may be the best indicator of early ma-lignant change.

35

There are no established guidelines for clinical fol-low-up in affected children. Annual skin examinationsby a dermatologist, with periodic photographic docu-mentation, are probably sufficient for a child with sta-

ble lesions. Children with multiple dysplastic nevi thatshow evidence of change, as well as those with a per-sonal or family history of melanoma, should be exam-ined at more frequent intervals. Regular use of sun-screen and avoidance of intense sun exposure should beadvised.

X

ERODERMA

P

IGMENTOSUM

Xeroderma pigmentosum is a rare inherited disordercharacterized by photosensitivity and defective cellularrepair of DNA damaged by ultraviolet radiation. Skincancer develops in affected children at an alarming rate(Fig. 5). Melanoma develops in 5 percent of these pa-

tients, at a median age of 19 years, usually on the head

or neck.

36

Children with xeroderma pigmentosum mustbe monitored very closely and evaluated at frequent in-tervals. Protective clothing and regular use of sun-screen are imperative.

I

MMUNOSUPPRESSION

Host immunity plays an important part in the bio-logic behavior of melanoma. Children with geneticallydetermined immunodeficiencies have a three- to sixfoldrisk of melanoma.

37

Melanocytic dysplasias may arise

in children who are treated with immunosuppressivemedications or are infected with the human immuno-deficiency virus.

38,39

Because of the possibility of accel-erated progression of melanocytic dysplasias to mela-noma in immunocompromised hosts, we advocate amore aggressive approach to the management of dys-plastic nevi in such patients. Prophylactic removal ofsuch lesions, unless they are too numerous, is prudent.

S

PITZ

N

EVUS

The Spitz nevus may have a benign clinical appear-ance, yet the histologic features can be alarming. Spitznevi are more common in children than in adults and

preferentially involve the head and neck.

40

They are al-

Figure 4. Dysplastic Nevi.

Panel A shows a young boy with a characteristic pattern of dys-plastic nevi on the torso. Dysplastic nevi tend to be multiple andappear slightly larger and more irregular than the common smallmelanocytic nevi appearing in childhood. Panel B shows a char-acteristic dysplastic nevus with a central hyperpigmented pap-ule, surrounded by a lighter macular component with slightlyirregular borders (courtesy of the Ronald O. Perelman Depart-

ment of Dermatology, New York University Medical Center).A

B




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most always less than 1 cm across, dome-shaped, andpink-tan in color. A Spitz nevus often resembles a ver-ruca or a hemangioma (Fig. 6). Microscopically, Spitznevi share many features with melanomas. In child-hood these lesions tend to appear even more ominousbecause of the frequent finding of pagetoid growth and

a high mitotic rate in the superficial aspects of the le-sion. Histologic attributes that strongly indicate mela-noma as opposed to Spitz nevus are a lack of matura-tion, mitoses in the deeper portion, marked nuclearpleomorphism and hyperchromasia, and an expansilearchitecture in the dermis. Ancillary techniques such asflow cytometry and silver staining of nucleolar-organiz-er regions have been explored in an attempt to improvethe histologic differentiation of these entities. Unfor-tunately, Spitz nevi may be aneuploid and some mel-anomas are diploid in DNA content, rendering flowcytometry an impractical tool. Silver staining of nucle-olar-organizer regions has been similarly unhelpful.

Cases of metastasizing Spitz nevi have been de-

scribed, in which metastases were confined to regionallymph nodes and patients had an excellent prognosisafter considerable follow-up.

41

These cases, as well assome cases of childhood melanoma that behave unpre-dictably, attest to the limitations of current diagnostictechniques.

M

ALIGNANT

B

LUE

N

EVUS

Although it is usually seen in adults,

42

the malignantblue nevus has also been documented in young chil-dren. It preferentially involves the scalp and presentsusually as a multinodular plaque at least 2 cm in diam-eter, with a history of progressive enlargement of along-standing dark-blue-to-black lesion. In metastaticmalignant blue nevus, which can be fatal, the depositsshow atypical cytologic features, increased mitoses, ple-omorphism, and necrosis.

42

Although this tumor mayarise independently, it is more commonly associated

with a precursor cellular blue nevus. Cellular blue nevimay generate benign metastases to regional lymphnodes in approximately 5.2 percent of cases.

42

However,

Figure 5. Eight-Year-Old Boy with Xeroderma Pigmentosum and

a Destructive Basal-Cell Carcinoma on the Nose.

The sun-exposed skin appears badly sun-damaged andprematurely aged.

Figure 6. Spitz Nevus on the Auricle of a Young Child.

The lesion is a dome-shaped, pink-red papule. Spitz nevi arefrequently nonpigmented (courtesy of the Ronald O. Perelman

Department of Dermatology, New York UniversityMedical Center).




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such metastases exhibit histologic fidelity to the pri-mary lesion that is, they are cytologically benign.The rate of malignant transformation of cellular bluenevi is unknown.

42

T

HERAPY

We strongly recommend that suspicious pigmentedlesions undergo excisional biopsy whenever possible.This is crucial, because excisional biopsy permits mi-croscopical evaluation of the entire lesion, includingits deepest portion. Furthermore, this approach allowsdetection of satellite lesions, vascular invasion, andin-transit metastases. We recommend incisional orpunch biopsy only when excision is precluded by thesize or location of the lesion. In this case, we recom-mend selective biopsy of elevated areas or, in flat le-sions, of the darkest areas. Once the diagnosis ofmelanoma has been established, definitive surgical ex-cision should be performed. The World Health Organ-

ization currently advocates an excision margin of 1.0cm for melanomas 1.0 mm thick or less.

43 Melanomasthicker than 1.0 mm should be excised with widermargins, ranging from 1.5 to 3.0 cm depending on le-sional depth.

44

Reexcision with margins greater than3 cm is no longer recommended, since it offers no sur-

vival advantage. Primary closure should be performedif possible. Modern tissue-expansion techniques, com-bined with the revised narrower margins of excision,permit primary closure (as opposed to skin grafting)in most children. Lymph-node dissection should beperformed if draining regional nodes are suspiciouslyenlarged.

Therapy for children with advanced disease is thesame as for adults, with some exceptions in veryyoung infants. The ability of interleukin-2 to expandT cells with antitumor reactivity has therapeutic ap-plications. Immunotherapy using interleukin-2 with or

without lymphokine-activated killer cells may inducepartial or complete remissions in adults with meta-static melanoma, with a combined response rate of 23percent.

45

However, relapses are the rule rather thanthe exception. Therapy with constant infusion of in-terleukin-2 alone has caused partial responses inadults with less toxicity.

46

The use of interleukin-2 inchildren over six months of age is under preliminary

investigation.

47

Adoptive immunotherapy with tumor-infiltratinglymphocytes is a promising therapeutic weapon againstmelanoma as well as other cancers because of the ca-pacity of these cells to recognize specific tumor anti-gens restricted by the major histocompatibility complex(MHC). The administration of harvested tumor-infil-trating lymphocytes in combination with interleukin-2and cyclophosphamide (or irradiation) has been stud-ied.

48,49

The up-regulation of class I MHC antigens intumor cells by interferon gamma or the introduction ofthe gene coding for class I antigen into tumor cellsenhances the effectiveness of tumor-infiltrating lym-

phocytes.

49

In addition, the synergistic role of cyclo-phosphamide is probably due to reduction of thetumor mass or an increase in local lymphocytic in-flammation. In one study, 38 percent of adult patientshad responses to immunotherapy with tumor-infiltrat-ing lymphocytes.

49

Cancer therapy with genetic modification, such as ret-rovirus-mediated transduction of genes into humans, isalso feasible. The tumor necrosis factor gene has beeninserted into tumor-infiltrating lymphocytes, which

were subsequently administered to patients with ad-vanced melanoma. These genetically modified tumor-infiltrating lymphocytes can be added to the list of im-munotherapeutic tools under investigation.

48

Most reported studies of melanoma therapy ex-clude children under 11 or 12 years of age. Variouschemotherapy regimens have been evaluated, includ-ing limb perfusion with melphalan in adolescents withlevel IV or V melanomas on the extremities ranging

from1 to 15 mm thick.

50

Some of the patients had re-gional-node metastases. The five-year survival ratewith this protocol was 93 percent. Furthermore, allthe patients with lesions more than 3 mm thick andstage I disease had excellent disease-free survival.

50

Intensive melphalan or carmustine therapy, combinedwith autologous bone marrow transplantation inadults with refractory melanoma, yielded 69 percentand 37 percent response rates, respectively,

51,52

butthis approach to treatment has not yet been reportedin children.

Chemotherapy with dacarbazine was successful infour children with high-risk melanomas and evidence

of disseminated disease.

53

Dacarbazine has thus farbeen the most effective single chemotherapeutic agentfor metastatic melanoma in adults, with response ratesbetween 15 and 25 percent (including partial andcomplete responses) and survival periods of severalmonths.

54

Combination treatments with alpha interfer-ons and dacarbazine are associated with greater over-all response rates (53 percent) than are treatments in

which either agent is administered singly (approxi-mately 20 percent).

54-56

Forty percent of adult patientshad complete responses with combination therapy, ascompared with 2 to 5 percent with single-agent dacar-bazine treatment.

54

However, the overall response to

treatment is closely related to the presence of soft-tis-sue and nodal metastases as opposed to visceral andskeletal metastases.

Whereas combinations of chemotherapeutic drugs donot improve response or survival statistics in adults,the study by Hayes and Green suggests that children

with metastatic melanoma may be more responsive tosuch treatment as a triple-drug regimen of cyclophos-phamide, vincristine, and dactinomycin.

57

Despite encouraging results, there is as yet no trulyeffective therapy for metastatic melanoma in adultsor children. Consequently, the importance of earlydiagnosis with prompt surgical excision of primary




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cutaneous melanoma cannot be overemphasized. Itremains the most reliable way to cure children of thisdisease.

R

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