Head And Neck Cancer, Squamous

Todd M. Blodgett, MD

Alex Ryan, MD

Marios Papachristou, MD

Key Facts

Terminology

Squamous cell carcinoma of the head and neck (SCCHN), squamous cell carcinoma (SCCA) nodes

Imaging Findings

Intensely FDG-avid nodes in the neck on PET or PET/CT
Enlarged or necrotic lymph nodes in the neck ± enhancement on CT
PET/CT key for several clinical scenarios
- Delineate extent of regional lymph node involvement
- Detect distant metastases
- Identify unknown primary tumor
- Detect occasional synchronous primary
Combined PET/CT may offer additional localization information and improve interpreting physician’s confidence level
Overall sensitivity and specificity of FDG PET and PET/CT > 90%; PET/CT sensitivity 96% and specificity 98%

Top Differential Diagnoses

Abscess or Suppurative Nodes
Lymphoma
Physiologic Activity
Reactive Nodes

Diagnostic Checklist

Consider PET/CT in patients with primary tumors that are prone to bilateral metastases, which are often less conspicuous on conventional imaging

Axial CT (left) and fused PET/CT (right) show a right parapharyngeal space mass

and a mucosal lesion only identified on the fused PET/CT

Follow-up axial CT (left) and fused PET/CT (right) after surgery demonstrate no residual or recurrent tumor.

TERMINOLOGY

Abbreviations and Synonyms

Squamous cell carcinoma of the head and neck (SCCHN)
Squamous cell carcinoma (SCCA) nodes
Unknown mucosal primary
Therapeutic assessment/restaging

Definitions

Primary, regional, and distant malignancy from tumors of squamous cell origin in the head and neck
Primary unknown: Metastatic squamous cell carcinoma of the neck without an identifiable mucosal primary lesion
- Undetectable mucosal lesions by clinical exam or
- Negative anatomical imaging
Head and neck cancers include those arising from the lip, oral cavity, nasal cavity, paranasal sinuses, pharynx, and larynx
- 90-95% are squamous cell carcinomas arising from mucosal linings of upper aerodigestive tract

IMAGING FINDINGS

General Features

Best diagnostic clue
- Intensely FDG-avid nodes in the neck on PET or PET/CT
- Enlarged or necrotic lymph nodes in the neck ± enhancement on CT
- Primary unknown
  - PET shows asymmetrical focal fluorodeoxyglucose (FDG) uptake, with or without an identifiable abnormality on CT
  - Sensitivity for PET and PET/CT is 26-43% in cases where primary has eluded diagnosis
  - Fused PET/CT images often helpful for determining whether potential FDG abnormalities are mucosal lesions
  - Helpful for directing clinicians to areas for directed biopsies
- Intense FDG activity in or around treated primary tumor with corresponding CT evidence of residual tumor
Location
- Primary squamous cell lesions may involve any mucosal surface
  - Commonly involve the base of tongue, tonsils, or adenoids
  - Mucosal surfaces of the oropharynx, nasopharynx, and hypopharynx
- Lymph node metastases involve neck nodes in expected drainage pattern based on primary tumor
- SCCHN has high propensity to harbor malignancy in small lymph nodes
- Most common metastatic sites: Lung, liver, skeletal system
Size
- Early primary SCCHN may be undetectable (unknown primary SCCHN)
- Lymph node metastases may range in size from normal (< 1 cm) to several centimeters
Morphology
- Mass effect, abnormal enhancement, or necrosis may exist in larger tumors
- Fatty lymph node hilum usually denotes benign lesion on CT (may be positive on PET if occult malignancy present)
- Indistinct borders usually denote extranodal spread

Imaging Recommendations

Best imaging tool
- PET/CT key for several clinical scenarios
  - Delineate extent of regional lymph node involvement
  - Detect distant metastases
  - Further evaluate potentially abnormal findings on another exam, such as mediastinal adenopathy detected by chest CT
  - Identify unknown primary tumor
  - Detect occasional synchronous primary
  - Monitor treatment response to select appropriate patients for salvage surgery
  - Conduct long-term surveillance for recurrence and metastases
  - Check any patient who presents with clinical evidence of recurrent disease
- TNM staging
  - MR better than CT for specific questions such as presence of perineural spread or invasion of bone marrow
- N stage
  - CT generally superior to MR for detection of regional lymph node metastases
- M stage
  - Only patients at substantial risk of nodal or hematogenous metastases, T3 or T4, should undergo routine PET/CT for staging
- Combined PET/CT may offer additional localization information and improve interpreting physician’s confidence level
  - Overall sensitivity and specificity of FDG PET and PET/CT > 90%; PET/CT sensitivity 96% and specificity 98%
  - PET/CT more helpful for radiation therapy planning; can lead to changes in gross tumor volume
  - Extended field FDG PET staging may detect disease outside of the head and neck in up to 21% of patients with head and neck cancer
  - Sensitivity for PET and PET/CT 26-43% in which primary has eluded diagnosis
  - Sensitivity for PET/CT better for accurate localization of lesion and directed biopsy recommendations
- MR typically initial imaging study of choice for staging
  - Compared to noncontrast PET/CT, more accurate delineation of tumor extent, perineural involvement, and intracranial extent
  - Nearly comparable in accuracy in detecting regional LN metastases
- Contrast-enhanced CT used only in laryngeal cancer; PET/CECT may be better for this indication than MR or CECT alone
- Restaging: Combined PET/CT is more sensitive and specific than CT alone
Protocol advice
- High resolution PET/CT from top of head to carina using standard head and neck protocol (especially for unknown primary)
- Scan with arms down on PET/CT to avoid beam hardening artifact
  - Whole-body scan performed with arms above head and shorter acquisition time
  - Use neck immobilization device
- Scan in mask for radiation planning PET/CT
  - Display images with PET intensity kept low-moderate (avoid “blooming”)
- Pre-treatment with benzodiazepines in patients with excessive muscular FDG uptake on FDG PET
- Warm patients before and after injection of FDG to reduce brown fat FDG uptake
- Restaging
  - Scan with arms down, CECT, and neck immobilization device
  - Consider dual-time point imaging to help differentiate between inflammatory and neoplastic FDG activity

CT Findings

CECT: Early enhancement, rim enhancement, central necrosis, indistinct borders
Post-therapy neck difficult to interpret
- Accuracy of CT ranges from 50-70%
- Loss of fat planes and extensive post-surgical changes reduce the specificity of CT
- Distortion of normal anatomy can be due to bony-cartilaginous necrosis, edema, and desmoplastic changes
- CT may show enhancement, necrosis, or mass effect with residual/recurrent tumor
- Best method of detection using CECT is serial examination
CT and MR may be negative for unknown primary if
- Tumor is subtle or difficult to separate from adjacent normal structures (as with lingual tonsillar tissue)
- Primary is superficial or very small
- Scan is limited by motion or streak artifact
Abnormal size criteria for CT: ≥ 1 cm for most nodes; ≥ 1.5 cm for level I-II nodes; ≥ 8 mm for retropharyngeal nodes
- FDG PET can detect smaller positive nodes (limited by spatial resolution)
Central necrosis specific for malignancy, but it is a late marker of metastatic adenopathy
- Usually seen only in nodes ≥ 20 mm, which is beyond the typical cutoff of 10 mm for suspicion of malignancy
Contrast enhancement generally improves detection of malignancy
Round morphology more suspicious than reniform

Nuclear Medicine Findings

PET/CT is more accurate than PET and CT separately; PET is more accurate than CT alone
- FDG PET sensitivity and specificity for residual disease 90% and 83%, respectively
- PET/CT sensitivity, specificity, and accuracy 98%, 92%, and 94%, respectively
- PET/CT decreases number of equivocal lesions by ˜ 50% and provides improved biopsy localization information
- 74% better localization with PET/CT compared to PET in regions previously treated; 58% for untreated regions
Initial diagnosis
- Squamous cell carcinoma almost always FDG avid
- Look for primary lesion along the mucosal surfaces
- Unknown primary: FDG PET typically shows focal asymmetrical FDG uptake in the mucosal primary
  - 5-10% of cases involve primary that cannot be found by physical exam, panendoscopy, or conventional radiographic imaging
  - PET/CT has been shown to find primary in 40% of patients whose primary was not identified in office or with surgical panendoscopy
  - False negatives with PET/CT means that this modality is a supplement to, but not a substitute for, endoscopy and biopsy with unknown primary
- FDG PET shows no advantage over traditional techniques for identification and characterization of primary head/neck tumors for stage I/II lesions
  - Rarely adds information regarding initial T staging of primary
  - Exception is unknown primary
Staging
- Screening for distant metastases advised for patients who have
  - Four or more lymph node metastases
  - Bilateral positive nodes
  - Nodes greater than 6 cm
  - Zone 4 nodes
  - Recurrent SCCHN
  - Second primary tumor
- In one study, 24% of patients newly diagnosed with SCCA of the oral cavity had distant metastases picked up by PET/CT
  - However, PET/CT cannot preclude neck dissection in patients with advanced primaries but clinically node-negative necks
- PET/CT may alter TNM score in 30-35% of patients by identifying nodal disease not apparent on CT, MR, or clinical exam
- PET/CT has advantage in identifying distant disease because it can detect occult metastatic disease (e.g., subtle bone metastases)
  - Present in as many as 10% of patients with advanced local-regional disease
- PET may alter treatment in many patients, decreasing toxic wide-field radiotherapy
- Unclear whether PET/CT useful in identification of nodal metastases in patients with SCCHN and N0 necks on exam
- Stage III/IV patients have high risk of distant metastases, creating a greater role for FDG PET
  - PET has a distinct advantage over CT/bronchoscopy, especially in the lung
- Target volumes for IMRT and stereotactic radiosurgery may be modified in as many as 20% of cases with PET/CT vs. CT alone
  - PET/CT used primarily to include normal-sized lymph nodes with increased metabolic activity as part of high dose target volume
  - Helpful for contouring primary tumors whose borders are difficult to distinguish by anatomic imaging alone, as with some tongue-based tumors
- PET/CT limited in staging local lymph node involvement if patient’s disease is clinically stage N0 after physical examination and anatomic imaging
  - Due to limited spatial resolution
  - Selective neck dissection or sentinal lymph node biopsy is more definitive
  - However, even in stage N0 disease PET/CT may be useful
  - Serves as a baseline to differentiate incidental physiologic FDG-avid foci from malignant foci on subsequent post-treatment exams
  - Otherwise a significant interpretive challenge if comparison images are not available
Restaging
- Following surgery, no detectable tumor should be present
  - Variable amounts of post-surgical change expected
- Post-surgery: Usually wait 4-6 weeks after to reevaluate with PET and PET/CT to avoid false positive studies due to inflammation
  - Reevaluation following surgery may be particularly helpful in cases where surgical margins are positive
- Post-radiation
  - Positive PET one month after XRT has a positive predictive value of ˜ 100%
  - Negative PET one month after XRT has a lower negative predictive value (14%) early; fewer false negatives with longer follow-up period
Response to therapy
- Following chemoradiation, metabolic response may precede reductions in tumor volume
- Post-chemotherapy (approximately 1 month after completion): Sensitivity and specificity of FDG PET 90% and 83%
  - Little data evaluating early response to chemotherapy
  - Inflammatory changes seen with radiotherapy are not seen, and PET can be performed at earlier time point, such as 4-8 weeks
- Post-chemoradiation
  - PET/CT has high negative predictive value and allows confident exclusion of residual cancer, thereby deferring planned neck dissection
- Pitfalls and limitations
  - Several structures in the neck with variable physiologic FDG activity
  - Common muscles with asymmetrical FDG activity: Pterygoids, sternocleidomastoid, strap muscles, and mylohyoid
  - Glands: Salivary glands (submandibular and parotid); can have intense FDG activity following some chemo regimens
  - Lymphoid tissue: Lingual tonsils, palatine tonsils, and adenoids (Waldeyer ring)
  - Brown fat: Can be symmetrical or asymmetrical, can be focal anywhere in the neck
  - FDG PET may not detect small areas of residual/recurrent disease, leading to early false negative exams after therapy
  - PET frequently fails to identify hypermetabolism in areas of marrow space infiltration and perineural extension
  - Cartilage necrosis may be FDG avid indefinitely
  - Cricoarytenoids typically FDG avid and often asymmetric

DIFFERENTIAL DIAGNOSIS

Metastatic Disease from Thyroid or Melanoma

May look identical to squamous cell carcinoma

Abscess or Suppurative Nodes

Usually has central necrosis; identical in appearance to necrotic lymph node
FDG PET not helpful for differentiation; biopsy required
Often indistinguishable from tumor; correlate clinically

Lymphoma

Difficult to differentiate from SCCHN based on imaging; associated mucosal lesion favors SCCHN
NHL: May mimic tonsillar inflammatory disease

Residual/Recurrent Malignancy

Often indistinguishable from abscess/inflammation
Short-term serial evaluation very helpful
CT may show asymmetrical mass effect

Radiation-Induced Inflammation

FDG uptake from inflammation usually present for 4-8 weeks following therapy
Osteoradionecrosis can cause false positive early (before frank necrosis causes negative PET)
Dual-time point PET imaging at 1 hour and 3 hour post FDG injection may be helpful in differentiating tumor vs. inflammation
- FDG uptake from 1-3 hours: Tumor may increase; inflammation may plateau or decrease

Physiologic Activity

Benign tonsil FDG uptake typically will be symmetrical but can be intense
Muscle activity may be focal and asymmetrical
- Correlate PET with CT; pre-treatment with benzodiazepines may reduce muscle uptake
Measure Hounsfield units (HU); -50 to -150 compatible with brown fat
- Warm patient before FDG injection to reduce brown fat uptake of FDG

Reactive Nodes

Tend to be normal to minimally enlarged, symmetrical, low level FDG uptake
May be associated with diffuse tonsillar uptake if recent upper respiratory or viral infection

Careful history for recent upper respiratory infection is advisable

PATHOLOGY

General Features

General path comments
- Nodal level classification scheme
- American Joint Committee on Cancer (AJCC) and American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS)
  - Level IA: Submental nodes between anterior digastrics
  - Level IB: Submandibular, lateral to IA anterior to the posterior margin of submandibular gland (SMG)
  - Level IIA: Upper internal jugular nodes; anterior, lateral, or posterior and touching the jugular vein
  - Level IIB: Posterior, not touching jugular
  - Level III: Mid-internal jugular nodes, extend from inferior hyoid to cricoid arch
  - Level IV: Low internal jugular nodes, extend from cricoid arch to the level of the clavicle
  - Level V: Spinal accessory group, nodes in the posterior triangle; level VA: Above cricoid; level VB: Below inferior cricoid border
  - Level VI: Upper visceral nodes; between the carotid arteries from bottom of the hyoid to the top of the manubrium
  - Level VII: Superior mediastinal nodes; between the carotid arteries from below the top of the manubrium above the innominate vein
  - Supraclavicular nodes: At or caudal to the level of the clavicle and lateral to the carotid artery
  - Retropharyngeal nodes: Within 2 cm of the skull base medial to the carotid arteries
  - Parotid: Nodes within the parotid gland
- Initial workup with physical exam, office endoscopy, and MR/CT
  - If definitive for nodal disease, PET/CT is appropriate for accurate evaluation of nodal metastases
  - Suggestive PET/CT findings should prompt fine needle aspiration (FNA)
  - If FNA is negative, definitive treatment is pursued and PET/CT is optional, to serve as baseline prior to therapy
- If a focus of unknown primary is suspected on metabolic imaging
  - Panendoscopy and frozen section biopsy
  - Panendoscopy includes oropharynx, hypopharynx, nasopharynx, larynx, and upper esophagus
- If negative, further biopsy specimens may be obtained from most common sites for primary tumors
  - Base of tongue
  - Nasopharynx
  - Contralateral tonsillar fossa
  - Pyriform sinus
  - Ipsilateral tonsillar fossa
- Reassessment
  - Biopsy areas that appear suspicious on PET or PET/CT
  - Alternatively, short-term interval follow-up PET or PET/CT
Etiology: Smoking, chewing tobacco, alcohol abuse
Epidemiology
- SCCHN newly diagnosed in 40,000 patients annually in United States
- Mortality is 23%
- Average 5 year survival 56%
Associated abnormalities: Risk factors also predispose to esophageal and lung cancer

Staging, Grading, or Classification Criteria

T stage: Assessment requires knowledge of size of primary lesions, depth of invasion, and involvement of surrounding structures
N stage: AJCC characteristics include number of nodes involved, size of nodes, location (laterality and level), and morphology
Staging of SCCHN requires
- Complete history and physical
- Histologic confirmation
- Characterization of primary
- Recognition of local/regional nodal disease
- Identification of distant metastatic disease

CLINICAL ISSUES

Presentation

Most common signs/symptoms
- May present with pain associated with primary mass or neck mass
- Symptoms of residual/recurrent tumor overlap with post-treatment complications; pain is most common
Other signs/symptoms: Mass on clinical exam

Demographics

Age: Generally > 40-45 years
Gender: M > F

Natural History & Prognosis

Nodal metastasis is most accurate prognostic factor for SCCHN
- Unilateral nodal involvement indicates 50% reduction in expected lifespan; bilateral nodal involvement indicates 75% reduction
- 10 year survival drops from 85% to 10-40% in patients with positive nodes
- Carotid artery involvement or encasement portends dismal prognosis with 100% mortality
- Majority of patients do not have metastatic disease within cervical nodes at presentation
  - 20% risk of occult metastasis in patients with clinically node-negative necks
10-15% of patients with SCCHN will present with distant metastases
Unknown primary
- PET and PET/CT can help direct biopsy
- 2-9% of SCCHN patients present with cervical lymph node metastases without clear evidence of primary site