Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger.

OBJECTIVE: A prospective multi-institutional randomized surgical trial involving 740 stage I and II melanoma patients was conducted by the Intergroup Melanoma Surgical Program to determine whether elective (immediate) lymph node dissection (ELND) for intermediate-thickness melanoma (1-4 mm) improves survival rates compared with clinical observation of the lymph nodes. A second objective was to define subgroups of melanoma patients who would have a higher survival with ELND. METHODS: The eligible patients were stratified according to tumor thickness, anatomic site, and ulceration, and then were prerandomized to either ELND or nodal observation. Femoral, axillary, or modified neck dissections were performed using standardized surgical guidelines. RESULTS: The median follow-up was 7.4 years. A multifactorial (Cox regression) analysis showed that the following factors independently influenced survival: tumor ulceration, trunk site, tumor thickness, and patient age. Surgical treatment results were first compared based on randomized intent. Overall 5-year survival was not significantly different for patients who received ELND or nodal observation. However, the 552 patients 60 years of age or younger (75% of total group) with ELND has a significantly better 5-year survival. Among these patients, 5-year survival was better with ELND versus nodal observation for the 335 patients with tumors 1 to 2 mm thick, the 403 patients without tumor ulceration, and the 284 patients with tumors 1 to 2 mm thick and no ulceration. In contrast, patients older than 60 years of age who had ELND actually had a lower survival trend than those who had nodal observation. When survival rates were compared based on treatment actually received (i.e., including crossover patients), the patients with significantly improved 5-year survival rates after ELND included those with tumors 1 to 2 mm thick, those without tumor ulceration, and those 60 years of age or younger with tumors 1 to 2 mm thick or without ulceration. CONCLUSION: This is the first randomized study to prove the value of surgical treatment for clinically occult regional metastases. Patients 60 years or age or younger with intermediate-thickness melanomas, especially with nonulcerative melanoma and those with tumors 1 to 2 mm thick, may benefit from ELND. However, because some patients still are developing distant disease, these results should be considered an interim analysis.     

A prospective randomized trial comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma

BACKGROUND: To compare operative morbidity, mortality, quality of life, and survival after pancreatoduodenectomy (PD) versus pancreatoduodenectomy with extended lymphadenectomy (PD/ELND) in patients with resectable pancreatic cancer. METHODS: From May 1997 to July 2003 there were 132 patients with biopsy examination-proven or suspected adenocarcinoma of the pancreatic head who agreed to participate in a single-institution, prospective, randomized trial. If resectable at operation, patients then were randomized to standard PD (40 patients) or PD/ELND (39 patients). Quality of life was assessed by using the Functional Assessment of Response to Cancer Therapy specific to the pancreas. Morbidity, mortality, and survival were analyzed. RESULTS: Demographics and pathologic characteristics for both groups were similar. When comparing PD/ELND with standard PD, the median operating time was greater for the PD/ELND group (7.6 h vs 6.2 h, P < .01), blood transfusion more likely (44% vs 22%, P < .05), and the median number of lymph nodes resected was greater (36 vs 15 nodes, P < .01). Morbidity and mortality rates were comparable. Median durations of stay were 11 and 10.5 days (P = NS), respectively. There were no significant differences in 1-year (71% vs 82%), 3-year (25% vs 41%), 5-year (16.5% vs 16.4%), and median (19 vs 26 mo) survival (P = .32). At 4 months postoperatively, diarrhea, body appearance, and bowel control scored lower on the Functional Assessment of Response to Cancer Therapy specific to the pancreas after PD/ELND (P < .05). CONCLUSIONS: Although a much larger study would have more power to compare statistically the survival between groups, both the decrement in quality of life and similar studies showing no survival difference make PD/ELND unattractive for further prospective investigation.     

Sentinel Node Biopsy Provides More Accurate Staging Than Elective Lymph Node Dissection in Patients With Cutaneous Melanoma

Background: In most major melanoma treatment centers, sentinel node biopsy (SNB), with complete regional lymph node dissection when a positive sentinel node is found, has now replaced elective lymph node dissection (ELND) for patients with primary cutaneous melanomas who are considered to be at moderate to high risk of nodal recurrence. As for ELND, however, no overall survival benefit for the SNB procedure has yet been demonstrated. The objective of this study was to compare the nodal staging accuracy and duration of survival for SNB and ELND.Methods: A retrospective cohort study was conducted among patients with American Joint Committee on Cancer (AJCC) stage II disease treated at a single center between 1983 and 2000 with either SNB (n = 672) or ELND (n = 793). Multivariate analyses were performed using the logistic regression model for nodal staging accuracy and Coxs proportional hazards regression model for survival.Results: Patient factors that influenced nodal positivity included age, Breslow thickness, ulceration, head or neck primary, and operation type (SNB or ELND). SNB was superior to ELND in the detection of micrometastases (odds ratio 1.23, 95% CI, 1.06 – 1.43) but operation type did not influence survival (P = .24).Conclusions: Sentinel node biopsy identified more nodal micrometastases than ELND but did not influence survival, although complete regional node dissection was performed in all patients who were SNB positive. This increase in staging accuracy likely results from the reliable identification of the appropriate lymph node field by preoperative lymphoscintigraphy, along with more detailed pathologic examination of the nodes removed by SNB.Presented to the Society of Surgical Oncology, New York, March 2004     

Surgical management of regional lymph nodes in patients with melanoma. Experience with 4682 patients.

OBJECTIVE: The purpose of this study was to evaluate a large number of patients with cutaneous melanoma who had or who were at risk for lymph node metastases to contribute to the understanding of the behavior of and appropriate management of draining nodes. A major goal of the study was to reassess the clinical impact of elective lymph node dissections (ELND) in a large patient population. SUMMARY BACKGROUND DATA: Large retrospective studies suggest that ELND may improve the prognosis of patients with intermediate thickness melanomas; however, that improvement has not been observed in two randomized prospective controlled trials. METHODS: The charts of 4682 patients treated at a single institution for localized or regional disease were reviewed individually. The median follow-up was 4.7 years, with 814 patients followed more than 10 years. The data were tabulated and evaluated with the aid of a computer data base system. RESULTS: Among patients with nodal metastases, 10% of nodal metastases were to contralateral nodes, and 6% were to nodal basins that would not be predicted by classic models of lymphatic drainage; in 13% of patients, nodal metastases occurred to greater than one nodal basin (3% of the entire study group). For all thickness ranges, the incidence of nodal metastases was comparable to the incidence of distant metastases; intermediate-thickness lesions had no relative predilection for nodal metastases. At the initial evaluation, regional nodal basins were clinically negative in 3550 patients, of whom 911 (25.7%) underwent ELND. Stratified into five thickness groups (< 0.76 mm, 0.76 to 1.5 mm, 1.5 to 2.5 mm, 2.5 to 4 mm, and > 4 mm), pathologically positive nodes were identified in 0%, 5%, 16%, 24%, and 36%, respectively (16% overall). Among the 911 patients who underwent ELND, 214 (23%) had nodal metastases, 143 at the time of ELND and 71 at a later date. Of these 71 patients, 31 (44%) had nodal metastases in a previously dissected nodal basin, and 40 (56%) had them in basins not previously dissected. The survival of patients with clinically negative nodes treated with and without ELND were compared. The two groups were well matched for major prognostic factors. Stratified by Breslow thickness and primary site, no significant improvement in survival was observed with ELND. CONCLUSIONS: Because of the significant incidence of metastases to contralateral and atypical nodal basins, lymphoscintigraphy may be justified for the preoperative evaluation of patients for ELND. However, the therapeutic value of ELND is questionable as a result of (1) the finding that the risk of nodal metastases is not relatively more common than is that of distant metastases among patients with intermediate-thickness melanomas, (2) the fact that only 16% of ELND were positive, (3) the finding that ELND may not prevent recurrent nodal disease in the dissected basin, and (4) the absence of any apparent impact on survival among patients who underwent ELND.     

Cutaneous thick melanoma. Prognosis and treatment

Among proponents of elective lymph node dissection (ELND) for clinical stage I melanoma, controversy exists as to whether there is an upper limit of tumor thickness beyond which ELND should not be considered. We reviewed 169 patients with clinical stage I and II melanoma that was greater than or equal to 3.0 mm thick and who were treated at the University of Illinois Hospital, Chicago. Of 139 patients with clinical stage I disease, 117 underwent ELND. Five- and ten-year survival rates were 55.7% and 48.9%, respectively. Multifactorial analysis demonstrated that anatomical location, level, pathologic stage, and ulceration were the best predictors of survival. Thickness did not emerge as a significant variable. Our findings do not support basing treatment decisions, eg, ELND in this group of patients, solely on the thickness of the primary tumor. We continue to recommend ELND in patients with either intermediate or thick melanomas.     

Long-Term Results of a Prospective Surgical Trial Comparing 2 cm vs. 4 cm Excision Margins for 740 Patients With 1–4 mm Melanomas

Background:The Intergroup Melanoma Surgical Trial began in 1983 to examine the optimal surgical margins of excision for primary melanomas of intermediate thickness (i.e., 1–4 mm). There is now a median 10-year follow-up.Methods:There were two cohorts entered into a prospective multi-institutional trial: (1) 468 patients with melanomas on the trunk or proximal extremity who randomly received a 2 cm or 4 cm radial excision margin and (2) 272 patients with melanomas on the head, neck, or distal extremities who received a 2 cm radial excision margin.Results:A local recurrence (LR) was associated with a high mortality rate, with a 5-year survival rate of only 9% (as a first relapse) or 11% (anytime) compared with an 86% survival for those patients who did not have a LR (P < .0001). The 10-year survival for all patients with a LR was 5%. The 10-year survival rates were not significantly different when comparing 2 cm vs. 4 cm margins of excision (70% vs. 77%) or comparing the management of the regional lymph nodes (observation vs. elective node dissection). The incidences of LR were the same for patients having a 2 cm vs. 4 cm excision margin regardless of whether the comparisons were made as first relapse (0.4% vs. 0.9%) or at anytime (2.1% vs. 2.6%). When analyzed by anatomic site, the LR rates were 1.1% for melanomas arising on the proximal extremity, 3.1% for the trunk, 5.3% for the distal extremities, and 9.4% for the head and neck. The most profound influence on LR rates was the presence or absence of ulceration; it was 6.6% vs. 1.1% in the randomized group involving the trunk and proximal extremity and was 16.2% vs. 2.1% in the non-randomized group involving the distal extremity and head and neck (P < .001). A multivariate (Cox) regression analysis showed that ulceration was an adverse and independent factor (P = .0001) as was head and neck melanoma site (P = .01), while the remaining factors were not significant (all with P > .12).Conclusion:For this group of melanoma patients, a local recurrence is associated with a high mortality rate, a 2-cm margin of excision is safe and ulceration of the primary melanoma is the most significant prognostic factor heralding an increased risk for a local recurrence.Presented at the 53rd Annual Cancer Symposium of the Society of Surgical Oncology at New Orleans, LA, on March 18, 2000     

Head and neck melanoma in 534 clinical Stage I patients. A prognostic factors analysis and results of surgical treatment.

Single and multifactorial analyses were used to evaluate prognosis and results of surgical treatment in 534 clinical Stage I patients with head and neck cutaneous melanoma treated at the University of Alabama in Birmingham (U.S.A.) and the University of Sydney (Australia). This computerized data base was prospectively accumulated in over 90% of cases. Melanomas were about equally distributed between men and women. They were located on the skin of the face in 47%, neck in 27%, scalp in 13%, and the ear in 13% of patients. Both the results of the prognostic factors analyses and the surgical treatment demonstrated that lentigo maligna melanoma (LMM) was distinct from the other two growth patterns, superficial spreading melanoma and nodular melanoma (SSM and NM). In a multifactorial analysis of the 453 patients with SSM and NM, the dominant prognostic variables were tumor thickness (p less than 0.00001), anatomic subsite (p = 0.0213), and ulceration (p = 0.0289). Patients with melanomas on the scalp or neck subsites fared worse than those with tumors located on the face or ear. The results differed for LMM, where thickness was not a significant predictor of survival, and the most dominant prognostic variable was ulceration (p = 0.0042). Local recurrence rates were low, being 2.4% for tumors less than 2.5 mm in thickness, but were 12.3% for tumors greater than or equal to 4.0 mm in thickness. Patients with SSM and NM lesions located on the head and neck had a lower survival rate than those with extremity melanomas in every tumor thickness category, although only those in the 0.76 to 1.49 mm thickness subgroup were significantly different (p = 0.0007). After 5 years of follow-up, patients who underwent an elective lymph node dissection for SSM and NM with a thickness range of 1.5 to 3.99 mm had a better survival (72%) than patients with melanomas of equivalent thickness whose initial treatment was wide excision alone (45%). LMM had a less aggressive biologic behavior compared to SSM or NM and was treated more conservatively. Thus, LMM lesions had an 85% 10-year survival rate with wide excision only, and there was no significant improvement in survival with ELND. Growth patterns, tumor thickness, ulceration, and anatomic subsites should be considered when evaluating risk factors and when making treatment decisions in head and neck melanoma patients.     

Efficacy of Lymphatic Mapping, Sentinel Lymphadenectomy, and Selective Complete Lymph Node Dissection as a Therapeutic Procedure for Early-Stage Melanoma

Background: Lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection (LM/SL/SCLND) is an increasingly popular alternative to elective lymphadenectomy (ELND) for patients with early-stage melanoma. Although several reports have demonstrated the accuracy of the LM/SL technique, there are no data on its therapeutic value.Methods: We performed a matched-pair statistical analysis of 534 patients with clinical stage I melanoma; one half of the patients were treated with LM/SL and the other half were treated with ELND. Patients in the two treatment groups were matched for age (54% were 50 years of age), gender (63% were male patients), site of the primary melanoma (49% were on the extremities, 36% on the trunk, and 15% on the head and neck), and thickness of the primary melanoma (7% were <0.75 mm, 42% between 0.75 and 1.5 mm, 43% between 1.51 and 4.0 mm, and 8% >4 mm). Patients in the LM/SL group underwent complete regional lymphadenectomy (SCLND) only if the LM/SL specimen contained metastatic melanoma.Results: The overall incidences of nodal metastases were no different (P = .18) between LM/SL (15.7%) and ELND (12%) groups, but the incidence of occult nodal disease was significantly (P = .025) higher among patients with intermediate-thickness (1.51–4.0-mm) primary tumors who underwent LM/SL (23.7%) instead of ELND (12.2%). Survival data were compared by the log-rank score test. LM/SL/SCLND and ELND resulted in equivalent 5-year rates of disease-free survival (79 ± 3.3% and 84 ± 2.2%, respectively; P = .25) and overall survival (88 ± 3.0% and 86 ± 2.1%, respectively; P = .98). The LM/SL and ELND groups also exhibited similar incidences of same-basin recurrences (4.8% vs. 2.1%, P = .10, respectively) and in-transit metastases (2.6% vs. 3.8%, P = .48) after tumor-negative dissections. Patients who underwent ELND showed a higher incidence of distant recurrences (8.9% vs. 4.0%, P = .03), but this may be related to the longer follow-up period for these patients (median, 169 months), compared with the LM/SL-treated patients (45 months). Among patients with tumor-positive nodal dissections, the 5-year overall survival rates were higher, and approached significance (P = .077) for patients treated by LM/SL/SCLND (64 ± 12%) compared with ELND (45 ± 10%).Conclusions: These findings suggest that LM/SL/SCLND is therapeutically equivalent to ELND but may be more effective for identifying nodal metastases in patients with intermediate-thickness primary tumors.Supported by National Institutes of Health Grants CA12582 and CA29605 and by funding from the Wrather Family Foundation (Los Angeles, CA). Richard Essner, MD, is the recipient of an American Cancer Society Career Development Award.Presented at the 51st Annual Cancer Symposium of The Society of Surgical Oncology, San Diego, California, March 26–29, 1998.     

Surgical margins and prognostic factors in patients with thick (>4 mm) primary melanoma

Background: Randomized trials have demonstrated the efficacy of 1- and 2-cm excision margins for thin and intermediate-thickness melanomas, respectively. The optimal margin of excision for thick melanomas is still unknown, however. We evaluated whether the margins used for intermediate-thickness melanomas can be applied safely to thicker lesions. Methods: The charts of 278 patients with thick primary melanomas treated between 1985 and 1996 were retrospectively reviewed. Patients with distant metastases at presentation or with follow-up less than 6 months were excluded. Median follow-up was 27 months. Known melanoma prognostic factors and excision margins were evaluated for their impact on local recurrence (LR), disease-free survival (DFS), and overall survival (OS). Results: Median tumor thickness was 6.0 mm, and 57% were ulcerated. At presentation, 201 patients (72%) were node negative and 77 (28%) were node positive (palpable or occult). The 5-year OS and DFS rates were 55% and 30%, respectively. The LR rate for all patients was 12%. Although nodal status, thickness, and ulceration were significantly associated with OS by multivariate analysis, neither LR nor excisional margin (<2 cm vs. >2 cm) significantly affected DFS or OS in these patients. Conclusions: Because margins of excision greater than 2 cm do not improve LR, DFS, or OS compared to a margin of 2 cm or less, a 2-cm margin of excision is adequate for patients with thick melanoma. Because nodal status is a significant prognostic factor in these patients, staging by sentinel node biopsy should be considered in patients with thick melanomas and clinically negative nodal basins to allow proper entry and stratification in adjuvant therapy trials. Presented at the 50th Annual Cancer Symposium of The Society of Surgical Oncology, Chicago, IL, March 20–23, 1997.     

Gender-related differences in outcome for melanoma patients

OBJECTIVE: To better understand the factors associated with the well-established gender difference in survival for patients with melanoma. SUMMARY BACKGROUND DATA: Gender is an important factor in patients with cutaneous melanoma. Male patients have a worse outcome when compared with females. The reasons for this difference are poorly understood. METHODS: This prospective multi-institutional study included patients aged 18 to 70 years with melanomas > or =1.0 mm Breslow thickness. Wide excision and sentinel lymph node (SLN) biopsy was performed in all patients. Clinicopathologic factors, including gender, were assessed and correlated with disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). RESULTS: A total of 3324 patients were included in the covariate analyses; 1829 patients had follow-up data available and were included in the survival analyses. Median follow-up was 30 months. On univariate analysis, men (n = 1906) were more likely than women to be older than 60 years (P < 0.0001), have thicker melanomas (P < 0.0001), have primary tumor regression (P = 0.0054), ulceration (P < 0.0001), and axial primary tumor location (P < 0.0001). On multivariate analysis, age (P = 0.0002), thickness (P < 0.0001), ulceration (P = 0.015), and location (P < 0.0001) remained significant in the model. There was no difference in the rate of SLN metastasis between men and women (P = 0.37) on multivariate analysis. When factors affecting survival were considered, the prognosis was worse for men as validated by lower DFS (P = 0.0005), DDFS (P < 0.0001), and OS (P < 0.0001). CONCLUSIONS: Male gender is associated with a greater incidence of unfavorable primary tumor characteristics without an increased risk for nodal metastasis. Nonetheless, gender is an independent factor affecting survival.     

Risk Factors for Nodal Recurrence After Lymphadenectomy for Melanoma

Background:The risk and outcome of regional failure after elective and therapeutic lymph node dissection (ELND/TLND) for microscopically and macroscopically involved lymph nodes without adjuvant radiotherapy were evaluated.Methods:Retrospective melanoma database review of 338 patients (ELND 85, TLND 253) from 1970 to 1996 with pathologically involved lymph nodes.Results:Regional recurrence occurred in 14% of patients treated with ELND (n = 12) and 28% of patients treated with TLND (n = 72; P = .009). Risk factors associated with nodal recurrence were advanced age, primary lesion in the head and neck region, depth of the primary lesion, number of involved lymph nodes, and extracapsular extension (ECE). For each nodal basin, the ELND group had a lower incidence of recurrence than the TLND group. The TLND group had larger lymph nodes, greater number of involved lymph nodes, and a higher incidence of ECE. The 10-year disease-specific survival was 51% vs. 30% for ELND and TLND, respectively (P = .0005). Nodal basin failure was predictive of distant metastasis, with 87% developing distant disease compared with 54% of patients without nodal recurrence (P < .0001). Of six patients who underwent a second dissection after isolated nodal recurrence, five patients have had a median disease-free interval of 79 months.Conclusions:After ELND or TLND, patients who have a large tumor burden (thick primary melanoma, multiply involved lymph nodes, ECE), advanced age, and a primary lesion located in the head and neck have a significantly increased likelihood of relapse and a decreased survival. Few patients present with an isolated nodal recurrence, but the majority can be salvaged by a second dissection.Presented at the Society of Surgical Oncology Cancer Symposium, New Orleans, Louisiana, March 16–19, 2000     

A Multifactorial Analysis of Melanoma: III. Prognostic Factors in Melanoma Patients with Lymph Node Metastases (Stage II)

Twelve prognostic features of melanoma were examined in a series of 185 patients with nodal metastases (Stage II), who underwent surgical treatment at our institution during the past 20 years. Forty-four per cent of the patients presented with synchronous nodal metastases (substage IIA), 44% of the patients had delayed nodal metastases (substage IIB), and 12% of the patients had nodal metastases from an unknown primary site (substage IIC). The patients with IIB (delayed) metastases had a better overall survival rate than patients with IIA (synchronous) metastases, when calculated from the time of diagnosis. These differences could be explained on the basis of tumor burden at the time of initial diagnosis (microscopic for IIB patients versus macroscopic for IIA patients). Once nodal metastases became evident in IIB patients, their survival rates were the same as for substage IIA patients, when calculated from the onset of nodal metastases. The survival rates for both subgroups was 28% at five years and 15% for ten years. Substage IIC patients (unknown 1° site) had better five-year survival rates (39%), but the sample size was small and the differences were not statistically significant. A multifactorial analysis was used to identify the dominant prognostic variables from among 12 clinical and pathologic parameters. Only two factors were found to independently influence survival rates: 1) the number of metastatic nodes (p = 0.005), and the presence or absence of ulceration (p = 0.0019). Additional factors considered that had either indirect or no influence on survival rates (p > 0.10) were: anatomic location, age, sex, remission duration, substage of disease, tumor thickness, level of invasion, pigmentation, and lymphocyte infiltration. All combinations of nodal metastases were analyzed from survival differences. The combination that showed the greatest differences was one versus two to four versus more than four nodes. Their five-year survival rates were 58%, 27% and 10%, respectively (p < 0.001). Ulceration of the primary cutaneous melanoma was associated with a <15% five-year survival rate, while nonulcerative melanomas had a 30% five-year survival rate (p < 0.001). The combination of ulceration and multiple metastatic nodes had a profound adverse effect on survival rates. While tumor thickness was the most important factor in predicting the risk of nodal metastases in Stage I patients (p < 10^-8), it had no predictive value on the patient's clinical course once nodal metastases had occurred (p = 0.507). The number of metastatic nodes and the presence of ulceration are important factors to account for when comparing surgical results, and when analyzing the efficacy of adjunctive systemic treatments.     

Prognosis of thick cutaneous melanoma

BACKGROUND: Ten percent of all patients with melanoma present with thick primary tumors (> or = 4 mm or Clark level V). To determine factors associated with outcomes, we performed a retrospective analysis of 120 patients who had definitive primary treatment of their thick cutaneous melanomas at Memorial Sloan-Kettering Cancer Center between January 1986 and April 1995. STUDY DESIGN: Data were collected via chart review and patient interview. Association between factors was determined by chi-square analysis. Survival analysis was performed by the method of Kaplan and Meier. Univariate analysis by log-rank testing and multivariate analysis using the Cox regression model were used to identify factors associated with disease-free and overall survival. RESULTS: Median age was 61 years (range 19 to 87 years). There were 80 males and 40 females. Median Breslow thickness was 6 mm (range 1.8 to 25.0 mm). Ninety-three patients (78%) underwent lymphadenectomy (52 elective and 41 therapeutic). Twenty-one percent (11 of 52) of the elective dissections were positive. Median followup was 3.8 years (5.2 years for patients no evident disease and 2.0 years for those dead of disease). Overall survival for the entire group was 62% at 5 years and 43% at 10 years. Age, gender, and anatomic site (axial versus extremity) were not factors predictive of overall survival. Increasing thickness, nodal status at presentation (American Joint Commission on Cancer stage II versus III), and the presence of ulceration were significant predictors of both disease relapse and disease-specific mortality in both univariate and multivariate analyses. There was no difference in postrelapse survival between patients suffering local, nodal, or distant relapse (p = 0.63). CONCLUSIONS: Patients presenting with thick cutaneous melanomas are expected to have more than 50% 5-year survival, and they should not be denied the opportunity for aggressive locoregional management. Thickness, positive nodal status, and ulceration are associated with a higher mortality rate. The fact that patients with local or nodal recurrences fare as poorly as those with overt distant metastases implies that the former events are predictors of subclinical systemic disease.     

Thin melanomas: predictive lethal characteristics from a 30-year clinical experience

OBJECTIVE: To guide treatment and clinical follow-up by defining the natural history of thin melanomas and identifying negative prognostic characteristics that may delineate high-risk patients. SUMMARY BACKGROUND DATA: In following > 10,000 patients with cutaneous melanoma over the past 30 years, our institution has observed nodal or metastatic disease in approximately 15% of patients with a thin (<1 mm) primary lesion. METHODS: A database query of patients with cutaneous melanoma returned 1158 patients with primary lesion < or = 1 mm thick and who received their initial treatment at a single institution. Median follow-up was 11 years (range, 1 to 34 years). Patient and melanoma characteristics as well as outcomes were recorded and statistically analyzed. RESULTS: 6.6% of patients had nodal or distant disease at presentation. Over time, an additional 9.4% developed metastases, including nodal and distal recurrences. Overall incidence of advanced disease was 15.3%. Univariate analysis identified male gender (P = 0.01), advanced age (>45 years; P = 0.05), and Breslow thickness (>0.75 mm; P = 0.008) as significant negative prognostic characteristics. Of patients with these 3 high-risk characteristics, 19.7% developed advanced disease (likelihood ratio 6.3; P = 0.007 versus nonhigh-risk patients). This group had more than twice the incidence of nodal recurrences. Patients with recurrence had significantly decreased 10-year survival (82% versus 45%; P < 0.0001). Surprisingly, neither ulceration nor Clark level predicted advanced disease. CONCLUSIONS: Thin melanomas are potentially lethal lesions. Long-term follow-up identified a high-risk population of older males with tumors between 0.75 mm and 1.0 mm whose risk of recurrent disease approaches 20%. Traditionally accepted negative prognostic factors such as ulceration and discordant Clark levels are not predictive for metastasis in this population. Given the poor prognosis associated with recurrent disease, we recommend close clinical evaluation and follow-up to maximize accurate staging and therapeutic options.     

Can Elective Lymph Node Dissection Decrease the Frequency and Mortality Rate of Late Melanoma Recurrences?

Background: Although more than 90% of the morbidity and mortality from localized cutaneous melanoma occurs in the first decade after initial surgical treatment, melanoma can recur after a 10-year disease-free interval (DFI) with fatal consequences. We reviewed our melanoma data base of more than 8500 prospectively acquired patients to identify clinicopathological factors that affect the type, rate of occurrence, and outcome of disease recurring 10 years or more after surgical treatment of primary cutaneous melanoma.Methods: From 1971 to 1997, 1907 melanoma patients treated at our cancer center reached or presented with a DFI of 10 years or more after surgical treatment of clinically localized melanoma. Of these, 217 (11%) patients had recurrences (mean DFI, 182 months). The sites of recurrence were local/in-transit in 26 (12%) patients, regional lymph nodes in 101 (47%) patients, and distant sites in 90 (41%) patients.Results: Univariate and multivariate analysis, using patient age and sex, type of initial treatment, and the site, Breslow thickness, and Clark level of the initial tumor, showed that the type of treatment for the primary tumor was a significant (P = .0005) prognostic factor in the development of late nodal recurrence. Of the 217 patients who had recurrences, 172 (79%) had undergone wide local excision for their primary melanoma, and 45 (21%) had undergone wide local excision plus elective lymph node dissection (ELND). The rates of nodal recurrence were 53% (92 of 172) and 20% (9 of 45), respectively, a significant (P = .0001) difference. When all patients with a DFI of 10 years or more were stratified by type of initial treatment, the ELND group demonstrated a significant improvement in disease-free survival and overall survival.Conclusions: The risk of late-recurring nodal disease increases and the chance of long-term survival decreases when wide local excision is performed without ELND. With the advent of sentinel lymphadenectomy, ELND can be selectively performed only for those nodal basins with occult tumor cells, thereby decreasing operative morbidity but allowing identification and early removal of nodal micrometastases.Presented at the 52nd Annual Meeting of the Society of Surgical Oncology, Orlando, Florida, March 4–7, 1999.     

Sentinel lymph node biopsy does not change melanoma-specific survival among patients with breslow thickness greater than four millimeters

Management of patients with cutaneous melanoma in the absence of lymph node metastases is still controversial. The experience at the National Cancer Institute in Naples was analyzed to evaluate 3-year disease-free survival and overall survival for all patients who underwent sentinel lymph node biopsy (SLB) with Breslow thickness greater than 4 mm. Data from 359 sentinel biopsies performed in the past 5 years were reviewed to determine the effect of the treatment on disease-free survival and overall survival after stratifying patients for node status, tumor ulceration, and Breslow thickness. Statistical analysis showed a better 3-year survival for sentinel node-negative patients than for sentinel node-positive cases (88.4% and 72.9%, respectively;P<.05). Tumor ulceration retained its prognostic significance despite lymph node status, indicating a higher risk for development of distant metastases. Survival curves associated with thicker melanomas did not show significant differences between negative- and positive-SLB patients. SLB provides accurate staging of nodal status in melanoma patients who have no clinical evidence of metastases. Longer follow-up and final results from ongoing trials are necessary to definitively clarify the role of this procedure.     

Cutaneous melanoma of the head and neck

We have reviewed a 21-year experience with 289 patients who received definitive surgical treatment for cutaneous melanomas arising in the skin of the head and neck. Elective lymphadenectomy was performed in 39 percent of those who presented with no clinical evidence of nodal metastasis. The cumulative 5- and 10-year survival was 56 percent and 45 percent, respectively. Increased tumor thickness, age greater than 55 years, male sex, ulceration, nodular morphology, and scalp site were significant adverse factors. Patients with ear or neck lesions had the best survival. The risk of distant metastasis was almost equivalent to that of nodal metastasis, regardless of thickness. Elective lymphadenectomy appeared to have minimal impact on survival.     

Pathologic and clinical features influencing outcome of thin cutaneous melanoma: correlation with newly proposed staging system

The incidence of malignant melanoma is increasing. Because of increased awareness, early recognition of malignant melanoma has become more common. In 1997, a new staging system for cutaneous melanoma was proposed, with reclassification of thin melanoma < 1 mm, with and without ulceration. This report evaluates the pathologic and clinical features of thin melanomas influencing recurrence and survival from a tertiary cancer center in an attempt to correlate findings with the proposed staging system. A review of the Roswell Park Cancer Institute tumor registry identified 352 patients with thin cutaneous melanomas (< 1.0 mm) seen during an 18-year period ending August 30, 1998. Overall survival was 93 and 87 per cent at 5 and 10 years, respectively. Disease-free survival was 94 and 93 per cent at 5 and 10 years, respectively. Local recurrence occurred in 3 per cent of patients, regional recurrence in 3 per cent, and metastatic disease in 3 per cent, for an overall recurrence of 7 per cent, with a median follow-up of 118 months. Only the presence of ulceration was a significant prognostic factor for recurrence by both univariate and multivariate analysis. Failure rates (any recurrence) by Clark levels I, II, and III/IV were 3, 5, and 10 per cent, respectively (P = 0.14). Failure rates by tumor thickness (mm), for 0.0-0.24, 0.25-0.49, 0.50-0.74, and 0.75-0.99 were 3, 4, 7, and 10 per cent, respectively (P = 0.49). Ten-year disease-free survival for ulceration versus no ulceration was 40 and 94 per cent, respectively (P < 0.0001). We conclude that thin cutaneous melanoma carries an excellent prognosis with appropriate treatment. Our findings support inclusion of ulceration in a new staging system. Lesions 0.76 to 0.99 mm and Clark level III and IV may warrant close observation as a separate subgroup.     

Natural History of Melanoma in 773 Patients with Tumor-Negative Sentinel Lymph Nodes

BACKGROUND: A tumor-negative sentinel lymph node (SLN) does not preclude recurrence of melanoma. We hypothesized that certain patient-related and tumor factors are predictive of a worse outcome in these patients. METHODS: Disease-free survival (DFS), overall survival (OS), and recurrence patterns were retrospectively analyzed in 773 patients who underwent lymphatic mapping and SLN biopsy for primary cutaneous melanoma at our institution between 1995 and 2002, and who had tumor-negative SLNs by standard pathological analysis. Patient sex, age, tumor site and thickness, ulceration status, Clark level, and histology were evaluated for their influence on outcome by univariate and multivariate Cox regression analysis and classification and regression tree analysis. RESULTS: DFS and OS at 5 years were 88% and 93%, respectively. Sixty-nine (8.9%) of 773 patients developed recurrence. Three-year OS was lower in patients with distant recurrence (17.1%) than in those with local/regional recurrence (55.5%). By multivariate analysis, primary tumor thickness (P < .0001), site on head/neck versus trunk (P = .0093) versus extremity (P = .0042), and ulceration status (P = .0024) were independently significant for DFS; primary tumor thickness (P = .0106) and ulceration status (P = .0001) also were independently significant for OS. Classification and regression tree analysis demonstrated DFS was shortest in patients who had ulcerated tumors >2 mm. CONCLUSIONS: Melanoma will recur in approximately 9% of patients with tumor-negative SLNs. Patients with thick, ulcerated melanomas on the head or neck have the highest risk for recurrence. This group should be followed closely for recurrence and considered for adjuvant therapy.     

Prognostic factors in young women with cutaneous melanoma

BackgroundGender is an established prognostic factor in cutaneous melanoma; women as a group have a better overall prognosis than men. However, the investigators hypothesized that melanoma in young women may have distinct clinicopathologic features and biologic behavior compared with melanoma in older women, possibly related to tanning bed use and excessive acute episodes of sun exposure.MethodsA retrospective analysis was performed of a large multicenter study that accrued patients between 1996 and 2003 and included patients aged 18 to 70 years with cutaneous melanoma ≥1 mm Breslow thickness and no evidence of regional or distant metastatic disease. All women with follow-up data were included. Univariate and multivariate analyses as well as Kaplan-Meier (KM) analysis were performed to test for differences in clinicopathologic variables, disease-free survival (DFS), and overall survival (OS) between female patients ≤40 and >40 years of age.ResultsA total of 1,056 female patients were divided into 2 groups: those >40 years of age (n = 757 [71.7%]) and those ≤40 years of age (n = 299 [28.3%]). Overall, there were no differences in Breslow thickness, ulceration, or sentinel lymph node status between groups. Compared with older women, younger women were more likely to have truncal melanomas (39.5% vs 29.5%, P = .0017) and less likely to have regression of the primary tumor (6.4% vs 11.5%, P = .0208). The mean number of sentinel lymph nodes removed was 2.82 for younger women and 2.29 for older women (P < .0001). Multivariate analysis revealed that Breslow thickness, ulceration, and tumor-positive sentinel lymph node were associated with worse DFS in both the younger and older groups; truncal location was associated with worse DFS in the younger group only. The same factors were predictive of OS in both groups, except that ulceration was not significant in the younger patient group. In the younger patient group, the 5-year KM DFS rates were 78.1% for truncal melanomas and 92.5% for nontruncal melanoma locations (P = .0009); the corresponding 5-year KM OS rates were 76.6% and 93.9% (P = .0003). In the older patient group, the 5-year KM DFS rates were 84.1% for truncal and 82.8% for nontruncal melanomas (P = NS), and the corresponding 5-year KM OS rates were 81.6% and 87.5% (P = .0049).ConclusionsAlthough women with cutaneous melanoma tend to have a better prognosis than men, women ≤40 years of age with primary melanoma of the trunk may represent a subgroup at higher risk for disease recurrence and metastasis.