RECONSTRUCTIVE Selective Sentinel Lymph Node Dissection in Lower Extremity Melanoma Suzette G. Miranda, M.D. Brian M. Parrett, M.D. Rui (Rachel) Li, Ph.D. Grant Lee, M.D. Tiffany Chang, M.D. Niloofar Fadaki, M.D. Servando Cardona-Huerta, M.D., Ph.D. James E. Cleaver, Ph.D. Mohammed Kashani-Sabet, M.D. Stanley P. Leong, M.D. San Francisco, Calif.
Background: There is debate as to whether deep inguinal lymph nodes should be removed with the superficial or femoral lymph nodes during sentinel lymph node biopsy for lower extremity melanoma, when both superficial and deep inguinal lymph nodes are identified by preoperative lymphoscintigraphy. This study evaluated the lymphatic drainage patterns in lower extremity melanoma to determine whether certain patterns could be used to limit the level of node removal and define the extent of dissection. Methods: A retrospective outcomes review was performed of lower extremity melanoma patients with excision and sentinel lymph node biopsy from 1995 to 2010. Outcomes included location of sentinel lymph node drainage basins, sentinel lymph node–positivity, and disease-free and overall survival, with drainage patterns compared between above- and below-knee melanomas. Results: Of 499 patients with lower extremity melanoma having sentinel lymph node biopsy, 356 had below-the-knee and 143 had above-the-knee melanoma. For below-knee melanoma, the node-positivity rate was 23 percent for superficial inguinal, 0 percent for deep inguinal, and 50 percent for popliteal basins. For above-knee melanoma, the positivity rate was 21 percent for superficial inguinal, 33 percent for deep inguinal basins, and 0 percent for popliteal basins. Importantly, no patients with a negative superficial inguinal sentinel lymph node had a positive deep inguinal sentinel lymph node on final pathologic evaluation. Conclusions: A difference was noted in patterns of sentinel lymph node drainage from lower extremity melanoma below and above the knee. Biopsy for deep inguinal basins may be deferred if there is simultaneous drainage to the superficial inguinal basin by preoperative lymphoscintigraphy. (Plast. Reconstr. Surg. 137: 1031, 2016.) CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.
M
orton et al. published the results of the first major prospective trial that advocated the role of selective sentinel lymph node biopsy in cutaneous melanoma in 1992.1 This method of staging primary melanoma has become the standard of care.1–4 Identification of sentinel lymph nodes using isosulfan blue dye (Lymphazurin; Hirsch Industries, Inc., Richmond, Va.) has From The Buncke Clinic, California Pacific Medical Center; the Departments of Surgery and Dermatology, University of California, San Francisco; Medivation Biostatistics; and the Center for Melanoma Research & Treatment, California Pacific Medical Center & Research Institute. Received for publication May 6, 2015; accepted November 2, 2015. Presented at the 93rd Annual Meeting of the American Association of Plastic Surgeons, in Miami, Florida, April 5 through 8, 2014. Copyright © 2016 by the American Society of Plastic Surgeons DOI: 10.1097/01.prs.0000479990.65243.eb
evolved to include intraoperative gamma probe– guided detection, with an increased identification rate of sentinel lymph nodes to 96 to 99 percent.5–7 Over the past decade, there has been debate as to which nodes (superficial versus deep inguinal) are sentinel lymph nodes and which sentinel lymph nodes should be removed during sentinel lymph node biopsy for lower extremity melanoma. Under the lymphatic spread theory, there is an orderly progression of cancer cells to firstechelon nodes.8,9 Therefore, it would appear reasonable to remove only the first-echelon nodes, as they are the true sentinel lymph nodes. It is known that most nodes on a direct lymphatic drainage pathway are located in the superficial groin from the lower extremity. In addition to Disclosure: The authors have no financial interest to declare in relation to the content of this article.
www.PRSJournal.com
1031
Copyright © 2016 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Plastic and Reconstructive Surgery • March 2016 the superficial inguinal nodal basin, the deep inguinal basin (which includes pelvic iliac and obturator nodes) and popliteal nodal basins have also been removed during sentinel lymph node biopsy.10–15 Whereas evidence exists that suggests removing more than two sentinel lymph nodes does not provide additional information during sentinel lymph node biopsy,10 others have argued for removing all blue nodes or nodes with radioactivity greater than 10 percent of background to reduce the false-negative rate.11,12 The Multicenter Selective Lymphadenectomy Trial-I validated the prognostic significance of sentinel lymph node biopsy, with a 5-year melanoma survival rate of 72 percent for sentinel lymph node–positive patients compared with 90 percent survival for sentinel lymph node–negative patients.13 However, what has not been clearly defined is the need for excising the deep inguinal sentinel lymph nodes in addition to removing superficial sentinel lymph nodes when preoperative lymphoscintigraphy shows increased radioactivity of lymph nodes in both basins. Our study was aimed at evaluating lymphatic drainage patterns in lower extremity melanoma to determine whether identification of certain drainage patterns could be used to limit the removal of deep inguinal sentinel lymph nodes removed to adequately stage patients with lower extremity melanoma. The aim was to identify the positivity of sentinel lymph nodes and whether there was any clinical advantage to deep inguinal sentinel lymph node biopsy versus superficial inguinal sentinel lymph node biopsy alone. Furthermore, the goal was to use these data to help refine the extent of completion node dissection in sentinel lymph node–positive patients.
PATIENTS AND METHODS Institutional review board approval was obtained, and the tumor registry at University of California, San Francisco and the California Pacific Medical Center was queried to identify all patients with lower extremity melanoma who underwent sentinel lymph node biopsy from 1995 to 2010. Patients who underwent sentinel lymph node biopsy had a lower extremity melanoma that was confirmed on biopsy to be greater than or equal to 1 mm or had a thinner melanoma with adverse features consistent with indications for sentinel lymph node biopsy.14 The lymphoscintigraphic images and report, operative note, and pathology report were scrutinized and required from each patient to be included in this study. Any
patient with a missing report was excluded from the study (14 patients in our study). The sentinel lymph node biopsy protocol called for either a single day for both lymphoscintigraphy and the operation or lymphoscintigraphy during the afternoon before the operation. Patients received an intradermal injection of filtered technetium-99m sulfur colloid around the tumor or the biopsy site. Static and dynamic images were taken with a gamma camera system. Sentinel lymph nodes were defined as the first lymph node in lymph node bed to receive lymphatic drainage from the tumor. These were identified and marked by the nuclear medicine physician. From the nuclear medicine report, the injection dosage, number of basins involved, number of channels, and nodal counts for each basin were recorded. The surgeon and nuclear medicine physician reviewed the lymphoscintigram before incision. For those patients who received blue dye, isosulfan blue was injected intradermally before the procedure around the primary melanoma site. An incision was made over the area of greatest activity as detected by the handheld gamma probe (Neoprobe 2000; Neoprobe Corp., Dublin, Ohio). The incision was carried down through the subcutaneous fat, and the superficial fascia was incised. Using the handheld gamma probe, any sentinel lymph nodes that were assessed greater than or equal to 10 percent of the radioactive count of the hottest sentinel lymph node were removed by one of three senior surgical oncologists. The gamma probe was used to search the resection bed to make sure that there was no residual elevated radioactivity. Further exploration was carried out if the resection bed count remained high. With some cases, the blue dye–stained lymphatics would be seen and this would confirm the finding of the radioisotope activity with resultant removal of the sentinel lymph node. In general, the sentinel lymph node was identified using a gamma probe, blue dye, or both. No frozen sections were taken intraoperatively. Nodes were examined by permanent sections for hematoxylin and eosin evaluation and immunohistochemical staining for melanoma-specific markers. Any indurated or enlarged lymph nodes by deep palpation would also be removed. The primary melanoma site was excised after the sentinel lymph node procedure.14 If the popliteal sentinel lymph node was found, usually above the popliteal crease, a longitudinal incision of approximately 3 cm would be made over the marking with the hot spot. The superficial fascia would be incised and the sentinel lymph node would be localized with a Neoprobe
1032 Copyright © 2016 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Volume 137, Number 3 • Sentinel Lymph Node Dissection binary/ordinal scale (e.g., sentinel lymph node– positivity) differed significantly between lower extremity melanoma above and below the knee. Values of p < 0.05 were considered significant. Statistical analyses were performed with STATA Version 10 (StataCorp, College Station, Texas).
and removed from the adjacent fatty tissue. Occasionally, the sentinel node would be found deeper adjacent to the neurovasculature and it would be dissected carefully from the nerve and the vessels. Outcomes assessed were (1) whether sentinel lymph nodes drained into the deep, superficial, or popliteal basins (or a combination of any) and (2) the sentinel lymph node status of lower extremity melanoma above and below the knee. The percentage of drainage into each location, the rate of sentinel lymph node positivity, and 5-year disease-free and overall survival were determined. Survival was compared between sentinel lymph node–positive and sentinel lymph node– negative patients with above- and below-knee primary melanomas. Disease-free survival was calculated from time of sentinel lymph node biopsy to the first recurrence of the patient’s primary melanoma (local, regional, and distant) or death as a result of melanoma. Overall survival was calculated as the interval between sentinel lymph node biopsy and death from any cause. Survival curves between groups were generated using the Kaplan-Meier nonparametric method and compared by log-rank test. Fisher’s exact test was performed to determine whether the proportion of a categorical factor in
RESULTS From 1995 to 2010, 499 patients underwent sentinel lymph node biopsy for lower extremity melanoma. One hundred forty-three patients had melanoma above the knee and 356 had melanoma below the knee. Table 1 shows the different characteristics of melanoma below and above the knee. The average age of patients was 49 years for those with melanoma above the knee and 56 years for those with melanoma below the knee (p
Background: There is debate as to whether deep inguinal lymph nodes should be removed with the superficial or femoral lymph nodes during sentinel lymph node biopsy for lower extremity melanoma, when both superficial and deep inguinal lymph nodes are identified by preoperative lymphoscintigraphy. This study evaluated the lymphatic drainage patterns in lower extremity melanoma to determine whether certain patterns could be used to limit the level of node removal and define the extent of dissection. Methods: A retrospective outcomes review was performed of lower extremity melanoma patients with excision and sentinel lymph node biopsy from 1995 to 2010. Outcomes included location of sentinel lymph node drainage basins, sentinel lymph node–positivity, and disease-free and overall survival, with drainage patterns compared between above- and below-knee melanomas. Results: Of 499 patients with lower extremity melanoma having sentinel lymph node biopsy, 356 had below-the-knee and 143 had above-the-knee melanoma. For below-knee melanoma, the node-positivity rate was 23 percent for superficial inguinal, 0 percent for deep inguinal, and 50 percent for popliteal basins. For above-knee melanoma, the positivity rate was 21 percent for superficial inguinal, 33 percent for deep inguinal basins, and 0 percent for popliteal basins. Importantly, no patients with a negative superficial inguinal sentinel lymph node had a positive deep inguinal sentinel lymph node on final pathologic evaluation. Conclusions: A difference was noted in patterns of sentinel lymph node drainage from lower extremity melanoma below and above the knee. Biopsy for deep inguinal basins may be deferred if there is simultaneous drainage to the superficial inguinal basin by preoperative lymphoscintigraphy. (Plast. Reconstr. Surg. 137: 1031, 2016.) CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.
M
orton et al. published the results of the first major prospective trial that advocated the role of selective sentinel lymph node biopsy in cutaneous melanoma in 1992.1 This method of staging primary melanoma has become the standard of care.1–4 Identification of sentinel lymph nodes using isosulfan blue dye (Lymphazurin; Hirsch Industries, Inc., Richmond, Va.) has From The Buncke Clinic, California Pacific Medical Center; the Departments of Surgery and Dermatology, University of California, San Francisco; Medivation Biostatistics; and the Center for Melanoma Research & Treatment, California Pacific Medical Center & Research Institute. Received for publication May 6, 2015; accepted November 2, 2015. Presented at the 93rd Annual Meeting of the American Association of Plastic Surgeons, in Miami, Florida, April 5 through 8, 2014. Copyright © 2016 by the American Society of Plastic Surgeons DOI: 10.1097/01.prs.0000479990.65243.eb
evolved to include intraoperative gamma probe– guided detection, with an increased identification rate of sentinel lymph nodes to 96 to 99 percent.5–7 Over the past decade, there has been debate as to which nodes (superficial versus deep inguinal) are sentinel lymph nodes and which sentinel lymph nodes should be removed during sentinel lymph node biopsy for lower extremity melanoma. Under the lymphatic spread theory, there is an orderly progression of cancer cells to firstechelon nodes.8,9 Therefore, it would appear reasonable to remove only the first-echelon nodes, as they are the true sentinel lymph nodes. It is known that most nodes on a direct lymphatic drainage pathway are located in the superficial groin from the lower extremity. In addition to Disclosure: The authors have no financial interest to declare in relation to the content of this article.
www.PRSJournal.com
1031
Copyright © 2016 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Plastic and Reconstructive Surgery • March 2016 the superficial inguinal nodal basin, the deep inguinal basin (which includes pelvic iliac and obturator nodes) and popliteal nodal basins have also been removed during sentinel lymph node biopsy.10–15 Whereas evidence exists that suggests removing more than two sentinel lymph nodes does not provide additional information during sentinel lymph node biopsy,10 others have argued for removing all blue nodes or nodes with radioactivity greater than 10 percent of background to reduce the false-negative rate.11,12 The Multicenter Selective Lymphadenectomy Trial-I validated the prognostic significance of sentinel lymph node biopsy, with a 5-year melanoma survival rate of 72 percent for sentinel lymph node–positive patients compared with 90 percent survival for sentinel lymph node–negative patients.13 However, what has not been clearly defined is the need for excising the deep inguinal sentinel lymph nodes in addition to removing superficial sentinel lymph nodes when preoperative lymphoscintigraphy shows increased radioactivity of lymph nodes in both basins. Our study was aimed at evaluating lymphatic drainage patterns in lower extremity melanoma to determine whether identification of certain drainage patterns could be used to limit the removal of deep inguinal sentinel lymph nodes removed to adequately stage patients with lower extremity melanoma. The aim was to identify the positivity of sentinel lymph nodes and whether there was any clinical advantage to deep inguinal sentinel lymph node biopsy versus superficial inguinal sentinel lymph node biopsy alone. Furthermore, the goal was to use these data to help refine the extent of completion node dissection in sentinel lymph node–positive patients.
PATIENTS AND METHODS Institutional review board approval was obtained, and the tumor registry at University of California, San Francisco and the California Pacific Medical Center was queried to identify all patients with lower extremity melanoma who underwent sentinel lymph node biopsy from 1995 to 2010. Patients who underwent sentinel lymph node biopsy had a lower extremity melanoma that was confirmed on biopsy to be greater than or equal to 1 mm or had a thinner melanoma with adverse features consistent with indications for sentinel lymph node biopsy.14 The lymphoscintigraphic images and report, operative note, and pathology report were scrutinized and required from each patient to be included in this study. Any
patient with a missing report was excluded from the study (14 patients in our study). The sentinel lymph node biopsy protocol called for either a single day for both lymphoscintigraphy and the operation or lymphoscintigraphy during the afternoon before the operation. Patients received an intradermal injection of filtered technetium-99m sulfur colloid around the tumor or the biopsy site. Static and dynamic images were taken with a gamma camera system. Sentinel lymph nodes were defined as the first lymph node in lymph node bed to receive lymphatic drainage from the tumor. These were identified and marked by the nuclear medicine physician. From the nuclear medicine report, the injection dosage, number of basins involved, number of channels, and nodal counts for each basin were recorded. The surgeon and nuclear medicine physician reviewed the lymphoscintigram before incision. For those patients who received blue dye, isosulfan blue was injected intradermally before the procedure around the primary melanoma site. An incision was made over the area of greatest activity as detected by the handheld gamma probe (Neoprobe 2000; Neoprobe Corp., Dublin, Ohio). The incision was carried down through the subcutaneous fat, and the superficial fascia was incised. Using the handheld gamma probe, any sentinel lymph nodes that were assessed greater than or equal to 10 percent of the radioactive count of the hottest sentinel lymph node were removed by one of three senior surgical oncologists. The gamma probe was used to search the resection bed to make sure that there was no residual elevated radioactivity. Further exploration was carried out if the resection bed count remained high. With some cases, the blue dye–stained lymphatics would be seen and this would confirm the finding of the radioisotope activity with resultant removal of the sentinel lymph node. In general, the sentinel lymph node was identified using a gamma probe, blue dye, or both. No frozen sections were taken intraoperatively. Nodes were examined by permanent sections for hematoxylin and eosin evaluation and immunohistochemical staining for melanoma-specific markers. Any indurated or enlarged lymph nodes by deep palpation would also be removed. The primary melanoma site was excised after the sentinel lymph node procedure.14 If the popliteal sentinel lymph node was found, usually above the popliteal crease, a longitudinal incision of approximately 3 cm would be made over the marking with the hot spot. The superficial fascia would be incised and the sentinel lymph node would be localized with a Neoprobe
1032 Copyright © 2016 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Volume 137, Number 3 • Sentinel Lymph Node Dissection binary/ordinal scale (e.g., sentinel lymph node– positivity) differed significantly between lower extremity melanoma above and below the knee. Values of p < 0.05 were considered significant. Statistical analyses were performed with STATA Version 10 (StataCorp, College Station, Texas).
and removed from the adjacent fatty tissue. Occasionally, the sentinel node would be found deeper adjacent to the neurovasculature and it would be dissected carefully from the nerve and the vessels. Outcomes assessed were (1) whether sentinel lymph nodes drained into the deep, superficial, or popliteal basins (or a combination of any) and (2) the sentinel lymph node status of lower extremity melanoma above and below the knee. The percentage of drainage into each location, the rate of sentinel lymph node positivity, and 5-year disease-free and overall survival were determined. Survival was compared between sentinel lymph node–positive and sentinel lymph node– negative patients with above- and below-knee primary melanomas. Disease-free survival was calculated from time of sentinel lymph node biopsy to the first recurrence of the patient’s primary melanoma (local, regional, and distant) or death as a result of melanoma. Overall survival was calculated as the interval between sentinel lymph node biopsy and death from any cause. Survival curves between groups were generated using the Kaplan-Meier nonparametric method and compared by log-rank test. Fisher’s exact test was performed to determine whether the proportion of a categorical factor in
RESULTS From 1995 to 2010, 499 patients underwent sentinel lymph node biopsy for lower extremity melanoma. One hundred forty-three patients had melanoma above the knee and 356 had melanoma below the knee. Table 1 shows the different characteristics of melanoma below and above the knee. The average age of patients was 49 years for those with melanoma above the knee and 56 years for those with melanoma below the knee (p
