|Year : 2022 | Volume
| Issue : 1 | Page : 12-16
Sentinel lymph node biopsy using methylene blue alone in an era of significance of the depth of invasion in oral cancers: A prospective study
Subbiah Shanmugam, Sujay Susikar, Syed Afroze Hussain, T Bharanidharan, Kishore Kumar Reddy
Centre for Oncology, Government Royapettah Hospital, Government Kilpauk Medical College, Chennai, Tamil Nadu, India
|Date of Submission||30-May-2021|
|Date of Acceptance||16-Jun-2022|
|Date of Web Publication||14-Oct-2022|
Prof. Subbiah Shanmugam
Centre for Oncology, Government Royapettah Hospital, Government Kilpauk Medical College, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Aim: To evaluate the accuracy of methylene blue dye alone in identifying sentinel nodes in oral cancers with clinically N0 neck and the significance of the depth of invasion (DOI) in combination with sentinel lymph node (SLN) biopsy in predicting nodal metastasis. Methods: This is a prospective study done over 24 months accruing 67 patients with cN0 neck admitted to our center for oncology. SLN harvesting was done adhering to the standard procedure using methylene blue dye for all early-stage oral cavity cancers with N0 neck clinically. Data were collected, grouped, and analyzed for deducing DOI, sensitivity, specificity, positive predictive value, and negative predictive value of the procedure and compared with other studies in the literature. Results: Out of 67 patients, males (76.1%) outnumbered female (23.9%) patients. The mean age of the patients was 51.5 years. Tongue (61.2%) was the most common site. Sentinel nodes were identified in 89.5% of patients. The mean number of Sentinel nodes identified was 1.9. The mean DOI was 7.3 mm. SLNs were most commonly identified in Level I (78.3%). Sensitivity, specificity, positive predictive value, and negative predictive value and accuracy deduced in this study were 75%, 97.9%, 90%, 94%, and 93.3%, respectively. Conclusion: Methylene blue dye alone can be successfully used for SLN identification in clinically node-negative oral cavity cancers, particularly with less DOI. DOI alone for predicting nodal involvement can be used with caution. Combination of DOI and sentinel node biopsy may help in better identification of nodal involvement.
Keywords: Depth of invasion, methylene blue, oral cancer, sentinel node
|How to cite this article:|
Shanmugam S, Susikar S, Hussain SA, Bharanidharan T, Reddy KK. Sentinel lymph node biopsy using methylene blue alone in an era of significance of the depth of invasion in oral cancers: A prospective study. Ann Indian Acad Otorhinolaryngol Head Neck Surg 2022;6:12-6
|How to cite this URL:|
Shanmugam S, Susikar S, Hussain SA, Bharanidharan T, Reddy KK. Sentinel lymph node biopsy using methylene blue alone in an era of significance of the depth of invasion in oral cancers: A prospective study. Ann Indian Acad Otorhinolaryngol Head Neck Surg [serial online] 2022 [cited 2023 Mar 26];6:12-6. Available from: https://www.aiaohns.in/text.asp?2022/6/1/12/358575
| Introduction|| |
Oral cavity carcinoma is considered an important part of the global burden of cancer mainly due to the widespread use of tobacco and alcohol. Cervical lymph node involvement results in a 50% decrease in survival and the possibility of distant metastases increases. Hence, cervical node involvement is an important prognostic indicator in oral cavity cancer. Elective neck dissection (END) is the current gold standard for staging the cervical lymph nodes in the carcinoma oral cavity. This procedure is both staging and therapeutic, which has potential benefits for patients who are subsequently found to have an occult disease. It has been routinely used in the surgical management of head-and-neck malignancy where the risk of occult metastases is significant (>20%). These procedures are associated with increased morbidity. However, occult disease is present in 25% of the patients, leading to overtreatment in the remaining 75%. Depth of invasion (DOI) is associated with a higher incidence of regional failure, but still has poor sensitivity and specificity for nodal involvement.
Sentinel lymph node biopsy (SLNB) allows for staging of the cervical lymph nodes with minimum morbidity compared to that of END. The dual technique of lymphoscintigraphy with radiolabelled particles and gamma probe localization combined with a blue dye injection is used commonly for SLNB.,, However, lymphoscintigraphy and gamma probe localization are not easily available in all centers. Therefore, alternate techniques for sentinel lymph node (SLN) identification need to be evaluated.
Methylene blue is an affordable, easily available, less allergic, and effective dye showing good results in SLN studies in breast cancer when used alone or in combination with lymphoscintigraphy.,, In this study, we evaluated the feasibility of using only methylene blue dye in identifying sentinel nodes in oral cancers with clinically N0 neck and the significance of the DOI in combination with SLNB in predicting nodal metastasis.
| Methods|| |
This is a prospective study done from 2018 to 2020, in which 67 patients with cN0 neck were accrued by the inclusion of patients fulfilling desired eligibility criteria in our center for oncology. Primary was evaluated clinically and with contrast-enhanced computed tomography magnetic resonance imaging from the base of the skull to neck whenever required and staged according to American Joint Committee on Cancer 8th Edition. Negative nodal status was confirmed clinically which included ultrasound neck. Informed consent was obtained from all patients. Just before making an incision, methylene blue dye was injected all around the tumor, subplatysmal flaps were raised and blue nodes dissected and sent for frozen. Neck dissection was continued with a minimum of selective neck dissection (SND) (extended supra omohyoid neck dissection [ESOHND] for tongue primary and supra omohyoid neck dissection [SOHND] for rest of subsites) if frozen was negative or modified radical neck dissection (MRND) if frozen was positive. The final specimen was sent for histopathological examination. All specimens were examined by serial sectioning with 2 mm cuts. The postoperative histopathology reports were analyzed for confirming the diagnosis, nodal status, and evaluation of DOI and grade/differentiation of disease.
Oral cavity cancers with no clinically palpable lymph nodes.
- Recurrent disease
- Clinically and sonologically node-positive cases
- Patients allergic to the dye
- Patients with previous neck surgery/radiation.
- Informed consent was obtained from all patients
- Just before making incision 0.5 ml of 1% methylene blue was injected around the tumor at 4 sites (total 2 ml)
- The time duration between the injection of dye and raising neck flaps will be 10–15 min
- Blue-stained lymph nodes were dissected out identifying the level and sent for frozen section
- In SND nodal tissue was excised in total separately, whereas in MRND en bloc dissection along with primary was done in continuity.
| Results|| |
There were 67 patients out of which 51 (76.1%) were male patients and 16 (23.9%) were female patients. The age of the patients was in the range of 30–80 with a mean age of 51.5 years. The tongue was the most common site involved, seen in 41 (61.2%) patients, followed by buccal mucosa in 17 (25.3%) patients, retromolar trigone in 4 (6%) patients, floor of the mouth in 1 (1.5%) patient, alveolus and hard palate in 2 (3%) patients each. Out of 67 patients T1 lesion was seen in 17 (25.3%) patients, T2 lesion in 40 (59.7%) patients, and T3 lesion in 10 (15%) patients. Well-differentiated lesion was seen in 41 (61.2%) patients and moderately differentiated lesion was seen in 25 (37.3%) patients and poorly differentiated lesion was seen in 1 (1.5%) patient. Thirty-six patients (53.7%) underwent ESOHND, 21 (31.3%) patients underwent SOHND and 10 (15%) patients underwent MRND, as shown in [Table 1].
Sentinel nodes were identified in 60 (89.5%) out of 67 patients. The number of Sentinel nodes identified was in the range of 1–5, with a mean of 1.9. Majority of sentinel nodes were identified in Level I in 47 (78.3%) patients, followed by Level II in 7 (11.7%) patients and Level III in 6 (10%) patients, as shown in [Table 2]. DOI was in the range of 4 mm–15 mm, with a mean of 7.3 mm, as shown in [Table 2]. Sentinel nodes were not identified in Level IV and Level V. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy value was 75%, 97.9%, 90%, 94%, and 93.3%, respectively, as shown in [Table 3]. Out of the 12 patients with nodal disease, five patients had T3 lesion (50% of T3) with DOI >10 mm and seven patients had T2 lesion (17.5% of T2) with DOI of 5–10 mm. None of the patients with DOI <5mm had positive nodes, as shown in [Table 4] and [Figure 1].
|Figure 1: Scatter plot showing correlation between DOI and SLN positivity. DOI: Depth of invasion, SLN: Sentinel lymph node|
Click here to view
|Table 4: Correlation of depth of invasion and sentinel lymph node positivity|
Click here to view
| Discussion|| |
The incidence of nodal metastases in oral cavity malignancies depends on the size of disease, subsite, depth of infiltration, differentiation, etc., and varies between <10% and up to 50%.
Management of the clinically negative neck in patients with carcinoma oral cavity is controversial. Choosing between END and wait-and-see policy based primarily on the characteristics of the primary tumor is a risky proposition because approximately 25% of clinically negative patients are reported to harbor occult metastases., Conversely, END for all patients is not justified because of associated morbidity.
SLNB is not the standard of care in oral cavity cancers. However, many single-institution studies,, and two multi-institution studies, have validated it in oral cancers with high detection rates (around 95%) and negative predictive values (88%–100%). In our study, the detection rate was 89.5% and the negative predictive value was 94%. Three meta-analyses by Paleri et al., Govers et al. and Thompson et al. based on pooled data samples have also confirmed its use in the staging and treatment of early-stage head-and-neck cancers.
The dual technique of lymphoscintigraphy with radiolabelled particles with gamma probe localization and blue dye injection is used in the majority of studies where ever facilities are available.,, Lymphoscintigraphy and gamma probe facilities are not widely available, leaving methylene blue dye alone as the widely used and easily available method. Methylene blue alone for SLN identification has provided equal or slightly inferior results compared to dual techniques in breast cancer.,, Similar studies in oral cancer are very few.,
In our study, sentinel node detection rate was 89.5% which was similar to that of Ramamurthy et al. study (90.6%). In our study, sentinel nodes were seen in Level I in 47 (78.3%) patients, followed by Level II in 7 (11.7%) patients and Level III in 6 (10%) whereas it was 54.3%, 37.1%, and 8.6%, respectively, in Vishnoi et al.'s study. Sentinel nodes were not identified in Level IV and V in any subsite. Shah reported similar findings for early cancers of the buccal mucosa. However, Woolgar and Byers reported 15.8% skip metastasis to Level IV in patients with carcinoma tongue.
Sensitivity in our study was 75%, whereas it was 80% in Ramamurthy et al. study and 84.6% in Vishnoi et al.'s study. Specificity and negative predictive value were 97.9% and 94%, respectively, whereas both were 95.8% and 95.8% in Ramamurthy et al. study; the negative predictive value was 93.9% in Vishnoi et al.'s study. Sensitivity and negative predictive values were 86% and 95%, respectively, in Schilling et al's. study where both lymphoscintigraphy and blue dye were used. Accuracy in our study was 93.3%, whereas it was 95.5% in Vishnoi et al.'s study.
Out of the 12 patients with nodal disease in our study, five patients had T3 lesion (50% of T3) with DOI >10 mm, and seven patients had T2 lesion (17.5% of T2) with DOI of 5–10 mm. None of the patients with DOI <5 mm had positive nodes. Huang et al. and Pentenero et al. conclude that DOI correlates with regional lymph node involvement. Both studies found a wide range for cut-off values of 1.5–10 mm, with a most optimal cut-off value of 4 mm in the meta-analysis of Huang et al. Goerkem et al. found an average DOI of 6.45 mm, concluding that DOI (and separately also tumor thickness) should not be used for assessment of END. Moreover, they suggested that SLNB should be used in all early-stage oral cavity carcinomas with a cN0 neck.
Limitations of using methylene blue dye alone for SLNB include mandatory elevation of the neck flaps before SLN identification. In the case of lymphoscintigraphy, the size of the neck incision can be minimized over hot spots before extending it for formal neck dissection. Other drawbacks are the inability to evaluate the contralateral neck, spillage of dye into surrounding tissue obscuring elevation of proper tissue planes, and the chance of missing some deeper nodes.
Limitations of the frozen section include errors of sampling and errors of interpretation. These include the initial selection of tissue by the surgeon, sampling of the tissue by the pathologist, preparation of slides, errors in interpretation, and delivery of the result back to surgeons., Quality of prepared sections during cryostat sectioning plays an important role in frozen section diagnoses. The use of frozen section with limitations in mind makes it a highly sensitive and specific technique playing a critical role in the management of patients.
In our study, the three patients with false-negative reports received 50Gy adjuvant radiotherapy and are on close follow-up. This technique should be evaluated in large multi-institutional studies for standardization, which will be of immense use in centers where adequate lymphoscintigraphy facilities are not available.
| Conclusion|| |
Methylene blue dye alone can be successfully used for SLN identification in clinically node-negative oral cavity cancers, particularly with less DOI. DOI alone for predicting nodal involvement can be used with caution. Combination of DOI and sentinel node biopsy may help in better identification of nodal involvement.
Ethical committee approval
Institutonal Ethics Committee of Govt. Kilpauk Medical College Protocol ID. No: 289/2019 dated on 05/12/2019.
Declaration of patient consent
The authors declare that they have obtained consent from patients. Patients have given their consent for their images and other clinical information to be reported in the journal. Patients understand that their names will not be published and due efforts will be made to conceal their identity but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Lambert R, Saulvage C, De Camargo Cancela M, Sankaranareyanan R. Epidemiology of cancer from the oral cavity and oropharynx. Eur J Gantroenterol Hepatol 2011;23:633-41.
Layland MK, Sessions DG, Lenox J. The influence of lymph node metas-tasis in the treatment of squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx: N0 versus N+. Laryngoscope 2005;115:629-39.
Pitman KT, Johnson JT, Myers EN. Effectiveness of selective neck dissection for management of the clinically negative neck. Arch Otolaryngol Head Neck Surg 1997;123:917-22.
Kligerman J, Lima RA, Soares JR, Prado L, Dias FL, Freitas EQ, et al
. Supraomohyoid neck dissection in the treatment of T1/T2 squamous cell carcinoma of oral cavity. Am J Surg 1994;168:391-4.
Werner JA, Dünne AA, Ramaswamy A, Dalchow C, Behr T, Moll R, et al
. The sentinel node concept in head and neck cancer: Solution for the controversies in the N0 neck? Head Neck 2004;26:603-11.
Liu KY, Durham JS, Wu J, Anderson DW, Prisman E, Poh CF. Nodal disease burden for early-stage oral cancer. JAMA Otolaryngol Head Neck Surg 2016;142:1111-9.
Schiefke F, Akdemir M, Weber A, Akdemir D, Singer S, Frerich B. Function, postoperative morbidity, and quality of life after cervical sentinel node biopsy and after selective neck dissection. Head Neck 2009;31:503-12.
Höft S, Maune S, Muhle C, Brenner W, Czech N, Kampen WU, et al
. Sentinel lymph-node biopsy in head and neck cancer. Br J Cancer 2004;91:124-8.
Chone CT, Magalhes RS, Etchehebere E, Camargo E, Altemani A, Crespo AN. Predictive value of sentinel node biopsy in head and neck cancer. Acta Otolaryngol 2008;128:920-4.
Alkureishi LW, Ross GL, Shoaib T, Soutar DS, Robertson AG, Thompson R, et al.
Sentinel node biopsy in head and neck squamous cell cancer: 5-year follow-Up of a European multicenter trial. Ann Surg Oncol 2010;17:2459-64.
Paleri V, Rees G, Arullendran P, Shoaib T, Krishman S. Sentinel node biopsy in squamous cell cancer of the oral cavity and oral pharynx: A diagnostic meta-analysis. Head Neck 2005;27:739-47.
Govers TM, Hannink G, Merkx MA, Takes RP, Rovers MM. Sentinel node biopsy for squamous cell carcinoma of the oral cavity and oropharynx: A diagnostic meta-analysis. Oral Oncol 2013;49:726-32.
Thompson CF, St John MA, Lawson G, Grogan T, Elashoff D, Mendelsohn AH. Diagnostic value of sentinel lymph node biopsy in head and neck cancer: A metaanalysis. Eur Arch Otorhinolaryngol 2013;270:2115-22.
Samant S. Sentinel node biopsy as an alternative to elective neck dissection for staging of early oral carcinoma. Head Neck 2014;36:241-6.
DeVita VT Jr., Lawrence TS, Rosenberg SA. Hellman and Rosenberg's Cancer: Principles and Practice of Oncology. 9th
ed., Ch. 70. USA: Lippincott Williams & Wilkins; 2011.
Yuen AP, Lam KY, Chan AC, Wei WI, Lam LK, Ho WK, et al
. Clinicopathological analysis of elective neck dissection for N0 neck of early oral tongue carcinoma. Am J Surg 1999;177:90-2.
van den Brekel MW, Stel HV, Castelijns JA, Nauta JJ, van der Waal I, Valk J, et al
. Cervical lymph node metastasis: Assessment of radiologic criteria. Radiology 1990;177:379-84.
Alex JC, Krag DN. The gamma-probe-guided resection of radiolabelled primary lymph nodes. Surg Oncol Clin N Am 1996;5:33-41.
Sobol S, Jensen C, Sawyer W 2nd
, Costiloe P, Thong N. Objective comparison of physical dysfunction after neck dissection. Am J Surg 1985;150:503-9.
Kowalski LP, Sanabria A. Elective neck dissection in oral carcinoma: A critical review of the evidence. Acta Otorhinolaryngol Ital 2007;27:113-7.
Ross GL, Soutar DS, Gordon MacDonald D, Shoaib T, Camilleri I, Roberton AG, et al
. Sentinel node biopsy in head and neck cancer: Preliminary results of a multicentre trial. Ann Surg Oncol 2004;11:690-6.
Cilantros FJ, Kitsch RP, Schuler DE, Agrawal A, Smith RB, Nason R, 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;28:1395-400.
List of Nuclear Medicine Centres in the Country. Central Bureau of Health Intelligence. Director General Health Services. Ministry of Health and Family Welfare, India. Available from: http://cbhidghs.nic.in/hii2000-01/10.283.html
. [Last accessed on 2021 May 12].
Li J, Chen X, Qi M, Li Y. Sentinel lymph node biopsy mapped with methylene blue dye alone in patients with breast cancer: A systematic review and meta-analysis. PLoS One 2018;13:e0204364.
Mathelin C, Croce S, Brasse D, Gairard B, Gharbi M, Andriamisandratsoa N, et al.
Methylene blue dye an accurate dye for sentinel lymph node identification in early breast cancer. Anticancer Res 2009;29:4119-25.
Varghese P, Abdel-Rahman AT, Akberali S, Mostafa A, Gattuso JM, Carpenter R. Methylene blue dye – A safe and effective alternative for sentinel lymph node localization. Breast J 2008;14:61-7.
Ramamurthy R, Kottayasamy Seenivasagam R, Shanmugam S, Palanivelu K. A prospective study on sentinel lymph node biopsy in early oral cancers using methylene blue dye alone. Indian J Surg Oncol 2014;5:178-83.
Suresh TN, Harendra Kumar ML, Thomas AK, Azeem M. Study of sentinel lymph node in oral Squamous cell carcinoma. J Clin Biomed Sci 2013;3:146-9.
Vishnoi JR, Kumar V, Gupta S, Chaturvedi A, Misra S, Akhtar N, et al
. Outcome of sentinel lymph node biopsy in early-stage squamous cell carcinoma of the oral cavity with methylene blue dye alone: A prospective validation study. Br J Oral Maxillofac Surg 2019;57:755-9.
Shah JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. Am J Surg 1990;160:405-9.
Woolgar JA. Pathology of the N0 neck. Br J Oral Maxillofac Surg 1999;37:205-9.
Byers RM. Modified neck dissection. A study of 967 cases from 1970 to 1980. Am J Surg 1985;150:414-21.
Schilling C, Stoeckli SJ, Haerle SK, Broglie MA, Huber GF, Sorensen JA, et al
. Sentinel European Node Trial (SENT): 3-year results of sentinel node biopsy in oral cancer. Eur J Cancer 2015;51:2777-84.
Huang SH, Hwang D, Lockwood G, Goldstein DP, O'Sullivan B. Predictive value of tumor thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity: A meta-analysis of reported studies. Cancer 2009;115:1489-97.
Pentenero M, Gandolfo S, Carrozzo M. Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature. Head Neck 2005;27:1080-91.
Goerkem M, Braun J, Stoeckli SJ. Evaluation of clinical and histomorphological parameters as potential predictors of occult metastases in sentinel lymph nodes of early squamous cell carcinoma of the oral cavity. Ann Surg Oncol 2010;17:527-35.
Hull ME, Humphrey PA, Pfeifer J. Frozen sections and other intraoperative consultations. In: Humprey P, Dehner L, editors. The Washington Manual of Surgical Pathology. 2nd
ed. India: Lippincott Williams and Wilkins; 2012. p. 832-37.
Evans CA, Suvarna SK. Intraoperative diagnosis using the frozen section technique. J Clin Pathol 2006;59:334.
Mishra S, Gupta M, Bharat V, Bansal R. Qualitative comparative study of frozen section with routine histological technique. Nat J Lab Med 2016;5:44-50.
Mayun AA, Pindiga UH, Abubakar A. Frozen section: The need for intra-operative consultation between the surgeon and the pathologist. BOMJ 2006;3:1-2.
[Table 1], [Table 2], [Table 3], [Table 4]