Hello. My name is Bonnie Conda. Thank you to the ASGE and the course organizers for inviting me to speak today. It is my pleasure to be speaking on the diagnosis and management of malignant and precancerous esophageal diseases. Here are my disclosures. My goals today are to provide an overview on the implications of diagnosis, histologic classification, clinical stage, and endoscopic information in terms of the management of esophageal cancer, to review Barrett's esophagus screening and surveillance recommendations, and review a high-quality endoscopic examination, and to highlight the management principles of superficial esophageal neoplasia. We will start with a question. A 68-year-old white male is referred for progressive dysphagia for six months. The dysphagia initially was with solid foods and more recently with both solids and liquids. He reports a 20-pound unintentional weight loss. An endoscopy was performed. The endoscopy demonstrated a circumferential mass-like lesion encountered at 33 centimeters from the incisors with a circumferential narrowing at 35 centimeters that did not allow for a regular diagnostic endoscope to pass. Which of the following next steps would be most appropriate? A, refer for endoscopic ultrasound with FNA for tissue sampling of the tumor. B, perform cytology brushings of the lesion and refer for endoscopic resection. C, call the on-call surgeon for urgent esophagectomy. D, perform eight biopsies of the lesion and plan for a CT scan with IV and oral contrast. The correct answer is D. This is because we want to provide a diagnosis to obtain a histologic classification with sufficient tissue, ideally six to eight biopsies with standard forceps, which can be at least done in the proximal portion of this lesion, and obtain information for clinical stage, which can be done with a CT scan to evaluate for metastatic disease as well as regional disease. The reasons for not considering the other options as appropriate are listed here. We will start by discussing esophageal cancer in general and provide an overview on what to consider when encountering a suspected esophageal cancer. There are two types of esophageal cancer, esophageal adenocarcinoma and esophageal squamous cell carcinoma. Esophageal adenocarcinoma is the predominant form in the West, and we can see the distribution of squamous cell carcinoma on the right as shown here. When symptoms from esophageal cancer are present, which may include dysphagia, weight loss, chest pain, worsening indigestion, coughing, or voice hoarseness, they often are associated with advanced stages of disease, which carry a prior prognosis of less than 20% five-year survival rates. On the other hand, early stage disease carry a much better prognosis with greater than 80% five-year survival rates. It's important we perform an endoscopy with biopsies as well as required documentation, which we'll review, and then also to consider staging with a CT scan to evaluate for metastatic or regional disease. If no evidence of metastatic disease, a PET-CT scan may be considered. And again, if no evidence of metastatic disease, an endoscopic ultrasound may be performed to evaluate for T staging as well as nodal staging. However, if there is early stage between T1A versus T1B consideration, endoscopic resection is most accurate. When we encounter a suspected esophageal cancer or tumor, we want to perform an adequate endoscopic examination and document it. We want to perform measurements of the landmarks, including the diaphragmatic pinch, gastroesophageal junction, and squamous clonal junction, as well as the presence or absence of Barrett's esophagus, and measure that length by PROG classification, which we'll touch on a little later. We want to document the presence of mucosal abnormalities, describe the tumor morphology, measure the lesion in terms of both the proximal and distal extent, as well as describe the size of the lesion. We want to describe any circumferential involvement or lumen obstruction. And we also want to describe specifically the epicenter in position to the relation of the gastroesophageal junction, as well as the distance of the extension into the cardia if present. And that is because adenocarcinomas with esophageal involvement and the epicenter within 2 cm of the gastric cardia are considered esophageal cancers, whereas those that extend with the epicenter beyond the 2 cm into the cardia are considered gastric cancers. Therefore, it's important to document this so we know whether to manage this like an esophageal cancer or a gastric cancer. We should also describe any skipped lesions if present, as well as any previous foregut surgery. We want to photograph all abnormalities, perform an adequate retroflex examination, as well as photograph it, and biopsy all suspicious lesions with at least 6 to 8 biopsies to improve diagnostic accuracy. I want to highlight your attention to some resources, including the AJCC Cancer Staging Manual, as well as the National Comprehensive Cancer Network guidelines. I will be showing you some tables and criteria and algorithms. And by no means do I want to go into the details of this, but just to make sure that you're aware of these resources. So first of all, there's a TNM staging classification system, which allows us to look at the tumor nodes and metastatic disease presence for staging purposes, which then allow us to look at the clinical stage. The clinical stage is basically what then dictates the management algorithm for each specific case. And this is different for squamous cell carcinoma and adenocarcinoma. Additional information that can be obtained by biopsies or histologic specimens include the grade of the tumor. This differentiation in terms of specific characteristics is different, again, for adenocarcinoma versus squamous cell carcinoma. And additional tumor characteristics, which often can be obtained by endoscopic resection specimens, include depth of invasion, specifically where it goes into the mucosal layers or the submucosal layers, and the presence of lymphovascular invasion or neural invasion. All of this information in terms of tumor type, clinical stage, as well as other tumor characteristics can then lead us down these different algorithms that are provided by the guidelines by the NCCN, which are available online. And this, again, is a good resource for you to look at if needed. In addition to discussing esophageal adenocarcinoma, we'll be also discussing screening, surveillance, and management principles with Barrett's esophagus as they are related. It used to be that squamous cell carcinoma was the predominant form of cancer worldwide, but esophageal adenocarcinoma has been increasing in incidence, as seen here. In addition to that, not only is the incidence of esophageal adenocarcinoma rising, as shown in the blue curve here, but the mortality is also closely following the incidence curve, as shown in the red curve on this graph, suggesting that many of the patients who are diagnosed with this disease may also die of this disease. Barrett's esophagus is a known risk factor for esophageal adenocarcinoma, and so it is fortunate we have a precursor lesion. Barrett's is the metaplastic transformation from the normal squamous lining in the esophagus to a columnar lined epithelium with the presence of goblet cells. It's associated with chronic reflux. Screening endoscopy is recommended to identify who has Barrett's esophagus and may be at risk for esophageal adenocarcinoma. The populations that are selected for screening endoscopy include those that have chronic GERD and multiple risk factors for esophageal adenocarcinoma. These additional risk factors include Caucasian race, male gender, older age, family history of Barrett's or esophageal adenocarcinoma, central obesity, cigarette smoking, the presence of a hiatal hernia. It is important to recognize we have a lower threshold to screen men compared to women given their risk for developing esophageal adenocarcinoma is greater than women. Also, it is important to recognize that we now have available non-endoscopic screening tools that may be acceptable screening modalities. These are coming in the form at various stages of investigation and commercial availability in the form of tethered collection cell devices that can be swallowed and collect cells from the esophagus without the need of a sedated endoscopy and used in conjunction with specific markers to be able to determine who may be at risk for developing esophageal adenocarcinoma. The risk of progression to cancer goes from the normal squamous lining to the metaplastic lesion of Barrett's esophagus to a spectrum of low-grade dysplasia to high-grade dysplasia and then to intramucosal carcinoma and then submucosal cancer. We know that the annual cancer incidence of those patients with high-grade dysplasia is on the order of 6% to 12%. And for those patients who have low-grade dysplasia, the risk is much lower on the order of 0.5% to 0.6%, but this population represents a very heterogeneous group of patients. And then those patients with nondysplastic Barrett's represents a risk of about 0.3% or less of an annual cancer incidence for progression to cancer. High-grade dysplasia is the best marker that we have to identify who's at risk for developing cancer. We can target this lesion for intervention to prevent cancer and it can be treated endoscopically. There is a high inter-observer variability among pathologists in the diagnosis of dysplasia and therefore all cases of dysplasia should be evaluated by an expert GI pathologist. For those patients who are diagnosed with nondysplastic Barrett's esophagus, endoscopy with a Seattle Protocol biopsy is recommended every three to five years. The Seattle Protocol biopsy suggests that we should biopsy all visible lesions and then perform a mapping protocol throughout the rest of the segment to evaluate for occult or subtle disease where we perform four-quadrant biopsies randomly every one to two centimeters throughout the rest of the Barrett's segment, specifically every one centimeter if there was ever a history of dysplasia. Recent additions from the ACG guidelines include the addition of virtual chromoendoscopy in addition to the white light endoscopy to perform our surveillance endoscopy examinations and also latitude to lengthen the surveillance intervals specifically for those patients with short segments who may not carry the same risk of progression to cancer as long segments such that three-year intervals may be most appropriate for long segments and five-year intervals may be most appropriate for short segments. Unfortunately, despite these patients getting endoscopy, you're still missing lesions which may be prevalent. In a meta-analysis with over 800 missed cancers, almost a quarter of these cancers were missed after index endoscopy among patients with nondysplastic Barrett's. Another VA study with over 600 patients with Barrett's had patients who were then diagnosed with dysplasia in 4% of the time within 18 months after an index endoscopy. This rate of missed dysplasia decreased over time. Therefore, it is important to perform a high-quality endoscopic examination to take advantage of that time that we have performing an endoscopy with that patient and doing everything we need to do to identify, recognize, and document what we need to perform that endoscopic examination. Again, the first thing we need to do is look at the landmarks as we mentioned earlier. Any displacement of the gastroesophageal junction from the diaphragmatic impression suggests there's a hiatal hernia. Any displacement of the squamo-culmonary junction from the gastroesophageal junction demonstrates that there is Barrett's esophagus. And any displacement of the squamo-culmonary junction from the gastroesophageal junction from the gastroesophageal junction as well as displacement from the diaphragmatic impression would suggest there's a Barrett's in the segment of a hiatal hernia. We want to assess the length of a Barrett's segment with the PROG classification system. This is where we look at the distance between the circumferential extent of the columnar lined epithelium from the top of the gastric folds and denote that distance as C. And then we look at the maximal extent from the top of the gastric folds and denote that distance as M. And any additional islands aren't included in these measurements but can be denoted as needed in addition in the documentation. In this example, we can see the diaphragmatic impression at 40, the top of the gastric folds at 39, suggesting a small hiatal hernia. No circumferential extent is noted and the maximal extent is at 36 cm with some islands noted at 35. We could characterize this esophagus with a small hiatal hernia, Barrett's segment with a C0M3 per PROG classification and diminutive islands located within 1 cm of the maximal extent of the Barrett's contiguous segment. Now there's always a question about whether or not to biopsy the irregular or variable Z line. We really should focus on the diagnosis of Barrett's esophagus on changes in the lining that are 1 cm or greater. The normal or variable Z line less than 1 cm very well could just be intestinal metoplasia of the cardia and it's not associated with the same increased risk of esophageal cancer. However, it is important to carefully inspect the squamo-columnar junction to identify any mucosal irregularities and biopsy if concerned for neoplasia. We want to really do an adequate job looking and the foundation for better detection requires tools, techniques, as well as training our eyes to inspect and recognize lesions. We want to use the best tool that we have. High-resolution endoscopy offers greater detail and you want to use the best scope that you have. In terms of techniques, we want to use irrigation, mucolytics to clean the surface, use tip deflection to adequately interrogate the mucosa. Consider the use of a soft distal attachment cap, which gives better visualization of the gastroesophageal junction folds as well as looking at the mucosa en face. And we can use the combination of insufflation and deflation to appreciate abnormalities in the mucosal contour of the wall. We want to inspect. Longer inspection time is associated with higher rates of detection. And we want to train our eye to recognize subtle flat lesions. We want to be familiar with regular pit patterns as seen above that are either ridged, circular, or a Cerebroformin pattern in Barrett's nondisplastic mucosa and compare those to irregular or distorted patterns or discoloration we can see below. Subtle lesions can be appreciated with training. We can use the BORN training module available online to better identify visible lesions by white light endoscopy. A training set where you can compare your findings with those of expert denoted lesions shows a significant improvement in the assessor's detection and delineation of lesions in all parameters. Digital or virtual chromoendoscopy can be easily implemented. Narrowband imaging is the most widely available and most investigated. It's a filtered blue light which enhances the mucosal pattern and vascular pattern. Post-processing platforms are also available. Overall, narrowband imaging provides a sensitivity of 94% and negative predictive value of 97% and a specificity of 94% for the detection of neoplastic lesions. The BING criteria allows us to look at narrowband imaging with two simple criteria, the mucosal pattern and the vascular pattern, and we're looking for any areas of irregular patterns in either to suggest areas suspicious for neoplasia. Once lesions are identified, we want to document tumor morphology. We can use the Paris classification as a way to communicate and document about these lesions. We know that those lesions that are protruding or depressed have a higher risk of submucosal invasive disease compared to those that are slightly raised or completely flat. Endoscopic mucosal resection is a widely available technique where a band can be deployed and then snare cautery can be used to resect the lesion to provide an accurate histologic specimen. As mentioned earlier, endoscopic mucosal resection is not only a therapeutic tool, but it's a diagnostic tool. It is more accurate for T1A staging versus T1B staging, and it has a higher inter-observer variability among pathologists compared to biopsy alone and demonstrates upstaging or downstaging of lesions in up to half the time compared to biopsies. Again, EUS is appropriate for nodal staging or deeper T staging, but inadequate for early T staging. And specifically, the differentiation between T1A versus T1B allows us to understand when we can start with endoscopic therapy versus maybe move more to surgery, and that's because of the risk of lymph node metastasis. For T1A lesions, the risk of lymph node metastasis is less than 2%, and so therefore, these lesions are often amenable to endoscopic resection, whereas T1B lesions are often associated with a much greater risk of lymph node metastasis and therefore require either surgery and or systemic therapy. The concept of total Barrett's eradication is based on removing not only the known neoplasia, but also to treat the rest of the at-risk epithelium to address any metacronous or synchronous lesions. The combination of performing endoscopic mucosal resection for visible lesions and then getting that accurate histologic diagnosis and stage and then moving forward with using a non-tissue acquiring modality such as radiofrequency ablation to treat the rest of the at-risk epithelium to ultimately get replacement of the Barrett's with neosquamous lining is a hybrid approach that allows us both accurate histologic information, removal of the known neoplasia, as well as ability to eradicate the rest of the lining. A beta analysis of this hybrid approach demonstrates a successful eradication of neoplasia on the order of 93.4% with an acceptable complication profile with a stricture rate of 10% and a negligible perforation rate. Other ablation modalities such as cryotherapy and hybrid APC are also available. A few words about submucosal cancer and adenocarcinoma. These lesions can be selected for low-risk lesions that are less than 2 centimeters in size, limited to the superficial third, the submucosa, well, moderately differentiated in grade, and no evidence of lymphovascular invasion. This specific subset of select submucosal cancers may be amenable to endoscopic therapy and that's because the risk of lymphometastasis is much less in these groups of patients compared to those with deeper submucosal invasive disease. The German experience, as well as the Netherland experience, underscore these findings of a low rate of lymphometastasis as well as ability to treat endoscopically. These cases, as well as some others, might be appropriate for endoscopic submucosal dissection. Endoscopic submucosal dissection provides an end-block specimen through the use of a combination of injection and knives. And it can be used in select cases of Barrett's-associated neoplasia, specifically those where there's concern for submucosal invasive disease, bulky or large disease, poorly lifting lesions, those cases with recurrent disease or positive margins on EMR, or equivocal pre-procedural histology. A brief word about low-grade dysplasia. Confirmed low-grade dysplasia may undergo endoscopic therapy and an alternative is close surveillance. Any visible lesion in the setting of dysplasia should be addressed with EMR to get an accurate diagnosis and stage. Ongoing and future directions include additional clarification on the benefit of treatment as well as opportunities for risk stratification to better identify who may best benefit from treatment among those patients. Thus, any suspicious lesion in Barrett's neoplasia should be addressed with endoscopic resection, with most cases of any visible lesion or mucosal irregularity being appropriate for either focal or piecemeal endoscopic mucosal resection. However, as mentioned earlier, certain cases might be appropriate for endoscopic submucosal dissection if available. And then the remainder of the flat segment, if the endoscopic resection was successful, can be addressed with ablation or a non-tissue acquiring modality. Those cases with evidence of lymph node metastasis, high-risk submucosal disease, lymphovascular or neural invasion, positive vertical margement involvement, or failure of endoscopic eradication therapy may be considered for esophagectomy. And those cases with low risks of mucosal carcinoma can be considered on a case-by-case basis. We're going to now shift gears to esophageal squamous cell carcinoma. Esophageal squamous cell carcinoma's risk factors vary from those that are for esophageal adenocarcinoma. Again, older age, male gender is there, but the race profile is more along the lines of African American, Asian, and Latino. Those patients that are smokers, as well as long-standing drinking, are at risk for esophageal squamous cell carcinoma. And the ingestion of hot liquids, which might over time cause injury to the esophagus, has been reported as an associated factor. Conditions such as telosis, which causes thickening of the palms and soles, as well as Plummer-Vinson syndrome, which is associated with anemia and esophageal webs, caustic or lye injury, and long-standing achalasia have been associated with esophageal squamous cell carcinoma. And in certain parts of the world, these cancers are associated with HPV infection. ESD for squamous cell neoplasia is indicated in most cases, and this is because squamous cell carcinoma is more aggressive for lymphometastasis per depth of tumor, as well as per lymphovascular invasion when compared to esophageal adenocarcinoma. And so therefore, ESD is considered, especially in any high-grade dysplasia, or M1 or M2 lesions. There's a higher risk of lymphometastasis for M3 or SM lesions, so this is more of an expanded indication. And then it's also important to recognize that extensive superficial lesions can be addressed with circumferential ESD, but this carries a significant risk of stricture formation. The approach to squamous cell neoplasia, again, is to address any suspicious lesions with endoscopic resection. However, the threshold to perform endoscopic submucosal dissection is much lower in these cases, and only those small lesions really should be reserved for endoscopic mucosal resection. And any of those cases with lymphovascular invasion, poor differentiation, evidence of lymphovascular invasion, or vertical margin involvement should be considered for esophagectomy. And those cases with muscular mucosal involvement or superficial submucosal involvement or circumferential lesion involvement may be considered on a case-by-case basis. Ultimately, esophageal neoplasia therapy is performed by a variety of modalities, such as ablation, like RFA, cryotherapy, or hybrid APC, endoscopic resection with ESD or EMR or surgery, like esophagectomy or chemotherapy or radiation therapy, and requires a whole host of medical team members, surgeons, gastroenterologists, oncologists, radiation oncologists, and requires a multidisciplinary approach. In conclusion, when encountering a suspected esophageal cancer, perform at least six to eight biopsies of the lesion and provide complete documentation in the report, including landmarks, characteristics, and measurements of the lesion, presence and length of the Barrett's esophagus, if present, and relationship to the gastroesophageal junction and distance into the cardia. Perform a high-quality endoscopic examination during screening and surveillance of patients with known or suspected Barrett's esophagus. Endoscopic eradication therapy is indicated for patients with Barrett's-associated high-grade dysplasia or intramucosal carcinoma. Select patients with low risks of mucosal carcinoma and may be considered for patients with confirmed low-grade dysplasia. And superficial squamous cell myoplasia is best addressed with end-block endoscopic resection. A multidisciplinary approach is often required in these patients.

esophageal cancer

diagnosis

management

Barrett's esophagus

treatment options

multidisciplinary approach