Dr. Supreeta Arya 1 , Dr. Ameya Kawthalkar 1 Dr. J. P. Agarwal 2

1. Control #: 1398 Detecting Neck Node Metastases in Head & Neck Squamous Cell Cancers : How Far Have We Reached? eEdE-91-8913 Dr. Supreeta Arya1,Dr. Ameya Kawthalkar1 Dr. J. P. Agarwal2 Department of Diagnostic Radiology Department of Radiation Oncology Tata Memorial Centre Mumbai, INDIA

2. Disclosure of Commercial Interest Neither we nor our immediate family members have a financial relationship with a commercial organization that may have a direct or indirect interest in the content.

3. Purpose N- To discuss the various imaging methods for detecting neck node metastases in head and neck squamous cell cancers (HNSCC) E - To review literature on these various imaging methods to evaluate their efficacy in detecting neck node metastases C - To discuss the characteristic imaging features of metastatic nodes from HNSCC on each imaging method K - To provide the radiologist with a key practice based approach to aid the clinician in staging the neck.

4. Imaging methods for neck node evaluation • Ultrasound (US) • Ultrasound guided Fine needle aspiration cytology (USgFNAC) • Contrast enhanced Ultrasound • CT scanning • MRI & Advanced MRI (diffusion & perfusion MRI) • Ultra-small particle iron oxide MRI • PETCT • Sentinel node biopsy

5. General principles • Evaluation of head & neck cancers requires staging of the primary and staging of the neck • Metastatic workup is needed only in advanced cancers ( stage III & IV) • In staging head & neck cancers, the neck can be clinically positive with palpable nodes ( cN+ neck) or clinically negative ( cN0 neck)

6. Clinically negative neck • Clinically negative neck can have occult metastases • Occult metastases are metastatic nodes not detected by palpation • Incidence of occult metastases varies according to primary site, in early stage oral cancers it varies from 27-40% 1 • Average incidence at all sites is 15% 2 • Expectation from imaging is to decrease the number of undetected occult metastasis

7. Role of imaging in neck evaluation in HNSCC Pretreatment Post treatment To evaluate neck following induction chemotherapy To look for recurrence in the neck following definitive treatment • To detect occult neck node metastases (in the cN0 neck) • To map the nodal burden prior to treatment 3 • To identify necrosis (poor prognosis) • To identify extra-nodal spread (ENS) --poor prognostic factor; if ENS + , to evaluate relation of the node with vessels & adjacent structures

8. General Tips to aid imaging • Know the expected lymphatic drainage from the primary site of head & neck cancer  examine these areas critically • Examine the radiological features  each imaging method can show typical features in metastatic nodes (described later)

9. Nodal metastases from various primaries 4

10. Nodal groups 5 Regions of the neck: 1- Submental 2-Submandibular 3-Parotid nodes 4-Upper jugular 5-Middle jugular 6-Lower jugular 7-Supraclavicular nodes 8-Posterior triangle nodes 3 2 1 4 5 8 6 7

11. AJCC Level based Nodal Classification 6 IA- Submental IB-Submandibular II-Upper jugular III-Middle jugular IV-Lower jugular V-Posterior triangle nodes VI-Pre/Paratracheal VII-Upper mediastinal I A IB IA II III V IV VI VII

12. Other sites of nodal metastases 3 Teaching point 1 & 2 may not be amenable to clinical examination; hence identification on imaging is important

13. US features of metastatic nodes7 • Necrosis • Cystic nodes- in HPV +ve cancers & thyroid cancers • Heterogenous internal echotexture • Eccentric cortical hypertrophy ( particularly with abnormal architecture in hypertrophied part) • Darkly hypoechoic node accompanied with • Absent hilum • Rounded shape • Calcification –in metastases from Thyroid cancer • Abnormal vascularity -Diffuse intrinsic hypervascularity –in metastases from Thyroid cancer -Hypovascular or peripheral vascularity- in metastases from squamous cancers

14. US features - Normal node 7 Hilum of the node ( ) Cortex of the node ( )

15. US features – Abnormal nodes7 Node with large area of necrosis (black region) Darkly hypoechoic node, no hilum Node with focus of coagulative necrosis (arrow) Node with abnormal vascularity Round node without hilum Node with micro calcification (arrows)

16. USgFNAC8-12 • Useful tool to needle nodes that are suspicious on US/ CT/MRI • Real time method to assess nodes; cost effective, and gives cytology diagnosis. Problem- • Requires expertise (right needle gauge, right technique, right operator) • Sampling errors in • small nodes ( as in the N0 neck) • nodes compressed against the mandible • nodes where metastatic focus is localized to one small region • Negative FNAC is not an entirely reliable method to rule out metastasis conclusively ( positive FNA is conclusive)

17. Factors that influence accuracy of USgFNAC in clinically negative necks 8-12

18. Analysis of literature on US g FNAC8-12 Besides expertise, the accuracy of UsgFNAC is also dependent on-- • Subsite of HNSCC ( lowest reported for oral cancers and highest for laryngeal cancer) • ? T stage of primary – Evidence to suggest that lower the T stage, lower the accuracy of USgFNAC of suspected neck nodes

19. Contrast enhanced Ultrasound (CEUS) 13 • Reports suggest that CEUS has a potential role to differentiate between benign and metastatic nodes • Heterogeneous enhancement and centripetal enhancement were features in favor metastatic nodes

20. CT features of metastatic nodes 6, 14 -Necrosis • Reliable even when seen in subcentimeter nodes • Seen best on contrast enhanced CT; as low density, poorly enhancing foci • Cystic necrosis seen in HPV + cancers; thyroid cancers -Internal heterogeneity -Rounded node with lost hilum -Enlargement • Nodal size criteria varied; short axis/ long axis used. • Short axis > 1.5cm for level II nodes, > 1cm for other nodes = abnormal • Size criteria unreliable and nodes in drainage areas with borderline size should be viewed with suspicion -Clustering 3-5 nodes in drainage site of primary – considered abnormal -Calcification In thyroid carcinoma

21. CT features - Abnormal nodes Necrotic enlarged left level III node Bilateral heterogeneous level II nodes with necrosis Normal sized enhancing rounded non-necrotic node at right level II in the draining region of posterior pharyngeal wall primary ( *) ; needs to be viewed with suspicion *

22. MRI features of metastatic nodes 6, 15 -Necrosis • Reliable even when seen in subcentimeter nodes • Seen best on contrast enhanced T1W images; as poorly enhancing foci /cystic regions • T2W & STIR images show high signal or hyperintensity -Internal heterogeneity on T2W sequences - Spiculated margins -Rounded node with lost hilum -Enlargement • Nodal size criteria similar as with CT -Clustering 3-5 nodes in drainage site of primary – considered abnormal

23. MRI- indeterminate and abnormal nodes A cluster of normal sized non- necrotic nodes are seen on the STIR images at both levels II . In the presence of a known primary (such as nasopharynx) these nodes are to be viewed with suspicion Case of left sided tongue carcinoma. Coronal T2W MRI image showing necrosis in a left level III node, which was metastatic on histopathology Case of right sided tongue carcinoma. Axial T2W sequence showing internal heterogeneity in a right level II node. On histopathology there was one metastatic node at this level of corresponding size

24. Diffusion weighted MRI ( DW-MRI) 16-18 • Based on the principle that metastatic nodes with high cellularity have restricted diffusion • Qualitative-seen as high signal on the high b value image and dark on the ADC maps • Quantitative- Metastatic nodes have been reported with low ADC values while benign nodes have higher ADC values Fallacy Recent reports mention overlapping ADC values of benign and metastatic nodes .

25. Can DW-MRI help?16-18 C A B A. White arrow shows a non necrotic unremarkable node at right level II in a known case of right oral tongue carcinoma ; B. Exponential apparent diffusion coefficient (EADC) image and C. ADC (apparent diffusion coefficient ) map . The node (arrows) shows high signal in B & dark signal on C suggesting true restriction of diffusion . The ADC value measures 0.76 X 10 -3mm2/sec. This node was metastatic on histopathology. Fallacy However overlapping ADC values in non necrotic small nodes have been reported in HNSCC by Lim et al; also supported by our unpublished data.

26. Perfusion MRI 19 Using Dynamic contrast enhanced (DCE) MRI • Early reports mention different characteristics of metastatic nodes compared to benign nodes • However conflicting results in various reports ( some report higher time to peak while others report lower time to peak in metastatic nodes) • Currently being investigated to assess control of the neck following induction chemotherapy.

27. Ultra-small particle iron oxide MRI (USPIO-MRI) • Promising early reports with USPIO-MRI for detecting metastatic nodes20 • Principle- Normal nodes take up USPIO and appear dark while metastatic nodes do not take up USPIO and appear bright • Problem- USPIO-MRI not available for clinical use as it has not been approved by recommending agencies. When available in the future, needs thorough investigation.

28. FDG PETCT for neck evaluation • Principle- Metastatic nodes have high uptake with higher SUV (standard uptake value). FDG PETCT useful • As baseline imaging for mapping nodal burden prior to radiotherapy to compare with post treatment imaging 3 • To characterize nodes if CT or MRI are equivocal • For evaluation of post treatment neck 3 Fallacy • Small/ necrotic nodes can be negative 3 • Not useful in the N0 neck where subcm occult metastases is expected 21 • Well differentiated thyroid cancers and medullary thyroid cancers can be PET negative 3 • Granulomatous and non- specific adenitis can cause false positives

29. Abnormal nodes on FDG-PETCTonFDGPET Figure A shows intense FDG uptake in a midline base tongue primary and a metastatic left level II node. The same node appears unremarkable on the contrast enhanced CT in B. B. also shows a subcm right II node which is rounded , but no uptake is seen in A. B A

30. Sentinel node biopsy (SNB) Principle • A tumor will have preferred nodal drainage basin, with a primary node. If that node could be identified and biopsied , metastasis could be ruled out with minimal intervention • A radioactive dye is injected (99m Tc-labelled Human Serum Albumin Nanocolloid; maximum 1mci) peritumorally • Lymphoscintigraphy & SPECT-CT performed, at surgery hot nodes identified with a hand held gamma probe • Nodes harvested and histopathological analysis done –with Hematoxylin & Eosin stain; ideally step serial sectioning and immunohistochemistry to be performed on the node.

31. SNB • A meta-analysis in 847 patients of T1/T2N0 oral & oropharyngeal SCC revealed an overall sensitivity of 93% for SNB 22 • Dutch multi-institutional trial ( 2014) on sentinel lymph node biopsy in oral cancer– showed that risk of occult metastasis reduces from 40% to 8% in T1 T2 oral cancer 23 • SNB being recognized as a viable alternative to elective neck dissection for staging the neck in early-stage oral cavity cancer 12, 22-23 • Problem Elective neck dissection (END) is the standard of care in HNSCC. No randomized controlled trial exists that compares END and SNB for SNB to conclusively replace END.

32. Many methods… How far have we reached?

33. Meta-analyses of imaging methods for neck node evaluation in HNSCC 21, 24-26

34. Discussion • END is the standard of care for the management of the neck, particularly in tongue cancers when tumor thickness > 4mm. • However 2/3rds of the ENDs are unnecessary and can result in morbidity in 30% 12. • It would be ideal to have a preoperative imaging method with high positive predictive value (PPV) and negative predictive value (NPV) to identify occult metastatic nodes so that unnecessary END can be avoided . • However despite advances in imaging, no imaging method has a 100% NPV and high specificity /PPV.

35. Teaching points Against such a disadvantage, the radiologist should play a vigilant role in identifying nodal metastases by • Careful imaging technique 2. Knowledge of the primary disease and spread patterns 3. Keen observation of the imaging features of the nodes 4. Suggest appropriate adjunct imaging methods to the clinician for problem solving if needed

36. Teaching points • CT or MRI ordered for imaging the primary are comparable for evaluating the neck • There is evidence that DW-MRI may not be useful for characterizing neck nodes • Use of DCE-MRI or CEUS may not be cost effective or conclusive • FDGPET / USgFNA may be added for problem solving • USgFNAC may not be helpful in early cancers with N0 necks • When very early lesions ( such as T1 tongue or buccal cancers) are not imaged with CT/MRI , US may be used to evaluate the cN0 neck to confirm the N0 status, if END is not being planned

37. Teaching points • When imaging reveals metastatic nodes, the radiologist should give a detailed report that includes • Level of abnormal nodes • Size & number of abnormal nodes • Presence of necrosis • Extracapsularspread • Relation to common carotid artery and internal carotid artery (circumferential contact : if < 180° easily resectable, if > 270° unresectable) • Invasion of IJV and other adjacent structures • FDG PETCT may be ordered and used to map the nodal burden prior to RT planning

38. Teaching points • When imaging does not reveal metastatic nodes despite careful scrutiny, the clinician might • Opt for END • Might observe the neck based on the site of the primary, its size/ thickness and histological grade. ( In this scenario, no imaging investigation is 100% accurate , however US may be used as a method of extended palpation as it is cost effective & involves no radiation exposure) • Attempt SNB prior to END especially in early stage cancers with N0 neck (both on clinical examination & imaging)

39. References • Huang SH, et al. 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. • Som PM, Brandwein-Gensler MS. Lymph Nodes of the Neck. In: Som PM, Curtin HD, editors, Head & Neck Imaging. Vol 2.5th ed. Elsevier Mosby; 2011 • Hoang JK, et al. Evaluation of cervical lymph nodes in head and neck cancer with CT and MRI: tips, traps, and a systematic approach.AJR 2013 • Mukherji SK et al. Cervical nodal metastases in squamous cell carcinoma of the head and neck: what to expect.Head Neck. 2001 • P C Hajek, et al. Lymph nodes of the neck: evaluation with US. al.Radiology 1986. • Som PM, et al. An imaging-based classification for the cervical nodes designed as an adjunct to recent clinically based nodal classifications. Arch Otolaryngol Head Neck Surg. 1999 • Ahuja AT, Ying M. Sonographic evaluation of cervical lymph nodes. AJR 2005 • van den Brekel MW, et al. Modern imaging techniques and ultrasound-guided aspiration cytology for the assessment of neck node metastases: a prospective comparative study. Eur Arch Otorhinolaryngol 1993. • Righi PD, et al. Comparison of ultrasound-fine needle aspiration and computed tomography in patients undergoing elective neck dissection. Head Neck 1997

40. References • Takes RP, et al. The value of ultrasound with ultrasound-guided fine-needle aspiration biopsy compared to computed tomography in the detection of regional metastases in the clinically negative neck. Int J Radiat Oncol Biol Phys 1998 • Borgemeester MC, et al. Ultrasound guided aspiration cytology for the assessment of the clinically N0 neck: factors influencing its accuracy. Head Neck 2008 • Chaturvedi P, et al. Prospective study of ultrasound-guided fine-needle aspiration cytology and sentinel node biopsy in the staging of clinically negative T1 and T2 oral cancer.Head Neck 2014. • Xiang D et al. Contrast-enhanced ultrasound (CEUS) facilitated US in detecting lateral neck lymph node metastasis of thyroid cancer patients: diagnosis value and enhancement patterns of malignant lymph nodes. EurRadiol. 2014 • Cantrell SC, et al. Differences in imaging characteristics of HPV-positive and HPV-Negative oropharyngeal cancers: a blinded matched-pair analysis. AJNR. 2013 • de Bondt RB, et al. Morphological MRI criteria improve the detection of lymph node metastases in head and neck squamous cell carcinoma: multivariate logistic regression analysis of MRI features of cervical lymph nodes.EurRadiol. 2009 • Vandecaveye V, et al. Head and neck squamous cell carcinoma: value of diffusion-weighted MR imaging for nodal staging. Radiology 2009 • Perrone A, et al. Diffusion-weighted MRI in cervical lymph nodes: differentiation between benign and malignant lesions.Eur J Radiol 2011

41. References • Lim HK, et al. Is diffusion-weighted MRI useful for differentiation of small non-necrotic cervical lymph nodes in patients with head and neck malignancies? Korean J Radiol. 2014 • Fischbein NJ, et al. Assessment of metastatic cervical adenopathy using dynamic contrast-enhanced MR imaging. AJNR Am J Neuroradiol 2003 • Baghi M, et al. The efficacy of MRI with ultrasmallsuperparamagnetic iron oxide particles (USPIO) in head and neck cancers.Anticancer research 25(5):3665-70. • Kyzas PA, et al. 18F-fluorodeoxyglucose positron emission tomography to evaluate cervical node metastases in patients with head and neck squamous cell carcinoma: a meta-analysis.JNatl Cancer Inst 2008 • Govers TM , et al. Sentinel node biopsy for squamous cell carcinoma of the oral cavity and oropharynx: a diagnostic meta-analysis. Oral Oncol 2013 • Flach GB, et al. Sentinel lymph node biopsy in clinically N0 T1-T2 staged oral cancer: the Dutch multicenter trial. Oral Oncol. 2014 • de Bondt RB, et al. Detection of lymph node metastases in head and neck cancer: a meta-analysis comparing US, USg FNAC, CT and MR imaging. Eur J Radiol. 2007 • Wu LM, et al . Value of magnetic resonance imaging for nodal staging in patients with head and neck squamous cell carcinoma: a meta-analysis. AcadRadiol. 2012 • Liao LJ, et al. Detection of cervical lymph node metastasis in head and neck cancer patients with clinically N0 neck- ameta-analysis comparing different imaging modalities. BMC Cancer 2012