PET > PET tumor imaging > Head and Neck Tumors

Head and Neck Tumors:

Head and neck cancers account for about 3% to 5% of cancers in the adult population in the US [9]. Approximately 40,000 to 50,000 new cases are diagnosed each year [31,35]. Squamous cell carcinomas represent the majority of all malignant head and neck tumors (more than 90% of all head and neck cancers) [15,43]. Most cases are diagnosed in patients between the ages of 50-70 years, with a 5 times higher rate in men than for women [43]. Smoking and HPV infection are among the main risk factors for oropharyngeal squamous cell carcinoma [57], but the lesions differ in their underlying molecular and genetic profiles [78].  HPV associated oropharyngeal squamous cell carcinomas now account for about 40-80% of cases [60].

The overall annual mortality ate for head and neck cancer in the US is 23% and the 5 year survival rate is 56% [35]. The overall survival for patients with advanced head and neck cancer is slightly less- about 40% [9]. However, survival varies by tumor location with cancers of the lip associated with a 90% 5-year survival and 32% for cancer of the hypopharynx [74]. Survival decreases with positive lymph node involvement [74].

About 40% of patients with squamous cell head and neck cancers have localized disease, while the remaining 60% have advanced disease [15]. Lymph node involvement is the most important prognostic factor affecting patient survival [15]. Number (single or multiple), distribution (ipsilateral, contralateral, or bilateral), and lymph node size (less than 3 cm, between 3-6 cm, or larger than 6 cm) are all important factors to consider when staging head and neck cancer [31]. The 5-year survival rate is less than 30% due to a high rate of lymph node metastases, the high recurrence rate, and an increased occurance of secondary malignancies [43].

HPV-positive oropharyngeal cancer:

An association between HPV infection and oropharyngeal squamous cell cancers is now recognized - especially arising from the lymphoepithelium in the tongue base and palatine and lingual tonsils [57,59,60]. Greater than 90% of HPV-positive oropharyngeal squamous cell cancers (HPV OPSCC) are associated with a single HPV type- HPV-16- which is the same sexually transmitted viral subtype responsible for cervical and anogenital malignancies [60,78]. Two HPV oncoproteins- E6 and E7 degrade p53 tumor suppressor protein and retinoblastoma protein pRB and interfere with DNA repair and apoptosis [78]. To restore cell cycle control, there is upregulation of cyclin-dependent kinase inhibitor p16 which can be detected in HPV-related tumors [78].

HPV OPSCC is characterized by a younger age (40-50 years) at onset, predominance in white men, and a strong association with sexual behavior [60,78]. Positive HPV status is associated with better response to radiation/chemotherapy, a better prognosis and overall progression-free survival (90% five year overall survival [78]) [57,59,60,74]. HPV positive lesions have higher rates of phosphatidylinositol-3'-kinase pathway alterations [74]. However, for recurrent oropharyngeal SCCa, a negative human papilloma status is associated with an overall survival advantage [68].

Despite the overall better prognosis, HPV OPSCCs are consistently poorly differentiated, demonstrate a high mitotic rate, are nonkeritonizing, and have a distinct basaloid appearance [60]. The tumors are often associated with cystic lymph node metastases and have a higher rate of nodal involvement (more advanced N-stage) than HPV-negative tumors [60]. HPB OPSCC tend to disseminate to multiple organs and unusual sites [60]. These metastases can also manifest later in the disease course- between 3-5 years after completion of treatment [60].

Non-HPV tobacco related OPSCC typically has TP53 mutations, does not have upregulation of p16, and has a worse prognosis (40% five year survival) [78].

Perineural involvement/Perineural spread: Perineural involvement (PNI) refers to tumor invasion into the neural space of small nerve branches confined to the tumor site [77]. Perineural spread (PNS) involves larger nerves accompanied by tumor spread along the nerves away from the primary site [77]. In head and neck mucosal squamous cell cancers, PNI confers a higher risk of local recurrence (23% vs 9%), a higher risk of metastases, and worse disease specific mortality (54% vs 25%) [77]. PNI has also been found to be a predictor of lymph node metastases [77]. Approximately, 40% of patients with PNS are asymptomatic [77]. On imaging, PNS appears as thickening, nodularity, and enhancement of the involved cranial nerve [77]. FDG PET imaging will demonstrate curvilinear increased uptake along the distribution of the involved cranial nerve [77]. In the chronic phase, there may be decreased FDG uptake in the affected musculature, which appears atrophic [77].

Accurate pre-operative TNM staging is essential for head and neck tumors in order to plan which type of surgical neck dissection will be used and in determining the need for post-operative chemotherapy and radiation treatment. The effectiveness of surgical treatment depends on the complete excision of all tumor tissue [15]. Early stage lesions are usually treated by surgery or radiation as a single treatment with generally good results [9,15]. More advanced cases of head and neck cancer require chemotherapy and surgery [9,15]. With greater emphysis on organ preservation, neck dissection is now commonly reserved for those with residual or recurrent disease following initial therapy [66]. Therefore, evaluation of nodal response is crucial to the adequate performance of salvage neck dissection [66].

Locoregional and distant recurrences occur in 25-50% of patients with advanced-stage head and neck cancer, predominantly within the first 3 years after treatment [68].

A meticulous technique is essential when performing head and neck FDG-PET imaging [8]. The muscles of mastication or laryngeal muscles can mimic metastases [14]. To avoid muscle uptake, it is important to keep the patient in the resting state with no eating or talking during the distribution phase following injection. Valium or Versed should be used for muscle relaxing purposes and patients should be appropriately monitored. The tonsils and adenoids can also demonstrate significant tracer uptake and should not be interpreted as pathologic [15].

Co-registered PET/CT imaging is particularly helpful for anatomic localization of lesions in head and neck imaging [29]. PET/CT has been suggested to be superior to PET or CT imaging alone [3,37]. PET/CT results in improved lesion localization, better recognition of physiologic uptake, fewer equivocal lesions, higher radiologist confidence, and can affect patient management in up to 18% of cases [3,29,37]. However, involuntary patient motion between the CT and PET exams can result in misregistration for both attenuation correction and lesion localization [33].  Customized head support devices,  immobilizing masks, vacuum-lock bags, and proper patient head support can be used to minimize involuntary patient motion [8,33].

The NCCN guidelines recommend consideration of FDG PET/CT in the assessment of the initial treatment strategy for advanced stage III/IV oral cavity, pharynx, and larynx cancers; nasopharyngeal cancer; head and neck cancers of unknown primary; and mucosal melanomas [74].

Staging and primary Tumor:

Most head and neck tumors are detected on physical exam with either direct or indirect visualization [6]. Conventional imaging of head and neck cancers with CT or MR can be hampered by artifacts associated with dental metallic implants (particularly for detection of oral cavity cancers), but this does not affect PET imaging [40,45]. FDG-PET is very accurate in identifying head and neck primary tumors. In a prospective evaluation, FDG-PET correctly identified 88% of primary laryngeal tumors and 100% of malignant parotid neoplasms [16]. In another prospective study, PET correctly identified 96% of primary head and neck malignancies- only two small lesions were not identified [25]. In a prospective study of oral cavity squamous cell carcinoma, FDG PET imaging had a sensitivity of for 98.4% for the identification of the primary tumor (compared to 87% for CT and 99% for MR) [2]. In a separate study of patients with a variety of head and neck tumors, FDG PET identified 100% of the primary tumors [10]. A literature survey in the use of PET in head and neck cancer compared to CT indicates PET has a higher sensitivity (87% vs 62%) and specificity (89% vs 73%) for staging cancer [30]. In a prospective study, overall TNM stage was altered in 31% of patients on the basis of the PET scan findings [41].

PET imaging has been shown to be a useful additional to conventional staging of patients with head and neck tumors [6]. Staging by PET imaging has better prognostic properties compared to conventional imaging (PET can upstage up to 35.5% of patients and patients that are upstaged by PET have been shown to have significantly worse progression free and overall survival) [76]. PET imaging results can also impact on patient management in up to 70% of cases by confirming local disease or identifying unsuspected metastases [9]. In another study with respect to surgical planning, PET provided additional information in 31% of patients with equivocal CT or MR findings [5]. A prospective study also found that patient management plans were altered in 34% of patients on the basis of the PET exam results [41]. Other studies have shown a change in management in 18-40% of patients based upon the PET findings [41]. Preliminary data also indicate that PET exam findings can play an important role in delineating the gross tumor volume and disease extent for radiation therapy planning purposes [31].

False positive exams can occur in association with acute inflammation (tonsillitis) [29] and benign parotid neoplasms such as Warthin?s tumor and pleomorphic adenomas are also positive on FDG imaging (this compromises the specificity of the exam for evaluation of parotid lesions).

False negative exams can be seen in salivary gland neoplasms and spindle cell neoplasms which have inherently low FDG uptake [1]. Necrotic neoplasms may also produce false negative exams due to insufficient metabolically active tissue [1]. False negative exams can also occur in areas of high physiologic activity such as pharyngeal lymphoid tissue [74].

Large laryngeal cancer: The patient shown below had a large laryngeal cancer (white arrows). The PET exam demonstrated very prominent uptake within the mass, but no evidence of metastatic disease.

Lymph nodes metastases:

In patients with squamous cell carcinoma of the head and neck, the presence of cervical lymph node metastases carries significant negative prognostic information [19,72]. The 5-year survival in the absence of nodal metastases is about 65%, while it decreases to 29% for patients with cervical nodal metastases (survival decreases by 40-50% in patients with positive nodes [74]) [19]. Between 21% to 45% of patients with clinical N0 disease and negative CT or MR exams, harbor lymph node metastases [34]. The oropharynx is generally richer in lymphatics than the oral cavity, and oropharyngeal cancers are therefore more likely to manifest with metastases to cervical lymph nodes [52]. Among patients with oral cavity SCC's, those in the retromolar trigone, floor of the mouth, and tongue show a strong predilection for lymphatic involvement [51].

Conventional imaging with CT or MRI is limited in the detection of nodal metastases because pathologic nodes are often considered solely on the basis of size criteria and up to 40% of metastases occur in nodes smaller than this size [15,26]. The usual size criteria is a maximal longitudinal diameter of more than 15 mm for jugulodiagastric nodes and more than 10 mm for other nodes (except for retropharyngeal nodes which are considered pathologic at a diameter of more than 8mm) [51]. However, if the minimal axial diameter is used for measurement a size of 11 mm for jugulodiagastric nodes (level II) and 10 mm for all other nodes is considered abnormal [51]. Normal nodes tend to be reniform, while pathologic nodes are more likely to be rounded [51]. Also- a node is considered pathologic if it contains a central region of necrosis (appearing hypodense on CT imaging) [51]. This central necrosis is often best appreciated on contrast enhanced imaging and some authors recommended contrast for CT imaging when performing PET/CT on head and neck cancer patients [62].

Specificity of conventional imaging is also poor- as low as 39% for CT and 48% for MR imaging [29]. Because of the inaccuracy of CT and MR in staging, elective lymph node dissection is recommended if the risk for nodal metastases exceeds 15-20% [34]. Unfortunately, using this strategy means that 60-80% patients are subjected to an unnecessary procedure [34].

In most studies, PET imaging has been shown to be more sensitive and specific than CT for the detection of nodal metastases [4,6,35], including contralateral nodal metastatic disease [70]. The sensitivity of FDG PET imaging for the staging of cervical lymph nodes is between 67% to 91%, and the specificity is between 80% to 100% [26,27,31,34,35,42]. Compare to a sensitivity and specificity of 65-82% and 47-85% for CT, and 80-88% and 41-79% for MR, respectively [4,31]. Overall, there is an approximately 5-10% improvement in sensitivity and specificity compared to CT or MRI [74]. For initial staging, the disease probability for PET positive lymph nodes is 81%, and 4.5% for PET negative nodes [4].

For lymph node metastases from squamous cell carcinoma of the mouth, FDG PET has a sensitivity of 75%- 91%, and a specificity of 88%-96%- this is superior to MRI (36%-78% and 71%-94%, respectively) [15, 16]. In a prospective study of patients with oral cavity squamous cell carcinoma PET had a level-by-level sensitivity for the detection of nodal metastases of almost 75%, compared to 53% for CT/MR (level-to-level accuracy of PET was 89.4%) [2]. The specificity of PET was 93%, compared to 94.5% for CT/MR [2]. False-positive PET exams occurred in association with reactive and inflammatory lymph nodes [2]. In this study, PET disclosed metastatic lesions in approximately half of morphologically benign nodes [2]. However- small volume metastatic disease (of about 5.5 mm of less) will generally not be detected on PET imaging [2,34,50]- hence- a negative PET scan does not necessarily limit the surgical dissection [2].

In another prospective study of patients with head and neck squamous cell cancer and negative neck palpation findings (clinical N0 patients), PET/CT was superior to conventional imaging (CT/MR) for the demonstration of nodal metastases (per patient sensitivity was 71% of PET, and 50% for CT/MR; specificity was 81% and 87%, respectively) [61]. The overall accuracy was 77% for PET and 71% of CT/MR [61]. False positive results occurred due to reactive or inflammatory lymph nodes, and false negative findings were seen in associaiton with small volume disease (average sized of missed mets was 5.7 mm) [61]. In a meta-analysis, of patients with clinically negative neck examinations, PET had a sensitivity of 66% and specificity of 87% for the detection of lymph node involvement [72].

Other limitations of PET imaging is its inability to identify macroscopic extranodal spread which is associated with a 10 fold increased risk of recurrence and a 50% reduction in survival compared to nodes with no (or microscopic) extranodal spread [31]. Also- intense tumor uptake of FDG may also obscure adjacent nodes [31] and nodal necrosis may cause false-negative findings on FDG PET imaging due to the loss of viable tumor cells [2]. However, PET/CT can overcome these limitations and result in overall more accurate staging [2,31].

PET can be particularly useful in the assessment of patients with clinical stage N0 disease [19]. In these cases between 16%-60% of patients are subsequently found to have occult lymph node metastases [19]. In cases of clinical N0 disease, PET has been shown to have a sensitivity of 78% and an accuracy of 92% (compared with a sensitivity of 57% and an accuracy of 76% for CT) for the detection of nodal metastases [19]. Therefore, PET can provide additional information compare to conventional imaging regarding the presence of lymph node metastases. However, PET imaging cannot completely replace surgical staging of cervical nodes.

Detection of metastatic disease:

The presence of metastatic disease can significantly impact on patient management. These patients can be spared the expense, morbidity, and mortality associated with extensive head and neck surgery [26]. By providing a whole body survey, FDG PET can detect distant sites of metastatic disease and other primary neoplasms. FDG PET has a sensitivity of 90% and a specificity of 94% for the detection of distant metastases [31,74]. FDG PET imaging has been shown to be superior to conventional imaging for the detection of distant metastatic disease [75].

The overall incidence of distant metastatic disease is generally low and quite variable (2-18%), but is higher in patients with more advanced disease [49,74]. The most common sites for distant metastatic disease in head and neck cancer are the lungs, bone, and liver [49,74]. Several studies have demonstrated that PET can detect unsuspected metastatic disease particular in patients with advanced local-regional disease [35]. In one study of patients with advanced stage head and neck tumors (Stage III or IV), PET imaging identified unsuspected mediastinal nodal metastases in 17% of patients [26]. Other authors have shown that combined diagnostic chest CT and PET imaging has the highest sensitivity for the detection of distant metastatic disease in high risk patients, and that this combination does not lead to additional cost [49]. By avoiding futile unnecessary surgery, the pre-operative identification of metastatic disease can result in a substantial cost savings [26]. In fact, PET imaging has been estimated to be cost effective if metastatic disease is found in just one of nine patients [26].

Patients with head and neck tumors also have a high incidence of secondary tumors of the aerodigestive tract  (between 6% to 36%) [5,15,16]. FDG PET imaging can easily identify other primary neoplasms which are routinely missed on coventional imaging and result in timely and appropriate treatment for these lesions [5,75].  

 

Unknown primary:

Between 2-9% of patients with squamous cell carcinoma of the head and neck present with metastatic cervical lymph nodes without an identifiable primary site by clinical exam [17,31,35]. A dedicated clinical exam and conventional CT/MR imaging will identify the site of the primary tumor in the majority of patients; however, between 32%-45% of patients will have still an unknown primary lesion [17]. In this subset of patients, PET imaging has been shown to be superior to convention CT/MR imaging and can provide additional useful information by identifying the primary site of the tumor in about 25% to 69% of patients [6,29,31,35,41,67] and in revealing additional unsuspected sites of disease [15,17,21]. False negative results can occur, particularly in association with small primary tumors (less than 10 mm) [67].

Treatment Planning:

Using PET/CT data improves target volume delination when compare to CT or MR imaging alone [55]. The PET exam findings can have significant influence on CT or MR based tumor contours by incorporating biologic/metabolic features of the tumor and thereby reducing the risk of geometric misses and minimizing dose to normal tissue [55]. Treatment plan can be changed in up to 15% of patients when PET data is incorporated into planning [55]

Response to therapy:

Between 50-70% of patients with head and neck squamous cell carcinoma achieve a complete response, while between 30-50% will have residual or recurrent disease [59]. Unsuspected residual disease can be found in up to 19.5% of patients [65]. Neoadjuvant chemotherapy or combined chemoradiotherapy is used to decrease tumor size before surgery in locally advanced-stage head and neck cancer [9]. Neoadjuvant therapy has been shown to improve rates of clinical complete response at the primary site, improve locoregional control, and improve survival [39]. A cure in locally advanced head and neck cancer is associated with complete remission following first-line therapy [22]. Neither CT or MR can reliably differentiate post-treatment change from residual tumor [9,10]. FDG-PET imaging can be used to monitor response to therapy and identify residual viable tumor when it is otherwise unsuspected [9,10,28]. Patients that have a favorable response to therapy generally demonstrate a significant reduction in FDG uptake from baseline values (mean reduction 82%) [27]. Positive results on intratherapy or post therapy scans are strongly predictive of an increased risk for progression, recurrence, and death, particularly within 2 years, but also for up to 5 years [69]. Early recognition of resistance to chemotherapy can result in prompt institution of secondary treatment strategies [9].

Tumor response can be assessed quantitatively or qualitatively [74]. The PRECIST criteria suggest a reduction of at least 30% in SUVmax is required to document a partial tumor response [74]. The EORTC criteria suggest a decrease in SUVmax of between 15-25% is indicative of a good treatment response [74]. Qualitative assessment can be performed to accurately assess lesion response using the Hopkins criteria which compares lesion FDG avidity to the liver and internal jugular vein [74,79]. 

Hopkins Criteria Five Point Post Therapy Assessment Scoring System:

Score	FDG Uptake Pattern	Response
1	Uptake in lesion and nodes less than IJV	Complete metabolic response
2	Focal uptake above IJV, but less than liver	Likely complete response
3	Diffuse uptake at primary site or nodes greater than IJV or liver	Likely post XRT inflammation
4	Focal uptake at primary or nodes above liver	Likely residual tumor
5	Focal and intense uptake at primary or in nodes	Positive residual tumor

Scores of 1, 2, or 3 are determined to be negative for residual disease, whereas a score of 4 or 5 are positive [79].

Results: Tumors that respond to treatment have decreased metabolic activity and hence, decreased FDG uptake [10,18,25]. The overall sensitivity of PET for residual cancer after therapy is between 68-100% [23,25,39,52,65,71]. Post therapy FDG PET/CT can add value to the clinical assessment in up to 35% of patients and influence subsequent patient management [71]. A literature survey in the use of PET for monitoring the effects of therapy in head and neck cancer compared to CT indicates PET has a higher sensitivity (84% vs 60%) and specificity (95% vs 39%) [30,39]. However, other authors indicate that the specificity of PET for residual or recurrent cancer following treatment is lower (61-93) [52]. Specificity is improved when patients are imaged more than 12 weeks after therapy- likely due to decreased post-treatment inflammation [52]. Delayed scanning with a long uptake phase of 90-120 minutes can also help to differentiate post-therapy inflammation from residual neoplasm [53]. Post-therapy PET imaging has been shown to serve as a prognostic marker for overall survival in patients with head and neck squamous cell cancer [59,61]. A negative PET scan following therapy is associated with a very good prognosis (high negative predictive value- 94-97% [39,71]), while a positive scan is associated with a higher likelihood for residual or recurrent neoplasm [25]. Unfortunately, false-positive exams are common (PPV has been reported to be 40-67%) [39,71]. Meta-analysis has suggested the pooled sensitivity, specificity, PPV, and NPV for assessing disease response to be 87.7%, 87.8%, 75.7%, and 94.3% (PET has higher diagnostic accuracy if performed more than 12 weeks after the completion of treatment) [58]. Another study suggested an overall accuracy of PET/CT of approximately 90% [59].

Qualitative assessment using a 5 point scale (or Hopkins criteria) has also been shown to be a sensitive and accurate method for exam interpretation [65,73] with a high specificity (91%) and high NPV (92%) [79]. Additionally, results based on Hopkins criteria analysis have been shown to alter patient management in about 64% of patients [79]. Qualitative results can be used to predict survival outcomes in patients with residual neck nodes post therapy better than conventional imaging [73]. Patients with residual cervical nodes that are negative by Hopkins criteria have been shown to have 7 times greater overall survival compared to those with PET positive nodes, and are 6 times less likely to have progression of disease [73].

When to scan: The timing of post-therapy PET imaging is important for an accurate assessment of response to treatment. The issue of when to scan is complex and there is conflicting data regarding this issue. PET imaging performed too soon after treatment may produce both false-positive and false-negative results [52]. Monitoring response to radiation therapy can be complex due to inflammatory and tissue healing responses [9]. Some authors advocate waiting 3 to 4 months following completion of radiation therapy prior to PET imaging to assess for residual or recurrent  [6,16,24,25,52,59]. Post-treatment scans performed earlier than this time may demonstrate decreased FDG uptake even in the presence of residual disease (ie: false-negative results) [16,25]. This may be related to altered FDG uptake kinetics related to derangements in cellular glucose transport or vascular damage (that hampers tracer accumulation [52]) rather than actual cell death [9] and residual microscopic disease would also go undetected. False positive FDG uptake within non-pathologic lymph nodes can be seen following radiation (and chemo) therapy possibly secondary to an inflammatory reactive change [10,29]. These nodes can usually be correctly identified as they generally do not demonstrate increased tracer uptake on the pre-therapy baseline exams [10]. In general, a waiting period of about 10-12 weeks following therapy completion is recommended, unless clinical management requires it at an earlier time [39].

However, early PET FDG imaging during therapy has been studied [22,27,56]. FDG PET exams performed early (at around 20 Gy) or 1 to 3 weeks following initiation of therapy can be used to predict treatment response, local control and survival [22,56] and persistent tumor uptake one month following radiation therapy is strongly suggestive of residual disease [18]. Authors have found that imaging as early as one month following completion of radiation therapy can be performed with excellent sensitivity (88%) and specificity (95%) [36]. The better prognotic value of early imaging may be partly explained by the inability of PET scans obtained later udring the course of therapy to identify miscroscopic residual disease that is ultimately responsible for tumor recurrence [56]. Also- post radiation inflammatory changes can also confound later PET imaging [56].

A waiting period of 5 to 7 days following needle biopsy or 6 weeks after surgical resection is recommended to avoid false-positive findings associated with inflammation [27]. Osteoradiation necrosis of the mandible and thyroid cartilage can also demonstrate increased FDG uptake in patients that have received radiation therapy.

Prognosis:

For non-surgical therapy in head and neck cancer patients it is difficult to predict treatment outcomes reliably even in patients within the same TN category [20]. The amount of FDG uptake (as measured by SUVmax) has been shown to correlate with predicting local control and disease free survival in patients with head and neck cancers [9,20,38,41,63]. Generally, the higher the SUV the lower the disease free survival rate [9,38,63], however, this has not been confirmed in all studies [25]. None-the-less, high FDG uptake (SUVmax greater than 5.5/or other authors suggest 10 [63]) may help to identify a subgroup of patients that will require more aggressive treatment protocols [20]. In a study of patients with squamous cell carcinoma of the oropharynx, high pre-treatment SUV values were an independent prognostic indicator and could also be used to guide more effective treatment strategies [38]. Another factor associated with overall worse prognosis is the presence of tumor metabolic heterogeneity on PET imaging [57].

For patients with non-squamous cell carcincoma of the head and neck, higher FDG uptake is also associated with decreased overall survival [54]. Another prospective study found that patients who had additional lesions identified on PET that were not seen on conventional imaging, were less likely to achieve a complete response and had a trend toward poorer disease free survival [41].

Other PET findings associated with decreased disease free and overall survival include the metabolic tumor burden/volume (> 20 cm³ - the mean tumor volume can be measured by contouring margins defined by thresholds, total lesion glycolysis (> 70 g - the TLG is calculated by multiplying MTV by the mean SUV), and a ring-shaped tumor uptake pattern (suggestive of central necrosis) [63,64]. Other authors suggest that a metabolic tumor volume greater than 41 mL is associated with a 2.4 fold higher recurrence or death rate [73]. The presence of lymph node necrosis or lymph node and 40% of the maximum nodal total lesion glycolysis of 38 g or greater are also poor prognostic features [66].

Following therapy, a positive PET scan has been found to be associated with a greater than 6-fold increase in the risk of death within 2 years [74].

Recurrent disease:

Locoregional recurrence of advanced head and neck squamous cell cancer (SCC) can occur in up to 45% of patients [46]. The risk for recurrence is highest for Stages III and IV (compared to stages I and II) [46]. Most local recurrences are seen within the first 2 years following radiation therapy [24,46,59].  Distant metastases are seen less often (5-10% of patients, other authors indicated 20-30% [52]) and are more commonly seen with oropharyngeal SSC (compared to SCC of the oral cavity) [46].

Early diagnosis of local recurrence is important for the prompt institution of salvage therapy [24,42]. A delay in the detection of recurrence has been shown to be associated with a deleterious clinical outcome [42]. Only about 20% of patients with recurrent disease survive at one year [9]. However, patients with recurrent, early stage disease who undergo salvage surgery have a 70% 2-year relapse free survival [42].

One of the most useful applications of PET imaging is the detection of residual or recurrent head and neck neoplasm [1]. Following treatment, there is distortion of the normal anatomy and it can be very difficult to distinguish post-therapeutic change from recurrent or residual tumor with conventional imaging modalities [6,32,42]. Even on laryngoscopy, it can be difficult to distinguish post-radiation change and edema from recurrence [24] and biopsy in this setting is also not without potential complications [24]. FDG PET imaging can be used to aid in identifying a subgroup of patients that should proceed to biopsy [24].

PET has been shown to have a sensitivity between 88% to 100% for the detection of recurrent cancer (specificity 60-100% [1,32,42,46]). A meta-analysis concluded FDG PET had 94% sensitivity, 82% specificity, 75% PPV, and 95% MPV in detecting residual or recurrent HNSCC [59]. Because the positive prdictive value of a positive scan is low (75%), a positive scan warrants further evaluation with biopsy [24,27,59]. Even if the biopsy result proves to be negative, patients with a positive PET scan should undergo close follow-up as some of these patients will subsequently be shown to actually have recurrence [24]. A literature survey in the use of PET for imaging recurrent head and neck cancer compared to CT indicates PET has a higher sensitivity (93% vs 54%) and specificity (83% vs 74%) [30]. PET/CT images are more accurate than PET alone for determining the exact anatomic location for a lesion [29]. A separate meta-analysis for the detection of tumor recurrence indicated a sensitivity of 92% and a specificity of 87% [68].

Compared to regular follow-up, the use of surveillance PET can result in a change in diagnostic procedures or patient treatment in up to 63% of patients [46]. When used for surveillance for tumor recurrence, the best time to perform PET imaging is between 3-6 months after completion of treatment in order to decrease the risk of false positive exams [46].

One point to remember is that a positive scan is not always due to malignancy (the specificity of a positive scan can be as low as 63% [24]). Infection, reactive lymph nodes, radiation necrosis, and dysplasia can all result in increased FDG uptake [24,42]. False negative exams can occur if a patient is scanned too soon after completion of chemo/radiaiton therapy [32]. A minimum of 3 to 4 months following completion of radiation therapy is recommended prior to PET imaging to minimize the chance of obtaining a false positive or a false negative exam [6,16,24,25,32].

Patients with a negative PET scan are at a very low risk for having recurrence and follow-up of these patients can be performed (ie: the exam has a very high negative predictive value) [24,42].

Another important role for FDG-PET imaging is in the evaluation of residual soft tissue abnormality following radiation therapy. The PET exam can very accurately distinguish residual tumor from scar with an accuracy of 81% (compared to 42% for the CT/MR exam) [16].

 

Other agents for head and neck cancer imaging:

¹⁸F-fluoromisonidazole (¹⁸F-FMISO) PET (a tumor hypoxia agent) has been shown to demonstrate significant tumor hypoxia in up to 78% of patients with head and neck cancer [44]. Both the degree of hypoxia and the size of the hypoxic volume were found to be independent predictors for survival (i.e.: the greater the degree of hypoxia, the overall worse disease-free survival) [44,47]. The absence of hypoxia was associated with a low risk of locoregional failure, even when treated with chemotherapy alone [47]. Hypoxia is one of the main factors associated with treatment resistance and a modest boost in dosing to hypoxic regions may result in increased tumor control [44]. Although ¹⁸F-FMISO imaging seems promising, one of the limitations of the agent is the requirement for late imaging (2.5 hours following injection) due to slow cellular uptake and slow washout from non-hypoxic tissues which limit image quality and the effectiveness of this agent [48].

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(72) AJR 2016; Kim SG, et al. Potential role of PET/MRI for imaging metastatic lymph nodes in head and neck cancer. 207: 248-256

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(79) AJR 2020; Banks KP, et al. It's about quality, not quantity: qualitative FDG PET/CT criteria for therapy response assessment in clinical practice. 215: 313-324