Accepted 24 January 2011 Published online 20 May 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: /hed.21764

Transcription

1 ORIGINAL ARTICLE INITIAL STAGING OF THE NECK IN HEAD AND NECK SQUAMOUS CELL CARCINOMA: A COMPARISON OF CT, PET/CT, AND ULTRASOUND-GUIDED FINE-NEEDLE ASPIRATION CYTOLOGY Sandro J. Stoeckli, MD, 1 Stephan K. Haerle, MD, 2 Klaus Strobel, MD, 3 Sarah R. Haile, PhD, 4 Thomas F. Hany, MD, 3 Bernhard Schuknecht, MD 5 1 Department of Otorhinolaryngology Head and Neck Surgery, Kantonsspital, St. Gallen, Switzerland. sandro.stoeckli@kssg.ch 2 Department of Otorhinolaryngology Head and Neck Surgery, University Hospital, Zurich, Switzerland 3 Department of Nuclear Medicine, University Hospital, Zurich, Switzerland 4 Clinical Trials Unit, Kantonsspital, St. Gallen, Switzerland 5 Diagnostic and Vascular Neuroradiology, Medizinisch Radiologisches Institut Zürich, Klinik Bethanien, Zurich, Switzerland Accepted 24 January 2011 Published online 20 May 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: /hed Abstract: Background. The aim of this study was to compare imaging modalities for staging the neck in a prospective cohort of patients evaluated by CT, ultrasound with fine-needle aspiration cytology (FNAC), and [ 18 F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/CT with the histologic evaluation of the neck dissection as the standard of reference. Methods. In all, 76 consecutive patients were prospectively enrolled. Results. Ultrasound-guided FNAC showed the highest level of agreement with histology for exact N classification. Ultrasound-guided FNAC showed the smallest percentage of overstaged patients, 7%, versus 16% with PET/CT, 13% with CT, and 13% with ultrasound. The rate of understaged patients was comparable between the imaging modalities. With regard to the endpoint N0 versus Nþ there were no statistically significant differences to be found. Conclusions. Ultrasound-guided FNAC seems to correlate best with histologic staging compared with PET/CT and CT. None of the modality is reliable enough to replace elective neck treatment in cn0 necks. VC 2011 Wiley Periodicals, Inc. Head Neck 34: , 2012 Keywords: head and neck squamous cell carcinoma; ultrasound; PET/CT; CT; imaging; neck dissection Head and neck squamous cell carcinoma (HNSCC) accounts for approximately 5% of all new cancers diagnosed per year in the United States 1 and represents the 10th most common cancer in the world. 2 Accurate staging of HNSCC is important for therapy decision and patient s prognosis. The status of the regional lymphatic involvement is considered the strongest prognosticator in these patients. 3 The 5-year survival drops considerably from 63% to 86% in patients with no nodal involvement to 20% to 36% in Correspondence to: S. J. Stoeckli VC 2011 Wiley Periodicals, Inc. patients with lymph node metastases. 4 The staging or classification of the neck has considerable impact on the treatment decision with regard to surgical and nonsurgical treatment options. In surgical cases patients with clinically negative necks will be offered minimally invasive sentinel node biopsy (SNB) 5 or risk-level based elective neck dissections (ENDs), 6 whereas patients with clinically evident lymph node involvement will undergo therapeutic modified radical neck dissection. 7 The clinical staging/classification of the neck is by definition based on physical examination and appropriate imaging. 8 In patients undergoing surgical therapy, the ultimate staging of the neck is achieved by the histologic assessment of the neck dissection specimen. In patients scheduled for primary (chemo)radiation, neck staging remains based on imaging. There is still some controversy on the most accurate way to image the neck prior to the therapy. Although contrast-enhanced CT and MRI remain the methods of choice for evaluation of the primary tumor because of their excellent anatomic resolution, their accuracy for the detection of nodal metastases has varied widely in recent reports. 9 Traditionally, most of the studies on nodal staging have focused on CT, MRI, and ultrasound with ultrasound-guided fine-needle aspiration cytology (FNAC). Thus, the highly enhanced glucose uptake in HNSCC renders these tumors very suitable for assessment with [ 18 F] fluoro- 2-deoxy-D-glucose ( 18 F-FDG) positron emission tomography (PET). 18 F-FDG PET coregistration with CT (PET/CT) has been shown to be highly accurate for initial staging of HNSCC in several studies. 10,11 It is thought to be superior to CT and MRI for staging of the cervical lymph nodes in accord with the most recent reports. 12,13 Initial Staging of Neck in HNSCC HEAD & NECK DOI /hed April

2 The aim of our study was to compare the results of the initial neck staging in a prospective and consecutive cohort of patients with previously untreated HNSCC evaluated simultaneously by CT, ultrasound, ultrasound-guided FNAC, and PET/CT with regard to the histologic evaluation of the neck dissection specimen as the standard of reference. PATIENTS AND METHODS Patients. The total number of 76 consecutive patients was prospectively enrolled in the study. The study protocol was approved by the local ethics committee and written informed consent was obtained from all patients prior to study entry. Patients with a previously untreated, histology proven SCC of the oral cavity, oropharynx, hypopharynx, and larynx scheduled for surgical therapy including neck dissection were eligible. All patients underwent imaging of the neck by contrast-enhanced helical CT, ultrasound with ultrasound-guided FNAC, and 18 F-FDG-PET/CT within 2 weeks prior to neck dissection. 18 F-FDG-PET/CT. 18 F-FDG-PET/CT imaging was acquired on a combined PET/CT in-line system (Discovery LS, Discovery STE or Discovery Rx; GE Health Systems, Milwaukee, WI). These dedicated systems integrate a PET scanner (GE Advance Nxi; GE Health Systems) with a multislice helical CT (LightSpeed plus, Lightspeed 16 or lightspeed VCT; GE Health Systems) and permit the acquisition of coregistered CT and PET images in a single imaging session. Patients fasted for at least 4 hours prior to the scanning, which started approximately 60 minutes after the injection of a standard dose of approximately 350 MBq of 18 F-FDG. Patients were examined in the supine position. Initially, the CT scan was acquired starting from the level of the head using the following parameters: 80 ma, 140 kv, 0.5 s/tube rotation, slice thickness 4.25 mm. The CT scan was acquired during breath holding in the normal expiratory position. Because the CT was used only for anatomical orientation and attribution of 18 F-FDG avid lesions to anatomic structures the slice thickness was considerably thicker than that in the diagnostic helical CT and no contrast was administered. Immediately following the CT acquisition, a PET emission scan was acquired with an acquisition time of 2 to 3 minutes per cradle position with a 1-slice overlap. The 8 to 9 cradle positions from the knees to the head resulted in an acquisition time of approximately 16 to 27 minutes. The CT data were used for the attenuation correction and the images were reconstructed using a standard iterative algorithm. The acquired images were viewed with dedicated software (Advantage Windows Workstation, GE Health Systems). The PET/CT images were retrospectively reviewed by a double-board certified radiologist and nuclear medicine physician with 10 years of experience in CT reading and 4 years of experience in reading combined PET/CT in patients with head and neck cancer for the presence of increased 18 F-FDG uptake in cervical lymph nodes. Nodes were judged as metastatic if the uptake was clearly higher than that in the background tissue and if the uptake matched with a lymph node on the corresponding CT image. Additionally, the maximum standardized uptake value of all suspicious lymph nodes was measured. Both the number and anatomic level of all metastatic nodes were given for all patients and the N classification was defined by the reader. The reader was blinded to the results of the clinical investigations and the other imaging modalities. For all patients, the attenuationcorrected PET images were used for analysis. CT. CT examinations of the neck were performed by use of a 4-row multidetector CT, with a collimation of 1 mm, table rotation of 0.5 second, and table feed of 2.5 mm/rotation. Slice reconstruction was 1.25 mm with an increment of 0.7 mm. Multiplanar reconstructions (MPRs) consisted of contiguous 3-mm slices in the axial, coronal, and sagittal planes; 80 ml of nonionic contrast media (300 mgi/ml) was applied intravenously with a flow rate of 2 ml/s, pushed with 20 ml of saline. The scan range was from the orbital floor to the tracheal bifurcation started after a delay of 30 seconds. Images were saved with a constant soft tissue window (300/100, width/length [w/l]) and bone window leveling (3200/700, w/l). The following criteria were used regarding lymph nodes as pathologic: nodes of any size with clear evidence of nonfat low density on contrast-enhanced CT; more than 15 mm (greatest diameter) for nodes level II and >10 mm for nodes located in other levels or maximum longitudinal/short axis diameter < 2.0; maximum transverse diameter of 8 mm in retropharyngeal nodes; spherical shape (supportive criterion in borderline sizes); groups of 3 borderline nodes. Images were reviewed by B.S., a neuroradiologist with 20 years of experience in head and neck radiology, on a picture archiving and communication system (PACS) workstation, blinded to the clinical information regarding the primary tumor location and lymph node assessment based on palpation. Ultrasound with FNAC. A Siemens Sonoline Antares ultrasonograph with a 10.5-MHz linear transducer (Siemens Medical Solutions, Erlangen, Germany) was used for these series. A 24-gauge biopsy needle attached to a 10-mL syringe and syringe holder (Cameco Ltd., London, UK) was chosen. Under sonographic guidance, the needle was gently pushed forward in the longitudinal direction to the transducer, through the skin, into the middle of the mass. 470 Initial Staging of Neck in HNSCC HEAD & NECK DOI /hed April 2012

3 The following ultrasound characteristics of the examined lymph nodes were evaluated: minimum axial diameter of 7 mm for level II and 6 mm for the remainder of the neck lymph nodes; long- to shortaxis diameter (<2) or spherical shape (supportive criterion in borderline sizes); hypoechoic sonomorphology with respect to the surrounding muscles; groups of 3 borderline nodes. All ultrasound examinations including color Doppler ultrasound were performed by head and neck surgeons with profound experience in ultrasound imaging. All suspicious lymph nodes were fine-needle aspirated under ultrasound guidance. Histopathologic Work-up. The neck dissection specimens were fixed in buffered formalin and searched for lymph nodes by experienced pathologists. The lymph nodes were bisected along their long axis and stained with conventional hematoxylin and eosin and immunohistochemistry with cytokeratin. The histopathologic work-up of the neck dissection specimen served as the standard of reference. The staging results obtained by the different imaging modalities were compared to the pathologic staging. Comparison of the pathologic staging with the imaging staging can be performed on a node-by-node, level-by-level, neck-by-neck, or patient-by-patient basis. Because it is almost impossible to correlate a specific lymph node suspicious for malignant involvement on imaging to the same node in the neck specimen the idea of a node-by-node basis of comparison was abandoned. Although the correlation of distinct levels would seem to be feasible, a patient-by-patient basis was ultimately chosen for the comparison of the exact N staging, and a neck-by-neck basis for the endpoint N0 versus Nþ. This, in our opinion, best represents the clinical decision-making situation. Statistics. To compare the exact nodal stage as assigned by each imaging method, the rate of patients correctly staged, overstaged, and understaged was computed. Agreement between the respective imaging method and histology was measured using equally weighted Cohen s kappa statistic, 14 with adjusted 95% bootstrap percentile confidence intervals (CIs). The kappa statistic was computed using the psy package in R. 15 With regard to the endpoint N0 versus Nþ the presence or absence of cervical metastases as assessed by the respective imaging modality was compared with the corresponding histologic assessment of the neck specimen. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated accordingly, assuming an Nþ prevalence of 80%. McNemar s test was used to test for significant departures in agreement between a diagnostic method and the results of the histologic assessment. It was of special interest to analyze positive and negative predictive values separately, to examine whether 1 of the diagnostic techniques was better than any of the others in, for example, avoiding false negatives. Pepe 16 presented a method that makes this possible using generalized estimating equations. 17 In this method, the effect of both diagnostic test (TEST: PET, CT, Ultrasound, or FNAC) and test result (RESULT: N0 or Nþ) on the probability that the test result agrees with the gold standard histology (AGREEMENT) is analyzed, making it possible to estimate both a relative negative predictive value (rnpv) and a relative positive predictive value (rppv) for a pair of tests. For each pair of diagnostic tests, a generalized estimating equation model was fit for AGREEMENT with predictors RESULT, TEST, and the interaction TEST RESULT, assuming a binomial family with (unusually) a log link and independent correlation with a robust variance estimate. The rnpv of test 1 versus that of test 2 was then estimated as exp(beta2), and rppv as exp(beta2 þ beta3), where beta2 is the coefficient for the TEST term and beta3 is the coefficient for the interaction. Stata software (StataCorp 2007, Stata Statistical Software: Release 10. StataCorp LP, College Station, TX) was used to fit the models using xtgee, and the function lincom was used to estimate rnpv and rppv and their associated CIs. RESULTS Seventy-six consecutive patients (47 men, 29 women) with a mean age of 59.6 years (range, years) were entered in this prospective study. All patients completed 3 examinations within 2 weeks prior to the neck dissection. The primary tumor was located in the oropharynx in 39 patients (51%), in the oral cavity in 22 patients (29%), in the hypopharynx in 7 patients (9%), and in the larynx in 6 patients (8%); in 2 patients, there was an unknown primary (3%). The distribution of the exact nodal stages as achieved by each imaging modality compared with the results obtained by the histopathologic work-up of the neck dissection specimens is given in Table 1. Almost half of the patients showed histologically a stage pn2b. Table 2 shows the percentage of necks that had been assessed correctly, underestimated, or overestimated by each imaging modality. Of the 4 imaging modalities, ultrasound-guided FNAC showed the highest level of agreement with histology (Cohen s kappa: 0.63; 95% CI: ). The other 3 showed slightly lower levels of agreement with histology: PET 0.53 (CI: ), CT 0.54 (CI: ), and ultrasound 0.54 (CI: ). According to Landis and Koch, 18 a kappa of 0.4 to 0.6 is considered as a moderate, and a kappa of 0.6 to 0.8 as a substantial agreement. According to Kirkwood and Sterne, 19 a kappa of 0.4 to 0.75 is considered as fair to good agreement. Ultrasound-guided FNAC also showed the Initial Staging of Neck in HNSCC HEAD & NECK DOI /hed April

4 Table 1. Distribution of N classifications as achieved by each imaging modality compared with histology. No. (%) by modality N classification Neck dissection PET/CT CT Ultrasound Ultrasound-guided FNAC N0 15 (20) 18 (25) 13 (19) 14 (21) 18 (26) N1 12 (16) 11 (15) 17 (25) 16 (24) 14 (21) N2a 4 (5) 5 (7) 5 (7) 2 (3) 2 (3) N2b 36 (47) 24 (33) 23 (34) 30 (44) 28 (41) N2c 6 (8) 11 (15) 6 (9) 4 (6) 4 (6) N3 3 (4) 4 (5) 4 (6) 2 (3) 2 (3) Abbreviations: PET, positron-emission tomography; FNAC, fine-needle aspiration cytology. smallest percentage of overstaged patients, 7%, versus 16% with PET/CT, 13% with CT, and 13% with ultrasound. The rate of understaged patients was comparable between the imaging modalities (25% vs 21%, 24%, and 25%). Table 3 compares the results stage by stage as achieved by histology with the different imaging modalities. Because it is routine to complement the ultrasound with ultrasound-guided FNAC in the case of suspicious nodes, and the results show that ultrasound-guided FNAC is superior to ultrasound alone, the results of ultrasound are not given stage by stage in a separate table. Table 4 displays the sensitivity, specificity, PPV, NPV, and accuracy for each imaging modality with regard to the endpoint N0 versus Nþ, as well as the results of McNemar s test, testing for significant departures from agreement with histology. The vast majority of patients, assessed as N0 by any of the imaging modality that turned out to be Nþ histologically, were staged pn1. This supports the concept that microscopic disease cannot be detected by imaging. Table 5 shows the rppv and rnpv for each of the pairs of imaging modalities, as well as their associated 95% CIs. A relative predictive value is computed as the ratio of the predictive value from 1 test to the predictive value from another, so that an rppv (rnpv, respectively) of 1.0 indicates that the 2 tests have the same positive (negative) predictive value. In all cases the rnpv was close to 1.0, with CIs containing 1.0, indicating no statistically significant differences in NPV between any of the imaging modalities. In all but 2 of the pairs rppv was not significantly different from 1.0. For ultrasound-guided FNAC versus CT and ultrasound-guided FNAC versus ultrasound, the CIs for rppv were 1.0 at the lower bound, indicating that ultrasound-guided FNAC showed slightly but statistically significant better PPV than that of CT or ultrasound. DISCUSSION The presence of lymph node metastases in HNSCC is the most important predictive factor with regard to survival of the patients. Furthermore, the presence or absence of clinically and radiologically overt lymph node metastases considerably influences therapy decision and treatment. Patients with no evidence of lymph node involvement will be treated with risklevel adapted elective neck dissection or even minimally invasive sentinel node biopsy in surgical cases, or with elective doses of radiation in nonsurgical cases. Therefore, the pretreatment identification of cervical lymph node metastases is of utmost importance. To date, there is still no consensus on the most accurate imaging modality for the assessment of regional disease in the neck. In 1990, van den Brekel et al 20 proposed radiologic criteria for the assessment of cervical metastasis. Three years later, the same authors reported on the validity of CT, MRI, ultrasound, and ultrasoundguided FNAC in a prospective comparative study including 132 patients. 21 In that study ultrasoundguided FNAC did significantly better than any of the other techniques used. However, these were results out of an institution with highly developed expertise and easy access to ultrasound-guided FNAC. In the literature, the reported sensitivity and specificity of ultrasound-guided FNAC for detecting lymph node metastases ranges from 63% to 97% and 74% to 100%, respectively. 9 The great advantage of ultrasound-guided FNAC is the low cost, the lack of radiation exposure, the low-threshold availability, and the Table 2. Proportions of correct staging, overstaging, and understaging by each imaging modality. Staging PET/CT, % CT, % Ultrasound, % Ultrasound-guided FNAC, % Correct Overstaging Understaging Agreement with histology, Cohen s kappa (95% CI) 0.53 (0.35, 0.67) 0.54 (0.35, 0.71) 0.54 (0.34, 0.70) 0.63 (0.44, 0.77) Abbreviations: PET, positron-emission tomography; FNAC, fine-needle aspiration cytology; CI, confidence interval. 472 Initial Staging of Neck in HNSCC HEAD & NECK DOI /hed April 2012

5 Table 3. Results of nodal staging by different imaging modalities compared stage by stage with histology. Clinical N classification Histologic N classification (pn, %) (cn, %) pn0 pn1 pn2a pn2b pn2c pn3 Nodal stage by PET/CT cn cn cn2a cn2b cn2c cn Nodal stage by CT cn cn cn2a cn2b cn2c cn Nodal stage by ultrasound-guided FNAC cn cn cn2a cn2b cn2c cn Abbreviations: PET, positron-emission tomography; FNAC, fine-needle aspiration cytology. possibility of confirmation of sonographic findings by cytology. The main drawback of ultrasound-guided FNAC is the dependence on the experience of the ultrasonographer and the cytologist and the inaccessibility of retropharyngeal and mediastinal nodes. Although CT and MRI remain the standard for the evaluation of the primary tumor because of their superior anatomic resolution, the assessment of the lymph node status remains controversial in that CT and MRI are mainly based on size and contrast enhancement as criteria for malignancy. Different authors suggest different size criteria, thus rendering the comparison of studies difficult The reported sensitivity and specificity of CT for detecting lymph node metastases ranges from 54% to 95% and 39% to 100%, respectively. 9,25 Contrast-enhanced CT of the neck represents the standard imaging modality to assess the primary tumor and the lymph node status in many centers. Meanwhile, PET/CT has been introduced to the staging/classification and proven high sensitivity for the detection of HNSCC. The reported sensitivity and specificity of PET/CT for the detection of lymph node metastases ranges from 67% to 96% and 82% to 100%, respectively. 12,13,26,27 The great advantage of PET/CT is the assessment of the primary tumor, the neck, potential synchronous second primaries, and distant metastases in a single modality. The main drawback of PET/CT is its limitation of resolution, which renders the detection of tumor deposits of <4 to 5 mm impossible, the possibility of false-negative findings due to necrotic lymph nodes, 28 the occurrence of false-positive findings due to inflammatory changes in reactive lymph nodes, 29 and its comparatively high costs and limited availability. In recent years, several authors compared PET/ CT with other different imaging modalities for the assessment of neck nodes in HNSCC. Many of the reported studies in the literature suffer from considerable drawbacks. Very often the design of the study is retrospective and the inclusion criteria are unclear. Nonconsecutive patient cohorts suggest a hidden selection bias. The study groups are inhomogeneous as a result of the inclusion of different primary sites and therapy regimens. Histology is not always used as a standard of reference. In contrast, the strength of our study is the consecutive patient inclusion, the clear and homogeneous inclusion criteria, the comparison of different imaging modalities, the evaluation of CT and PET/CT by experienced radiologists with clear and uniform criteria, and the use of histologic evaluation of the neck specimen as a standard of reference. The drawback of our study is the limited number of patients included, although the number is still quite high compared with the published literature. Although a post hoc power analysis is generally not recommended, 30 it was of interest to determine how many patients would be needed for such a study were it to be done again prospectively. For this power analysis, agreement between methods in choosing either node negative or node positive status would be examined as a primary endpoint using McNemar s test. The proportion of discordant pairs was 16% on average in this data set. The use of histology determined nodes to be positive in approximately 82% of cases, whereas approximately 80% of cases were positive using other techniques. To show such a small difference in the rate of agreement, a 2-sided McNemar s test with significance level 5% would require 3128 Table 4. Statistics of each imaging modality for the endpoint N0 versus Nþ. Imaging modality Sensitivity, % Specificity, % PPV, % NPV, % Accuracy, % Significantly different from histology?* PET/CT p ¼.15 CT p ¼.79 Ultrasound p ¼.79 Ultrasound-guided FNAC p ¼.11 Abbreviations: PPV, positive predictive value; NPV, negative predictive value; PET, positron-emission tomography; FNAC, fine-needle aspiration cytology. *McNemar s test. Initial Staging of Neck in HNSCC HEAD & NECK DOI /hed April

6 Table 5. Relative negative and positive predictive values for each pair of imaging modalities and associated 95% confidence intervals. Imaging modality pair rnpv rppv CT versus PET 0.78 ( ) 0.94 ( ) Ultrasound versus PET 0.78 ( ) 0.94 ( ) Ultrasound-guided FNAC 1.05 ( ) 1.02 ( ) versus PET Ultrasound versus CT 1.00 ( ) 1.00 ( ) Ultrasound-guided FNAC 1.35 ( ) 1.08 ( ) versus CT Ultrasound-guided FNAC versus ultrasound 1.35 ( ) 1.08 ( ) Abbreviations: rnpv, relative negative predictive value; rppv, relative positive predictive value; PET, positron-emission tomography; FNAC, fine-needle aspiration cytology. patients to have 80% power. To show a slightly larger difference of 5%, 491 patients would be needed. 31 This power analysis clearly shows that almost all published studies so far were considerably underpowered because of small patient groups. The aim of our study was to assess the best modality, available at present, for the cervical assessment in HNSCC. To answer this question ultrasound, ultrasound-guided FNAC, CT, and PET/CT were analyzed separately for nodal disease in a cohort of patients with advanced HNSCC. The histologic evaluation of the neck specimen served as a standard of reference. In our study ultrasound-guided FNAC overperformed the other imaging modalities for the prediction of the exact N classification with a clearly superior level of agreement with histology (Cohen s kappa: 0.63). Ultrasound-guided FNAC overstaged the neck considerably less (7% vs 16%) than PET/CT, with its greater number of false positives arising from inflammatory changes in reactive lymph nodes. Whereas ultrasound-guided FNAC was revealed to be superior to PET/CT for the determination of the exact N classification, PET/CT and CT showed comparable results. Although the agreement with histology was good for ultrasound-guided FNAC and still fair for PET/CT and CT, approximately 1/3 of patients were incorrectly staged/classified with any of the imaging methods. This is of special interest and impact in patients undergoing primary chemoradiation because these patients lack histologic determination of the exact N classification. One third of all irradiated patients are treated and reported with a potentially wrong N classification. This has to be taken into consideration, when comparing surgical with nonsurgical patient cohorts. When addressing the endpoint Nþ versus N0, which often reflects the clinical decision-making process, ultrasound-guided FNAC, PET/CT, and CT showed good to excellent results with regard to sensitivity, accuracy, and PPV, with no statistically significant differences. In other words, ultrasound-guided FNAC as a low-cost, easily available modality with no radiation exposure achieves comparably good results compared with more sophisticated and expensive technology. As the result of a considerable number of false negatives, the specificity and NPV were considerably worse for all imaging modalities. None of the imaging modalities was accurate enough to be able to replace elective neck treatment in the clinically N0 neck. Even in the most experienced hands the NPV of ultrasound-guided FNAC does not exceed 80% in a wait-and-scan model for the cn0 neck, which corresponds to a regional recurrence rate of approximately 20%. 32 Moreover, PET/CT is not accurate enough to exclude neck metastases with a sufficient certainty to avoid elective neck treatment. This fact has been underlined by previous studies assessing PET/CT for the N0 neck 33 or comparing PET/CT to sentinel node biopsy. 34 Because not many centers perform ultrasoundguided FNAC on a regular basis for HNSCC, there is very limited literature available to compare ultrasound-guided FNAC with PET/CT. In a recent study by Hwang et al, 35 PET/CT was compared with ultrasound-guided FNAC for the initial staging of the neck. Because only 42 of 637 patients were ultimately analyzed for comparison, and most patients were assessed for thyroid cancer, no conclusion can be taken from that study with regard to neck metastases. Yoon et al 25 in 2009 published a study similar to ours and compared CT, MRI, ultrasound, and PET/ CT. The values for accuracy, specificity, and NPV for all imaging methods were superior to the results achieved in our study, but similarly showed no statistically significant differences between the modalities. The drawback of that study was that patients underwent neck dissection only in the case of radiological overt metastases, and that only patients with advanced neck disease were referred for PET/CT. Considering the fact that upstaging of a radiological negative neck to a histologically positive N1 neck contributes to the majority of false negative necks, suggests that this study design probably overestimated the imaging performance. Several other studies compared PET/CT with conventional imaging with either MRI or CT Most of the studies revealed a superiority of PET/CT over CT or MRI, although the study designs varied considerably. In a recent meta-analysis Kyzas et al 41 reviewed 32 studies. The overall sensitivity and specificity of PET/CT for the assessment of nodal disease was 79% and 86%, respectively, but dropped to 50% and 87% for cn0 patients. Similar to our study, the meta-analysis failed to reveal a statistically significant difference for neck assessment between PET/CT, CT, MRI, or ultrasound-guided FNAC. The authors concluded that there is no solid evidence to support the routine clinical application of PET/CT in the pretreatment evaluation of the lymph node status in patients with HNSCC, including patients with clinically negative neck; and that other imaging modalities appear to have a similarly limited diagnostic performance. It seems that PET/CT 474 Initial Staging of Neck in HNSCC HEAD & NECK DOI /hed April 2012

7 performs best in trials including only patients with cnþ, whereas the inclusion of patients with cn0, as in our study, considerably reduces the accuracy. Therefore, PET/CT is not suited for routine use in all patients with HNSCC. This statement has been supported meanwhile by a distinguished author group in a recent consensus paper. 42 The systematic review of the literature revealed only moderate-quality evidence supporting a benefit of PET/CT for nodal staging. In summary, PET/CT performed best in those studies where the pretest probability was high because of the inclusion of mainly clinically positive necks. In studies including all patients regardless of the neck status, PET/CT performed considerably worse. CONCLUSIONS In conclusion, there is a lack of prospective comparative studies in homogeneous patient cohorts with uniform inclusion criteria for the evaluation of the most accurate imaging modality for the assessment of lymph node metastases in patients with HNSCC. In this prospective and consecutive patient cohort assessed simultaneously with CT, PET/CT, and ultrasound-guided FNAC for neck metastases ultrasoundguided FNAC seems to correlate best with the exact histologic staging and to perform equally well as more sophisticated and expensive technology in the differentiation of the N0 from the Nþ neck. However, none of the imaging modality is reliable enough to replace elective neck treatment in cn0 necks. At our institution morphologic imaging with CT or MRI for the assessment of the primary tumor will always be complemented with ultrasound-guided FNAC for the assessment of the neck. Because of its costs and the lack of additional value for the assessment of the primary tumor and the cervical lymph nodes PET/CT will be added for the additional assessment of distant disease only in patients with advanced tumor stages. REFERENCES 1. Parker SL, Tong T, Bolden S, et al. Cancer statistics CA Cancer J Clin 1996;46: Yeole BB, Sankaranarayanan R, Sunny L, Swaminathan R, Parkin DM. Survival from head and neck cancer in Mumbai (Bombay), India. Am Cancer Soc 2000;89: Layland MK, Sessions DG, Lenox J. The influence of lymph node metastasis in the treatment of squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx: N0 versus Nþ. Laryngoscope 2005;115: Grandi C, Alloisio M, Moglia D, et al. Prognostic significance of lymphatic spread in head and neck carcinomas: therapeutic implications. Head Neck 1985;82: Stoeckli SJ. Sentinel node biopsy for oral and oropharyngeal squamous cell carcinoma of the head and neck. Laryngoscope 2007;117: Robbins KT, Medina JE, Wolfe GT, Levine PA, Sessions RB, Pruet CW. Standardizing neck dissection terminology. Official report of the Academy s Committee for Head and Neck Surgery and Oncology. Arch Otolaryngol Head Neck Surg 1991;117: Byers RM. Modified neck dissection: a study of 967 cases from 1970 to Am J Surg 1985;150: Greene FL, Page DL, Fleming ID, et al. AJCC cancer staging handbook, 6th ed. New York: Springer; de Bondt RB, Nelemans PJ, Hofman PA, et al. Detection of lymph node metastases in head and neck cancer: a meta-analysis comparing US, USgFNAC, CT, and MR imaging. Eur J Radiol 2007;64: Schmid DT, Stoeckli SJ, Bandhauer F, et al. Impact of positron emission tomography on the initial staging and therapy in locoregional advanced squamous cell carcinoma of the head and neck. Laryngoscope 2003;113: Schöder H, Yeung HWD, Gonen M, Kraus D, Larson SM. Head and neck cancer: clinical usefulness and accuracy of PET/CT image fusion. Radiology 2004;231: Murakami R, Uozumi H, Hirai T, et al. Impact of FDG PET/CT imaging on nodal staging for head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2007;68: Jeong HS, Baek CH, Son YI, et al. Use of integrated 18F-FDG PET/CT to improve the accuracy of initial cervical nodal evaluation in patients with head and neck squamous cell carcinoma. Head Neck 2007;29: Cohen J. Weighted kappa: nominal scale agreement with provision for scaled disagreement or partial credit. Psychological Bulletin 1968;70: R Development Core Team ( 2009). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN , URL Pepe M. The statistical evaluation of medical tests for classification and prediction Oxford University Press, USA, Liang K, Zeger S. Longitudinal data analysis using generalized linear models. Biometrika, Biometrika Trust 1986;73: Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33: Kirkwood B, Sterne J. Essential Medical Statistics 2 nd ed. 2003, pg 434. John Wiley and Sons. 20. Van den Brekel MW, Stel HV, Castelijins JA, et al. Cervical lymph node metastasis: assessment of radiologic criteria. Radiology 1990;177: Van den Brekel MW, Castelijns JA, Stel HV, Golding RP, Meyer CJ, Snow GB. Modern imaging techniques and ultrasoundguided aspiration cytology for the assessment of neck node metastases: a prospective comparative study. Eur Arch Otorhinolaryngol 1993;250: Castelijns JA, van den Brekel MW. Detection of lymph node metastases in the neck: radiologic criteria. Am J Neuroradiol 2001;22: Curtin HD, Ishwaran H, Mancuso AA, et al. Comparison of CT and MR imaging in stagin of neck metastases. Radiology 1998;207: Som PM. Detection of metastasis in cervical lymph nodes: CT and MR criteria and differential diagnosis. AJR Am J Roentgenol 1992;158: Yoon DY, Hwang HS, Chang SK, et al. CT, MR, US, 18F-FDG PET/CT, and their combined use for the assessment of cervical lymph node metastases in squamous cell carcinoma of the head and neck. Eur Radiol 2009;19: Gordin A, Golz A, Keidar Z, Daitzchman M, Bar-Shalom R, Israel O. The role of FDG-PET/CT imaging in head and neck malignant conditions: impact on diagnostic accuracy and patient care. Otolaryngol Head Neck Surg 2007;137: Ng SH, Ko SF, Toh CH, Chen YL. Imaging of neck metastases. Chang Gung Med J 2006;29: Haerle SK, Strobel K, Ahmad N, Soltermann A, Schmid DT, Stoeckli SJ. Contrast-enhanced 18 F-FDG-PET/CT for the assessment of necrotic lymph node metastases. Head Neck (22 July 2010). DOI: /hed Nakagawa T, Yamada M, Suzuki Y. 18 F-FDG uptake in reactive neck lymph nodes of oral cancer: relationship to lymphoid follicles. J Nucl Med 2008;49: Hoenig J, Heisey D. The abuse of power. Am Statist 2001; 55: Miettinen O. The matched pairs design in the case of all-or-none responses biometrics. JSTOR 1968;24: Nieuwenhuis EJ, Castelijns JA, Pijpers R, et al. Wait-and-see policy for the N0 neck in early-stage oral and oropharyngeal squamous cell carcinoma using ultrasonography-guided cytology: is there a role for identification of the sentinel node? Head Neck 2002;24: Initial Staging of Neck in HNSCC HEAD & NECK DOI /hed April

8 33. Schöder H, Carlson DL, Kraus DH, et al. 18 F-FDG PET/CT for detecting nodal metastases in patients with oral cancer staged N0 by clinical examination and CT/MRI. J Nucl Med 2006; 47: Stoeckli SJ, Steinert H, Pfaltz M, Schmid S. Is there a role for positron emission tomography with 18 F-fluorodeoxyglucose in the initial staging of nodal negative oral and oropharyngeal squamous cell carcinoma. Head Neck 2002;24: Hwang HS, Perez DA, Orloff LA. Comparison of positron emission tomography/computed tomography imaging and ultrasound in staging and surveillance of head and neck and thyroid cancer. Laryngoscope 2009;119: Ng SH, Yen TC, Liao CT, et al. 18 F-FDG PET and CT/MRI in oral cavity squamous cell carcinoma: a prospective study of 124 patients with histologic correlation. J Nucl Med 2005;46: Roh JL, Yeo NK, Kim JS, et al. Utility of 2-[ 18 F]fluoro-2-deoxy- D-glucose positron emission tomography and positron emission tomography/computed tomography imaging in the preoperative staging of head and neck squamous cell carcinoma. Oral Oncol 2007;43: Lonneux M, Hamoir M, Reychler H, et al. Positron emission tomography with [ 18 F]fluorodeoxyglucose improves staging and patient management in patients with head and neck squamous cell carcinoma: a multicenter prospective study. J Clin Oncol 2010;28: Driesel S, Grammerstorff J, Schwenzer K, et al. [ 18 F]-FDG imaging of head and neck tumors: comparison of hybrid PET and morphological methods. Eur J Nucl Med Mol Imaging 2003;30: Rodrigues RS, Bozza FA, Christian PE, et al. Comparison of whole-body PET/CT, dedicated high-resolution head and neck PET/CT, and contrast-enhanced CT in preoperative staging of clinically M0 squamous cell carcinoma of the head and neck. J Nucl Med 2009;50: Kyzas PA, Evangelou E, Denaxa-Kyza D, Ioannidis JPA. 18 F-Fluorodeoxyglucose positron emission tomography to evaluate cervical node metastases in patients with head and neck squamous cell carcinoma: a meta-analysis. J Natl Cancer Inst 2008; 100: Fletcher JW, Djulbegovic B, Soares HP, et al. Recommendations on the use of 18F-FDG PET in oncology. J Nucl Med 2008; 49: Initial Staging of Neck in HNSCC HEAD & NECK DOI /hed April 2012