The role of FDG PET in the clinical management of head and neck cancer
Introduction
Positron emission tomography (PET) by means of F18-fluorodeoxyglucose (FDG) allows the visualization of metabolic tissue activity. PET imaging relies on the use of radioisotopes which decay with emission of positively charged particles. These positrons travel short distances in tissues before combining with a negatively charged electron. When the masses annihilate, two photons (gamma-rays) are produced, which are emitted at approximately 180° from each other. The simultaneous detection of two such photons by opposed detectors is then used to reconstruct a three-dimensional image. Depending on which tracer is used, different aspects of regional tissue metabolism and organ functions can be measured. Use of FDG in in-vivo cancer imaging is based on the observation of enhanced glycolysis in tumor cells. A high rate of degradation of glucose to lactic acid in cancer cells was first described by Warburg et al.1, 2. Uptake of glucose and FDG into malignant cells is facilitated by an increased expression of the glucose transporter (GLUT) molecules at the tumor cell surface. Seven glucose transporters are currently known (GLUT1–7). It has been found, that overexpression of GLUT1 and GLUT3 has been observed in several tumors3, 4, 5. Just like glucose, FDG uptake in cells is followed by phosphorylation to FDG-6-phosphatase by hexokinase, the first enzyme of glycolysis. In contrast with glucose, however, glucose-6-phosphate isomerase does not react with FDG-6-phosphate, so further metabolism is not possible. On the other hand, degradation of FDG-6-phosphate is very slow resulting in an accumulation of FDG. In summary, the FDG concentration is a representative of the glycolytic activity of exogenous glucose6, 7. It has to be realized that uptake of FDG in malignant tumors is not only dependent of an increased expression of GLUT, but also depends on physiologic factors, such as tissue oxygenation, blood flow and peritumoral reactions8, 9. Consequently, FDG PET therefore may be considered as a highly sensitive technique, but with a relative low specificity. Therefore, a careful selection of patient groups must be performed to overcome this problem.
In vivo experiments have demonstrated the potential use of FDG PET in squamous cell head and neck tumors and the detection of tumor involvement in lymph nodes10, 11, 12. In these studies, a clear correlation was found between the proportions of the cells in the S+G2/M phases and the FDG uptake. The results suggested that enhanced glucose metabolism is associated with the proliferative activity of the head and neck tumors and justified further studies to assess the value of FDG PET in clinical practice. Since its introduction in this area, several papers have appeared on the use of this imaging modality. It is, therefore, appropriate to review the advantages and limitations of FDG as a tumor-seeking agent and its present and potential role in the clinical management of head and neck cancer.
Initial diagnosis of head and neck carcinomas is based on clinical examination. This is usually quite successful as most tumors are reasonably accessible to observation and palpation by the surgeon. To assess bone involvement and extension into adjacent tissue, CT and/or MRI are used to assess tumor stage. By CT, only 77% and by MRI, 81% of the tumors are correctly staged[13]. In this study, there were mainly advanced tumor stages. For correct identification of small tumors, i.e. T1 tumors, the sensitivity of both techniques decreases. Primary tumors that do not distort tissue planes or invade contiguous structures may not be detected. In this respect, FDG PET may offer some advantages over anatomical imaging. It can detect superficial or submucosal primary tumor infiltration without adjacent tissue deformation.
The value of PET in assessing prognosis at initial presentation by using FDG uptake in primary tumors has still to be established. It was found by Minn et al.[14]that high uptake of FDG in untreated head and neck cancer was associated with advanced disease and may portend poor survival. In small in vivo series10, 11, 12, however, accumulation of FDG poorly correlated with the histologic grade which has been confirmed in vitro by McGuirt et al.[15]. Despite the fact that quantification is often used as a measure to characterize and to grade lesions, it was demonstrated by Keyes[16]and Laubenbacher et al.[17]that this is of little or no additional value in clinical practice. Moreover, it has been described that the commonly used quantitative parameters widely vary with the time of measurement[18], with the body weight of a patient[19]and with metabolic alterations[20]. Consequently, the parameters should be interpreted with more caution. Up to now, evaluation of the accuracy of FDG PET in the diagnosis and the grading of the primary tumor has been performed to validate its potential use than to support its clinical use. It is not to be expected that PET is cost-effective in this setting.
Where PET has an important role is in the identification of occult primary tumors. Patients with an unknown primary cancer represent 5–10% of all cancer patients[21]. The location of the involved nodes may indicate the location of the primary tumor. When the lymph nodes of the upper and middle cervical level are involved, a primary tumor in the head and neck region is more likely. In 20–40% of patients presenting with metastatic disease in cervical lymph nodes, a primary site can be identified during the diagnostic phase, which allows the delivery of a higher treatment dose to the primary tumor or even allows complete surgical excision of the tumor. These potential alterations in management can lead to a reduction in treatment morbidity and possibly improvement in survival. Mukherji et al.[22]found that among 11 histologically proven occult primary tumors, FDG PET depicted nine tumors compared to four lesions depicted by CT scanning. Braams et al.[23]studied 13 patients with various histologic types of cervical metastases of unknown primary tumors. In this study, PET identified in 30% of these patients the primary tumor. The other patients remained free from primary manifestation after a follow-up period of 18–30 months following standard treatment. FDG PET can reveal useful information that results in more appropriate treatment and it can be of value in guiding endoscopic biopsies for histologic diagnosis.
An accurate evaluation of the cervical lymph nodes plays an important role in the management and prognosis of patients with squamous cell carcinoma of the head and neck24, 13. The incidence of metastases depends mainly on the site and size of the primary tumor, varying from as low as 1% for very small glottic carcinomas up to 80% for nasopharyngeal tumors. The incidence of cervical metastases in oral cancer is approximately 50%[25].
The survival of patients with head and neck cancer depends mainly on the presence or absence of metastases. The average 5-year survival rate is about 50% in the absence of metastases compared to only 30% if malignant adenopathy is present26, 27.
Currently, despite the progress made in imaging techniques, the clinical evaluation of the head and neck still plays an important role in the preoperative assessment of cervical lymph nodes. However, the overall error rate in this ranges from 20 to 28%28, 29. Therefore, the treatment of patients with clinical stage N0 neck is controversial. In the elective neck dissections, up to 77% prove to be tumor-free at pathologic examination of the specimen. On the other hand, up to 32% of the patients with clinical stage N0 who are not treated develop lymph node metastases30, 31.
Computed tomography (CT) and magnetic resonance imaging (MRI) have advanced the ability to detect cervical metastases. In patients with a N0 neck by palpation, it was found that both CT and MRI increased the identification of metastasis from 60–75 to 85–94%32, 33, 34, 35, 36. However, the overall error rate of assessing the presence or absence of cervical lymph node metastases by CT is in the range of 7.5–28% and for MRI 16%32, 36. Ultrasound guided fine needle aspiration cytology (FNAC) may give cytologic evidence of tumor in a large percentage of metastatic nodes. By using this technique, the specificity has been described to improve[37], but this inevitably resulted in a decreased sensitivity for metastatic disease. Whether or not pathologic nodes can be identified at CT, MRI or US-guided FNAC depends on the experience and expertise of the radiologist. In addition, volume averaging effects, patient’s compliance and selected techniques may influence the interpretation of the CT or MRI measurements. Finally, the images may be negatively influenced by artefacts caused by dental prosthesis and fillings. Therefore, it would be helpful to have an alternative imaging modality that accurately identifies cervical lymph node metastases. In this respect, several studies have appeared in the literature describing the role of FDG PET in the preoperative lymph node assessment. In Table 1 an overview is given of the sensitivity and specificity found in the literature. In most of these reports, PET was found to have a similar sensitivity to CT scanning, whereas both techniques were found to be superior to the clinical assessment. Moreover, in histopathologic studies, Eichhorn et al.[47]showed that more than 40% of all lymph node metastases are localized in lymph nodes smaller than 1.0 cm, which limits the use of radiologic criteria. The smallest lymph node detected by FDG PET measures about 4 mm which may result in an increased justification of performing elective neck dissections in these patients. On the other hand, due to its high specificity lymph node dissection may be omitted in patients with PET-negative neck sides. Consequently, morbidity will decrease if unnecessarily performed dissections can be prevented. From these studies it is concluded that FDG PET can be an improvement in the evaluation of the neck in head and neck cancer. Since PET currently does not provide the anatomical information that is so vitally important to surgeons, it is not to be expected that this technique will exclude CT scanning in the evaluation of neck nodal disease. However, due to the improvements in PET’s resolution and experience in its use this current perception may change.
FDG PET has been used to monitor tumor response to various therapy regimens. Since some of the biochemical pathways involved in the repair of damage are known to be energy, i.e. glycolysis and respiration, dependent, FDG uptake can be enhanced following radiotherapy and chemotherapy. It is known from PET studies in patients with colorectal cancer that the uptake of FDG may be elevated up to several months following radiotherapy[48]. Therefore, it may be difficult to distinguish treatment response from residual tumor at early stage. Chaiken et al.[49]found that elevated FDG activity after radiation therapy was indicative for persistent disease in eight of nine patients, while a significant decrease in activity was observed in patients achieving local control. However, it has been decribed by Greven et al.[50]that clearly negative results on 1-month scans were not accurate indicators of absence of disease. PET studies performed at 4 months after completion of treatment may more accurately reflect disease status. Minn et al.[51]described that the administered dose of radiotherapy correlated with the decrement in FDG activity in patients achieving complete or partial response, but not in those showing no change or progressive disease. These results were confirmed by Rege et al.[52]in 11 patients with biopsy proven head and neck cancer. They found a dramatic decrease in FDG uptake following treatment, whereas uptake in normal structures did not change.
Comparable results have been described in the early assessments of chemotherapeutic effects. Lowe et al.[53]found a mean reduction of 82% in FDG uptake in those achieving complete response compared to a decrease of 34% uptake in those demonstrating recurrent disease. Haberkorn et al.[54]described a comparable response in FDG metabolism to chemotherapy in lymph nodes and tumors. In addition, they found that lesions with a higher FDG uptake prior to therapy were associated with a higher decrease in volume than lesions with low FDG uptake. From these studies it may be concluded that by using FDG PET early identification of non-responders is possible which may help to improve survival if alternative therapy could be started at an earlier stage in the course of these patients.
PET is clearly superior to clinical examination and to CT or MRI in the postirradiation patient who exhibits a spectrum of marked soft tissue changes ranging from persistent or excessive laryngeal edema, through ulcerated or granular endolaryngeal soft tissue changes, to perilaryngeal neck erythema, edema and tenderness. Biopsy, although usually required for diagnosis, is frequently equivocal. In addition, the surgeon is often reluctant to obtain a multiple or deep biopsy specimen in such cases for fear of initiating or aggravating radionecrosis. The accuracy of FDG PET in differentiating tumor from necrosis is in the range of 82 to 88%, as compared to 45% of CT or MRI50, 55, 56. Therefore, PET is a valuable diagnostic tool in such cases. But, as stated before, analysis of postirradiation PET studies indicated that FDG uptake up to 4 months after irradiation may not be reliable to differentiate persistent or recurrent tumor from necrosis. Differentiation is more reliable four or more months postirradiation.
One of the most striking limitations is that FDG is not a very tumor-specific substance. False positive results may occur due to tracer accumulation in benign lesions, such as reactive lymph nodes and biopsy sites[57]. Furthermore, interpretation of these PET images requires experience with normal variations in scans that could cover or mimic disease. Moderate uptake is usually noted around the eyes, in the mucosal and lymph node tissue of the mouth, nasopharynx and pharynx. In addition, muscular activity depends on the muscle tension58, 59, so complete rest is indicated to avoid muscle artefacts.
An additional factor that may influence the uptake of FDG in tumor cells is patient’s glucose level. FDG is transported like glucose into the cell, so increased glucose levels, such as in diabetic patients, will result in decreased FDG uptake[60]. Consequently, the patient should be fasting for a minimum of 4–6 h before injection time, whereas the blood glucose levels in diabetic patients should be properly regulated.
Finally, owing to the high cost, dedicated PET scanners are of limited availability. Therefore, alternative methods of imaging the 511-KeV photons of positron emitters have been sought. This has led to a renewed interest in the use of the more widely available Anger gamma camera. Two alternative forms can be considered: either the detection of the photons as single events using specially designed ultra high-energy collimators or using coincidence detection without physical collimation. The low cost and the possibility to use these cameras for the detection of low-energy photons, such as used in bone scanning or cardiac imaging, favor the use of these techniques. However, using a collimated camera the spatial resolution and sensitivity are severely degraded in comparison with a dedicated PET scanner61, 62. Furthermore, dynamic tomographic imaging is impossible and only long-lived radionuclides, such as FDG, will be accessible to this technique. By using the coincidence technique, the sensitivity slightly improves. The spatial resolution, however, significantly increases to a value more or less comparable to those measured with dedicated PET scannners[63]. The limitations in the performance characteristics of these systems has implications for their potential role, although applications in cardiology and oncology are being pursued.
Section snippets
Conclusions
FDG PET is a promising diagnostic tool in the clinical management of patients with head and neck cancer. In patients with cervical metastases of an unknown primary tumor, PET can reveal useful information that results in a more appropriate treatment. Compared with anatomic methods, such as CT scanning or MRI, metabolic imaging using FDG has an improved diagnostic accuracy for recurrent head and neck cancer. In both clinical situations, positron emission tomography may become the first choice in
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