Is Completion Lymphadenectomy After a Positive Sentinel Lymph Node Biopsy for Cutaneous Melanoma Always Necessary?

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PAPER Is Completion Lymphadenectomy After a Positive Sentinel Lymph Node Biopsy for Cutaneous Melanoma Always Necessary?

Nahel Elias, MD; Kenneth K. Tanabe, MD; Arthur J. Sober, MD; Michele A. Gadd, MD; Martin C. Mihm, MD; Barrett Goodspeed, MS; A. Benedict Cosimi, MD

Hypothesis: Completion lymph node dissection (CLND) Results: In 28 patients, all SLNs were found to con- has usually been recommended after metastatic disease is tain metastatic melanoma. Seven (25%) of these identified in the sentinel lymph node (SLN) biopsy to eradi- patients had additional metastases identified in the cate further metastases in nonsentinel nodes. We hypoth- CLND specimen. In 52 patients, 1 or more SLNs did esized that patients with negative lymph nodes included not contain metastatic melanoma. Five (10%) of these in the initial SLN specimen have low risk of metastases in patients had additional metastases in the CLND speci- the residual draining basin and may not require CLND. men (P=.02).

Design: Chart review. Conclusions: Although no evidence of metastatic melanoma was found on CLND in most patients in whom Setting: University-affiliated tertiary care referral center. negative nodes had been removed with positive SLNs at the initial biopsy, 10% of these patients did have further Patients: Between January 1, 1997, and May 31, 2003, metastases. This subgroup of patients (positive SLNs and 506 consecutive patients underwent SLN biopsy for stag- negative nodes in the SLN biopsy specimen) is at signifi- ing of primary cutaneous melanoma. cantly lower risk for further metastasis, but CLND cannot be safely omitted even for these patients. Intervention: The SLN biopsy identified 87 patients (17.2%) with metastatic melanoma, of whom 80 underwent CLND. Arch Surg. 2004;139:400-405

HE INCIDENCE OF MELA- survival of these patients by approxi- noma in the United States mately 40%, independent of, and super- has been increasing more seding, any primary tumor characteris- rapidly than that of any other tics.2 Thus, it was incorporated into the cancer during the past few new American Joint Committee on Can- decades. The lifetime risk of developing cer staging system for cutaneous mela- T 3 melanoma in 1960 was 1 in 600 individu- noma. The logical goal, therefore, has been als; it is currently approximately 1 in 70 in- to develop therapeutic strategies that dividuals; and it is projected to be 1 in 50 would remove involved lymph nodes early individuals by 2010.1 It is the most deadly in the course of the disease. Until re- form of skin cancer and currently the eighth cently, one such approach included elec- most common cancer in the United States. tive lymph node dissection (ELND) for pa- Moreover, melanoma affects young per- tients with high-risk primary lesions. sons who are in the most productive years Despite the theoretical benefits of this pro- of their lives; accordingly, it constitutes a cedure, prospective trials have failed to major public health problem. confirm a survival advantage for the pa- Primary treatment of cutaneous mela- tients randomized to ELND4-6 except for noma has always included wide local ex- perhaps selected subgroups.7 Obviously, From the Departments of cision, but the assessment and manage- this results from the inclusion, in the Surgery (Drs Elias, Tanabe, ment of regional nodes has remained ELND group, of all high-risk patients, most Gadd, and Cosimi), Dermatology (Dr Sober), and controversial. Clearly, regional lymph node of whom do not have positive nodes and Pathology (Dr Mihm and metastasis in patients with primary cuta- therefore could not have benefited from Mr Goodspeed), Massachusetts neous melanoma is the most important regional node dissection. General Hospital and Harvard prognostic factor for tumor recurrence and The introduction and validation of Medical School, Boston. survival. Its presence decreases the 5-year sentinel lymph node (SLN) mapping and

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 biopsy during the past decade now permits identification of a subgroup of patients with metastatic disease with minimal morbidity. This technique has gained wide ac- ceptance since the first report by Morton and colleagues in 1992,8 in particular since SLN results in significantly less morbidity than ELND and also identifies unsus- pected draining nodal basins with the aid of lymphoscintigraphy. Completion lymph node dissection (CLND) is recommended for the approximately 20% of patients with metastatic disease identified in sentinel nodes,9,10 based on the apparent benefit provided to this subgroup compared with delayed lymph node dissection at the time that clinical metastases are identified.6 As a result, SLN biopsy has evolved as the accepted regional nodes staging method, ELND has become a concept of historical in- terest, and approximately 80% of patients with high- risk primary lesions are spared the morbidity associated with ELND. The SLN is identified by intraoperative lymphoscintigraphy with the use of a handheld gamma counter and by direct visualization of blue-stained tissue (Figure 1) in the draining lymphatic basin after intradermal injec- 99m tion of a radioactive tracer (technetium Tc 99m [ Tc] Figure 1. Intraoperative photograph of a sentinel lymph node and the sulfur colloid) and isosulfan blue around the primary mela- afferent lymphatic. Note the isosulfan blue staining of the sentinel node and noma biopsy site. The use of the blue dye in combination the afferent lymphatic. with the radioactive colloid has been demonstrated to lead to optimal detection and identification of the SLNs.11-18 Since only 15% to 20% of patients with a positive consecutive patients treated between January 1, 1997, and May 31, 2003. None of the patients had clinical evidence of meta- SLN biopsy specimen are found to have further meta- 19 static melanoma at the time of their lymphatic mapping as as- static disease in the CLND specimen, many authors have sessed by clinical history and physical examination findings. sought to identify prognostic factors that predict the re- All of these patients underwent SLN biopsy with the plan to sidual nodal basin disease status after SLN biopsy be- perform CLND if SLN metastases were identified; none of these fore CLND and, thereby, limit CLND to patients with patients underwent an initial ELND. probable further metastases. Previous multi-insti- Of these patients, we identified and further evaluated the tution20 and single-institution21 studies have concluded subgroup that had histologically positive SLNs. The pathologi- that primary tumor features, such as thickness or ulcer- cal characteristics of the primary melanoma, the number of nodes ation, cannot reliably identify patient subpopulations with recovered during SLN biopsy, the number of nodes with evi- minimal risk of metastatic disease in the nonsentinel dence of metastatic melanoma, the number of patients who un- 22 derwent CLND after SLN biopsy, and the pathology reports of nodes. More recently, Reeves et al used a more com- the CLND specimens were reviewed. plex scoring system that combines primary tumor ulceration and size of SLN metastases. They concluded that SLN MAPPING TECHNIQUE patients with a score of 0 are unlikely to have nonsentinel node metastases or to benefit from CLND. Since only The technique of SLN mapping was previously reported in de- 21 patients were included in this group, however, this tail by Gadd et al.23 In brief, approximately 3 hours before the 99m recommendation requires validation in larger studies. operation, Tc sulfur colloid (CIS-US Inc, Bedford, Mass) was We have questioned whether the finding of histo- injected into the dermis surrounding the site of the primary logically negative lymph nodes together with histologi- melanoma or biopsy scar. The total dose was typically divided into 4 equal parts. Planar gamma images were obtained 5 to cally positive SLNs in the biopsy specimen accurately pre- 60 minutes after injection to define the location of the SLNs. dicts the absence of further metastasis in the remaining In the operating room, most patients then received an injec- nodes in the sampled basin, and consequently elimi- tion of 0.5 to 1.5 mL of 1% isosulfan blue vital dye (Lymp- nates the necessity for CLND. hazurin; Zenith Parenterals, Rosemont, Ill) into the dermis cir- cumferentially around the biopsy scar or melanoma. A handheld METHODS gamma detector (Care Wise Medical Products, Morgan Hill, Ca- lif, or Neoprobe Corp, Dublin, Ohio) was used intraopera- tively to precisely identify the location of the SLNs. Sentinel PATIENTS lymph nodes were defined as those that were stained with Lym- We reviewed the records of the Department of Pathology da- phazurin dye and/or concentrated 99mTc sulfur colloid. Accept- tabase and the Department of Surgery case log at the Massa- able basin counts after SLN excision were defined as less than chusetts General Hospital, Boston, to identify all patients who 10% of the counts of the most radioactive lymph node. In all underwent intraoperative lymphatic mapping for cutaneous patients, the entire SLN was immediately placed into isotonic melanoma with a primary tumor thickness of greater than 1 sodium chloride solution. The primary melanoma site was widely mm or invasive to Clark level IV or greater. This identified 506 reexcised during the same operation in most patients.

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Characteristic Negative CLND Positive CLND No CLND Patients No. 68 12 7 Sex, No. M/F 37/31 6/6 6/1 Age, mean ± SD, y 46.29 ± 15.31 50.16 ± 17.54 46.57 ± 14.18 Primary tumor site, No. Trunk 29 3 6 Upper extremity 14 2 0 Lower extremity 15 6 0 Head/neck 10 1 1 Primary tumor criteria* Ulceration, No. 22 7 1 Ulceration, median ± SD, mm 2.85 ± 3.58 6.40 ± 3.79 0.5 Thickness, median ± SD, mm 2.5 ± 1.70 3.9 ± 2.28 1.79 ± 0.29 Clark level, median ± SD 4 ± 0.42 4 ± 0.63 4 ± 0 SLN site, No. Axilla 42† 4 6‡ Groin 16 7 0 Head/neck 15† 1 3‡

Abbreviations: CLND, completion lymph node dissection; SLN, sentinel lymph node. *No significant difference was found when any of these characteristics were compared between the 3 groups by unpaired t test. †Three patients had 2 basins (2 axilla and neck, and 1 both axillae), and 1 patient had 3 basins (neck and both axillae). ‡Two patients had 2 basins (one in axilla and neck, and the other in both axillae).

HISTOLOGIC AND clinical and pathological characteristics of those pa- IMMUNOHISTOCHEMICAL ANALYSIS tients are summarized in Table 1. The number of nodes procured from each basin during SLN biopsy ranged from Details of the lymph node analysis have been previously re- 24 1 to 10 (mean±SD, 3.20±2.13), and the number of posi- ported. Briefly, 3 serial tissue sections, each 4 mm thick, were tive nodes identified in the SLN specimen ranged from obtained from the paraffin-embedded lymph node tissue blocks at 3 levels 80 mm apart. One section was stained with hema- 1 to 3 (1.19±0.45). After identification of metastasis in toxylin-eosin. The remaining sections were subjected to im- the SLN biopsy specimen, all patients were offered CLND munohistochemical analyses. Further unstained sections from and interferon chemotherapy; 80 patients (92%) under- the third level were kept for repeat staining if necessary. went CLND. Of the other 7 patients, 3 had 8 or more his- A diagnosis of metastatic melanoma was made when all tologically negative SLNs harvested at the time of SLN of the following criteria were fulfilled: (1) individual cells in a biopsy and were considered to be at low risk for further linear array or nests of epithelioid or spindle cells foreign to lymph node metastasis; 3 refused further surgical treat- the lymph node were present; (2) the cells demonstrated cel- ment; and 1 was lost to follow-up. Only 1 of the 6 pa- lular atypia defined as cellular enlargement, prominent nucleoli, tients available for examination had evidence of recur- nuclear pleomorphism, or dusty cytoplasmic melanin gran- rence that was not in the sampled nodal basin (iliac nodes), ules; (3) positive staining was present for 1 or more of the melanocytic markers S-100, HMB-45, NKIC3, or MART-1; and (4) but in the axilla (after a follow-up of 6-47 months). the cells in question could be identified on the hematoxylin- Twelve (15%) of the 80 patients who underwent eosin–stained sections. CLND were found to have further metastases in the fi- A diagnosis of capsular nevus was made when all of the nal surgical specimen. No significant differences in the following criteria were fulfilled: (1) individual cells in a linear primary tumor characteristics for these patients were iden- array and/or nests of epithelioid or spindle cells foreign to the tified when compared with those with negative CLND lymph node were present; (2) the cells demonstrated no cel- (Table 1). lular atypia; (3) the cells showed positive staining for 1 or more We further assessed the patients with positive SLN of the melanocytic markers S-100, HMB-45, NKIC3, or MART-1; biopsy specimens by grouping them on the basis of the and (4) the cells in question could be identified on the hema- number of positive SLNs and the presence of negative toxylin-eosin–stained sections. lymph nodes in the SLN biopsy specimen submitted. STATISTICAL ANALYSES Twenty-eight SLN specimens from patients who underwent CLND included only histologically positive nodes Categorical data were examined in a univariate analysis by means (1, 2, or 3). Seven of these patients (25%) had addi- of the ␹2 test; continuous data were analyzed by unpaired t test tional nodes with metastatic melanoma in the CLND or Mann-Whitney test. specimen (Table 2). The other 52 patients in whom CLND was done had negative nodes along with 1 (n=48, RESULTS 92%) or 2 (n=4, 8%) positive SLN(s). The 48 patients who had CLND and who had only Examination of the SLN biopsy specimen identified 87 1 positive SLN also had 1 to 9 histologically negative nodes patients with metastatic melanoma; these patients had in the SLN biopsy specimen per sampled basin. Four (8%) SLNs in 94 regional nodal basins (a range of 1 to 3). The of these patients had additional nodes with metastastic

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 2. CLND Status in Patients With Positive SLN Table 3. Categorization of Patients With Positive and Negative Nodes on SLN Biopsy Based on Number Node Status on SLN Biopsy, No. (%)* of Positive Nodes

Positive and Negative Positive Only Node Status on SLN Biopsy, No. (%)* CLND Findings (n = 58) (n = 29) Negative 47 (90) 21 (75) 1 Positive, 2 Positive, Positive 5 (10)† 7 (25)† With Negative With Negative Positive Only CLND Findings (n = 52) (n=6) (n = 29) Not done 6 1 Negative 44 (92) 3 (75) 21 (75) Abbreviations: CLND, completion lymph node dissection; SLN, sentinel Positive 4 (8)† 1 (25) 7 (25)† lymph node. Not done 4 2 1 *Percentages are of the patients who underwent CLND (52 and 28, respectively). Abbreviations: CLND, completion lymph node dissection; SLN, sentinel ␹2 †Statistically significant difference; P = .04 by test. lymph node. *Percentages are of the patients who underwent CLND (48, 4, and 28, respectively). melanoma in the CLND specimen (Table 3). The 4 pa- †Statistically significant difference; P = .02 by ␹2 test. tients who had CLND with 2 positive SLNs had 2 to 4 negative SLNs. Of this group, 1 (25%) was found to have

further positive nodes on CLND (Table 3). These data n = 46 thus showed that patients with only positive nodes ob- 1/10 tained during SLN biopsy had a statistically signifi-

cantly greater chance (25%) of having further positive 1/8 nodes on CLND than did patients with both positive and negative nodes on SLN biopsy (10%). This increased risk was most pronounced when the former group (positive 1/6 nodes only) was compared with patients whose SLN bi- n = 5 opsy had shown only 1 positive node plus negative nodes 1/4 (8% metastases on CLND). Nevertheless, no patient subgroup with any SLN metastasis was found to have mini- SLN Specimen: No. Positive/Total Nodes SLN Specimen: No. Positive/Total 1/2 mal risk of further metastases in the CLND specimen. Positive Negative We also questioned whether the proportion of posi- CLND Findings tive vs total nodes in the SLN specimen might accu- Figure 2. Completion lymph node dissection (CLND) status vs proportion of rately predict the status of the remaining nonsentinel positive to total lymph nodes in the sentinel lymph node (SLN) biopsy nodes. The number of negative nodes obtained from the specimen. There was overlap at lower proportions, but no patients with a same basin as the positive node(s) in SLN biopsy speci- proportion of greater than 1/4 had further metastases on CLND. mens ranged between 1 and 9. The proportion of positive vs total ranged from 1 of 2 to 1 of 10 in the negative will improve their survival. Admittedly, studies have shown CLND subgroup, and from 1 of 2 to 1 of 4 in the posi- this survival benefit only when this subgroup of patients tive CLND subgroup (Figure 2). This analysis, there- is compared with patients undergoing delayed lymph node fore, did show that no patients with a positive to total dissection at the time of clinically evident lymph node me- SLN proportion of greater than 1 of 4 had further metastasis.6 Thus, the validity of this assumption is depen- tastases found on CLND. However, since only 9 pa- dent on prospective randomized trials that are under way.25 tients fit this criterion in our study, the clinical validity Although some authors have suggested that rou- of this observation will require further evaluation. tine CLND should not be recommended until results of these trials are available, most clinicians and patients find COMMENT it unacceptable to proceed with simple observation after the finding of a positive SLN biopsy specimen. Vari- Sentinel lymph node mapping and biopsy has been en- ous literature reports have noted that 8% to 50% of pa- thusiastically adopted as the most precise method for stag- tients with positive SLNs will be found to have further ing primary cutaneous melanoma of 1.0 mm thick or metastases in the final surgical specimen.20,26 In our ex- greater, or Clark level IV or greater. It is a minimally in- perience, 12 (15%) of 80 patients with a positive SLN bi- vasive and highly accurate procedure for identifying oc- opsy specimen were found to have further metastasis on cult nodal metastasis and thus significantly influences the CLND. It should be emphasized that CLND specimens prognosis and survival of these patients. Approximately are analyzed only by the lymph node “bivalve” tech- 80% of patients are determined to be node negative by nique, and thus some positive nodes were probably this technique and can be predicted to have a 5-year dis- missed. Therefore, the incidence of further metastases in ease-free survival rate of 65% to 95% (depending on other the CLND specimen may even be higher. primary tumor characteristics) without further therapy.3 Since no diagnostic criteria are currently available Completion lymph node dissection is currently recom- to identify this subgroup and spare the remaining SLN- mended for the remaining 15% to 20% of patients with positive patients the costs and morbidity of CLND, CLND demonstrated SLN metastases, on the assumption that remains the uniform recommendation for all patients with clearing the regional node basin of microscopic disease positive SLNs.

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Our review identified 3 criteria in patients with his- rotid selective lymphadenectomy in malignant melanoma. Ann Plast Surg. 1999; tologically positive SLN that significantly lower their risk 43:1-6. 15. Lenisa L, Santinami M, Belli F, et al. Sentinel node biopsy and selective lymph for further metastasis on CLND: first, and most appre- node dissection in cutaneous melanoma patients. J Exp Clin Cancer Res. 1999; ciably, having negative nodes together with positive SLNs 18:69-74. in the initial SLN biopsy specimen; second, having only 16. Glass LF, Messina JL, Cruse W, et al. The use of intraoperative radiolymphos- 1 positive SLN; and third, having a proportion of posi- cintigraphy for sentinel node biopsy in patients with malignant melanoma. Der- matol Surg. 1996;22:715-720. tive to total SLNs of greater than 1 to 4. Nevertheless, 17. Wells KE, Rapaport DP, Cruse CW, et al. Sentinel lymph node biopsy in mela- further lymph node metastases on CLND were present noma of the head and neck. Plast Reconstr Surg. 1997;100:591-594. in 10% of even patients with the most significantly cor- 18. Bartolomei M, Testori A, Chinol M, et al. Sentinel node localization in cutaneous related criteria (negative nodes in the SLN specimen). This melanoma: lymphoscintigraphy with colloids and antibody fragments versus blue was a significantly lower risk than that in the group of dye mapping. Eur J Nucl Med. 1998;25:1489-1494. 19. Cascinelli N, Clemente C, Bifulco C, et al. Do patients with tumor-positive sen- patients with only positive SLNs, 25% of whom had fur- tinel nodes constitute a homogeneous group? Ann Surg Oncol. 2001;8(9, suppl): ther metastases in the CLND specimen. 35S-37S. This review has confirmed that this subgroup of pa- 20. McMasters KM, Wong SL, Edwards MJ, et al. Frequency of nonsentinel lymph tients (with histologically positive SLNs and negative non- node metastasis in melanoma. Ann Surg Oncol. 2002;9:137-141. 21. Shaw HM, Thompson JF. Frequency of nonsentinel lymph node metastasis in sentinel nodes in the initial SLN biopsy specimen) is at melanoma [letter]. Ann Surg Oncol. 2002;9:934. significantly lower risk for further metastasis, but CLND 22. Reeves ME, Delgado R, Busam KJ, Brady MS, Coit DG. Prediction of nonsenti- cannot be safely omitted even for these patients. nel lymph node status in melanoma. Ann Surg Oncol. 2003;10:27-31. 23. Gadd MA, Cosimi AB, Yu J, Duncan LM, et al. Outcome of patients with mela- Accepted for publication December 23, 2003. noma and histologically negative sentinel lymph nodes. Arch Surg. 1999;134: 381-387. This study was presented at the 84th Annual Meeting 24. Yu LL, Flotte TJ, Tanabe KK, et al. Detection of microscopic melanoma me- of the New England Surgical Society; September 19, 2003; tastases in sentinel lymph node. Cancer. 1999;86:617-627. Newport, RI; and is published after peer review and revision. 25. Morton DL, Thompson JF, Essner R, et al, Multicenter Selective Lymphadenec- The discussions that follow this article are based on the origi- tomy Trial Group. Validation of the accuracy of intraoperative lymphatic map- nally submitted manuscript and not the revised manuscript. ping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. Ann Surg. 1999;230:453-463. Corresponding author and reprints: Nahel Elias, MD, 26. Wagner JD, Gordon MS, Coleman JJ, et al. Predicting sentinel and residual lymph Department of Surgery, White 515, Massachusetts Gen- node basin disease after sentinel lymph node biopsy for melanoma. Cancer. 2000; eral Hospital, 55 Fruit St, Boston, MA 02114 (e-mail: 89:453-462. [email protected]). DISCUSSION REFERENCES Blake Cady, MD, Providence, RI: I think this brings up the 1. Rigel DS, Carucci JA. Malignant melanoma: prevention, early detection, and treatment in the 21st century. CA Cancer J Clin. 2000;50:215-236. whole issue of what is a positive lymph node. Is it immuno- 2. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 histochemistry only? Is it some size by histochemistry? Is it a melanoma patients: validation of the American Joint Committee on Cancer Mela- certain number of cells? Is it hematoxylin-eosin? As you know, noma Staging System. J Clin Oncol. 2001;19:3622-3634. American Joint Committee on Cancer, sixth edition, in breast 3. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Com- cancer says that cells that are metastatic less than 0.2 mm in mittee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001; diameter characterizes N0 because there are no data that indi- 19:3635-3648. cate that those patients have an adverse prognosis and I sus- 4. Veronesi U, Adamus J, Bandiera DC, et al. Inefficacy of immediate node dissec- pect somewhat similar to what may be found in melanoma. The tion in stage 1 melanoma of the limbs. N Engl J Med. 1977;297:627-630. question I have is, are your data based on the size of the sen- 5. Sim FH, Taylor WF, Pritchard DJ, Soule EH. Lymphadenectomy in the management of stage I melanoma: a prospective randomized study. Mayo Clin Proc. 1986; tinel node metastases? That applies both to the sentinel node 61:697-705. that is positive and to the nonsentinel node that is positive. In 6. Cascinelli N, Morabito A, Santinami M, MacKie RM, Belli F, WHO Melanoma Pro- other words, you might be calling some of these patients who gramme. Immediate or delayed dissection of regional nodes in patients with mela- have a positive nonsentinel node positive on the basis of a few noma of the trunk: a randomised trial. Lancet. 1998;351:793-796. cells in the capsule. 7. Balch CM, Soong S, Ross MI, et al. Long-term results of a multi-institutional ran- In breast cancer there is a very important trial going on domized trial comparing prognostic factors and surgical results for intermedi- that is having difficulty recruiting, the Z-11 trial by the Col- ate thickness melanoma (1.0 to 4.0 mm): Intergroup Melanoma Surgical Trial. lege of Surgeons. In that trial a positive sentinel node is ran- Ann Surg Oncol. 2000;7:87-97. domized to axillary dissection vs observation. I believe there is 8. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127:392-399. also a trial in melanoma. It is the College of Surgeons, and are 9. Leong SP. Selective sentinel lymphadenectomy for malignant melanoma. Surg there any preliminary data from that? I wonder what your Clin North Am. 2003;83:157-185. thoughts are about that. 10. McMasters KM, Swetter SM. Current management of melanoma: benefits of sur- Dr Elias: Others have attempted to evaluate the nodes gical staging and adjuvant therapy. J Surg Oncol. 2003;82:209-216. based on the size of metastases. There is a recent publication 11. Albertini JJ, Cruse CW, Rapaport D, et al. Intraoperative radio-lympho- by Reeves et al (Reeves ME, Delgado R, Busam KJ, Brady MS, scintigraphy improves sentinel lymph node identification for patients with mela- Coit DG. Prediction of non-sentinel lymph node status in melanoma. Ann Surg. 1996;223:217-224. noma. Ann Surg Oncol. 2003;10:27-31), where they designed a 12. Gershenwald JE, Tseng CH, Thompson W, et al. Improved sentinel lymph node scoring system based on the size and the ulceration of the le- localization in patients with primary melanoma with the use of radiolabeled col- sion. Patients with positive nodes had significantly higher scores. loid. Surgery. 1998;124:203-210. 13. Morton DL, Thompson JF, Essner R, et al, Multicenter Selective Lymphadenec- Again, I am referring to the size of the metastases in the SLN, tomy Trial Group. Validation of the accuracy of intraoperative lymphatic map- which is similar to what you have mentioned about breast can- ping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. cer (new American Joint Committee on Cancer guidelines), al- Ann Surg. 1999;230:453-463. though that study did not have a large number of patients, and 14. Wells KE, Stadelmann WK, Rapaport DP, Hamlin R, Cruse CW, Reintgen D. Pa- again I guess the jury is still out on that issue.

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Robert Osteen, MD, Boston, Mass: I have a similar ques- that maybe the number that is looked at, for example, if one tion to Blake’s. Did you process the nonsentinel nodes the same did 4 or 5 nodes in that area and the rest of those were nega- way you processed the sentinel nodes? Our pathologists pro- tive, is relevant to whether a subsequent dissection would be cess the sentinel nodes by step section, the hematoxylin- needed? This might provide a rationale to avoid a subsequent eosin, and the negative nodes then get immunohistochemis- procedure of which 90% are probably unnecessary. try. They would not process the nonsentinel node with Dr Elias: As I have mentioned, we evaluated the ratio of immunohistochemistry, so you may be prejudicing yourself by positive to total number of nodes. When we had a higher num- not processing the nonsentinel nodes the same way. ber of nodes, the ratio will be lower. This was noted only in Dr Elias: That is true. Most of CLND nodes are not pro- the negative completion group. A ratio of 1 to 4 or greater had cessed the same way, although the nodes that I have referred only negative CLND; thus, it might be beneficial to get more to in my presentation as the negative nodes in the SLN speci- than 1 or 2 nodes. But looking at our data: the earlier specimen were nodes processed the same way as the SLN in our study. mens from 1997 had higher numbers of nodes than the more When we compare the groups with positive only vs positive recent specimens. As we have more experience with this, more and negative nodes, these are all nodes processed with both he- surgeons feel more comfortable taking only 1 or 2 nodes, and matoxylin-eosin and immunohistochemistry. when these are negative, no further nodes are needed. Harold Wanebo, MD, Providence: In the group that had Thomas Colacchio, MD, Lebanon, NH: Did you look at the combined sentinel node negative and positive, the nega- the group that didn’t have CLND and evaluate for any clinical tive sentinel nodes were part of the same process. They were recurrences, and did you apply your criteria to that group to identified either by the blue dye or you used the gamma probe see if you could have predicted whether the recurrences would detector, one of those, so they were presumably positive nodes have occurred? but only one was positive. Is that right? Dr Elias: Actually, we did. Only 1 out of the 7 patients, Dr Elias: Correct. with up to 47 months of follow-up, had recurrence. We lost 1 Dr Wanebo: So they all had characteristics for being in patient to follow-up, so we do not have any further data on him, the sentinel node area. The question is, do you have a feeling but the other 5 do not have any recurrences.

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ARCHIVES OF INTERNAL MEDICINE Evaluation of the Benefits and Risks of Low-Dose Aspirin in the Secondary Prevention of Cardiovascular and Cerebrovascular Events Steven M. Weisman, PhD; David Y. Graham, MD Background: In spite of the clear evidence of benefit of aspirin in the secondary prevention of cerebrovascular and cardiovascular thrombotic events, its use in patients at high risk due to a previous event remains suboptimal. A possible explanation for this underuse is concern regarding the relative benefit in relation to the potential risk for serious gastrointestinal events. Objective: To compare the benefit and gastrointestinal risk of aspirin use for the secondary prevention of thromboembolic events. Design: A meta-analysis was conducted using 6 trials (6300 patients) meeting the inclusion requirement of use of low-dose aspirin (Յ325 mg/d) in approved secondary prevention indications. Results: Aspirin reduced all-cause mortality by 18%. In addition, aspirin use reduced the number of strokes by 20%, myocar- dial infarctions by 30%, and other “vascular events” by 30%. Alternately, patients who took aspirin were 2.5 times more likely than those in the placebo group to have gastrointestinal tract bleeding. The number needed to treat for aspirin to prevent 1 death from any cause of mortality was 67, while 100 needed to be treated to detect 1 nonfatal gastrointestinal tract bleeding. Conclusion: Aspirin use for the secondary prevention of thromboembolic events has a favorable benefit-to-risk profile and should be encouraged in those at high risk. (2002;162:2197-2202) Corresponding author and reprints: Steven M. Weisman, PhD, 13 James St, Morristown, NJ 07960 (e-mail: [email protected]).

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