Does the tumor status of the regional lymph nodes really matter in melanoma?
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Humans↗
Biomedical subjects
D L Morton
Publications and source records attributed to D L Morton.
Molecular clonality of in-transit melanoma metastasis.
In-transit melanoma is characterized by an aggressive pattern of recurrence that is associated with a poorer prognosis. Because in-transit melanoma is considered to result from the intralymphatic trapping of melanoma cells between the primary tumor and regional lymph nodes, it provides an excellent model to assess genetic events associated with early metastasis. The hypothesis of this study was to determine whether in-transit metastases are clonal in origin and therefore, may have specific genetic alterations uniquely associated with this disease and the development of early metastasis. This was assessed using loss of heterozygosity (LOH) analysis for specific DNA microsatellite loci. Seventy-nine paraffin-embedded in-transit melanoma lesions from 25 patients (range, 2 to 9 lesions per patient; average, 3.4 lesions per patient) were assessed for LOH using eight microsatellite DNA markers on six chromosomes. In 19 of 25 patients (76%) LOH was demonstrated for at least one marker. The most frequent microsatellite marker demonstrating LOH was D9S157 (56%). Using LOH microsatellite markers to assess intertumor heterogeneity, six of 79 tumors (7.6%) demonstrated different profiles when compared to other lesions from the same patient. In-transit metastases from those patients demonstrating intertumor heterogeneity were further assessed using laser capture microdissection and DNA analysis, and revealed no significant intratumor heterogeneity. In conclusion, LOH was frequently observed in in-transit melanoma metastasis. Based on LOH analysis, in-transit metastases are clonal in origin. The establishment of clinically successful in-transit melanoma metastasis requires specific genetic events that seem to be unique and homogeneous for each patient.
Clone Cells↗
The use of sentinel lymphadenectomy to identify candidates for postoperative adjuvant therapy of melanoma and breast cancer.
Sentinel lymphadenectomy (SLND) is fast becoming the procedure of choice for staging primary breast carcinoma and melanoma. This simpler and less morbid alternative to standard lymph node dissection can increase the rate of detecting nodal disease. Because the tumor status of the regional lymph nodes remains a significant prognostic tool in both diseases, clinicians may use SLND to facilitate selection of patients for adjuvant chemotherapy. Although SLND has been validated by institutions worldwide, it continues to evolve. The following review will examine current data and controversies surrounding this emerging technology.
Antineoplastic Agents↗
Sentinel lymph nodes show profound downregulation of antigen-presenting cells of the paracortex: implications for tumor biology and treatment.
The sentinel lymph node (SN) is the first node on the direct lymphatic drainage pathway from a tumor. Melanoma-associated SNs are the most likely site of early metastases and their immune functions are strikingly down-modulated. We evaluated histologic and cytologic characteristics of 21 SNs and 21 nonsentinel nodes (NSNs) from melanoma patients who had clinically localized (AJCC Stage I--II) primary cutaneous melanoma. SNs showed highly significant reductions in total paracortical area and in the area of the paracortical subsector occupied by dendritic cells. The frequency of paracortical interdigitating dendritic cells (IDCs) was dramatically reduced in SNs, and most IDCs (approximately 99%) lacked the complex dendrites associated with active antigen presentation. The release of immunosuppressive factors from the primary melanoma may induce a localized and specific paralysis in the SN, which prevents the recognition of otherwise immunogenic melanoma antigens by IDCs. This immune paralysis may facilitate the implantation and growth of melanoma cells in the SN. Cytokine therapy may be able to reverse this immune paralysis. These findings have an important practical application in the histopathologic confirmation that a node is truly sentinel. They also offer an hypothesis to explain the failure of the immune surveillance mechanisms to identify and respond to a small primary melanoma that expresses immunogenic tumor antigens.
Antigen-Presenting Cells↗
Lymphatic mapping and sentinel lymphadenectomy for melanoma: past, present, and future.
Intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) is a minimally invasive technique to determine whether a primary melanoma has metastasized to the sentinel node in the regional drainage basin. The sentinel node is the first node that receives lymph from any primary solid neoplasm whose drainage pattern is determined by its anatomical site and by the normal variations in lymphatic anatomy. Data from an ongoing multicenter phase III trial indicate that LM/SL for melanoma is accurate and reproducible when undertaken after a 30-case learning phase during which LM/SL is followed by complete lymphadenectomy. Although the optimal postoperative management of patients with sentinel node micrometastases identified by immunohistochemical staining has not been determined, adjuvant vaccine immunotherapy is a promising nontoxic approach that takes advantage of melanoma's intrinsic immunogenicity. Among the current adjuvant immunotherapy trials is a multicenter phase III study of CancerVax vaccine, an allogeneic polyvalent melanoma cell vaccine; results will indicate whether this vaccine should become standard therapy after complete surgical resection of melanoma metastatic to sentinel nodes.
Cancer Vaccines↗
Aberrant drainage and missed micrometastases: the value of lymphatic mapping and focused analysis of sentinel lymph nodes in gastrointestinal neoplasms.
Lymph node analysis is essential for staging gastrointestinal (GI) neoplasms. Our group has conducted several studies of intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) for the staging of GI neoplasms. LM is performed following injection of 0.5-1 ml of isosulfan blue dye, and blue-stained sentinel lymph nodes (SLNs) are analyzed by hematoxylin and eosin (H&E) staining, multiple sectioning, and cytokeratin immunohistochemistry. In feasibility trials, LM identified at least one SLN in 121 of 126 patients. Of the 58 cases with nodal metastasis, 50 (89%) had at least one positive SLN and 24 (42%) had nodal metastasis only in the SLN. In 25 cases, tumor deposits were identified by multiple sectioning (n = 8) or immunohistochemistry (n = 17) only. In 10 cases (8%), LM identified aberrant lymphatic drainage that altered the extent of the lymphadenectomy. Our cumulative experience indicates that focused analysis of the SLNs draining GI neoplasms can increase the detection of micrometastases and may improve selection of patients for adjuvant treatment.
Adenocarcinoma↗
The Augsburg Consensus. Techniques of lymphatic mapping, sentinel lymphadenectomy, and completion lymphadenectomy in cutaneous malignancies.
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Humans↗
Gangliosides as targets for immunotherapy for pancreatic adenocarcinoma.
BACKGROUND: Pancreatic adenocarcinoma cells express gangliosides and sialyl Lewis (sLe) antigens. It is not known whether these carbohydrate antigens can be targeted by immunotherapy. The authors measured the expression of GM(2) and sLe antigens on the surface of pancreatic carcinoma cells and the serum levels of total gangliosides, GM(2), and antiganglioside antibodies in patients with pancreatic carcinoma. METHODS: Cell surface GM(2) and sLe antigens were measured by cell suspension enzyme linked immunoadsorbent assay (ELISA) in four pancreatic carcinoma cell lines. Sera from 20 pancreatic carcinoma patients and 20 age- and gender-matched healthy volunteers were analyzed for antiganglioside and anti-sLe immunoglobulin (Ig) M titers by ELISA. Serum levels of total gangliosides and GM(2) also were measured. RESULTS: All cell lines expressed GM(2) and sLe antigens. When compared with age- and gender-matched volunteers, patients had significantly higher serum levels of total gangliosides (25.6 +/- 9.0 mg/dL vs. 15.6 +/- 2.7 mg/dL; P < 0.001), GM(2) (0.278 +/- 0.415 mg/dL vs. 0.013 +/- 0.018 mg/dL; P = 0.02), ELISA units of anti-GM(2) IgM antibody (368 +/- 95 vs. 155 +/- 25; P = 0.04) and anti-GD(1b) IgM antibody (351 +/- 91 vs. 138 +/- 26; P = 0.03), but not anti-sLe(x) IgM (1389 +/- 345 vs. 1081 +/- 224; P = 0.46) or anti-sLe(a) IgM antibody (1097 +/- 253 vs. 1200 +/- 315; P = 0.80). Patients with unresectable tumors had higher serum levels of total gangliosides compared with patients with resectable tumors, and a serum level > 25 mg/dL was found to correlate significantly with poor overall survival (P < 0.02). CONCLUSIONS: Increased serum levels of total gangliosides and GM(2) may reflect shedding or release of gangliosides from the surface of tumor cells. Production of IgM antibody against GM(2) and GD(1b) indicates that these gangliosides are immunogenic antigens that may be potential targets for effective active immunotherapy.
Adenocarcinoma↗
Molecular markers in blood as surrogate prognostic indicators of melanoma recurrence.
Improvement is needed in the ability to evaluate the prognosis of melanoma patients who are clinically disease-free but likely to develop recurrent metastatic disease. The detection of circulating melanoma cells in blood is a potential surrogate marker of subclinical residual disease. We assessed the prognostic clinical utility of a multimarker melanoma reverse transcriptase-PCR (RT-PCR) assay using blood of 46 patients who were clinically disease-free. All patients were followed up for more than 4 years for disease recurrence. There was a significant correlation between number of RT-PCR markers present in blood and American Joint Committee on Cancer stage (P = 0.009). The number of RT-PCR markers detected in blood was an independent prediction factor of disease recurrence in a Cox proportional hazard model (P = 0.02). A risk factor model using American Joint Committee on Cancer stage and number of positive RT-PCR markers significantly predicted disease recurrence in 2, 3, and 4 years of follow-up. These studies demonstrate that molecular detection of circulating melanoma cells may be of significant prognostic value in determining early disease recurrence and may be useful for stratifying patients for adjuvant therapy.
Biomarkers, Tumor↗
A new American Joint Committee on Cancer staging system for cutaneous melanoma.
The Melanoma Staging Committee of the AJCC has proposed major revisions of the melanoma TNM and stage grouping criteria. The committee members represent most of the major cooperative groups and cancer centers worldwide with a special interest in melanoma; the committee also collectively has had clinical experience with over 40,000 patients. The new staging system better reflects independent prognostic factors that are used in clinical trials and in reporting the outcomes of various melanoma treatment modalities. Major revisions include 1) melanoma thickness and ulceration, but not level of invasion, to be used in the T classification; 2) the number of metastatic lymph nodes, rather than their gross dimensions, the delineation of microscopic versus macroscopic lymph node metastases, and presence of ulceration of the primary melanoma to be used in the N classification; 3) the site of distant metastases and the presence of elevated serum LDH, to be used in the M classification; 4) an upstaging of all patients with Stage I,II, and III disease when a primary melanoma is ulcerated; 5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into Stage III disease; and 6) a new convention for defining clinical and pathologic staging so as to take into account the new staging information gained from intraoperative lymphatic mapping and sentinel lymph node biopsy. The AJC Melanoma Staging Committee invites comments and suggestions regarding this proposed staging system before a final recommendation is made.
Biopsy↗
Cryosurgical ablation and radiofrequency ablation for unresectable hepatic malignant neoplasms: a proposed algorithm.
BACKGROUND: Thermal ablation of unresectable hepatic tumors can be achieved by cryosurgical ablation (CSA) or radiofrequency ablation (RFA). The relative advantages and disadvantages of each technique have not yet been determined. HYPOTHESIS: Radiofrequency ablation of malignant hepatic neoplasms can be performed safely, but is currently limited by size. Cryosurgical ablation, while associated with higher morbidity, is more effective for larger unresectable hepatic malignant neoplasms. DESIGN: Retrospective analysis of prospective patient database. PATIENTS AND METHODS: Between July 1992 and September 1999, 308 patients with liver tumors not amenable to curative surgical resection were treated with CSA and/or RFA (percutaneous, laparoscopic, celiotomy). No patient had preoperative evidence of extrahepatic disease. All patients underwent laparoscopy with intraoperative ultrasound if technically possible. Both RFA and CSA were performed under ultrasound guidance. Resection, as an adjunctive procedure, was combined with ablation in certain patients. RESULTS: Laparoscopy identified extrahepatic disease in 12% of patients, and intraoperative hepatic ultrasound identified additional lesions in 33% of patients, despite extensive preoperative imaging. Radiofrequency ablation alone or combined with resection or CSA resulted in reduced blood loss (P<.05), thrombocytopenia (P<.05), and shorter hospital stay compared with CSA alone (P<.05). Median ablation times for lesions greater than 3 cm were 60 minutes with RFA and 15 minutes with CSA (P<.001). Local recurrence rates for lesions greater than 3 cm were also greater with RFA (38% vs 17%). CONCLUSIONS: Laparoscopy and intraoperative ultrasound are essential in staging patients with hepatic malignant neoplasms. Radiofrequency ablation when combined with CSA reduces the morbidity of multiple freezes. Although RFA is safer than CSA and can be performed via different approaches (percutaneously, laparoscopically, or at celiotomy), it is limited by tumor size (<3 cm). Percutaneous RFA should be considered in high-risk patients or those with small local recurrences.
Catheter Ablation↗
Lymphatic mapping and focused analysis of sentinel lymph nodes upstage gastrointestinal neoplasms.
BACKGROUND: Lymph node analysis is essential for staging gastrointestinal (GI) neoplasms. Intraoperative lymphatic mapping and sentinel lymphadenectomy were originally described for melanoma but have not yet been investigated for most GI neoplasms. HYPOTHESES: (1) Lymphatic mapping and sentinel lymphadenectomy is feasible in GI neoplasms, (2) the sentinel node (SN) status reflects the regional node status, and (3) focused analysis of the SN improves staging accuracy. DESIGN: Prospective patient series. PATIENTS AND METHODS: Lymphatic mapping was performed in 65 patients with GI neoplasms by injecting 0.5 to 1 mL of isosulfan blue dye around the periphery of the neoplasm. Blue-stained SNs were analyzed by hematoxylin-eosin staining, multiple sectioning, and cytokeratin immunohistochemistry. RESULTS: Lymphatic mapping identified at least 1 SN in 62 patients (95%). Of the 36 cases with nodal metastasis, 32 (89%) had at least 1 positive SN and 15 (42%) had nodal metastasis only in the SN. In 11 cases, tumor deposits were identified by multiple sectioning (n = 2) or immunohistochemistry (n = 9) only. In 5 cases (8%), lymphatic mapping identified aberrant lymphatic drainage that altered the extent of the lymphadenectomy. CONCLUSIONS: Lymphatic mapping and sentinel lymphadenectomy are feasible in GI neoplasms and identify aberrant lymphatic drainage. The SN status accurately reflects the regional node status. Focused analysis of the SN increases the detection of micrometastases and may improve selection of patients for adjuvant treatment.
Adult↗
Sentinel node detection in malignant melanoma.
The initial application of intraoperative lymphatic mapping and sentinel lymphadenectomy followed by selective complete lymphadenectomy (LM/SL/SCLND) was in melanoma. This arose as a solution to the ongoing debate concerning immediate vs. delayed lymph node dissection. Acceptance of the concept and advances in nuclear medicine, surgery, and pathology aspects of the sentinel node procedure have brought it into widespread use for melanoma and have expanded its application for other solid tumors that progress through the lymphatic route. Although the diagnostic accuracy of the procedure has been demonstrated in multicenter trials, caution should be exercised regarding therapeutic aspects until definitive benefit can be shown from well-designed clinical trials. Current issues of active discussion and debate are reviewed including ideal nomenclature, clinical significance of occult metastatic disease, quality assurance, and the role of LM/SL/SCLND outside high-volume melanoma centers.
Animals↗
Does endogenous immune response determine the outcome of surgical therapy for metastatic melanoma?
BACKGROUND: Although the presence of tumor cells in the blood of patients with metastatic melanoma suggests widely disseminated disease, many of these patients enjoy prolonged survival or cure after surgical resection. Our previous study of adjuvant vaccine therapy after complete resection of metastatic melanoma revealed a strong correlation between postoperative survival and elevated antibody titers to a 90-kDa tumor-associated antigen (TA90) expressed by melanoma cells of the vaccine. We hypothesized a similar correlation between postoperative survival and endogenous anti-TA90 antibody titers induced by the patient's melanoma in the absence of postoperative adjuvant immunotherapy. METHODS: From 1970 to 1996, 64 patients underwent complete resection of distant melanoma metastases and did not receive postoperative adjuvant immunotherapy. Serum collected within 4 months after surgery was tested in a coded and blinded fashion for anti-TA90 IgG and IgM by enzyme-linked immunosorbent assay, and for total IgG and IgM (controls) by radial immunodiffusion. RESULTS: Median follow-up for the study population was 19 months (range, 3-147 months). There was no significant correlation between anti-TA90 IgG titer and total IgG level (P = .4785), or between anti-TA90 IgM and total IgM (P = .0989). Univariate analysis showed that postoperative anti-TA90 IgM titer as a continuous variable was significantly associated with overall survival (OS); i.e., the higher the anti-TA90 IgM titer, the longer the OS. Using an established cutoff titer of 800, median OS was 42 months for patients with high anti-TA90 IgM titers (n = 28) vs. 9 months for patients with low titers (n = 36) (P = .0001). There was no significant correlation between total IgG/IgM and survival (P = .4107 and .4044, respectively). Multivariate analysis identified anti-TA90 IgM as the most significant independent variable influencing OS after complete resection of distant melanoma metastases (P = .0001). CONCLUSIONS: We conclude that the endogenous immune response to metastatic melanoma determines the outcome after surgical therapy. Enhancement of this specific immune response may prolong the survival of patients with distant melanoma metastases.
Antigens, Neoplasm↗
Is adjuvant radiotherapy necessary after positive lymph node dissection in head and neck melanomas?
INTRODUCTION: Postoperative radiotherapy (PR) has been recommended in patients with advanced head and neck melanomas to improve regional control. This study examined the incidence of cervical recurrence among patients who did not receive PR after surgical management of node-positive head and neck melanomas. METHODS: A computerized search of a database listing more than 10,000 patients with melanoma prospectively acquired between 1971 and 1998 identified 217 patients with pathologically positive nodes who had undergone regional lymph node dissection (RLND). Of these patients, 21 had received PR and 196 had not. RESULTS: Median follow-up after RLND was 20 months for nonsurvivors and 32 months for survivors. The overall incidence of cervical recurrence was 14% (27/196). The 5-year cervical recurrence-free survival rate was 83%. Five-year cervical recurrence-free survival rates were 69% vs. 87% for patients with vs. without extranodal disease (P = .004), 96% vs. 81% for patients with nonpalpable vs. palpable nodes (P = .0761), and 82% vs. 91% for patients with one to three positive nodes vs. more than three positive nodes (P = .256). Multivariate analysis, which included the timing of nodal disease presentation and the effect of systemic adjuvant therapy, identified extranodal disease as the only independent predictor of cervical recurrence (P = .034). Cervical recurrence was significantly related to the subsequent occurrence of distant relapse. CONCLUSIONS: The low incidence of cervical recurrence after RLND in patients with node-positive head and neck melanomas does not justify the routine use of PR. The only subset of patients who may benefit from PR are those with extranodal disease.
Adolescent↗
Can elective lymph node dissection decrease the frequency and mortality rate of late melanoma recurrences?
BACKGROUND: Although more than 90% of the morbidity and mortality from localized cutaneous melanoma occurs in the first decade after initial surgical treatment, melanoma can recur after a 10-year disease-free interval (DFI) with fatal consequences. We reviewed our melanoma data base of more than 8,500 prospectively acquired patients to identify clinicopathological factors that affect the type, rate of occurrence, and outcome of disease recurring 10 years or more after surgical treatment of primary cutaneous melanoma. METHODS: From 1971 to 1997, 1907 melanoma patients treated at our cancer center reached or presented with a DFI of 10 years or more after surgical treatment of clinically localized melanoma. Of these, 217 (11%) patients had recurrences (mean DFI, 182 months). The sites of recurrence were local/in-transit in 26 (12%) patients, regional lymph nodes in 101 (47%) patients, and distant sites in 90 (41%) patients. RESULTS: Univariate and multivariate analysis, using patient age and sex, type of initial treatment, and the site, Breslow thickness, and Clark level of the initial tumor, showed that the type of treatment for the primary tumor was a significant (P = .0005) prognostic factor in the development of late nodal recurrence. Of the 217 patients who had recurrences, 172 (79%) had undergone wide local excision for their primary melanoma, and 45 (21%) had undergone wide local excision plus elective lymph node dissection (ELND). The rates of nodal recurrence were 53% (92 of 172) and 20% (9 of 45), respectively, a significant (P = .0001) difference. When all patients with a DFI of 10 years or more were stratified by type of initial treatment, the ELND group demonstrated a significant improvement in disease-free survival and overall survival. CONCLUSIONS: The risk of late-recurring nodal disease increases and the chance of long-term survival decreases when wide local excision is performed without ELND. With the advent of sentinel lymphadenectomy, ELND can be selectively performed only for those nodal basins with occult tumor cells, thereby decreasing operative morbidity but allowing identification and early removal of nodal micrometastases.
Adolescent↗
TA90-IC, a new marker for advanced colon cancer.
BACKGROUND: Although carcinoembryonic antigen (CEA) is the most frequently used marker for colon cancer, it is elevated in only 70% of patients with advanced disease and in even fewer patients with earlier stages of disease. We previously identified a 90-kDa glycoprotein, TA90, which is present in serum in the form of circulating immune complexes. TA90 is found in a variety of solid neoplasms but rarely in healthy controls (3.2%). We hypothesized that this new tumor-associated antigen may be a useful marker for colon cancer. METHODS: Serum samples from 59 patients with known colon adenocarcinoma were analyzed for the presence of CEA and TA90. Fifty-one (86%) patients had distant metastases; the remaining patients had clinically localized primary colon cancer. A murine monoclonal antibody-based enzyme-linked immunosorbent assay was used to measure concentrations of TA90-specific circulating immune complexes (TA90-IC). A positive value was defined as an optical density of more than 0.410 at 405 nm. Forty-seven (80%) of the 59 patients had serum samples for TA90 and CEA drawn at the same time. RESULTS: TA90-IC concentrations were elevated more frequently than CEA concentrations (82.9% vs. 70.2%; P = .134). The combination of both markers identified more patients with colon carcinoma than did either marker alone (93.6%; P < .001). CONCLUSIONS: Concomitant use of TA90-IC and CEA identified 93.6% of patients with advanced colon cancer. The role of TA90-IC in screening and monitoring progression of earlier disease deserves further investigation.
Adult↗
The concept of sentinel node localization: how it started.
Intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) followed by selective complete lymphadenectomy (SCLND) has revolutionized the management of the regional lymph node basin in patients with solid tumors. Many investigators over the centuries have contributed to the understanding of the progression of tumor cells through the lymphatic system. This article discusses the conceptual background for the development of LM/SL in the original model of melanoma. The sentinel node hypothesis has been validated by a multicenter clinical trial showing that LM/SL in melanoma can be accurately performed in a uniform manner by multidisciplinary teams at cancer centers worldwide. Although the diagnostic and prognostic accuracy of LM/SL has been established, demonstration of the therapeutic use of this procedure awaits analysis of survival data from the multicenter randomized trial of wide excision alone versus wide excision plus LM/SL/SCLND.
Humans↗