What are the best modalities for accurately staging early oesophageal adenocarcinoma?

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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.[1] Early oesophageal adenocarcinomas (EOA) are those defined as intra-mucosal adenocarcinoma (T1m) or superficial submucosal adenocarcinoma (T1sm1).[2] 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.[3][4] 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%).[5][6] 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%.[7] 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%.[6] 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)

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Endoscopic biopsy

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.[8] The use of jumbo biopsy forceps still misses unsuspected adenocarcinoma in Barrett’s Oesophagus with HGD.[9] 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.[10][11]

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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.[12][13] 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).[14] In other series, ER results in a change of pre-treatment histopathologic diagnosis in 25-55%.[10][15][16] 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.[11] In nodular lesions, ER with histological examination provides greater utility than staging by EUS.[17][18]

ER does carry risks of perforation, bleeding and anaesthetic-associated risk although rates of these adverse events were low in most series.[11][18][19] 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.

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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.[20] 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.[21] 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%).[22] 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.[23][24] High frequency miniprobe EUS, with improved image resolution, still has limited accuracy in the detection of submucosal invasion of early oesophageal cancers.[24] 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.[25] 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).[20] 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.[26] 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.[27] EUS-FNA has been shown to be superior to EUS alone and CT for nodal staging.[20][28]

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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.[29] 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.[26] 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.[30] CT has also been found to be inferior to EUS for T-staging and detection of locoregional lymph node metastases[20] 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.

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Evidence summary and recommendations

Evidence summary Level References
Endoscopic resection (ER) results in a change in pre-treatment diagnosis after systematic biopsies in patients with Barrett’s-related dysplasia or adenocarcinoma. IV [10], [14], [15], [16]
ER allows improved pathological staging of high grade dysplasia and T1m and T1sm adenocarcinoma as compared with biopsy and endoscopic ultrasound (EUS). IV [16], [18]
Rates of adverse events following ER performed at expert centres are low. IV [11], [18], [19]
Evidence-based recommendationQuestion mark transparent.png Grade
Endoscopic resection is the most accurate staging modality for early oesophageal adenocarcinoma for suitable lesions and where appropriate expertise is available.

Evidence summary Level References
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 [21], [24]
Endoscopic ultrasound and EUS-guide fine-needle aspiration (EUS-FNA) are superior to computed tomography (CT) for locoregional lymph node staging IV [20], [28]
Evidence-based recommendationQuestion mark transparent.png Grade
Endoscopic ultrasound can be used prior to endoscopic resection for the identification of deeply invasive adenocarcinoma (≥T2) and locoregional lymph node metastasis, particularly for lesions with ulcerated or depressed morphology.

Evidence summary Level References
FDG-PET cannot reliably differentiate oesophageal high grade dysplasia from invasive T1 adenocarcinoma. IV [29]
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 [26], [30]
Evidence-based recommendationQuestion mark transparent.png Grade
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.

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