Volume 35, Issue 4 , Pages 332-336, April 2006
PET/CT in the evaluation of patients with squamous cell cancer of the head and neck
Article Outline
Abstract
The purpose of this study was to compare the findings of positron emission tomography (PET) with fused PET and computed tomography (CT) in patients with suspected locoregional and distant head and neck cancer and to evaluate the impact of those findings on clinical management.
Studies of 25 patients were retrospectively evaluated. PET findings were classified as malignant, benign or equivocal. PET/CT findings were then similarly classified and the PET-only results were amended accordingly. Comparison of findings was done on lesion and patient levels. A total of 45 foci of increased 18F-fluorodeoxyglucose (FDG) uptake were noted in 18 patients. PET/CT imaging defined anatomic localization of 41/45 lesions and clarified 6/10 equivocal PET findings. Additional information was provided by PET/CT regarding 9/45 (20%) of the lesions. PET/CT significantly affected patient management in 3/25 patients (12%) by limiting the extent of disease in one and excluding viable disease in two others. The accuracy of PET/CT was 88%, the sensitivity 100% and the specificity was 77%. The negative predictive value was 100% in this combined group of patients with locoregional and distant head and neck cancer.
PET/CT is highly contributory for initial staging and in the evaluation of patients with suspected recurrent SCC of the head and neck, in whom anatomic imaging is inconclusive due to the locoregional distortions rendered by surgery and radiotherapy.
Key words: PET/CT, head and neck, squamous cell carcinoma
Squamous cell carcinoma (SCC) is the most common malignant tumour of the head and neck (HNC) and represents 93% of all malignant tumours of the oral cavity. Totalling 3–4% of all carcinomas, it is the 11th most frequent cause of cancer deaths, with a tendency to dominate the 50- to 60-year-old male population, particularly heavy smokers and drinkers20. Due to delayed diagnosis, prognosis of oral cavity disease is generally poor with an estimated recurrence rate of 30%. The therapy of choice for small HNC tumours (T1, T2, N0, M0) includes surgery, external beam radiation therapy (RT) or a combination of radio- and chemotherapy. Larger tumours (T3, T4, N1, M1) are treated with a combination of surgery and radio-chemotherapy. The initial surgical treatment entails excision and complex reconstructive surgery involving distant soft and bony tissue transfer, which significantly distorts anatomy and renders postoperative imaging challenging. Additional RT further distorts local structures. Consequently, when recurrent HNC is suspected, anatomic imaging is often inconclusive. In fact, since normal tissue planes are substantially altered, CT and MR imagings have relatively poor specificity in the assessment of residual or recurrent disease following radical HNC therapy2, 11, 17.
Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) allows functional metabolic imaging of malignant tissue. The well-documented mechanism of FDG uptake is based on increased glucose metabolism and increased expression of glucose transporters in malignant cells as compared to normal tissue6. The changes in tumour metabolism precede morphological changes and, as opposed to CT and MR, which rely on criteria such as nodal size and contrast-enhancement patterns, the information obtained is practically independent of tumour location and size. Limitations of lesion size are essentially only technical, due to system's resolution. Thus, the metabolic rate as determined from PET can be used to define the presence and extent of active disease.
PET scanning has been reported to be contributory in the initial staging as well as in the evaluation of recurrent SCC in the head and neck region. A tabulated summary of the early FDG-PET literature compiled in 2000 by Gambhir et al.8 presented an estimated 33% change in patient management related to the use of the PET scan when it was performed for diagnosis and staging. The same report states an estimated 33% change in management resulting from PET imaging when recurrent disease is suspected. Recent works have reported the successful use of FDG-PET for the assessment of tumour aggressiveness5, staging of nodal neck disease1, 10, evaluation of treatment response6 and the detection of recurrent disease13, 14, 22, 23.
While the sensitivity of dedicated PET for HNC lesions has consistently been reported to be in the range of 85–100%4, 7, 16, the lack of anatomic detail affects image interpretation and remains a major limitation of PET.
The recently introduced combined PET/CT technique helps to overcome this drawback by providing fused images of functional PET and anatomic CT studies. The almost synchronous image acquisition and exact co-registration of anatomic and metabolic data improves the anatomic localization of PET abnormalities and reduces the number of equivocal PET interpretations3, 15.
In a report by Rodel et al.18 the fusion of PET and native CT imaging significantly improved sensitivity, specificity and accuracy of both PET and CT alone and allowed accurate diagnosis of 93% of lesions in 90% of patients with head and neck oncology. In another recently published report by Schoder et al.19 describing the use of PET/CT in patients with head and neck cancer, the combined technology improved the diagnostic accuracy and reduced the number of equivocal PET findings leading to a change in patient care in 18% of cases.
The results of PET/CT in patients with newly diagnosed or suspected recurrent HNC were retrospectively evaluated with the aims of assessing the accuracy of the technique for detecting locoregional and distant disease and evaluating the therapeutic impact of PET/CT findings on patient care at our centre.
Patients and methods
Patient population
This retrospective study population consisted of 25 consecutive referrals of patients with SCC of the head and neck (20M, 5F, aged 17–84 years, mean 64). Twenty-three patients had known oral or oropharyngeal SCC, and two patients were referred after presenting with neck lymph node involvement from an unknown primary SCC, assumed to be of head and neck origin.
Clinical indications for PET/CT included staging of newly diagnosed head and neck cancer (n
=6), detection of an unknown primary tumour (n=2), evaluation of residual disease after radiation therapy (n=2) and clinically suspected recurrent disease (n=15). All the 15 patients suspected of having recurrent disease had previously undergone surgery (excision and reconstruction) for HNC; and 9/15 had also received radiotherapy (RT). The two patients evaluated for residual disease had local excisions and radiotherapy. In all the 11 patients who received RT, it was completed at least 4–7 months prior to scanning. All 15 patients with suspected recurrent disease presented at follow-up with suggestive clinical findings (masses, lymphadenopathy, cough) and radiographic findings, which were inconclusive due to the extensively distorting surgery and radiotherapy. Table 1 summarizes patients’ clinical data including indications for PET/CT.
Table 1. Patient data at presentation
| Patient characteristic | Value |
|---|---|
| Age mean | 64 |
| Age range | 17–84 |
| Males | 20 |
| Females | 5 |
| Location of primary tumour | |
| Oral cavity (tongue, lip, floor) | 8 |
| Oropharynx | 2 |
| Nasopharynx | 6 |
| Hypopharynx | 2 |
| Primary larynx | 5 |
| Indication for scan | |
| Staging of new disease | 6 |
| Detection of unknown primary | 2 |
| Evaluation of residual disease after treatment | 2 |
| Suspected recurrences | 15 |
PET/CT imaging protocol
All patients were imaged with a Gemini PET/CT Imaging System (Philips Co., USA) which provides three-dimensional acquisition, processing and display of CT, PET and PET/CT images with 4.5mm PET spatial resolution and a dual slice MX800 EXP CT scanner. Whole body PET/CT imaging was performed in fasting patients (4–6h) following i.v. administration of 370MBq (10mCi) of 18F-FDG. Neither oral nor intravenous contrasts were administered. After a 60-min uptake period, during which patients were instructed to rest silently, images were acquired. First, a CT surview (30mA, 120kVp, FOV 500mm length of scan 1.0m (1.5m for whole body scan) with a speed of 100mm/s and a spatial resolution of 1mm) was performed from the level of the middle of the skull to the level of the pelvic floor. This was followed by a spiral CT (50mAs per slice, 120kVp, with spatial resolution of 6.5mm, length of scan according to result of surview, with a bed speed of approximately 20mm/s, rotation time of 0.75s, a pitch of 1.5 and FOV of 600mm). Finally, the acquisition of PET emission images was performed (2–3min per bed position of 8.4cm). The total acquisition time, accumulating between 100 and 150 million useful events, varied between 25 and 35min per patient. The CT data were used for attenuation correction of PET emission images. Reconstruction of attenuation-corrected data was executed concurrently. Nonattenuated data was reconstructed after scan acquisition was completed.
Image interpretation
Both attenuation-corrected and nonattenuation-corrected scans were co-registered with the CT for interpretation using Syntegra (Version 2.0j, Philips) software. A workstation (Sunblade 1000, Sun Microsystems Computer Company, Palo Alto, CA) was used for image display and analysis. All studies were interpreted jointly and in consensus by physicians from the two specialties (Nuclear Medicine and Diagnostic Radiology).
Initially, the attenuation-corrected PET images were analyzed visually and lesions with abnormal FDG uptake were noted. The lesions were graded as benign, equivocal or malignant based on their location and the degree of uptake. Later, the CT and fused PET/CT images were used to amend the initial findings (i.e. grading and localization of lesions). The low-dose, nonenhanced CT-only data were not evaluated as a separate entity.
Evaluation of accuracy and statistical analysis
PET/CT scans were validated by comparison with contrast-enhanced conventional anatomic imaging (CT and MR), histopathological findings, and at least 6 months of clinical follow-up. PET/CT findings were interpreted on the patient level as true-positive (presence of cancer), true-negative (absence of cancer), false-positive (increased FDG uptake unrelated to cancer) or false-negative (missed diagnosis of proven cancer).
Results
Results are summarized in Table 2. Overall, PET and PET/CT were equally contributory in excluding active disease. Seven scans indicated normal physiological 18F-FDG uptake and excluded the presence of viable tumour. The negative PET scans correctly excluded active disease in lesions located by PET/CT are as follows: one suspected base of skull lesion, three clinically suspicious lymph nodes, one local laryngeal and one local nasopharyngeal fullness. The fact that i.v. contrast was not administered was of no consequence as no PET findings were disclosed, and therefore, no elucidation of unclear findings was required.
Table 2. Summary of PET vs. PET/CT results for 45 lesions
| Malignant | Equivocal | Benign | |
|---|---|---|---|
| PET (n=45) (32 LR, 13 D) | 32 (20 LR, 12 D) | 10 (9 LR, 1 D) | 3 (3 LR) |
| PET/CT (32 LR, 13 D) | 36 (24 LR, 12 D) | 4 (4 LR) | 5 (4 LR, 1 D) |
Overall 45 hypermetabolic foci were detected by PET in 18/25 patients. Positive PET findings were measured ranging in size from 0.6 to 1.8cm and were comparable to those demonstrated on concurrent contrast-enhanced anatomic imaging (when available). Findings were mostly in head and neck (32/45) with 13/45 in thorax or abdomen. Distant lesions included five skeletal findings, four hilar, one axillary, one lung and one adrenal lesion. Lesions were classified as malignant (n=32), benign (n=3) or equivocal (n=10) on PET and then reclassified following interpretation of fused PET/CT images.
Of the 32 lesions thought to be malignant on PET, one was a hilar granuloma, i.e. a benign lesion. Of the three thought to be benign PET findings, two localized to lymph nodes and were reclassified as malignant lesions. The 10 equivocal PET findings were reclassified as follows: three malignant lymph nodes, three benign findings (granulation in tracheostomy, pulmonary inflammation and thyroid) and four remained equivocal findings in neck muscle, salivary gland, cervical vertebra and tonsil. The uptake in these regions was asymmetrical, and may have been physiological, yet disease could not have been excluded. This is the classification of equivocal findings. Interestingly, the majority of equivocal PET findings (9/10) and all four of the equivocal PET/CT findings were in the locoregional anatomically distorted regions. With the exception of the vertebral lesion, these findings may have been elucidated on CT-enhanced with i.v. contrast. The reclassifications after PET/CT are summarized in Table 3.
Table 3. Re-classification of PET findings by PET/CT
| PET/CT malignant | PET/CT benign | PET/CT equivocal | |
|---|---|---|---|
| PET | |||
| Malignant (n=1) | Hilar granuloma (D) | ||
| Equivocal (n=10) | LN (LR) | Tracheostomy granulation (LR) | Vertebra (LR) |
| LN (LR) | Lung inflammation (D) | Salivary gland (LR) | |
| LN (LR) | Thyroid (LR) | Tonsil (LR) | |
| Neck muscle (LR) | |||
| Benign (n=2) | LN (LR) | ||
| LN (D) | |||
One unsuspected liver granuloma and one inguinal lymph node were disclosed on PET/CT yet these did not demonstrate increased uptake of FDG and were of slight clinical relevance.
On the basis of lesions, the additional information provided by PET/CT was associated with a 60% decrease in the number of equivocal PET findings (Table 4). Five lymph nodes were reclassified as malignant (two were thought to be benign lesions and three equivocal), yet none of these significantly altered the overall diagnosis at the patient level, as other PET-positive diseases were present as well.
Table 4. Summary of net PET vs. PET/CT results for 25 patients
| No disease | Malignant (LR/D) | Benign (LR/D) | Equivocal (LR/D) | |
|---|---|---|---|---|
| PET | 7 | 12 (6 LR, 6 D) | 1 (LR) | 5 (LR) |
| PET/CT | 7 | 12 (7 LR, 5 D)*, † | 3 (2 LR, 1 D) | 3 (LR) (tonsil, salivary gland, vertebra) |
*One patient had malignant disease and an equivocal PET/CT neck muscle lesion. Summarized on the patient level as malignant. |
†One suspected hilar LN was found on CT to be a benign granuloma, thus distant disease excluded. |
On the basis of patient outcome, the PET/CT findings excluded distant disease in one patient with a PET-positive hilar finding, limiting the disease to locoregional as opposed to distant spread. PET/CT clearly defined benign lesions in two patients with equivocal PET findings (tracheostomy granulation, lung inflammation).
The additional information provided by PET/CT was noted for 9/45 (20%) of the lesions (five reclassified as malignant, four defined as benign) significantly affecting 3/25 (12%) of the population.
Follow-up and diagnostic accuracy
PET was negative in seven patients and PET/CT excluded disease by defining benign lesions in three patients with equivocal PET findings. These 10/25 patients were diagnosed to be free of active disease and a 6-month follow-up proved these findings to be true (10 TN). There were no false-negative interpretations. All 12 patients with malignancy were verified and summarized as 12 true-positive findings (12 TP). One equivocal PET/CT finding was present in the neck muscle of a patient with diagnosed malignancy elsewhere, and on the patient level, the patient was TP. Three equivocal PET/CT findings were the only findings in three patients who were ultimately considered to be disease free. These three were summarized as false-positive (3 FP) cases.
The overall accuracy of PET/CT imaging was 88% in this combined, newly diagnosed and suspected recurrent SCC study group.
The sensitivity of the PET/CT in this group was calculated to be 100%, with a specificity of 77%, positive predictive value of 80% and negative predictive value of 100%.
The additional information provided by the CT component of the study allowed more confidently localizing and defining the observed locoregional and distant lesions. The lack of contrast may have been a hindrance in the four cases where increased FDG uptake was observed but the localization and characterization by CT were inconclusive.
Effect on patient care
The clinical impact of the PET/CT scan on patient management was evaluated by the referring physicians after a minimum follow-up period of 6 months. The effect on patient management was considered positive if surgery/treatment was either initiated or withheld based on the PET result. As a result of the negative PET/CT (seven had no PET findings, three had benign lesions) treatment was withheld in 10 patients. All 10 were followed clinically and they remained stable with no evidence of overt disease for the duration of at least 6 months.
All seven with local recurrence were referred to surgery for excision of the tumour. All five PET/CT diagnoses of distant metastases were verified by correlation with anatomic imaging, and these patients were subsequently referred for chemotherapy. The three patients with equivocal findings were referred for further investigation, and they remained disease free at follow-up.
Discussion
Over a decade ago functional imaging with fluorodeoxyglucose-positron emission tomography (FDG-PET) was first suggested to be contributory in the evaluation of patients with advanced HNC receiving radio- and chemotherapy. In the years since, the applications of 18F-FDG-PET imaging have grown to include the assessment of tumour aggressiveness5, staging of nodal neck disease1, 10, evaluation of treatment response5 and the detection of recurrent disease13, 22, 14, 23. Recent advances now include fused PET/CT technology with early reports describing diagnostic advantages of the fusion18, 19.
When a local recurrence is suspected after radiotherapy for cancer of the larynx and pharynx regions, an FDG-PET has been suggested to be the first diagnostic step22. Four-month post-RT scans are clearly superior to clinical examination and conventional imaging in differentiating tumour recurrence from soft-tissue effects of irradiation9. All scans in this study were performed after a minimum of 4 months interval post-RT. Although three studies were concluded to be false-positive, none were attributed to postradiation pitfalls.
Although not reported specifically in relation to squamous cell carcinoma, performing PET scans within days of chemotherapy has been reported to yield false-negative results due to an apparent ‘stunning’ of the cells. Patients in this study were all months away from their last exposure to chemotherapeutic agents. No false-negative results were obtained in this study.
The role of FDG imaging in the initial staging and consequent follow-up of patients with tumours of the head and neck has not yet been determined and clear criteria and procedure guidelines have yet to be developed. Some have suggested that since technical limitations of resolution prevent detection of micrometastases, there appears to be a little role for the scan in the clinical staging of SCC of the neck with negative nodes (N0)21. Others dispute the inclusion of the chest in PET studies of patients with primary HNSCC as a very low rate of synchronous primary tumours was found12. The mid-skull to mid-thigh protocol of routine PET scanning allowed the demonstration of distant chest, intra-abdominal and skeletal findings. While synchronous disease was not found, the diagnosis of distant metastases was made in nearly half (5/12) of patients with active HNC in our group.
The methodology applied in this study utilized low-dose CT for attenuation correction and localization purposes only. No i.v. contrast was administered to the patients evaluated. Despite the low dose and lack of enhancement, sufficient information was obtained to allow definitive localization of foci of 18F-FDG uptake in 41/45 lesions. The majority of equivocal PET findings in this group (9/10) and all four of the equivocal PET/CT findings were in the locoregional anatomically distorted regions. In four lesions, the PET/CT result remained equivocal, and contrast enhancement, known to improve CT image quality and accuracy of interpretation, would likely have been contributory. Nonetheless, the low-dose, nonenhanced CT also provided findings not seen in the PET scan. While these were of slight, if any, clinical significance, these findings should not be dismissed.
PET results serve to confirm the pathology of suspected yet questionable clinical and radiograghic findings. Findings of this study demonstrate that fused PET/CT improves anatomic localization and definition of PET findings. This improvement was associated with a 60% decrease in the number of equivocal PET findings. This is similar to the result reported by Schoder et al.19 who describe a 53% decrease in equivocal results. On the patient level, the additional information from the fused PET/CT data amended the outcome in 12% of the patient group. This too is similar to the 18% previously reported by Schoder et al.
The results of the current study contribute to the growing body of data and support previously reported findings describing the use of FDG-PET imaging in patients with SCC of the head and neck. Similar to the majority of reports describing the use of dedicated PET systems and to the few available reports describing hybrid PET in head and neck cancer6, 24, the PET/CT results reported here were found to have considerable effect on patient management in the group evaluated. Not only does the scan provide information regarding initial staging, particularly regarding distant metastases, but it also appears to be warranted in the evaluation of patients with suspected recurrent SCC of the head and neck, in whom anatomic imaging is inconclusive due to the locoregional distortions rendered by surgery and radiotherapy.
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PII: S0901-5027(05)00271-7
doi:10.1016/j.ijom.2005.08.003
© 2005 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.
Volume 35, Issue 4 , Pages 332-336, April 2006
