Endoscopic ultrasound staging in gastric cancer: Does it help management decisions in the era of neoadjuvant treatment?^[*]

• Introduction
• Patients and methods
• Locoregional EUS and histopathologic staging
• Outcome parameters
• Statistical analysis
• Results
• T and N staging accuracy
• Impact of EUS on treatment decisions
• Discussion
• References

Background and study aims: Endoscopic ultrasonography (EUS) has been shown to be the most accurate test for locoregional staging of upper gastrointestinal tumors; however, recent studies have questioned its accuracy level in daily clinical application. The present retrospective study analyzes the accuracy of EUS in guiding interdisciplinary treatment decisions.

Patients and methods: 123 primarily operated patients (63 % men, mean age 61.4 years) were included; only cases with tumor-free resection margins and without evidence of distant metastases were selected. EUS and histopathological findings were compared. Main outcome parameter was the distinction between tumors to be primarily operated (T1 /2N0) and those to be treated by neoadjuvant or perioperative chemotherapy (T3/4, or any N + ), based on an assumed algorithm for treatment stratification.

Results: Overall staging accuracy of EUS was 44.7 % for T and 71.5 % for N status irrespective of tumor location. Overstaging was the main problem (44.9 % for T, 42.9 % for N staging). The overall EUS classification was correct in 79.7 % (accuracy), with a sensitivity 91.9 % and specificity 51.4 %; only 19 out of 37 cases with histopathological T1/2N0 were correctly classified by EUS. Positive and negative predictive values of EUS in diagnosing advanced tumor stage for assignment to neoadjuvant therapy were 81.4 % and 73.1 %, respectively.

Conclusions: Whereas EUS has a high sensitivity in the diagnosis of locally advanced gastric cancer, endosonographic overstaging of T2 cancers appears to be a frequent problem. EUS stratification between local (T1 /2N0) and advanced (T3/4 or any N + ) tumors would thus result in incorrect assignment to neoadjuvant treatment in half of cases.

Introduction

Long-term survival of gastric cancer is closely associated with primary tumor stage and nodal involvement. Tumors limited to the gastric wall and without evidence of nodal involvement (T1/2N0] are associated with a 5-year survival probability of 65 – 85 % whereas locally advanced tumors (T3/4, any N + ) carry a considerably worse prognosis, with 5-year survival probabilities ranging from 20 % to 50 % [1] [2]. Therefore, to improve outcomes for locally advanced carcinoma, at most institutions these tumors are treated with neoadjuvant or perioperative chemotherapy regimens; in fact, two large randomized studies have shown a considerable impact of perioperative therapy on prognosis [3] [4]. The decision whether or not to subject patients to these treatment strategies is essentially based on preoperative staging.

Among multiple imaging tests for staging of gastric cancer, endoscopic ultrasound (EUS) has emerged as the most accurate tool for pretherapeutic locoregional tumor staging, with somewhat better results in advanced than in early tumors [5] [6]. However, recent studies have shown somewhat contradictory results for EUS accuracy in routine clinical practice [7] [8] [9] [10]. Similarly, more modern imaging technology appears to equal the superiority of EUS over other imaging modalities, although again study findings are somewhat variable [11] [12] [13] [14] [15].

The aim of our retrospective study was to assess the potential influence of EUS on decision making regarding gastric cancer without distant metastases. The assumption was that chemotherapy, either neoadjuvant or perioperative, would be applied only in the case of locally advanced cancers (T3/4 or any N + ), whereas primary surgery would be performed with T1 /2N0 tumors [16] [17]. This assumption was based on the two randomized trials [3] [4] showing a survival benefit of perioperative chemotherapy which mostly included T3 /4 tumors (65 – 70 %) and N + tumors (75 – 80 %), as well as on the excellent surgical results in T1 /2 and N0 cancers [18] [19] [20].

Patients and methods

A total of 372 patients with gastric carcinoma treated at the Department of General, Visceral, and Thoracic Surgery at the University Medical Center of Hamburg, Germany, between 1993 and 2008 were considered for the study; data were analyzed from a computerized database. Proximal gastric tumors (carcinoma of the gastroesophageal junction [GEJ] types II and III) were also included, whereas distal esophageal adenocarcinoma (GEJ type I) was not. These data included locoregional endosonographic, and histopathological staging, metastasis status as assessed by computed tomography (CT) scan and/or intraoperatively, together with data on morbidity and mortality. Cases with distant metastases had already been excluded.

Among the 372 surgical patients, only those with primarily and radically operated tumors were to be included in the retrospective study. Thus, 65 patients with some form of preoperative oncologic treatment and 58 with palliative surgery had to be excluded. The remaining cases included, in general, only patients who had undergone radical gastrectomy in gastric carcinoma with D2-lymphadenectomy or radical extended gastrectomy with D2-lymphadenectomy and lymphadenectomy of the lower mediastinum in cases of cardia carcinoma (GEJ II and III), and microscopically tumor-free resection margins (R0); however in “true“ cardia carcinoma (GEJ II) staged as T1, limited resection of the GEJ had been performed. A further 126 patients were excluded because EUS was either not performed (n = 72) or was done elsewhere (n = 54). The remaining 123 cases formed the basis of this study.

Locoregional EUS and histopathologic staging

All examinations had been carried out by six experienced endoscopists (K. Binmoeller, B. Brandt, A. Fritscher-Ravens, S. Seewald, H. Seifert, N. Soehendra) in a specialized highly dedicated unit for endoscopy chaired until 2008 by Dr. Nib Soehendra; all examiners had performed at least 300 gastrointestinal endosonographies before the start of the retrospective study inclusion period.

EUS was performed using a 7.5, 10, 12-MHz echo endoscope standard radial scanner (Olympus Optical Co., Tokyo, Japan). By filling the stomach with various amounts of water (up to 300 ml), the normal gastric wall was imaged as a 5-layer structure, and cancer was imaged as a hypoechoic thickening of those layers. In the cardia region (GEJ) EUS was carried out mainly using a combination of the water-filling and balloon method. EUS TN-staging was done on the basis of published criteria [21] [22] [23] [24]. Briefly, stage T1 was diagnosed when the tumor infiltration was limited to the submucosa, stage T2 when the wall layer structure was destroyed but the outer margin was smooth or only slightly irregular, stage T3 when there was transmural tumor growth, and stage T4 in cases of infiltration into adjacent structures or organs. A malignant lymph node was diagnosed if at least two or more of the following EUS criteria were present: hypoechoic pattern; lymph node size greater than 5 mm; round shape, and smooth border.

Histopathologic tumor staging and grading were done according to the 6th edition of the TNM classification of the International Union Against Cancer (UICC) [25].

Outcome parameters

The main outcome parameter was the diagnostic value (accuracy, sensitivity, specificity, and positive and negative predictive values [PPV and NPV]) of EUS in distinguishing between early stage (T1 /2N0) and locally advanced (T3 /4 or any N + ) tumors. This distinction was made to reflect a suggested algorithm for focusing neoadjuvant/perioperative therapy to those patients that may need it most.

Secondary outcome parameters were the accuracy of EUS in diagnosing each individual T stage (correct classification of each stage versus all other stages) and of N staging (N0 versus N1 /2). No distinction between N1 and N2 was made since these data were not available from the EUS reports.

Statistical analysis

To compare EUS with pathological findings we calculated accuracy, sensitivity, and specificity. Sensitivity is defined as the proportion of histopathologically confirmed advanced stage tumors (T3 /4 or any N + ) that were correctly classified as such by EUS, while accuracy is the proportion of all tumors whose stage was correctly classified by EUS. Statistical analysis was done using SPSS software (SPSS Inc. Chicago, Illinois, USA).

Results

Demographic and tumor-related characteristics of the 123 patients finally included (mean age 61 ± 7.6 years, age range 28 – 84) are shown in [ Table 1 ].

T and N staging accuracy

Details are shown in [ Table 2 ]. Regarding overall T staging, depth of invasion was correctly determined by EUS in 55 patients (44.7 %), with overstaging in 53 patients (43.1 %) and understaging in 15 patients (12.2 %). Overstaging was more frequent in stages T1 and T2 (57.7 % and 66.1 %) than in stage T3 (2.8 %).

A total of 6436 lymph nodes were removed. The mean number (standard error of the mean [SEM]) of lymph nodes retrieved per patient was 17 (10.4). A total of 81 patients (65.9 %) had histopathologically proven lymph node metastases (pN + ). Overall, the diagnostic accuracy of EUS in relation to N status was 71.5 % (n = 88). Out of 81 tumors categorized as pN + , EUS correctly detected positive N status in 64 (79 %), whereas the remaining 17 patients with pN + tumors (21 %) had their tumor status preoperatively understaged by EUS as uN0. Out of 42 tumors categorized as pN0, 24 (57.1 %) were classified as uN0, whereas 18 tumors (42.9 %) were overstaged as uN + . Thus lymph node involvement was detected with a sensitivity of 79 % and a specificity of 57 %.

Statistical analysis found no trend towards improvement or deterioration of EUS results over the years (data not shown).

Impact of EUS on treatment decisions

When tumors were grouped together only according to the T status, the distinction between T1/2 and T3/4 tumors was made with 50 % sensitivity (correct recognition of T1/2) and 80.5 % specificity (correct recognition of T3/4). When patients were stratified according to their nodal status (uN0 vs. uN + ), 17 (41.4 %) of the 41 uN0 tumors were histopathologically classified as pN + , and these patients had therefore been wrongly assigned to primary surgery, while 18 (22 %) of the 82 uN + tumors had a pN0 status with patients therefore incorrectly assigned to neoadjuvant treatment.

The analysis of our data according to T status alone showed that correct decisions based on EUS results for allocation to primary surgery or to neoadjuvant therapy were made in 55 patients. In 68 patients, EUS findings were incongruent with the histopathologic TN status.

Taking both the T and N status together for outcome grouping, T1 /T2N0 tumors are treated by primary surgery, and T3/T4 or any nodal positive (N +) tumors are treated by chemotherapy (neoadjuvant or palliative, depending on local tumor extent and patient operability). Following this grouping, 37 patients in the reported cohort would have required primary surgery (pT1/2N0), while in 86 patients (pT2N + , n = 45; pT3 /4 any N, n = 41), neoadjuvant therapy followed by secondary surgery represented best medical care. In the event that the treatment strategy had depended on EUS results, 7 of the patients (27 %) staged as uT1/2N0 were wrongly treated by primary surgery, because histopathology showed more advanced tumor stages, and conversely 18 of the pT1/2N0 patients (48.6 %) would have been overtreated by neoadjuvant therapy due to inaccurate EUS staging (uT3/4 and/or uN + ) ([ Table 3 ]).

The incorrect EUS diagnoses were as follows:

Group I (pT1 /2N0): T overstaging in 9 cases; N overstaging in 13 cases. Among the latter, in 9 cases the T staging was correct.

Group II (pT1 /2N + or pT3 /4 any N): T understaging of pT3 /4 cancers as uT1 /2 in 8 cases; N understaging in the pT1 /2 group in 4 cases, and in the pT3 /4 group in 3 cases.

Discussion

Patients with locoregionally advanced gastric and cardia cancer are at significant risk for recurrence and death even after potentially curative resection. Depth of invasion and lymph node status are the most important predictors of survival following gastrectomy [1] [2] [26]. Neoadjuvant or perioperative chemotherapy with or without radiotherapy, have been investigated [27] [28] [29] [30], showing a survival benefit in two randomized controlled trials [3] [4]. Both these trials indeed included all patients with gastric cancer with a variable percentage of tumors at the esophagogastric junction, but neither trial was analyzing results according to tumor stage and they did not give their clinical staging results prior to therapy; the locoregional stage distribution was indicated only from the control groups undergoing surgery alone, and one assumes the initial stage distribution was similar in the chemotherapy groups. On this basis the T1 /2 proportion was 36.8 % in the MAGIC trial [3] and 32 % in the French study [4]; N0 was diagnosed in the surgery-only group in 26.9 % and 20 %, respectively, but no data on the T1/2 N0 cases are available, but one would suppose the rates to be somewhat lower. Thus, the vast majority (probably 80 % or more) of cases in these trials had either initial T3/4 stage and/or stage N + . Given these assumptions, and the results of surgery in T1/2 N0 gastric cancer cases which achieve 5-year survival in 68 % – 90 % [18] [19] [20], we speculated that preoperative chemotherapy should be best focused on T3/4 and/or N + cases. We realize that this model is not evidence-based in the form of a stage-differentiated randomized trial, but we think there is enough indirect evidence to support such a model.

Nevertheless, it appears necessary that further studies with adequate endoscopic, pathological, and surgical quality control should include a subgroup randomization, as well as more exact definition of prediction and evaluation of the response following chemotherapy. Further studies could then focus on neoadjuvant vs. perioperative chemotherapy, or a risk-adapted adjuvant treatment vs. surgery alone. In any event, such protocols would strictly require a standardized preoperative staging, re-evaluation for response to neoadjuvant treatment, and radical D2-lymphadenectomy.

Preoperative locoregional staging of gastric and cardia carcinoma is generally done on the basis of EUS [31] [32] although in routine clinical practice the staging results may be altered by information from other diagnostic procedures, such as CT, magnetic resonance imaging, or positron emission tomography, which may impact on the treatment strategy. Studies comparing the accuracy of CT and EUS in T and N staging of gastric carcinoma have shown conflicting results. A recent meta-analysis showed high accuracy rates of EUS in all T stages (> 80 % sensitivity and > 95 % specificity), results which did not change over the years, while N-staging accuracy was substantially lower [5]. Recent studies however have reported substantially lower T-staging accuracy, often in the range 50 % – 60 % [7] [10]. On the other hand, other recent analyses, also from surgical centers, showed accuracy results of 78 % for T and 77 % for N staging [8]. Another outcome study that simulated clinical decision making, found that treatment decisions were changed in 34 % of cases based on the EUS results, and the majority of these changes were toward nonsurgical and palliative treatments (85 %) [9].

Despite these differing results, several features of these and of our own study deserve more detailed comment:

1. Overstaging of T1and T2 cancers. With regard to T1 cancers, although a variety of studies have reported low accuracy rates for EUS in discrimination between mucosal and submucosal infiltration in stage T1, overstaging in T1 cancers in general has not been reported to the same extent as found in our study [5] [6]. It may be that selection bias may be partially responsible for our poor results, since only or mainly cases thought to represent more advanced stages not amenable to endoscopic therapy were sent to surgery, and tumors that were staged as T1 and endoscopically resected are not included in this analysis. Regarding the overstaging of T2 cancers, this is a well known issue in the literature [5] [6], and even in series with excellent staging results, T2 staging usually fares less well. EUS is inherently unable to distinguish between the pathologic stages of T2 infiltration of subserosa and T3 infiltration of serosa. Furthermore, parts of the proximal stomach are not covered by serosa, which further complicates imaging for locoregional staging in this area. Finally, the poor discrimination between inflammation surrounding the tumor and the tumor itself, which may result in overestimation of the tumor infiltration depth is also well established [33] [34]. Thus, any imaging that aims to distinguish T2 from T3 as a basis for treatment decisions will have inherent limitations. Although higher accuracies and good results were achieved by grouping locally (T1/2) and advanced (T3/4) tumors only, the challenge of accurate staging of T2 tumors remains a preoperative problem since this T stage is commonly overstaged. However, in an era of neoadjuvant treatment there is an emerging discussion on whether the distinction between T2 and T3 tumors is relevant any longer.

2. Understaging of more advanced stages is much less common, and there is broad consensus on this in the literature, and this was also confirmed by our data.

3. The general weakness of EUS in discriminating between benign and malignant nodes is also well documented [5] [6], and this may be especially true for gastric cancer.

4. Endoscopy can play a crucial role in help with staging, since it has been shown that combined endoscopy and EUS results fare better than EUS alone [35]. In the present study, only EUS results were analyzed. Furthermore, results during routine application are usually of lower accuracy than those generated during the conditions of prospective studies. This has been extensively documented for EUS, but much less for other imaging methods.

Our data show that the diagnostic accuracy of EUS in the clinical staging of gastric and cardia carcinoma is limited. We focused on the predictive accuracy of information available before surgery. In this study, the results are possibly biased by the fact that the data were obtained by numerous endoscopists, surgeons and pathologists over a long study duration time, which has some influence on these results. The present series included only patients without neoadjuvant therapy who underwent primary surgery. Given that patients with locally advanced tumor (T3/T4, any N + ) will benefit from neoadjuvant therapy, while those with early stage carcinoma (T1/T2, N0) will not, the key finding of this investigation is that reliance on EUS findings regarding T status would have resulted in incorrect assignment to neoadjuvant therapy in 50 %. The EUS results for an advanced tumor have therefore limited predictive value despite the high sensitivity. Endosonographic understaging of advanced cancer is however infrequent, so incorrect assignment to the surgical group would be less of a problem. Further studies will show how these moderate staging results can be improved, either by better EUS imaging using contrast or other sophisticated imaging tools, or by using other imaging techniques which would also require proof of superiority in routine clinical practice.

Competing interests: None

^* A. Kutup and Y. K. Vashist contributed equally.

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Corresponding author

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