What are the best modalities for accurately staging early oesophageal adenocarcinoma?
What are the best modalities for accurately staging early oesophageal adenocarcinoma?
The TNM staging system for oesophageal adenocarcinoma (American Joint Committee on Cancer, the International Union Against Cancer) is universally accepted and correlates with patient survival. Early oesophageal adenocarcinomas (EOA) are those defined as intra-mucosal adenocarcinoma (T1m) or superficial submucosal adenocarcinoma (T1sm1). A more comprehensive sub-classification of early oesophageal cancers has been proposed with mucosal disease and submucosal disease divided into three categories respectively (m1-3, and sm1-3) based on depth of invasion. The risk of nodal involvement correlates with the depth of invasion with tumour invasion deeper than the muscularis mucosa associated with a significant increase in prevalence of lymph node metastases. Cancers that are confined to the mucosa have a low risk of nodal involvement (0% in most series) and can be managed successfully with endoscopic resection (ER). When the cancer has invaded the superficial third of the submucosa (T1sm1), if the tumour is well differentiated with no lymphovascular invasion and of low histological grade, some studies suggest the risk of positive lymph nodes remains low (<1%). Other studies have shown superficial (sm1) submucosal invasion in oesophageal carcinoma is associated with a low but not negligible rate of lymph node metastasis of 12.9%. However, if there is deeper submucosal invasion (T1sm2, T1sm3) or these other criteria are not met, then the risk of lymph node involvement increases to 44%. There are a range of management options for EOA, including endoscopic resection, surgical oesophagectomy, radiation therapy and chemotherapy and their appropriateness is dependent on accurate staging.
Options for staging of EOA include:
1. Endoscopic biopsy
2. Endoscopic resection (ER) (also known as endoscopic mucosal resection or EMR)
3. Endoscopic ultrasound (EUS) with or without fine needle aspirate (FNA)
4. Positron emission tomography-computerised tomography (PET-CT)
Diagnostic accuracy of high grade dysplasia and EOA has improved due to advances in endoscopic technology including high-definition white light endoscopy, digital chromoendoscopy and systematic biopsy protocols. However, the potential for diagnostic inaccuracy persists due to biopsy sampling error and variability in histopathologic interpretation. Studies have reported the presence of occult adenocarcinoma at oesophagectomy in patients with Barrett’s Oesophagus with HGD after endoscopic surveillance with systematic biopsies. The use of jumbo biopsy forceps still misses unsuspected adenocarcinoma in Barrett’s Oesophagus with HGD. In comparison to systematic biopsy protocols, endoscopic resection (ER) together with expert pathological review, alters the histological grade or T-stage in the majority of patients with Barrett’s-associated neoplasia.
Endoscopic resection (ER)
Endoscopic resection (ER, also known as endoscopic mucosal resection EMR) involves local snare excision of the lesion down to the level of the submucosa and has been increasingly used as both a staging tool and a therapeutic treatment option for management of dysplastic Barrett’s Oesophagus and EOA. ER is recommended for dysplasia associated with any visible lesions within Barrett’s segment as it allows more accurate assessment of the severity of dysplasia and local T-staging, particularly for the assessment of submucosal invasion, compared with targeted biopsies alone. It may also be curative in intramucosal (T1a) adenocarcinoma. In a multicentre cohort study, ER resulted in a change of diagnosis for approximately 30% of Barrett’s Oesophagus patients with early neoplasia (with and without visible lesions). In other series, ER results in a change of pre-treatment histopathologic diagnosis in 25-55%. In a prospective series of 75 patients at two Australian tertiary centres, ER histology resulted in altered grading or staging in 48% of patients (down 28%, up 20%) and complete Barrett’s excision was successful in 94% with no metachronous lesions detected after a mean follow-up of 31 months. In nodular lesions, ER with histological examination provides greater utility than staging by EUS.
ER does carry risks of perforation, bleeding and anaesthetic-associated risk although rates of these adverse events were low in most series. Stricturing is an additional risk, particularly where long segment circumferential ER is performed. Contraindications to ER may include ulcerated or depressed lesions, coagulopathy, stricturing or poor endoscopic access to the lesion. If ER is performed with curative intent in EOA, it is important to enrol patients into a strict surveillance program with high-definition white light endoscopy and digital chromoendoscopy, due to the risk of developing metachronous lesions.
Endoscopic ultrasound (EUS)
EUS has been used as a staging tool in EOA to determine depth of infiltration and the presence of lymph node metastases prior to referral for endoscopic therapy or oesophagectomy. Studies have shown that EUS is superior to computed tomography (CT) for delineating tumour depth staging and the presence of pathological lymph nodes. The T-staging accuracy of EUS for EOA and high grade dysplasia in the setting of Barrett’s Oesophagus has been questioned. A systematic review of 12 studies with data on 292 patients with oesophageal high grade dysplasia or EOA comparing EUS with surgery or ER pathology staging found a T-stage concordance of 65% across all studies and 56% concordance in 8 studies with individual patient level data. In another meta-analysis of patients with either superficial oesophageal squamous cell carcinoma (SCC) or adenocarcinoma, a subgroup analysis found the overall EUS accuracy for differentiating mucosal (T1a) from submucosal (T1b) oesophageal adenocarcinoma was 143 of 170 lesions (84%). Other studies confirm a significant false positive rate for diagnosis of submucosal invasion (up to 84%) which may lead to unnecessary oesophagectomy in patients that could be successfully treated with ER. High frequency miniprobe EUS, with improved image resolution, still has limited accuracy in the detection of submucosal invasion of early oesophageal cancers. Chemaly et al demonstrated in their study of 91 patients with superficial Barrett’s adenocarcinoma or SCC, that the overall accuracy of miniprobe EUS was 73.5%. In the same study, a statistically significant difference in the accuracy rate of EUS was noted, dependant on lesion location within the oesophagus, with 87.1% of proximal and mid oesophagus lesions staged accurately compared with 47.6% of distal oesophagus lesions. The endoscopic morphology of visible lesions within Barrett’s Oesophagus may also be useful for predicting the histologic T-stage, with one series demonstrating that Paris type 0–IIb (flat) lesions were always confined to the mucosal layer, whereas Paris type 0-IIc (depressed) lesions almost invariably had submucosal invasion. EUS evaluation before ER therefore appears to have limited value in the absence of suspicious endoscopic features.
It is important to differentiate the relatively poor performance of EUS in staging EOA, as distinct from staging for more advanced lesions (≥T2) and lymph node metastasis. In a study of 100 consecutive patients with Barrett’s Oesophagus and EOA, EUS proved to be highly accurate in differentiating T1 from >T1 lesions (sensitivity, specificity, PPV, and NPV all 100%) but not sufficiently reliable at differentiating T1m and T1sm (sensitivity 89% and 27% respectively). In a meta-analysis of patients with oesophageal cancer (SCC and adenocarcinoma) undergoing staging EUS, CT or 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), EUS had the highest sensitivity at 80% but also the lowest specificity 70% for detection of regional lymph node metastases. EUS with fine-needle aspirate (FNA) increases specificity by allowing sampling of suspicious mediastinal or coeliac axis lymph nodes, which may significantly impact treatment decisions. EUS-FNA has been shown to be superior to EUS alone and CT for nodal staging.
Positron Emission Tomography/Computed Tomography (PET/CT)
FDG-PET and CT have a limited role in staging EOA due to small tumour size in many cases and infrequent regional lymph node and distant metastases. In a retrospective series of 58 patients with superficial oesophageal adenocarcinoma, FDG-PET could not differentiate high grade dysplasia (Tis) from invasive T1 cancer, with 45% of Tis tumours having FDG uptake compared with 55% of T1 tumours. For the evaluation of distant metastases, FDG-PET probably has a higher sensitivity than CT although its combined use allows more precise anatomical location of metastases. In a prospective series of 139 patients with oesophageal cancer (85 adenocarcinoma, 53 SCC), PET/CT changed the stage group in 40% and resulted in a change in management in one third of patients, and had powerful prognostic stratification. CT has also been found to be inferior to EUS for T-staging and detection of locoregional lymph node metastases and should be reserved for staging of distant metastases in combination with FDG-PET or alone when PET is unavailable. However, in patients where surgery is being considered (for example due to submucosal invasion in the ER specimen), a PET-CT scan would usually be requested by the surgeon prior to proceeding with surgery.
Evidence summary and recommendations
|Endoscopic resection (ER) results in a change in pre-treatment diagnosis after systematic biopsies in patients with Barrett’s-related dysplasia or adenocarcinoma.||IV||, , , |
|ER allows improved pathological staging of high grade dysplasia and T1m and T1sm adenocarcinoma as compared with biopsy and endoscopic ultrasound (EUS).||IV||, |
|Rates of adverse events following ER performed at expert centres are low.||IV||, , |
|Endoscopic resection is the most accurate staging modality for early oesophageal adenocarcinoma for suitable lesions and where appropriate expertise is available.||D|
|Endoscopic ultrasound has inadequate accuracy in determining the stage of early oesophageal adenocarcinoma, especially distinguishing T1m from T1sm tumours. In contrast, EUS is effective for differentiating between T1 and >T1 stages.||IV||, |
|Endoscopic ultrasound and EUS-guide fine-needle aspiration (EUS-FNA) are superior to computed tomography (CT) for locoregional lymph node staging||IV||, |
|FDG-PET cannot reliably differentiate oesophageal high grade dysplasia from invasive T1 adenocarcinoma.||IV|||
|For the evaluation of distant metastases, FDG-PET probably has a higher sensitivity than CT although its combined use allows more precise determination of location of metastases.||IV||, |
|FDG-PET or PET/CT is not routinely indicated in staging early oesophageal adenocarcinoma. It is best used for the staging of distant metastases or in cases of suspected more advanced local disease.||D|
- Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010 Jun;17(6):1471-4 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20180029.
- Bennett C, Vakil N, Bergman J, Harrison R, Odze R, Vieth M, et al. Consensus statements for management of Barrett's dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process. Gastroenterology 2012 Aug 1;143(2):336-46 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22537613.
- Leers JM, DeMeester SR, Oezcelik A, Klipfel N, Ayazi S, Abate E, et al. The prevalence of lymph node metastases in patients with T1 esophageal adenocarcinoma a retrospective review of esophagectomy specimens. Ann Surg 2011 Feb;253(2):271-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21119508.
- Rice TW, Zuccaro G Jr, Adelstein DJ, Rybicki LA, Blackstone EH, Goldblum JR. Esophageal carcinoma: depth of tumor invasion is predictive of regional lymph node status. Ann Thorac Surg 1998 Mar;65(3):787-92 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9527214.
- Buskens CJ, Westerterp M, Lagarde SM, Bergman JJ, ten Kate FJ, van Lanschot JJ. Prediction of appropriateness of local endoscopic treatment for high-grade dysplasia and early adenocarcinoma by EUS and histopathologic features. Gastrointest Endosc 2004 Nov;60(5):703-10 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15557945.
- Westerterp M, Koppert LB, Buskens CJ, Tilanus HW, ten Kate FJ, Bergman JJ, et al. Outcome of surgical treatment for early adenocarcinoma of the esophagus or gastro-esophageal junction. Virchows Arch 2005 May;446(5):497-504 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15838647.
- Badreddine RJ, Prasad GA, Lewis JT, Lutzke LS, Borkenhagen LS, Dunagan KT, et al. Depth of submucosal invasion does not predict lymph node metastasis and survival of patients with esophageal carcinoma. Clin Gastroenterol Hepatol 2010 Mar;8(3):248-53 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19948247.
- Nigro JJ, Hagen JA, DeMeester TR, DeMeester SR, Theisen J, Peters JH, et al. Occult esophageal adenocarcinoma: extent of disease and implications for effective therapy. Ann Surg 1999 Sep;230(3):433-8; discussion 438-40 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10493489.
- Falk GW, Rice TW, Goldblum JR, Richter JE. Jumbo biopsy forceps protocol still misses unsuspected cancer in Barrett's esophagus with high-grade dysplasia. Gastrointest Endosc 1999 Feb;49(2):170-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9925694.
- Ayers K, Shi C, Washington K, Yachimski P. Expert pathology review and endoscopic mucosal resection alters the diagnosis of patients referred to undergo therapy for Barrett's esophagus. Surg Endosc 2013 Aug;27(8):2836-40 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23389078.
- Moss A, Bourke MJ, Hourigan LF, Gupta S, Williams SJ, Tran K, et al. Endoscopic resection for Barrett's high-grade dysplasia and early esophageal adenocarcinoma: an essential staging procedure with long-term therapeutic benefit. Am J Gastroenterol 2010 Jun;105(6):1276-83 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20179694.
- Ell C, May A, Pech O, Gossner L, Guenter E, Behrens A, et al. Curative endoscopic resection of early esophageal adenocarcinomas (Barrett's cancer). Gastrointest Endosc 2007 Jan;65(1):3-10 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17185072.
- Manner H, May A, Pech O, Gossner L, Rabenstein T, Günter E, et al. Early Barrett's carcinoma with "low-risk" submucosal invasion: long-term results of endoscopic resection with a curative intent. Am J Gastroenterol 2008 Oct;103(10):2589-97 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18785950.
- Wani S, Abrams J, Edmundowicz SA, Gaddam S, Hovis CE, Green D, et al. Endoscopic Mucosal Resection Results in Change of Histologic Diagnosis in Barrett's Esophagus Patients with Visible and Flat Neoplasia: A Multicenter Cohort Study. Dig Dis Sci 2013 Apr 30 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23633158.
- Conio M, Repici A, Cestari R, Blanchi S, Lapertosa G, Missale G, et al. Endoscopic mucosal resection for high-grade dysplasia and intramucosal carcinoma in Barrett's esophagus: an Italian experience. World J Gastroenterol 2005 Nov 14;11(42):6650-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16425359.
- Mino-Kenudson M, Brugge WR, Puricelli WP, Nakatsuka LN, Nishioka NS, Zukerberg LR, et al. Management of superficial Barrett's epithelium-related neoplasms by endoscopic mucosal resection: clinicopathologic analysis of 27 cases. Am J Surg Pathol 2005 May;29(5):680-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15832094.
- Bulsiewicz WJ, Dellon ES, Rogers AJ, Pasricha S, Madanick RD, Grimm IS, et al. The impact of endoscopic ultrasound findings on clinical decision making in Barrett's esophagus with high-grade dysplasia or early esophageal adenocarcinoma. Dis Esophagus 2012 Sep 27 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23016606.
- Larghi A, Lightdale CJ, Memeo L, Bhagat G, Okpara N, Rotterdam H. EUS followed by EMR for staging of high-grade dysplasia and early cancer in Barrett's esophagus. Gastrointest Endosc 2005 Jul;62(1):16-23 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15990814.
- Pech O, May A, Günter E, Gossner L, Ell C. The impact of endoscopic ultrasound and computed tomography on the TNM staging of early cancer in Barrett's esophagus. Am J Gastroenterol 2006 Oct;101(10):2223-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17032186.
- Young PE, Gentry AB, Acosta RD, Greenwald BD, Riddle M. Endoscopic ultrasound does not accurately stage early adenocarcinoma or high-grade dysplasia of the esophagus. Clin Gastroenterol Hepatol 2010 Dec;8(12):1037-41 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20831900.
- Thosani N, Singh H, Kapadia A, Ochi N, Lee JH, Ajani J, et al. Diagnostic accuracy of EUS in differentiating mucosal versus submucosal invasion of superficial esophageal cancers: a systematic review and meta-analysis. Gastrointest Endosc 2012 Feb;75(2):242-53 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22115605.
- Fernández-Sordo JO, Konda VJ, Chennat J, Madrigal-Hoyos E, Posner MC, Ferguson MK, et al. Is Endoscopic Ultrasound (EUS) necessary in the pre-therapeutic assessment of Barrett's esophagus with early neoplasia? J Gastrointest Oncol 2012 Dec;3(4):314-21 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23205307.
- Chemaly M, Scalone O, Durivage G, Napoleon B, Pujol B, Lefort C, et al. Miniprobe EUS in the pretherapeutic assessment of early esophageal neoplasia. Endoscopy 2008 Jan;40(1):2-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18058614.
- Thomas T, Gilbert D, Kaye PV, Penman I, Aithal GP, Ragunath K. High-resolution endoscopy and endoscopic ultrasound for evaluation of early neoplasia in Barrett's esophagus. Surg Endosc 2010 May;24(5):1110-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19915911.
- van Vliet EP, Heijenbrok-Kal MH, Hunink MG, Kuipers EJ, Siersema PD. Staging investigations for oesophageal cancer: a meta-analysis. Br J Cancer 2008 Feb 12;98(3):547-57 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18212745.
- Shami VM, Villaverde A, Stearns L, Chi KD, Kinney TP, Rogers GB, et al. Clinical impact of conventional endosonography and endoscopic ultrasound-guided fine-needle aspiration in the assessment of patients with Barrett's esophagus and high-grade dysplasia or intramucosal carcinoma who have been referred for endoscopic ablation therapy. Endoscopy 2006 Feb;38(2):157-61 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16479423.
- Vazquez-Sequeiros E, Wiersema MJ, Clain JE, Norton ID, Levy MJ, Romero Y, et al. Impact of lymph node staging on therapy of esophageal carcinoma. Gastroenterology 2003 Dec;125(6):1626-35 Available from: http://www.ncbi.nlm.nih.gov/pubmed/14724814.
- Little SG, Rice TW, Bybel B, Mason DP, Murthy SC, Falk GW, et al. Is FDG-PET indicated for superficial esophageal cancer? Eur J Cardiothorac Surg 2007 May;31(5):791-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17337344.
- Barber TW, Duong CP, Leong T, Bressel M, Drummond EG, Hicks RJ. 18F-FDG PET/CT has a high impact on patient management and provides powerful prognostic stratification in the primary staging of esophageal cancer: a prospective study with mature survival data. J Nucl Med 2012 Jun;53(6):864-71 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22582047.