Dr. Supreeta Arya1, Dr. Ameya Kawthalkar1

Dr. J. P. Agarwal2

1. Department of Diagnostic Radiology 2. Department of Radiation Oncology

Tata Memorial CentreMumbai, INDIA

Control #: 1398

Detecting Neck Node Metastases in Head & Neck Squamous Cell Cancers : How Far Have

We Reached?eEdE-91-8913

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.

PurposeN - 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.

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

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)

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

Role of imaging in neck evaluation in HNSCCPretreatment• 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

Post treatment • To evaluate neck following induction

chemotherapy

• To look for recurrence in the neck following definitive treatment

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)

N o d al m etastases fro m vario u s p rim aries 4

Primary site Most frequent levels of Nodal metastases

Nasopharynx II , V, retropharyngeal, supraclavicular ; contralateral II in 36%

Soft Palate II, III; contralateral in 29%

Tonsil II, III; contralateral in 13%

Base tongue II, III; contralateral in 31%

Gingival , Buccal & Retromolar trigone

IB, II

Oral tongue II, I, III; contralateral when crossing midline

Floor of mouth IA,IB, II; contralateral when crossing midline

Hard palate Nodal metastases rare

Supraglottic larynx II, III

Glottic larynx (advanced) II, III

Pyriform sinus II, III

Thyroid cancers VI, VI, III, supraclavicular

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

8

3

7

6

5

421

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

IA II

III

IV

I A IB

V

VI

VII

Other sites of nodal metastases 3

Nodal site Possible site of primary

1 Parotid nodes Nasopharyngeal cancers, skin cancers

2 Retropharyngeal nodes Nasopharyngeal cancer , Thyroid cancer

3 Isolated left supraclavicular node ( Virchow’s node)

Abdominal /Thoracic primary or thyroid malignancy

Teaching point 1 & 2 may not be amenable to clinical examination; hence identification on imaging is important

US features of metastatic nodes 7

1. Necrosis2. Cystic nodes- in HPV +ve cancers & thyroid cancers3. Heterogenous internal echotexture4. Eccentric cortical hypertrophy ( particularly with abnormal

architecture in hypertrophied part) 5. Darkly hypoechoic node accompanied with6. Absent hilum7. Rounded shape8. Calcification – in metastases from Thyroid cancer9. Abnormal vascularity-Diffuse intrinsic hypervascularity –in metastases from Thyroid cancer-Hypovascular or peripheral vascularity- in metastases from squamous cancers

Hilum of the node ( ) Cortex of the node ( )

US features - Normal node 7

Node with large area of necrosis (black region)

Darkly hypoechoic node, no hilum

Node with focus of coagulative necrosis (arrow)

Round node without hilum Node with micro calcification (arrows)

Node with abnormal vascularity

US features – Abnormal nodes 7

USgFNAC 8-12

• 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)

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

Author No of patients

Site of HNSCC

Clinical T Stage

USg-FNACSensitivity specificity

Van den Brekkel et al , 1991

54 All sites ALL 76 % 100%

Takes et al., 1998

64 All sites All 48% 100%

Righi et al, 1997 25 All sites All 50% 100%

Borgemeester & Van den Brekel , 2008

126 All sites All 39% (but was lowest at 27% in oral cancers)

100%

Chaturvedi , Datta & Arya, 2014

51 Oral cancers T1 & T2 14% 100%

Analysis of literature on US g FNAC 8-12

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

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

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

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

CT features - Abnormal nodes

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

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

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

MRI- indeterminate and abnormal nodes

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

FallacyRecent reports mention overlapping ADC values of benign and metastatic nodes .

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.

A B C

FallacyHowever overlapping ADC values in non necrotic small nodes have been reported in HNSCC by Lim et al; also supported by our unpublished data.

Can DW-MRI help? 16-18

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.

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.

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

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. A B

Abnormal nodes on FDG-PETCTon FDGPET

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.

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

• ProblemElective 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.

Many methods…

How far have we reached?

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

Year Methods studied & compared

Conclusion Comment

2007 ( Eur J radiol) , de Bondt et al

USgFNAC, US, CT,MRI, and USPIOMRI(17 studies)

USgFNAC had the highest diagnosticodds ratio withdecreasing performance for US alone, USPIO MRI, CT, and MRI in that order.

The meta-analysis included only three studies with ultrasound-guided FNAC, two of which had both cNo and cN+ necks. In the solitary study with cN0 neck, the sensitivity of USgFNAC was only 48%.

2008 ( J Natl Cancer Inst.), Kyaz P et al

FDG PET ( 32 studies)

FDGPET does not detect disease in nearly 50% of patients with neck metastasis and cN0 in HNSCC

Both cN+ necks and cN0 necks studied.Separate subgroup analysis in cN0 neck.

2012, (Acad Radiol.) , Wu et al

MRI ( 16 studies) With few studies on DW-MRI .Also compared with CT, PET and US

MRI has sensitivity of 76% and specificity of 76%.A small number of studies showed DW-MRI to be slightly superior

Meta-analysis had both cNo and cN+ necks. It also found the other methods ( CT, PET & US) comparable to MRI.

2012, ( BMC cancer) Liao LJ et al

CT (7 studies), MRI (6studies), PET( 11 studies) and US (8 studies)

All methods with similar sensitivity and specificity, except for higher specificity of CT over US

The only meta-analysis till date in the cN0 neck

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.

Teaching pointsAgainst such a disadvantage, the radiologist should play a vigilant role in identifying nodal metastases by

1. 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

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

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 Extracapsular spread 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

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)

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involvement in squamous cell carcinoma of the oral cavity: a meta-analysis of reported studies. Cancer 2009.

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3. 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

4. Mukherji SK et al. Cervical nodal metastases in squamous cell carcinoma of the head and neck: what to expect.Head Neck. 2001

5. P C Hajek, et al. Lymph nodes of the neck: evaluation with US. al.Radiology 1986.6. 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

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aspiration cytology for the assessment of neck node metastases: a prospective comparative study. Eur Arch Otorhinolaryngol 1993.

9. Righi PD, et al. Comparison of ultrasound-fine needle aspiration and computed tomography in patients undergoing elective neck dissection. Head Neck 1997

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aspiration biopsy compared to computed tomography in the detection of regional metastases in the clinically negative neck. Int J Radiat Oncol Biol Phys 1998

11. Borgemeester MC, et al. Ultrasound guided aspiration cytology for the assessment of the clinically N0 neck: factors influencing its accuracy. Head Neck 2008

12. 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.

13. 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. Eur Radiol. 2014

14. Cantrell SC, et al. Differences in imaging characteristics of HPV-positive and HPV-Negative oropharyngeal cancers: a blinded matched-pair analysis. AJNR. 2013

15. 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.Eur Radiol. 2009

16. Vandecaveye V, et al. Head and neck squamous cell carcinoma: value of diffusion-weighted MR imaging for nodal staging. Radiology 2009

17. Perrone A, et al. Diffusion-weighted MRI in cervical lymph nodes: differentiation between benign and malignant lesions.Eur J Radiol 2011

References 18. 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

19. Fischbein NJ, et al. Assessment of metastatic cervical adenopathy using dynamic contrast-enhanced MR imaging. AJNR Am J Neuroradiol 2003

20. Baghi M, et al. The efficacy of MRI with ultrasmall superparamagnetic iron oxide particles (USPIO) in head and neck cancers.Anticancer research 25(5):3665-70.

21. 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.J Natl Cancer Inst 2008

22. Govers TM , et al. Sentinel node biopsy for squamous cell carcinoma of the oral cavity and oropharynx: a diagnostic meta-analysis. Oral Oncol 2013

23. Flach GB, et al. Sentinel lymph node biopsy in clinically N0 T1-T2 staged oral cancer: the Dutch multicenter trial. Oral Oncol. 2014

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25. Wu LM, et al . Value of magnetic resonance imaging for nodal staging in patients with head and neck squamous cell carcinoma: a meta-analysis. Acad Radiol. 2012

26. 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