Improved detection of metastatic lymph nodes in oesophageal squamous cell carcinoma by combined interpretation of fluorine-18-fluorodeoxyglucose positron-emission tomography/computed tomography

Oesophageal cancer is the sixth most common cause of cancer-related mortality worldwide, leading to 3.2% of all deaths [1, 2]. The two most common histologic types found in more than 95% of all oesophageal cancer are squamous cell carcinoma (SCC) and adenocarcinoma. In particular, the SCC type has dominated for most of the twentieth century, particularly in Asian countries [3]. Surgical resection is the standard treatment approach for patients with early oesophageal cancer [4, 5]. Because the stage of oesophageal cancer is strongly associated with appropriate treatment options and its prognosis, accurate determination of clinical staging is essential. In particular, lymph node staging in oesophageal cancer is an important independent prognostic factor that can affect the surgical extent of lymph node dissection and the long-term survival of patients [6‐10].

Lymph node metastasis in oesophageal cancer occur early and quickly to adjacent or regional lymph nodes because of the submucosal lymphatic drainage system of the oesophagus [11]. In cases of early-stage SCC, lymph node involvement is more widely distributed and the rates of metastatic lymph nodes are higher versus in those in adenocarcinoma [12, 13]. In a previous study, the prevalence of nodal metastasis differed significantly between SCC and adenocarcinoma cases (36% vs. 21%) in early oesophageal cancer [13]. Therefore, accurate lymph node staging is important in oesophageal carcinoma, especially in early-stage SCC.

For initial staging including the detection of nodal metastasis, fluorine-18-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) has been widely used in patients with oesophageal cancer in recent years [14‐17]. However, the results about the accuracy of regional nodal metastasis on ¹⁸F-FDG PET/CT are controversial, with relatively low sensitivity. Furthermore, in tuberculosis endemic areas, specificity for nodal staging has been reported to be reduced due to false-positive FDG-avid lymph nodes in oesophageal cancer [14, 18]. In several previous reports, mediastinal lymph nodes that show increased FDG uptake on PET images but high attenuation and/or calcification on the CT component of a PET/CT scan had a high probability for benign node in lung cancer [19, 20]. In other words, the combined interpretation of PET/CT images was helpful to improve the specificity for detecting metastatic lymph nodes in lung cancer. Recently, the usefulness of both measurements of X-ray attenuation taken from unenhanced CT images and FDG uptake in the PET/CT of lymph node metastasis in oesophageal cancer was reported [21]. However, this study was somewhat limited by its relatively small size and ambiguity of the PET criteria due to evaluation by visual analysis.

Therefore, the aim of this study was to evaluate the diagnostic performance of ¹⁸F-FDG PET/CT in detecting metastatic lymph nodes via the combined interpretation of PET/CT images in patients with oesophageal squamous cell carcinoma. Optimal PET/CT criteria for detecting metastatic lymph nodes were also investigated.

We performed a study to determine the diagnostic performance of ¹⁸F-FDG PET/CT in the detection of individual lymph node metastasis in patients with oesophageal SCC. The combined interpretation of SUV_max on PET images with CT attenuation on noncontrast CT component was more accurate than that single assessment of SUV_max, size, or CT attenuation of PET/CT images. When lymph node status determined by SUV_max was more than 2.6 with iso-attenuation or low attenuation on noncontrast CT images, the accuracy was improved in detecting individual lymph node metastasis in patients with oesophageal SCC (Fig. 2). The specificity was also increased in the combined interpretation of PET/CT images compared to the single evaluated methods, although sensitivity was decreased.

Lymph node involvement in oesophageal cancer has a great impact on both treatment decision and prognosis of the patient. To detect such lymph node metastasis of the patient diagnosed by oesophageal cancer, pretreatment evaluations have used many modalities including endoscopic ultrasonography (EUS), chest CT, and ¹⁸F-FDG PET/CT. Meta-analysis studies have revealed that EUS is the most sensitive of these options, whereas CT and FDG PET are more specific tests for the detection of regional lymph node metastasis but overall offer similar diagnostic performance [23, 24]. EUS has limitations for evaluating the nodal status of oesophageal cancer patients with the presence of stenosis or strictures, which may affect low accuracy and nodal overstaging. In addition, interobserver variation and machine-dependent factors may exist and patient cooperation is essential for safe and successful EUS practice [25].

Chest CT is the most commonly used imaging technique for the staging of oesophageal cancer and helps to evaluate lymph nodes dependent on size criteria. Because the criteria of enlarged lymph nodes vary according to anatomical location and the detection of metastasis in normal-sized lymph nodes, the sensitivity and specificity of nodal metastasis assessment are low and remain a challenge [24]. In our study, the size on ¹⁸FDG PET/CT was significantly different between the benign and malignant groups, but the scores of sensitivity and accuracy were poor at 55.3 and 69.3% and the diagnostic performance was significantly lower than that of either SUV_max only or combined interpretations. This is supported by several reports that benign nodes might be enlarged as a result of benign processes such as reactive hyperplasia, obstructive pneumonia, or atelectasis, whereas metastatic nodes may appear normal in size if metastasis is present [26, 27].

Previous studies have evaluated the accuracy of oesophageal cancer lymph node staging by using PET/CT. Hsu, et al. reported that although positive nodal FDG uptake on PET/CT was related to the pathologic findings of regional lymph node, the ability of PET/CT to predict lymph node metastasis remained inadequate [28]. Jeong, et al. also found PET/CT missed nodal metastasis detection in more than half of the patients with early stage oesophageal SCC [29]. A recent meta-analysis study indicated the ¹⁸F-FDG PET/CT for detecting regional lymph node metastasis had a sensitivity and specificity with 95% CI of 62% (40–79) and 96% (93–98) [30]. In other meta-analysis, the pooled sensitivity and specificity for PET/CT were 0.59 (0.53–0.64) and 0.81 (0.74–0.86) [24]. Therefore, lymph node staging on PET/CT is challenging because it has some limitations in the detection of regional lymph node metastasis. Our study showed a similar performance with a sensitivity and specificity of 72.7 and 76.1%, retrospectively, and the ability of SUV assessment to predict node metastasis was deemed unsatisfactory. When microscopic lymph node metastasis is present, the ¹⁸F-FDG uptake of the lymph node may not be increased on PET/CT, whereas inflammatory lymph nodes are shown to be falsely increased in various FDG uptakes on PET/CT, making it difficult to distinguish such from malignancy. Budiawan, et al. found that the mean SUV_max of inflammatory/benign lymph nodes in lung cancer patient was 4.96 ± 2.08 (range 2.20–11.22) [31]. In Lin, et al. study, the SUV_max of pathologically negative lymph nodes in lung cancer was 7.34 ± 6.1 [32]. These nodes showed follicular hyperplasia in the cortex and anthracitic pigmentation and macrophage infiltration in the medulla, and these inflammatory changes can provoke high false-positive rates and low specificity with ¹⁸F-FDG PET/CT [18, 20]. Although 27 patients with pulmonary tuberculosis history on CT images were enrolled in the present study, these patients did not affect the results of the study.

To check the best performance of ¹⁸F-FDG PET/CT for detecting individual nodal involvement of metastasis, we included the data from the without contrast enhancement and did not include chest CT data. The noncontrast CT component of PET/CT images, which yields X-ray attenuation values, can be helpful for characterizing lymph nodes because higher attenuations than those of mediastinal structures with/without containing calcification may be observed in inflammatory lymph nodes [20, 33]. Therefore, several reports have suggested that lymph nodes with high attenuation and/or containing calcification on noncontrast CT images, even if they show increased FDG uptake on PET, should be regarded as benign, especially where chronic granulomatous disease is endemic [19, 20]. However, our study revealed there was no significant difference between benign and malignant lymph nodes in terms of mean HU, while conversely the visual attenuation pattern was significantly different between them. This result is discordant with those of a previous study that revealed a significant difference for mean HU between the malignant and benign lymph nodes groups [21]. This might be due to their small number of study subjects. This result is also the reason for why we considered visually high-attenuated lymph nodes as benign, unlike in previous studies which usually employed a mediastinal structure to 70 HU criterion for the high attenuation value.

In the present study, when interpreting ¹⁸F-FDG PET/CT, combined interpretation considering SUV_max on PET images with visual attenuation assessment on noncontrast CT component was significantly more specific than SUV_max-only evaluation on PET images for the detection of regional lymph node metastasis without a significant difference in sensitivity. The overall diagnostic performance for the SUV_max-only method in our and previous studies was around 70% (range: 63–73.1%), which significantly increased to 84.5% in the combined interpretation of an SUV_max of more than 2.6 with iso- or low CT attenuation. Kim et al., who had similar study settings, showed concordance with our study, but they couldn’t obtain the optimal SUV_max because of PET image evaluation by visual analysis (12). They also concluded that the assignment of highly attenuated lymph nodes with increased FDG uptake as benign could improve diagnostic accuracy for metastatic lymph nodes. Therefore, performing the combined interpretation considering FDG uptake and attenuation on ¹⁸F-FDG PET/CT could improve the specificity of lymph node staging of oesophageal cancer by reducing false-positives and could influence the surgical extent of lymphadenectomy, especially in populations where chronic granulomatous disease is endemic.

Our study possesses several limitations. First, it is a retrospective study and we included only patients who had underwent oesophagectomy with lymph node dissection. Thus, we might have selection bias and both the sensitivity and accuracy may have been underestimated. Second, because oesophageal adenocarcinoma is very rare in Asia including our country, this study included patients with SCC only. Therefore, further study is needed for patients with oesophageal adenocarcinoma to investigate whether our results can be applied for those patients. Third, this study was localized to a single hospital; therefore, further multicentre and prospective studies may be needed to evaluate the value of PET/CT for regional nodal metastasis in oesophageal cancer patients. Finally, because the optimal cutoff values of mean SUV_max and size for individual lymph nodes were calculated by the sum of maximum sensitivity and specificity, the performance ability may be overestimated.

The diagnostic accuracy of PET/CT for nodal metastasis in oesophageal squamous cell carcinoma is improved by the combined interpretation of ¹⁸F-FDG uptake and visual CT attenuation pattern. In other words, when ¹⁸F-FDG-avid lymph nodes of more than a SUV_max of 2.6 with iso- or low CT attenuation were considered as metastasis, and nodes that showed high CT attenuation and/or calcification were regarded as benign even if SUV_max was 2.6 or higher, the accuracy is enhanced by reducing the false-positive rate in endemic areas of granulomatous disease. The high specificity of the combined interpretation of SUV_max and visual CT attenuation on PET/CT images for nodal assessment may be helpful in determining therapeutic plans in patients with oesophageal SCC.