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

Esophagectomy remains the treatment of choice forthe appropriate patient with Barrett’s adenocarci-noma invading beyond the mucosa, without evidenceof distant metastasis or invasion of adjacent organs.On the other hand, therapeutic management of pa-tients with Barrett’s high-grade dysplasia (HGD) ormucosal adenocarcinoma should be individualized,taking into account the patient’s preferences, willing-ness to return for frequent endoscopic biopsies, andmedical fitness to undergo esophagectomy. Surgeryhas to be considered the best treatment for HGD orsuperficial carcinoma, unless contraindicated by se-vere comorbidities, because it has proven to be theonly treatment that is successful in curing the condi-tion and preventing recurrent HGD or the develop-ment of invasive cancer. Nonsurgical treatment byphotodynamic therapy or endoscopic mucosal resec-tion may be a less invasive and organ-sparing optionfor elderly, poor-risk patients but it is still to be con-sidered an investigational therapy that should only beconducted under a clinical trial protocol. Finally, in-tensive endoscopic biopsy surveillance of patientswith HGD is another investigational option that mayallow prompt treatment of cancer if it develops. How-ever, few data document the safety of this observa-tional approach. © 2004 Elsevier Inc. All rights reserved.

Key Words: Barrett’s esophagus; high-grade dyspla-sia (HGD); adenocarcinoma.

INTRODUCTION

In the last two decades, a growing body of literaturefrom North America and Western Europe has revealedthat adenocarcinoma of the esophagus is increasing inincidence more rapidly than any other cancer; parallel,

1 To whom correspondence and reprint requests should be ad-dressed at Clinica Chirurgica 3°, Universita’ di Padova, ViaGiustiniani, 2. 35128 Padova, Italy. Fax: �39-049-8213152. E-mail:

alberto.ruol@unipd.it.

440022-4804/04 $30.00© 2004 Elsevier Inc. All rights reserved.

steadily rising incidence rates of adenocarcinoma of thecardia are reported [1–5]. Although this could reflectincreased awareness of adenocarcinoma concomitantwith Barrett’s esophagus, it probably represents anabsolute increase.

Adenocarcinoma of the esophagus arises through aprogression of molecular, genetic, and histologicalchanges characterized by specialized intestinal meta-plasia of the esophageal mucosa (Barrett’s metaplasia)and evolving through progressive grades of dysplasiato high-grade dysplasia (HGD) and ultimately invasivecancer. The risk of Barrett’s mucosa to progress toadenocarcinoma is not well established: published es-timates of the annual risk of cancer range from 0.2 to2.9%, and a calculated risk from 30 to 125 times higherthan in the general population is reported [6, 7]. It isestimated, in North America, that 25,000 to 35,000people suffer from HGD associated with Barrett’sesophagus, and that approximately 5000 to 7000 newpatients are diagnosed with this condition each year[8]. Estimates of the risk that HGD will progresswithin 5 years to invasive cancer range widely, from 16to 59% [6, 9]. The risk of developing adenocarcinomamay also depend on the length of Barrett’s metaplasia[10] and the extent of dysplasia, with a worse prognosisfor patients with diffuse dysplastic changes. Buttarfollowed 100 patients with HGD with continued endo-scopic surveillance and found cancer at 1 and 3 years in38 and 56% of the patients with diffuse HGD, and in 7and 14% of patients with focal HGD [11]. During thefollow-up period of up to 8 years, 32 of the 100 patientswith HGD were found to have cancer.

Current strategies for improved survival in patientswith Barrett’s adenocarcinoma focus on cancer detec-tion at an early and potentially curable stage. This canbe obtained by screening programs in high-risk cohortsof patients and/or endoscopic biopsy surveillance of

patients with known Barrett’s esophagus. The current

45RUOL ET AL.: BARRETT’S HIGH-GRADE DYSPLASIA AND CANCER

goal of surveillance is the detection of dysplasia, whichis still the best available marker of cancer risk. Despitethe continuing debate on the cost-effectiveness ofscreening and surveillance programs in patients withBarrett’s esophagus, in Europe and North America,adenocarcinoma of the esophagus is increasingly diag-nosed at early stages just because of endoscopic sur-veillance. Ferguson has recently reported on 80 pa-tients who underwent resection for Barrett’sadenocarcinoma [12]. Pathological stage was 0 or 1 in 9(75%) of 12 patients who were followed with endoscopicsurveillance compared to 12 (18%) of 68 of those in theno surveillance group. Median survival for patients inthe surveillance group was 107 months compared to 12months for those in the no surveillance group. Also,Corley reported that surveillance detected cancer pa-tients had earlier tumor stage and longer survival thannon-surveillance-detected patients [13]. However, only3.9% of the 589 patients with esophageal adenocarci-noma had Barrett’s diagnosed before their cancer andwere therefore eligible for surveillance. This indicatesthat Barrett’s esophagus goes undetected in the vastmajority of patients with esophageal adenocarcinomaand that the potential benefit of endoscopic surveil-lance seems to be limited to only a fraction of thoseindividuals at risk. Similar results are reported byother authors [14].

Current screening and surveillance strategies, even ifpotentially beneficial on a single patient basis, are veryexpensive, far from efficient, and their cost-effectivenessis questionable [12, 13]. Because the focal nature ofdysplasia makes targeting of biopsy specimens prob-lematic, endoscopic biopsy surveillance, using novelmodalities such as vital staining chromoendoscopy,high-magnification endoscopy [15], fluorescence endos-copy, or molecular biomarkers (e.g., p53, p16, abnor-mal ploidy) in biopsied tissue [9, 16–20], may allow thebetter recognition of patients with dysplastic lesionsand any mucosal abnormalities that are at increasedrisk of cancer progression. In the near future, the use ofa panel of molecular markers in patients with Barrett’sesophagus may prove to represent a superior diagnos-tic tool to identify patients with elevated malignantpotential, to establish the diagnosis of malignancy atan early stage, and to expedite a patient’s tailoredtherapy.

Treatment strategies, when Barrett’s HGD or ade-nocarcinoma is detected, often depend on the fact thatmany patients are older than 60 years of age and sufferfrom severe comorbidities that may preclude esopha-gectomy. Because the diagnostic accuracy andtreatment-related morbidity and mortality rates arebetter in institutions where a high number of patientswith Barrett’s HGD or cancer are observed, consider-ation should be given to the referral of these patients to

specialty centers that have adequate expertise and

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 in-stances, especially in the presence of severe inflamma-tion, there is an interobserver disagreement on thediagnosis and grading of dysplasia. It may also bedifficult to distinguish between HGD and intramucosalcarcinoma. To improve diagnostic accuracy when se-vere inflammation is present, biopsies should be re-peated after 1 month of intensive acid suppressionusing proton pump inhibitors. The new guidelines ofthe American College of Gastroenterologists recom-mend that patients who have a diagnosis of HGD un-dergo a second endoscopic biopsy procedure to mini-mize sampling error and maximize the chance ofdetecting cancer, if present, and that all biopsies arereviewed by a second expert pathologist [7, 26]. It isnow widely recommended that patients with Barrett’sHGD should have four-quadrant biopsies, using jumboforceps, at every 1-cm interval along the entire lengthof the Barrett’s lining, as well as additional biopsiestargeted to any mucosal abnormalities of the Barrett’slining [7, 21, 26–29].

The management of patients with HGD in Barrett’sesophagus is controversial [7, 26, 30–33]. At thepresent, treatment options for HGD include resectionsurgery (i.e., esophagectomy), endoscopic ablationtherapies, and intensive endoscopic biopsy surveil-lance. Esophagectomy is the standard recommendedtreatment for Barrett’s HGD because 30 to 50% of thepatients who undergo esophagectomy for HGD actuallyhave an invasive adenocarcinoma detected in the re-sected specimen [25, 30, 31, 34–40]. Endoscopic abla-tion techniques represent an alternative therapeuticoption: they are promising but still investigationaltreatments. Schnell has recently reported that the ac-tual risk of developing invasive cancer from Barrett’sHGD has been overstated and that endoscopic surveil-lance alone may be a reasonable approach [41]. There-fore, since a significant number of patients with HGDmay not develop cancer when followed for many yearsby endoscopic biopsy surveillance [9, 11, 40–44], athird option is to enter these patients in a surveillanceprogram, reserving treatment for cancer if it develops[7, 21, 26–28, 41]. The strategy chosen in patients withBarrett’s HGD or early cancer depends on histologicalcharacterization of the lesion, and the clinical assess-ment of a patient’s suitability and willingness to un-dergo an operation. Therapeutic decision-making mustalways include a thorough explanation of the risks andbenefits of the different therapeutic options to the pa-

tient.

46 JOURNAL OF SURGICAL RESEARCH: VOL. 117, NO. 1, MARCH 2004

Surgery

Esophagectomy is generally considered the treat-ment of choice for patients with Barrett’s HGD or earlyadenocarcinoma [5, 7, 26, 35], provided that the patientis a good surgical candidate. This recommendation hasbeen largely based on the frequent multicentricity ofneoplastic alterations within Barrett’s mucosa, and onsurgical studies showing that 30–50% of the patientswith Barrett’s HGD actually have invasive carcinomaon the resected specimen [25, 30, 31, 34–40]. Also, thepresence of lymph node metastases should be takeninto account because they are detected in less than 5%of the patients with mucosal (T1a) adenocarcinomaand in 18–30% of the cases with submucosal (T1b)cancer [45]. Results have also shown that early detec-tion of adenocarcinoma and subsequent esophageal re-section, preferably at the stage of HGD or early cancerinvading the mucosa, is extremely important in termsof long-term survival [4, 5, 12, 34, 39, 41, 45].

Headrick performed prophylactic esophagectomy in54 patients with HGD: the incidence of occult invasiveadenocarcinoma was 36%; postoperative morbidity was57%; operative mortality was 1.8%, and the overall5-year survival rate was 86%. The survival was signif-icantly better for HGD compared to infiltrating carci-noma, 96 and 68%, respectively [46].

Tseng and Heitmiller performed prophylactic esoph-agectomy in 60 patients with Barrett’s HGD, using atranshiatal surgical approach in 82% of the cases. Theincidence of invasive adenocarcinoma in the resectedspecimen was 30%; postoperative morbidity was 29%,and operative mortality was 1.7%. In the last 30 pa-tients, operated from 1994 to 2001, operative mortalitydeclined from 3.3% (1 of 30) to 0%. Patients were fol-lowed up for a median of 4.6 years: the actuarial 5-yearsurvival rate was 88% [47].

Esophagectomy with regional lymphadenectomy isthe only proven treatment of esophageal HGD andearly cancer that cures the condition, completely elim-inates the risk of recurrence and prevents the develop-ment of incurable cancer. Esophagectomy also liber-ates patients with Barrett’s HGD from rigorousendoscopic surveillance for the rest of their lives. Onthe other hand, esophagectomy is reported to have asignificant postoperative morbidity, up to 45%, and amortality rate of 2–6% [22–24, 35, 48]. Furthermore,because of the presence of severe comorbidities, a sig-nificant proportion of patients may not be candidatesfor surgery, and some patients, despite being suitablefor surgery, may refuse the operation.

To summarize, esophagectomy for patients with Bar-rett’s HGD or early adenocarcinoma can be accom-plished with low mortality and excellent long-term sur-vival 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 somealternative form of endoscopic ablation therapy.

Endoscopic Ablation Techniques

Endoscopic ablative treatments can be performed byeither a chemical, a thermal, or a mechanical methodthat causes destruction or removal of the Barrett’sepithelium or mucosa. The various endoscopic ablationtechniques are often to be considered complementaryrather than competitive to each other. Therefore, pa-tients should be referred to centers that have adequateexpertise, the appropriate equipment, and also highvolume of patients. Following initial therapy, patientsrequire aggressive acid suppression and acid refluxcontrol to allow the normal squamous epithelium togrow back in place of the Barrett’s lining. Patientsmust also remain in intensive endoscopic biopsy sur-veillance for the rest of their lives.

Unfortunately, all these techniques are not stan-dardized and can have significant complications, in-cluding perforation, bleeding, and strictures; anotherproblem that cannot be minimized is that Barrett’smetaplasia, and even dysplasia or invasive cancer, ly-ing beneath the neosquamous epithelium may persistor develop during follow-up [33, 49–52]. There are stilllimited long-term data regarding endoscopic ablativetherapies in patients with Barrett’s HGD or intramu-cosal carcinoma. Therefore, ablative therapies are to beconsidered investigational treatment modalities andshould be reserved for nonsurgical candidates who areboth educated and motivated to pursue a protractedcourse of endoscopic surveillance and multimodal en-doscopic therapy. Despite the above problems, some ofthe ablative therapies show promise in the treatmentof HGD and early carcinoma in Barrett’s esophagus.

Chemical ablation. Chemical ablation using photo-dynamic therapy (PDT) is based on the accumulation ofexternally administered photosensitizing drugs (i.e.,intravenous Photofrin or oral 5-aminolevulinic acid),which accumulate rather selectively in Barrett’s epi-thelium. The drug is then activated by endoscopic ap-plication of low-power laser light. This results in aphotochemical reaction that leads to selective destruc-tion of Barrett’s epithelium. PDT may prove to be asafe, highly effective, outpatient option for patientswho are not candidates for surgery. Complications in-clude chest pain in most patients, esophageal stric-tures requiring dilation in one-third of the patients,severe photosensitivity reactions, pleural effusions,and tachyarrhythmias.

Overholt reported the largest series of patientstreated with PDT, of whom 80 had HGD and 9 hadintramucosal cancer [51]. Complete eradication of bothdysplasia and Barrett’s mucosa was achieved in 54% ofthe patients with HGD; another 24% of the patients

had eradication of dysplasia but persistence of Bar-

47RUOL ET AL.: BARRETT’S HIGH-GRADE DYSPLASIA AND CANCER

rett’s metaplasia. Complete eradication of disease wasobtained in 3 of 9 patients with early adenocarcinoma,and one more patient had eradication of cancer anddysplasia with persistent Barrett’s metaplasia. Duringa mean follow-up period of 50 months, 30% of thepatients developed significant strictures that requireddilation and three patients with HGD developed sub-squamous adenocarcinoma after PDT.

The use of Photofrin-PDT has received recent ap-proval from the U.S. FDA in the ablation of HGD inBarrett’s esophagus patients who do not undergoesophagectomy, based on the results of a study on 138patients who received PDT and omeprazole. Patientswere followed every 3 months until four consecutiveendoscopic results were negative for HGD and thensemiannually until the last enrolled patient had com-pleted at least 24 months of follow-up. The length offollow-up ranged from 2 to 3.6 years. PDT resulted inthe complete ablation of HGD in 77% of treated pa-tients. Patients who failed to achieve complete re-sponse had an approximately 10-fold higher risk ofprogression to cancer than patients who achieved acomplete response (from http://www.pslgroup.com/dg/237e52.htm).

ALA-PDT seems to be associated with less stricturesand a shorter period of photosensitivity. Gossner re-ported on 10 patients with HGD and 22 with mucosalcancer who were treated with ALA-PDT. Dysplasiawas eradicated in all of the patients with HGD, andthere was complete remission in 17 of 22 (77%) pa-tients with carcinoma. However, ALA was ineffectivein the treatment of tumors greater than 2 mm in depth[53].

Thermal ablation. Thermal ablation is done usingmultipolar electrocoagulation, heater probe electroco-agulation, argon plasma coagulation (APC), Nd:YAGlaser, or KTP laser photoablation. These techniquesare still considered experimental for the treatment ofBarrett’s HGD because, to date, little information isavailable in this regard [49, 54]. Complications afterthese procedures include chest pain, esophageal stric-tures, pleural effusion, and, more important, the pos-sibility that metaplastic tissue may persist deeper tothe normal-appearing neosquamous epithelium [49].

Mechanical ablation. Mechanical ablation is doneusing ultrasonic aspiration or endoscopic mucosal re-section (EMR). EMR, which allows the separation ofthe target lesion from the muscularis propria by inject-ing fluid into the submucosa directly beneath the le-sion, can also be used in the treatment of early carci-noma. EMR is appealing because it also provides thediagnostic tissue that permits the histological assess-ment of the adequacy of therapy. EMR has been usedextensively in Japan for the treatment of early gastriccancer, and most Japanese studies suggest that the

long-term recurrence rate and mortality in patients

treated with EMR are equivalent to those achieved bysurgical resection. However, limited information on therole of EMR in Barrett’s HGD or early adenocarcinomais available to date.

Nijhawan performed EMR in 25 patients suspectedof having either early cancer or HGD within Barrett’smucosa: superficial cancer was found in 13, and HGDin 4. On the other hand, three lesions thought to haveHGD or cancer had no evidence of dysplasia or carci-noma. Forty-four percent of the patients had their di-agnoses modified after EMR. Therefore, EMR is notonly potentially therapeutic, but it has diagnostic im-plications as well [55].

May reported the results of EMR in 7 patients withHGD and 63 with early carcinoma [56]. No major com-plications, such as perforation and severe bleeding,occurred after EMR; minor complications, such as mildbleeding episodes and cicatricial strictures, occurred in10% of the patients. Overall, 98% of the patients hadcomplete local remission. During a mean follow-up of34 months (range 24–60 months), metachronous/recurrent HGD or cancer was detected in 21 (30%) ofthe 70 patients. All these patients except one, who diedfrom Barrett’s adenocarcinoma, underwent successfulrepeat endoscopic treatment. In a previous report, thesame group reported that complete remission wasachieved in only 59% of the patients with high-risklesions characterized by the following features: diam-eter � 20 mm, poorly differentiated histology, lesionextending into the submucosa, or ulcerated lesion [57].

Multimodal treatments. Because of incompleteeradication or recurrence of the lesion, a combinationof different types of treatment can be used: series ofpatients treated with PDT followed by other forms oflocal ablation or EMR followed by PDT as salvagetherapy have been published [56, 58]. In clinical prac-tice, it is likely that improved results may be obtainedby using the various endoscopic ablation techniques ascomplementary therapeutic modalities. In fit patients,esophagectomy can be the final option.

Panjehpour reported his experience with PDT fol-lowed by Nd:YAG laser ablation or retreatment withPDT for residual or recurrent disease [59]. Sixty pa-tients with Barrett’s dysplasia or early cancer weretreated, and follow-up endoscopies were performed ev-ery 3–6 months to evaluate response. All cancers weresuccessfully eradicated, and persistent HGD was de-tected in only 2 of 43 patients (eradication rate, 96%).Barrett’s mucosa was totally eliminated in 25 of 60patients (42%).

In a recent report, Wolfsen reported results on 34patients with HGD and 14 patients with superficialcancer (T1N0) who were treated with PDT followed 4 to6 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-

48 JOURNAL OF SURGICAL RESEARCH: VOL. 117, NO. 1, MARCH 2004

plete remission, and 1 patient was found to harboradenocarcinoma deeper to the overlying neosquamousepithelium [52].

To summarize, mucosal ablative therapy cannot beaccepted as standard therapy at the present time be-cause of its questionable ability to completely eradicatethe abnormal mucosa and to limit follow-up, and be-cause patients require continued rigorous endoscopicsurveillance for the rest of their lives.

Intensive Endoscopic Biopsy Surveillance

The argument for continuing endoscopic biopsy sur-veillance in patients with Barrett’s HGD is that pro-gression to invasive carcinoma may take many yearsand is not inevitable [9, 11, 21, 27, 40–44]. In patientswith a diagnosis of HGD, endoscopic biopsy surveil-lance has to be performed 1 month after the initialdiagnosis, then after 3 months, and subsequently atleast every 6 months for the rest of their lives to detectcancer, if it develops, when it is early and curable withsurgery [7, 28]. Prolonged delay of treatment may re-sult in undue risk of spread of tumor to a degree whichis no longer curable. Contrasting data are reported inthe literature on this subject. Reid, in a large study of76 patients with HGD, reported a 59% probability ofdeveloping cancer over a 5-year period [9]. On the otherhand, Schnell reported another large study of 79 pa-tients with HGD without evidence of cancer: 4 (12%) ofthe 34 patients with prevalent HGD had unsuspectedcancer diagnosed during the first year, and 2 additionalpatients with prevalent HGD plus 10 of the 45 patientswith incident HGD developed cancer during surveil-lance; 5 (42%) of the above 12 patients who developedcancer had their cancer diagnosed within 1 year of thediagnosis of HGD [41]. Overall, it has to be emphasizedthat the time interval between the first diagnosis ofHGD and the diagnosis of cancer was less than 10months in 9 (60%) of 15 patients who eventually devel-oped cancer.

Endoscopic biopsy surveillance has been questionedbecause of its clinical impracticality, high costs, in-creased workload for endoscopic and pathology units,possibility of sampling errors, procedure-related com-plications, discomfort to the patient, and patient’s riskof developing invasive, and perhaps incurable, cancer.On the other hand, these drawbacks of endoscopic sur-veillance have to be weighed against the potential mor-tality and morbidity rates of esophagectomy, which arenot negligible.

To summarize, since many patients with Barrett’sHGD are elderly and not ideal candidates for surgery,or some patients may refuse surgery, surveillance en-doscopy may be one possible option, reserving esopha-gectomy 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 esophagogas-tric junction carries one of the lowest 5-year survivalrates of all malignancies [6, 12]. Because of the pres-ence of comorbid illness and/or advanced tumor stage,a significant proportion of these patients are not can-didates for surgery. Surgery remains the only poten-tially curative option for esophageal adenocarcinomawithout evidence of distant metastasis or invasion ofadjacent structures even though the overall prognosisafter surgery alone remains dismal, with a 25% 5-yearsurvival rate [4, 5, 60]. Therefore, esophageal adeno-carcinoma must be detected early, before the patientdevelops symptoms, in order for the patient to have ahigh likelihood of a cure [12, 27, 34, 35, 61, 62]. Themost frequently used surgical technique is esophago-gastric resection and gastric pull-up, which is per-formed through a laparotomy and right thoracotomy.Transhiatal esophagectomy can be used in patients forwhom thoracotomy is contraindicated. Excision volumeshould include the whole length of Barrett’s mucosaand at least 4–6 cm of healthy esophagus above thetumor, the gastric fundus, the lesser gastric curvature,and regional lymph nodes in the upper abdomen andmid-lower mediastinum.

In cases of potentially resectable adenocarcinomathat invades beyond the mucosa, surgical resection isthe standard of care for patients with an acceptableoperative risk. However, the overall long-term progno-sis after esophagectomy, even after complete R0 resec-tion, remains dismal and significant postoperativemorbidity (up to 45%) and mortality rates (range, �2–6%) are reported [5, 39, 63, 64]. To improve long-termprognosis, neoadjuvant chemoradiation is frequentlyused, within study protocols, in patients with a poten-tially resectable tumor [5, 60]. Today there is no abso-lute evidence that neoadjuvant treatments prolongsurvival of patients with potentially resectable esoph-ageal adenocarcinoma. However, a recent meta-analysis of randomized clinical trials showed thatthere seems to be a modest survival advantage (of 6.4%at 2 years, and of 5.1% at 3 years) for patients withresectable adenocarcinoma of the esophagus and thegastroesophageal junction who receive chemotherapyor chemoradiation followed by surgery as comparedwith surgery alone [60]. Rates of complete pathologicresponse ranged from 2.5 to 26%. Responders hadlonger survival than nonresponders. Treatment-related mortality increased by 1.7% with neoadjuvantchemotherapy and by 3.4% with chemoradiation com-pared with surgery alone.

The prognosis of patients with locally advanced (T4or T3 N positive), presumably not completely resect-able, adenocarcinoma of the esophagus or esophago-gastric junction is very poor [5, 39, 63, 65, 66]. Evidence

from recent trials indicates that in these patients, the

49RUOL ET AL.: BARRETT’S HIGH-GRADE DYSPLASIA AND CANCER

use of preoperative chemoradiation is effective in in-creasing the chance for a curative resection and inprolonging survival in responding patients [5]; there-fore, the use of multimodal treatments has becomeroutine in many institutions.

THE PADOVA EXPERIENCE

We recently evaluated the presence of invasive can-cer in patients with Barrett’s HGD who underwentprophylactic esophagectomy [67]. Our updated dataare as follows: from 1983 to 2002, 28 patients withBarrett’s HGD were observed. Nine patients were notoperated because of medical contraindications or re-fusal of surgery, and 19 patients underwent esopha-gectomy. Invasive carcinoma (pT1N0) was detected in7 (37%) of 19 surgical specimens. There were no oper-ative deaths. During a mean follow-up period of 42months, no recurrence of the disease was observed.

In a previous surgical study we compared adenocar-cinoma in Barrett’s esophagus with adenocarcinoma ofthe esophagogastric junction. Fifteen (27%) of 56 Bar-rett’s cancers had an early-stage tumor compared toonly 11 (3.7%) of 294 cancers of the cardia, probablythanks to endoscopic biopsy surveillance which pa-tients with known benign Barrett’s esophagus hadbeen subjected to. However, stratifying patients whounderwent resection surgery by pathologic tumorstage, the prognosis of Barrett’s adenocarcinoma andthat of cancer of the cardia were comparable [68].

From 1980 to 2002, we observed 3813 primary can-cers of the esophagus or esophagogastric junction: theprevalence of adenocarcinomas rose from 21% in the1980s to 36% during the last two years. Of 911 patientswith adenocarcinoma of the esophagus or esophagogas-tric junction, 623 (68%) underwent surgery. Postoper-ative in-hospital mortality declined from 4.2% at thebeginning of the 1980s to 0.6% during the last eightyears. Thirty-two (30%) of 107 patients with adenocar-cinoma arising in Barrett’s esophagus had an earlystage (pT0–Ia) tumor compared to only 24 (4.6%) of 516patients with adenocarcinoma of the esophagus oresophagogastric junction without evidence of Barrett’smetaplasia. The overall 5-year survival after completeR0 resection was 33%. Prognosis was strictly related topathological tumor stage: the 5-year survival rate was88% 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 tu-mors.

CONCLUSIONS

Novel diagnostic modalities such as chromoendos-copy, magnification endoscopy, and fluorescence endos-

copy may help to better recognize patients with lesions

that are progressing to cancer. In the near future,molecular and genetic markers in biopsied tissue willalso help to identify patients with an increased risk ofcancer progression.

Esophagectomy remains the treatment of choice forthe appropriate patient with Barrett’s adenocarcinomainvading beyond the mucosa, without evidence of dis-tant metastasis or invasion of adjacent organs. On theother hand, there is extensive investigation directedtoward better defining the therapeutic approach to pa-tients with Barrett’s HGD or mucosal adenocarcinoma.Therapeutic management of these patients should beindividualized, taking into account patient’s prefer-ences, willingness to return for frequent endoscopicbiopsies, and medical fitness to undergo esophagec-tomy. Surgery has to be considered the best treatmentfor HGD or early carcinoma, unless contraindicated bysevere comorbidities, because it has proven to be theonly treatment that is successful in curing the condi-tion and preventing recurrent HGD or the develop-ment of invasive cancer. Nonsurgical treatment byPDT or EMR may be a less invasive and organ-sparingoption for elderly, poor-risk patients with HGD, orearly carcinoma, but it is still to be considered aninvestigational therapy that should only be conductedunder a clinical trial protocol. Finally, intensive endo-scopic biopsy surveillance of patients with HGD, the“watching and waiting” attitude [69], is another inves-tigational option that may allow prompt treatment ofcancer if it develops. However, few data document thesafety of this observational approach. Since the diag-nostic accuracy and treatment-related morbidity andmortality rates are better in institutions where a highnumber of patients with Barrett’s HGD or cancer areobserved, consideration should be given to referral ofthese patients to specialty centers.

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