Robert M Genta Caris Diagnostics and University of Texas

Transcription

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H. PYLORI-NEGATIVE GASTRITIS
WHAT TO DO WHEN HELICOBACTERS AREN'T THERE
Robert M Genta
Caris Diagnostics
and
University of Texas Southwestern Medical Center
Dallas, Texas
INTRODUCTION
H. pylori infection was recognized as the main cause of chronic active gastritis and peptic ulcer
disease just over two decades ago 1, and shortly thereafter the first effective treatments were
introduced 2, 3. Since then, and likely even before its discovery, the prevalence of H. pylori
infection has been steadily declining, particularly in industrialized and emerging economy
countries; this is probably a reflection of improved sanitary conditions, widespread treatment
of infected patients, and the pervasive use of antibiotics 4. In parallel with this decline, an
increased proportion of H. pylori-negative ulcers has been reported, both in the United States 5,
6
and elsewhere 7-9. Furthermore, although no studies documenting this phenomenon have
been published to date, there is a common perception amongst pathologists practicing in the
Western world that chronic active gastritis with no detectable H. pylori organisms (“H. pylori –
negative chronic active gastritis”) is on the rise 10 11. The often cited 1990s axiom that even a
small number of polymorphonuclear neutrophils in a gastric biopsy is an almost certain
indication of current H. pylori infection is no longer applicable. While no formal hypothesis has
been put forward and tested, commonly offered explanations include antibiotic therapy
administered to treat other infections, the masking effect of proton-pump inhibitors (PPIs), and
failure to detect organisms because of inadequate sampling or sub-optimal staining techniques.
The purpose of this presentation is to help the practicing pathologist confronted with a
gastric biopsy that "looks like H. pylori should be there, but is not."
WHEN AND HOW TO SEARCH FOR H. PYLORI
Just as we used to say that active gastritis means H. pylori infection, we also said that there is
no H. pylori infection without active gastritis. As it turns out, we were wrong on both accounts.
As any experienced gastrointestinal pathologist will know, when an anti-H. pylori
immunohistochemical stain (HP/IHC) is used in all gastric biopsies, one will occasionally find
organisms in unexpected backgrounds, such as a virtually normal mucosa, an antral mucosa
with reactive gastropathy and no active inflammation, or a fundic mucosa with a minimal subepithelial rim of lymphocytes and plasma cells and no neutrophils. Having been fooled by a few
such cases, I advocate the preemptive use of HP/IHC in all gastric biopsies.
2
Those who cannot or choose not to routinely use the HP/IHC or other appropriate
special stains for the detection of H. pylori must decide when to request such stains. When H.
pylori are not detected by whatever means one uses routinely, a more sensitive stain (ideally
the HP/IHC) should be used in the following circumstances:
1 - Chronic active gastritis (CAG)
2 - Focal active gastritis ("focally enhanced") 12
3 - Chronic inactive gastritis with lymphoid follicles 13
4 - Atrophic corpus gastritis, to exclude H. pylori before suggesting autoimmune gastritis
5 - When a duodenal or gastric ulcer is described in the endoscopy report, irrespective
of the appearance of the gastric mucosa in the biopsy
6 - When the biopsies are obtained to confirm the success of eradication therapy
7 - Whenever suspicious speckles that could be H. pylori are seen
8 - If a MALT lymphoma is either seen or reported to have been treated in the past 14, 15
In circumstances 2 through 7 the expected (and desirable) finding is the absence of H. pylori, as
in the case of a treated MALT lymphoma. H. pylori-negative MALT lymphomas do exist, but
they are a distinct minority (<10%); therefore, a diligent search for the organisms is necessary.
If they are not found, a suggestion for more representative sampling is usually well received by
clinicians, who also need to determine the extent of the lymphoma. The true dilemma occurs
in the case of H. pylori-negative CAG.
THE 3R APPROACH TO H. PYLORI-NEGATIVE CAG
Reconsider. When H. pylori is not found by HP/IHC one should first reconsider the initial
diagnosis of CAG. 16 After critically reviewing ~400 gastric biopsy specimens that had been
diagnosed as "CAG - No H. pylori detected by the H. pylori Blue stain" we found that only
approximately 120 cases represented true CAG; most of the other cases were reactive
gastropathy with small erosions (where neutrophils are usually abundant) 17; chronic inactive
gastritis (neutrophils may have been present in the lamina propria, but were not found in the
epithelium); and specimens from the cardia (where active inflammation is usually associated
with reflux and not with H. pylori infection) 18, 19. Of the real CAG cases, the HP/IHC yielded a
little over another 25% new positives. If going back to one's own dubious diagnoses seems
futile or painful, it may be helpful to consider that each previously undetected case is a patient
who will be treated and will not develop peptic ulcers, and whose risk of gastric cancer will be
reduced by more than 70%. Table 1 shows possible sources of inaccurate diagnoses of CAG.
Re-stain. If one is convinced that the histologic appearance is unequivocally that of CAG, a
more sensitive stain should be examined. Thus, if only H&E-stained slides were prepared, a
Giemsa (modified to Blue or Yellow) or a silver stain should be done; if still negative, the HP/IHC
(which ought to be done in first place) should then be ordered. If the HP/IHC is negative and
the impression of H. pylori gastritis is overwhelming, a second HP/IHC may be appropriate,
particularly if the control was not perfect.
This sequential strategy will eventually yield cases of unequivocal CAG with no H. pylori.
This is the time to
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Retreat. After reviewing the slides, restaining, and perhaps staining once more, those who
adhere to the precept "You are not obliged to finish the task, but neither are you free to neglect
it" will be probably satisfied that they have not neglected the task and will feel free to desist
from further action. They will issue a well-worded report stating that, in spite of the
characteristic histologic appearance, no H. pylori was found after a meticulous search (and a
long list of CPT codes). Such reports, however, are unlikely to gratify an inquisitive clinician,
who will be left wondering what should be done. Therefore, striving to finish the task is a
better alternative.
AFTER A DIAGNOSIS OF H. PYLORI-NEGATIVE CAG
Calling the clinician and explaining the circumstances that lead to an equivocal diagnosis is
probably the best way to avoid being perceived as a timid pathologist. Before discussing a case,
however, it is necessary to be maximally informed.
Two common clinical circumstances may decrease the gastric H. pylori load: recent use
of antibiotics and proton-pump inhibitors. Other causes for the failure to detect organisms in a
gastric biopsy are listed in table 2.
Antibiotic regimens not specifically prescribed for the treatment of H. pylori can
temporarily attenuate or eradicate the infection in a proportion of patients, depending on the
type of antibiotic used, the length of the treatment, and whether or not the patient was
coincidentally using PPIs. In most patients intentional or unintentional eradication causes the
disappearance of polymorphonuclear neutrophils from the gastric mucosa within days of the
start of the therapy 20, 21, leaving the histopathologic impression of a chronic inactive gastritis.
Incomplete and unsuccessful eradication, however, may greatly reduce the bacterial load (thus
making them undetectable in certain parts of the stomach) with little or no decrease of active
inflammation. If one can elicit a history of recent antibiotic treatment, a significant step is
made in finding an explanation for H. pylori CAG. Furthermore, the pathologist can predict that
the infection, inadequately treated, will soon reemerge, and a new set of biopsies in a few
weeks will likely show organisms.
A much more common reason for the apparent disappearance of H. pylori from some
compartments of the stomach (particularly the antrum) is the use of proton pump inhibitors
(PPIs). 10 Now available in more than ten different preparations, some of which can be obtained
over the counter, PPIs alter the gastric acid environment and induce shifts in the H. pylori
populations within the stomach, usually reducing the bacterial burden in the antrum 22 while
increasing the inflammation in the corpus23-25 26-28. Not only do these changes cause false
negative urea breath tests 29-31, but they have also been shown to hinder the histopathologic
detection of H. pylori in gastric biopsies 28. Thus, many diagnoses of H. pylori-negative CAG in
antral biopsies could be avoided if samples from the gastric coypus were also available.
These explanations may convince the clinician to perform a non-invasive test (serology,
urea breath test, fecal antigen detection) or to repeat the endoscopy and take more
representative biopsies. Nothing could be worse than leaving the impression that H. pylorinegative CAG is a final diagnosis and the patient does not need further workup.
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Table 1 - Causes of Helicobacter pylorinegative chronic active gastritis
 Crohn’s Disease

Focally enhanced gastritis

Lymphocytic gastritis with a strong
active component

Autoimmune gastritis with a strong
active component

Reflux carditis (activity limited to the
cardia)

Drug-related (e.g NSAIDs)

Biopsy near an erosion or ulcer

Granulomatous gastritis

Infectious (CMV, staphylococcus,
syphilis)
Table 2 - Possible reasons for failure to detect H.
pylori
Diagnostic error
Bacteria were missed
Condition is not chronic active gastritis
Sampling error
Proton pump inhibitors shift bacteria from
antrum into body
Factors causing an unfavorable local environment
for bacteria
Intestinal metaplasia
Ulcer
Suppression resulting from incidental antibiotic or
proton pump inhibitors use
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and peptic ulceration. Lancet 1984;1:1311-1315.
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3. Marshall BJ. Campylobacter pylori infection: diagnosis and therapy. Med J Aust
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4. Fennerty MB. Helicobacter pylori: why it still matters in 2005. Cleve Clin J Med 2005;72
Suppl 2:S1-7; discussion S14-21.:S1-S7.
5. Jyotheeswaran S, Shah AN, Jin HO, Potter GD, Ona FV, Chey WY. Prevalence of
Helicobacter pylori in peptic ulcer patients in greater Rochester, NY: is empirical triple
therapy justified? Am J Gastroenterol 1998;93:574-578.
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Kim HY. Has peptic ulcer disease changed during the past ten years in Korea? A
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10. Genta RM, Schuler CM, Lash RH. Helicobacter pylori-negative chronic active gastritis: a
new entity or the result of widespread acid inhibition? 134 ed. 2008:A - 125.
11. Genta RM. Where have all the Helicobacters gone? J Clin Gastroenterol 2007;41:727-728.
12. Oberhuber G, Hirsch M, Stolte M. High incidence of upper gastrointestinal tract
involvement in Crohn's disease. Virchows Arch 1998;432:49-52.
13. Genta RM, Hamner HW. The significance of lymphoid follicles in the interpretation of
gastric biopsy specimens. Arch Pathol Lab Med 1994;118:740-743.
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14. Fischbach W, Chan AO, Wong BC. Helicobacter pylori and Gastric Malignancy.
Helicobacter 2005;10 Suppl 1:34-9.:34-39.
15. Fischbach W, Goebeler ME, Ruskone-Fourmestraux A, Wundisch T, Neubauer A, Raderer
M, Savio A. Most patients with minimal histological residuals of gastric MALT lymphoma
after successful eradication of Helicobacter pylori can be managed safely by a watch and
wait strategy: experience from a large international series. Gut 2007;56:1685-1687.
16. Lash RH, Lauwers GY, Odze RD, Genta RM. Inflammatory Disorders of the Stomach. In:
Odze RD and Goldblum JR, eds. Surgical Pathology of the GI TRact, Liver, Biliary Tract, and
Pancreas. Second ed. Philadelphia: Sunders Elsevier, 2009:269-320.
17. Genta RM. Differential diagnosis of reactive gastropathy. Semin Diagn Pathol
2005;22:273-283.
18. Glickman JN, Fox V, Antonioli DA, Wang HH, Odze RD. Morphology of the cardia and
significance of carditis in pediatric patients. Am J Surg Pathol 2002;26:1032-1039.
19. Odze RD. Pathology of the gastroesophageal junction. Semin Diagn Pathol 2005;22:256265.
20. Go MF, Lew GM, Lichtenberger LM, Genta RM, Graham DY. Gastric mucosal
hydrophobicity and Helicobacter pylori: response to antimicrobial therapy. Am J
Gastroenterol 1993;88:1362-1365.
21. Franceschi F, Genta RM, Sepulveda AR. Gastric mucosa: long-term outcome after cure of
Helicobacter pylori infection. J Gastroenterol 2002;37 Suppl 13:17-23.:17-23.
22. Graham DY, Genta R, Evans DG, Reddy R, Clarridge JE, Olson CA, Edmonds AL, Siepman N.
Helicobacter pylori does not migrate from the antrum to the corpus in response to
omeprazole. Am J Gastroenterol 1996;91:2120-2124.
23. Genta RM. Acid suppression and gastric atrophy: sifting fact from fiction. Gut 1998;43
Suppl 1:S35-8.:S35-S38.
24. Genta RM. Atrophy, acid suppression and Helicobacter pylori infection: a tale of two
studies. Eur J Gastroenterol Hepatol 1999;11 Suppl 2:S29-33; discussion S43-5.:S29-S33.
25. Genta RM, Rindi G, Fiocca R, Magner DJ, D'Amico D, Levine DS. Effects of 6-12 months of
esomeprazole treatment on the gastric mucosa. Am J Gastroenterol 2003;98:1257-1265.
26. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, Havu N, Festen HP, Liedman B, Lamers CB,
Jansen JB, Dalenback J, Snel P, Nelis GF, Meuwissen SG. Atrophic gastritis and Helicobacter
pylori infection in patients with reflux esophagitis treated with omeprazole or
fundoplication. N Engl J Med 1996;334:1018-1022.
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27. Kuipers EJ, Uyterlinde AM, Pena AS, Hazenberg HJ, Bloemena E, Lindeman J, KlinkenbergKnol EC, Meuwissen SG. Increase of Helicobacter pylori-associated corpus gastritis during
acid suppressive therapy: implications for long-term safety. Am J Gastroenterol
1995;90:1401-1406.
28. Graham DY, Opekun AR, Yamaoka Y, Osato MS, El-Zimaity HM. Early events in proton
pump inhibitor-associated exacerbation of corpus gastritis. Aliment Pharmacol Ther
2003;17:193-200.
29. Adachi K, Fujishiro H, Mihara T, Komazawa Y, Kinoshita Y. Influence of lansoprazole,
famotidine, roxatidine and rebamipide administration on the urea breath test for the
diagnosis of Helicobacter pylori infection. J Gastroenterol Hepatol 2003;18:168-171.
30. Graham DY, Opekun AR, Hammoud F, Yamaoka Y, Reddy R, Osato MS, El-Zimaity HM.
Studies regarding the mechanism of false negative urea breath tests with proton pump
inhibitors. Am J Gastroenterol 2003;98:1005-1009.
31. Laine L, Estrada R, Trujillo M, Knigge K, Fennerty MB. Effect of proton-pump inhibitor
therapy on diagnostic testing for Helicobacter pylori. Ann Intern Med 1998;129:547-550.
Gastric Lumps and Bumps: A tale of two polyps
Henry D. Appelman, M.D.
Department of Pathology
University of Michigan
[email protected]
General Comments
The stomach is far less rich in polyps than is the colon. As a result, we know much less
about gastric polyps than colonic polyps, and the literature tends to be much more recent
and sparser. About 5 to 10% of biopsies of endoscopic gastric polyps are normal
mucosa. The reasons for this include the biopsy forceps missing the lesion, an intramural
lesion that is not available to endoscopic biopsy, normal mucosa that somehow turned
into an endoscopic bump and finally the pathologist doesn’t know a polyp when he or she
sees one. There are about 10 named gastric polyps involving the mucosa including two
surface adenomas, a deep adenoma, two heterotopias, juvenile and Peutz-Jeghers polyps,
polyps with no names and no literatures and finally the two that will be discussed here,
fundic gland polyps and hyperplastic polyps. From a clinician’s standpoint, the main
issue is whether the polyp is neoplastic, and if it is, then whether it is benign or
malignant. If it is not neoplastic, then in general, there does not seem to be a great
interest in polyp type, but we type it anyway. There are a few exceptions to this. It
appears from our practice that there is so little interest on the part of the endoscopists in
the mucosa adjacent to a polyp or in the mucosa in the rest of the stomach, that it is only
biopsied infrequently.
The two common polyps, hyperplastic and fundic gland, have not been rigidly defined in
the literature or in the textbooks, and as a result, we do not know their histologic limits.
Hyperplastic polyps
Historical perspective: During the 1960’s and 1970’s, the most common gastric polyp
had three names from 3 different years, regenerative polyp in 1965 1, hyperplastic polyp
in 19712 and hyperplaseogenous in 19734. The hyperplastic designation won over the
other two. In the early literature, these polyps were described as mainly single, although
a few patients made multiples. Histologically, they had a complex surface architecture,
deep cysts, and excess stroma. The architecture included coarse villiform changes on the
surface, ulcers both in the flat and villiform areas, an edematous inflamed lamina propria,
striking distortion of the pits, and glands did not participate. There were a variety of
different types of epithelium including normal pit or foveolar epithelium, hypertrophic pit
epithelium with huge distended goblet cells, and regenerative epithelium with the typical
syncytial undifferentiated cytoplasm and vesicular nuclei that characterize regenerative
epithelium everywhere. In some polyps, the epithelium is more atypical with elongated
stratified nuclei, more frequent mitoses, and less cytoplasmic mucin. Intestinal
metaplasia occurs, but is not a dominant component, and in one study from Japan, it was
mentioned that the likelihood of finding intestinal metaplasia in the polyp was less than
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finding it in the surrounding mucosa11. Of course this comment was based on Japanese
stomachs which commonly have intestinal metaplasia. I cannot find comparable
information on intestinal metaplasia in United States stomachs with these polyps.
Hyperplastic polyps are said to occur in three settings. The first, the sporadic
polyp is the most common. The second and third settings are based on the findings of
somewhat similar changes in polypoid mucosa on the gastric side of a gastroenteric
anastomosis, and on the top of the proximal-most gastric folds, originally described in
refluxers, but also found in non-refluxers. It turns out that the anastomosis and proximal
fold polyps never quite achieve the distortion, exuberance and stroma of the sporadic
polyps, so it is questionable whether they are all the same.
Elster in 1976 stated that “hyperplastic polyps of the stomach have no counterpart
in other parts of the gastrointestinal tract and are thereby organotypical”4. This was
reemphasized by Hattori from Japan nine years later, and it is clear that this is a true
analysis11. We see occasional polyps in other sites, especially the colon, that have
somewhat similar architecture and stroma, but they never quite look the same.
Is there a universally accepted, clear-cut definition of the hyperplastic polyp? In the
literature and in the textbooks it becomes hardly any author ever actually defines it, but
the authors do describe it, although the descriptions are not necessarily comparable. In
one description from Stolte et al from Germany in 199512, a hyperplastic polyp was
characterized by lengthening, tortuosity, and variable cystic dilatation of foveolae,
widening of the stroma and edema, increased numbers and dilatation of the capillaries
and apical erosions. However, this is a description and not a definition, and it does not
tell us what features are required for the diagnosis of hyperplastic polyp and to what
extent they must be present. As a result, whenever a study on hyperplastic polyps was
published, it was not clear if the authors of those studies actually analyzed the same
lesions. We also have no idea how the full-blown polyp develops. Does it start from a
localized focus of pit expansion and stromal edema and inflammation or simply from a
small polyp containing only elongated foveolae, a lesion which has been designated as
focal or polypoid foveolar hyperplasia? Not only don’t we know how this lesion evolves,
but we have no clue as to what is the stimulus for its development. We don’t know if it is
inflammatory or neoplastic or a mixture. If we look at small lesions that have all of the
architectural and stromal features, they appear to arise in the pit or foveolar compartment
and look like they are tacked onto the surface. We must be aware of the possibility that
since there are no minimal requirements for the diagnosis of hyperplastic polyp, a lot of
things are thrown into that category that may not belong there, and some of these are
presumably included in published studies of hyperplastic polyps. This is a common
situation throughout not just pathology but medicine in general, namely a tendency to try
to fit everything into existing categories, rather than separating them into categories that
currently are not named.
There is a fact (or rumor) that hyperplastic polyps occur in inflamed stomachs 13, 14,
as much as 40% with Helicobacter pylori, and others with atrophic gastritis including the
autoimmune type. Reports also indicate that there may be additional chemical or reactive
gastropathy, but this is so common in stomachs these days, that its significance is
questionable. Data such as this suggests that these are inflammatory lesions, but we don’t
know that for a fact.
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It is also stated that dysplasia occurs in anywhere from 1 to 20% of hyperplastic
polyps, and this is size related with more dysplasia in larger lesions. Cancers have even
been described in a very, very few polyps. There is clearly something wrong with data
that puts anything between 1 and 20%. The inflammatory and dysplastic data had been
based on studies of a polyp that had and still has no minimal diagnostic criteria and also
on publications some of which are based on studies including only whole intact polyps
and on other studies that included biopsies as well which potentially introduced sampling
problems.
What separates low-grade dysplasia from regenerative epithelium in these polyps
is exactly the same thing that separates low-grade dysplasia from regenerative epithelium
everywhere else in the gastrointestinal tract. It is sometimes impossible to tell which
kind of epithelium is present. These polyps are sitting in stomachs that contain a lot of
solid material and which have churning and mixing motility activities, so these polyps are
probably banged around a lot. Therefore, whatever the authors call this epithelium is
what it gets published as, and perhaps this accounts for the dysplasia rate that varies from
1 to 20%. Furthermore, is there anything that separates a hyperplastic polyp with
dysplasia from an adenoma with secondary hyperplastic polyp changes? We have seen
some adenomas in which fairly extensive hyperplastic polyp-like changes involve the
surface. Biopsies may exacerbate this distinction because of sampling.
The neoplastic associations, regardless of how we interpret the data, color
surveillance recommendations. For instance, the American Society for Gastrointestinal
Endoscopy has published guidelines in 2006 that are available on its website
(www.ASGE.org). These guidelines state that the polyps should be endoscopically
excised wherever feasible and clinically appropriate. No surveillance endoscopy is
necessary after adequate sampling (there is no definition of adequate sampling) or
removal of nondysplastic polyps. Topographical biopsy “mapping” may be useful to
detect the presence of gastritis and intestinal metaplasia.
Topographical biopsy mapping is not done at our institution. I am sure that there
are institutions where it is the rule, but I don’t even know that for a fact.
Summary: we do not know what hyperplastic polyps are, what causes them, what their
precursors are, and there are no minimal criteria for diagnosis. It is not clear that all
hyperplastic polyp studies have actually studied the same polyps, so the results of these
studied probably should not be pooled for analysis. The dysplasia/carcinoma risk is not
settled. Nevertheless, we will keep trying!
Fundic gland polyps
General Comments: Beginning in the 1970’s we started seeing another gastric polyp
which also had little published information. This is what we now call a fundic gland
polyp (FGP). These days it is the most common of all gastric polyps, probably 7 to 1 over
its closest competitor, the hyperplastic polyp. Sometimes these are part of a syndrome,
familial adenomatous polyposis, that includes cancers, but cancers for all intents and
purposes don’t occur in fundic gland polyps. They also tend to carpet the fundus in the
body, especially in the patients with FAP. As with hyperplastic polyps, they also appear
to be tacked onto the top of the normal oxyntic mucosa indicating that they have
developed within the pit compartment.
3
Historical perspective: It appears that the first recognition or name for fundic gland
polyp was by Elster in 1976. He referred to these as “cysts of gastric glands”, and then a
year later he changes the name to “fundic gland cysts”4,15. These were described as
“fundic glandular cysts in otherwise normal gastric mucosa”. However, an analysis of
the illustrations in his papers indicates that this otherwise normal gastric mucosa is really
not normal but the superficial glands are disorganized, clustered, often budding and
branching. Watanabe from Japan in an analysis of gastric lesions in FAP may have been
the first to use the fundic gland polyp designation16. In his paper, there was no definition
of fundic gland polyp, just many illustrations and descriptions such as “simple
hyperplasia of fundic glands”. Actually, it is difficult to recognize any hyperplasia, since
there are fewer glands per unit area in FGPs than in normal oxyntic mucosa. What was
mentioned in Watanabe’s paper was the fact that the glands were irregular, tortuous,
sometimes branching; that is, they were disorganized. Before the Elster and Watanabe
papers, we only recognized two types of gastric polyps, adenomas and hyperplastic
polyps. Fundic gland polyps were probably included in the mix. We did not recognize
them as separate, so we probably called them hyperplastic, since they did not look like
adenomas. They don’t have adenoma-like dysplasia.
Diagnostic criteria: In the twelve months from August, 2005 through July, 2006, four
pathologists in the gastrointestinal subspecialty sign-out service at the University of
Michigan made the diagnosis of fundic gland polyps in 306 patients, 16 of whom had
familial adenomatous polyposis. The age distribution of patients with these polyps
corresponds to the age of the patients who were biopsied during upper endoscopy. There
were twice as many women as men, but this has been found in other studies. Regardless,
when I asked my colleagues, and even myself how to define a fundic gland polyp and to
list the minimal diagnostic criteria, there was no consensus. Nevertheless, I showed them
several polyps which had a variety of changes including short pits, long pits, clusters of
glands beneath the surface that varied from area to area, cysts, some of which were gland
cysts, some pit cysts and some mixed cysts, and expanded lamina propria which often
had a lot of smooth muscle. Everybody diagnosed them as fundic gland polyps, and the
basic reasons for diagnosis boiled down to “because they looks like it”. I showed the
same polyps to a bunch of our house officers and they came up with the same diagnosis
for the same reason. Therefore, we seem to know what a fundic gland polyp looks like,
and we can teach other people how to recognize it, but we have a great deal of difficulty
defining what it is leads us to that diagnosis.
As was true for hyperplastic polyps, there are no published minimal criteria that
will allow a bump in the gastric oxyntic mucosa to be called a FGP. A look at the
literature and in the textbooks and even in the World Health Organization Classification
of Tumors published in 2000, the definitions are anything but uniform.
The Appelman Approach: FGPs for dummies (for what it is worth): FGPs are
architecturally complex but cytologically simple lesions. They are architecturally
complex in that the entire mucosa is structurally altered when compared to normal, and
they are cytologically simple because all cells are mature gastric epithelial cells. Perhaps
because of this combination, they have been referred to as hamartomas. There are two
sets of architectural abnormalities, epithelial and stromal. The intensity of these changes
varies greatly from one polyp to another. The epithelial architectural alterations involve
both the pits and the glands. The pit changes involve length. In most areas of these
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polyps, the pits are shorter than normal, but in some polyps, they are longer. Pits also
extend deeply into the mucosa and form cysts. The gland changes are more complex and
include clusters of glands beneath the surface, parietal cells in the upper parts of the pits
or even on the surface, glands with irregular branches and buds, and cystic glands toward
the middle and deeper parts of the polyps. Actually, there are many cysts that have a
mixture of pit and gland epithelium. The stromal changes include an increase in the
amount of lamina propria when compared to normal oxyntic mucosa. This bonus stroma
may be edematous, may have inflammation, and often has smooth muscle bundles,
probably not extending from the muscularis mucosae, considering that these polyps are
tacked onto the surface. The bigger the polyp, the larger the number and size of the cysts.
This suggests that these polyps enlarge by an increase in number and size of cysts.
Fundic gland polyps are said to occur in three settings. First are those that are
associated with familial adenomatous polyposis, in other words in patients with a
germline mutation in the FAP gene. Second are sporadic polyps, that is, not in FAP
patients, but occurring in people who are not taking proton pump inhibitors. Third are
sporadic polyps occurring in patients who have been treated with proton pump inhibitors.
Genetic Changes: The polyps in different patients with FAP do not look the same, but
neither do the polyps from single FAP patients. However, they all have variations on the
same abnormalities including pit and gland architecture and lamina propria changes. In
one study on FAP patients with known germline APC gene mutations, APC gene
alterations were found in at least one polyp in 9 of these 11 patients, but not all polyps
from individual patients had the detectable gene alterations23. Conceivably, this variation
may be due to the fact that this is a 9-year-old study, and there may be better detection
systems now. Furthermore, no individual patient had more than one APC gene alteration
in the polyps.
Genetic changes were also analyzed in sporadic fundic gland polyps that have no
APC gene defects. In one study from the USA, 52 of 57 polyps from 40 patients have
beta-catenin mutations24. In this study, there was no mention if the patients were taking
proton pump inhibitors. In another study from Japan, 29 of 45 such polyps from 35
patients had the beta-catenin mutation, and none of these patients were on long term
proton pump inhibitors25. In both these studies, the mutations were found in both the pit
epithelium and in the gland cyst epithelium in almost all polyps, and different mutations
were found in different polyps from the same patients, in contrast to the findings of the
FAP patients. In another study of patients taking proton pump inhibitors, CpG island
methylation was found to be more common in sporadic polyps, but we have not had any
data since the publication of that study 6 years ago28.
Do proton pump inhibitors cause FGPs? Twenty years ago these polyps were
curiosities, but there has been a striking increase in incidence that seems to coincide with
the increased use of PPIs. The data regarding cause and effect are conflicting. In one
study from the USA, two groups of patients were compared, a larger group not taking
proton pump inhibitors who only had a single upper endoscopy, and a smaller group
taking PPIs who had both an initial exam and a follow-up exam if they had no polyps at
the first exam20. Comparing these two groups, FGPs were much more common in the
PPI group, but so were other polyps, and in this study, there was no second endoscopy for
the group not taking PPIs. Also, FGPs were described simply as composed of cystic
fundic glands, nothing more and nothing less.
5
The second study from Germany compared over 28,000 patients not taking PPIs
with over 2200 patients on the drugs, and the prevalence of FGPs was identical22. We do
know that PPIs induce hypertrophy of parietal cells with formation of apical snouts, and
they also induce fundic gland cysts. Both of these changes appear to increase with
increasing length of time the patients are taking PPIs. Both of these changes appear to be
secondary to the hypergastrinemia that results from inhibition of gastric acid production
by the drugs.
FGPs contain many parietal cells. The parietal cells in the polyps seem to
respond to PPIs as do the native parietal cells, namely they undergo hypertrophy and
develop snouts. Perhaps PPIs do not cause FGPs, but they may make tiny ones bigger
and endoscopically apparent as a result of the parietal cell hypertrophy and increase in
gland cysts21.
Finally, there is some literature suggesting that in patients with fundic gland polyps,
there is an increased risk for colonic adenomas and carcinomas. However, the
studies do not all come to the same conclusion9, 30. In a recent study, FGPs were
associated with increased prevalence of hyperplastic colonic polyps in men and colonic
adenomas in women mainly over 60 years of age, but there was no increased association
with adenocarcinoma.
Summary: Fundic gland polyps occur in familial adenomatous polyposis but also
spontaneously, and their incidence has increased at the same time as has the use of proton
pump inhibitors. They are architecturally complex and cytologically simple polyps.
There is no proof that PPIs induce polyps with the same architectural complexity that
occurs in FAP patients. The parietal cells in FGPs respond to PPIs exactly like parietal
cells in flat mucosa. This may make some tiny FGPs enlarge and become endoscopic
polyps. Genetic abnormalities have been found in both FAP and sporadic FGPs, and
there may be some alteration in PPI associated polyps. The association between FGPs
and colonic neoplasia is not clearly established. Finally, until we have a rigid definition
of the minimal criteria for a fundic gland polyp, we will have no clue as to whether PPIs
or anything else cause them.
References for Stomach Polyps
General Polyp References
1. Ming S-C, Goldman H. Gastric polyps. A histogenetic classification and its relation
to carcinoma. Cance. 18:721-726, 1965
2. Tomasulo J. Gastric polyps. Histologic types and their relationship to gastric
carcinoma. Vanver. 27:1346-1355, 1971
3. Goldman DS, Appelman HD: Gastric mucosal polyps. Am J Clin Pathol
1972;58:434-444
4. Elster K. Histologic classification of gastric polyps. In: Morson BC, ed. Pathology of
the Gastrointestinal Tract. Berlin: Springer-Verlag, 1976:77-93
5. Nakamura T, Nakano G-I. Histopathological classification and malignant change in
gastric polyps. J Clin Pathol. 38:754-764, 1985
6
6. Appelman HD. Localized and extensive expansions of the gastric mucosa: mucosal
polyps and giant folds. In: Appelman HD, ed. Pathology of the Esophagus, Stomach
and Duodenum. New York: Churchill Livingstone, 1984:79-104
7. Appelman HD. Chapter 9, Non-neoplastic tumor-like lesions, predominantly
epithelial, in Lewin KJ, Appelman HD. Tumors of the Esophagus and Stomach.
Fascicle 18, Third Series, Atlas of Tumor Pathology, Armed Forces Institute of
Pathology, Washington, D.C., 1996:183-232
8. Park DY, Lauwers GY. Gastric polyps: classification and management. Arch Pathol
Lab Med. 132:633-640, 2008
9. Carmack SW, Genta RM, Schuler CM, Saboorian MH. The current spectrum of
gastric polyps: a 1-year national study of over 120,000 patients. Am J Gaastroenterol.
104:1524-1532, 2009
10. Carmack SW, Genta RM, Graham DY, Lauwers GY. Management of gastric polyps: a
pathology-based guide for gastroenterologists. Nat. Rev. Gastroenterol. Hepatol 6:331-341,
2009
Hyperplastic Polyp References
11. Hattori T. Morphologic range of hyperplastic polyps and carcinomas arising in
hyperplastic polyps of the stomach. J Clin Pathol. 1985;38:622-630
12. Stolte M, Bethke B, Sticht T, Burkhard U. Differentiation of focal foveolar
hyperplasia from hyperplastic polyps in gastric biopsy material. Path Res Pract.
191:1198-1202, 1995
13. Abraham SC, Singh VK, Yardley JH, Wu T-T. Hyperplastic polyps of the stomach.
Association with histologic patterns of gastritis and gastric atrophy. Am J Surg
Pathol. 25:500-507, 2001
14. Jain R, Chetty R. Gastric hyperplastic polyps: a review. Dig Dis Sci. 54:1839-46, 2009.
Fundic Gland Polyp References
15. Elster K, Eidt H, Ottenjann R, Rosch W, Seifert E. The glandular cyst, a polypoid
lesion of the gastric mucosa. Dtsch Med Wochenschr. 1977 Feb 11;102(6):183-7.
16. Watanabe H, Enjoji M, Yao T, Ohsato K. Gastric lesions in familial adenomatosis
coli. Their incidence and histologic analysis. Hum Pathol. 9:269-283, 1978
17. Sipponen P, Laxen F, Seppala K. Cystic “hamartomatous” gastric polyps: a disorder
of oxyntic glands. Histopathol. 7:729-737, 1983
18. Iida M, Yao T, Watanabe H, Itoh H, Iwashita A. fundic gland polyposis in patients
without familial adenomatosis coli: its incidence and clinical features. Gastroenterol.
86:1437-1442, 1984
19. Lee RG, Burt RW. The histopathology of fundic gland polyps of the stomach. Am J
Clin Pathol. 86:498-503, 1986
20. Choudhry U, Boyce HW Jr, Coppola D. Proton pump inhibitor-associated gastric
polyps. A retrospective analysis of their frequency, and endoscopic, histologic and
untrastructural characteristics. Am J Clin Pathol. 110:615-621, 1998
21. Cats A, Schenk BE, Bloemena E, et al. Parietal cell trotrusions and fundic gland cysts
during omeprazole maintenance treatment. Hum Pathol. 31:684-690, 2000
22. Vieth M. Stolts M. Fundic gland polyps are not induced by proton pump inhibitor
therapy. Am J Clin Pathol. 116:716-720, 2001
23. Abraham SC, Nobukawa B, Giardiella FM, et al. Fundic gland polyps in familial
adenomatous polyposis. Neo-plasms with frequent somatic adenomatous polyposis
coli gene alterations. Am J Pathol. 157:747-754, 2000
7
24. Abraham SC, Nobukawa B, Giardiello FM, et al. Sporadic fundic gland polyps.
Common gastric polyps arising through activating mutations in the ß-catenin gene.
Am J Pathol. 158:1005-1010, 2001
25. Sekine S, Shibata T, Yamauchi Y, et al. ß-catenin mutations in sporadic fundic gland
polyps. Virchows Arch. 440:381-386, 2002
26. Abraham SC, Park SJ, Mugartegui L, et al. Sporadic fundic gland polyps with
epithelial dysplasia. Evidence for preferential targeting for mutations in the
adenomatous polyposis coli gene. Am J Pathol. 161:1735-1742, 2002
27. Torberson M, Le J-H, Cruz-Correa M, et al. Sporadic fundic gland polyposis: a
clinical, histological, and molecular analysis. Mod Pathol. 15:716-723, 2002
28. Abraham SC, Park SJ, Cruz-Correa M, et al. Frequent CpG island methylation in
sporadic and syndromic gastric fundic gland polyps. Am J Clin Pathol. 122:740-746,
2004
29. Burt RW. Gastric fundic gland polyps. Gastroenterol. 125:1462-1469, 2003
30. Teichmann J, Weickert U, Riemann JF. Gastric fundic gland polyps and colonic
polyps—is there a link, really? Eur J Med Res. 13:192-195, 2008
8
Lauwers-Early gastric neoplasms
1
EARLY GASTRIC NEOPLASMS: DIAGNOSES AND IMPLICATIONS
Gregory Y. Lauwers, M.D.
Director, Division of Surgical Pathology
Director, Gastrointestinal Pathology Service
Massachusetts General Hospital and
Harvard Medical School
Boston, Massachusetts, USA
[email protected]
Despite a marked decline in incidence in the West and some decrease in the East, gastric
cancer remains a significant cause of morbidity and cancer related deaths worldwide. The
prevalence of gastric cancer is closely related to prevalence of Helicobacter pylori infection and
shows wide geographic variation. Subsequent chronic gastritis, atrophy, and intestinal metaplasia
are lesions that confer a high risk for the development of gastric cancer, while gastric dysplasia, the
penultimate stage of the carcinogenetic cascade, is a direct neoplastic precursor lesion.2, 4, 14-16, 18, 22,
36, 41, 60, 64
Evidence for gastric dysplasia as a direct precursor of adenocarcinoma stems from
observational studies reporting high-grade dysplasia (HGD) in close proximity to 40-100% of early
gastric cancers and 5-80% of advanced adenocarcinomas.48, 61, 95 Moreover, dysplasia is also a
marker of increased risk for cancer elsewhere in the gastric mucosa.
As with gastric cancer, the prevalence of dysplasia shows wide geographic variations. The
difference is likely related to variations in the genetic makeup of the population, as well as
variations in environmental factors, such as the prevalence of Helicobacter pylori infection (and
subtype) and the age at which the infection is acquired.2, 6, 11, 14-16, 18, 22, 25, 51, 60, 64, 79, 95 The frequency of
dysplasia also varies with the underlying etiology. For instance, prevalence rates of up to 40%
have been reported in patients with pernicious anemia but the disease confers only a moderate
increase in risk of developing gastric cancer.3, 6, 33, 94 In the setting of familial adenomatous polyposis
(FAP), flat or polypoid dysplasias, typically antral in location, are frequently multiple and may be
seen in 2-50% of patients.7, 8, 10, 21, 31, 38, 74, 75, 80, 82, 86, 87 Patients with a gastric remnant status post
gastrectomy, Menetrier’s disease, or Peutz-Jegher’s syndrome also are at increased risk.5, 44, 81, 89
2
Classification of Gastric Epithelial Dysplasia
The classification of dysplastic lesions has been controversial, with various diagnostic
criteria used across the world. Japanese authors refer to these as borderline (Group 3 or 4)
lesions, while the terms gastric adenoma (for raised lesions) and gastric dysplasia (for
flat/depressed lesions) have been widely used in the Western literature.32, 67, 77
Earlier guidelines for the diagnosis and grading of gastric dysplasia embraced a threetiered system of mild, moderate and severe dysplasia. As in any segment of the gastrointestinal
tract, dysplasia was defined as "unequivocally neoplastic epithelium that may be associated with or
give rise to invasive adenocarcinoma."54, 57, 66 Later schemes have proposed a two-tiered system of
low- and high-grade dysplasia,48, 69, 70, 78 which has proven to be more reproducible and provides a
clinically meaningful risk stratification.32, 47 The WHO recommends the terminology of non-invasive
low-grade and high-grade intraepithelial neoplasia, and defines carcinoma as invasion into the
lamina propria or beyond.34 However, the terminology of adenoma/dysplasia is widely entrenched,
and continues to be used, particularly in North America.
A significant debate has occurred over differentiating adenocarcinoma from high-grade
dysplasia. Furthermore, the complexity of cyto-architectural features has been considered to be of
paramount importance for the diagnosis of carcinoma in Japan, while breach of the basement
membrane and invasion into the lamina propria has been considered the sine qua non of
malignancy and hence a prerequisite for the diagnosis of cancer in the West.47, 76 As an attempt to
bridge differences, the Vienna classification was developed as a consensus between Western and
Asian investigators.78 This consensus view takes into account the discrepancies in the reporting of
dysplasia between Japanese and Western pathologists. For example, non-invasive intramucosal
neoplastic lesions with high-grade cellular and/or architectural atypia are classified as
"intramucosal carcinoma" in Japan, whereas similar lesions are diagnosed as high-grade dysplasia
by most Western pathologists. In the Vienna classification, high-grade lesions without invasion of
the lamina propria and adenocarcinomas with invasion confined to the lamina propria, are now
placed into a single diagnostic category, a rationale supported by current endoscopic management.
3
Phenotypic variants of gastric dysplasia
Most examples of dysplasia have an "intestinal" phenotype, i.e., resembling colonic
adenomas. These lesions are commonly referred to as adenomatous (or type I) dysplasia. The
histologic characteristics include crowded glands lined by tall columnar cells with pencillate,
overlapping, and hyperchromatic nuclei which show pseudostratification and inconspicuous
nucleoli.42 Other less common histologic variants of include foveolar (type II or non-adenomatous)
dysplasia and pyloric type dysplasia.42 The distinctive feature of Type II dysplasia is the presence
of glands lined by either low cuboidal or columnar epithelium with pale-clear cytoplasm, round-oval,
vesicular nuclei and variably prominent nucleoli. Although prior studies have suggested that this
form of dysplasia is almost always low-grade,1 more recent studies indicate that Type II dysplasia
may be associated with distinct clinico-pathological characteristics and is more often high-grade
when evaluated in a high-risk population.63 Some authors have indicated that Type II dysplasia is
more commonly associated with poorly-differentiated adenocarcinoma.42, 56, 58
Pyloric type dysplasia is a recently recognized type of dysplasia. Frequently observed in
the body fundus, it is commonly seen in the older population. Some series indicate that it is
commonly shows high grade dysplasia.13
Tubule neck (or globoid) dysplasia is exceedingly rare and is believed to be a precursor of
diffuse-type gastric carcinoma.30 It occurs in non-metaplastic gastric epithelium and appears as
enlarged, clear cells occupying the gland neck region and confined within the basement
membrane.
In the setting of inherited germline E-cadherin/CDH1 gene mutation, prophylactic
gastrectomies have shown examples of "signet ring cell carcinoma in situ," often with a "pagetoid"
spread between the gastric foveolar and glandular epithelium within the basement membrane. 12, 50
These changes are often multifocal and have a predilection for the proximal stomach and the bodyantral transitional zone.
4
Grading of gastric dysplasia
The two-tiered scheme of low and high grade is widely used in all classification schemes.
Practically, gastric biopsies need to be categorized into one of several categories: negative for
dysplasia, indefinite for dysplasia, low grade dysplasia/adenoma, high grade dysplasia/adenoma,
intramucosal carcinoma or an invasive adenocarcinoma.
Indefinite for dysplasia
There are cases for which one cannot establish a diagnosis with certainty. Commonly it
means differentiating between reactive epithelial changes and dysplasia. It should be seen as a
provisional designation that emphasizes the need to follow up the patient and to obtain additional
biopsies. Alternatively, it should not be used as a wastebasket term for all cases with reactive
atypia which are obviously in response to inflammatory or direct mucosal injury. Clues to the
reactive nature of the epithelial changes includes the presence of vascular congestion and a
gradual rather then abrupt transition between the atypical and adjacent normal cells.54, 66
Low-grade dysplasia (Adenoma; Non-invasive intraepithelial neoplasia-low grade)
We used the term "adenoma" for elevated mucosal lesions and low grade dysplasia for flat
lesions that show minimal architectural disarray and cytological atypia.32, 47, 54, 66, 95 As mentioned
earlier, in most cases, the morphological appearance is reminiscent of colonic adenomas and the
lesions often occur in a background of intestinal metaplasia. The criteria for separating Type II
dysplasia into low and high grade categories are not well established. The presence of gastric
foveolar type epithelium with elongated, hyperchromatic nuclei that show some degree of
pseudostratification is categorized as low-grade Type II dysplasia. Although a designation of lowgrade implies a comparatively reduced risk of malignant transformation, it must be recognized that
low-grade dysplasia occurring in a background of extensive intestinal metaplasia may be
associated with a higher risk of malignancy.71
5
High-grade dysplasia (Adenoma with high-grade dysplasia; Non-invasive intraepithelial neoplasiahigh grade)
Marked cytological atypia or architectural complexity deserve a diagnosis of high-grade
dysplasia. High grade dysplastic glands are commonly lined by rounded, pleomorphic nuclei that
show prominent nucleoli and loss of polarity. Marked irregularities of the nuclear membrane and
clumping of chromatin are also features often associated with high grade dysplasia. However,
marked glandular crowding, budding, and intra-luminal bridges should raise the question of early
gastric cancer. Typical or atypical mitoses may be present in either low grade or high grade
dysplasia, but are more often and more easily discernible in the latter category.32, 47, 69
Intramucosal adenocarcinoma
The controversy and disparity in literature regarding separation of "dysplasia" from
"carcinoma" has already been alluded to above. The current approach to this problem is based on
two facts: 1) "invasion," particularly when limited to the lamina propria, is difficult to identify on
routine histology, and 2) intramucosal adenocarcinomas have a less than 10% risk of nodal
metastases24 and neoplastic lesions with invasion of the lamina propria but confined to the mucosa
are, therefore, amenable to a conservative approach through endoscopic resection. Currently,
lesions which show marked architectural atypia in the form of fused glandular pattern, cribriforming
or intra-luminal necrosis, as well as those that show definite evidence of invasion into the lamina
propria in the form of single cells or small clusters of cells, are categorized as intramucosal
adenocarcinoma.
Characteristics of intramucosal of adenocarcinomas
Intramucosal adenocarcinoma belong to the category of early gastric cancers (EGC),
which are defined as invasive adenocarcinomas confined to the mucosa or submucosa, whether
lymph node metastasis is present or not.29, 49 In Western series, EGCs represent between 15% and
21% of all newly diagnosed cancers, while in Japan, they account for over 50% of the cases.23, 28, 37,
83
The higher prevalence of gastric cancer, a more liberal use of upper endoscopy, perhaps a
better technique including chromoendoscopy, and a difference in diagnostic criteria may explain
the difference.
6
Most EGCs are small, measuring between 2 cm and 5 cm and localized on the lesser
curvature and around the angulus.49, 55 Multiple tumors are seen in 3% to 13% of the patients, and
are associated with a worse prognosis.23, 53
The Paris classification divides EGCs into 3 types based on the endoscopic macroscopic
appearance (figure 2): Protruded (type I), superficial (type II), and excavated (type III). 40 Type II is
further subdivided into IIa (elevated type), IIb (flat type), and IIc (depressed type). Superficial (type
II) EGCs account for about 80% of the cases, with type IIc being the most common subtype. 90 Type
IIb accounts for 58% of small tumors measuring less than 5 mm. 45 Notably, this endoscopic
classification has shown to be a good indicator of the risk for nodal metastasis, reportedly low in
type Ia or IIa EGC.19
The majority of EGCs are well differentiated glandular carcinomas. Tubular and papillary
variants represent 52% and 37% of cases, respectively, and can be difficult to differentiate from
dysplasia (see above). Signet ring cell carcinoma and poorly differentiated carcinoma represent
26% and 14% of the cases, and are usually depressed or ulcerated (types IIc and III).23, 49, 90 Diffuse
type EGCs tend to have a greater depth of invasion.19
Progression and outcome of early gastric neoplasms
A) Low –grade dysplasia
Although assessing regression of low-grade dysplasia is difficult because of sampling
issues and inter-observer variation in the diagnosis, it has been reported in 38-75%, while
persistence is seen in 19-50% of cases.6, 9, 46
Historical data have reported progression to adenocarcinoma in 0-23% of patients with
LGD within a span of 1-4 years, but recent studies indicated a lower risk of progression (0-9%),
while there is a significant risk of malignant transformation associated in high-grade (10-100%).68, 91
7
B) High-grade dysplasia
This diagnosis is more ominous, since HGD has been noted to persist in 14-58% of the
cases and to progress to cancer in 60-85% of patients over a median interval of 4-48 months.20, 27,
43, 46, 70, 73, 91
Regression, though, also has been reported, and varies from 0-16%.
C) Intramucosal adenocarcinoma
In a series of patients diagnosed with EGC and followed without surgery, 63% of the
tumors progressed to advanced carcinomas over a span of 6 to 88 months. 84 However, when
resected, the prognosis of EGCs is excellent, with a five-year survival rate greater than 90% in
most series.17, 23, 26, 39, 83 The size and depth of invasion are the two major prognostic indicators, with
the larger the diameter, the greater the risk of submucosal infiltration. 28, 52, 93 Notably, the risk of
invasion should not be overlooked even in very small tumors. In one series, 15.5% of 3-5 mm
EGCs invaded the submucosa.62 Even for intramucosal EGCs, lymph node metastases have been
reported in up to 7% of cases. However, the five-year survival remains close to 100%.23, 52, 93 For
EGCs extending into the submucosa, the rate of lymph node metastases is between 8% and 25%,
and the five-year survival is 80% to 90%.23, 93
Management of early gastric neoplasms
Given the demonstrated low rate of malignant transformation of low grade dysplasis and
the development of newer endoscopic imaging techniques, such as chromoendoscopy, annual
endoscopic surveillance with re-biopsy is typically performed and surgical resection is not
necessary.72,
88
Similarly, a diagnosis of indefinite for dysplasia should also prompt endoscopic
surveillance and biopsy.
Although a diagnosis of high-grade dysplasis in years past was the indication for surgery,
nowdays, this diagnosis as well as a diagnosis of intramucosal adenocarcinoma (provided deep
submucosal invasion is ruled out with certainty with endoscopic ultrasound) will be managed
endoscopically since endoscopic mucosal resection and submucosal dissection offer definitive
therapy.
8
Endoscopic mucosal resection has rapidly become the treatment of choice in association
with endoscopic ultrasound for staging. The primary criteria of EGC amenable to EMR are elevated
lesions less than 2 cm in size, depressed lesions less than 1 cm in size without ulceration, and the
absence of lymph node metastasis. Endoscopic submucosal dissection (ESD) is a more recent
method developed in order to increase the en bloc and R0 resection rate, especially for lesions
larger than 20 mm in diameter. Drawbacks of endoscopic submucosal dissection include the fact
that it is technically a substantially more difficult procedure and that it is associated with a higher
perforation rate.35, 59, 65, 92 Finally, the eradication of H. pylori improves prognosis of patients with
early neoplasms. In a study of 132 patients with EGC who underwent EMR, no new cases of
gastric cancer were observed after resection when H. pylori was eradicated; in contrast, 13.5% of
untreated patients had new early-stage intestinal-type gastric cancer.85
9
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Update On Gastric Cancer: Molecular Pathology and Targeted Therapies
Antonia R. Sepulveda MD., PhD,
Department of Pathology and Laboratory Medicine,
University of Pennsylvania, Philadelphia, PA
Gastric carcinoma is the fourth most frequent cancer worldwide, representing the second most
common cause of death from cancer (approximately 700,000/year)1. In the United States 21,259
new cases of stomach cancer were estimated in 2007, remaining stable at 21,130 new cases in
2009 2. The incidence of gastric cancers (GC) involving the distal stomach, body and fundus,
which have been associated with Helicobacter infection have declined over past decades, while
adenocarcinomas of the cardia and gastroesophageal GE-junction (GEJ) is increasing. Combined
figures for GE junction and gastric cancer indicate 1.4 million new cases diagnosed annually
with 1.1 million attributed deaths 3.
Clinical trials of targeted therapies for advanced gastric cancer have generally included gastric
and gastroesophageal junction adenocarcinomas. Additionally, some trials used the classification
of GE junction adenocarcinomas as described by Siewert, classifying GE junction carcinomas
into types I, II and III depending on the relative extent of involvement of the esophagus and
stomach 4.
Histopathologically and genetically, gastric and gastro-esophageal junction cancers are
heterogeneous and are influenced by gene-environment interactions resulting in activation of
multiple molecular pathways. The molecular subtypes of gastric cancer include three main
groups of tumors characterized by either the chromosomal instability pathway (CIN), the
microsatellite instability pathway (MSI), and the CpG island methylator phenotype pathway
(reviewed in 5). Currently, it is not clear whether and how these subtypes of gastric and GEJ
carcinomas can be useful in clinical practice to predict specific pathways with mutational and
regulatory alterations that may interfere with targeted therapies.
Surgical resection is the only potentially curative option for gastric cancer and is recommended
for stages Tis-T3N0-N2M0 or T4N0M0 6. For tumors not amenable to surgical curative
resection, including locally advanced, recurrent, or metastatic cancers, a number of
chemotherapy regimens can be used, albeit with limited success, such that 5 year survival rates
for advanced gastric and GE junction cancers remain extremely poor at 20-50% for stages II-III
and 5-10% for stage IV tumors. Recently, a number of agents that target specific molecules in
cancer related pathways have become available and are being tested in patients with gastric and
GE junction carcinomas. Here we will review the targeted therapies that have advanced to phase
II or III clinical trials and offer promise in the treatment of these cancers. In addition, the specific
roles of pathology and molecular testing as it relates to specific targeted therapies will be
discussed.
Cell surface receptor inhibitors
EGFR Family Inhibitors
Current available therapies target the EGFR pathways through inhibition of the EGFR using two
different mechanisms:1) inhibition of the EGFR via monoclonal antibodies (i.e. cetuximab,
matuzamab, panitumumab, trastuzumab) or 2) tyrosine kinase inhibitors (i.e. gefitinib, erlotinib).
1
The EGFR family of transmembrane receptor tyrosine kinases is composed of four members:
HER1 (also known as the EGFR and erbB1), HER2 (p185, HER2/neu, ErbB-2), HER3 (also
termed ErbB-3), and HER4 (also termed ErbB-4). The molecular structures of EGFRs include an
extracellular ligand-binding domain, a short transmembrane domain, and an intracellular domain
with tyrosine kinase (TK) activity (except HER3). The binding of different ligands, including
epidermal growth factor (EGF) and TGF-alpha to the extracellular domain initiates a signal
transduction cascade that contributes to neoplastic behavior including cell proliferation,
apoptosis, adhesion, migration, and differentiation. Ligand binding induces EGFR
homodimerization as well as heterodimerization with other types of HER proteins. HER2 does
not bind to any known ligand, but it is the preferred heterodimerization partner for other
members of the HER family. Ligand binding to the EGFR extracellular domain leads to EGFR
activation followed by dimerization, resulting in phosphorylation of the intracellular tyrosine
kinase which results in a series of intracellular signals including the activation of
Ras/Raf/mitogen activated kinase (MAPK) or the AKT/mTOR pathways (reviewed in 7).
Table 1: Cell surface receptor inhibitors: Ongoing phase II and III trials for gastric and GEJ
cancers (adapted from 7)
Inhibitor-type
Drug
Clinical trials phase
Cetuximab
III
EGFR Antibody
Panitimumab
III
Matuzumab
I-II
Gefitinib
II
EGFR tyrosine kinase
inhibitors
Erlotinib
II
Trastuzumab
III
HER2-R Antibody
Lapatinib
II
EGF/HER2-R
BIBW 2992
II
Bevacizumab
III
VEGF-R antibody
Vatalanib
II
VEGF-R tyrosine kinase
inhibitors
EGFR (HER1; erbB1) targeted therapy
Cetuximab is a recombinant chimeric IgG1 monoclonal antibody that binds specifically to the
extracellular domain of EGFR and competitively inhibits the binding of EGF and other ligands
such as TGF-alpha. Cetuximab also mediates antibody-dependent cell cycle toxicity. Cetuximab
is currently approved for patients with advanced colorectal and head and neck cancer 8. Currently
there are several ongoing phase III trials evaluating cetuximab in combination with other
chemotherapy agents for patients with advanced gastric and GE junction cancers.
Whether the molecular testing considerations regarding mutations in the Kras pathway will be
used for treatment of gastric and GE junction cancers with cetuximab, as they are for colorectal
cancer is not established 9, 10. A recent study 11 presented at the 2009 ASCO annual meeting
assessed whether the mutational profile of KRAS and BRAF genes affected the response to
cetuximab combination therapy in GC. In this study, the frequency of mutations in KRAS and
2
BRAF was lower as compared to colorectal cancer, and the mutational status of KRAS and
BRAF genes did not correlate with the response to cetuximab-based therapy in advanced gastric
cancer patients. Forty four tumor samples were collected from patients with locally advanced or
metastatic GC undergoing cetuximab combination therapy as first-line treatment in two
consecutive phase II studies, FOLCETUX Study and DOCETUX Study. The mutational status of
KRAS (exon 2) and BRAF (exon 15) was detected by PCR amplification followed by direct
sequencing. KRAS and BRAF mutations were detected in 5 (11.4%) and 1 (2.3%), respectively,
of the 44 tumors analyzed. These frequencies are consistent with those previously reported in
GC. The only BRAF mutation found in 1 sample was the classic V600E substitution. As a
whole, 13.6 % of the analyzed tumors carried a mutation in either KRAS or BRAF genes. KRAS and BRAF mutations were, as expected, mutually exclusive. As this study examined a
small cohort, additional studies are warranted before clinical guidelines can be established.
Panitumumab is the first fully human monoclonal antibody (IgG2) specific to EGFR. It has been
used successfully in patients with advanced colorectal cancer who failed standard therapies 12. A
phase III trial (REAL III) is due to start investigating the role of panitumumab in combination
therapy for locally advanced or metastatic gastric or GEJ cancer.
The EGFR tyrosine kinase inhibitors have proved minimal evidence of efficacy in gastric
carcinomas, but studies are ongoing 7.
HER2 (HER2/neu, ErbB-2) targeted therapies
HER2 has no known ligand (orphan receptor), and preferentially heterodimerizes with HER3
which lacks intrinsic tyrosine kinase activity. The HER2, and the HER2/HER3 heterodimer is
likely to be the most effective complex for activating pathways downstream of EGF receptors 13,
14
.
Overexpression and amplification of HER2 has been described in 6-35% of gastric and GEJ
adenocarcinomas 15;16 (Table 2).
Trastuzumab (Herceptin) is a monoclonal antibody which specifically targets HER2 protein by
directly binding the extracellular domain of the receptor. Trastuzumab enhances survival rates in
both primary and metastatic HER2-positive breast cancer patients. The efficacy of trastuzumab
in breast cancer patients has led to investigate its antitumor activity in patients with HER2positive cancers, including gastric adenocarcinomas.
HER2/neu positivity rates have been reported to be more frequent in intestinal type gastric
cancer (21.5%) than in diffuse gastric cancer (2%) or mixed types (5%) 15; these findings were
confirmed in the ToGA trial with HER2 positivity being more frequent in intestinal than
diffuse/mixed cancer (32.2% vs 6.1%/20.4%), respectively 17. In addition, HER-2/neu
amplification in gastric carcinoma is associated with poor outcome 15 and has been shown to be
an independent prognostic factor 18.
Results from the largest study to date (ToGA trial) evaluating the addition of trastuzumab
(Herceptin) to chemotherapy in HER2-positive advanced gastric cancer were reported at the
2009 ASCO meeting 17, 19. The ToGA trial is the first randomized Phase III trial providing
prospective information on HER2-positivity rates in GC (Table 2). The trial enrolled 3,883
patients from 24 countries. A HER2-scoring system modified from the protocol in breast cancer
was used: a score of IHC 3+ and/or FISH positive was defined as HER2 positive. The modified
HER2-scoring system showed concordance between IHC and FISH results of 87.5%. In breast
cancer most IHC 0/1 samples are FISH negative but, in the ToGA cohort, the frequency of IHC
3
0/1 samples testing FISH positive was almost as high as IHC 2/FISH-positive samples (23% vs.
26%). The study reported an overall HER2-positivity rate of 22.1% evaluated from 3807 patients
17
.
In the ToGA trial, patients with HER2-positive gastroesophageal and gastric adenocarcinoma
(locally advanced, recurrent, or metastatic) were randomized to receive Trastuzumab (H;
Herceptin) H+CT (5-fluorouracil or capecitabine and cisplatin) q3w for 6 cycles or CT alone.
The primary end point was overall survival (OS); secondary end points included overall response
rate (ORR), progression-free survival, time to progression, duration of response, and safety.
Median OS was significantly improved with H+CT compared to CT alone: 13.5 vs. 11.1 months,
respectively (p=0.0048; HR 0.74; 95% CI 0.60, 0.91). ORR was 47.3% in the H+CT arm and
34.5% in the CT arm (p=0.0017). This first randomized trial investigating anti-HER2 therapy in
advanced GC showed that H+CT is superior to CT alone. The OS benefit indicates that H is a
new, effective, and well-tolerated treatment for HER2-positive GC 19.
Authors
Number
Region
Amplification
(%)
27
if IHC 2+
Method
Japan
Europe
OverIHC
expression
method
(%)
23
HercepTest
13
HercepTest
Yano et al. 20
Gravalos et al.
200
166
Allgayer et al.
Park et al. 18
203
Gast: 182
Europe
Korea
91
16
Elite kit
HercepTest
7 patients
Lordick et al.
1527
22*
HercepTest
-
Tanner et al. 15
Gast: 131
GEJ:100
Gast; GEJ
Europe;
Asia;
Latin
America
Europe
FISH/
CISH
FISH
-
-
12.2
24
FISH
FISH
16
Bang et al. 17
CISH
14
countries
Gast: 20.9 HercepTest
FISH**
GEJ: 32.2
Table 2. HER2 expression and amplification in gastric and GEJ cancers (modified from
Gravalos et al. 16) * HER2 overexpression by IHC or FISH** (PharmDx). IHC
(immunohistochemistry); CISH (chromogenic in situ hybridization).
Antiangiogenic agents
The current status of anti-angiogenic agents for gastric and GE junction tumors has been recently
reviewed 7. Tumor associated angiogenesis requires a number of pro-angiogenic factors, among
which vascular endothelial growth factors (VEGF family A-D) play a key role in vasculogenesis
and angiogenesis. A number of anti-angiogenic agents has been investigated or are undergoing
clinical trials.
4
Bevacizumab is a chimeric monoclonal antibody that binds the VEGF-receptor and prevents the
interaction of VEGF to its receptors (Flt1 and KDR) on the surface of endothelial cells. Clinical
data of bevacizumab therapy in patients with advanced gastric or GEJ cancer is promising but is
limited to phase II trials.
Another approach to inhibit the VEGF pathway uses tyrosine kinase inhibitors directed against
the receptors of VEGF (Flt1 and KDR). There are several compounds available, some
specifically targeting VEGF receptors, such as PTK787/ZK222584 (Vatalanib) and others that
inhibit both the VEGF receptors and other tyrosine kinase receptors such as sunitinib and
sorafenib. Phase II results are available for sorafenib, in which 44 patients with advanced gastric
or GE junction cancers were treated with a combination of docetaxel, cisplatin and sorafenib,
with an objective response rate of 38.6%. The median PFS was 5.8 months and the median OS
was 14.9 months.
Other targeted therapies for gastric and GEJ cancers
A large number of specific inhibitors of molecular targets in gastric and GE junction cancer
pathways are in the early stages of clinical trials, while supporting data for others is limited to
pre-clinical studies. Among these agents are the insulin-like growth factor-I (IGF-IR) receptor
inhibitors, fibroblast growth factor (FGF) receptor inhibitors and c-Met signaling pathway
inhibitors. A number of cell cycle associated drug targets including Aurora kinase inhibitors,
polo-like kinase inhibitors and cyclin dependent kinase (cdk) inhibitors are being tested.
Another approach has involved the use of inhibitors of cancer associated epigenetic changes.
Histone deacetylase (HDAC) inhibitors are under considerable research given the potential to reexpress tumor suppressor genes silenced by hypermethylation in cancer cells. A phase II clinical
trial is ongoing.
Other agents under current trials include heat shock protein 90 (HS90) inhibitors, ubiquitinproteasome pathway inhibitors, PI3K/Akt/mTOR pathway inhibitors and matrix
metalloproteinase (MMP) inhibitors.
5
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Cutsem EV, Kang Y, Chung H, Shen L, Sawaki A, Lordick F, Hill J, Lehle M,
Feyereislova A, Bang Y. Efficacy results from the ToGA trial: A phase III study of
trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth
factor receptor 2 (HER2)-positive advanced gastric cancer (GC). J Clin Oncol 2009;
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Yano T, Doi T, Ohtsu A, Boku N, Hashizume K, Nakanishi M, Ochiai A. Comparison of
HER2 gene amplification assessed by fluorescence in situ hybridization and HER2
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2006;15:65-71.
7
GASTRIC LYMPHOMAS:
25+ Years of Revolution/Evolution
Jerome S. Burke, MD
Department of Pathology
Alta Bates Summit Medical Center
Berkeley, California
The gastrointestinal tract is the most common location of extranodal lymphomas
and the stomach in particular serves as an excellent model to illustrate many of the
general issues concerning extranodal lymphomas. The stomach is the most frequent site
of involvement of extranodal gastrointestinal lymphomas with small intestine second in
frequency. Large intestinal and rectal lymphomas are less common, but are found in
patients with AIDS and occasionally as a complication of ulcerative colitis and Crohn
disease. In a study of 371 patients with primary gastrointestinal lymphomas registered
in a German Multicenter Study, stomach accounted for 277 of cases ((74.8%). Curiously,
the incidence of primary gastric lymphomas in the United States is increasing,
specifically in patients over 60 years of age; this increase appears independent of the
AIDS epidemic and the now common diagnosis of extranodal marginal zone lymphoma
of mucosa-associated lymphoid tissue (MALT) type.
The concept of extranodal marginal zone lymphoma of MALT type has
revolutionized the criteria for the morphologic diagnosis of an extranodal lymphoma,
specifically those lymphomas dominated by small lymphocytes. Moreover, since the
initial descriptions of lymphomas of MALT in 1983 and 1984 by Drs. Peter Isaacson and
Dennis Wright, the criteria have evolved and expanded to encompass not only
morphologic standards, specifically a more precise definition of various cell types in
MALT lymphoma, the proposals for ―lymphoepithelial lesions‖ and ―follicular
colonization,‖ the relationship between MALT lymphomas and marginal zone B cells,
and a scoring system for diagnosis of gastric MALT lymphoma, but also to embrace
immunophenotypic, biologic, molecular genetic and clinical discoveries. Such
developments include refinement of the immunophenotype, the association of gastric
MALT lymphoma and Helicobacter pylori infection, the notion of acquired MALT, the
biology of auto-antigen activation and continuous somatic mutations, genetic
aberrations, as for example the discovery of the t(11;18)(q21;q21) chromosomal
translocation in lymphomas of MALT, and the clinical implications of specific
cytogenetic alterations.
Revolution – Florid Gastric Lymphoid Hyperplasia (“Pseudolymphoma”) is Likely
Malignant Lymphoma!
Gastric Lymphomas; Burke - 2
In establishing a histologic diagnosis of an extranodal lymphoma, pathologists
are aware that various reactive lymphoid hyperplasias exist that mimic extranodal
lymphomas clinically and pathologically, such as gastric lymphoid hyperplasia and
chronic lymphocytic gastritis. To complicate matters, malignant lymphoma of
extranodal marginal zone (MALT) type may develop in association with these reactive
lymphoid infiltrates in the stomach.
In the 1960’s and 1970’s, the morphologic criteria to distinguish extranodal
lymphoma from extranodal lymphoid hyperplasia were extrapolated from those used
traditionally to distinguish malignant lymphoma from lymphoid hyperplasia in lymph
nodes. The major criteria for this distinction included monomorphic lymphocytic
infiltrates, cellular atypia, germinal centers and architectural disruption (Table 1).
Table 1
Traditional Histologic Criteria for Distinguishing Extranodal Lymphomas from
Lymphoid Hyperplasias
Extranodal Lymphomas
Lymphoid Hyperplasias
Infiltrate monomorphous
Infiltrate polymorphous
(lymphocytes in stages of
transformation)
Cytologic atypia
Cytologic maturity
(lymphocytes, plasma cells, and
immunoblasts)
Germinal centers uncommon
Germinal centers common
(usually in center of infiltrate)
Massive infiltration with
architectural destruction
Random infiltration with
architectural retention
Because more than 50% of gastric lymphomas are large B cell lymphomas with
associated monomorphism, cellular atypia, and architectural destruction (e.g.,
obliteration of glands), these traditional criteria generally have proven to be reliable and
applicable Reactive lymphoid conditions that are at the opposite end of the spectrum
equally do not pose diagnostic problems. Lymphocytic infiltrates that exhibit
polymorphism, that display a range of mature lymphocytes (including plasma cells and
immunoblasts), that are associated with well-defined germinal centers and that do not
destroy completely the architectural landmarks of the stomach usually can be
diagnosed confidently as benign and reactive.
The main difficulty in the separation of gastric extranodal lymphomas from
lymphoid hyperplasias concerns MALT lymphomas that are composed of small
lymphocytes and that frequently are associated with germinal center formation. For
these cases, the traditional histological criteria are not applicable. Multiparameter
studies have revealed that many histologically ambiguous extranodal small
lymphocytic proliferations in stomach are, in fact, monoclonal and, therefore, are
presumed to be malignant lymphomas especially of MALT type. The application of
immunologic and molecular genetic analyses to gastric small lymphocytic proliferations
has served to vividly alter the traditional histologic criteria and has revealed myriad
inconsistencies in these criteria (Table 2). For example, in a review of 97 cases originally
diagnosed as gastric pseudolymphoma between 1970 and 1985 at the AFIP, 79% were
reclassified as malignant lymphoma, with fully two-thirds of the newly classified
lymphomatous cases interpreted as lymphomas of MALT type. The remaining cases
were regarded as examples of lymphoid hyperplasia or atypical lymphocytic infiltrates.
Consequently, the term ―pseudolymphoma‖ is regarded as imprecise and anachronistic
and no longer is acceptable as a diagnostic category.
Table 2
Modifications of the Traditional Histologic Criteria for Distinguishing Extranodal
Lymphomas From Lymphoid Hyperplasia

Extranodal lymphomas may be polymorphous (e.g., peripheral T cell lymphomas)

Extranodal lymphomas may be composed of cytologically mature-appearing
lymphocytes (marginal zone lymphoma of MALT type and other low-grade
lymphomas with or without plasma cell differentiation)

Germinal centers may be observed at the periphery of extranodal lymphomas
and in the centers of many low-grade extranodal lymphomas, especially those of
MALT type

Degree of infiltration, architectural and epithelial destruction is highly variable in
benign and malignant extranodal lymphocytic infiltrates
The conventional view was that extranodal lymphomas are characterized by
nuclear membrane irregularities or atypia. Marginal zone lymphomas of MALT type,
however, are cytologically mutable. Although MALT lymphomas typically are
composed of marginal zone or centrocyte-like cells in the marginal zones, they also may
have a monocytoid appearance, or they be composed of plasma cells, or they may have
no, or only subtle, nuclear membrane irregularities similar to the cells of chronic
lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); the latter variant
often is readily confused with extranodal lymphoid hyperplasia. A small lymphocytic
proliferation that appears mature is the histologic norm of most cases of gastric
lymphoid hyperplasia, yet cytologic maturity or minimal atypia is equally the histologic
hallmark of most low-grade malignant lymphomas including those of MALT. How then
can these two groups be distinguished in a small biopsy specimen? In many cases, it is
impossible to do when applying only histological criteria. This histologic dilemma
prompted the use of the noncommittal term ―extranodal small lymphocytic
proliferation‖ to describe histologically ambiguous or indeterminate extranodal
lymphocytic infiltrates. Current morphologic criteria used to separate a benign small
lymphocytic infiltrate from a malignant small lymphocytic infiltrate includes the
designations of whether the infiltrate is monomorphous, dense, or exhibits cytologic
atypia or Dutcher bodies and whether this results in destruction of glands, follicles, or
other structures indigenous to the stomach. If these morphologic features are
unequivocally present, then the lymphocytic infiltrate likely is malignant lymphoma
(see Table 3).
Our perspective of the small extranodal lymphocytic proliferations that appear
mature has revised dramatically with the application of immunologic markers to
analyze the clonality of these lesions. Correlative immunopathologic studies have now
reduced the number of cases regarded as atypical or indeterminate. Naturally, cases
remain, especially small biopsy specimens, in which the histologic features or
immunologic findings remain equivocal; these cases should receive not only a
descriptive diagnosis but also a request for a repeat biopsy with reservation of fresh
tissues to determine clonality, whether by immunohistochemistry, flow cytometry,
molecular techniques, or a combination thereof. When only fixed, paraffin-embedded
tissues are available, a consistent determination of clonality in a biopsy specimen
dominated by small lymphocytes usually is not possible in most laboratories. In some
cases, however, immunologic studies of paraffin-embedded tissues can reveal an
aberrant phenotype in the suspicious small lymphocytic population, such as the
coexpression of B cell antigen CD20 and T cell antigen CD43. In most instances, the
aberrant immunophenotype supports the diagnosis of an extranodal gastric B cell
lymphoma. Prudence is necessary in the evaluation of immunoglobulin gene
rearrangement studies employing polymerase chain reaction (PCR) techniques in fixed
paraffin-embedded tissues; small monoclonal bands may occur in extranodal reactive
lymphoid hyperplasias, as for example in chronic active gastritis associated with
Helicobacter pylori.
As well as diagnostic problems encountered with the gastric lesions dominated
by small lymphocytes, benign reactive germinal centers (lymphoid follicles) pose
another risk in diagnosis. The presence of germinal centers is a commonly accepted
histologic attribute of extranodal lymphoid hyperplasias. Germinal centers, however,
are regular constituents of most gastric lymphomas of MALT. The essential
morphologic characteristic of MALT lymphomas is their emulation of normal MALT as
typified by Peyer patches found in the terminal ileum. The neoplastic B cells of MALT
lymphomas are found in marginal-type zones surrounding reactive follicles and
frequently attenuated rims of mantle zone lymphocytes. The germinal centers vary in
appearance but commonly appear atrophic as a result of impingement by the
surrounding small lymphocytes. In MALT lymphomas of the stomach associated with
peptic ulceration, germinal centers occur at the base of the ulcer and in the adjacent
mucosa where they seem encroached upon and entrapped by the monotonous marginal
zone lymphocytes. In some cases, the neoplastic B cells in the marginal zone invade the
germinal centers in a process referred to as ―follicular colonization.‖ Follicular
colonization may simulate follicular lymphoma in cases where there are numerous
follicles. At times, the lymphomatous proliferation may be so extensive as to result in
architectural obliteration with masking of any residual germinal centers; however, the
presence of former germinal centers can be highlighted by the immunohistochemical
demonstration of follicular dendritic cells employing an antibody against CD21 or
CD23.
Evolution – Refinement of Morphologic Criteria, Immunophenotype, Biology,
Molecular Genetics and Clinical Therapy of Gastric MALT Lymphomas
The morphologic features of extranodal marginal zone lymphoma of MALT type
have witnessed gradual changes since the initial descriptions by Isaacason and Wright.
Although originally thought to be of follicular center cell origin, the lymphoma cells of
MALT were later designated as ―centrocyte-like‖ and currently are termed as ―marginal
zone cells.‖ Gastric lymphomas of MALT type typically are characterized by an
expansion of the marginal-like zones surrounding benign germinal centers. As
described, marginal zone cells constitute a variety of cell types ranging from small, to
intermediate-sized lymphocytes, to large cells resembling immunoblasts. The marginal
zone or centrocyte-like cells are small to medium-sized lymphocytes with variable
nuclear membrane irregularities resembling a centrocyte or small cleaved cell. The most
common form has abundant pale-staining cytoplasm and is referred to as monocytoid.
Others forms of gastric MALT exhibit plasmacytoid features or resemble small
lymphocytes. Occasionally, signet ring-type cells are observed in gastric MALT
lymphomas and appear to represent a peculiar type of lymphoepithelial lesion in which
the foveolar cells, disaggregated by the lymphomatous infiltrate, acquire a globoid,
signet ring-type appearance. Regardless of cytologic composition, the marginal zone
cells of MALT cells share immunophenotypic characteristics. Gastric MALT lymphomas
are B cell derived with CD20 expression and frequently containing numerous admixed
CD3-positive reactive T cells. Up to 50% of cases exhibit aberrant coexpression of CD43
which can prove helpful in diagnosis. Unlike CLL/SLL and mantle cell lymphomas, the
lymphomas of MALT origin lack CD5 and are without bcl-1 gene rearrangements.
MALT lymphomas differ from follicular lymphomas in that they are CD10 negative and
do not exhibit rearrangements of the bcl-2 proto-oncogene. The absence of CD10 and bcl2 positivity in gastric lymphoma with an apparent follicular architecture has been
rationalized by the concept of ―follicular colonization‖. As discussed above, follicular
colonization refers to the simulation of a follicular lymphoma as a result of invasion by
the marginal zone cells of MALT into pre-existing reactive follicles.
The marginal zone cells of MALT not only are thought to invade residual
reactive follicles, but also epithelium. As mentioned previously, epithelial invasion by
the centrocyte-like cells of MALT has been referred to as a ―lymphoepithelial lesion‖
and is an important morphologic feature in the diagnosis of gastric MALT-derived
lymphomas. Such lesions may be accentuated by an immunohistochemical stain for
cytokeratin. Lymphoepithelial lesions are most significant as a diagnostic characteristic
in the stomach, but are less relevant in other extranodal sites since they may be
observed in non-lymphomatous extranodal lymphocytic infiltrates. In stomach,
lymphoepithelial lesions usually are defined as invasion of gastric epithelium by three
or more lymphomatous cells. A decade following the primary proposal for a lymphoma
of MALT, a histologic scoring system for gastric MALT lymphoma was proposed in
which invasion of epithelial structures or lymphoepithelial lesions is considered
paramount to the diagnosis (Table 3).
Table 3
Gastric Marginal Zone (MALT) Lymphomas: Histologic Scoring*
Grade Description
0
Normal
Histologic Features
Plasma cells in lamina propria
No lymphoid follicles
1
Chronic active gastritis
Lymphocyte clusters in lamina propria
No follicles, lymphoepithelial lesions
2
Chronic active gastritis with
florid lymphoid follicle
formation
Prominent follicles with surrounding
mantle zone & plasma cells
No LELs
3
Suspicious lymphoid infiltrate
in LP, probably reactive
Follicles surrounded by lymphocytes
that infiltrate diffusely in LP and +/epithelium
4
Suspicious lymphoid infiltrate
in LP, probably lymphoma
Follicles surrounded by CCL cells (MZC)
that infiltrate diffusely in LP & epithelium
5
MZ (MALT) lymphoma
Dense diffuse infiltrate of CCL cells
in LP with prominent LELs
*Lancet 1993:342:575-577
Employing the scoring system, a definite diagnosis of low-grade B cell
lymphoma of MALT is based on the presence of a dense diffuse infiltrate of centrocytelike cells/marginal zone cells in the lamina propria with prominent lymphoepithelial
lesions. Cases regarded as suspicious lymphocytic infiltrates are those in which reactive
follicles are surrounded by marginal zone cells that diffusely infiltrate into the lamina
propria and into epithelium in small groups. However, caution is required as there may
be dense infiltrates, slight cytologic atypia, and also lymphoepithelial-like lesions in
cases of lymphoid hyperplasia in the stomach. As well, the criteria may be difficult to
apply. In an interobservor study, 41 H&E sections of stomach that ranged from simple
gastritis to lymphoma were reviewed by 17 pathologists, including hematopathologists,
gi pathologists and general pathologists. Interobservor reproducibility was suboptimal
and the degree of disagreement was directly related to the pathologist’s experience in
evaluating gastric biopsies for MALT lesions. The study recommended that diagnostic
accuracy would be enhanced by clinical information, extensive sampling, recognition of
lymphoepithelial lesions, immunophenotypic information and cytogenetic results. This
recommendation was supported by another report stating that a combination of the
morphologic scoring system and B cell clonality analysis by an advanced PCR method
accurately discriminated chronic gastritis from covert gastric marginal zone lymphoma.
PCR was particularly valuable in the interpretation of cases that exhibited an
ambiguous score of grade 3 or 4.
Paradoxically, most MALT-type lymphomas arise in extranodal sites without
normal MALT, such as the stomach, while non-MALT lymphomas, for example Burkitt
lymphoma, arise in MALT sites. In order to resolve this apparent paradox, it was
proposed that lymphomas in non-MALT sites arise in a setting of ―acquired‖ MALT.
This non-indigenous extranodal lymphoid tissue is thought to be acquired secondary to
an infection, such as Helicobacter pylori in the stomach, or an autoimmune disease. The
lymphoid infiltrates in stomach associated with Helicobacter pylori seemingly predispose
patients to malignant lymphoma. There currently is sufficient histological, clinical, and
epidemiologic evidence for the virtually fixed association of gastric MALT lymphomas
with Helicobacter pylori infection, particularly the CagA strain. For example, in a
collaborative study of more than 230,000 patients whose serum had been stored, 33
cases of gastric lymphoma developed a median of 14 years after serum collection. The
patients with gastric lymphoma were significantly more likely than matched controls to
have evidence of previous Helicobactor pylori infection. In contrast, no association was
discovered among 31 patients who had developed nongastric non-Hodgkin lymphoma
and previous Helicobactor pylori infection. In addition, molecular analysis by PCR has
documented the clonal progression from Helicobacter pylori-associated chronic gastritis
to MALT lymphoma of the stomach and Helicobactor pylori provides the antigenic
stimulus for prolonging the clonal expansion of gastric MALT lymphomas. This view
has been supported by Isaacson’s group who have exhibited evidence of ongoing Ig
gene mutations in most case of MALT-type lymphoma. The discovery of ongoing
mutations reinforces the perception that direct antigen stimulation is paramount in the
clonal expansion of gastric MALT lymphomas.
Clinically, gastric MALT lymphomas arise in adults with a peak in the seventh
decade and with a male:female ratio of approximately 1.5:1. Patients commonly present
with nonspecific gastritis and/or a peptic ulcer and at endoscopy, there often are
reddened and slightly thickened rugae with superficial spreading of lesions without
formation of a tumor mass. The gastric lesions commonly are multifocal and most
patients have stage IE disease. The linkage of Helicobacter pylori with gastric MALT
lymphoma led to antibiotic therapy for treatment of low-grade gastric lymphomas of
MALT and this therapy may induce sustained remissions in about 75% of patients.
There are no apparent differences in survival and relapse-free survival between patients
treated with antibiotics and with other modalities, such as local treatment, combined
treatment, or chemotherapy; in fact, no consensus exists for the optimal treatment of
primary gastric lymphoma. In one study of gastric MALT lymphomas treated by
various modalities, the five year projected overall survival was 82%. One significant
issue for pathologists is the interpretation of stomach biopsy specimens following
antibiotic therapy for gastric MALT lymphoma. Clearly, no diagnostic problem exists if
the biopsy reveals regression of the lymphoma with loss of lymphocytic aggregates in
the lamina propria or if the biopsy exhibits a total absence of histological regression
with persistence of lymphoma. Parallel to the histological scoring system employed for
the initial diagnosis of gastric marginal zone lymphoma, a histological grading system
has been proposed for treated patients. (Table 4).
Table 4
Gastric MZ (MALT) Lymphoma: Post-Therapy Grading*
Score
CR
Lymphoid Infiltrate
Absent or scattered plasma cells
& small lymphoid cells in the LP
LEL
–
pMRD
Aggregates of lymphoid cells or
lymphoid nodules in the LP/MM
&/or SM
–
rRD
Dense, diffuse, or nodular
+/extending around glands in the LP
Focal empty LP &/or
fibrosis
NC
Dense, diffuse, or nodular
No changes
+/-
Stromal Changes
Normal or empty LP
&/or fibrosis
Empty LP &/or
fibrosis
CR, complete histologic remission; pMRD, probable minimal residual disease;
rRD, responding residual disease; NC, no change;
LEL, lymphoepithelial lesions; LP, lamina propria; MM, muscularis mucosa; SM, submucosa
*Gut 2003;52:1656
The probable minimal disease category (pMRD) does not signify a requirement
for further therapy and patients are managed with followup as though they were in
remission. Of interest, approximately 50% of patients with histologically negative postantibiotic therapy gastric biopsies (CR/pMRD) exhibit persistent monoclonality,
although in some patients the clone disappears with prolonged followup. In other
patients, continued monoclonality may result in a delay in realizing remission.
However, following antibiotic therapy for gastric MALT lymphoma, the association
between ongoing monoclonality and risk of relapse is tenuous. One bone of contention
is that that serial gastric biopsy specimens frequently exhibit an oscillating clonal status,
due perhaps to sampling or recurrent Helicobacter pylori infection. Therefore, except for
clinical investigations, the determination of clonality employing PCR currently is not
considered pragmatic or recommended in the evaluation of post-therapy gastric MALT
lymphoma biopsy specimens.
The establishment of extranodal gastric marginal zone lymphoma of MALT type
as a recognized clinicopathologic entity has progressed to incorporate molecular
genetics and specific chromosomal translocations. For MALT lymphomas in general,
the genetic abnormalities encompass trisomies 3, 12 and 18, as well as balanced
translocations, specifically t(11;18)(q21;q21), t(14;18)(q32;q21), t(1;14)(p22;q32) and
t(3;14)(p14;q32). The most common translocation in gastric MALT lymphoma arising in
approximately 20-30% of cases (although lower in North America) is t(11;18)(q21;q21) in
which the t(11;18) fuses with amino terminal of the inhibitor of apoptosis API2 at 11q21
to the carboxyl terminal of MALT1 at 18q21 leading to a chimeric fusion product.
MALT1 is involved in antigen receptor-mediated NFB activation. The API2-MALT1
fusion product is detectable by FISH. The t(11;18)(q21;q21) is restricted to extranodal
MALT lymphomas and has not been reported in other forms of marginal zone
lymphoma, such as splenic or nodal, or in chronic gastritis associated with Helicobacter
pylori. Gastric MALT lymphomas without a t(11;18)(q21;q21) often exhibit aneuploidy,
as for example trisomy 3 or 18.
In this decade, the discovery of t(11;18)(q21;q21) in some patients with gastric
MALT lymphoma has led to exciting clinical prognostic correlations. Specifically,
patients with gastric MALT lymphoma who prove positive for t(11;18)(q21;q21) often
fail to respond to Helicobacter pylori therapy and this translocation frequently arises in
patients who are Helicobacter pylori negative. Employing endosonographic staging, such
t(11;18)(q21;q21) positive patients who do not respond to Helicobacter pylori eradication
with antibiotics are found to have disease that has spread beyond the gastric submucosa
into muscularis and/or serosa in contrast to patients with lymphoma limited to the
mucosa and submucosa who generally are t(11;18)(q21;q21) negative. Moreover,
t(11;18)(q21;q21) is uncommon in extranodal diffuse large B cell lymphoma and patients
with this translocation rarely metamorphose to diffuse large B cell lymphoma. In
contrast, aneuploid t(11;18)(q21;q21) negative patients who are unresponsive to
Helicobacter pylori treatment are at risk to evolve to diffuse large B cell lymphoma. For
example, microsatellite screening of gastric MALT and large B cell lymphomas display
alleic imbalances limited to t(11;18)(q21;q21) negative patients that are shared by both
MALT and diffuse large B cell lymphomas; this observation indicates that
t(11;18)(q21;q21) negative patients are the genesis of MALT lymphomas than convert to
one of large B cell type. It is therefore paramount to ascertain as to whether or not the
gastric marginal zone lymphoma of MALT type is t(11;18)(q21;q21) positive since this
information has prognostic and therapeutic repercussions.
In the 1990’s, many diffuse large B cell lymphoma cases of stomach were
designated as ―high-grade MALT lymphoma‖ based on the belief that these cases had
transformed from ―low-grade MALT lymphoma‖ especially when both components
were present in a single specimen. Despite the likelihood that such transformations
occur, the term ―high-grade MALT lymphoma‖ presently is discouraged and all such
cases are interpreted as large B cell lymphoma. By current definition, marginal zone
lymphoma of MALT type is strictly an indolent or low-grade extranodal lymphoma.
Despite the considerable recent emphasis on MALT-type lymphomas, in fact, greater
than 50% of gastric lymphomas are high-grade, diffuse large B cell lymphomas. Except
in small gastroscopic biopsy specimens, differentiation of large cell lymphoma from
carcinoma usually is not a problem in view of the tendency of the lymphomas to be
diffuse, massive, and lacking in cohesive cell aggregates. Nonetheless,
immunohistochemical verification of diagnosis is recommended and is particularly
valuable in delineating cases of large cell lymphoma from gastric adenocarcinoma. The
infiltration by lymphoma around, or into, partially intact gastric glands, negative mucin
and keratin stains, positive reactivity for CD20, and the lack of syncytial cell aggregates
or malignant acinar formation aid in the distinction of large cell lymphoma from poorly
differentiated adenocarcinoma, even in small biopsy specimens. Small gastric biopsy
specimens, however, are subject to sampling errors and artifactual distortion, and on
occasion it may be necessary to request a second biopsy, in order to render a more
complete pathologic examination.
One consequential diagnostic issue is the observation of large cells in a
background of a marginal zone lymphoma of MALT type in a gastric biopsy specimen.
No current consensus exists as to how many large cells are required to establish the
evolution from MALT lymphoma to one of diffuse large B cell type. Clearly, the
presence of large cells in discrete nodular aggregates or sheets is likely an indication of
transformation; however, diagnostic difficulties remain for cases in which the large cells
are numerous and diffusely admixed with small marginal zone lymphocytes. In one
study of 106 patients with gastric MALT lymphomas, the prognostic impact of a large
cell component was assessed by semiquantitative analysis of clusters and diffusely
intermingled malignant large cells; in MALT lymphomas, the observation of a diffuse
large cell component in the range of 1-10%, with and without non-confluent clusters of
large cells, predicted a significantly worse prognosis. In a report from Italy, the presence
of scattered large cells that comprised 5–10% of the MALT lymphoma cell population
was regarded as prognostically irrelevant, whereas compact clustered large cells that
represented more than 10% of the MALT lymphoma proved significant, as they were
associated with a worse survival.
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Robert M Genta Caris Diagnostics and University of Texas

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