Risk Stratification of Patients with Stage I Cutaneous Melanoma Using 31-Gene Expression Profiling

BackgroundWhile patients with localized cutaneous melanoma (CM) generally have good five-year melanoma-specific survival rates, identifying patients with localized disease at a high risk of recurrence could allow them access to additional follow-up or surveillance.ObjectiveWe sought to examine the prognostic value of the 31-gene expression profile (31-GEP) test for the risk of recurrence in stage I CM patients according to 31-GEP main class (low risk: Class 1 vs. high-risk: Class 2) and the lowest and highest risk 31-GEP subclasses (Class 1A vs. Class 2B).MethodsData from a previously described meta-analysis detailing the 31-GEP results for patients with stage I CM (N = 623) were re-analyzed to determine 31-GEP accuracy.ResultsPatients with stage I CM and a Class 1 31-GEP result were less likely to have a recurrence (15/556; 2.7% vs. 6/67; 9.0%; p=0.018) than patients with a Class 2 result and had a higher five-year recurrence-free survival (RFS) (96% vs. 85%). Patients with a Class 2 result were 2.8 times as likely to experience a recurrence (positive likelihood ratio: 2.82; 95% confidence interval: 1.38–5.77). In a subset of patients with stage I CM stratified further into 31-GEP subclasses (n = 206), patients with a Class 1A result had a higher five-year RFS than those with a Class 2B result (98% vs. 73%). Patients with a Class 2B result were also 6.5 times as likely to experience a recurrence (positive likelihood ratio: 6.45; 95% confidence interval: 2.44–17.00) than those with a Class 1A result, and the 31-GEP had a negative predictive value of 96.3% (95% confidence interval: 92.3%–98.4%).ConclusionThe 31-GEP test significantly differentiates between low and high recurrence risk in patients with stage I CM.     

Primary Cutaneous Melanoma with Regression Does not Require a Lower Threshold for Sentinel Lymph Node Biopsy

Introduction Histological evidence of primary tumor regression (RG) is observed in 35% or fewer patients with cutaneous melanoma. Some advocate a lower threshold for sentinel lymph node (SLN) biopsy when RG is present. Methods We identified 1,349 patients presenting to our center with clinically localized cutaneous melanoma between 1995 and 2004. Of these, 344 demonstrated histological RG in their primary melanoma. A retrospective analysis of their medical records was performed to obtain clinical and pathological information. Results The median Breslow depth for the 344 patients with RG was 1.1 mm versus 1.5 mm for 1,005 patients with no regression (NRG) (P < 0.005). SLN biopsy was performed in 64% of patients with RG and 72% without. Positive SLN was more common in those with NRG than in those with RG (18% vs 10%, P = 0.005). Only one RG patient with thin melanoma (≤1 mm, Clark IV) had a positive SLN. When stratified by Breslow depth, patients with RG had lower rates of SLN positivity in all groups (≤1.0mm, >1.0 and ≤2.0mm, >2 and ≤4 mm, and >4.0 mm). Recurrence was more common in patients with NRG (21% vs 12%; P < 0.005). Both local and systemic recurrence occurred more commonly in patients with NRG (4% vs 1%, P = 0.002 and 8% vs 3%, P < 0.005, respectively) Conclusions The presence of histological RG in a primary melanoma predicts neither SLN positivity when stratified by Breslow depth nor increased risk of recurrence when compared with melanomas with NRG.     

Cutaneous desmoplastic melanoma: reappraisal of morphologic heterogeneity and prognostic factors

Desmoplastic melanoma (DM) is a variant of melanoma, which may be confused with nonmelanocytic benign or malignant spindle cell proliferations. The histologic hallmark of DM is the presence of fusiform melanocytes dispersed in a prominent collagenous stroma. Phenotypic heterogeneity of DM is underrecognized. Desmoplasia may be prominent throughout the entire tumor ("pure" DM) or represent a portion of an otherwise nondesmoplastic melanoma ("combined" DM). We reviewed melanomas with desmoplasia from 92 patients seen at a single institution between 1980 and 2002. Fifty-five of the tumors were pure DM. Thirty-seven were classified as combined. Mean follow-up of patients was 46 months for those alive at the last follow-up. Univariate analysis of clinical and pathologic parameters revealed four significant variables for disease-free survival: Clark level (IV vs. V; P = 0.005), DM subtype (pure vs. combined; P = 0.01), tumor mitotic rate (<1, 1-4, >4 mitoses/mm; P = 0.01), and tumor thickness (<1 mm, 1-4 mm, >4 mm; P = 0.02). Only histologic subtype (P = 0.02) and Clark level (P = 0.05) were independently significant by Cox regression analysis. Our results indicate that distinguishing pure from combined forms of DM is clinically relevant for prognosis (pure forms being associated with longer disease-specific survival). Failure to make this distinction may account for conflicting reports in the literature on the biologic behavior and prognosis of DM.     

Dermoscopic Features of Difficult Melanoma

BACKGROUND: The dermoscopic diagnosis of cutaneous melanoma (CM) may be difficult because some CM lack specific dermoscopic features for melanoma diagnosis. OBJECTIVE: To evaluate whether a diagnosis of CM could be achieved using the classic dermoscopic melanoma-specific criteria, we conducted a retrospective multicenter study of 508 CM samples. METHODS: All the dermoscopic images were analyzed to identify the dermoscopic criteria found in dermoscopically difficult melanomas (DDM) and to examine the possible relation of dermoscopic diagnosis with respect to the difficulty of the dermoscopic diagnosis and the melanoma thickness. RESULTS: A significant percentage of melanomas, 89 of 508 (17.5%), were DDM. The criteria leading to a significant increased risk of DDM were presence of streaks [odds ratio (OR), 2.26; 95% confidence interval (CI), 1.15-4.47), absence or presence of regular pigmentation (OR, 3.41; 95% CI, 1.70-6.85), absence of a blue-whitish veil (OR, 4.04; 95% CI, 2.33-6.99), absence of regression structures (OR, 4.31; 95% CI, 2.42-7.66), and the presence of hypopigmentation (OR, 2.61; 95% CI, 1.49-4.58). CONCLUSION: A significant number of melanomas defy even dermoscopic diagnosis. Only a meticulous comparative and interactive process based on an assessment of all the individual's other nevi ("ugly ducking" sign) and a knowledge about recent changes can lead to the recognition of DDM.     

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     

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.     

Angiogenesis Correlates With Metastasis in Melanoma

Background: Angiogenesis has been correlated with melanoma progression, but its role in melanoma metastasis is unclear.Methods: To determine whether angiogenesis correlates with the presence of melanoma metastases, we compared the number of microvessels in the primary melanomas of 12 patients presenting with metastases to those of 13 patients without metastases. Patient groups were matched for gender, age, tumor depth, and histological type and anatomical location of the primary melanoma. Microvessels were stained with factor VIII antibody and counted.Results: Microvessel counts were significantly greater for the metastatic than the nonmetastatic melanomas (51.63 ± 14.95 vs. 24.86 ± 8.415; P < .0001). One hundred percent of the metastatic melanomas had a mean microvessel count of 37, whereas only 8% of the nonmetastatic melanomas had a mean microvessel count of 37 (sensitivity = 1.00, specificity = .92). Interestingly, patients with lymph node metastases had significantly lower microvessel counts than did patients with distant metastases (42.00 ± .482 vs. 58.50 ± 16.40; P < .05), and significantly higher microvessel counts than did patients without metastases (42.00 ± 3.482 vs. 24.86 ± 8.415; P < .001).Conclusions: An increased number of microvessels in the primary tumors of patients with melanoma correlates with the simultaneous presence of metastases. This suggests that angiogenesis may be important in the process of melanoma metastasis.Presented at the 51st Annual Cancer Symposium of The Society of Surgical Oncology, San Diego, California, March 26–29, 1998.     

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.     

Hepatic Resection for Metastatic Melanoma: Distinct Patterns of Recurrence and Prognosis for Ocular Versus Cutaneous Disease

Background Resection of melanoma metastatic to the liver remains controversial. We evaluated the efficacy of hepatic resection in patients with metastatic ocular and cutaneous melanoma and assessed factors that could affect survival after resection. Methods Forty patients with hepatic melanoma metastasis underwent resection at four major hepatobiliary centers. Clinicopathologic factors were evaluated with regard to recurrence and survival by using χ² and log-rank tests. Results The primary tumor was ocular in 16 patients and cutaneous in 24. The median disease-free interval from the time of primary tumor treatment to hepatic metastasis was the same for both groups (ocular, 62.9 months; cutaneous, 63.1 months; P = .94). Most patients underwent either an extended hepatic resection (37.5%) or hemihepatectomy (22.5%). Twenty-six patients (65%) received perioperative systemic therapy. Thirty (75.0%) of 40 patients developed tumor recurrence. The median time to recurrence after hepatic resection was 8.3 months (ocular, 8.8 months; cutaneous, 4.7 months; P = .3). Patients with primary ocular melanoma were more likely to experience recurrence within the liver (53.3% vs. 17.4%; P = .015), whereas patients with a cutaneous primary tumor more often developed extrahepatic involvement. The 5-year survival rate for patients with a primary ocular melanoma was 20.5%, whereas there were no 5-year survivors for patients with cutaneous melanoma (P = .03). Conclusions Patterns of recurrence and prognosis after resection of hepatic melanoma metastasis differ depending on whether the primary melanoma is ocular or cutaneous. Resection should be performed as part of a multidisciplinary approach, because recurrence is common.     

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     

Clinical and Pathologic Factors Associated with Distant Metastasis and Survival in Patients with Thin Primary Cutaneous Melanoma

Background

Approximately 3?C5% of patients with thin (??1?mm) cutaneous melanomas develop distant metastases. We sought to identify clinical and pathologic factors associated with distant metastasis and survival in a large number of patients with thin melanoma treated at a single institution.

Methods

We identified patients with a single invasive melanoma ??1?mm in thickness diagnosed between January 1983 and December 2003 who developed distant metastasis (cases), and matched patients with no recorded recurrence during follow-up (control subjects). Cases and control subjects were matched for age, sex, and year of primary melanoma diagnosis. Associations of clinical and pathologic parameters with distant metastasis-free survival and melanoma-specific survival were analyzed.

Results

A total of 178 cases and 178 control subjects were identified. Factors associated with development of distant metastasis were: increasing Breslow thickness (P?P?P?=?0.001), ulceration (P?=?0.025), and American Joint Committee on Cancer T subcategory (P?Conclusions Clinical and pathologic predictors of distant metastasis and survival identified in this large study of patients with thin primary cutaneous melanomas will enable more accurate stratification of risk of distant metastasis and poor survival in such patients, and will assist in formulating clinical management and follow-up regimens based on the level of risk.     

Sentinel Node Location in Trunk and Extremity Melanomas: Uncommon or Multiple Lymph Drainage Does Not Affect Survival

Background

Patients with cutaneous melanoma (CM) on the trunk have a worse prognosis than those with extremity CM. One reason could be multiple or uncommon (outside axilla or groin) sentinel node locations (SNLs).

Methods

We identified 859 patients who underwent sentinel node biopsy for trunk (n = 465) or extremity (n = 394) CM in three Swedish healthcare regions from 2000 to 2008. We collected patient, tumor, and sentinel node characteristics through clinical registers and medical records. We investigated the distribution of SNLs in a logistic regression model, and risk of overall and melanoma-specific death through 2011 in a multivariable Cox regression model.

Results

Trunk CM was associated with multiple SNLs (31 vs. 7 %; odds ratio [OR] 7.1; 95 % confidence interval [CI] 4.6–11.5; p < 0.001) but not uncommon SNLs (8 vs. 7 %; OR 1.1; 95 % CI 0.6–1.9; p = 0.75) compared with extremity CM. The increased risk of melanoma-specific death was confirmed for trunk CM (hazard ratio [HR] 1.9; 95 % CI 1.3–2.9; p = 0.003), especially on the upper back (HR 2.3; 95 % CI 1.4–3.6; p < 0.001) compared with extremity CM. Uncommon SNLs (HR 0.5; 95 % CI 0.2–1.4; p = 0.21) or multiple SNLs (HR 1.1; 95 % CI 0.4–2.9; p = 0.81) were not associated with melanoma-specific death compared with those with common/single SNL.

Conclusions

Trunk melanomas were associated with multiple lymph drainage, but the worse prognosis of trunk melanomas could not be explained by the increased frequency of multiple or uncommon SNLs.     

Lymph Node Biopsy Does Not Impair Survival After Therapeutic Dissection for Palpable Melanoma Metastases

Background: To determine the effects of disrupting a nodal basin in patients with American Joint Committee on Cancer stage III melanoma with clinically palpable lymph nodes, we studied patients who underwent therapeutic lymph node dissection after excisional lymph node biopsy, after fine-needle aspiration (FNA) biopsy, or without a preoperative biopsy.Methods: We performed a retrospective review of our patients with American Joint Committee on Cancer stage III melanoma who were treated between January 1972 and June 1995, using data acquired from our 8200-patient database. The study group included 670 patients with melanoma, with known primary tumors, who underwent therapeutic lymph node dissection for palpable nodal metastases diagnosed by open biopsy (227 patients), by FNA (66 patients), or by clinical observation without biopsy (377 patients). Regional node recurrence, 5-year disease-free survival, and overall survival rates were calculated.Results: The same-basin regional node recurrence rates were similar for the three groups (open biopsy, 4.6%; FNA, 3.2%; no biopsy, 4.6%; P = .14). The 5-year disease-free survival rates were 36.8% for the open-biopsy group, 29.6% for the FNA group, and 28.9% for the no-biopsy group (P = .08); corresponding 5-year overall survival rates were 40.6%, 43.9%, and 36.1%, respectively (P = .18). Multivariate analysis failed to identify preoperative biopsy as a significant risk factor. Matched-pair analysis using age, gender, primary tumor site, Breslow thickness, and tumor burden showed no differences in the 5-year disease-free survival rates (33% for the open-biopsy group vs. 27% for the FNA and no-biopsy groups, P = .42) and the 5-year overall survival rates (41% vs. 35%, P = .32).Conclusions: For patients with melanoma with palpable regional adenopathy, histological confirmation of clinical suspicion with either FNA or excisional lymph node biopsy does not adversely affect survival or recurrence rates.Supported by Grants CA12582 and CA29605 from the National Cancer Institute and by funding from the Wrather Family Foundation (Los Angeles, CA)Presented at the Pacific Coast Surgical Association Annual Meeting, Maui, Hawaii, February 15-18, 1998     

Observation After a Positive Sentinel Lymph Node Biopsy in Patients with Melanoma

Background

The benefit of completion lymph node dissection (CLND) in melanoma patients with a positive sentinel lymph node (SLN) remains unknown.

Methods

We identified patients with a positive SLN from 1994 to 2012. Patient and tumor characteristics, reasons for not undergoing CLND, patterns of recurrence, and melanoma-specific survival data were analyzed.

Results

Of 4,310 patients undergoing SLN biopsy (SLNB), 495 (11 %) had a positive SLN—167 (34 %) patients underwent nodal observation and 328 (66 %) had immediate CLND. Patients in the no-CLND group were older (66 vs. 56 years; p < 0.001) and more likely to have lower extremity lesions (57 vs. 42 %; p = 0.006). There were no differences in tumor thickness, Clark level of invasion, ulceration, or SLN tumor burden. Median follow-up was 23 and 80 months for the no-CLND and CLND groups, respectively, and median time to recurrence was similar at 9 and 12 months, respectively (p = 0.48). There was no difference in local and in transit recurrence rates between groups (16 %, no CLND, and 18 %, CLND; p = 0.48). Nodal disease as a site of first recurrence occurred in 15 % of patients in the no-CLND group and 6 % of CLND patients (p = 0.002). In contrast, systemic recurrences occurred in 8 % of no-CLND patients compared with 27 % of CLND patients (p < 0.001). While median recurrence-free survival was higher after CLND (34.5 vs. 20.9 months; p = 0.02), melanoma-specific survival was similar (not reached, no CLND vs. 110 months, CLND; p = 0.09).

Conclusions

Immediate CLND after a positive SLNB is associated with fewer initial nodal basin recurrences but similar melanoma-specific survival. These results support ongoing equipoise in the Multicenter Selective Lymphadenectomy Trial II (MSLT-II).     

A Sentinel Node Biopsy Does Not Increase the Incidence of In-Transit Metastasis in Patients With Primary Cutaneous Melanoma

Background It has been suggested that performing a sentinel node biopsy (SNB) in patients with cutaneous melanoma increases the incidence of in-transit metastasis (ITM).Methods ITM rates for 2018 patients with primary melanomas ≥1.0 mm thick treated at a single institution between 1991 and 2000 according to 3 protocols were compared: wide local excision (WLE) only (n = 1035), WLE plus SNB (n = 754), and WLE plus elective lymph node dissection (n = 229).Results The incidence of ITM for the three protocols was 4.9%, 3.6%, and 5.7%, respectively (not significant), and as a first site of recurrent disease the incidence was 2.5%, 2.4%, and 4.4%, respectively (not significant). The subset of patients who were node positive after SNB and after elective lymph node dissection also had similar ITM rates (10.8% and 7.1%, respectively; P = .11). On multivariate analysis, primary tumor thickness and patient age predicted ITM as a first recurrence, but type of treatment did not. Patients who underwent WLE only and who had a subsequent therapeutic lymph node dissection (n = 149) had an ITM rate of 24.2%, compared with 10.8% in patients with a tumor-positive sentinel node treated with immediate dissection (n = 102; P = .03).Conclusions Performing an SNB in patients with melanoma treated by WLE does not increase the incidence of ITM.Published by Springer Science+Business Media, Inc. © 2005 The Society of Surgical Oncology, Inc.     

Locoregional Lymphadenectomy in the Surgical Management of Anorectal Melanoma

Background

The effect of lymph node metastasis on local tumor control and distant failure in patients with anorectal melanoma has not been fully studied. Understanding the significance of lymphatic dissemination might assist in stratifying patients for either organ preservation or radical surgery.

Methods

A retrospective review of all patients with anorectal melanoma who underwent surgery at our institution between 1985 and 2010. Abdominoperineal resection (APR) was performed in 25 patients (39 %), and wide local excision (WLE) in 40 (61%). Extent of primary surgery and locoregional lymphadenectomy (mesorectal vs. inguinal vs. none) and pattern of treatment failure were analyzed. Recurrence-free survival (RFS) and disease-specific survival (DSS) were calculated.

Results

In patients undergoing APR, DSS was not associated with presence (29 %) or absence (71 %) of metastatic melanoma in mesorectal lymph nodes. There was a trend toward improved DSS in patients with clinically negative inguinal lymph nodes (n = 17) compared with patients with proven inguinal metastasis (n = 6; P = 0.12). Type of surgery (WLE vs. APR) was not associated with subsequent development of distant disease. Twelve patients (18 %) had synchronous local and distant recurrence. Synchronous recurrence was not associated with surgical strategy used to treat primary tumor (P = 0.28). Perineural invasion (PNI) was significantly correlated with RFS (P = 0.002).

Conclusions

Outcome following resection of anorectal melanoma is independent of locoregional lymph node metastasis; lymphadenectomy should be reserved for gross symptomatic disease. PNI is a powerful prognostic marker warranting further exploration in clinical trials.     

Positive Nonsentinel Node Status Predicts Mortality in Patients with Cutaneous Melanoma

While sentinel lymph node biopsy (SLN) is a highly accurate and well-tolerated procedure for patients with cutaneous melanoma, the role of the completion lymph node dissection (CLND) for patients with positive SLN biopsy remains unknown. This study aimed to look at the prognostic value of a positive nonsentinel lymph node (NSLN). A prospectively maintained database identified 222 patients with cutaneous melanoma and a positive SLN biopsy, without evidence of distant disease. All of these patients underwent CLND, and 37 patients (17%) had positive NSLN. With median follow-up of 33 months, patients with negative NSLN had median survival of 104 months, while patients with positive NSLN had median survival of 36 months (p < 0.001). There were no survivors in the patients with positive NSLN beyond 6 years. When patients with an equal number of positive nodes were analyzed, the presence of a positive NSLN was still associated with worse melanoma-specific survival (66 months for NSLN− versus 34 months for NSLN+, p = 0.04). While increasing age, tumor thickness, and male sex were associated with an increased risk of death on multivariate analysis, a positive NSLN was the most important predictor of survival (hazard ratio 2.5). We conclude that positive NSLN is an independent predictor of disease-specific survival in patients with cutaneous melanoma.     

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.     

Effects of various extenders and permeating cryoprotectants on cryopreservation of cynomolgus monkey (Macaca fascicularis) spermatozoa

The cryoprotective effects of 11 different extenders, TTE, DM, mDM, LG-DM, G-DM, TCG, TEST, TSM, Test-M, Test-H, and LM, on sperm cryopreservation of cynomolgus monkey (Macaca fascicularis) have been compared with glycerol as cryoprotectant. Sperm motility, plasma membrane, and acrosomal integrity were examined to evaluate frozen-thawed sperm function. The results showed that TTE, DM, mDM, LG-DM, G-DM, and TCG exhibited the best and similar protective efficiencies for cynomolgus monkey sperm cryopreservation in terms of sperm motility and plasma membrane integrity (P > .05). The acrosomal integrity for spermatozoa cryopreserved in TCG was statistically lower than that of TTE, DM, mDM, LG-DM, and G-DM (P < .05) but was significantly higher than that of TEST, TSM, Test-M, Test-H, and LM (P < .05). The postthaw sperm motility for 5 other extenders (TEST, TSM, Test-M, Test-H, and LM) did not exceed 30%, and the 3 sperm parameters evaluated for them were significantly lower than that of TTE, DM, mDM, LG-DM, G-DM, and TCG (P < .05). On the basis of these findings, 5 commonly used permeating cryoprotectants, glycerol, ethylene glycol, dimethyl sulfoxide, acetamide and propylene glycol have further been tested for their effectiveness on sperm cryopreservation in extenders of TTE, DM, mDM, LG-DM, G-DM, and TCG. The results showed that the sperm cryoprotective efficiencies of glycerol and ethylene glycol were similar and best among 5 permeating cryoprotectant treatments (P > .05). Dimethyl sulfoxide or acetamide resulted in average cryoprotection for cynomolgus monkey spermatozoa: poorer than glycerol or ethylene glycol but better than that of propylene glycol (P < .05). In addition, the action of permeating cryoprotectant appeared to be independent of extenders. The results in the present study demonstrate that 1) TTE, DM, mDM, LG-DM, G-DM, and TCG are excellent extenders and suitable for cynomolgus monkey sperm cryopreservation; 2) the mechanism of action of permeating cryoprotectants are not affected by extender composition; 3) ethylene glycol has a similar cryoprotective efficacy to glycerol that makes it a successful cryoprotectant for sperm cryopreservation in cynomolgus monkeys.     

The Unique Clinical Characteristics of Melanoma Diagnosed in Children

Background

Studies have demonstrated a higher rate of nodal metastases in melanoma of childhood, but there is controversy about the overall prognosis relative to adults. We describe a large single-institution experience with pediatric melanoma and assess prognostic characteristics.

Methods

Retrospective review identified 126 patients diagnosed with melanoma at <21?years of age and referred for treatment from 1986 to 2011. Atypical lesions were excluded. Clinicopathologic characteristics were correlated with sentinel lymph node (SLN) status and outcomes.

Results

SLN biopsy was positive in 18 of 62 cases (29?%). Increasing Breslow thickness correlated with a positive SLN (p?<?0.05). After a median follow-up of 5?years, there were 27 recurrences and 20 deaths. Positive SLN patients had significantly worse recurrence-free survival (RFS, p?<?0.05) and significantly worse melanoma-specific survival (MSS, p?=?0.05) compared with negative SLN patients. The 5-year RFS and MSS for positive SLN patients were 59.5 and 77.8?%, compared with 93.7 and 96.8?% for negative SLN patients. Recurrences and melanoma-related deaths were often seen beyond 5?years. No deaths have occurred in patients <12?years, but 9.1?% of patients 12?C17?years and 17.2?% of patients 18?C20?years died from melanoma (p?=?0.291).

Conclusions

Children with melanoma have higher rates of SLN metastases (29?%) than adults with comparable melanomas. Despite the higher incidence of nodal metastases, survival is equal to or better than what is reported for adults. However, long-term follow-up is necessary in this population since recurrences and deaths are often seen beyond 5?years.