Sentinel Node Navigation Surgery Research Articles

Sentinel Lymph Node Detection in Patients with Oral Cancer by MR Lymphography using Superparamagnetic Iron Oxide

The purpose of this study was to examine the feasibility of interstitial MR lymphography using Superparamagnetic Iron Oxide (SPIO) to detect sentinel lymph nodes (SLNs) in head and neck cancer. For two patients with cT2N0 squamous cell carcinoma of the tongue, the submucosal injection of SPIO as well as sentinel lymph node navigation surgery (SLNNS) was performed before undergoing surgical treatment. SPIO was used for MR lymphography and Tc-99m phytate for SPECT. We compared the images by both modalities. Berlin blue stain was also performed postoperatively to verify if SLNs had the uptake of SPIO. The lymph nodes with MR signal attenuation and those with hot spots were probed to be anatomically identical. All the lymph nodes detected as a SLN by a gamma-probe contained the blue granules from SPIO. These data suggest that SPIO can be a novel tracer for performing SLNNS and SLN biopsy (SLNB) in oral cancer patients with cN0 neck.

肺癌におけるセンチネルリンパ節ナビゲーション手術

肺癌におけるセンチネルリンパ節ナビゲーション手術

食道癌に対するセンチネルリンパ節ナビゲーション手術

食道癌に対するセンチネルリンパ節ナビゲーション手術

Endoscopic submucosal dissection with sentinel node navigation surgery for early gastric cancer

We combined endoscopic submucosal dissection (ESD) and sentinel node navigation surgery with the purpose of achieving complete resection of early gastric cancer while preserving the organ and assessing pathological nodal status. A total of 13 patients with cT1( ≤ 3 cm)N0 early gastric cancer underwent combined ESD and sentinel node navigation surgery (ESN) at a single tertiary referral center. Sentinel node navigation surgery using indocyanine green was performed during ESD and all suspected sentinel nodes were removed laparoscopically and examined intraoperatively. ESN was converted to gastrectomy with D2 dissection if there was evidence of metastasis on frozen section. ESN was completed in 12 patients and in 1 patient was converted to gastrectomy after sentinel node navigation surgery. En bloc tumor resection was achieved in all cases. Two patients underwent additional gastrectomy because they had tumor-positive vertical margins. In all cases ESN was conducted without intraoperative or postoperative adverse events. ESN is a feasible minimally invasive procedure that allows en bloc tumor resection to be achieved while assessing the pathological status of the lymph nodes.

A Comparison of Indocyanine Green Fluorescence Imaging Plus Blue Dye and Blue Dye Alone for Sentinel Node Navigation Surgery in Breast Cancer Patients

To evaluate two methods of sentinel node navigation surgery (SNNS) using blue dye with and without indocyanine green (ICG) fluorescence imaging (FI) to determine the usefulness of combined ICG and blue dye. Between 2005 and 2010, a total of 501 patients underwent SNNS in our hospital. Detection of sentinel lymph node (SLN) was performed with sulfan blue (SB) alone until 2008 and with a combination of SB and ICG-FI since 2009. ICG 5 mg and SB 15 mg were injected in the subareolar region, and FI was obtained by a fluorescence imaging device. We attempted to identify SLNs in 393 patients by SB alone and in 108 patients by a combination of SB and FI. The mean number of SLNs detected was 1.6 (0-5) for SB alone and 2.2 (1-6) for the combination method. The SLN identification rate was 95.7 % for SB alone and 100 % for the combination method so that the combination was significantly superior to SB in terms of the identification rate (p = 0.0037). In patients who received the combination method, detection of SLN was made through only SB in 1 patient, only ICG in 8 patients, and both in 99 patients. Lymph node metastasis was found in 56 patients with SB alone and in 16 patients with the combination method. Recurrence of an axillary node was observed in 3 patients (0.8 %) with SB alone and in no patients with the combination method. ICG-FI is a useful method and is especially recommended in cases where no radiotracers are available.

Sentinel Node Navigation Surgery with 99mTc-tin Colloid in Breast Cancer: Radiation Safety Considerations

Purpose: The incident at the Fukushima Daiichi nuclear power station in 2011 has again raised concerns with the public regarding radiation exposure, especially so in medical workers and patients undergoing treatment involving the use of radiation. Radioisotopes are currently used during sentinel node navigation surgery (SNNS) in operating rooms without radiation monitoring. To re-evaluate the safety issues, the potential effective dose (Epoten) from 99m Tc-tin (-Sn) colloid in breast cancer surgery was estimated and personal dose equivalents, Hp(10) and Hp(0.07), were measured during SNNS. Materials and methods: Seventeen breast cancer patients were enrolled. One day before SNNS, 99m Tc-Sn colloid was injected around the tumor and radiation exposure rates were measured using survey meters. Personal dose equivalents for the surgical workers were measured. Hp(10) and Hp(0.07) for the body and Hp(0.07) for the hands were recorded using semiconductor detectors and ring-type glass dosimeters. Results: The maximum Epoten was 29 μSv per 74 MBq injection. The maximum Hp(10) for the primary and assisting surgeons, nurse, and anesthetist was 3.7, 1.4, 0.3 and 0.6 μSv per SNNS, respectively. The maximum Hp(0.07) for the hands was 100 μSv. Maximum radiocontamination 20 times higher than background (0.05 μSv/h) was detected in bloody gauze. Conclusion: The workers' radiation dose exposure from SNNS was not high, although radiation management such as a temporary cooling off period may be required.

Intraoperative Molecular Assessment for Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma Using One-Step Nucleic Acid Amplification (OSNA) Assay

Conventional intraoperative pathological examination for Sentinel node navigation surgery (SNNS) has been controversial. We evaluated the efficacy of one-step nucleic acid amplification (OSNA) assay for intraoperative diagnosis of cervical lymph node (CLN) metastasis compared with histopathological examination in patients with head and neck squamous cell carcinoma (HNSCC). A total of 175 CLNs dissected from 56 patients with HNSCC who underwent surgery at Aichi Cancer Center, Kyorin University, Gunma University or Fukushima Medical University, between April 2008 and December 2011 were enrolled. CLN samples were sectioned into four equal pieces, with two of each used for OSNA assay and other histopathological examinations. The diagnostic value of OSNA assay in HNSCC patients in predicting the results of histopathological diagnosis was evaluated using the area under the receiver operating characteristic (AUROC) curve. OSNA assay showed acceptable efficacy in the detection of pathological CLN metastasis (AUROC 0.918, 95% confidence interval [CI] 0.852-0.984). Regarding the CK19mRNA cutoff value, the optimum cutoff point in HNSCC patients was 131copies/μl (sensitivity: 82.4, 95% CI 65.5-93.2; specificity: 99.3, 95% CI 96.1-100.0; positive likelihood ratio 116.1; negative likelihood ratio 0.2]. We demonstrated that OSNA assay is useful in intraoperative diagnosis for CLN metastasis in patients with HNSCC. OSNA assay could be applied for SNNS in HNSCC patients.

Prognosis of early breast cancer patients treated with sentinel node biopsy: A prospective study from the Japanese society for sentinel node navigation surgery.

1106 Background: Sentinel node biopsy (SNB) is a new standard of care for clinically node-negative breast cancer patients. Our society conducted a prospective study on SNB for early breast cancer patients from Jul 2004 to Oct 2005 (UMIN000006126). A preliminary result regarding with success rates of multiple mapping methods and the adverse events was presented at the 2007 ASCO. We observed patient’s outcome for 5 years. Methods: Of the 1,411 cases registered, the objects were 1,107 cases excluding cases with bilateral breast cancer, non-invasive breast cancer, past history of other malignancy or failure of SNB and cases treated with primary chemotherapy or endocrine therapy. Adjuvant therapy and breast irradiation were decided by physician’s discretion and patient’s preference. To evaluate the risk of isolated tumor cells or micrometastases in sentinel lymph nodes (SLN), clinicopathological factors were analyzed using the Cox regression model. Results: After a median follow-up of 62 months, there were 85 recurrences and 14 deaths. 5-year Kaplan-Meire estimates for disease-free survival and overall survival (OS) were 92.6% and 97.5% in 848 cases with pN0(sn), 96.2% and 100% in 26 with pN0(i+)(sn), 89.3% and 95.3% in 68 with pN1mi(sn) and 82.8% and 92.0% in 165 with pN1(sn) or greater nodal metastases. No axillary lymph node dissection (ALND) was performed in 809 cases (95.4%), 18 (69.2%), 38 (55.9%), and 24 (14.5%), respectively. Regional node recurrence was found in 8 cases (0.9%), 0 (0%), 2 (2.9%) and 2 (1.2%), respectively. Univariate analysis showed that pN1(sn) or greater nodal metastases, pT2-4, nuclear grade 3, lymphovascular invasion, negative hormone receptor status, SNB followed by ALND, chemotherapy therapy were significant risk factors for OS. However, from multivariate analysis, nuclear grade 3, lymphovascular invasion and SNB followed by ALND were independent unfavorable prognostic factors (hazard ratio: 3.21, 2.61 and 3.93). Conclusions: Although a non-randomized prospective study, isolated tumor cells and micrometastases in SLN did not affect patient’s survival. ALND should be omitted for early breast patients with those metastases.

666 Endoscopic Submucosal Dissection With Sentinel Node Navigation Surgery (ESN) for Early Gastric Cancer

The risk of nodal metastasis is low in EGCs that meet the criteria for ESD. However, the only definite diagnostic method for nodal metastasis is pathologic examination. We combined ESD and Sentinel node navigation surgery (SNN) with the purpose of achieving complete resection of the tumor while preserving the organ and assessing pathological nodal status. Materials and

Comparison of animal studies between interstitial magnetic resonance lymphography and radiocolloid SPECT/CT lymphoscintigraphy in the head and neck region

To comparatively assess two techniques, radiocolloid SPECT/CT lymphoscintigraphy and interstitial MR lymphography using SPIO and gadoxetate disodium, in animal models. We used twenty one 8-week-old male nude mice of strain BALB/c Slc-nu/nu, weighing 23-27g. The 4.7-T MRI equipment was used to detect the SNs. T2*WI of gradient-echo sequences was acquired sequentially up to 24h after administering SPIO, ferucarbotran. T1WI was acquired sequentially up to 80min after administering gadoxetate disodium. (99m)Tc-phytate SPECT/CT lymphoscintigraphy was taken at 30min after the injection to detect the SNs using animal-dedicated whole-body SPECT/CT hybrid scanner. The injection was submucosally performed in the right tongue margin of each mouse. Reading performances concerning SN visualization and its quality on interstitial MR lymphogram and SPECT/CT lymphoscintigram were performed by 3 radiologists. The SN intensities were 0.43 for the right, 0.61 for the left at 30min after ferucarbotran injection, with gradual decrease in intensity, and 1.43 for the right, 1.33 for the left at 10min after gadoxetate disodium injection with a fast decrease in intensity. The base value of 1.0 was at pre-examination. The mean numbers of lymph nodes visualized were 4.00 nodes for on SPECT/CT lymphoscintigram and 2.0 for interstitial MR lymphogram. There was a statistically significant difference in the mean scores between SPECT/CT lymphoscintigraphy and interstitial MR lymphography (two factor mixed design with repeated measures on one factor: p<0.0002). In our comparative study using mice, the results of radiocolloid SPECT/CT lymphoscintigraphy were superior to those of interstitial MR lymphography, while both SPIO and gadoxetate disodium have a potential of being employed for sentinel node navigation surgery by interstitial MR lymphography in the head and neck region.

胃癌センチネルリンパ節生検における術中リンパ節微小転移診断

胃癌センチネルリンパ節生検における術中リンパ節微小転移診断

Sentinel Node Navigation Surgery in Early-Stage Esophageal Cancer

The sentinel node (SN) concept has revolutionized the surgical staging of both melanoma and breast cancer over the past two decades. However, the validity of the SN hypothesis has been controversial for esophageal cancer, because SN mapping for esophageal cancer is technically complicated, and the number of early-stage esophageal cancer is very limited. Nevertheless previous studies nicely demonstrated that SN mapping may be feasible in patients with early-stage esophageal cancer. Transthoracic extended esophagectomy with three-field radical lymph node dissection has been recognized as a curative procedure for thoracic esophageal cancer in Japan. However, uniform application of this highly invasive procedure might increase the morbidity and markedly reduce the quality of life (QOL) after surgery. Although further accumulation of evidence based on multicenter clinical trials using a standard protocol is needed, SN mapping and SN navigation surgery would provide significant information to perform individualized selective lymphadenectomy which might reduce the morbidity and retain the patients' QOL. In addition, technical innovation including the development of new tracers is expected to confirm the accuracy and reliability of SN mapping in esophageal cancer.

Sentinel Node and Mechanism of Lymphatic Metastasis

The validity and clinical usefulness of the sentinel node (SN) concept for breast cancer has been confirmed, and individualized limited surgery based on diagnosis of SN metastasis is presently performed. In the future, SN navigation surgery (SNNS) will be actively applied to the treatment of early gastric cancer, and an intraoperative real-time reverse transcription-polymerase chain reaction (RT-PCR) assay to detect SN micrometastasis of gastric cancer is under development. Not only anatomical factors, but also many other factors such as local immunosuppression in the SN and lymphoangiogenesis may be involved in development of SN micrometastasis, and clarification of the mechanisms of metastasis and development of treatment methods are awaited. (*English Translation of J Jpn Col Angiol 2008; 48: 137-142.).

What Is the Problem in Clinical Application of Sentinel Node Concept to Gastric Cancer Surgery?

More than ten years have passed since the sentinel node (SN) concept for gastric cancer surgery was first discussed. Less invasive modified surgical approaches based on the SN concept have already been put into practice for malignant melanoma and breast cancer, however the SN concept is not yet placed in a standard position in gastric cancer surgery even after two multi-institutional prospective clinical trials, the Japan Clinical Oncology Group trial (JCOG0302) and the Japanese Society for Sentinel Node Navigation Surgery (SNNS) trial. What is the problem in the clinical application of the SN concept to gastric cancer surgery? There is no doubt that we need reliable indicator(s) to determine with certainty the absence of metastasis in the lymph nodes in order to avoid unnecessary lymphadenectomy. There are several matters of debate in performing the actual procedure, such as the type of tracer, the site of injection, how to detect and harvest, how to detect metastases of SNs, and learning period. These issues have to be addressed further to establish the most suitable procedure. Novel technologies such as indocyanine green (ICG) fluorescence imaging and one-step nucleic acid amplification (OSNA) may overcome the current difficulties. Once we know what the problems are and how to tackle them, we can pursue the goal.

Local tissue reaction after injection of contrast media on gastric wall of mouse: experimental study for application of contrast media to computed tomography lymphography

PurposeComputed tomography (CT) lymphography is a simple technique of sentinel node navigation but tissue reaction after injection of contrast media has not been reported yet.MethodsNinety mice used in this study were divided into three groups: lipiodol, iopamidol, and normal saline. The test compounds were given by submucosal injection to the gastric wall of anesthetized mice. The specimens were subjected to histopathological examination.ResultsThe mean grades of acute inflammatory response after iopamidol and lipiodol injection were significantly higher than control group. However, there was no significant difference between iopamidol and lipiodol injection. The mean grade of chronic inflammatory response and fibrosis showed no differences between groups. The presence or absence of fibrinoid necrosis and mesothelial hyperplasia showed no statistical differences at each time point between groups. The foam cell, which is similar to human signet ring cell carcinoma, were not identified in normal saline and iopamidol group, but were detected by postoperative day 7 in lipiodol group.ConclusionWe conclude that iopamidol and lipiodol when used as a contrast media of CT lymphography is an available material for preoperative sentinel node navigation surgery for gastric cancer with an acceptable incidence of pathological alterations in a mouse model. Our results are potentially useful to clinical (human) application.

Sentinel Node Biopsy in Early Gastric Cancer: Constant Exertion for Clinical Application

Lymph node status is the most important prognostic factor in gastric cancer. Standard surgery, therefore, is radical subtotal or total gastrectomy with wide dissection of regional lymph nodes. Recently, the proportion of early gastric cancer has increased to more than 60% in Korea and Japan because of screening gastroscopy. The rate of lymph node metastasis in early gastric cancer ranges from 5 to 20%, which means that more than 80% of patients with early gastric cancer undergo unnecessarily wide excision of the stomach with aggressive lymphadenectomy. If there is a tool to predict the exact status of lymph nodes, radical gastrectomy with lymphadenectomy can be substituted with limited resection of stomach without lymph node dissection. However, preoperative endoscopic ultrasound and computed tomography have limited accuracy for nodal staging in gastric cancer patients. The sentinel node (SN) concept has been introduced into various solid tumors, including stomach cancer, to predict lymph node status. Ideally, if the SN has no metastasis, extensive lymphadenectomy can be avoided, the extent of resection of the stomach reduced, function preserved, complications lessened, recovery accelerated, and the quality of life for the patient improved. SN navigation surgery has been widely performed for the treatment of breast cancer and malignant melanoma. Regarding gastric cancer, it seemed that SN concept is difficult to apply because the lymphatic flow is multidirectional. However, many studies reported that SN mapping is feasible in gastric cancer especially in early gastric cancer even though many issues still remain to be solved. Sensitivity of SN biopsy is highly important in gastric cancer compared with breast cancer and malignant melanoma. When false-negative cases develop in patients with malignant melanoma or breast cancer, other treatment options, such as chemotherapy and radiotherapy exist. Because gastric cancer has no other treatment option except surgery, a gastric cancer patient with false-negative SN loses an opportunity for cure. The detection rate is not as important as sensitivity in gastric cancer SN biopsy. Surgeons should perform just conventional lymphadenectomy for detection failure cases. Sensitivities of SN mapping in gastric cancer reported until now are not adequate for clinical application. Until now, the sensitivities were generally low and even the studies with high sensitivity had small number of cases with lymph node metastasis. There are several methods to increase the sensitivity of SN biopsy in gastric cancer. As pathologic methods, multiple sections of the SN may raise the rate of detecting lymph node metastases. Immunohistochemistry (IHC) staining with anti-cytokeratin antibody helps to detect micrometastases in SNs in addition to conventional hematoxylin and eosin (HE) staining. Reverse transcription-polymerase chain reaction (RT-PCR) using tumor markers, such as carcinoembryonic antigen, cytokeratin, or CD44, also is good tool for molecular detection of SN micrometastases. Rapid IHC or real-time RT-PCR is needed so that IHC or RT-PCR is applicable to SN biopsy for gastric cancer. Takeuchi et al. 1 introduced a novel realtime multiplex RT-PCR assay that is suitable for intraoperative detection of micrometastasis in SNs for the patients with clinical N0 gastric carcinoma. In the present study, 31% of patients with no metastasis over histological diagnosis were RT-PCR positive and the diagnostic accuracy is significantly higher in their multiplex RT-PCR assay than in intraoperative histopathology. Because the time taken for the assay is just 80 minutes, real-time multiplex RT-PCR is thought to be applicable for use in the intraoperative diagnosis of SN. Society of Surgical Oncology 2011

Sentinel node navigation surgery attenuates the functional disorders in early gastric cancer

The purpose of this study was to evaluate the merits of the sentinel node (SN)-navigated reduced gastrectomy (SNRG) procedure. The subjects (sT1N0) were divided into the SNRG group (n=34) and the GL group, that consisted of patients which underwent gastrectomy according to the Japanese Gastric Cancer Association guidelines (n=33). We compared the area of the resected stomach and evaluated their body weight changes, and the results of a questionnaire survey about postoperative symptoms, and nutritional effects by blood tests administered at postoperative months (POM) 3, 6 and 12. The median area of the resected stomach was 104cm2 in the SNRG group vs. 192cm2 in the GL group. The body weight loss ratio was -5.9±5.8 vs. -9.3±4.1% at POM3, and the henoglobin (g/dl) change rate was -1.1±7.9 vs. -6.4±6.5% at POM 12 in the SNRG and GL groups, respectively. There were no significant differences regarding the passage of food, reflux, the incidence of dumping syndrome, digestive and excretory function, or general condition and the satisfaction levels of the patients. In conclusion, SNRG has some advantages over GL in terms of postoperative disorders for at least one year after surgery, and is the recommended choice of a surgical procedure for early gastric cancer.

Sentinel Node Navigation Surgery by Thoracoscopic Fluorescence Imaging System and Molecular Examination in Non-Small Cell Lung Cancer

The application of sentinel node navigation surgery in non-small cell lung cancer (NSCLC) is not popular because of the difficulty of sentinel node identification and the low incidence of complications after systemic lymph node dissection. We report the intraoperative assessment of sentinel node metastasis by thoracoscopic ICG fluorescence imaging system and real-time reverse transcription-polymerase chain reaction (RT-PCR). Sixty-one patients who underwent surgery between January 2009 and December 2010 were investigated for sentinel node biopsy. ICG fluorescence imaging was applied by an infrared light CCD system, and sentinel nodes were identified and dissected. Intraoperative real-time quantitative RT-PCR to determine the expression of cytokeratin 19 (CK-19) was performed for evaluation of metastasis and finally histologic examination of hematoxylin and eosin-stained, paraffin-embedded sections. Sixteen (80%) of 20 patients with segmentectomy and 33 (80.5%) of 41 with lobectomy were identified for sentinel lymph nodes. The total identification rate was 80.3% (49 of 61). The false-negative rate was 2.1% (1 of 49). The overall accuracy rate was 78.7% (48 of 61 patients). Disease of four of these patients was upstaged to stage IIA by RT-PCR for CK-19 expression, which was positive for sentinel nodes and micrometastases. These results demonstrated that thoracoscopic ICG fluorescence imaging-guided surgery and real-time quantitative RT-PCR were useful for sentinel node biopsy and might be a powerful tool for more focused pathologic or molecular evaluation for staging.

The efficiency of micrometastasis by sentinel node navigation surgery using indocyanine green and infrared ray laparoscopy system for gastric cancer

The clinical application of sentinel node navigation surgery (SNNS) for patients with gastric cancer requires accurate intraoperative diagnosis of lymph node metastasis. However, the clinical significance of the diagnosis of lymph node micrometastasis for gastric cancer has not been established. In this study, we evaluated lymph nodes dissected during SNNS by immunohistochemistry with anti-cytokeratin antibody (IHC) staining for gastric cancer to investigate the usefulness of SNNS. The subjects were 130 patients with gastric cancer (3,381 lymph nodes) who underwent SNNS with infrared ray observation and lymph node dissection of D1+α or more. The dissected lymph nodes were stained with IHC (CAM 5.2), and the results were compared with intra- and postoperative diagnoses by hematoxylin and eosin (H&E) staining. In addition, the association of metastatic lymph nodes and ICG-positive lymph nodes was examined. The number of patients (lymph nodes) with lymph node metastasis by HE and IHC staining was 16 (52 nodes) and 31 (91 nodes), respectively. Fifteen patients (27 nodes) diagnosed with pN0 by HE staining were diagnosed to be metastatic by IHC staining. The tumor depth of these patients was pT1 in ten patients (m, 3; sm, 7) and pT2 in five (mp, 4; ss, 1). Regarding the histological type, three patients were classified as well-differentiated type, while six patients each had moderately and poorly differentiated types. The grade of lymphatic invasion was ly0 in 5, ly1 in 6, and ly2 in 4, respectively. Histological assessment of 27 IHC-positive and HE-negative cells indicated 5 single cells, 16 clusters, and 6 micrometastases. These lymph nodes were all included in the sentinel nodes (SN) identified during surgery. All but one patient (0.8%) were recurrence-free at 2-8 years after surgery (median 74.7 months). The one patient developed anastomotic recurrence 4.5 years after the first operation and died. Since all 27 lymph nodes in 15 patients with metastasis by IHC staining but not by HE staining were micrometastasis or less and included in the SN, ICG-positive lymphatic basin dissection by SNNS with infrared ray observation seems to be an adequate method of lymph node dissection for gastric cancer.

Quantitative expression study of four cytokeratins and p63 in squamous cell carcinoma of the tongue: suitability for sentinel node navigation surgery using one-step nucleic acid amplification

AimsSentinel node navigation surgery (SNNS) is currently considered to provide better staging of regional metastasis. For rapid and accurate sentinel lymph node analysis, one-step nucleic acid amplification using cytokeratin 19...