Transcript Document

….. 12 YEARS OF BASIC-CLINICAL H PYLORI CONTROVERSIES…. CONCEPCION GROUP
GASTROENTEROLOGY - INTERNAL MEDICINE DEPT. FAC. OF MEDICINE. CONCEPCION UNIVERSITY
Dr. Fernando Kawaguchi (1,2,3)
Dr Patricio Ortiz(1)
DR Carlos Briceño(1)
Dr Fernando Riquelme(1)
Dr Rodrigo Loaiza(1)
Dr Gonzalo Zuloaga(1)
Dr Germán Abrigo(1)
Dr Vicente Vera(1)
Dr Germán Errazuriz(4)
Dra Apolinaria García(2)
Dr Carlos Gonzalez(2)
Mag Juan Luis Castillo(2)
Mag Marcelo Castillo(1)
Dra CG Yañez(3)
Dr Guillermo Venegas(1)
Dr Alberto Rossle(1)
Dr Oscar Venegas(1)
Dr. Jaime Madariaga Boero (1)
Dra. Alejandra Martínez, MsSc(2)
Prof Jorge Roa Sandoval, PhD (1)
EU Edith Vega(3)
EU Lorena Ruiz(1)
ET ALS. Ignacio Alfaro Pérez, Tamara Perez, Nelson
Perez Lynch, Marcela Lefer, Cristián Vasquez
1)
FACULTY OF MEDICINE AND HOSP. REGIONAL CONCEPCION
(2)
FACULTY OF CS. BIOLOGY
(3)
HOSPITAL TRABAJADOR CONCEPCION
(4)
HOSPITAL OF PUERTO MONTT
THE H. PYLORI YING-YANG
WGCOG MONTREAL 2005
P
H
FIRST CONTROVERSY
40%
70%
30%
50%
90% 70%
30%
70%
90%
80%
70%
70%
60%
70%
20%
BASIC MECHANISM TO CLINICAL H.PYLORI –THE ORGANISM- NOVEL ACQUISITIONS.
THE AMPHIBIOTIC RELATIONSHIP OF HELICOBACTER PYLORI AND HUMANS.
G. Venegas MD Research Chief Departament Pediatric.
VS
BASIC MECHANISM TO CLINICAL H.PYLORI –THE ORGANISM- NOVEL ACQUISITIONS. H. PYLORI
PATHOGENIC FLORA.
C. Gonzalez PhD Dean of. FACULTY SCS. BIOLOGIC.
DEPARTMENT MICROBIOLOGY
CONCEPCION UNIVERSITY WGCOG MONTREAL 2005
The amphibiotic relationship of Helicobacter pylori and Humans
G. Venegas MD Research Chief Departament Pediatric
•
¿Risk or Benefit?
•Beneficts
against
(potencially
lethal)
diarrheal
diseases in
childhood .
•Development of
ulcer diseases.
•Development of
gastric
malignances
•Decrease the
risk of GER
disease and
especially its
pre-malignant
sequelae.
Is it advisable to eradicate to HP of gastric mucosa?
BASIC MECHANISM TO CLINICAL H.PYLORI –THE ORGANISM- NOVEL
ACQUISITIONS. THE AMPHIBIOTIC RELATIONSHIP OF HELICOBACTER PYLORI
AND HUMANS. G. Venegas MD Research Chief of Medicine
Microbe have classically been considered to have either parasitic or symbiotic relationship with their
hosts.
However , circumstances arise in which either of these relationship can occur between a given host and
microbe, depending on context.
The indigenous microbial biota of humans provide numerous examples of this phenomenon, which hass
been termed “ amphibiosis” .
However these organisms often leave the mucosal surface and are transiently present in the bloodstream,
which in particular hosts leads to endocarditis.
Since these organisms have both symbiotic and pathogenic properties , depending on context .
Term “ amphibiotic relationship ” is appropriate.
The paradigm involving a-hemolytic streptococci also illustrates how a microbe can be NON
PATHOGENOUS early in life, but have its major expression as a PATHOGENOUS later in life.
There is increasing evidence that Helicobacter pylori has colonized the gastric mucosa of humans since time immemorial,
just as other Helicobacter and related species colonize all mammalian hosts studied to date.
Such colonization in human populations has progressively declined, concomitant with improving living standard , and
probably accelerated by the widespread use of antibiotics.
This shift has been a major change in human ecology , and parenthetically probably reflects other similarly massive but
still-hidden shifts in our micro-ecology.
From numerous studies, it is clear that carriage of H. Pylori has cost to humans , chiefly in the form of ulcer disease, and
gastric malignances , all of which predominantly occur after reproductive age.
The potential benefits of H. Pylori colonization also are emerging, in the course of contemporary research.
Specially interesting is the concept that H. Pylori may provide benefits against (potentially lethal) diarrheal diseases in
childhood.
Mechanisms by which this may occur.
VS
.
HP
Pathogen or commensal flora
C. Gonzalez PhD DEAN
FACULTY BIOLOGY SCIENCES
Before
*Ancient
organism that
evolved to inhabit
the ecological
niche of gastric
mucus .
*Probably it has
always induced an
inflamation but
without
consequences.
Now
Cancer
Ulcers
Gastritis
Gastric Acid
Production
Changes in diet
(+)
Lost intestinal
parasites that
supress acid
production
* Pathogen Organism
Aging of
population
=
*Increased reflux and
increased risk of a
very rare tumour , like
the gastric cancer of
the cardia.
*Changes in microbial
flora by use of
antibiotics.
Conclusion: H. pylori was a COMMENSAL. But, now is a major
PATHOGEN and SHOULD NOT BE SAVED !!!.
In the previous abstract, were outlined the arguments for the gastric
Helicobacter Pylori as a member of the human commensal flora.
This arguments are very convincing and I completely agree with him.
H pylori is a very ancient organism that evolved to inhabit the ecological
niche of gastric mucus(sialomucin), just as the mucus of the lower bowel
became colonised with bacterias from gut flora.
The local environment changed such that now the infection damaged
the host.
Probably it was commensal flora.
But actually it is a pathogenic flora.
H pylori evolved to its human host as normal flora but then... host
changed.....
Gastric cancer was very rare as the host usually died before they were
30-40 years old.
Thus with no cancer and no ulcers, H. Pylori caused no disease and so
fulfilled most of the criteria of the commensal flora.
So what changed?
Our hypothesis , substantiated by much circumstantial evidence, is that
the human host started to make slightly more gastric acid due to changes
in diet and lost intestinal parasites known to supress acid production.
This lead firstly to the bacterium causing gastric ulcers and
later duodenal ulcers .
Another consequence in this improvement in health is that life expectancy increased and, as
people lived past their forties , gastritis progressed to cancer as long as certain dietary
factors were also present .
Infection with H.pylori now possed significant risk of cancer and could cause ulcers in
around 10% of the population in their lifetime.
H. Pylori was no longer a commensal
¡ A further consequence of a develop society it that we lost immunological
tolerance to our own H. Pylori .
My learned opponent has sought to claim a link between this loss of H. Pylori and the
increase of cardia cancer and based on this bacterium as commensal flora.
He has choosen the benefit of this organism to human and suggest that we should be
cautious with respect to its removal .
H. pylori WAS a commensal. But now is a major PATHOGEN and SHOULD
NOT BE SAVED!!!.
SECOND CONTROVERSY
H. PYLORI-PREVALENCE. FACTORS ASSOCIATED WITH
DISAPPEARENCE H.P. IN THE FAR EAST.
R. Loaiza, MD. Gastroenterology Section, Internal Medicine
VS
DIFFERENCES IN PREVALENCE OF H.PYLORI ACCORDING TO RACE
ENVIROMENTAL FACTORS.
F. Riquelme, MD. Gastroenterology Section, Internal Medicine
H. PYLORI-PREVALENCE. FACTORS ASSOCIATED WITH DISAPPEARENCE H.P. IN THE FAR
EAST. R. Loaiza, MD. Gastroenterology Section, Internal Medicine
• Improvement in sanitary
and hygienic conditions .
72.2 %
39.5 %
1974
1994
HP infection
What
Happened
in these
20 years?
•( Main reason).
THE ANSWER COULD BE
•Antimicrobial therapy has
probably contributed only a
small part in the control of H.
pylori infection.
< Infected by HP.
R.I.P.
•By the way, in the last 20
years It has been observed,
some changes in diseases
asociated with HP.
What are
the
changes?
•
Peptic Ulcers
•
Gastric cancer
•
EGR.
It´s Really!! H. pylori is dissappearing even in Asia
While existing data are few , epidemiological data from Japan showed that
the prevalence of H. pylori infection has dropped dramatically in the last
20 years from 72,2% in 1974 to 39.35 in 1994.
Peptic ulcer diseases and gastric cancers are both declining in Asia,
whereas gastro-esophageal reflux diseases may be on the rising trend.
Interestingly , the disappearence of H. pylori actually started BEFORE the
bacterium was discovered by Marshall and Warren in 1982!
Epidemiological studies suggest that H. Pylori is transmitted via humanhuman interaction.
The risk of infection is increased in extense family size, poor
socioeconomic conditions and high population density.
Fecal –oral , routes are commonly accepted modes of transmission.
In Asia, adquisition of H.pylori infection occurs in early childhood .
(SAME THAN OUR LATINOAMERICAN SOCIETY??)
The habit of boiling water before drinking also reduce the risk of water –
borne transmission.
Changes in socioeconomic conditions in Asia in the past decades, and
hence improvement in sanitary and hygienic conditions , is likely to be
the most important reason for the disappearance of H.pylori.
While the economic growth in the region, population growth has reduced ,
GNP growth per capita is rising , life expectancy is lengthening , infant
mortality is dropping and supply of fresh water is improving.
Antimicrobial therapy has probably contributed only a small part in the
population- based control of H. pylori infection.
However , re-infection after successful cured of the infection for up to 24
months , H. pylori recurred only in 2% of cases .
The low re- infection rate is true both in adults and children above the
age of 5 years.
VS
DIFFERENCES IN PREVALENCE OF H.PYLORI ACCORDING TO RACE ENVIROMENTAL
FACTORS.
F. Riquelme, MD. Gastroenterology Section, Internal Medicine
Races from South East Asia
chinese
Malay
Indian.
Prevalence Infection by HP.
Prevalence Cancer Gastric
•Host , bacterial or
enviroment factors, which
may modulate the expression
of clinical disease.
Prevalence Pectic Ulcer
1.
2.
Close contact within a racial
group and within families
appears to be crucial for
transmission and perpetuation
of infection by HP.
Peptic ulcer disease and
gastric cancer appears to be
correlated with the high H.
pylori prevalence.
In India
this was not The answer could be
seen.
WHY?
*Dietary or other
enviromental factors may
serve as ulcer of cancer
“ protective factors” in the
face of high
H. pylori prevalence.
The multiracial countries in South East Asia provide a living experimental
model to study differences in H. pylori prevalence and its disease
outcomes.
Malaysia epitomizes the multiratiality of these countries with three major Asian
races living together in the same country: Malay , Chinese and Indian.
Consistently , H. pylori prevalence is lowest amongst Malays and Highest
amongst the Chinese and Indians.
This points to a racial cohort phenomenon where close contact within a racial
group and within families appears to be crucial for transmission and
perpetuation of infection.
The high prevalence amongst the Chinese and India where the overwhelming
majority of immigrants came form , at the turn of the century.
Differences in the prevalence of gastric diseases between races have been
noted with respect to peptic ulcer disease and gastric cancer.
Peptic ulcer disease appears to be most common amongst the Chinese . And
appears to be correlated with the high H. pylori prevalence.
However the relative low prevalence of ulcers amongst Indians despite
the high prevalence of H. pylori is an enigma.
The prevalence of gastric cancer is low amongst the Malays and Indian
and highest amongst the Chinese.
Again the reasons for the low prevalence of gastric cancer amongst
Indians despite de high H. pylori prevalence are not enterely clear .
The differences in outcomes of H. pylori infection are intriguing and
point to host , bacterial or enviroment factors, wich may modulate the
expression of clinical disease .
This may be the case in Indians , where dietary or other enviromental
factors may serve as ulcer of cancer “ protective factors” in the face of
high H. pylori prevalence.
THIRD CONTROVERSY
THE REAL ROL OF CRITERIA FOR A
VIRULENCE FACTORS.
Dr. Carolina Delgado
Human Anatomy Pathology Department, Faculty of
Medicine of Concepción University, Chile.
VS
WHAT’S NEW IN TESTING? WHAT’S WRONG WITH
TESTING?
Dr. Carlos Briceño, MD,
Gastroenterology Section, Internal Medicine Faculty of Concepción
University, Chile.
THE REAL ROL OF CRITERIA FOR VIRULENCE FACTORS
Inflamation and Risk of a
symptomatic outcome.
Virulence Factors.
cagA
Mucosal IL-8 levels are
proportional to the nº cagA+
Has not predictive value.
Ice A
Biological and epidemiological
evidence for a role for iceA as a
virulence factors disease-specifity
Duodenal ulcer.
vacA
Clinically
useful
Gastric MALT
lymphoma
The criteria for a true virulence factors includes meeting the tests of
biologically plausibility with the associations being both experimentally
and epidemiologically consistent.
Now, there are sufficient data to conclusively state that none these
putative virulence factors have disease specifity.
The presence of so call “ functional cag pathogenicity island”, increases
inflammation and it is likely that any factor that results in an increase in
inflamation also increase the risk of a symptomatic outcome.
Mucosal IL-8 levels are proportional to the numbers of cagA(+) H Pylori
independent of the disease from which the H Pylori were obtained and the
presence of a functional “cag Pathogenicity Island” has not predictive
value.
But actually, the hypothesis that iceA has disease-specifity and currently
biological and epidemiological evidence for a role for iceA as a virulence
factors and claims that vacA genotyping might prove clinically useful, e.i.
to predict vacA sm1 presentation represents such us duodenal ulcer or
sm2 genotype to gastric MALT lymphoma make possible to
observe the great role of Virulence Factors.
VS
WHAT’S NEW IN TESTING? WHAT’S WRONG WITH TESTING?
Dr. Carlos Briceño, MD, Gastroenterology Section, Internal Medicine Faculty of Concepción University.
Culture
Test to
assesment
HP
INVASIVE
Endoscopy
Histology
Biopsia
infection
NOW
(+) urease test)
Biochemical reaction product
of urease with the use of
13C(C14) urea breath test.
Test, Treatment and
control HP erradication.
VS
HP antigen
detection in feces.
*Not assessing treatment
efficacy
NO
INVASIVE
Detection acs
against HP
*Need validation.
*?Persitent or
reminiscence of infection.
*Sensivity and
specifity GOOD.
*Determine
different virulence
pattern of H Pylori.
•Test accuracy with all different methods it is crucial to consider the medications on which
patient is on. The choice of the individual tests for H.P. detection depend on the purpose.
a)
b)
c)
The methods for assessment of H pylori infection embrace three levels of acccess:
endoscopy based with direct detection in culture and
histology or by
a positive urease test on biopsies.
These tests represent actually the “golden standard” in testing for H. Pylori;
a) all further developments of new tests needs to be done in reference to this group of tests.
b) Non invasive tests are based on the biochemical reaction product of urease with the use
of 13C(C14) urea breath test. Several new technologies and different test protocols
have been proposed for the 13C-UBT-TEST becoming widely used for the “test and
treatment strategy”. As well as for controlling the efficacy of H Pylori erradication
therapies.
A new Test procedure and heavy competitor for the 13C- UBT is the newly introduced H
Pylori antigen detectiontest in feces.
This test based on determination of H Pylori specific antigens in stool by ELISA will be
further developed as a test to be performed in phisician ‘ s office.
This test will find great acceptance in primary care and be adopted in the test and treat
strategy.
c) Non invasive tests based on detection of antibodies against H Pylori antigens in several
biological specimen (blood, saliva, urine).
These Tests have been further developed and increased their sensivity
and specifity but still requires regional validation.
The limitation of these tests is that they depend on the immune reaction and harbour the
uncertainty if they depend on the immune reaction in case of detection are still indicators
for a persistent infection or just a reminiscence of a progressed and resolved infection.
The tests are not useful in practice for assessing treatment efficacy.
An advantage of these tests based on the immunological principle system(immunoblotting)
is the possibility to determine different virulence pattern of H Pylori.
The choice of the individualtests for H Pylori detection of highly depend on the purpose
(ie Clinical Practice, Epidemiological Studies) .
There several pitfalls inherent to each methodology, which need to be
addressed on a case by case basis.
Concerning the test accuracy with all different methods it is crucial to consider the
medications on which the patient is on .
As an example patient on PPI treatment may be false negative if biopsy
specimens are taken from antrum for histology, urease and culture, but is
invariably positive if the biopsies are taken from other proximal gastric sites.
The spectrum for H Pylori testing is the most complete one can expect for
detection of an infectious disease but the use of the individuals tests
needs to consider the specifical clinical question as well as the particular
FOURTH CONTROVERSY
WHICH IS THE BEST TREATMENT? ARE CLO TEST USEFUL? ANTIMICROBIALS
RESISTANCE IN VITRO IS TRUE? EXIST SOME EXPERIENCES FROM OTHERS
SAME GROUPS AS OUR PUBLIC HOSPITAL REALITY?
G Zuloaga Chief of Gastroenterology Section,
F Riquelme MD Gastroenterologist from Clinical Hospital of Concepcion,
R Loaiza MD Gastroenterologist from Clinical Hospital of Concepcion,
V Vera MD, Gastroenterologist from Clinical Hospital of Concepcion.
Hospital Clinico regional of Concepcion , Chile
VS
CLINICAL AND HISTOPATHOLOGICAL CHARACTERISTIC OF H.PYLORI
INFECTION IN CHILENA PEOPLE.
F. Kawaguchi, A.Martinez, A. García, C. Gonzalez, A. Montoya, J. Madariaga, F. Salgado, F.
Daroch, I. Alfaro, T. Pérez, P. De Veer, C.Vasquez N. Pérez.
Department of Internal Medicine, and Anatomy Pathology ,
Faculty of Medicine; and Departament of Microbiology.
University of Concepión
Hospital del Trabajador , Concepcion , Chile.
WGCOG MONTREAL 2005
WHICH IS THE BEST TREATMENT? ARE CLO TEST USEFUL? ANTIMICROBIALS RESISTANCE IN VITRO IS
TRUE? EXIST SOME EXPERIENCES FROM OTHERS SAME GROUPS AS OUR PUBLIC HOSPITAL REALITY?
G Zuloaga Chief of Gastroenterology Section,
F Riquelme MD Gastroenterologist from Clinical Hospital of Concepcion,
R Loaiza MD Gastroenterologist from Clinical Hospital of Concepcion,
V Vera MD, Gastroenterologist from Clinical Hospital of Concepcion.
Ramón Abrigo MD, Gastroenterologist from Clinical Hospital of Concepcion
*Serological exam
*Histology
*13C Urease Breath
Test
H
P
Only test dependent
from place were it
come
Different resistance
and antibiotic
susceptibility
clarithromycin, metronidazole
tetracicline, levofloxacine,
lanzoprazol, bismuth subcitrate,
omeprazol and amoxicillin
WHY
*Different environments.
* Infectious diseases in
some countries afectt
drugs suceptiblility.
These results confirm the need
for culture and susceptibility
testing to define Hp resistance
patterns in particular
geographical areas before the
general use of an erradication
schedule.
Ureasa Test for Helicobacter pylori (CLO TEST)
is currently the tissue based gold standart for diagnosis of the presence of the bacteria from gastric
biopsy(almost the methods to study this bacterium here in our hospitals) .
It identifies the urease enzyme of H. pylori via a color change indicating the enzyem-substrate reaction.
By understanding the mechanism involved in this reaction we hypothesize that a CLO Test which has
been used but has had a negative result until it yields a positive result.
To obtain antral biopsy from patients with symptoms of gastritis and tested them on previously used CLO
test wich had given negative results.
The period between the first used of the CLO test and their reuse varied from one week to several months
and it is different for each test.
During this time the CLO tests were stored in the endoscopy unit at differents Temp. Of each biopsy was
compared to the following tests: 13C Urease Breath Test, serological exam (Flex Pack) ad histology. In
some cases the CLO tests were reused three or more times until a biopsy yielded a positive result.
But, this only test has many variables dependent from place were it come.
For example sensibility and specifity of HEPY TEST and our own UREASE TEST
are quite different in many aspects, making not possible to repeat this methods
with the same results in the same population
To determine antibiotic susceptibility of Helicobacter Pylori to clarithromycin,
metronidazole and amoxicicillin isolated from some studies with dyspepsia and
past or present history o peptyc ulcer disease and a positive CLO TEST,
We collected samples from antrum and corpus and culture in according to the rules of
FONDEF from Pylori obtained during this year, which allowed us to obtain some
pediatrics endoscopes and to culture these samples with sensidisk elaborated by
our same microbiological study group.
It follows the International rules allowing us to test some antibiotics like
clarithromycin, metronidazole tetracicline, levofloxacine, lanzoprazol,
bismuth subcitrate, omeprazol and amoxicillin.
If we compare our results with other cultures close to us like Puerto Rico
Sensitivity to clathromycin was 84.2% .
Metronidazole had a sensitivity of 42%.
Patients had 100% sensitivity to amoxicillin .
Among female patients there was a 75% resistance to metronidazole.
In view of increased resistence to metronidazole among Puerto Rican patients , its use
should be avoided in H. pylori eradication therapy in this group of patients .
Our findings support the importance of conducting sensitivity studies among different
ethnic groups, as response to antibiotics appears to vary with race, and this could influence
treatment choices .
Again, hundreds of antihelicobacter pylori treatment trials have been reported.
Clinicians need to know which treatments are effective in their patient population.
To provide summary estimates of the absolute effect of anti Helicobacter Pylori therapies
within groups responding similarly to treatment.
Data extracted from studies from MEDLINE database, bibliographies
Just half of them with double triple or quadruple therapies met the selection criteria.
To evaluate the level of primary antimicrobial resistance in H Pylori clinical isolates
collected during last 10 years from patients in Moscow, were tested for the enrollment into
clinicals trials.
No one of these patients had been treated before with anti H Pylori theraphy.
Here, Minimal inhibitory concentrations(MIC) of antibiotics used to define resistance in 169
patients were: AMOX> 0.5 mg/l, CLARITROM > 1 mg/l and METRONID > 8 mg/l respectively,
Metronidazol: 56.6% resistance; Claritromicin: 14.4% resistance, Amoxicillin: 0% resistance,
Poliresistantce: 6%
(Isakov, Koudryavtseva, Ivanikov, Basic Mechanisms to Clinical Cure, 2000, P33).
H Pylori infection causes chronic digestive diseases of major impact, but prevention
measures are not obvious due to limited knowledge of the natural history and risk factors
for adquisition.
The Pasitos Cohort Study (MEXICO), follows children from birth through three years to
investigate the determinants of this infection in a setting where developed and developing
countries interface.
The US-Mexico border permits follow up of two cohorts from distinct environments by one
research team using identical study methods.
In this way, we estimated the seroprevalence of H Pylori and identify associate factors in
pregnant women
Adjusted from multivariate model containing many of these factors age, household
crowding.
Use of bottled water and inadequate excreta disposal system among El Paso women, age,
education, with adjustment for sociodemographic factors, and high prevalence among
pregnant women from this border Place of Pasitos confirms that this setting is well suited
to longitudinal studies of H pylori infection in infants and children .
And finally,demonstrated the importance of these factors in the incresing
resistance of some antibiotics because the increased infectious diseases
like amebiasis increased Metronidazol indications in our region.
Althought there are
many, many data about the prevalence of this bacterium in developing
countries, there little data on the susceptibility of H pylori to antimicrobials commonly used
in erradication schedules in these countries.
Among another very similar country culture like Brazil, the resistance to metronidazol,
clarithromycin, amoxycillin, tetracycline and furazolidone in dyspeptic patients.
It was detected in 42% of the patients. Amoxycillin in 20% , Clarithromycin in 7%
Tetracycline in 7% and Furazolidone in 4%.
These results confirm the need for culture and susceptibility testing to define Hp resistance
patterns in particular geographical areas before the general use of an erradication schedule.
Actually, recent study suggests that bismuth can reach toxic levels when coprescribed with
proton pump inhibitors(Gut 97; 41) .
To monitor blood and urine bismuths levels in patients using subcitrate of bismuth and
lanzoprazole associated in Hpylori duodenal ulcers patients and blood urine was collected,
concluding this therapy or another with Lanzoprazol(omeprazol) (+) Amoxicyllin (+) bismuth
subcitrate can be safely prescribed for Hp treatment, with good results after 6 - 24 months of
clinical and endoscopical controls.
VS
CLINICAL AND HISTOPATHOLOGICAL CHARACTERISTIC OF H.PYLORI INFECTION
IN Chilean people
F. Kawaguchi, A.Martinez, A. García, C. Gonzalez, A. Montoya, J. Madariaga, F. Salgado, F. Daroch, I. Alfaro, T. Pérez,
P. De Veer, C.Vasquez N. Pérez.
Department of Internal Medicine, and Anatomy Pathology , Faculculty of Medicine; and Departament of Microbiology.
University of Concepión Hospital del Trabajador , Concepcion , Chile.
WGCOG MONTREAL 2005
Upper
endoscopy
+
Biopsy
+
RESULTS
Rapid urease test,
culture and
histopathology
Prevalence , the clinic
manifestations and
histopathological aspects of
H, pylory infection in our
patients.
5 years ago
Now
HP (+)
60.5% (male >)
77%
(male = female)
AGE HP (+)
45.5  15
 Young people
HP(+) esophageal
disease
53.8%
there are no
differences
NON
Gastroduodenal
Ulcers HP(+)
52%
Ulcers Simil
Gastric HP(+)
79.8%
47%
(now is called
funtional
dyspepsia)
87.5%
Ulcers-Simil HP
(+) Duodenal
63.4%
75%
Erosive
gastropathy with
active epitelial
hiperplastic HP (+)
Correlation in
HP(+) hiperplase
with CD16 with
HLA-DR
Resistance HP
Citrate Bismut
Claritromicine
Amoxiciline
64.5%
87%
20.9
¿73.5?
56%
14%
0%
0%
75%
18%
25%
0%
This study was realized because International Congress of Bermudas
about Basic Mechanisms to Clinical Cure 2000.
It is good time to remember and compare with our actual findings and
methods to the original aim of this Clinico-histopathological correlation
almost 5 years ago.
To deterrmine the prevalence , the clinic manifestations and
histopathological aspects of H, pylory infection in our patients.
A total of 200 consecutive patients undegoing upper endoscopy were
biopsied and tested for H pylori infection by rapid urease test, culture and
histopathology(Now we are closed to 600 patients).
Patients were considered positive if at least one of the three biopsy
specimen-based methods yielded positive results (Now from two years
ago we take 8 samples: 4 from antrum and 4 from middle and upper
corpus, for histology, culture, PCR and Urease Test).
Rome I and Rome II were used to determined ulcer-simil and non ulcersimil(functional) Dyspepsia.
Histopathological gastritis was classified according to the modified
The average age of infected people(Hp+) was 45.5+- 15.6 and not infected
(Hp-) was 47.5+- 15.7 y.o.
( Now we recognized clear significance Hp(+) distribution in younger
patients even without any symptoms (p<0.001).
This is another reason to start examinating childs at younger ages.
H pylori infection was 53.8% in patients with esophageal disease(Now not
exist any differences with the 5 years ago findings).
At That times non-gastroduodenal ulcer Hp(+) patients were 52%,
(actually this so-call Functional Dyspepsia,is closed to 47.8% ).
In Ulcer-simil Hp(+) patients with active gastric ulcer(A1 to H2) our
findings were almost 87.5% patients(79.8% 5 years ago).
Moreover, A1 to A2 ulcer were close to 95% of the patients, and 71.7% in
Scar stage.
In Ulcer-simil Hp(+) duodenal ulcers(63.4% before, 75 % now , have not
significant differences), but significantly lower than Ulcer-simil Hp(+)
gastric ulcer patients.
Among lymphoid hyperplasia in correlation with CD16 and HLA-DR,
increases now to an very significative 73.5% (before 20.9% in Hp(+)) in
CD16 and HLA-DR over 80% (through Flow Cytometry analysis).
Resistance also changed from 56% 5 years ago to an significant 75%
today, and Citrate bismuth from 14% to 18% today.
Clarithromycin from 0 resistance to actual 25% and Amoxycillin from 0 to
0 actually.
New surprise are levofloxacin: 2 resistant cultures from first time
treatment Hp(+) patients in almost 124 patients.
Another good surprise are Proton Bumb Inhibitor: Rabeprazol over
others omeprazols.
Intersesting what happen with Amoxycillin and Bismuth even they are
commonly used in our Protocols. Some relative with In Vitro
Resistance??.
It is in study from our group now.
WHAT DO
YOU
THINK?
GASTRIC MALT. CONCEPT
AND ETIOLOGY.
CLASIFICATION. CLINICAL
ASPECTS.
ENDOSCOPICAL AND
HISTOLOGICAL.
TREATMENTS VARIANTS.
Overview
Although the incidence of stomach cancer has declined dramatically in
the United States and Western Europe in the last 50 years, the disease
remains a serious problem in much of the rest of the world, where it's a
leading cause of cancer death.
This global variation is almost certainly linked to two factors that play a
major role in the development of stomach cancer: Infection with
Helicobacter pylori (H. pylori) bacteria and the type of diet.
Stomach cancer is more readily treated when caught early.
Unfortunately, by the time it causes symptoms, the disease is often at an
advanced stage and may have spread beyond the stomach.
Yet there is encouraging news. You can reduce your risk of this serious
cancer by making a few changes in your lifestyle.
Image
• :StomachYour
stomach is a muscular
sac about the size of a
small melon that
expands when you eat
or drink to hold as
much as a gallon of
food or liquid. ...
Causes
• The stomach is a muscular sac located in the upper middle of your abdomen, just
below your ribs.
• The stomach walls are lined with three layers of powerful muscles that mix food
with enzymes and acids produced by glands in the stomach's inner lining.
• Under normal conditions, your stomach produces 2 to 3 quarts of gastric juices
every day.
• One of these, hydrochloric acid, is so corrosive it can dissolve iron nails. Your
stomach's delicate tissues are protected from this powerful acid by a thick, jellylike mucus that coats the stomach lining(SIALOMUCYN).
• Once the food in your stomach is thoroughly broken down and mixed, muscular
contractions push it toward the pyloric valve, which leads into the upper portion of
your small intestine (duodenum).
• The valve opens just enough to release a scant eighth of an ounce of food at a
time. It may take three to four hours for your stomach to empty after you eat,
depending on your diet.
•
Foods high in fat increase the amount of time it takes for your stomach to empty.
Overview
Although the incidence of stomach cancer has declined dramatically in the United
States and Western Europe in the last 50 years, the disease remains a serious
problem in much of the rest of the world.
This global variation is almost certainly linked to two factors:
A) Infection with Helicobacter pylori (H. pylori) bacteria and,
B) The type of diet.
.
.
Under normal conditions, our stomach produces 2 to 3 quarts of gastric juices every day.
Stomach's delicate tissues are protected from this powerful acid by a thick, jelly-like mucus
that coats the stomach lining: sialomucyn.
Once the food inside the stomach is thoroughly broken down and mixed, muscular
contractions push it toward the pyloric valve, which leads into the upper portion of your
small intestine (duodenum).
The valve opens just enough to release a scant eighth of an ounce of food at a time.
It may take three to four hours for stomach to empty after eat, depending on
our diet.
Foods high in fat increase the amount of time it takes for your stomach to
empty.
INTRODUCCION
Factores de virulencia: CagA y VacA
vacA
s
cagA
s1a
m
89%
cagA+ > cagA- s1b
m1
>
m2
20%
s2
DAÑO
EPITELIO GASTRICO
ENFERMEDAD
PEPTICA ULCEROSA
MAYOR RIESGO DE INDUCIR ENF. PEPTICA ULCEROSA (EPU)
vacA
cagA+
Atherton, 1998
s1
m1
Overview
Although the incidence of stomach cancer has declined dramatically in the United
States and Western Europe in the last 50 years, the disease remains a serious
problem in much of the rest of the world, where it's a leading cause of cancer
death.
This global variation is almost certainly linked to two factors that play a major role
in the development of stomach cancer: Infection with Helicobacter pylori (H.
pylori) bacteria and the type of diet.
Stomach cancer is more readily treated when caught early.
Unfortunately, by the time it causes symptoms, the disease is often at an
advanced stage and may have spread beyond the stomach.
Yet there is encouraging news. You can reduce your risk of this serious cancer by
making a few changes in your lifestyle.
Although adenocarcinomas account for about 95 percent of all stomach
cancers, other forms of the disease can sometimes occur, including:
Lymphomas.
• These are cancers of immune system tissue in the
stomach wall.
• Some lymphomas are aggressive whereas others grow
much more slowly.
• The latter, known medically as mucosa-associated
lymphoid tissue (MALT) lymphomas, usually stem from
H. pylori infection and are often curable when found in
the early stages(Endoscopy, EUS, and eventually
complementary Oncotherapy.
H. pylori infection frequently occurs in childhood and can last
throughout life if not treated
•
It's the primary cause of stomach ulcers, accounting for at least 80 percent of all cases.
It may also be the main cause of stomach cancer.
•
According to the World Health Organization, close to half the annual new cases of
stomach cancer can be attributed to H. pylori infection.
•
Having ulcers doesn't necessarily put you at higher risk of stomach cancer, but having H.
pylori infection does.
•
That's because long-term infection causes inflammation that can lead to precancerous
changes in the stomach lining.
•
One of these changes is atrophic gastritis, a condition in which the acid-producing
glands are slowly destroyed.
•
It's likely that low acid levels prevent cancer-causing toxins from being properly broken
down or flushed out of your stomach.
•
Countries such as China and Colombia, where a majority of children are infected with H.
pylori, have a correspondingly high rate of stomach cancer.
Risk factors
• Having H. pylori infection makes you more likely to develop stomach cancer than
someone who doesn't have the infection.
• Even so, most people with H. pylori don't get stomach cancer, and researchers
believe that genetic factors make some people more susceptible to the disease.
• Having both H. pylori and a form of a gene that causes low stomach acid greatly
increases your risk of stomach cancer and MALT.
DIRECT PCR FROM UREASE TEST
AND Helicobacter pylori GENOTYPE
WCOG MONTREAL 2005
EVOLUTION
H. pylori INFECTION
Infection from
H. pylori
Spontaneous
curation
Gastritis antral
superficial
Persistence
Without complic.
Duodenal Ulcer
NIH Concensus, 1994
Hiperprolif. Limphoma
linfoide
MALT
Parsonnet, 1994;
Wotherspoon,1993
Chronic
Gastric Ulcer
NIH Concensus, 1994
Atrophic Gastritis
Gastric Cancer
Crabtree, 1993; Nomura, 1991; Parsonnet, 1991
Modified by Gomollón F. Medicine 1996; 7(3):81-88.
H. pylori Infection
Colonization
•flagel
•Adhes molecules
•urease
Action over epitelium
 LPS or endotoxin
● citotoxin o VacA
● CagA
● hsp
Gastric
Epitelium
Immune Response
● IL-8
● TNF alfa
PMN
Virulence Factors : CagA and VacA
vacA
s
cagA
s1a
m
89%
cagA+ > cagA- s1b
m1
>
20%
s2
Gastric Damage (+) DUS
Dyspepsia Ulcer Simil (DUS)
DUS and Virulence Factors Correlation
vacA
cagA+
Atherton, 1998
m2
s1
m1
Genotipe vacA Prevalence
s1a-s1b/m1
s1b/m1
s1a-s1b/m1
s1b/m1
s1a/m1
s1a/m1
s1a/m1
s2/m2
s1b/m1
Martínez, Kawaguchi et al, Rev Med Chile 2001, 129:1147-1153
4th International Workshop on Pathogenesis and Host Response in
Helicobacter Infections. Denmark, 2000
UREASE TEST BIOPSIA
¿
PCR and
GENOTYPE
?
ANTIBIOTIC RESISTENCE and
VIRULENCE FACTORS
OBJETIVE
● Determine Direct PCR from Samples of Urease Test
● Pathogenetic Rol of Helicobacter pylori
Antibiotic
Resistance
presence cagA
● genotipe vacA
●
METHODOLOGY and RESULTS
METHODOLOGY
Biopsy SAMPLES
ENDOSCOPY
BIOPSY FROM ANTRUM(4) AND BODY-FUNDUS(4)
Urease (+)
Histopathology
Urease Test: He-Py test
METHODOLOGY
DNA Extraction
DNA
10 min
Chelex 100
Rudi et al, 1999
Centrifugate
12000 rpm * 5 min
METHODOLOGY
Amplification by PCR 16S RNAr
Helicobacter pylori DNA: 16S RNAr
UHP1
UHP2
5’- CTA TGA CGG GTA TCC GGC -3’ 5’-ATT CCA CCT ACC TCT CCC A -3’
376 pb
16S RNAr
ELECTROPHORESIS
IN AGAROSE
Rudi et al, 1999
RESULTS
Amplification through PCR (gen cagA)
1
2
3
4
5
6
7
1353 pb
1078 pb
872 pb
603 pb
349 pb
310 pb
Pacient Nº
2
5
6
7
8
9
METHODOLOGY
PCR Amplification : cagA and vacA
vacA
s
cagA
Tummuru et al., 1993
m
Atherton et al., 1995
s1a: 187 pb
349
pb
m1: 290 pb
s1b: 190 pb
m2: 352 pb
s2: 199 pb
ELECTROPHORESIS
AGAROSE 3%
Atherton et al., 1995; Tummuru et al, 1999
RESULTS
Amplification gen vacA (Signal Sequence)
1
2
3
4
5
6
7
8
1353 pb
1078 pb
872 pb
603 pb
310 pb
199 pb
187 pb
Pacient Nº
1
7
5
9
RESULTS
Amplification gen vacA Middle Region
1
2
3
4
5
6
7
1353 pb
1078 pb
872 pb
603 pb
352 pb
290 pb
310 pb
Pacient Nº
1
2
3
6
7
9
Genotipes detected at ACHS
Pte. Diagnosis
Pte. Diagnóstico cagA
1
2
3
4
5
6
7
DNU
DNU
DNU
DNU
EPU
EPU
DNU
(+)
(+)
(-)
(-)
(-)
(+)
(+)
vacA
cagA
s
vac A
s
s2
s1a
s1a
s1a
s1a-s2
s1a
s1a-s1b
m
m2
m1
m1
m1
m2
m1
m1
m
Genotipes detected at San Borja
Pte. Diagnosis
1
2
3
4
5
6
7
8
9
10
DNU
DNU
DNU
DNU
EPU
DNU
EPU
DNU
EPU
DNU
NT = no typificated
cagA
(-)
(-)
NT
(-)
(-)
(-)
(-)
(+)
(-)
(-)
vacA
s
m
s2
s1b-s2
NT
s1a-s2
s1b-s2
s1a
s2
s2
s1a
s1b-s2
m1
m1
NT
m2
m2
m1
m1-m2
m2
m1
m1-m2
CONCLUSIONS
● PCR technic allow us to
determine
characteristics from
many H Pylori subtypes.
● It is possible to use
urease samples for PCR
Study..
● Eventually to determine
antibiotic resistant
subtypes to
claritromicyn, without
culture and antibiogram.
FONDEF FOUNDATION
CHILE 2005-8.
RESEARCH GROUP
Dr. Fernando Kawaguchi (1,2,3)
DR Carlos Briceño(1)
Dr Patricio Ortiz(1)
Dr Fernando Riquelme(1)
Dr Rodrigo Loaiza(1)
Dr Gonzalo Zuloaga(1)
Dr Germán Abrigo(1)
Dr Vicente Vera(1)
Dra Apolinaria García(2)
Dr Carlos Gonzalez(2)
COLABORADORES
Dr. Mauricio González (4)
Prof. Rolando Montoya (2)
Mag Juan Luis Castillo(2)
Mag Marcelo Castillo(1)
Dra CG Yañez(3)
Dr German Errazuriz(5)
Dr Alberto Rossle(1)
Dr Oscar Venegas(1)
Dr. Jaime Madariaga Boero (1)
Dra. Alejandra Martínez, MsSc(2)
Prof. Jorge Roa Sandoval, PhD (1)
EU Edith Vega(3)
EU Lorena Ruiz(1)
ALUMNOS AYUDANTES
Ignacio Alfaro Pérez
Srta Tamara Perez
Nelson Perez Lynch
Mracela Lefer
Sr Cristián Vasquez
(1) FACULTAD DE MEDICINA y HOSPITAL REGIONAL
(2)FACULTAD DE CS. BIOLOGICAS
(3) HOSPITAL TRABAJADOR CONCEPCION
(4) HOSP. SAN BORJA ARRIARAN
(5) HOSPITAL PUERTO MONTT
• CLINICAL ASPECTS And MINIMAL THERAPY:
• Gastric lYMPHOMA MALT is diagnosed more frequently
as EARLY AS 30-50 years old, with a predominance of the
men on the women of 1,7/1.
• At the moment of its diagnosis it is a tumor of low degree
in a 70-85% of the cases.
• It seats preferently in ulcers: 41%, being able to be
multifocal in a 33% (11). Gastric lymphoma MALT is one
neoplasia that produces little clinical manifestations in its
initial stages, being able even to be non symptoms.
• Usually it causes a dispepsia ulcer simil or functional.
• The advanced tumors very rarely produce a clinical
picture similar to gastric carcinoma, with loss of weight,
anorexy, bleeding and mass
• Diagnosis Strategy: Dr Rodrigo Loaiza, Dr Vicente Vera
•
The diagnosis of lymphoma MALT is based on the gastroscopy,
with biopsies. Barium radiology is a method clearly inferior to
the endoscopy.
• Endoscopically we will be able to be so single with a mucosa of
eroded aspect, with a solution of continuity in the endoscopy,
with the presence of ulcer, with fold frequently thickened and
with irregular or polipoids masses.
• The mucosa can have an infiltrative aspect of isolated, diffuse or
multicentric form.
• The finding of thickened fold and multiple ulcers, sometimes
confluent, that even can exceed pilorous and to affect the
duodenum is suggestive of linphomatous injury.
•
IN Submucosal compromise, Pathologist needs more samples which are taken under
EUS , with biopsy in biopsy.
•
We have already all this technics under Protocolus (ISO 9000), between endoscopist,
pathologist, nurse and assistant.
•
The tumorlike cells are generally lymphocytes B of small-medium size with somewhat
abundant cytoplasm and nucleus of irregular form, resembling itself the centrocites,
reason why denominates centrocitoid lymphocytes to them.
•
Less frequently they can be monocitoids, or in form of small lymphocytes.
•
In a same injury it can have a clear one predominant cellular type, or coexist several
of them (3).
•
•
Although the graduation of Wotherspoon (6), facilitates the histologyc diagnosis,
this diagnosis based single on the morphology can be difficult, specially as opposed to
certain cases of follicular gastritis.
•
It is considered as the morphologic characteristic more characteristic of limphoma
MALT to the presence of linfoepitelial, consisting of injury the invasion of cripta by
aggregates of centrocitoids lymphocytes.
• Other histologycal findings are with moderate atipia cellular of the tumorlike
lymphocytes and the presence of lymphocytes with bodies of Dutcher, although its
absence does not discard the diagnosis.
• Sometimes we need immunohistopathology, and Flow cytometry.
•
Although false positives can occur and negatives, the monoclonality supports the
diagnosis of limphoma.
• The inmunohistologics studies show positivity in CD20, CD21, CD35 and IgM
and negatividad to CD5, CD10 and CD23 (8).
• The monoclonality of lymphocytes B studies by Southern Blot or techniques of
PCR is not equivalent to malignance, being able to have monoclonality without
lymphoma or to persist this one during a time after the disappearance of the
tumor.
• The meaning of the monoclonality must be interpreted in the context of the
morphologic injuries (10).
• The division in lymphoma of low and high degree becomes according to the
proportion of blastics cells in the injury (9).
• The classification of the tumor in stop or under degree is important, since the high
degree entails more aggressive a clinical picture and a worse prognosis.
•
El diagnóstico histológico del grado puede ser difícil en determinados pacientes, ya
que ambos grados pueden coexistir en una misma lesión o en diferentes lesiones
multifocales, habiéndose descrito la transformación evolutiva de bajo a alto grado en
los linfomas MALT (2).
•
Se considera que la presencia de islotes de más de 20 células transformadas, o una
proporción superior al 15-20% de células de alto grado tiene significación clínica (8).
•
En determinados linfomas de alto grado no se aprecia ningún signo de lesión de bajo
grado, por lo que estos tumores pueden considerarse de alto grado "de novo".
•
No obstante, este dato carece de significación pronóstica al no haberse registrado
diferencias clínicas con los linfomas que progresan de bajo a alto grado (3).
•
Además del grado histológico es muy importante la clasificación de los linfomas
MALT según su estadio tumoral. La clasificación más empleada es la Ann Arbor (12),
modificada por Musshoff (13), que resumimos en la Tabla II, y que abarca desde el
estadio E I: tumor limitado a las paredes del estómago al E IV: afectación diseminada
a otros órganos.
• Logically an advanced tumorlike stage entails a worse prognosis.
• In the case of lymphoma of low degree, at the moment of the
diagnosis a 80% are in stage and I1, are to say that the tumor limits
the mucosa and gastric submucosa, without affecting deeper
structures(EUS STUDY).
•
In general, and unlike others lymphomas extra-nodals, gastric
MALT tends to remain located in the wall of the stomach during
long time, years, even allowing endoscopical treatment (+) H. Pylori
treatment during 3 months and new control until two years. (3).
• Occasionally MALT can propagate through the stomach and have
progression a distance, including the invasion of intestine, bone
marrow and spleen.
In a study conducted in Spanish Hospitals, the relative risk to develop
MALT was 81.1 times superior between the infected population that between not
infected by Helicobacter.
The etiology fraction of the risk was of 99, which in terms epidemiologists
indicates that a 99% of gastric MALT were positive for Helicobacter Pylori, (5).
Histologic Correlation:
Helicobacter Pylori produces a chronic gastritis, in the course of which they can
appear linfoides follicles and lymphatic aggregates in the base of the gastric
mucosa, which constitutes so call MALT.
This MALT is necessary established an anatomical graduation, in which the
progression of the injuries is outlined from a normal mucosa to linfoma MALT of
low degree (6).
• At the moment the echo-endoscopy is very useful to even carry out a correct
estadification of the tumor (14), that will be completed with the habitual
techniques of image like TAC, and with the medullar punction.(Dr Fernando
Kawaguchi, during last the 10 years)
• In our opinion the diagnostic strategy of gastric MALT needs:
• 1. - Confirmation of the infection by Helicobacter Pylori by means of fast test of
urease and histologic study.
•
2. - Exhaustive Maping of the gastric mucosa and even of the duodenum, with
biopsies at multiple levels to discard multifocal injuries.
• (HOSPITAL TRABAJADOR CONCEPCION PROTOCOL DURING LAST 10
years)
•
3. - Histologycal study, that can include macrobiopsies in the vegetating injuries,
to confirm MALT and its degree.
•
The anatomopathological study must be completed with inmunohistological and
flowcytometry study and PCR to confirm the monoclonality of the lymphocytes.
treatment
•
Nowadays we have several therapeutic possibilities to gastric MALT, which include:
•
•
•
•
•
1. - Erradicate treatment of the infection by Helicobacter Pylori;
2. - Surgical treatment; (Dr Oscar Lynch)
3. - Nonsurgical oncológical complementary treatment.
(According to Protocol Dr Alberto Rossle, Dr Mario Fernandez, Dr Caesar Diaz)
These modalities of treatment can be complemented to each other.
•
In the case of low degree significant differences in the survival have not been after
erradicate treatment, surgery, chemotherapy and surgery more chemotherapy or
radiotheraphy (Depend on deeper compromise- EUS)(11).
•
•
Treatment by means of the eradication of the Helicobacter Pylori:
We have already commented that the practical totality of MALT are Helicobacter Pylori
(+).
In the tumors of low degree the immunological stimulus was demonstrated that the
eradication of the bacterium was followed of the regression of neoplasia (15), when
interrupting that maintained its growth.
•
•
This tumorlike remission seems permanent, having itself confirmed in the 5 cases
presented/displayed (2000-2005), passed 5 years of erradicación(3 of 5 patients In last
bibliographical revisions of 203 published cases, objective a total remission of the tumor in
80%, partisan in a 10% and nonregression in 10%.
• It has been observed that most of the failures after the eradication
of the Helicobacter Pylori corresponds to linfomas of high degree
or low degree with stage superior to and I1, is to say with the
tumor escaping submucosa(sm3).
• At the time to obtain the result after the eradication it is very
important to consider that the tumorlike regression can require an
important period of time.
•
In a multicentric series of 49 patients, the passed average time
from the eradication to the complete histológica remission was of 5
months, but in a 30% of patients a very superior time was needed
(11), having itself published complete remissions that took up to 12
and 18 months (8).(6 months in our experience).
• For that reason, before considering like definitive a lack of
tumorlike remission, endoscopy and echo-endoscopy of control
must take place.
•
If the neoplasic injury stay stable not need more agresive treatment, without it increases the
risk for the patient (3).
•
At sight of these results, the treatment of election for lymphoma of low degree and
tumorlike stage and I1, that we remembered supposes 80% of all MALT,
would be the eradication of the Helicobacter Pylori.(During at least 3 months according to
our experrience, according to sensitivity and antibiotic resistance. Corroborating this study
with the later genotipificación).
•
•
•
•
In neoplasias locally from high degree, and although have obtained some cases of
tumorlike remission, is advised that the erradicador treatment has character of complement
to the rest of the therapeutic possibilities.
The patients whose tumor sent with the eradication must be followed in specialized Centers,
since they are going to need a strict evolutionary control.
Although the type and the frequency of the controls post-eradication are in discussion, an
advisable guideline could be the following one:
•
•
endoscopical control to 3, 6 and 12 months after the eradication,
Every 6 months during the second annual years.
•
Given the recent erradication treatment, still there is no agreement on the duration .
•
A period which includes up to 15 years, with multiple biopsies for morphologic study and
of monoclonality, as well as technical of urease and histologyc examination has set out to
discard a recidiva of the infection by Helicobacter
BIBLIOGRAPHY
•
•
•
•
•
•
•
•
•
•
-1.- Isaacson P., Wright D.H. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive
type of B-cell lymphoma. Cancer. 1.983; 52: 1410-1416
2.- Gisbert J.P., Boixeda D., Martin de Argila C. Infección por Helicobacter Pylori y cáncer gástrico.
En: Infección por Helicobacter Pylori. ¿Dónde está el límite?. Boixeda D., Gisbert J.P., Martin de
Argila C. ed. Prous Science. Barcelona. España. 1.996: 179-197
3.- Zucca E. B-cell lymphoma of MALT type: a review with special emphasis on diagnostic and
management problems of low-grade gastric tumours. Br. J. Haematol. 1.998; 100: 3-14
4.- Stolte M., Eidt S., Bayerdorffer E., Fischer R. Helicobacter Pylori associated gastric lymphoma.
En: Helicobacter Pylori, basic mechanisms to clinical use. De Hunt R.H., Tytgat G.N. ed. Kluwer
Academic Publishers. Lancaster U.K. 1.994: 498-503
5.- Borda F., Martinez-Peñuela J.M., Echarri A., Valenti C. y cols. Linfoma Gástrico primario e
infección por Helicobacter Pylori: ¿Puede haber una relación epidemiológica de causalidad?. Anales.
1.998; 21 supl.2: 55-59
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gastric lymphoma of mucosa-associated lymphoid tissue after eradication of Helicobacter Pylori.
Lancet. 1.993; 342: 575-577
7.- Du M., Diss T.C., Xu C., Peng H. y cols. Ongoing mutation in MALT lymphoma immunoglobulin
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1190-1197
8.- Isaacson P.G. Primary gastric lymphoma. Haematologica (ed. Esp.). 1.998; 83 supl. 1: 509-513
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Pylori, un paso más. Huelin J. ed. Prous Science. Barcelona. España. 1.997: 59-63
10.- Stolte M., Meining A. Helicobacter Pylori y linfoma MALT. Efecto del tratamiento. En: Infección
por Helicobacter Pylori en lesiones gastroduodenales. La segunda década. Pajares J.M. ed. Prous
Science. Barcelona. España. 1.998: 223-230
•
•
•
•
•
•
•
•
11.- Pinotti G., Zucca E., Roggero E., Pascarella A. y cols. Clinical features, treatment
outcome in a series of 93 patients with low-grade gastric MALT lymphoma. Leukemia
and Lymphoma. 1.997; 26: 527-537
12.- Carbone P.P., Kaplan H. S., Musshoff K., Smithers D.W. y cols. Report of the
comitee on Hodgkin´s disease staging procedures. Cancer Res. 1.971; 31: 1860-1861
13.- Musshoff K. Klinische Stadieneitenlung der nicht-Hodgkin lymphome.
Strahlentherapie. 1.977; 153: 218-221
14.- Pavlick A.C., Gerdes H., Porlock C.S. Endoscopic ultrasound in the evaluation of
gastric small lymphocitic mucosa-associated lymphoid tumours. J. Clin. Oncol. 1.997;
15: 1761-1766
15.- Stolte M., Eidt S. Healing MALT lymphomas by eradicating Helicobacter Pylori?.
Lancet. 1.993; 342: 56816.- Hammel P., Haioun C., Chaumette M.T., Gaulard P. Y cols.
Efficacy of single agent chemotherapy in low-grade B-cell mucosa-associated lymphoid
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gastric small lymphocitic mucosa-associated lymphoid tumours. J. Clin. Oncol. 1.997;
15: 1761-1766
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Ann-Arbor Clasification lymphomas extra-nodals. Modification of
Musshoff
Stadium
E I:
Description
LINFOMA LIMITADO AL TRACTO GASTROINTESTINAL, SIN REBASAR EL
DIAFRAGMA
- E I-1:
Infiltración tumoral limitada a la mucosa y submucosa(sm1)
- E I-2:
Infiltración tumoral que rebasa la submucosa(sm3/mp1)
E II:
LINFOMA QUE ADEMAS INFILTRA LOS GANGLIOS LINFATICOS, SIN REBASAR
EL DIAFRAGMA
- E II-1:
Infiltración de los ganglios linfáticos regionales
- E II-2:
Infiltración de ganglios linfáticos a distancia
E III:
LINFOMA CON INFILTRACION GASTROINTESTINAL Y/O DE LOS GANGLIOS
LINFATICOS A AMBOS LADOS DEL DIAFRAGMA
E IV:
INFILTRACION LOCALIZADA DE GANGLIOS LINFATICOS ASOCIADA A
AFECTACION DISEMINADA DE ORGANOS NO GASTROINTESTINALES
Histological Graduation : infection by Helicobacter PyloriMALT
•
•
•
•
•
1. Normal
2. Active Chronic Gastritis
3 . Active Chronic Gastritis with limphoid nodes
4 . Lymphoid Infiltrate in lamina propia
5. Lymphoid Infiltrate in lamina propia. Probably
Lymphoma
• 6. MALT of Low Grade
Indicaciones y efectividad clínica.
• La EUS posee una serie de indicaciones establecidas en las que es
superior a otras técnicas de imagen incluyendo la tomografía axial
computarizada (TAC) y la arteriografía
• La EUS permite la identificación y la estadificación de tumores
gastrointestinales, del esófago, estómago, recto y del páncreas y vías
biliares, tanto en el grado de infiltración parietal ( etapificación T)
como en la detección de adenopatías (estadificación N), con una
certeza diagnóstica superior a la de otras técnicas de imagen.
• En el caso del linfoma MALT de bajo grado, la EUS permite
predecir la respuesta al tratamiento erradicador.
• En un estudio del grupo de Bayerdoerffer , si el linfoma estaba
localizado en la mucosa o submucosa (estadío E-I1), la probabilidad
de regresión completa fue del 100% a los 14 meses, mientras que
ninguno de los pacientes con estadío más avanzado mostraron
regresión completa
Características a determinar en un Tsm por EUS.
• Recientemente, un estudio prospectivo y multicéntrico ha definido
los criterios ecoendoscópicos por los que deben remitirse a cirugía
aquéllos Tsm que cumplan uno o más de los criterios expuestos en
la tabla III.
• En este estudio se analizaron 122 Tsm en 120 pacientes y se
remitieron a cirugía aquéllos pacientes cuyos TSM tenían una de
estas características.
• Se resecaron 46 TSM y dado que el valor predictivo positivo para
malignidad fue del 68%, se recomienda la cirugía si se cumple
alguna de estas circunstancias.
• La EUS en el estudio de los TSM y compresiones extrínsecas ha
demostrado en estudios controlados, reducir el número de pruebas
diagnósticas (algunas invasivas), proporciona una indicación
racional de cirugía y la relación coste-beneficio depende del coste de
la EUS y el de las otras técnicas evitadas.
PUNCION-ASPIRACION BIOPSIA CON AGUJA FINA
• Los patrones ecográficos orientativos descriptivos que intentaban
diferenciar entre adenopatías inflamatorias o metastásicas han
quedado obsoletos con la PA-EUS.
• Se han comparado estos criterios ecográficos frente a los hallazgos
finales citológicos, obteniéndose una especificidad del 24% y del
93%, respectivamente.
• La PA-EUS proporciona además de un diagnóstico por imagen, uno
de certeza anatomopatológico.
• Por razones técnicas, existen diferencias de rendimiento de la PAEUS dependiendo de la naturaleza de la lesión diana.
• Así, en un estudio multicéntrico de Wiersema, la sensibilidad y la
certeza diagnóstica fueron superiores en adenopatías y masas
extramurales frente a las lesiones murales
Tabla VI. Rendimiento diagnóstico dependiendo de la naturaleza de la
lesión
Adenopatías
•
Masa
extramural
Lesion
intramural
Sensibilidad
92%
88%
61%
Especificidad
93%
95%
79%
Certeza
92%
90%
67%
Implicancias terapéuticas en la etapificación tumoral por PA-EUS.
MUCOSECTOMY.
•
La resección endoscópica de tumores localizados en la capa mucosa o mucosectomía,
puede realizarse en esófago, estómago y recto-colon.
•
En Japón esta técnica es un tratamiento establecido en la terapia radical del cáncer
gástrico en vez de la cirugía, en adenocarcinomas bien diferenciados, no ulcerados,
limitados a la mucosa(o sm1) y menores de 2 cms de diámetro(Según últimos Protocolos de
Consenso de París)
•
Los tumores localizados en la capa mucosa pueden ser subsidiarios de resección
endoscópica con asa de diatermia, tras inyectar adrenalina 1/20 en su base.
Pero, para realizar esta técnica la tumoración debe estar confinada a la capa mucosa, o
sm1. Es una técnica curativa del cáncer totalmente endoscópica, con pocas
complicaciones.
•
•
En el trabajo de Kida se analizan los resultados en una serie de 246 resecciones
endoscópicas de tumores mucosos, con una tasa de resección radical del 68.3% (168 de
246), de recurrencia tumoral del 2.8% (7 casos) y sin mortalidad debida al tumor.
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