Annals of Surgical Oncology Cite Track
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10.1245/ASO.2006.09.023
Annals of Surgical Oncology 13:1130-1135 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Radiolocalized Sentinel Lymph Node Biopsy in Squamous Cell Carcinoma of the Oral Cavity and Analysis of Various Parameters

Ching-Yu Yen, DDS1, Sheng-Yang Lee, DDS2, Jih-Fang Hsieh, MD3, Dun-Zheng Wang, DDS2, Gin-Nan Lin, MD4, Chih-Mong Tsai, DDS2 and Shyun-Yui Liu, DDS1,2

1 Department of Oral and Maxillofacial Surgery, Chi Mei Medical Center, 901 Chung Hwa Road, Yung Kang City, Tainan 710, Taiwan
2 School of Dentistry and Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan
3 Department of Radiology, Division of Nuclear Medicine, Chi Mei Medical Center, Tainan, Taiwan
4 Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan

Correspondence: Address correspondence and reprint requests to: Shyun-Yui Liu, MD; E-mail: ycysmc{at}yahoo.com.tw.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background: Sentinel lymph node (SLN) biopsy seems to be a method that solves the problem of neck management with oral squamous cell carcinoma. Using blue dye methods for detection of neck SLNs from the surface of the operative field seems difficult; therefore, we used radiolocalization alone to detect and extract sentinel nodes. Aside from the various histological and clinical parameters examined in this procedure, we also determined whether they had any clinical significance in relation to the detection of SLNs during the operation.

Methods: Enrolled subjects had preoperative clinical N0 stage squamous cell carcinoma of the oral cavity and had received an unfiltered 99mTc sulfur colloid peritumoral injection. Localization of the SLNs was performed by using lymphoscintigraphy and a handheld gamma probe.

Results: In total, 28 oral squamous cell carcinoma patients were included in this prospective study. Sixty-four SLNs in 27 patients were identified by this method. The identification rate was 96.4%. No false-negative predictions of SLN were noted among any of the patients studied. The numbers of the SLNs found during the operation were larger in patients with positive findings than those with negative findings (P < .05 by the Mann-Whitney U-test).

Conclusions: SLN radiolocalization provided an acceptable identification rate. The cases of positive findings for metastasis seemed to statistically have more SLNs than did those with negative findings, but more evidence is needed to prove this point. Therefore, SLN biopsies for extracting all possible high-risk nodes may be conducive for oral squamous cell carcinoma surgery.

Key Words: Sentinel lymph node biopsy • Radiolocalized • Oral cavity • Squamous cell carcinoma


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Among patients with oral cancer, 20% to 30% of patients at clinical stage N0 were found to have occult metastases.1,2 Sentinel lymph node (SLN) biopsy seems to be a method that resolves the long-term problem of neck management of oral squamous cell carcinoma. The lymph tissue in the neck lies where the muscles and vessels overlap each other, and thus the use of blue dye methods for detection of neck SLNs from the surface of the operative field seems difficult. Therefore, in the past several years, radiolocalization alone has been applied to detect and extract high-risk SLNs for SLN biopsies of head and neck cancers. In a study by Shoaib et al.,3 the identification rate of SLNs in oral squamous cell carcinoma was 95%, the sensitivity rate for metastasis of positive SLNs was 94%, and no patient with negative SLN findings underwent neck dissection. In that study, the handling of head and neck cancers depended on a gamma probe and lymphoscintigraphy-guided SLN biopsies. The identification rate of SLNs can be as high as 100%,4–8 in contrast with the 40% rate reported by Koch et al.9 Except for the Koch study, the rate was almost the same as that (90%–100%8–11) via the radioisotope method combined with blue dye. The false-negative rate of negative SLNs for tumor metastasis in various head and neck cancers was 0% to 6%.3,4,12,13 There have been few oral cancer-related SLN studies, so SLN biopsies cannot be used presently as a standard surgical protocol for oral cancer at the preoperative clinical stage N0. Therefore, analyzing the factors that may influence SLN identification and its sensitivity for tumor metastasis prediction is important. In this study, we attempted to determine whether variability in certain parameters can affect the identification and sensitivity rates.

Performing an SLN biopsy is theoretically easy but technically difficult. Therefore, it is not easy to exclude differences among different doctors’ techniques and, thus, be able to evaluate the efficiency. Whether the primary tumor-related parameters—e.g., primary tumor site, tumor size, tumor cell differentiation, tumor morphology, and time interval between injection and collection—affect the number of SLNs identified in oral cancer cases was investigated. Oral cancer lymphoscintigraphic delay mapping over 20 minutes implemented by Nieuwenhuis et al.14 produced hot spot numbers (52%) larger than those of immediate mapping, which revealed that surgically extracted SLNs were not all first-echelon nodes, but it is easy to understand that a small number of SLNs have a higher metastasis risk than others. In terms of oral cancer therapy, extracting high-risk nodes is more important than being picky as to whether or not they are first-echelon nodes. In this study, we investigated the feasibility of using the SLN concept in neck management of oral cancer.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Before surgery, subjects had clinical N0 stage untreated squamous cell carcinoma of the oral cavity. The entire tumor margin should be accessible for peritumoral submucosal injection of a radiotracer. On the operation day, patients were scheduled by the nuclear medicine department for tumor injection of 3 mCi of unfiltered 99mTc sulfur colloid radioisotope. Two physicians, one each from the department of oral and maxillofacial surgery and the department of nuclear medicine, were present during each injection. Four syringes each with .75 mCi of 99mTc sulfur colloid in a .05-mL volume were prepared from a commercially available sulfur colloid kit (CIS-US, Bedford, MA). Approximately an hour before surgery, patients received four injections submucosally at equidistant points as near as possible to the periphery of the tumor margin. Immediately after the injections, scintigraphic images of the anterior and lateral projections were acquired with a dual-head gamma camera (Genesys; ADAC, Milpitas, CA). After 1 hour, repeat images of the same projections were obtained. During surgery, we identified the SLNs by using a handheld gamma probe (Navigator GPS; Diagnostic Technologies, Norwalk, CT). SLNs in this study were defined as nodes with at least 20-fold the background radioactivity. These were removed, and then their locations and intensities were registered. Subsequently, elective neck dissection was also performed. After tumor excision, the gamma probe was used to recheck the surgical field to identify any residual SLNs. After surgery, all specimens were fixed in 10% formalin and processed routinely. All SLNs were bread-loafed into 1- to 2-mm-thick slices and were submitted entirely in cassettes. The non-SLNs were bisected longitudinally and subjected to processing. One hematoxylin and eosin (H&E)-stained section was performed for each block and was examined for metastasis. For the negative nodes revealed by the first H&E sections, which were either SLNs or non-SLNs, the block was step-serially sectioned in triplicate at 40-µm intervals to produce three H&E sections. If the node still seemed to be free of tumor, an immunohistochemical study using a cytokeratin cocktail (AE1/AE3) was performed on 1 additional deeper serial section at a 40-µm interval. Cytokeratin positivity was compared with the adjacent H&E-stained sections for a confirmatory diagnosis. Detailed records of all nodes and tumors covered the location, size, morphology, time interval, pathological outcome, and level of the dissected nodes according to the Memorial Sloan-Kettering Cancer Center classification.15


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Totally, 28 oral cavity squamous cell carcinoma cases at the preoperative clinical stage of N0 were included in this study from October 2002 to March 2004. All patients were men aged 30 to 66 years (average, 47.8 years). The sites of the primary tumor were the bucca in 15, the tongue in 7, the lip in 3, the gingiva in 2, and the floor of the mouth in 1. According to the American Joint Committee on Cancer (6th edition) classification of tumor size, there were 14 T1 cases, 11 T2 cases, and 3 T3 cases. The types of tumors distinguished morphologically included 15 exophytic, 10 ulcerative, and 3 deeply invasive. Histological analysis revealed that 10 of the oral cancer cases were well differentiated, 16 were moderately differentiated, and 2 were poorly differentiated. There were 27 successfully detected and extracted SLN cases out of a total of 28. The identification rate for the 27 cases with 64 nodes was 96.4%. The range of numbers of SLNs found in each case was 1 to 5. The data regarding the number of SLNs per case were as follows: 6 had 1 SLN, 11 had 2 SLNs, 5 had 3 SLNs, 4 had 4 SLNs, and 1 had 5 SLNs. No SLN was found in case 23 (Tables 1Go and 2Go).


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  		TABLE 1. Number and location of sentinel lymph nodes
 

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  		TABLE 2. Individual parameters and number of sentinel lymph nodes
 
The average number of SLNs (ANSLN) of all cases was 2.4. By the site of the primary tumor, the ANSLN in the buccal mucosa was 2.4 (36/15), and in the tongue it was 2.1 (15/7). On the basis of the tumor cell differentiation analysis for ANSLN, the ANSLN for well-differentiated cancer was 2.4 (24/10), that of moderately differentiated cancer was 2.1 (34/16), and that of poorly differentiated cancer was 3.0 (6/2). For tumor size correlated with ANSLN data, T1 was 2.5 (35/14), T2 was 2.2 (24/11), and T3 was 1.7 (5/3). The data demonstrated that the number of SLNs decreased as the tumor size increased. The ANSLN in terms of tumor morphology was 2.7 (27/10) for exophytic morphology, 2.1 (32/15) for ulcerative morphology, and 1.7 (5/3) for deeply invasive morphology. These data revealed no significant differences (P > .05; Table 3Go). The recorded and analyzed parameters that contained consecutive variables, such as age, tumor area, and injection time interval, in relation to the numbers of SLNs found revealed no prominent differences (Table 4Go).


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  		TABLE 3. Tumor-related parameters and the average number of sentinel lymph nodes
 

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  		TABLE 4. Correlations of the consecutive variables and the number of sentinel lymph nodes (SLNs)
 
There were six cases of positive SLNs. Thus, the occult metastasis rate was 22.2% (6 of 27). All cases with nonmetastatic SLNs had positive SLNs, and all cases without nonmetastatic SLNs had negative SLNs. The false-negative rate was 0%. Five (83%) of six positive cases had the hottest nodes, which were positive in each case. The ANSLN of the positive cases was 3.7 (22/6); that of the negative cases was 1.9 (42/22). Significant differences (P < .05 by the Mann-Whitney U-test) appeared in the data.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
The SLN identification rate (96.4%) in this study was acceptable as a clinical operational mode for oral cancer. Our result was as good as that (90%–100%)3,10,11,16,17 with a combination of radioisotope and blue dye for SLN identification of head and neck cancers. The ANSLN (2.3) of all cases combined was almost the same as that (2.5–2.9)11,13 of other studies of head and neck cancer in the literature.

Consequently, tumor parameters such as location, cell differentiation degree, morphology, and size had no obvious relevance to SLN detection. Regarding the findings of SLNs, our results were similar to those of a breast cancer study in which none of the tumor parameters analyzed, such as size, histological characteristics, differentiation, receptor status, patient age, breast quadrant, or surgery type, was significantly related to the number of SLNs removed. Removal of more than three SLNs did not increase the accuracy for finding a positive node.18

One of the factors analyzed was the time interval between radioisotope injection and node extraction. The result revealed that the ANSLN had no relation to this factor (Table 2Go). In breast cancer, no association was found between injection of the radioisotope at greater or less than 5 hours before surgery and the successful intraoperative identification of the SLN.15 When normal surgery was implemented for SLN detection, SLN extraction required no strict time limit. The findings revealed that adding the SLN detection procedure to the operation had no effect on the smooth completion of the operation.

In the data obtained by comparing the pathologic results between postoperative SLNs and non-SLNs, there were six cases with metastatic cancer cells in the SLNs (positive lymph nodes). If a positive SLN presented with neck lymph node metastasis, the sensitivity of a positive SLN for metastasis was 100% in our study. A similar result with a sensitivity of 100% was reported by Stoeckli et al.10 The false-negative rate of negative SLNs herein was nil. The SLN detection sensitivity achieved in our study of clinically N0 head and neck cancers was 94%. The specificity of negative SLNs after surgery at the N0 stage was 100%.3 Our results and those of others allow us to conclude that SLNs play an important role in surgical treatment, especially with regard to N0 staging specificity.12 To further analyze metastases in the node-positive cases manifesting ANSLNs, the ANSLN of positive cases was 3.7 (22/6), and that of negative cases was 1.9 (42/22). The data denote a conspicuous difference. When the data were characterized to evaluate whether better or greater fluidity of the reticuloendothelial system appeared in SLNs, the characteristic was more beneficial for detecting tumor metastases. Nevertheless, in a study by Schrenk et al.,18 an increased number of SLNs did not affect the number of positive node findings.

Micrometastasis of SLNs is hard to detect during the postoperative examination with traditional surgery, which usually dissects dozens of lymph nodes when the operation is performed for neck lymph node dissection. The amount of tissue is usually too large to be sensed pathologically. Conversely, a case with a limited number of SLNs can receive a serial micro-section biopsy. The biopsy tissues at 2-mm intervals may increase the specificity for SLN micrometastases. Aside from the traditional H&E stain, cytokeratin immunohistochemistry, and reverse transcription-polymerase chain reaction, tumor marker detection has been used to explain how SLNs can evidently increase the sensitivity to tumor metastases.19

Out of six cases with positive SLNs, five (83%) comprised the hottest nodes. The percentage was higher than that for breast cancer (60%) (Eubus et al., unpublished data). This finding indicates that the path via the hottest nodes was not the only route for cancer cell metastasis. Various methods of injection in tumor parts or the perimeter might affect the detection of relatively hotter nodes.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
SLN radiolocalization provides an acceptable identification rate. The cases of positive findings for metastasis seem to statistically have more SLNs than those with negative findings, but more evidence is needed to prove this point. Therefore, SLN biopsies for extracting all possible high-risk nodes may be conducive for oral squamous cell carcinoma surgery.

Received for publication September 29, 2004. Accepted for publication November 8, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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  14. Nieuwenhuis EJC, Pijpers R, Castelijins JA, Snow GB. Lymphoscintigraphic details of sentinel lymph node detection in 82 patients with squamous cell carcinoma of the oral cavity, oropharynx. Nucl Med Commun 2003; 24:651–6.[CrossRef][Medline]
  15. Shah JP, Strong E, Spiro RH, Vikram B. Surgical grand rounds. Neck dissection: current status and future possibilities. Clin Bull 1981; 11:25–33.[Medline]
  16. Ross GL, Soutar DS, Shoaib T, et al. The ability of lymphoscintigraphy to direct sentinel node biopsy in the clinically N0 neck for patients with head and neck squamous cell carcinoma. Br J Radiol 2002; 75:950–8.[Abstract/Free Full Text]
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  18. Schrenk P, Rehberger W, Shamiyeh A, Wayand W. Sentinel node biopsy for breast cancer: does the number of sentinel nodes removed have an impact on the accuracy of finding a positive node?. J Surg Oncol 2002; 80:130–6.[CrossRef][Medline]
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