Dysplastic Nevus Syndrome Research Articles

Genetic and Epidemiologic Evaluation of Dysplastic Nevi

Dysplastic Nevus Syndrome (DNS) has been defined as that trait characterized by the presence of at least one dysplastic melanocytic nevus. DNS was originally described in kindreds having multiple members with melanoma. Various types DNS have been described in other situations to include individuals with apparently sporadic cases, familial DNS without melanoma and individuals with apparently sporadic DNS with melanoma. These categories are based on historical information in general, and not on examination of family members. In all cases, the presence of dysplastic nevi appear to confer some increased risk of melanoma, which varies between the groups. Similarly cutaneous melanoma is thought to occur in several distinct populations‐random individuals without DNS, individuals with sporadic DNS, and those with familial DNS.Genetic analysis of DNS has been largely confined to the classically ascertained kindreds associated with melanoma. These studies have usually used diagnostic criteria based on pathology of clinically selected material, and that evidence suggests that DNS is inherited as an autosomal dominant trait in these families. Surveys of the general population have detected rates of dysplastic nevi of 5% 20%. In our Utah‐based studies, we have evaluated probands and family members from three groups. These included kindreds with multiple occurrences of melanoma, random individuals with at least one dysplastic nevus, and cases of melanoma with unknown family history. Controls were spouses of study subjects. We sought to determine the percentage of each group associated with dysplastic nevi and/or genetic DNS. The range of phenotype of patients with dysplastic nevi was large with some individuals having few nevi, none of which were clinically atypical, and others having greater than 100 nevi. The prevalence of dysplastic nevi in at least one of two biopsies in Utah population controls is presently Wtimated at 62%. Some probands with melanoma as well as some of their relatives had elevated numbers of nevi, suggesting that this predisposition to melanoma may be inherited.

Phenotypic Variation and Systemic Cancer in the FAMMM Syndrome

Familial atypical multiple mole melanoma (FAMMM) syndrome, a cancer‐associated genodermatosis, is a dominantly inherited heterogeneous disorder with variable expressivity of both its cutaneous and cancer phenotypes. By using a verified historical review technique of cancer documentation (idout patient health records, pathology reports/slides, autopsy reports/slides, and death certificates) of all anatomic sites in all members of a modified nuclear pedigree (first‐degree relatives plus maternal and paternal grandparents, aunts, and uncles) over several generations, we showed that the FAMMM syndrome is similar to the majority of autosomal dominant inherited cancer‐associated genodermatoses and has excessive risk for cancer of multiple anatomic sites. With respect to the FAMMM syndrome, these cancers involved the breast, respiratory tract, gastrointestinal system, the eye (intraocular melanoma), and the lymphatic system. These FAMMM pedigrees showed some of the following distinctive characteristics of hereditary cancer: 1) integral patterns of cancer within and between pedigrees; 2) early age of onset of cancer; 3) prolonged survival of some pedigree members with cancer; and 4) an excess of multiple primary melanomas and cancers of variable anatomic sites. The presence of these features indicates that these cancers of variable anatomic sites may be etiologically associated with the FAMMM syndrome. Heterogeneity should be investigated in FAMMM pedigrees with attention to consistent differences in size and distribution of atypical lesions, age at cancer onset, and pattern of tumor occurrences. The occurrence of FAMMM pedigrees in the general population or among pedigrees of probands with atypical nevi is not known. The occurrence of systemic cancers in these FAMMM pedigrees requires the development of cancer surveillance programs that are specifically modified to the particular cancer pattern of each pedigree.

Dysplastic nevus syndrome--biological significance.

Dysplastic nevus syndrome--biological significance.

Dysplastic Nevus Syndrome in The Netherlands

In Europe, the occurrence of familial melanoma in combination with the occurrence of dysplastic nevi in melanoma patients has been reported by groups from Scotland, France, Italy, and The Netherlands. The major publications of these groups are briefly mentioned and summarized. This report specifically describes nine extensive Dutch pedigrees. Clinical an genetic studies were performed in kindreds among whom three or more individuals with melanoma occurred in at least two consecutive generations. Three hundred sixty‐two living persons older than 10 years were screened. The mean number of family members was 60, which makes these pedigrees preeminently suited for genetic studies. Spouses were not included in the study. One hundred eighty individuals were recognized as gene carriers. After correction for bias of ascertainment, we calculated a segregation rate of 0.45, compatible with dominant inheritance. Of the 180 living or alive at the start of the study, 40 had a melanoma, 118 had dysplastic nevi, and 22 were regarded as obligate gene carriers on the basis of their position in the pedigree. The finding of nonpenetrance and reduced penetrance of the characteristic phenotype of the dysplastic nevus syndrome has important consequences for daily practice. When a family is requested to attend the pigmented lesion clinic, all members have an a priori risk of 50% of carrying the gene. Individuals without any abnormalities form the majority, and cases of nonpenetrance and low penetrance are mixed in with the seemingly normal cases. The consequence for our research group was to follow all family members until it is possible to distinguish definitely gene carriers from normal family members. Other malignancies occurred at an increased rate among these families. In two families, the occurrence of several kinds of cancer was obvious. Twenty‐four instances of nonmelanoma cancer were found, among which were seven cases of pancreatic carcinoma

Chromosome rearrangements in dysplastic nevus syndrome predisposing to malignant melanoma.

The dysplastic nevus syndrome (DNS) is an autosomal dominant trait characterized by multiple atypical skin moles and a propensity to malignant melanoma. We studied chromosomes from a three-generation DNS family in 1977. Cells cultured from normal skin and dysplastic nevi showed an elevation in chromosome rearrangements with nonrandom breakpoints and clonal proliferation marked by chromosome change. The DNS qualifies as a chromosome instability disorder, the first known to manifest dominant inheritance and a clear discernible premalignant state. The DNS road to malignancy may logically proceed by genomic alterations including translocations, duplications, and deletions.

Plasma 5-S-cysteinyldopa differentiates patients with primary and metastatic melanoma from patients with dysplastic nevus syndrome and normal subjects

To determine whether plasma 5-S-cysteinyldopa levels are useful in following up patients at risk for melanoma, we measured plasma 5-S-cysteinyldopa in patients with dysplastic nevus syndrome and/or malignant melanoma and in control subjects. In patients with dysplastic nevus syndrome, plasma 5-S-cysteinyldopa levels did not differ from those in control subjects. Conversely, patients with malignant melanomas had significantly higher plasma 5-S-cysteinyldopa levels than did controls. Those with localized cutaneous malignant melanoma and no distant metastases (Stages I and II disease) had 5-S-cysteinyldopa levels twofold greater than those of control subjects, whereas the levels of those with regional lymph node involvement (Stage III disease) were fourfold greater than those of control subjects. Levels of those with extraregional metastases (Stage IV disease) were 7- to 450-fold higher than those of control subjects. Moreover, plasma 5-S-cysteinyldopa levels correlated with the spread of disease and were useful in distmguishing primary melanoma and Stages III and IV melanoma. We conclude that plasma 5-S-cysteinyldopa may be an important tool for identifying melanoma at an earlier, more curable stage and for following up patients at risk for the development of melanoma, for example, those with dysplastic nevus syndrome.

What naevus is dysplastic, a syndrome and the commonest precursor of malignant melanoma? A riddle and an answer.

This assay examines critically the concept of 'dysplasia' as it applies to melanocytic neoplasia and concludes that the concept is flawed. Doubt is cast also upon the validity of the concepts of a dysplastic naevus and a dysplastic naevus syndrome. The author is of the view that most malignant melanomas arise de novo and not in pre-existing dysplastic naevi. Because so-called dysplastic naevi are considered by the author to be the commonest melanocytic naevi in man and devoid of nuclear atypia, he proposes that they be re-named 'common naevi' in the interest of simplicity, accuracy, and care of patients. Lastly, it is suggested that resolution of problems in the sphere of melanocytic neoplasia might be accomplished more readily were terms like dysplasia, dysplastic cells, dysplastic naevi, and the dysplastic naevus syndrome eschewed.

Skin Types in Dysplastic Nevus Syndrome

In order to determine if individuals with dysplastic nevi (DN) are relatively more sun-sensitive than controls who do not have DN, the sun-reactivity skin types (based on the Harvard classification) were determined in these two groups. Compared with controls, sun-sensitive types were significantly overrepresented in the DN group. This is consistent with the hypothesis that the fundamental defect in the dysplastic nevus syndrome is the genetically unstable melanocyte, which is susceptible to neoplastic transformation induced by sunlight.

The dysplastic nevus syndrome

The dysplastic nevus syndrome

Cutaneous malignant melanoma in survivors of heritable retinoblastoma.

Six survivors of bilateral retinoblastoma developed cutaneous malignant melanoma 20 to 51 years (average, 31 years) after initial therapy for the ocular tumor. Five patients received radiation therapy to the orbital area. In two patients the cutaneous malignant melanoma developed in the field of irradiation. Two patients developed multiple cutaneous melanomas and are thought to have the dysplastic nevus syndrome. At this writing two patients are alive and well after wide resection of their skin tumors. A review of the literature suggests that cutaneous malignant melanoma accounts for about 7% of second malignant neoplasms in survivors of heritable retinoblastoma.

Vitamin A derivatives in the prevention and treatment of human cancer.

Vitamin A is essential for normal cellular growth and differentiation. A vast amount of laboratory data have clearly demonstrated the potent antiproliferative and differentiation-inducing effects of vitamin A and the synthetic analogues (retinoids). Recent in-vitro work has led to the exciting proposal that protein kinase-C may be centrally involved in many of retinoids' anticancer actions including the effects on ornithine decarboxylase induction, intracellular polyamine levels, and epidermal growth factor receptor number. Several intervention trials have clearly indicated that natural vitamin A at clinically tolerable doses has only limited activity against human neoplastic processes. Therefore, clinical work has focused on the synthetic derivatives with higher therapeutic indexes. In human cancer prevention, retinoids have been most effective for skin diseases, including actinic keratosis, keratoacanthoma, epidermodysplasia verruciformis, dysplastic nevus syndrome, and basal cell carcinoma. Several noncutaneous premaligancies, however, are currently receiving more attention in retinoid trials. Definite retinoid activity has been documented in oral leukoplakia, laryngeal papillomatosis, superficial bladder carcinoma, cervical dysplasia, bronchial metaplasia, and preleukemia. Significant therapeutic advances are also occurring with this class of drugs in some drug-resistant malignancies and several others that have become refractory, including advanced basal cell cancer, mycosis fungoides, melanoma, acute promyelocytic leukemia, and squamous cell carcinoma of the skin and of the head and neck. This report comprehensively presents the clinical data using retinoids as anticancer agents in human premalignant disorders and outlines the ongoing and planned studies with retinoids in combination and adjuvant therapy.

The Dysplastic Nevus Syndrome

The following constellation of traits constitutes the familial dysplastic nevus syndrome: (1) a distinctive clinical appearance of abnormal melanocytic nevi 1-3 ; (2) unique histologic features, including an abnormal architectural pattern of intraepidermal melanocytes, cytologically atypical intraepidermal melanocytes, connective tissue changes, and a lymphocytic infiltrate 4,5 ; (3) an autosomal dominant inheritance, possibly linked to a susceptibility gene on the short arm of chromosome 1 near the Rh locus 6 ; and (4) hypermutability of fibroblasts and lymphoblasts. (Fibroblasts and lymphoblasts from patients with the dysplastic nevus syndrome and hereditary cutaneous melanoma are abnormally sensitive to ultraviolet radiation damage, simulated sunlight, and exposure to 4-nitroquinoline-1-oxide. 7,8 Their fibroblasts are also hypersensitive to G 2 chromatid radiation damage. 9 ) The syndrome is, in all likelihood, one of the hypermutability disorders. The familial dysplastic nevus syndrome is presently recognized by its clinical and histologic features, but, in due course, it may

Sporadic dysplastic nevus syndrome in a tyrosinase-positive oculocutaneous albino

A case of dysplastic nevus syndrome in a 41-year-old tyrosinase-positive oculocutaneous albino man is presented. Clinically the patient exhibited multiple amelanotic lesions; histologic examination provided the diagnosis of dysplastic nevus syndrome. Fontana-Masson silver staining revealed the presence of melanin in the nevus cells. Hair bulbs incubated in tyrosine buffer produced melanin. This is the second reported case of dysplastic nevus syndrome in an oculocutaneous albino and the first case of dysplastic nevus syndrome in a tyrosinase-positive albino of which we are aware.

Quadrant Distribution of Dysplastic Nevus Syndrome

A 59-year-old man with numerous aggregated pigmented lesions confined to the left upper quadrant of his body is described. The lesions consist of lentigines, common acquired nevi, and dysplastic nevi. In addition, within this quadrant two malignant melanomas at different stages of progression developed from dysplastic nevi. This patient presents a hitherto undescribed quadrant type of dysplastic nevus syndrome. As quadrant syndromes are due to single mutations, our observation strongly supports the concept of an autosomal-dominant trait in dysplastic nevus syndrome.

Dysplastic naevus in non-familial melanoma. A clinicopathological study of 101 cases.

In 101 patients with non-familial cutaneous melanoma (CM), melanocytic naevi were counted and classified according to clinical criteria. Only 8% of the patients had very atypical naevi. These atypical naevi were few in number and only one patient exhibited dysplastic naevus syndrome. An histological study was undertaken on the hypothesis that, in a given individual, if the most clinically atypical naevus is not histologically dysplastic it is unlikely that any of the others are. The most clinically atypical naevus in each patient was biopsied. Estimated in this way the prevalence of dysplastic naevi in patients with non-familial CM was only 18%. Comparison of patients with and without dysplastic naevi did not suggest that they constituted two different subsets. An attempt to correlate clinical diagnosis and histological features in this group of patients showed that the diagnosis of dysplastic naevi on the basis of clinical criteria alone is difficult and not reliable.

Quadrant distribution of dysplastic nevus syndrome

Quadrant distribution of dysplastic nevus syndrome

Independence of dysplastic nevi from total nevi in determining risk for nonfamilial melanoma

In the determination of risk for melanoma, relatively little is known about the possible independence of two important predictors, total nevi and clinically dysplastic nevi. From a study conducted in Sydney, Australia [see J. J. Nordlund et al., Cancer Res. 45, 1855–1861 (1985)], 246 cases of melanoma (excluding 7% of targeted patients with a history of melanoma in a first-degree relative) were compared with 134 nonmelanoma controls. Participants had been examined by a dermatologist and an oncologist. Logistic regression analysis was used and included an age-sex interaction term in computing all estimates of relative risk in this report. Relative risk for melanoma in those with 16+ total nevi was significantly elevated at 1.8 but declined to a statistically nonsignificant level of 1.2 (95% confidence limit (CL): 0.7, 2.0) after adjustment for dysplastic nevi. In contrast, relative risk for melanoma in those with any dysplastic nevi was 7.6 (95% CL: 3.6, 16.0) but was maintained at a similarly elevated and statistically significant level of 7.7 (95% CL: 3.5, 17.1) after adjustment for total nevi. These patterns were even more evident in the younger half of the study population. The analyses suggest that much of the association between TN and nonfamilial melanoma is explained by the presence of dysplastic nevi and, conversely, they imply that dysplastic nevi represent a clinically distinct, qualitative disorder rather than simply a quantitative disorder wherein dysplastic nevi stem merely from an increase in total nevi. The dysplastic nevus syndrome accounts for 32% of all nonfamilial melanomas.

Thymine dimer repair in fibroblasts of patients with dysplastic naevus syndrome (DNS).

Dysplastic naevus syndrome (DNS) is frequently observed in association with familial melanoma and xeroderma pigmentosum (XP), but the role of UV-light in the development of DNS has not been elucidated. Previous work has shown that UV-induced unscheduled DNA synthesis is associated with the early loss of antigenicity observed in immunoassays using a monoclonal antibody specific for thymine-thymine dimers. We now show that the rate of loss of antigenicity, which reflects the relative amount of bound antibody, observed during the first 60 min following 10 Jm-2 UVC irradiation is significantly reduced (p = 0.02) in cultures of fibroblasts from 7 out of 8 DNS patients compared with the results from cells of a group of 30 healthy volunteers. This observation suggests an early event in excision repair is altered in the majority of DNS patients.

Dysplastic nevi and germ cell tumors of the testis--a possible further tumor in the spectrum of associated malignancies in dysplastic nevus syndrome.

Even though the exact spectrum of tumors is not yet defined in the dysplastic nevus syndrome (DNS), the increasing frequency of associated cancers is remarkable. The observation of 4 patients with sporadic form of DNS suffering from seminoma or embryonal carcinoma of the testicle suggests that germ cell tumors of the testis represent another form of associated cancer in DNS.

HYPERSENSITIVITY TO G 2 CHROMATID RADIATION DAMAGE IN FAMILIAL DYSPLASTIC NAEVUS SYNDROME

Skin fibroblasts from 25 members of nine kindreds with familial dysplastic naevus syndrome (DNS), 12 apparently normal spouses, and 11 additional unrelated normal individuals were tested for G 2 cell-cycle phase sensitivity to ionising radiation. The cells from individuals with DNS or hereditary cutaneous malignant melanoma with DNS (HCMM/DNS) had significantly more chromatid breaks and gaps when entering metaphase 0.5-1.5 h after G 2 phase X-irradiation (1 Gy) than those from unaffected controls. In two cases, the test results positively identified individuals before the clinical diagnosis of DNS. A clinically normal obligate carrier of the HCMM/DNS gene showed the enhanced G 2 radiosensitivity. Moreover, in a test on 1 proband, the sensitivity was apparent in peripheral blood lymphoblasts. Enhanced G 2 chromatid radiosensitivity may be a marker of genetic susceptibility to HCMM/DNS.