- Email: [email protected]
Melanoma in children and adolescents
ARTICLE IN PRESS Surgical Oncology (2007) 16, 215–220
Available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/suronc
REVIEW
Melanoma in children and adolescents Cynthia D. Downard, Louis B. Rapkin, Kenneth W. Gow Division of Pediatric Surgery and the Department of Hematology/Oncology/BMT, Aflac Cancer Center, Emory School of Medicine, Atlanta, GA, USA
KEYWORDS Melanoma; Children; Adolescents
Summary Melanoma is rarely described in the pediatric population. However, recent studies show that the incidence may be increasing. The diagnosis of melanoma presents unique challenges in this age group. There may be predisposing factors that affect children more than adults. A high index of suspicion is necessary in order to make a timely diagnosis. Prompt surgical treatment by individuals with expertise in care of patients with melanoma with potentially curative excision and appropriate lymph node evaluation is important to optimize survival. Careful review of all specimens by an experienced dermatopathologist is important. Through cooperation with adult trials and potential inclusion of pediatric patients in evaluations of new therapies, further progress against this disease can hopefully be addressed in all age groups. & 2007 Elsevier Ltd. All rights reserved.
Contents Introduction . . . . . . . . . . . Epidemiology . . . . . . . . . . Predisposing conditions . . . . Presentation and evaluation . Treatment . . . . . . . . . . . . Adjuvant therapy. . . . . . . . Outcomes . . . . . . . . . . . . References . . . . . . . . . . . .
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Introduction The incidence of cutaneous melanoma has increased markedly in the last 30 years. Although patients under 20 Corresponding author. 4800 Sand Point Way NE, M/S W-7729, P.O.
Box 5731, Seattle, WA 98105-0371, USA. Tel.: +1 206 979 6800. E-mail address: [email protected] (K.W. Gow). 0960-7404/$ - see front matter & 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.suronc.2007.09.006
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years of age account for only 1% of patients diagnosed with melanoma, approximately 1 in 58 individuals born today will be diagnosed with melanoma at some point in their lifetime [1]. Melanoma is the most common cancer diagnosed in females between the ages of 25 and 29 years. Early detection and intervention in patients with melanoma are the mainstays of cure. Preventive counseling and treatment of those diagnosed with melanoma early in life is therefore
ARTICLE IN PRESS 216 of importance to the practicing pediatrician, family practitioner, and surgeons who treat children and adolescents [2]. Malignant melanoma is categorized histologically into four types: Lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma, and nodular melanoma. Superficial spreading melanoma is the most common type. Of note, nodular melanoma undergoes an early vertical growth phase, which is important since depth of invasion at diagnosis is closely associated with the ultimate prognosis in cutaneous melanoma [3].
Epidemiology With the advent of computerized databases, the incidence of rare malignancies such as pediatric cutaneous melanoma has been more accurately recorded over the last two decades. As a result, the rise in the incidence of melanoma has become readily apparent. This careful recording of patients also allows retrospective reviews of preserved histological samples as new discoveries are made. Conti and colleagues reported a series of 212 European children (age less than 15 years) with melanoma identified through the EUROCARE database over an 11 year time period and attempted to evaluate the population-based survival for this disease in different national populations [4]. Due to the relative rarity of the disease, however, they could only make generalizations about the survival of children diagnosed with melanoma compared to adult statistics. They found that the overall 5-year survival for all children diagnosed with any type of melanoma was 79%. Five-year survival was best for children diagnosed with cutaneous melanoma (87%) and worst for patients with melanoma not of the skin or eye (57%). Within the cutaneous melanoma population, survival was negatively impacted by having a primary lesion on the trunk (76%). They point out that 5-year survival in the adult population over a similar time period was 77% for all patients diagnosed with melanoma and suggest that this minimal improvement in survival may be aided by earlier detection and excision of suspicious lesions in children. Sander and colleagues from the Huddinge Hospital in Sweden reviewed specimens from 130 patients with melanoma diagnosed prior to 20 years of age to evaluate if histological differences from adult melanoma were evident [5]. In addition, they investigated if the microscopic features of melanoma had changed during the 20 years over which the specimens were collected. They found that over the time period evaluated, it seemed that the thickness of the tumors decreased at the time of diagnosis from 1.3 mm in the first 10 years to 0.8 mm in the second decade, possibly due to enhanced screening efforts. Overall mortality rate for the population studied was 10%. In addition, they reviewed all the slides previously obtained to determine the ‘‘over diagnosis’’ rate of melanoma. Their concordance with the prior diagnosis was 85%, and only the patients they diagnosed as having melanoma were included in the study. In their review, all of the pediatric melanoma specimens had features similar to adult melanomas, with the most common type being superficial spreading melanoma. Over the course of their study the incidence of melanoma in Swedish youth increased fourfold.
C.D. Downard et al.
Predisposing conditions Cutaneous malignant melanoma differs in children in that it may arise from conditions unique to the pediatric population. Because of this, pediatric melanoma is classified by the mode of occurrence as well as the histological subtype: [6] (I) Transplacental melanoma, transmitted from the mother with melanoma to the fetus in utero. (II) Transformation from giant congenital melanocytic nevus. (III) In association with congenital predisposing conditions such as xeroderma pigmentosum, dysplastic nevus syndrome, and albinism. (IV) Development from healthy skin. (V) Development from a preexisting nevus. Giant congenital melanocytic nevi occur in approximately 1 in 20,000 newborns [7]. Giant congenital melanocytic nevi are classically defined as being greater than 20 cm in largest diameter. An alternate definition is any congenital nevus requiring a graft for closure after excision. Approximately 30% of pediatric melanomas arise from these lesions, while the lifetime risk of malignant degeneration of these lesions is thought to be between 2% and 20%. Many of the malignant melanomas that arise from giant congenital melanocytic nevi do so in the first 5 years of life. Some groups recommend routine complete excision of the entire lesion early in childhood due to the risk of malignancy, but this can often require a staged removal and advanced plastic surgical techniques such as the use of tissue expanders for coverage. If the lesion is not easily excised, serial follow up by a physician familiar with these patients is mandatory for early detection of malignant change. Any alteration in appearance should prompt biopsy. Plans for removal are dependent on the size and location of the lesion. X. pigmentosum is an autosomal recessive disorder that is first noted around the age of 1 or 2 years by marked photosensitivity or freckling [8]. The genetic aberration involves a defect in the repair of DNA after damage induced by UV rays and is associated with multiple types of skin cancer. Malignant melanoma occurs approximately 2000 times more commonly in this population that in the general population, usually in the early teen years. Reduction in sun exposure and early detection and treatment of melanoma in this population is absolutely critical. Immunosuppression as a result of a hematologic or infectious disorder or induced immunosuppression after organ or bone marrow transplant puts the pediatric patient at a 3-fold to 6-fold increased risk of malignant melanoma. Monitoring of nevi in these populations should therefore be a routine part of their long-term evaluation. Dysplastic nevi syndromes can occur in a familial or sporadic form [7]. Often these children will have multiple nevi present by the age of 5 years, and the lesions will then progress to become dysplastic nevi in the teen years. Frequent evaluation of the nevi by an individual with experience in treatment of cutaneous malignancies is advised.
ARTICLE IN PRESS Melanoma in children and adolescents
Presentation and evaluation As previously stated, several patient populations, including those with congenital melanocytic nevi, x. pigmentosum, immunosuppression for any reason, and dysplastic nevi syndromes are at increased risk for development of melanoma and warrant serial examinations by clinicians familiar with cutaneous pathology. However, approximately 50% of melanomas in the pediatric population develop de novo and therefore when suspicious skin lesions are noted by the general pediatrician prompt referral for further evaluation should follow. Biopsy of suspicious skin lesions should be done with the expectation that the lesion is malignant. Full thickness biopsies best allow determination of the depth of invasion of a lesion, which is one of the most important prognostic factors in cutaneous melanoma. The initial physical examination of a patient with a cutaneous lesion should include a thorough evaluation of the entire skin surface with special attention to additional suspicious lesions. Mucus membranes and the digits and interdigital spaces are important not to be overlooked. Photography may be helpful if lesions are being followed over time. The initial area of concern can be assessed with the traditional ABCD criteria of melanoma (asymmetry, border irregularity, color, and diameter 46 mm), although these criteria may not be as universally applicable in children as they are in adults [9]. In addition, attention must be paid to regional lymph node basins as they may harbor metastatic disease. If a lesion is determined to be suspicious either on initial evaluation or after serial examination, the evaluation of choice is an excisional full thickness skin biopsy. It is not necessary to perform this with excessive margins, as a diagnosis of melanoma would lead to a re-excision of the lesion. Occasionally in a very cooperative teen this initial biopsy could be performed in the office, but for younger children it is generally performed in the operating room under heavy sedation or general anesthesia. Incisional biopsy is to be considered if removing an entire lesion initially would be disfiguring [10]. Evaluation by an experienced dermatopathologist is critical in obtaining the proper diagnosis, particularly in the pediatric age group. The difficulty of differentiating a Spitz nevus from melanoma can be quite challenging, and is best done by one with extensive expertise in the area.
217 adequate to prevent local recurrence. The end result of these studies is a recommendation of 0.5–1 cm margin for melanoma in situ lesions, margins of 1 cm for lesions less than 1 mm in thickness, and 2 cm margins for all other lesion thicknesses. It is important to remember when excising these lesions that the margins are circumferential, completely surrounding the prior biopsy site. As such, the excision sites for an intermediate (1–4 mm) or thick (44 mm) lesion are actually at least 4 cm in diameter (Figure 1). In the last 20 years, the advent of sentinel lymph node biopsy for staging of melanoma has been critical in altering the treatment of adult patients with this disease. More recently, sentinel lymph node biopsy for children with melanoma has gained acceptance as a useful modality. In addition, sentinel lymph node biopsy can be of unique utility in the pediatric population in determining the difference between melanoma, which may metastasize to regional lymph nodes, and a Spitz nevus, which should not metastasize. Sentinel lymph node biopsy is usually performed concurrent with re-excision of the primary lesion. The procedure involves injection of the primary cutaneous lesion site with technetium-99m sulfur colloid followed by lymphoscintigraphy in the nuclear medicine suite. This is typically done on the morning of scheduled re-excision, and the patient is brought to the operating room in the afternoon. Once under anesthesia in the operating room, the lesion is injected with approximately 1 ml of 1% isosulfan blue dye. It is important to maintain the area of injection within the intended resection margins as the dye does tattoo the skin (Figure 2). The dye is allowed to travel through lymphatics for several minutes, and a hand held gamma counter is used to determine the area of maximal
Treatment Once a diagnosis of melanoma has been made, the focus turns to adequately staging the disease. The importance of full thickness initial biopsies cannot be overemphasized as the thickness of the lesion helps to determine the next step in care. Re-excision of the lesion is the first step in treatment, and prospective, randomized trials have determined the necessary margin to minimize local recurrence related to lesion depth [11–16]. In trials addressing adequacy of margins, patients were enrolled based on the thickness of their tumors and randomized to either narrow or wide margins, with most trials suggesting that the narrower margins were
Figure 1 The margin of resection for a lesion of less than 1 mm thickness is 1 cm in all directions. Therefore, a defect of at least 2 cm in diameter will be created. An elliptical incision aids with closure of the defect.
ARTICLE IN PRESS 218
C.D. Downard et al. dissection is based on errant assumptions of how melanoma spreads, and it could actually be assumed to be systemically metastatic at that point [19]. In our own experience, the sentinel lymph node is often the only positive lymph node in the draining basin.
Adjuvant therapy
Figure 2 It is important to keep the isosulfan blue dye within the planned resection margin to minimize risk of tattooing the skin.
Figure 3 Sentinel lymph nodes are those nodes that are blue, radioactive (as determined by the gamma probe), or palpable. All sentinel nodes are excised and sent fresh to pathology.
radiolabeled tracer intensity for lymph node sampling. An incision is made over the area identified to have the most active uptake of radiolabeled tracer as determined by the handheld gamma probe and the preoperative lymphoscintigraphy. Upon examination of the draining lymph node basin, all nodes that are blue, palpable, or show significant activity with the gamma probe are excised and sent fresh to pathology (Figure 3). Selective sampling of lymph nodes allows more directed study of samples using immunohistochemical methods to determine if lymph node metastases are, in fact, present. The primary lesion is then re-excised with the margins determined by depth of the initial lesion as previously mentioned [17]. Currently, evidence of melanoma cells in regional lymph nodes sampled during sentinel lymph node biopsy warrants offering a completion lymph node dissection of the draining basin. It is unclear if completion lymph node dissection confers a survival advantage in melanoma, and this is actively being investigated in the Sunbelt Melanoma Trial [18]. It may be that offering completion lymph node
Melanoma cells that have spread to regional lymph nodes have demonstrated a propensity to travel to other parts of the body, and consideration of systemic therapy in this situation is under investigation. Unfortunately, pediatric patients are not included in most trials of adjuvant therapy for melanoma, and therefore treatment plans for children must be extrapolated from adult studies. Traditional chemotherapy regimens have not had significant activity against melanoma. Biologic agents such as interferon alfa-2b are currently used for adjuvant therapy against high-risk melanoma after surgical resection. Adult studies have evaluated the use of high dose interferon alfa2b in patients with high-risk melanoma and have shown an improvement in relapse-free survival and overall survival when compared with observation [20]. Vaccination against defined melanoma antigens for patients with high-risk melanoma has also held interest, but has not proven more effective than treatment with high dose interferon alfa-2b in adult trials [21]. Given the favorable results with use of interferon alfa-2b in adults, Pappo and colleagues at St. Jude Children’s Research Hospital investigated the feasibility of treating pediatric melanoma patients with high dose interferon [22]. Their series included 15 patients less than 18 years of age with Stage III melanoma, defined as having a primary tumor thickness of greater than 4 mm or having lymph node or in-transit metastases, but no distant metastasis. In their protocol, patients were treated with interferon alfa2b intravenously during a 4-week induction phase, followed by maintenance therapy with subcutaneous administration of interferon alfa-2b three times a week for 48 weeks. All patients had completed induction therapy, and nine had completed maintenance therapy at the time of publication. The most common serious toxicity was neutropenia. Four of 15 patients required dose reduction due to toxicity during the induction phase, and 3 of 15 patients required dose reduction during the maintenance phase. They concluded that interferon alfa-2b could be used in pediatric melanoma patients with acceptable toxicity. The study was not controlled, and therefore no conclusions about efficacy of the treatment could be reached. A recent report from Toronto examined the use of high dose interferon in pediatric melanoma patients identified as having metastatic disease on sentinel lymph node biopsy [23]. Of a total of 10 patients who underwent sentinel lymph node biopsy for melanoma or melanoma-like lesions, 6 patients were found to have sentinel lymph nodes containing melanoma cells. All patients in their series who had positive sentinel lymph nodes then underwent completion lymph node dissection. Five of these patients were treated with high dose interferon therapy, and one patient refused further therapy. At the conclusion of their study, four
ARTICLE IN PRESS Melanoma in children and adolescents patients had completed therapy and were in remission while one was still receiving interferon therapy. Dose adjustments due to myelosuppression were required in two patients, while two patients required dose adjustments due to abnormal hepatic function tests. In short, although most of the patients did complete their therapy, almost all required alterations in dosage due to toxicity; 10 of the 11 patients survived with a median follow-up of 26 months. The one patient who died presented with metastatic disease. Because melanoma is a relatively rare disease in the pediatric population it is difficult to accrue adequate numbers of patients in clinical trials to evaluate adjuvant therapies. Due to the histologic and clinical similarities in adult and pediatric melanoma, it would likely be helpful to include children in adult therapeutic trials.
Outcomes A longstanding debate over the similarities and differences of adult and pediatric melanoma has recently been addressed with a case-matched controlled analysis of melanoma patients from the Massachusetts General Hospital [24]. In this study, 73 melanoma patients less than 21 years of age were matched to 146 adult patients based on tumor stage and year of diagnosis, and outcomes were compared. They chose to match the cases and controls based on tumor thickness because many case series of pediatric patients have shown that pediatric patients often have a thicker melanoma lesion at the time of presentation, and tumor thickness is an important determinant of outcome. In this series, two adult control patients with melanoma were selected for each pediatric melanoma patient in order to achieve greater statistical power. Cases and controls were also matched for year of diagnosis since the treatment of melanoma varied greatly over the 32 years included in the study, specifically with the use of lymphatic mapping and sentinel lymph node biopsy in the later years of the study. After comparisons were carried out, a specific analysis of patients who underwent lymph node evaluation either by lymph node dissection or sentinel lymph node biopsy showed a higher rate of lymph node metastasis in the pediatric group (44%) as compared to the adult group (23.9%). However this difference did not reach statistical significance due to the small sample size. In addition, there was no statistically significant difference in the 5-year and 10-year disease-free and cause-specific survival rates between the pediatric and adult melanoma patients. In this series, pediatric patients who had either Stage I or Stage II (localized disease) had a 94.4% 10-year survival, while patients presenting with Stage III melanoma (metastasis to lymph nodes) had a 60.1% 10-year survival.
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References [21] [1] Ries LAG, Melbert D, Krapcho M, et al. SEER cancer statistics review, 1975–2004. November 2006 [cited August 2007]; Available from: /seer.cancer.gov/csr/1975_2004S. [2] Strouse JJ, Fears TR, Tucker MA, Wayne AS. Pediatric melanoma: risk factor and survival analysis of the surveillance,
epidemiology and end results database. Journal of Clinical Oncology 2005;23:4735–41. Townsend CM, Beauchamp RD, Evers BM, Mattox KL, editors. Sabiston textbook of surgery. 17th ed. Saint Louis, MO: Saunders; 2004. Conti EM, Cercato MC, Gatta G, et al. Childhood melanoma in Europe since 1978: a population-based survival study. European Journal of Cancer 2001;37:780–4. Sander B, Karlsson P, Rosdahl I, et al. Cutaneous malignant melanoma in Swedish children and teenagers 1973–1992: a clinico-pathological study of 130 cases. International Journal of Cancer 1999;80:646–51. Handfield-Jones SE, Smith NP. Malignant melanoma in childhood. British Journal of Dermatology 1996;134:607–16. Fishman C, Mihm Jr MC, Sober AJ. Diagnosis and management of nevi and cutaneous melanoma in infants and children. Clinical Dermatology 2002;20:44–50. Ruiz-Maldonado R, Orozco-Covarrubias ML. Malignant melanoma in children. A review. Archives of Dermatology 1997;133: 363–71. Bono A, Ferrari A. Early diagnosis remains the most reliable way to cure children with melanoma. Pediatric Blood Cancer 2005;45:355 [author reply 356]. Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. New England Journal of Medicine 2004;351: 998–1012. Cascinelli N. Margin of resection in the management of primary melanoma. Seminars in Surgical Oncology 1998;14:272–5. Veronesi U, Cascinelli N, Adamus J, et al. Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. New England Journal of Medicine 1988; 318:1159–62. Khayat D, Rixe O, Martin G, et al. Surgical margins in cutaneous melanoma (2 cm versus 5 cm for lesions measuring less than 2.1 mm thick). Cancer 2003;97:1941–6. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al. Long term results of a randomized study by the Swedish Melanoma Study Group on 2 cm versus 5 cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8–2.0 mm. Cancer 2000;89:1495–501. Balch CM, Soong SJ, Smith T, et al. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1–4 mm melanomas. Annals of Surgical Oncology 2001;8:101–8. Thomas JM, Newton-Bishop J, A’Hern R, et al. Excision margins in high-risk malignant melanoma. New England Journal of Medicine 2004;350:757–66. Pacella SJ, Lowe L, Bradford C, et al. The utility of sentinel lymph node biopsy in head and neck melanoma in the pediatric population. Plastic and Reconstructive Surgery 2003;112: 1257–65. McMasters KM, Reintgen DS, Ross MI, et al. Sentinel lymph node biopsy for melanoma: controversy despite widespread agreement. Journal of Clinical Oncology 2001;19:2851–5. Pharis DB. Cutaneous melanoma: therapeutic lymph node and elective lymph node dissections, lymphatic mapping, and sentinel lymph node biopsy. Dermatologic Therapy 2005;18: 397–406. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. Journal of Clinical Oncology 1996;14:7–17. Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB–III melanoma: results of intergroup trial E1694/S9512/C509801. Journal of Clinical Oncology 2001;19:2370–80.
ARTICLE IN PRESS 220 [22] Navid F, Furman WL, Fleming M, et al. The feasibility of adjuvant interferon alpha-2b in children with high-risk melanoma. Cancer 2005;103:780–7. [23] Shah NC, Gerstle JT, Stuart M, et al. Use of sentinel lymph node biopsy and high-dose interferon in pediatric patients with high-
C.D. Downard et al. risk melanoma: the Hospital for Sick Children experience. Journal of Pediatric Hematology Oncology 2006;28:496–500. [24] Livestro DP, Kaine EM, Michaelson JS, et al. Melanoma in the young: differences and similarities with adult melanoma: a case-matched controlled analysis. Cancer 2007;110:614–24.
Available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/suronc
REVIEW
Melanoma in children and adolescents Cynthia D. Downard, Louis B. Rapkin, Kenneth W. Gow Division of Pediatric Surgery and the Department of Hematology/Oncology/BMT, Aflac Cancer Center, Emory School of Medicine, Atlanta, GA, USA
KEYWORDS Melanoma; Children; Adolescents
Summary Melanoma is rarely described in the pediatric population. However, recent studies show that the incidence may be increasing. The diagnosis of melanoma presents unique challenges in this age group. There may be predisposing factors that affect children more than adults. A high index of suspicion is necessary in order to make a timely diagnosis. Prompt surgical treatment by individuals with expertise in care of patients with melanoma with potentially curative excision and appropriate lymph node evaluation is important to optimize survival. Careful review of all specimens by an experienced dermatopathologist is important. Through cooperation with adult trials and potential inclusion of pediatric patients in evaluations of new therapies, further progress against this disease can hopefully be addressed in all age groups. & 2007 Elsevier Ltd. All rights reserved.
Contents Introduction . . . . . . . . . . . Epidemiology . . . . . . . . . . Predisposing conditions . . . . Presentation and evaluation . Treatment . . . . . . . . . . . . Adjuvant therapy. . . . . . . . Outcomes . . . . . . . . . . . . References . . . . . . . . . . . .
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Introduction The incidence of cutaneous melanoma has increased markedly in the last 30 years. Although patients under 20 Corresponding author. 4800 Sand Point Way NE, M/S W-7729, P.O.
Box 5731, Seattle, WA 98105-0371, USA. Tel.: +1 206 979 6800. E-mail address: [email protected] (K.W. Gow). 0960-7404/$ - see front matter & 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.suronc.2007.09.006
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years of age account for only 1% of patients diagnosed with melanoma, approximately 1 in 58 individuals born today will be diagnosed with melanoma at some point in their lifetime [1]. Melanoma is the most common cancer diagnosed in females between the ages of 25 and 29 years. Early detection and intervention in patients with melanoma are the mainstays of cure. Preventive counseling and treatment of those diagnosed with melanoma early in life is therefore
ARTICLE IN PRESS 216 of importance to the practicing pediatrician, family practitioner, and surgeons who treat children and adolescents [2]. Malignant melanoma is categorized histologically into four types: Lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma, and nodular melanoma. Superficial spreading melanoma is the most common type. Of note, nodular melanoma undergoes an early vertical growth phase, which is important since depth of invasion at diagnosis is closely associated with the ultimate prognosis in cutaneous melanoma [3].
Epidemiology With the advent of computerized databases, the incidence of rare malignancies such as pediatric cutaneous melanoma has been more accurately recorded over the last two decades. As a result, the rise in the incidence of melanoma has become readily apparent. This careful recording of patients also allows retrospective reviews of preserved histological samples as new discoveries are made. Conti and colleagues reported a series of 212 European children (age less than 15 years) with melanoma identified through the EUROCARE database over an 11 year time period and attempted to evaluate the population-based survival for this disease in different national populations [4]. Due to the relative rarity of the disease, however, they could only make generalizations about the survival of children diagnosed with melanoma compared to adult statistics. They found that the overall 5-year survival for all children diagnosed with any type of melanoma was 79%. Five-year survival was best for children diagnosed with cutaneous melanoma (87%) and worst for patients with melanoma not of the skin or eye (57%). Within the cutaneous melanoma population, survival was negatively impacted by having a primary lesion on the trunk (76%). They point out that 5-year survival in the adult population over a similar time period was 77% for all patients diagnosed with melanoma and suggest that this minimal improvement in survival may be aided by earlier detection and excision of suspicious lesions in children. Sander and colleagues from the Huddinge Hospital in Sweden reviewed specimens from 130 patients with melanoma diagnosed prior to 20 years of age to evaluate if histological differences from adult melanoma were evident [5]. In addition, they investigated if the microscopic features of melanoma had changed during the 20 years over which the specimens were collected. They found that over the time period evaluated, it seemed that the thickness of the tumors decreased at the time of diagnosis from 1.3 mm in the first 10 years to 0.8 mm in the second decade, possibly due to enhanced screening efforts. Overall mortality rate for the population studied was 10%. In addition, they reviewed all the slides previously obtained to determine the ‘‘over diagnosis’’ rate of melanoma. Their concordance with the prior diagnosis was 85%, and only the patients they diagnosed as having melanoma were included in the study. In their review, all of the pediatric melanoma specimens had features similar to adult melanomas, with the most common type being superficial spreading melanoma. Over the course of their study the incidence of melanoma in Swedish youth increased fourfold.
C.D. Downard et al.
Predisposing conditions Cutaneous malignant melanoma differs in children in that it may arise from conditions unique to the pediatric population. Because of this, pediatric melanoma is classified by the mode of occurrence as well as the histological subtype: [6] (I) Transplacental melanoma, transmitted from the mother with melanoma to the fetus in utero. (II) Transformation from giant congenital melanocytic nevus. (III) In association with congenital predisposing conditions such as xeroderma pigmentosum, dysplastic nevus syndrome, and albinism. (IV) Development from healthy skin. (V) Development from a preexisting nevus. Giant congenital melanocytic nevi occur in approximately 1 in 20,000 newborns [7]. Giant congenital melanocytic nevi are classically defined as being greater than 20 cm in largest diameter. An alternate definition is any congenital nevus requiring a graft for closure after excision. Approximately 30% of pediatric melanomas arise from these lesions, while the lifetime risk of malignant degeneration of these lesions is thought to be between 2% and 20%. Many of the malignant melanomas that arise from giant congenital melanocytic nevi do so in the first 5 years of life. Some groups recommend routine complete excision of the entire lesion early in childhood due to the risk of malignancy, but this can often require a staged removal and advanced plastic surgical techniques such as the use of tissue expanders for coverage. If the lesion is not easily excised, serial follow up by a physician familiar with these patients is mandatory for early detection of malignant change. Any alteration in appearance should prompt biopsy. Plans for removal are dependent on the size and location of the lesion. X. pigmentosum is an autosomal recessive disorder that is first noted around the age of 1 or 2 years by marked photosensitivity or freckling [8]. The genetic aberration involves a defect in the repair of DNA after damage induced by UV rays and is associated with multiple types of skin cancer. Malignant melanoma occurs approximately 2000 times more commonly in this population that in the general population, usually in the early teen years. Reduction in sun exposure and early detection and treatment of melanoma in this population is absolutely critical. Immunosuppression as a result of a hematologic or infectious disorder or induced immunosuppression after organ or bone marrow transplant puts the pediatric patient at a 3-fold to 6-fold increased risk of malignant melanoma. Monitoring of nevi in these populations should therefore be a routine part of their long-term evaluation. Dysplastic nevi syndromes can occur in a familial or sporadic form [7]. Often these children will have multiple nevi present by the age of 5 years, and the lesions will then progress to become dysplastic nevi in the teen years. Frequent evaluation of the nevi by an individual with experience in treatment of cutaneous malignancies is advised.
ARTICLE IN PRESS Melanoma in children and adolescents
Presentation and evaluation As previously stated, several patient populations, including those with congenital melanocytic nevi, x. pigmentosum, immunosuppression for any reason, and dysplastic nevi syndromes are at increased risk for development of melanoma and warrant serial examinations by clinicians familiar with cutaneous pathology. However, approximately 50% of melanomas in the pediatric population develop de novo and therefore when suspicious skin lesions are noted by the general pediatrician prompt referral for further evaluation should follow. Biopsy of suspicious skin lesions should be done with the expectation that the lesion is malignant. Full thickness biopsies best allow determination of the depth of invasion of a lesion, which is one of the most important prognostic factors in cutaneous melanoma. The initial physical examination of a patient with a cutaneous lesion should include a thorough evaluation of the entire skin surface with special attention to additional suspicious lesions. Mucus membranes and the digits and interdigital spaces are important not to be overlooked. Photography may be helpful if lesions are being followed over time. The initial area of concern can be assessed with the traditional ABCD criteria of melanoma (asymmetry, border irregularity, color, and diameter 46 mm), although these criteria may not be as universally applicable in children as they are in adults [9]. In addition, attention must be paid to regional lymph node basins as they may harbor metastatic disease. If a lesion is determined to be suspicious either on initial evaluation or after serial examination, the evaluation of choice is an excisional full thickness skin biopsy. It is not necessary to perform this with excessive margins, as a diagnosis of melanoma would lead to a re-excision of the lesion. Occasionally in a very cooperative teen this initial biopsy could be performed in the office, but for younger children it is generally performed in the operating room under heavy sedation or general anesthesia. Incisional biopsy is to be considered if removing an entire lesion initially would be disfiguring [10]. Evaluation by an experienced dermatopathologist is critical in obtaining the proper diagnosis, particularly in the pediatric age group. The difficulty of differentiating a Spitz nevus from melanoma can be quite challenging, and is best done by one with extensive expertise in the area.
217 adequate to prevent local recurrence. The end result of these studies is a recommendation of 0.5–1 cm margin for melanoma in situ lesions, margins of 1 cm for lesions less than 1 mm in thickness, and 2 cm margins for all other lesion thicknesses. It is important to remember when excising these lesions that the margins are circumferential, completely surrounding the prior biopsy site. As such, the excision sites for an intermediate (1–4 mm) or thick (44 mm) lesion are actually at least 4 cm in diameter (Figure 1). In the last 20 years, the advent of sentinel lymph node biopsy for staging of melanoma has been critical in altering the treatment of adult patients with this disease. More recently, sentinel lymph node biopsy for children with melanoma has gained acceptance as a useful modality. In addition, sentinel lymph node biopsy can be of unique utility in the pediatric population in determining the difference between melanoma, which may metastasize to regional lymph nodes, and a Spitz nevus, which should not metastasize. Sentinel lymph node biopsy is usually performed concurrent with re-excision of the primary lesion. The procedure involves injection of the primary cutaneous lesion site with technetium-99m sulfur colloid followed by lymphoscintigraphy in the nuclear medicine suite. This is typically done on the morning of scheduled re-excision, and the patient is brought to the operating room in the afternoon. Once under anesthesia in the operating room, the lesion is injected with approximately 1 ml of 1% isosulfan blue dye. It is important to maintain the area of injection within the intended resection margins as the dye does tattoo the skin (Figure 2). The dye is allowed to travel through lymphatics for several minutes, and a hand held gamma counter is used to determine the area of maximal
Treatment Once a diagnosis of melanoma has been made, the focus turns to adequately staging the disease. The importance of full thickness initial biopsies cannot be overemphasized as the thickness of the lesion helps to determine the next step in care. Re-excision of the lesion is the first step in treatment, and prospective, randomized trials have determined the necessary margin to minimize local recurrence related to lesion depth [11–16]. In trials addressing adequacy of margins, patients were enrolled based on the thickness of their tumors and randomized to either narrow or wide margins, with most trials suggesting that the narrower margins were
Figure 1 The margin of resection for a lesion of less than 1 mm thickness is 1 cm in all directions. Therefore, a defect of at least 2 cm in diameter will be created. An elliptical incision aids with closure of the defect.
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C.D. Downard et al. dissection is based on errant assumptions of how melanoma spreads, and it could actually be assumed to be systemically metastatic at that point [19]. In our own experience, the sentinel lymph node is often the only positive lymph node in the draining basin.
Adjuvant therapy
Figure 2 It is important to keep the isosulfan blue dye within the planned resection margin to minimize risk of tattooing the skin.
Figure 3 Sentinel lymph nodes are those nodes that are blue, radioactive (as determined by the gamma probe), or palpable. All sentinel nodes are excised and sent fresh to pathology.
radiolabeled tracer intensity for lymph node sampling. An incision is made over the area identified to have the most active uptake of radiolabeled tracer as determined by the handheld gamma probe and the preoperative lymphoscintigraphy. Upon examination of the draining lymph node basin, all nodes that are blue, palpable, or show significant activity with the gamma probe are excised and sent fresh to pathology (Figure 3). Selective sampling of lymph nodes allows more directed study of samples using immunohistochemical methods to determine if lymph node metastases are, in fact, present. The primary lesion is then re-excised with the margins determined by depth of the initial lesion as previously mentioned [17]. Currently, evidence of melanoma cells in regional lymph nodes sampled during sentinel lymph node biopsy warrants offering a completion lymph node dissection of the draining basin. It is unclear if completion lymph node dissection confers a survival advantage in melanoma, and this is actively being investigated in the Sunbelt Melanoma Trial [18]. It may be that offering completion lymph node
Melanoma cells that have spread to regional lymph nodes have demonstrated a propensity to travel to other parts of the body, and consideration of systemic therapy in this situation is under investigation. Unfortunately, pediatric patients are not included in most trials of adjuvant therapy for melanoma, and therefore treatment plans for children must be extrapolated from adult studies. Traditional chemotherapy regimens have not had significant activity against melanoma. Biologic agents such as interferon alfa-2b are currently used for adjuvant therapy against high-risk melanoma after surgical resection. Adult studies have evaluated the use of high dose interferon alfa2b in patients with high-risk melanoma and have shown an improvement in relapse-free survival and overall survival when compared with observation [20]. Vaccination against defined melanoma antigens for patients with high-risk melanoma has also held interest, but has not proven more effective than treatment with high dose interferon alfa-2b in adult trials [21]. Given the favorable results with use of interferon alfa-2b in adults, Pappo and colleagues at St. Jude Children’s Research Hospital investigated the feasibility of treating pediatric melanoma patients with high dose interferon [22]. Their series included 15 patients less than 18 years of age with Stage III melanoma, defined as having a primary tumor thickness of greater than 4 mm or having lymph node or in-transit metastases, but no distant metastasis. In their protocol, patients were treated with interferon alfa2b intravenously during a 4-week induction phase, followed by maintenance therapy with subcutaneous administration of interferon alfa-2b three times a week for 48 weeks. All patients had completed induction therapy, and nine had completed maintenance therapy at the time of publication. The most common serious toxicity was neutropenia. Four of 15 patients required dose reduction due to toxicity during the induction phase, and 3 of 15 patients required dose reduction during the maintenance phase. They concluded that interferon alfa-2b could be used in pediatric melanoma patients with acceptable toxicity. The study was not controlled, and therefore no conclusions about efficacy of the treatment could be reached. A recent report from Toronto examined the use of high dose interferon in pediatric melanoma patients identified as having metastatic disease on sentinel lymph node biopsy [23]. Of a total of 10 patients who underwent sentinel lymph node biopsy for melanoma or melanoma-like lesions, 6 patients were found to have sentinel lymph nodes containing melanoma cells. All patients in their series who had positive sentinel lymph nodes then underwent completion lymph node dissection. Five of these patients were treated with high dose interferon therapy, and one patient refused further therapy. At the conclusion of their study, four
ARTICLE IN PRESS Melanoma in children and adolescents patients had completed therapy and were in remission while one was still receiving interferon therapy. Dose adjustments due to myelosuppression were required in two patients, while two patients required dose adjustments due to abnormal hepatic function tests. In short, although most of the patients did complete their therapy, almost all required alterations in dosage due to toxicity; 10 of the 11 patients survived with a median follow-up of 26 months. The one patient who died presented with metastatic disease. Because melanoma is a relatively rare disease in the pediatric population it is difficult to accrue adequate numbers of patients in clinical trials to evaluate adjuvant therapies. Due to the histologic and clinical similarities in adult and pediatric melanoma, it would likely be helpful to include children in adult therapeutic trials.
Outcomes A longstanding debate over the similarities and differences of adult and pediatric melanoma has recently been addressed with a case-matched controlled analysis of melanoma patients from the Massachusetts General Hospital [24]. In this study, 73 melanoma patients less than 21 years of age were matched to 146 adult patients based on tumor stage and year of diagnosis, and outcomes were compared. They chose to match the cases and controls based on tumor thickness because many case series of pediatric patients have shown that pediatric patients often have a thicker melanoma lesion at the time of presentation, and tumor thickness is an important determinant of outcome. In this series, two adult control patients with melanoma were selected for each pediatric melanoma patient in order to achieve greater statistical power. Cases and controls were also matched for year of diagnosis since the treatment of melanoma varied greatly over the 32 years included in the study, specifically with the use of lymphatic mapping and sentinel lymph node biopsy in the later years of the study. After comparisons were carried out, a specific analysis of patients who underwent lymph node evaluation either by lymph node dissection or sentinel lymph node biopsy showed a higher rate of lymph node metastasis in the pediatric group (44%) as compared to the adult group (23.9%). However this difference did not reach statistical significance due to the small sample size. In addition, there was no statistically significant difference in the 5-year and 10-year disease-free and cause-specific survival rates between the pediatric and adult melanoma patients. In this series, pediatric patients who had either Stage I or Stage II (localized disease) had a 94.4% 10-year survival, while patients presenting with Stage III melanoma (metastasis to lymph nodes) had a 60.1% 10-year survival.
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