Twyla B. Bartel and Tracy L. Yarbrough Abstract
Fluorine-18-fluorodeoxyglucose positron emission tomogra- phy/computed tomography (FDG-PET/CT) is now used routinely for the guidance of initial staging and for posttreatment monitoring as well as for the localization of an unknown primary in head and neck cancer patients. Along with qualitative image review, the semiquantitative parameter, standardized uptake value (SUV), allows not only assessment of a treatment response, but also provides prognostic information. In particular, one of the greatest utilities of FDG-PET/CT for head and neck malignancies is its high negative predictive value after treatment.
Keywords: head and neck, fluorodeoxyglucose, PET/CT
15.1 Introduction
Fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) provides in vivo functional information on the metabolic behavior of various tissues. It has proven to be very useful for head and neck (H&N) malignancies. When integrated with computed tomography (CT) as FDG-PET/CT, valuable combined functional and anatomical information is provided, which assists in the appropriate clinical management of patients. Also, by combining PET with CT, more accurate anatomic lesion localization and size measurements can be made than with PET alone. In most cases, PET/CT allows metabolically active malignancy to be differentiated from benign entities.
15.2 Technique
15.2.1 Fluorodeoxyglucose Dose and Administration
The patient should refrain from eating or drinking (water permitted) 6 to 8 hours prior to FDG injection. Typically, between 10 and 20 mCi (370-740 MBq) of FDG are administered intravenously (IV), and the patient is then placed in a quiet room with his or her eyes closed during what is termed the FDG “uptake period.” During this time, the patient is discouraged from reading, chewing, or talking.
15.2.2 Image Acquisition
Approximately 1 hour after FDG administration, PET/CT imaging of the patient is acquired from the top of the head to the midthighs (occasionally extending to the soles of the feet in patients with tumors such as melanoma and myeloma). At some institutions, a second dedicated H&N PET/CT acquisition is acquired about 30 minutes later from the base of the skull through the aortic arch. This second set of images should be acquired with a higher matrix to improve visualization of H&N abnormalities and allow a longer uptake period for tumor accumulation of FDG. This second acquisition may also help differentiate between malignant and inflammatory or infectious conditions (i.e., uptake in benign conditions may peak early on, while malignancies frequently have gradually increasing uptake over time).1 Placing the head at a slightly greater tilt (increasing the degree of neck extension) during the second acquisition may also assist in visualization of oral cavity abnormalities when there is excessive dental artifact in the region.
15.2.3 Intravenous Contrast
Depending upon the institution, the CT portion of the examination will be performed with or without (more common) IV contrast enhancement. In the majority of cases, the CT portion of PET/CT is performed without IV contrast and used mainly for attenuation correction and localization purposes. The PET scan is attenuation corrected by utilizing coefficients obtained from scaling the CT numbers to the PET energy level of 511 keV.2 It has been demonstrated that IV contrast does not interfere significantly with semiquantitative evaluation known as SUV.
15.3 Fluorodeoxyglucose Mechanism of Uptake
FDG is the most commonly utilized radiopharmaceutical for oncology imaging. It is a positron-emitting radionuclide with fluorine-18 (F-18) substituted for a hydroxyl group on the glucose molecule. FDG is essentially a “radioactive sugar,” or glucose analog, which is taken up physiologically by various tissues in the body and, to a greater degree, by tumor cells. Once FDG enters a cell, it is trapped within that cell after initial phosphorylation by hexokinase without further metabolism. Essentially, FDG accumulates in the cells as FDG-6-phosphate and cannot enter glycolysis at this point. Given that tumor cells, in general, have a higher glucose utilization than nonmalignant tissues, there is an elevated amount of FDG trapped in these cells, and therefore greater radioactivity. Thus, the areas of increased radioactivity accumulation are visualized as “hot spots” when viewing FDG-PET images.
15.4 Standardized Uptake Value
If a region of interest (ROI) is drawn around any given “hot spot,” an SUV can be calculated as an estimation of the metabolic activity within that specific tissue area or ROI. SUV is a semiquantitative measure of the metabolic activity of body tissues and corrects for the variability of FDG uptake related to differences in patient size and the dose of the injected FDG.3 In general, the SUV is the ratio of the radioactivity concentration in the ROI (drawn on images on a computer monitor) divided by the whole-body concentration of the injected radioactivity:
SUV = (ROI radioactivity concentration)/(whole - body injected radioactivity concentration)
The SUV is especially useful in monitoring response to therapy, as the uptake at one time point can be compared to the uptake in that same tissue at a subsequent time point.
15.5 Lesion Size and Positron Emission Tomography Resolution
PET-reconstructed resolution is typically about 4 to 6 mm; therefore, evaluation of the metabolic activity of lesions below this size is not reliable. Newer time-of-flight (TOF) PET systems provide improved resolution, contrast, and signal-to-noise ratio.4
15.6 Indications for FDG-PET or FDG-PET/CT
15.6.1 TNM Staging
Accurate TNM (tumor size, node involvement, and metastasis status) staging at the time of initial diagnosis is of utmost important in accurate treatment planning. An important benefit of FDG-PET and PET/CT in this aspect derives from the whole- body approach, thereby not only assessing the primary tumor, but also evaluating for nodal and/or distant metastases. FDG- PET has been reported to have higher sensitivity (87 compared to 62%) and specificity (89 compared to 73%) than CT for initial staging.5 Integrated FDG-PET/CT has even higher sensitivity and specificity at greater than 90% each for this purpose.6
Primary Tumor
Tumor Extent
The literature suggests that FDG-PET/CT is at least as sensitive as anatomic imaging (i.e., CT or MRI) in detecting primary H&N malignancies (especially oral cancers), but may be somewhat lacking in providing assessment of the tumor extent and involvement of adjacent structures. Therefore, it is not routinely utilized clinically for this purpose. Contrast-enhanced MRI or CT typically provides greater anatomic soft-tissue details for this purpose. MRI is also superior to both FDG-PET/CT and CT alone for providing information on possible perineural involvement of tumor. On the other hand, when IV contrast is given for the CT portion, FDG PET/CT, it may be the most practical single imaging study for management/surgical planning purposes by providing acceptable anatomic detail combined with functional information. This obviates the need to have the patient schedule two separate imaging sessions.
Unknown Primary
In the case of biopsy-proven cervical neck nodal metastases with an unknown primary H&N malignancy, FDG-PET/CT has been shown to successfully localize the primary malignancy in about 30 to 50% of cases when other imaging modalities do not.7,8 A recent meta-analysis determined the overall sensitivity, specificity, and accuracy of FDG-PET/CT for detecting an unknown primary H&N malignancy as 82.5, 80.2, and 81.4%, respectively, without a significant difference between PET alone and combined PET/CT. The most common histological tumor type for unknown primary detection in these cases was squamous cell carcinoma (SCC; 68.6%), with the most common primary location being the tonsils at 21.6%9.10 (Fig. 15.1).
Nodal Metastases
FDG-PET/CT has been shown to play a role in both pretreatment evaluations of possible nodal metastases and posttreatment monitoring.
Pretherapy Evaluation
In the preoperative setting, FDG PET/CT yields a statistically significant improvement in detecting and predicting true pathologic cervical nodal metastasis in general (p = 0.005), and when occurring only in the contralateral neck (p = 0.013), as compared to CT or MRI, with sensitivity and specificity above 80%.11.12 Regarding patients with clinically negative nodal disease, FDG- PET/CT is about twice as sensitive as conventional imaging (CT or MRI) in the detection of occult nodal metastases, thereby having a significant impact on treatment planning.13.14
Fig.15.1 This patient had biopsy-proven squamous cell carcinoma metastasis to a right neck node. The primary malignancy was unknown. A subsequent FDG-PET/CT scan showed uptake in the known right neck metastatic node (green arrows) and also localized the primary malignancy to the left tonsillar pillar (blue arrows).
Posttherapy Evaluation
It is recommended that FDG-PET/CT imaging be delayed for 10 to 12 weeks after completion of therapy, particularly after surgery or radiation treatment, in order to allow posttreatment inflammation to resolve and therefore to obtain higher diagnostic accuracy. This is true not only for nodal evaluation but also for the primary tumor. The high negative predictive value (NPV) of posttreatment FDG-PET/CT imaging is one of its greatest assets in directing management. If neck nodes are not metabolically active after treatment, they do not likely contain viable tumor. Therefore, if a postradiotherapy FDG-PET/CT scan is negative, neck dissection can be avoided with high confidence.
Distant Metastases
FDG-PET/CT offers a whole-body imaging approach, and therefore a single image acquisition to evaluate for possible distant metastatic disease; it has been shown to be very reliable for this purpose. Rohde et al15 performed a recent prospective cohort study for head-to-head comparison of three imaging approaches for detection of distant metastases in patients with oral, pharyngeal, or laryngeal squamous cell cancer: (1) combined chest X-ray and H&N MRI (CXR/MRI), (2) combined chest CT and H&N MRI (CHCT/MRI), and (3) FDG-PET/CT. The study evaluated a total of 307 patients. FDG-PET/CT was shown to have a much higher detection rate for distant metastatic disease in this patient population as compared to the other two imaging ap- proaches—CXR/MRI detected distant disease in 1% of patients, CHCT/MRI in 4%, and FDG-PET/CT in 8%. The most common site for distant metastasis was the lung (72% of cases). In addition, FDG-PET/CT was superior for the detection of synchronous carcinomas, with the most common site being a second H&N malignancy (20% of cases; Fig. 15.2).
15.6.2 Treatment Monitoring/Response
Anatomical response criteria applied to FDG PET/CT are commonly based upon the World Health Organization (WHO) or Response Evaluation in Solid Tumors (RECIST). On the other hand, the European Organization for Research and Treatment of Cancer (EORTC) Response Criteria incorporates FDG uptake and tumor metabolic response based upon SUV calculations and is broken down into categories of complete metabolic response (complete resolution of FDG uptake in the tumor), partial metabolic response (15 to>25% SUV reduction), progressive metabolic disease (increase of tumor SUV of >25%), and stable metabolic disease (increase in SUV of <25% or decrease of< 15%). A more recent approach to response assessment is the Hopkins criteria, which assign a score of 1 through 5 based upon the visual assessment of tumor FDG uptake pattern and intensity. A score of 1, 2, or 3 is considered negative for residual disease and scores of 4 or 5 are considered positive for residual disease.
15.6.3 Radiation Therapy Planning
Methods
There are two methods for incorporating FDG-PET data into radiation treatment planning: (1) PET images are fused with
Fig.15.2 Distant metastatic disease was detected on initial staging FDG-PET/CT in the L4 vertebral body (arrow). The primary tumor was head and neck squamous cell carcinoma.
separately acquired radiotherapy planning CT images or (2) acquired integrated PET/CT images are used directly. When integrated PET/CT images are to be used directly for radiotherapy, images are acquired with the patient in the planned treatment position (frequently with the patient positioned on a flat radiotherapy treatment bed mounted to the PET/CT bed) and allows for more accurate target volume delineation. Automatic delineation of the tumor can be performed by using a specified SUV cutoff value to separate target from background uptake. In order to minimize motion caused by patient respiration, “4D” PET/CT (which incorporates respiratory motion correction) can be utilized, or, when possible, the patient can be instructed to inhale deeply and then hold his/her breath during the acquisition over the thoracic field of view (“breath- hold” technique).
Effect of FDG-PET/CT on Radiation Therapy Planning
For H&N cancer patients, FDG-PET/CT has been shown to modify radiation treatment planning in up to 55% of cases, owing primarily to significant differences in tumor volume delineation between PET/CT and CT alone. In addition, PET/CT outperforms CT in identification of nodal metastases.16
15.7 Prognostic Information
15.7.1 Staging
Adding FDG-PET/CT routinely to a staging protocol for patients with H&N cancer (especially SCC) improves management and prognostic stratification, changing the TNM classification in about 32% of cases. FDG-PET/CT is also more sensitive and accurate than conventional imaging (p <0.001) for this purpose. FDG-PET/CT can also upstage disease—positive findings on FDG-PET/CT are associated with significantly worse progression-free survival (PFS) and overall survival (OS) as compared to conventional imaging (3-year PFS = 56.8 vs. 74.5%, p = 0.043; 3-year OS = 61.3 vs. 85.3%, p = 0.006).17
In untreated patients, there is a linear relationship between SUV and clinical outcomes (i.e., higher SUV = worse clinical outcome). In particular, Torizuka et al demonstrated a poorer outcome in patients with lesion SUVs greater than 7.0. The primary tumor SUV especially is an independent predictor for local control and disease-free survival in H&N cancer patients.18
15.7.2 Posttherapy Evaluation
Pertaining to posttreatment, FDG-PET/CT has high prognostic utility regarding PFS and OS given the high NPV it offers. It is very useful in predicting therapeutic response19 (Fig. 15.3).
15.8 Selected Tumor Types
15.8.1 Squamous Cell Carcinoma
SCC is the most common type of H&N malignancy and is typically very FDG-avid. Although FDG-PET/CT has a high sensitivity (> 95%) for detecting primary SCC in the H&N, its primary role to date has been for the evaluation of possible cervical neck node involvement prior to treatment. There is strong evidence that FDG-PET/CT outperforms anatomic imaging in this arena as well as in the detection of distant metastatic disease. In fact, there is an approximately 13% frequency of change in management when FDG-PET/CT is utilized for distant disease detec- tion.20 Specific to clinically N0 H&N SCC patients, preliminary data from the ACRIN 6885 trial showed FDG-PET/CT to have a high NPV for node negativity in these patients, obviating the need for neck dissection.21
15.8.2 Salivary Gland Malignancies
Most studies thus far on salivary gland malignancies and PET imaging have enrolled only small numbers of patients. However, there is general agreement among these studies that FDG-PET/CT is clinically useful for staging and monitoring of treatment for these types of malignancies.
Degree of Fluorodeoxyglucose Uptake
Higher-grade salivary gland malignancies tend to have higher SUVs as compared to those that are intermediate- or low-grade. Cystic or mucinous tumors (such as mucoepidermoid or adenoid cystic carcinomas) tend to have lower uptake and SUVs. Hadi- prodjo et al looked specifically at parotid gland tumors and demonstrated by ROC analysis that a cutoff maximum SUV greater than 4.2 was 88.9% sensitive and 80.2% specific for malignancy rather than a benign entity. A maximum SUV cutoff of greater than 11.6 was 100% specific for malignant parotid gland tu- mor.22 FDG-PET/CT is particularly useful for higher-grade salivary gland malignancies in its ability to detect possible distant metastatic disease, which is more common in these types of tumors. As such, it has been suggested that PET imaging is more useful in general for higher-grade salivary gland tumors than for lower-grade tumors.23 Pleomorphic adenoma, the most common salivary gland tumor, tends to have high FDG uptake. Mention must also be made of Warthin’s tumors in the parotid glands, as they are also typically very FDG-avid and can mimic malignancy (such as pleomorphic adenoma) with a similar degree of uptake and SUVs.
Fig. 15.3 Only head and neck portions of PET imaging are shown. The baseline pretreatment PET (left image) demonstrates intense uptake in the laryngeal malignancy (green arrow) and left-sided metastatic neck nodes (blue arrow). The posttreatment PET (right image) shows near complete resolution of the hypermetabolic primary laryngeal malignancy and left-sided neck nodes.
15.8.3 Melanoma
Melanoma is also usually very FDG-avid. For nodes measuring over 6 mm in size, FDG-PET/CT detects about 83% of metastatic melanomatous lymph nodes. FDG-PET/CT also outperforms whole-body MRI for detection of cutaneous or subcutaneous metastases. Findings on FDG-PET/CT result in a change in management about 48.6% of the time in patients with melanoma with an overall accuracy of 98.7% as compared to FDG-PET alone (88.8%) or CT alone (69.7%).
15.8.4 Merkel Cell
Merkel cell tumors localize to the H&N in close to 50% of cases. Regarding nodal involvement, CT has a sensitivity of approximately 47%, while FDG-PET/CT has a much greater sensitivity of 83% and can also detect additional nodal meta- stases not seen on CT.24 MRI outperforms both of these modalities when evaluating for central nervous system involvement in patients with Merkel cell tumors. A study by Siva et al included 102 patients from a 15-year period and demonstrated a significant impact of staging FDG-FDG/PET, which changed management in 37% of cases. Upstaging occurred in most of these cases due to localization of distant metastatic disease.25
15.8.5 Low Fluorodeoxyglucose-Avidity Tumors
In general, FDG uptake is low to moderately increased in lower- grade, well-differentiated, or mucinous-type tumors.26 There may also be little FDG uptake in a necrotic node or tumor of any cell type.
15.8.6 Thyroid Carcinoma
Incidental Thyroid Uptake
Incidental thyroid uptake on FDG-PET/CT imaging may be characterized generally as either diffuse or focal. Diffuse uptake is most commonly benign such as that due to thyroiditis, most often Hashimoto’s in the context of hypothyroidism.27 Focal uptake is more concerning, given that focal uptake represents thyroid malignancy in approximately 30% of cases— most commonly papillary thyroid carcinoma.28 When focal uptake is seen, additional evaluation should follow, such as thyroid ultrasound.
Dedifferentiated Thyroid Cancer
FDG-PET/CT has been most useful for detection of post-thyroidectomy residual thyroid cancer that has dedifferentiated after radioiodine ablation, no longer showing uptake on radioiodine scans but resulting in a rising thyroglobulin level. The “flip-flop phenomenon” refers to this loss of radioiodine accumulation in thyroid carcinoma that has become dedifferentiated and accumulates radioactive glucose (FDG) instead of radioiodine. A 2012 meta-analysis revealed a pooled sensitivity of FDG-PET/CT in cases of flip-flop phenomenon of 93 to 95% with PET/CT having a higher diagnostic accuracy than PET alone. Note is also made that the diagnostic accuracy of FDG-PET/CT is higher with elevated thyroglobulin levels.29
Aggressive Thyroid Cancer
FDG-PET/CT is also useful for staging and posttreatment follow-up in those patients with aggressive histological subtypes such as Hurthle cell carcinoma, which typically does not concentrate radioiodine well. The sensitivity and specificity of FDG-PET/CT for Hurthle cell thyroid carcinoma is on the order of 90 + %. Conversely, FDG-PET/CT does not perform as well in patients with recurrent medullary thyroid carcinoma, having a detection rate of only about 59%; this increases to nearly 75% when the calcitonin level is 1,000 ng/mL or more. Detection of anaplastic thyroid carcinoma is somewhat more complicated, as these tumors typically are not very radioiodine-avid and may not be associated with elevated thyroglo- bulin levels. On the other hand, all anaplastic thyroid cancer lesions (primary tumor, nodes, and distant disease) tend to be extremely FDG-avid. Therefore, FDG-PET/CT is used in patients with anaplastic thyroid tumors for staging, treatment monitoring, and follow-up, and has also been shown to have a direct impact on patient management in about 50% of cases30 (Fig. 15.4, Fig. 15.5).
15.8.7 Parathyroid Carcinoma
Brief mention is made of parathyroid carcinoma and FDG-PET. In general, FDG-PET/CT can be considered a complementary technique to conventional imaging for parathyroid carcinoma. FDG-PET/CT has been shown to be a sensitive modality for parathyroid carcinoma initial staging, tumor recurrence detection, and posttreatment evaluation, although small lesion size may limit evaluation in some cases.31
15.9 Potential FDG-PET/CT Imaging Pitfalls in the Head and Neck Region
Recognition of normal benign versus pathologic patterns of increased uptake in the H&N region is necessary when interpreting PET scans.32 Consequently, it is of utmost importance to have an experienced reader perform this task.
Fig. 15.4 Flip-flop phenomenon. Radioiodine scan on the left (whole-body posterior and anterior images) demonstrates only physiologic uptake. FDG-PET/CT image on the right demonstrates FDG-avid dedifferentiated malignancy in the left neck (arrow).
15.9.1 Physiologic Fluorodeoxyglucose Uptake
Brown Fat
One of the most common causes of false-positive uptake in the neck is physiologic brown fat activation, which can potentially obscure abnormal FDG uptake in neck nodes. At some imaging centers, valium is administered or warming techniques are employed (such as warmed towels placed around the neck) prior to FDG administration to prevent potential brown fat uptake.
Muscular Uptake
Another common confounding source of physiologic activity in the H&N is muscular uptake, which can also obscure abnormal findings in the adjacent small, complicated H&N structures. To minimize muscle uptake, the patient is asked to not chew (including gum and mints) or talk prior to FDG administration and during the uptake period.
Other Causes
Physiologic uptake can be seen in the vocal cords and arytenoid cartilages due to phonation. Physiologic uptake can also be seen in the salivary glands and diffusely in the thyroid gland.
15.9.2 Posttreatment Changes
Knowledge of any prior treatment and date of this treatment is vital information prior to imaging the patient.
Paralyzed or Injected Vocal Cord
Iatrogenic nerve injury can result in seemingly increased focal uptake in the contralateral, nonparalyzed vocal cord. In contrast, injections, including Teflon, into a paralyzed vocal cord can cause increased focal inflammatory uptake in the area of injection (i.e., within the paralyzed vocal cord itself; Fig. 15.6).33
Radiation and Surgery
Radiation or surgery can cause asymmetrically increased uptake to the treated side (usually in a diffuse pattern). In general, it is recommended that FDG-PET/CT imaging be performed 10 to 12 weeks after these treatments in order to minimize associated inflammatory uptake when evaluating for any residual disease.32
Technical and Artifactual Limitations
The spatial resolution of PET/CT has been previously addressed. Lesions below 4 mm may not be reliably detected on PET. In addition, excessive patient motion or misaligned PET and CT images may obscure findings. Finally, artifacts related to dental hardware can significantly limit evaluation of the neck.
Lesions with Low FDG-Avidity
As previously mentioned, mucinous or cystic lesions may not demonstrate significant FDG uptake. Necrotic nodes/lesions or neuroendocrine and spindle cell tumors may yield false-negative FDG uptake, also.
15.9.3 FDG-PET/MR Imaging
There is now a small volume of literature examining FDG-PET/ MR for H&N malignancies. However, much more research needs to be conducted in this area to determine the clinical impact FDG-PET/MR may or may not have for these tumors. Current literature does state, however, that PET/MR does not offer incremental value for initial staging as compared to MR alone. PET/MR is, however, more sensitive (with similar accuracy) than FDG-PET/CT when evaluating for recurrent tumor. Platzek et al performed a prospective study in a small sample of patients (n = 38), demonstrating that FDG-PET/MR did not significantly improve diagnostic accuracy for nodal metastases in the neck as compared to MR or PET alone.34
15.10 Conclusion
Obtaining a baseline FDG-PET/CT imaging study prior to therapy is not only useful regarding prognostication, but also aids in determining whether there has been a positive treatment response and/or whether there should be a change in management (via no response, upstaging, or downstaging). FDG-PET/CT
imaging has proven to be most valuable for patients with H&N cancer in (1) detecting distant disease and (2) providing confidence regarding the absence of residual malignancy given its high NPV, frequently changing management in this patient population. Finally, it is important that PET/CT images be interpreted by an experienced reader to avoid misinterpretation of findings in the H&N region given the various pitfalls and intricate anatomy of the region.
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