Continuing Education Activity

Positron emission tomography-computed tomography (PET-CT) is a radiographic technique used to diagnose, stage, and survey hypermetabolic tissue, primarily cancer. This activity summarizes guidelines for when PET-CT is appropriate for evaluating head and neck cancer. PET-CT requires specific patient preparation and understanding of potential false positive and false negative test results depending on whether PET-CT is used for diagnosing, initial staging, or post-treatment staging of different head and neck cancer subtypes.

Objectives:

• Identify when PET-CT is appropriate according to the NCCN guidelines: National Comprehensive Cancer Network. Head and Neck Cancers (Version 1.2021).
• Outline causes for false-positive PET-CT interpretations for head and neck cancer.
• Explain causes for false-negative PET-CT interpretations for head and neck cancer.
• Review next steps after an uncertain interpretation of PET-CT for head and neck cancer.

Introduction

Positron emission tomography-computed tomography (PET-CT) is a radiographic technique used to diagnose, stage, and survey hypermetabolic tissue, primarily cancer. PET is used primarily to assess physiology, while CT is used primarily to assess anatomy. Combining these two methods can but does not always improve outcomes, such as survival or selecting the least invasive treatment method.

This paper focuses on the use of PET-CT for head and neck cancer. The term 'head and neck cancer' (HNC) includes several types of cancers based primarily on anatomic distributions (discussed below). HNC has several pathophysiologic types. The majority of HNC is due to squamous cell carcinoma (SCC), and most HNC SCC emerges from the oropharynx. Most HNC is associated with tobacco and alcohol use and with a mucosal primary lesion.[1] 

High-risk strains of human papillomavirus (HPV) are the next most common cause of oropharyngeal cancer.  This type of cancer has a different natural history: it is more likely to be found in young patients and has better outcomes than HNC not caused by HPV. Another category of HNC develops in lymph nodes without another discernible primary lesion (but is SCC and not lymphoma). Lymphomas, glandular adenocarcinomas (e.g., of the thyroid and salivary glands), and skin cancers are less common types of HNC, and all have different natural histories and treatment regimens. They are not covered in this article but are reviewed in the National Comprehensive Cancer Network (NCCN) guidelines.

Anatomy and Physiology

Management of HNC SCC is subdivided based on the anatomic region of the primary tumor:

• Nasopharynx
• Larynx
• Hypopharynx
• Oral cavity
• Oropharynx
• Nasal cavity
• Paranasal sinuses

Because each of these different anatomic locations has its own physiologic function(s) and approaches to surgical revision, each location has one or more unique treatment pathways. Lymphatic spread of HNC usually follows a certain pattern that depends on the primary HNC site.

The American Joint Committee on Cancer (AJCC) and American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) classify neck lymph nodes using seven ‘levels.’  This anatomic classification has remained stable since the 1990s, is important for use in PET-CT reports to enable consistency in communication, and is widely published and can be obtained elsewhere. The staging of HNC, which affects the recommended treatment options, depends on which lymph nodes are involved. Therefore, the physician interpreting PET-CT should attempt to define the primary tumor site and describe lymph node involvement or lack thereof using the AJCC/AAO-HNS lymph node anatomic classification.

The FDA-approved clinical application of PET for HNC uses a radioisotope of fluorine. The unstable isotope has 9 neutrons and 9 protons for an atomic mass of around 18 (18-F) instead of stable fluorine’s normal atomic mass of around 19. The 18-F atom is chemically bonded to a glucose molecule to substitute for an oxygen atom (deoxyglucose or DG). 18-FDG can be injected into patients with no adverse biological side effects and, as with normal glucose, localizes to hypermetabolic cells that use glucose for energy, such as cancer cells. 18-FDG undergoes normal cell membrane transport. Like glucose, 18-FDG is quickly phosphorylated upon entering a cell, which prevents its transport back out of the cell. Cells are not able to use phosphorylated 18-FDG for glycolysis or the electron transport chain, which delays molecular metabolism for several hours and allows enough time for imaging without concerns for image interpretation interference due to molecule breakdown or redistribution.[2]

Normal tissues that conduct cell membrane transport of 18-FDG at high rates include: left ventricular myocardium, brain, gastrointestinal tract mucosa, and kidney tubules. In addition, brown fat, skeletal muscle, and breast ducts undergoing normal physiologic activity can also concentrate 18-FDG. If other tissue takes up 18-FDG, then it can be assumed that the tissue is undergoing a pathologic process, such as benign or malignant tumor growth, infection (e.g., abscess), or another type of inflammation (e.g., arterial wall atherosclerosis).

The degree of 18-FDG cellular uptake can be quantified and assigned a standard uptake value (SUV) value. The SUV represents a relative (not absolute) amount of 18-FDG uptake compared to background radiation. SUV is calculated by computer software based on values (body mass, 18-F dose, dose-to-scan time) recorded in the software at the time of the scan. SUVs vary due to scanner parameter calibrations, partial volume effects (i.e., SUV becomes less accurate with smaller lesions), and patients' rate of glucose metabolism (which depends on many factors such as blood glucose level). Therefore, despite the name including the word “standardized,” there is no standard value available to determine the normal range of 18-FDG uptake across a patient population for any given cancer or other inflammatory condition. SUVs also vary depending on the organ and physiology of the particular cancer involved. Thus, determining what SUV should be used as a threshold between ‘normal’ and ‘abnormal’ or between benign tumor cell activity and malignant tumor cell activity remains a subjective process that leads to false positive and false negative scan interpretations.

Indications

Initial Diagnosis

18-FDG PET-CT is one of the most accurate methods for diagnosing the primary HNC lesion. The lesion cannot be assessed via visual inspection with or without concurrent vision-guided biopsy. The sensitivity and specificity of PET-CT for identifying inspection-occult oropharyngeal SCC have been measured as being over 90%. According to the NCCN, PET-CT is indicated for initial diagnosis for the following types of physical-exam occult HNC: oral cavity, oropharynx, glottic larynx, supraglottic larynx, ethmoid sinus, and maxillary sinus.

For suspected primary HNC that is occult on physical exam and is occult or indeterminate on CT or MRI that may be present in level 4 or lower 5 lymph nodes, the NCCN recommends PET-CT.

Cancer Staging

PET-CT can be used for cancer staging.[3]

The NCCN recommends PET-CT as the imaging modality of choice to detect neck lymph node locoregional metastasis.

For detection of distant metastases in the setting of HNC that has clinical features suggesting it may have spread beyond the neck, the NCCN recommends PET-CT as the first-line imaging modality, except in the setting of nasopharynx cancer, where the NCCN says that chest CT with contrast is an equivalent option.

PET-CT has low sensitivity and specificity for detecting brain metastases, and therefore MRI is a more appropriate imaging modality for that indication. Additionally, PET-CT has a low specificity for differentiating distant SCC metastases from concurrent melanomas, high-grade neuroendocrine carcinomas, and adenocarcinomas.

Surveillance Using PET-CT Post-treatment/Therapy

PET-CT can be superior to CT and MRI for distinguishing between tumor persistence/recurrence and benign inflammation in the correct clinical context.

Although some data from non-clinical trials have suggested imaging as early as 6 weeks following an attempt at definitive surgical resection for HNC, the NCCN recommends surveillance (re-staging) PET-CT 12 weeks after such an attempt. If after 12 weeks the PET-CT indicates negative results and the patient is asymptomatic, then no further imaging is recommended unless new signs or symptoms occur. If after 12 weeks the PET-CT is ambiguous, then the NCCN recommends obtaining a subsequent PET-CT or subsequent CT if no biopsy is performed.[4]

For HNC patients initially treated with induction (also known as neoadjuvant) chemotherapy prior to an attempt at definitive surgical or other treatment, the NCCN states that either PET-CT or CT may be used to monitor for locoregional or distant metastasis progression to aid in the decision whether to offer an attempt at definitive therapy.

For locoregionally advanced HNC in which no surgery is offered, but an attempt at cure is made with radiation and chemotherapy, the NCCN recommends assessing for residual disease with PET-CT 3 to 6 months after treatment. PET-CT performed prior to 12 weeks after chemotherapy and radiation tend to result in false-positive interpretations and therefore should be avoided. In addition, if imaging is delayed after six months, PET-CT has not been found to offer a diagnostic advantage over other imaging modalities.

For post-treatment surveillance after 6 months, there is no PET-CT algorithm that has been proven to increase survival or other meaningful outcomes compared to CT or MRI. Therefore, the NCCN suggests that PET-CT could be performed at a 12 or 24-month interval post-treatment. However, if the result of a 3-month PET-CT scan is negative for cancer, then the NCCN consensus is that there is likely no value added by obtaining additional scans at longer intervals.

Equipment

As unstable 18-F decays, it releases positrons. Within about 2 mm of travel from their origination site in tissue, positrons collide with electrons and release gamma energy (photons). The photons strike scintillator crystals housed in a device that encircles the patient. Crystals used in modern imaging machines vary by manufacturer, each with its own photon detection yield and resolution; a common crystal type used for PET is lutetium oxyorthosilicate. The crystals transmit the photoelectric energy into circuits that convert the electric energy into computer data. The scintillation (photon) detector is designed to detect only photons that simultaneously register when traveling in opposing 180-degree directions (meaning they have originated from the same location). Thus, a computer algorithm can be used to directly pinpoint the source of the two photons within several millimeters of error in three dimensions. The resolution of scanning using 18-FDG PET is typically considered to be 8 mm, meaning that a hypermetabolic tissue that is smaller than 8 mm may not be visible.

Similarly, a CT machine envelops a patient with an external source of radiation, detects the photons that pass through the patient to a photon receptor, and produces images that demonstrate the size, shape, and composition of organs and abnormalities within the body based on the distribution of absorbed photons. 

At the outpatient or inpatient facility where it is performed, PET-CT requires an extensive list of additional equipment, including laboratory equipment for containing, measuring, and administering the pharmaceuticals involved.  The sample of liquid containing the 18-FDG injected intravenously into the patient is normally shipped to the imaging facility based on a pre-calculated dose per patient because 18-FDG is synthesized using a particle accelerator, which very few medical institutions own. 18-FDG pharmacology and PET equipment are reviewed in further detail elsewhere.[5]

PET-CT image interpretation also depends on the type of computer software used. For example, many programs superimpose the PET images onto the CT images and show the PET images in a 3D-like fashion.

In 2016 the American College of Radiology (ACR) published guidelines for imaging patients with PET-CT (ACR–SPR Practice Parameter or Performing FDG-PET/CT in Oncology (Res 25)). The guidelines specify criteria that imaging equipment should meet or exceed, including PET scanner and CT scanner pixel resolution, photon detection sensitivity, CT slice thickness, and scan time.

The ACR left open several technical parameters to the discretion of the imaging facility, such as:

• PET scintillation detector type and photon detection method. The ACR reported the absence of any head-to-head trials showing one type of scanning equipment superior in quality and cost.
• Whether to inject the same amount of 18-FDG for every patient or use a formula to vary the dose between patients, dose amounts can be based on parameters that can change from among patients, such as body mass, crystal photon detector settings, and percentage of scan slice overlap.
• Whether to use intravenous contrast media. Contrast may or may not add diagnostic information. It can artifactually lower tissue SUVs, but the impact of this on diagnostic interpretation is usually limited.[6][7]
• Injection to scan time. Most facilities obtain transmission images 60 minutes following 18-FDG administration. However, this time may be shorter (no less than 45 minutes) or longer for clinical trials or unique clinical situations. SUVs obtained at injection-to-scan times of 60 minutes were found to vary little compared to injection-to-scan times of 55 to 75 minutes (Radiological Society of North America. FDG-PET/CT UPICT V1.0. 2014).

Preparation

The 2016 ACR guidelines state that the healthcare professional requesting the PET-CT should provide the imaging facility with documentation that satisfies insurance approval for the medical necessity of the exam, including patient 1) signs and symptoms and/or 2) other relevant clinical histories (such as known medical diagnoses). In addition, information regarding a provisional diagnosis and information about past surgeries, radiation, biopsies, chemotherapy, and other scan findings of interest should also be provided. It may at times be critical to enable proper performance and interpretation of the examination.

PET-CT requires patient communication and cooperation. Therefore, prior to arriving for the scan, the ACR recommends that the patient should:

• Avoid exercise of any type during the 24 hours before the scan.
• Avoid exposure to inflammatory substances (smoking of any kind, tobacco, alcohol) during the 24 hours before the scan.
• Eat low-carbohydrate meals for at least 24 hours before the scan.
• Fast (including no parenteral nutrition or oral/intravenous fluids containing sugar or dextrose) for at least 4 hours before the scan.
• Hydrate with a goal of 1 L (34 oz) ingested within 2 hours before the scan.[8][9]

For interpretation of 18-FDG uptake based on a normal physiologic distribution, serum glucose should be in the range of 70-200 mg/dL. Therefore, the ACR recommends that serum glucose analysis should be performed immediately before 18-FDG administration under the following conditions:

• If the serum glucose is >300 mg/dL, then the patient should be rescheduled.
• If the serum glucose is >200 mg/dL, then the patient may be rescheduled, but a repeat measurement could instead be performed about 20 to 30 minutes later.
  • If the serum glucose level has decreased to less than 200 mg/dL, the scan can be performed.
  • If the serum glucose level has decreased but is still >200 mg/dL, then the cycle can continue until the glucose is <200 mg/dL or FDG can be administered at the discretion of the interpreting physician.
• If the serum glucose is <70 mg/dL because the patient has taken an anti-diabetic medication, then waiting 30 minutes and repeating a finger-stick glucose measurement should be considered before rescheduling the exam.
• If the serum glucose is <70 mg/dL for another reason, then the exam should be rescheduled, and the cause should be treated.

Brown fat is a subtype of fat that is relatively hypermetabolic to white fat and is stimulated by processes such as shivering or anxiety.  To avoid false-positive interpretations due to brown fat uptake:

• Keep the patient warm (use heated blankets and a warm waiting room).
• Administer oral beta-blockers, such as propranolol 20 mg, 60 minutes prior to 18-FDG injection.
• Administer intravenous narcotics, such as fentanyl, shortly before the 18-FDG injection.[10]

To avoid false-positive interpretations due to muscle uptake:

• Keep the patient seated or recumbent in a quiet room.
• Administer oral alprazolam 0.5 mg immediately after 18-FDG injection PMID: 8965182.

To avoid patient motion that causes the scanning equipment to produce anatomic imaging artifacts (called misregistration artifacts):

• Train the patient for using breathing and motion-reducing behaviors. Breathing should be shallow and consistent and should be performed the same way for both PET and CT imaging.
• Train the patient to think relaxing, calming thoughts.  Mindfulness techniques can help patients stay still for the 30-60 minutes that PET scanning is performed.

Technique or Treatment

Given that the head and neck are the key areas of interest, scanning should be performed with arms down to avoid CT beam hardening artifacts in the head and neck area. In addition, a neck immobilization device should be used to prevent patient motion that can cause anatomic misregistration artifacts. The timing of image acquisition can be modified using breathing-gating software to correct for respiratory motion, but this technique lengthens scan time.

If tumor staging is the only purpose of the PET-CT, then low-dose CT can be performed. If the scan is performed for treatment planning purposes, regular dose CT should be performed to better anatomic resolution and interpretation.[3]

The method used to favor a benign vs. malignant process can use an average SUV or use the highest detected (SUV) inside the region of interest. Many clinical studies performed with 18-FDG pre-defined 2.5 as the critical threshold, with the interpretation of the finding as benign if its average SUV was below this value and interpretation of a finding as malignant if its average SUV was above this value.  This strategy is based on the assumption that background tissue activity always has an average SUV below 2.5.[11][3]

However, some radiologists believe that using a threshold SUV higher than that measured in the blood pool is the most accurate means of predicting whether a finding is malignant.  Radiologists also use other factors, such as the shape of the abnormality, to guide image interpretation. For example, linear uptake is most likely a result of a benign process, such as post-radiation inflammation.

Clinicians should realize that radiologic interpretation of cancer using PET-CT remains a subjective process.

Complications

Numerous situations can lead to false-positive interpretations, including image artifacts, normal tissue uptake of 18-FDG, and benign inflammatory processes and tumors.

Image artifacts from high-density objects (such as metal implants or contrast) can result in falsely high SUV (due to computer attenuation correction error when the average x-ray photon energy is less than the PET’s 511 keV photon annihilation energy). In addition, misalignment between fused PET and CT data can cause photon attenuation correction artifacts that result in incorrect SUVs. For this type of artifact, the PET images can be interpreted without using computer software that is pre-set to correct for tissue photon attenuation.

Normal 18-FDG physiologic uptake in the head and neck can occur from:

• Thyroid and salivary glands
• Brown adipose and lymphoid tissue (e.g., thymus)
• Orbital, speech, and swallowing muscles (especially in children)
• Other skeletal muscles used prior to or during the exam, and
• Smooth muscle (particularly within the gastrointestinal tract). 

Muscle uptake increases in the setting of hyperinsulinemia. The tissue density’s Hounsfield units (HU) should be measured using CT to differentiate brown fat from abnormal tissue.  If the tissue average HU measures -50 to –150, then it can be concluded that the tissue is fat.

The list of inflammatory processes that can mimic cancer is extensive, and only several (iatrogenic ones) are mentioned here:

• Post-surgical/biopsy inflammation, infection, or hematoma
• Post-radiation/post-chemotherapy inflammation
• Inflammation from therapy is indirectly related to cancer therapy (e.g., tracheostomy site, feeding, and drainage tubes).

If patients have active infection or hematoma, then the PET-CT scan will likely indicate a false-positive result.

The list of benign tumors, hyperplastic conditions (e.g., bone marrow hyperplasia after chemotherapy), and dysplastic conditions (e.g., fibrous dysplasia) that can increase SUVs in the head, and neck tissues are also extensive.

The following list details situations that can lead to false-negative FDG-PET/CT interpretation:

• Small lesion size (<2x the resolution of the imaging system, usually between 8 to 10 mm)
• Hyperglycemia and hyperinsulinemia
• Recent medical therapy (chemotherapy, radiotherapy, steroid therapy)
• Tumors with low metabolic activity (such as medullary thyroid cancer and adenocarcinoma)

There are other situations where PET-CT can lead to a correct conclusion of malignancy but not be able to distinguish between types of malignancy. For example, lymphoma is difficult to differentiate from HNC based on imaging; the presence of associated mucosal lesions and/or necrotic nodes favors a diagnosis of HNC.

Clinical Significance

HNC affects many Americans yearly, primarily due to tobacco use, alcohol abuse, and HPV.[1] Patients with HNC may present with pain that is involved with primary mass or neck mass. It is typical for patients to have mouth or throat soreness, dysphagia, otalgia, and odynophagia. Most patients with HNC SCC are older than 40 years old.  The 5-year survival depends on the stage at which the cancer is identified:

• Localized tumor only: 77% to 92%
• Regional metastasis: 38% to 60%
• Distant metastasis: 20% to 39%

HPV-associated HNC in young patients has a better 5-year survival of 85-90%.

HNC is ideally diagnosed based on a physical exam.  When this is not possible, then CT with IV contrast can detect most tumors due to disturbance in normal tissue size and density. MRI can add additional sensitivity for detecting inflammatory changes that do not result in tissue size or density changes. However, PET-CT retains roles in multiple circumstances for diagnosis:

• When a primary lesion cannot be discerned despite lymphadenopathy (unknown primary)
• When one or more lymph nodes have abnormal morphology, but suspicion for cancer is low.
• When there is suspicion that metastatic disease is present that is not detected by other imaging modalities.

Despite PET-CT having limited specificity for distinguishing cancer from other inflammatory processes, it may still aid in the plan for biopsying a lesion that offers the best and safest route for obtaining a tissue diagnosis.  

PET-CT's primary utility is in sparing unnecessary radical, modified radical, or selective neck dissections, which involve the following measures:

• Radical neck dissection: excision of the ipsilateral lymph nodes in levels I-V, the sternocleidomastoid muscle, internal jugular vein, and cranial nerve XI.
• Modified radical neck dissection: excision of the ipsilateral lymph nodes in levels I-V ± cranial nerve XI.
• Selective neck dissection: excision of selective ipsilateral lymph node groups.

When PET-CT use is limited to appropriate clinical scenarios (following NCCN guidelines), the percentage of PET-CTs that add no diagnostic information compared to what could have been obtained from other less expensive means can be reduced.

Enhancing Healthcare Team Outcomes

PET-CT has never been shown to be cost-effective for HNC in a prospective trial.  Nor has it been shown to be a cost-effective means for extending recurrence-free survival in HNC (vs. other imaging modalities or surgery alone). However, three papers using parameters for American patients have been published, all retrospective and/or theoretical in nature, suggesting cost-savings in three circumstances:

• In 2001, PET-CT was estimated to have a cost-savings per quality-adjusted-life-year (QALY) compared to CT alone for N0 patients undergoing radiologic staging.[12]
• In 1010, PET-CT was estimated to be cost-effective for deciding for or against definitive surgery after neoadjuvant chemotherapy and radiation at a threshold QALY value of $500,000.[13]
• In 2012, PET-CT was estimated to be more cost-effective than proceeding straight to node dissection for N2 disease (spread of cancer to one ipsilateral 3-6 cm lymph node, multiple ipsilateral lymph nodes <6 cm, or in bilateral or contralateral lymph nodes <6 cm) at a cost-savings per PET-CT of around $8,000.[14]

Thus, it is likely but still unproven that PET-CT is a cost-effective measure for HNC initial staging.  There is no literature that PET-CT is cost-effective for HNC diagnosis or surveillance.  Healthcare professionals can enhance the performance of the medical system by obtaining PET-CT only in high pre-test probability situations following NCCN guidelines.