- Email: [email protected]
CT for diagnosing cervical nodal metastases in patients with oral cavity or oropharynx carcinoma
Vol. 108 No. 6 December 2009
ORAL AND MAXILLOFACIAL RADIOLOGY
Editor: Allan G. Farman
Evaluation of 18F-FDG PET/CT for diagnosing cervical nodal metastases in patients with oral cavity or oropharynx carcinoma Yongnan Piao, MD,a Bayarkhuu Bold, MD,a Abulajiang Tayier, MD,a Ryuji Ishida, MD,a Ken Omura, DDS,b Norihiko Okada, DDS,c and Hitoshi Shibuya, MD, PhD,a Tokyo, Japan TOKYO MEDICAL AND DENTAL UNIVERSITY
(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:933-938)
One of the characteristics of oral cavity or oropharynx cancer is the considerably high frequency of metastasis to the lymph node.1-5 Since the improvement of local control of early-stage oral or oropharynx carcinoma, treatments for the subsequent development of nodal metastases have become extremely important.1-2 The cure rate declines by almost 50% with the involvement of regional lymph nodes and increasing nodal stage.3-5 Between 21% and 45% of N0 oral or oropharynx cancer patients have been reported to harbor metastases in their neck lymph nodes.2,5 Accurate diagnosis of cervical lymph node metastasis and early treatment has therefore become critically important for prognostic purposes. Unfortunately, currently used radiologic criteria are not sensitive enough to diagnose occult metastases.6 Because computerized tomography (CT) and magnetic resonance imaging (MRI) are inaccurate for assessing lymph node status, many head and neck surgeons have adopted a strategy of elective neck dissection with diagnostic and therapeutic intent considering the location and extent of the primary tumor and the likelihood of neck metastasis.6-8 The clinical implications of positron-emission tomography (PET) for nodal staging a
Department of Radiology. Oral and Maxillofacial Surgery. c Diagnostic Oral Pathology. Received for publication Mar 17, 2009; returned for revision Jul 13, 2009; accepted for publication Jul 29, 2009. 1079-2104/$ - see front matter © 2009 Published by Mosby, Inc. doi:10.1016/j.tripleo.2009.07.054 b
of primary head and neck carcinoma may be greatest in a subset of patients who are staged as N0 by clinical examination and CT or MRI.9 If an imaging test can identify or exclude metastasis with reasonable accuracy, patients could be spared unnecessary elective neck dissection. The clinical introduction of combined PET/CT machines has improved the accuracy of PET image interpretation. However, several studies evaluating the role of 18F-fluorodeoxyglucose (FDG) PET/CT have reported contradictory results.9-10 The present study examined the diagnostic accuracy of 18F-FDG PET/CT in patients with oral or oropharynx SCCs who were scheduled to undergo elective neck dissection. MATERIALS AND METHODS From December 2005 to August 2007, 89 consecutive patients who were initially diagnosed as having squamous cell carcinoma (SCC) of the oral cavity or oropharynx underwent 18F-FDG PET/CT. Thirty of these 89 patients were excluded from further analysis because of the long time interval between PET/CT examination and subsequent operation (⬎30 days). Three other cases were excluded because of the small number of nodes examined after sentinel node dissection (⬍10 nodes). The regular type of neck dissection was radical neck dissection (RND) for 55 patients, and 1 case underwent extended supraomohyoid neck dissection (SOHND). Five cases also underwent a contralateral neck dissection (modified RND: 1; extended SOHND: 2; SOHND: 2). Finally, 56 patients (46 men and 10 women), aged 29-78 years, with oral cavity or oropharynx carcinoma were included in this study. All 933
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Table I. Comparison of metastasis to neck nodal levels and nodes identified using positron-emission tomography/computerized tomography (PET/CT) and pathologically Pathology PET/CT Node levels Positive Negative Nodes Positive Negative
Positive
Negative
71 (TP) 14 (FN)
24 (FP) 236 (TN)
103 (TP) 61 (FN)
40 (FP) 2501 (TN)
TP, true positive; FP, false positive; FN, false negative; TN, true negative.
Table II. Sensitivity, specificity, and accuracy of positron-emission tomography/computerized tomography for identifying cervical lymph node level metastasis Sensitivity (%)
Specificity (%)
Accuracy (%)
Fig. 1. Neck lymph node levels: IA, submental; IB, submandibular; II, upper jugular; III, middle jugular; IV, lower jugular; V, posterior triangle.
Node levels Nodes
71/85 (83.5)
236/260 (90.8)
307/345 (89.0)
103/164 (62.8)
2,501/2,541 (98.4)
2,604/2,705 (96.3)
56 patients accepted prophylactic cervical neck dissection. The carcinoma sites were as follows: the tongue in 27 patients (48%), the gingiva in 14 patients (25%), the buccal mucosa in 6 patients (11%), the floor of the mouth in 4 patients (7%), and the oropharynx in 5 patients (9%). During the PET/CT examination, the patients received an intravenous injection of 18F-FDG (3.7 MBq/kg body weight) at least 4 hours after a meal. The PET/CT images were then acquired using a PET/CT system (Aquidio; Toshiba Medical Systems, Tokyo, Japan) combining a full-ring PET scanner with lutetium oxyorthosilicate crystals (4.4 ⫻ 4.0 ⫻ 20 mm) and a 16-detector-row CT scanner. First, CT images were acquired from the head to the upper thigh. The technical parameters for the CT scanning were as follows: a detector-row configuration of 2.0 ⫻ 3.2 mm, a pitch of 0.938, a gantry rotation time of 0.5 seconds, a table time of 30 mm/s, automatic exposure control (SD 20), 120 kVp, and a 2.0 mm slice thickness. A whole-body emission PET scan of the same region followed (2 min emission time per bed, 7 or 8 bed positions, 3.375 mm slice thickness, 128 ⫻ 128 matrix). The PET and CT images were then coregistered using positional information for the table and patient. Attenuation correction of the PET images was performed using CT data and the hybrid segmentation method. Then the PET images
were reconstructed using an iterative reconstruction with an ordered-subset expectation maximization algorithm (3 iterations, 8 subsets). Each of the patients provided their written informed consent before undergoing the PET/CT procedure. The PET/CT findings were interpreted by 2 experienced radiologist physicians, who were required to arrive at a consensus, and were then compared with the histopathologic results. The criterion to distinguish between positive and negative nodes was standardized uptake value (SUV) ⬎2.5. Sites with focal 18F-FDG uptake in the neck were recorded on the basis of the neck side (left or right) and the lymph node level using a widely accepted scheme (IA, IB, II, III, IV, V; Fig. 1).11-12 During the histopathologic examinations, each dissected node in the surgical specimen was classified as either nonmetastatic or metastatic. Based on the histopatologic confirmation, the sensitivity, specificity, and accuracy of the PET/CT results for the detection of cervical lymph node metastasis were then obtained. RESULTS Elective neck dissections (51 unilateral, 5 bilateral: a total of 61 neck sides) involving 366 nodal levels were performed. A total of 2,705 lymph nodes were identified in all 56 dissected neck specimens (mean 44 lymph nodes per neck side). Histopathologically, 17 of the 56
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Fig. 2. Carcinoma of the tongue and metastasis to left submental nodes (IB level) (71 years old, male, SUV 3.8, size 14 ⫻ 10 mm).
Fig. 3. Carcinoma of the gingiva on the right side and metastasis to left upper jugular nodes (II level) (65 years old, female, SUV 3.3, size 6 ⫻ 9 mm).
patients had a negative neck (N0) and 39 had a positive neck (N⫹). Histopathologic examination revealed 164 nodal metastases in 43 of the 61 neck sides and 85 of the 345 nodal levels (Table I). Abnormal 18F-FDG uptakes were noted in 95 of the 366 nodal levels. The intensity of the 18F-FDG uptakes in these lesions ranged from mild to very intense, with a delayed SUV range of 2.6-11.1. As for the detection
of metastasis at the cervical nodal level, the sensitivity, specificity, and accuracy were 83.5% (71/85), 90.8% (236/260), and 89.0% (307/345), respectively (Table II). The false-positive rate (FPR) and the false-negative rate (FNR) were 25.3% (24/95) and 5.6% (14/250), respectively. Abnormal 18F-FDG uptakes were noted in 103 of all 164 histopathologically positive nodes. The PET/CT
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findings were true-positive in 103 nodes (sensitivity 62.8%), false-negative in 61 nodes, true-negative in 2,501 nodes (specificity 98.4%), and false-positive in 40 nodes; the accuracy was 96.3% (2,604/2,705) (Table II). False-negative metastases included 61 nodes, 57 of which had a maximum diameter of ⬍10 mm, as determined using the surgical specimens. All 90 lymph nodes with a maximum diameter of ⬎10 mm were metastatic (Fig. 2). Only 13 of the 70 histopathologically positive nodes with a maximum diameter of ⬍10 mm were positive on 18F-FDG PET/CT (Fig. 3). Of the 164 histopathologically positive nodes, 94 had a maximum diameter of ⬎10 mm, and 70 of the 164 histopathologically positive nodes had a maximum diameter of ⬍10 mm (Table III). Three nodes with micrometastases of ⬍10 mm in diameter were found in otherwise normal lymph node tissue; these nodes were negative on 18F-FDG PET/CT. DISCUSSION Early-stage oral or oropharynx SCC can be successfully treated using surgery and/or radiotherapy, and both modalities yield equivalent local control rates.1-3 Because good primary control can be achieved, the subsequent development of nodal metastases is extremely important. The treatment of neck node metastases in patients with head and neck SCC can be divided into 2 schools of thought: the wait and watch approach, and the routine performance of selective neck dissection during which sentinel lymph nodes are removed en bloc from the neck.13 Shöder Heiko et al.9 reported PET/CT findings of metastasis of nodal levels, with similar results to ours of sensitivity (67% and 84%, respectively), specificity (95% and 91%), positive predictive value (PPV; 50% and 75%), negative predictive value (NPV; 98% and 94%), and accuracy (94% and 89%) of 18F-FDG PET/CT for identifying cervical node levels metastases (Table IV). Furthermore, the sensitivity and PPV of our study were higher than those of Shöder Heiko group. Detection of level of nodal metastases is more important than the detection of nodal metastases to help clinicians to decide treatment plan for patients, 18F-FDG PET/CT scanning is valuable to provide this kind of information to clinicians. To assess nodal metastasis, many clinicians rely on imaging studies to determine the need for further surgical interventions. MRI and CT studies can be used to visualize macroscopic features, such as the size, shape, and patterns of enhancement and the presence of hypodense centers suggesting lymph node metastasis.14 Regarding N⫹ necks, the sensitivity and specificity of CT scanning have been reported to be 78%-83% and 83%86%, respectively.15
Table III. Classification by size for cervical lymph nodes with the metastasis confirmed by histopathology PET/CT Size (mm)
TP
FN
⬎10 ⬍10 Total
90 13 103
4 57 61
Abbreviations as in Table I.
Table IV. Comparison of sensitivity, specificity, PPV, NPV, and accuracy for node levels between Shöder Heiko group9 and the present study results TP FP TN FN Total Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%)
Shöder Heiko
Present study
6 6 127 3 142 67 95 50 98 94
71 24 236 14 345 84 91 75 94 89
PPV, Positive predictive value; NPV, negative predictive value; other abbreviations as in Table I.
In many studies evaluating patients with N⫹ necks, 18F-FDG PET has been generally reported to be the procedure of choice, with the highest sensitivity (67%100%) and specificity (64%-100%) compared with CT or MRI for detecting lymph node metastases, although 1 study reported a higher specificity (90%) and sensitivity (84%) for CT compared with 18F-FDG PET (83% and 82%, respectively).16-17 Other groups reported the sensitivity of 18F-FDG PET to be 67% and the specificity to be between 85% and 95%.9,18 Those groups concluded that a negative test could exclude metastatic deposits with a high specificity but that the clinical application of PET/CT in N0 necks may be of limited value because of the relatively high number of false-positive findings. Another group of investigators reported that 18F-FDG PET failed to identify nodal disease in all 4 of their patients with histologically proven lymph node metastases and concluded that they could not recommend the use of 18F-FDG PET for the evaluation of N0 necks in patients with early-stage oral SCC.19 Nahmias et al.10 reported the sensitivity and specificity of 18F-FDG PET/CT for identifying N⫹ necks with nodal metastases to be 95% and 25%, respectively. They also reported a sensitivity of 79% and a specificity of 82% for identifying N0 necks with nodal metastasis. Although a sensitivity of 63% for the diagnosis of
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individual nodal metastasis in our analysis may seem low, the sensitivity according to the nodal level was 83%, which was not low compared with the reported diagnostic performance of 18F-FDG PET.20-22 The idea of grouping neck nodes at each level may be appropriate for the treatment of neck node metastases, because neck surgery is usually undertaken according to the neck level. The disparity between the results of many clinical preoperative studies and the surgical findings may be related to the surgical approach as well as the detail to which the lymph nodes in the neck are examined by the pathologist. Van den Brekel et al.23 carried out a meticulous histopathologic examination of 119 complete neck dissections and found an average of 45.5 lymph nodes in each specimen. In all, 338 nodes (5.7%) in 92 neck dissection specimens (60%) from 77 patients (67%) proved to contain metastases on routine histopathologic examination. They compared the CT findings and the histopathologic size of the lymph nodes and noted that metastatic nodes larger than 12 mm were diagnosed as metastases. In our analysis, an average of 44 lymph nodes were found in the 61 neck dissection specimens, and 164 nodes (6%) in the 43 neck dissection specimens (70%) were found to contain metastases. Even though the error rate of 18F-FDG PET/CT for the detection of nodal disease was relatively low at 3.7% in the present study (a total of 101 nodes were misdiagnosed out of 2,705 nodes examined), the sensitivity of the histopathologically positive nodes according to 18F-FDG PET/CT was 63% (103/164). The main reason for the low sensitivity was the size of the metastatic nodes. Approximately 37% (61/164) of all the metastatic nodes and 81% (57/70) of the metastatic nodes with a maximum diameter of ⬍10 mm escaped detection in our study, but a greater proportion of positive nodes might have escaped detection by 18FFDG PET imaging alone. During the diagnosis of metastatic nodes, the entire metastatic node is assumed to be occupied by malignant cells. This assumption is not always true, however, because a number of nodes that are reported as being histopathologically positive only contain micrometastases. Metastatic deposits small enough to evade detection on clinical or radiographic examination may exist, but these deposits are likely to be detected by hematoxylin and eosin staining and light microscopy. Although the prognostic significance of such microscopic occult metastases has not been completely elucidated, pathologic up-staging of clinically N0 necks can occur in as many as one-third of patients.24 Other groups have reported that 18F-FDG PET has a poor sensitivity (20%-33%) for detecting occult metastasis.25-26 Limited sensitivity related to the size of the metastatic
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deposits is a particular problem in oral SCC, because ⬎50% of metastases occur in lymph nodes that are ⬍10 mm in diameter.27-28 Positron-emission tomography is limited because of poor anatomic information and localization of the viscera; CT or MRI clearly shows morphologic information, and the combination of CT or MRI with PET can solve this problem to a large extent owing to the precise measurement of tumor or node size by CT or MRI. Ogura et al.29 reported that the sensitivity of CT varied with the level in the neck and ranged from 85% at level I to 25% at level V. The sensitivity of levels I-II and levels III-V was 80.9% and 53.6%, respectively. Thus, the combination of CT with PET can improve accuracy for early detection of metastastic nodes and can help clinicians to decide the proper treatment for patients. Although 18F-FDG PET/CT may be more accurate for lymph node staging than other diagnostic imaging studies, this study by itself is insufficient to affect patient management. For instance, the treatment approach would not change if PET were to detect additional lymph node metastases unless those metastases were located outside of the planned surgical or radiation field. On the other hand, over one-fourth (40 out of 143) of the neck regions identified as positive using 18F-FDG PET/CT did not contain any disease. This leads to the conclusion that a positive test result would not help the clinician in the management of patients with clinically N0 disease. Although the limited spatial resolution and contrast recovery of PET reduces the sensitivity of 18F-FDG PET/CT for identifying individual malignant lymph nodes, fused images provide excellent anatomic depictions of positive lymph nodes. Regarding the patients with clinically negative necks, a negative test result does not help the clinician to manage patients, because of the possibility of false-negative results. Regarding nodal levels, the sensitivity of the imaging procedure (83%) is such that the results may help the clinician to decide which level to treat and which to spare. Nevertheless, oral/head and neck oncologists should not base the need for neck surgery in clinically negative or clinically positive necks based on the results of 18F-FDG PET/CT imaging alone. CONCLUSIONS Combined PET/CT enabled the early detection of cervical nodal metastasis of oral or oropharynx cancers, but the diagnosis of metastasis was not accurate if the metastases had a maximum diameter of ⬍10 mm. Combined PET/CT can accurately detect lymph node metastases levels to supply good information to surgeons for early treatment of patients.
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REFERENCES 1. Yii NW, Patel PH, Rhys-Evans PH, Breach NM. Management of the N0 neck in early cancer of the oral tongue. Clin Otolaryngol 1999;24:75-9. 2. Nakagawa T, Shibuya M, Yoshimura R, Miura M, Okada N, Kishimoto S, et al. Neck node metastasis after successful brachytherapy for early stage tongue carcinoma. Radiother Oncol 1991;21:100-6. 3. Tankere F, Camproux A, Barry B, Guedon C, Depondt J, Gehanno P. Prognostic value of lymph node involvement in oral cancers: a study of 137 cases. Laryngoscope 2000;110:2061-5. 4. Brockstein B, Haraf DJ, Rademaker AW, et al. Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience. Ann Oncol 2004;15:1179-86. 5. Woolgar JA, Rogers SN, Lone D, Brown JS, Vaughan ED. Cervical lymph node metastasis in oral cancer: the importance of even microscopic extracapsular spread. Oral Oncol 2003;39: 130-7. 6. Castelijns JA, van den Brekel MW. Imaging of lymphadenopathy in the neck. Eur Radiol 2002;12:727-38. 7. Robbins KT, Clayman G, Levine PA, Medina J, Sessions R, Shaha A, et al. Neck dissection classification update: revisions proposed by the American Head and Neck Society and the American Academy of Otolaryngology–Head and Neck Surgery. Arch Otolaryngol Head Neck Surg 2002;128:751-8. 8. Ferlito A, Rinaldo A, Silver CE, Gourin CG, Shah JP, Clayman GL, et al. Elective and therapeutic selective neck dissection. Oral Oncol 2006;42:14-25. 9. Shöder Heiko, Carison DL, Kraus DH, Stambuk HE, Gönen M, Erdi YE, et al. 18F-FDG PET/CT for detecting nodal metastases in patients with oral cancer staged N0 by clinical examination and CT/MRI. J Nucl Med 2006;47:755-62. 10. Nahmias C, Carison ER, Duncan LD, Blodgett TM, Kennedy J, Long MJ, et al. Positron emission tomography/computed tomography (PET/CT) scanning for preoperative staging of patients with oral/head and neck cancer. J Oral Maxillofac Surg 2007; 65:2524-35. 11. Shah JP, Strong E, Spiro RH, Vikram B. Surgical grand rounds. Neck dissection: current status and future possibilities. Clin Bull 1981;11:25-33. 12. Som PM, Curtin HD, Mancuso AA. Imaging-based nodal classification for evaluation of neck metastatic adenopathy. AJR Am J Roentgenol 2000;174:837-44. 13. Nieuwenhuis EJ, Castelijns JA, Pijpers, van den Brekel MW, Brakenhoff RH, van der Waal I, 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; 24:282-9. 14. Curtin HD, Ishwara H, Mancuso AA, Dalley RW, Caudry DJ, McNeil BJ. Comparison of CT and MR imaging in staging of neck metastases. Radiology 1998;207:123-30. 15. Akog˘lu E, Dutipek M, Bekis¸ R, Deg˘irmenci B, Ada E, Güneri A. Assessment methods in patients with head and neck squamous cell carcinoma. J Otolaryngol 2005;34:384-94. 16. Hao SP, Ng SH. Magnetic resonance imaging versus clinical palpation in evaluating cervical metastasis from head and neck cancer. Otolaryngol Head Neck Surg 2000;123:324-7. 17. McGuirt WF, Williams DW 3rd, Keyes JW Jr, Greven KM,
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Watson NE Jr, Geisinger KR, Cappellari JO. A comparative diagnostic study of head and neck nodal metastases using positron emission tomography. Laryngoscope 1995;105:373-5. Brouwer J, de Bree R, Comans EF, Castelijns JA, Hoekstra OS, Leemans CR. Positron emission tomography using [18F] fluorodeoxyglucose (FDG-PET) in the clinically negative neck: Is it likely to be superior? Eur Arch Otorhinolaryngol 2004;261: 479-83. Hyde NC, Prvulovich E, Newman L, Waddington WA, Visvikis D, Ell P. A new approach to pre-treatment assessment of the NO neck in oral squamous cell carcinoma: the role of sentinel node biopsy and positron emission tomography. Oral Oncol 2003; 39:350-60. Ng SH, Yen TC, Liao CT, Chang JT, Chan SC, Ko SF, et al. 18F-FDG PET and CT/MRI in oral cavity squamous cell carcinoma: a prospective study of 124 patients with histologic correlation. J Nucl Med 2005;46:1136-43. Wong RJ, Lin DT, Shoder H, Patel SG, Gonen M, Wolden S, et al. Diagnostic and prognostic value of [18F] fluorodeoxyglucose positron emission tomography for recurrent head and neck squamous cell carcinoma. J Clin Oncol 2002;20:4199-208. Stoeckli SJ, Steinert H, Pfalts M, Schmid S. Is there a role for positron emission tomography with 18F-fluorodeoxyglucose in the initial staging of nodal negative oral and oropharyngeal squamous cell carcinoma. Head Neck 2002;24:345-9. Van den Brekel MW, Stel HV, Van der valk P, van der Waal I, Meyer CJ, Snow GB. Micrometastases from squamous cell carcinoma in neck dissection specimens. Eur Arch Otorhinolaryngol 1992;249:349-53. Ross GL, Ross DG, MacDonald DG, Shoaib T, Camilleri IG. Robertson AG. Improved staging of cervical metastases in clinically node-negative patients with head and neck squamous cell carcinoma. Ann Surg Oncol 2004;11:213-8. Civantos FJ, Gomez C, Duque C, Pedroso F, Goodwin WJ, Weed DT, et al. Sentinel node biopsy in oral cavity cancer: correlation with PET scan and immunohistochemistry. Head Neck 2003;25:1-9. Wensing BM, Vogel WV, Marres HA, Merkx MA, Postema EJ, Oyen WJ, van den Hoogen FJ. FDG-PET in the clinically negative neck in oral squamous cell carcinoma, Laryngoscope 2006;116:809-13. Van den Brekel MW, van der Waal I, Meijer CJ, Freeman JL, Castelijns JA, Snow GB. The incidence of micrometastases in neck dissection specimens obtained from elective neck dissections. Laryngoscope 1996;106:987-91. Don DM, Anzai Y, Lufkin RB, Fu YS, Calcaterra TC. Evaluation of cervical lymph node metastases in squamous cell carcinoma of the head and neck. Laryngoscope 1995;105:669-74. Ogura I, Kurabayashi T, Amagasa T, Sasaki T. Diagnostic accuracy of computed tomography for cervical metastases at different anatomical levels in carcinoma of the tongue. Dentomaxillofac Radiol 2001;30:246-8.
Reprint requests: Yongnan Piao, MD Department of Radiology Tokyo Medical and Dental University 5-45 Yushima 1 chome Bunkyo-ku, 113-8519 Japan [email protected]
ORAL AND MAXILLOFACIAL RADIOLOGY
Editor: Allan G. Farman
Evaluation of 18F-FDG PET/CT for diagnosing cervical nodal metastases in patients with oral cavity or oropharynx carcinoma Yongnan Piao, MD,a Bayarkhuu Bold, MD,a Abulajiang Tayier, MD,a Ryuji Ishida, MD,a Ken Omura, DDS,b Norihiko Okada, DDS,c and Hitoshi Shibuya, MD, PhD,a Tokyo, Japan TOKYO MEDICAL AND DENTAL UNIVERSITY
(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:933-938)
One of the characteristics of oral cavity or oropharynx cancer is the considerably high frequency of metastasis to the lymph node.1-5 Since the improvement of local control of early-stage oral or oropharynx carcinoma, treatments for the subsequent development of nodal metastases have become extremely important.1-2 The cure rate declines by almost 50% with the involvement of regional lymph nodes and increasing nodal stage.3-5 Between 21% and 45% of N0 oral or oropharynx cancer patients have been reported to harbor metastases in their neck lymph nodes.2,5 Accurate diagnosis of cervical lymph node metastasis and early treatment has therefore become critically important for prognostic purposes. Unfortunately, currently used radiologic criteria are not sensitive enough to diagnose occult metastases.6 Because computerized tomography (CT) and magnetic resonance imaging (MRI) are inaccurate for assessing lymph node status, many head and neck surgeons have adopted a strategy of elective neck dissection with diagnostic and therapeutic intent considering the location and extent of the primary tumor and the likelihood of neck metastasis.6-8 The clinical implications of positron-emission tomography (PET) for nodal staging a
Department of Radiology. Oral and Maxillofacial Surgery. c Diagnostic Oral Pathology. Received for publication Mar 17, 2009; returned for revision Jul 13, 2009; accepted for publication Jul 29, 2009. 1079-2104/$ - see front matter © 2009 Published by Mosby, Inc. doi:10.1016/j.tripleo.2009.07.054 b
of primary head and neck carcinoma may be greatest in a subset of patients who are staged as N0 by clinical examination and CT or MRI.9 If an imaging test can identify or exclude metastasis with reasonable accuracy, patients could be spared unnecessary elective neck dissection. The clinical introduction of combined PET/CT machines has improved the accuracy of PET image interpretation. However, several studies evaluating the role of 18F-fluorodeoxyglucose (FDG) PET/CT have reported contradictory results.9-10 The present study examined the diagnostic accuracy of 18F-FDG PET/CT in patients with oral or oropharynx SCCs who were scheduled to undergo elective neck dissection. MATERIALS AND METHODS From December 2005 to August 2007, 89 consecutive patients who were initially diagnosed as having squamous cell carcinoma (SCC) of the oral cavity or oropharynx underwent 18F-FDG PET/CT. Thirty of these 89 patients were excluded from further analysis because of the long time interval between PET/CT examination and subsequent operation (⬎30 days). Three other cases were excluded because of the small number of nodes examined after sentinel node dissection (⬍10 nodes). The regular type of neck dissection was radical neck dissection (RND) for 55 patients, and 1 case underwent extended supraomohyoid neck dissection (SOHND). Five cases also underwent a contralateral neck dissection (modified RND: 1; extended SOHND: 2; SOHND: 2). Finally, 56 patients (46 men and 10 women), aged 29-78 years, with oral cavity or oropharynx carcinoma were included in this study. All 933
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Table I. Comparison of metastasis to neck nodal levels and nodes identified using positron-emission tomography/computerized tomography (PET/CT) and pathologically Pathology PET/CT Node levels Positive Negative Nodes Positive Negative
Positive
Negative
71 (TP) 14 (FN)
24 (FP) 236 (TN)
103 (TP) 61 (FN)
40 (FP) 2501 (TN)
TP, true positive; FP, false positive; FN, false negative; TN, true negative.
Table II. Sensitivity, specificity, and accuracy of positron-emission tomography/computerized tomography for identifying cervical lymph node level metastasis Sensitivity (%)
Specificity (%)
Accuracy (%)
Fig. 1. Neck lymph node levels: IA, submental; IB, submandibular; II, upper jugular; III, middle jugular; IV, lower jugular; V, posterior triangle.
Node levels Nodes
71/85 (83.5)
236/260 (90.8)
307/345 (89.0)
103/164 (62.8)
2,501/2,541 (98.4)
2,604/2,705 (96.3)
56 patients accepted prophylactic cervical neck dissection. The carcinoma sites were as follows: the tongue in 27 patients (48%), the gingiva in 14 patients (25%), the buccal mucosa in 6 patients (11%), the floor of the mouth in 4 patients (7%), and the oropharynx in 5 patients (9%). During the PET/CT examination, the patients received an intravenous injection of 18F-FDG (3.7 MBq/kg body weight) at least 4 hours after a meal. The PET/CT images were then acquired using a PET/CT system (Aquidio; Toshiba Medical Systems, Tokyo, Japan) combining a full-ring PET scanner with lutetium oxyorthosilicate crystals (4.4 ⫻ 4.0 ⫻ 20 mm) and a 16-detector-row CT scanner. First, CT images were acquired from the head to the upper thigh. The technical parameters for the CT scanning were as follows: a detector-row configuration of 2.0 ⫻ 3.2 mm, a pitch of 0.938, a gantry rotation time of 0.5 seconds, a table time of 30 mm/s, automatic exposure control (SD 20), 120 kVp, and a 2.0 mm slice thickness. A whole-body emission PET scan of the same region followed (2 min emission time per bed, 7 or 8 bed positions, 3.375 mm slice thickness, 128 ⫻ 128 matrix). The PET and CT images were then coregistered using positional information for the table and patient. Attenuation correction of the PET images was performed using CT data and the hybrid segmentation method. Then the PET images
were reconstructed using an iterative reconstruction with an ordered-subset expectation maximization algorithm (3 iterations, 8 subsets). Each of the patients provided their written informed consent before undergoing the PET/CT procedure. The PET/CT findings were interpreted by 2 experienced radiologist physicians, who were required to arrive at a consensus, and were then compared with the histopathologic results. The criterion to distinguish between positive and negative nodes was standardized uptake value (SUV) ⬎2.5. Sites with focal 18F-FDG uptake in the neck were recorded on the basis of the neck side (left or right) and the lymph node level using a widely accepted scheme (IA, IB, II, III, IV, V; Fig. 1).11-12 During the histopathologic examinations, each dissected node in the surgical specimen was classified as either nonmetastatic or metastatic. Based on the histopatologic confirmation, the sensitivity, specificity, and accuracy of the PET/CT results for the detection of cervical lymph node metastasis were then obtained. RESULTS Elective neck dissections (51 unilateral, 5 bilateral: a total of 61 neck sides) involving 366 nodal levels were performed. A total of 2,705 lymph nodes were identified in all 56 dissected neck specimens (mean 44 lymph nodes per neck side). Histopathologically, 17 of the 56
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Fig. 2. Carcinoma of the tongue and metastasis to left submental nodes (IB level) (71 years old, male, SUV 3.8, size 14 ⫻ 10 mm).
Fig. 3. Carcinoma of the gingiva on the right side and metastasis to left upper jugular nodes (II level) (65 years old, female, SUV 3.3, size 6 ⫻ 9 mm).
patients had a negative neck (N0) and 39 had a positive neck (N⫹). Histopathologic examination revealed 164 nodal metastases in 43 of the 61 neck sides and 85 of the 345 nodal levels (Table I). Abnormal 18F-FDG uptakes were noted in 95 of the 366 nodal levels. The intensity of the 18F-FDG uptakes in these lesions ranged from mild to very intense, with a delayed SUV range of 2.6-11.1. As for the detection
of metastasis at the cervical nodal level, the sensitivity, specificity, and accuracy were 83.5% (71/85), 90.8% (236/260), and 89.0% (307/345), respectively (Table II). The false-positive rate (FPR) and the false-negative rate (FNR) were 25.3% (24/95) and 5.6% (14/250), respectively. Abnormal 18F-FDG uptakes were noted in 103 of all 164 histopathologically positive nodes. The PET/CT
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findings were true-positive in 103 nodes (sensitivity 62.8%), false-negative in 61 nodes, true-negative in 2,501 nodes (specificity 98.4%), and false-positive in 40 nodes; the accuracy was 96.3% (2,604/2,705) (Table II). False-negative metastases included 61 nodes, 57 of which had a maximum diameter of ⬍10 mm, as determined using the surgical specimens. All 90 lymph nodes with a maximum diameter of ⬎10 mm were metastatic (Fig. 2). Only 13 of the 70 histopathologically positive nodes with a maximum diameter of ⬍10 mm were positive on 18F-FDG PET/CT (Fig. 3). Of the 164 histopathologically positive nodes, 94 had a maximum diameter of ⬎10 mm, and 70 of the 164 histopathologically positive nodes had a maximum diameter of ⬍10 mm (Table III). Three nodes with micrometastases of ⬍10 mm in diameter were found in otherwise normal lymph node tissue; these nodes were negative on 18F-FDG PET/CT. DISCUSSION Early-stage oral or oropharynx SCC can be successfully treated using surgery and/or radiotherapy, and both modalities yield equivalent local control rates.1-3 Because good primary control can be achieved, the subsequent development of nodal metastases is extremely important. The treatment of neck node metastases in patients with head and neck SCC can be divided into 2 schools of thought: the wait and watch approach, and the routine performance of selective neck dissection during which sentinel lymph nodes are removed en bloc from the neck.13 Shöder Heiko et al.9 reported PET/CT findings of metastasis of nodal levels, with similar results to ours of sensitivity (67% and 84%, respectively), specificity (95% and 91%), positive predictive value (PPV; 50% and 75%), negative predictive value (NPV; 98% and 94%), and accuracy (94% and 89%) of 18F-FDG PET/CT for identifying cervical node levels metastases (Table IV). Furthermore, the sensitivity and PPV of our study were higher than those of Shöder Heiko group. Detection of level of nodal metastases is more important than the detection of nodal metastases to help clinicians to decide treatment plan for patients, 18F-FDG PET/CT scanning is valuable to provide this kind of information to clinicians. To assess nodal metastasis, many clinicians rely on imaging studies to determine the need for further surgical interventions. MRI and CT studies can be used to visualize macroscopic features, such as the size, shape, and patterns of enhancement and the presence of hypodense centers suggesting lymph node metastasis.14 Regarding N⫹ necks, the sensitivity and specificity of CT scanning have been reported to be 78%-83% and 83%86%, respectively.15
Table III. Classification by size for cervical lymph nodes with the metastasis confirmed by histopathology PET/CT Size (mm)
TP
FN
⬎10 ⬍10 Total
90 13 103
4 57 61
Abbreviations as in Table I.
Table IV. Comparison of sensitivity, specificity, PPV, NPV, and accuracy for node levels between Shöder Heiko group9 and the present study results TP FP TN FN Total Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%)
Shöder Heiko
Present study
6 6 127 3 142 67 95 50 98 94
71 24 236 14 345 84 91 75 94 89
PPV, Positive predictive value; NPV, negative predictive value; other abbreviations as in Table I.
In many studies evaluating patients with N⫹ necks, 18F-FDG PET has been generally reported to be the procedure of choice, with the highest sensitivity (67%100%) and specificity (64%-100%) compared with CT or MRI for detecting lymph node metastases, although 1 study reported a higher specificity (90%) and sensitivity (84%) for CT compared with 18F-FDG PET (83% and 82%, respectively).16-17 Other groups reported the sensitivity of 18F-FDG PET to be 67% and the specificity to be between 85% and 95%.9,18 Those groups concluded that a negative test could exclude metastatic deposits with a high specificity but that the clinical application of PET/CT in N0 necks may be of limited value because of the relatively high number of false-positive findings. Another group of investigators reported that 18F-FDG PET failed to identify nodal disease in all 4 of their patients with histologically proven lymph node metastases and concluded that they could not recommend the use of 18F-FDG PET for the evaluation of N0 necks in patients with early-stage oral SCC.19 Nahmias et al.10 reported the sensitivity and specificity of 18F-FDG PET/CT for identifying N⫹ necks with nodal metastases to be 95% and 25%, respectively. They also reported a sensitivity of 79% and a specificity of 82% for identifying N0 necks with nodal metastasis. Although a sensitivity of 63% for the diagnosis of
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individual nodal metastasis in our analysis may seem low, the sensitivity according to the nodal level was 83%, which was not low compared with the reported diagnostic performance of 18F-FDG PET.20-22 The idea of grouping neck nodes at each level may be appropriate for the treatment of neck node metastases, because neck surgery is usually undertaken according to the neck level. The disparity between the results of many clinical preoperative studies and the surgical findings may be related to the surgical approach as well as the detail to which the lymph nodes in the neck are examined by the pathologist. Van den Brekel et al.23 carried out a meticulous histopathologic examination of 119 complete neck dissections and found an average of 45.5 lymph nodes in each specimen. In all, 338 nodes (5.7%) in 92 neck dissection specimens (60%) from 77 patients (67%) proved to contain metastases on routine histopathologic examination. They compared the CT findings and the histopathologic size of the lymph nodes and noted that metastatic nodes larger than 12 mm were diagnosed as metastases. In our analysis, an average of 44 lymph nodes were found in the 61 neck dissection specimens, and 164 nodes (6%) in the 43 neck dissection specimens (70%) were found to contain metastases. Even though the error rate of 18F-FDG PET/CT for the detection of nodal disease was relatively low at 3.7% in the present study (a total of 101 nodes were misdiagnosed out of 2,705 nodes examined), the sensitivity of the histopathologically positive nodes according to 18F-FDG PET/CT was 63% (103/164). The main reason for the low sensitivity was the size of the metastatic nodes. Approximately 37% (61/164) of all the metastatic nodes and 81% (57/70) of the metastatic nodes with a maximum diameter of ⬍10 mm escaped detection in our study, but a greater proportion of positive nodes might have escaped detection by 18FFDG PET imaging alone. During the diagnosis of metastatic nodes, the entire metastatic node is assumed to be occupied by malignant cells. This assumption is not always true, however, because a number of nodes that are reported as being histopathologically positive only contain micrometastases. Metastatic deposits small enough to evade detection on clinical or radiographic examination may exist, but these deposits are likely to be detected by hematoxylin and eosin staining and light microscopy. Although the prognostic significance of such microscopic occult metastases has not been completely elucidated, pathologic up-staging of clinically N0 necks can occur in as many as one-third of patients.24 Other groups have reported that 18F-FDG PET has a poor sensitivity (20%-33%) for detecting occult metastasis.25-26 Limited sensitivity related to the size of the metastatic
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deposits is a particular problem in oral SCC, because ⬎50% of metastases occur in lymph nodes that are ⬍10 mm in diameter.27-28 Positron-emission tomography is limited because of poor anatomic information and localization of the viscera; CT or MRI clearly shows morphologic information, and the combination of CT or MRI with PET can solve this problem to a large extent owing to the precise measurement of tumor or node size by CT or MRI. Ogura et al.29 reported that the sensitivity of CT varied with the level in the neck and ranged from 85% at level I to 25% at level V. The sensitivity of levels I-II and levels III-V was 80.9% and 53.6%, respectively. Thus, the combination of CT with PET can improve accuracy for early detection of metastastic nodes and can help clinicians to decide the proper treatment for patients. Although 18F-FDG PET/CT may be more accurate for lymph node staging than other diagnostic imaging studies, this study by itself is insufficient to affect patient management. For instance, the treatment approach would not change if PET were to detect additional lymph node metastases unless those metastases were located outside of the planned surgical or radiation field. On the other hand, over one-fourth (40 out of 143) of the neck regions identified as positive using 18F-FDG PET/CT did not contain any disease. This leads to the conclusion that a positive test result would not help the clinician in the management of patients with clinically N0 disease. Although the limited spatial resolution and contrast recovery of PET reduces the sensitivity of 18F-FDG PET/CT for identifying individual malignant lymph nodes, fused images provide excellent anatomic depictions of positive lymph nodes. Regarding the patients with clinically negative necks, a negative test result does not help the clinician to manage patients, because of the possibility of false-negative results. Regarding nodal levels, the sensitivity of the imaging procedure (83%) is such that the results may help the clinician to decide which level to treat and which to spare. Nevertheless, oral/head and neck oncologists should not base the need for neck surgery in clinically negative or clinically positive necks based on the results of 18F-FDG PET/CT imaging alone. CONCLUSIONS Combined PET/CT enabled the early detection of cervical nodal metastasis of oral or oropharynx cancers, but the diagnosis of metastasis was not accurate if the metastases had a maximum diameter of ⬍10 mm. Combined PET/CT can accurately detect lymph node metastases levels to supply good information to surgeons for early treatment of patients.
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Reprint requests: Yongnan Piao, MD Department of Radiology Tokyo Medical and Dental University 5-45 Yushima 1 chome Bunkyo-ku, 113-8519 Japan [email protected]