- Email: [email protected]
Sentinel node assessment for melanoma
Surgical Oncology
Sentinel Node Assessment for Melanoma Guest Reviewer: J. Michael McGee, MD SENTINEL LYMPH NODE BIOPSY FOR MELANOMA.
Gogel BM, Kuhn JA, Ferry KM, et al. Am J Surg 1998;176:544 –547.
Objective
318
To determine if sentinel lymph node biopsy is technically feasible and if it accurately assesses the lymph node basin.
Design
A multicenter, prospective, uncontrolled study.
Setting
Department of Surgery, Baylor University Medical Center, Dallas, Texas, and the Department of Surgery, University of Vermont, Burlington, Vermont.
Participants
Sixty-eight melanoma patients with primary lesions thicker than 0.4 to 7.8 mm. Five patients had previous wide local excision.
Methods
Forty male and 28 female patients aged 24 to 83 years were enrolled with primary lesions on the trunk (27 patients), head and neck (13 patients), upper extremity (12 patients), and lower extremity (12 patients). All patients had preoperative lymphoscintigraphy with technetium (Tc)-99 sulfur colloid. After 60 to 420 minutes, patients were taken to the operating room for sentinel lymph node biopsy with a hand-held gamma counter. Counts/10 seconds were recorded for sentinel nodes (SN), defined by increased radioactivity. If the count ratio did not return to normal, then additional nodes were sought with the background normalized. The sentinel nodes were placed in formation routinely for hematoxylin and eosin (H&E) staining, reserving immunohistochemistry for suspicious areas or H&E. There was a 22-month mean follow-up.
Results
At least 1 sentinel lymph node was found for each patient. Only 31 patients had 1 sentinel node, 14 had 2 sentinel nodes, 8 had 3 sentinel nodes, 6 had 4 sentinel nodes, 5 had 5 sentinel nodes, and 4 had 6 sentinel nodes. Six patients had a positive sentinel node. At a mean follow-up of 22 months, 2 more patients, originally negative, had nodal recurrence requiring lymph node dissection. Upon further sectioning and immunostaining, 1 of these patients was found to have been positive originally. Two additional patients recurred systemically and presented with lesions of 4.5 and 8.0 mm. Of the original 6 patients with positive SN, 4 are alive with no evidence of disease, 1 is alive with lung metastases, and 1 is dead of systemic disease at 34-months postbiopsy. Disease free (94% to 67%) and overall (100% to 86%) survival was better for SN-negative patients.
Conclusions
Gamma-probe– guided (only) sentinel lymph node biopsy can be performed with success, and it provides fairly accurate pathologic staging with a low rate of nodal basin recurrence. CURRENT SURGERY
•
Volume 56 / Number 6 • July/August 1999
REVIEWER COMMENTS. This article represents the initial experience of these authors. Lack of homogeneity in the study group, lack of a control group, and lack of statistical analysis weaken the study. The authors contend that they were able to find the sentinel node with only the handheld gamma probe, and at least one author is a proponent of their particular probe. They further state that their accuracy is high and recurrent disease is low. The national standard seems to include immunohistochemistry, and this, by their admission, would have improved their accuracy. Of 68 patients, 6 had a positive node and underwent completion lymph node dissection. Two of those 6 patients died of systemic disease, leaving only 4 patients to have been helped by the procedure. Two of the 62 SN-negative patients went on to develop metastatic disease in the previously evaluated nodal basin for a false-negative rate of 3.2%, which seems acceptable and may have been improved by more intensive pathologic evaluation. These authors were able to successfully perform the procedure in 5 patients who previously had wide local excision. MINIMALLY INVASIVE STAGING IN PATIENTS WITH MELANOMA: SENTINEL LYMPHADENECTOMY AND DETECTION OF THE MELANOMA-SPECIFIC PROTEINS MART-1 AND TYROSINASE BY REVERSE TRANSCRIPTASE POLYMERASE CHAIN.
Goydos JS, Ravikumar TS, Germino FJ, et al. J Am Coll Surg 1998;187:182–190. To demonstrate that sentinel lymph node biopsy is feasible under local anesthesia and that routine use of reverse transcriptase polymerase chain reaction (RT-PCR) should become the standard of care.
Objective
This study is a phase II, prospective, uncontrolled study.
Design
Departments of Surgery, Medicine, Nuclear Medicine, and Pathology, Robert Wood Johnson Medical School, New Brunswick, New Jersey.
Setting
Fifty patients, 30 male and 20 female, with primary melanoma 1 or more mm thick, underwent sentinel lymph node biopsy under local anesthesia, using blue dye, Tc-99 sulfur colloid, and a handheld gamma probe. Each sentinel node was sectioned along its long axis. One half was sent for routine H&E stains and immunohistochemistry “when appropriate,” and the other half was frozen in liquid nitrogen for RT–PCR for tyrosinase and MART-1.
Participants
All patients tolerated SN biopsy under local anesthesia, and SN were obtained in 100% of patients, mean, 2.1 SN/patient. Usable RNA was obtained from 90% of patients. Ten patients had 15 positive nodes by routine histopathology, 20% of the total number of patients and 14% of the total number of nodes. Three more histopathologically negative patients were positive by PCR. Two patients were positive for both tyrosinase and MART-1, and 1 was positive only for MART-1. These 3 patients received observation only and did not have completion lymph node dissection. The average cost of these outpatient procedures was 38% less than that of similar operations performed in the operating room.
Results
Sentinal node biopsy is feasible under local anesthesia in an outpatient setting, with intraoperative SN preservation in liquid nitrogen. Tyrosinase and MART-1 are promising markers to detect occult melanoma in SN.
Conclusions
REVIEWER COMMENTS. The cost of RT-PCR is substantial. The handling of the tissue, even by these authors, is not trivial. Only 90% of the tissues were adequate for analysis. They found 2 more “positive” patients by this technique, but did not believe their findings enough to complete the nodal dissection in these patients. Whether RT-PCR is helpful is important. Only long-term follow-up of those patients who are H&E and immunohistochemically negative, but PCR positive can answer it. This is precisely the question asked by at least 1 large national trial. The ability to diagnose cancer by molecular means is upon us, but we must be able to make sense of it in clinical terms. THE SENTINEL NODE DEBATE: HISTORICAL PERSPECTIVE OF LYMPHATIC TUMOR SPREAD AND THE EMERGENCE OF THE SENTINEL NODE CONCEPT.
Borgstein P, Meijer S. Eur J Surg Oncol 1998:24:85–95. To explore the role of sentinel lymph node biopsy in the context of treatment and staging of the regional nodal basin.
Objective
Literature review.
Design
CURRENT SURGERY
•
Volume 56 / Number 6 • July/August 1999
319
Setting
Department of Surgical Oncology, Vrije University, Amsterdam, The Netherlands.
Results
The sentinel node concept is explored historically and defined as follows: (1) an orderly and predictable pattern of lymph flow from the primary site to the regional lymph node basin exists; (2) a sequential progression of tumor cells passes through the lymph vessels to a primary draining lymph node; and (3) the first lymph node effectively filters the afferent lymph, whereby the tumor cells become entrapped. The lymphatic anatomy is reviewed, revealing an orderly and predictable pattern. Tumor cell kinetics is explored. Passage through lymph vessels remains passive, allowing tumor cell embolism. However, lymphatic valves can trap tumor cells. A sequential passage of cells to a primary draining lymph node occurs. Lymph node function is classified by three groups: (1) primary—receiving most of the afferent vessels; (2) intermediary or mixed function nodes—receiving lymph from primary nodes and afferent lymphatics; and (3) passage nodes—through which only the lymph from other nodes flows. Lymph nodes act as filters and may retain tumor cells for long periods of time. The mechanism of actual metastasis to lymph nodes remains obscure. Important immune functions occur along sinusoids in lymph nodes where macrophages are placed. Antigens are processed and presented to lymphocytes generating cellular and humoral immunity. The importance of lymph node metastases to prognosis and the evidence of so many patients doing well with locoregional treatment give corroboration to the importance of lymph node function.
Conclusions
Lymph drainage is orderly and predictable, going first to primary nodes. Although the biologic significance of lymph node metastases is controversial, removing the involved nodes and leaving the uninvolved seems to make sense. The success of sentinel lymph node biopsy depends on the accuracy of detection methods preoperatively and intraoperatively. REVIEWER COMMENTS. This paper is a nice review of the issues surrounding sentinel lymph node biopsy, providing an extensive historical context and excellent bibliography for those who want more. One more conclusion should be added: the success and acceptance of this procedure also depends on the ability and compulsiveness of the pathologist.
SUMMARY It cannot be proven that elective lymph node dissection confers improved survival for all patients with melanoma, only for those with intermediately thick lesions.1 Nevertheless, the rationale for early removal of lymph node metastases can be supported by the improved survival noted for patients with nonpalpable nodal metastases (50% to 60%, 5-year survival rate), as compared with patients that develop clinically palpable nodal metastases (20% to 25%, 5-year survival rate).2 Furthermore, if the lymph nodes containing metastases can be identified more precisely, then improvements in the precision of therapy and survival could be expected. The concept of the sentinel node takes the treatment of melanoma to that next level. The history of this development is nicely outlined in the reviewed articles, as is the technique. Simply stated, if the exact node or nodes that drain a precise portion of the integument can be identified and accurately analyzed for metastatic disease, then only those patients with lymph nodal metastases would undergo regional lymph node dissection. Therefore, patients with disease confined to the skin will be spared from the morbidity of node dissection, and elective lymph node dissection could finally be put to rest. These reviewed articles seem to indicate that, at least for melanoma, the concept of the sentinel lymph node is a sound one. Since accurately finding the sentinel node in the first crucial step, adherence to protocol and use of radionuclide and
320
blue dye would seem important. Veering from the proven methods must now be substantiated with well-designed studies. It is equally important that the pathologist adequately examine these nodes. Multiple sections and immunohistochemistry are a must. Efficacy of RT-PCR is yet to be established, but looks promising. This is an exciting topic. These reviewed papers cover most of the essential points. A few more references are provided for your review.3–5 J. MICHAEL McGEE, MD Department of Surgery College of Medicine University of Oklahoma Tulsa, Oklahoma
References 1. Balch CM, Soong SJ, Bartolucci AA, et al. Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg 1996;224:255–266. 2. Reintgen DS, Cox EB, McCarty KS Jr, et al. Efficacy of elective lymph node dissection in patients with intermediate thickness primary melanoma. Ann Surg 1983;198:379 –385. 3. Krag DN. Minimal access surgery for staging regional lymph nodes: the sentinel-node concept. Curr Probl Surg 1998;35:951– 1018. 4. Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer: a multicenter validation study. N Engl J Med 1998;339:941– 946. 5. McMasters KM, Giuliano AE, Ross MI, et al. Sentinel-lymph node biopsy for breast cancer—not yet the standard of care. N Engl J Med 1998;339:990 –995.
CURRENT SURGERY
•
Volume 56 / Number 6 • July/August 1999
Sentinel Node Assessment for Melanoma Guest Reviewer: J. Michael McGee, MD SENTINEL LYMPH NODE BIOPSY FOR MELANOMA.
Gogel BM, Kuhn JA, Ferry KM, et al. Am J Surg 1998;176:544 –547.
Objective
318
To determine if sentinel lymph node biopsy is technically feasible and if it accurately assesses the lymph node basin.
Design
A multicenter, prospective, uncontrolled study.
Setting
Department of Surgery, Baylor University Medical Center, Dallas, Texas, and the Department of Surgery, University of Vermont, Burlington, Vermont.
Participants
Sixty-eight melanoma patients with primary lesions thicker than 0.4 to 7.8 mm. Five patients had previous wide local excision.
Methods
Forty male and 28 female patients aged 24 to 83 years were enrolled with primary lesions on the trunk (27 patients), head and neck (13 patients), upper extremity (12 patients), and lower extremity (12 patients). All patients had preoperative lymphoscintigraphy with technetium (Tc)-99 sulfur colloid. After 60 to 420 minutes, patients were taken to the operating room for sentinel lymph node biopsy with a hand-held gamma counter. Counts/10 seconds were recorded for sentinel nodes (SN), defined by increased radioactivity. If the count ratio did not return to normal, then additional nodes were sought with the background normalized. The sentinel nodes were placed in formation routinely for hematoxylin and eosin (H&E) staining, reserving immunohistochemistry for suspicious areas or H&E. There was a 22-month mean follow-up.
Results
At least 1 sentinel lymph node was found for each patient. Only 31 patients had 1 sentinel node, 14 had 2 sentinel nodes, 8 had 3 sentinel nodes, 6 had 4 sentinel nodes, 5 had 5 sentinel nodes, and 4 had 6 sentinel nodes. Six patients had a positive sentinel node. At a mean follow-up of 22 months, 2 more patients, originally negative, had nodal recurrence requiring lymph node dissection. Upon further sectioning and immunostaining, 1 of these patients was found to have been positive originally. Two additional patients recurred systemically and presented with lesions of 4.5 and 8.0 mm. Of the original 6 patients with positive SN, 4 are alive with no evidence of disease, 1 is alive with lung metastases, and 1 is dead of systemic disease at 34-months postbiopsy. Disease free (94% to 67%) and overall (100% to 86%) survival was better for SN-negative patients.
Conclusions
Gamma-probe– guided (only) sentinel lymph node biopsy can be performed with success, and it provides fairly accurate pathologic staging with a low rate of nodal basin recurrence. CURRENT SURGERY
•
Volume 56 / Number 6 • July/August 1999
REVIEWER COMMENTS. This article represents the initial experience of these authors. Lack of homogeneity in the study group, lack of a control group, and lack of statistical analysis weaken the study. The authors contend that they were able to find the sentinel node with only the handheld gamma probe, and at least one author is a proponent of their particular probe. They further state that their accuracy is high and recurrent disease is low. The national standard seems to include immunohistochemistry, and this, by their admission, would have improved their accuracy. Of 68 patients, 6 had a positive node and underwent completion lymph node dissection. Two of those 6 patients died of systemic disease, leaving only 4 patients to have been helped by the procedure. Two of the 62 SN-negative patients went on to develop metastatic disease in the previously evaluated nodal basin for a false-negative rate of 3.2%, which seems acceptable and may have been improved by more intensive pathologic evaluation. These authors were able to successfully perform the procedure in 5 patients who previously had wide local excision. MINIMALLY INVASIVE STAGING IN PATIENTS WITH MELANOMA: SENTINEL LYMPHADENECTOMY AND DETECTION OF THE MELANOMA-SPECIFIC PROTEINS MART-1 AND TYROSINASE BY REVERSE TRANSCRIPTASE POLYMERASE CHAIN.
Goydos JS, Ravikumar TS, Germino FJ, et al. J Am Coll Surg 1998;187:182–190. To demonstrate that sentinel lymph node biopsy is feasible under local anesthesia and that routine use of reverse transcriptase polymerase chain reaction (RT-PCR) should become the standard of care.
Objective
This study is a phase II, prospective, uncontrolled study.
Design
Departments of Surgery, Medicine, Nuclear Medicine, and Pathology, Robert Wood Johnson Medical School, New Brunswick, New Jersey.
Setting
Fifty patients, 30 male and 20 female, with primary melanoma 1 or more mm thick, underwent sentinel lymph node biopsy under local anesthesia, using blue dye, Tc-99 sulfur colloid, and a handheld gamma probe. Each sentinel node was sectioned along its long axis. One half was sent for routine H&E stains and immunohistochemistry “when appropriate,” and the other half was frozen in liquid nitrogen for RT–PCR for tyrosinase and MART-1.
Participants
All patients tolerated SN biopsy under local anesthesia, and SN were obtained in 100% of patients, mean, 2.1 SN/patient. Usable RNA was obtained from 90% of patients. Ten patients had 15 positive nodes by routine histopathology, 20% of the total number of patients and 14% of the total number of nodes. Three more histopathologically negative patients were positive by PCR. Two patients were positive for both tyrosinase and MART-1, and 1 was positive only for MART-1. These 3 patients received observation only and did not have completion lymph node dissection. The average cost of these outpatient procedures was 38% less than that of similar operations performed in the operating room.
Results
Sentinal node biopsy is feasible under local anesthesia in an outpatient setting, with intraoperative SN preservation in liquid nitrogen. Tyrosinase and MART-1 are promising markers to detect occult melanoma in SN.
Conclusions
REVIEWER COMMENTS. The cost of RT-PCR is substantial. The handling of the tissue, even by these authors, is not trivial. Only 90% of the tissues were adequate for analysis. They found 2 more “positive” patients by this technique, but did not believe their findings enough to complete the nodal dissection in these patients. Whether RT-PCR is helpful is important. Only long-term follow-up of those patients who are H&E and immunohistochemically negative, but PCR positive can answer it. This is precisely the question asked by at least 1 large national trial. The ability to diagnose cancer by molecular means is upon us, but we must be able to make sense of it in clinical terms. THE SENTINEL NODE DEBATE: HISTORICAL PERSPECTIVE OF LYMPHATIC TUMOR SPREAD AND THE EMERGENCE OF THE SENTINEL NODE CONCEPT.
Borgstein P, Meijer S. Eur J Surg Oncol 1998:24:85–95. To explore the role of sentinel lymph node biopsy in the context of treatment and staging of the regional nodal basin.
Objective
Literature review.
Design
CURRENT SURGERY
•
Volume 56 / Number 6 • July/August 1999
319
Setting
Department of Surgical Oncology, Vrije University, Amsterdam, The Netherlands.
Results
The sentinel node concept is explored historically and defined as follows: (1) an orderly and predictable pattern of lymph flow from the primary site to the regional lymph node basin exists; (2) a sequential progression of tumor cells passes through the lymph vessels to a primary draining lymph node; and (3) the first lymph node effectively filters the afferent lymph, whereby the tumor cells become entrapped. The lymphatic anatomy is reviewed, revealing an orderly and predictable pattern. Tumor cell kinetics is explored. Passage through lymph vessels remains passive, allowing tumor cell embolism. However, lymphatic valves can trap tumor cells. A sequential passage of cells to a primary draining lymph node occurs. Lymph node function is classified by three groups: (1) primary—receiving most of the afferent vessels; (2) intermediary or mixed function nodes—receiving lymph from primary nodes and afferent lymphatics; and (3) passage nodes—through which only the lymph from other nodes flows. Lymph nodes act as filters and may retain tumor cells for long periods of time. The mechanism of actual metastasis to lymph nodes remains obscure. Important immune functions occur along sinusoids in lymph nodes where macrophages are placed. Antigens are processed and presented to lymphocytes generating cellular and humoral immunity. The importance of lymph node metastases to prognosis and the evidence of so many patients doing well with locoregional treatment give corroboration to the importance of lymph node function.
Conclusions
Lymph drainage is orderly and predictable, going first to primary nodes. Although the biologic significance of lymph node metastases is controversial, removing the involved nodes and leaving the uninvolved seems to make sense. The success of sentinel lymph node biopsy depends on the accuracy of detection methods preoperatively and intraoperatively. REVIEWER COMMENTS. This paper is a nice review of the issues surrounding sentinel lymph node biopsy, providing an extensive historical context and excellent bibliography for those who want more. One more conclusion should be added: the success and acceptance of this procedure also depends on the ability and compulsiveness of the pathologist.
SUMMARY It cannot be proven that elective lymph node dissection confers improved survival for all patients with melanoma, only for those with intermediately thick lesions.1 Nevertheless, the rationale for early removal of lymph node metastases can be supported by the improved survival noted for patients with nonpalpable nodal metastases (50% to 60%, 5-year survival rate), as compared with patients that develop clinically palpable nodal metastases (20% to 25%, 5-year survival rate).2 Furthermore, if the lymph nodes containing metastases can be identified more precisely, then improvements in the precision of therapy and survival could be expected. The concept of the sentinel node takes the treatment of melanoma to that next level. The history of this development is nicely outlined in the reviewed articles, as is the technique. Simply stated, if the exact node or nodes that drain a precise portion of the integument can be identified and accurately analyzed for metastatic disease, then only those patients with lymph nodal metastases would undergo regional lymph node dissection. Therefore, patients with disease confined to the skin will be spared from the morbidity of node dissection, and elective lymph node dissection could finally be put to rest. These reviewed articles seem to indicate that, at least for melanoma, the concept of the sentinel lymph node is a sound one. Since accurately finding the sentinel node in the first crucial step, adherence to protocol and use of radionuclide and
320
blue dye would seem important. Veering from the proven methods must now be substantiated with well-designed studies. It is equally important that the pathologist adequately examine these nodes. Multiple sections and immunohistochemistry are a must. Efficacy of RT-PCR is yet to be established, but looks promising. This is an exciting topic. These reviewed papers cover most of the essential points. A few more references are provided for your review.3–5 J. MICHAEL McGEE, MD Department of Surgery College of Medicine University of Oklahoma Tulsa, Oklahoma
References 1. Balch CM, Soong SJ, Bartolucci AA, et al. Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg 1996;224:255–266. 2. Reintgen DS, Cox EB, McCarty KS Jr, et al. Efficacy of elective lymph node dissection in patients with intermediate thickness primary melanoma. Ann Surg 1983;198:379 –385. 3. Krag DN. Minimal access surgery for staging regional lymph nodes: the sentinel-node concept. Curr Probl Surg 1998;35:951– 1018. 4. Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer: a multicenter validation study. N Engl J Med 1998;339:941– 946. 5. McMasters KM, Giuliano AE, Ross MI, et al. Sentinel-lymph node biopsy for breast cancer—not yet the standard of care. N Engl J Med 1998;339:990 –995.
CURRENT SURGERY
•
Volume 56 / Number 6 • July/August 1999