Defining Adequate Surgery for Primary Melanoma
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《新英格兰医药杂志》
The incidence of malignant melanoma has been rising over the past three decades.1 Much of the increase is accounted for by thin, localized cutaneous melanomas with the potential to be cured by surgery. Once melanoma spreads beyond the primary lesion, however, the likelihood of cure decreases dramatically. Five-year relative survival rates for patients with melanoma in the United States between 1992 and 1998 were 96 percent for those with local lesions but only 60 percent for patients whose melanomas had spread regionally and 14 percent for those with distant metastases.1 The thickness of the tumor and the presence or absence of ulceration are the strongest independent predictors of outcome for localized melanomas and are included as criteria in the recently modified American Joint Committee on Cancer (AJCC) melanoma staging system,2 which includes criteria for clinical and pathological staging.
When melanoma is apparently localized to the primary site, the aim of surgery is to remove not only the primary tumor but also sufficient surrounding tissue to eliminate clinically inapparent malignant cells present in cutaneous lymphatics adjacent to the lesion and capable of local growth and regional or distant spread. Exactly how much tissue to remove in order to accomplish this goal without causing excessive surgical complications has been the subject of considerable debate and investigation.
Decisions about the extent of surgery for primary melanomas have been informed by the results of several randomized trials that compared narrow (1 to 2 cm) and wide (3 to 5 cm) surgical margins.3 With one exception,4 however, these trials excluded patients whose tumors were thicker than 2 mm, and none included patients with tumors thicker than 4 mm. For melanomas that are less than 2 mm thick, the available evidence suggests that a surgical margin of 1 cm is sufficient and that wider margins do not improve disease-free or overall survival.3 Most current treatment guidelines agree that a 1-cm margin is inadequate for melanomas that are more than 2 mm thick and recommend the use of 2-cm margins,3 but optimal surgical margins for such tumors have not been determined.
In this issue of the Journal, Thomas and colleagues5 address the question of adequate margins for lesions that are at least 2 mm thick. Starting in 1993, 900 patients were randomly assigned to undergo surgery involving either a 1-cm or a 3-cm excision margin and were followed for a median of 60 months. More than 25 percent of the patients had tumors thicker than 4 mm. The risk of local or regional recurrence was significantly greater in the 1-cm group than in the 3-cm group. Various measures of survival did not differ significantly between the groups, but the hazard ratio for melanoma-specific survival favored the wider margin.
Patients in this study did not have palpable regional lymph nodes and were not permitted to undergo sentinel-lymph-node mapping or regional lymphadenectomy to detect occult micrometastases. Over the past 10 years, however, intraoperative lymphatic mapping with biopsy of sentinel lymph nodes has become widely used to evaluate such patients and is required for pathological staging in the revised AJCC staging system.2 Approximately 15 percent of patients with primary melanomas and no palpable lymphadenopathy (i.e., clinical stage I or II) will be found to have melanoma involving one or more sentinel lymph nodes (i.e., pathological stage III) when the nodes are examined after staining with hematoxylin and eosin. Detection of a positive sentinel lymph node usually triggers removal of the regional-lymph-node basin, but additional involved lymph nodes are found in only about 15 percent of patients and are extremely rare in cases in which no more than 1 percent of the sentinel node is replaced by melanoma.6 The likelihood of nodal involvement increases in proportion to the depth of the primary melanoma and the number of histologic sections examined.
Newer, more sensitive techniques have been used to analyze sentinel lymph nodes and detect melanoma cells not identified by standard histologic methods.7 The polymerase chain reaction (PCR) can be used to amplify RNA extracted from fresh tissue or paraffin-embedded specimens and detect one or more melanoma differentiation genes with a high degree of sensitivity.8 Data from several investigations indicate that patients with sentinel lymph nodes that are positive for melanoma genes on PCR but negative on histologic analysis have a risk of recurrence that is intermediate between that of patients whose sentinel nodes are negative on both histologic analysis and PCR and that of patients whose sentinel nodes are histologically positive.9,10,11 Patients whose sentinel nodes are negative on both histologic analysis and PCR have a very low risk of recurrence.8
The detection of melanoma in a sentinel lymph node is an adverse prognostic finding, but it is unclear whether removing the sentinel lymph node simply provides prognostic information or is beneficial in itself. Thomas et al. speculate that, in their patients, biopsy of the sentinel lymph node would merely have modified the observed pattern of recurrence,5 but there is evidence that the procedure may have a therapeutic effect. An analysis of more than 1400 patients with surgically excised metastases of regional lymph nodes showed a significantly lower survival rate among patients with palpable nodal metastases than among those with equal numbers of nonpalpable nodal metastases.2 These findings suggest that removal of involved but nonpalpable lymph nodes could increase survival and not merely change the pattern of recurrence. To assess the therapeutic value of sentinel-lymph-node biopsy, the Multicenter Selective Lymphadenectomy Trial I has enrolled 2001 patients with primary melanomas deeper than 1 mm who underwent tumor excision with wide surgical margins and were randomly assigned to undergo biopsy of the sentinel lymph node or observation. The primary end points of this trial are disease-free and overall survival, but the results will not be known for several years.
Even if biopsy of the sentinel lymph node turns out not to influence survival, knowledge of nodal status is required for accurate pathological staging. This permits informed discussions about prognosis and identification of patients who might benefit from adjuvant therapy. Although we and others share the doubts expressed by Thomas et al.5 about the value of adjuvant therapy with interferon for pathological stage III melanoma, the poor prognosis for such cancers provides a strong rationale for investigating novel approaches to reducing the risk of recurrence. Of particular interest are vaccines intended to immunize high-risk patients against antigens present on melanoma cells.12 In addition to whole-cell, ganglioside, and peptide vaccines, current approaches include immunization with plasmid DNA encoding melanoma antigens and autologous dendritic cells loaded with melanoma antigens.
The current study establishes conclusively that primary melanomas at least 2 mm thick require excision margins that exceed 1 cm but does not address the question of whether a 3-cm margin is better than a 2-cm margin. It is unlikely that this question will ever be rigorously studied, and it is not clear that the findings of the current study will change surgical practice. In any event, no matter how wide the surgical margins, a substantial proportion of thicker melanomas will recur, but some will not. Melanomas destined to recur despite the best surgical technique and those cured with surgery most likely have inherent biologic differences that transcend currently recognized prognostic characteristics of patients and tumors. In the future, genomic and proteomic techniques may be applied that will identify genes and proteins associated with recurrence, explain how they lead to a more aggressive phenotype, and suggest targets for therapy.
Source Information
From the Clinical Immunology Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York.
References
Cancer facts & figures 2003. Atlanta: American Cancer Society, 2003. (Accessed January 29, 2004, at http://www.cancer.org/downloads/STT/CAFF2003PWSecured.pdf)
Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001;19:3622-3634.
Lens MB, Dawes M, Goodacre T, Bishop JA. Excision margins in the treatment of primary cutaneous melanoma: a systematic review of randomized controlled trials comparing narrow vs wide excision. Arch Surg 2002;137:1101-1105.
Balch CM, Soong SJ, Smith T, et al. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 2001;8:101-108.
Thomas JM, Newton-Bishop J, A'Hern R, et al. Excision margins in high-risk malignant melanoma. N Engl J Med 2004;350:757-766.
Cochran AJ, Wen R, Wang HJ, Elashoff R, Morton DL. Prediction of metastatic melanoma in non-sentinel nodes and clinical outcome based on the primary melanoma and the sentinel node. Mod Pathol (in press).
Busam KJ. Advances in molecular staging of melanoma patients: multimarker analysis of archival lymph node tissue. J Clin Oncol 2003;21:3550-3551.
Kuo CT, Hoon DS, Takeuchi H, et al. Prediction of disease outcome in melanoma patients by molecular analysis of paraffin-embedded sentinel lymph nodes. J Clin Oncol 2003;21:3566-3572.
Shivers SC, Li W, Lin J, et al. The clinical relevance of molecular staging for melanoma. Recent Results Cancer Res 2001;158:187-199.
Rimoldi D, Lemoine R, Kurt AM, et al. Detection of micrometastases in sentinel lymph nodes from melanoma patients: direct comparison of multimarker molecular and immunopathological methods. Melanoma Res 2003;13:511-520.
Bostick PJ, Morton DL, Turner RR, et al. Prognostic significance of occult metastases detected by sentinel lymphadenectomy and reverse transcriptase-polymerase chain reaction in early-stage melanoma patients. J Clin Oncol 1999;17:3238-3244.
Wolchok JD, Livingston PO. Vaccines for melanoma: translating basic immunology into new therapies. Lancet Oncol 2001;2:205-211.
Related Letters:
Excision Margins in High-Risk Malignant Melanoma
Hellman S., Hurt M. A., Thomas J. M., A'Hern R., Newton-Bishop J.(Susan E. Krown, M.D., and)
When melanoma is apparently localized to the primary site, the aim of surgery is to remove not only the primary tumor but also sufficient surrounding tissue to eliminate clinically inapparent malignant cells present in cutaneous lymphatics adjacent to the lesion and capable of local growth and regional or distant spread. Exactly how much tissue to remove in order to accomplish this goal without causing excessive surgical complications has been the subject of considerable debate and investigation.
Decisions about the extent of surgery for primary melanomas have been informed by the results of several randomized trials that compared narrow (1 to 2 cm) and wide (3 to 5 cm) surgical margins.3 With one exception,4 however, these trials excluded patients whose tumors were thicker than 2 mm, and none included patients with tumors thicker than 4 mm. For melanomas that are less than 2 mm thick, the available evidence suggests that a surgical margin of 1 cm is sufficient and that wider margins do not improve disease-free or overall survival.3 Most current treatment guidelines agree that a 1-cm margin is inadequate for melanomas that are more than 2 mm thick and recommend the use of 2-cm margins,3 but optimal surgical margins for such tumors have not been determined.
In this issue of the Journal, Thomas and colleagues5 address the question of adequate margins for lesions that are at least 2 mm thick. Starting in 1993, 900 patients were randomly assigned to undergo surgery involving either a 1-cm or a 3-cm excision margin and were followed for a median of 60 months. More than 25 percent of the patients had tumors thicker than 4 mm. The risk of local or regional recurrence was significantly greater in the 1-cm group than in the 3-cm group. Various measures of survival did not differ significantly between the groups, but the hazard ratio for melanoma-specific survival favored the wider margin.
Patients in this study did not have palpable regional lymph nodes and were not permitted to undergo sentinel-lymph-node mapping or regional lymphadenectomy to detect occult micrometastases. Over the past 10 years, however, intraoperative lymphatic mapping with biopsy of sentinel lymph nodes has become widely used to evaluate such patients and is required for pathological staging in the revised AJCC staging system.2 Approximately 15 percent of patients with primary melanomas and no palpable lymphadenopathy (i.e., clinical stage I or II) will be found to have melanoma involving one or more sentinel lymph nodes (i.e., pathological stage III) when the nodes are examined after staining with hematoxylin and eosin. Detection of a positive sentinel lymph node usually triggers removal of the regional-lymph-node basin, but additional involved lymph nodes are found in only about 15 percent of patients and are extremely rare in cases in which no more than 1 percent of the sentinel node is replaced by melanoma.6 The likelihood of nodal involvement increases in proportion to the depth of the primary melanoma and the number of histologic sections examined.
Newer, more sensitive techniques have been used to analyze sentinel lymph nodes and detect melanoma cells not identified by standard histologic methods.7 The polymerase chain reaction (PCR) can be used to amplify RNA extracted from fresh tissue or paraffin-embedded specimens and detect one or more melanoma differentiation genes with a high degree of sensitivity.8 Data from several investigations indicate that patients with sentinel lymph nodes that are positive for melanoma genes on PCR but negative on histologic analysis have a risk of recurrence that is intermediate between that of patients whose sentinel nodes are negative on both histologic analysis and PCR and that of patients whose sentinel nodes are histologically positive.9,10,11 Patients whose sentinel nodes are negative on both histologic analysis and PCR have a very low risk of recurrence.8
The detection of melanoma in a sentinel lymph node is an adverse prognostic finding, but it is unclear whether removing the sentinel lymph node simply provides prognostic information or is beneficial in itself. Thomas et al. speculate that, in their patients, biopsy of the sentinel lymph node would merely have modified the observed pattern of recurrence,5 but there is evidence that the procedure may have a therapeutic effect. An analysis of more than 1400 patients with surgically excised metastases of regional lymph nodes showed a significantly lower survival rate among patients with palpable nodal metastases than among those with equal numbers of nonpalpable nodal metastases.2 These findings suggest that removal of involved but nonpalpable lymph nodes could increase survival and not merely change the pattern of recurrence. To assess the therapeutic value of sentinel-lymph-node biopsy, the Multicenter Selective Lymphadenectomy Trial I has enrolled 2001 patients with primary melanomas deeper than 1 mm who underwent tumor excision with wide surgical margins and were randomly assigned to undergo biopsy of the sentinel lymph node or observation. The primary end points of this trial are disease-free and overall survival, but the results will not be known for several years.
Even if biopsy of the sentinel lymph node turns out not to influence survival, knowledge of nodal status is required for accurate pathological staging. This permits informed discussions about prognosis and identification of patients who might benefit from adjuvant therapy. Although we and others share the doubts expressed by Thomas et al.5 about the value of adjuvant therapy with interferon for pathological stage III melanoma, the poor prognosis for such cancers provides a strong rationale for investigating novel approaches to reducing the risk of recurrence. Of particular interest are vaccines intended to immunize high-risk patients against antigens present on melanoma cells.12 In addition to whole-cell, ganglioside, and peptide vaccines, current approaches include immunization with plasmid DNA encoding melanoma antigens and autologous dendritic cells loaded with melanoma antigens.
The current study establishes conclusively that primary melanomas at least 2 mm thick require excision margins that exceed 1 cm but does not address the question of whether a 3-cm margin is better than a 2-cm margin. It is unlikely that this question will ever be rigorously studied, and it is not clear that the findings of the current study will change surgical practice. In any event, no matter how wide the surgical margins, a substantial proportion of thicker melanomas will recur, but some will not. Melanomas destined to recur despite the best surgical technique and those cured with surgery most likely have inherent biologic differences that transcend currently recognized prognostic characteristics of patients and tumors. In the future, genomic and proteomic techniques may be applied that will identify genes and proteins associated with recurrence, explain how they lead to a more aggressive phenotype, and suggest targets for therapy.
Source Information
From the Clinical Immunology Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York.
References
Cancer facts & figures 2003. Atlanta: American Cancer Society, 2003. (Accessed January 29, 2004, at http://www.cancer.org/downloads/STT/CAFF2003PWSecured.pdf)
Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001;19:3622-3634.
Lens MB, Dawes M, Goodacre T, Bishop JA. Excision margins in the treatment of primary cutaneous melanoma: a systematic review of randomized controlled trials comparing narrow vs wide excision. Arch Surg 2002;137:1101-1105.
Balch CM, Soong SJ, Smith T, et al. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 2001;8:101-108.
Thomas JM, Newton-Bishop J, A'Hern R, et al. Excision margins in high-risk malignant melanoma. N Engl J Med 2004;350:757-766.
Cochran AJ, Wen R, Wang HJ, Elashoff R, Morton DL. Prediction of metastatic melanoma in non-sentinel nodes and clinical outcome based on the primary melanoma and the sentinel node. Mod Pathol (in press).
Busam KJ. Advances in molecular staging of melanoma patients: multimarker analysis of archival lymph node tissue. J Clin Oncol 2003;21:3550-3551.
Kuo CT, Hoon DS, Takeuchi H, et al. Prediction of disease outcome in melanoma patients by molecular analysis of paraffin-embedded sentinel lymph nodes. J Clin Oncol 2003;21:3566-3572.
Shivers SC, Li W, Lin J, et al. The clinical relevance of molecular staging for melanoma. Recent Results Cancer Res 2001;158:187-199.
Rimoldi D, Lemoine R, Kurt AM, et al. Detection of micrometastases in sentinel lymph nodes from melanoma patients: direct comparison of multimarker molecular and immunopathological methods. Melanoma Res 2003;13:511-520.
Bostick PJ, Morton DL, Turner RR, et al. Prognostic significance of occult metastases detected by sentinel lymphadenectomy and reverse transcriptase-polymerase chain reaction in early-stage melanoma patients. J Clin Oncol 1999;17:3238-3244.
Wolchok JD, Livingston PO. Vaccines for melanoma: translating basic immunology into new therapies. Lancet Oncol 2001;2:205-211.
Related Letters:
Excision Margins in High-Risk Malignant Melanoma
Hellman S., Hurt M. A., Thomas J. M., A'Hern R., Newton-Bishop J.(Susan E. Krown, M.D., and)