Research ArticleClinical Studies

Detection Ability of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Clinical T Classification of Synchronous Esophageal Cancer in Pharyngeal Cancer

HIDENORI TSUZUKI, HIDENORI SUZUKI, TSUNEO TAMAKI, MICHIHIKO SONE and NOBUHIRO HANAI
Anticancer Research September 2022, 42 (9) 4597-4602; DOI: https://doi.org/10.21873/anticanres.15963

Abstract

Background/Aim: The utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) for clinical T classification of synchronous esophageal cancer (SEC) in pharyngeal cancer has not been fully elucidated. We investigated the association between 18F-FDG-PET/CT and clinical T classification for SEC. Patients and Methods: We retrospectively enrolled 90 patients with pharyngeal cancer having both Lugol chromoendoscopy and 18F-FDG-PET/CT at pretreatment. The association between 18F-FDG-PET/CT and pathological examination was compared by the Fisher’s exact test. Results: Pathologically, 12 patients with SEC were diagnosed. The number of locations for SEC with cT1a, cT1b, and cT3 was 20, 1, and 1, respectively. Sensitivity for cT1a-cT3, cT1b-cT3, and cT3 was 9.1%, 100%, and 100%, respectively. Locations of SEC with cT1b-cT3 were significantly detected. The locations of SEC with cT1b-cT3 were more frequently detected than those without cT1b-cT3 by 18F-FDG-PET/CT (p<0.01). Conclusion: Detection of SEC with clinical T1b-T3 in comparison to clinical T1a on pretreatment 18F-FDG-PET/CT for patients with pharyngeal cancer, was achieved with high sensitivity.

Key Words:

Synchronous esophageal cancer (SEC) in pharyngeal squamous cell carcinoma (SCC) can be diagnosed by various methods (1-10), one of which is biopsy with upper gastrointestinal (UGI) endoscopy (1-8). However, there are cases where endoscopy cannot be performed due to stenosis caused by pharyngeal cancer. Recently, a systemic review and meta-analysis revealed that UGI Lugol chromoendoscopy had a high diagnostic accuracy, enabling early T classification of SEC in pharyngeal SCC (1).

Screening methods for synchronous cancers based on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) are widely accepted in various types of primary cancers, including pharyngeal SCC (9-11). However, 18F-FDG-PET/CT’s ability to detect SEC in head and neck cancers, including pharyngeal SCC, was inferior (1-5). Previously, we reported the detection of synchronous UGI cancer in 26 patients with pharyngeal SCC, between 2003 and 2006, with a sensitivity of 17% and specificity of 100% and compared these results with Lugol UGI chromoendoscopy (2). A recent study for detecting synchronous cancer in 65 patients with oropharyngeal cancer retrospectively compared 18F-FDG-PET/CT with endoscopy which did not use narrow band imaging (12). This study concluded that 18F-FDG-PET/CT, having detected one esophageal cancer, is superior to endoscopy in ruling out synchronous primary tumor, and discussed that the efficacy of 18F-FDG-PET/CT for detecting synchronous cancer should be compared to endoscopy with narrow band imaging (12).

The ability of 18F-FDG-PET/CT for detecting clinical T classification of SEC in pharyngeal SCC has not been analyzed fully. Therefore, the present study aimed to analyze 18F-FDG-PET/CT’s ability for the detection and clinical T classification of SEC in pharyngeal SCC in comparison to endoscopy including narrow band imaging.

Patients and Methods

Patients. For this retrospective study, we recruited 125 patients with no history of malignant neoplasms who were newly diagnosed with index oropharyngeal or hypopharyngeal SCC by pathological examination at the Department of Head and Neck Surgery, Aichi Cancer Center Hospital from January 2008 to August 2013. Inclusion criteria were: 1; pretreatment of Lugol UGI chromoendoscopy at Aichi Cancer Center Hospital, 2; pretreatment of 18F-FDG-PET/CT at East Nagoya Imaging Diagnosis Center, 3; serum glucose level at the first visit of less than 200 mg/dl with no use of insulin. Patients who consumed insulin or those with serum glucose concentrations of ≥200 mg/dl were excluded. Our Institutional Review Board approved the study and all its protocols. Informed consent was obtained for examinations and treatments. The review Board at the Aichi Cancer Center approved this study (Number 2021-0-013).

Staging for pharyngeal cancer. A routine physical examination, nasopharyngoscopy, chest radiography, and blood chemistry, including serum glucose levels, was performed during the first visit to our hospital. Clinical staging for pharyngeal SCC was determined from the results of these examinations as well as the findings of enhanced cervical computed tomography (CT) or magnetic resonance imaging (MRI) and 18F-FDG-PET/CT. We used the Tumor, Node, Metastasis (TNM) classification system of the International Union Against Cancer (6th or 7th edition) (13, 14).

18F-FDG-PET/CT. All patients were scanned with an 18F-FDG-PET/CT scanner (Biograph True Point PET/CT scanner 40 with TrueV; Siemens Healthcare, Medical Solutions Inc., Malvern, PA, USA). Prior to imaging, patients fasted for 6 hours, and PET/CT scans were performed 1.5 hours after the administration of intravenous 18F-FDG (dosage: 3.7MBq 18F-FDG/kg body weight). The PET images [2-mm slice thickness, 168×168 pixels, trans-axial field of view (FOV) 605 mm, axial FOV of 216 mm, and 2-min acquisition time/bed position] were reconstructed using a high-definition PET reconstruction algorithm with the point spread function and 3-dimensional ordered-subset expectation maximization. Following attenuation correction of PET data using low-dose CT images, reconstruction of the 18F-FDG-PET/CT images was evaluated by an experienced radiologist who was blinded to the UGI endoscopy reports. A location was considered abnormal by visual inspection as described previously (2), if the activity was significantly higher than the anticipated background and could not be explained as a normal structure. All 18F-FDG-PET/CT imaging protocols have been described previously (15). Based on recommendations for additional examinations of locations with an abnormal FDG-uptake, pathological diagnosis for the location was performed if possible. The radiologist’s recommendation for additional examination of a particular location with abnormal FDG-uptake was taken as a positive finding of 18F-FDG-PET/CT.

Lugol chromoendoscopy. Lugol UGI chromoendoscopy was performed by experienced endoscopists. After the esophagus, stomach, and duodenum were observed, using white-light and narrow-band images, the detectable esophageal tumors’ locations on Lugol chromoendoscopy were recorded, and biopsies were performed. Pathologically, diagnoses of biopsy specimens were made by two experienced pathologists. All other endoscopy methods have been described previously (2). The clinical staging of SEC based on the findings of CT imaging, contrast examination of the esophagus, UGI endoscopy, and 18F-FDG-PET/CT was determined by a discussion of oncologists, including endoscopists, radiotherapists, chemotherapists, and surgeons.

Statistical analysis. Statistical analysis was performed using the JMP Pro software (version 11; SAS, Cary, NC, USA). Following our previously reported protocol, with minor modifications (16), the identification sensitivity of esophageal tumor location was defined as the number of true positive locations divided by the sum of true-positive and false-negative locations. A total of 102 assessed locations were the sum of 22 locations with SEC, 2 locations with false-positive findings from 18F-FDG-PET/CT, and 78 locations from patients without SEC. Specificity was defined as the number of true-negative locations divided by the sum of true-negative and false-positive locations. Sensitivity and specificity were calculated with 95% confidence intervals. We used three models (Model 1: presence vs absence of cT1a-cT3 SEC, Model 2: presence vs absence of cT1b-cT3 SEC, Model 3: presence vs absence of cT3 SEC) to evaluate the results. For example, the true positive locations in model 2 were defined as the presence of both cT1b-cT3 SEC and positive 18F-FDG-PET/CT findings; true negative locations in model 2 were defined by the absence of cT1b-cT3 SEC and positive 18F-FDG-PET/CT findings. In clinical T classification of the three models, the difference between true-positive and false-negative locations was assessed using the Fisher’s exact test. Statistical significance was accepted at p<0.05.

Results

Clinical characteristics among all patients. Of the 125 patients recruited for this study, 90 patients defined by the presence/absence of both SEC and positive findings for 18F-FDG-PET/CT, met the inclusion criteria and were enrolled. The 18F-FDG-PET/CT results were compared with pathological results, which performed biopsy by Lugol UGI chromoendoscopy. Of the 90 patients with pharyngeal cancer, 12 patients (13.3%) were diagnosed with SEC from pathological examination. Seventy-eight locations were diagnosed in 78 patients with the absence of both SEC and positive findings for 18F-FDG-PET/CT. The number of SEC locations in these 12 patients were one SEC in 5 patients, two synchronous esophageal cancers (SECs) in 5 patients, three SECs in 1 patient, and four SECs in 1 patient, totaling 22 locations. Pathological diagnoses of other synchronous cancers were made for seven patients (two with stomach adenocarcinoma, two with colon adenocarcinoma, two with rectum adenocarcinoma, and one with prostate adenocarcinoma). The patients’ clinical characteristics are shown in Table I.

View this table:
Table I.

Characteristics of the 90 patients with pharyngeal cancer included in the study.

Twenty-four locations with cancer and false-positive 18F-FDG-PET/CT findings in the esophagus. Among the 22 locations of SEC, the frequency of cT1a, cT1b, and cT3 were 90.9% (20/22), 4.5% (1/22), and 4.5% (1/22), respectively. Only the two locations of cT1b and cT3 SEC were detected by 18F-FDG-PET/CT. There were two false-positive findings from 18F-FDG-PET/CT (location number: 11 and 21). The clinical characteristics of the 24 locations (with esophageal cancer and false-positive 18F-FDG-PET/CT findings in the esophagus) in these 12 patients are shown in Table II.

View this table:
Table II.

Characteristics of the 24 esophageal locations of synchronous esophageal SCC in 12 patients included in the study.

Detectability. The association between SEC and presence/absence of positive findings for 18F-FDG-PET/CT are shown in Table III. Sensitivity for cT1a-cT3, cT1b-cT3, and cT3 was 9.1%, 100%, and 100%, respectively. Locations with cT1b or cT3 SEC were detected by 18F-FDG-PET/CT, but not locations with cT1a SEC. The 18F-FDG-PET/CT detected locations with cT1b and cT3 SECs more frequently than those without it (p<0.01). The 18F-FDG-PET/CT also detected location with cT3 SEC more frequently than those without (p<0.05). However, 18F-FDG-PET/CT findings revealed no significant association between the presence and absence of cT1a-cT3 SEC (p=0.2). Representative locations are shown in Figure 1 and Figure 2, respectively.

View this table:
Table III.

Relationships between clinical T stage and 18F-FDG-PET/CT findings for the 102 esophageal locations of SEC in 90 patients.

Figure 1.
Figure 1.

White arrows indicate (A) 18F-fluorodeoxyglucose positron emission tomography/computed tomography with abnormal uptake and (B) Lugol chromoendoscopy with no staining of Lugol solution in a 60-year-old man with synchronous esophageal squamous cell carcinoma of cT3.

Figure 2.
Figure 2.

The red arrows indicate (A) 18F-fluorodeoxyglucose positron emission tomography/computed tomography without abnormal uptake and (B) Lugol chromoendoscopy with no staining of Lugol solution in a 68-year-old man with synchronous esophagus squamous cell carcinoma of cT1a.

Discussion

In the present study, we demonstrated that the 18F-FDG-PET/CT detects the presence of cT1b-cT3 SEC in pharyngeal SCC more frequently than its absence.

Lugol UGI chromoendoscopy is widely used in Asian Institutions as a diagnostic technique for early detection of SEC of pharyngeal cancer (1-6). Outside Asia, the French Society of Otorhinolaryngology described Lugol chromoendoscopy’s utility during explorations for SEC (7). A recent systemic review and meta-analysis of 15 articles involving 3,386 patients in 2019 showed Lugol chromoendoscopy to be useful for detecting early SEC in head and neck cancer (1).

The low detection rate of SEC in head and neck cancer, including pharyngeal SCC, by 18F-FDG-PET/CT has been described as inferior for detecting early esophageal cancer (1-5). For example, Kondo, et al. reported that the diagnostic sensitivity of PET for SEC in 230 cases of head and neck cancer was 7.6% (1/13) (3). The present study revealed the low detectability of cT1a SEC by 18F-FDG-PET/CT in 22 locations, in good agreement with these previous studies (1-5). To the best of our knowledge, this low detectability based on the assessment of statistical test was shown for the first time. We previously reported that, among 23 patients with oral cancer, tumors with cT2-4 oral SCC were significantly more detectable by 18F-FDG-PET/CT than those with cT1 oral SCC (15). The present study demonstrated that, among 90 patients with pharyngeal SCC, the presence of cT1b-cT3 SEC significantly increased 18F-FDG-PET/CT’s detection frequency. A significant association between cT1a SEC and low detection by 18F-FDG-PET/CT in the present study was supported by the previous result (16).

Wang, et al. reported the presence of stenosis due to advanced pharyngeal SCC, which prevented Lugol chromoendoscopy (6). The present study suggested that 18F-FDG-PET/CT is an effective screening approach for advanced SEC in pharyngeal SCC in the case of stenosis due to pharyngeal SCC, and thus provides an alternative to Lugol chromoendoscopy.

The present study did not use a standard uptake value, because standardized uptake values are thought not to improve the detectability of 18F-FDG-PET/CT in comparison to visual inspection (17). Muller et al. reported that future study of 18F-FDG-PETCT for detecting synchronous esophageal cancer is necessary to be compared to endoscopy having narrow band imaging as an emerging modality for workup (12). Therefore, we believe there is a need for researching the ability of detecting synchronous esophageal cancer of 18F-FDG-PET/CT compared to endoscopy with narrow band imaging.

The present study suggested that 18F-FDG-PET/CT is an effective imaging with high sensitivity for detecting SEC of clinical T1b-T3, but there were several limitations. The retrospective setting and small number of subjects introduced inherent limitations. The number of patients with pharyngeal cancer with SEC was as low as 13%, and the statistical significance was weak. Future prospective analyses, involving more participants, would improve the accuracy of results.

Conclusion

The present study demonstrated in pharyngeal SCC that locations with cT1b-cT3 SEC on 18F-FDG-PET/CT are detected at a higher frequency than locations without cT1b-cT3 SEC. In cases where patients with advanced pharyngeal cancer with stenosis are unable to be diagnosed for SEC on endoscopy, 18F-FDG-PET/CT might be a clinically viable alternative method.

Footnotes

  • ↵* These Authors contributed equally to this study.

  • Authors’ Contributions

    Conceptualization, H. S.; interpretation of data, H.T. and T. T.; analysis, H.T.; writing draft, H.T. and H.S.; review, M.S. and N.H. All Authors read and agreed to the manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest.

  • Received June 1, 2022.
  • Revision received July 2, 2022.
  • Accepted July 8, 2022.

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Detection Ability of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Clinical T Classification of Synchronous Esophageal Cancer in Pharyngeal Cancer
HIDENORI TSUZUKI, HIDENORI SUZUKI, TSUNEO TAMAKI, MICHIHIKO SONE, NOBUHIRO HANAI
Anticancer Research Sep 2022, 42 (9) 4597-4602; DOI: 10.21873/anticanres.15963
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