CT in Squamous Cell Carcinoma of the Head and Neck

Author’s Accepted Manuscript Chapter 3: The Role of PET/CT in Squamous Cell Carcinoma of the Head and Neck Hrishikesh Kale, Tanya J. Rath

www.elsevier.com/locate/enganabound

PII: DOI: Reference:

S0887-2171(17)30065-3 http://dx.doi.org/10.1053/j.sult.2017.06.001 YSULT765

To appear in: Seminars in Ultrasound, CT, and MRI Cite this article as: Hrishikesh Kale and Tanya J. Rath, Chapter 3: The Role of PET/CT in Squamous Cell Carcinoma of the Head and Neck, Seminars in Ultrasound, CT, and MRI, http://dx.doi.org/10.1053/j.sult.2017.06.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Chapter 3: The Role of PET/CT in Squamous Cell Carcinoma of the Head and Neck

Author order: Hrishikesh Kale, MD and Tanya J. Rath, MD Institution: University of Pittsburgh Medical Center Acknowledgement of grant funding: No grant funding was utilized Disclosures: The authors have nothing to disclose Contact information: [email protected], [email protected] Corresponding Author: Hrishikesh Kale, MD Abstract Head and neck squamous cell carcinoma is an important cause of cancer morbidity worldwide and has been stratified into HPV-related and HPV-unrelated subgroups which impact prognosis and now staging. Conventional anatomic imaging methods are suboptimal for the detection of regional and distant metastases which are important prognosticators associated with poor outcomes. Functional imaging with FDG PET/CT is a useful tool in the management of head and neck squamous cell carcinoma, providing complementary physiologic and anatomic information. In this article, optimal PET/CT technique will be reviewed and the pre-treatment and post-treatment applications of PET/CT will be described. A simplified approach to imaging interpretation, including review of pearls and pitfalls will discussed. An initial framework for follow-up evaluation will be provided. Introduction Head and neck cancers accounts for approximately 3-5% 1 of all primary malignancies in the United States and include malignancies of the lip, oral cavity, sinonasal cavity, pharynx, larynx, salivary glands and cutaneous squamous cell carcinomas of the head and neck.2 The majority of head and neck cancers are squamous cell carcinoma (90%), 3 though other histologies such as adenocarcinoma and mucosal melanoma occur as well. In recent years, there has been a reduction in the incidence of traditional tobacco and alcohol related head and neck squamous cell carcinomas (HNSCC), while the 1

incidence of HPV-related HNSCC has increased.4 HPV- related HNSCCs, which primarily arise in the oropharynx, have a markedly better prognosis with half the risk of death compared to HPV-unrelated HNSCC.5 Consequently, HNSCCs are now stratified by HPV status (HPV-related vs HPV-unrelated) and the latest American Joint Committee on Cancer (AJCC) 8th edition staging system now includes an entirely separate staging algorithm for HPV-related OPSCC in an effort to provide more accurate staging prognostication for these tumors which have a unique biological behavior.2 Imaging is a useful tool in the staging and follow-up evaluation of head and neck cancer patients. Available guidelines for imaging recommendations vary according to stage.6 (F18)-fluorodeoxyglucose (FDG) PET/CT plays a critical role in the management of HNSCC patients including pre-treatment staging, detection of occult primary, radiotherapy planning, assessing response to therapy and surveillance for disease recurrence. It provides functional information regarding the tumor in addition to the anatomic extent of disease, a benefit in an era of personalized medicine with efforts directed at identifying non-anatomic prognosticators that can direct patient specific treatment. In this article, optimal PET/CT technique will be reviewed, the various roles of PET/CT in the management of HNSCC will be discussed and a framework for imaging interpretation will be provided. Principles and Technique Routine clinical PET/CT for HNSCC is typically performed using F18-FDG, a radiolabeled glucose analog that is transported into the cell but not metabolized, serving as a surrogate marker for glucose metabolism. It accumulates within cells and its uptake is dependent upon multiple physiologic and molecular factors, including the amount of GLUT1 receptors. Cells with increased glucose metabolism, including cancer cells such as HNSCC, preferentially accumulate FDG. FDG avidity also occurs in normal tissues (ex. muscles and brain) and non-neoplastic tissues (ex. sites of inflammation or bone healing) with high glucose metabolism. Consequently, correlation with high quality contrast – enhanced cross sectional imaging and the clinical picture is critical to distinguish neoplastic versus nonneoplastic FDG avidity and optimize PET/CT interpretation. FDG PET/CT for complete staging and 2

disease characterization is best for performed with a diagnostic contrast enhanced CT. The contrast enhanced CT is critical to assess morphologic imaging features of solid organ metastasis and regional metastasis including nodal size, presence of nodal necrosis or cystic change (which is often not FDG avid), and imaging features of extracapsular extension, which impacts staging and prognosis (Figure 1).7,8 Institutional PET/CT protocols are variable. Typically, patients fast 6 hours before the FDGPET/CT examination and blood glucose is monitored with imaging performed when the glucose level is below 200 mg/dL. Patients receive 10–17 mCi of IV F18- FDG followed by a quiet, resting 60-minute uptake period. At our institution, we perform an initial low dose, inspiration breath-hold chest CT first, which improves the accuracy of staging the chest, providing greater sensitivity in the detection of nodules not otherwise detected on non-breath hold CT and characterizing aspiration related changes that are common in head and neck cancer patients (Figure 2). 9,10 This is followed by a contrast-enhanced (iopamidol, Isovue-370; Bracco Diagnostics, Princeton, New Jersey) whole body CT with the arms down extending from the top of the skull through the abdomen. After the CT, PET data are acquired. Images of the neck are reconstructed with a small FOV to improve visualization of the primary tumor site and regional nodes.7 Contrast is critical to accurately characterize complex neck anatomy (particularly in the post-treatment neck), delineate primary tumor volume and assess regional lymph node morphology. Pre-treatment Applications of PET/CT Staging Complete staging of HNSCC requires assessing HPV status (for oropharynx) or EBV status (for nasopharynx), characterizing the size and extent of the primary tumor (T), identifying the size and extent of regional lymph node metastases (N) and evaluating for the presence of absence of distant metastases (M).2 The detailed description of the updated 8th edition AJCC staging criteria2 for HPV-related and HPV-unrelated HNSCC are provided in Chapter 1 of this edition. Correct staging is important as the presence of lymph node and distant metastases at presentation in HNSCC is associated with poor prognosis and may alter management, particularly in HPV-unrelated HNSCC. 11-13 An important benefit 3

of cross-sectional imaging is the ability to define the deep extent of the primary tumor and demonstrate clinically occult metastatic lymph nodes which may impact treatment planning, including nodes not amenable to palpation, such as retropharyngeal nodes (Figure 1). PET/CT improves staging accuracy in advanced HNSCC, offering the advantage of providing both functional and anatomical characteristics in assessing for the extent of locoregional and distant disease.14-18 Tissue confirmation is recommended with uncertain findings as false positives occur due to areas of inflammatory and reactive uptake.19 Primary Tumor Clinical exam, endoscopic evaluation and high resolution conventional contrast-enhanced CT and/or MRI are the standard for assigning the T stage of the primary tumor. PET/CT has been shown to have high sensitivity for detecting primary HNSCC, but has limited value in the detection of small tumors less than a centimeter which are below the spatial resolution of PET.16,19,20 PET/CT may be helpful when there is dental amalgam artifact degrading CT image quality as the PET offers high soft tissue contrast (Figure 1).7 CT is used to assess for cortical bone erosion and MRI offers improved sensitivity for medullary cavity invasion.21,22 Lymph Nodes Conventional imaging features of nodal metastasis including assessment of primary echelon drainage pathways and nodal features such as central necrosis, size, clustering and heterogeneous enhancement pattern provide suboptimal sensitivity for detection of nodal metastasis.23 While there is not clear consensus in the literature on the benefit of PET/CT in the staging of the neck in HNSCC, several studies have demonstrated that FDG PET or PET/CT improved regional staging accuracy compared with conventional imaging, particularly in advanced stage head and neck cancer (stage III and IV).17,24-27 The variation in results is likely partly due to the retrospective nature of many studies, the heterogeneity of patient populations studied and the different imaging techniques employed. In a recent meta-analysis of 3460 neck levels, Sun et al found that PET/CT outperformed conventional imaging on a per-neck level

4

with a sensitivity of 0.84 compared 0.63 for conventional imaging, though specificity (0.96) was the same (Figure 3). 28 The role of PET/CT to exclude nodal metastases in patients a known HNSCC and no clinical evidence of regional metastasis (N0 neck) has been investigated.17,24,29 In 2006, Ng et al, prospectively evaluated the accuracy of FDG-PET, CT and MRI in staging the neck in 134 patients with clinically N0 oral cavity HNSCC.24 The authors found that FDG PET had a level by level sensitivity for detecting regional nodal metastasis of 41.2% which was nearly two-fold the sensitivity of conventional CT/ MRI and which was improved when correlated with CT or MRI. When including review of the FDG PET and CT/ MRI results, the authors found the probability of imaging occult metastasis in the clinically N0 neck was T-stage dependent and as low as 3.3% in T1 tumors and as high as 25% in T4 tumors, indicating that FDG PET cannot be used to exclude nodal metastasis in the clinically N0 neck, particularly in high T stage tumors. In 2008, Kyzas et al performed a meta-analysis of 1236 patients with HNSCC from 32 studies to evaluate the accuracy of FDG PET compared with CT, MRI and ultrasound guided FNA.17

In

studies where both 18 F-FDG PET and conventional tests were performed, the sensitivity and specificity of 18 F-FDG PET were 80% and 86% compared with 75% and 79% of conventional tests. In the clinically N0 neck, however, the sensitivity of FDG-PET was reduced to only 50%. These studies indicate FDG PET is not accurate to detect micrometastases and defer elective neck dissection in the clinically N0 neck when the risk of occult metastasis is expected to be high based on the primary tumor characteristics. Current research suggests there may be a future role for sentinel node biopsy as an alternative to neck dissection in select patients with HNSCC and clinically N0 neck.30-33 Distant Metastases Patients with locally advanced HNSCC and lymph node involvement are at greater risk for distant metastases and a thorough staging evaluation for distant disease is warranted in these patients. Features of regional metastasis including clinically palpable neck nodes (N1-3), greater than 3 metastatic lymph nodes, bilateral metastatic lymph nodes, lymph nodes greater than 6 cm, extracapsular spread (ECS) and 5

low jugular chain lymph node metastases have all been associated with an increased incidence of distant metastases with a poor prognosis.34-37 The presence of jugular vein and soft tissue involvement have also been shown to increase the likelihood of distant metastases. 38 Reported rates of distant metastasis at staging are as high as 21%, depending on the screening methods.34,39-43 Pulmonary metastases are by far the most common. Additional metastases typically occur with pulmonary metastases, seen most often in mediastinal lymph nodes, bone and liver. 35,42,43 Identifying distant metastases in high risk patients at staging is useful to avoid aggressive treatment that may not offer a therapeutic benefit and to guide therapy, including participation in clinical trials or providing palliation when appropriate (FIGURE 4). Several studies suggest that PET or PET/CT is more accurate than conventional imaging for detecting distant metastases in advanced HNSCC.40,41,44 There is substantial variation in the reported sensitivity and specificity for PET or PET/CT to accurately identify distant metastases in the literature due to the heterogeneity of patient populations studied and variable follow up time used as the reference standard.45,46 Ng et al prospectively evaluated the detection of distant metastases or second primary tumors by FDG-PET compared with contrast-enhanced CT in 160 patients with oropharyngeal or hypopharyngeal HNSCC.44 Distant malignancy was found in twenty-six patients (16.3%). FDG-PET had substantially higher sensitivity of 76.9% compared with 50.0% for contrast-enhanced CT, and a slightly lower specificity (94.0% vs. 97.8%). Combined correlation of FDG-PET with contrast-enhanced CT provided the best results with a sensitivity and specificity to 80.8% and 98.5%. Senft et al found in a multi-center prospective study of 92 patients with risk factors for distant metastasis and a minimum follow up of 12 months, that the overall incidence of distant metastasis was 21%. FDG-PET outperformed CT in the detection of thoracic metastases and FDG-PET combined with CT had the highest sensitivity (63%) for detection of distant metastasis.40 A meta-analysis by Xu et al in assessing the accuracy of staging whole body PET-CT at staging and re-staging found a pooled sensitivity and specificity of 88% and 95%, respectively, amongst heterogenous populations of patients with head and neck cancer, including patients with nasopharyngeal cancer.47 Distant malignancy (metastases or second primary) occurred in 81 (17.9%) of 452 patients during post-treatment surveillance. 6

Recently, Senft et al demonstrated the time dependence of PET/CT accuracy in a retrospective review of 46 patients with high risk HNSCC and screening FDG PET/CT with a mean follow up of 39.4 months. FDG-PET/CT had high sensitivity (83.3%) and negative predictive value (NPV, 97.2%) at 6 months, which serially decreased at 12 months (60% sensitivity and 89.9% specificity) and 30 months (37.5% sensitivity and 72.2% specificity). The authors found a similar time dependent trend of reduced sensitivity and NPV of staging FDG-PET/CT in a review of published studies using similar reference standards.46

In a retrospective study of 170 patients with head and neck cancer, Spector confirmed that

PET was more likely to diagnose multiple distant metastases than CT or chest x-ray, but there was no difference in life expectancy according to diagnostic modality.43 Nonetheless, there are studies, that suggest that FDG-PET combined with CT is a cost-effective screening tool for high risk HNSCC patients by reducing unnecessary operations and directing appropriate non-operative therapy without additional increased costs.41,48 Given the incidence of pulmonary metastases and improved staging accuracy of FDG PET/CT compared with conventional imaging, FDG PET/CT with a dedicated diagnostic CT including at least the chest is a useful screening protocol for detection of distant malignancy in high risk HNSCC patients.40,42,44 Second Primary Patients with HPV-unrelated HNSCC are at increased risk for both synchronous and metachronous second primary malignancy (SPM) due to the high prevalence of alcohol consumption and smoking in this population, leading to field cancerization.49,50 The most common sites of SPMs include the head and neck, esophagus and lung (FIGURE 5).51 Rates of synchronous SPMs vary from 1-18% and are important to identify as they can impact treatment planning.40,51-55 Not surprisingly, the risk of SPMs in patients with oropharyngeal malignancies has currently declined to the lowest risk of the HNSCC subsites due to the high prevalence of HPV-related malignancy in this group.51 Haerle et al found FDG-PET/CT to be highly accurate in detecting synchronous SPMs in 311 patients with HNSCC (primarily advanced stage) who underwent both pan-endoscopy and FDG-PET/CT 7

for initial staging.56 The sensitivity of FDG-PET/CT (100%) was superior to panendoscopy (74%) for detecting synchronous SPMs, and offered the advantage of detecting additional SPMs outside of the neck. The PPV was suboptimal at 59%, emphasizing the importance of performing PET/CT prior to endoscopy to identify potential biopsy sites and ensure tissue confirmation of suspicious PET/CT findings. Strobel et al found in a retrospective review of 589 patients with HNSCC, a prevalence of 9.5% synchronous SPMs, 84% of which were detected with FDG-PET/CT and changed management in 80% of the SPM group.57 Unknown Primary A small percentage of head and neck cancers (3-9%) present as a cancer of unknown primary (CUP), defined as biopsy proven cervical nodal metastasis with an occult primary tumor despite thorough evaluation.58 Squamous cell carcinoma is the most common histology (in 75%) and the most common sites of CUP include the tongue base, faucial tonsil, pyriform sinus and nasopharynx.58 PET/CT offers high lesion to background contrast and can be useful in the identification of a CUP prior to panendoscopy, optimizing target delineation and minimizing biopsy and treatment related morbidity (FIGURE 6). PET/CT has been shown to be more sensitive in localizing primary tumors when compared to contrast enhanced CT/MR imaging, with variable detection rates near 30% or greater particularly when performed prior to endoscopy.25,59-63 In a prospective study including 60 patients with a CUP, the preendoscopy detection rate of FDG-PET for CUP was 37%.63 FDG-PET localized a primary tumor or metastatic disease in 50% of all patients, impacted patient management in 25% of patients and yielded sensitivity, specificity, and positive predictive value of 86%, 69%, and 60%, respectively.63 In a metaanalysis of 16 studies, 18F FDG PET detected 25% of primary tumors in 302 patients with CUP and detected unsuspected regional or distant disease in 27% of patients. The overall sensitivity and specificity of FDG-PET for detecting CUP was 88.3% and 74.9%, respectively, with higher false positive results found in the faucial tonsils and reduced sensitivity for tumors found in the base of tongue.60 The reported 8

specificities are sub-optimal and re-iterate that suspicious PET/CT findings should be confirmed with biopsy. Physiological FDG avidity in the lymphoid tissue of Waldeyer’s ring can mimic or obscure tumor and confounds evaluation for CUP by FDG PET. This can be particularly problematic for small tumors that are less than 1 cm and below the spatial resolution of FDG PET.19 If conventional diagnostic tests do not indicate a primary tumor, current NCCN guidelines recommend performing PET/CT prior to exam under anesthesia.6 HPV testing and EBV testing can also be performed as an HPV positive test is strongly associated with an occult tumor in the tongue base or faucial tonsils and may be useful to direct diagnostic biopsies and treatment. In the setting of a negative minimally invasive work-up including PET/CT, exam under anesthesia is typically performed in an attempt to surgically localize a primary tumor. Effect of Staging PET/CT on Patient Management The improved accuracy of PET/CT compared with conventional imaging in the staging of advanced HNSCC has been shown to impact management. In a prospective study of 233 patients comparing staging by conventional cross-sectional imaging with whole body PET-FDG, conventional imaging with PET TNM classification was found to be more accurate than conventional staging and the FDG PET results altered management in nearly 14% of patients.18 Recently, Cacicedo et al confirmed that PET CT TNM staging was more accurate than conventional staging in a prospective study of 84 HNSCC patients with PET/CT findings changing management in 26% of patients.64 The improved accuracy of PET/CT staging translates into a cost-benefit by avoiding operative therapy that may not offer improved outcomes for patients with advanced HNSCC.41,48 Based on the available literature, the current NCCN guidelines recommend the use of PET/CT for staging in patients with STAGE III AND IV HNSCC. 6 Radiation Therapy Planning The primary imaging modality in radiation therapy planning is CT. PET/CT can be used in conjunction with physical exam and diagnostic CT and/or MRI to improve accurate target delineation for radiation therapy planning (RTP). PET approximates the closest gross tumor volume (GTV) to 9

pathologic specimens, but there is no current standardized or validated operator independent segmentation method for estimating GTV as this time.64 Post-treatment applications Following definitive therapy, assessing the post-treatment neck is diagnostically challenging for both the clinician and the radiologist due to treatment related anatomical distortion and altered physiology that occurs. Treatment failure in advanced stage disease HNSCC occurs in up to 40% of patients, typically within the first 2 years following therapy.65-67 The goal of post-treatment assessment is early identification of patients with incomplete treatment response or disease recurrence, intended to provide the best opportunity for cure. PET/CT provides functional information that complements anatomic evaluation of the distorted post-treatment neck, and is useful for therapy assessment, surveillance and prognostication. Treatment Response Studies suggest that PET/CT has greater accuracy in assessment of the post-treatment neck compared with conventional imaging.68,69 The high NPV value of PET/CT exceeding 90% for residual or recurrent tumor in the post-treatment setting is established in the literature, with variation in the results partly affected by the timing of imaging. 70-75 In a retrospective study of 84 heminecks in 65 patients treated non-operatively for HNSCC with a median follow up time of 43 months, Ong et al found PET/CT had a sensitivity of 71%, specificity of 89%, high NPV of 97%, poor PPV of 38% and overall accuracy of 88% for nodal disease.74 NPV for the primary tumor was also high at 97%. Compared with conventional CT, PET/CT notably performed favorably and reduced the number of false positive findings by 50%. Recently, McDermott et al found in a retrospective study of 582 surveillance PET/CTs in 214 patients, one negative PET/CT had a NPV of 91% and two consecutive negative PET/CTs within a 6 month period had a NPV of 98%. 72 A large meta-analysis by Gupta et al of 2335 HNSCC patients across 51 studies assessed the accuracy of post-treatment PET/CT for locoregional recurrence and confirmed a high NPV (95%) of PET CT for both the primary tumor and regional lymph nodes. For the primary tumor site and 10

regional nodes, specificity was 82 and 88% with a PPV of 59% and 52%, respectively.70 The suboptimal specificity and false positive rates of PET/CT re-emphasize the importance of tissue confirmation of PET positive findings prior to altering treatment regimens. There is a lack of consensus on the optimal timing of PET/CT after definitive non-operative therapy. Early imaging may result in reduced accuracy, mainly due to false positive studies from treatment related inflammation. Delay of imaging may unnecessarily defer salvage treatment. Ong et al found there was a greater fraction of false positive studies when PET/CT was performed between 8-12 weeks versus >12 weeks post-treatment, while the NPV remained high for both groups.74 Andrade et al found greater accuracy of PET/CT performed 8 weeks after definitive RT compared with studies performed between 4-8 weeks.68 A study by Leung et al showed post-treatment PET/CT performed earlier than 2 months had lower accuracy while there was no difference in accuracy between scans performed at 2 and 3 month intervals.

76

Two meta-analyses support imaging with PET/CT no earlier

than 12 weeks after completion of definitive therapy.70,77 These variable results suggest post-treatment PET/CT should not be performed earlier than 8 weeks to optimize accuracy and timely response assessment. In patients with clinical evidence of response, treated with radiation therapy with or without systemic therapy, current NCCN guidelines include FDG-PET/CT with contrast enhanced CT at a minimum of 12 weeks post-therapy as the first option to assess response to treatment.6 Early small retrospective studies suggested that the high NPV of PET/CT in the post-treatment setting was reliable enough to defer planned neck dissection following non-operative therapy in HNSCC.73,74,78

A prospective study of 112 patients with regional metastatic HNSCC treated with

definitive non-operative therapy and median follow up of 28 months demonstrated that patients can be spared neck dissection in the setting of post-treatment PET-negative CT residual nodal abnormalities without increased risk of regional treatment failure.79 Recently, Mehanna et al demonstrated in a large prospective randomized controlled trial of 564 patients with HPV-related and HPV-unrelated N2 or N3 HNSCC that PET/CT surveillance was non-inferior to planned neck dissection. Both groups that

11

underwent planned neck dissection and deferred neck dissection based on PET/CT findings had similar 2 year overall survival rates. PET/CT surveillance was also found to be cost effective compared with planned neck dissection. 80 Surveillance PET/CT has recognized accuracy in detecting treatment failure in curatively treated HNSCC patients with a pooled sensitivity and specificity of 0.92 and 0.87 in a meta-analysis of 2247 PET/CT studies performed at least 4 months after definitive therapy.81 However, optimal HNSCC PET/CT surveillance strategies addressing the frequency and duration of PET/CT following definitive therapy are not established in the literature. Furthermore, while PET/CT has high accuracy in the post-treatment setting, it is still unclear whether the use of PET/CT surveillance improves survival in the management of HNSCC patients. In a large retrospective study of 388 HNSCC patients treated definitively with chemoradiation therapy (CRT) at our institution, with a median follow-up period of 27 months, the overall treatment failure rate was 28.4% (110/388). Most recurrences (66%, 73/110) were detected by PET/CT and were clinically asymptomatic (Figure 7). Forty-five percent, 79 % and 95% of recurrences were detected within 6 months, 12 months and 24 months of completing CRT, respectively. These results suggest there is no substantial benefit to PET/CT surveillance in asymptomatic patients beyond 2 years of completing therapy. Our current initial post-treatment PET/CT algorithm in asymptomatic patients definitively treated for HNSCC is demonstrated in Figure 8, and has evolved taking this into consideration the temporal patterns of treatment failure in HNSCC, NCCN guidelines and the high NPV of 2 consecutive negative scans performed within a 6 month interval. 72 According to the NCCN guidelines for follow-up of patients treated with chemoradiation or radiation of the neck,6 patients categorized as having clinically persistent disease or progression should undergo contrast enhanced CT or PET/CT. If treatment failure is confirmed, patients proceed with salvage surgery when appropriate. If there is clinical response, a PET/CT 12 weeks post-treatment or CT/MRI in 8-12 weeks post-treatment are performed. With PET/CT, the results are categorized as follows: (1) 12

PET/CT negative (2) lymph node <1 cm, PET suspicious with FDG avidity (3) lymph node > 1 cm, PET with no or low grade FDG avidity (4) lymph node > 1 cm and FDG avid/PET positive. Patients who are PET/CT negative are observed. Patients that fall in the 2nd and 3rd third category may be observed, undergo image guided biopsy or undergo neck dissection depending on the surgeon’s discretion. Patients in category 4 undergo salvage neck dissection when appropriate candidates. 6 NCCN guidelines for surveillance imaging following initial post-treatment assessment are less defined and include consideration of repeated pre-treatment baseline imaging of the primary and neck within 6 months of treatment (category 2B) with further re-imaging based on risk factors, symptomatology and clinically difficult to assess areas. The modalities for surveillance imaging are not specified.6 Prognostic Value of PET/CT The prognostic value of quantitative PET/CT variables at staging, during treatment and following definitive therapy in HNSCC has been an area of active research.82-85 The most studied quantitative PET parameters are defined in Table 1 and include the standardized uptake value (SUV), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Pre-Treatment Prognostication Studies suggest there is predictive value of quantitative pretreatment FDG PET/CT parameters to in patients with HNSCC. Pre-treatment maximum SUV(SUVMax), because of its ease of use, is one of the most clinically widely used and studied semi-quantitative PET parameters. High SUVMax has been correlated with decreased overall survival and disease free survival, but there is substantial variation in reported threshold SUV values, limiting clinical applicability.86-88 In a meta-analysis of 45 studies with 2928 patients reporting on the utility of quantitative PET/CT parameters in patients with locally advanced head and neck cancer, high MTV/TLG correlated with reduced overall survival and disease free survival and outperformed the predictive value of SUVMax.86

Koyasu et al assessed the predictive value of both quantitative (SUVMax, MTV, TLG) and

subjective (uptake patter sphere or ring shaped) parameters in 108 patients with HNSCC. MTV > 20 cm3

13

and a ring shaped pattern of FDG uptake (of the primary tumor or lymph node) were associated with decreased disease specific survival in multivariate analysis.89 Similar to SUVMax, the reproducibility of MTV and TLG are also problematic because these parameters are defined by an absolute or relative SUV threshold which affects the measured absolute MTV or TLG. Consequently, there are not established threshold MTV/TLG threshold values for prognostication. Intra-therapy and Post-treatment Prognostication The predictive value of intra-therapy and post-treatment PET/CT has been investigated in an effort to provide patient specific treatment regimens and prognostication. Following definitive therapy, high SUVMax has been correlated with poor patient outcomes, though threshold values are not established.86 In a meta-analysis of 26 studies of FDG PET or PET/CT performed during or after completion of definitive primary treatment for head and neck cancer, Sheikhbahaei et al found the estimated relative risk for 2-year mortality for positive PET/CT results was 3.99 for intra-therapy PET/CT and 8.31 for post-therapy PET/CT.81 A positive FDG PET or PET/CT result was associated with a greater than six-fold increase in the risk of death within 2 years. FDG PET or PET/CT was a better predictor of the 2-year risk of death when performed after completion of treatment or ≥ 12 weeks after completing treatment compared with intra-therapy PET/CT. Approach to Interpretation There have been recent efforts towards standardizing the reporting system in surveillance of head and neck cancer. Towards this end, NIRADS (Neck Imaging Reporting and Data System) and Hopkins criteria (for PET/CT) have been proposed.90,91 These systems incorporate structured reporting of imaging findings according to the degree of suspicion for local and regional disease. The NIRADS system is modeled after the successful American College of Radiology Breast Imaging-Reporting and Data System (BIRADS) approach to categorized imaging interpretation and is in the process of being refined. A numeric code indicating the degree of suspicion for viable tumor, is assigned to the primary site and regional nodes based on assessment of the CT and PET characteristics of the primary tumor site and regional lymph nodes. The categories are as follows: (1) No evidence of recurrence (2) Questionable 14

recurrence (3) High suspicion (4) Known recurrence.90 Recommendations are linked to the categories assigned to the primary and regional nodes. The Hopkins Qualitative Posttherapy Assessment Scoring System91 assigns a score of 1-5 based on the degree of lesion FDG uptake relative to the internal jugular vein and liver with categories 4 and 5 corresponding to likely residual tumor and residual tumor, respectively, and new lesions considered progressive disease.91 CT criteria are not listed in the scoring system.91 At our institution, we currently utilize a NIRADS based approach to PET/CT interpretation in our reports, also using 4 categories (1-negative, 2-probably benign, 3-suspicious and 4-malignancy) for the primary tumor and regional nodes, but also assigning one of these 4 categories for distant disease assessment as well (Figure 9 and 10). Currently, we do not routinely report standard uptake values (SUV) as there are no optimal established SUV values distinguishing benign from malignant tissue and it is not likely that such a threshold value exists given the numerous technical and patient variables that influence SUV. Use of quantitative parameters has not been clearly shown to improve the accuracy of PET/CT interpretation.74,77 We qualitatively assess FDG avidity relative to background normal tissue uptake and correlate all PET findings with contrast-enhanced CT morphologic assessment . Pearl and Pitfalls in the Interpretation of PET/CT in the head and neck There are numerous pitfalls in the interpretation of PET/CT related to variable patterns of physiologic FDG avidity, spatial resolution and areas of non-neoplastic FDG avidity, particularly in the post-treatment neck where normal physiology is altered. Benign masses as well as inflammatory processes can be FDG avid while areas of low grade, necrotic or cystic tumor may have little or no FDG avidity.19 Careful correlation of PET findings with contrast enhanced CT or MRI and interpreted with the relevant clinical history is critical to optimize the accuracy of interpretation. Physiologic muscle activity: Virtually any group of muscles may show increased FDG avidity. Common sites in the neck include the sternocleidomastoid muscles, paraspinal musculature, muscles of mastication/ speech and

15

face. Frequently the uptake may be bilateral and relatively symmetric, which may help in making the diagnosis. However, in the post-treatment neck altered mechanics and physiology can occur resulting in asymmetric patterns of physiologic FDG uptake. Correlation with contrast-enhanced imaging is useful to delineate areas of normal muscle morphology or muscular atrophy and exclude an underlying enhancing mass in areas of asymmetric FDG avidity (FIGURE 11).92 Infection/inflammation: The presence of inflammation or infection can be intensely FDG avid, especially in the posttreatment setting, and may be mistaken for disease recurrence. Appropriate timing of the initial PET/CT scan at least 8-12 weeks after therapy is essential to optimize accuracy and avoid pitfalls. In the posttreatment neck, reactive lymph nodes, radiation induced ulcers, fistulas, chondroradionecrosis and osteroradionecrosis are examples of inflammatory and/or infectious processes that can be intensely FDG avid and mimic treatment failure (FIGURE 12).76 Correlation with contrast-enhanced CT or MRI can be helpful in distinguishing these non-neoplastic causes from tumor recurrence, though at times soft tissue sampling may be required if there is continued uncertainty. Patients with HNSCCs have frequently have impaired swallowing function and are prone to develop aspiration pneumonitis, particularly after initiation of treatment. Dedicated breath-hold CT of the chest with careful evaluation of the CT features is helpful to distinguish FDG avid aspiration and inflammatory changes from pulmonary metastases (FIGURE 2). In cases where there is uncertainty, short interval follow up imaging or tissue sampling may be needed to clarifying the diagnosis. Brown fat Brown fat can show significant FDG uptake. Typically in the neck it is bilateral, symmetric and supraclavicular. Atypical patterns of brown fat uptake can occur in the posterior neck, left paratracheal area, mediastinum, axillae, perirenal area, and retrocrural region.93 Correlation with the CT distinguishes brown fat uptake from FDG avid regional lymph nodes (Figure 13). Methods to reduce physiologic 16

muscle and brown fat FDG avidity include avoiding excessive muscle activity 48 hours prior to scan, benzodiazepines and placing the patient in a quiet, warm room during the uptake phase. Lymphoid tissue The uptake of FDG in normal or reactive lymphoid tissue may pose a diagnostic dilemma. The bilateral symmetric nature of the uptake and attention to CT morphology may be useful to distinguish physiologic from neoplastic uptake. In PET/CT studies performed for unknown primary, normal FDG avidity in the lymphoid tissue of Waldeyer’s ring can be intense and confound detection of the unknown primary. Correlating the PET findings with endoscopic results and a contrast enhanced CT can be helpful, though all of these modalities can be insensitive for detection of small occult primary tumors, necessitating exam under anesthesia in an attempt to localize CUP.19 Salivary glands Salivary glands can normally take up variable amounts of FDG, which is often relatively symmetric. Following radiation therapy, FDG uptake can be asymmetric in the salivary glands related to radiation induced injury. PET/CT cannot be used to distinguish benign from malignant parotid lesions.92 Benign parotid tumors such as Warthin’s tumor and pleomorphic adenoma can be FDG avid while malignancies such as adenoid cystic carcinoma may have little to no FDG avidity. Careful evaluation of the conventional contrast enhanced images and correlation with the clinical history is important when assessing salivary gland lesions. Thyroid Gland FDG avidity in the thyroid gland is variable and when diffuse is typically not malignant as can be seen in hypothyroidism and auto-immune thyroid disease. Incidental thyroid nodules are not uncommon on PET/CT and this risk of malignancy in focal FDG avidity within a thyroid nodule may be as a high as 35%, warranting additional evaluation.94,95

17

False negative causes of FDG uptake Low FDG uptake may be secondary to multiple causes. Small size of tumor (usually less than 5mm-10mm),96 tumors of certain histologic cell type (such as adenoid cystic carcinoma) and cystic/necrotic lymph nodes may all contribute to lack of significant FDG avidity, re-emphasizing the importance of correlating FDG PET findings with diagnostic contrast enhanced CT or MRI. Perineural spread of tumor is also difficult to evaluate on PET/CT, particularly in areas which have a background of high FDG uptake.97 Contrast enhanced MRI is more sensitive for the detection of perineural spread of tumor in HNSCC. 19 Areas of Research FDG PET/MRI is a promising novel hybrid function imaging modality which offers improved soft tissue contrast compared with PET/CT. It may be advantageous in characterizing the full extent of primary oral cavity and oropharynx tumors by reducing dental amalgam artifact (Figure 14). While clinical PET/MRI is technically feasible, it is not yet widely available and its role in the management of HNSCC is a current area of active research.98,99 The development of novel tracers is an area of research interest as well in an effort to provide patient specific prognostication and therapy. Understanding the molecular mechanisms contributing to the pathogenesis of HNSCC is important to developing relevant imaging tracers that are predictive. Current areas of investigation include molecular target imaging and development of tracers targeting cell proliferation, tumor angiogenesis and tumor hypoxia. 100 Conclusion PET/CT plays a critical role in the staging, treatment response assessment and surveillance of advanced stage HNSCC. Pre-treatment PET/CT is not sensitive to defer elective neck dissection in the clinically N0 neck in patients at high risk for occult regional metastases. Post-treatment, PET/CT has high negative predictive value and may be useful to tailor treatment and surveillance regimens. However, 18

it remains unclear whether surveillance PET/CT improves overall survival in patients with definitively treated HNSCC.

REFERENCES 1. 2. 3. 4. 5. 6. 7.

8.

9. 10.

11. 12. 13.

14. 15.

16.

17.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30. Amin MB, Edge SB, American Joint Committee on Cancer. AJCC cancer staging manual. Eighth edition. ed. New York: Springer; 2017. Schoder H, Fury M, Lee N, Kraus D. PET monitoring of therapy response in head and neck squamous cell carcinoma. J Nucl Med. 2009;50 Suppl 1:74S-88S. Pytynia KB, Dahlstrom KR, Sturgis EM. Epidemiology of HPV-associated oropharyngeal cancer. Oral Oncol. 2014;50(5):380-386. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24-35. Network NCC. Head and neck cancers (version 1.2017). https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#head-and-neck. 2017. Rodrigues RS, Bozza FA, Christian PE, et al. Comparison of whole-body PET/CT, dedicated high-resolution head and neck PET/CT, and contrast-enhanced CT in preoperative staging of clinically M0 squamous cell carcinoma of the head and neck. J Nucl Med. 2009;50(8):1205-1213. Haerle SK, Strobel K, Ahmad N, Soltermann A, Schmid DT, Stoeckli SJ. Contrast-enhanced (1)(8)F-FDG-PET/CT for the assessment of necrotic lymph node metastases. Head Neck. 2011;33(3):324-329. Escott EJ. Positron emission tomography-computed tomography protocol considerations for head and neck cancer imaging. Semin Ultrasound CT MR. 2008;29(4):263-270. Juergens KU, Weckesser M, Stegger L, et al. Tumor staging using whole-body high-resolution 16-channel PET-CT: does additional low-dose chest CT in inspiration improve the detection of solitary pulmonary nodules? Eur Radiol. 2006;16(5):1131-1137. Whitehurst JO, Droulias CA. Surgical treatment of squamous cell carcinoma of the oral tongue: factors influencing survival. Arch Otolaryngol. 1977;103(4):212-215. Snow GB, Annyas AA, van Slooten EA, Bartelink H, Hart AA. Prognostic factors of neck node metastasis. Clin Otolaryngol Allied Sci. 1982;7(3):185-192. Subramaniam RM, Truong M, Peller P, Sakai O, Mercier G. Fluorodeoxyglucose-positronemission tomography imaging of head and neck squamous cell cancer. AJNR Am J Neuroradiol. 2010;31(4):598-604. Branstetter BFt, Blodgett TM, Zimmer LA, et al. Head and neck malignancy: is PET/CT more accurate than PET or CT alone? Radiology. 2005;235(2):580-586. Fleming AJ, Jr., Smith SP, Jr., Paul CM, et al. Impact of [18F]-2-fluorodeoxyglucose-positron emission tomography/computed tomography on previously untreated head and neck cancer patients. Laryngoscope. 2007;117(7):1173-1179. Roh JL, Yeo NK, Kim JS, et al. Utility of 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography and positron emission tomography/computed tomography imaging in the preoperative staging of head and neck squamous cell carcinoma. Oral Oncol. 2007;43(9):887893. Kyzas PA, Evangelou E, Denaxa-Kyza D, Ioannidis JP. 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;100(10):712-720. 19

18.

19. 20.

21.

22.

23.

24.

25.

26.

27.

28.

29. 30. 31. 32. 33.

34.

35. 36.

Lonneux M HM, Reychler H. Positron Emission Tomography With [18F]Fluorodeoxyglucose Improves Staging and Patient Management in Patients With Head and Neck Squamous Cell Carcinoma: A Multicenter Prospective Study Journal of Clinical Oncology. 2010;28:1190-1195. Fukui MB, Blodgett TM, Snyderman CH, et al. Combined PET-CT in the head and neck: part 2. Diagnostic uses and pitfalls of oncologic imaging. Radiographics. 2005;25(4):913-930. Baek CH, Chung MK, Son YI, et al. Tumor volume assessment by 18F-FDG PET/CT in patients with oral cavity cancer with dental artifacts on CT or MR images. J Nucl Med. 2008;49(9):14221428. Mukherji SK, Isaacs DL, Creager A, Shockley W, Weissler M, Armao D. CT detection of mandibular invasion by squamous cell carcinoma of the oral cavity. AJR Am J Roentgenol. 2001;177(1):237-243. Abd El-Hafez YG, Chen CC, Ng SH, et al. Comparison of PET/CT and MRI for the detection of bone marrow invasion in patients with squamous cell carcinoma of the oral cavity. Oral Oncol. 2011;47(4):288-295. de Bondt RB, Nelemans PJ, Hofman PA, et al. Detection of lymph node metastases in head and neck cancer: a meta-analysis comparing US, USgFNAC, CT and MR imaging. Eur J Radiol. 2007;64(2):266-272. Ng SH, Yen TC, Chang JT, et al. Prospective study of [18F]fluorodeoxyglucose positron emission tomography and computed tomography and magnetic resonance imaging in oral cavity squamous cell carcinoma with palpably negative neck. J Clin Oncol. 2006;24(27):4371-4376. Roh JL, Kim JS, Lee JH, et al. Utility of combined (18)F-fluorodeoxyglucose-positron emission tomography and computed tomography in patients with cervical metastases from unknown primary tumors. Oral Oncol. 2009;45(3):218-224. Cacicedo J, Fernandez I, Del Hoyo O, et al. Should PET/CT be implemented in the routine imaging work-up of locally advanced head and neck squamous cell carcinoma? A prospective analysis. Eur J Nucl Med Mol Imaging. 2015;42(9):1378-1389. Park JT, Roh JL, Kim JS, et al. (18)F FDG PET/CT versus CT/MR Imaging and the Prognostic Value of Contralateral Neck Metastases in Patients with Head and Neck Squamous Cell Carcinoma. Radiology. 2016;279(2):481-491. Sun R, Tang X, Yang Y, Zhang C. (18)FDG-PET/CT for the detection of regional nodal metastasis in patients with head and neck cancer: a meta-analysis. Oral Oncol. 2015;51(4):314320. Ozer E, Naiboglu B, Meacham R, Ryoo C, Agrawal A, Schuller DE. The value of PET/CT to assess clinically negative necks. Eur Arch Otorhinolaryngol. 2012;269(11):2411-2414. Broglie MA, Haile SR, Stoeckli SJ. Long-term experience in sentinel node biopsy for early oral and oropharyngeal squamous cell carcinoma. Ann Surg Oncol. 2011;18(10):2732-2738. Flach GB, Bloemena E, Klop WM, et al. Sentinel lymph node biopsy in clinically N0 T1-T2 staged oral cancer: the Dutch multicenter trial. Oral Oncol. 2014;50(10):1020-1024. Schilling C, Stoeckli SJ, Haerle SK, et al. Sentinel European Node Trial (SENT): 3-year results of sentinel node biopsy in oral cancer. Eur J Cancer. 2015;51(18):2777-2784. 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(8):726-732. Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB. Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma. Cancer. 1993;71(2):452-456. Alvi A, Johnson JT. Development of distant metastasis after treatment of advanced-stage head and neck cancer. Head Neck. 1997;19(6):500-505. de Bree R, Deurloo EE, Snow GB, Leemans CR. Screening for distant metastases in patients with head and neck cancer. Laryngoscope. 2000;110(3 Pt 1):397-401. 20

37.

38. 39.

40.

41.

42.

43.

44.

45. 46.

47. 48.

49. 50.

51.

52.

53. 54.

Peters TT, Senft A, Hoekstra OS, et al. Pretreatment screening on distant metastases and head and neck cancer patients: Validation of risk factors and influence on survival. Oral Oncol. 2015;51(3):267-271. Ferlito A, Shaha AR, Silver CE, Rinaldo A, Mondin V. Incidence and sites of distant metastases from head and neck cancer. ORL J Otorhinolaryngol Relat Spec. 2001;63(4):202-207. Brouwer J, de Bree R, Hoekstra OS, et al. Screening for distant metastases in patients with head and neck cancer: is chest computed tomography sufficient? Laryngoscope. 2005;115(10):18131817. Senft A, de Bree R, Hoekstra OS, et al. Screening for distant metastases in head and neck cancer patients by chest CT or whole body FDG-PET: a prospective multicenter trial. Radiother Oncol. 2008;87(2):221-229. Uyl-de Groot CA, Senft A, de Bree R, Leemans CR, Hoekstra OS. Chest CT and whole-body 18F-FDG PET are cost-effective in screening for distant metastases in head and neck cancer patients. J Nucl Med. 2010;51(2):176-182. Yankevich U, Hughes MA, Rath TJ, et al. PET/CT for Head and Neck Squamous Cell Carcinoma: Should We Routinely Include the Head and Abdomen? AJR Am J Roentgenol. 2017;208(4):844-848. Spector ME, Chinn SB, Rosko AJ, et al. Diagnostic modalities for distant metastasis in head and neck squamous cell carcinoma: are we changing life expectancy? Laryngoscope. 2012;122(7):1507-1511. Ng SH, Chan SC, Liao CT, et al. Distant metastases and synchronous second primary tumors in patients with newly diagnosed oropharyngeal and hypopharyngeal carcinomas: evaluation of (18)F-FDG PET and extended-field multi-detector row CT. Neuroradiology. 2008;50(11):969979. de Bree R, Haigentz M, Jr., Silver CE, et al. Distant metastases from head and neck squamous cell carcinoma. Part II. Diagnosis. Oral Oncol. 2012;48(9):780-786. Senft A, Yildirim G, Hoekstra OS, Castelijns JA, Rene Leemans C, de Bree R. The adverse impact of surveillance intervals on the sensitivity of FDG-PET/CT for the detection of distant metastases in head and neck cancer patients. Eur Arch Otorhinolaryngol. 2017;274(2):11131120. Xu GZ, Guan DJ, He ZY. (18)FDG-PET/CT for detecting distant metastases and second primary cancers in patients with head and neck cancer. A meta-analysis. Oral Oncol. 2011;47(7):560-565. Kurien G, Hu J, Harris J, Seikaly H. Cost-effectiveness of positron emission tomography/computed tomography in the management of advanced head and neck cancer. J Otolaryngol Head Neck Surg. 2011;40(6):468-472. Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953;6(5):963-968. Lewin F, Norell SE, Johansson H, et al. Smoking tobacco, oral snuff, and alcohol in the etiology of squamous cell carcinoma of the head and neck: a population-based case-referent study in Sweden. Cancer. 1998;82(7):1367-1375. Jain KS, Sikora AG, Baxi SS, Morris LG. Synchronous cancers in patients with head and neck cancer: risks in the era of human papillomavirus-associated oropharyngeal cancer. Cancer. 2013;119(10):1832-1837. Erkal HS, Mendenhall WM, Amdur RJ, Villaret DB, Stringer SP. Synchronous and metachronous squamous cell carcinomas of the head and neck mucosal sites. J Clin Oncol. 2001;19(5):13581362. Jones AS, Morar P, Phillips DE, Field JK, Husband D, Helliwell TR. Second primary tumors in patients with head and neck squamous cell carcinoma. Cancer. 1995;75(6):1343-1353. Stoeckli SJ, Zimmermann R, Schmid S. Role of routine panendoscopy in cancer of the upper aerodigestive tract. Otolaryngol Head Neck Surg. 2001;124(2):208-212. 21

55.

56.

57.

58. 59.

60.

61.

62. 63.

64.

65.

66.

67. 68.

69.

70.

71.

72.

Stokkel MP, Moons KG, ten Broek FW, van Rijk PP, Hordijk GJ. 18F-fluorodeoxyglucose dualhead positron emission tomography as a procedure for detecting simultaneous primary tumors in cases of head and neck cancer. Cancer. 1999;86(11):2370-2377. Haerle SK, Strobel K, Hany TF, Sidler D, Stoeckli SJ. (18)F-FDG-PET/CT versus panendoscopy for the detection of synchronous second primary tumors in patients with head and neck squamous cell carcinoma. Head Neck. 2010;32(3):319-325. Strobel K, Haerle SK, Stoeckli SJ, et al. Head and neck squamous cell carcinoma (HNSCC)-detection of synchronous primaries with (18)F-FDG-PET/CT. Eur J Nucl Med Mol Imaging. 2009;36(6):919-927. Califano J, Westra WH, Koch W, et al. Unknown primary head and neck squamous cell carcinoma: molecular identification of the site of origin. J Natl Cancer Inst. 1999;91(7):599-604. Lee JR, Kim JS, Roh JL, et al. Detection of occult primary tumors in patients with cervical metastases of unknown primary tumors: comparison of (18)F FDG PET/CT with contrastenhanced CT or CT/MR imaging-prospective study. Radiology. 2015;274(3):764-771. Rusthoven KE, Koshy M, Paulino AC. The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor. Cancer. 2004;101(11):2641-2649. Yabuki K, Tsukuda M, Horiuchi C, Taguchi T, Nishimura G. Role of 18F-FDG PET in detecting primary site in the patient with primary unknown carcinoma. Eur Arch Otorhinolaryngol. 2010;267(11):1785-1792. Johansen J, Petersen H, Godballe C, Loft A, Grau C. FDG-PET/CT for detection of the unknown primary head and neck tumor. Q J Nucl Med Mol Imaging. 2011;55(5):500-508. Johansen J, Buus S, Loft A, et al. Prospective study of 18FDG-PET in the detection and management of patients with lymph node metastases to the neck from an unknown primary tumor. Results from the DAHANCA-13 study. Head Neck. 2008;30(4):471-478. Cacicedo J, Navarro A, Del Hoyo O, et al. Role of fluorine-18 fluorodeoxyglucose PET/CT in head and neck oncology: the point of view of the radiation oncologist. Br J Radiol. 2016;89(1067):20160217. Ang KK, Trotti A, Brown BW, et al. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001;51(3):571-578. Beswick DM, Gooding WE, Johnson JT, Branstetter BFt. Temporal patterns of head and neck squamous cell carcinoma recurrence with positron-emission tomography/computed tomography monitoring. Laryngoscope. 2012;122(7):1512-1517. Ritoe SC, Krabbe PF, Kaanders JH, van den Hoogen FJ, Verbeek AL, Marres HA. Value of routine follow-up for patients cured of laryngeal carcinoma. Cancer. 2004;101(6):1382-1389. Andrade RS, Heron DE, Degirmenci B, et al. Posttreatment assessment of response using FDGPET/CT for patients treated with definitive radiation therapy for head and neck cancers. Int J Radiat Oncol Biol Phys. 2006;65(5):1315-1322. Taghipour M, Mena E, Kruse MJ, Sheikhbahaei S, Subramaniam RM. Post-treatment 18F-FDGPET/CT versus contrast-enhanced CT in patients with oropharyngeal squamous cell carcinoma: comparative effectiveness study. Nucl Med Commun. 2017;38(3):250-258. Gupta T, Master Z, Kannan S, et al. Diagnostic performance of post-treatment FDG PET or FDG PET/CT imaging in head and neck cancer: a systematic review and meta-analysis. Eur J Nucl Med Mol Imaging. 2011;38(11):2083-2095. Kao J, Vu HL, Genden EM, et al. The diagnostic and prognostic utility of positron emission tomography/computed tomography-based follow-up after radiotherapy for head and neck cancer. Cancer. 2009;115(19):4586-4594. McDermott M, Hughes M, Rath T, et al. Negative predictive value of surveillance PET/CT in head and neck squamous cell cancer. AJNR Am J Neuroradiol. 2013;34(8):1632-1636. 22

73.

74.

75.

76.

77.

78.

79.

80. 81.

82.

83.

84.

85.

86.

87. 88. 89.

Nayak JV, Walvekar RR, Andrade RS, et al. Deferring planned neck dissection following chemoradiation for stage IV head and neck cancer: the utility of PET-CT. Laryngoscope. 2007;117(12):2129-2134. Ong SC, Schoder H, Lee NY, et al. Clinical utility of 18F-FDG PET/CT in assessing the neck after concurrent chemoradiotherapy for Locoregional advanced head and neck cancer. J Nucl Med. 2008;49(4):532-540. Porceddu SV, Burmeister BH, Hicks RJ. Role of functional imaging in head and neck squamous cell carcinoma: fluorodeoxyglucose positron emission tomography and beyond. Hematol Oncol Clin North Am. 2008;22(6):1221-1238, ix-x. Leung AS, Rath TJ, Hughes MA, Kim S, Branstetter BFt. Optimal timing of first posttreatment FDG PET/CT in head and neck squamous cell carcinoma. Head Neck. 2016;38 Suppl 1:E853858. Cheung PK, Chin RY, Eslick GD. Detecting Residual/Recurrent Head Neck Squamous Cell Carcinomas Using PET or PET/CT: Systematic Review and Meta-analysis. Otolaryngol Head Neck Surg. 2016;154(3):421-432. Porceddu SV, Jarmolowski E, Hicks RJ, et al. Utility of positron emission tomography for the detection of disease in residual neck nodes after (chemo)radiotherapy in head and neck cancer. Head Neck. 2005;27(3):175-181. Porceddu SV, Pryor DI, Burmeister E, et al. Results of a prospective study of positron emission tomography-directed management of residual nodal abnormalities in node-positive head and neck cancer after definitive radiotherapy with or without systemic therapy. Head Neck. 2011;33(12):1675-1682. Mehanna H, Wong WL, Dunn J. Management of Advanced Head and Neck Cancer. N Engl J Med. 2016;375(5):492-493. Sheikhbahaei S, Taghipour M, Ahmad R, et al. Diagnostic Accuracy of Follow-Up FDG PET or PET/CT in Patients With Head and Neck Cancer After Definitive Treatment: A Systematic Review and Meta-Analysis. AJR Am J Roentgenol. 2015;205(3):629-639. Sherriff JM, Ogunremi B, Colley S, Sanghera P, Hartley A. The role of positron emission tomography/CT imaging in head and neck cancer patients after radical chemoradiotherapy. Br J Radiol. 2012;85(1019):e1120-1126. Kim JW, Roh JL, Kim JS, et al. (18)F-FDG PET/CT surveillance at 3-6 and 12 months for detection of recurrence and second primary cancer in patients with head and neck squamous cell carcinoma. Br J Cancer. 2013;109(12):2973-2979. Paidpally V, Chirindel A, Chung CH, et al. FDG volumetric parameters and survival outcomes after definitive chemoradiotherapy in patients with recurrent head and neck squamous cell carcinoma. AJR Am J Roentgenol. 2014;203(2):W139-145. Pak K, Cheon GJ, Nam HY, et al. Prognostic value of metabolic tumor volume and total lesion glycolysis in head and neck cancer: a systematic review and meta-analysis. J Nucl Med. 2014;55(6):884-890. Castelli J, De Bari B, Depeursinge A, et al. Overview of the predictive value of quantitative 18 FDG PET in head and neck cancer treated with chemoradiotherapy. Crit Rev Oncol Hematol. 2016;108:40-51. Zhang B, Geng J, Nie F, Li X. Primary tumor standardized uptake value predicts survival in head and neck squamous cell carcinoma. Oncol Res Treat. 2015;38(1-2):45-48. Kubicek GJ, Champ C, Fogh S, et al. FDG-PET staging and importance of lymph node SUV in head and neck cancer. Head Neck Oncol. 2010;2:19. Koyasu S, Nakamoto Y, Kikuchi M, et al. Prognostic value of pretreatment 18F-FDG PET/CT parameters including visual evaluation in patients with head and neck squamous cell carcinoma. AJR Am J Roentgenol. 2014;202(4):851-858.

23

90.

91.

92.

93. 94.

95.

96. 97.

98. 99.

100.

Aiken AH, Farley A, Baugnon KL, et al. Implementation of a Novel Surveillance Template for Head and Neck Cancer: Neck Imaging Reporting and Data System (NI-RADS). J Am Coll Radiol. 2016;13(6):743-746 e741. Marcus C, Ciarallo A, Tahari AK, et al. Head and neck PET/CT: therapy response interpretation criteria (Hopkins Criteria)-interreader reliability, accuracy, and survival outcomes. J Nucl Med. 2014;55(9):1411-1416. Blodgett TM, Fukui MB, Snyderman CH, et al. Combined PET-CT in the head and neck: part 1. Physiologic, altered physiologic, and artifactual FDG uptake. Radiographics. 2005;25(4):897912. Paidisetty S, Blodgett TM. Brown fat: atypical locations and appearances encountered in PET/CT. AJR Am J Roentgenol. 2009;193(2):359-366. Soelberg KK, Bonnema SJ, Brix TH, Hegedus L. Risk of malignancy in thyroid incidentalomas detected by 18F-fluorodeoxyglucose positron emission tomography: a systematic review. Thyroid. 2012;22(9):918-925. Barrio M, Czernin J, Yeh MW, et al. The incidence of thyroid cancer in focal hypermetabolic thyroid lesions: an 18F-FDG PET/CT study in more than 6000 patients. Nucl Med Commun. 2016;37(12):1290-1296. Agarwal V, Branstetter BFt, Johnson JT. Indications for PET/CT in the head and neck. Otolaryngol Clin North Am. 2008;41(1):23-49, v. Paes FM, Singer AD, Checkver AN, Palmquist RA, De La Vega G, Sidani C. Perineural spread in head and neck malignancies: clinical significance and evaluation with 18F-FDG PET/CT. Radiographics. 2013;33(6):1717-1736. Platzek I. (18)F-Fluorodeoxyglucose PET/MR Imaging in Head and Neck Cancer. PET Clin. 2016;11(4):375-386. Schaarschmidt BM, Heusch P, Buchbender C, et al. Locoregional tumour evaluation of squamous cell carcinoma in the head and neck area: a comparison between MRI, PET/CT and integrated PET/MRI. Eur J Nucl Med Mol Imaging. 2016;43(1):92-102. Mena E, Thippsandra S, Yanamadala A, Redy S, Pattanayak P, Subramaniam RM. Molecular Imaging and Precision Medicine in Head and Neck Cancer. PET Clin. 2017;12(1):7-25.

Figure 1. Faucial tonsil squamous cell carcinoma with metastatic right retropharyngeal and conglomerate right level II lymphadenopathy on staging PET/CT. (A). Axial contrast-enhanced CT is degraded by marked dental amalgam streak artifact obscuring the primary tumor. (B,C) Fused PET/CT provides excellent soft tissue contrast with (B) intense FDG avidity seen in the right faucial tonsil tumor and in the (C) metastatic right level II nodal mass. (D) Axial contrast-enhanced CT nicely demonstrates features of extracapsular extension with the right level II nodal mass obliterating the right internal jugular vein and invading the overlying right sternocleiomastoid muscle with stranding of surrounding soft tissue planes. (E) Maximum intensity projection image demonstrates a third suspicious focus of FDG avidity (black arrow) superior to the FDG avid right faucial tonsil tumor and the metastatic right level II nodal mass. (F) Axial fused PET/CT demonstrates this corresponds to an FDG avid metastatic right retropharyngeal node (arrow) (G) which is enlarged on the axial contrast-enhanced CT (arrow), but could be easily overlooked without the excellent soft-tissue contrast of the PET. Figure 2. Early distant metastasis and aspiration pneumonia in a patient with treated hypopharyngeal HNSCC. (A,B) Axial breath-hold chest CT at staging (A) and 3 month follow up (B) demonstrates growth of the small left upper lobe pulmonary nodule (arrows) below the resolution of the PET and which 24

was confirmed to represent a metastasis with FNA. (C) Maximum intensity projection image demonstrates moderately intense FDG avidity in the right lower lobe (D) Axial breath-hold chest CT demonstrates the uptake in the right lower lobe corresponds to characteristic aspiration related pneumonia which is common in head and neck cancer patients and can occur with metastasis as is seen in this patient. Figure 3. Metastatic right level II non-enlarged cervical lymph node in a patient with right pyriform sinus squamous cell carcinoma. (A) On axial contrast enhanced CT, the small right pyriform sinus squamous cell carcinoma and the adjacent right level II non-enlarged hyperenhancing cervical lymph node could both be easily overlooked. (B) Fused radiation treatment planning PET/CT provides excellent soft tissue contrast, demonstrating suspicious intense FDG avidity in the right level II node non-enlarged lymph node, despite its small size and intense FDG avidity in the small right pyriform sinus tumor. Figure 4. Abdominal metastases in a patient with left faucial tonsil and glossotonsillar sulcus squamous cell carcinoma. (A) Anterior oblique maximum intensity projection image demonstrates ares of suspicious FDG avidity in the neck, within the liver and right mid abdomen. (B,C) Axial fused PET/CT images demonstrate (A) the FDG AVID left faucial tonsil, lateral oropharyngeal wall and glossotonsillar sulcus squamous cell carcinoma with (B) FDG avid metastatic left level II enlarged lymph node. (D) Coronal fused PET/CT reformat demonstrates FDG avid hepatic mass and suspicious periportal FDG avid lymph nodes, which were sampled via endoscopic ultrasound guided biopsy and are biopsy proven periportal squamous cell carcinoma metastases. Figure 5. Second primary lung cancer on staging PET/CT in a patient with oropharynx squamous cell carcinoma. (A) On the anterior maximum intensity projection image, areas of suspicious intense FDG avidity are seen in the neck, right lung and mediastinum. (B,C) Axial fused PET/CT images demonstrate (B) the large FDG avid posterior oropharyngeal wall biopsy proven squamous cell carcinoma. (C) The right lung anterior FDG avid mass (arrowhead) is a biopsy proven second primary small cell carcinoma. There is malignant right paratracheal lymphadenopathy (arrow). Figure 6. PET/CT localizes cancer of unknown primary in a patient with palpable right level II lymphadenopathy. (A) Axial contrast-enhanced CT demonstrates a cystic right level II lymph node (arrow) which was confirmed to represent HPV-related metastatic HNSCC by fine needle aspirate with no primary mucosal tumor seen on endoscopy or conventional imaging. (B) Fused PET/CT image demonstrates asymmetric intense FDG avidity in the right faucial tonsil(arrow) suspicious for a primary mucosal neoplasm, which was confirmed with directed soft tissue sampling. Note the left faucial tonsil also demonstrates normal moderate FDG avidity. Figure 7. Locoregional complete response with distant treatment-failure on surveillance PET-CT in a patient with HPV-related HNSCC. (A). Fused radiation treatment planning axial PET/CT image demonstrates a large FDG avid base of tongue tumor (asterisk) extending into the oral tongue. (B). Axial contrast-enhanced CT demonstrates the large base of tongue tumor (asterisk) but better delineates the metastatic non-FDG avid left level II node (arrow) and a hyperenhancing faintly FDG avid right level II node (arrowhead). (C,D). Axial fused post-treatment PET/CT (C) and axial contrast-enhanced CT (D) show a complete response to treatment with no residual mass and fatty atrophy of the right hemi-tongue with normal physiologic FDG avidity in the left hemi-tongue. The lymph nodes have resolved. (E). MIP image demonstrates suspicious areas of FDG avidity (circles) in the inguinal region bilaterally (F). Coronal fused PET/CT reformat demonstrates asymptomatic suspicious enlarged FDG bilateral inguinal lymph nodes (arrows). Fine needle aspiration of the right inguinal node confirmed HPV-related metastatic lymphadenopathy.

25

Figure 8. Current PET/CT initial post-treatment assessment and surveillance algorithm in patients with advanced stage III and IV HNSCC following definitive therapy. Initial PET/CT at 8-12 weeks following completion of definitive therapy is obtained with diagnostic contrast enhanced CT including the neck and chest (high resolution breath-hold) at a minimum. If the initial post-treatment PET/CT is negative for locoregional and distant disease, another PET/CT is obtained 6 months later and surveillance PET/CT is stopped if the PET/CT remains negative. If the initial post-treatment PET/CT demonstrates probably benign findings, a short-term follow-up PET/CT is obtained to assess for interval change. If the initial post-treatment PET/CT findings are suspicious, soft tissue sampling in the form of image guided biopsy, surgical biopsy or salvage neck dissection are considered. When there is clear evidence of persistent or progressive malignancy, the management options are discussed by the multi-disciplinary oncology team and treatment is customized for each individual patient Figure 9. Pre- and Post-treatment PET/CT in a patient with right base of tongue squamous cell carcinoma. (A) Fused radiation treatment planning PET/CT localizes the intensely FDG avid right base of tongue and glossotonsillar sulcus tumor with metastatic enlarged FDG right level II node and suspicious FDG avid non-enlarged left level II node. (A,B) Axial fused PET/CT (A) 12 weeks post-treatment demonstrates mild residual FDG avidity (arrow) relative to background at the right base of tongue without a discrete mass, interpreted as probably benign post-treatment change and negative at the level II nodal stations bilaterally (B) On the 24 weeks post-treatment repeat PET/CT, the study is negative at the right base of tongue with no residual FDG avidity or mass and negative at the level II nodal stations. Figure 10. Right base of tongue squamous cell carcinoma with residual suspicious nodal mass following completion of definitive chemoradiotherapy. (A, B) Axial Fused PET/CT images demonstrate (A) FDG avid right base of tongue tumor with a metastatic FDG avid enlarged right level II node at staging (B) Twelve weeks following chemoradiotherapy, the study is negative at the primary site with resolution of the base of tongue mass and FDG avidity at the primary tumor site. An enlarged residual right level II lymph node with FDG avidity mildly greater than background was suspicious for residual viable tumor with incomplete treatment response. Elective salvage right neck dissection demonstrated no residual viable tumor in the right level II nodal mass and post-therapy changes. Figure 11. Asymmetric physiologic laryngeal FDG avidity in a patient status post-treatment for squamous cell carcinoma with left vocal cord paralysis. (A) Fused PET/CT image demonstrates asymmetric FDG avidity (arrows) along the normal right true cord which should not be misinterpreted as tumor (B) Axial contrast-enhanced CT confirms normal morphology of the right true cord which is isodense to the normal adjacent strap muscles. There is a characteristic chronic left vocal cord paralysis with a dilated left laryngeal ventricle (arrowhead) and fatty atrophy of the medialized left true cord (arrow). Figure 12. FDG avid chondroradionecrosis following radiation therapy. (A) Fused PET/CT image demonstrates intense FDG avidity along the left thyroid cartilage and supraglottic larynx. (B) Contrastenhanced CT demonstrates gas in the left thyroid cartilage characteristic of chondroradionecrosis and low density radiation induced edema in the supraglottic larynx. Figure 13. FDG avid brown fat in the neck. (A)Axial fused PET/CT demonstrates areas of intense FDG avidity symmetrically in the posterior neck triangle which on (B) axial contrast-enhanced CT corresponds to metabolically active brown fat with no suspicious lymphadenopathy seen. Figure 14. FDG avid oral cavity squamous cell carcinoma obscured by dental amalgam artifact on PET/CT. (A) On the non-contrast attenuation correction only axial CT the right oral tongue squamous cell carcinoma is obscured by extensive dental amalgam artifact and the enlarged right level II node (arrow) could be easily overlooked (B) the PET offers excellent soft tissue contrast and localizes the FDG 26

avid right oral tongue tumor (asterisk) crossing the midline and the metastatic FDG avid right level II node (arrow). (C) On axial fused PET/MRI, the excellent soft tissue contrast of both PET and MRI, without substantial dental amalgam artifact, nicely delineates the full extent of the large right oral tongue tumor crossing the midline and demonstrates the solid FDG avid (arrow) and necrotic non-FDG avid (arrowhead) portions of the metastatic right level II nodal mass. Normal physiologic FDG avidity is noted in the left faucial tonsil on the PET images.

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

Key points: 1. Optimization of PET/CT technique with a contrast enhanced CT can improve interpretation accuracy and avoid numerous pitfalls. 2. Staging PET/CT has greater accuracy than conventional imaging in advanced stage III and IV HNSCC. 3. PET/CT may be helpful in localizing a cancer of unknown primary prior to exam under anesthesia. 4. PET/CT has high negative predictive value in the post-treatment setting. It should not be performed earlier than 8-12 weeks after therapy completion and can be used to defer elective neck dissection when negative. 5. Post-treatment PET/CT results have prognostic value that can be used to tailor surveillance regimens. Optimal long-term PET/CT surveillance regimens for HNSCC are not yet established.

42

Table 1 Commonly used Quantitative PET Parameters QUANTITATIVE PET PARAMATER

DEFINITION

Standard uptake value (SUV)

Ratio of radioactivity concentration in a region of interest and the decay corrected amount of FDG dose adjusted by body weight

SUVmax

Maximum SUV pixel value in a region of interest

SUVmean

The average SUV within a region of interest (ROI) Sum of the volume of voxels in a tumor that

Metabolic tumor volume (MTV)

exceed a threshold SUV value Total lesion glycolysis (TLG)

Metabolic tumor volume x SUVmean

43