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Sentinel lymph node biopsy versus elective neck dissection in patients with cT1-2N0 oral tongue squamous cell carcinoma
Vol. 117 No. 2 February 2014
Sentinel lymph node biopsy versus elective neck dissection in patients with cT1-2N0 oral tongue squamous cell carcinoma Su-Feng Fan, MD,a Zong-Yuan Zeng, MD,a Han-Wei Peng, MD, PhD,b Zhu-Ming Guo, MD,a Shun-Lan Wang, MD,c and Quan Zhang, MD, PhDa State Key Laboratory of Oncology in South China, Guangzhou; Sun Yat-sen University Cancer Center, Guangzhou; Shantou University, Shantou; First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
Objective. This study aimed to compare the value of sentinel lymph node biopsy (SLNB) with that of elective neck dissection (END) for the prediction of cervical lymph node metastasis in patients with clinically diagnosed T1-2N0 (cT1-2N0) oral tongue squamous cell carcinoma (OTSCC), and it aimed to examine the prognostic value of individualized treatment in sentinel lymph node (SLN)-negative patients. Study Design. The study entailed a retrospective review of 82 patients with cT1-2N0 OTSCC. Thirty patients underwent SLNB, and 52 patients underwent END. Results. There was a significant difference between the SLNB and END groups in the incidence of occult cervical lymph node metastasis in initial specimens (30% vs 11.5%; P ¼ .037). However, there were no significant differences between the groups for 10-year overall and cervical recurrence-free survival rates and 10-year overall survival rate. Conclusions. SLNB is superior to END for the prediction of cervical lymph node metastasis in patients with cT1-2N0 OTSCC. Neck dissection may be reduced for SLN-negative patients, owing to the comparable prognosis of SLNB. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:186-190)
Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cancer and has a high propensity for occult cervical lymph node metastasis.1 A sentinel lymph node (SLN) is any node that receives lymph drainage directly from the primary tumor site, which is most likely to contain malignancy if the tumor has metastasized.2 Sentinel lymph node biopsy (SLNB) is conducted based on the phenomenon that malignancy metastasizes to remaining cervical lymph nodes through SLNs.3 Therefore, the status of the SLN reflects the neck status. If the SLN is positive, modified radical neck dissection (MRND) is recommended; if negative, no further treatment is necessary.4 Thus, SLNB is cost effective and minimizes the overall surgical complications.5-9 In 2013, the National Comprehensive Cancer Network recommended elective neck dissection (END) treatment for patients clinically diagnosed with T3-4N0 OTSCC and recommended MRND for patients identified as having a positive node. However, it is controversial as to whether END is necessary for a clinical classification of
a Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou. b Department of Head and Neck Surgery, Tumor Hospital, Medical College, Shantou University, Shantou. c Department of Otorhinolaryngology, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou. Received for publication Jun 9, 2013; returned for revision Sep 3, 2013; accepted for publication Sep 19, 2013. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.09.012
186
T1-2N0 (cT1-2N0) oral tongue carcinoma.10-12 The incidence of occult cervical lymph node metastasis is 20% to 40% in cT1-2N0 cancers13-14; thus, neck dissection is unnecessary for over 60% of patients, but END may not be adequate for those with occult cervical lymph node metastasis.15-16 The accurate detection of occult metastases is therefore important for the planning of treatment. Currently, the most accurate method of detection available for cN0 patients is END, but only 20% to 40% of patients have the risk of occult cervical lymph node metastases. For these reasons, SLNB is an attractive option for patients with cT1-2N0 OTSCC. SLNB is currently used as a staging procedure in squamous cell carcinoma (SCC) of the head and neck at some European centers4,9; however, it is unknown whether the associated long-term survival rates are comparable with those of END treatments. We therefore conducted a retrospective study to compare the long-term survival rates between an SLNBassessed group and an END-treated group in a cohort of patients with cT1-2N0 OTSCC with an aim to improve the individualized treatment of tongue carcinoma.
Statement of Clinical Relevance It is feasible that the extent of neck dissection can be reduced in patients with cT1-2N0 oral tongue squamous cell carcinoma for sentinel lymph nodee negative patients, owing to the noninferior prognosis associated with sentinel lymph node biopsy, which can improve individualized treatment.
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MATERIALS AND METHODS Our retrospective study and chart reviews were exempt or not applicable to the institutional review board standards of our individual institutions. The guidelines of the Helsinki Declaration were followed in this investigation. Patient characteristics Patients who presented with unique T1 or T2 OTSCC, with necks clinically and radiologically staged as N0, and who were treated surgically in Sun Yat-sen University Cancer Center between January 2000 and December 2002 were enrolled in the study. None of the patients had received preoperative chemotherapy or radiotherapy. The patients were clinically diagnosed before surgery on the basis of computed tomography, magnetic resonance imaging, or ultrasonographic findings. Cervical recurrence was treated by neck dissection only, and neither group received postoperative radiotherapy or chemotherapy. Surgical procedure SLNB group. The day before surgery, patients attended the Nuclear Medicine Department, whereupon they were injected with 0.5 to 1.0 mL 99mTc-phytate solution (1 mCi; 37 MBq, 0.2 mL, China Institute of Atomic Energy Isotope Service Center, Guangzhou, China) in approximately 0.3 mL of 2% lidocaine. This was injected into the deep submucosal layer surrounding the tumor at 4 selected sites and 1 basal site. All patients were offered topical local anesthetic immediately before being injected with radiocolloid. An alcohol-free mouthwash was used immediately after the injection to minimize the risk of residual radioactive material being swallowed. Static lymphoscintigraphy was performed at 30 minutes, 60 minutes, 120 minutes, and 6 hours after injection, or until the first appearance of SLNs within the neck. After first stop lymph node imaging, the hot spot was marked on the overlying skin with a skin marker and checked just before the skin incision with an intraoperative handheld gamma probe. During surgery, the patients were injected with methylene blue (2 mL, Yongkang Pharmaceutical Factory, Beijing, China) using the aforementioned parts per 0.3 to 0.4 mL (a total of 1 to 2 mL). After a few minutes, a 2- to 3-cm incision was made on the neck at the site marked by a skin marker. The SLN identified by both the blue dye and radioactivity was removed and checked using frozen-section techniques. Patients underwent MRND only if the SLN frozen section was positive. These SLNs were further checked by the pathologic examination of paraffin blocks.
ORIGINAL ARTICLE Fan et al. 187
Table I. Patient characteristics Variable Gender Male Female Pathologic grade I II III Age (y) Mean
SLNB group END group (n ¼ 30) (n ¼ 52) 21 9
30 22
14 9 7
23 14 15
48
52
c2
P*
1.226
.268
0.305
.859
1.339 (t value) .184
SLNB, sentinel lymph node biopsy; END, elective neck dissection. *A value of P < .05 indicates a statistically significant difference.
END group. Fifty patients were treated by ipsilateral END, which consisted of 36 END level I and II cases and 14 END level I to III cases. Two patients were treated by ipsilateral MRND (levels I to V). Lymph node testing All lymph nodes were studied using standard histologic techniques with hematoxylin and eosin. Each lymph node was divided into multiple sections, and each was examined. The gold standard for the confirmation of positive nodes was the pathologic results of paraffin sections.17-18 Statistical analysis All data were analyzed using SPSS software (version 17.0; SPSS Inc, Chicago, IL, USA). The 2 groups were compared using the c2 test. Survival curves were generated using the Kaplan-Meier method. The logrank test was used for univariate analysis. A value of P < .05 indicated a statistically significant difference.
RESULTS Demographic data The SLNB group comprised 30 patients (21 men and 9 women), with a mean age of 48 years (range, 27-75 years). Their preoperative clinical tumor classifications were T1N0M0 (n ¼ 17) and T2N0M0 (n ¼ 13). The minimum follow-up period was 10 years. The END group comprised 52 patients (30 men and 22 women), with a mean age of 52 years (range, 20-80 years). Their preoperative clinical tumor classifications were T1N0M0 (n ¼ 27) and T2N0M0 (n ¼ 25). The minimum follow-up period was 10 years. Gender, age, and pathologic grade data for the 2 groups are shown in Table I. Occult cervical lymph node metastasis In the SLNB group, the SLN detection rate was 100% (30/30). In total, 81 SLNs were identified. One SLN
ORAL AND MAXILLOFACIAL SURGERY 188 Fan et al.
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Table II. Occult cervical lymph node metastasis in initial surgery Lymph node SLN Occult metastasis in SLN Occult metastasis in LN in END group
Level I
Level II
Level III
Level IV
Level V
Contralateral level II
Total
21 2 4
35 5 7
20 6 2
3 1 1
0 0 0
2 0 0
81 14 14
SLN, sentinel lymph node; LN, lymph node; END, elective neck dissection.
Table III. Outcomes of cervical lymph node recurrence
Patient No. SLNB group 1 2 3 4 END group 1 2 3 4 5
Initial surgery of cervical lymph node status
Recurrence time (mo)
þ þ þ
8 6 24 7
I III III, IV I, II
10 9 30 45 60
II I, III III, IV IV V
Table IV. Occult cervical lymph node metastasis comparison
Recurrence site (ipsilateral)
SLNB, sentinel lymph node biopsy; END, elective neck dissection.
was found in 3 patients, 2 SLNs were found in 6 patients, 3 SLNs were found in 18 patients, and 4 SLNs were found in 3 patients. In the SLNB and control groups, 9 and 6 patients, respectively, were identified as having occult cervical lymph node metastasis in initial surgery (Table II). During follow-up, 9 cases of cervical lymph node recurrence were confirmed by pathology without tongue recurrence, consisting of 4 cases in the SLNB group and 5 cases in the control group (Table III). Occult lymph node metastasis rates of the 2 groups were compared using the c2 test (Table IV). Recurrence-free survival Recurrence-free survival (RFS) curves (Figures 1 and 2) were generated using the Kaplan-Meier method, and the log-rank test was used for univariate analysis. (Recurrences included cervical lymph node recurrence and primary recurrence.) The 10-year cervical RFS and overall RFS for the SLNB group and control group were, respectively, 86.4% vs 88.2% (c2 ¼ 0.311; P ¼ .577) and 72.3% vs 73.3% (c2 ¼ 0.060; P ¼ .806). Neither of these differences was significant. Overall survival Overall survival (OS) curves were generated using the Kaplan-Meier method, and the log-rank test was used for univariate analysis. Figure 3 shows the 10-year OS curves.
Discovery period Initial surgical specimens SLNB group END group Follow-up SLNB group END group Overall metastasis SLNB group END group
Occult cervical lymph node Without metastasis metastasis (cases) (cases)
c2
P*
9 6
21 46
4.338 .037
4 5
26 47
0.023 .879
10 11
20 41
1.481 .224
SLNB, sentinel lymph node biopsy; END, elective neck dissection. *A value of P < .05 indicates a statistically significant difference.
The 3-, 5-, and 10-year OS rates for the SLNB group and control group were, respectively, 76.7% vs 84.6%, 60.0% vs 63.5%, and 43.3% vs 44.2% (c2 ¼ 0.047, P ¼ .828). The 10-year OS differences were not statistically significant.
DISCUSSION Approximately 94% to 97% of tongue cancer lymph node metastasis occurs ipsilaterally at levels I to III; thus, some scholars have advocated END for patients with cN0 tongue cancer and MRND for suspicious lymph nodes on biopsy.19-21 Although END is associated with less morbidity than MRND, measurable morbidity exists, including shoulder dysfunction, pain, contour changes, and lower lip paresis.6 Moreover, if all cN0 tongue carcinoma patients underwent END, this would result in overtreatment for about 60% of patients without metastasis.15-16 The SLNs as specific anatomic sites underlie the theoretical basis of SLNB. Wei et al.13 have described how, if the SLN is negative, no further treatment is necessary. In recent years, SLNB has been reported to be an excellent classification method in early stage oral cancers, with a negative predictive value of about 95%.6,8 Furthermore, Lawson et al.22 evaluated the reliability of the SLNB in early supraglottic tumors and reported a negative predictive value of 100%. These findings indicate that SLNB in head and neck SCC has broad application prospects.
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Fig. 1. Ten-year cervical recurrence-free survival curves for the 2 groups. (SLNB, sentinel lymph node biopsy; END, elective neck dissection.)
Fig. 2. Ten-year overall recurrence-free survival curves for the 2 groups. (SLNB, sentinel lymph node biopsy; END, elective neck dissection.)
The current study showed that the incidence of occult cervical lymph node metastasis in initial surgical specimens was significantly different between the SLNB group and the control group (30% vs 11.5%). We predicted that SLNB would be better than END in determining the probability of occult cervical lymph node metastasis. Therefore, the SLN tracer method was used during surgery, and the surgeon could clearly identify high-risk occult metastasis lymph nodes. Our study indicated that SLNB was feasible and could be used to predict cervical lymph node metastasis in patients with cT1-2N0 OTSCC, because suspected lymph nodes were the prime target for SLNB. In most of the recent literature on patients with cT1-2N0 tongue cancer who underwent SLNB, the follow-up time was approximately 1 to 3 years4,8-9; thus, it is difficult to observe the impact of this treatment on long-term survival. Moreover, in contrast to the recent literature,4,6,8,12,14,17 our study was limited to patients with cT1-2N0 tongue cancer, which made our
ORIGINAL ARTICLE Fan et al. 189
Fig. 3. Ten-year overall survival curves for the 2 groups. (SLNB, sentinel lymph node biopsy; END, elective neck dissection.)
study more targeted. Our study investigated the 10-year OS and the cervical and overall RFS rates, which for SLNB and control groups were 43.3% vs 44.2%, 86.4% vs 88.2%, and 72.3% vs 73.3%, respectively. None of the differences were significant (P > .5). This suggests that SLNB did not reduce the 10-year OS, or cervical or overall RFS compared with END. However, this study comprised only a limited number of cases; more multicenter prospective studies with larger sample sizes will be necessary to establish the long-term prognosis for patients that undergo SLNB. Nevertheless, this study showed that SLNB was reasonable in clinical applications; it improved patient’s individualized treatment and did not affect prognosis. However, preoperative radionuclide scanning is associated with the risk of radioactive contamination. In addition, intraoperative methylene blue tracer will interfere with the judgment of tumor safety margins. Sometimes, the limitation of intraoperative frozen section examination may lead to individual micrometastases being missed. Therefore, if future studies can find better alternative approaches to identify SLN, SLNB will have a higher clinical value. It has been reported that SLNB with step sectioning and immunohistochemistry can improve the detection rate of micrometastases.6,17 Unfortunately, this method is difficult to apply to intraoperative rapid diagnosis. These problems are prevalent in the clinical application of SLNB; therefore, a rapid, accurate intraoperative test for the presence of metastatic disease in SLN may support widespread acceptance of SLNB in cases of SCC of the head and neck. SLNB can be used to predict cervical lymph node metastasis in patients with cT1-2N0 OTSCC. It is feasible that the extent of neck dissection can be reduced for SLN-negative patients, owing to the noninferior prognosis associated with SLNB, which can improve individualized treatment.
ORAL AND MAXILLOFACIAL SURGERY 190 Fan et al. REFERENCES 1. Pitman KT. Sentinel node localization in head and neck tumors. Semin Nucl Med. 2005;35:253-256. 2. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127:392-399. 3. Reintgen D, Cruse CW, Wells K, et al. The orderly progression of melanoma nodal metastases. Ann Surg. 1994;220:759-767. 4. Mozzillo N, Chiesa F, Caracb C, et al. Therapeutic implications of sentinel lymph node biopsy in the staging of oral cancer. Ann Surg Oncol. 2004;11:263S-266S. 5. Borgstein PJ, Meijer S, Pijpers RJ, Diest PJ. Functional lymphatic anatomy for sentinel node biopsy in breast cancer. Ann Surg. 2000;232:81-89. 6. Civantos FJ, Zitsch RP, Schuller DE, et al. Sentinel lymph node biopsy accurately stages the regional lymph nodes for T1-T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial. J Clin Oncol. 2010;28:1395-1400. 7. Shoaib T, Soutar DS, MacDonald DG, et al. The accuracy of head and neck carcinoma sentinel lymph node biopsy in the clinically N0 neck. Cancer. 2001;91:2077-2083. 8. Melkane AE, Mamelle G, Wycisk G, et al. Sentinel node biopsy in early oral squamous cell carcinomas: a 10-year experience. Laryngoscope. 2012;122:1782-1788. 9. Ross GL, Soutar DS, MacDonald DG, et al. Sentinel node biopsy in head and neck cancer: preliminary results of a multicenter trial. Ann Surg Oncol. 2004;11:690-696. 10. Yuen AP, Wei WI, Wong YM, Tang KC. Elective neck dissection versus observation in the treatment of early oral tongue carcinoma. Head Neck. 1997;19:583-588. 11. Manola M, Aversa1 C, MosCillo L, et al. Status of level IIb lymph nodes of the neck in squamous cell carcinoma of the oral tongue in patients who underwent modified radical neck dissection and lymph node sentinel biopsy. Acta Otorhinolaryngol Ital. 2011;31:130-134. 12. Dias FL, Kligerman J, Matos De Sa G, et al. Elective neck dissection versus observation in stage I squamous cell carcinomas of the tongue and floor of the mouth. Otolaryngol Head Neck Surg. 2001;125:23-29. 13. Wei WI, Ferlito A, Rinaldo A, et al. Management of the N0 neckdreference or preference. Oral Oncol. 2006;42:115-122.
OOOO February 2014 14. Keski-Säntti H, Kontio R, Törnwall J, et al. Sentinel lymph node biopsy or elective neck dissection for patients with oral squamous cell carcinoma? Eur Arch Otorhinolaryngol. 2008;265: S13-S17. 15. Chepeha DB, Taylor RJ, Chepeha JC, et al. Functional assessment using constant’s shoulder scale after modified radical and selective neck dissection. Head Neck. 2002;24:432-436. 16. Rogers SN, Ferlito A, Pelliteri PK, Shaha AR, Rinaldo A. Quality of life following neck dissections. Acta Otolaryngol. 2004;124: 231-236. 17. Ferris RL, Kraus DH. Sentinel lymph node biopsy versus selective neck dissection for detection of metastatic oral squamous cell carcinoma. Clin Exp Metastasis. 2012;29:693-698. 18. Yamauchi K, Fujioka Y, Kohno N. Sentinel node navigation surgery versus observation as a management strategy for early tongue carcinoma. Head Neck. 2012;10:568-572. 19. Khafif A, Lopez-Garza JR, Medina JE. Is dissection of level IV necessary in patients with T1-T3 N0 tongue cancer? Laryngoscope. 2001;111:1088-1090. 20. Schmitz S, Machiels JP, Weynand B, Gregoire V, Hamoir M. Results of selective neck dissection in the primary management of head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol. 2009;266:437-443. 21. Kowalski LP, Bagietto R, Lara JR, Santos RL, Silva JF Jr, Magrin J. Prognostic significance of the distribution of neck node metastasis from oral carcinoma. Head Neck. 2000;22: 207-214. 22. Lawson G, Matar N, Nollevaux MC, et al. Reliability of sentinel node technique in the treatment of N0 supraglottic laryngeal cancer. Laryngoscope. 2010;120:2213-2217. Reprint requests: Quan Zhang, MD, PhD State Key Laboratory of Oncology in South China Department of Head and Neck Surgery Sun Yat-sen University Cancer Center 651 Dongfeng Dong Road Guangzhou 510060 China [email protected]
Sentinel lymph node biopsy versus elective neck dissection in patients with cT1-2N0 oral tongue squamous cell carcinoma Su-Feng Fan, MD,a Zong-Yuan Zeng, MD,a Han-Wei Peng, MD, PhD,b Zhu-Ming Guo, MD,a Shun-Lan Wang, MD,c and Quan Zhang, MD, PhDa State Key Laboratory of Oncology in South China, Guangzhou; Sun Yat-sen University Cancer Center, Guangzhou; Shantou University, Shantou; First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
Objective. This study aimed to compare the value of sentinel lymph node biopsy (SLNB) with that of elective neck dissection (END) for the prediction of cervical lymph node metastasis in patients with clinically diagnosed T1-2N0 (cT1-2N0) oral tongue squamous cell carcinoma (OTSCC), and it aimed to examine the prognostic value of individualized treatment in sentinel lymph node (SLN)-negative patients. Study Design. The study entailed a retrospective review of 82 patients with cT1-2N0 OTSCC. Thirty patients underwent SLNB, and 52 patients underwent END. Results. There was a significant difference between the SLNB and END groups in the incidence of occult cervical lymph node metastasis in initial specimens (30% vs 11.5%; P ¼ .037). However, there were no significant differences between the groups for 10-year overall and cervical recurrence-free survival rates and 10-year overall survival rate. Conclusions. SLNB is superior to END for the prediction of cervical lymph node metastasis in patients with cT1-2N0 OTSCC. Neck dissection may be reduced for SLN-negative patients, owing to the comparable prognosis of SLNB. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:186-190)
Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cancer and has a high propensity for occult cervical lymph node metastasis.1 A sentinel lymph node (SLN) is any node that receives lymph drainage directly from the primary tumor site, which is most likely to contain malignancy if the tumor has metastasized.2 Sentinel lymph node biopsy (SLNB) is conducted based on the phenomenon that malignancy metastasizes to remaining cervical lymph nodes through SLNs.3 Therefore, the status of the SLN reflects the neck status. If the SLN is positive, modified radical neck dissection (MRND) is recommended; if negative, no further treatment is necessary.4 Thus, SLNB is cost effective and minimizes the overall surgical complications.5-9 In 2013, the National Comprehensive Cancer Network recommended elective neck dissection (END) treatment for patients clinically diagnosed with T3-4N0 OTSCC and recommended MRND for patients identified as having a positive node. However, it is controversial as to whether END is necessary for a clinical classification of
a Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou. b Department of Head and Neck Surgery, Tumor Hospital, Medical College, Shantou University, Shantou. c Department of Otorhinolaryngology, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou. Received for publication Jun 9, 2013; returned for revision Sep 3, 2013; accepted for publication Sep 19, 2013. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.09.012
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T1-2N0 (cT1-2N0) oral tongue carcinoma.10-12 The incidence of occult cervical lymph node metastasis is 20% to 40% in cT1-2N0 cancers13-14; thus, neck dissection is unnecessary for over 60% of patients, but END may not be adequate for those with occult cervical lymph node metastasis.15-16 The accurate detection of occult metastases is therefore important for the planning of treatment. Currently, the most accurate method of detection available for cN0 patients is END, but only 20% to 40% of patients have the risk of occult cervical lymph node metastases. For these reasons, SLNB is an attractive option for patients with cT1-2N0 OTSCC. SLNB is currently used as a staging procedure in squamous cell carcinoma (SCC) of the head and neck at some European centers4,9; however, it is unknown whether the associated long-term survival rates are comparable with those of END treatments. We therefore conducted a retrospective study to compare the long-term survival rates between an SLNBassessed group and an END-treated group in a cohort of patients with cT1-2N0 OTSCC with an aim to improve the individualized treatment of tongue carcinoma.
Statement of Clinical Relevance It is feasible that the extent of neck dissection can be reduced in patients with cT1-2N0 oral tongue squamous cell carcinoma for sentinel lymph nodee negative patients, owing to the noninferior prognosis associated with sentinel lymph node biopsy, which can improve individualized treatment.
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MATERIALS AND METHODS Our retrospective study and chart reviews were exempt or not applicable to the institutional review board standards of our individual institutions. The guidelines of the Helsinki Declaration were followed in this investigation. Patient characteristics Patients who presented with unique T1 or T2 OTSCC, with necks clinically and radiologically staged as N0, and who were treated surgically in Sun Yat-sen University Cancer Center between January 2000 and December 2002 were enrolled in the study. None of the patients had received preoperative chemotherapy or radiotherapy. The patients were clinically diagnosed before surgery on the basis of computed tomography, magnetic resonance imaging, or ultrasonographic findings. Cervical recurrence was treated by neck dissection only, and neither group received postoperative radiotherapy or chemotherapy. Surgical procedure SLNB group. The day before surgery, patients attended the Nuclear Medicine Department, whereupon they were injected with 0.5 to 1.0 mL 99mTc-phytate solution (1 mCi; 37 MBq, 0.2 mL, China Institute of Atomic Energy Isotope Service Center, Guangzhou, China) in approximately 0.3 mL of 2% lidocaine. This was injected into the deep submucosal layer surrounding the tumor at 4 selected sites and 1 basal site. All patients were offered topical local anesthetic immediately before being injected with radiocolloid. An alcohol-free mouthwash was used immediately after the injection to minimize the risk of residual radioactive material being swallowed. Static lymphoscintigraphy was performed at 30 minutes, 60 minutes, 120 minutes, and 6 hours after injection, or until the first appearance of SLNs within the neck. After first stop lymph node imaging, the hot spot was marked on the overlying skin with a skin marker and checked just before the skin incision with an intraoperative handheld gamma probe. During surgery, the patients were injected with methylene blue (2 mL, Yongkang Pharmaceutical Factory, Beijing, China) using the aforementioned parts per 0.3 to 0.4 mL (a total of 1 to 2 mL). After a few minutes, a 2- to 3-cm incision was made on the neck at the site marked by a skin marker. The SLN identified by both the blue dye and radioactivity was removed and checked using frozen-section techniques. Patients underwent MRND only if the SLN frozen section was positive. These SLNs were further checked by the pathologic examination of paraffin blocks.
ORIGINAL ARTICLE Fan et al. 187
Table I. Patient characteristics Variable Gender Male Female Pathologic grade I II III Age (y) Mean
SLNB group END group (n ¼ 30) (n ¼ 52) 21 9
30 22
14 9 7
23 14 15
48
52
c2
P*
1.226
.268
0.305
.859
1.339 (t value) .184
SLNB, sentinel lymph node biopsy; END, elective neck dissection. *A value of P < .05 indicates a statistically significant difference.
END group. Fifty patients were treated by ipsilateral END, which consisted of 36 END level I and II cases and 14 END level I to III cases. Two patients were treated by ipsilateral MRND (levels I to V). Lymph node testing All lymph nodes were studied using standard histologic techniques with hematoxylin and eosin. Each lymph node was divided into multiple sections, and each was examined. The gold standard for the confirmation of positive nodes was the pathologic results of paraffin sections.17-18 Statistical analysis All data were analyzed using SPSS software (version 17.0; SPSS Inc, Chicago, IL, USA). The 2 groups were compared using the c2 test. Survival curves were generated using the Kaplan-Meier method. The logrank test was used for univariate analysis. A value of P < .05 indicated a statistically significant difference.
RESULTS Demographic data The SLNB group comprised 30 patients (21 men and 9 women), with a mean age of 48 years (range, 27-75 years). Their preoperative clinical tumor classifications were T1N0M0 (n ¼ 17) and T2N0M0 (n ¼ 13). The minimum follow-up period was 10 years. The END group comprised 52 patients (30 men and 22 women), with a mean age of 52 years (range, 20-80 years). Their preoperative clinical tumor classifications were T1N0M0 (n ¼ 27) and T2N0M0 (n ¼ 25). The minimum follow-up period was 10 years. Gender, age, and pathologic grade data for the 2 groups are shown in Table I. Occult cervical lymph node metastasis In the SLNB group, the SLN detection rate was 100% (30/30). In total, 81 SLNs were identified. One SLN
ORAL AND MAXILLOFACIAL SURGERY 188 Fan et al.
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Table II. Occult cervical lymph node metastasis in initial surgery Lymph node SLN Occult metastasis in SLN Occult metastasis in LN in END group
Level I
Level II
Level III
Level IV
Level V
Contralateral level II
Total
21 2 4
35 5 7
20 6 2
3 1 1
0 0 0
2 0 0
81 14 14
SLN, sentinel lymph node; LN, lymph node; END, elective neck dissection.
Table III. Outcomes of cervical lymph node recurrence
Patient No. SLNB group 1 2 3 4 END group 1 2 3 4 5
Initial surgery of cervical lymph node status
Recurrence time (mo)
þ þ þ
8 6 24 7
I III III, IV I, II
10 9 30 45 60
II I, III III, IV IV V
Table IV. Occult cervical lymph node metastasis comparison
Recurrence site (ipsilateral)
SLNB, sentinel lymph node biopsy; END, elective neck dissection.
was found in 3 patients, 2 SLNs were found in 6 patients, 3 SLNs were found in 18 patients, and 4 SLNs were found in 3 patients. In the SLNB and control groups, 9 and 6 patients, respectively, were identified as having occult cervical lymph node metastasis in initial surgery (Table II). During follow-up, 9 cases of cervical lymph node recurrence were confirmed by pathology without tongue recurrence, consisting of 4 cases in the SLNB group and 5 cases in the control group (Table III). Occult lymph node metastasis rates of the 2 groups were compared using the c2 test (Table IV). Recurrence-free survival Recurrence-free survival (RFS) curves (Figures 1 and 2) were generated using the Kaplan-Meier method, and the log-rank test was used for univariate analysis. (Recurrences included cervical lymph node recurrence and primary recurrence.) The 10-year cervical RFS and overall RFS for the SLNB group and control group were, respectively, 86.4% vs 88.2% (c2 ¼ 0.311; P ¼ .577) and 72.3% vs 73.3% (c2 ¼ 0.060; P ¼ .806). Neither of these differences was significant. Overall survival Overall survival (OS) curves were generated using the Kaplan-Meier method, and the log-rank test was used for univariate analysis. Figure 3 shows the 10-year OS curves.
Discovery period Initial surgical specimens SLNB group END group Follow-up SLNB group END group Overall metastasis SLNB group END group
Occult cervical lymph node Without metastasis metastasis (cases) (cases)
c2
P*
9 6
21 46
4.338 .037
4 5
26 47
0.023 .879
10 11
20 41
1.481 .224
SLNB, sentinel lymph node biopsy; END, elective neck dissection. *A value of P < .05 indicates a statistically significant difference.
The 3-, 5-, and 10-year OS rates for the SLNB group and control group were, respectively, 76.7% vs 84.6%, 60.0% vs 63.5%, and 43.3% vs 44.2% (c2 ¼ 0.047, P ¼ .828). The 10-year OS differences were not statistically significant.
DISCUSSION Approximately 94% to 97% of tongue cancer lymph node metastasis occurs ipsilaterally at levels I to III; thus, some scholars have advocated END for patients with cN0 tongue cancer and MRND for suspicious lymph nodes on biopsy.19-21 Although END is associated with less morbidity than MRND, measurable morbidity exists, including shoulder dysfunction, pain, contour changes, and lower lip paresis.6 Moreover, if all cN0 tongue carcinoma patients underwent END, this would result in overtreatment for about 60% of patients without metastasis.15-16 The SLNs as specific anatomic sites underlie the theoretical basis of SLNB. Wei et al.13 have described how, if the SLN is negative, no further treatment is necessary. In recent years, SLNB has been reported to be an excellent classification method in early stage oral cancers, with a negative predictive value of about 95%.6,8 Furthermore, Lawson et al.22 evaluated the reliability of the SLNB in early supraglottic tumors and reported a negative predictive value of 100%. These findings indicate that SLNB in head and neck SCC has broad application prospects.
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Fig. 1. Ten-year cervical recurrence-free survival curves for the 2 groups. (SLNB, sentinel lymph node biopsy; END, elective neck dissection.)
Fig. 2. Ten-year overall recurrence-free survival curves for the 2 groups. (SLNB, sentinel lymph node biopsy; END, elective neck dissection.)
The current study showed that the incidence of occult cervical lymph node metastasis in initial surgical specimens was significantly different between the SLNB group and the control group (30% vs 11.5%). We predicted that SLNB would be better than END in determining the probability of occult cervical lymph node metastasis. Therefore, the SLN tracer method was used during surgery, and the surgeon could clearly identify high-risk occult metastasis lymph nodes. Our study indicated that SLNB was feasible and could be used to predict cervical lymph node metastasis in patients with cT1-2N0 OTSCC, because suspected lymph nodes were the prime target for SLNB. In most of the recent literature on patients with cT1-2N0 tongue cancer who underwent SLNB, the follow-up time was approximately 1 to 3 years4,8-9; thus, it is difficult to observe the impact of this treatment on long-term survival. Moreover, in contrast to the recent literature,4,6,8,12,14,17 our study was limited to patients with cT1-2N0 tongue cancer, which made our
ORIGINAL ARTICLE Fan et al. 189
Fig. 3. Ten-year overall survival curves for the 2 groups. (SLNB, sentinel lymph node biopsy; END, elective neck dissection.)
study more targeted. Our study investigated the 10-year OS and the cervical and overall RFS rates, which for SLNB and control groups were 43.3% vs 44.2%, 86.4% vs 88.2%, and 72.3% vs 73.3%, respectively. None of the differences were significant (P > .5). This suggests that SLNB did not reduce the 10-year OS, or cervical or overall RFS compared with END. However, this study comprised only a limited number of cases; more multicenter prospective studies with larger sample sizes will be necessary to establish the long-term prognosis for patients that undergo SLNB. Nevertheless, this study showed that SLNB was reasonable in clinical applications; it improved patient’s individualized treatment and did not affect prognosis. However, preoperative radionuclide scanning is associated with the risk of radioactive contamination. In addition, intraoperative methylene blue tracer will interfere with the judgment of tumor safety margins. Sometimes, the limitation of intraoperative frozen section examination may lead to individual micrometastases being missed. Therefore, if future studies can find better alternative approaches to identify SLN, SLNB will have a higher clinical value. It has been reported that SLNB with step sectioning and immunohistochemistry can improve the detection rate of micrometastases.6,17 Unfortunately, this method is difficult to apply to intraoperative rapid diagnosis. These problems are prevalent in the clinical application of SLNB; therefore, a rapid, accurate intraoperative test for the presence of metastatic disease in SLN may support widespread acceptance of SLNB in cases of SCC of the head and neck. SLNB can be used to predict cervical lymph node metastasis in patients with cT1-2N0 OTSCC. It is feasible that the extent of neck dissection can be reduced for SLN-negative patients, owing to the noninferior prognosis associated with SLNB, which can improve individualized treatment.
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