Barrett's esophagus and - Hindawi

REVIEW

Barrett's esophagus and adenocarcinorna Z W. LI MD. R. WFNS~I.. MD, FRCP, A.B.R. THOl-tSON. MD. PHO. FRCPC, FACP

ABSTRACT: As association between Barrett's esophagus and adcnocarc inoma of

the esophag141:, is relatively frcqL1cnt. Survival with adenocarcinoma is generally poor. Routine surveillance endoscopy is suggested with generous biopsy material and brush cytology to detect either high grade dysp lasia or intramucosa l ca rcinoma in patien ts , with Barrett's esophagus. Individual cases of high grade dysplasia should be independently confi rm ed by anoth e r pathologist familiar with dysplasia grading. Esophagectomy should be recommended for those patients with high grade dysplas1a whose risk fo r su rgery is outweighed by the possible presence or deve lopment of cancer. Ca n J Gastroe nterol 1988;2(2):75-78 Key Words: Adenocamnorna. Esophagi tis. Gascroesophageal reflux disease

B

ARRETT"S ESOPHAGUS IS A CON-

dition in which normal esophageal stratified squamous mucosa is replaced bv column ar mu cosa. Much hns been learned about Barrett's esophagus since its initial description in 1950 (I). It develops in about 10'1(, of patients with chronic gastroesophageal reflux (2-5). Barrett's esophagus is a condition of clin1cal concern bernuse of an increased ri sk

o f adenocarcinoma as first described by Allison and Johnstone in 1953 (6). Since then there have been numerous reports relating co an ac.lenocarcinoma occu1Ting in as many as 10% of patients with Bar· rett's esophagus ( 7-11 ). The risk of esophageal adenocarcino· ma in patients with Barrett's esophagus appears to be about 30 to 40 times that in the general population ( 12). In the

Nucriuon unJ Mecabolism Research Group. Div1s1011 of Guscrocncerology, Deparrm.eni of Medicme, Uni1,ersicy uf Aibena, EJmoncun, Alberw Corres/>ondence ,md repnncs; Dr A.B.R. Thomson. 519 Hoberc Newron Research Buildmg, Uni1-ersicy of A Iberra, EJmonron. A Iberra T6G 2C2. Teie/>hone (403) 432-6490 Dr L1 Zhang-W,m, 1s cm associwe professor ,md assoc1uce cllle/ />hy,iciun oj mcernal medicine, fosr Hospira/ Harbin Medical Uni11crsiry. Heiloniuiang. PRC Receu:ed for p11blic-ac1011 Febrnary 1988. Accepced April 1988

Vol.2 No. 2.Junc 1988

past, glandular tumours involving the esophagogastric junction were often dismissed u ncritically as cance rs of the gastric cardia that invaded the esophagus. However, strong circumstantial evidence now suggests that many adenocarcino· mas of the esophagogastric junction ac· cually arise in Barrett's mucosa. Adeno· carcinoma with Barrett's esophagus accoun ts for about 5 to 10% of all eso· phageal cancers, (the majority being squa mous cell carcinoma). AJenocarcinoma of the esophagus has a poor prognosis. San fey et al ( 13) re· ported on 32 patients with adenocarcinoma arising in a Barrett's esophagus of whom 21 underwent esophagogastrec· tomy with a surv ival rate of 34% at two years and 15% at five years. Skinner and associates ( 14) report a 22% su rvival rate fo r five years, and a median su rviva l of 23 months ( 15). Because of the relatively high frequency of adenocarcinoma, poor patient surv ival, rhe lateness of clinical symptoms and the relative diag· nostic insensitivity of radiologic exam inations. surveillance by sequential endoscopic examinations is currently recom· mended fo r patients with Barrett's esophagus ( 4.5 .16,17)

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LI ~r al

Barrett':, muco:,al change is thought to he secondary ro chronic gastroesoph agca l rcnux. Acid insult to the lower c:,ophagus result:, in ulceration with reepilheliali zat1on taki ng place from th e gastric side. ln wch patients the distal ponion of Lhc esoph agus becomes lined with columnar mucosa. wilh a potential to undergo dy,plasia and malignant degeneration. Cigarette smoking and alcohol ingestion may act as co-carci nogens in adenocarci nl,ma of lhe esophagus. San fey er al (13) reported that life histories regarding cigarette smoking were available for 2 3 o f 32 patients with adenocarcinoma arisi ng in Barrett's esophagus. Only two of the 23 patien ts had never smoked. Orhcr authors have reported an association between Barrett's adenocarcinoma, cigarette smoking and regular alcoho l intake ( 14.18). Thus, cigarette smoking and alcohol ingestion may be important factors in cancer developing in Ba rrett"s esophag us, as is also the case with sqw1mous carcinoma.

CLINICAL FEATURES Adcnocarcinoma in association with Barrett's esophagus is most common in males in the fifth and six th decade of life who often smoke, drink and h ave a past history of esophagi tis, hiaral hernia or stricture. Patients with reflu x esoph agi t is ~econJarv ro sclerode rm a, and those with reflux caused by a cardiomyotomy for achalasia, arc also at risk of developing cancer. In a review of l21 patients with adenocarcinoma arising in a Barrett's esophagus as reported by Siogren and colleagues ( 5), the mean age at diagnosis wns 5 7 years rnnge 2, to 88 years. The male to female ratio was 'i. 5: 1, an cxaggcnncd male predominance over that of Barrett's esophagus in genera l. Oysphagia was the predomina m presenting symptom in 87°0. a hiatal hernia was often present in 71%, and 64°1, of patients had symptoms of reflux esophagi tis for one to 40 years. The site of adenocarcinoma in relation to the gastroesophageal junction and the squamocolumnar junction is variable, although the incidence appears highest in the distal one-th ird of the esophagus.

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DIAGNOSIS Surveillance by serial e ndoscopic ex• aminations with esophageal biopsies: Barren' s mucosa is classified as: distinctive specia lized type, cardiac type. fund ic type or dysplastic. Dysplasia is classified as intermediate grade or high grade, and is based on th e classification used for gastric dysplasia. Specia lized columnar epithelium is the most common of the three types of mucosa in adult~ with Barrett's esophagus. In a study of both endoscopic biopsy specimens and esophagecmmy specimens, Hamilton and colleagues ( 19) assessed the relationship between dysplasia in Barrett's esophagus and invasive ad enocarcinoma. 0 ( 14 patients with Barrett's esophagus and endoscopic biopsy specimens indicating dysplasia, six pmients had high grade l 43'lo), three h ad intermediate grade (21'l;,) and five had low grade ( 36'1.,) dysplasia. Distinctive type columnar epithelium was both the most common type of epi th elium noted in the group ( 13 of 14) and the most common type associated with high grade dysplasia (six of six). Of the six patients with h igh grade dysplasia, five underwent esophagectomy and three of these were found to have superficially invasive adenocarcinoma. ln one patient rumour extended only to the muscularis mucosa and in two patients rumour reached the submucosa. The other patient with high grade dysplasia and the eight patients with interm ediate or low grade dysp lasia were not yet known to have developed carcinoma on follow-up. ln a study of the resected specimens ( 19). high grade dysplasia was strongly nssociated w ith adjoining invasive adcnocarc inoma; 84'':, of areas wi th invnsion had high grade dysplasia and 92°{, of areas with high grade dysplasia showed invasion . Intermed iate grade dysplasia was found in six o f the areas and low grade in one of the areas adjacent to microscopically in vasive carcinoma. In areas of Barrett's esophagus that did nm adjoin in vasive carci noma in the resectcd specimens, h igh grade dysplasia was noted infrequen tly. Lee (20) h as also con firmed previous observations suggesting that high grade dysplasia is closely linked to the presence of adenocarcin oma. He performed a

careful retrospective analysis of a large number of rescctcd specim ens from patients with Barrett's esophagus who deve loped adenocarcinoma. The presence of high grade dysplasia was both a sensitive and specific marker for the presence of adjacent invasive rnrcinoma. T he strong association between high grade dysplasia and adenocarcinoma in resecrcd specimens would appear co argue for patients with high grade dysplnsia being consid ered for elective esophagectomy. In as much as the prognosis of in vasive adenocarcinoma arising in Barrett's esophagus is so poor, identification of a high risk group or ea rl ier identification of the lesion itself might im prove su rvival. By regu lar endoscopy with adequate biopsy it may be possible to detect early intramucosal carcinomas in certain patien ts. Lt is fe lt th at endoscopic biopsy specimens should be taken with a jumbo biopsy forceps 2 cm apart throughout the entire Barrett's area. [f dysplasia is identified annual examinations arc recom mendcd. If hi gh grade dysplas1a develops csophagectomy should be considered . Esophagea l eyto log ic exam inati on: Brush cytology is an excellent addition to endoscopic biopsies and may provide independent confirmation of the presence of cancer (2 l ). Radiologic examinatio n : The barium swallow has a diagnostic sensitivity for Barrett's esophagus of only 24% (22). A reticular pattern of the esophageal mucosa may be observed with use of double contrast esophagography, hut th b findi ng is neither sensitive nor specific for Barrett"s esophagus. It more probably reflects difficulty· in prospectively diagnosing a mucosa! lesion that usuall y has on ly nonspeci fi c radiographic findings. The combination of hiatal hernia, esophageal ulcer and mid-esophageal strictu re is h ighly suggestive of Barrett's esoph agus. Unfortunately, in retrospective series. no more than 25 to 30% of patients with Barrett's esophagus have been found to h ave this triad (23.24) Thus, radiological exami nation of the esophagus is not recommended for detecting or fo llowing Barrett's esophagus. Flow eytometry: Reid e t al (25) used flow cytometry and h istology to eval uate 317 biopsy sped mens from 64 conCAN JGASTROENTEROL

Barrett's and adenocarcinoma

secutive patients who were in a cancer surveillance program for Barrett's esophagus, plus three additiona l patiencs wirh adenocarcinoma in Barrett's esophagus. All patients wi th dysplasia or adenocarcinoma had evidence of genomic in stability (a neuploidy) (lr abnorma lities of mucosa! proliferation as detected by flow cytometry. In a small subset of patients with specialized meta p lastic epithelium whose specimens were hiscologically negative or indefinite for dysplasia, the mucosa had a ncuplo1d cell populations or proliferati ve abnor maliti es tha t were otherwi se found on ly in dys pl asia or carcinoma. Further stud y may prove rh.:it this subset of patients mcnrs more frequent e ndoscopic biopsy w rvcillance because of an increased risk for developing carcinoma. Thus. flow cytome try is capable of detecting al terations in DNA content o r proliferation or both , that arc present in high frequency in Barrecc's dysplas1a and carcinoma. Becau se the abnormalities detected by flow cytomecry correlate well with the conve ntional hisrologic diagno·isof dysplasia a nd carcinoma, rhc\ may prove to be a val ua b le objective adjunct m the diagnosis of dysplasia and carcinoma 111 Barrett's esophagus. Acid sulphated mucins: Other markers have recently been proposed ro detect early ca ncer of chc esophagus including changes in mucin sta ining to detect acid s ulphated mucins. Unfor tunately, recent studies have shown chat acid su lphated mucins a rc p resent coo frequently in Barre tt's epithelium with out dysplasia co be of use in defining a subgroup ar increased risk of d ysplasia .

STAGING SYSTEM Rosenberg and co-workers ( 18) reported an anaiysis of adcnocarcmoma in Barrett's esophagus, utili zing a staging system . They unde rtook a study of che p rogression of changes cha t take place in patients with adenocarcinoma arising in

REFERENCES I. Barrett's NR . C hronic pepur ulce r of the esophagus and esophagitis Br J Surg

1950;38:175-82 2. Bremner CG, Lynch VP, Ellis FH . Barrett'~ esophagus· Congemtal or

Vol.2 No.2.Ju ne 1988

a Barrett's esophagu s and developed a staging system based on the extent of the malignancy (as dete rmined by su rge ry and by pathologic examinatio n of the tumo ur) . Thb staging syste m is as foll ows: { I) Ca rcmoma limi ted co rhe mucosa ( 111cluding carcinoma in si tu) nor extending beyond the muscularis mucosa with ncgnrive nodes; (I!) ca rc ino ma limited to the esophageal wall but not extending to the adventitia, with negative nodes; (Ill) a ny of the above with involved regional lymph node~ or full thickness wall penetration of the tumou r co the adventiua, without invasion of adjacent organs; a nJ (IV J ca rcinoma invading adjacent organ!> or with distant metastases. The finding of a progression of changes from dysplasia to in situ neoplasia to invasive malignancy suggests mecaplasia as the first step in this process Multiple foci o f malignant change in Barrett's esophagus have been frequently re ported.

MANAGEMENT Medical treatment: Patients who have symptomatic or objective evidence of reflux esophagi tis should receive vigorous standard medical treatment including H 2 antagonists, prokinetic agen ts and dieta ry restriction~ Kothari and associates ( 2 7 ) reported that ulcers in five patients w ith Barrett's, refractory to antacids, h ealed in e ight t0 16 weeks w ith cimeridine 1.26 ml/day. Lt is n ot known if the risk of dysplasia or carcinoma 1s reduced by such m ed ical therapy Surgical treatment. Antircflu..x sur• gery: Some in vestigators have cla imed at least partial regressio n o f Barrett's e pithelium after s uccessful antire Ou x procedures (3, IO). Seve ral authors advocate an anti reflu x p rocedure for most pa tients with Barrett's esophagu s, b ut it is not known whe ther the occurrence of adenocarcinoma can be prevented . Esophagectomy: A difficult problem facing doctors who deal with patients

acquired 1 An experimental study of esophagea l mucosa! regeneration in the dog Surgery 1970;6R 175-82 l Goldm::m MC, Beckman RC Barre u \ syndrome: Case report with discussion about concer1, o f pathogenesis.

having Barren 's esophagu s b the ti m ing o f a surgical resec tion before invasive adenocarcinoma develops Endoscopic surveil la nce biopsies arc rea ssuri ng 1f they arc negative fo r dysplas1a. However, if dysplasia is found on light microscopy, it may be difficult to determine whether the morbidity of a surgical resection is offset by a sufficiently high chan ce for discovering concomitant early mvas1ve adcnocarcinoma. Several workers { 17- l9) suggest that the dysplasia-carcinoma sequence most common ly occurs 111 Ba rrett's mucosa of the d istmcti ve type. High grade dyspla!>ia in Barrett's mLtcosa is a marker indicating high p robability of invasive carcinoma and, therefore, th e presence of high grade dysplasm in biopsy specimens of Ba rrett 's mucosa is probably an indication for total csophagccromy in suitable su rgi ca l candidates. A more extensive csoph agccromy is required than can be performed usmg the Lewis approach or a left thoracoto my. Rosenberg and others ( 18 ) CL1rren tly favour a procedLtre that places the esoph agogastric anasto mosb in the neck When either the stomach or che colon is Ltsed as an esoph ageal replacement, It is brought up to the neck through a substcrna l tunnel. This operative approach is best for all patients with esophageal cancer. irrespective of the cell type. Patients foun d to h ave low grade dysplasia sho uld receive intensive medical treatment for reflux csoph agius for up to 12 weeks, at which time esophagoscopy sho uld be repeated ro obtam multiple esoph ageal biopsy specimens. Patients whose biopsy specime n s s how histologic im provement wi ll require intense surveillance (cg, an examination every three co six mo n ths) until at least two consecu tive endoscopic examinations reveal n o dysplast1 c epithelium Continued intensive treatment a nd surveillance arc recommended in patients whose repeat biopsies reveal persistent low grade dysplasia .

Gamoen ccrology 1960; W 104-10. 4 Bozymski EM. Herlihy K. Orlando RC Barrett's esophagus Ann Intern Med

1982;97· IOH 5 Siogren RW. Johnson LF Barrett's esophagus A review. Am J MeJ

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Li et ul

1983,74. 31J-20. 6 A llison PR , Johnstone AS. The oesophagus lined with gastric mucous membrane Thorax 1953:8:87-101. 7 Spechler SJ, Robbins AH. Rubins HB , et al. Ad enocarcinoma and Barrett's esorhagus: An overrated risk? Gasl rocn terology 1984:87 :9 Z7-3 3 8. Cameron AJ, Ou BJ. Payne WS. Incidence of ad enocarcinoma 111 columnar-lined (Barrett's) esorhagus. N EnglJ Med 1985:)13:857 9 Mes,i:rn RA, HcrmosJA. Robbins AH. et al. Barrett's esorhagus: Cli nical review of 26 ca,es Am J Gastroen terol

1978;69.458-66.

ct al. Carcinoma arising in Barrett's esophagus. Surg Gynecol Obstel

l98'i, 161 :570-4. 14. Skinner DB , Welther BC. Riddell RH, et a l. Barre1t's esoph agus: Comparison of benign a nd malignant cases. Am J Surg

1983; 198:554-66. 15. Smith RRL. Hamilton SR, BoimonJR, er al. The spectrum of carcinom a arising 111 Barrett's esophagus: A clin1copmhologic stlldy of 26 patients. AmJ Surg Parhol 1984:8:'i63-73. 16. Berardi RS, Devaiah KA. Barrett's esophagus. Surg Gynccol Obstet

1983: 156:521-38. 17. Skinner DB. T he columnar-lined

10 Sarr MG. Ha mil ton SR, Marrone GC, ct al Barreu's esophagus: Its rre\'alcncc and association with adcnocarcinoma in patients with symptoms of gastroesophagcal reflux. Am J Surg 1985: 149: 187-92. I I Sau bier EC. Goui llat C, Samaniego C, ct al. Adcnocarc1noma in columnarli ned Fh1rretr's esophagus. Analysb of U esnrhagcctomics Am J Surg

1985; 150:365-9 12. Spcchlcr SJ, Goyal RK. Barrett 's esophagu,. N Engl) Med

e:,ophagus and ,1Jcnocarc111oma Ann Thorne Surg 1985:40: 321-2. (Edit) 18 Rosenberg JC, Budev H, Edwards RC. cl al. Analysis of adenocarcinoma 111 Barrett's esophagus utilizing a smging sy,tem Cancer 1985;55: 1353-60. 19 H:unilton SR. Smith RRL The relationsh ip between columna r .::pithclial dysplasia and invasive adcnticarcinoma arising in Barrett's esophagus. Am J Clin Pathol

1987 ;87:30 1- 12. 20. Lee RG. Dysplasia 111 Barr.::u's

1986;315: 362-71. 13. Sanfcy H, Hamilton SR. Smith RRL,

csorhagu s. A cli nicopachologic study of

six patien ts. Am J Surg Pmhol

1985;9:845-52. 21. BelladonnaJA, Hajdu Sl. Bains MS , ct al Adenocarc111o m a in situ of Barrell', esophag us diagnosed by e ndoscopic cyrokigy. N Engl J Med 1974:291:895-6 22. Winters C. S purling TJ , Chobanian SJ, ct al. Barrett's esophagus. Gastroenterolngy 1987;92: 118-24. 23. Robbins AH, Vincent ME, Sai ni M. et al. Revised radiologic concepts of chc Barrett's .::sophagus. Gastroi nte:,t Radio!

1978; 3:3 77-81. 24. Levine MS. Kresse! HY, Caroline OF, ct al. Barrett's esophagu s. Reticular pattern of the mucosa. Radiology

1983:147:663-7 25. Reid B. Haggin RC. Rubm CE Rabinov1cch PS. Flarrctt's esophagus: Correlation between flow cytometry and histology in detection of patien1s at n sk fo r adcnocarcinoma Gas1roenterology 1987;93:l- ll. 26. Jass JR Mucin histochemistry of the col um nar epithelium of the oesophagu,. A retrospective scu dy. J Clin Pmhol

1981,34:866-70 27 Kothari T M:rngla JC. Kalra TMS. Barrell\ ulcer and treatment with cimetidine Arch Intern Med

1980; 140:475-7.

Clinical quiz - Answers COLON

NUTRITION

1. Causes, clinical manifestations and treatment of solitary rec tal ulcer

1. Majo r clinical manifestations of vitamin A toxicity

Causes Constipation Ergotamine suppositories Idiopathic Manifestations Pain Blood a nd mucus Treatment Stool softeners Stop ergotamine Local analgesics Rare ly, surgery to correct associated rectal prolapse 5-ASA. steroids

2. Clinical features which would make you suspect that a patient was suffering from cathartic colon

Skin lesion - dry, pruritic. coarse and scaly skin Hair loss Sore mouth, anorexia . vomiting Headache, d rowsiness, irritability. increased intracranial pressure and papilledema Enlarged liver progressing to fibrosis and cirrhosis Lymphadenopathy Bone pain (painful hyperostosis) Congenital abnormal ity in pregnant wome n

2. Clinical manifestations of zinc deficiency Diarrhea Disturbance of central nervous system with mental irritability and depression Skin lesion of the face, limbs. skin folds a nd perineum Alopecia Loss of taste - ageusia Defect in the immunologic mechanisn

Recurrent diarrhea with persistent hypokalemia in a female Melanosls coll in sigmoidoscopy (anthracenes) Narrow featureless colon o n barium enema Positive sodium hydroxide test - pink stool (phenolphthalein)

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CAN JGASTROE1'TEROL

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