arhiv 2002

8/6/2019 arhiv 2002

1/60

8/6/2019 arhiv 2002

2/60

ARCHIVES OF

GASTROENTEROHEPATOLOGY

EDITOR-IN-CHIEFGLAVNI I ODGOVORNIUREDNIK

Vojislav N. Peri{i}De~ija klinikaTir{ova 10

11000 Beograd

FOUNDING EDITORUREDNIK-OSNIVA^

Obren Popovi}

CHAIRPERSON OFEDITORIAL BOARDPREDSEDNIKURE\IVA^KOG ODBORA

Gradimir Golubovi}

DESK EDITORUREDNIK DESKA

Bojan [timec

TECHNICAL EDITORTEHNI^KI UREDNIK

Milovan Stevanovi}

ASSOCIATE EDITORSUREDNICI

Radoje olovi}Branka Dap~evi}Goran Jankovi}Njegica Joji}Du{an Jovanovi}Miodrag N. Krsti}Nada Kova~evi}

EDITORIAL BOARDURE\IVA^KI ODBOR

Mihajlo Boàni}Ivan Bori~i}Mirko Bulaji}Zoltan VargaJulijana Vojvodi}Tamara Vukavi}Vladimir Vuk~evi}Radivoje Grbi}Sa{a GrgovBranibor Guduri}Branislav Dani~i}Dragan Deli}Du{an \ur|evi}Miodrag @ivanovi}Slobodan Jankovi}Tibor JesenskiRada Je{i}Julija Kova~evi}Zoran Krivokapi}Miodrag Krsti}Ana LabanJano{ Lemberger

Stojan Luka~evi}Predrag Mijailovi}Jovica Milanovi}Ivanka Mileti}Nikola Milini}Svetlana Milutinovi}-\uri}Ljubomir Muzikravi}Vladislav Nikoli}Predrag Nikoli}Vladimir Obradovi}Andrija PaljmMirjana Peri{i}Milija Petrovi}Milorad Petrovi}Ljiljana Petronijevi}

Milo{ Popovi}Milica ProstranBoìna Radevi}Nedeljko Radlovi}Dragan Sagi}Ranka Samardì}Stojan Sekuli}Ivanka Stamenkovi}Neboj{a Stankovi}Miodrag Stojkovi}Zorica Stoj{i}Tomislav Tasi}Dragan Tomi}Ljiljana Hadna|evTihomir [ija~i}

INTERNATIONALADVISORYBOARDME\UNARODNISAVETODAVNI ODBOR

Monica Acalovschi, Cluj-NapocaMihailo Ali}, San FranciscoAthanasios Archimadritis, AthensConstantine Arvanitakis, Thessaloniki

Serge Bonfils, FranceIan W.Booth, BirminghamMartin C.Carey, BostonWolfgang F.Caspary, Frankfurt/MainR.Herman Dowling, LondonM.J.G.Farthing, LondonKenneth Hobbs, LondonAlan F.Hofmann, San DiegoRichard H.Hunt, West HamiltonPeter Katelaris, SydneyM.S.Khuroo, SrinagarS.J.Konturek, KrakowGuenter J.Krejs, GrazAnatolij S.Loginov, MoscowZdenek Maratka, PrahaOrestes N.Manousos, Crete

Neil McIntyre, LondonJoseph R.Armengol-Miro, BarcelonaJ.J.Misiewicz, LondonGabriel Nagy, St.LeonardsRobert K.Ockner, San FranciscoH.Selwyn Odes, Beer ShevaKunio Okuda, Chiba CityG.Bianchi Porro, MilanoJean C.Rambaud, ParisMario Rizzetto, TurinRudi Schmid, San FranciscoDame Sheila Sherlock, LondonJ.J.Sidorov, HalifaxMarvin H.Sleisenger, KentfieldHoward M.Spiro, New Haven

Sandor Szabo, Long BeachB.N.Tandon, New DelhiAldo Torsoli, RomaJerry S.Trier, BostonAndreas Tzakis, MiamiMichalis Tzivras, AthensVince Varro, SzegedChristopher B.Williams, LondonGordan Vujani}, CardiffRodger Williams, LondonHenrik R.Wulff, Herlev

A QUARTERLY JOURNAL DEVOTED TO CLINICALAND BASIC STUDIES OF THE DIGESTIVE TRACT AND LIVER

PUBLISHED BY THE SERBIAN MEDICALASSOCIATION - SECTION FOR GASTROENTEROLOGYTROMESE^NI ASOPIS ZA KLINI^KA I BAZI NA ISTRA@IVANJA DIGESTIVNOG SISTEMA I JETREIZDAJE SRPSKO LEKARSKO DRU[TVO - GASTROENTEROLO[KA SEKCIJA

During the spring 1982 by joint effort of agroup of enthusiasts, gastroenterohepatologists theArchives of Gastroenterohepatology was created. Inmemory of these pioneers, Editorial Board of theArchives of Gastroenterohepatology is noticing theirnames (alphabetically): Milan Andrejevic, MirkoBulajic, Mihailo Elakovic, Nada Kovacevic,Milenko Lalic, Ljubisa Glisic, Vera Perisic, ObrenPopovic, Milentije Petrovic, Jovan Teodorovic.

Marjan Micev

Tomica Milosavljevi}Aleksandar Nagorni\or|ije [aranovi}Neda [virtlihMilenko Uglje{i}

8/6/2019 arhiv 2002

3/60

Reappointed Editor-in-Chief from 2002 to 2006Dr Vojislav N. Perisic

Current appointments:Full Professor of Paediatrics,Faculty of Medicine, Belgrade

Vice-Chairmen, Board of Pediatrics,Medical Faculty, Belgrade

Head, Department of Hepatology andSection of Digestive Endoscopy,University Children, s Hospital, Belgrade

Reappointed Chairperson of the EditorialBoard from 2002 to 2006Dr Gradimir Golubovic

Current appointments:Full Professor of Internal Medicine,Faculty of Medicine, Belgrade

Head, Internal Medicine Service,Clinical and Hospital Center Zemun-Belgrade

Head, Department of Gastroenterology,Clinical and Hospital Centre, Zemun-Belgrade

8/6/2019 arhiv 2002

4/60

ARCHIVES OF GASTROENTEROHEPATOLOGY pub-lishes original papers, case reports, multi-center trials, edito-rials, review articles, letters to the Editor, other articles andinformations concerned with practice and research in thefield of gastroenterology and hepatology, written in English.

Address manuscripts to:

Dr. Vojislav N. Peri{i}Editor, ARCHIVES OFGASTROENTEROHEPATOLOGYUniversity Children's Hospital10 Tir{ova Str., 11000 BeogradSerbia, YugoslaviaTel. (38111) 361 60 61; Fax (38111) 684-672

E-mail: [email protected]

Manuscripts are prepared in accordance with Uniformrequirements for manuscripts submitted to biomedical jour-nals developed by the international committee of medical

journal editors (N Engl J Med 1991; 324; 424-428). Consultthese instructions and a recent issue of Archives ofGastroenterohepatology in preparing your manuscript.

Original manuscripts will be accepted with the under-standing that they are solely contributed to Archives ofGastroenterohepatology. Manuscripts, accepted for publica-tion, become the property of the Journal, and may not be pub-lished elsewere without written permission from both the edi-tor and publisher. The Journal does not publish papers con-taining material that has been published elsewhere except asan abstract of 400 words or less; previous publication inabstract form must be disclosed in a footnote.

Cover letterA covering letter contains pertinent explanations and clar-

ifications, if any, concerning the manuscript. Authors are

encouraged to provide on a separate sheet the names andaddresses of one to three experts who, in their oppinion, are

best qualified to peer review the paper.

ManuscriptThe manuscripts have to be submitted on a 3.5-inch disk.

The word-processing package is Word for Windows. Also, themanuscripts must be printed out in two copies which exactlymatch the disk. The copies must be printed double-spacedthroughout (including references, tables, figure legends, andfootnotes) on A4 (21 cm x 29.7 cm) paper with wide margins.

The manuscript is arranged as follows: title page, abstract,introduction, patients and methods/material and methods,results, discussion, references, tables, and figures.

Each manuscript component (title, page, etc.) begins on aseparate page. All pages are numbered consecutively begin-ning with the title page. The first author's last name is typedat the top right corner of each page.

All measurements, except blood pressure, are reported inSysteme International (SI) and, if necessary, in conventionalunits (in parenthesis). Generic names are used for drugs.Brand names may be inserted in parenthesis.

Authors are advised to retain extra copies of the manu-script. Archives of Gastroenterohepatology is not responsiblefor the loss of manuscripts in the mail.

Title pageTitle page contains the title, short title, full names of all

the authors, names and full location of department and insti-tution where work was performed, acknowledgements, abbre-viations used, and name of corresponding author.

The title of the article is concise but informative, and

includes animal species if appropriate. A subtitle can be addedif necessary.A short title of less than 50 spaces, for use as a running

head, is included.A brief acknowledgement of grants and other assistance, if

any, is included.A list of abbreviations used in the paper, if any, is includ-

ed. List abbreviations alphabetically followed by an explana-tion of what they stand for. In general, use of abbreviations isdiscouraged unless they are essential for improving the read-ability of the text.

The name, telephone number, fax number, and exact postal address of the author to whom communications andreprints should be sent are typed in the lower right corner ofthe title page.

Abstract pageAn abstract of less than 180 words concisely states the

objective, findings, and conclusion of the studies described inthe manuscript. The abstract does not contain abbreviations,footnotes or references.

Below the abstract, 3 to 8 short keywords are provided forindexing purposes.

Introduction pageThe introduction in concise, and states the reason and spe-

cific purpose of the study.Patients and methods / Material and methodsSelection of patients or experimental animals, including

controls is described. Patient's names and hospital numbersare not used.

Methods are described in sufficient detail to permit evalu-ation and duplication of the work by other investigators.

When reporting experiments on human subjects, it is indi-cated whether the procedures followed were in accordancewith ethical standards of the Committee on human experi-mentation of the institution in which they were done and inaccordance with the Declaration of Helsinki. Hazardous pro-cedures or chemicals, if used, are described in detail, includ-ing the safety precautions observed. When appropriate, astatement is included verifying that the care of laboratory ani-mals followed accepted standards.

Statistical methods used are outlined.

ResultsResults are clear and concise, and include a minimum

number of tables and figures necessary for proper presenta-tion.

DiscussionAn exhaustive review of literature is not necessary. The

major findings should be discussed in relation to other pub-lished work. Attempts should be made to explain differences

between the results of the present study and those of others.

INSTRUCTIONS TO AUTHORS AND CHECKLIST

8/6/2019 arhiv 2002

5/60

Hypothesis and speculative statements should be clearly iden-tified. The Discussion section should not be a restatement ofresults, and new results should not be introduced in the dis-cussion.

ReferencesReferences are identified in the text by Arabic numerals in

parenthesis. They are numbered consecutively in the order in

which they appear in the text. Personal communications andunpublished observations are not cited in the reference list, but may be mentioned in the text in parenthesis.Abbreviations of journals conforms to those used in IndexMedicus. The style and punction conform to Archives ofGastroenterohepatology style requirements. The followingare examples:

Article (all authors are listed if there are six or fewer; oth-erwise only the first three are listed followed by "et. al.").

12 - Talley NJ, Zinsmeister Ar, Schleck CD, Melton LJ III:Dyspepsia and dyspeptic subgroups: A population-basedstudy. Gastroenterology 1992; 102: 1259-68.

Book

17 - Sherlock S, Diseases of the liver and biliary system,8th ed. Oxford: Blackwell Sci Publ, 1989.

Chapter or article in a book24 - Trier JJ, Celiac sprue. In: Sleisenger MH, Fordtran JS,

eds. Gastrointestinal disease, 4th ed. Philadelphia: WBSaunders Co, 1989; 1134-52.

The authors are responsible for the exactiness of referencedata.

TablesTables are typed on separate sheets with figure numbers

(Arabic) and title above the table and explanatory notes, ifany, below the table.

Figure legendsAll illustrations (photographs, graphs, diagrams) are to be

considered figures, and are numbered consecutively in thetext and figure legend in Arabic numerals. The number of fig-ures included is the least required to convey the message ofthe paper, and no figure duplicates data present in the tablesor text. Figures do not have titles. Letters, numerals and sym-

bols must be clear in proportion of each other, and largeenough to be legible when reduced for publication. Figuresare submitted as near to their printed size as possible. Figuresare reproduced in one of the following width sizes: 8 cm, 12cm or 17 cm, and with a maximal length of 20 cm.

If magnification is significant (photomicrographs) it is

indicated by a calibration bar on the print, not by a magnifi-cation factor in the figure legend. The length of the bar is indi-cated on the figure or in the figure legend.

Two complete sets of high quality unmounted glossyprints are submitted in two separate envelopes, and shieldedby an appropriate cardboard. The backs of single or groupedillustrations (plates) bear the first author's last name, figurenumber, and an arrow indicating the top. This information is

pencilled in lightly or placed on a typed self-adhesive label inorder to prevent marking the front surface of the illustration.

Photographs of identifiable patients are accompanied by

written permission from the patient.For figures published previously the original source is

acknowledged, and written permission from the copywrightholder to reproduce it is submitted.

Color prints are available by request at the author'sexpense.

Letters to the Editor

Both letters concerning and those not concerning articlesthat have been published in Archives ofGastroenterohepatology will be considered for publication.They may contain one table or figure and up to five refer-ences.

ProofsAll manuscripts will be carefully revised by the publish-

er's desk editor. Only in case of extensive corrections will themanuscript be returned to the authors for final approval. Inorder to speed up publication no proof will be sent to theauthors but will be read by the editor and the desk editor.

Reprints

Twentyfive reprints, for full-length papers only, are pro-vided free of charge.

Checklist for authorsComplete this checklist before sending your manu-

script.- Cover letter- Two complete copies of manuscript (including

glossy prints of illustrations)- 3.5 - inch disk containing manuscript file

Title page- Title- Short running head of no more than 50 spaces

- Author(s) and affiliation(s)- Acknowledgement (if any)- Abbreviations (if any)

- Address, telephone and fax numbers of corre-sponding author

Article proper (double spaced)- Abstract- Key words- Introduction- Patients and methods / Material and methods- Results- Discussion- References

- Tables- Figure legends- Figures- Permission to reproduce any previously published

material and patient releases to publish photographs (ifany).

Submission of a manuscript implies that the workhas not been published before and that is not under con-sideration elsewhere.

8/6/2019 arhiv 2002

6/60

Aleksandar Nagorni,

Vuka Katic,

Jovica Milanovic,Vesna Zivkovic,

Goran Bjelakovic.

AbstractLynch syndrome (HNPCC-hereditary non-polyposis colorectal cancer) is an autosomal dominant inher-

ited disorder characterized by early onset of colorectal cancer (CRC), a preponderance of CRC in prox-

imal colon, occurrence of multiple CRC, mucinous and poorly differentiated adenocarcinoma. We report

family "S" with 11 (25.5%) affecting members. Metachronous CRC were observed in 27.2% affecting

members. In tumour spectrum of Family "S" there were stomach, ovarian and endometrial cancer.

Genetic tests are not routinely available in our country, so periodic screening of all family members have

to be perform according to recommendation.

Key Words:Lynch syndrome,

metachronous CRC,

stomach cancer

Saètak

Lynch-ov sindrom (HNPKK- hereditarni ne-polipozni kolorektalni karcinom) je autozomno domi-

nantni nasledni poreme}aj koji se karakteri{e ranim po~etkom kolorektalnog karcinoma (KRK), pre-

dispozicijom za proksimalni kolon, pojavom multiplih KRK, mucinozni i slabo diferentovani ade-

nokarcinomi. Saop{tavamo porodicu "S" sa 11 (25.5%) obolelih ~lanova. Metahroni KRK su

zapaèni u 27.2% obolelih ~lanova. U tumorskom spektru porodice "S" otkriveni su karcinomi

èluca, ovarijuma i endometrijuma. Genetski testovi jos uvek nisu rutinski dostupni u na{oj zemlji,

pa periodi~no pra}enje svih ~lanova porodice treba izvoditi u skladu sa preporukama.

Klju~ne re~i:

Lynchov sindrom,

metahroni KRK,

karcinom èluca

Abbreviations used in this article: CRC,colorectal cancer;

HNPCC,hereditary non-polyposis colorectal cancer; ICG

HNPCC,International Collaborative Group Hereditary Non-

Polyposis Colorectal Cancer; MMR,Mismatch Repair.

Professor: Aleksandar V. Nagorni, MD, PhD,

Clinic for gastroenterology and hepatology,

Clinical Center Nis,

48 Brace Taskovica St.,Yu-18000 Nis, Serbia, Yugoslavia.

Fax: +381 18 335 186


Gastroenterolo{ka sekcija SLD-

01732, 2002.

Alimentary tract and pancreas

Alimentarni trakt i pankreas

Clinic for Gastroenterology and Hepatology and

Clinic for Pathology, Clinical Center,Ni{

ARCH GASTROENTEROHEPATOL 2002; 21 (No 1 - 2): 5 - 8

The Lynch syndrome: Report

on family "S"

Lynch-ov sindrom: Prikaz porodice "S"

( accepted June 20th, 2002 )

INTRODUCTION

Colorectal cancer (CRC) is the fourth most common cancer and

the second leading cause of cancer deaths in many countries world-

wide. In the past few years, advances in the molecular biology and

genetics of CRC have not only broadened our understanding of this

disease, but have also provided insight into the pathogenesis of both

sporadic and hereditary CRC syndromes (1).

Hereditary non-polyposis colorectal cancer (HNPCC) firstly

was recognized in 1895. Famous pathologist Aldred Warthin then

heard from his seamstress who was depressed because she was con-

vinced, based on her family history, that one day she would die of

cancer of the female organs or bowels. As she had predicted, she

died of endometrial carcinoma at a young age. In 1913 Warthin

published Family G with endometrial, colorectal and gastric carci-

noma as a predominant malignancy in this kindred (2).

In the fame of Henry Lynch who studied this problem in the

middle sixties International Collaborative Group Hereditary Non-

Polyposis Colorectal Cancer (ICG-HNPCC) was named HNPCC

as Lynch syndrome.

Lynch syndrome is an autosomal dominant inherited cancer

syndrome characterized by the development of (CRC) at an earlyage of onset, a preponderance of cancers in the proximal segments

of colon, an excess of multiple CRC, synchronous and metachro-

nous CRC, and poorly differentiated and mucinous CRC (3 - 6).

Lynch syndrome is associated with a small number of adenomas

that are located predominantly on the right side of the colon (7).

ICG-HNPCC proposed the "Amsterdam minimal criteria" in 1990

to facilitate the clinical diagnosis of HNPCC (8). "Minimal" crite-

ria include: 1) the presence of three or more relatives with CRC,

8/6/2019 arhiv 2002

7/60

one who is a first degree relative of the other two, 2) that the rela-

tives affected by CRC span two or more generations, 3) and at least

one relative is affected by CRC before the age of 50 (8).

In addition to CRC patients with Lynch syndrome are at risk of

developing extracolonic tumours including endometrial, ovarian,

ureteral, stomach, renal pelvis, small bowel, hepatobiliary and skin,

which are included in the modified Amsterdam criteria (9).

The genetic defect underlying Lynch syndrome is a defect inDNA mismatch repair genes. In the presence of normal DNA mis-

match repair, abnormally paired nucleotides are excised and

replaced with the proper nucleotide base pair. However, if inactiva-

tion of mismatch repair system, characteristic of Lynch syndrome,

is present, errors in base pairing can accumulate and predispose the

cell to malignant progression. This persistent error in base pairing in

the DNA from patients with Lynch syndrome has been referred to

as the "mutator" phenotype, the "replication error repair" phenotype,

or microsatellite instability (1).

Six human genes have been identified as participating in the

function of mismatch repair. These genes include hMSH2, hMLH1,

PMS1, PMS2, hMSH6 and hMSH3 (10-15), although germline

mutations in MSH2 and MLH1 account for the majority of Lynch

syndrome families (16,17).

REPORT OF A FAMILY

Our interesting for hereditary CRC began in 1989 when a 58-

year old man (proband) was admitted to the Clinic for gastroen-

terology and hepatology, Clinical Center of Nis, because of intesti-

nal bleeding and changes in the large bowel movements. First

episode was recorded six months before admission. Twenty-three

years ago adenocarcinoma of transverse colon was diagnosed and

right hemicolectomy was done. In the same time his son was admit-

ted to the Clinic because of liver metastasis of colorectal cancer, two

years after surgery for cecal adenocarcinoma. Colonoscopy

revealed adenocarcinoma of descending colon at the splenic flexure.

Additional analyses: laboratory, abdominal ultrasound and CT are

excluded disease spread and left hemicolectomy was done.

The proband was followed-up by colonoscopy and ultrasound,

but four years after the second operation of metachronous CRC,

stomach cancer was diagnosed (adenocarcinoma), and patient was

operated.

We began to collect family data and pedigree of family "S" wasmade (Fig. 1).

We report the family "S" more than a 10 years after collecting

data.

In family "S" there are 43 members, but 11 (25.5%) members

are involved with a total of 16 malignant tumours. In nine patients

there were one or more CRC (metachronous), but in two family

members, single stomach and ovarian cancer were detected. Most

malignant tumours are CRC, but two stomach cancer and endome-

trial and ovarian cancer were diagnosed, too (12) . In 3 (27.2%) of

involved family members, metachronous CRC were observed 4-23

years after diagnostics of initial CRC. The earliest onset of the dis-

ease was diagnosed in the proband (35 years), and in more than a

half of involved patients, malignancy was detected before 50 years

of age.

There were 9 (75%) of right sided, but 3 (25%) of left-sided

CRC. In one family member, metachronous sigmoid CRC was

small (6 mm) flat lesion revealed four years after surgery for cecaladenocarcinoma. Histology revealed in most of cases mucinous and

poorly differentiated adenocarcinoma.

The proband is under regular control, without any sign for

metachronous growth. The proband is responsible not only for our

interest in hereditary cancers, but for the other healthy family mem-

bers, who follow him and come for regular, determinated gastroen-

terological and gynecological examinations.

DISCUSSION

Lynch syndrome is an autosomal dominantly inherited disorder

of cancer susceptibility with very high penetrance rate of 80-85%

(18-21). This syndrome accounts for about 1-2% of all CRC occur-

rences (22). Mutations of the major mismatch repair (MMR) genes

MLH1 and MSH2 are detected in 30-80% of HNPCC kindreds

from different ethnic backgrounds (23-26). To date the only known

cause is an inherited mutation in one of the following (MMR)

genes: hMSH2, hMLH1, PMS1, PMS2, hMSH6, hMSH3 (10-15).

ICG-HNPCC at its meeting held in Amsterdam in 1990 was

established a set of selection criteria for families with Lynch syn-

drome to provide a basis for uniformity in collaborative studies. By

the time the Amsterdam criteria have also been criticized. Some

investigators feel that the criteria exclude some classic Lynch fami-

lies because they do not take into account the extracolonic cancers

that are tumor spectrum of the syndrome (8). It is now concluded

that many true HNPCC families would be missed if the criteria are

applied to clinical diagnosis, and that families not meeting the crite-

ria might be falsely reassured and excluded from genetic counsel-

ing, DNA testing, or surveillance (27). To resolve some of these

problems Rodriguez-Bigas et al. developed additional taking into

account the molecular and pathologic features of CRC and adeno-

mas in addition to family history (28).

Taking into account some new reported data ICG proposed def-

inition of Lynch syndrome (17-21): Familial clustering of colorectal and/or endometrial cancer

Associated cancers: cancer of the stomach, ovary,

ureter/renal pelvis, brain, small bowel, hepatobiliary tract,

and skin (sebaceous tumours)

Development of cancer at early age

Development of multiple cancers

Features of CRC: 1) predilection for proximal colon; 2)

improved survival; 3) multiple CRC; 4) increased proportion

6 Arch gastroenterohepatol 2002; 21 (No 1 - 2): 5 - 8 Aleksandar Nagorni

8/6/2019 arhiv 2002

8/60

of mucinous tumours, poorly differentiated tumours, and

tumours with marked host-lymphocytic infiltration and lym-

phoid aggregation at the tumor margin

Features of colorectal adenoma: 1) the numbers vary from

one to a few; 2) increased proportion of adenomas with a vil-

lous growth pattern; 3) a high degree of dysplasia, and 4)

probably rapid progression from adenoma to carcinoma

High frequency of MSI (MSI-H) Immunohistochemistry: loss of MLH1, MSH2, or MSH6

protein expression

Germline mutation in MMR genes (MSH2, MLH1, MSH6,

PMS1, PMS2).

The new set of clinical criteria (Amsterdam criteria II-Revised

ICG-HNPCC criteria) was proposed and accepted by the majority

of ICG-HNPCC group (27):

There should be at least 3 relatives with and HNPCC-associ-

ated cancer (CRC, cancer of the endometrium, small bowel

ureter, or renal pelvis)

One should be a first-degree relative of the other two

At least two successive generations should be affected

At least one should be diagnosed before age 50

Familial adenomatous polyposis should be excluded in the

CRC(s) if any

Tumours should be verified by pathological examination.

It is important in the discussion of criteria, that criteria aim to

provide a common nomenclature for the selection of families for

studies and for the comparison of the results of these studies.

Criteria are not permanent, they will change as our knowledge of

Lynch syndrome advances (27).

There are a few forms or variants of HNPCC. Muir-Torre syn-

drome is characterized by tumor spectrum of Lynch syndrome and

skin tumours (6,29-31).

"Caf-au-lait spots"(macular, sharply demarcated, evenly oval

pigmented spots, present at birth) is another variant of the Lynch

syndrome (32), characterized with early onset of CRC, oligopoly-

posis, glioblastoma and lymphoma.

To the best of my known this report is the first in our literature.

Reported family "S" fulfills "minimal Amsterdam"(Amsterdam

Criteria I) and Revised ICG criteria (Amsterdam Criteria II). More

than 25% of family members were affected with malignancy; three

successive generations were involved (11). In 75% of affected

members CRC was detected proximal to the splenic flexure and cor-

relate with literature data (33-35). Metachronous CRC were detect-

ed 4-23 years after initial CRC in 27.2% of affected family mem-

bers and this finding correlate with literature data (36,37).

In 2 (18.3%) patients stomach cancer was detected. There are

conflicting data in literature about inclusion of the stomach cancer

in the tumor spectrum of the Lynch syndrome (27,38). Someauthors considered that gastric carcinoma is the second most com-

mon extra-colonic malignancy associated with Lynch syndrome

(39,40). The cumulative risk of carcinoma of the stomach in puta-

tive HNPCC gene carriers has been estimated at 19 % (41). The pre-

dominance of intestinal type of gastric cancer in Lynch syndrome

families (as in our report) was unexpected because the diffuse type

usually is associated with familial occurrence (42). It is considered

that high prevalence of stomach cancer in some Asian countries may

occasionally result in the chance of familial aggregation of CRC and

stomach cancer; the inclusion of stomach cancer in the criteria

might therefore decrease the certainty that we were dealing with

HNPCC (27).

Periodic screening of patients with Lynch syndrome and healthy

family members of HNPCC families is a secondary prevention of

carcinoma and may lead to reduction of morbidity and mortality.

Patients should be screened not only for CRC, but also for other

malignancy of HNPCC tumor spectrum.

The American College of Gastroenterology recommend that a

complete colonoscopy be performed in members of a family who

meet any of the revised Amsterdam criteria for Lynch syndrome

every 1-3 years beginning at the age of 20-25 years when the earli-

est cases of CRC can occur, until the of 40 years (40,43,44). From

40 years, yearly colonoscopy should then be performed (43,45).

Genetic tests are available for the diagnosis of Lynch syndrome

in families suspected of having the disease based on the revised cri-

teria (27). Unfortunately these tests are not available routinely in our

country. The first test should be perform in the youngest family

member with CRC (46). If the mutation is detected in the index

patient, then the accuracy of the test in family members approaches

100% since all family members inherit the same mutation. These

results are important to decide who needs colonoscopic screening.

Genetic tests for HNPCC are far from ideal, so periodical screening

of all family members of Lynch syndrome families have to be per-

formed until genetic tests become routinely available.

Lynch syndrome Arch gastroenterohepatol 2002; 21 (No 1 - 2): 5 - 8 7

50 CRC (transverse)

50 CRC (sigmold)

35 CRC (transverse)58 CRC (descending)62 GCa

54 CRC (cecum)

58 CRC (sigmold)

48 CRC(cecum)

39 CRC(cecum) 36 OCa52 CRC (cecum)

60 GCa

54 CRC (cecum)

60 CRC (cecum) 60 CRC

50 ECa

Figure 1. Pedigree of family "S". (CRC - colorectal cancer, GCa - gastric cancer; ECa - endometrial cancer; OCa - ovarian cancer)

8/6/2019 arhiv 2002

9/60


REFERENCES:

1. Souza RF. Review article: a molecular rationale

for the how, when and why colorectal cancer

screening. Aliment Pharmacol Ther 2001; 15:

451-62.

2. Warthin AS. Heredity with reference to carcino-

ma. Arch Intern Med 1913; 12: 546-55.3. Lynch HT, Watson P, Lanspa SJ, et al.Natural his-

tory of colorectal cancer in hereditary nonpolypo-

sis colorectal cancer (Lynch syndromes I and II).

Dis Colon Rectum 1988; 31: 439-44.

4. Vasen HFA, den Hartog Jager FCA, Menko FH,

Nagengast FM. Screening for hereditary non-

polyposis colorectal cancer. A study of 22 kin-

dreds in the Netherlands. Am J Med 1989; 86:

278-81.

5. Mecklin JP, Sipponen P, Jrvinen HJ.

Histopathology of colorectal carcinoma and ade-

nomas in cancer family syndrome. Dis Colon

Rectum 1986; 29: 849-53.

6. Rustgi AK. Hereditary gastrointestinal polyposis

and nonpolyposis syndromes. N Engl J Med

1994; 331: 1694-702.7. Lynch HT, Schuelke GS, Kimberling WJ, et al.

Hereditary nonpolyposis colorectal cancer (Lynch

syndromes I and II). II. Biomarker studies. Cancer

1985; 56: 939-51.

8. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The

International Collaborative Group on Hereditary

Non-Polyposis Colorectal Cancer (ICG-HNPCC).


9. Watson P, Lynch HT. Extracolonic cancer in

hereditary nonpolyposis colorectal cancer. Cancer

1993; 71: 677-85.

10.Fishel R, Lescoe MK, Rao MR, et al. The human

mutator gene homolog MSH2 and its association

with hereditary non-polyposis colon cancer. Cell

1994; 77: 167.11.Leach FS, Nicolaides NC, Papadopoulos N, et al.

Mutatuons of a mutS homolog in hereditary non-

polyposis colorectal cancer. Cell 1993; 75: 1215-

25.

12. Bronner CE, Baker SM, Morrison PT, et al.

Mutation in the DNA mismatch repair gene

homologue hMLH1 is associated with hereditary

non-polyposis colon cancer. Nature 1994; 368:

258-61.

13. Nicolaides NC, Papadopoulos N, Liu B, et al.

Mutations of two PMS homologues in hereditary

nonpolyposis colon cancer. Nature 1994; 371: 75-

80.

14. Malkhosyan S, Rampino N, Yamamoto H,

Perucho M. Frameshift mutator mutations. Nature

1996; 382: 499-500 (Letter).15. Yin J, Kong D, Wang S, et al. Mutation of hMSH3

and hMSH6 mismatch repair genes in genetically

unstable human colorectal and gastric carcinomas.

Hum Mutat 1997; 10: 474-8.

16.Liu B, Parsons RE, Hamilton SR, et al. hMSH2

mutations in hereditary nonpolyposis colorectal

cancer kindreds. Cancer Res 1994; 54: 4590-4.

17. Han HJ, Maruyama M, Baba S, Park JG,

Nakamura Y. Genomic structure of human mis-

match repair gene, hMLH1, and its mutation

analysis in patients with hereditary non-polyposis

colorectal cancer (HNPCC). Hum Mol Genet

1995; 4: 237-42.

18.Lynch HT, Smyrk TC, Watson P, et al. Genetics,

natural history, tumor spectrum, and pathology of

hereditary nonpolyposis colorectal cancer: an

updated review. Gastroenterology 1993; 104:

1535-49.

19. Marra G, Boland CR. Hereditary nonpolyposis

colorectal cancer: the syndrome, the genes, and

historical perspectives. J Natl Cancer Inst 1995;

87: 1114-25.

20. Lynch HT, Smyrk T, Lynch J.An update of

HNPCC (Lynch syndrome). Cancer Genet

Cytogenet 1997; 93: 84-99.

21. Jass JR. Diagnosis of hereditary nonpolyposis

colorectal cancer. Histopathology 1998; 32: 491-7.

22. Aaltonen LA, Salovaara R, Kristo P, et al.

Incidence of hereditary nonpolyposis coloectal

cancer and the feasibility of molecular screening

for the disease. N Engl J Med 1998; 338: 1481-7.23.Liu B, Parsons R, Papadopoulos N, et al. Analysis

of mismatch repair gene in hereditary non poly-

posis colorectal cancer patients. Nat Med 1996; 2:

169-74.

24.Nystrom-Lahti M, Wu Y, Moisio M, et al. DNA

mismatch repair gene mutations in 55 kindreds

with verified or putative hereditary non-polyposis

colorectal cancer. Hum Mol Genet 1996; 38: 763-

76.

25. Viel A, Genuardi M, Capozzi E, et al.

Characterization of MSH2 and MLH1 mutations

in Italian families with hereditary non-polyposis

colorectal cancer. Genes Chromosom Cancer

1997; 18: 8-18.

26. Weber TK, Conlon W, Petrelli NJ, et al. Genomic

DNA-based hMSH2 and hMLH1 mutation

screening in 32 eastern United States hereditary

nonpolyposis colorectal cancer pedigrees. Cancer

Res 1997; 57: 3798-803.

27. Vasen HFA, Watson P, Mecklin J-P, Lynch HT, and

the ICG-HNPCC. New clinical criteria for hered-

itary Nonpolyposis colorectal cancer (HNPCC,

Lynch syndrome) proposed by the International

Collaborative Group on HNPCC.

Gastroenterology 1999; 116: 1453-6.

28.Rodriguez-Bigas MA, Boland CR, Hamilton SR,

et al. A National Cancer Institute workshop on

HNPCC syndrome: meeting hihglights and

Bethesda guidelines. J Natl Cancer Inst 1997; 89:

1785-1792.

29.Anderson DE. An inherited form of large bowelcancer: Muir's syndrome. Cancer 1980; 45: 1103-

7.

30.Lynch HT, Lynch PM, Restep J, Fusaro KM. The

cancer family syndrome: Rare cutaneous pheno-

typic linkage of Torre's syndrome. Arch Intern

Med 1981; 141: 607-11.

31. Godard V, Coulet F, Bernaudin J-F, Housset M,

Soubrier F. Mutation oh MSH2 gene in Muit-

Torre syndrome. Ann Dermatol Venereol 1999;

126: 1-4.

32. Trimbath JD, Petersen GM, Erdman SH, Ferre M,

Luce MC, Giardiello FM. Caf-au=lait spots and

early onset colorectal neoplasia; a variant of

HNPCC? Familial Cancer 2001; 1: 101-5.

33. Nagorni A. Hereditary non-polyposis colorectal

cancer. Arch Gastroenterohepatol 1996; 15: 116-

22.

34.Lovett E. Family studies in cancer of the colon and

rectum. Br J Surg 1976; 63: 13-8.

35. Lynch PM, Lynch HT, Harris RE. Hereditary

proximal colonic cancer. Dis Colon Rectum 1977;

20: 661-8.

36.Mecklin JP, Jrvinen HJ. Clinical features of col-

orectal carcinoma in cancer family syndrome. Dis

Colon Rectum 1986; 29: 160-4.

37.Lynch HT, Watson P, Lanspa SJ, et al.Natural his-

tory of colorectal cancer in hereditary nonpolypo-

sis colorectal cancer (Lynch syndrome I and II).


38.Aarnio M, Salovaara R, Aaltonen LA, Mecklin J-

P, Jrvinen HJ. Features of gastric cancer inhereditary non-polyposis colorectal cancer syn-

drome. Int J Cancer 1997; 74: 551-5.

39. Vasen HFA, Offerhaus GJA, Den Hartog Jager

FCA, et al. The tumor spectrum in hereditary non-

polyposis colorectal cancer: a study of 24 kin-

dreds in the Netherlands. Int J Cancer 1990; 46:

31-4.

40.Lynch HT, Smyrk TC, Watson P, et al. Genetics,

natural history, tumor spectrum, and pathology of

hereditary non-polyposis colorectal cancer: an

updated review. Gastroenterology 1993; 104:

1535-49.

41.Aarnio M, Mecklin J-P, Aaltonen LA, Nystrom-

Lahti M, Jrvinen HJ. Life-time risk of different

cancers in hereditary non-polyposis colorectal

cancer (HNPCC) syndrome. Int J Cancer 1995;

64: 430-433.

42.Lehtola J. Family study of gastric carcinoma: with

special reference to histological types. Scand J

Gastroenterol 1978; 13 (suppl. 50): 1-54.

43. Rex DK, Johnson DA, Lieberman DA, Burt RW,

Sonnenberg A. Colorectal cancer prevention

2000: screening recommendations of the

American College of Gastroenterology. Am J

Gastroenterol 2000; 95: 868-77.

44. Terdiman JP, Conrad PG, Sleisenger MH.

Genetic testing in hereditary colorectal cancer:

indications and procedures. Am J Gastroenterol

1999; 94: 2344-56.

45. Jrvinen HJ, Mecklin JP, Sistonen P. Screening

reduces colorectal cancer rate in families withhereditary nonpolyposis colorectal cancer (see

comments). Gastroenterology 1995; 108: 1405-11.

46. Burt RW. Colon cancer screening.

Gastroenterology 2000; 119: 837-53.

8/6/2019 arhiv 2002

10/60

Aleksandar Nagorni,

Vuka Katic,

Jovica Milanovic,Vesna Zivkovic,

Goran Bjelakovic.

AbstractLynch syndrome (HNPCC-hereditary non-polyposis colorectal cancer) is an autosomal dominant inher-

ited disorder characterized by early onset of colorectal cancer (CRC), a preponderance of CRC in prox-

imal colon, occurrence of multiple CRC, mucinous and poorly differentiated adenocarcinoma. We report

family "S" with 11 (25.5%) affecting members. Metachronous CRC were observed in 27.2% affecting

members. In tumour spectrum of Family "S" there were stomach, ovarian and endometrial cancer.

Genetic tests are not routinely available in our country, so periodic screening of all family members have

to be perform according to recommendation.

Key Words:Lynch syndrome,

metachronous CRC,

stomach cancer

Saètak

Lynch-ov sindrom (HNPKK- hereditarni ne-polipozni kolorektalni karcinom) je autozomno domi-

nantni nasledni poreme}aj koji se karakteri{e ranim po~etkom kolorektalnog karcinoma (KRK), pre-

dispozicijom za proksimalni kolon, pojavom multiplih KRK, mucinozni i slabo diferentovani ade-

nokarcinomi. Saop{tavamo porodicu "S" sa 11 (25.5%) obolelih ~lanova. Metahroni KRK su

zapaèni u 27.2% obolelih ~lanova. U tumorskom spektru porodice "S" otkriveni su karcinomi

èluca, ovarijuma i endometrijuma. Genetski testovi jos uvek nisu rutinski dostupni u na{oj zemlji,

pa periodi~no pra}enje svih ~lanova porodice treba izvoditi u skladu sa preporukama.

Klju~ne re~i:

Lynchov sindrom,

metahroni KRK,

karcinom èluca

Abbreviations used in this article: CRC,colorectal cancer;

HNPCC,hereditary non-polyposis colorectal cancer; ICG

HNPCC,International Collaborative Group Hereditary Non-

Polyposis Colorectal Cancer; MMR,Mismatch Repair.

Professor: Aleksandar V. Nagorni, MD, PhD,

Clinic for gastroenterology and hepatology,

Clinical Center Nis,

48 Brace Taskovica St.,Yu-18000 Nis, Serbia, Yugoslavia.

Fax: +381 18 335 186



01732, 2002.



Clinic for Gastroenterology and Hepatology and

Clinic for Pathology, Clinical Center,Ni{


The Lynch syndrome: Report

on family "S"

Lynch-ov sindrom: Prikaz porodice "S"

( accepted June 20th, 2002 )

UVOD

Kolorektalni karcinom (KRK) je ~etvri naj~e{}i karci-

nom i drugi vode}i uzrok smrti od karcinoma u mnogim

zemljama {irom sveta. U proteklih nekoliko godina, ino-

vacije u molekularnoj biologiji i genetici KRK nisu

pro{irili samo na{e razumevanje bolesti, nego su

omogu}ili i shvatanje patogeneze sporadi~nog i naslednih

sindroma KRK (1).

Nasledni ne-polipozni KRK (HNPKK) je prvi put pre-

poznat 1895 godine. Poznati patolog Aldred Warthin je

tada ~uo od svoje {valje, koja je bila depresivna, jer je bila

uverena zbog porodi~ne anamneze, da }e jednog dana

umreti od karcinoma ènskih organa ili creva. Kao {to je i

predpostavila, umrla je u mladosti od karcinoma

endometrijuma. Warthin je 1913 godine publikovao

Porodicu G sa endometrijalnim, kolorektalnim i

èluda~nim karcinomom kao predominantnim maligniteti-

ma u ovoj porodici (2).

U slavu Henrija Lyncha-a, koji je ovaj problem

prou~avao sredinom {ezdesetih godina, Internacionalna

Kolaborativna Grupa za Nasledni Ne-PolipozniKolorektalni Karcinom (IKG-HNPKK) nazvala je

HNPKK njegovim imenom (Lynch sindrom).

Lynchov sindrom je autozomno dominantni sindrom

naslednog karcinoma koga karakteri{e razvoj KRK sa

po~etkom u ranim godinama, predominacijom karcinoma

u proksimalnim segmentima kolona, multiplim KRK,

sinhronim i metahronim KRK (3,4), slabo diferentovanim

i mucinoznim KRK (5,6). Lynchov sindrom je udruèn sa

8/6/2019 arhiv 2002

11/60

malim brojem adenoma koji su predominantno lokalizo-

vani u desnom kolonu (7). IKG-HNPKK je 1990 godine

predloìla "Minimalne amsterdamske kriterijume" da bi

olaka{ala klini~ku dijagnozu HNPKK (8). "Minimalni"

kriterijumi uklju~uju: 1) tri ili vi{e ro|aka sa KRK, jedan

je ro|ak prvog kolena srodstva drugoj dvojici, 2) oboleli

ro|aci obuhvataju dve ili vi{e generacija, 3) najmanje

jedan od ro|aka oboli od KRK pre 50-te godine ìvota (8).Osim KRK, bolesnici sa Lynchovim sindromom imaju

rizik da razviju ekstrakoloni~ne tumore uklju~uju}i karci-

nome endometrijuma, ovarjuma, uretera, èluca, karlice

bubrega, tankog creva, hepatobilijarnog trakta i koè, {to je

uklju~eno u modifikovane amsterdamske kriterijume (9).

Osnovni genetski defekt u Lynchovom sindromu je

defekt DNA rasparene popravke gena. U prisustvu nor-

malne DNA rasparene popravke, patolo{ki upareni nukleo-

tidi se isecaju o zamenjuju sa pravim parom nukleotidnih

baza. Me|utim, u prisustvu inaktivisanog sistema ras-

parene popravke, karakteristike Lynchovog sindroma,

gre{ke u sparivanju baze se mogu kumulorati i predisponi-

rati }eliju na malignu progresiju. Ova perzistentna gre{ka u

sparivanju baza DNA u bolesnika sa Lynchovim sindro-

mom je saop{tena kao "mutator" fenotip, "popravka rep-

likacione gre{ke", ili mikrosatelitna nestabilnost (1).

Identifikovano je 6 humanih gena koji u~estvuju u

funkciji rasparene popravke. Ovi geni uklju~uju hMSH2,

hMLH1, PMS1, PMS2, hMSH6 i hMSH3 (10-15), premda

su klicine mutacije u MSH2 i MLH1 obja{njenje za ve}inu

porodica sa Lynchovim sindromom (16,17).

PRIKAZ PORODICE

Na{e interesovanje za nasledni KRK je zapo~elo 1989

godine kada je 58-godi{nji mu{karaca (proband) primljen

na Kliniku za gastroenterologiju i hepatologiju Klini~kog

Centra Ni{ zbog intestinalnog krvarenja i promena

crevnom motilitetu. Prve tegobe su otpo~ele 6 meseci pre

prijema. Trideset godina ranije dijagnostikovan je ade-

nokarcinom transverzalnog kolona i ura|ena je desna

hemikolektomija. U isto vreme na Kliniku je primljen nje-

gov sin zbog jetrenih metastaza KRK, dve godine nakon

operacije adenokarcinoma cekuma. Kolonoskopija jeotkrila adenokarcinom descendentnog kolona na lijenalnoj

fleksuri. Dodatne analize: laboratorija, ultrazvuk abdome-

na, KT su isklju~ile {irenje bolesti i ura|ena je leva

hemikolektomija.

Zapo~eli smo sa sakupljanjem porodi~nih podataka i

sa~injeno je geneolo{ko stablo porodice "S" (Slika 1).

Proband je pra}en kolonoskopski i ultrazvu~no i 4 god-

ina nakon druge operacije zbog metahronog KRK, dijag-

nostikovan je èluda~ni karcinom (adenokarcinom) i

bolesnik je operisan.

Prikazujemo porodicu "S" posle vi{e od 10 godina

prikupljanja podataka.

Porodica "S" je brojala 43 ~lana, 11 (25.5%) ~lana su

obolela sa ukupno 16 malignih tumora. U 9 bolesnika su

otkrivena jedan ili vi{e KRK (metahroni), u dva ~lana

porodice otkriveni su po jedan karcinom èluca i ovariju-

ma. Ve}ina (12) malignih tumora su KRK, tako|e sudijagnstikovana i 2 karcinoma èluca i po jedan karcinom

endometrijuma i ovarijuma. U 3 (27.2%) obolelih ~lanova

porodice otkriveni su metahroni KRK, 4-23 godine nakon

dijagnostikovanja inicijalnog KRK. Najraniji po~etak

bolesti je otkriven u probanda (35 godina), u vi{e od

polovine obolelih bolesnika malignitet je otkriven pre 50-

te godine ìvota.

Otkriveno je 9 (75%) desno-stranih, i 3 (25%) levo-

stranih KRK. U jednog ~lana porodice metahroni, sig-

moidni KRK je bio mali (6 mm) zaravnjena promena

otkrivena 4 godine nakon operacije karcinoma cekuma. U

ve}ije slu~ajeva histologija je pokazala mucinozni i slabo

diferentovani adenokarcinom.

Proband se redovno kontroli{e i nema znake za

metahroni rast. Proband je zasluàn ne samo za na{e

interesovanje za nasledne karcinome, nego i za zdrave

~lanove porodice koji ga slede na redovnim gastroentero-

lo{kim i ginekolo{kim pregledima.

DISKUSIJA

Lynchov sindrom je nasledni autozomno dominantni

poreme}aj osetljivosti na kacinom sa veoma visokom

stopom penetracije od 80-85% (18-21). Ovaj sindrom

obja{njava oko 1-2% od svih KRK (22). Mutacije glavnih

gena rasparene popravke, MLH1 i MSH2 su otkrivene u

30-80% HNPKK srodnika razli~itog etni~kog porekla (23-

26). Do danas jedini poznati uzrok je nasledna mutacija

jednog od slede}ih gena rasparene popravke: hMSH2,

hMLH1, PMS1, PMS2, hMSH6, hMSH3 (10-15).

IKG-HNPKK na sastanku odrànom 1990 godine u

Amsterdamu je utvrdilo grupu selekcionih kriterijuma za

porodice sa Lynchovim sindromom da bi obezbedila

osnovu za jednolikost u kolaborativnim studijama.Vremenom su amsterdamski kriterijumu kritikovani. Neki

istraìva~i su ose}ali da kriterijumi isklju~uju neke

klasi~ne poorodice sa Lynchovim sindromom jer ne uzi-

maju u obzir ekstrakoloni~ne karcinome koji su tumorski

spektar ovog sindroma (8). Zaklju~eno je da bi mnoge

prave HNPKK porodice nedostajale ako bi se primenili

kriterijumi za klini~ku dijagnozu, a da porodica ne ispun-

java kriterijume i da bi se pogre{no ponovo uverili i


8/6/2019 arhiv 2002

12/60

isklju~ili iz genetskog savetovali{ta, DNA testiranja, ili

pra}enja (27). Da bi re{ili neke od ovih problema

Rodriguez-Bigas i sar. (28) su razvili dodatne kriterijume

koji uzimaju u obzir molekularne i patolo{ke osobine CRC

i adenoma uz porodi~nu anamnezu.

Uzimaju}i u obzir nove saop{tene podatke (17-21) IKG

je predloìla definiciju Lynchovog sindroma;

! Porodi~no gomilanje KRK i/ili karcinomaendometrijuma

! Udruèni kacinomi: karcinom èluca, ovarijuma,

uretera/bubre`ne karlice, mozga, tankog creva, hepa-

tobilijarnog trakta i koè (tumori lojnih `lezdi)

! Razvoj karcinoma u ranim godinama

! Razvoj multiplih karcinoma

! Osobine KRK: 1) predilekcija za proksimalni kolon;

2) pobolj{ano preìvljavanje; 3) multipli KRK; 4)

pove}ana proporcija mucinoznih tumora, slabo difer-

entovanih tumora, tumori sa zna~ajnom host limfoc-

itnom infiltracijom i limfoidnom agregacijom na

ivici tumora

! Osobine kolorektalnog adenoma: 1) broj varira od

jednog do nekoliko; 2) pove}ana proporcija adenoma

sa viloznim strukturom; 3) visok stepen displazije,

and 4) verovatno brza progresija od adenoma do kar-

cinoma

! Visoka u~estalost mikrosatelitne nestabilnosti (MSI-

H)

! Imunohistohemija: gubitak MLH1, MSH2, ili MSH6

ekspresije proteina

! Klicine mutacijegena rasparene popravke (MSH2,

MLH1, MSH6, PMS1, PMS2).

Novi klini~ki kriterijumi (Amsterdamski kriterijumi II-

Prera|eni IKG-HNPKK kriterijumi) su predloèni i prih-

va}eni od ve}ine ~lanova IKG-HNPKK (27):

! Najmanje tri ro|aka sa i HNPKK-udruènim karci-

nomima (KRK, karcinom endometrijuma, tankog

creva, uretera ili bubre`ne karlice)

! Jedan je ro|ak drugoj dvojici u prvom kolenu

! Najmanje dve uzastopne generacije su zahva}ene

! Najmanje jedan je dijagnostikovan pre 5o-te godine

! Porodi~na adenomatozna polipoza treba da se

isklju~i kod KRK

! Tumore treba verifikovati patolo{kim ispitivanjem.

Va`no je u diskusiji kriterijuma, da kriterijumi maju cilj

da obezbede zajedni~ku nomenklaturu za selekciju porod-

ica za studije i za upore|enje rezultata ovih studija.

Kriterijumi nisu stalni, menja}e se kako na{e znanje o

Lynchovom sindromu (27).

Postoji nekoliko formi ili varijanti HNPKK. Muir-

Torreov sindrom (6,29-31) se karakteri{e tumorskim spek-trom Lynchovog sindroma i ko`nim.

"Caf-au-lait fleke"(makularne, o{tro ograni~ene,

glatke, ovalno pigmentisane fleke, prisutne na ro|enju) je

druga varijanta Lynchovog sindroma (32), karakteri{e se

ranim po~etkom KRK, oligopolipozom, glioblastomom i

limfomom.

Iz nama dostupne literature ovo je prvi prikaz u na{oj

literaturi. Prikazana porodica "S" ispunjava "minimalne

amsterdamske (Amsterdamski kriterijumi I) i {rera|ene

IKG kriterijume (Amsterdamski kriterijumi II). Vi{e od

25% ~lanova porodice je zahva}eno malignitetima,

uklju~ene su tri uzastopne generacije. U 75% zahva}enih

~lanova KRK je otkriven proksimalno od lijenalne fleksure

i korelira sa literaturnim podacima (33-35). Metahroni

KRK su otkriveni 4-23 godine nakon inicijalnog KRK u

27.2% obolelih ~lanova porodice, ovaj nalaz korelira sa lit-

eraturnim podacima (36,37).

U 2 (18.3%) bolesnika otkriveni su karcinomi èluca.

Postoje dijametralni podaci u literaturi (27,38) o

uklju~ivanju karcinoma èluca u tumorski spektar

Lynchovog sindroma. Neki autori smatraju da je karcinom

èluca drugi naj~e{}i ektrakoloni~ni malignitet udruèn sa

Lynchovim sindromom (39,40). Kumulativni rizik karci-

noma èluca u predpostavljenih HNPKK nosioca gena je

procenjena na 19% (41). Predominacija intestinalnog tipa

èluda~nog karcinoma u porodicama sa Lynchovim sin-

dromom (kao i u na{em prikazu) je neo~ekivano jer difuzni

tip karcinoma èluca obi~no udruèn sa porodi~nim ispol-

javanjem (42). Smatra se da je visoka prevalenca karcino-

ma èluca u nekim azijskim zemljama moè povremeno

rezultirati slu~ajnom porodi~nom agregacijom KRK i kar-

cinoma èluca; uklju~ivanje karcinoma èluca u kriteri-

jume moè stoga da smanji sigurnost da postupamo sa

HNPKK (27).

Lynch syndrome Arch gastroenterohepatol 2002; 21 (No 1 - 2): 5 - 8 7

50 CRC (transverse)

50 CRC (sigmold)

35 CRC (transverse)58 CRC (descending)62 GCa

54 CRC (cecum)

58 CRC (sigmold)

48 CRC(cecum)

39 CRC(cecum) 36 OCa52 CRC (cecum)

60 GCa

54 CRC (cecum)

60 CRC (cecum) 60 CRC

50 ECa

Figure 1. Pedigree of family "S". (CRC - colorectal cancer, GCa - gastric cancer; ECa - endometrial cancer; OCa - ovarian cancer)

8/6/2019 arhiv 2002

13/60

Periodi~no pra}enje bolesnika sa Lynchovim sindro-

mom i zdravih ~lanova porodice je sekundarna prevencija

karcinoma i mo`e da dovede do smanjenja morbiditeta i

mortaliteta. Pacijente treba pratitit ne samo za KRK, nego

i na druge malignitete tumorskog spektruma HNPKK.

Ameri~ki Koled` Gastroenterologa je savetovao da se

izvr{i kompletna kolonoskopija u ~lanova porodice koji

izpunjavaju neki od prera|enih amsterdamskih kriterijumaza Lynchov sindrom svake 1-3 godine sa po~etkom od 20-

25 godine kada se najraniji slu~ajevi KRK mogu ispoljiti,

sve do 40-te godine (40,43,44). Od 40-te godine, treba

izvoditi kolonoskopije jednom godi{nje (43,45).

Za dijagnozu Lynchovog sindroma u sumnjivim

porodicama zasnovano na prera|enim kriterijumima dos-

tupni su geneski testovi (27). Na nesre}u ovi testovi nisu

rutinski dostupni u na{oj zemlji. Prvi test treba izvr{iti u

najmla|eg ~lana porodice sa KRK (46). Kada se otkrije

mutacija u indeksnog bolesnika onda ta~nost testa u ~lano-

va porodice dosti`e 100% po{to svi ~lanovi porodice

nasle|uju istu mutaciju. Ovi rezultati su va`ni za odluku kozahteva kolonoskopsko pra}enje. Genetski testovi za

HNPKK su daleko od idealnih, tako da periodi~no

pra}enje svih ~lanova porodice Lynchovog sindroma treba

da se sprovodi sve dok genetski testovi ne postanu rutinski

dostupni.


8/6/2019 arhiv 2002

14/60

1Miodrag N. Krsti},2Gradimir Golubovi},1

Marijan Micev,1Predrag Dugali},1Dragan Tomi},1Aleksandra Pavlovi}.

Abstract

The evaluation of patients with giant gastric rugal folds presents many problems to the gastroenterolo-

gist and pathologist. The variety of benign and malignant diseases must be considered in the differential

diagnosis and all of them are difficult to separate by means of endoscopy and even biopsy. The unique

ability of endoscopic ultrasound ( EUS ) to visualize the all layers of the gut wall makes it very useful

in assessing patients with large gastric folds. EUS can precisely define which layers are thickened, char-

acterise the echo pattern of thickness and whether the layer structure is preserved.

Mntrier's disease is a prototype disease wich caracterises deep mucosal thickening which can be clear-

ly delineated by EUS. Here, we report the very first case of Mntrier's disease which was assessed byEUS in our country. The role of EUS in differential diagnosis of large gastric folds is discussed in detail.

Key Words:

Menetrier's disease,

large gastric folds,

EUS.

Saètak

Evaluacija pacijenata sa uve}anim èluda~nim naborima je te{ka i za gastroenterologe i za patologe.

Veliki broj benignih i malignih stanja mora da se uzeme u razmatranje dok endoskopija, pa ~ak i

biopsija naj~e{}e ne mogu da napravi razliku izmedju njih. Endoskopski ultrazvuk je posebno pre-

cizan u prikazivanjui slojeva zida digestivnog trakta te se stoga se veoma uspe{no koristi u ispiti-

vanju pacijenata sa velikim èluda~nim naborima. On moè jasno da ukaè koji sloj je zadebljao,

kakva je ehogenost zadebljanja i postoji li o~uvan kontinuitet slojeva zida.

Menetrierova bolest je tipi~an predstavnik ove grupe obolenja i ona se odlikuje zna~ajnim zadebl-

janjem dubokog dela mukoze koje se jasno prikazuje na endosonogafiji. U radu je prikazan prvi

pacijent sa Menetrierovom bole{}u koji je u na{oj zemlji analiziran endoskopskim ultrazvukom. Uradu je takodje detaljno diskutovana uloga EUS-a u diferencijalnoj dijagnozi uve}anih nabora

èluca.

Klju~ne re~i:

Menetrierova bolest,

uve}ani èluda~ni nabori,

endoskopska ultrasonografija.

Abbreviations used in this article: :

LGF, large gastric folds; EUS, endoscopic ultrasound.

Docent Dr Miodrag N. Krstic,

Institute of Digestive Diseases,

Clinical Center of Serbia,

6 Koste Todorovica St, YU-11000 BelgradeSerbia, Yugoslavia



01730, 2002.

Alimentary tract and pancreasAlimentarni trakt i pankreas

1 Institute of Digestive Diseases,

Clinical Center of Serbia, Belgrade,2 Department of Internal Medicine.

Clinical Hospital Zemun, Belgrade.


Case report

Endoscopicultrasonoghraphy inMntrier 's disease

Prikaz slu~aja

Endoskopska ultrasonorafija uMenetrijerovoj bolesti

( accepted February 10th, 2002 )

`

8/6/2019 arhiv 2002

15/60

INTRODUCTION

The evaluation of the patients with giant gastric mucos-

al usually imposes many problems to the gastroenterolo-

gist, the pathologist and even surgeons (1). A large scale

of benign and malignant diseases should be considered in

the differential diagnosis (2). Standard endoscopic biopsy

is oftenly superficial for adequate histological diagnosis.

The unique ability of endoscopic ultrasound to visualize

the layers of the gut wall makes it very useful in assessing

such patients (3).

Menetrier's disease is a prototype disease in this cate-

gory with typical thickening of deep mucosa (4). Here, wereport a EUS finding in a patients with Menetrier's disease.

CASE REPORT

A middle aged man with Menetrier's disease was

refeered from Clinical Hospital Zemun for EUS assess-

ment in October 1999. The diagnosis of Menetrier's dis-

ease was established on previous hospitalization a couple

of months ago. He had typical symptoms: profound weght

loss, anorexia, voliting, diarrhoea as well as symetric

edema on legs. Biochemical blood tests disclosed iron-def-ficiency anemia and marked hypoalbuminemia (10mm) were

observed in the stomach body and fundus. Histology dis-

closed foveolar hyperplasia and glandular atrophy without

inflammation in lamina propria mucosae. Thus, the diag-

nosis of advanced Menetrier's disease was confirmed on

the basis of typical clinical, laboratory, endoscopical and

histology findings.

On EUS, extended and diffuse thickening of the secondlayer corresponding to deep mucosa was clearly demon-

strated. A strict preservation of five layer pattern of gastric

wall was observed, too. The depth of 3rd (submucosal) and

4th (muscle) layers was not changed. The thickeness of

2nd layer was inhomogenous and more hyperechoic.

DISCUSSION

A broad spectrum of malignant and benign stomach

diseases may clinically and endoscopically present with

giant mucosal folds (1-7). TABLE 1. Barium X ray stud-

ies, CT, MR are of no value in differential diagnosis of this

condition. In the majority of cases endoscopic biopsies are

not sensitive enough (3). Full-thickeness surgical biopsy

used to be the golden standard for diagnosis in past

decades.

However, EUS is highly accurate in visualisation of the

gut wall (3) Echo-endoscopes with 12MHz transducers

allows demonstration of the 5-layer gut wall structue

which almost completely correlates with anatomic layers

of the normal gut wall (I and II layer belongs to the

10 Arch gastroenterohepatol 2002; 21 (No 1 - 2): 9 - 12 Miodrag N. Krsti}

Figure 1. Menetrier disease: endoscopic view of large gastric folds

in body and fundus.Figure 2. EUS in Menetrier: thickening of II layer corresponding

to deep mucosa.

BEN IGN DISEASES MALIGNANT DISEASES

Menetrier's disease CarcinomaZollinger-Ellison syndrome LymphomaLymphocytic and Eosinophylic gastritis Lymphoma of MALTNormal hyperrugosity Carcinoid

Sarcoidoses and amyloidosesCrohn's diseaseTB and syphilisH.pyloris; CMV and H.simplex virus

Table 1. Classification of large gastric folds.

8/6/2019 arhiv 2002

16/60

mucosa; III layer ressembles submucosa, IV muscularispropria and V is adventitia or serosa). EUS can accurately

disclose the disruption in the continuity of the normal layer

pattern which is invariably observed in malignant diseases

(4,5). EUS can also determine with high sensitivity which

layers are thickened as well as ECHO pattern of such

enlargement (6). Infiltrative gastric neoplasms, such as

lymphoma or linitis plastica type carcinoma produce dif-

fuse thickening of all layers (6). Thus, EUS can facilitate

the differentation of benign from malignant aetiololgies (1-

6).

Recent studies confirmed this statement (7-10) Diffuse

thickening of all layers or significant enlargement of 4thlayer (muscularis propria) was recorded only in malignant

conditions (7). Diffuse enlargement of 3 and 4 layer (sub-

mucosa and muscularis propria) was present in patients

with scihirrous carcinoma (7,8). On the other hand, malig-

nancy did not develop in all patients with gastric wall

thickening limited to layer 2 (deep mucosa) during a mean

follow-up period of 35 months (8). When the second layer

alone is thickened, Mntrier's disease should be at first

considered as possible diagnosis and when third layer

alone is abnormally enlarged, anisakiasis might be sus-

pected (8). However, 2 and 3 layer enlargement may be

present in healthy subjects with hyperrugosity, but also in

patients with lymphoma (8,9). In all malignant conditions,

thickening of the second layer was hypoechoic, too (1-9).

EUS finding in our patient was typical: isolated, pre-

dominantly hyperechoic enlargement of second layer (deepmucosa) with preservation of 5-layer wall structure. These

features strongly suggested benign aetiology of giant gas-

tric folds, accoridng to the literature data (4-9). On the

EUS in Mntrier , s disease Arch gastroenterohepatol 2002; 21 (No 1 - 2): 9 - 12 11

Figure 4. Mntrier disease. Hystology show marked foveolar,

semicystic hyperplasia of deep mucosa (lamina propria mucosae).

Figure 3. EUS in Mntriers disease: Thickening of deep mucosa

with unchanged submucosa and muscularis propria.Figure 5. EUS in linitis plastica: uniform thickening of mucosa,

submucosa and muscularis propria; hypoechoic lamina propria

mucosae between black arrowheds; submucosa and muscularis

propria between white arrowheds.

Figure 6. EUS in linitis plastica: Thickening of whole gut wall`

`

8/6/2019 arhiv 2002

17/60

other hand, EUS finding in Menetrier's disease, although

typical is not pathognomonic and diagnosis cannot be

made with certainity without histology (8-10). Histologic

hallmark of diagnosis is marked elongation and turtuosity

of the pits (foveolar hyperplasia), accompanied by a reduc-

tion in the number of oxyntric glands. Lamina propria is

markedly edematous as well (10). Endoscopic biopsy may

not sample the full thickness of the mucosa thus revealing

only the foveolar hyperplasia. This is suggestive of diag-

nosis, but does not prove it (10).

Typical EUS finding in conjuction with foveolar hyper-

plasia on biopsy diminish the need for surgical biopsy

(10). It can provide reassurance that Menetrier's disease is

likely or at least that thickened folds are benign (10). In our

case this was confirmed too.

12 Arch gastroenterohepatol 2002; 21 (No 1 - 2): 9 - 12 Miodrag N. Krsti}

REFERENCES:

1. Yasuda K. High-resolution endoluminal sonogra-

phy of the upper gastrointestinal tract: The radial

scanning ultrasound probe. Part II. In: Van Dam J,

Sivak MV. Gastrointestinal endosonography.

Philadelphia: W.B.Saunders; 1999;95-100.

2. Yasuda K. The handbook of endoscopic ultra-

sonography in digestive tract. Ied. Oxford.:Blackwell Science; 2000.

3. Dancygier H, Lightdale C, Stevens P. Endoscopic

ultrasonography of the upper gastrointestinal tract

and colon. In: Dancygier H, Lightdale J.

Endosonography in gastroenterology Ied.

Stuttgart-New York: Thieme-Verlag; 1999; 13-

174.

4. Michael B. Kimmey, Peter Vilmann: Endoscopic

ultrasonography In. Yamada, et al: Textbook of

gastroenterology VIed. Philadelphia : Lippnicott

Wiliams and Wilkins; 1999; Chapter 136.

5. Carletti G, Fusaroli P, Bocus P. Endoscopic

Ultrasonography. Digestion 1998; 59: 509-530.

6. Chak A. Endoscopic Ultrasonography. Endoscopy

2000; 32: 146-152

7. Mendis RE, Gerdes H, Lightdale C, et al. Largegastric folds: a diagnostic approach using endo-

scopic ultrasonography. Gastrointestinal Endosc

1994;40:437-441.

8. Songur Y, Okai T, Watanabe H, et al.

Endosonographic evaluation of giant gastric folds.

Gastrointestinal Endos 1995; 41: 468-474.

9. Manuory V, Klein O, Houcke ML, et al.

Endoscopic ultrasonography in the diagnosis of

hypertrophic gastropathy (letter).

Gastroenterology 1994; 106:820.

10. Okuda M, Iiyuka Y, Oh K, et al. Gastritis cystica

profunda presenting as giant gastric mucosal

folds. The role of endoscopic ultrasonography and

mucosectomy in the diagnostic work up.

Gastrointestinal Endosc 1994; 40: 640-44.

8/6/2019 arhiv 2002

18/60

Zoran Krivokapic,

Radoje Colovic,

Nikica Grubor,Marjan Micev

Abstract

Stenosis of the small bowel due to mesenteric ischemia is rare and, to our best knowledge, a case of the

entero-enteral fistula caused by that condition has not been described in literature so far. According to

the clinical picture, patological features and localization, small bowel ischemic strictures can be divided

into two groups: First, where ischemia goes unnoticed with symptoms only when intestinal stenosis is

developed and where a short segment of the bowel is affected, and second, with episodes of acute

ischemia followed by asymptomatic periods as well as by symptoms of intestinal obstruction, where

the involved segment is longer and usually localized in jejunum. The diagnosis is based on the history,

enteroclysis and pathohystological examination. In the differential diagnosis Crohn's disease and others

causes of the acquired stenosis of the small bowel have to be considered. The therapy is surgical imply-

ing the removal of the stenosed segment of the small bowel with the additional angioplastical operation,

when necessary.

We present a case of 66-year old patient previously treated for mesenteric vascular occlusion with instil-

lation of Novocain solution in the radix of the mesentery. The diagnosis of intestinal stenosis was estab-

lished by upper GI series and confirmed itraoperatively. Double jejunal stenosis was found. Segmental

resection of the affected intestine and end-to-end anastomosis were performed. Examination of the

resected specimen revealed a jejuno-jejunal fistula in the stenotic segments. Crohn's disease was ruled

out. The postoperative course was uneventful and the patient was discharged several days later. He is

symptom-free three months after surgery.

Key Words:

mesenteric ischemia,

intestinal obstruction,

entero-enteral fistula.

Professor Dr Zoran Krivokapi}

Instut za digestivne bolesti, KCS

6 Koste Todorovica Str,

YU-11000 Beograd, Serbia, Yugoslavia.Tel./Fax: +381 11 361 8669



01728, 2002.



Institute for Digestive Diseases,

Clinical Center of Serbia, Belgrade.


Stenosis of the small intes-

tine and entero-enteral fistu-la due to mesenteric vascu-

lar occlusion

Stenoza tankog creva i entero-enteralna

fistula prouzrokovani mezentericnomvaskularnom okluzijom

( accepted April 24th, 2002 )

8/6/2019 arhiv 2002

19/60

Ischemic disease of the small intestine is not frequent.

In the acute form it is characterized with high mortality

(over 50%). To our best knowledge, small bowel stenosis

due to mesenterial ischemia is rare, while entero-enteral

fistula caused by ischemia has not been described until

now.

CASE REPORT

Four months before admission to our institution, the

patient, a 66 years old man, undergone emergency explo-

rative laparatomy due to simptoms and signs of mesenteric

ischemia. The patient has passed medical history of arter-

ial hypertension for about 30 years. He experienced acute

myocardial infarction in 1979, and in 1983 a triple arterio-

coronary bypass due to coronary disease. He never used

digitalis or potassium chloride medication. At operation

mesentery radix was infiltrated with Novocain solution

resulting in improvement of bowel perfusion thus making

the bowel resection unnecessary. Three months later he became pyrexial. Nausea and protracted diarrhoea

appeared as well.

During the following month, most of the symptoms

abated except abdominal colic, malaise, and progressive

weight loss. Physical examination revealed no abnormali-

ties except mild tenderness of the lower abdomen.

Laboratory findings were within the normal limits. Plain

abdominal x-ray films demonstrated air-fluid levels.

Barium enema and sygmoidoscopy were suggestive of

14 Arch gastroenterohepatol 2002; 21 (No 1 - 2): 13 - 17 Zoran Krivokapi}

Saètak

Stenoze tankog creva prouzrokovane mezenterijskom sudovnom ishemijom su retke. Prema na{em

uvidu u medicinsku literaturu slu~aj entero-enteralne fistule prouzrokovane ovakvim stanjem do

sada nije opisan. Zavisno od klini~ke slike, patolo{kih promena i lokalizacije, ishemijske strikture

tankog creva mogu da se podele u dve grupe. U prvu grupu spadaju ishemije koje prolaze klini~ki

nezapaèno i koje se ispoljavaju tek onda kada nastanu simptomi stenoze tankog creva. U drugoj

grupi su slu~ajevi u kojih su epizode crevne ishemije manifestne i iza kojih sledi asimptomski peri-od sve do ispoljavanja simptoma i znakova stenoze tankog creva. Dijagnoza se zasniva na ana-

mneznim podacima, enteroklizi, i patohistolo{kom pregledu reseciranog dela creva. U diferencija-

lnoj dijagnozi uvek treba da se razmotri Crohn-ova bolest i drugi uzroci ste~enih stenoza tankog

creva. Le~enje je hirursko i podrazumeva odstranjenje stenozantnog segmenta sa dodatnom

angioplastikom ukoliko je to indicirano.

U radu se prikazuje slu~aj pacijenta ìvotne dobi 66 godina koji je prethodno bio le~en od mezen-

terijske vaskularne okluzije instilacijom Novocaina u radiks mezenterijuma. Dijagnoza intestinalne

stenoze je postavljena radioloskim pregledom alimentarnog trakta. Itraoperativno je otkrivena

dvostruka stenoza jejunuma. Segmentna resekcija izmenjenog dela creva i termino-terminalna anas-

tomoza je bila na~injena. Pregled reseciranih delova creva je otkrio jejuno-jejunalnu fistulu u

stenoticnom segmentu. Crohno-va bolest je bila isklju~ena. Postoperativni tok je bio bez kom-

plikacija i pacijent je otpu{ten desetog dana izle~en.

Klju~ne re~i:

mesentrijska ishemija,

intstinalna opstrukcija,

entero-enteralna fistula.

Figure 1. Enteroclysis showing two jejunal stenosis with

prestenotic dilatations.

8/6/2019 arhiv 2002

20/60

dolichocolon. Examination of the small intestine with ente-

roclysis showed presence of two jejunal stenosis with large

prestenotic dilatations. Doppler ultrasonography of portal

system did not reveal any pathological findings. There

were no signs of thrombosis, decreased flow or presence of

collateral venous vessels. Abdominal aortography and

selective visceral angiography showed: stenosis of the

coeliac trunc up to 60-70%, occlusion of superior mesen-

teric artery in the middle part with rich collateral vascular-

isation and an arcus of Riolan that vascularised the coecum

with normal features of mesenteric and portal veins.

Accordingly, mesenteric ischemia was recognized as the

aetiological factor. The patient was operated on

26.07.1999. After the adhesions were removed a subtotal

occlusion of the small intestine, 80-100 cm of Treitz andan intestinal jejuno-jejunal fistula was found. Resection of

the affected segment of the small intestine was performed

in the length of 70 cm with a stapled side-to-side anasto-

mosis. Postoperative recovery was uneventful. The patient

was discharged 9 days after the operation and was symp-

tom-free at the time. On the last follow-up examination the

patient had no complaints. Histopathological examination

of the resected part of the small intestine showed chronic

inflammation of the mucosa with ulceration, Crohn's dis-

ease-like chronic lymphocytic inflammation of the submu-

cosa without granulomata or other histopathological fea-

tures of Crohn's disease. This was nonspecific finding thatmight correspond to the ischemic origin of the changes.

DISCUSSION

Mesenteric ischemia can be chronic, with functional

bowel changes (malabsorption), but without impaired

intestinal vitality or acute, where ischemic damage of the

bowel is so severe that jeopardizes the vitality of the intes-

tine thus leading to structural changes. In the acute mesen-

teric ischemia, ischemic damage may vary from transientimpairment of the bowel function to transmural ischemic

necrosis resulting in intestinal perforation. Between these

two extremes is the so-called "subnecrotizing ischemia",

when ischemic lesion does not damage all layers, but the

mucosa only, which is the most vulnerable (1). Resistance

to ischemic damage rises from the lumen inside out. The

level of ischemic damage progression depends on the

degree of ischemia and of efficacy of compensatory mech-

anisms. When ischemic damage reaches the lamina mus-

cularis mucosis, then it leads to formation of fibrous tissue

and, subsequently, to retraction and formation of the bowel

stenosis (2). Acute mesenteric ischemia usually is sosevere that in more than 50% cases of cases it ends lethal-

ly (3). All causes of acute mesenteric ischemia belong to

Entero-enteral fistula due to mesenteric occulsion Arch gastroenterohepatol 2002; 21 (No 1 - 2): 13 - 17 15

Figure 2. Abdominal aortography and selective visceral angiogra-

phy showing stenosis of the celiac truncus, occlusion of superior

mesenteric artery with rich collateral vascularisation.Figure 3. Stenosed jejunal segment with large prestenotic dilata-

tion.

Figure 4. Resected specimen showing stenosis of the small bowel

with prestenotic dilatation and jejuno-jejunal communication

(fistula).

8/6/2019 arhiv 2002

21/60

this type of ischemic damage. Thrombosis of the superior

mesenteric vein is very rare (4). Embolisation of the supe-

rior mesenteric artery (SMA), thrombosis of the SMA,

nonocclusive ischemic disease and, especially, focal seg-

mental ischemia are causes of ischemic intestinal strictures

( 5,6,7). In embolisation of the SMA major emboli may be

present in 85-90%, usually lodged in the beginning of ileo-

colic artery and minor emboli, present in 10-15%, in thedistal part. The latter are mostly the cause of intestinal

stenosis (2). Experimental studies support that opinion.

Embolisation of branches of the SMA in dogs with gelatin

sponges provoked segmental intestinal stenosis (8).

Reasons for focal segmental ischemia of bowel include

atheroembolism, strangulated hernias, vasculitis, blunt

abdominal trauma, segmental venous thrombosis, radio-

therapy, drugs (oral contraceptives, digoxins, NSAID,

cocaine) where, due to a range of damage of the intestinal

vascular bed, adequate collateral circulation prevents

transmural necrosis of small intestine (2,9.10). That is the

reason why acute focal segmental ischemia is probably the

most common cause of the ischemic bowel stenosis.

Clinical manifestations of mesenteric ischemia correlate

with the level of ischemic damage of the bowel, and less

with the underlying cause (2).

Based on histopathological findings, clinical picture

and evolution of the disease, we can divide all acquired

ischemic strictures of the small bowel into two major types

(11):

1) Asymptomatic form of mesenteric ischemia. This

clinically manifests with insidously but progressively

developing intestinal obstruction. Usually short segment of

the small intestine is affected (usually middle or terminal

ileum). .

2) Symptomatic form is when symptoms and signs of

the acute mesenterial ischemia are present from the begin-

ning. This was followed by asymptomatic period and grad-

ually developing symptoms and signs of the intestinal

occlusion thereafter. In this case larger part of the bowel,

oftenly jejunum, is affected.

It is not always possible to make a clear distinction

between these two types of intestinal ischemic strictures,

since transitive forms and variations are not rare

(5,7,12,13). Our patient, however, fits into to this classifi-cation. Kradijan and associates described 6 patients with

large ischemic lesions of the small intestine who had an

asymptomatic phase followed by clinical picture of ileus

and perforation in two cases. The strictures were localized

in the ileum and involved short segments up to 3 cm in

length, with normal appearance of bowel under stenosis.

The confusion is produced by the fact that 5 of 6 patients

had enteric-coated potassium chloride in therapy, later

found to be the culprit of formation of strictures and bowel

perforation, while the lesions completely matched the

lesions accompanying this form of medication, in their

appearance (pylorus-like annular and tubular stenoses) and

localization (distal ileum) (14).

It difficult to determine why ischemic stricturing is

more frequent in certain portions of the small intestine.

This is partly due to poor vascularisation of the terminal

part of the ileum and rich vascularization of the jejunum.That is the reason why larger segment of the jejunum can

be involved with ischemic process without causing a per-

foration, but only stenosis. Macroscopic and radiographic

appearance of this type, where stenosis involves long seg-

ments of the small bowel, is similar to findings in the

Crohn's disease. Therefore, histopathological examination

is necessary for differential diagnosis (1,5,11).

It is important to distinguish ischemic strictures from

nonischemic ones due to Crohn's disease, neoplasm, other

inflammatory tumors (for example, acute pancreatitis), use

of enteric-coated potassium chloride, and cause of intesti-

nal ischemia: trauma, irradiation, mechanical occlusion,

vasculitis, drugs (NSAID's, digitalis, oral contraceptives),

embolisation or thrombosis of the mesenteric artery,

because further treatment depends on this (7,15).

The diagnosis of the intestinal stenosis is simple.

Contrast radiography of the small bowel is the diagnostic

modality of choice in such a case (16). Ischemic small

intestinal lesions may often be the cause of the acquired

small bowel stenosis and therefore angiographic examina-

tions are necessary to diagnosed it.

The treatment includes resection of strictured segment

of the small intestine and end-to-end anastomosis. Also,

depending on the cause of ischemia, reconstructive surgery

of mesenteric arteries directed towards improvement of

perfusion of mesenteric vascular bed is required, as well

discontinuation of related drugs. Therefore, depending of

the cause of intestinal stenosis the type of treatment is not

limited only to resection of stenotic segment.

In conclusion, our case of double jejunal stenosis and

jejuno-jejunal fistula was caused by mesenteric ischemia,

namely SMA thrombosis, which was of limited range due

to the localization and previous intraoperative Novocain

treatmen. According to these facts and to angiographyfindings, which showed well developed collateral circula-

tion, the treatment was limited to resection of the stenotic

segments. The continuity of digestive tract was established

with termino-terminal jejuno-jejunal anastomosis.

16 Arch gastroenterohepatol 2002; 21 (No 1 - 2): 13 - 17 Zoran Krivokapi}

8/6/2019 arhiv 2002

22/60

Entero-enteral fistula due to mesenteric occulsion Arch gastroenterohepatol 2002; 21 (No 1 - 2): 13 - 17 17

REFERENCES:

1. Wayt DM, Helwig EB: Small-bowel ulceration-

iatrogenic or multifactorial origin? Amer J Clin

Path 1968,49:26-40.

2. Brandt LJ, Smithline AE: Ischemic lesions of the

bowel. In Feldman M, Sleisenger MH,

Scharschmidt BF (eds): Sleisenger and Fordtran's

Gastrointestinal and Liver Disease:

Pathophysiology, Diagnosis, Management, ed 6.

Philadelphia, WB Saunders, 1998, pp 2009-2024.

3. Bastidas JA, Reilly PM, Bulkley GB: Mesenteric

vascular insufficiency. In Yamada Y, Alpers DH,

Owyang C et al (eds): Texbook of

Gastroenterology, ed 2. Philadelphia, JB

Lippincott, 1995, pp 2490-2523.

4. Eugene C, Valla D, Wesenfelder L et al. Small

intestine stricture complicating superior mesen-

teric vein thrombosis. A study of three cases. Gut

1995; 37: 292-5.

5. Feurle GE, Haag B. Acute small bowel ischemia

without transmural infarction. Z Gastroenterol

1991; 29: 349-52.

6. Thaker P, Weingarten L, Friedman IH. Stenosis of

the small intestine due to nonocclusive ischemic

disease. Arch Surg 1977; 112: 1216-7.

7. Saegesser F, Borgeaud J, Schnyder P et al.

Stenosis of the small intestine of ischemic origin

in the adult. Schweiz Med Wochenschr 1976; 106:

367-76.

8. Cho KJ, Schmidt RW, Lenz J. Effects of experi-

mental embolization of superior mesenteric artery

branch on the intestine. Invest Radiol 1979; 14:

207-12.

9. Allen JC. Post-traumatic small bowel obstruction.

J R Army Med Corps 1994; 140: 47-8.

10.De Backer AI, De Schepper AM, Vaneerdeweg W,

Pelckmans P. Intestinal stenosis from mesenteric

injury after blunt abdominal trauma. Eur Radiol

1999; 9: 1429-31.

11.Mozes M, Adar R, Tsur N et al. Intestinal obstruc-

tion due to mesenteric vascular occlusion. Surg

Gynecol Obstet 1971; 133: 583-7.

12.Haraguchi M, Matsushima S, Fujie Y, Sugimachi

K: Ischemic stricture of the jejunum-report of a

case. Jpn J Surg 1990,20:715-719.

13.Kradjian RM. Ischemic stenosis of small intes-

tine. Arch Surg 1965; 91: 829-34.

14. Grosdidier J, Boissel P, Bresler L, Vidrequin A.

Stenosing and perforated ulcers of the small intes-

tine related to potassium chloride in enteric-coat-

ed tablets. Apropos of 11 cases. Chirurgie 1989;

115: 163-9.

15.Kato T, Morita T, Fujita M et al. Ischemic stricture

of the small intestine associated with acute acute

pancreatitis. Int J Pancreatol 1998; 24: 237-42.

16. Ginai AZ, Hussain SM, Hordijk ML, den

Hollander JC. Case report: solitary ischaemic

small bowel stenosis. Br J Radiol 1994; 67: 405-7.

17.Lietz H, Meissner K. Mysterious segmental steno-

sis of the small intestine. Dtsch Med Wochenschr

1982; 107: 299-303.

8/6/2019 arhiv 2002

23/60

1Tamara Vukavi},1M. Stoji},2

Ljiljana Savi},2Ivica Stankovi},3M. Peroevi},4K. Ajdànovi},5Lj. Stoli}6B. Kaì}.

Abstract

Oral rehydration is a mainstay of treatment for acute diarrhoea, both, in developing and in industrialized

countries. ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition)

Working Group on Acute Diarrhoea initiated European multicentre survey covering main aspects of the

management of water and electrolyte losses and refeeding. Yugoslavia was one of 29 countries partici-

pating from Europe. The results showed that physicians often advice oral rehydration solution - ORS

(Yugoslavia 70%, others 84%), less frequently ORS with 60 mmol/L sodium (Yugoslavia 62%, others

66%), and seldom practice fast rehydration over 3-4h (Yugoslavia 15%, others 16%). Advice for contin-

ued supplementation with ORS for watery stools after initial fast rehydration varies among physicians(Yugoslavia 93%, others 37%). Reintroduction of normal diet after fast rehydration is not in a frequent

practice (Yugoslavia 6%, others 21%). Contrary to ESPGHAN recommendations, lactose-free or lactose-

free cow's milk protein-free formula is recommend often (Yugoslavia 51% and 24%, others 35% and

19%, respectively). However, breast-feeding is continued at high rate (Yugoslavia 96%, others 77%).

Physicians also advise antidiarrhoeal drugs (Yugoslavia 47%, others 25%), antibiotics and probiotics

(Yugoslavia 79.6% and 60%).

Key Words:

acute gastroenteritis,

treatment,

infant,

Yugoslavia.

Saètak

Oralna rehidracija ~ini osnovu terapije kod akutne dijareje u nerazvijenim i u razvijenim zemljama. Radna

grupa za akutnu dijareju Evropskog udruènja za de~iju gastroentrologiju, hepatologiju i ishranu

(ESPGHAN), pokrenula je multicentri~nu evropsku studiju za primenu prepopruka za nadoknadu vode i

elektrolita i realimentaciju nakon inicijalne rehidracije, u kojoj je Jugoslavija bila jedna 29 zemalja

u~esnica zapadne, centralne i isto~ne Evrope. Ispitivanje je pokazalo da lekari ~esto

arhiv 2002

Documents

Transcript of arhiv 2002