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Annals of Surgical Oncology 9:929-933 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

The Definition of the Sentinel Lymph Node in Melanoma Based on Radioactive Counts

Grant W. Carlson, MD, Douglas R. Murray, MD, Vinod Thourani, MD, Andrea Hestley, BA and Cynthia Cohen, MD

From the Departments of Surgery (GWC, DRM, VT, AH) and Pathology (CC), Emory University School of Medicine, Atlanta, Georgia.

Correspondence: Address correspondence and reprint requests to: Grant W. Carlson, MD, Winship Clinic, 1365B Clifton Road, Atlanta, GA 30322; Fax: 404-778-4255; E-mail: grant_carlson{at}emory.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background: There is no consensus on the definition of a hot, nonblue sentinel lymph node (SLN), despite the widespread use of radiocolloid in SLN mapping.

Methods: A retrospective review of 592 patients with malignant melanoma who underwent SLN mapping was performed. Ex vivo SLN counts and nodal bed counts were obtained by using a gamma probe. The size of each metastatic deposit in an SLN was defined as macrometastases (>2 mm), micrometastases (<=2 mm), a cluster of cells, or isolated melanoma cells.

Results: A total of 1175 SLNs (SLN-, n = 1041; SLN+, n = 134) were evaluated. The mean SLN count/bed counts were SLN-, 322 ± 980 and SLN+, 450 ± 910 (not significant [NS]) (>2 mm, 270 ± 792 [NS]; <=2 mm, 446 ± 693 [NS]; isolated melanoma cells/cluster of cells, 677 ± 1189 [P = .036]). Overall, 16 (1.4%) of the SLNs collected had an overall ratio of <=2. This included two positive SLNs (1.5%), both of which contained macrometastatic disease. Forty-seven positive nodal basins had at least one negative SLN. The hottest SLNs in these basins were negative for metastatic disease in nine cases (19.1%). In one basin (2.1%), the positive SLN count was <10% of the hottest lymph node count.

Conclusions: Removal of lymph nodes until the bed count is 10% of the hottest lymph node will remove 98% of positive SLNs. Lymph node tumor burden influences radioactive counts.

Key Words: Melanoma • Sentinel lymph node • Radioactive counts • Lymph node basin


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A sentinel lymph node (SLN) is the first draining lymph node on the direct lymphatic drainage pathway from the primary tumor site.1 Blue staining of the afferent lymphatic channel and node after peritumoral injection of vital blue dye is the established definition of an SLN. The use of radioactive colloid in combination with blue dye has markedly improved the success of lymphatic mapping. There is no consensus, however, on the definition of a radioactive, nonblue SLN, despite the widespread use of radiocolloid in SLN mapping. Morton and Bostick2 have stated that "the definition of the SN (sentinel node) will always be somewhat ambiguous when lymphatic mapping is performed with radiopharmaceuticals alone."

The radioactivity of the identified lymph node has been reported in some instances as in vivo and in others as ex vivo.3,4 The background may be defined as the radioactivity of the nonsentinel nodes, the surrounding lymph node basin, or an area of the body outside the lymph node basin. The ratio of lymph node to background radioactivity, depending on the author, has been defined as 2:1 or 3:1 in vivo or 10:1 ex vivo.4–8 This study attempts to define the sentinel lymph in melanoma on the basis of radioactive counts. The amount of tumor in the involved node, the time to SLN collection, and the location of the nodal basin are examined as influencing factors.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A retrospective review was performed of 592 consecutive patients (354 men and 238 women) with clinical 2002 American Joint Committee on Cancer stage I and II malignant melanoma who were treated with dynamic lymphoscintigraphy and gamma probe–guided SLN biopsy from January 1, 1994, to December 31, 1999, at Emory University Hospital.

SLN Mapping
Lymphatic mapping with dynamic lymphoscintigraphy and gamma probe–guided SLN biopsy were performed as previously described.9 The indication for SLN mapping and biopsy was melanoma tumor thickness of >=1 mm. Tumors <1 mm thick were considered candidates if there was evidence of tumor regression or ulceration. All patients underwent cutaneous lymphoscintigraphy with filtered 99mTc-labeled sulfur colloid (100–450 µCi; CIS-US, Inc., Bedford, MA). The radioactive tracer was injected intradermally around the circumference of the primary melanoma or biopsy site. Dynamic lymphoscintigraphy was performed with planar gamma camera imaging every 10 seconds for 10 minutes to identify focal areas of accumulation, followed by multiple 5-minute static images up to 60 minutes. In some patients, 2-hour postinjection delayed images were obtained. A mark was placed on the skin overlying these areas to correlate with intraoperative localization.

Measurements of radioactivity in the radiolabeled lymph nodes were made during surgery with a handheld gamma probe; SLNs demonstrated increased focal radiotracer uptake (hot spots). Counts were accumulated during a 10-second interval and recorded. Areas of increased activity, or hot spots, were removed and individual lymph nodes dissected out to find focal uptake of radioactivity. The lymphoscintigram was used as a guide to the number of nodes to be removed in many cases. Ex vivo counts of the SLNs were obtained and compared with the nodal bed counts after removal. Vital blue dye injected at the time of surgery was used routinely only in the last 2 years of the study.

The nodal basins were stratified by location. The anterior cervical group was anterior to the posterior border of the sternocleidomastoid muscle. This included nodes along the internal jugular vein, greater auricular nerve, and facial vessels. The posterior cervical node basin was posterior to the posterior border of the sternocleidomastoid muscle. This included nodes along the spinal accessory nerve, along the transverse cervical vessels, and over the mastoid and occiput. Parotid nodes were found on or within the parotid substance. In-transit nodes were exclusive of the main nodal basins and included epitrochlear, popliteal, and parascapular lymph nodes.

SLN Analysis
All collected SLNs were carefully labeled, and after serial 5-µm sectioning, they were examined histopathologically with routine hematoxylin and eosin and immunochemical staining for S-100 protein and melanoma-associated antigen HMB-45. The slides were reviewed, and the size of each metastatic deposit in an SLN was measured with an ocular micrometer. The SLN tumor burden was stratified into four groups: macrometastases (>2 mm), micrometastases (<=2 mm), a cluster of cells (10–30 grouped cells) in the subcapsular space or interfollicular zone, or isolated melanoma cells (1 to >=20 individual cells) in subcapsular sinuses.10,11 The pathology of each SLN was correlated with the SLN count/bed count ratio.

Statistical Analysis
The mean ± SD radioactivity count ratios of ex vivo SLNs per nodal bed were calculated. The differences in mean count rates and ratios associated with positive and negative SLNs were assessed with Student’s t-test. A P value of <=.5 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The clinicopathologic characteristics of the study group are listed in Table 1. There were 354 men and 238 women with a mean age of 51.8 years (range, 19–85 years). The primary tumor sites were head and neck (n = 86; 14.5%), trunk (n = 247; 41.7%), and extremities (n = 259; 43.8%). The pathologic data included only patients who underwent successful SLN mapping and biopsy.


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  		TABLE 1. The clinicopatholgic characteristics
 
SLN Mapping
Five hundred eighty-seven patients (99.2%) had successful SLN mapping and biopsy. In 459 cases (78.1%), a single draining nodal basin was identified. In 128 cases (21.9%), there were multiple draining nodal basins. A total of 1179 lymph nodes were collected. Four histologically uninvolved SLNs did not have documented radioactive counts. There were 134 positive SLNs found in 110 nodal basins in 104 patients. The overall positive SLN rate was 17.7% (104 of 587). Forty-seven positive nodal basins had at least one negative SLN. The hottest SLNs in these nodal basins were negative for metastatic disease in nine cases (19.1%). The mean number of SLNs collected per patient was 2.0. The distribution of the number of SLNs collected per patient is depicted in Fig. 1.



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  		FIG. 1. Number of sentinel lymph nodes (SLNs) collected; 587 patients with SLNs were identified.

 
SLN Collection Time Interval
Four hundred seventy-six patients had documented injection and SLN collection times. Nine hundred sixty-eight SLNs had recorded times; the mean time interval from injection to collection was 283.6 minutes, the median was 270 minutes, and the range was 20 to 1110 minutes. The mean number of SLNs collected as a function of time is listed in Table 2. The mean ex vivo SLN count/bed count ratios as a function of time to collection were <=360 minutes, 353 ± 997 and >360 minutes, 327 ± 648 (not significant).


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  		TABLE 2. Mean number of SLNs harvested per patient as a function of time
 
SLN Tumor Burden
The number of metastases in each positive SLN was isolated melanoma cells/cluster of cells, n = 40 (29.8%), <=2 mm, n = 45 (33.6%), and >2 mm, n = 49 (36.7%). The mean ex vivo SLN count/bed counts were overall, 337 ± 973; SLN negative, 322 ± 980; and SLN positive, 450 ± 910 (not significant). The ex vivo SLN count/bed count ratio distribution stratified by SLN status is listed in Table 3. Sixteen (1.4%) of the collected SLNs had ratios of <=2. The ex vivo SLN count/bed count ratio distribution stratified by nodal basin location is listed in Table 4. Four (13.8%) of the 29 parotid SLNs had ratios of <=2. The positive SLN count/bed count distribution stratified by nodal basin location is listed in Table 5. The positive ex vivo SLN count/bed count distribution stratified by SLN tumor burden is listed in Table 3. Two positive SLNs had ratios of <=2. Both of the SLNs contained metastases >2 mm in diameter. The mean ex vivo SLN count/bed count ratios stratified by various factors are listed in Table 6.


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  		TABLE 3. The positive ex vivo SLN count/bed count distribution stratified by SLN tumor burden
 

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  		TABLE 4. Ex vivo SLN count/bed count ratio distribution stratified by nodal basin location
 

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  		TABLE 5. The positive ex vivo SLN count/bed count distribution stratified by nodal basin location
 

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  		TABLE 6. The mean ex vivo SLN count/bed count ratios stratified by various factors
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
The hottest SLN in a nodal basin does not always reflect the status of the entire nodal basin. In this study, 47 positive nodal basins had at least one negative SLN. The hottest SLNs in these basins were negative for metastatic disease in nine cases (19.1%). The Sunbelt Melanoma Group recently reported their experience with 288 patients with melanoma SLN metastases in 306 nodal basins.12 One hundred seventy-five positive nodal basins had at least one negative SLN. In 40 (23.4%) of these basins, the most radioactive SLN was negative for tumor when another less radioactive SLN was positive for tumor. They found that the cervical nodal basin (which included the parotid) was associated with an increased likelihood of finding a positive SLN other than the hottest node.

The effect of nodal basin location on SLN counts has received little attention. The parotid gland takes up free technetium, resulting in high bed counts and reduced ex vivo SLN count/bed count ratios (Table 4). This can make SLN localization difficult, as evidenced by 4 of the 29 parotid SLNs having ratios of <=2. In our series previously reported of 58 patients with head and neck melanomas, SLN mapping in the parotid gland was unsuccessful in 3 (16.7%) of 18 cases.13

The 10% rule has been used to determine the number of lymph nodes removed from a nodal basin during SLN mapping.12 Nodes are removed until the bed count is 10% of the hottest lymph node count. In our study, the 10% rule would have missed 2.1% (1 of 47) of the positive SLNs. Bostick et al.14 performed SLN mapping in 100 lymphatic basins and found 17 positive SLNs. Sixteen (94.1%) had ex vivo SLN count/bed count ratios of >2, which is similar to our findings.13

There seem to be two patterns of tracer distribution within lymphatic circulation after peripheral injection.15 Initially, there is a period during which particles small enough to freely enter lymphatics travel to nodes. This is the result of passive diffusion, and significant accumulation of tracer within cells has not had time to occur. This is supported by the rapidity in which tracer can be identified in lymph nodes after injection. A second pattern of distribution seems to be immunologically mediated. Antigen-presenting cells (APCs) within the lymph node take up the tracer. The success of SLN mapping is probably the result of tracer retention by the APCs. A large metastatic deposit in an SLN could result in a loss of APCs, which leads to a loss of the node’s ability to take up and retain tracer. In a recent large series of SLN biopsies for breast cancer, three of five false-negative cases occurred in patients with nodes considered suspicious during the procedure.16

In this study, tumor burden within a metastatic SLN influenced the uptake of radioactive colloid (Tables 3 and 6). Macrometastases (>2 mm) in SLNs had ex vivo count/bed count ratios of <10 in 18.4% (9 of 49) of cases. Nine (69.2%) of the 13 SLNs with radioactive count ratios of <10 contained macrometastases (>2 mm) that potentially could have been found by intraoperative physical examination.

The time from injection of radioactive colloid to SLN node collection did not affect the count ratios or number of SLNs collected (Tables 2 and 6). Essner et al.17 found that ex vivo node/background count ratios were significantly higher when recorded within 4 hours of injections than >=18 hours afterward. They also found no differences in the number of SLNs collected as a function of time.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
There is no precise definition of a melanoma SLN based on radioactive counts. Removal of lymph nodes until the bed count is reduced to 10% of the hottest collected lymph node count and an ex vivo SLN count/bed count of >2 will remove approximately 98% of positive SLNs. There is a correlation between the tumor burden in an SLN and the ex vivo SLN count/bed count. The parotid gland takes up free radioactive colloid, which increases the bed counts.Go


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  		TABLE 7. Ex vivo SLN count/bed count ratio distribution
 


   Footnotes
 
There is no established definition of a sentinel lymph node in melanoma based on radioactive counts. Removal of lymph nodes until the bed count is 10% of the hottest lymph node will remove 98% of positive sentinel lymph nodes. Lymph node tumor burden and nodal location influence radioactive counts.

Received for publication November 27, 2001. Accepted for publication June 19, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127: 392–9.[Abstract]
  2. Morton DL, Bostick PJ. Will the true sentinel node please stand? Ann Surg Oncol 1999; 6: 12–4.[CrossRef][Medline]
  3. Kapteijn BA, Nieweg OE, Muller SH, et al. Validation of gamma probe detection of the sentinel node in melanoma. J Nucl Med 1997; 38: 362–6.[Abstract/Free Full Text]
  4. Albertini JJ, Cruse CW, Rapaport D, et al. Intraoperative radio-lympho-scintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg 1996; 223: 217–24.[CrossRef][Medline]
  5. Alex JC, Weaver DL, Fairbank JT, Rankin BS, Krag DN. Gamma-probe-guided lymph node localization in malignant melanoma. Surg Oncol 1993; 2: 303–8.[Medline]
  6. Brobeil A, Kamath D, Cruse CW, et al. The clinical relevance of sentinel lymph nodes identified with radiolymphoscintigraphy. J Fla Med Assoc 1997; 84: 157–60.
  7. Glass LF, Messina JL, Cruse W, et al. The use of intraoperative radiolymphoscintigraphy for sentinel node biopsy in patients with malignant melanoma. Dermatol Surg 1996; 22: 715–20.[CrossRef][Medline]
  8. 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: 536–9.[CrossRef][Medline]
  9. Murray DR, Carlson GW, Greenlee R, et al. Surgical management of malignant melanoma using dynamic lymphoscintigraphy and gamma probe-guided sentinel lymph node biopsy: the Emory experience. Am Surg 2000; 66: 763–7.[Medline]
  10. Dowlatshahi K, Fan M, Snider HC, Habib FA. Lymph node micrometastases from breast carcinoma: reviewing the dilemma. Cancer 1997; 80: 1188–97.[CrossRef][Medline]
  11. Hermanek P, Hutter RV, Sobin LH, Wittekind C. International Union Against Cancer. Classification of isolated tumor cells and micrometastasis. Cancer 1999; 86: 2668–73.[CrossRef][Medline]
  12. 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: 192–7.[Abstract/Free Full Text]
  13. Carlson GW, Murray DR, Greenlee R, et al. Management of malignant melanoma of the head and neck using dynamic lymphoscintigraphy and gamma probe-guided sentinel lymph node biopsy. Arch Otolaryngol Head Neck Surg 2000; 126: 433–7.[Abstract/Free Full Text]
  14. 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: 43–9.[Abstract/Free Full Text]
  15. Faries MB, Bedrosian I, Reynolds C, Nguyen HQ, Alavi A, Czerniecki BJ. Active macromolecule uptake by lymph node antigen-presenting cells: a novel mechanism in determining sentinel lymph node status. Ann Surg Oncol 2000; 7: 98–105.[Abstract]
  16. Hill AD, Tran KN, Akhurst T, et al. Lessons learned from 500 cases of lymphatic mapping for breast cancer. Ann Surg 1999; 229: 528–35.[CrossRef][Medline]
  17. Essner R, Bostick PJ, Glass EC, et al. Standardized probe-directed sentinel node dissection in melanoma. Surgery 2000; 127: 26–31.[CrossRef][Medline]



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