CUTANEOUS MALIGNANT MELANOMA IN SWEDISH CHILDREN AND TEENAGERS : A CLINICO-PATHOLOGICAL STUDY OF 130 CASES

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1 Int. J. Cancer: 80, (999) 999 Wiley-Liss, Inc. Publication of the International Union Against Cancer Publication de l Union Internationale Contre le Cancer CUTANEOUS MALIGNANT MELANOMA IN SWEDISH CHILDREN AND TEENAGERS : A CLINICO-PATHOLOGICAL STUDY OF 30 CASES B. SANDER *, P. KARLSSON 2,I.ROSDAHL 2,P.WESTERMARK and B. BOERYD Department of Environment and Health, Division of Molecular and Immunological Pathology, Faculty of Health Sciences, University of Linköping, Linköping, Sweden 2 Department of Biomedicine and Surgery, Division of Dermatology, Faculty of Health Sciences, University of Linköping, Linköping, Sweden To assess whether there has been a change in histological features and prognostic factors of primary cutaneous malignant melanoma (CMM) in young individuals in Sweden, an unselected, population-based study was undertaken; 77 cases of primary CMM in persons below 20 years of age were reported to the Swedish National Cancer Registry between 973 and 992. In 87% of the cases, original tumor tissue was available for histo-pathological review. The original diagnosis was verified in 88% (n 26) of these cases. All tumors had histological features similar to adult CMM; 7% had an associated precursor lesion. Superficial spreading melanoma (SSM) was the most common sub-type, constituting 20/36 cases in the first decade and 59/90 in the second. Corresponding figures for nodular melanoma (NM) were /36 and 23/90. Only 5 melanomas in situ were diagnosed. In girls, the mean thickness of SSM decreased from.5 to 0.6 mm (p F 0.00). Overall mortality was 0%, 22% in the group with CMM diagnosed 0 5 years of age and 8% in individuals 5 9 years. Fatal CMM cases diagnosed below 5 years of age (n 4) were NM G.6 mm thick and in subjects 5 9 years (n 9) 44% of fatal tumors were NM with a mean thickness of 2.2 mm. Breslow index was the single most important prognostic factor. However, when known prognostic factors were adjusted for in a Cox regression analysis, young age remained an independent risk factor, with a relative death rate of 0.2 for individuals aged 5 9 compared with children F5 years of age. Int. J. Cancer 80:646 65, Wiley-Liss, Inc. Cutaneous malignant melanoma (CMM) in children has been considered a rare disease and has been reported with such a low frequency as to make young age a factor arguing against malignancy (McWhorter and Woolner, 954; Malec and Lagerlöf, 977; Peters and Goellner, 986; Partoft et al., 989). However, occurrence of skin melanoma in children and adolescents is increasing, at least in some parts of the world (McWhirter et al., 996). At the same time, histological interpretation of melanomas in children and adolescents remains difficult. There are a number of tumors, most notably the Spitz (948) nevus, that have so many histological features in common with malignant melanoma that over-diagnosis as melanoma is not infrequent, ranging 40% to 96% in different studies (Saksela and Rintala, 968; Malec and Lagerlöf, 977; Partoft et al., 989; Spatz et al., 996). Therefore, it is especially important that a thorough histo-pathological re-evaluation is included in epidemiological studies of CMMs in young patients. Karlsson et al. (998) have estimated the incidence of CMM in Swedish children and adolescents 0 9 years of age in A marked increase of the adjusted mean annual incidence rate was found, from 0.2 to 0.5/ in the second 0-year period, compared with the first. CMM remained extremely rare in children below 2. In subjects aged 2 9 years, incidence increased with time and with increasing age. The study was based on 30 histo-pathologically confirmed cases reported to the Swedish Cancer Registry. The importance of a histo-pathological reevaluation in epidemiological studies of malignant melanoma in younger age groups is re-inforced by Berg and Lindelöf (997). By analyzing plain registry data, the incidence of CMM was overestimated by 40% in and by 20% in the subsequent 0-year period, leading to an under-estimation of the increase in incidence (Rosdahl et al., 997; Karlsson et al., 998). In the present report, we have analyzed the clinical and detailed histo-pathological features of the 30 histologically confirmed tumors, to clarify whether there has been a change in tumor type and prognostic factors during the 20-year period studied. This is the largest reported series of cases describing the histological characteristics of melanoma in childhood and adolescence. MATERIAL AND METHODS Data were obtained from the Swedish National Cancer Registry about all cases of CMM diagnosed in in persons younger than 20 years (Karlsson et al., 998). Information on melanoma site and cause of death, according to ICD-7 (International Classification of Disease, 7th revision), was also obtained by the registry. Only cases with malignant melanoma of the skin (ICD-code 90) were included. Cases with ocular melanoma (ICD-92) or genital melanoma (ICD-codes 76 and 79) were excluded. The reliability of the Swedish National Cancer Registry is high since notification must be done by both the surgeon and the diagnosing pathologist. The registry also obtains information from death certificates and reports in cases where autopsies have been performed. The reporting rate for lethal skin tumors has been estimated at 99% (Mattsson and Wallgren, 984). No family history of malignant melanoma could be obtained from the registry. Original histo-pathological material was provided by all Departments of Pathology in Sweden. In 54/77 (87%) of the reported cases, original microscopic slides or recent slides from tissue blocks were available for review. The initial histological sections were stained with either hematoxylin and eosin or van Gieson s stain. When the quality of the original slides was poor, new sections were prepared. In some cases, sections were subjected to immunohisto-pathological investigation, to assess tumors for the presence of S-00 and HMB-45 antigens. The histological material in all cases was independently studied by 2 or 3 of the pathologists (BB, BS and PW) without knowledge of the previous histo-pathological record or the clinical outcome. In 7 of the cases, one of these pathologists was involved in making the original diagnosis. Diagnostic criteria used were essentially those currently accepted (Elder and Murphy, 99). Histological subtype was classified according to the guidelines of McGovern et al. (986), including superficial spreading melanoma (SSM), nodular melanoma (NM) and acral lentiginous melanoma (ALM). Level of invasion was categorized according to Clark et al. (969): level I (intra-epidermal growth), level II (invasion into the papillary dermis), level III (invasion through papillary dermis to interface Grant sponsor: Swedish National Cancer Institute; Grant numbers: 357-B96-03XAB; 3800-B96-0XAB; 357-B96-02PAC; Grant sponsors: Foundation for Cancer Research (Östergötland); Welander/Finsen Foundation. *Correspondence to: Laboratory for Clinical Pathology and Cytology, Huddinge Hospital, S-4 86 Huddinge, Sweden. Received 8 May 998; Revised 3 August 998

2 MALIGNANT MELANOMA IN THE YOUNG 647 with reticular dermis) and level V (invasion into s.c. fat). Tumor thickness in millimeters was measured according to Breslow (970): the vertical dimension was measured from the deepest part of invasion to the top of the granular layer or to the most superficial cells under an ulceration, using an ocular micrometer. Ulceration was noted as interrupted epithelium involved by the tumor, often with leukocytes and fibrin on the surface, and was graded yes or no. The presence of benign nevus cells was investigated. Such cells remaining within the tumor or its margin was a sign of a pre-existing nevus. This was graded yes or no. Statistical analysis was performed using Student s t-test, the log-rank test, multivariate analysis, Cox s regression analysis and the Kaplan-Meier method, as indicated. Survival time was taken to be the period between the date of diagnosis and the date of death or last follow-up. RESULTS Distribution of the material During the years , a total of 20,729 cases of CMM were reported to the Swedish National Cancer Registry. During the same time period, 77 cases were reported as primary CMM in individuals younger than 20 years (Table I). The number of cases re-examined was 54. Of these, 4 tumors had originally been classified as nevi and 2 as metastases of malignant melanoma, but they had been mis-reported as primary malignant melanomas to the registry. Of the remaining 48 cases, 26 were re-evaluated as malignant melanomas. In 4 cases, the diagnoses differed between the 3 reviewing pathologists: Spitz nevi (2 tumors), dysplastic nevi (2 tumors) or malignant melanoma. These tumors were classified as suspected malignant melanomas; 8 cases initially diagnosed as malignant melanoma were considered upon review to be Spitz nevi (5 tumors), dysplastic nevi (5 tumors), atypical compound nevi (5 tumors), atypical junction nevus ( tumor), compound nevus with a large nodulus in dermis ( tumor) and non-melanocytic tumor ( tumor). Thus, the diagnosis malignant melanoma or suspected malignant melanoma was confirmed in 88% of the correctly reported, re-examined tumors. Melanoma sub-types Among the 26 cases re-evaluated as malignant melanoma, 36 were diagnosed in the first decade studied ( ) and 90 in the second decade (Table I). All of the malignant melanomas had histological features similar to those seen in adults (Elder and Murphy, 99). Two of the NMs (0.7 mm, Clark III and 7.7 mm, Clark IV) and melanoma of unclassified sub-type (.3 mm, Clark III) were diagnosed as minimal deviation melanomas. The 7.7-mmthick, Clark level IV tumor was located on the skin superficial of the Achilles tendon. This tumor was, upon reference, classified as a TABLE I DISTRIBUTION OF MATERIAL Reported cases 60 7 Not available for re-examination 0 3 Mis-reported Re-examined cases Non-melanoma diagnoses 7 Suspected malignant melanomas 3 Malignant melanomas Histo-pathological sub-types 3 In situ malignant melanomas 3 2 SSM NM 23 ALM 0 3 Unclassified 2 3 Two nevi, 2 metastases of malignant melanoma. 2 Two nevi. 3 SSM, superficial spreading melanoma; NM, nodular melanoma; ALM, acral lentiginous melanoma. Spitz variant of minimal deviation melanoma by Dr. R.Y. Reed (New Orleans, LA). The patient is alive with no recurrence 6 years after diagnosis. The other 2 minimal deviation melanomas were of the halo nevus variant. Only 5 Clark level I (in situ) melanomas were found. Prognostic variables During the time periods studied, the mean thickness of SSM decreased from.3 in the first decade to 0.8 mm in the second decade (statistically significant at the 5% level, Student s -sided t-test). A statistically significant decrease in SSM thickness was noted in tumors diagnosed in girls (.3 to 0.6 mm, n 47, p 0.0 using Student s t-test) but not in boys (.3 to.0 mm, n 9, not significant) (Fig. ). However, there was no statistically significant difference in the ratio of SSM Clark level II to total SSM diagnosed compared with the ratio in the second decade (50% vs. 62%) (Fig. 2). The mean thickness of NMs remained approximately constant during the 2 decades, 2.5 mm and 2.6 mm, respectively. A majority of NMs were Clark III in the first time period (64%) and Clark IV in the second decade (49%). Most SSMs were non-ulcerated (7/20 tumors in the first decade, 55/59 in the second), while 8/ NMs in the first and 7/23 NMs in the second decade were ulcerated. Associated precursor lesions An associated precursor lesion was found in 9/3 diagnosed SSMs and NMs (7%) and in of the suspected melanomas (Table II). Only 5 of these precursor lesions had histological features indicative of a congenital nevus. None of these was a congenital giant nevus. Malignant melanomas diagnosed before 5 years of age In individuals below the age of 5 years, 24 malignant melanomas were registred, 5 cases during the first decade and 9 during the second. Of these, 20 were reviewed, and in 7 of them the diagnosis malignant melanoma was confirmed. An additional case was diagnosed as suspected malignant melanoma (Table III). In children below 0 years of age, only 3 cases of malignant melanoma were reported. The first case, registered in 974, was a boy aged year and 4 months. We were not able to review this case, but the child died of malignant melanoma 0 months after diagnosis. In 989 malignant melanoma was reported in a 7-yearold boy and a 9-year-old girl. Both children are alive and free of disease 7 years later. In the boy, the histo-pathological picture did not support a melanoma diagnosis, but the final diagnosis for the girl was SSM, Clark level II with a thickness of 0.6 mm. In Swedish children aged 0 to 5 years, 2 cases of CMM were reported during the 20 years studied, 4 in the years and 7 in the last decade. Only 2 of the 4 cases from the first decade could be reviewed; in both, the diagnosis was confirmed, and one of these children died of disease. The 2 patients with lesions that were not reviewed are disease-free according to the registry. In the second decade studied, 6/7 cases were reviewed; 4 of these were diagnosed as malignant melanoma, as suspected malignant melanoma and as epidermal tumor. The one tumor that was not reviewed has not metastasized according to the registry. Clinical course Follow-up of surviving patients ranged from 5 to 27 months. According to the registry, none of the patients with minimal deviation melanoma, suspected melanoma or non-melanoma died of malignant melanoma; 3 of the 26 patients with histologically verified malignant melanoma died of disease (7 diagnosed in the first decade and 6 in the second) for an overall mortality rate of 0%. The histological and clinical data of the fatal malignant melanomas are presented in Table IV. Eight (6%) of the lethal malignant melanomas were NM and all had a Breslow index of at least 0.8 mm. The majority of tumors were Clark III or IV, with only being Clark level II. Four patients were below 5 years at diagnosis, resulting in a mortality rate of 22% in the age group 5

3 648 SANDER ET AL. FIGURE Breslow index in millimeters of SSMs and NMs diagnosed in male ( ) and female ( ) patients during the 2 decades and Bar indicates mean thickness: for SSM ,.3 mm (males) and.5 mm (females); for SSM ,.0 mm (males) and 0.6 mm (females); for NM , 2.8 mm (males) and.9 mm (females); for NM , 3.2 mm (males) and 2. mm (females). The decrease in Breslow index in malignant melanoma diagnosed in females is statistically significant ( p 0.00, Student s t-test). In 4 SSMs, Breslow index could not be measured; these are not included in the figure. years and 83.2 months in patients aged 5 to 9 years (Table IV). Statistical analysis of invasive melanoma (excluding Clark I and suspected melanomas) demonstrated a significantly higher mortality in children 5 years compared with individuals 5 to 9 years of age ( p 0.09, log-rank test). This is also demonstrated in a survival analysis (Fig. 3). As expected, a multivariate analysis showed that the Breslow index was the strongest prognostic factor ( p 0.02), but Clark level of invasion was significantly correlated with survival (data not shown). However, when known prognostic factors were corrected for in a Cox regression analysis, the difference in mortality persisted, resulting in a relative death rate of 0.2 in the older individuals (5 to 9 years of age) compared with the children ( 5 years, confidence interval ) (Table V). FIGURE 2 Clark levels of invasive SSM and NM during the 2 decades. In SSM, Clark level could not be assessed; this is excluded from the figure. years compared with 8% in the melanomas diagnosed at ages 5 to 20 years. Mean survival time in patients with fatal melanoma was 68.2 months (range 3 to 84): 34.5 months in patients below 5 DISCUSSION Studies of malignant melanoma in adults have demonstrated that diagnostic criteria have remained constant during several decades (Van der Esch et al., 99). The accuracy in diagnosis in adults is high, and only 4% to 6% of cases originally diagnosed as primary CMM have been changed upon review (Van der Esch et al., 99; Måsbäck et al., 994). However, previous Scandinavian studies have revealed an over-diagnosis of malignant melanoma in young individuals (Skov-Jensen et al., 966; Saksela and Rintala, 968; Malec and Lagerlöf, 977; Partoft et al., 989). More recent studies have established that considerable over-diagnosis of CMM in children still occurs. In a European multicenter study of 02 lesions originally diagnosed as CMM in children below 6, 4% of tumors

4 MALIGNANT MELANOMA IN THE YOUNG 649 TABLE II PRECURSOR LESIONS SSM in conjunction with NM in conjunction with Congenital nevi Common nevi Congenital nevi Common nevi (5%) 0 (9%) (7%) (22%) TABLE III CLINICAL AND HISTOLOGICAL FEATURES IN 8 CASES OF MELANOMA OR SUSPECTED MELANOMA DIAGNOSED BEFORE THE AGE OF 5 Case Age at diagnosis (years, months) Sex Site Type 6 Breslow index (mm) Clark level Ulceration Associated nevus 3, 6 F Trunk SSM 0.5 II No Common 2 5 4, 5 M Trunk NM 5.0 IV No None 3 4, M n.s. 2 SSM. II No None 4 5 2, 0 F Trunk NM.8 IV No None 5 4, 9 F Arm SSM 0.5 II No None 6 3, 9 F Trunk SSM.3 IV No None 7 5 2, 9 M Trunk NM 3. IV Yes None 8 4, 0 M L.leg 3 SSM Regression II No None 9 4, 8 F L.leg SSM Regression II No None 0 3, 0 M L.leg susp..8 n.d. No None 5 4, 7 M Trunk NM 6.8 IV Yes None 2 3, F L.leg SSM 0.7 III No None 3 4, 6 F L.leg SSM 0.8 III No None 4 4, 4 F L.leg SSM 0.2 II No None 5 9, 6 F L.leg SSM 0.6 II No None 6 2, 9 F h/n 4 NM.6 III n.d. None 7 3, M Leg SSM 0.8 III No None 8 4, 7 M Trunk NM 3.6 IV No None Cases and 2 were diagnosed and cases n.s., primary CMM, site not specified. 3 L.leg, lower leg. 4 h/n, head and neck. 5 Died of disease. 6 SSM, superficial spreading melanoma; NM, nodular melanoma; susp., suspected. Age at diagnosis (years, months) TABLE IV CLINICAL AND HISTOLOGICAL FEATURES IN 3 CASES OF FATAL MELANOMA Sex Site Type 2 Thickness (mm) Level Ulceration Associated nevus Time to death (months) 9, 0 M Trunk NM 4.0 III Yes No 5 9, F Lower leg SSM 5.0 IV Yes No 0 9, 4 M Lower leg NM.8 IV Yes No 95 6, 3 F Trunk NM 0.8 III Yes Common 84 9, F Trunk SSM 2.9 IV No No 00 6, 6 F Arm SSM.8 III No No 37 4, 5 M Trunk NM 5.0 IV No No 83 9, 5 M Upper leg SSM.4 III Yes No 9 7, 9 M Not specified SSM.3 III No No 46 7, 9 M Head and neck NM.0 II Yes Common 43 4, 7 M Trunk NM 6.8 IV Yes No 3 2, 9 M Trunk NM 3. IV Yes No 25 2, 0 F Trunk NM.8 IV No No 7 The first 7 cases were diagnosed in and the remaining cases in SSM, superficial spreading melanoma; NM, nodular melanoma. were reclassified as nevi (Spatz et al., 997). This most likely reflects the difficulty in histological distinction between malignant melanomas and benign nevi arising in young individuals (Peters and Goellner, 986). One aim of the present study was to investigate if and to what extent such an over-diagnosis may have taken place during a longer time period in Sweden and in individuals up to 20 years of age. After having reviewed 48 cases of malignant melanoma registred below 20 years of age, the diagnosis of malignant melanoma or suspected malignant melanoma was confirmed in 85% of those diagnosed and in 89% of those diagnosed Thus, the concordance in diagnosis is much higher than in previous Scandinavian studies and has increased during the time period studied. In children below the age of 5, the accuracy of melanoma diagnosis was also high since the diagnosis malignant melanoma or suspected malignant melanoma was confirmed in 8 of the 20 reviewed cases (90%). From the pathology reports of our cases it was evident that 39% of the tumors had originally been subjected to consultation with one or several pathologists. The use of internal or external consultation about difficult cases has probably been an important factor leading to an increasing agreement in diagnosis. Several investigators have suggested that most malignant melanomas in children and teenagers histologically are similar to adult melanomas (Peters and Goellner, 986; Crotty et al., 992). However, Barnhill et al. (995) have described several histological variants of childhood melanoma, including variants with a morphology of adult malignant melanoma but also Spitz-like variants and a small-cell variant located in the head-and-neck region and associated with high mortality. We have now investigated an unselected population of malignant melanomas in young individuals extracted from a population-based registry. Our study represents the largest

5 650 SANDER ET AL. FIGURE 3 Kaplan-Meier curve demonstrating the cumulative proportion of surviving patients aged 5 to 9 years ( ) and 5 years at diagnosis ( ). The difference in survival between the groups was statistically significant ( p 0.09, log-rank test). Follow-up time in surviving patients ranged from 52 to 27 months in patients 5 to 9 years of age and from 5 to 238 months in patients 5 years at diagnosis. TABLE V MULTIVARIATE COX REGRESSION ANALYSIS OF AGE, TIME PERIOD AND BRESLOW INDEX IN RELATION TO SURVIVAL Variable category Death rate ratio 95% Confidence Interval Age (years) Time period Breslow index Reference category. 2 Expressed per millimeter increase. report published of the histological characteristics of CMM in the young to date and analyzes to what extent these differ from melanomas diagnosed in adults. Histologically, all of our unselected melanomas had characteristics of adult-type melanomas, including the superficial spreading and nodular and acral lentiginous variants typically observed in older patients. Three melanomas had characteristics of minimal deviation melanomas. No melanomas of the small-cell variant localized to the scalp as described by Barnhill et al. (995) were found, and it is possible that the findings of Barnhill et al. (995) might in part reflect the high number of consultation cases included in their study. p Only 7% of NMs and SSMs had demonstrable precursor lesions, either congenital or common nevi. Variable frequencies of associated precursor lesions have been reported: 9% in childhood skin melanoma (Barnhill et al., 995), 33% in teenagers (McCarthy et al., 994) and 63% in children aged 5 and younger (Scalzo et al., 997). In the latter study, the precursor lesion was not histopathologically examined but defined as a clinical history of a nevus present at the site of the subsequent melanoma. It is therefore possible that some of these precursor lesions might instead have been the first manifestation of the CMM itself. The Swedish population aged 0 to 9 years remained fairly constant, with a tendency to decrease, during the time periods studied (Karlsson et al., 998). Thus, there was a 2.5-fold increase in the number of malignant melanomas diagnosed in the second decade compared with the first decade studied. The number of SSMs diagnosed increased almost 3 times, from 20 to 59, and the number of NMs doubled, from in the first decade to 23 in the second decade studied. The incidence of childhood melanoma (diagnosed in individuals 0 years of age) remains extremely low. However, in Swedish children aged 0 to 5 years, malignant melanoma appears to occur about 8 to 9 times more frequently than in children below 0 and has increased almost 4 times during the years compared with In individuals below 5, there was a slightly larger proportion of NMs (3% of the tumors compared with 25% of the melanomas in individuals 5 to 9 years of age). In fact, among the reviewed tumors in this age group, all fatal melanomas were of the nodular sub-type, at least.6 mm thick and Clark level IV. In the 9 cases of fatal melanoma in individuals 5 to 9 years of age, there was also a large proportion of NMs (44%) and a mean tumor thickness of 2.2 mm. In a limited number of cases of CMM in individuals 2 years or younger, the disease-free survival appeared better for patients below 4 than for those 4 to 2 years of age; this difference was, however, not statistically significant (Zhu et al., 997). In the larger study of CMMs in children below 6, Spatz et al. (997) reported that the only significant parameter associated with the development of metastases or fatal outcome was thickness of more than 2 mm. This is in contrast with our finding that young age per se is a prognostic marker for metastasis. We have found that children below 5 had a higher mortality compared with children 5 to 9, also after adjustment for other known risk factors such as the Breslow index. This emphasizes the importance of early diagnosis and radical treatment. Our results, demonstrating an increasing frequency of thin, Clark II melanomas, suggest that malignant melanoma not only has a higher incidence today among Swedish teenagers than 20 years ago but is diagnosed earlier. The fact that every 5th melanoma in Swedish children and adolescents arose in connection with a nevus emphasizes the importance of not neglecting changes in nevi in young individuals. 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