Factors Predictive of Nonsentinel Lymph Node Involvement and Clinical Outcome in Melanoma Patients With Metastatic Sentinel Lymph Node

BACKGROUND: Identification of melanoma patients who need completion lymphadenectomy and adjuvant treatment after positive sentinel lymph node (SLN) biopsy would be a fundamental step forward toward personalized medicine. This study tested the hypothesis that the microscopic features of metastatic SLNs might predict not only nonsentinel lymph node (NSLN) status, but also patients' clinical outcomes. METHODS: A retrospective analysis was performed on 96 consecutive melanoma patients who underwent completion lymphadenectomy after positive SLN biopsy. Patients' age and sex, primary tumor Breslow thickness, number of positive SLNs, the largest diameter and depth of invasion of metastatic deposits in the SLN, S stage, and pattern of nodal involvement were correlated with the presence of metastatic disease in NSLNs as well as with the likelihood of tumor recurrence and patient death. RESULTS: At pathological examination, 20 patients (20.8%) had metastatic melanoma in the NSLN. Pattern of nodal involvement, depth of invasion of SLN by metastatic disease, and S stage were statistically significantly associated with the presence of metastatic disease in NSLN. Multivariate analysis revealed that only the SLN depth of invasion was an independent predictor of NSLN status (P = .0035). This parameter was also significantly associated with disease-free and overall survival, both by univariate (P < .0001 and P = .0006, respectively) and multivariate (P < .0001 and P = .0013, respectively) survival analysis. CONCLUSIONS: These findings support further investigation of SLN depth of invasion as a predictive factor of potential clinical use to select patients as candidates for completion lymphadenectomy and adjuvant treatment.     

Lymph Node Tumor Volumes in Patients Undergoing Sentinel Lymph Node Biopsy for Cutaneous Melanoma

Background: Regional lymph node tumor volumes in patients undergoing sentinel lymph node (SN) biopsy (SNB) for treatment of cutaneous melanoma have not been described. The objectives of this study were to describe the lymph node tumor volumes typically seen in this population and to correlate tumor volumes with tumor thickness and positive SN characteristics.Methods: Review of a consecutive series of patients with clinically localized cutaneous melanoma who underwent SNB of nonpalpable regional lymph node basins followed by complete lymphadenectomy (LND) was performed. Multiple lymph node sections from positive SNs and nonsentinel nodes (NSNs) in LND specimens were examined microscopically. Individual tumor deposit diameters were measured using an ocular micrometer. Aggregate tumor volumes were calculated for SN and LND specimens. Tumor volumes and SN and LND positivity rates were correlated with tumor thickness, the number of positive SNs, and the presence of multiple SN tumor deposits.Results: SNB procedures were performed for 149 melanomas in 189 regional nodal basins. The mean tumor depth was 2.48 mm. The mean number of SNs/basin was 2.1. Thirty-two of 149 SNB procedures (21.5%) revealed a total of 34 nodal basins with at least one positive SN. The median tumor volume in positive SNs was 4.7 mm³ (range, 0.1-3618 mm³; mean, 209 mm³). The median aggregate tumor volume in positive LND specimens was 4.9 mm³ (range, 0.1-3618 mm³; mean, 224 mm³). Six basins (17.6%) contained at least one positive NSN. The regional node aggregate tumor volume correlated weakly with tumor thickness (Pearsons correlation coefficient = .302, P = .0934). NSN positivity was not predicted by tumor thickness, American Joint Committee on Cancer tumor stage, number of positive SNs, or number of metastatic deposits within SNs.Conclusions: Most melanoma-positive SNs contain minute tumor volumes. Tumor thickness and patterns of SN metastases may not be predictive of tumor burden or the presence of positive NSNs.     

Sentinel Lymph Node Biopsy in Cutaneous Melanoma: A Case-Control Study

Abstarct Background Sentinel lymph node biopsy (SLNB) is the most precise method for staging invasive cutaneous melanoma, but its therapeutic effect has been difficult to assess, and SLNB is not routinely used in all melanoma treatment centers. Methods This case-control study of 305 prospective SLNB patients compared them with 616 retrospective patients who had not undergone invasive nodal staging at diagnosis. Thin melanomas were included in both study groups. Results A total of 50 SLNB patients were sentinel positive (16.4%) and 255 were sentinel negative (83.6%). A total of 49 of the 50 sentinel-positive patients underwent completion lymph node dissection, and 9 of them (18%) had additional metastases in the nonsentinel nodes. The false-negative rate was 1.6% (five same-basin nodal recurrences during follow-up). There was a significant difference in melanoma-related overall survival (OS) between sentinel-positive and sentinel-negative patients (P < .001). The tumor burden of the sentinel nodes was a significant prognostic factor for melanoma-related OS (P < .001). There was no significant difference in melanoma-related OS or disease-free survival between the study groups, but the nodal disease-free survival was significantly longer among the SLNB patients (P = .004). Conclusions SLNB is recommended for routine use in the treatment of cutaneous melanoma because the sentinel node status carries unique prognostic information on the survival of melanoma patient. Improved regional disease control is an obvious therapeutic advantage of SLNB and immediate completion lymph node dissection.     

Criteria in Sentinel Lymph Nodes of Melanoma Patients that Predict Involvement of Nonsentinel Lymph Nodes

Background Previous studies described various criteria in sentinel lymph nodes (SLN) of melanoma patients that predict the involvement of further, nonsentinel lymph nodes (NSLN). Such criteria may facilitate the selection of patients who might benefit from a completion lymph node dissection (CLND). However, it is currently unclear which parameters are most important. Methods A total of 180 melanoma patients with positive SLNB and subsequent CLND were investigated. Histopathologic parameters in the SLN were systematically evaluated and compared with regard to NSLN positivity. Twenty-eight of these patients (16.0%) had positive NSLN. Results By univariate analysis several criteria with regard to tumor burden and location of melanoma cells in the SLN correlated with NSLN involvement, such as positivity by hematoxylin-eosin (H&E) staining (P < .001), largest diameter of clusters (P < .001), capsular involvement (P = .001), extranodal extension (P < .001), and tumor penetrative depth (P < .001). Multivariate analysis revealed three independent parameters: (1) positivity of the SLN by H&E staining (versus by immunohistochemistry alone), (2) relative tumor burden >10% of total lymph node tissue, and (3) perinodal intralymphatic tumor. In 23 of 28 patients with positive NSLN the SLN was positive by H&E staining, in 15 of 28 patients the relative tumor burden was >10%, and 13 of 28 showed perinodal intralymphatic tumor. In 5 of 28 patients with NSLN involvement, these three parameters were negative. Conclusions Histopathologic examination of the SLN can identify patients at risk for NSLN positivity.     

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     

Patterns of First-Recurrence and Post-recurrence Survival in Patients with Primary Cutaneous Melanoma After Sentinel Lymph Node Biopsy

Background Sentinel lymph node biopsy (SLNB) has become well accepted in management of patients with primary cutaneous melanoma. An understanding of the pattern of recurrence after SLNB is helpful in coordinating a rational plan of follow-up in these patients. We sought to determine the site and timing of initial recurrence and post-recurrence survival after SLNB. Methods Stage I/II melanoma patients who underwent SLNB during 1991–2004 were identified from a prospective single-institution database. Site and date of first recurrence after SLNB were recorded. Patterns of recurrence after SLNB and post-recurrence survival were analyzed. Results One thousand and forty-six patients underwent SLNB. The sentinel lymph node (SLN) was positive in 164 patients (16%). Median follow-up was 36 months for survivors. Median and 3-year relapse-free survival for SLN-positive patients were 41 months and 56%, and for SLN-negative patients were not reached and 87%, respectively (P < .0001). Of the SLN-positive patients, 47% experienced recurrence, compared with 14% SLN-negative patients. The pattern of recurrence stratified by SLN status was similar between the two groups (P = NS). After recurrence, the site of recurrence was the only significant prognostic factor influencing survival (P < .0001). Conclusions Although SLN-positive patients experience recurrence far earlier and more frequently than SLN-negative patients, the pattern of recurrence is similar. After recurrence, its site is the primary determinant of survival.     

Significance of Multiple Nodal Basin Drainage in Truncal Melanoma Patients Undergoing Sentinel Lymph Node Biopsy

Background: Although previous studies have demonstrated that truncal site is associated with an adverse prognosis, explanations for such risk are lacking. In addition, the number of nodal basins as well as the number of lymph nodes containing regional metastases are important prognostic factors in these patients. Because the lymphatic drainage pattern of truncal melanoma often includes more than one basin, we designed a study to evaluate (1) whether patients with multiple nodal basin drainage (MNBD) were at an increased risk of lymph node metastases identified by sentinel lymph node (SLN) biopsy, and (2) whether the histological status of an individual basin reliably predicted the status of the other draining basins in patients with MNBD.Methods: The records of 295 consecutive truncal melanoma patients who were managed primarily with intraoperative lymphatic mapping and SLN biopsy, between 1991 and 1997, were reviewed. All patients underwent preoperative lymphoscintigraphy, which established the number and location of draining nodal basins. Univariate and multivariate analyses of relevant clinicopathological factors were performed to assess which factors may predict the presence of a pathologically positive SLN.Results: At least one SLN was identified in 281 patients. MNBD was present in 86 (31%) patients, and a pathologically positive SLN was found in 56 (20%) patients. By multivariate analysis, the presence of MNBD (relative risk = 1.9; P = .03), tumor thickness (P = .007), and tumor ulceration (relative risk = 2.4; P = .01) were significant independent risk factors for the presence of at least one pathologically positive SLN. SLN pathology in one basin did not predict the histology of other basins in 19 (22%) of 86 patients with MNBD.Conclusions: MNBD is independently associated with an increased risk of nodal metastases in truncal melanoma patients. Because the histological status of an individual basin did not reliably predict the status of the other draining basins in patients with MNBD, it is important to adequately identify and completely assess all nodal basins at risk, as defined by lymphoscintigraphy, in truncal melanoma patients.Presented at the 52nd Annual Meeting of the Society of Surgical Oncology, Orlando, Florida, March 4–7, 1999.     

Early Recurrence After Lymphatic Mapping and Sentinel Node Biopsy in Patients With Primary Extremity Melanoma: A Comparison With Elective Lymph Node Dissection

Introduction: Although sentinel node biopsy with completion lymphadenectomy in node-positive patients (SLND) has been widely adopted in the management of patients with early stage melanoma, reports detailing the outcome of patients after SLND are limited. To address this issue, we analyzed our experience with SLND and provided a comparison to patients treated with elective lymph node dissection (ELND).Methods: All patients who underwent SLND (1991–1998) and ELND (1974–1994) were identified from single institution melanoma databases.Results: A total of 152 and 329 patients with early-stage melanoma of the extremity underwent SLND and ELND, respectively. Nodal metastases were present in 44 of 329 ELND patients (13%) and in 31 of 152 SLND patients (20%). Early relapse-free and disease-specific survivals were similar for the entire population, although in patients at higher risk for recurrence (age >50 years, thickness >3.0 mm), there was an increased rate of relapse in the SLND group (P = .04). Among all sites of early recurrences, locoregional sites were more common in patients undergoing SLND (72%) compared with ELND (39%, P < .01). SLN-negative patients with nodal recurrence had evidence of metastases on retrospective enhanced pathologic analysis in four of seven cases.Conclusions: Although overall relapse-free and disease-specific survivals are similar, there is a higher rate of relapse in a subset of SLND node-negative patients who are at high risk for nodal metastases. ELND and SLNB should not be thought of as equivalent approaches until studies with longer follow-up are available.     

Prediction of Nonsentinel Lymph Node Status in Melanoma

Background: Most melanoma patients with a positive sentinel lymph node dissection (SLND) undergo a completion lymph node dissection (CLND) that does not yield additional positive nonsentinel lymph nodes (NSLN). This study was designed to determine if NSLN status can be predicted using patient, primary tumor, and sentinel lymph node (SLN) characteristics.Methods: The study population includes melanoma patients who had a positive SLND and subsequently underwent CLND retrieved from our prospective institutional melanoma database. The primary tumor and SLN pathologies were prospectively determined. An Size/Ulceration (SU) score was derived by assigning 1 point for primary tumor ulceration and 1 point for SLN tumor size >2 mm.Results: Ninety-eight patients had a positive SLND and underwent CLND. Sixteen of these patients had a positive NSLN. On univariate analysis, primary tumor characteristics (thickness, ulceration, no regression), SLN metastasis characteristics (size >2 mm, location nonsubcapsular), and SU score were all significantly associated with positive NSLN status. However, on multivariate analysis, only the SU score was a significant independent predictor of NSLN status. No patient with an SU score of 0 had a positive NSLN.Conclusions: The SU score is predictive of NSLN status in patients with a positive SLND. Patients with an SU score of 0 are very unlikely to have positive NSLNs at CLND.     

Intraoperative Evaluation of Sentinel Lymph Nodes for Metastatic Melanoma by Imprint Cytology

Background Sentinel lymph node biopsy (SLN) has revolutionized nodal staging. Accurate intraoperative evaluation of SLN permits a single procedure, with lymphadenectomy being performed during the initial operative procedure when the SLN is positive. There is a paucity of literature on intraoperative imprint cytology (IIC) evaluation of the SLN in melanoma. The purpose of this article is to present an update to our experience with IIC for SLN in melanoma. Methods Melanoma patients had SLNs examined by IIC. SLNs were bisected, and imprints were made from each half. Imprints were stained with hematoxylin and eosin and with Diff-Quik. Paraffin-embedded sections were examined with multiple hematoxylin and eosin–stained sections from the SLNs in conjunction with immunohistochemical staining for S-100, Melan-A, and HMB-45 proteins. Results Metastases were identified in 40 (17%) of 229 patients. Of these, 13 patients were detected by IIC (sensitivity, 33%). The negative predictive value was 88%. No false-positive results were identified (specificity, 100%). The positive predictive value was 100%. The accuracy of IIC was 78%. The sensitivity for detecting macrometastases (>2 mm) was better than that for detecting micrometastases (≤2 mm): 62% vs. 16% (P < .01). Patients with positive SLNs by IIC had lymphadenectomy under the same anesthetic. A total of 533 nonsentinel lymph nodes were identified in 42 patients. Only two patients (8%) had positive nonsentinel lymph nodes after a negative IIC. Conclusions IIC is a viable alternative to frozen sectioning when intraoperative evaluation is desired. IIC is significantly more sensitive for macrometastases. IIC evaluation of SLNs in melanoma makes a single operative procedure possible for a significant proportion of patients with regional nodal metastases. Presented at the Society of Surgical Oncology, San Diego, California, March 24, 2006.     

The Prognostic Importance of Sentinel Lymph Node Biopsy in Thin Melanoma

Background Sentinel lymph node biopsy (SLNB) is prognostically useful in patients with cutaneous melanoma with Breslow thickness >1 mm. The objective of this study was to determine whether sentinel node histology has similar prognostic importance in patients with thin melanomas (≤1 mm). Methods This was a retrospective study of patients who underwent SLNB for clinically localized melanoma at Indiana University Medical Center between 1994 and 2003. SLNB results and traditional melanoma prognostic indicators were studied in univariate log-rank tests. Results One hundred eighty-four patients with melanomas ≤1 mm thick underwent SLNB. SLNB was tumor positive in 12 patients (6.5%). Univariate analysis of SLNB results revealed that Breslow thickness, Clark level of invasion, and mitotic index were associated with SLNB status. Tumor positivity was observed at different rates in tumor thickness subsets: <.75 mm, 2.3%; and .75 to 1.0 mm, 10.2% (P = .0372). Disease-free survival and overall survival were significantly associated with SLNB results in melanomas ≤1 mm (log-rank test: P < .0001 and P = .0125, respectively) at a median follow-up of 26.3 months. Conclusions SLNB histology in melanomas ≤1.0 mm deep is a significant predictor of outcome. SLNB should be considered for selected patients with melanomas .75 to 1.0 mm.     

Sentinel Lymph Node Biopsy in Cutaneous Melanoma: The WHO Melanoma Program Experience

Background: We report the experience of the World Health Organization (WHO) Melanoma Program concerning sentinel lymph node (SLN) biopsy for detecting patients with occult regional nodal metastases to submit to selective regional node dissection.Methods: From February 1994 to August 1998, in 12 centers of the WHO Melanoma Program, 892 SLN biopsies were performed in 829 patients with clinical stage I melanoma (male: 370; female: 459; median age: 50 years old). The location of the primary melanoma was as follows: trunk, 35%; lower limbs, 45%; upper limbs, 18%; and head and neck, 2%. Blue dye injection for SLN identification was performed in all cases; preoperative lymphoscintigraphy was one in 440 patients, and an intra-operative probe for a radio-guided biopsy was used in 141 cases. Overall, the SLN identification rate was 88%. In 68% of the patients, only one SLN was identified, whereas two and three or more SLN were detected in 24% and 8% of the remaining cases, respectively.Results: Overall SLN positivity rate was 18%. Intra-operative frozen section examination was performed in 39% of the cases and was helpful in detecting occult localizations only in 47% of the positive SLNs. Distribution of positive cases by primary thickness was as follows:,1mm: 2%; 1–1.99 mm: 7%; 2–2.99 mm: 13%; and 3 mm: 31%. Positive nonsentinel lymph nodes were found in 22% of cases with positive SLN submitted for selective dissection. No complications due to the procedure were registered. Of 710 patients who were evaluated, 40 (6%) presented a regional nodal relapse after a negative SLN biopsy and underwent a delayed therapeutic dissection. From the 710 enrolled cases, 638 (88.5%) were alive without evidence of disease at the time of this writing. A multivariate analysis showed SLN status as one of the most significant prognostic factors (P 5 .000) along with thickness (P 5 .001) and ulceration (P 5 .015) of primary tumor.Conclusions: These data confirm the feasibility and safety of the SLN technique for selecting patients to submit to a radical node dissection. The data represent the basis for a future trial by the WHO Melanoma Program in this field to evaluate the most appropriate surgical approach for treating patients with occult regional nodal metastases.     

Significance of Multiple Lymphatic Basin Drainage in Truncal Melanoma Patients Undergoing Sentinel Lymph Node Biopsy

Background Truncal melanoma involving metastases to multiple lymph node basins has a much worse prognosis than tumor involvement of a single lymph node basin. Recent results also suggest that, independently of the status of lymph node involvement, patients with multiple lymphatic basin drainage (MLBD) on lymphoscintigraphy have an increased risk of lymph node metastasis and a worse prognosis than those with a single lymphatic drainage basin. Because published reports have conflicting results, the authors compared their experience at the University of Michigan Comprehensive Cancer Center with recently published findings.Methods The authors searched a prospectively maintained melanoma database at the University of Michigan for patients with primary truncal melanoma who underwent lymphoscintigraphy and sentinel lymph node biopsy between 1997 and 2004. The association of MLBD with the clinical and pathologic characteristics collected and the presence of regional metastases was tested by using contingency tables and the χ² test statistic and by using the Fisher’s exact test statistic when cell frequencies were small. The product-limit method of Kaplan and Meier was used to estimate disease-free and overall survival probabilities.Results Of 423 patients with primary truncal melanoma who underwent sentinel lymph node biopsy, 123 (29%) had a positive result, and 98 patients (23.2%) had MLBD. Patients with tumors located in the middle of the trunk and tumor ulceration were more likely to have MLBD (P < .0001 and P = .045, respectively). Patients with a single lymphatic drainage basin and MLBD had a similar risk of lymph node metastasis and similar disease-free and overall survival.Conclusions Patients with truncal melanomas tend to have MLBD when the tumor is located in the middle of the trunk or when ulceration is present. In our experience, drainage to multiple lymphatic basins was not an independent risk factor for sentinel lymph node metastasis and has no independent prognostic significance.     

Complete Lymph Node Dissection for Sentinel Node-Positive Melanoma: Assessment of Practice Patterns in the United States

Background Currently, complete lymph node dissection (CLND) is recommended after identification of a metastatic lymph node by sentinel lymph node biopsy (SLNB). Guidelines suggest that CLND should be performed as a separate procedure, and a sufficient number of nodes should be examined. Our objective was to examine the utilization, timing, and adequacy of CLND for melanoma in the United States. Methods From the National Cancer Data Base, patients diagnosed with stage I to III melanoma during 2004–2005 were identified. Multiple logistic regression was used to assess factors associated with CLND utilization, timing (separate operation from SLNB), and adequacy (examination of ≥10 nodes). Results Of the 44,548 patients identified, 47.5% were pathologic stage IA, 23.8% stage IB, 14.1% stage II, and 14.6% stage III. Of the 17% (2942 of 17,524) with nodal metastases on SLNB, only 50% underwent a CLND. Patients were significantly less likely to undergo a CLND after SLNB if >75 years old or had lower extremity melanomas. Of the patients who underwent a CLND, only 42% underwent the CLND at a separate procedure after the SLNB. Of those who underwent a CLND, 69.2% had ≥10 nodes examined. Patients were significantly less likely to have ≥10 nodes examined if they were >75 years old or had lower extremity melanomas. Patients treated at NCCN/NCI-designated centers were significantly more likely to undergo nodal evaluation in concordance with established guidelines. Conclusions Only half of patients with sentinel node-positive melanoma underwent CLND. Quality surveillance measures are needed to monitor, standardize, and improve the care of patients with malignant melanoma. Presented in part at the Society of Surgical Oncology Annual Meeting, March 14, 2008, Chicago, IL.     

Isolated Tumor Cells in the Sentinel Node Affect Long-Term Prognosis of Patients with Melanoma

Background The clinical significance of isolated tumor cells (ITCs) in the melanoma-draining sentinel nodes (SNs) is unclear. Methods Records of patients who underwent SN biopsy (SNB) for stage I/II melanoma at our institute between 1991 and 2003 were reviewed to identify patients whose SNs were tumor-free or contained only ITC (≤0.2 mm). Tumor-positive SNs were reevaluated by the study pathologist to confirm the diagnosis and microstage the SN. Characteristics of the primary melanoma, tumor status of regional lymph nodes, and other prognostic variables were recorded. Melanoma-specific survival (MSS) rates were compared by the log-rank test. Results Of 1382 patients who underwent SNB, 1168 (85%) had tumor-free SNs; among the 214 remaining patients with tumor-positive SNs, 57 had metastases limited to ITC. Completion lymphadenectomy (CLND) was performed in 52 of 57 patients: six (12%) had metastases in nonsentinel nodes (NSNs). At a median follow-up of 57 months, 5-year and 10-year MSS was significantly higher (P = .02) for the 1168 patients with tumor-negative SNs (94 ± 1% and 87 ± 2%, respectively) than the 57 patients with ITC-positive SNs (89 ± 4% and 80 ± 7%, respectively). Multivariate analysis identified ITC (P = .002), Breslow’s thickness (P < .0001), ulceration (P < .0001), and primary site (P = .04) as significant for MSS. Conclusion Patients with ITC in SNs have a significantly higher risk of melanoma-specific death than those with tumor-negative SNs. The 12% incidence of nonsentinel node metastasis is similar to rates reported for patients with more extensive SN involvement. Patients with ITC should be considered for CLND. Presented at the annual meeting of the Society of Surgical Oncology, March 15–18, 2007, Washington, DC.     

Ultrasound-guided Fine Needle Aspiration Cytology prior to Sentinel Lymph Node Biopsy in Melanoma Patients

Background Sentinel lymph node biopsy (SLNB) allows early detection of metastases, thereby enabling early treatment in melanoma patients likely to benefit from adjuvant therapies. This prospective study analyzes the possible benefits of additional ultrasound (US) and fine needle aspiration cytology (FNAC) of sentinel nodes (SN) prior to SLNB.Method Over a 2-year period 127 melanoma patients with 151 SN were scheduled for SLNB. All SN were initially identified with lymphoscintigraphy, then identified and evaluated by US and the cells aspirated for cytology (FNAC). US findings and FNAC results were compared to surgical findings.Results Of 127 patients, 114 had one SN each, 12 had two, and one had three. In vivo US achieved a sensitivity of 79% (95% CI: 62–91%) and a specificity of 72% (95% CI: 62–81%). FNAC showed a sensitivity of 59% (95% CI: 41–76%) and a specificity of 100% (95% CI: 95–100%). The combination of these two in vivo methods achieved an overall sensitivity of 82% (95% CI: 65–93%) and an overall specificity of 72% [95% CI: 62–81%].Conclusion Combined US and FNAC provides important information prior to SLNB in that both procedures identify metastases in the lymph nodes (sensitivity > 80%). Patients with positive FNAC may proceed directly to complete lymph node dissection (cLND) instead of having initial SLNB. Thus, combined US and FNAC may prevent unnecessary anesthesia and surgical management as well reduce costs. In our study 16% (19/121) fewer SLNB procedures were carried out, subsequently replaced by cLND. For patients with a negative combination of in vivo US and FNAC, SLNB remains the best diagnostic option.Part of this work was presented in May 2003 at the Melanoma session of the 39^th Annual Meeting of the American Society of Clinical Oncology in Chicago, Illinois, and at the Oral Melanoma Poster Discussion session of the 40^th Annual Meeting of the American Society of Clinical Oncology in New Orleans, Louisiana.     

Revised American Joint Committee on Cancer Staging Criteria Accurately Predict Sentinel Lymph Node Positivity in Clinically Node-Negative Melanoma Patients

Background: The American Joint Committee on Cancer (AJCC) has recently modified staging criteria for primary melanoma patients and recommends sentinel lymph node (SLN) biopsy in many because microscopic nodal metastasis represents the most important factor predicting survival. The purpose of this study was to correlate the incidence of SLN metastasis with revised AJCC staging.Methods: The records of 1375 melanoma patients undergoing SLN biopsy were reviewed. Univariate and multivariate analyses were performed to identify predictors of a positive SLN. Patients were stratified by using revised AJCC criteria to determine whether such groups also predicted positive SLNs.Results: A positive SLN was found in 16.9% of patients. By multivariate analysis, tumor thickness (relative risk [RR], 3.4) and ulceration (RR, 2.2) were dominant independent predictors of SLN metastases; age 50 years (RR, 1.8) and axial tumor location (RR, 1.5) were also significant. When patients were stratified by AJCC staging criteria, a significant increase in SLN metastases between successive stages was demonstrated.Conclusions: Stratification of patients by using AJCC classification reveals an increasing risk of SLN metastases with successive stage groups. Given the significant association of SLN status and survival, the ability of the revised AJCC staging system to predict survival is likely due to its ability to predict the risk of occult nodal disease.Presented at the Society of Surgical Oncology Annual Meeting, Denver, Colorado, March 14–17, 2002.     

Significance of Plasma Cytokine Levels in Melanoma Patients With Histologically Negative Sentinel Lymph Nodes

Introduction:Although sentinel lymph node (SLN) status is the most powerful predictor of prognosis in patients with clinically localized melanoma, a proportion of melanoma patients with histologically negative SLNs will still recur. It is hypothesized that tumor response may be altered or mediated by specific cytokines. We therefore investigated whether levels of IL-4, IL-6, IL-10, TNF-, or IFN- would predict disease recurrence in melanoma patients with histologically negative SLNs.Methods:This prospective cohort study involved 218 patients with clinically localized melanoma who underwent a histologically negative SLN biopsy. Preoperative plasma cytokine levels were determined by enzyme-linked immunosorbent assay on these patients, as well as on 90 healthy controls. Kaplan-Meier life tables were constructed, and Cox proportional hazards analyses were performed to assess predictors of disease-free survival (DFS).Results:At a median follow-up of 43 months, 33 of 218 patients (15%) had suffered disease recurrence. Melanoma patients had significant elevations of IL-4, IL-6, and IL-10 compared to healthy controls; levels of IFN- were less elevated in melanoma patients compared to controls. Despite this, melanoma patients with detectable IFN- levels were at significantly higher risk for recurrence compared to patients with undetectable levels (5-year DFS 70% vs. 86%, P = .03). On multivariate analysis including standard melanoma prognostic factors, only tumor thickness (P = .004) and the presence of detectable IFN- levels (P = .05) were significant independent prognostic factors for disease-free survival.Conclusions:Among melanoma patients with clinically localized disease who have undergone a histologically negative SLN biopsy, presence of a detectable plasma level of IFN- is an independent predictor of disease recurrence. Elevated levels of IFN- may identify a group of early-stage melanoma patients who are more likely to have recurrence of disease and who may benefit from adjuvant therapies, including immunotherapies.Presented at the 52nd Annual Meeting of the Society of Surgical Oncology, New Orleans, Louisiana, March 17, 2000     

Histological Features of Melanoma Sentinel Lymph Node Metastases Associated with Status of the Completion Lymphadenectomy and Rate of Subsequent Relapse

Background The current recommendation for patients with cutaneous melanoma and a positive sentinel lymph node (SLN) biopsy is a completion lymph node dissection (CLND). This study sought to define a population of SLN-positive patients, based on their histological pattern of SLN metastases, who may not require CLND. Methods All patients with SLN-positive cutaneous melanoma who underwent CLND between March 1999 and December 2004 at a single academic institution were enrolled. Metastatic deposits in the SLN were categorized by their histological zone of involvement (subcapsular, parenchymal and/or sinusoidal). Logistic regression was used to examine the effect of SLN zone, size of nodal metastases, and other histological factors on CLND positivity. Kaplan-Meier and Cox models were used to study disease recurrence. Results A total of 127 patients were included, and 15.8% had positive non-sentinel nodes. In adjusted analyses, the size of the largest tumor deposit in the SLN was the only factor associated with CLND status. No patients with a tumor deposit ≤0.20 mm had a positive CLND. Although a specific zone of tumor involvement was not predictive of CLND status, involvement of all three zones was independently associated with increased recurrence. Size of the largest tumor deposit was also associated with recurrence, with no recurrences in patients with nodal deposits ≤0.20 mm. Conclusion Histologic features of tumor metastases in positive SLN may be useful in defining a population of patients who may be spared CLND and a group at high risk of recurrence.