Journal of Surgical Research 117, 44 –51 (2004) doi:10.1016/j.jss.2003.10.021

Barrett’s Esophagus: Management of High-Grade Dysplasia and Cancer Alberto Ruol, M.D., 1 Giovanni Zaninotto, M.D., Mario Costantini, M.D., Giorgio Battaglia, M.D., Matteo Cagol, M.D., Rita Alfieri, M.D., Magdalena Epifani, and Ermanno Ancona, M.D. Clinica Chirurgica 3°, University of Padova, Padova, Italy Submitted for publication October 29, 2003

steadily rising incidence rates of adenocarcinoma of the cardia are reported [1–5]. Although this could reflect increased awareness of adenocarcinoma concomitant with Barrett’s esophagus, it probably represents an absolute increase. Adenocarcinoma of the esophagus arises through a progression of molecular, genetic, and histological changes characterized by specialized intestinal metaplasia of the esophageal mucosa (Barrett’s metaplasia) and evolving through progressive grades of dysplasia to high-grade dysplasia (HGD) and ultimately invasive cancer. The risk of Barrett’s mucosa to progress to adenocarcinoma is not well established: published estimates of the annual risk of cancer range from 0.2 to 2.9%, and a calculated risk from 30 to 125 times higher than in the general population is reported [6, 7]. It is estimated, in North America, that 25,000 to 35,000 people suffer from HGD associated with Barrett’s esophagus, and that approximately 5000 to 7000 new patients are diagnosed with this condition each year [8]. Estimates of the risk that HGD will progress within 5 years to invasive cancer range widely, from 16 to 59% [6, 9]. The risk of developing adenocarcinoma may also depend on the length of Barrett’s metaplasia [10] and the extent of dysplasia, with a worse prognosis for patients with diffuse dysplastic changes. Buttar followed 100 patients with HGD with continued endoscopic surveillance and found cancer at 1 and 3 years in 38 and 56% of the patients with diffuse HGD, and in 7 and 14% of patients with focal HGD [11]. During the follow-up period of up to 8 years, 32 of the 100 patients with HGD were found to have cancer. Current strategies for improved survival in patients with Barrett’s adenocarcinoma focus on cancer detection at an early and potentially curable stage. This can be obtained by screening programs in high-risk cohorts of patients and/or endoscopic biopsy surveillance of patients with known Barrett’s esophagus. The current

Esophagectomy remains the treatment of choice for the appropriate patient with Barrett’s adenocarcinoma invading beyond the mucosa, without evidence of distant metastasis or invasion of adjacent organs. On the other hand, therapeutic management of patients with Barrett’s high-grade dysplasia (HGD) or mucosal adenocarcinoma should be individualized, taking into account the patient’s preferences, willingness to return for frequent endoscopic biopsies, and medical fitness to undergo esophagectomy. Surgery has to be considered the best treatment for HGD or superficial carcinoma, unless contraindicated by severe comorbidities, because it has proven to be the only treatment that is successful in curing the condition and preventing recurrent HGD or the development of invasive cancer. Nonsurgical treatment by photodynamic therapy or endoscopic mucosal resection may be a less invasive and organ-sparing option for elderly, poor-risk patients but it is still to be considered an investigational therapy that should only be conducted under a clinical trial protocol. Finally, intensive endoscopic biopsy surveillance of patients with HGD is another investigational option that may allow prompt treatment of cancer if it develops. However, few data document the safety of this observational approach. © 2004 Elsevier Inc. All rights reserved. Key Words: Barrett’s esophagus; high-grade dysplasia (HGD); adenocarcinoma. INTRODUCTION

In the last two decades, a growing body of literature from North America and Western Europe has revealed that adenocarcinoma of the esophagus is increasing in incidence more rapidly than any other cancer; parallel, 1 To whom correspondence and reprint requests should be addressed at Clinica Chirurgica 3°, Universita’ di Padova, Via Giustiniani, 2. 35128 Padova, Italy. Fax: ⫹39-049-8213152. E-mail: [email protected].

0022-4804/04 $30.00 © 2004 Elsevier Inc. All rights reserved.

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RUOL ET AL.: BARRETT’S HIGH-GRADE DYSPLASIA AND CANCER

goal of surveillance is the detection of dysplasia, which is still the best available marker of cancer risk. Despite the continuing debate on the cost-effectiveness of screening and surveillance programs in patients with Barrett’s esophagus, in Europe and North America, adenocarcinoma of the esophagus is increasingly diagnosed at early stages just because of endoscopic surveillance. Ferguson has recently reported on 80 patients who underwent resection for Barrett’s adenocarcinoma [12]. Pathological stage was 0 or 1 in 9 (75%) of 12 patients who were followed with endoscopic surveillance compared to 12 (18%) of 68 of those in the no surveillance group. Median survival for patients in the surveillance group was 107 months compared to 12 months for those in the no surveillance group. Also, Corley reported that surveillance detected cancer patients had earlier tumor stage and longer survival than non-surveillance-detected patients [13]. However, only 3.9% of the 589 patients with esophageal adenocarcinoma had Barrett’s diagnosed before their cancer and were therefore eligible for surveillance. This indicates that Barrett’s esophagus goes undetected in the vast majority of patients with esophageal adenocarcinoma and that the potential benefit of endoscopic surveillance seems to be limited to only a fraction of those individuals at risk. Similar results are reported by other authors [14]. Current screening and surveillance strategies, even if potentially beneficial on a single patient basis, are very expensive, far from efficient, and their cost-effectiveness is questionable [12, 13]. Because the focal nature of dysplasia makes targeting of biopsy specimens problematic, endoscopic biopsy surveillance, using novel modalities such as vital staining chromoendoscopy, high-magnification endoscopy [15], fluorescence endoscopy, or molecular biomarkers (e.g., p53, p16, abnormal ploidy) in biopsied tissue [9, 16 –20], may allow the better recognition of patients with dysplastic lesions and any mucosal abnormalities that are at increased risk of cancer progression. In the near future, the use of a panel of molecular markers in patients with Barrett’s esophagus may prove to represent a superior diagnostic tool to identify patients with elevated malignant potential, to establish the diagnosis of malignancy at an early stage, and to expedite a patient’s tailored therapy. Treatment strategies, when Barrett’s HGD or adenocarcinoma is detected, often depend on the fact that many patients are older than 60 years of age and suffer from severe comorbidities that may preclude esophagectomy. Because the diagnostic accuracy and treatment-related morbidity and mortality rates are better in institutions where a high number of patients with Barrett’s HGD or cancer are observed, consideration should be given to the referral of these patients to specialty centers that have adequate expertise and

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availability of the different treatment modalities [21– 25]. HIGH-GRADE DYSPLASIA AND EARLY CANCER

It is of paramount importance, first and foremost, that the correct diagnosis is established. In many instances, especially in the presence of severe inflammation, there is an interobserver disagreement on the diagnosis and grading of dysplasia. It may also be difficult to distinguish between HGD and intramucosal carcinoma. To improve diagnostic accuracy when severe inflammation is present, biopsies should be repeated after 1 month of intensive acid suppression using proton pump inhibitors. The new guidelines of the American College of Gastroenterologists recommend that patients who have a diagnosis of HGD undergo a second endoscopic biopsy procedure to minimize sampling error and maximize the chance of detecting cancer, if present, and that all biopsies are reviewed by a second expert pathologist [7, 26]. It is now widely recommended that patients with Barrett’s HGD should have four-quadrant biopsies, using jumbo forceps, at every 1-cm interval along the entire length of the Barrett’s lining, as well as additional biopsies targeted to any mucosal abnormalities of the Barrett’s lining [7, 21, 26 –29]. The management of patients with HGD in Barrett’s esophagus is controversial [7, 26, 30 –33]. At the present, treatment options for HGD include resection surgery (i.e., esophagectomy), endoscopic ablation therapies, and intensive endoscopic biopsy surveillance. Esophagectomy is the standard recommended treatment for Barrett’s HGD because 30 to 50% of the patients who undergo esophagectomy for HGD actually have an invasive adenocarcinoma detected in the resected specimen [25, 30, 31, 34 – 40]. Endoscopic ablation techniques represent an alternative therapeutic option: they are promising but still investigational treatments. Schnell has recently reported that the actual risk of developing invasive cancer from Barrett’s HGD has been overstated and that endoscopic surveillance alone may be a reasonable approach [41]. Therefore, since a significant number of patients with HGD may not develop cancer when followed for many years by endoscopic biopsy surveillance [9, 11, 40 – 44], a third option is to enter these patients in a surveillance program, reserving treatment for cancer if it develops [7, 21, 26 –28, 41]. The strategy chosen in patients with Barrett’s HGD or early cancer depends on histological characterization of the lesion, and the clinical assessment of a patient’s suitability and willingness to undergo an operation. Therapeutic decision-making must always include a thorough explanation of the risks and benefits of the different therapeutic options to the patient.

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Surgery

Esophagectomy is generally considered the treatment of choice for patients with Barrett’s HGD or early adenocarcinoma [5, 7, 26, 35], provided that the patient is a good surgical candidate. This recommendation has been largely based on the frequent multicentricity of neoplastic alterations within Barrett’s mucosa, and on surgical studies showing that 30 –50% of the patients with Barrett’s HGD actually have invasive carcinoma on the resected specimen [25, 30, 31, 34 – 40]. Also, the presence of lymph node metastases should be taken into account because they are detected in less than 5% of the patients with mucosal (T1a) adenocarcinoma and in 18 –30% of the cases with submucosal (T1b) cancer [45]. Results have also shown that early detection of adenocarcinoma and subsequent esophageal resection, preferably at the stage of HGD or early cancer invading the mucosa, is extremely important in terms of long-term survival [4, 5, 12, 34, 39, 41, 45]. Headrick performed prophylactic esophagectomy in 54 patients with HGD: the incidence of occult invasive adenocarcinoma was 36%; postoperative morbidity was 57%; operative mortality was 1.8%, and the overall 5-year survival rate was 86%. The survival was significantly better for HGD compared to infiltrating carcinoma, 96 and 68%, respectively [46]. Tseng and Heitmiller performed prophylactic esophagectomy in 60 patients with Barrett’s HGD, using a transhiatal surgical approach in 82% of the cases. The incidence of invasive adenocarcinoma in the resected specimen was 30%; postoperative morbidity was 29%, and operative mortality was 1.7%. In the last 30 patients, operated from 1994 to 2001, operative mortality declined from 3.3% (1 of 30) to 0%. Patients were followed up for a median of 4.6 years: the actuarial 5-year survival rate was 88% [47]. Esophagectomy with regional lymphadenectomy is the only proven treatment of esophageal HGD and early cancer that cures the condition, completely eliminates the risk of recurrence and prevents the development of incurable cancer. Esophagectomy also liberates patients with Barrett’s HGD from rigorous endoscopic surveillance for the rest of their lives. On the other hand, esophagectomy is reported to have a significant postoperative morbidity, up to 45%, and a mortality rate of 2– 6% [22–24, 35, 48]. Furthermore, because of the presence of severe comorbidities, a significant proportion of patients may not be candidates for surgery, and some patients, despite being suitable for surgery, may refuse the operation. To summarize, esophagectomy for patients with Barrett’s HGD or early adenocarcinoma can be accomplished with low mortality and excellent long-term survival when it is performed at a center with high volume and experience. Patients who are poor surgical risks, or

if they refuse surgery, have to be referred for some alternative form of endoscopic ablation therapy. Endoscopic Ablation Techniques

Endoscopic ablative treatments can be performed by either a chemical, a thermal, or a mechanical method that causes destruction or removal of the Barrett’s epithelium or mucosa. The various endoscopic ablation techniques are often to be considered complementary rather than competitive to each other. Therefore, patients should be referred to centers that have adequate expertise, the appropriate equipment, and also high volume of patients. Following initial therapy, patients require aggressive acid suppression and acid reflux control to allow the normal squamous epithelium to grow back in place of the Barrett’s lining. Patients must also remain in intensive endoscopic biopsy surveillance for the rest of their lives. Unfortunately, all these techniques are not standardized and can have significant complications, including perforation, bleeding, and strictures; another problem that cannot be minimized is that Barrett’s metaplasia, and even dysplasia or invasive cancer, lying beneath the neosquamous epithelium may persist or develop during follow-up [33, 49 –52]. There are still limited long-term data regarding endoscopic ablative therapies in patients with Barrett’s HGD or intramucosal carcinoma. Therefore, ablative therapies are to be considered investigational treatment modalities and should be reserved for nonsurgical candidates who are both educated and motivated to pursue a protracted course of endoscopic surveillance and multimodal endoscopic therapy. Despite the above problems, some of the ablative therapies show promise in the treatment of HGD and early carcinoma in Barrett’s esophagus. Chemical ablation. Chemical ablation using photodynamic therapy (PDT) is based on the accumulation of externally administered photosensitizing drugs (i.e., intravenous Photofrin or oral 5-aminolevulinic acid), which accumulate rather selectively in Barrett’s epithelium. The drug is then activated by endoscopic application of low-power laser light. This results in a photochemical reaction that leads to selective destruction of Barrett’s epithelium. PDT may prove to be a safe, highly effective, outpatient option for patients who are not candidates for surgery. Complications include chest pain in most patients, esophageal strictures requiring dilation in one-third of the patients, severe photosensitivity reactions, pleural effusions, and tachyarrhythmias. Overholt reported the largest series of patients treated with PDT, of whom 80 had HGD and 9 had intramucosal cancer [51]. Complete eradication of both dysplasia and Barrett’s mucosa was achieved in 54% of the patients with HGD; another 24% of the patients had eradication of dysplasia but persistence of Bar-

RUOL ET AL.: BARRETT’S HIGH-GRADE DYSPLASIA AND CANCER

rett’s metaplasia. Complete eradication of disease was obtained in 3 of 9 patients with early adenocarcinoma, and one more patient had eradication of cancer and dysplasia with persistent Barrett’s metaplasia. During a mean follow-up period of 50 months, 30% of the patients developed significant strictures that required dilation and three patients with HGD developed subsquamous adenocarcinoma after PDT. The use of Photofrin-PDT has received recent approval from the U.S. FDA in the ablation of HGD in Barrett’s esophagus patients who do not undergo esophagectomy, based on the results of a study on 138 patients who received PDT and omeprazole. Patients were followed every 3 months until four consecutive endoscopic results were negative for HGD and then semiannually until the last enrolled patient had completed at least 24 months of follow-up. The length of follow-up ranged from 2 to 3.6 years. PDT resulted in the complete ablation of HGD in 77% of treated patients. Patients who failed to achieve complete response had an approximately 10-fold higher risk of progression to cancer than patients who achieved a complete response (from http://www.pslgroup.com/dg/ 237e52.htm). ALA-PDT seems to be associated with less strictures and a shorter period of photosensitivity. Gossner reported on 10 patients with HGD and 22 with mucosal cancer who were treated with ALA-PDT. Dysplasia was eradicated in all of the patients with HGD, and there was complete remission in 17 of 22 (77%) patients with carcinoma. However, ALA was ineffective in the treatment of tumors greater than 2 mm in depth [53]. Thermal ablation. Thermal ablation is done using multipolar electrocoagulation, heater probe electrocoagulation, argon plasma coagulation (APC), Nd:YAG laser, or KTP laser photoablation. These techniques are still considered experimental for the treatment of Barrett’s HGD because, to date, little information is available in this regard [49, 54]. Complications after these procedures include chest pain, esophageal strictures, pleural effusion, and, more important, the possibility that metaplastic tissue may persist deeper to the normal-appearing neosquamous epithelium [49]. Mechanical ablation. Mechanical ablation is done using ultrasonic aspiration or endoscopic mucosal resection (EMR). EMR, which allows the separation of the target lesion from the muscularis propria by injecting fluid into the submucosa directly beneath the lesion, can also be used in the treatment of early carcinoma. EMR is appealing because it also provides the diagnostic tissue that permits the histological assessment of the adequacy of therapy. EMR has been used extensively in Japan for the treatment of early gastric cancer, and most Japanese studies suggest that the long-term recurrence rate and mortality in patients

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treated with EMR are equivalent to those achieved by surgical resection. However, limited information on the role of EMR in Barrett’s HGD or early adenocarcinoma is available to date. Nijhawan performed EMR in 25 patients suspected of having either early cancer or HGD within Barrett’s mucosa: superficial cancer was found in 13, and HGD in 4. On the other hand, three lesions thought to have HGD or cancer had no evidence of dysplasia or carcinoma. Forty-four percent of the patients had their diagnoses modified after EMR. Therefore, EMR is not only potentially therapeutic, but it has diagnostic implications as well [55]. May reported the results of EMR in 7 patients with HGD and 63 with early carcinoma [56]. No major complications, such as perforation and severe bleeding, occurred after EMR; minor complications, such as mild bleeding episodes and cicatricial strictures, occurred in 10% of the patients. Overall, 98% of the patients had complete local remission. During a mean follow-up of 34 months (range 24 – 60 months), metachronous/ recurrent HGD or cancer was detected in 21 (30%) of the 70 patients. All these patients except one, who died from Barrett’s adenocarcinoma, underwent successful repeat endoscopic treatment. In a previous report, the same group reported that complete remission was achieved in only 59% of the patients with high-risk lesions characterized by the following features: diameter ⬎ 20 mm, poorly differentiated histology, lesion extending into the submucosa, or ulcerated lesion [57]. Multimodal treatments. Because of incomplete eradication or recurrence of the lesion, a combination of different types of treatment can be used: series of patients treated with PDT followed by other forms of local ablation or EMR followed by PDT as salvage therapy have been published [56, 58]. In clinical practice, it is likely that improved results may be obtained by using the various endoscopic ablation techniques as complementary therapeutic modalities. In fit patients, esophagectomy can be the final option. Panjehpour reported his experience with PDT followed by Nd:YAG laser ablation or retreatment with PDT for residual or recurrent disease [59]. Sixty patients with Barrett’s dysplasia or early cancer were treated, and follow-up endoscopies were performed every 3– 6 months to evaluate response. All cancers were successfully eradicated, and persistent HGD was detected in only 2 of 43 patients (eradication rate, 96%). Barrett’s mucosa was totally eliminated in 25 of 60 patients (42%). In a recent report, Wolfsen reported results on 34 patients with HGD and 14 patients with superficial cancer (T1N0) who were treated with PDT followed 4 to 6 weeks later by APC for residual metaplastic mucosa: after PDT, 27 of the patients had complete eradication; after bimodal therapy 47 of 48 patients showed com-

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plete remission, and 1 patient was found to harbor adenocarcinoma deeper to the overlying neosquamous epithelium [52]. To summarize, mucosal ablative therapy cannot be accepted as standard therapy at the present time because of its questionable ability to completely eradicate the abnormal mucosa and to limit follow-up, and because patients require continued rigorous endoscopic surveillance for the rest of their lives. Intensive Endoscopic Biopsy Surveillance

The argument for continuing endoscopic biopsy surveillance in patients with Barrett’s HGD is that progression to invasive carcinoma may take many years and is not inevitable [9, 11, 21, 27, 40 – 44]. In patients with a diagnosis of HGD, endoscopic biopsy surveillance has to be performed 1 month after the initial diagnosis, then after 3 months, and subsequently at least every 6 months for the rest of their lives to detect cancer, if it develops, when it is early and curable with surgery [7, 28]. Prolonged delay of treatment may result in undue risk of spread of tumor to a degree which is no longer curable. Contrasting data are reported in the literature on this subject. Reid, in a large study of 76 patients with HGD, reported a 59% probability of developing cancer over a 5-year period [9]. On the other hand, Schnell reported another large study of 79 patients with HGD without evidence of cancer: 4 (12%) of the 34 patients with prevalent HGD had unsuspected cancer diagnosed during the first year, and 2 additional patients with prevalent HGD plus 10 of the 45 patients with incident HGD developed cancer during surveillance; 5 (42%) of the above 12 patients who developed cancer had their cancer diagnosed within 1 year of the diagnosis of HGD [41]. Overall, it has to be emphasized that the time interval between the first diagnosis of HGD and the diagnosis of cancer was less than 10 months in 9 (60%) of 15 patients who eventually developed cancer. Endoscopic biopsy surveillance has been questioned because of its clinical impracticality, high costs, increased workload for endoscopic and pathology units, possibility of sampling errors, procedure-related complications, discomfort to the patient, and patient’s risk of developing invasive, and perhaps incurable, cancer. On the other hand, these drawbacks of endoscopic surveillance have to be weighed against the potential mortality and morbidity rates of esophagectomy, which are not negligible. To summarize, since many patients with Barrett’s HGD are elderly and not ideal candidates for surgery, or some patients may refuse surgery, surveillance endoscopy may be one possible option, reserving esophagectomy as a treatment of cancer if it develops [7, 9, 21, 26, 41]. However, few data document the safety of this observational approach.

INVASIVE ADENOCARCINOMA

Adenocarcinoma of the esophagus or esophagogastric junction carries one of the lowest 5-year survival rates of all malignancies [6, 12]. Because of the presence of comorbid illness and/or advanced tumor stage, a significant proportion of these patients are not candidates for surgery. Surgery remains the only potentially curative option for esophageal adenocarcinoma without evidence of distant metastasis or invasion of adjacent structures even though the overall prognosis after surgery alone remains dismal, with a 25% 5-year survival rate [4, 5, 60]. Therefore, esophageal adenocarcinoma must be detected early, before the patient develops symptoms, in order for the patient to have a high likelihood of a cure [12, 27, 34, 35, 61, 62]. The most frequently used surgical technique is esophagogastric resection and gastric pull-up, which is performed through a laparotomy and right thoracotomy. Transhiatal esophagectomy can be used in patients for whom thoracotomy is contraindicated. Excision volume should include the whole length of Barrett’s mucosa and at least 4 – 6 cm of healthy esophagus above the tumor, the gastric fundus, the lesser gastric curvature, and regional lymph nodes in the upper abdomen and mid-lower mediastinum. In cases of potentially resectable adenocarcinoma that invades beyond the mucosa, surgical resection is the standard of care for patients with an acceptable operative risk. However, the overall long-term prognosis after esophagectomy, even after complete R0 resection, remains dismal and significant postoperative morbidity (up to 45%) and mortality rates (range, ⬍2– 6%) are reported [5, 39, 63, 64]. To improve long-term prognosis, neoadjuvant chemoradiation is frequently used, within study protocols, in patients with a potentially resectable tumor [5, 60]. Today there is no absolute evidence that neoadjuvant treatments prolong survival of patients with potentially resectable esophageal adenocarcinoma. However, a recent metaanalysis of randomized clinical trials showed that there seems to be a modest survival advantage (of 6.4% at 2 years, and of 5.1% at 3 years) for patients with resectable adenocarcinoma of the esophagus and the gastroesophageal junction who receive chemotherapy or chemoradiation followed by surgery as compared with surgery alone [60]. Rates of complete pathologic response ranged from 2.5 to 26%. Responders had longer survival than nonresponders. Treatmentrelated mortality increased by 1.7% with neoadjuvant chemotherapy and by 3.4% with chemoradiation compared with surgery alone. The prognosis of patients with locally advanced (T4 or T3 N positive), presumably not completely resectable, adenocarcinoma of the esophagus or esophagogastric junction is very poor [5, 39, 63, 65, 66]. Evidence from recent trials indicates that in these patients, the

RUOL ET AL.: BARRETT’S HIGH-GRADE DYSPLASIA AND CANCER

use of preoperative chemoradiation is effective in increasing the chance for a curative resection and in prolonging survival in responding patients [5]; therefore, the use of multimodal treatments has become routine in many institutions. THE PADOVA EXPERIENCE

We recently evaluated the presence of invasive cancer in patients with Barrett’s HGD who underwent prophylactic esophagectomy [67]. Our updated data are as follows: from 1983 to 2002, 28 patients with Barrett’s HGD were observed. Nine patients were not operated because of medical contraindications or refusal of surgery, and 19 patients underwent esophagectomy. Invasive carcinoma (pT1N0) was detected in 7 (37%) of 19 surgical specimens. There were no operative deaths. During a mean follow-up period of 42 months, no recurrence of the disease was observed. In a previous surgical study we compared adenocarcinoma in Barrett’s esophagus with adenocarcinoma of the esophagogastric junction. Fifteen (27%) of 56 Barrett’s cancers had an early-stage tumor compared to only 11 (3.7%) of 294 cancers of the cardia, probably thanks to endoscopic biopsy surveillance which patients with known benign Barrett’s esophagus had been subjected to. However, stratifying patients who underwent resection surgery by pathologic tumor stage, the prognosis of Barrett’s adenocarcinoma and that of cancer of the cardia were comparable [68]. From 1980 to 2002, we observed 3813 primary cancers of the esophagus or esophagogastric junction: the prevalence of adenocarcinomas rose from 21% in the 1980s to 36% during the last two years. Of 911 patients with adenocarcinoma of the esophagus or esophagogastric junction, 623 (68%) underwent surgery. Postoperative in-hospital mortality declined from 4.2% at the beginning of the 1980s to 0.6% during the last eight years. Thirty-two (30%) of 107 patients with adenocarcinoma arising in Barrett’s esophagus had an early stage (pT0 –Ia) tumor compared to only 24 (4.6%) of 516 patients with adenocarcinoma of the esophagus or esophagogastric junction without evidence of Barrett’s metaplasia. The overall 5-year survival after complete R0 resection was 33%. Prognosis was strictly related to pathological tumor stage: the 5-year survival rate was 88% for pStage 0 –Ia tumors (i.e., pT0 –T1/N0/M0), 65% for pStage Ib tumors (i.e., pT1/N1/M0 or pT2/N0/M0), 44% for pStage II tumors (i.e., pT1/N2/M0 or pT2/ N1/M0 or pT3/N0/M0), and 16% for pStage III–IV tumors.

that are progressing to cancer. In the near future, molecular and genetic markers in biopsied tissue will also help to identify patients with an increased risk of cancer progression. Esophagectomy remains the treatment of choice for the appropriate patient with Barrett’s adenocarcinoma invading beyond the mucosa, without evidence of distant metastasis or invasion of adjacent organs. On the other hand, there is extensive investigation directed toward better defining the therapeutic approach to patients with Barrett’s HGD or mucosal adenocarcinoma. Therapeutic management of these patients should be individualized, taking into account patient’s preferences, willingness to return for frequent endoscopic biopsies, and medical fitness to undergo esophagectomy. Surgery has to be considered the best treatment for HGD or early carcinoma, unless contraindicated by severe comorbidities, because it has proven to be the only treatment that is successful in curing the condition and preventing recurrent HGD or the development of invasive cancer. Nonsurgical treatment by PDT or EMR may be a less invasive and organ-sparing option for elderly, poor-risk patients with HGD, or early carcinoma, but it is still to be considered an investigational therapy that should only be conducted under a clinical trial protocol. Finally, intensive endoscopic biopsy surveillance of patients with HGD, the “watching and waiting” attitude [69], is another investigational option that may allow prompt treatment of cancer if it develops. However, few data document the safety of this observational approach. Since the diagnostic accuracy and treatment-related morbidity and mortality rates are better in institutions where a high number of patients with Barrett’s HGD or cancer are observed, consideration should be given to referral of these patients to specialty centers. REFERENCES 1.

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