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Barrett’s esophagus is defined as a condition when the normal squamous epithelium of the distal esophagus has been replaced by a metaplastic columnar epithelium. We found that this metaplastic columnar epithelium actually contains a wide variety of cell types including gastric, small bowel, pancreatic, and colonic cells. For the past several years intensive focus on the histopathology of this condition has resulted in the discovery that the intestinal cell types, predominantly intestinal metaplasia (which is an epithelium with a villous surface and goblet cells) is the tissue type of concern which has a higher propensity to degenerate into adenocarcinoma. Endoscopically, Barrett’s esophagus is seen as a change in color of the tissue lining of the distal esophagus. The normal squamos epithelium is typically seen as a grayish or silver-like lining with Barrett’s esophagus taking on a pinker, orangish, or salmon-colored hue. If biopsies were obtained from these fields one would see how the normal squamos epithelium differs from that of the intestinal metaplasia of Barrett’s. Barrett’s esophagus has been a definition in evolution. It has been a moving target with multiple influences, primarily anatomic, endoscopic, and histologic. As increased anatomic knowledge of the GE junction has come about definitions and criteria have changed somewhat. With widespread use of endoscopy and direct video assessment of the distal esophagus we have been confronted with the question of how much salmon-colored mucosa is too much. Then again, one must remember that histologic review is an interpretive field and as various advances have been made with strains and sectioning techniques this has impacted our definitions as well.
The history of Barrett’s esophagus dates back to the 1950’s when a British surgeon, Norman Barrett, stated that gastric mucosa extending into the distal esophagus was normal and was of congenital origin. By the 1960’s there was question that this may be an acquired condition and may be related to gastroesophageal reflux disease. In the 1970’s multiple studies were done that confirmed that Barrett’s esophagus was indeed related to gastroesophageal reflux disease. At the same time histologic refinements were made. It was discovered the multiple cell lines were involved and that these cell types could become dysplastic and association was further made with adenocarcinoma of the distal esophagus and GE junction. In the 1980’s there was intensive focus on a particular cell type, that of the intestinal metaplasia and goblet cells. Into the 1990’s until today there has been much scrutiny regarding the issues of screening, surveillance, and treatment of this condition. Barrett’s esophagus does represent somewhat of a clinical conundrum. As described earlier, anatomic, endoscopic, and histolgic issues are at play. Anatomically, the distinction between the end of the distal esophagus and the beginning of the proximal stomach may not be entirely clear. The major components of the gastroesophageal (GE) junction are the diaphragmatic crura, lower esophageal sphincter, and squamocolumnar junction. By way of definition, the gastroesophageal junction is defined as the most proximal aspect of the gastric folds where the tubular esophagus flares into the gastric cavity. These anatomical landmarks can be distorted due to hiatal herniation (which is quite common in patients with severe reflux disease), inflammation such as esophagitis and ulceration which obscure the squamocolumnar junction, as well as movement at the time of biopsy. It must be remembered that endoscopy is a dynamic procedure. There is patient movement, endoscopist movement, and the entire field is mobile.
The epidemiology of this condition, Barrett’s esophagus, is quite interesting. If one looks at autopsy studies it has been estimated that one out of 57-105 patients have the condition of Barrett’s esophagus. Expressed another way this would be 376 cases of Barrett’s out of every 100,000 patients in the population, so it is quite evident that there are entirely more people walking around with Barrett’s esophagus that never reach clinical diagnosis. It is estimated that on routine upper endoscopy Barrett’s esophagus accounts for 1 out of every 100 cases. If you refine your search to upper endoscopy for patients with symptoms of GERD it is found in 10-15 patients out of 100. It is estimated to occur in 8%-12% of patients with GERD symptoms, and this calculates to an estimated 700,000 adults in the United States. Demographically, it occurs much more frequently in whites than blacks, and more frequently in males than females. If one looks at the associated condition adenocarcinoma review of the epidemiology literature reveals that adenocarcinoma of the distal esophagus and GE junction has been rapidly rising in incidence and prevalence since the turn of the century. Prevalence data obtained from 1926-1976 states that adenocarcinoma accounted for only 0.8%-3.7% of all esophagela cancers. However, data obtained from 1979-1992 suggested that adenocarcinoma accounted for up to 54%-68% of all esophageal cancers. As you can see, this is quite a dramatic increase, and some of this is related to the development of refined data collection as well as improvement in diagnosis predominantly provided by the role of endoscopy. If one looks at incidence data it appears that the diagnosis of adenocarcinoma in the distal esophagus has increased almost 3-fold since the 1970’s. This is felt to represent a true increase, not simply a revision in data collection. Reviewing risk factors for adenocarcinoma, they match those of Barrett’s esophagus. Adenocarcinomas tend to occur in Caucasians 95% of the time, males more than females in a 5:1 ratio, and almost 80% of adenocarcinomas of the esophagus occur in the distal esophagus over a field of Barrett’s mucosa. When looking at the incidence of adenocarcinoma in the setting of Barrett’s esophagus 18 various studies have been reviewed, and it is felt that a patient with Barrett’s esophagus has a 40-fold increased risk of adenocarcinoma of the distal esophagus as compared to the general population. Additionally, adenocarcinoma has been found in patients with long-segment Barrett’s esophagus with surrounding dysplasia at the time of esophagectomy. The theory being that patients with longer segments of Barrett’s esophagus have more surface area for dysplasia, and therefore an increased risk for adenocarcinoma. As we know, tumors do not arise de novo overnight. Transition into frank neoplasia occurs over a period of time and through a sequence of histologic changes. One gradually develops metaplasia, then as the tissue characteristics degenerate one approaches a dysplastic cell type which further degenerates into frank neoplasia or cancer. Various studies have looked at the rate of progression to frank neoplasia. In 1992 a study published in Gastroenterology suggested that it took a mean of 29 months to progress from low-grade dysplasia to high-grade dysplasia, an additional 14 months to progress from high-grade dysplasia to frank adenocarcinoma. An additional study published in 1996 suggested that progression from dysplasia to adenocarcinoma occurred over the course of 18-48 months. Also, there have been multiple series reported in the literature that state that occult adenocarcinoma is present in many patients thought to only have high-grade dysplasia. It is estimated that this occurs in 30%-40% of patients with high-grade dysplasia.
Given these epidemiologic statistics and the link to edenocarcinoma many people advocate the surveillance of patients with Barrett’s esophagus with biopsies taken every 1-3 years to look for early changes of dysplasia and neoplasia. Proponents of this state that while Barrett’s esophagus is associated with gastroesophageal reflux disease, and there are an estimated 26 million Americans with reflux disease, it is estimated that there are 700,000 patients with Barrett’s esophagus in the United States. Barrett’s is now accepted as a premalignant condition of the esophagus. There is an adequate interval of opportunity, as stated carcinoma or adenocarcinoma does not occur overnight, and during these years of dysplasia one has the chance to intervene. It has been shown that early detection of cancer improves survival, and conversely delayed detection allows the disease progression and developement of comorbid conditions and decreases survival. Various studies have been performed which compare patients with Barrett’s esophagus placed in screening protocols versus no screening, and it has been shown that patients in screening protocols typically present with lower stage or earlier grade cancers and have an increased 5-year survival as compared to those patients without screening. Conversely, those that argue against screening or surveillance for Barrett’s esophagus state that the prevalence of Barrett’s esophagus is 20 times higher in autopsy studies as opposed to clinical diagnoses suggesting that many people have the condition of Barrett’s esophagus but never progress to cancer. It has been noted in the literature in multiple studies in patients that actually develop adenocarcinoma only a very few of these patients actually die of complications from the adenocarcinoma themselves. It has been estimated that of all the Barrett’s patients only approximately 10% are actually estimated to develop adenocarcinoma. 90% of patients with Barrett’s esophagus are estimated to develop no adenocarcinoma. In addition, the cost of surveillance is not negligible and there are procedural-related risks involved.
Various surveillance techniques have been employed. Prior to the 1990’s various abrasive balloons were used, cytology brushes were placed via NG tubes, and random biopsies were obtained. By the early 1990’s regimented biopsy protocols had come into fashion, and by the late 1990’s various refinements of biopsy protocols using jumbo size or standard size forceps were employed. Currently in the new millennium there is the discussion using the role of endoscopic ultrasound in various experimental techniques to improve diagnosis and surveillance. Endoscopically finding a focus of dysplasia and adenocarcinoma can be quite difficult. The area of concern may be a microscopic area or clustering of abnormal cells on an entire field of Barrett’s esophagus. This area of concern is certainly not readily visible endoscopically and is very much akin to searching for a needle in a haystack. There has been a nice study performed by Cameron, et al, in 1997 in which he mapped 30 esophagectomy specimens that were resected from patients with proven high-grade dysplasia. In this study the mean surface area for Barrett’s esophagus, which is intestinal metaplasia, was 32 centimeters. The area of low-grade dysplasia was much smaller at 1.3 centimeters. The focus of adenocarcinomas was tremendously reduced to that of 1.1 centimeters. He went on to state that three smallest adenocarcinomas has surface area of 0.02, 0.3, and 0.4 cm square. Thus one sees that the identification of such small area of concern in a broad field is quite difficult when there is no discernible differences to the naked eye. Given these findings regimented biopsy protocols have been defined where the endoscopist is asked to take four quadrant biopsies every 2 cm throughout the entire length of Barrett’s esophagus. Various broad field technologies are undergoing research including chromoendoscopy and optical coherence tomography. Additionally, the use of endoscopic ultrasound, which allows dilineation of various cell layers of the esophagus, is being experimented with. Chromoendoscopy is simply the use of vital stains to highlight mucosal abnormalities. Various stains are selectively taken up and accumulated by different types of epithelia. Lugol’s iodine stains squamos epthelium black. Methylene blue stains intestinal metaplasia blue, and indigo carmine highlights various mucosal surfaces. After the dyes are employed and selectively taken up by areas of dusplasia it is felt that more selected biopsies can be taken and are targeted at the region of concern. Various studies have been performed evaluating the role of chromoendoscopy, and at this time there are currently 16 studies in the literature. Seven favor this technique, and nine are opposed. Endoscopic ultrasound allows dilineation of microscopic layers of the esophageal wall, and when carefully applied allows detection of early foci cancer. This requires special equipment and has been reserved for tertiary care centers with active research programs in this area.
Reviewing the management options brings up several interesting questions regarding Barrett’s esophagus. If a patient is diagnosed with straight forward intestinal metaplasia or Barrett’s esophagus the treatment recommendations are to treat their underlying gastroesophageal reflux disease with proton pump inhibitors and to have them undergo upper endoscopy with random biopsies taken every 1-3 years. If a patient is given the diagnosis of low grade dysplasia in a field of Barrett’s esophagus then it is recommended that they undergo 12 weeks of aggressive proton pump inhibitor therapy and have an increased surveillance interval. In the rare patient where high-grade dysplasia or early adenocarcinoma in situ is detected then several treatment options are available ranging from total surgical excision of the esophagus to simply continued surveillance. In between these two extremes new endoscopic therapies are emerging such as endoscopic mucosal resection as well as endoscopic ablative therapies. Let’s review these management options. Total esophagectomy is theoretically curative. Studies have shown that patients with high grade dysplasia or early carcinoma who were detected while enrolled in a surveillance program had 2-year survival rates at 86% as opposed to patients who presented with disease spread to local lymph nodes who had 2-year survivals of less than 43%. Proponents of total esophagectomy contend that in patients with high-grade dysplasia occult adenocarcinoma exists in 30% – 40% of these patients and that adenocarcinoma is a cancer that has an early rate of metastasis. Total esophagectomy has an operative mortality which means death from the operation occurring 0-3% of the time. The immediate perioperative mobidity is approximately 50% and typically results in ICU stay of 1-2 days and hospitalization for a full 8-14 days. Anastomotic leaks from the resection occur in 8% of patients, and stricture formation at the site of the anastomosis occurs in up to 33% of patients. Given these statistics and the highly invasive nature of a total esophagectomy there is an emerging body of literature which supports ongoing endoscopic surveillance of patients with high-grade dysplasia.
Those that advocate continued surveillance state that dysplasia can be over-diagnosed by pathologists, that endoscopic biopsies can accurately differentiate high-grade dysplasia from adenocarcinoma, and the morbidity and mortality of a total esophagectomy is quite significant, especially in older patients. Two various sites have embarked on serial followup of several patients with high-grade dysplasia in surveillance protocols. At the Hines VA Medical Center in Chicago 31 out of 40 patients with high-grade dysplasia had no progression to adenocarcinoma over a period of seven years. additionally, at the University of Washington 43 out of 58 patients, or 74% had no progression from high-grade dysplasia to adenocarcinoma over a mean of 2.5 years. These centers advocate watchful waiting and ongoing surveillance in these patients as this preserves their quality of life and avoids an invasive surgery. Between these two extremes are two emerging technologies. That of endoscopic mucosal resection and various ablative therapies. Endoscopic mucosal resection is simply a lift and snare technique requiring submucosal injection of saline beneath an identified lesion. The lesion is then lifted with forceps and a snare is placed at the base of the lesion and small cautery current is applied to remove the lesion. This technique may be amended with the use of endoscopic caps to fit over the end of the endoscope as well as endoscopic banding procedure. Ablative therapies simply induce superficial injury to the dysplastic columnar epithelium in order to allow replacement with a normal squamos epithelium. This is typically reserved for patients that are considered poor surgical candidates or those that refuse to undergo esophagectomy. Various devices have been employed to induce superficial injury such as multipolar electrocoagulation, Argon plasmacoagulation, and photodynamic therapy. Multipolar electrocoagulation, the least expensive method, is widely available at endoscopic units around the United States, induces a very superficial level of tissue injury and has been associated with a 90% complete response rate. However, you are inducing a field of tissue injury in the esophagus and some disadvantages to this do exist such as procedure-related bleeding, chest pain, and odynophagia in some patients. Additionally, this does require multiple treatment sessions for complete response. Argon plasmacoagulation is a newer technology in which argon gas is allowed to stream through a catheter and cross a high frequency electrode which conducts energy via an ionized current directed to the lesion. This technique does not require tissue contact with the probe and allows the endoscopist more freedom of movement and accessibility of previously difficult to reach lesions. The advantage of Argon plasmacoagulation (APC) are that it is contact free, has minimal tissue penetration, and has been effective in 86% of patients responding with a complete response to therapy. Again, one is inducing superficial tissue injury to a broad field in the esophagus and therefore some patients will experience odynophagia, burning sensations in the chest, and occasionally stricture formation. Once again, multiple treatment sessions are required. Photodynamic therapy (PDT) is an interesting new technique that has been taken from the armamentarium of dermatology and altered for endoscopic usage. PDT requires the use of a photosensitizing drug known as Porphyrin which is selectively taken up in dysplastic or abnormal tissue. The drug is then chemically activated by a laser light set at 630 nanometer wavelength. This releases free radicals within the tissue causing local tissue injury and cell death. A typical treatment regimen for a course of PDT would entail injection of the chemical agent on Monday with return for upper endoscopy and laser light application on Wednesday, and a return visit again for a second laser light application and debridement on Friday. In various reported series anywhere from 75%-80% of patients with Barrett’s esophagus have been converted to a normal squamos epithelium after PDT treatments. In a study of 100 patients, 78 patients had elimination of their dysplasia, and 10 out of 13 superficial malignancies were ablated.
In summary, ablative therapies are effective but at this time are reserved for patients that are considered high surgical risk or those that refuse surgery. In patients with high-grade dysplasia total esophagectomy is considered the first line of treatment at this time.
Future directions in the detection and management of Barrett’s esophagus will require advancement on three levels, the first being a cellular level where active research is being performed to look for genetic or bio-markers which will allow focusing of surveillance biopsies on those patients at increased risk. The second level would be advancement in endoscopic broad-field technologies that will allow more directed application of biopsies. Thirdly, improved epidemiology and data collection will help define the appropriate patient population for whom screening and surveillance should be directed.
Wayne Adkisson, M.D.