Le lymphome imaginaire

Human PATHO LOGY VOLUME 29

August 1998

NUMBER 8

Editorial

Le Lymphome Imaginaire When Helicobacter pylori still eluded pathologists' unfocused eyes, mucosa-associated lymphoid tissue (MALT) was just chronic inflammation, and most gastric lymphoid proliferations were still pseudolymphomas, Klaus Lewin et al published an elegant account of the morphology of the gastric mucosa in patients with pernicious anemia. 1 The first figure of their article illustrated the histopathological features of the normal corpus; its legend, after a description of foveolae and glands, almost parenthetically mentions "a lymphoid follicle adjacent to the rnuscularis mucosae, m "O tempora, o folliculi," would exclaim a pathologically inclined end-of-Millennium Cicero. Only two decades later Torkalovic et al 2 claimed that 85% of the subjects they studied with " H pylori gastritis and lymphoid hyperplasia" had evidence of B cell monoclonality in the gastric mucosa. But when Savio et al perf o r m e d a similarly aimed study they f o u n d that only 1% of the patients with "MALT and no histological features of lymphoma" had monoclonal populations. 3 Several other studies published in the last 4 or 5 years have yielded a range of figures between 1% and 85%. Such a profusion of discrepant data leaves the mystified reader to wonder: does every stomach h a r b o r a monocl0nal proliferation ready to explode into a lymphoma? Can Moli6re's celebrated aphorism (recently paraphrased by the editor of the New England Journal of Medicine propos of laboratory tests) be recycled again to fit gastric lymphomas? If you think you d o n ' t have a lymphoma in your stomach, it is because you have not done e n o u g h tests. O r will the entire issue of monoclonal populations in the gastric mucosa soon fade away, obscured by new and trendier lines of investigation? In this issue of Human Pathology de Mascarel and his colleagues do not provide a definite answer to this problem (how could they?), but they do bring a n e e d e d voice of moderation.4 In a well-designed study of biopsy samples of gastric mucosa with grade 2 or 3 lymphoid infiltrates (therefore, with neither histopathological evidence n o r suspicion of lymphoma) from 302 patients with duodenal ulcer, these authors f o u n d a B cell monoclonal population in only three patients. Their

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poignant discussion barely disguises the authors' dominant concern: how can the widely discordant data be reconciled? How can we all be right? When similar studies conducted by different investigators yield radically divergent results, the explanation can often be f o u n d in the interplay of three elements: populations, methods, and definitions. As a group, the published studies on the monoclonality of MALT in the gastric mucosa are representative of the difficulties that arise when one tries to compare studies whose fundamental differences are disguised by the veil of a similar topic. In these studies, patients have been drawn from geographical areas (Great Britain, Italy, France, North America, Japan) in which the prevalence of H pylori infection, the genotypes of the infecting strains, the age of acquisition of the infection, and the incidence of MALT lymphoma are widely different. The study subjects were also extraordinarily heterogeneous in their manifestations of Hpylori infection, virtually representing the entire range of conditions associated with chronic gastritis. One study included British patients with lymphoma, adenocarcinoma, and uncomplicated chronic active Hpylori gastritis. 5 A n o t h e r study involved North American subjects with chronic active gastritis. 6 A group of Italians with "simple dyspepsia" were f o u n d to have a surprisingly high prevalence of monoclonality, irrespective of their H pylori status, in one study, 7 but among a n o t h e r group of Italians selected because of "a dense lymphocytic infiltrate associated with H pylori," monoclonality was rare, unless a MALT lymphoma was histologically detectable. 3 Another study included two groups of North American patients with MALT lymphomas, one with and one without "lymphoid hyperplasia. ''2 All patients reported by de Mascarel in this issue of Human Pathology had duodenal ulcer; thus, they were likely to consist of a h o m o g e n e o u s group with antralp r e d o m i n a n t gastritis. In addition to environment, host factors, and nosological categories, a n o t h e r possible reason for the wide range of prevalence of monoclonality f o u n d by different groups of investigators could be the strain of H

HUMAN PATHOLOGY

Volume 29. No. 8 (August 1998)

pylori infecting their subjects. In most of these studies the genotype of the infecting Hpylori strain with respect

mura et al discovered that B cell monoclonality was present 3 to 4 years earlier in the gastric biopsies of 79% of patients who developed a gastric MALT lymphoma, but only in the biopsies of 24% of subjects who did not develop a lymphoma during the follow-up period, n This interesting study is a step in the right direction, but both sensitivity and specificity of monoclonality tests are clearly too low to make a clinically relevant prediction. What should we do then? De Mascarel and colleagues conclude their article stating that "the need to use molecular analyses of benign histopathological lesions is questionable. ''4 1 fully endorse their statement, but I would make it even stronger. Such studies are of great interest in the elucidation of the responses to bacterial pathogens and may provide invaluable insights into the pathogenesis of lymphoid proliferations. However, unless we want to detect imaginary lyanphomas, the molecular analysis of histologically benign lymphocytic aggregates must not enter the practice of diagnostic pathology.

to the Cag pathogenicity island was not determined. The importance of this element is presently unknown, because one study reports a positive association between Cag A-positive H pylori strains and gastric MALT lymphoma, s whereas a n o t h e r group concludes that no relationshi p between the two exists. 9 In any case, it is not inconceivable that the products of this cluster of genes, or other yet undiscovered bacterial factors, might make a host more or less likely to m o u n t a monoclonal response. Methodological differences may also play a substantial role in the generation of discrepant results. Some investigators (like de Mascarel et al) searched for monoclonality by p e r f o r m i n g polymerase chain reaction (PCR) on frozen biopsy specimens selected because the fixed counterpart of each frozen specimen contained "a dense lymphoid infiltrate." Other researchers chose areas with lymphoid follicles in fixed tissues, whereas others used both frozen and formalin-fixed unselected mucosal biopsy specimens. The presence of lymphoepithelial lesions correlated with monoclonality in one study, a but this feature was not a criterion in the selection of the specimens to be tested in most other reported series. Finally, as Dixon has stated in a recent review, the demonstration of monoclonality in gastric infiltrates is replete with limitations. 1° Because of the mixture of reactive polyclonal B cells that are almost always present in the inflammatory infiltrates that accompany Hpylori infection, light chain restriction is often difficult to show both in frozen and fixed tissues. On the other hand, because of the oligoclonal B cell populations that almost invariably arise in response to bacterial infections, "pseudomonoclonality" may be detected and interpreted as true monoclonality. Thus, the complex cellular mucosal responses to Hpylori infection and the imperfect methods now available to analyze them may conspire to cause investigators to both underestimate and overestimate the prevalence of B cell monoclonality in subjects with chronic gastritis. Years ago, when I first peeked into the world of biomedical research, the mandate was to be basic. Applied research was considered almost a second-class endeavor. Later, to compete for funding from certain agencies, a proposal had to be clinically relevant. This year we are told to cross these unnatural barriers separating basic from clinical: we must now b e c o m e proficient in translational research. Loosely defined, the concept indicates an inquiry into ways to convert the results of basic research into information useful to clinical medicine. When we look at monoclonality studies of gastric infiltrates, what can we translate from the b e n c h to the patient's bed? As things stand today, there is not m u c h usable information. The crucial study, one that would prove that we can use the results of monoclonality studies in a gastric biopsy specimen to estimate a patient's probability of developing a MALT lymphoma, has not been published yet. Recently, in a retrospective analysis of two groups of subjects, Naka-

ROBERT M. GENTA, MD Departments of Pathology, Medicine, and Microbiology and Immunology Veterans Affairs Medical Center and Baylor College of Medicine

Houston, Texas

REFERENCES 1. Lewin KJ, Dowling F, WrightJP, et al: Gastric morphology and serum gastrin levels in pernicious anaemia. Gut 17:551, 1976 2. Torlakovic E, Cherwitz DL, Jessurun J, et al: B-cell gene rearrangement in benign and malignant lymphoid proliferations of mucosa-associated lymphoid tissue and lymph nodes. HUM PATHOL 28:166, 1997 3. Savio A, Franzin G, Wotherspoon AC, et al: Diagnosis and posttreatment follow-up of Helicobacter pylori-positive gastric lymphoma of mucosa-associated lymphoid tissue: Histology, polymerase chain reaction, or both? Blood 87:1255, 1996 4. de Mascarel A, Dubus P, Belleann6e G, et al: Low prevalence of monoclonal B cells in Helicobacterpylori gastritis patients with duodenal ulcer. HUM PATHOL29:784-790, 1998 5. Calvert RJ, Evans PA, Randerson JA, et al: The significance of B-cell clonality in gastric lymphoid infiltrates.J Patho1180:26, 1996 6. Hsi ED, Greenson JK, Singleton TP, et al: Detection of immunoglobulin heavy chain gene rearrangement by polymerase chain reaction in chronic active gastritis associated with Helicobacter pylori. HUM PATHOL27:290, 1996 7. Sori-entino D, Ferraccioli GF, DeVita S, et al: B-cell clonality and infection with Helicobacter pylori: Implications for development of gastric lymphoma. Gut 38:837, 1996 8. Eck M, Schmausser B, Haas R, et al: MALT-type lymphoma of the stomach is associated with Helicobacterpylori strains expressing the CagA protein. Gastroenterology 112:1482, 1997 9. de Jong D, Van der Hulst RW, Pals G, et al: Gastric nonHodgkin lymphomas of mucosa-associated lymphoid tissue are not associa.ted with more aggressive Helicobacter pylori strains as identified by CagA. AmJ Clin Pathol 106:670, 1996 10. Dixon MF: The gastric lymphomas and the role of Helicobacter pyloriin mmour development: Have criteria been set for diagnosis?, in Hunt RH, Tytgat G (eds): Helicobacter pylori: Basic mechanisms to clinical cure 1996. Dordrecht, Kluwer, 1996, p 205 11. Nakamura S, Aoyagi K, Furuse M, et al: B-cell monoclonality precedes the development of gastric MALT lymphoma in Helicobacter pylori-associated chronic gastritis. A m J Patho1152:1271, 1998

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