Predictors of occult nodal metastasis in patients with thin melanoma.

HYPOTHESIS: Thin primary lesions are largely responsible for the rapid increase in melanoma incidence, making identification of appropriate candidates for nodal staging in this group critically important. We hypothesized that common clinical variables may accurately estimate the risk of nodal metastasis after wide excision and determine the need for sentinel node biopsy. DESIGN: Review of prospectively acquired data in a large melanoma database. SETTING: A tertiary referral center. PATIENTS: A total of 2211 patients with thin melanoma treated by wide local excision alone were identified in the database between January 1, 1971, and December 31, 2005. Of those, 1732 met entry criteria. MAIN OUTCOME MEASURES: We examined the rate of regional nodal recurrence and the impact of clinical and demographic variables by univariate and multivariate analyses. RESULTS: The overall nodal recurrence rate was 2.9%; median time to recurrence was 38.3 months. Univariate analysis of 1732 patients identified male sex (P < .001), increased Breslow thickness (P < .001), and increased Clark level (P < .001) as significant for nodal recurrence. Multivariate analysis identified male sex (hazard ratio, 3.5; 95% confidence interval, 1.8-7.0; P < .001), younger age (0.45; 0.24-0.86; P = .001), and increased Breslow thickness (2.5; 1.6-3.7; categorical P < .001) as significant for nodal recurrence. The Clark level was no longer significant (P = .63). Breslow thickness, age, and sex were used to develop a scoring system and nomogram for the risk of nodal involvement. Predictions ranged from 0.1% in the lowest-risk group to 17.4% in the highest-risk group. CONCLUSIONS: Many patients with thin melanoma will have nodal recurrence after wide excision alone. Three simple clinical variables may be used to estimate recurrence risk and select patients for sentinel node biopsy.

Improved survival for stage IV melanoma from an unknown primary site.

PURPOSE We previously demonstrated a survival advantage for nodal metastasis of melanoma from an unknown primary (MUP) versus melanoma from a known primary (MKP). We hypothesized that this survival benefit would extend to MUP patients with distant (stage IV) metastasis. PATIENTS AND METHODS We reviewed prospectively acquired data for 2,247 patients diagnosed with American Joint Committee on Cancer stage IV melanoma at our cancer center between 1971 and 2005. Cox regression analysis in a multivariate model identified prognostic factors significant for survival. MUP and MKP patients were then matched by significant covariates. Overall survival (OS) was estimated by Kaplan-Meier method and compared by log-rank analysis. Results There were 1,849 MKP and 398 MUP patients. Multivariate analysis of patients with complete data sets identified known/unknown primary (hazard ratio [HR], 1.141; P = .032) and five other significant covariates: age (HR, 1.148; P = .007), sex (HR, 1.17; P = .001), site of metastasis (HR, 1.336; P < .001), number of different metastatic sites (HR, 1.303; P < .001), and decade of diagnosis (HR, 0.713; P < .001). Prognostic matching yielded 392 MUP-MKP pairs. Median OS and 5-year OS rate were significantly greater (P < .001) for MUP patients than for all matched MKP patients or for MKP patients matched by M1 category (for M1b and M1c) or number of metastatic sites. CONCLUSION The survival advantage previously reported for patients with stage III MUP also applies to patients with stage IV MUP. The mechanism responsible for this improved survival may provide clues for more effective treatment of stage IV melanoma and therefore warrants further investigation. The improved results for MUP suggest that these patients deserve aggressive therapy.

Improved survival after lymphadenectomy for nodal metastasis from an unknown primary melanoma.

PURPOSE: No primary lesion is identified in 10% to 20% of patients presenting with palpable evidence of regional metastatic melanoma. Because the prognostic significance of unknown primary melanoma (MUP) is unclear, we compared clinical outcomes of patients with MUP and known primary melanoma (MKP) with regional nodal metastases. PATIENTS AND METHODS: We reviewed our 13,000-patient prospective melanoma database (1971 through 2005) to identify patients managed with regional lymphadenectomy for palpable nodal metastases from MUP or MKP. Multivariate analysis identified prognostic factors significant for survival. MUP and MKP were then matched by significant covariates. Overall survival (OS) was estimated by Kaplan-Meier method and compared by log-rank analysis. RESULTS: Multivariate analysis of data from 1,571 study patients identified four significant covariates associated with worse prognosis: age >or= 60 years (hazard ratio [HR] = 1.294; P = .0017), male sex (HR = 1.335; P = .0004), nodal tumor burden >or= one (HR = 1.256; P < .0001), and known primary (HR = 1.507; 95% CI, 1.220 to 1.862; P = .0001). Five-year OS was significantly higher for 262 patients with MUP than for 1,309 patients with MKP (55% +/- 6% v 44% +/- 3%; P = .0021). Computerized matching of MUP and MKP by four significant covariates (age, sex, nodal tumor burden, and decade of diagnosis) yielded 221 matched pairs. Median and 5-year OS rates were 165 months and 58% +/- 7%, respectively, for MUP as compared with 34 months and 40% +/- 7%, respectively, for MKP (P = .0006). CONCLUSION: Lymphadenectomy is effective for nodal metastasis from MUP. The significantly better postoperative survival for MUP versus MKP suggests a strong endogenous immune response against the primary melanoma. Immunologic studies to identify cell-mediated and antibody components of this response may lead to new approaches for determining melanoma prognosis and treatment.

Surgical management of the groin lymph nodes in melanoma in the era of sentinel lymph node dissection.

HYPOTHESIS: Intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) has become an increasingly popular surgical technique for staging the regional lymph nodes in early-stage melanoma. The technique of LM/SL has potentially great advantage for the groin, where the morbidity of superficial groin dissection or iliac dissection can be high. The surgical management of these basins is unknown for patients with tumor-positive sentinel lymph nodes (SNs). DESIGN: Cohort of successive patients undergoing LM/SL over 18 years. Those patients found to have tumor-positive SNs underwent sentinel complete lymph node dissection. Postoperatively, patients were followed up on a routine basis with serial examinations and chest radiography. The median follow-up was 50 months. SETTING: Tertiary cancer center. PATIENTS: The technique of LM/SL was performed for 431 consecutive patients. Sentinal lymph nodes were identified in each case. Patients with tumor-positive SNs underwent sentinel complete lymph node dissection. INTERVENTION: Cutaneous lymphoscintigraphy and blue dye with or without use of the gamma probe-directed LM/SL. Sentinel lymph nodes were examined by hematoxylin-eosin staining and immunohistochemistry staining with HMB-45 and S100 protein. Only patients with tumor-positive SNs had sentinel complete lymph node dissection. Main Outcome Measure Computer-assisted database with statistical analyses using log-rank tests and Cox regression models. RESULTS: Of the 431 patients, 264 (61%) were women and the median age was 50 years (age range, 15-89 years). A majority (86%) of the primary tumors were on the lower extremities, 54% were of Clark level IV or V, and there was a mean +/- SD thickness of 1.89 +/- 1.59 mm (range, 0.30-14.00 mm). Ninety-three patients (21%) were found to have tumor-positive SNs. After LM/SL and sentinel complete lymph node dissection, 62 patients (67%) were found to have a single tumor-positive lymph node, 25 (27%) had 2 tumor-positive lymph nodes, and 6 (6%) had 3 or more tumor-positive lymph nodes. Only 12 patients (4%) with tumor-negative SNs have had recurrence in the dissected basin. The 5-year overall survival was significantly better for patients with tumor-negative lymph nodes (mean +/- SD 5-year overall survival, 94% +/- 5%) than for patients with tumor-positive lymph nodes (mean +/- SD 5-year overall survival, 75% +/- 4%) (P < .01). The tumor status of the Cloquet lymph node was predictive of the tumor status of the iliac lymph nodes. Multivariate analyses with a Cox regression model identified tumor-positive SN (P = .001), primary tumor thickness (P = .03), and ulceration (P = .001) as being predictive of survival. Sex, age, Clark level, and primary site were not significant (P > .05). CONCLUSIONS: Our results demonstrate the prognostic significance of LM/SL for early-stage melanoma draining to the groin basin. The accuracy of LM/SL measured by the rare recurrences suggests that this surgical procedure should become standard for patients with early-stage melanoma of the lower extremities and trunk. Sampling of the Cloquet node should be used to determine the need for iliac dissection when a tumor-positive SN is identified in the groin.

Can surgical therapy alone achieve long-term cure of melanoma metastatic to regional nodes?

BACKGROUND: Anecdotal reports of melanoma recurrence 15 years after complete lymphadenectomy have led to claims that the onset of nodal metastasis invariably signals systemic metastases and a terminal diagnosis. Few series in the literature are able to refute this assertion. We therefore examined rates of long-term (> 15-25 years) survival for patients with regional (nodal) melanoma. PATIENTS AND METHODS: We performed an analysis of patients with American Joint Committee on Cancer stage III melanoma entered into a prospective database for the last 30 years. All patients were seen at the treating institution within 4 months of their diagnosis and monitored thereafter. All patients underwent complete lymphadenectomy. Patients receiving melanoma vaccines were excluded. Statistical comparisons used Chi-square analysis and the log-rank test. RESULTS: At a maximum follow up of 386 months (32 years) for the population of 1422 patients, rates of 15-, 20-, and 25-year melanoma-specific survival were 36% +/- 1%, 35% +/- 1%, and 35% +/- 1%, respectively. When patients were stratified by clinical status of regional lymph nodes, survival rates were significantly lower (P = 0.001) if nodes were palpable. The number of tumor-positive nodes (P < 0.0001), the pathological primary tumor stage (P = 0.005), age (P = 0.0001), and gender (P = 0.002) also were significantly related to long-term survival. DISCUSSION: Long-term survivors of melanoma metastatic to regional lymph nodes are not uncommon, and the extremely low rate of recurrence beyond 15 years suggests that this disease-free interval is usually synonymous with cure. Although some risk factors decrease the likelihood of long-term survival, the high overall rates of extended survival in all risk groups clearly support surgical management as the primary treatment for regional metastatic melanoma.

Sentinel lymphadenectomy does not increase the incidence of in-transit metastases in primary melanoma.

PURPOSE: Recent reports by European investigators suggest that sentinel lymphadenectomy (SLND), a mainstay of melanoma diagnosis and treatment planning, increases the risk of in-transit metastasis (ITM) and should be abandoned. This study compared the incidence of ITM after wide local excision (WLE), WLE plus SLND (SLND), or WLE plus elective lymphadenectomy (ELND) for primary melanoma. PATIENTS AND METHODS: Review of our prospective database identified 4,412 patients who underwent WLE (n = 2,771), SLND (n = 1,016), or ELND (n = 625) for stage I/II melanoma (1971 through 2002). The incidence of ITM overall and as a first recurrence was examined before and after computerized prognostic matching of treatment groups. Intergroup statistical comparisons used chi(2) analysis and log-rank test. RESULTS: The incidence of ITM increased with Breslow depth, Clark level, and T stage. Although overall incidence of ITM was significantly higher (P = .0008) after ELND (6.56%) versus WLE (3.36%) or SLND (3.64%), the ELND group had higher risk primaries. Treatment groups matched by T stage (1,875 patients; 625 per group) or by age, sex, Breslow depth, and primary location (1,680 patients; 560 per group), showed no significant differences in ITM overall or as a first recurrence. CONCLUSION: There is no relationship between SLND and ITM. Recent reports to the contrary reflect analysis of significantly smaller cohorts not matched for confounding variables such as T stage. The phase III Multicenter Selective Lymphadenectomy Trial will definitively settle the issue; until then, use of SLND, the most accurate staging procedure for early-stage melanoma, should continue.

Contemporary surgical treatment of advanced-stage melanoma.

HYPOTHESIS: The clinical treatment of patients with stage IV melanoma according to criteria of the American Joint Committee on Cancer (AJCC) is controversial because the 5-year survival rate is approximately 5%. Specific clinicopathologic factors are predictive of survival following curative surgery. DESIGN: Cohort analysis of 1574 successive patients undergoing surgical resection of metastatic melanoma for a 29-year period. Patients received follow-up on a routine basis with serial examinations and radiographic studies. The median follow-up time was 19 months (range, 1-382 months). SETTING: Tertiary cancer center. PATIENTS: Surgical resection was performed in 1574 patients. The decision to perform surgery was individualized for each patient. INTERVENTION: The technique of surgical resection was based on the site of metastasis. Main Outcome Measure Computer-assisted database with statistical analyses using log-rank tests and Cox regression models. RESULTS: Of the 4426 patients with AJCC stage IV melanoma, 1574 (35%) underwent surgical resection; 970 (62%) were men, with a median age of 50 years. Of the primary melanomas, 46% arose on the trunk, and 56% were Clark level IV or V with a median thickness of 2.2 mm. We found 697 patients (44%) to have AJCC stage III melanoma (lymph node) prior to the development of stage IV metastases. The most common site for resection was the lung (42%), followed by the skin or lymph node (19%) and the alimentary tract (16%). Of our patients, 877 (56%) had melanoma at a single site. The 5-year survival rate was significantly (P<.001) better for patients with a solitary melanoma (mean +/- SD, 29% +/- 2%) than those with 4 or more metastases (n = 147; mean +/- SD, 11% +/- 3%). Skin and lymph node metastases had the most favorable survival rate (median, 35.1 months). Multivariate analyses identified an earlier primary tumor stage (I vs II) (P<.001), an absence of intervening stage III metastases (P =.02), solitary metastasis (P<.001), and a long (>36 months) disease-free interval from AJCC stage I or II to stage IV (P =.005) as predictive of survival. CONCLUSIONS: Our results demonstrate the benefit of surgical resection for advanced-stage melanoma. Patients with limited sites and numbers of metastases should be considered for curative resection regardless of the location of the disease.

Endogenous immune response to early- and intermediate-stage melanoma is correlated with outcomes and is independent of locoregional relapse and standard prognostic factors.

BACKGROUND: Standard prognostic factors, including precise staging of the regional lymph nodes, cannot accurately determine which early-stage melanomas will metastasize. The immune response to a 90-kd tumor-associated antigen correlates with occult nodal disease and survival of patients receiving vaccine therapy for melanoma. We hypothesized that this response might have prognostic significance independent of standard prognostic features. STUDY DESIGN: Patients with primary melanomas 1.01 to 2.00 mm and tumor-negative regional lymph nodes were identified. Group 1 comprised 50 patients who died of metastases within 7 years after complete surgical treatment; group 2 comprised 50 patients who were matched with group 1 for six standard prognostic features but who lived at least 10 years without recurrence. Postoperative sera were analyzed for an immune complex to TA90 and for immunoglobulin-G and immunoglobulin-M antibodies against TA90. RESULTS: Median thickness of the primary melanoma was 1.40 +/- 0.31 mm and 1.42 +/- 0.32 mm in groups 1 and 2, respectively; median Clark's level of invasion was III in both groups, and 26 patients in each group had ulcerated primaries. Median TA90-IC level and rate of TA90-IC positivity (optical density greater than 0.410) were 0.557 +/- 0.43 and 82%, respectively, in group 1 and 0.305 +/- 0.15 and 18%, respectively, in group 2 (p < 0.001). The anti-TA90 IgM level was significantly elevated in 12% of group 1 (median titer 1:150) and 62% of group 2 (median titer 1:800) (p < 0.001). There was no significant difference in anti-TA90 IgG levels between the two groups. CONCLUSIONS: A positive TA90-IC level and absence of an anti-TA90 IgM response correlate with distant metastasis when melanoma is low risk or intermediate risk by standard prognostic factors.

Is sentinel lymph node mapping indicated for isolated local and in-transit recurrent melanoma?

OBJECTIVE: To determine the feasibility of sentinel lymph node mapping in local and in-transit recurrent melanoma. SUMMARY BACKGROUND DATA: The accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) for identification of occult lymph node metastases is well established in primary melanoma. We hypothesized that LM/SL could be useful to detect regional node metastases in patients with isolated local and in-transit recurrent melanoma (RM). METHODS: Review of our prospective melanoma database of 1600 LM/SL patients identified 30 patients who underwent LM/SL for RM. Patients with tumor-positive sentinel nodes (SNs) were considered for completion lymph node dissection. RESULTS: Of the 30 patients, 17 were men and 13 were women; their median age was 57 years (range, 29-86 years). Primary lesions were more often on the extremities (40%) than the head and neck (33%) or the trunk (8%). At least 1 SN was identified in each lymph node basin that drained an RM. Of the 14 (47%) patients with tumor-positive SNs, 11 (78%) underwent complete lymph node dissection; 4 had tumor-positive non-SNs. The median disease-free survival after LM/SL was 16 months (range, 1-108 months) when an SN was positive and 36 months (range, 6-132 months) when SNs were negative. At a median follow-up of 20 months (range, 2-48 months), there were no dissected basin recurrences after a tumor-negative SNs. CONCLUSIONS: LM/SL can accurately identify SNs draining an RM, and the high rate of SN metastases and associated poor disease-free survival for patients with tumor-positive SN suggests that LM/SL should be routinely considered in the management of patients with isolated RM.

Lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: therapeutic utility and implications of nodal microanatomy and molecular staging for improving the accuracy of detection of nodal micrometastases.

OBJECTIVE: Lymphatic mapping and sentinel lymphadenectomy (LM/SL) have been applied to virtually all solid neoplasms since our original description of LM/SL for melanoma. Our objectives were to determine the diagnostic and therapeutic utility of LM/SL, investigate carbon dye for mapping the microanatomy of lymphatic flow within the sentinel node (SN), and determine the prognostic accuracy of molecular assessment of the SN. METHODS: Since 1985, 1599 patients with AJCC Stage I/II melanoma have been treated by LM/SL at our institution and 4590 have been treated by wide excision (WE) without nodal staging. We examined the incidence of clinical nodal recurrence after WE alone, the incidence of subclinical nodal metastases found by LM/SL, and the incidence of nodal recurrence in basins with histopathology-negative SNs. RESULTS: In 1514 LM/SL patients with a primary of known Breslow thickness, the incidence of metastasis in nodes claimed to be sentinel was 7.3%, 19.7%, 33.2%, and 39.7% for primary lesions 4.0 mm, respectively. In 3652 WE-only patients, the corresponding rates of nodal recurrence were 12.0%, 32.0%, 34.4%, and 30.1%. Thus, LM/SL detected only 60% of expected nodal metastases from primary melanomas <2.01 mm. Forty of 1599 (3.1%) patients developed recurrence in basins with immunohistochemistry (IH)-negative SNs. To determine whether nonrandom intranodal distribution of tumor cells could explain missed SN metastases, we coinjected carbon particles and blue dye during LM/SL in 166 patients: 25 (16%) patients had nodal metastases, all of which were found only in nodal subsectors containing carbon particles. When paraffin-embedded SNs from a subset of 162 IH-negative patients were re-examined by quantitative multimarker reverse-transcriptase polymerase chain reaction (qRT) assay, 49 (30%) gave positive signals. These patients had a significantly higher risk of disease recurrence and death than did patients whose IH and qRT results were negative (p < 0.0001). Comparison of 287 prognostically matched pairs of patients who underwent immediate (after LM/SL) versus delayed (after observation) dissection of nodal metastases revealed 5-, 10-, and 15-year survival rates of 73%, 69%, and 69% versus 51%, 37%, and 32%, respectively (P < or = 0.001). CONCLUSIONS: SN assessment based on intranodal compartmentalization of lymphatic flow (carbon dye mapping) should increase the accuracy of IH and, in combination with multimarker qRT assessment, will allow confident identification of most patients for whom surgery alone is curative. Our data suggest a significant therapeutic benefit for immediate dissection based on identification of a tumor-involved SN.

Role of sentinel lymphadenectomy in thin invasive cutaneous melanomas.

PURPOSE: Regional lymph node status is the strongest prognostic determinant in early-stage melanoma. Lymphatic mapping and sentinel lymphadenectomy (LM/SL) is standard to stage regional nodes because it is accurate and minimally morbid, yet its role for thin (

Prolonged survival of patients receiving active immunotherapy with Canvaxin therapeutic polyvalent vaccine after complete resection of melanoma metastatic to regional lymph nodes.

OBJECTIVE: To determine whether adjuvant postoperative active specific immunotherapy with a therapeutic polyvalent vaccine (PV) called Canvaxin can prolong survival following complete resection of melanoma metastatic to regional nodes (American Joint Committee on Cancer [AJCC] stage III melanoma). SUMMARY BACKGROUND DATA: Despite complete lymphadenectomy, 5-year overall survival (OS) for patients with melanoma metastatic to regional lymph nodes is only 20% to 50%, depending on the number of tumor-involved nodes. In 1984, the authors began phase II trials of Canvaxin PV as postsurgical adjuvant therapy for AJCC stage III melanoma. METHODS: Patients who received PV between 1984 and 1998 were compared with patients who did not receive PV postsurgical therapy between 1971 and 1998. The seven covariates recently defined by the AJCC Melanoma Staging Committee (number of metastatic nodes, palpable status, ulceration, age, primary site, pT stage, and gender) were included by Cox regression in a multivariate model of OS. A computerized program matched PV and non-PV patients by these covariates. RESULTS: Of 2,602 patients who underwent complete lymphadenectomy for AJCC stage III melanoma with regional nodal metastases and were followed up by the same team of oncologists between 1971 and 1998, 935 received PV and 1,667 did not. Median OS and 5-year OS were significantly higher in PV than non-PV patients (56.4 vs. 31.9 months and 49% vs. 37%, respectively; P =.0001). When the non-PV patients were matched by the four most significant covariates, 447 matched pairs were formed between patients seen before or after January 1, 1985, and the OS was not different between the two time periods ( P=.789). However, when the PV patients were matched with non-PV patients by six covariates forming 739 pairs, the PV patients survived longer ( P=.0001). Detailed analysis of the 1,505 patients who were seen or who began vaccine therapy within 4 months after lymphadenectomy, and who had more complete data on the seven prognostic covariates showed that median OS and 5-year OS were higher in 445 PV patients than in 1,060 non-PV patients: 70.4 versus 31 months and 52% versus 37%, respectively (P =.0001). Multivariate Cox regression analysis identified six significant prognostic factors: number of metastatic nodes, size of metastatic nodes, pT stage, ulceration, age, and PV therapy. PV therapy reduced the relative risk of death to 0.64 (95% confidence interval, 0.55-0.76) ( P=.0001); sex and site of primary were of borderline significance. CONCLUSIONS: This large single-institution study independently confirmed the significance of prognostic covariates in the new AJCC staging system. By using modern statistical methods that controlled for all known prognostic factors, it also demonstrated PV's ability to significantly enhance OS. A multicenter phase III randomized trial is underway to validate the efficacy of PV as a postsurgical adjuvant.

Enhanced humoral immune response correlates with improved disease-free and overall survival in American Joint Committee on Cancer stage II melanoma patients receiving adjuvant polyvalent vaccine.

PURPOSE: Although the improved overall survival (OS) of patients who receive Canvaxin (CancerVax Corp, Carlsbad, CA) polyvalent vaccine (PV) immunotherapy for metastatic melanoma has been correlated with cellular and humoral immune responses, the mechanisms of vaccine immunotherapy for early-stage melanoma are unclear. Specific immune responses to tumor-associated antigens might correlate with disease-free survival (DFS) and OS in patients receiving adjuvant PV therapy for primary melanoma. PATIENTS AND METHODS: Eighty-three patients received PV plus bacille Calmette-Guérin after wide excision of American Joint Committee on Cancer stage II melanoma. Humoral and cellular responses during the first 12 weeks of adjuvant immunotherapy were assessed by serum antibody titers to a tumor-associated 90-kd glycoprotein antigen (TA90) expressed by PV, and by delayed-type hypersensitivity (DTH) skin testing with PV (PV-DTH). RESULTS: At a median follow-up period of 46.6 months (range, 10.7 to 93.6 months), an increased PV-DTH response seemed to be associated with improved 5-year DFS (54% v 20%) and 5-year OS (75% v 60%), but the correlations were not statistically significant. Anti-TA90 immunoglobulin (Ig) M levels > or = 1:800 were significantly correlated with improved 5-year DFS and improved 5-year OS, and multivariate analysis identified anti-TA90 IgM as an independent prognostic factor for OS and DFS. CONCLUSION: These findings suggest that an increased IgM response in patients receiving PV therapy for stage II melanoma is associated with decreased recurrence and improved survival.