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Ann Thorac Surg 2009;87:1564-1568. doi:10.1016/j.athoracsur.2009.02.065
© 2009 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Positron Emission Tomography–Computed Tomography in Predicting Locoregional Invasion in Esophageal Squamous Cell Carcinoma

Wen-Hu Hsu, MDa,b,*, Po-Kuei Hsu, MDa,c, Shyh-Jen Wang, MDd, Ko-Han Lin, MDd, Chien-Sheng Huang, MDa, Chih-Cheng Hsieh, MDa, Yu-Chung Wu, MDa

a Division of Thoracic Surgery, Department of Surgery, Taipei-Veterans General Hospital, and National Yang-Ming University School of Medicine, Taipei, Taiwan
b Taipei Medical University School of Medicine, Taipei, Taiwan
c Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
d Department of Nuclear Medicine, Taipei-Veterans General Hospital, Taipei, Taiwan

Accepted for publication February 23, 2009.

* Address correspondence to Dr Wen-Hu Hsu, Division of Thoracic Surgery, Department of Surgery, Taipei-Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Rd, Taipei, Taiwan (Email: whhsu{at}vghtpe.gov.tw).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: In order to clarify the role of positron emission tomography–computed tomography (PET/CT) in thoracic esophageal squamous cell carcinoma we investigated its value in predicting locoregional invasion.

Methods: Forty-five patients receiving curative esophagectomy and lymph node dissection were included. The relationship between PET/CT findings and pathology results were studied. Correlation between nodal uptake and the modified lymph node staging, which is based on number of involved nodes (N0 = no nodes; N1 = 1 to 3 nodes; N2 = more than 3 nodes), was evaluated.

Results: The mean maximal standardized uptake value (SUVmax) was 5.09 ± 4.00 in T1, 14.17 ± 2.46 in T2, 13.32 ± 3.96 in T3, and 10.37 ± 1.94 in T4 primary tumor. The SUVmax was significantly lower in stage T1 tumors than in stage T2 and T3 tumors. For regional nodal involvement, PET/CT findings significantly correlated with pathology results. However, the sensitivity, specificity, and accuracy of PET/CT were only 57.1%, 83.3%, and 71.1%, respectively, and even lower for detecting nonregional lymph node metastasis. When stratified by the modified staging system, the mean SUVmax was 0.64 ± 1.60 in N0, 1.43 ± 2.08 in N1, and 4.67 ± 4.32 in N2 regional lymph node metastases, and was significantly higher in patients with N2 metastasis than in patients with N0 and N1 metastases.

Conclusions: Locoregional invasion in esophageal cancer can be predicted by PET/CT. The SUVmax of the primary tumor helped identify T1 tumor, and the SUVmax of the regional lymph nodes correlated with the severity of nodal involvement.


   Introduction
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 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Information regarding tumor invasion depth, lymph node involvement, and distant metastasis is vital in deciding the appropriate treatment for esophageal cancer. To determine whether complete resection is feasible, locoregional disease extent must be assessed [1]. Conventional imaging tools, including computed tomography (CT) scan and endoscopic ultrasonography (EUS), reveal morphologic features useful for evaluating disease extent, such as size and length. In contrast, 18F-2-deoxy-D-glucose positron emission tomography (FDG-PET) defines lesions on the basis of altered tissue glucose metabolism, complementing the results of anatomic imaging methods [2–4]. For example, FDG-PET can detect metastatic lymph nodes that are not enlarged on CT scan, and usually nonspecifically enlarged lymph nodes do not take up FDG. Tumor uptake of FDG measured as the maximal standardized uptake value (SUVmax) by FDG-PET even provides a quantitative estimate of tumor aggressiveness [2].

Recent studies demonstrate that FDG-PET not only can be used for pretreatment staging, but also for assessment of treatment response, detection of recurrence, and prediction of survival in esophageal cancer patients [2, 5, 6]. However, the spatial resolution of FDG-PET is low compared with that of CT scans. When metastatic nodes abut the primary tumor, it can be difficult to distinguish the uptake of the nodes from the intense activity of the primary tumor. Previous reports indicated that FDG-PET is of limited value in esophageal cancer assessment because its accuracy in staging locoregional lymph nodes is low [7–9]. However, the advent of PET/CT imaging, which is able to coregister both anatomic and functional information, may overcome this disadvantage and improve localization of increased FDG uptake [10].

Although the literature about the use of FDG-PET or PET/CT in esophageal cancer is growing, most of it is focused on esophageal adenocarcinoma [6, 11]. In this report, we evaluate the role of PET/CT in predicting locoregional invasion (tumor invasion depth and nodal involvement) in thoracic esophageal squamous cell carcinoma.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
This retrospective analysis was based on prospectively collected data. From March 2007 to December 2008, 200 patients with esophageal cancer were admitted to the division of thoracic surgery of the department of surgery at Taipei-Veterans General Hospital. The staging workup included physical examination, laboratory tests, esophagogastroduodenoscopy, flexible bronchoscopy, barium esophagography, CT scan from neck to upper abdomen, and whole body PET/CT. Patients without distant metastasis or definite evidence of extensive adjacent organ invasion underwent surgical resection. Lymph node enlargement was not a contraindication to resection as long as the nodes were included in the resection. The exclusion criteria included (1) lack of PET/CT as part of the staging workup; (2) histology other than squamous cell carcinoma; (3) tumor located in the upper segment of the esophagus or at the esophagogastric junction; (4) neoadjuvant chemoradiation; and (5) the absence of curative esophagectomy or three-field (cervical, thoracic, and abdominal) lymph node assessment. The cohort of this study consisted of 45 patients who met the above criteria. Informed consents were given before entry into the study. This study design was approved by the Institutional Review Board of Taipei-Veterans General Hospital.

PET/CT Imaging
All patients fasted at least 6 hours before imaging. The PET/CT imaging was obtained from head to upper portion of the thigh on an integrated PET/CT scanner (Discovery VCT; GE Healthcare, Waukesha, WI) 45 minutes after intravenous injection of 10 mCi (370 MBq) of FDG. Low-dose CT for attenuation correction was performed first with a 64-slice multidetector CT component of the combined PET/CT, and was followed by reconstruction of the PET scan images into a three-dimensional representation using the ordered-subset expectation maximization method. Two experienced nuclear medicine physicians (S.J.W. and K.H.L.) performed all measurements independently. For quantitative analysis of FDG uptake, standardized uptake value (SUV) was assessed. We used the maximal SUV (SUVmax) instead of the mean SUV. The uptake of each lesion was determined in the slice with the maximal SUV. An SUVmax greater than 2.5 was considered positive.

Operative Methods
Most patients were treated using a tri-incisional approach (McKeown type), which included right thoracotomy, midline laparotomy, and left cervicotomy. In the thoracic phase, en-bloc esophagectomy and radical dissection of mediastinal lymph nodes (including recurrent laryngeal nerve nodes, paratracheal nodes, posterior and anterior mediastinal nodes, subcarinal nodes, paraesophageal nodes, and inferior pulmonary ligament nodes) were performed. In the abdominal phase, mobilization of the esophageal substitute and dissection of paracardial nodes and enlarged celiac axis nodes (including celiac nodes, left gastric nodes, common hepatic nodes, and splenic nodes) were performed. Then, the substitute was pulled up and anastomosed to the cervical esophagus. Cervical lymph nodes were sampled during the cervical phase. In the video-assisted thoracoscopic (VATS) esophagectomy group, the esophagus was thorascopically mobilized. The principles of cervical, thoracic, and abdominal lymphadenectomy were the same as mentioned above. In the thoracoabdominal approach group, the incision extended from below scapula, across the costal margin, and obliquely toward umbilicus. The left pleural cavity and abdominal cavity were exposed simultaneously. The surgical principles were the same, too.

Pathology Examination
After esophagectomy, the periesophageal tissue and lymph nodes were dissected from the esophageal specimen. Each dissected node was labeled according to the American Joint Committee on Cancer lymph node classification system [12]. Thereafter, the specimens were preserved in 10% neutral buffered formalin overnight and sent for pathology examination. Description of the tumor (appearance, invasion depth, and differentiation) and the lymph nodes (number in each station) were recorded. The pathologic tumor stage was determined according to the TNM classification system [12]. The lymph nodes were classified as regional or nonregional. The regional lymph nodes included recurrent laryngeal nerve nodes, paratracheal nodes, posterior and anterior mediastinal nodes, subcarinal nodes, paraesophageal nodes, inferior pulmonary ligament nodes, and pericardial nodes. The nonregional lymph nodes included cervical (supraclavicular) and celiac nodes. The regional nodal status was further stratified using the modified staging system previously proposed by Hofstetter and colleagues [13]. In the modified lymph node staging system, the nodal status was classified according to the number of involved nodes: N0 = no nodes; N1 = 1 to 3 nodes; N2 = more than 3 nodes.

Statistics
Continuous variables are expressed as the mean ± SD. A {chi}2 test or Fisher's exact test was used to compare categorical variables. Analysis of variance with post hoc Bonferroni analysis or nonparametric tests (Mann-Whitney U test or Kruskal-Wallis test) were used to compare continuous variables. A receiver operating characteristic curve (ROC) analysis was used to identify the value that optimized the sensitivity and specificity for detecting locoregional invasion. All calculations were performed using SPSS 15.0 software and a p value of less than 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Tumor Invasion Depth
The patient characteristics are summarized in Table 1. The mean SUVmax of the primary tumor was 11.64 ± 5.00 (range, 0 to 23.00). The mean SUVmax of the primary tumor in patients grouped according to T stage was 5.09 ± 4.00 for T1 lesions, 14.17 ± 2.46 for T2; 13.32 ± 3.96 for T3, and 10.37 ± 1.94 for T4. The SUVmax was significantly lower for T1 stage tumors than for T2 and T3 stage tumors (T1 versus T2, p = 0.001; T1 versus T3, p < 0.001). We further stratified patients into two groups using the SUVmax value of 6.5 (ROC analysis generated the value of 6.5 as the optimal cutoff value for predicting T1 and non-T1 status, area under curve = 0.901, p < 0.001). We found T1 lesions in 88.9% of patients (8 of 9) with SUVmax below 6.5, but in only 2.8% of patients (1 of 36) with SUVmax above 6.5 (p < 0.001; Table 2).


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  		Table 1 Demographics
 

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  		Table 2 Relationship Between Tumor Invasion Depth and Tumor SUVmax Below or Above 6.5
 
Lymph Node Involvement
On average, 32 lymph nodes were dissected in each patient. Regional and nonregional lymph node involvement was found in 21 patients (46.7%) and 11 patients (24.4%), respectively. The relationship between positive PET/CT findings (SUVmax > 2.5) and pathology results was evaluated. For regional nodal involvement, this relationship was significant (p = 0.006; Table 3). The sensitivity, specificity, and accuracy of PET/CT in detecting regional lymph node metastasis were 57.1%, 83.3%, and 71.1%, respectively; and for detecting nonregional lymph node metastasis, only 36.4%, 82.4%, and 71.1%, respectively. Thus, PET/CT did not reliably detect nodal involvement.


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  		Table 3 Relationship Between Positive PET/Computed Tomography Findings and Pathology Results for Nodal Involvement
 
The regional nodal involvement was further stratified according to the number of involved nodes (N0 = no nodes; N1 = 1 to 3 nodes; N2 = more than 3 nodes). In the modified lymph node staging system, nodal involvement was classified as N0 in 24 patients, N1 in 11 patients, and N2 in 10 patients. The mean regional lymph node SUVmax in patients grouped according to N stage was 0.64 ± 1.60 for nodal stage N0, 1.43 ± 2.08 for N1, and 4.67 ± 4.32 for N2. The regional lymph node SUVmax was significantly higher in patients with N2 status than in patients with N0 and N1 status (N2 versus N1, p = 0.017; N2 versus N0, p < 0.001). When stratified by the SUVmax value of 3.9 (ROC analysis generated the value of 3.9 as the optimal cutoff value for predicting N2 status, area under curve = 0.814, p = 0.003), modified N status was significantly related to the level of SUVmax (p = 0.021; Table 4). An N2 status was found in 55.6% of patients with regional lymph node SUVmax above 3.9 and in only 13.9% of patients with regional lymph node SUVmax below 3.9.


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  		Table 4 Relationship Between Modified Lymph Node Staging System and Lymph Node SUVmax Below or Above 3.9
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
Although many studies suggest the value of FDT-PET or PET/CT in staging as well as prediction of treatment response and prognosis, the results for esophageal cancer have been contradictory [2, 5, 6]. Van Westreenen and associates [14] reported high false positive (7.5%) and false negative (4.5%) rates for FDG-PET in detecting distant metastasis. They also proposed that FDG-PET has a limited role in staging esophageal cancer, especially in patients with early tumors [14]. A study by Gillham and associates [15] found that FDG uptake failed to predict pathologic tumor response after neoadjuvant chemoradiation in esophageal cancer. The experience of using PET/CT in evaluating squamous cell carcinoma of the esophagus is less than that in evaluating adenocarcinoma of the esophagus. The present study investigated the role of PET/CT in detecting locoregional invasion in thoracic esophageal squamous cell carcinoma.

Only few reports have discussed the value of PET/CT in predicting tumor invasion depth in esophageal cancer. According to Cerfolio and colleagues [2], median SUVmax differs among high-grade dysplasia, T1 to T2 tumors, and T3 to T4 tumors. Rizk and coworkers [11] used a SUVmax cutoff level of 4.5 to stratify patients and found that a lower SUVmax significantly predicted earlier T stage (p < 0.001). However, their result was limited to patients with adenocarcinoma of the esophagogastric junction and distal esophagus [11]. In the present study, the SUVmax was significantly lower for T1 stage esophageal squamous cell carcinoma. Only 1 of 36 patients with SUVmax above 6.5 had T1 stage disease, and only 1 of 9 patients with SUVmax below 6.5 had tumor invasion deeper than the submucosal layer. This SUVmax value helped identifying patients with T1 stage tumors, which could be safely and completely resected with VATS techniques. In the present series, 5 of the 7 patients receiving VATS esophagectomy were in T1.

Endoscopic ultrasonography was not routinely performed in the present study because most patients had dysphagia with near total obstruction of the esophageal lumen, which made EUS infeasible. Although EUS is highly effective in defining tumor invasion depth and nodal involvement in esophageal cancer, its accuracy was reportedly less when tumors are greater than 5 cm in diameter or located at the esophagogastric junction [16–18]. Furthermore, the EUS procedure is operator dependent, invasive, and unable to evaluate tumors that prevent passage of the endoscope [16–18]. In a meta-analysis of the results of EUS, CT, and FDG-PET used in esophageal cancer staging, the random effects pooled sensitivity and specificity of EUS for N stage were 80% and 70%, respectively, whereas the random effects pooled sensitivity and specificity of FDG-PET for regional lymph node metastases were 57% and 85%, respectively. Using the summary ROC approach, differences between EUS and FDG-PET for N staging were not statistically significant. It was concluded that although EUS was more sensitive than FDG-PET for detecting regional lymph node metastases, there were no significant differences in overall diagnostic performance between EUS and PET [19].

In this study, PET/CT, which is a more objective and less invasive method, was used to evaluate nodal involvement. Although positive PET/CT findings and pathologic findings of regional lymph node involvement were significantly correlated, the ability of PET/CT to predict lymph node metastasis remained unsatisfactory. The sensitivity and specificity for detecting regional nodal involvement were 57.1% and 83.3%, respectively. Our result was comparable to the pooled sensitivity and specificity reported in a systematic review, namely, 51% and 84%, respectively [8]. High false negative and false positive rates of PET/CT in detecting nonregional nodal involvement were noted. Microscopic spread, which is low glucose utilization, may account for the false negative rate. Classification as cervical nodes on PET/CT study of some positive nodes located high in the thoracic inlet, removed during thoracic phase surgery, and regarded as regional nodes by pathologists, may account for the false positive rate.

In this study, the relationship between regional lymph node uptake and the modified lymph node staging system (N0 = no involved nodes; N1 = 1 to 3 nodes; N2 = more than 3 nodes) was studied. We found that regional lymph node SUVmax was significantly related to N stage. The SUVmax was significantly higher in N2 stage cases. Therefore, the nodal uptake on PET/CT indicates not only the presence of lymph node metastasis, but also the severity of nodal involvement [13], providing a quantitative measure of lymph node involvement unobtainable by EUS.

In conclusion, the current study showed that PET/CT predicts locoregional invasion in esophageal squamous cell carcinoma. The SUVmax of the primary tumor helps to identify patients with T1 tumors. Positive regional nodal uptake on PET/CT is related to the presence of pathologic lymph node metastasis. Although the sensitivity, specificity, and accuracy of PET/CT in detecting nodal involvement were only moderate, the regional lymph node SUVmax can help evaluating the severity of nodal involvement. Many modifications of esophageal cancer staging system have been proposed [13, 20]; an investigation into the relationship between PET/CT findings and these modifications is needed.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Pennathur A, Luketich JD. Resection for esophageal cancer: strategies for optimal management Ann Thorac Surg 2008;85(Suppl):751-756.
  2. Cerfolio RJ, Bryant AS. Maximum standardized uptake values on positron emission tomography of esophageal cancer predicts stage, tumor biology, and survival Ann Thorac Surg 2006;82:391-395.[Abstract/Free Full Text]
  3. Kato H, Kuwano H, Nakajima M, et al. Comparison between positron emission tomography and computed tomography in the use of the assessment of esophageal carcinoma Cancer 2002;94:921-928.[Medline]
  4. Luketich JD, Schauer PR, Meltzer CC, et al. Role of positron emission tomography in staging esophageal cancer Ann Thorac Surg 1997;64:765-769.[Abstract/Free Full Text]
  5. Ott K, Weber W, Siewert JR. The importance of PET in the diagnosis and response evaluation of esophageal cancer Dis Esophagus 2006;19:433-442.[Medline]
  6. Swisher SG, Maish M, Erasmus JJ, et al. Utility of PET, CT, and EUS to identify pathologic responders in esophageal cancer Ann Thorac Surg 2004;78:1152-1160.[Abstract/Free Full Text]
  7. Westerterp M, Van Westreenen HL, Sloof GW, et al. Role of positron emission tomography in the staging of esophageal cancer Scan J Gastroenterol 2006;41:116-122.
  8. Van Westreenen HL, Westerterp M, Bossuyt PMM, et al. Systematic review of the staging performance of 18F-Fluorodeoxyglucose positron emission tomography in esophageal cancer J Clin Oncol 2004;22:3805-3812.[Abstract/Free Full Text]
  9. Kim K, Park SJ, Kim BT, et al. Evaluation of lymph node metastasis in squamous cell carcinoma of the esophagus with positron emission tomography Ann Thorac Surg 2001;71:290-294.[Abstract/Free Full Text]
  10. Erasmus JJ, Munden RG. The role of integrated computed tomography positron emission tomography in esophageal cancer: staging and assessment of therapeutic response Semin Radiat Oncol 2006;17:29-37.
  11. Rizk N, Downey RJ, Akhurst T, et al. Preoperative 18F-Fluorodeoxyglucose positron emission tomography standardized uptake values predict survival after esophageal adenocarcinoma resection Ann Thorac Surg 2006;81:1076-1082.[Abstract/Free Full Text]
  12. Greene FL, Page DL, Fleming ID, et al. Esophagus American Joint Committee on Cancer (AJCC) cancer staging manual. 6th ed.. New York, NY: Springer; 2002. pp. 167-178.
  13. Hofstetter W, Correa AM, Bekele N, et al. Proposed modification of nodal status in AJCC esophageal cancer staging system Ann Thorac Surg 2007;84:365-375.[Abstract/Free Full Text]
  14. van Westreenen HL, Westerterp M, Sloof GW, et al. Limited additional value of positron emission tomography in staging esophageal cancer Br J Surg 2007;94:1515-1520.[Medline]
  15. Gillham CM, Lucey JA, Keogan M, et al. 18FDG uptake during induction chemoradiation for esophageal cancer fails to predict histomorphological tumor response Br J Cancer 2006;965:1174-1179.
  16. Hunerbein M, Ulmer C, Handke T, et al. Endosonography of upper gastrointestinal tract cancer on demand using miniprobes or endoscopic ultrasound Surg Endosc 2003;4:615-619.
  17. Kelly S, Harris SK, Berry E, et al. A systematic review of the staging performance of endoscopic ultrasound in gastroesophageal carcinoma Gut 2001;49:534-539.[Abstract/Free Full Text]
  18. Choi JY, Lee KH, Shim YM, et al. Improved detection of individual nodal involvement in squamous cell carcinoma of the esophagus by FDG PET J Nucl Med 2000;41:808-815.[Abstract/Free Full Text]
  19. Van Vliet EPM, Heijenbrok-Kal MH, Hunink MGM, et al. Staging investigations for esophageal cancer: a meta-analysis Br J Cancer 2008;98:547-557.[Medline]
  20. Dhar DK, Hattori S, Tonomoto Y, et al. Appraisal of a revised lymph node classification system for esophageal squamous cell cancer Ann Thorac Surg 2007;83:1265-1272.[Abstract/Free Full Text]



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