Cytogenet Cell Genet 59:159-160 ( 1992)
Description o f the National Cancer Institute melanoma families S. J. Bale, A. M. Goldstein, and M. A. Tucker
Family Studies Section, National Cancer Institute, Bethesda, MD (USA)
Interest of the Family Studies Section, NCI, in iamilial melanoma dates back to 1976, at which time Dr. Michael Mastrangelo of Fox Chase Cancer Center referred a melanomaprone kindred to the NCI Epidemiology Branch. The reason tor the referral was that the proband in the family (Richard K.) was convinced that his melanomas had developed as a consequence of his unusual mole pattern. Three other family members also had a history of melanoma and Richard K. reported that they, too, had unusual moles. When 25 members of the “ K ” family were examined, it was found that the three surviving melanoma patients, as well as several other family members, had numerous unusual moles. A previously unrecognized melanoma in another family member who had thought he was free of disease was also detected. The histology of the many pigmented nevi previously excised from the “ K” family members was reviewed by Dr. Wallace Clark of the University of Pennsylvania. He noted that they displayed a number of unusual features he had seen recently in the moles of another melanoma patient, Susan B. Further investigation revealed that Susan was also a member of a melanoma prone family. The unusual moles were named “ B-K moles” after these two families (Family 255 and Family 481 in the GAW data) in which they were described. As more melanoma families were studied, the relationship between the unusual moles and familial melanoma became apparent. The term “B-K mole” was changed to “dysplastic nevus” (DN) when the histologic characteristics of these lesions were described. It was clear that DN differed in appearance from common acquired nevi in that they tended to be more numerous, larger, irregularly shaped with a macular component, variably pigmented, and located at body sites where common acquired nevi rarely occurred (Elder et al., 1982; Reimer et ah, 1978). On histologic exam these lesions were found to have basilar melanocytic hyperplasia of large epithelioid melanocytes with variable nuclear atypia, a patchy lymphocytic infiltrate, concentric eosinophilic fibroplasia, and lamellar fibroplasia (Clark et ah, 1984; Greene et ah, 1985). Dr. Clark hypothesized that moles evolved along a continuum (from a new common acquired nevus to a mature nevus), and that melanomas arose from those moles which veered abnormally off this pathway. The abnormal moles were the DN. Support for this premise came from several sources including observation of melanoma arising directly from DN (Clark et ah, 1978), and the finding that about half of excised melanomas showed remnants of DN at their margins (Clark et ah, 1984; Elder et ah, 1981; Rhodes et ah, 1983).
Many of these observations were made in the course of studies of a series of high-risk CMM kindreds at the NCI which have been ongoing since 1979. To date, 23 CMM-prone families have been evaluated clinically and histologically by Section investi gators and the Pigmented Lesion Group at the University of Pennsylvania. These kindreds came to the attention of NCI investigators in various ways including self-referral, referral by local physicians, and referral by other NIH investigators. Generally, the ascertainment of the families is unknown and unknowable, as the clinical investigators, Dr. Mark Greene, and later Dr. Margaret Tucker, accepted for study any family with multiple living confirmed cases of CMM. These families (14, as of 1982) were also investigated for any laboratory-based abnormalities which might give clues as to the etiology of CMM; segregation analysis and genetic linkage studies were included. In 1983, Greene et ah (1983) published a tentative finding of linkage between RH on chromosome 1p and the combined CMM/DN phenotype in the 14 kindreds. This result stimulated a collaboration with investigators at the Massachusetts Institute of Technology to develop restriction fragment length polymorphisms (RFLP) in the region of RH in order to confirm this preliminary finding. Limited resources were available, so only five families on whom fibroblasts were stored could be evaluated at this point in the project. The selection of these particular families was based on negative or uninformative linkage results with RH, and they were selected regardless of clinical findings. By 1988 a variety of chromosome 1 RFLP and other markers were developed and tested in these families by Dr. Nicholas Dracopoli in Dr. David Housman’s lab. Linkage results from these five families, plus a sixth ascertained by Dr. Margaret Tucker, showed evidence of linkage between CMM/DN and two lp loci, D1S47 and PND. These data were published in 1989 (Bale et al., 1989). Since that time, eight new families have been evaluated and results will soon be submitted for publication. The GAW data For GAW7 we submitted clinical and laboratory information on 99 relatives and 26 spouses in the six families recently pub lished (Bale et al., 1989). Thirty-four family members had CMM and 31 of these also had histologically proven DN. Twenty-four family members had only DN (without CMM), of whom four had clinical DN without histologic confirmation. Both clinical and histologic DN were diagnosed using criteria detailed above. Variables provided for the workshop included nevus number categorized, presence/absence of nevi on non-sun-exposed areas of the body, presence/absence of clinical DN, date of birth, year
Downloaded by: Nagoya University 133.6.82.173 - 1/12/2019 2:08:09 AM
Introduction
Bale/Goldstein/T ucker
160
of first exam at NCI, and year of first CMM diagnosis. No histologic data were submitted to the workshop. Typings of the chromosome lp markers RH, PND, D1S47, LMYC, PGM1,
AMY2, and FY were provided for ali family members on whom they were available. The pedigrees for these families can be found in Bale et al. (1989).
References 15:1147-1165(1984). Elder DE, Greene MH, Bondi EE, Clark WH Jr: Acquired melanocytic nevi and melanoma. The dysplastic nevus syndrome, in: Ackerman AB (ed): Pathology of Malignant Melanoma, pp 185-215 (Masson, New York, 1981). Elder DE, Greene MH, Guerry D IV, Kraemer KH, Clark WH Jr: The dysplastic nevus syndrome: our definition. Am J Dcrmatopathol 4:455-460(1982). Greene MH, Goldin LR, Clark WH Jr, Lovricn E, Kraemer KH, Tucker MA, Elder DE. Fraser MC, Rowe S: Familial cutaneous malignant melanoma: autosomal dominant trait possibly linked to the RH locus. Proc Natl Acad Sei USA 80:6071-6075 (1983). Greene MH. Clark WH Jr, Tucker MA. Elder DE.
Kraemer KH, Gucrry D IV, W inner WK. Thompson J, Matozzo I. Fraser MC: Acquired precursors of cutaneous malignant melanoma. The familial dysplastic nevus syndrome. New EnglJ Med 312: 91-97(1985). Reimer RR. Clark WH Jr, Greene MH, Ainsworth AM, Fraumcni JF Jr: Precursor lesions in familial mela noma. A new genetic prencoplastic syndrome. JAMA 239: 744-746 (1978). Rhodes AR, Harrist TJ. Day CL, Mihm MC Jr, Fitz patrick TB, Sober AJ: Dysplastic melanocytic nevi in histologic association with 234 primary cutaneous melanomas. J Am Acad Dermatol 9:563-574 (1983).
Downloaded by: Nagoya University 133.6.82.173 - 1/12/2019 2:08:09 AM
Bale SJ, Dracopoli NC, Tucker MA, Clark WH Jr., Fraser MC, Stangcr BZ, Green P, Donis-Kcller H. Housman DE, Greene MH: Mapping the gene for hereditary cutaneous malignant mclanoma-dysplastic nevus tochromosome lp. New EnglJ Med 320:13671372 (1989). Clark WH Jr, Reimer RR, Greene M, Ainsworth AM, Mastrangelo MJ: Origin of familial malignant melanoma from heritable melanocytic lesions: the B-K mole syndrome. Arch Dermatol 114:732-738 (1978). Clark WH Jr, Elder DE. Gucrry D IV. Epstein MN. Greene MH, Van Horn M: A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Hum Pathol
Description o f the National Cancer Institute melanoma families S. J. Bale, A. M. Goldstein, and M. A. Tucker
Family Studies Section, National Cancer Institute, Bethesda, MD (USA)
Interest of the Family Studies Section, NCI, in iamilial melanoma dates back to 1976, at which time Dr. Michael Mastrangelo of Fox Chase Cancer Center referred a melanomaprone kindred to the NCI Epidemiology Branch. The reason tor the referral was that the proband in the family (Richard K.) was convinced that his melanomas had developed as a consequence of his unusual mole pattern. Three other family members also had a history of melanoma and Richard K. reported that they, too, had unusual moles. When 25 members of the “ K ” family were examined, it was found that the three surviving melanoma patients, as well as several other family members, had numerous unusual moles. A previously unrecognized melanoma in another family member who had thought he was free of disease was also detected. The histology of the many pigmented nevi previously excised from the “ K” family members was reviewed by Dr. Wallace Clark of the University of Pennsylvania. He noted that they displayed a number of unusual features he had seen recently in the moles of another melanoma patient, Susan B. Further investigation revealed that Susan was also a member of a melanoma prone family. The unusual moles were named “ B-K moles” after these two families (Family 255 and Family 481 in the GAW data) in which they were described. As more melanoma families were studied, the relationship between the unusual moles and familial melanoma became apparent. The term “B-K mole” was changed to “dysplastic nevus” (DN) when the histologic characteristics of these lesions were described. It was clear that DN differed in appearance from common acquired nevi in that they tended to be more numerous, larger, irregularly shaped with a macular component, variably pigmented, and located at body sites where common acquired nevi rarely occurred (Elder et al., 1982; Reimer et ah, 1978). On histologic exam these lesions were found to have basilar melanocytic hyperplasia of large epithelioid melanocytes with variable nuclear atypia, a patchy lymphocytic infiltrate, concentric eosinophilic fibroplasia, and lamellar fibroplasia (Clark et ah, 1984; Greene et ah, 1985). Dr. Clark hypothesized that moles evolved along a continuum (from a new common acquired nevus to a mature nevus), and that melanomas arose from those moles which veered abnormally off this pathway. The abnormal moles were the DN. Support for this premise came from several sources including observation of melanoma arising directly from DN (Clark et ah, 1978), and the finding that about half of excised melanomas showed remnants of DN at their margins (Clark et ah, 1984; Elder et ah, 1981; Rhodes et ah, 1983).
Many of these observations were made in the course of studies of a series of high-risk CMM kindreds at the NCI which have been ongoing since 1979. To date, 23 CMM-prone families have been evaluated clinically and histologically by Section investi gators and the Pigmented Lesion Group at the University of Pennsylvania. These kindreds came to the attention of NCI investigators in various ways including self-referral, referral by local physicians, and referral by other NIH investigators. Generally, the ascertainment of the families is unknown and unknowable, as the clinical investigators, Dr. Mark Greene, and later Dr. Margaret Tucker, accepted for study any family with multiple living confirmed cases of CMM. These families (14, as of 1982) were also investigated for any laboratory-based abnormalities which might give clues as to the etiology of CMM; segregation analysis and genetic linkage studies were included. In 1983, Greene et ah (1983) published a tentative finding of linkage between RH on chromosome 1p and the combined CMM/DN phenotype in the 14 kindreds. This result stimulated a collaboration with investigators at the Massachusetts Institute of Technology to develop restriction fragment length polymorphisms (RFLP) in the region of RH in order to confirm this preliminary finding. Limited resources were available, so only five families on whom fibroblasts were stored could be evaluated at this point in the project. The selection of these particular families was based on negative or uninformative linkage results with RH, and they were selected regardless of clinical findings. By 1988 a variety of chromosome 1 RFLP and other markers were developed and tested in these families by Dr. Nicholas Dracopoli in Dr. David Housman’s lab. Linkage results from these five families, plus a sixth ascertained by Dr. Margaret Tucker, showed evidence of linkage between CMM/DN and two lp loci, D1S47 and PND. These data were published in 1989 (Bale et al., 1989). Since that time, eight new families have been evaluated and results will soon be submitted for publication. The GAW data For GAW7 we submitted clinical and laboratory information on 99 relatives and 26 spouses in the six families recently pub lished (Bale et al., 1989). Thirty-four family members had CMM and 31 of these also had histologically proven DN. Twenty-four family members had only DN (without CMM), of whom four had clinical DN without histologic confirmation. Both clinical and histologic DN were diagnosed using criteria detailed above. Variables provided for the workshop included nevus number categorized, presence/absence of nevi on non-sun-exposed areas of the body, presence/absence of clinical DN, date of birth, year
Downloaded by: Nagoya University 133.6.82.173 - 1/12/2019 2:08:09 AM
Introduction
Bale/Goldstein/T ucker
160
of first exam at NCI, and year of first CMM diagnosis. No histologic data were submitted to the workshop. Typings of the chromosome lp markers RH, PND, D1S47, LMYC, PGM1,
AMY2, and FY were provided for ali family members on whom they were available. The pedigrees for these families can be found in Bale et al. (1989).
References 15:1147-1165(1984). Elder DE, Greene MH, Bondi EE, Clark WH Jr: Acquired melanocytic nevi and melanoma. The dysplastic nevus syndrome, in: Ackerman AB (ed): Pathology of Malignant Melanoma, pp 185-215 (Masson, New York, 1981). Elder DE, Greene MH, Guerry D IV, Kraemer KH, Clark WH Jr: The dysplastic nevus syndrome: our definition. Am J Dcrmatopathol 4:455-460(1982). Greene MH, Goldin LR, Clark WH Jr, Lovricn E, Kraemer KH, Tucker MA, Elder DE. Fraser MC, Rowe S: Familial cutaneous malignant melanoma: autosomal dominant trait possibly linked to the RH locus. Proc Natl Acad Sei USA 80:6071-6075 (1983). Greene MH. Clark WH Jr, Tucker MA. Elder DE.
Kraemer KH, Gucrry D IV, W inner WK. Thompson J, Matozzo I. Fraser MC: Acquired precursors of cutaneous malignant melanoma. The familial dysplastic nevus syndrome. New EnglJ Med 312: 91-97(1985). Reimer RR. Clark WH Jr, Greene MH, Ainsworth AM, Fraumcni JF Jr: Precursor lesions in familial mela noma. A new genetic prencoplastic syndrome. JAMA 239: 744-746 (1978). Rhodes AR, Harrist TJ. Day CL, Mihm MC Jr, Fitz patrick TB, Sober AJ: Dysplastic melanocytic nevi in histologic association with 234 primary cutaneous melanomas. J Am Acad Dermatol 9:563-574 (1983).
Downloaded by: Nagoya University 133.6.82.173 - 1/12/2019 2:08:09 AM
Bale SJ, Dracopoli NC, Tucker MA, Clark WH Jr., Fraser MC, Stangcr BZ, Green P, Donis-Kcller H. Housman DE, Greene MH: Mapping the gene for hereditary cutaneous malignant mclanoma-dysplastic nevus tochromosome lp. New EnglJ Med 320:13671372 (1989). Clark WH Jr, Reimer RR, Greene M, Ainsworth AM, Mastrangelo MJ: Origin of familial malignant melanoma from heritable melanocytic lesions: the B-K mole syndrome. Arch Dermatol 114:732-738 (1978). Clark WH Jr, Elder DE. Gucrry D IV. Epstein MN. Greene MH, Van Horn M: A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Hum Pathol
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