Dr. Rajendran is an Assistant Professor of Nuclear Medicine in the Department of Radiology at the University of Washington, Seattle, WA.

Head and neck cancer is a major public health problem, affecting nearly 50,000 new patients a year in the United States (4% of all new cancers). Ironically, even though it is largely preventable because of close association with common carcinogens, such as tobacco and alcohol, its incidence remains unchanged, is disproportionately higher in lower socioeconomic groups, and is prevalent among military veterans (8% of all new cancers). The majority of these cancers are squamous cell carcinomas, although other tumor types, particularly those arising from the salivary glands, cause greater challenges in management. In spite of several advances in diagnosis, a vast majority of head and neck cancers are still diagnosed in advanced stages and show poor response to treatment, with recurrences in half of patients. The clinical course of these neoplasms is difficult to predict based on current clinicopathological prognostic criteria.

Radiotherapy is an important primary treatment modality for the majority of patients with head and neck cancer. Use of concurrent chemotherapy has further improved treatment results but is associated with higher normal tissue toxicity. While neck irradiation effectively controls microscopic disease, it results in a higher morbidity when the radiation dose is intensified to a larger treatment volume using conventional techniques. Currently, treatment decisions are based on data extrapolated from retrospective institutional series and cannot be applied reliably to treatment planning for individual patients, limiting the ability to tailor the intensity and apply targeted therapy for an individual patient without increasing toxicity. Close proximity of important normal tissues/organs, such as salivary glands, requires more stringent radiation dosimetry. Biological insights on these cancers obtained by positron emission tomography (PET) imaging will permit selection and targeting of more efficacious and less morbid treatments.

PET principles

F-18 fluorodeoxyglucose (FDG) is identical to glucose and is taken up and phosphorylated in cells, but cannot proceed past hexose-6-phosphate chemically and becomes trapped inside the cell. Uptake and utilization of FDG reflects the rate of glycolysis and, thus, the rate of glucose metabolism in tumors. While there is no single explanation for the increased glycolysis seen in neoplastic tissues, cancer cells in general have increased aerobic glycolysis (Warburg effect). This, combined with a higher concentration of neoplastic cells in a tumor form the basis for the successful use of FDG in tumor imaging. Diagnosis of malignancy by PET depends on higher FDG uptake in tumor tissue than that of the background. For that reason, it is important to make sure that the blood glucose levels are not high (¾ 150 mg) in patients with diabetes mellitus. The use of insulin to lower the blood sugar prior to FDG scan is generally not advisable, as it would pump the FDG into the muscles, resulting in interpretive difficulties.

Uptake of FDG has been expressed in several ways--the most common one being the standardized uptake value (SUV). It is the ratio of FDG concentration in a region of interest to its concentration in the whole body. Several factors affect the calculated SUV, including body surface area, partial volume effect, and time after tracer injection. Commercial availability of FDG radiopharmaceutical and dedicated PET scanners have resulted in the popularity, and widespread clinical use of PET imaging. Recent Medicare approval of the use of PET in head and neck cancer has boosted its clinical application.

The popularity of PET has increased significantly in recent times with predicted future annual revenues approaching nearly a billion dollars by 2007. Bold commercial ventures in marketing PET tracers, such as FDG, from a nationwide network of radiopharmacies seem to have been successful, obviating the need for on-site cyclotrons in PET facilities.

Greater resolution of modern PET scanners allows detection of tumors as small as 4.5 to 8 mm. ¹ However, because of the influence of partial volume effects, caution should be used in interpreting smaller lesions, particularly when semiquantitative methods, such as SUV, are used to establish malignancy. Several authors have attempted making adjustments to SUV to improve its accuracy. ^2-4

Staging

Tumors located in certain anatomical sites (eg, piriform sinus, epiglottis, or Waldeyer's ring) are often inaccessible to clinical examination, and anatomic imaging, such as magnetic resonance imaging (MRI) and computed tomography (CT), may not be helpful in their evaluation. However, FDG-PET has proven very successful in these locations.

Although up to 11% of patients with oral carcinoma are reported to have distant metastases at presentation, nearly 30% will ultimately fail in distant sites. ⁵ In view of this, some authors have recommended whole-body scan for all patients imaged. ⁶ In such cases, FDG-PET compares favorably with CT, MRI, and ultrasound (US); PET: sensitivity 70%, specificity 82%, accuracy 75%; US: 84%, 68%, 76%; CT: 66%, 74%, 70%; MRI: 64%, 69%, 66%. ^7,8 Including the chest and at least the upper abdomen in the imaging fields will help identify distant metastases and improve staging. This approach might also increase the chances for detecting synchronous primary sites in the aerodigestive tract that are exposed to the same carcinogens associated with the cancer originally diagnosed. In spite of high sensitivity, FDG-PET has a limited role in establishing the diagnosis of primary tumors.

Patients with occult nodal disease have the worst prognosis. Positron emission tomography will help assess nodes that are equivocal on CT or MRI. Evaluation of patients with unknown primary tumors can be clinically challenging, and both clinical and standard radiological imaging show poor sensitivity in this situation. FDG-PET has been found to be useful in diagnosing nearly one-third of these cases. ^9-11

FDG-PET gives better results in detecting cervical lymph nodes than do conventional imaging techniques that essentially have a size criteria of >1 cm. FDG-PET has a sensitivity of 93% and nodes as small as 4 mm have been detected; it has a high negative predictive value (98%) for node-negative (N0) disease. ¹² Thus, negative FDG uptake in the neck has a high reliability for excluding lymph-node metastases and helps limit the extent of treatment--surgery and or radiotherapy.

Lack of anatomic details might cause problems in localizing metabolically active tissues. This can be circumvented by fusion of PET images with CT or MRI. Popularity and usage of combined PET/CT systems is likely to increase during the next decade. ^5,13,14

Pitfalls

Nonspecific muscle uptake in the neck could mask uptake in smaller nodes, as can intense uptake in the primary tumor. Muscle uptake can be minimized by using low doses of a muscle relaxant such as lorazepam. FDG-PET also shows nonspecific uptake in sites of inflammation or infection and in certain normal organs or sites that might pose difficulties in interpretation. Palatine tonsils, tongue, and laryngeal muscles show uptake normally, which is considered physiologic unless correlative abnormality is identified on CT or MRI. ^15,16 Inflammatory reactions induced by radiation therapy dictate that follow-up scans are sufficiently delayed in order for the uptake to normalize, in some cases up to 4 months. While it is not a significant problem for patients receiving only chemotherapy, superimposed infections associated with chemotherapy might still pose challenges for interpretation. Uptake can be seen in the normal thyroid gland and is frequently seen in thyroiditis, hyperthyroidism, and, on occasions, in malignant nodules. The SUV is also frequently used to establish malignancy (see below).

Recurrent or persistent neck disease after chemotherapy/radiation therapy

Recurrent cancer can be difficult to diagnose using conventional imaging studies, mainly because of treatment-induced changes in normal tissue. Postradiotherapy reactive fibrosis produces problems in interpreting CT images, especially in differentiating it from active residual disease. ¹⁷ FDG-PET has been found to be superior in identifying recurrence with a high degree of accuracy (88%) when compared with standard imaging--CT, MRI, or both (66%). ^18-21 Serial FDG-PET scans used to follow patients undergoing radiotherapy have indicated a mixed use for SUV. Four-month, rather than 1-month post-radiation scans are found to be a more accurate predictor of the presence of cancer. The SUV has been used by many authors as a means to differentiate these two conditions. A value above the threshold value range of 2 to 3.5 is usually used to diagnose malignant disease. However, there is a wide variation in the cut-off values used by various studies. In general, tumors with higher pathologic grade have a higher SUV. ^3,22-24 Dual-time point imaging has been recommended as a means to differentiate neoplastic conditions from inflammation. ²⁵

Evaluation of treatment response

Both absolute pretreatment SUV and its change on serial FDG scans have been investigated as a prognostic indicator and as a measure of response in patients undergoing radiation therapy or chemotherapy. The SUV can characterize tumors with aggressive biological and clinical behavior prior to treatment and the information used to institute more aggressive treatment strategies. Tumors with a high initial SUV tend to show greater local failure after treatment. ²⁶ It can also be used to decide the intensity of treatment. ²⁷ Metabolic activity declines in tumors that respond to treatment.

PET-directed treatment

High sensitivity and negative predictive value of FDG-PET can be used to select the appropriate treatment or define radiation treatment fields as well as dose intensity of both radiotherapy and chemotherapy. A negative PET finding in the neck has a high negative predictive value for nodal disease and can be used in reducing the amount of normal tissue included in radiation treatment volume or in modifying the extent of surgical neck dissection. Image fusion and use of intensity-modulated radiotherapy (IMRT) promise the ability for dose modulation with lower toxicity.

Other PET tracers for use in head and neck cancer

Fluorodeoxyglucose is the most commonly used tracer in the evaluation of head and neck cancer. However, a number of other PET radiopharmaceuticals are being investigated and appear promising for answering specific questions and in directing treatment. These include cell proliferation tracers [C-11]-thymidine and [F-18]-fluorothymidine; amino acids, such as [C-11]-methionine; membrane synthesis tracers [C-11]-acetate; and hypoxia tracers, such as [F-18]-fluoromisonidazole (FMISO). While these agents are not yet in routine clinical use, they hold the promise for successful applications in specific clinical situations.

Conclusion

The role of PET in evaluating head and neck cancer is evolving rapidly. Its sensitivity and accuracy in diagnosing nodal disease, evaluation of unknown primary disease, and in the follow-up of posttherapy recurrence are primarily responsible for evolution. It is a valuable tool in following response to treatment (radiotherapy and chemotherapy) and has the ability to direct more intensified and less morbid radiotherapy to metabolically active foci. Lack of anatomic details in PET can be circumvented by either image fusion with CT or MRI or by using combined PET/CT systems, which are gaining greater popularity among radiologists. AR