Journal of Plastic, Reconstructive & Aesthetic Surgery (2014) 67, 316e319

Hot or not? The 10% rule in sentinel lymph node biopsy for malignant melanoma revisited* A.D. Murphy a,*, A. Britten b, B. Powell a a

St. George’s Melanoma Unit, Dept. of Plastic Surgery, St. George’s Hospital, Blackshaw Road, London SW17 0QT, UK b Dept. of Medical Physics, St. George’s Hospital, Blackshaw Road, London SW17 0QT, UK Received 24 May 2013; accepted 12 November 2013

KEYWORDS Melanoma; Sentinel node; Staging

Summary Background: The surgeon needs a practical rule to follow when deciding whether to excise a lymph node during sentinel node biopsy (SLNB). The “10% rule” dictates that all nodes with a radiation count of greater than 10% of the hottest node and all blue nodes should be removed, and this study observes the effects of following this rule in SLNB in melanoma. Methods: We reviewed the records of 665 patients with primary melanoma who underwent sentinel lymph node over a 5-year period (2007e2011). Results: 2064 nodes were identified in 898 nodal basins in 665 patients. 141 (21%) patients had at least one positive sentinel node. 105 positive nodal basins were identified in which more than one sentinel node was removed. In 18 of these, a less radioactive node was positive for tumour when the most radioactive node was negative. Of 175 positive nodes 157 (90%) contained blue dye staining. For cases in which the positive sentinel node was not the hottest node, the positive node had apparent blue dye staining in all 18 cases (100%), and was the second hottest node in the basin. Conclusion: In this series removing just the hottest node and all blue nodes would not have missed a single positive basin and would have resulted in a 38% reduction in the number of nodes removed compared to those taken following the 10% rule, without changing the staging in any patient. ª 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

*

Presented at BAPRAS Winter Scientific Meeting, London, 5th Dec. 2012. * Corresponding author. Tel.: þ44 20 8725 0090. E-mail address: [email protected] (A.D. Murphy).

1748-6815/$ - see front matter ª 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bjps.2013.11.008

The rule in sentinel lymph node biopsy

Introduction Introduced by Morton et al. in 1992, sentinel lymph node biopsy (SLNB) has become standard of care in lymph node basin staging in malignant melanoma.1 A sentinel lymph node is the first draining node on a direct lymphatic channel from the primary tumour site. The sentinel lymph nodes are identified by intradermal injection of a vital blue dye, a radioactive tracer, or both around the site of the primary tumour. Preoperative lymphoscintigraphy as well as intra-operative gamma probe localization and visualization of the blue dye increase the diagnostic accuracy of the sentinel node procedure.2 The radiocolloids are only partially filtered in the sentinel nodes, so secondary nodes are seen to have some degree of radioactivity, which would have not been detected with blue dye alone. Some of these were found to be positive for tumour presence.3e5 A number of early studies sought to define the sentinel node in terms of absolute radiation count, in vivo or ex vivo radiation count relative to the background radioactivity, or relative to the most radioactive node in the basin.5e9 Since McMasters’ paper analysing the results of the Sunbelt Melanoma Trial in 20019 the “10% rule” has been widely followed. That is that all blue nodes and all nodes containing 10% or more of the radioactive count of the ex vivo count of the hottest node should be removed and considered a sentinel node, along with any macroscopically abnormal nodes. While this approach reduces the risk of missing a positive node with a low radiation count compared to hotter negative nodes in the lymphatic basin, it may result in a large number of nodes being removed during the sentinel lymph node biopsy procedure. This study aims to re-evaluate the 10% rule by retrospectively examining the outcomes of 665 patients undergoing SLNB over a 5-year period for malignant melanoma.

Materials & methods A retrospective review was performed of 665 consecutive patients undergoing sentinel lymph node biopsy for malignant melanoma between January 2006 and December 2011. All patients with American Joint Committee on Cancer10 stage 1B or greater melanoma, who had no clinically detectable nodal, regional or distant metastases, and were medically fit to undergo a completion lymphadenectomy should the result of SLNB be positive were offered sentinel lymph node biopsy. After informed consent was obtained patients underwent sentinel node localization using triple method identification; dynamic lymphoscintigraphy, intra-operative gamma probe localization and intra-dermal Patent Blue V injection. All patients underwent lymphoscintigraphy with 99m Tc-human serum albumin colloid (nanocoll GE Healthcare). Four depots of 0.2 mL of radiocolloid was injected intradermally around the primary melanoma biopsy site on the morning of surgery or the evening prior. Dynamic scanning was carried out with a planar dual-head gamma camera (Siemens). Images were taken every 10 s for 10 min post-injection followed by multiple static images up to

317 90 min post-injection. A mark was made on the skin overlying the node(s) and the depth estimated. The pre-operative lymphoscintogram was used as a guide to the location, and number of nodes, to be removed. Radioactivity in the nodes was measured intraoperatively using a hand-held gamma probe (Neoprobe, Neoprobe Corp., Ohio, USA). Pre-operatively 0.5e1 mL of Patent Blue V dye (Guerbet Laboratories Ltd., Solihull, UK) was injected in the dermis around the excision site. Ex-vivo counts of the removed sentinel nodes were obtained and blue dye staining was recorded. All nodes containing blue dye staining and/or 10% or more of the radioactive count of the hottest node were removed. Sentinel nodes underwent hematoxylin& eosin staining at multiple levels followed by immunohistochemical staining for S100 protein. The pathology of each sentinel node was correlated with the node count/hottest node count and blue dye status. Statistical analysis was performed with Student’s t-test. Significance was determined at p  0.05.

Results The demographics of the study group are represented in Table 1. There were 665 patients in total; 318 male and 347 female. The mean age was 54 years. A total of 2064 nodes were sampled (median, 3/patient). The mean and median tumour thicknesses were 2.36 mm and 1.70 mm respectively. The mean Breslow thickness in the node positive group was 2.7 mm, significantly greater than the node negative group, which was 2.1 mm (p < 0.05). 141 patients had at least one positive sentinel node (21.5%). These 141 patients had nodes sampled from 190 lymph node basins. 115 patients had only one basin sampled whereas18 patients had nodes taken from 2 basins, another6 patients had 3 lymphatic basins sampled, and 2 patients had nodes taken from 4 basins. Nodal metastases were found in 143 basins in these 141 patients. In 105 basins more than one sentinel node was removed e the cohort of interest in this study. In 18 of these 105 basins a less radioactive node was positive for disease when another, more radioactive, node was negative for disease. Overall, in Table 1

Study demographics.

Number of cases (%) Sex (%) Male Female Mean age Breslow thickness (mm) 0e1.0 (T1) 1.01e2.0 (T2) 2.01e4.0 (T3) >4 (T4) Mean number of nodes sampled Median number of nodes sampled

All cases

Negative Positive

665

524 (79)

141 (21)

318 (48) 347 (52) 54.42 Number (%) 69 (10.5) 320 (48) 192 (29) 84 (12.5) 3.1

235 (45) 289 (55) 54.93

83 (58) 58 (42) 52.26

62 (12) 267 (51) 134 (25) 61 (12) 3.05

7 (5) 53 (38.5) 58 (40.5) 23 (16) 3.3

3

3

3

318 18 of 190 basins (9.5%), the hottest node was negative when a colder node was positive. The mean radiation read relative to the hottest node was 56% with a range of 14e86%. In all cases the positive node was the second hottest node in the basin. In the 175 positive sentinel lymph nodes blue dye staining was seen in 157 (90%). In the 232 negative nodes blue dye was seen in only 133 (57%). In the 18 basins where the positive node was not the hottest node all positive nodes had blue dye staining present.

Discussion SLNB allows the surgeon to determine the presence or absence of nodal spread from a primary melanoma through the lymphatic channels. It has been shown to be the most accurate predictor of disease progression and outcome.11,12 Since the original description of the sentinel node concept in lymphatic basin staging by Morton et al., in 19921 there have been various rules to guide the surgeon in deciding when to stop removing nodes. The original paper described using between 0.5 and 1 mL of patent blue-V or isosulfan blue dye that was tracked to the regional lymph node basin(s) and all blue lymph nodes removed. The authors described successfully finding at least one sentinel node in 82% of cases. The addition of radiolabelled colloid to the blue dye technique increased the identification of at least one sentinel node to over 96%.5 Several different definitions of the sentinel lymph node were proposed after the introduction of this technique. McMasters et al. showed that sampling just the hottest node, that is the node with the highest radiation count, would result in 13% of basins having a negative sentinel node result when another less radioactive node was positive for tumour.9 In 99% of basins the positive node was either the hottest or second hottest node present. This study led to the establishment of the 10%rule, which has become standard of care since. In our study we show that removing just the hottest node would have resulted in a miss rate of 12.5% (18 of 143 basins). However, in all of these cases the second hottest node was positive for tumour presence. In no basin did the third or subsequent node change the staging of that basin. These results are in keeping with the findings or Porter et al. who showed that the hottest two nodes defined the basin staging in 633 patients with malignant melanoma.13 Recent works advocating in favour of continued use of the 10%-rule have not looked at the order of the nodes removed, merely the percentage radiation read compared to the hottest node.14,15 Liu et al. dismiss the role of blue dye in SLNB and suggest using only radiation count as a means to select which nodes to sample. 90% of positive nodes in our series had macroscopic evidence of blue dye staining, whereas only 57% of negative nodes did. Since the presence of blue dye implies a direct lymphatic channel from the primary tumour site, it is prudent to harvest these nodes regardless of radiation levels. While it may appear that removing only the hottest node plus any blue nodes would result in the same results as removing the hottest two plus all blue nodes (308 vs. 309) we would caution against this approach as we have shown that 10% of positive nodes did not contain blue dye. Using

A.D. Murphy et al. Table 2 Outcomes using different criteria for node sampling. Criteria for node sampling

No. missed þ Miss ve nodes/number rate basins with þ ve nodes

Hottest node only Hottest node þ blue nodes Hottest þ second hottest nodes Hottest two þ blue 10% þ Blue nodes

18/143 0/143

12.50% 190 0% 308

0/143

0%

293

0/143 0/143

0% 0%

309 470

Number of nodes removed

radiation count and blue dye presence independently to determine which nodes to sample potentially reduces the risk of a false negative result. Following the 10%-rule in our cohort resulted in the removal of a mean of 3.1 lymph nodes per patient, 2064 nodes in total. In those who had at least one positive node following the 10%-rule resulted in removal of 470 lymph nodes. Were we to have only removed the hottest two nodes we could have reduced this number to 293, a 38% reduction, with no compromise of accuracy of SLNB (Table 2). Taking the two hottest as well as all blue nodes adds only an extra 18 nodes to this number (309). Replacing the 10%-rule with a “Hottest Two þ Blue” has the potential to reduce the operative time and cost associated with sentinel lymph node biopsy without increasing the false negative rate of this procedure. In our 5-year series we would have removed 1357 lymph nodes in total rather than 2064 which has a significant cost-saving potential.

Conflict of interest/funding None.

Acknowledgements The work of the staff of the Nuclear Medicine Department St George’s Hospital in carrying out the Lymphoscintigraphy is acknowledged.

References 1. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127:392e9. 2. Bostick P, Essner R, Glass E, et al. Comparison of blue dye and probe-assisted intraoperative lymphatic mapping in melanoma to identify sentinel nodes in 100 lymphatic basins. Arch Surg 1999;134:43e9. 3. Bartolomei M, Testori A, Chinol M, et al. Sentinel node localization in cutaneous melanoma: lymphoscintigraphy with colloids and antibody fragments versus blue dye mapping. Eur J Nucl Med 1998;25:1489e94.

The rule in sentinel lymph node biopsy 4. Morton DL, Thompson JF, Essner R, et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. Multicenter Selective Lymphadenectomy Trial Group. Ann Surg 1999;230:453e63 [discussion 463e455]. 5. Albertini JJ, Cruse CW, Rapaport D, et al. Intraoperative radiolympho-scintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg 1996;223:217e24. 6. Alex JC, Weaver DL, Fairbank JT, Rankin BS, Krag DN. Gammaprobe-guided lymph node localization in malignant melanoma. Surg Oncol 1993;2:303e8. 7. Bostick P, Essner R, Sarantou T, et al. Intraoperative lymphatic mapping for early-stage melanoma of the head and neck. Am J Surg 1997;174:536e9. 8. Brobeil A, Kamath D, Cruse CW, et al. The clinical relevance of sentinel lymph nodes identified with radiolymphoscintigraphy. J Fla Med Assoc 1997;84:157e60. 9. McMasters KM, Reintgen DS, Ross MI, et al. Sentinel lymph node biopsy for melanoma: how many radioactive nodes should be removed? Ann Surg Oncol 2001;8:192e7.

319 10. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:6199e206. 11. Leong SP. Sentinel lymph node mapping and selective lymphadenectomy: the standard of care for melanoma. Curr Treat Options Oncol 2004;5:185e94. 12. Balch CM, Morton DL, Gershenwald JE, et al. Sentinel node biopsy and standard of care for melanoma. J Am Acad Dermatol 2009;60:872e5. 13. Porter GA, Ross MI, Berman RS, et al. How many lymph nodes are enough during sentinel lymphadenectomy for primary melanoma? Surgery 2000;128:306e11. 14. Emery RE, Stevens JS, Nance RW, Corless CL, Vetto JT. Sentinel node staging of primary melanoma by the “10% rule”: pathology and clinical outcomes. Am J Surg 2007;193:618e22 [discussion 622]. 15. Liu LC, Parrett BM, Jenkins T, et al. Selective sentinel lymph node dissection for melanoma: importance of harvesting nodes with lower radioactive counts without the need for blue dye. Ann Surg Oncol 2011;18:2919e24.

Hot or not? The 10% rule in sentinel lymph node biopsy for malignant melanoma revisited.

The surgeon needs a practical rule to follow when deciding whether to excise a lymph node during sentinel node biopsy (SLNB). The "10% rule" dictates ...
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