AIM: To investigate potential therapeutic recommendations for endoscopic and surgical resection of T1a/T1b esophageal neoplasms.

METHODS: A thorough search of electronic databases MEDLINE, Embase, Pubmed and Cochrane Library, from 1997 up to January 2011 was performed. An analysis was carried out, pooling the effects of outcomes of 4241 patients enrolled in 80 retrospective studies. For comparisons across studies, each reporting on only one endoscopic method, we used a random effects meta-regression of the log-odds of the outcome of treatment in each study. “Neural networks” as a data mining technique was employed in order to establish a prediction model of lymph node status in superficial submucosal esophageal carcinoma. Another data mining technique, the “feature selection and root cause analysis”, was used to identify the most important predictors of local recurrence and metachronous cancer development in endoscopically resected patients, and lymph node positivity in squamous carcinoma (SCC) and adenocarcinoma (ADC) separately in surgically resected patients.

RESULTS: Endoscopically resected patients: Low grade dysplasia was observed in 4% of patients, high grade dysplasia in 14.6%, carcinoma in situ in 19%, mucosal cancer in 54%, and submucosal cancer in 16% of patients. There were no significant differences between endoscopic mucosal resection and endoscopic submucosal dissection (ESD) for the following parameters: complications, patients submitted to surgery, positive margins, lymph node positivity, local recurrence and metachronous cancer. With regard to piecemeal resection, ESD performed better since the number of cases was significantly less [coefficient: -7.709438, 95%CI: (-11.03803, -4.380844), P < 0.001]; hence local recurrence rates were significantly lower [coefficient: -4.033528, 95%CI: (-6.151498, -1.915559), P < 0.01]. A higher rate of esophageal stenosis was observed following ESD [coefficient: 7.322266, 95%CI: (3.810146, 10.83439), P < 0.001]. A significantly greater number of SCC patients were submitted to surgery (log-odds, ADC: -2.1206 ± 0.6249 vs SCC: 4.1356 ± 0.4038, P < 0.05). The odds for re-classification of tumor stage after endoscopic resection were 53% and 39% for ADC and SCC, respectively. Local tumor recurrence was best predicted by grade 3 differentiation and piecemeal resection, metachronous cancer development by the carcinoma in situ component, and lymph node positivity by lymphovascular invasion. With regard to surgically resected patients: Significant differences in patients with positive lymph nodes were observed between ADC and SCC [coefficient: 1.889569, 95%CI: (0.3945146, 3.384624), P < 0.01). In contrast, lymphovascular and microvascular invasion and grade 3 patients between histologic types were comparable, the respective rank order of the predictors of lymph node positivity was: Grade 3, lymphovascular invasion (L+), microvascular invasion (V+), submucosal (Sm) 3 invasion, Sm2 invasion and Sm1 invasion. Histologic type (ADC/SCC) was not included in the model. The best predictors for SCC lymph node positivity were Sm3 invasion and (V+). For ADC, the most important predictor was (L+).

CONCLUSION: Local tumor recurrence is predicted by grade 3, metachronous cancer by the carcinoma in-situ component, and lymph node positivity by L+. T1b cancer should be treated with surgical resection.

Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), in addition to local ablation techniques, are now more extensively employed for the management of early adenocarcinoma (ADC) or squamous cell carcinoma (SCC) of the esophagus. The aim of endoscopic resection is to maintain the integrity of the esophagus and avoid the considerable morbidity and mortality of esophagectomy[1].

Several cohort studies[2-5] suggest the use of EMR or ESD for T1a esophageal neoplasia (including high grade dysplasia, adenocarcinoma, or squamous-cell carcinoma) confined to the superficial mucosa and not extending into the muscularis mucosa. Other studies contemplate endoscopic resection, even in muscularis mucosa invasion and in selected cases where upper third submucosal involvement is present[6]. T1b disease may be treated by esophagectomy.

At present, there are no reliable pre-excision molecular, biological or immunohistochemical predictive markers of lymph node metastasis in T1 esophageal cancer. Moreover, the current diagnostic workup has a low diagnostic performance for N1-disease which is considered the most influential predictor of long term prognosis[7].

The pros and cons of each endoscopic resection method have yet to be established, and level I evidence of their safety and efficacy is missing from the literature. Predictive markers of lymph node metastasis in mucosal and submucosal esophageal cancer are also an unsolved issue.

Answers to the aforementioned issues might enable researchers to formulate curative treatment strategies and considerations for neoadjuvant referral in early esophageal carcinoma cases.

The objectives of this study were: (1) to compare the safety and efficacy of EMR and ESD in the management of early esophageal neoplasia; (2) to investigate their role as part of the diagnostic workup; (3) to establish predictors of lymph node status, local recurrence and metachronous cancer development in superficial esophageal carcinoma; and (4) to investigate potential therapeutic recommendations.

According to NCCN guidelines version 1.2011 for esophageal and esophagogastric junction cancers, in the absence of evidence of lymph node metastases, lymphovascular invasion or poor differentiation grade, T1a disease can be treated with full EMR. In cases of unfavorable characteristics, the choice lies between EMR plus ablation or esophagectomy. T1b disease may be treated by esophagectomy.

The present meta-analysis: (1) investigated the particular role of each of the two endoscopic modalities in treating early esophageal cancer; (2) analyzed the issue of local recurrence and metachronous cancer development in patients treated endoscopically; and (3) analyzed for potential unfavorable tumor characteristics (besides those found by imaging) that obviate the need for neoadjuvant or perioperative therapy. To our knowledge, level I evidence related to these issues is missing from the literature. The only published meta-analysis based on retrospective studies (seven full-text and eight abstracts) compares EMR vs ESD for esophageal, gastric, and colorectal neoplasms jointly[87].

In addition to a variety of local ablation techniques, EMR and ESD are now extensively used for the treatment of stage Tis (high-grade dysplasia) and T1a ADC or SCC, aiming to reduce the considerable morbidity and mortality associated with esophagectomy.

The possibility of lymph node metastases, completeness of endoscopic resectability, early and late complications, local recurrence and development of a metachronous cancer, are concerns that should be measured when deciding whether to proceed with EMR, ESD or surgery.

According to our pooled analysis there were no significant differences between EMR and ESD for the following parameters: procedural complications, number of patients submitted to surgery, positive specimen margins, lymph node positivity, local recurrence rates and metachronous cancer development. In instances of piecemeal tumor resection, in particular, ESD performed better since the number of cases was significantly less (P < 0.001); hence, local recurrence rates were significantly lower (P < 0.01). An important point that should be kept in mind is the higher rate of esophageal stenosis observed following ESD (P < 0.001). Data on circumferential spread and tumor size were scarce among the studies.

There were no considerable differences in the application of endoscopic methods to each of the main histologic types of early esophageal cancer, other than the fact that a significantly greater number of SCC patients were submitted for surgery (P < 0.05).

Another significant finding was the high percentage of patient restaging after endoscopic intervention. EUS staging prior to proceeding with mucosal resection in the setting of carcinoma is recommended. In a recent meta-analysis[7], the pooled sensitivity (95%CI) and specificity (95%CI) for regional lymph node metastases was 0.764 (0.741-0.785) and 0.724 (0.693-0.753), respectively. The pooled diagnostic odds ratio (95%CI) was 8.001 (6.369-10.051). Although EUS has a better diagnostic performance compared to computed tomography (CT) scanning and positron emission tomography CT, the question of regional lymph node detection has yet to be satisfactorily addressed.

With regard to preoperative staging, endoscopic resection after endoscopic biopsy plays a key role. The odds for re-classification of tumor stage after endoscopic resection were 53% and 39% for ADC and SCC, respectively. This was possibly due to biopsy sampling failure, lack of adequate specimen and pathologist misinterpretation of the muscular anatomy. This obviates the need to optimize pre-treatment diagnostics and reconsider treatment strategies. The introduction of endoscopic resection in selected cases as part of the diagnostic workup should be strongly taken into consideration. This particular issue is supported by our data mining analysis: local tumor recurrence was best predicted by grade 3 differentiation and piecemeal resection, metachronous cancer development by the carcinoma in situ component and lymph node positivity by lymphovascular invasion. All the aforementioned predictors/histologic features can easily be retrieved from the EMR/ESD sample.

However, ESD is a technically demanding procedure that is not widely available. Although we were not able to perform a direct comparison of the outcomes of ESD vs surgery due to lack of relevant data, the likelihood of lymph node metastases and endoscopic resectability being factors that should be considered in deciding whether to pursue ESD or surgery is high, as stated by some authors[17]. According to our results, the presence of grade 3, piecemeal resection, the carcinoma in situ component and lymphovascular invasion would prompt surgical resection.

Available evidence from our esophagectomy series with radical lymph node dissection database suggests that the frequency of lymph node metastasis increases in proportion with tumor depth.

The diagnostic performance of sentinel lymph node biopsy for esophageal and gastric cardia cancer provides sensitivity between 75%-100% and accuracy between 78%-100%. Albeit applied in only a small number of patients, CT-lymphography seems to be the most promising method[7].

Considering the low incidence of lymph node metastasis (the odds are 5% for ADC and approximately 1% for SCC) and the absence of lymphovascular invasion in neoplasms limited to the mucosa, endoscopic resection is oncologically adequate for well-differentiated cancers, resected completely and lacking in situ foci. With regard to Barrett’s patients in particular, close endoscopic surveillance should be life-long and requires the commitment of both the patient and the physician since according to our results, the odds for lymph node metastasis are 5% and for metachronous cancer development 6%.

When endoscopic therapy for early esophageal cancer is considered, EMR or ESD should be applied first prior to the use of ablative techniques. According to our analysis, the application of ablative techniques has not gained significance as an independent predictor of local recurrence or metachronous cancer development.

Considering studies including surgically resected patients, lymph node positivity was statistically greater in SCC, while lymphovascular and microvascular invasion and grade 3 percentages were comparable between ADC and SCC patients. In rank order of importance, the predictors of lymph node metastasis in the prediction model were: Grade 3, Sm3 invasion, lymphovascular invasion, microvascular invasion, Sm2 invasion and Sm1 invasion, respectively. The best predictors of lymph node positivity in SCC were Sm3 invasion and microvascular invasion. For ADC, the most important predictor was lymphovascular invasion. According to the above, the present study supports the surgical rather than the endoscopic resection of T1b esophageal cancer, since even Sm1 invasion was included in our model. In consequence, Sm1 lesions should not be removed endoscopically. Interestingly, the presence of specific histologic features should prompt consideration of a more aggressive management, such as the use of neoadjuvant or perioperative treatment. This perception also poses the question as to the endorsement of EMR/ESD as part of the diagnostic workup.

Since there is a lack of apposite molecular-biological markers that can predict lymphatic spread in T1a and T1b-esophageal carcinoma with high diagnostic yield and the inconsistent success of the diagnostic work-up, the predictors found in our data mining analysis would possibly be of relevance in clinical decision making.

The analysis of surgically only resected patients is an updated version of an already published study by our group[88]. Although more studies have been included, the results were identical.

The current work is not without its limitations: (1) The report included studies of retrospective case series; thus, a formal meta-analysis could not be applied; (2) Parameters, such as dysplasia grade, segment length of Barrett’s and small areas of intestinal metaplasia hidden underneath neosquamous mucosa, the so-called “buried Barrett’s”, could not be analyzed due to paucity of data; (3) Overall patient survival and disease-free survival could not be assessed due to data inconsistency; (4) the type of resection (en-bloc, transhiatal, Ivor Lewis, minimally invasive) and differences according to the location of the tumor, with regard to lymph node, L and V invasion, may have influenced, to a degree, the prevalence of node positivity; and (5) in some studies, the stratification of data for distribution of the lymphovascular involvement according to the depth of tumor infiltration, and similar stratification for nodal involvement (m1, m2, m3, sm1, sm2 and sm3), were not available.

The value of patient data mining has already been established by The Medical Quality Improvement Consortium[89]. This large clinical data warehouse contains patient data including their problem lists, test results, procedures and medication lists, all of which help identify valid associations.

Currently, the National Comprehensive Cancer Network recommends an esophagectomy over endoscopic therapy for fit patients with T1b cancer. This study suggests the option of neoadjuvant treatment for those patients with unfavorable histological characteristics in terms of tumor histologic entity, aiming at a R0 resection.

In summary, according to this study, there were no significant differences between EMR and ESD concerning procedural complications, number of patients submitted to surgery, positive specimen margins, lymph node positivity, local recurrence rates and metachronous cancer development. In instances of a predicted piecemeal tumor resection, ESD performed better since the number of cases was significantly less and local recurrence rates were therefore significantly lower. A higher rate of esophageal stenosis was observed following ESD.

Local tumor recurrence after endoscopic resection was best predicted by grade 3 differentiation, metachronous cancer development by the carcinoma in situ component, and lymph node positivity by lymphovascular invasion.

T1b esophageal cancer should be managed with surgical resection and systematic lymphadenectomy since even Sm1 invasion was in the constructed model, while the histologic type and presence of specific predictors could likely alter the surgeon’s policy and perspective of multimodality management. The best predictors of lymph node positivity in SCC were Sm3 invasion and microvascular invasion. For ADC, the most important predictor was lymphovascular invasion. Prospective studies, or preferably randomized controlled trials, are needed in order to validate the refinements for patient selection made by this study.