Precursors Of Melanoma Research Articles

Fluorescence Imaging Analysis of Upstream Regulators and Downstream Targets of STAT3 in Melanoma Precursor Lesions Obtained from Patients Before and After Systemic Low-Dose Interferon-α Treatment

Atypical nevi are the precursors and risk markers of melanoma. Apart from persistently monitoring these nevocytic lesions and resecting them at the earliest signs of clinical changes, there is as yet no systemic clinical treatment available to interfere with their progression to melanoma. To explore clinical treatments that might interfere with and possibly prevent atypical nevus progression, a previous study documented that 3 months systemic low-dose interferon-alpha (IFN-alpha) treatment of patients with a clinical history of melanoma and numerous atypical nevi, led to inactivation of the STAT1 and STAT3 transcription factors in atypical nevi. Based upon this finding, we initiated a second study to determine whether systemic low-dose IFN-alpha treatment also impairs the expression of upstream regulators and downstream targets of STAT1 and STAT3 in atypical nevi. Using cyanine dye-conjugated antibodies, fluorescence imaging analysis revealed expression of JAK2, JNK1, AKT1, NF-kappa B, and IFN-alpha/beta receptor in benign and atypical nevi, and early- and advanced-stage melanomas. To determine possible changes in the level of expression of these molecules in atypical nevi, excised before and after 3 months of systemic low-dose IFN-alpha treatment, newly designed optical imaging software was used to quantitate the captured fluorescent hybridization signals on a cell-by-cell basis and across an entire nevus section. The results of this analysis did not provide evidence that systemic low-dose IFN-alpha treatment alters the level of expression of upstream regulators or downstream targets of STAT1 and STAT3.

Premalignant melanocytic dysplasia and malignant melanoma of the oral mucosa

Although malignant melanoma of the oral cavity frequently arises in pre-existing melanosis of the oral mucosa, little is known about oral melanoma precursor lesions. We reviewed three patients with premalignant melanocytic dysplasia and 14 with malignant melanoma of the oral mucosa. Thirteen of the 14 malignant melanoma cases had radial growth phases similar to those of acral lentiginous melanoma (ALM) of the skin. The prognosis of oral melanoma was not poor in contrast to that of cutaneous melanoma. Premalignant melanocytic dysplasia of the oral mucosa showed lentiginous or pagetoid proliferation of atypical melanocytes in the lower epithelium in the central part of the lesion, and lentiginous proliferation of dendritic melanocytes or simple hyperpigmentation in the basal cell layer in the peripheral part. These findings were similar to those of the radial growth phase of ALM of the oral mucosa.

Surface microscopy features of congenital nevi

Congenital melanocytic nevi (CMN) are pigmented skin lesions (PSL) that are present at birth. The frequency of PSLs at birth is estimated to be 2.5%, and 1% of newborns have biopsyconfirmed melanocytic nevi.1–3 The most widely used classification of congenital nevi is based on their size, subdividing the lesions into three groups: small ( 1.5 cm), medium (1.5–19.9 cm), and large (20 cm or greater).4 It is well established that giant congenital nevi have a potential risk of malignant transformation, and the probable lifetime risk is quoted between 5% and 15%.4–9 Small and medium-size CMNs (SCMNs) are considerably more common than large ones and are thus of greater epidemiologic significance if they represent precursors of melanoma. The risk for the occurrence of melanomas in SCMNs, however, is still under debate.3,4,10–15 The problem is that until the SCMN cannot be precisely diagnosed because of the lack of specific clinical and histologic criteria and the frequent unreliability of patient history, their melanoma risk cannot be evaluated. In fact, ascertainment of congenital nevi beyond the newborn period may be difficult because the prevalence of acquired nevi rises rapidly during early childhood. Although histologic examination is useful in distinguishing whether or not a nevus is congenital or acquired, there are no features that are completely specific and sensitive.16 A careful history, therefore, is at times more sensitive than histologic examination in diagnosing a nevus as congenital, although the reliability of anamnesis regarding the congenital nature of the lesion cannot always be proven. Yet, this issue is of practical importance: routine prophylactic removal of all SCMNs has been suggested by some authors,6,8,12 and it is necessary to balance the cost and risk of surgery with any possible risk of malignant change. The introduction of instrumental devices allowing the observation of subsurface structures has enabled the identification of morphologic features characterizing different pigmented skin lesions.17–22 Therefore, the identification of specific surface microscopic aspects of SCMNs appears to be relevant to correlate different morphologic subgroups to different risk classes in prospective studies assessing the incidence of melanomas arising from CMNs. We recently proposed a classification of SCMNs according to their macroscopic and surface microscopic appearance.23 The following data refer to a series of SCMNs (mean diameter of 18 mm) that were examined and recorded by means of a polarized-light surface microscope using 20-fold images for the description of the global aspect of the lesion and 50-fold ones for identification of the characteristic patterns. An equal number of acquired melanocytic nevi randomly selected from our database was examined for comparison of the two series of PSLs. Images were acquired by a VMS-110A videomicroscope (Scalar, Mitsubishi, Japan), based on the polarizing-light method24 and the Videocap 8.09 (DS-Medica, Italy) software.

Current concepts in the management of patients with melanoma.

Melanoma is a significant health problem. Despite public education and free cancer screenings, the incidence and mortality of melanoma continues to rise; however, many currently diagnosed melanomas are thin lesions, suggesting that education and awareness is having an impact. In addition, there are still subsets of patients who need increased surveillance in order to increase their survival. Although large congenital nevi may be precursors of melanoma, small and medium congenital nevi have an insignificant risk for melanoma development. Large congenital nevi, which are axial in location, appear to be more likely to develop melanoma and are associated with melanocytosis and melanoma of the CNS, both of which portend a poor prognosis. Recently, the recommended margins of excision have become more conservative so that many of the surgical defects can be closed primarily. Lymphoscintigraphy and sentinel node biopsy have replaced elective node dissections, thus decreasing the morbidity associated with the surgical management of melanoma. Although controversy still exists as to whether or not sentinel lymph node biopsy alters a patient's prognosis, it has been shown to be a powerful prognostic indicator. Although most melanomas are managed by routine surgical excision, other modalities are sometimes employed. For example, cryosurgery or radiation therapy may be indicated in the frail, elderly individual with a large facial lentigo maligna. Mohs surgery is the treatment of choice for head and neck melanomas and those located in areas where maximum preservation of tissue is required and for desmoplastic and acral lentiginous melanomas. Much more work remains in the area of adjuvant therapy, chemotherapy, and immunotherapy. Dacarbazine remains the drug of choice in disseminated melanoma, but remissions are usually short lived. Interleukin and biochemotherapy has yielded good results but the percentage benefiting is small. Although high dose interferon increases disease-free and overall survival in some patients, it remains a controversial drug which is not easily tolerated. In the new staging system for melanoma, ulceration is second only to Breslow's thickness. In transit (satellite) lesions have also been included in this new system. The new system also recognizes that patients with only microscopic metastatic nodal disease fare better than patients with clinically enlarged metastatic nodes and that it is the number of nodes involved with metastases, not their size, that determines the patient's prognosis. Except for lesions <1mm thick, the Clark's level of invasion has been de-emphasized.

Loss of heterozygosity and microsatellite instability in acquired melanocytic nevi: towards a molecular definition of the dysplastic nevus.

Acquired melanocytic nevi may show signs of histological dysplasia, and epidemiological studies have demonstrated that dysplastic melanocytic nevi (DMN) are associated with an elevated melanoma risk. Nevertheless, the concept of DMN as precursors of melanoma has remained a concept, in view of the difficulty of establishing unambiguous cytological and histological criteria for DMN. Recent molecular data suggest that genetic instability is more frequent in DMN than in benign acquired melanocytic nevi. We have analyzed 54 benign melanocytic nevi and 6 DMN for loss of heterozygosity (LOH) at microsatellite markers D9S171, IFNA, D9S270, D9S265. LOH at one or more loci was detected in 17 out of 54 benign nevi and in 4 out of 6 DMN. LOH was demonstrated at 26 out of 103 amplified and informative microsatellites in benign nevi and at 6 out of 11 microsatellites in DMN. In addition, 6 benign nevi and 6 DMN were microdissected in 4-15 regions per lesion and analyzed for LOH and microsatellite instability (MSI) at D9S162 and D14S53. Both LOH and MSI were detected more frequently in dysplastic nevi (LOH frequency 0.61 vs 0.18; MSI frequency 0.27 vs 0.05). These results confirm that genetic instability is more prevalent in DMN than in benign acquired melanocytic nevi. Therefore, DMN might be defined as a monoclonal and genetically unstable, but limited, melanocytic proliferation that distinguishes this entity from the benign nevus and from malignant melanoma.

Ultraviolet A and melanoma: A review

The incidence and mortality rates of melanoma have risen for many decades in the United States. Increased exposure to ultraviolet (UV) radiation is generally considered to be responsible. Sunburns, a measure of excess sun exposure, have been identified as a risk factor for the development of melanoma. Because sunburns are primarily due to UVB (280-320 nm) radiation, UVB has been implicated as a potential contributing factor to the pathogenesis of melanoma. The adverse role of UVA (320-400 nm) in this regard is less well studied, and currently there is a great deal of controversy regarding the relationship between UVA exposure and the development of melanoma. This article reviews evidence in the English-language literature that surrounds the controversy concerning a possible role for UVA in the origin of melanoma. Our search found that UVA causes DNA damage via photosensitized reactions that result in the production of oxygen radical species. UVA can induce mutations in various cultured cell lines. Furthermore, in two animal models, the hybrid Xiphophorus fish and the opossum (Mondelphis domestica), melanomas and melanoma precursors can be induced with UVA. UVA radiation has been reported to produce immunosuppression in laboratory animals and in humans. Some epidemiologic studies have reported an increase in melanomas in users of sunbeds and sunscreens and in patients exposed to psoralen and UVA (PUVA) therapy. There is basic scientific evidence of the harmful effects of UVA on DNA, cells and animals. Collectively, these data suggest a potential role for UVA in the pathogenesis of melanoma. To date evidence from epidemiologic studies and clinical observations are inconclusive but seem to be consistent with this hypothesis. Additional research on the possible role of UVA in the pathogenesis of melanoma is required. (J Am Acad Dermatol 2001;44:837-46.)

Surgical management of primary melanoma.

Melanoma precursor lesions and stage I malignant melanomas are preferentially removed by excisional surgery. Several studies have supported the concept of a more conservative excision strategy. Reduced safety margins with a maximum of 2-3 cm enable us to cover most defects by simple skin flap techniques. In critical anatomical sites and in lentigo maligna melanoma micrographic surgery has recently gained importance. The value of adjuvant surgical procedures remains controversial. Possibly, the technique of sentinel-node-biopsy provides a better approach towards a more selective use of lymphadenectomy in patients with clinically occult micrometastases.

The genetics of hereditary melanoma and nevi. 1998 update.

Although the first English-language report of melanoma in 1820 contained a description of a melanoma-prone family, it was 1983 before formal genetic analysis suggested an autosomal dominant mode of inheritance for both melanoma and the then newly described melanoma precursor, dysplastic nevi (DN). Subsequent genetic studies have assumed this model to be correct, although when viewed in aggregate, the data are inconsistent. The first proposed melanoma gene (CMM1) was mapped to chromosome 1p36. This gene assignment has not been confirmed. A second melanoma gene, designated CMM2, has been mapped to chromosome 9p21. This gene assignment has been confirmed, and the cell cycle regulator CDKN2A has been proposed as the candidate gene. Germline mutations in this gene have been identified in about 20% of melanoma-prone families that have been studied to date. Pancreatic cancer occurs excessively in melanoma families with germline mutations in CDKN2A. Germline mutations in the cyclin-dependent kinase gene CDK4 (chromosome 12q14) have been described in three melanoma families. This finding represents a third melanoma gene but one that accounts for only a tiny fraction of all hereditary melanoma. Recently, a familial melanoma-astrocytoma syndrome has been reported. Large germline deletions of 9p21 occur in these families, with the p19 gene implicated in its pathogenesis. At present, clinical predictive genetic testing for mutations in the CDKN2A gene is available commercially, but its use has been limited by uncertainty as to how test results would affect the management of melanoma-prone family members. Currently, management recommendations include monthly skin self-examination, clinical skin examination once or twice yearly, a low threshold for simple excision of changing pigmented lesions, moderation of sun exposure, and appropriate use of sunscreens. A heritable determinant for total nevus number has been suggested by twin studies. Other data suggest the presence of a major gene responsible for "total nevus density" in melanoma-prone families. Approximately 55% of the mole phenotype in multiplex melanoma families was explained by this proposed gene. An autosomal dominant mode of inheritance has been proposed for DN, and data exist to suggest that DN may be a pleiotropic manifestation of the 1p36 familial melanoma gene. However, there clearly are melanoma-prone families that do not express the dysplastic nevus trait, and some of the families linked to CDKN2A also present with dysplastic nevi. Several studies have shown a surprisingly high prevalence of DN on the skin of family members of probands with DN. In light of the extensive evidence documenting that persons with DN (both sporadic and familial) have an increased prospective risk of melanoma, these family studies suggest that relatives of persons with DN should be examined for both DN and melanoma. Genetic determinants play a major role in the pathogenesis of normal nevi, DN, and melanoma. Identifying the molecular basis of these genetic events promises to enhance melanoma risk-reduction strategies and, ultimately, reduce melanoma-associated mortality.

Macroscopic Spectral Imaging and Gene Expression Analysis of the Early Stages of Melanoma

The stages of melanocytic progression are defined as atypical (dysplastic) nevus, melanoma in situ, melanoma in the radial growth phase (RGP), melanoma in the vertical growth phase (VGP), and melanoma in the metastatic growth phase (MGP). Melanoma in situ and RGP melanoma often develop in contiguous association with atypical nevi. This frequently poses a problem with respect to their early detection. Furthermore, unlike cells obtained from VGP and MGP melanomas, cells derived from melanoma in situ and RGP melanoma do not proliferate in vitro. Thus, compared to the late stages of the disease, less information is available regarding genes expressed in the early stages. To determine whether spectral imaging, a recently developed optical imaging technique, can detect melanoma in situ and RGP melanoma arising in melanoma precursor lesions, atypical nevi in patients with a clinical history of melanoma were subjected to noninvasive macroscopic spectral imaging. To determine at what stage in the progression pathway of melanoma genes having important biological functions in VGP and MGP melanomas are activated and expressed, lesions of melanoma in situ were analyzed by immunohistochemistry and in situ hybridization for expression of some of these known molecular and immunologic markers. The present study demonstrates the capability of noninvasive spectral imaging to detect melanoma in situ and RGP melanoma that arise in contiguous association with atypical nevi. Furthermore, the study provides evidence that genes and antigens expressed in VGP and MGP melanoma are also expressed in melanoma in situ. Because of the dark and variegated pigmentation of atypical nevi, melanoma in situ and RGP melanoma that arise in these melanoma precursor lesions are often difficult to recognize and thus frequently go unnoticed. The application of new optical screening techniques for early detection of melanoma and the identification of genes expressed in the early stages of melanoma development are two important avenues in the pursuit of melanoma prevention. The investigations presented here document that macroscopic spectral imaging has the potential to detect melanoma in its early stage of development and that genes essential for the proliferation and cell adhesion of VGP and MGP melanoma are already expressed in melanoma in situ.

Non-random spatial association of melanoma and naevi--a morphometric analysis.

Previous studies have shown that congenital as well as acquired melanocytic naevi indicate an increased risk for developing melanoma in individual patients. Most studies stress the importance of melanocytic naevi as melanoma markers, while in some studies they are considered to be direct melanoma precursors. The latter opinion is favoured by the common co-occurrence of melanoma and naevus within one biopsy. The present study examines the question of whether the co-occurrence of melanoma and naevus is a random event or whether melanomas significantly co-localize with pre-existent naevi, which would suggest a precursor role for these naevi. Seven hundred biopsies of primary melanoma were examined for the presence of congenital or acquired naevi according to standard histological criteria. A naevus was found in 143 of the 700 biopsies (20.4%), of which 90 were acquired (12.9%) and 53 were congenital (7.6%). Within each biopsy the exact location of the melanoma and the naevus was determined using an ocular micrometer at a final magnification of 20 x. From these data the frequency of finding a naevus with increasing distance from the melanoma margin was calculated. The frequency of finding a naevus decreased from 2.6% immediately at the melanoma border to 0.3% at a distance of 4.5 mm and 0% at a distance of 5.0 mm. This decrease was statistically highly significant (P<0.001). Similar results were obtained when congenital and acquired naevi were evaluated separately. These data strongly indicate that melanoma and naevi are non-randomly distributed and that both congenital and acquired naevi may be precursors of melanoma.

Dimensionalities: Borderline and intermediate melanocytic neoplasia

The concept of minimal deviation melanoma is presented in diagrammatic form. In this approach, the precursors of melanoma are presented as having two dimensions and melanomas as having three dimensions. In turn, the relativity between dimensionalities and recommendations for treatment (as indirect correlates of prognostications) provides guidelines for the structuring of two major boundaries along the axis of the diagram. Finally, the domains defined by the two boundaries include borderline lesions, intermediate lesions, and “real melanomas.” The lesions in the borderline and intermediate categories qualify as melanocytic neoplasias of indeterminant malignant potential; in these two categories, the predictability of metastases hardly justifies the use of the designation, malignant melanoma.

Systemic Interferon-α (IFN-α) Treatment Leads to Stat3 Inactivation in Melanoma Precursor Lesions

In the setting of familial melanoma, the presence of atypical nevi, which are the precursors of melanoma, is associated with a nearly 100% risk of developing primary melanoma by age 70. In patients with sporadic melanoma, it is estimated that 40-60% of melanomas develop in contiguous association with atypical nevi. Currently, the only way to prevent atypical nevi from progressing to melanoma is to monitor and excise them as soon as they exhibit changes in their clinical features. Activation of the transcription factor, Stat3, has been linked to abnormal cell growth and transformation as well as to interferon alpha (IFN-alpha)-mediated growth suppression in vitro. To determine whether IFN-alpha, used for adjuvant therapy of high-risk, resected melanoma, induces changes in Stat3 in atypical nevi, patients with a clinical history of melanoma who have multiple atypical nevi were treated for 3 months with low-dose IFN-alpha. Thereupon, the new technology of microscopic spectral imaging and biochemical assays such as electrophoretic mobility shift assays (EMSAs) and immunoblot analysis were used for the study of atypical nevi, obtained before and after IFN-alpha treatment. The results of the investigations provided evidence that, as a result of systemic IFN-alpha treatment, Stat1 and Stat3, which are constitutively activated in melanoma precursor lesions, lose their ability to bind DNA, and as shown in the case of Stat3, become dephosphorylated. Unlike primary and metastatic melanomas, melanoma precursor lesions cannot be established as cell cultures. Thus, the only way to explore pathways and treatment regimens that might help prevent progression to melanoma is within the context of a melanoma precursor lesion study conducted prospectively. The findings presented here suggest that down-regulation of the transcription factors Stat1 and Stat3 by systemic IFN-alpha treatment may represent a potential pathway to prevent the activation of gene(s) whose expression may be required for atypical nevus cells to progress to melanoma.

DNA content and cell proliferation in giant congenital melanocytic naevi (GCMN). An analysis by image cytometry.

GCMN may be precursors of melanoma, and it has been suggested that the presence of atypical foci could increase the risk of malignant transformation. In order to better define atypical GCMN, we analyzed DNA content and proliferative activity in 21 samples of GCMN, with (n=13) or without (n=8) cytologic atypia. Six benign acquired naevi (AN) and 6 malignant melanoma (MM) were used as controls. DNA content was determined with the CAS 200 image analyzer, and DNA histograms were classified according to the Auer classification. The proliferative indices (PI) were measured after Ki 67 immunostaining using the CAS 200 system. All AN and GCMN without atypia showed class I histograms (normal DNA content) and low PI (mean 1.9 and 2.1). Atypical GCMN showed in 10 cases an abnormal DNA content (class III or IV histograms) with low PI (mean 2.7), and in 3 cases a normal DNA content (class I histograms) with higher PI (mean 16.2). All MM displayed abnormal DNA content and high PI (mean 32.6). In conclusion, abnormal DNA content seems to correlate with cytologic atypia in GCMN. Atypical GCMN exhibit an overall pattern of DNA content and cell proliferation intermediate between non-atypical naevi and MM.

Rapid increase in diagnosis of cutaneous melanoma in situ in Sweden, 1968-1992.

We analyzed incidence trends of cutaneous melanoma in situ in Sweden in 1968-1992. Among men, age-standardized rates increased from 0.1/100,000 in 1968 to 2.9/100,000 in 1992, which corresponds to an average annual increase of 15.0%. Among women, rates increased from 0.3 to 3.7, and the annual increase was 12.8%. Age-specific rates increased since 1978, predominantly in men aged 45 years and older, whereas in women rates increased in all ages. Multivariate analysis showed that incidence rates could be explained by both cohort effects and period effects in addition to age. However, cohort effects seemed more important among men than among women, in whom period effects dominated. Thus, factors associated with the development of melanoma in situ may differ between the sexes. Melanoma in situ is an immediate precursor of invasive melanoma, and the increased detection and surgical excision of these tumors will prevent the occurrence of invasive melanoma.

Photobiological and molecular mechanisms of ultraviolet a radiation-induced gene expression in human keratinocytes

The incidence and mortality rates of melanoma have risen for many decades in the United States. Increased exposure to ultraviolet (UV) radiation is generally considered to be responsible. Sunburns, a measure of excess sun exposure, have been identified as a risk factor for the development of melanoma. Because sunburns are primarily due to UVB (280-320 nm) radiation, UVB has been implicated as a potential contributing factor to the pathogenesis of melanoma. The adverse role of UVA (320-400 nm) in this regard is less well studied, and currently there is a great deal of controversy regarding the relationship between UVA exposure and the development of melanoma. This article reviews evidence in the English-language literature that surrounds the controversy concerning a possible role for UVA in the origin of melanoma. Our search found that UVA causes DNA damage via photosensitized reactions that result in the production of oxygen radical species. UVA can induce mutations in various cultured cell lines. Furthermore, in two animal models, the hybrid Xiphophorus fish and the opossum (Mondelphis domestica), melanomas and melanoma precursors can be induced with UVA. UVA radiation has been reported to produce immunosuppression in laboratory animals and in humans. Some epidemiologic studies have reported an increase in melanomas in users of sunbeds and sunscreens and in patients exposed to psoralen and UVA (PUVA) therapy. There is basic scientific evidence of the harmful effects of UVA on DNA, cells and animals. Collectively, these data suggest a potential role for UVA in the pathogenesis of melanoma. To date evidence from epidemiologic studies and clinical observations are inconclusive but seem to be consistent with this hypothesis. Additional research on the possible role of UVA in the pathogenesis of melanoma is required. (J Am Acad Dermatol 2001;44:837-46.)

Cancer precursors.

A significant proportion of cutaneous malignancies arise from well-defined precursor lesions that have often been present for many years. This provides an opportunity to reduce rates of skin cancer by recognition and treatment of these lesions. Precursors of keratinocytic malignancy, such as actinic keratoses and Bowen's disease, are extremely common in the older, white population and will frequently be encountered by generalist physicians in the context of examinations for noncutaneous conditions. Less common conditions, such as erythroplasia of Queyrat and nevus sebaceous, are associated with a higher risk of malignant change, and their recognition is therefore imperative. The management of the various precursors of melanoma remains controversial, as the exact risk of malignant transformation of many of these lesions is still unclear.

The Xiphophorus-derived antibody, XMEL, shows sensitivity and specificity for human cutaneous melanoma but is not a prognostic marker.

XMEL is a monoclonal antibody raised against part of the extracellular domain of the putative tyrosine kinase receptor protein implicated in the pathogenesis of melanoma formation in the Xiphophorus fish melanoma model. Our objective in this study was to determine the diagnostic and prognostic utility of XMEL for human melanoma. Formalin-fixed tissue from 82 melanomas, 42 carcinomas, 23 neural tumors, 12 lymphomas and 12 sarcomas were immunostained with XMEL and compared with a widely used melanoma antibody, HMB-45. The sensitivity of HMB-45 (83.1%) was similar to that of XMEL (79.8%). XMEL detected 7 melanomas that were HMB-45 negative. Specificity for detection of melanoma was greater with HMB-45 (95.5%) as compared to XMEL (80.9%). Of interest, all 4 prostatic adenocarcinomas were XMEL positive. These data suggest that XMEL is as sensitive but not as specific as HMB-45 in the detection of cutaneous melanoma but may serve as an ancillary antibody to improve diagnostic yield. The consistent positivity of XMEL in melanoma lends support to the hypothesis that the detected protein plays a role in melanoma pathogenesis. XMEL reactivity is not an independent prognosticator of death from melanoma in 37 melanomas from patients with at least 10 years' follow-up. These data and the fact that XMEL shows variable reactivity with metastatic melanomas but almost 100% reactivity with the primary melanomas suggest that the antigen recognized by the XMEL antibody may be important in the early stages of melanoma progression. This is supported by our earlier observation that XMEL is reactive with dysplastic nevi, a precursor of malignant melanoma.

The Monitoring of Potential Long-Term Complications in Treated Adult Cancer Patients

A wide variety of long-term complications may be noted following conventional cancer treatment. These include overwhelming postsplenectomy sepsis syndrome, central and peripheral nervous system toxicity, cardiovascular complications, chronic liver damage, and secondary malignancy. Follow-up monitoring usually incorporates both physical examination and the result of radiological and laboratory investigations. Primary care physicians will often be responsible for the majority of the follow-up monitoring involving cured cancer patients and need to be aware of possible long-term therapy-related problems, especially those that present years after successful treatment of the original malignancy.

Genetics of Cutaneous Melanoma and Nevi

To provide a state-of-the-art summary of currently available data about the genetics of cutaneous melanoma and nevi, we reviewed the pertinent literature and outlined the important findings on genetic analyses. Although the first English-language report of melanoma in 1820 contained a description of a melanoma-prone family, seminal studies by investigators at the National Cancer Institute and the University of Pennsylvania identified dysplastic nevi (DN) as an important melanoma precursor, suggested an autosomal dominant mode of inheritance for both melanoma and DN, and proposed that a melanoma-susceptibility gene (CMM1) was located on chromosome 1p36. This gene assignment has not yet been confirmed by independent investigators. A second melanoma gene, designated CMM2, has been mapped to chromosome 9p21. This gene assignment has been confirmed independently, and the cell cycle regulator p16INK4a has been proposed as a candidate gene; germline mutations in this gene have been identified in about half of melanoma-prone families. Germline mutations in the cyclin-dependent kinase gene CDK4 (chromosome 12q14) have recently been described in two melanoma kindreds; this finding likely represents a third melanoma gene. A heritable determinant for total nevus number has been suggested, as has the presence of a major gene responsible for total nevus density in melanoma-prone families. An autosomal dominant mode of inheritance for DN has been proposed, and evidence suggests that DN may be a pleiotropic manifestation of the 1p36 familial melanoma gene. Several studies have shown a surprisingly high prevalence of DN on the skin of family members of probands with DN. In light of the extensive evidence documenting that persons with DN (both sporadic and familial) have an increased prospective risk for melanoma, these family studies suggest that relatives of persons with DN should be examined for DN and for melanoma. Overall, genetic determinants have a major role in the pathogenesis of normal nevi, DN, and melanoma. Elucidating the molecular basis of these genetic events promises to enhance melanoma risk reduction strategies and thereby reduce melanoma-associated mortality.

Nevus Spilus: A Potential Precursor of Cutaneous Melanoma Worthy of Aggressive Surgical Excision?

Nevus Spilus: A Potential Precursor of Cutaneous Melanoma Worthy of Aggressive Surgical Excision?