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Monitoring of Kindreds With Hereditary Predisposition for Cutaneous Melanoma and Dysplastic Nevus Syndrome: Results of a Swedish Preventive Program

Johan Hansson, Mia Bergenmar, Per-Åke Hofer, Göran Lundell, Eva Månsson-Brahme, Ulrik Ringborg, Ingrid Synnerstad, Annika Ternesten Bratel, Ann-Marie Wennberg, Inger Rosdahl

From the Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm; Department of Dermatology and Pathology, University Hospital, Umeå; Department of Dermatology, Linköping University Hospital, Linköping; Consultant Group Histopathology, Capio Diagnostics; and the Department of Dermatology, Sahlgrenska University Hospital, Gothenburg, Sweden

Address reprint requests to Johan Hansson, MD, PhD, Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital Solna, S-171 76 Stockholm, Sweden; e-mail:johan.hansson{at}ki.se

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose To evaluate a program initiated in 1987 by the Swedish Melanoma Study Group aiming to provide preventive surveillance to kindreds with hereditary cutaneous melanoma and dysplastic nevus syndrome.

Patients and Methods Overall, 2,080 individuals belonging to 280 melanoma families were followed for 14 years between 1987 and 2001 at 12 participating centers. Data were registered in a central database.

Results Among 1,912 skin lesions excised during follow-up, 41 melanomas were removed in 32 individuals. Of these, 15 (37%) were in situ melanomas and 26 (63%) invasive melanomas. The median tumor thickness of invasive melanomas was 0.5 mm. Ulceration was absent in 24 of 26 invasive melanomas (92%) and 12 (46%) lacked vertical growth phase. Compared with melanomas in the general Swedish population, the melanomas identified in these kindreds during follow-up had better prognostic characteristics. All melanomas except one were diagnosed in families with two or more first-degree relatives with melanoma. Diagnosis of melanoma occurred in three of eight kindreds with germline CDKN2A mutations, supporting that families with such mutations are at increased risk for melanoma development. Of the 32 individuals who developed melanoma during follow-up, 21 (66%) had had at least one previously diagnosed melanoma.

Conclusion This study shows that a coordinated program aimed at detecting and offering skin surveillance in kindreds with hereditary cutaneous melanoma results in a low incidence of melanomas during the follow-up period and that the tumors that do arise have favorable prognostic characteristics.

	INTRODUCTION

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Up to 10% of all cases of cutaneous malignant melanoma (CMM) occur in kindreds with hereditary CMM predisposition.¹ In the first description of CMM, Norris² reported a family in which two members had CMM and several had large moles. In 1978, Clark³ reported six melanoma-prone families in which members had large nevi designated as potential precursors of CMM. This syndrome has several eponyms: "dysplastic nevus syndrome" (DNS),⁴ "familial atypical multiple mole melanoma syndrome,"⁵ and "atypical mole syndrome"⁶; and the nevi are called "dysplastic nevi" (DN) or "atypical moles."

In an early report of 14 DNS families, 95% of CMM patients and 50% of relatives had DN.⁷ During follow-up, new CMMs were diagnosed only in individuals with DN. In an another early report "D-2 kindreds" were defined, with at least two family members with CMM and two or more with DN.⁸ In a study of 23 D-2 kindreds, individuals with DN had a 89-fold increased CMM risk and those with a previous CMM a 229-fold increased risk for a second CMM⁹

In 1994, germline mutations in the CDKN2A tumor suppressor gene in kindreds with hereditary CMM (HCMM) were demonstrated.^10,11 Worldwide, germline CDKN2A mutations are found in approximately 20% of HCMM kindreds.¹ However, such mutations are present in less than 10% of Swedish HCMM kindreds.^12,13 In Sweden, one CDKN2A founder mutation (insertion of an extra arginine in codon 113, p.R112_L113insR) is predominant.¹⁴ Thus, the genetic background remains unknown in most kindreds.¹ GenoMEL (The Melanoma Genetics Consortium), has published consensus statements on counseling and genetic testing of individuals perceived to be genetically predisposed to CMM.^15,16

In 1987 The Swedish Melanoma Study Group initiated a national preventive program for kindreds with HCMM-DNS. The aim is to reduce the risk of CMM by regular skin examinations, excision of suspicious lesions, and information about skin self-examination and behavior to avoid harmful exposure to ultraviolet irradiation. We now present a 14-year follow-up of 280 Swedish HCMM-DNS families—to our knowledge, the largest prospectively followed population-based cohort of such kindreds so far reported.

	PATIENTS AND METHODS

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We used the original definition of D-2 kindreds: CMM in at least two blood relatives as well as clinical DN in two or more relatives.⁸ The program was carried out in 12 clinics, covering 7.3 million inhabitants, 82% of the Swedish population.¹⁷ Data was collected in a central database. The project was approved by the ethics committee of the Karolinska Institutet, Stockholm, Sweden.

HCMM-DNS kindreds were identified through questioning of newly diagnosed CMM patients regarding relatives with CMM. CMM in relatives was verified by pathology reports and/or clinical records. Melanoma in situ (Tis) was included in the diagnosis of CMM. A pedigree was established and blood relatives contacted by the proband and invited to participate in the program.

At the initial visit, participants received written and oral information regarding protection from damaging sunlight and skin self-examination. A skin examination was performed. For diagnosis of DN, ABCD criteria¹⁸ were used and nevi not fulfilling these criteria were registered as common nevi (CN). Photographic documentation included whole-body photographs and detailed pictures of all DN. Dermoscopy was performed, and in many centers computerized digital image systems were used for documentation. Individuals who were diagnosed with melanoma and unaffected individuals with DN were followed-up at 6-month intervals. Patients with newly diagnosed CMM were followed-up on more frequently, according to guidelines for CMM follow-up. Nevi with changing appearance, and lesions raising suspicion of melanoma for other reasons, were excised for histopathologic examination.

At the initial visit information on previous CMM and other malignant tumors, skin type, hair and eye color, and number and sites of CN and DN were registered. At follow-up visits, new or changing DN and histopathology of excised skin lesions were registered. In the present study, data on members of all HCMM-DNS kindreds entered in the database between 1987 and 2001 were analyzed. Melanomas excised during follow-up were reevaluated by a reference pathologist (A.T.B.). In some kindreds, screening of germline CDKN2A mutations was performed in a separate project.¹³ Statistical analyses were performed using the ² test and t test as appropriate.

	RESULTS

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Characteristics of HCMM-DNS Kindreds
The present report is based on 280 kindreds with 2,080 individuals registered 1987 to 2001. In these kindreds, 614 index CM cases were identified before or at the initial examination. The median age at diagnosis of index melanomas was 45 years (range, 12 to 90 years). The number of CMM cases in kindreds ranged between two and nine, whereas 88% had only two CMM cases (Table 1). In 193 families (69%), at least two first-degree relatives had CMM; in 52 families (19%), CMM was diagnosed in second-degree relatives only; and in 35 kindreds (12%), in third-degree or more distant family members.

There were significant differences in skin and pigmentation characteristics, between the three categories of family members. Melanoma patients had a significantly more sensitive skin type than did unaffected individuals both with and without DN (P = .008). Likewise, there was a significantly increased proportion of individuals with red hair and fewer persons with dark hair among melanoma patients compared with unaffected individuals with or without DN (P = .013). No significant differences in eye color were seen.

There was a wide variation in both CN and DN between individuals at the initial examination (Table 3). Unaffected individuals without DN had significantly fewer CN than did those with DN and melanoma patients (P < .001). Melanoma patients had a small but significantly (P = .004) increased number of DN compared with the group of unaffected individuals with DN, whereas there was no significant difference in CN between these two groups.

Results of the Follow-Up Program
Overall, 1,784 family members visited the participating centers for examination, and only melanoma patients and individuals with DN were followed regularly, whereas unaffected individuals without clinical DN were not followed. In total, 13,113 visits by members of the HCMM-DNS kindreds were registered, corresponding to an observation time of 17,539 person-years (Table 4). The larger number of visits and longer median follow-up in melanoma patients is probably explained by more frequent and prolonged follow-up after treatment for CMM.

Skin Lesions Excised During Follow-Up
During follow-up, 1,912 skin lesions were excised (Table 6). The most common histopathologic diagnoses were CN (53%) and DN (40%). Importantly, 41 CMMs (2.1%) were diagnosed in 32 patients, 18 male (56%) and 14 female (44%). Most patients, 25, had a single CMM, whereas six patients had two CMMs, and one patient four CMMs. The 32 individuals belonged to 25 different kindreds. Interestingly, all melanomas except one were diagnosed in members of families where two or more first-degree relatives had been previously diagnosed with CMM. The remaining melanoma occurred in a family with two second-degree relatives with CMM. Of the 32 individuals with CMM diagnosed during follow-up, 21 (66%) had at least one previous CMM diagnosis. Thus, 18 patients had a single previous CMM, one patient had two previous CMMs, one patient had three previous CMMs, and one patient had four previous CMMs.

The median age at diagnosis of CMM during follow-up was 43 years, which is slightly lower than the median age of 45 years for all CMMs registered in the families The median time from the first visit to the participating center to diagnosis of melanoma was 38 months (range, 0 to 126 months) and 10 (24%) of 41 tumors were diagnosed within the first year of follow-up. In 29 cases (71%), the patient did not report any signs or symptoms, and the tumor was identified by the examining physician. In 12 cases (29%), the patient reported signs or symptoms: in four cases the patient had discovered a new lesion, in five cases changing appearance of an existing lesion, and in three cases itching.

Histopathologic examinations showed that 15 (37%) of the 41 tumors were noninvasive Tis (Table 7). As expected, a majority (85%) of invasive tumors were superficial spreading melanomas (SSMs). Of the invasive CMMs, most (77%) were Clark level II. Likewise, the majority of tumors were thin, with a median thickness of 0.5 mm, and only three tumors had a thickness above 1.0 mm. Histopathologic signs of ulceration were present in two tumors, and in one of those only punctuate ulceration was seen. Importantly, of the 26 invasive melanomas, 12 (46%) were pure radial growth phase tumors, thus lacking metastatic capacity. When Tis are included, 66% of all primary CMM detected during follow-up lacked vertical growth phase and are, therefore, expected to carry no risk of metastasis.

	DISCUSSION

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During follow-up of these 280 HCMM-DNS kindreds, 41 primary melanomas were excised. To compare these lesions to melanomas diagnosed in the general Swedish population, we used data from a Swedish national database on 12,533 invasive CMMs diagnosed in Sweden 1990 to 1999.¹⁹ The median age of diagnosis of CMM during follow-up of family members was 43 years, which is almost two decades below that of melanomas in the general Swedish population (61 years). This difference may be attributed both to the lower age at CMM development in HCMM kindreds¹ and possibly to earlier diagnoses resulting from the follow-up program. The latter is supported by the lower median age at diagnosis of melanomas in the follow-up program (43 years) compared with all melanomas in members of the participating kindreds (45 years). Moreover, a large proportion, 37%, of melanomas detected during follow-up were Tis, which is considerably higher than the proportion of Tis of 19.7% in the Stockholm-Gotland Regional Melanoma Registry, which contains 7,365 melanomas registered 1976 to 1999 (H. Hellborg, personal communication, October 2005). This suggests that the follow-up program has led to an early diagnosis of CMMs, which has been achieved already at the noninvasive stage in a many tumors.

The median thickness of invasive CMMs detected during follow-up was 0.5 mm, considerably below the median CMM thickness of 0.9 mm in the Swedish population.¹⁹ Of the invasive melanomas diagnosed during follow-up, most (77%) were limited to Clark level II, whereas five (19%) reached level III and one (4%) level IV. Again, this is in marked contrast to invasive melanomas in the Swedish population, of which 31% are level II, 36% level III, 29% level IV and 4% level V. Among the 26 invasive melanomas excised during follow-up of family members, 23 (88%) were T1 tumors and three (12%) T2 tumors, compared with 55% T1, 20% T2, 15% T3% and 10% T4 in the Swedish population.¹⁹ Moreover, only two (8%) of the tumors detected during follow-up showed signs of ulceration, which was present in 24% of melanomas in the Swedish population.²³ Importantly, more than half of the invasive melanomas in the present study lacked vertical growth phase and should carry no risk of metastasis. There has also been no report of a disease recurrence that may be attributed to a CMM diagnosed during follow-up. Together, these data indicate that the preventive program has contributed to an early diagnosis of melanomas, preventing the development of metastatic disease. Results similar to ours have been reported from follow-up of 33 HCMM kindreds at the National Cancer Institute. Of 86 new CMMs identified, 72 were early (T1a) lesions, and 63 of the melanomas had only radial growth phase.²⁰

Compared with the risk estimates of CMM development in HCMM-DNS kindreds in the literature, the number of melanomas in our families is unexpectedly small. The number of histologically dysplastic nevi excised during follow-up was much higher than the number of melanomas, indicating that the follow-up program led to early excisions of precursor lesions, thereby reducing the numbers of melanomas. This achievement has been reached through the excision of a large number of pigmented skin lesions. Of more than 1,900 lesions excised, 53% received a histopathologic diagnosis of CN. The high proportion of CN probably indicates a need for better clinical diagnosis of potential precursor lesions in order to avoid unnecessary excisions. However, the histopathologic criteria for diagnosis of DN are still controversial, and the high proportion of lesions diagnosed as CN may in part result from differences in criteria among pathologists. Moreover, excisions of nevi were sometimes made at the patients' request for cosmetic or other reasons, and not solely because of suspicion of CMM.

Our finding that 40 of 41 melanomas diagnosed during follow-up occurred in kindreds with at least two first-degree relatives with CMM confirms the need for monitoring of such families. Interestingly, diagnosis of CMM occurred in three of eight kindreds with germline CDKN2A mutations, supporting that these families have a particular risk for CMM development. This is in accordance with the high estimated penetrance of germline CDKN2A germline mutations for melanoma development, in affected kindreds, corresponding to a 67% risk of CMM development by age 80 years.²¹ Moreover, the finding that 21 (66%) of 32 individuals with CMM during follow-up had a previous diagnosis of at least one melanoma, demonstrates that previously affected members of melanoma kindreds are at particular risk for developing further melanomas. All of these findings are of importance for the design of follow-up strategies in HCMM kindreds.

A limitation in the reported data is that individuals without DN were not followed with skin examinations because, at the time of design of the program, we considered the presence of DN a marker for melanoma risk individuals. Also, we believed that surveillance should be aimed at following DN, and it seemed reasonable not to follow individuals without DN. All family members were, however, instructed in self-examination of the skin. Subsequently, it has been shown that DN is not an appropriate marker for mutation carrier status and CMM risk in families with germline CDKN2A mutations,²² indicating that individuals without DN should also have the opportunity of skin examinations. To address the issue of whether melanomas have occurred in family members who have lacked DN and who, therefore, have not been followed with skin examinations, we will analyze the occurrence of tumors in all family members using the Swedish National Cancer Registry. This will also give information on other cancers in these families.

It is important to improve primary prevention, because previous studies have shown disappointing results regarding harmful sun-related behavior in young members of Swedish HCMM-DNS families^23-25

Our study cannot assess the cost effectiveness of the program. However, it is clear that individuals with a family history of CMM and who often have a large number of nevi would be frequent consumers of health care resources, requiring a large number of examinations and excisions of many pigmented lesions. Coordinated programs such as ours represent a rational way to develop more cost-effective methods of identifying and defining high risk kindreds and designing optimal preventive interventions for the family members.

In conclusion, our study shows that a coordinated program aimed at detecting CMM and performing preventive activities in HCMM-DNS kindreds results in a low number of diagnosed CMMs during follow-up among participating family members. Those tumors that do arise include a large proportion of Tis, and the invasive CMMs have considerably better prognostic characteristics than those in the general population. This indicates that the program efficiently prevents the development of high-risk melanomas in these CMM-prone individuals.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Johan Hansson, Mia Bergenmar, Per-Åke Hofer, Eva Månsson-Brahme, Ulrik Ringborg, Inger Rosdahl

Financial support: Johan Hansson, Ulrik Ringborg

Administrative support: Johan Hansson

Provision of study materials or patients: Johan Hansson, Per-Åke Hofer, Eva Månsson-Brahme, Ulrik Ringborg, Ann-Marie Wennberg, Inger Rosdahl

Collection and assembly of data: Johan Hansson, Mia Bergenmar, Per-Åke Hofer, Eva Månsson-Brahme, Ingrid Synnerstad, Annika Ternesten Bratel, Ann-Marie Wennberg, Inger Rosdahl

Data analysis and interpretation: Johan Hansson, Mia Bergenmar, Göran Lundell, Eva Månsson-Brahme, Ulrik Ringborg, Ingrid Synnerstad, Annika Ternesten Bratel, Ann-Marie Wennberg, Inger Rosdahl

Manuscript writing: Johan Hansson, Mia Bergenmar, Per-Åke Hofer, Göran Lundell, Eva Månsson-Brahme, Ulrik Ringborg, Annika Ternesten Bratel, Ann-Marie Wennberg, Inger Rosdahl

Final approval of manuscript: Johan Hansson, Mia Bergenmar, Per-Åke Hofer, Göran Lundell, Eva Månsson-Brahme, Ulrik Ringborg, Ingrid Synnerstad, Annika Ternesten Bratel, Ann-Marie Wennberg, Inger Rosdahl

Other: Göran Lundell [provided database software]

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The following are participating investigators in the Swedish Melanoma Study Group network of HCMM-DNS clinics: Gävle: Johan Ahlgren, Beatrice Tinge. Göteborg: Frida Appelqvist, Charlotta Enerbäck, Johan Paoli, Carin Sandberg, Ulrika Stierner, Annika Ternesten Bratel, Ann-Marie Wennberg. Jönköping: Jana Rudel, Kalmar: Iréne Jeansson, Lennart Mellblom. Karlstad: Gunnel Särhammar. Linköping: Bernt Boeryd, Marianne Maroti, Inger Rosdahl, Ingrid Synnerstad. Lund: Johan Westerdahl. Stockholm: Mia Bergenmar, Yvonne Brandberg, Johan Hansson, Lena Kanter, Diana Lindén, Göran Lundell, Eva Månsson-Brahme, Bengt Lagerlöf (deceased), Boel Ragnarsson-Olding, Ulla Platten, Ulrik Ringborg, Lena Westerberg. Uddevalla: Joanna Holm. Umeå: Ronny Anderson (deceased), Per-Åke Hofer, Torgny Rasmuson, Janine Schmitt-Egenolf, Virginia Zazo. Uppsala: Berit Berne. Västervik: Hans Overgaard-Petersen. Örebro: Mats Breivald.

	ACKNOWLEDGMENTS

 
The preventive program was organized as a collaboration within the Swedish Melanoma Study Group. We thank Diana Lindén for her excellent help with data management and analysis.

	NOTES

 
Supported by grants from the Swedish Cancer Society and the Research Funds of Radiumhemmet, Stockholm, Sweden.

Presented in part at the 3rd EUROSKIN Conference, Stockholm, Sweden, September 16-19, 2003.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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14. Hashemi J, Bendahl P-O, Sandberg T, et al: Haplotype analysis and age estimation of the 113 insR CDKN2A founder mutation in Swedish melanoma families. Genes Chromosomes Cancer 31:107-116, 2001[CrossRef][Medline]

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Submitted February 21, 2007; accepted April 9, 2007.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hansson, J. Articles by Rosdahl, I. Search for Related Content PubMed PubMed Citation Articles by Hansson, J. Articles by Rosdahl, I. Social Bookmarking                            What's this?