LES

Physiologically, the LES is a 3- to 4-cm long segment of tonically contracted smooth muscle. An effective LES must have an adequate total and intra-abdominal length and an adequate resting pressure. However, a normal LES pressure does not exclude GERD, because abnormal transient relaxations may occur. Periodic relaxations of the LES in normal individuals have been termed transient LES relaxations (TLESRs) to distinguish them from relaxations triggered by swallowing. TLESRs account for the physiologic reflux found in normal subjects. However, when TLESRs become more frequent and prolonged, they can contribute to the development of GERD, and this phenomenon seems to explain the reflux observed in about 40% of patients with GERD whose resting LES pressure is normal. The cause of TLESRs is unknown, but postprandial gastric distention is probably involved. It seems that TLESRs play a role in patients with no mucosal injury or low grades of esophagitis, whereas a mechanically incompetent LES (short and hypotensive) is more often associated with worse mucosal damage such as in BE.

Medical treatment has been traditionally directed toward the decrease of acid production. At present, the focus is on medications that can affect the LES. For instance, initial studies with lesogaberan, a γ-aminobutyric acid type B receptor agonist, have shown a decreased number of TLESRs and reflux episodes and an increased LES pressure. These data underline that an incompetent LES represents a permanent defect of the gastroesophageal barrier. It is well proven that a fundoplication can correct the functional and mechanical profile of the LES, resulting in the control of any type of reflux from the stomach into the esophagus.

Peristalsis

Esophageal peristalsis is an important component of the antireflux mechanism because it is the main determinant of esophageal clearance of the gastric refluxate. Defective peristalsis is associated with more severe GERD, both in terms of symptoms and mucosal damage.

It is known that 40% to 50% of patients with GERD have abnormal peristalsis. This dysmotility is particularly severe in about 20% of patients because of very low amplitude of peristalsis and/or abnormal propagation of the peristaltic waves (ineffective esophageal motility). Because esophageal clearance is slower when peristalsis is ineffective, the refluxate is in contact with the esophageal mucosa for a longer period and is able to reach the upper esophagus and pharynx more often. Thus, these patients are prone to more severe mucosal injury (including BE) and more frequent extraesophageal symptoms such as cough or hoarseness.

It is still unclear whether esophageal dysmotility is a primary condition leading to GERD or a consequence of esophageal inflammation. Medical therapy does not ameliorate esophageal peristalsis. However, it has been shown that an effective fundoplication often improves abnormal peristalsis, suggesting that the dysmotility in most patients is the consequence rather than the cause of abnormal reflux.

Diaphragm

The LES and the diaphragmatic crura work together to form a sphincter, in which the smooth muscle of the LES coordinates with the striated muscle of the diaphragm to protect against reflux. The pinchcock action of the diaphragm is particularly important as protection against reflux induced by sudden increases in intra-abdominal pressure, such as during coughing and bending. This mechanism is disrupted by the presence and size of the hiatal hernia. It has been shown that in patients with a large hiatal hernia (>5 cm), the LES is shorter and weaker, the amount of reflux is greater, and the acid clearance is slower. As a consequence, the degree of mucosal injury is greater. The presence of a hiatal hernia has been associated with early recurrence and failure of medical therapy for GERD. On the other end, the reduction of a hiatal hernia with the narrowing of the esophageal hiatus is a key element in the performance of a fundoplication.

In a study of 502 consecutive patients with GERD (documented by pH monitoring), Campos and colleagues identified 3 factors that predicted the presence of BE: (1) a hiatal hernia measuring more than 4 cm, (2) an incompetent LES, and (3) long reflux episodes. This study suggests that there is a more severe compromise of the antireflux mechanism in patients with BE. These abnormalities can be corrected by a properly constructed fundoplication.

The Refluxate

Gastric and duodenal contents play a role in the development of GERD. Today, it is recognized that bile salts and pancreatic enzymes are part of the refluxate and are injurious to the esophageal mucosa. The definitive proof that bile reflux contributes to the pathogenesis of GERD was possible with the Bilitec 2000 (Medtronic, Minneapolis, MN, USA), which uses bilirubin as a marker for duodenal reflux. In a seminal study from the University of Southern California, Kauer and colleagues demonstrated that 58% of patients with GERD had mixed reflux, with increased esophageal exposure to gastric and duodenal juices. In addition, patients with Barrett metaplasia had a higher prevalence of abnormal esophageal bilirubin exposure than those with erosive esophagitis or no injury. In a subsequent study involving a large cohort of patients, the investigators showed that reflux of bile was the leading factor associated with BE and early cancer and that it can be suppressed by a fundoplication but not by acid suppression alone.

Implications For Treatment

Acid-reducing medications or a laparoscopic fundoplication are used today for the treatment of GERD. Treatment with proton pump inhibitors (PPIs) has the following major limitations:

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  As shown by pH-impedance monitoring, PPIs only change the pH of the gastric refluxate, not the occurrence and the number of reflux episodes, through a functionally or mechanically incompetent LES.

  
  
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  The duodenal components of the refluxate are unaffected by PPI treatment.

  
  
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  When pH monitoring is performed in patients with Barrett metaplasia who are asymptomatic during PPI treatment, about 40% to 80% of them still have abnormal acid reflux.

On the other hand, a fundoplication controls any type of reflux. The operation is effective because it improves esophageal motility, both in terms of LES competence and quality of esophageal peristalsis. Control of reflux is not influenced by the pattern of reflux, being equally effective when reflux is upright, supine, or bipositional. In addition, the operation is equally safe and effective in young or elderly patients.

A fundoplication can be done laparoscopically with a short hospital stay, minimal postoperative discomfort, fast recovery time, and excellent results. Long-term studies have shown that laparoscopic fundoplication controls symptoms in about 90% of patients after 10 years.

The role of surgery in the modern treatment of GERD and BE is reviewed step by step, from symptoms to metaplasia and from HGD to EAC.

GERD and Symptoms

PPIs or antireflux surgery is the option available for the treatment of GERD. Surgery is indicated in the following circumstances:

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  When symptoms (heartburn and especially regurgitation) are not completely controlled by medical treatment

  
  
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  When it is thought that respiratory symptoms are induced by gastroesophageal reflux. Mainie and colleagues have shown that a laparoscopic Nissen fundoplication is the treatment of choice in patients resistant to PPIs, in whom nonacid or acid reflux is demonstrated by multichannel intraluminal pH-impedance monitoring, and in those with a positive symptom index

  
  
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  Poor patient compliance

  
  
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  High cost of medical therapy

  
  
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  Postmenopausal women with osteoporosis. PPIs and histamine2 receptor antagonists increase the risk of hip and femur fractures

  
  
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  Young and symptomatic patients for whom lifelong medical treatment is not advisable.

Based on the data present in the literature, there is no definitive evidence that one form of treatment is better than the other in preventing progression to Barrett metaplasia. However, few studies seem to suggest that an antireflux operation might be more effective than medical treatment. Using endoscopy, Oberg and colleagues studied 69 patients with reflux symptoms but no metaplasia; 49 were treated with chronic acid suppression therapy and 20 underwent a fundoplication (19 with normalization of the acid reflux as determined by postoperative pH monitoring). The investigators showed that surgery was associated with a 10-fold decreased chance of developing intestinal metaplasia. Similar findings were reported by Wetscher and colleagues in a prospective study of patients with GERD who were treated either medically (83 patients with PPIs and cisapride) or by a fundoplication (42 patients). Barrett metaplasia developed in 14.5% of patients treated medically (median follow-up, 2 years) but in none of the patients treated surgically (median follow-up, 3.5 years). These results seem to suggest that antireflux surgery is more effective than acid suppression, probably because it restores the LES competence and stops any type of reflux, acid or bilious.

Metaplasia

About 10% to 15% of patients with GERD (proved by pH monitoring) eventually develop metaplasia. Long duration of symptoms, a large hiatal hernia, an incompetent LES, and the presence of acid and bile reflux are considered potential risk factors for the progression from symptoms to metaplasia. It is controversial whether medical or surgical treatment can cause regression and affect the natural history of the disease. However, it seems that a fundoplication causes regression to nonmetaplastic epithelium in 30% to 60% of patients with a short-segment BE (SSBE, <3 cm). For instance, Oelschlager and colleagues studied the effect of laparoscopic antireflux surgery in 106 consecutive patients with BE. Heartburn resolved or improved in 96% of patients and regurgitation in 84%. Among 90 patients who had endoscopic follow-up, 54 had an SSBE and 36 had a long-segment BE (LSBE). Postoperative endoscopy and pathology revealed complete regression of intestinal metaplasia in 56% of patients with SSBE but in none with an LSBE. One of the patients with LSBE developed an adenocarcinoma within 10 months of operation. Bowers and colleagues demonstrated loss of intestinal metaplasia in the tubular esophagus in 47% of patients after a fundoplication. None of the patients developed HGD or adenocarcinoma during follow-up. About 97% of patients were satisfied with the results of the operation.

In summary, it seems that antireflux surgery is effective in symptom control in patients with BE and that it can cause regression when SSBE, but not LSBE, is present. Based on these data and the understanding of the pathophysiology of the disease, the authors propose that patients should be treated initially with radiofrequency ablation (RFA) to eliminate the metaplastic epithelium and subsequently have a fundoplication. Even though most of the protocols currently in place use PPI therapy after RFA, this approach is not useful for the following reasons:

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  Pathophysiology of GERD, as previously described. PPIs do not affect the overall occurrence of reflux and do not improve the abnormal motility.

  
  
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  Some patients develop metaplasia while being treated with PPIs.

  
  
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  RFA does not alter the genetic or environmental causes of GERD.

There is some concern about the side effects of an antireflux operation and the long-term results. Referral of these patients to centers where proven expertise is present is recommended. Although the concept of outcome linked to volume is now accepted for high-risk operations, such as esophagectomy for cancer, it is not equally established for benign esophageal diseases. For operations such as antireflux surgery, the expertise of the team managing these patients, particularly the surgeon’s experience, is of key importance in the performance of a safe, effective, and long-lasting laparoscopic fundoplication.

Low-Grade Dysplasia

For patients with low-grade dysplasia, the same therapeutic approach as that for patients with metaplasia is recommended. However, after the initial endoscopy, patients should be treated for about 8 weeks with high doses of PPI and subsequently have a repeat endoscopy. Once the inflammation is resolved, it is easier for the pathologist to determine if the patient has metaplasia, low-grade dysplasia, or HGD.

HGD and Adenocarcinoma

The introduction of new endoscopic techniques such as RFA and endoscopic mucosal resection (EMR) has revolutionized the treatment of BE associated with HGD and early EAC, obviating an esophagectomy in most patients with these conditions.

In the past, the presence of HGD and early EAC was usually considered as an indication for esophagectomy. This recommendation was based on the following 2 considerations:

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  Progression of the disease. Many studies had shown a high rate of progression from HGD to EAC, of about 50% at 5 years and 80% at 8 years.

  
  
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  It was believed that in about 40% of patients in whom an esophagectomy was performed for HGD, an invasive adenocarcinoma was instead found in the resected specimen.

However, most of these studies had major flaws. In most patients, the diagnosis was based on an endoscopy with random biopsies only. If a more rigid protocol (4-quadrant biopsies every cm) had been used, an EAC would have been detected preoperatively in many patients. In addition, often a second pathologist did not review the slides of the endoscopic biopsies. This review process is important because of the difficulty in distinguishing between HGD and a superficial cancer and the existence of well-known interobserver variation. Had these procedures been properly done, the 40% rate of EAC found in the resected specimen would have been much lower.

Although in the past the differentiation between HGD and superficial cancer was often a moot point because a resection was ultimately performed, it is of paramount importance today because of the use of RFA and EMR. HGD (carcinoma in situ) is a neoplastic process without invasion of the basement membrane. According to the American Joint Commission on Cancer, an intramucosal carcinoma (IMC) or T1a is a tumor limited to the lamina propria and a submucosal carcinoma or T1b is a tumor that has invaded past the muscularis mucosae, which is considered an invasive adenocarcinoma (IEAC). Each stage has a different risk of lymph node metastases; it is 0% for HGD, around 7% for a T1a cancer, and about 25% for a T1b cancer.

In a recent study, Konda and colleagues reviewed reports of patients who had esophagectomy for HGD in BE to determine the true incidence of IEAC. Although the overall rate was around 40%, it decreased to 12.7% when studies that differentiated between intramucosal and submucosal invasion were considered. Differentiating between IMC (T1a) and IEAC (T1b and beyond) is of paramount importance because HGD and IMC can be treated endoscopically in most cases, thereby restricting esophageal resection to a small subset of patients. When there is a need to distinguish between T1a and T1b, EMR is useful as a diagnostic and staging procedure. EMR is important in the case of visible lesions in the setting of HGD because they are associated with a higher risk of IEAC.

Based on these considerations, the patients in whom an esophagectomy should still be considered can be determined as follows:

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  Patients in whom lymph node involvement is clearly shown by endoscopic ultrasonography (EUS)-guided fine-needle aspiration, even if it is an IMC.

  
  
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  Patients who are young. Surveillance for 20 to 40 years is not a viable and reasonable option because of the risk of losing patients to follow-up, with some of them coming back with dysphagia caused by advanced cancer.

  
  
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  Patients who are not willing or cannot afford the rigorous follow-up associated with endoscopic treatment. For instance, in the Wiesbaden experience, patients underwent intensive staging with EUS, high-resolution videoendoscopy, and a rigid biopsy protocol with review by 2 different pathologists. After treatment, patients had follow-up endoscopy at 1, 2, 3, 6, 9, 12, 16, 24, 30, and 36 months, again with high-resolution chromoendoscopy, computed tomography, EUS, and multiple biopsies. It seems reasonable to assume that many patients would not be compliant over time and that after 3 to 5 years the dropout rate could be high.

  
  
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  Patients with multifocal disease and a LSBE. In these patients, there is the risk of missing synchronous or metachronous lesions.

  
  
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  Patients in whom BE is still present after RFA and/or EMR. The risk of developing an IEAC in the remaining BE epithelium is quite high. In a study of 261 patients with dysplasia or IMC, Badreddine and colleagues found that significant predictors of recurrence on a multivariate model were history of smoking, old age, and presence of residual nondysplastic BE. Recurrence occurred in 47 of 261 (17%) patients treated with photodynamic therapy, with or without EMR. LSBE (7 and 10 cm) was present before ablation in 2 patients with recurring adenocarcinoma.

  
  
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  Patients who are healthy and do not want to have a lifelong and rigid follow-up or who are concerned about developing an IEAC.

Even though it is recognized that an esophagectomy is curative because it removes all the BE, there is still concern about the mortality rate of the operation and the quality of life afterward. There is a major difference between resections done for advanced esophageal cancer and those performed for T1 lesions. Many series have, in fact, shown that the mortality rate for early cancer is close to 0% and that after the immediate postoperative period, the quality of life is excellent. For instance, the Luketich group has shown that esophagectomy for T1 lesions can be done with a 0% mortality rate. In addition, the use of minimally invasive techniques has brought an improvement in the immediate postoperative course because it is associated with less postoperative pain, a shorter hospital stay, and a faster recovery time. Chang and colleagues showed that postoperative symptoms caused by esophagectomy are common but mild and do not interfere with the quality of life, which is excellent and similar to that of the general population.