Positive relationship of clinical and serologic responses to vaccinia melanoma oncolysate

In this phase Ia/Ib trial, vaccinia melanoma oncolysate (VMO) is a virus-augmented melanoma cell membrane vaccine that has been shown to be safe and to stimulate the production of antimelanoma antibodies in high-risk melanoma patients treated in a surgical adjuvant setting. One patient with stage I and 38 patients with stage II melanoma were entered in the study between December 1984 and October 1985, with a mean follow-up of approximately 17 months. Each patient received a smallpox booster injection followed one week later by the first of 13 weekly intradermal injections of 2.0 mg of VMO. At the end of 13 weeks, injections were given every other week for 12 months or until recurrence. Clinical results show that 25 of the 39 patients had no evidence of disease as of December 1986. Moreover and more importantly, statistical comparison of patients in this study with 39 matched controls shows a significant increase in disease-free survival for the patients treated with VMO. Serum obtained prior to treatment and at three-month intervals during treatment was tested in a Staphylococcus protein A rosette assay for reactivity with melanoma cell lines. All pretreatment samples (39/39) were negative, and 64% became positive by 12 months after appropriate dosage escalations. Moreover, enzyme-linked immunosorbent assay showed a positive correlation between anti-melanoma IgG antibody titer and disease-free survival.     

Favorable clinical responses in subsets of patients from a randomized,multi-institutional melanoma vaccine trial

Background: A phase III, randomized, double-blind, multi-institutional trial was performed evaluating active specific immunotherapy using vaccinia melanoma oncolysate (VMO) in the surgical adjuvant setting in patients with stage II melanoma (UICC staging). The first interim analysis showed no significant difference in disease-free and overall survival. The data were further analyzed to identify subsets of patients with improved outcome when treated with VMO. Methods: Patients received either VMO or placebo of live vaccinia vaccine virus (V), once a week for 13 weeks and then once every 2 weeks for an additional 39 weeks or until recurrence. Having stratified patients according to sex, age, number of positive nodes, tumor thickness, and clinical stage, data were analyzed for disease-free survival and overall survival. Results: Male patients showed a 17% difference in overall survival at 4 years when treated with VMO (p=0.19). A subset of male patients <57 years of age with one to five positive nodes showed a 30% difference at 4 years with VMO (p=0.06). Patients with clinical stage I but pathological stage II disease (both male and female), who had undergone prophylactic node dissection, showed a 23% difference in survival at 3 years with VMO (p=0.11). Conclusions: This subset analysis shows encouraging survival benefit in certain subsets of patients and an increasing trend in overall survival. Further follow-up of this phase III trial from a second interim analysis will be forthcoming.Results of this study were presented at the 48th Annual Cancer Symposium of The Society of Surgical Oncology, Boston, Massachusetts, March 23–26, 1995.     

Increased survival of patients treated with a vaccinia melanoma oncolysate vaccine: second interim analysis of data from a phase III, multi-institutional trial.

OBJECTIVE: The efficacy of vaccinia melanoma oncolysate (VMO) vaccine to increase overall survival and disease-free survival of patients with surgically resected International Union Against Cancer (UICC) stage II melanoma was studied in a phase III, randomized, multi-institutional trial. SUMMARY BACKGROUND DATA: Phase I and II trials with VMO showed minimal toxicity and clinical efficacy in patients with melanoma. In a recently completed phase III VMO trial, the first interim analysis performed in April 1994 showed an increasing trend in the survival of patients treated with VMO. The second interim analysis was performed in April 1995. METHODS: Patients with surgically resected stage II (UICC) melanoma were treated with VMO (N = 104) or placebo vaccinia vaccine virus (V) (N = 113) once a week for 13 weeks and then once every 2 weeks for a total of 12 months. Patients' clinical data were collected as of May 1995 and analyzed for survival. RESULTS: In this second interim analysis, the mean follow-up time is 42.28 months. No survival difference was observed between VMO and V treatments. However, in a retrospective subset analysis, a subset of males between the ages of 44 and 57 years and having one to five positive nodes (at 2-, 3-, and 5-year intervals, 13.6%, 15.9%, and 20.3% difference insurvival in favor of VMO [N = 20] when compared to V [N = 18] [p = 0.037]) and another subset of patients with clinical stage I (at 3- and 5-year intervals, 30% and 7% difference in survival in favor of VMO [N = 20] when compared to V [N = 23], [p = 0.05]) showed significant survival advantage with VMO. CONCLUSIONS: Although VMO vaccine therapy in surgical adjuvant setting did not produce a significant survival benefit to all patients with melanoma, patients from the above two subsets had significant survival benefit.     

Surgical management of primary anorectal melanoma

BACKGROUND: This aim of this study was to analyse outcome after surgery for primary anorectal melanoma and to determine factors predictive of survival. METHODS: Records of 40 patients treated between 1977 and 2002 were reviewed. RESULTS: Twelve men and 28 women of mean age 58.1 (range 37-83) years were included in the analysis. Overall and disease-free survival rates were 17 and 14 per cent at 5 years. Median overall survival was 17 months and disease-free survival was 10 months. The 5-year survival rate was 24 per cent for patients with stage I tumours, and zero for those with stage II or stage III disease. There was no significant difference in overall survival after wide local excision (49 and 16 per cent at 2 and 5 years respectively) and abdominoperineal resection (33 per cent at both time points). In patients with stage I and stage II disease, there was a significant association between poor survival and duration of symptoms (more than 3 months), inguinal lymph node involvement, tumour stage and presence of amelanotic melanoma. CONCLUSION: Anorectal melanoma is a rare disease with a poor prognosis. Wide local excision is recommended as primary therapy if negative resection margins can be achieved.     

Resection of pulmonary metastases from malignant melanoma: results of a 16-year experience

Between 1970 and 1986, 49 patients had resection of presumed pulmonary metastases from malignant melanoma. Sixteen patients were found to have benign disease only despite the appearance of a new nodule in 13. Patients with benign disease had a significantly longer mean survival (169 months) compared with the group with malignant disease (22 months). Median survival for all patients with malignant disease was 13 months. Survival after resection did not correlate with the Clark level of the original lesion, lymph node status, disease-free interval, or number of nodules on preoperative tomograms. Two of 10 patients with 1 nodule resected are long-term survivors (88 and 120 months). Exploration in patients with presumed pulmonary metastases from melanoma is justified to rule out benign disease even if a new solitary nodule is detected. There are no prognostic indicators predicting survival after resection of melanoma metastases, and a significant number of patients will have benign disease.     

Patterns of recurrence after sentinel lymph node biopsy for cutaneous melanoma

BACKGROUND: Previous sentinel lymph node (SLN) studies for cutaneous melanoma have shown that the SLN accurately reflects the nodal status of the corresponding nodal basin. However, there are few long-term studies that describe recurrence site patterns, predictors for recurrence, and overall survival and disease-free survival after SLN biopsy. METHODS: A retrospective review of patients over a 6-year period was performed to determine patient outcomes and the patterns of recurrence. In all cases, Tc-99 sulfur colloid along with isosulfan blue dye was injected at the primary melanoma site. After resection, the SLN was serially sectioned and evaluated by hematoxylin and eosin staining and immunohistochemistry. RESULTS: One hundred ninety-eight patients were identified who underwent SLN biopsy for cutaneous melanoma including T1 (n = 21), T2 (n = 88), T3 (n = 75), and T4 (n = 14) primary tumors. Of these patients, 38 had a positive SLN. Of the 38 patients with a positive SLN (mean follow-up 38 months), recurrent disease was identified in 10 (26.3%) at a mean interval of 14.2 months. The site of first recurrence was distant (n = 4) and local (n = 6). Regional lymphatic basin recurrence was not identified. Of the 160 patients with a negative SLN (mean follow-up 50 months), recurrent disease was identified in 16 (10.0%) at a mean interval of 31.3 months. The site of first recurrence was systemic (n = 11), local (n = 4), and nodal (n = 1). Overall survival and disease-free survival for patients with a positive SLN at 55 months was 53.3% and 47.7% respectively, while overall survival and disease-free survival for patients with a negative SLN at 53 months was 92.2% and 87.7% respectively (P <0.01). Univariate and multivariate analysis of the entire cohort (n = 198) identified primary tumor depth and positive SLN status as significant predictors of recurrence. CONCLUSIONS: The incidence of nodal basin recurrence after SLN biopsy was found to be 0.6%. Primary tumor depth and pathological status of the SLN are significant predictors of local and systemic recurrence. Long-term follow-up indicates that patients with a positive SLN clearly recur sooner and have decreased overall survival than those with a negative SLN.     

Surgical therapy for anorectal melanoma

BACKGROUND: Anorectal melanoma is a rare but highly lethal malignancy. Historically, radical resection was considered the "gold standard" for treatment of potentially curable anorectal melanoma. The dismal prognosis of this disease has prompted us to recommend wide local excision as the initial therapeutic approach. The purpose of this study was to review our results in patients who underwent wide local excision or radical surgery (abdominoperineal resection [APR]) for localized anorectal melanoma. STUDY DESIGN: We reviewed the charts of all patients referred for resection of anorectal melanoma between 1988 and 2002. Endpoints included overall survival, disease-free survival, and local, regional, or systemic recurrence. RESULTS: Fifteen patients underwent curative-intent surgery; four underwent APR and 11 underwent wide local excision. Eight patients (53%) are alive; 7 (47%) are disease-free (followup 6 months to 13 years). Of 12 patients who have been followed for more than 2 years, 4 are alive (33%) and 3 are disease-free (25%). Seven patients have been followed for more than 5 years and two are alive and disease-free (29%). All of the longterm survivors underwent local excision as the initial operation. There were no differences in local recurrence, systemic recurrence, disease-free survival, or overall survival between the APR group and the local excision group. Local recurrence occurred in 50% of the APR group and 18% of the local excision group; regional recurrence occurred in 25% versus 27%. Distant metastases were common (75% versus 36%). CONCLUSION: In patients who have undergone resection with curative intent for anorectal melanoma, most recurrences occur systemically regardless of the initial surgical procedure. Local resection does not increase the risk of local or regional recurrence. APR offers no survival advantage over local excision. We advocate wide local excision as primary therapy for anorectal melanoma when technically feasible.     

Pulmonary metastasectomy in a patient with malignant melanoma after a disease-free interval of 15 years

Prognosis in melanoma patients after resection of pulmonary metastases is poor. Little information is available about the relationship between long-term disease-free interval and survival rate after pulmonary metastasectomy. We report a patient treated for malignant melanoma of the forehead who developed a pulmonary metastasis after a disease-free interval of 15 years. Lobectomy was performed, but unfortunately 12 months later the patient died of brain metastases.     

Angiotropism is an independent predictor of local recurrence and in-transit metastasis in primary cutaneous melanoma

The migration of melanoma cells along the external surface of blood vessels (angiotropism) has recently been proposed as a mechanism for melanoma metastasis (termed extravascular migratory metastasis). To determine whether the presence of angiotropism, as seen in the routine hematoxylin and eosin sections of primary cutaneous melanomas (PCMs), predicts the development of local or in-transit melanoma recurrence, 32 patients with a PCM who developed local or in-transit recurrence were matched for Breslow thickness with 59 "control" patients with a PCM who did not. The slides from both groups of patients were analyzed in a "blinded" manner for evidence of angiotropism. Other histologic and clinical variables were also assessed. Angiotropism was found more often in patients who developed local or in-transit recurrence (cases) compared with those patients who did not (controls) (P=0.02). Variables that showed a statistically significant association with angiotropism on univariate analysis were: increasing Breslow thickness (P<0.0001), greater Clark level (P<0.001), increasing mitotic index (P<0.0001), presence of ulceration (P<0.01), and absence of regression (P<0.05). The median disease-free survival was 72 months for patients with angiotropism and 104 months for those without (P=0.02). On multivariate analysis the presence of angiotropism was an independent predictor of decreased disease-free survival (P=0.02). This is the first reported study to identify a statistically significant association between the development of local or in-transit recurrence of PCM and the histologic presence of angiotropism and that angiotropism is an independent predictor of decreased disease-free survival, as far as we are aware. Our findings support the hypothesis that angiotropism represents a pathogenic mechanism for metastasis in patients with PCM.     

A phase I/II SECSG (Southeastern Cancer Study Group) pilot study of surgical adjuvant immunotherapy with vaccinia melanoma oncolysates (VMO)

Forty-eight patients with nonrecurrent high risk Stage I and II malignant melanoma were treated with Vaccinia Melanoma Oncolysates (VMO). Six different dose levels and two different treatment regimens were tested. Thirty-two out of 48 patients completed the 12 months of therapy. Side effects were mild to moderate. Twenty-eight out of 48 patients remain free from disease with a mean survival of 19 months, while 20/48 patients have recurred with a mean time to recurrence of 6 months.     

The prognostic implications of microscopic satellites in patients with clinical stage I melanoma.

Controversy exists as to whether microscopic satellites influence prognosis or patterns of progressive disease in patients with clinical stage I melanoma. Fifty patients with clinical stage I melanoma and microscopic satellites were prospectively studied from 1972 to 1984. To allow for complete histopathology assessment, 30 patients with microscopic satellites who were prospectively seen from 1972 to 1979 were matched to a cohort of 77 patients with vertical growth-phase melanoma without microscopic satellites according to six attributes. The matched cohort study showed that the presence of microscopic satellites appeared to be associated with increased local regional cutaneous and regional nodal disease and a significantly decreased actuarial disease-free survival. A Cox multivariate regression analysis that involved 384 patients with vertical growth-phase clinical stage I melanoma showed that the presence of microscopic satellites independently predicted a poorer disease-free survival and overall survival. Therefore, this study demonstrated that the presence of microscopic satellites correlated with a significantly decreased survival.     

Long-term survivor of brain metastases from malignant melanoma

Malignant melanoma is notorious for distant metastases. Median survival for stage IV melanoma is 6-10 months and 5 year survival is less than 5%. Median survival for melanoma with brain metastases is even lower i.e. 2 to 9 months. Here a case is reported who was treated for melanoma of sole of left foot with ipsilateral inguinal adenopathy and brain metastases in 2001 and is still surviving disease-free after a lapse of 8 years.     

Isolated limb perfusion for unresectable melanoma of the extremities

HYPOTHESIS: In patients with truly unresectable melanoma of the extremities, results after isolated limb perfusion (ILP) are absent in the literature. Complete response rates are probably lower than the reported 54% for locoregional recurrent melanoma. In these patients, ILP with melphalan and tumor necrosis factor alpha (TNF-alpha) could be superior to ILP with melphalan alone. DESIGN: Retrospective analysis with a median follow-up period of 21 months (interquartile range, 9-40 months). SETTING: Two tertiary care cancer centers in the Netherlands. PATIENTS: We assessed all 130 consecutive patients who underwent ILP for unresectable melanoma of the extremities, performed between 1978 and 2001. Of these patients, 38% had stage IIIA melanoma and 45% had stage IIIAB melanoma according to criteria of the MD Anderson Cancer Center. Lesions were considered unresectable on the basis of their size, number, or localization. INTERVENTIONS: Forty ILPs were performed with melphalan, and 90 were done with TNF-alpha and melphalan. MAIN OUTCOME MEASURES: Response rate, disease-free survival, limb salvage rate, and overall survival. RESULTS: In 45% of the patients, a complete response was attained after ILP with melphalan (95% confidence interval, 29%-61%) compared with 59% after ILP with TNF-alpha and melphalan (95% confidence interval, 49%-69%; P = .14). The time to complete response was 3 months (interquartile range, 2-6 months) vs 2 months (interquartile range, 1-3 months; P = .01), respectively. The recurrence rate and median limb recurrence-free survival were not significantly different for both ILP types. The overall limb salvage rate was 96%. Overall 5-year survival was 29% (95% confidence interval, 20%-38%). The ILP type was not an independent prognostic factor for complete response, nor was limb recurrence-free survival, whereas stage IIIA was a favorable prognostic factor (P = .01 and P = .02, respectively). Favorable prognostic factors for improved survival were complete response (P<.001) and a tumor size of 3 cm or less (P = .01). CONCLUSIONS: In more than half of the patients with truly unresectable melanoma of the extremities, a complete response was obtained after ILP with melphalan with or without TNF-alpha. The ILP type was not an independent prognostic factor for complete response, limb recurrence-free survival, or overall survival.     

Clinical node-negative thick melanoma

BACKGROUND: Patients with T4 N0 M0 melanoma are considered at high risk for having occult metastases, and adjuvant therapy is usually recommended. HYPOTHESIS: Long-term survival in patients with thick melanoma is not universally poor. DESIGN: A retrospective study. SETTING: University teaching hospital. PATIENTS: We evaluated clinical node-negative thick (> or = l4.0 mm) melanoma in 151 patients who received their primary definitive surgical treatment in our department. None of these patients received any adjuvant therapy. RESULTS: Median follow-up was 44 months; median thickness, 5.5 mm. Median overall (OS) and disease-free survivals (DFS) were 70 (5-year survival, 52%) and 51 months (5-year survival, 47%), respectively. Patients with node-positive disease faired significantly worse than did those with node-negative disease. Median OS and DFS for patients with node-positive disease were 49 and 32 months (5-year survival, 35%), respectively, compared with 209 (5-year survival, 61%) and 165 months (5-year survival, 56%), respectively, for patients with node-negative disease. Similarly, OS and DFS were significantly lower when the primary tumor had at least 5 mitoses/mm(2) or was located in the head and neck region. After multivariate analysis, status of the lymph nodes was the most predictive variable for OS and DFS. CONCLUSIONS: The thickness of melanoma, by itself, should not be used as a criterion for adjuvant therapy. Other prognostic factors should be considered.     

Anorectal melanoma: clinical characteristics and the role of abdominoperineal resection.

Twenty-four patients with primary anorectal melanoma diagnosed since 1974 have been retrospectively studied. The most common presenting symptom was rectal bleeding, typically misdiagnosed as hemorrhoids. Progressive disease most commonly presented as a large pelvic mass, diffuse bilateral pulmonary nodules, or diffuse liver metastases. Twenty-one patients (88%) died of their disease; none survived more than 6 years. Among the patients who have died of their disease, mean survival was 2.2 years. Among assessable stage I patients initially managed with abdominoperineal resection (APR), 50% developed recurrent local regional disease (mean disease-free interval = 23 months), compared with 100% of those managed with more limited surgery (mean disease-free interval = 16 months). Even after APR, however, distant metastases were common, and there was no prolongation of survival for patients treated with APR. Primary melanoma of the anorectum has a high metastatic potential and carries a grave prognosis. APR appears to have some effect in controlling local and regional disease, but prolongation of survival will depend both on earlier diagnosis and on development of more successful therapeutic approaches.     

The current management and prognosis of acral lentiginous melanoma.

A computer-aided retrospective analysis was performed on 359 patients with stage I and II melanoma at the time of diagnosis (disease confined to the primary melanoma), at the University of South Florida (Tampa, FL). Eighteen patients were identified with primary melanoma in acral locations, most being acral lentiginous melanoma. A comparison of actuarial survival curves of patients with melanoma in four different locations (acral, head and neck, trunk, and other extremity site) was performed. The patients with melanoma in acral locations did not have a statistically different actuarial survival than those with primary melanoma in other sites. When actuarial disease-free survival curves were constructed, however, acral primary melanoma had a shorter interval to recurrence than those located on the trunk or other extremity sites. Differences between actuarial disease-free survival for the head and neck and for acral primary sites were not significant. To identify prognostic factors responsible for the decreased disease-free survival of the acral lentiginous population, a regression analysis was performed. Three prognostic factors were analyzed for stage I and II melanoma, including Breslow tumor thickness, ulceration of the primary lesion, and primary site location. In the univariate analysis, with each prognostic factor acting independently, tumor thickness (p less than 0.01) and ulceration (p = 0.02) were significant variables influencing the disease-free interval. Primary site did not, however, add prognostic information to the model (p = 0.54). A stepwise multivariate analysis confirmed this finding.     

Low-dose adjuvant interferon for stage III malignant melanoma

The role of interferon as adjuvant therapy in stage III melanoma has recently been questioned. Prospective randomized studies have shown conflicting results regarding the efficacy of adjuvant treatment. The purpose of this study was to examine the use of low-dose adjuvant interferon alpha2-b (IFN) in stage III melanoma patients treated at a single institution. This study was a retrospective analysis of 60 stage III melanoma cases from Wake Forest University treated between 1983 and 1998. Cases were identified via the tumor registry. All patients underwent standard lymphadenectomy after diagnosis. After recovery from surgery patients were offered low-dose IFN (3 million units subcutaneous TIW for 1 month and then 6 million units subcutaneous TIW for 11 months) as adjuvant therapy for stage III melanoma. The patients were followed up jointly by medical and surgical oncology. There were 39 male and 21 female patients with mean age of 60.0 (range 37-89) years. The average number of positive nodes was 3.6 (median = 1) for the treated group and 1.8 (median = 1) for those untreated (P = 0.71). The average tumor thickness was similar between groups: 4.71 versus 4.88 mm for the IFN and observation groups respectively. The IFN group (N = 25) that received low-dose treatment had a median survival of 7.9 years with a 5-year survival rate of 69 per cent. The 35 cases that did not receive interferon had a median survival of 6.5 years and a 5-year survival rate of 52 per cent. These survival rates were not significantly different (P = 0.91). The median disease-free survival for patients who did not receive IFN treatment was 2.4 years and 1.4 years for the treated group (P = 0.19). The data show that there was similar survival for those who did and did not receive the low-dose IFN treatment. Although only large prospective trials can conclusively exclude a small survival time this experience suggests that there is no significant survival advantage to low-dose adjuvant IFN therapy for stage III melanoma patients. Hopefully upcoming cooperative group trials will clarify the potential value of adjuvant IFN in this setting. However, although the toxicity of this regimen was mild we suggest that low-dose adjuvant IFN for stage III melanoma should not be utilized outside the setting of a clinical trial.     

Thick melanoma in the elderly

The objective of this analysis is to ascertain the natural history of elderly patients greater than 65 years of age with thick melanoma (T4) who were treated with surgery only. Although there are multiple data on elderly patients, there is not a systematic review of survival in elderly patients over 65 years, and with our analysis we tried to enlighten this field in view especially of the growing population of the elderly in the United States. We retrospectively evaluated 112 patients with thick (> or = 4 mm) melanoma aged 65 or greater. Mean age was 73 years. Mean follow-up was 36 months. The overall survival (OS) and disease-free survival (DFS) were 69 and 52 months, respectively. Univariate analysis predicted worse OS and DFS when patients have positive lymph nodes, high mitotic rate, and increasing thickness. By multivariate analysis, lymph node status was most predictive of OS and DFS. Lymph node status is the most important prognostic factor in elderly patients with thick melanoma. Our analysis has shown that elderly patients that received no adjuvant treatment did significantly worse than the historical controls. Patients with nodal metastases are candidates for adjuvant therapy. Those without nodal disease constitute a favorable patient group and thus have much better prognosis and may not need adjuvant therapy. However, they must be closely monitored or enrolled in randomized trials. Thus, treatment for melanoma patients older than 65 should be as aggressive as in younger patients, and these patients should not be denied adjuvant treatment based on their age only.     

Role of sentinel lymph node biopsy in patients with thick (>4 mm) primary melanoma

Lymphatic mapping and sentinel lymphadenectomy have become a routine part of the treatment algorithm for primary melanoma. Their role in the management of thick (>4 mm) lesions is evolving. Our purpose was to evaluate the influence of single lymph node (SLN) histology on survival of patients with thick melanomas. A computerized patient database was accessed to obtain records on patients with thick melanomas. Survival curves were constructed with the Kaplan-Meier method, and a Cox regression analysis was used to establish statistical significance. Between 1997 and 2002, 266 SLN biopsy procedures were performed, using both radioisotope and blue dye, in 259 patients with malignant melanoma. Forty-five patients (17%) had thick melanomas. Twenty patients (44%) had at least one positive sentinel lymph node. The mean disease-free survival (DFS) of SLN-positive patients was 44 months compared with 53 months in SLN-negative patients (P = 0.0221). Increasing Breslow thickness was associated with a decrease in DFS, whereas no other histologic parameters such as Clark level, mitotic rate, or ulceration had an influence on DFS. Our data indicate that the status of the SLN node is predictive of disease-free survival in patients with thick melanomas. SLN biopsy is thus justified in patients with thick melanoma.     

Impact of multiple lymphatic channel drainage to a single nodal basin on outcomes in melanoma

OBJECTIVE: To determine the impact of multiple lymphatic channels (MLCs) on outcome in melanoma. DESIGN: Retrospective cohort study. SETTING: Academic tertiary care center. PATIENTS: Of 1198 consecutive selective sentinel lymphadenectomies performed from 1995 to 2000 for primary invasive melanoma, 502 patients were identified with extremity or truncal melanoma that drained to a single nodal basin. Three cohorts were formed based on lymphatic channels (none, single, and multiple). Tumors with drainage to multiple nodal basins as well as all head and neck tumors were excluded. MAIN OUTCOME MEASURES: Multiple variables, including patterns of lymphatic drainage, were analyzed for impact on disease-free and overall survival. RESULTS: Demographics were similar among groups, with a median follow-up of 5.6 years. Univariate analysis revealed MLCs as an independent risk factor for both disease-free (P = .04) and overall survival (P = .003). Multivariate analysis confirmed that tumor depth, sentinel lymph node status, and MLCs were risk factors for both disease-free and overall survival. Kaplan-Meier analysis showed worse survival in the MLCs group. CONCLUSIONS: Our study reveals that MLCs are an independent risk factor for recurrence and mortality in melanoma. Multiple lymphatic channels may facilitate the process of metastasis.