Sentinel lymph node biopsy is unsuitable for routine practice in young female patients with unilateral low-risk papillary thyroid carcinoma
Ou Huang, MD1,3, WeiLi Wu, MD2,3, OuChen Wang, MD1, Jie You, MD1,Quan Li, MD1, Kai Yang, MD1, ShuMei Zhou, MD1, XueMin Chen, MD1, YiFei Pan, MD1, GuiLong Guo, MD1, XiaoHua Zhang, MD1,*
1 Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine Shanghai 200025, China
2 Department of Surgical Oncology, the Third Affiliated Hospital of Wenzhou Medical College, Wenzhou 325000, Zhejiang Province, China
3 These authors contributed equally to this work
* Correspondence to: XiaoHua Zhang, Email address:
BACKGROUD: Sentinel lymph node (SLN) technique makes the possible to identify patients with occult lymph node metastasis. Studies have shown that the finding that nodal metastases are present in young female patients with unilateral low- risk papillary thyroid carcinoma (PTC) does not provide much prognostic information. This study aimed to define the role of the SLN biopsy as a guide for evaluating the cervical lymph nodes in young female patients with unilateral low- risk PTC by using intraoperative methylene blue only or the combined techniques (preoperative lymphoscintigraphy scanning by sulfur colloid labeled with 99m Technetium, gamma-probe guided surgery, and blue dye injection).
METHODS: From January 2004 to January 2007, 90 young female patients with unilateral low-risk PTC (T1-2N0M0) were identified and diagnosed with papillary thyroid cancer before operation by fine needle biopsy; the average age of patients was 35.1 years (range, 23-44 years), and mean tumor size was 1.3cm (range, 0.8-3.7cm). SLN biopsy was randomly performed by methylene blue alone or the combined techniques. After SLN detection, all patients underwent unilateral modified neck dissection to determine the false-negative rate (FNR). All surgical specimens were stained with hemtoxylin-eosin.
RESULTS: In methylene blue group, the SLN was identified in 39 of 45 patients (86.7%), 28 of 39 patients (71.8%) had positive cervical lymph nodes (pN+), and 21 patients (53.8%) had pSLN+; 7 of 28 pN+ patients (25%) was detected metastases in non-SLN, thus giving a FNR of 38.9% (7/18), a negative predictive value (NPV) of 61.1% (11/18), and an accuracy of 82.1% (32/39). In the combined technique group, the identification rate (IR) of SLN was 100% (45/45), 27 of 45 patients (60.0%) had pN+, 24 patients (53.3%) had pSLN+, and a FNR of 14.3% (3/21), a NPV of 85.7% (18/21), and an accuracy of 93.3% (42/45). The combined techniques group was remarkably superior to the methylene blue group in IR (p=0.035). There were no significant difference between two groups in sensitivity, specificity, NPV, and accuracy. Location of pN+ (55 patients) in 84 patients was: no patient in level I and V, 1 patient (1.2%) in level II, 6 patients (7.2%) in level III, 8 patients (9.5%) in level III and IV, 8 patients (9.5%) in level IV, and 32 patients (38.1%) in level VI. In all of 90 patients, IR of SLN was 93.3%, and a FNR of 25.6%, a NPV of 74.4%, and an accuracy of 88.1%.
CONCLUSIONS: For young female patients with ipsilateral low-risk PTC (T1-2N0M0), the combined technique of SLN biopsy could help more accurate lymph node staging and better identification of SLN located out of the central compartment. Regardless of the acceptable identification rate of SLN by whichever of the both procedures was adopted, high FNR renders the SLN technique unsuitable for routing practice; Prophylactic node dissection of level VI might be considered rather than routine practice for patients who did not had SLN biopsy, where only 38.1% of patients had node metastasis.
Keywords: Papillary thyroid carcinoma; Sentinel lymph node;
Nodal metastases are a significant risk factor for survival in patients with differentiated thyroid cancer (DTC)(1). Recent studies suggested the use of sentinel lymph node (SLN) detection as a less invasive method for studying the lymphatic metastatic spread in patients with breast cancer(2, 3), melanoma(4), cervical cancer(5, 6), and thyroid cancer(7, 8). SLNB has potential advantages, for example, reduced morbidity compared with elective lymph node dissection and could offer a standardized technique of lymph node evaluation. Because of its high sensitivity, accuracy and low false-negative rate in predicting axillary lymph node status, SLN biopsy has obtained widespread consensus and replaced axillary node dissection as a standard technique for axillary staging in breast cancer, which makes it possible to avoid unnecessary axillary node dissection(9). The success application of SLNB in breast cancer set a good example for other types of solid cancers(3, 4, 6), including thyroid cancer(7, 8).Dixon et al. and Stoeckli et al. have demonstrated that SLNB for thyroid disease is feasible and safe by isosulfan blue vital dye or preoperative lymphoscintigraphy scanning(7, 8).However, there were some differences between thyroid cancer and breast cancer, and many questions need be answered before the utility of SLNB. For example, lymphatic drainage is largely orderly progression in breast cancer, while it is quite intricate and not predictable in thyroid cancer. Dixon et al. suggested further investigation before the procedure can be recommended for patients with thyroid disease(7).Whether SLNB has the similar predictive value of replacing neck dissection in thyroid cancer as it in breast cancer is unconfirmed.
Most studies concerning the SLNB were conducted among Western populations(7, 8, 10-20), while similar data is not available for the Chinese population. Moreover, the means used to identify the SLN varies from country to country. Some surgeons rely on the intraoperative use of both blue dye (isosulfan blue dye in the Canada(7), patent blue dye [Patent Blue-V] in Hong Kong(17), methylene blue in Japan(13)) as well as radiotracer (99mTc-colloid in the Turkey(21); 99mTc sulfur colloid in Switzerland(19); 99mTc nanocolloid in Italy(19)) to identify the sentinel nodes; others rely on blue dye alone. Furthermore, the risk of nodal metastases varies considerably between different age and tumor size groups(22). Age is the most important prognostic factor for thyroid cancer. According to the National Thyroid Cancer Treatment Cooperative Study (NTCTCS) staging classification registration, patients older than aged 45 years with cervical lymph node metastases were classified as stage III (high risk), whereas those younger than aged 45 years and demonstrating cervical lymph node metastases were considered as stage I (low risk)(22). The comparative analyses of SLNB by methylene blue only and the combined technique have not yet been reported in young female patients with ipsilateral low-risk PTC (T1-2N0M0) in both Western and Chinese population, which may help the standard application of SLNB in PTC.
For those reasons mentioned above, we hypothesized that SLNB could provide accurate assessment of neck lymph node as it do in breast cancer, and started a clinical trial to define the role of SLNB as a guide for evaluating the cervical lymph nodes in young female patients with ipsilateral low-risk PTC (T1-2N0M0) by using intraoperative methylene blue only or the combined techniques (preoperative lymphoscintigraphy scanning by sulfur colloid labeled with 99m Technetium, gamma-probe guided surgery, and blue dye injection). Further, we sought to identify which technique had better predictive value in such population.
PATIENTS AND METHODS
Patients
The study was approved by the institutional review board of my institution, and informed consent was obtained in writing from all patients after discussion of risks and benefits with the operating surgeon. From January 2004 to January 2007, all patients with a preoperative diagnosis of PTC by fine-needle aspiration, clinically node-negative detected by clinical exam and ultrasound were asked to participate in this study. All patients were female and only had one unilateral tumor site by ultrasound. Exclusion criteria were a previous history of neck operation, pregnancy, and known hypersensitivity to the methylene blue, age younger than 15 years or older than 45 years at diagnosis, tumor more than 4cm in greatest dimension limited to the thyroid or extending beyond the thyroid under ultrasound, tumor in isthmus. Preoperative evaluation included clinical history with complete physical examination, routine laboratory evaluation including TSH measurement, ultrasound of thyroid and neck including adjacent cervical lymph nodes, chest x-ray. All patients underwent attempted SLN biopsy followed by unilateral modified radical neck dissection.
SLN Biopsy
All surgeons had performed more than 20 SLN biopsies before the study. The day before the operation, lymphoscintigraphy was performed. One dose of 99mTc sulfur colloid (about 0.5ml) was injected in the primary tumor for lymphoscintigraphy and intraoperative lymph node detection. 10 to 15 minutes after injection, dynamic images are detected by single photon emission computed tomography (SPECT) to visualize lymphatic drainage. The position of the sentinel node was marked on the skin overlying the” hot spots”(23). The operation was performed within 24h after lymphoscintigraphy. After inducting anesthesia, a standard transverse cervical incision was made, cutaneous flaps were developed and the strap muscles were retracted laterally. The thyroid lobe containing the tumor was exposed, dividing the medial thyroid vein and the upper pedicle. Both parathyroid glands were identified. Approximately 1.0 mL of 1% methylene blue was administered in the primary tumor with a 26-gaugee needle. Care was taken not to stain any surrounding tissue with the blue dye. The thyroid gland was replaced in its normal position, and gentle massage was applied for 3 minute. A combination of lymphoscintigraphy, blue lymph vessel, blue node and a hand-held probe were used for tracing to the SLN. An SLN was defined as any blue node, nor any node that could be identified as substantially radioactive above background. A specific SLN-to-background ratio was more than two for defining an SLN(24). After the first radioactive SLN was removed, any node that contained radioactive counts that were >= 10% or more of the ex vivo count of the hottest SLN was considered to be an additional SLN. The sentinel lymph node is excised and the radioactivity is measured ex vivo to confirm the nodal activity. After SLN was harvested, unilateral total lobectomy and modified radical neck dissection are completed. Axillary lymph nodes including each SLN were examined by routine hematoxylin-eosin (H-E) staining. The location of positive lymph nodes (pN+) was recorded according to the Neck dissection classification update: revisions proposed by the American Head and Neck Society and the American Academy of Otolaryngology-Head and Neck Surgery(25). Statistical Analysis
The results of sentinel lymph node biopsy were quantified using the following definitions: accuracy= (true positive + true negative) / (total patients); sensitivity = (true positive) / (true positive + false negative); and specificity = (true negative) / (true negative + false positive). All data were statistically analyzed using chi-squared test. Fisher’s exact test was used for comparison if necessary. All statistical tests were two sided and P < 0.05 was considered significant. All statistical analyses were performed with SPSS statistical software package 15.0.
RESULTS
Between January 2004 to January 2007, 90 patients were enrolled into the study and randomly divided into two groups. Mean age was 35.1 years (range, 23-44 years). Mean tumor size was 1.3 cm (range, 0.8-3.7cm). 52% of tumor was localized in the right lobe of the thyroid gland, 48% in the left lobe. It was the incidence rate of positive lymph nodes of 65.5%, overall successful identification of SLN of 93.3%, false negative rate of 25.6%, and accuracy of 88.1% for all patients (Table I). SLN biopsy was performed using single-agent injection (methylene blue dye) in 45 patients and dual-agent injection (blue dye plus radioactive colloid) in 45 patients, respectively. Comparison of the results using single- or dual-agent injection is listed in Table I. In methylene blue group, the SLN was identified in 39 of 45 patients (success rate=86.7%), and 28 of 39 patients (71.8%) had positive cervical lymph nodes (pN+); 7 of 28 pN+ patients (25%) was detected metastases in non-SLN, thus giving a false-negative rate of 38.9%, a negative predictive value of 61.1% (11/18), and an accuracy of 82.1% (32/39). In the combined technique group, the detection rate of SLN was 100% (45/45), and 27 of 45 patients (60.0%) had pN+, and giving a false-negative rate of 14.3% (3/21), a negative predictive value of 85.7% (18/21), and an accuracy of 93.3% (42/45) [Table I].
No positive lymph nodes in the level I and V were identified in 84 patients. In only one patient (1.2%), the pN was located in the level II, in 6 patients (7.2%) in the level III, in 8 patients (9.5%) in the level III and IV, 8 patients (9.5%) in level IV, and 32 patients (38.1%) in level VI.
Discussion
In solid cancer, lymph node status is the most important indicator for clinical outcome. Substantial data exists that indicated no survival difference between patients who undergo regional node dissection those who undergo lesser dissections or no dissection, for melanoma, head and neck cancers, gastric, colorectal cancers, and particularly breast cancer. These clinical studies all confirm the indicator function, or statistical relationship, but question the outcome-governing role of lymph node metastases(26). Thus, it is generally accepted that traditional regional lymph node dissection may have local therapeutic benefit in primary breast or thyroid cancers with clinical metastases to remove a palpable lesion that might undergo progressive growth and create local palliative problem.
Recent developments in the SLN concept and technology have resulted in the application of this innovative approach to define the first draining or SLN to which the cancer may have metastasized(27, 28). The underlying thesis in solid cancer biology is that metastasis generally begins with an orderly progression, spreading through the lymphatic channels to the SLN that should reflect the pathological status of the remaining lymph node basin. Thus, the purpose of a SLNB is not to improve survival, since that has not been clearly demonstrated, but to collect diagnostic and prognostic information to help select systemic therapy disease, but from systemic metastases in vital organs, prognosis can only be improved by preventing distant micrometastases form occurring or developing in the vital organs.
The SLN technique is nowadays largely used to aid surgery for breast cancer and melanoma but its use is increasing in other types of solid tumors(3, 4, 6) , including DTC(7, 8). The SLN procedure has proven to be a win/win situation and very quickly has become the standard for the surgical approach to staging the axilla lymph node, which could help avoid unnecessary dissection in up to 70-80% of early-stage breast cancer patients(9) . Adjuvant chemotherapy regimen selection and whether adjuvant radiotherapy should be performed or not are relation to the number of axillary lymph node (ALN) involvement(29). Thus, accurate assessment of the ALN by axillary lymph node dissection (ALND) is important not only for staging and prognosis, but also for guiding treatment selection, when SLNB is positive(30).