Author:
Ashraf Anas Zytoon⁽¹⁾⁽²⁾, Koji Murakami⁽²⁾, Shingo Hagiwara⁽³⁾
(1) Radiology Department, Menoufiya University School of Medicine (Egypt)
(2) PET Center, Dokkyo University School of Medicine (Japan)
(3) Surgical Department, Dokkyo University School of Medicine (Japan)

Introduction:

Head and neck carcinomas constitute approximately 5% of all malignancies worldwide⁽¹⁾. Squamous cell carcinoma (SCC) is the major histological type of neoplasm arising from the head and neck area. Lymph node involvement is the most important prognostic factor affecting survival in evaluating patients with head and neck cancer. The average 5-year survival is >50% in patients without, but only 30% in patients with cervical lymph node metastases⁽²⁾.

CT and MRI are the standard techniques that provide structural information at a high spatial resolution and are therefore used routinely in the initial staging of tumors in these patients. On the other hand, they rely on certain criteria, such as nodal size and contrast-enhancement patterns, that are not very specific⁽³⁾. For instance, specific cities of as low as 39% for CT and 48% for MRI have been reported for the detection of nodal metastases in patients with head and neck cancer⁽⁴⁾.

After radiation/chemotherapy, changes in tumor metabolism precede morphologic changes. Similarly, after radical surgery or radiation therapy for head and neck malignancies, normal tissue planes are altered substantially. Therefore, CT and MRI have relatively poor specificity in the assessment of residual or recurrent disease following radical therapy⁽⁵⁾. Positron emission tomography (PET), on the other hand, helps in evaluation of tumor metabolism. For these reasons, FDG-PET with the glucose analogue ?uorodeoxyglucose (FDG) has been used successfully for the assessment of tumor aggressiveness⁽⁶⁾, staging of nodal disease in the neck^(2,7), treatment evaluation⁽⁶⁾, and detection of recurrent disease⁽⁸⁾ in patients with head and neck cancer. Unfortunately, the lack of anatomic detail remains a major limitation of PET if used without CT fusion.

Fluorine-18 fluorodeoxyglucose (18F-FDG) is a marker of tumor viability, based upon the increased glycolysis that is associated with malignancy as compared with most normal tissues. It has also been suggested that tumors with increased FDG uptake appear more aggressive and are associated with less favorable prognosis⁽²⁾. Head and neck carcinomas have high glycolytic activity and increased FDG uptake⁽⁹⁾. Therefore, 18FDG-PET has been advocated more and more acceptance as an additional diagnostic tool in the staging of head and neck carcinoma and for the staging of otherwise N0 necks⁽¹⁰⁾. However, to interpret FDG-PET images accurately, it is essential to be fully familiar with the normal patterns of physiologic tracer uptake, intensities, and frequencies of FDG distribution in the head and neck area⁽¹¹⁾.

In view of the foregoing, our aim in this study is to compare CT, MRI, and FDG-PET for the detection of head and neck cancer and lymph nodes metastasis and to validate the results with histopathological data.

Patients and Methods

Patients Characteristics and Study Design
The study group included 26 patients (18 male and 8 female). They were referred to Radiology Department, National Cancer Center Hospital East, Japan, for diagnostic imaging. Mean age was 57.9±12.2 years (range 19-77 years). Various head and neck tumors were investigated (Table 1). Clinical examination was performed by a head and neck surgeon. All were scheduled for surgery, radiation/chemotherapy. Twelve patients were evaluated for initial staging of primary head and neck cancer and 14 patients for recurrence after therapy. Patient's evaluation for detection of recurrence or residual tumor after therapy was performed not less than 8 weeks after therapy to avoid post operative or post radiation inflammatory reaction.

Table 1.Data for Individual Patients

M: Male, F: Female, Ca.: Cancer, SCC: Squamous cell carcinoma.

Image Acquisition
Three imaging modalities (CT, MRI and FDG-PET) were used for diagnosis; CT and FDG-PET in 6 patients, MRI and FDG-PET in 9 patients, CT, MRI and FDG-PET in 10 patients, FDG-PET only in 1 patient.

CT
Scans of the cervical region were obtained in 16 patients with a multi-detector CT scanner (Toshiba Acquilion 16 row). Slice thickness was 4-5 mm. Contrast material enhancement was achieved by intravenous administration of 100 ml of non-ionic contrast material Iopamidol 300 (Iopamiron 300; Schering, Osaka, Japan), or Omnipaque 300 (iohexol; Daiichi Pharmaceutical, Tokyo, Japan) with a power injector rate of 2 ml/sec.

MRI
Nineteen patients underwent MRI with a 1.5-T unit (Signa; Philips). We first obtained non-enhanced transversal slices with fast spin-echo technique or gradient echo (T2-weighted slices) with a slice thickness of 5 mm (gap 2 mm). In addition, coronal slices (T1weighted) were performed with a slice thickness of 5 mm and interslice gap 2 mm. All patients had transversal T1-weighted slices before and after intravenous administration of contrast medium [0.1 mmol of gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA)/kg body weight; slice thickness 5 mm and interslice gap 1.4 mm].

FDG-PET
FDG-PET study was performed in all patients (n = 26). They were scanned on GE Advance NXi full-ring PET camera (GE Medical Systems, Waukesha, Wis., USA). PET camera has an axial field-of-view 15.2 cm, transaxial 55 cm and spatial resolution of 5 mm full-width at half-maximum at the centre of the field of view (slice thickness 5 mm). Prior to the 18F-FDG-PET, patients had been fasting for 6 hours. Patients with known diabetes mellitus were excluded from the study, so normal glucose plasma levels (<100 mg%) were confirmed in all patients.

The patients were instructed not to chew or talk during the FDG uptake time in order to minimize muscular uptake. Patients were asked to evacuate the urinary bladder before the scan, which was acquired from the pelvic floor to the head. Forty-five up to sixty minutes after intravenous administration of 230-300 MBq 18F-FDG, PET studies were performed using a whole-body technique (six to seven bed positions; acquisition time per position: 4 min; 3 min for emission, 1 min for transmission). In addition, static regional scans of the head and neck region with attenuation correction were acquired by means of a transmission scan acquired by the built-in germanium-68 sources. Attenuation data were segmented (conventional transmission scan) and all images were reconstructed using an iterative algorithm (OSEM, 28 subsets, two iterative steps). FDG was produced in-house using a 18-MeV Cyclotron and an automated FDG synthesis module (HM-18 Cyclotron, Sumitomo Heavy Industries, Japan). The original transverse images were three-dimensionally reconstructed by filtered back-projection.

Image Interpretation And Analysis
CT, MRI and FDG-PET imaging were interpreted individually without knowledge of the other techniques findings. Results of conventional imaging were classified preoperatively according to the TNM classification. Malignancy of primary tumors and lymph nodes were diagnosed using established morphologic criteria including a lymph node size larger than 10 mm, a conglomeration of a minimum of three lymph nodes, central necrosis, indistinct nodal margins^(4,9) or if pathological contrast material enhancement was encountered. For lymph node staging, we used the standard VII levels AJCC classification (American Joint Committee on Cancer).

Histopathological examination
All resected tissues (open or excision biopsy) were exactly localized and documented to allow correlation between histopathological results and imaging findings. Classification of the primary tumor and regional lymph node metastases was based on the TNM system of the International Union Against Cancer. Histopathologic results were taken as the gold standard of diagnostic accuracy for CT, MRI and FDG-PET.

Results

Primary Tumor and Local recurrence Detection
MRI and FDG-PET correctly detected primary tumor and local recurrence with high sensitivity and specificity of 100%, CT failed to differentiate between post operative granulation tissue from local recurrence in one patient (100% sensitivity, 67% specificity). Although the negative predictive value was higher for FDG-PET and MRI than CT (FDG-PET = 100%, MRI = 100%, CT = 93%), all three modalities had equally high positive predictive value (FDG-PET, CT and MRI = 100%) (Table 2).

Lymph Node Staging

According to the histopathological examinations, there are lymph node metastasis in 12 patients while the rest of patients (n=14) are N0. According to imaging, the sensitivity of CT (7/10; 70%) was almost identical to that of MRI (6/9; 67%). FDG-PET scored the highest sensitivity (12/12; 100%). For the specificity; MRI was the most specific (90%; 9/10) than FDG-PET (79%; 11/14) and CT (67%; 4/6). In 3 locations FDG-PET showed focal lymph node uptake and these findings were assigned as false-positive, which caused by non cancerous inflammatory reaction (pathologically confirmed). From these 3 false-positive cases, 2 were correctly diagnosed by MRI. Although the positive predictive value was higher for MRI (MRI = 86%, FDG-PET = 80%, CT = 78%), the highest negative predictive value was achieved by FDG-PET (FDG-PET = 100%, MRI = 75%, CT = 57%) (Table 2). All false-negative (underestimated) metastatic lymph nodes by CT (n=3) or MRI (n=1), were correctly evaluated by FDG-PET. FDG-PET was more efficient for nodal factor assessment than MRI or CT. FDG-PET.

Distant Metastasis and Synchronous Malignancy Detection

Only FDG-PET by its unique advantage as a whole-body examination detected distant metastases (liver, para-aortic lymph nodes, and bone metastases) in 3 patients, and synchronous breast cancer in one patient.

Table 2.Diagnostic accuracy of primary tumors/recurrence and lymph node metastasis by CT, MRI and FDG-PET

PPV : Positive Predictive Value
NPV : Negative Predictive Value

In comparative analysis of accuracy for local lymph node metastasis assessment, nodal factor was correctly estimated by CT in 11/16 patients (true positive n=7, true negative n=4), by MRI in 15/19 patients (true positive n=6, true negative n=9) and by FDG-PET in 23/26 patients (true positive n=12, true negative n=11). Nodal factor over-staging was not frequent (CT 2/16, MRI 1/19 and FDG-PET 3/26). Nodal factor under-staging was slightly higher among CT (3/16) and MRI (3/19) but not FDG-PET (0/26). Imaging outcome was confirmed by histopathological findings (Fig.4).

Discussion

The present management of head and neck cancer mainly consists of resection of the primary tumor, which may be coupled with neck surgery or subsequent radiotherapy and chemotherapy. When distant metastasis is detected preoperatively, appropriate palliation instead of surgical excision or neck dissection is indicated. Therefore, a decision regarding curative or palliative treatment is crucial for untreated head and neck cancer patients.
Primary head and neck tumors could be detected easily by clinical examination. Additional information about tumor extension into the deep spaces, the relationship to adjacent structures, and bone infiltration is needed for treatment planning. Both MRI and CT met these requirements in all tumors of our series. FDG-PET had no additional value in this situation because of the lack of morphologic information⁽¹²⁾. CT or MRI, by virtue of their higher anatomic resolution, remain the methods of choice for evaluation of the primary tumor with reliable T-staging in 80%-90% of cases⁽¹³⁾.

Superior diagnostic accuracy of FDG-PET for primary staging of head and neck cancer patients, metastatic lymph nodes and tumor recurrence has been shown by many authors^{(8, 14-18)}. However, only a few studies have reported the sensitivity of FDG-PET for preoperative staging of primary head and neck cancer and/or compared it with the conventional diagnostic modalities, for example, functional images such as 67Ga and bone scintigraphy, as well as anatomic images such as CT and MRI^{(19, 20, 21, 22, 23)}. These clinical series have been too small to allow statistical comparison or did not apply high-end CT or MRI techniques⁽¹²⁾. The prognosis for patients with head and neck cancer is strongly influenced by the presence of lymph node metastases⁽¹⁹⁾, therefore, we focused the aim of our study on metastatic lymph node work up.

Tumor Staging

It is evident from the literatures^{(21, 24, 7, 25)} that FDG-PET is very sensitive for detecting primary tumors in head and neck region, and our data further supports these findings. Our data demonstrates an accuracy, 100% for FDG-PET in the detection of clinically diagnosed primary tumors, 100% for MRI and 94% for CT in this setting. Our results demonstrate that CT, MRI and FDG-PET can detect all primary tumors or local recurrence with high sensitivity (100%). However, in the detection of metastatic cervical lymph nodes, 30% of the metastatic nodes were missed using CT (70% sensitivity), 33% by using MRI (67% sensitivity). On the contrary no metastatic lymph node missed by FDG-PET (100% sensitivity).

In our series, the sensitivity and specificity of FDG-PET diagnoses were significantly higher than those of CT. Previous reports^{(7, 19-22, 26-27)} showed that FDG-PET had a higher sensitivity (range, 78%-100%) than did CT and MRI (57%-82%). Also, Yoshimasa et al. 2003, in his study compared the FDG-PET sensitivity with CT and MRI for detection of head and neck carcinoma, concluded that the sensitivity of FDG-PET for primary tumor detection was 100% (similar to our results) and it was lower for MRI and CT, 78.3% and 68.2% respectively (lower than our results)⁽²³⁾. The higher CT and MRI sensitivity recorded in our series, could be explained in view of technical improvement (CT examinations was performed by using 16 multi-slice CT scanner with high spatial resolution, moreover, the MR examinations were performed by using 1.5-T machine, which ensure higher image quality (higher signal-to-noise ratio, better spatial resolution through lowering the section thickness and increasing image matrices). Cumulative experience is another important factor due to pooling of many cancer patients to our hospital (National Cancer Center, Japan). MRI and FDG-PET provided similar specificity, levels of confidence, and potential for primary tumor detection.

Precise evaluation of the presence or absence of residual viable tumor is particularly important to the preservation of vital organs and functions by avoiding unnecessary surgery or performing a reduced form of surgery after neoadjuvant chemoradiotherapy. Fourteen out of the total patients were investigated for detection of residual tumors or local recurrence after therapy (monitoring). FDG-PET, MRI and CT had almost equal sensitivity (100%). However, in patients with no viable tumor cells, the specificity of posttreatment FDG-PET (100%) was similar to MRI (100%) but superior to CT (67%), since by CT alone we can not differentiate post operative reaction from residual tumor in one patient. These sensitivity and specificity rates regarding estimation of tumor recurrence are in agreement with Yoshimasa results, except for MRI specificity as he recorded 41.2% specificity for MRI (23). This difference is mainly due to a different number of recurrence free patients (true negative) examined by MRI between the two studies (n=5 for our study, n=17 for Yoshimasa study). Another factor is the therapeutic approach; most of our patients are treated surgically and evaluated post-surgically while all of the patients in

Yoshimasa series are treated by radiotherapy and chemotherapy

Yoshimasa et al. 2003 settled the superiority of FDG-PET in the investigation of the floor of the mouth, the parapharyngeal space, the base of the tongue, and the cheek where these areas were sometimes difficult to assess using anatomic imaging because posttreatment fibrosis, diffuse edematous swelling, and granulation tissue demonstrated such contrast enhancement could not differentiate the persistent residual tumor ⁽²³⁾. Also the artifact created by teeth is a problem during CT and MRI examination that could mask important data. FDG-PET correctly identified residual tumors independent of their site and can exclude residual tumors with high specificity.

We agree with Yoshimasa et al. 2003 in his conclusion, that increased FDG uptake on FDG-PET images obtained >4 wk after treatment strongly indicated the presence of residual tumor, whereas the absence of FDG uptake suggested that no viable tumor remained⁽²³⁾.

Lymph Node Staging

Similar to the results of the previous reports^{(2, 12)}, metastatic lymph node disease was confirmed in approximately half of the patients in our series. Complete removal of all metastatic lymph nodes is a prerequisite to achieve curative treatment. Morphologic imaging methods, including CT and MRI, are reported to provide a high rate of false-negative diagnoses, which can be explained by micrometastases within otherwise normal lymph nodes^{(4, 9)}. It should be noted that more than 40% of all lymph node metastases are localized in nodes smaller than 1.0 cm in diameter⁽²⁸⁾. According to many authors, the smallest lymph node metastasis detected by CT was only 1 cm in diameter, whereas FDG-PET, as functional imaging, was able to localize smaller lymph node metastases (4-6 mm in diameter)^{(2, 9, 29, 30)}. On the other hand, false-negative FDG-PET results were reported in large lymph nodes up to 20 mm in diameter⁽²⁹⁾ or in necrotic lymph nodes⁽⁹⁾. The reported sensitivities of FDG-PET for nodal disease range from 67% to 91% ^{(2, 9, 21-22, 26, 29-31)}, similar values were found for CT (67-90%)^{(2, 4, 9, 29, 32)} and MRI (71-91%) ^{(2, 4, 9, 19, 26)}. The results of our series are within this range with slightly higher sensitivity for FDG-PET.

The reported specificity of FDG-PET ranges from 88% to 100%^{(2, 21, 26, 29, 30)} (79% for the current study) compared with a wide range of reported specificity values for CT (38-97%) (67% for the current study) and MRI (48-94%) (90% for the current study)^{(2, 4, 29, 33)}. Slightly lower specificity for FDG-PET in the current study might be explained in view of the inhomogeneity of the examination protocols or the difference in the number of patients included in each series.

In accordance with the most published articles^{(2, 9, 21-22, 24, 26, 29, 34-36)}, in our study, FDG-PET was significantly superior to CT/MRI for identifying metastatic neck lymph nodes (100% sensitivity for FDG-PET versus 67% for MRI and 70 % for CT). However, Shu-Hang et al. 2005, report lower sensitivity for FDG-PET just 74.7% (but still higher than CT/MRI 52.6%)⁽²⁵⁾. Shu-Hang study focused his study on oral cavity SCC and the mean nodal size in his study was relatively small to be detected by FDG-PET.

Previous studies^(37-38) showed that the extent of the intranodal tumor deposit is a more limiting determinate to surgical dissection than the nodal size. FDG-PET has been reported to have a higher specificity than CT/MRI in detecting cervical nodal disease in most of the published literature^{(2, 7, 9, 21-22, 24, 26, 29, 34-35, 37)}. Three articles^{(25, 30, 36)} reported that, FDG-PET had a lower specificity. Our study showed the specificity of FDG-PET was lower than MRI (79% vs. 90%) but higher than CT (79% vs. 67%). False-positive FDG-PET findings were mainly due to its inherent inability to discriminate inflammatory processes from tumor infiltration since high-level metabolic changes occur in both instances. Spatial inaccuracy contributed to a portion of the false-positive results.

Table 3. Sensitivity and specificity of CT, MRI, and FDG-PET for diagnosis of head and neck lymph node metastasis, Current literatures report:

Distant Metastatic Workup and Secondary tumors

As for whole-body evaluation, FDG-PET has a clinical impact on the management of patients with head and neck cancer through reliable detection of second primary malignancies as well as distant metastases⁽³⁹⁾. FDG-PET with whole-body imaging would replace the conventional functional imaging modalities of 67Ga and bone scintigraphy.

Synchronous secondary tumors are found in about 8% of all head and neck malignant carcinomas^{(40, 41)}. In his series, Florian 2005⁽¹²⁾, a simultaneous malignancy was histologically confirmed in five (8.5%) of the 59 patients, including three lesions outside the head and neck region. Regarding our study, there is only one patient (4%) with synchronous tumor (breast cancer) and 3 patients (11.5%) with distant metastases (liver, para-aortic lymph nodes, bone metastases). All were outside the head and neck region. Similar to Florian 2005⁽¹²⁾ in his series, all of the synchronic tumors and the distant metastasis were clearly diagnosed by a FDG-PET whole-body scan and missed by the initial CT and MRI examinations of the head and neck region.

Conclusion

This histopathologically controlled study proves FDG-PET as the procedure with the highest sensitivity for detecting lymph node metastases of head and neck cancer and has become a routine method in our National Cancer Center. Although FDG-PET provides information not available by means of MRI or CT, it cannot replace these anatomic modalities. We conclude that FDG-PET and MRI or CT are essential imaging tools for the management of head and neck cancer. In view of our experience, we think that FDG-PET is a highly sensitive exam and if combined with CT as the new era of PET-CT combinations scanners, its accuracy for cancer staging definitely will be increased.

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