Subungual Melanoma of the Hand.

BACKGROUND: The diagnosis of subungual melanoma (SUM) can be challenging and SUMs generally have a worse prognosis than melanomas arising elsewhere. Due to their rarity, the evidence to guide management is limited. This study sought to identify clinicopathological features predictive of outcome and to provide guidelines for management. METHODS: From a large, single-institution database, 103 patients with in situ (n = 9) or invasive (n = 94) SUMs of the hand treated between 1953 and 2014 were identified and their features analyzed. RESULTS: The most common site of hand SUMs was the thumb (53%). Median tumor thickness was 3.1 mm, and SUMs were commonly of the acral subtype (57%), ulcerated (58%), amelanotic (32%), and had mitoses (73%). Twenty-one patients reported prior trauma to the tumor site. Twenty-two patients were stage III at diagnosis; 7 underwent therapeutic lymph node dissection and 22 underwent elective lymph node dissection (5 positive), while 36 had sentinel node biopsy (SNB), 28% of which were positive. Forty percent of SNB-positive patients had involved non-sentinel nodes (SNs) in their completion lymph node dissection. Five-year melanoma-specific survival (MSS) and disease-free survival (DFS) rates were 70% and 52%, respectively. On multivariate analysis, regional node metastasis and right-hand tumor location were significant predictors of shorter DFS and MSS, whereas mitoses negatively impacted DFS only and increasing Breslow thickness impacted MSS only. CONCLUSIONS: This study confirms that SUMs on the hand usually present at an advanced stage. Distal amputation appears safe for invasive SUMs, and SNB should be considered as these patients have a high risk of both SN and non-SN metastasis.

Prognostic significance of leukocyte-dependent antibody activity in melanoma patients.

Sera from patients with melanoma and control subjects were examined for leukocyte-dependent antibody (LDA) activity against cultured melanoma and control nonmelanoma target cells in 51Cr release cytotoxicity assays. In over a third of 344 melanoma patients, LDA activity against melanoma cells was related to tumor growth, shown by disappearance of the LDA after surgical removal of melanoma. Tumor-related LDA activity was not detected in 143 controls with various nonmelanoma malignant conditions and benign skin lesions. Approximately 5% of the patients had high-titer melanoma LDA that was unchanged by surgical removal of the tumor, and 15% had melanoma LDA revealed in their sera only after the sera had been treated to dissociate immune complexes. In patients with stage I melanoma, the disease-free interval was significantly longer in those with tumor-related LDA compared to those with no LDA. Analysis of the data in relation to known prognostic variables suggested that the main influence of LDA on prolongation of the disease-free interval was in males. An association between tumor-related LDA and a longer disease-free interval was also apparent in patients with stage II melanoma at first presentation but not in those with recurrence after prior treatment of primary melanoma. The results suggest that LDA activity against melanoma cells in the sera of patients after surgical removal of stage I or stage II melanoma is a favorable prognostic factor. Further studies are needed to determine whether induction of melanoma LDA by immunotherapy may improve the outcome in patients without naturally occurring LDA.

Relationship between natural killer cell activity and histological features of lymphocyte infiltration and partial regression of the primary tumor in melanoma patients.

A group of 194 melanoma patients with Stage I melanoma was studied in an attempt to correlate histological features of prognostic importance in malignant melanoma with the level of natural killer cell (NK) activity in blood mononuclear cells. Histological features examined were lymphocytic infiltrate of the tumor base, lymphocyte infiltration at the tumor margin, and evidence of partial regression in the tumor. NK activity against melanoma cells and non-melanoma cells was studied in the same patients before and after surgical removal of melanoma. Patients with high NK activity against melanoma and Chang cells had less lymphocyte infiltrate at the base of the tumor irrespective of its thickness than did those with low NK activity. Patients with low NK activity and thin tumors had more lymphocyte infiltration at the base of the tumor than did those with high NK activity. Similar results were obtained in certain subsets of cases with respect to lymphocytic infiltration at the tumor margins and to the presence of partial regression. Although the nature of the association between these histological features and NK activity in blood is unknown, it is suggested that previously unexplained associations between histological features and prognosis may be accounted for by their association with NK activity. If this proves to be correct, measurement of NK activity may be an important additional prognostic factor in patients with melanoma.

Cancer by another name: a randomized trial of the effects of euphemism and uncertainty in communicating with cancer patients.

PURPOSE: In this study we tested some assumptions about the use of euphemism in communicating with cancer patients. Does an explicit statement about the diagnosis of cancer cause patients to respond with greater anxiety than when uncertainty or ambiguity is allowed to persist? Do patients believe they cope better with cancer when the diagnosis is explicit? METHODS: A heterogeneous sample of 165 cancer patients completed a new measure of emotional adjustment to cancer using random assignment among four testing variables: agent (self-report v interview), terminology (the words cancer v illness), identification (patient identified v anonymous), and supervision (clinic v home). Internal consistency (Cronbach's alpha) for the 39-item set was 0.74 and face and content validity were determined using the focus-group technique and preliminary factor analysis. After answering the adjustment measures, subjects completed the Spielberger State-Trait Anxiety Inventory (STAI). RESULTS: Overall anxiety levels were significantly lower in the sample than published norms for general medical and surgical patients. Exposure to the word cancer as distinct from illness increased anxiety, but did not alter adjustment scores. Supervision and agent conditions did not affect anxiety, but reported adjustment was poorer in the interview condition compared with the self-report condition. Ambiguous instructions, such as asking patients to complete the questionnaire anonymously but return it in person to staff in the clinic, resulted in poorer adjustment, which was reversed by the consistent instruction to complete the questionnaire anonymously at home and return it by mail. CONCLUSION: Use of the word cancer generated anxiety to levels similar to those reported in general medical and surgical patients, but did not produce any distortion in reported adjustment. However, any ambiguity associated with the conditions under which adjustment is assessed may lead to distortion and an increase in the patient's reported psychologic distress.

Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system.

PURPOSE: To critically review the accuracy of the current American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma and propose a more useful staging system. METHODS: Retrospective evaluation of the published data as well as a reanalysis of the University of Alabama and Sydney Melanoma Unit (UAB/SMU) data bases (n = 4,568) for patients with primary melanoma was performed to examine specifically the impact of level of invasion and ulceration on the prognostic value of tumor thickness. In addition, an overlay graphic technique was used to compare the Kaplan-Meier survival curves of patients with local recurrences, satellites, in-transit metastases, and nodal metastases reported in the literature. RESULTS: Tumor thickness and ulceration remained the most powerful prognostic indicators in patients with stage I and II disease. Level of invasion provided statistically significant prognostic information only in the subgroup of patients with tumor thickness < or = 1 mm, but the absolute 10-year survival differences were small and inconsistent (level II, 95%; level III, 85%; level IV, 89%). The best statistical fit for tumor thickness cutoffs was at 1 versus 2 versus 4 mm. The overlay graphic technique showed that patients who developed satellite lesions or local recurrence had prognoses similar to those of patients with stage III disease. The most important prognostic factor for patients with nodal metastases was number of involved nodes rather than size. CONCLUSION: Our analysis showed that the current AJCC staging system has many inaccuracies that should be modified to conform to published data. On the basis of our analysis and review of the literature, we propose a new and more accurate staging system.

Determinants of outcome in melanoma patients with cerebral metastases.

PURPOSE: To analyze prognostic factors, effects of treatment, and survival for patients with cerebral metastases from melanoma. PATIENTS AND METHODS: All melanoma patients with cerebral metastases treated at the Sydney Melanoma Unit between 1952 and 2000 were identified. From 1985 to 2000, patients were diagnosed and treated using consistent modern techniques and this cohort was analyzed in detail. Multivariate analysis of prognostic factors for survival was performed. RESULTS: A total of 1137 patients with cerebral metastases were identified; 686 were treated between 1985 and 2000. For these 686 patients, the median time from primary diagnosis to cerebral metastasis was 3.1 years (range, 0 to 41 years). A total of 646 patients (94%) have died as a result of melanoma. The median survival from the time of diagnosis of cerebral metastasis was 4.1 months (range, 0 to 17.2 years). Treatment was as follows: surgery and postoperative radiotherapy, 158 patients; surgery alone, 47 patients; radiotherapy alone, 236 patients; and supportive care alone, 210 patients. Median survival according to treatment received for these four groups was 8.9, 8.7, 3.4, and 2.1 months, respectively; the differences between surgery and nonsurgery groups were statistically significant. On multivariate analysis, significant factors associated with improved survival were surgical treatment (P <.0001), no concurrent extracerebral metastases (P <.0001), younger age (P =.0007), and longer disease-free interval (P =.036). Prognostic factors analysis confirmed the important influence of patient selection on treatment received. CONCLUSION: This large series documents the characteristics of patients who developed cerebral metastases from melanoma. Median survival was dependent on treatment, which in turn was dependent on patient selection.

Detection of unsuspected spinal cord compression in melanoma patients by 18F-fluorodeoxyglucose-positron emission tomography.

AIM: Positron emission tomography (PET) using (18)F-fluorodeoxyglucose can detect early or small metastatic deposits of melanoma and guide subsequent correlative anatomical imaging and treatment. The aim of this study was to assess the value of PET in demonstrating spinal cord compression by otherwise unsuspected metastatic disease. METHODS: Reports of 1365 PET studies performed on patients with melanoma were reviewed. Fifty patients considered to be at risk of spinal cord compression on the basis of PET were identified and 35 patients were analysed. Magnetic resonance imaging and computed tomography were used to confirm or refute the diagnosis. The symptoms and signs at the time of PET and follow-up status were compared between patients with and without confirmed spinal cord compression. RESULTS: In nine patients (26%) compression of the spinal cord or adjacent neurological structures was confirmed and eight of these patients had immediate treatment. Survival was poor in both patient groups, but three patients with confirmed compression maintained good neurological functional status following treatment. CONCLUSION: PET can detect imminent, unsuspected spinal cord compression in patients with metastatic melanoma. Immediate anatomical imaging of the spine is recommended in patients who have evidence of spinal cord compression on PET.

Immunocytochemical analysis of the cellular infiltrate in primary regressing and non-regressing malignant melanoma.

Spontaneous regression occurs in a small proportion of malignant melanomas, and it is important to understand the processes involved in its induction as this may give a guide to future therapies for this disease. We have examined 36 primary malignant melanomas (19 regressing, 17 non-regressing) and identified the cellular phenotypes and activation states of the cells infiltrating regressing and non-regressing primary melanomas by immunochemistry. We have found a significantly increased number of CD3-positive cells and an increased ratio of CD4/CD8-positive cells infiltrating regressing compared to non-regressing tumors. In addition, the expression of the interleukin 2 receptor, an activation marker for T cells, was increased. However, there were no significant differences in class II MHC, CD1, intercellular adhesion molecule 1 (ICAM1), or melanoma-associated differentiation-antigen expression in these tumors. These data are consistent with melanoma regression being induced by activated CD4 T cells and do not seem to be related to the differentiation markers we have examined on these tumors.

Synchronous cisplatin infusion during radiotherapy for the treatment of metastatic melanoma.

In two pilot studies, 55 patients with symptomatic metastases from malignant melanoma were treated with irradiation and concurrent cisplatin. In the first group, cisplatin was given as a continuous intravenous infusion of 20 mg/m2 per day on days 1-5 and 22-26, with irradiation on days 2, 5, 9, 16, 23 and 26. The second group received 20 mg cisplatin over 24 h commencing 1 h before each fraction of irradiation on days 1, 4, 8, 11, 15 and 18. The first series of 28 patients had 30 lesions treated. Nine (30%) of these lesions responded completely and 10 (33%) achieved partial response for an overall response rate of 63% (95% confidence interval 44-80%). Survival was not evaluated in this group. The second group was comprised of 27 patients, with one irradiated lesion each. 1 patient achieved a complete response and 13 (48%) a partial response for an overall response rate of 52% (32-71%). Median survival was 21 weeks (16-31 weeks). Treatment was well tolerated with nausea and vomiting being the most common toxicity. Synchronous cisplatin infusion with radiotherapy achieves high response rates in metastatic melanoma. Whether it is superior to radiotherapy alone will require evaluation in a randomised trial.

Nephelometric detection of circulating immune complexes using monoclonal rheumatoid factor.

A nephelometric technique for the estimation of immune complexes (IC) in serum was developed using purified monoclonal rheumatoid factor from a human patient (mRhF) specific for complexed IgG. Standardisation of the assay was carried out with heat aggregated normal human IgG as a model complex and with IC composed in vitro from ovalbumin and rabbit antisera to ovalbumin. The nephelometric method was compared with [125I]Clq radioimmunoassay (C1q RIA). The lower limits of detection by the two methods were similar for both aggregated IgG and performed ovalbumin/rabbit anti-ovalbumin IC. However, recognition of IC by the two methods differed with different ratios of antigen and antibody. When IC were formed at 10 times antigen excess the nephelometric technique was more sensitive than when IC were formed at equivalence or 10 times antibody excess. The Cuq RIA method was most sensitive in detection of IC in antibody excess but failed to detect IC in antigen excess. Complexes formed in antigen excess also showed potentiated light scattering when 1.5% polyethylene glycol was used in the nephelometric system. The incidence of IC detected by the mRhF in sera from patients with rheumatoid arthritis and systemic lupus erythematosus was lower than with C1q RIA suggesting that the IC in these patients contain antibodies not detected by the mRhF used. IC in the sera of patients with melanoma were detected more frequently by the mRhF assay which may indicate the IC in these sera were in antigen excess. Detection of IC by mRhF nephelometry was rapid, technically simple and yielded results which complemented those of the established C1q RIA method. This assay system is a useful addition to methods currently available for detection of IC and the similar use of rheumatoid factors against different classes of antibody should extend its usefulness.

Cutaneous melanomas that defy conventional prognostic indicators.

Tumor thickness is usually an accurate prognostic indicator for the patient with melanoma. However, very thin primary melanomas occasionally recur locally or metastasize, whereas some patients with very thick primary melanomas survive far longer than expected. There is also a group of patients with primary melanomas of various thicknesses who relapse after a very long disease-free interval. The large database of the Sydney Melanoma Unit which now contains comprehensive long-term follow-up on more than 13,000 patients treated over a 45-year period, has provided a unique opportunity to study melanomas that defy conventional prognostic indicators. Recurrence developed in 2.8% of melanoma patients classified as stage I (pTNM staging system) and with very thin lesions (< 0.50 mm). These recurrences developed more frequently in women than men and histologically were found to be associated with ulceration, high mitotic activity, and invasion to Clark's level IV, but not with regression. Concurrent lymph node metastases (stage III) were present in 3.1% of patients with very thin lesions (< 0.50 mm). In this group, most patients were men, and every lesion displayed regression. Total survival exceeded 15 years in 15.7% of stage II and III patients with very thick lesions (> 5.5 mm). In 1.7% of patients with lesions of any thickness, the disease-free interval before relapse was > 15 years. Neither in patients with very thick lesions surviving for > 15 years, nor in those with a disease-free interval of > 15 years was it consistently possible to show the presence or absence of any of the histological features usually considered to be of prognostic significance.

The pharmacokinetics of p-Boronophenylalanine.fructose in human patients with glioma and metastatic melanoma.

PURPOSE: To study the biodistribution of p-Boronophenylalanine in patients undergoing surgery for intracranial tumors or metastatic melanoma. METHODS AND MATERIALS: D,L-p-Boronophenylalanine was administered as boronophenylalanine.fructose in an intravenous bolus 1-4 h before the operation. Blood samples were collected for 24 h from the time of administration of the compound, and the blood boron elimination parameters were determined. For the glioma patients tumor samples were obtained and skin, dura, periosteum, and surrounding brain samples were collected whenever possible. For the metastatic melanoma patients tumor, fat, skin, and muscle were collected. Determination of the boron content was performed using inductively coupled plasma-atomic emission spectrometry. Twelve melanoma patients and six glioma patients participated in the study. The melanoma patients included four cases of cutaneous metastatic melanoma, six cases of metastatic melanoma to the lymph nodes and two cases of cerebral metastasis. RESULTS: The results for the metastatic melanoma patients are encouraging with an average tumor:blood boron concentration ratio and standard deviation of about 4.4 +/- 3.2 and a maximum value of 10 for the cerebral metastasis. The glioma patients involved high grade glioma for which the tumor:blood ratio was 2.2 +/- 1.2. CONCLUSION: The tumor:blood ratios for melanoma fulfil requirements for epithermal boron neutron capture therapy for cerebral melanoma metastases, whereas those for high grade glioma do not.

Lymphoscintigraphy in high-risk melanoma of the trunk: predicting draining node groups, defining lymphatic channels and locating the sentinel node.

Lymphoscintigraphy was performed in 209 patients with high-risk melanoma of the trunk referred to the Sydney Melanoma Unit and considered for lymph node dissection. Lymphoscintigraphy accurately defined the draining lymph node groups and was 94% sensitive in detecting draining sites that contained metastases. When combined with the clinical finding of palpable lymph nodes, the sensitivity rose to 98%. Most patients showed lymph drainage to one or two node groups and only 22 patients showed drainage to 3 or more node groups. The major lymph channels could also be marked on the skin prior to incontinuity dissection. Most patients had multiple draining lymph channels and these often diverged significantly from each other in the path to the draining node group. The number and location of interval nodes could be determined and marked on the skin. These and the major lymph channels could thus be excised at the time of surgery. Unusual drainage patterns were sometimes seen; for example, three patients displayed a new lymph pathway with direct drainage from the back anteriorly to the para-aortic nodes. The location of the sentinel nodes in each draining lymph-node group could also be marked on the skin prior to surgery, enabling quick and accurate identification of this node, using the blue-dye technique if biopsy were to be performed. These findings lead us to recommend lymphoscintigraphy prior to wide local excision in patients with truncal melanoma who are candidates for surgery. Lymphoscintigraphy results will help plan surgery and lead to minimum surgical intervention, consistent with effective surgical management.

Lymphatic drainage to triangular intermuscular space lymph nodes in melanoma on the back.

METHODS: Lymphoscintigraphy with 99mTc-antimony sulphide colloid was performed on patients with cutaneous melanoma of the back to define draining node fields and sentinel nodes before surgery. RESULTS: One patient was found to have drainage from the back to sentinel lymph nodes in the triangular intermuscular spaces bilaterally, above and lateral to the scapula. Subsequently, drainage to this node field has been found in 26% of 42 consecutive patients who have had lymphoscintigraphy performed for melanoma on the back. CONCLUSION: When performing lymphoscintigraphy to locate draining node fields and sentinel nodes in patients with melanoma on the back, it is important to look for drainage to the triangular intermuscular space node field by obtaining posterior and lateral scans. Any sentinel lymph nodes found in this field should be marked prior to surgery in the same way as nodes in other node fields are delineated so that they may be removed at surgery.

Clinical outcomes of localized melanoma of the foot: a case-control study.

The controversy over whether melanoma of the foot has a poorer prognosis than melanoma of the leg remains unresolved. This investigation used a case-control design to address this issue. This design consisted of a survival analysis of 119 cases with localized melanoma of the foot and 238 controls with localized melanoma of the leg that were matched on prognostic factors including tumor thickness, ulceration, surgical treatment, gender, year of diagnosis, and age. There was a statistically significant difference between the survival rates of cases and controls. The 5-year survival rate for cases was 74.3% compared to 85.2% for controls. At 10 years, the survival rate was 63.6% for cases and 77.2% for controls. Cases experienced a higher percentage of distant recurrences than controls. These results imply that patients with melanoma of the foot have a poorer survival than patients with melanoma of the leg after controlling for prognostic factors.

Complete regression of primary cutaneous malignant melanoma.

While partial spontaneous histopathological regression is a common finding in invasive primary melanoma, proven complete regression is rare, with only 33 cases having been documented. None of the patients in these reported cases had a biopsy specimen taken from the original lesion, which would unequivocally prove the diagnosis of complete regressing melanoma. Over 4 years, we saw a 62-year-old white man who refused treatment of a biopsy specimen-proved superficial spreading melanoma (Breslow thickness, 0.7 mm) that eventually regressed completely. A biopsy specimen confirmed complete histopathological regression. There was no clinical evidence of regional or distant metastases throughout the 4 years. To our knowledge, this is the first documented case of a biopsy specimen-proved primary melanoma completely regressing. We present sequential photographic documentation and review the literature about this phenomenon. While the prevalence of such an event is unknown, evidence is presented that it may be more common than previously thought.

Thin malignant melanomas and recurrence potential.

Of 846 patients with stage I malignant melanoma that was less than 0.76-mm thick who were followed up for two to 31 years, 61 (7.2%) developed a recurrence. For those patients who did not initially undergo an elective lymph node dissection, the majority of first recurrences were at regional lymph nodes. Attempts have been made to identify those patients at risk of relapsing. Axial lesions, particularly those on the scalp, had the highest recurrence rate, with 15% of all thin scalp lesions recurring compared with only 4% of all thin extremity lesions. Three histological features proved to be useful prognostic indicators when analyzed by single-factor analysis. Evidence of ulceration in the primary lesion increased the recurrence rate from 6.7% to 26.1%. While only 4.3% of lesions displaying low mitotic activity recurred, this rate rose to 23.8% for those lesions of a high mitotic grade. Only 5% of Clark's level II lesions recurred, compared with about 12% of lesions at either level III or IV. Evidence of regression in thin lesions had no deleterious effect on prognosis. This study defines a small subset of patients who may benefit from elective lymph node dissection.

Late relapse from cutaneous stage I malignant melanoma.

In 1,283 patients with cutaneous stage I malignant melanoma who had ten or more years of follow-up, the incidence of late recurrence (first evidence of metastases occurring ten or more years after melanoma diagnosis) was 2.7%. None of the factors of prognostic importance (anatomic site, tumor thickness, ulcerative state of primary lesion, or initial surgical treatment) proved useful in predicting those patients with late recurrence. There was no sex or age difference in either incidence of late recurrence or prognosis subsequent to recurrence. Prognosis subsequent to late recurrence depended on the site of the recurrence. Survival after distant metastases became evident was extremely short. However, in the majority (53%) of patients, late recurrence was local and survival subsequent to treatment of these metastases was often protracted, emphasizing the importance of long-term follow-up in all patients with cutaneous melanoma.

Interval nodes: the forgotten sentinel nodes in patients with melanoma.

BACKGROUND: Any sentinel lymph node that receives lymph drainage directly from a primary melanoma site, regardless of its location, may contain metastatic disease. This is true even if the sentinel node does not lie in a recognized node field. Interval (in-transit) nodes that lie along the course of a lymphatic vessel between a primary melanoma site and a recognized node field are sometimes seen during lymphatic mapping for sentinel node biopsy. If drainage to such interval nodes is ignored by the surgeon during sentinel node biopsy, metastatic melanoma will be missed in some patients. HYPOTHESIS: When lymph drains directly from a cutaneous melanoma site to an interval node, that sentinel node has the same chance of harboring micrometastatic disease as a sentinel node in a recognized node field. DESIGN: Preoperative lymphoscintigraphy with technetiumTc 99m antimony trisulfide colloid was performed to define lymphatic drainage patterns and, since 1992, to locate the sentinel lymph nodes for surgical biopsy or for permanent skin marking of their location with point tattoos. SETTING: Melanoma unit of a university teaching hospital. PATIENTS: A total of 2045 patients with cutaneous melanoma were studied in 13 years. RESULTS: Interval nodes were found in 148 patients (7.2%). The incidence of interval nodes varied with the site of the primary melanoma. Interval nodes were more common with melanomas on the trunk than with those on the lower limbs. Micrometastatic disease was found in 14% of interval nodes that underwent biopsy as sentinel nodes. This incidence is similar to that found in sentinel nodes located in recognized node fields, confirming the potential clinical importance of interval nodes. CONCLUSIONS: Interval nodes should be removed surgically along with any additional sentinel nodes in standard node fields if the sentinel node biopsy procedure is to be complete. In some patients, an interval node will be the only lymph node that contains metastatic disease.

Hereditary melanoma in Australia. Variable association with dysplastic nevi and absence of genetic linkage to chromosome 1p.

Hereditary cutaneous malignant melanoma in association with the presence of multiple precursor lesions termed the dysplastic nevus syndrome (DNS) has been reported to display autosomal dominant inheritance with high penetrance. The gene for this disease was recently assigned to the distal short arm of chromosome 1 on chromosomal band 1p36, 7.6 centimorgans distal to the locus for the pronatrodilatin (PND) gene. We assessed 119 family members of eight newly described Australian families, 30 of whom had cutaneous malignant melanoma. Only eight of these affected individuals also had dysplastic nevi (DN). An additional 15 family members had DN alone. Pedigrees fell into three groups: 1) hereditary melanoma alone with no associated DN, 2) hereditary melanoma with occasional DN-affected individuals, and 3) hereditary melanoma with DN. All families displayed an autosomal dominant pattern of inheritance. An analysis of the cosegregation of the cutaneous malignant melanoma/DN trait with eight polymorphic DNA markers on the short arm of chromosome 1, including the distally located DNA markers D1S47 and PND yielded a strongly negative probability of linkage. The putative gene for susceptibility to melanoma in these families was effectively excluded from this region of the short arm of chromosome 1. No evidence for linkage was found at any of the other chromosome 1 markers examined. These findings suggest that hereditary melanoma is heterogeneous in relation to the genetic basis and its association with the DNS.