oligoclonal bands, visual evoked prolonged, and her complete major histocompatibility complex phenotype was HLA-DR2, DQwl, B7,



fluid contained


B35, Cw7. In November, 1987, at 26 years of age, she received a third intramuscular inoculation with 20 ug recombinant hepatitis B vaccine (’Engerix-B’, SmithKline Beecham, Genval, Belgium). 6

reported left-sided hemiparesis with impaired sensation. Magnetic resonance imaging of the brain showed multiple hyperintense T2 lesions throughout the white matter of the cerebral hemispheres. She was treated with intravenous methylprednisolone 500 mg daily for 5 days, with moderate weeks later she

improvement. 2 weeks later she

was readmitted with left-sided and became comatose over the next 24 h. Magnetic resonance imaging revealed a very large right frontoparietal hyperintense T2 lesion surrounded by oedema, with signs of transtentorial herniation. Dexamethasone (8 mg, 4 times daily) and mannitol were given intravenously, with substantial improvement over the next few days. Left-sided hemiparesis persists but there have been no further clinical relapses during 4 years’ follow-up.


hepatitis B appear greatly to outweigh the hazard of such an event. Although a causal link between vaccination and demyelination is not proved by these two case histories, our findings, particularly in view of previous reports of post-vaccination optic neuritis and Guillain-Barre syndrome, indicate that recombinant hepatitis B vaccination might best be avoided in patients with known multiple adverse

sclerosis. REFERENCES FE, Graham DJ, Guess HA, et al. Postmarketing surveillance for neurologic adverse events reported after hepatitis B vaccination. Experience of the first three years. Am J Epidemiol 1988; 127: 337-52. 2. Anonymous. Hepatitis B vaccines: reported reactions. WHO Drug Information 1990; 4: 129. 3. Sriram S, Steinman L. Postinfectious and postvaccinial encephalomyelitis. Neurol Clin 1984; 2: 341-53. 4. Ebers GC. Genetic factors in multiple sclerosis. Neurol Clin 1983; 1: 1. Shaw


The second

patient, a 28-year-old nurse, was vaccinated with recombinant hepatitis B vaccine (’Engerix-B’) in March, 1990. She had known hypertension, treated with bisoprolol 10 mg daily, but no previous symptoms or signs of neurological disease. In March, 1991, she received a single intramuscular booster injection with 20 g of the same vaccine. 6 weeks later, she noticed weakness and tingling in her right arm and leg. On examination she had right inferior homonymous quadrantanopia and paresis of the right arm and leg, with diminished sensation for pinprick in the right leg; tendon reflexes were brisk with an extensor right plantar response. Routine blood biochemical and haematological investigations were normal. T2-weighted magnetic resonance imaging showed 3 hyperintense lesions in the white matter of the left cerebral hemisphere. Cerebrospinal fluid contained 9 leucocytes/pl and a slightly raised protein concentration (0-61 g/1), but no oligoclonal bands. Visual evoked responses and brainstem auditory evoked responses were normal. 500 mg methylprednisolone daily was given intravenously for 5 days, with a slight improvement in muscle strength. 1 month later severe right hemiparesis occurred, with dense right homonymous hemianopia. Cerebrospinal fluid analysis was normal and there were no oligoclonal bands. Magnetic resonance imaging showed an additional area of demyelination in the left internal capsule and extension of the lesion in the left occipital lobe. Visual evoked responses were of normal latency. 3 months later, she still had a spastic right-sided hemiparesis and incomplete right homonymous hemianopia, but no new lesions on magnetic resonance imaging. Her complete majorhistocompatibility-complex phenotype was HLA-DR2, DQwl, A3, B7, Cw7. Both patients had neurological symptoms and signs, with

demyelinating lesions in the brain, 6 weeks after administration of a recombinant hepatitis B vaccine that consists of hepatitis B surface antigen. The underlying pathogenetic process remains unclear but is probably immune mediated; postvaccinial acute disseminated encephalomyelitis or, respectively, relapse and the onset of multiple sclerosis are two possible explanations. The first patient had clinically definite multiple sclerosis before immunisation. Although case-reports of recurrent acute disseminated encephalomyelitis have been described,3 the relapsing character of the illness in our second patient lends support to the theory that vaccination may have triggered the onset of multiple sclerosis in a genetically susceptible individual. Both patients have DR2 and B7 HLA haplotypes, which are known to be associated with multiple sclerosis.4 Recombinant hepatitis B vaccine has been widely administered and we know of no similar published reports in which neurological symptoms and signs are associated with evidence of central-nervous-system demyelination; the preventive benefits of the vaccine in subjects at high risk for

ADDRESS. Department of Neurology, University Hospital, Free University of Brussels, Laarbeeklaan 101, B-1090 Brussels, Belgium (L. Herroelen, MD, Prof J. de Keyser, PhD, Prof G. Ebinger, PhD) Correspondence to Dr L Herroelen

Helicobacter pylori-associated gastritis and primary B-cell gastric


Although lymphoid tissue is absent in normal gastric mucosa, primary lymphomas arise in the stomach and most of these recapitulate the features of mucosa-associated lymphoid tissue (MALT). Gastric lymphoid tissue is known to be acquired in response to local infection by Helicobacter pylori, and we have confirmed this in 450 patients with H pylori-associated gastritis of whom 125 showed mucosal lymphoid follicles. In 8 patients, B lymphocytes infiltrated epithelium, which is a feature characteristic of MALT. We also examined 110 cases of gastric MALT lymphoma and found H pylori infection in 101 of these (92%). We conclude that gastric MALT is acquired in H pylori infection and that this provides the necessary background in which MALT lymphoma might develop.

Low-grade B-cell lymphomas that arise in the stomach, lung, salivary gland, and thyroid recapitulate the structural features of mucosa-associated lymphoid tissue (MALT) as typified in Peyer’s patches.1,2 These lymphomas, together with the high-grade lesions that may evolve from them,3are collectively known as MALT lymphomas.1 Paradoxically, however, MALT is not present in either the normal stomach or other sites in which MALT lymphomas arise. In the salivary gland4 and thyroidMALT is acquired as a component of autoimmune disorders such as Sjogren’s syndrome and Hashimoto’s thyroiditis, and are necessary precursors for development of MALT lymphoma in these organs. In the stomach, lymphoid tissue is acquired as a


haematoxylin and eosin stained sections (confirmed by special stains in 35 patients). In the remaining 9 patients (one biopsy, six resection, and two biopsy and resection specimens), no H pylori were seen, although material for special stains was not available in 3 patients in whom scanty organisms could have been overlooked. Despite the absence of lymphoid tissue in normal gastric mucosa, primary lymphomas arise in the stomach and most of these are of MALT type.1 At other sites in which MALT lymphomas arise, such as the salivary gland and thyroid, they do so in a background of MALT acquired as part of an autoimmune disease.4s Wyatt et al6 and Stolte and Eidt7 have shown that the acquisition of organised lymphoid tissue in the stomach is almost always associated with infection by Hpylori. In this study, we have shown that such

Helicobacterpylori-associated gastritis. Upper figure shows part of a lymphoid follicle with lymphocytes infiltrating gastric epithelium (arrows); lower figure shows CD20 (L26) staining and confirms that intraepithelial lymphocytes are B cells (arrows).

lymphoid tissue has the features of MALT. The frequency of H pylori infection in patients with gastric MALT lymphoma (92 %) is similar to that for other conditions in which this organism has been implicated (56-96% of patients with gastric ulceration8 and 19-80% with gastric carcinoma9), but is substantially higher than that found in the background population (50-60%)." Although the temporal sequence cannot be confirmed in our study, we suggest the MALT acquired in response to H pylori infection provides the background on which other as

result of colonisation of the gastric mucosa by Helicobacter pylori.6,7 We have investigated the possibility that, as in the salivary gland and thyroid, this acquired lymphoid tissue may be of MALT type, and provide the setting in which lymphoma may subsequently arise. We reviewed the histology of 450 cases of H pylori-associated gastritis, which were retrieved from the surgical files of the Department of Histopathology, University College and Middlesex School of Medicine. In each patient, the presence of H pylori had been confirmed by a modified Giemsa stain. Lymphoid tissue identified in biopsy specimens was investigated further with immunocytochemical stains that included antibodies to CD3 (pan-T cell marker; Dako, UK), CD20 (pan-B-cell marker: L26, Dako, UK), and CD21 (follicular dendritic cell [FDC] marker: IF8, Dako, UK) with a streptavidin-biotin complex technique. In addition, 110 patients with primary B-cell gastric lymphoma of MALT were examined for the presence of H pylori. Only patients in whom intact gastric mucosa was present in either the diagnostic pretreatment biopsy specimen (23 patients), the gastric resection specimen (73 patients), or both (14 patients) were included in the study. In each case, haematoxylin and eosin stained sections were examined and, where additional material was available, the H pylori status was confirmed by either a modified Giemsa or cresyl violet stain (41 patients).


125/450 cases (28%) of H pylori-associated gastritis,

lymphoid follicles were identified and confirmed by finding FDC with CD21 immunostaining. These lymphoid follicles were often seen resting on the muscularis mucosae, closely surrounded by an adjacent infiltrate of B and T cells (shown by immunostaining for CD20 and CD3). Elsewhere, the mucosa contained both a heavy infiltrate of plasma cells and focal collections of neutrophils. B lymphocytes frequently surrounded the gastric glands, and isolated intraepithelial B cells were often present. In 8 patients, B cells infiltrated into the epithelium in groups to form structures that could be confused with the lymphoepithelial lesion characteristic of gastric MALT lymphoma (figure). These features were reminiscent of the histological features of MALT (Peyer’s patches).2 Each of the 110 patients with lymphoma examined showed features of B-cell MALT lymphoma.’ In 101/110 patients (92%), H pylori could be identified on

yet unidentified factors act, which then lead



development of lymphoma in a small proportion of cases. A similar mechanism has been suggested to explain the association between H pylori infection and the development of gastric adenocarcinoma.11 This mechanism would explain the presence of H pylori in almost all our cases of MALT lymphoma. Eradication of H pylori should result in the eventual loss of MALT, thereby removing the lymphoid tissue in which a lymphoma may arise. REFERENCES PG, Spencer J. Malignant lymphoma of mucosa-associated lymphoma tissue. Histopathology 1987; 11: 445-62. 2. Spencer J, Finn T, Isaacson PG. Human Peyer’s patches: an immunohistochemical study. Gut 1986; 27: 405-10. 3. Chan JKC, Ng CS, Isaacson PG. Relationship between high-grade lymphoma and low-grade B-cell mucosa associated lymphoid tissue lymphoma (MALToma) of the stomach. Am J Pathol 1990; 136: 1. Isaacson

1153-64. 4.

Hyjek E, Smith WJ, Isaacson PG. Primary B-cell lymphoma of salivary glands and its relationship to myoepithelial sialadenitis. Hum Pathol 1988; 19: 766-76.

Hyjek E, Isaacson PG. Primary B cell lymphoma of the thyroid and its relationship to Hashimoto’s thyroiditis. Hum Pathol 1988; 19: 1315-26. 6. Wyatt JI, Rathbone BJ. Immune response of the gastric mucosa to Campylobacter pylori. Scand J Gastroenterol 1988; 23 (suppl 142): 5.

44-19. 7. Stolte M, Eidt S.

Lymphoid follicles in the antral mucosa: immune Campylobacter pylori. J Clin Pathol 1989; 42: 1269-71. 8. Crabtree JE, Taylor JD, Wyatt JI, et al. Mucosal IgA recognition of Helicobacter pylori 120kDa protein, peptic ulceration, and gastric pathology. Lancet 1991; 338: 332-35. 9. Wyatt JI. Gastritis and its relationship to gastric carcinogenesis. Semin Diag Pathol 1991; 8: 137-48. 10. Shallcross TM, Rathbone BJ, Heatley RG. Campylobacter pylori and non-ulcer dyspepsia. In: Rathbone BJ, Heatley RV, eds. Campylobacter pylori and gastroduodenal disease. Oxford: Blackwell response to

Scientific Publications, 1989: 155-66. 11. Parsunnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 1991; 325: 1127-31.

ADDRESS: Department of Histopathology (A. C Wotherspoon, MB, C Ortiz-Hidalgo, MD, M. R. Falzon, MRCPath, Prof P G. Isaacson, FRCPath), University College and Middlesex School of Medicine, University Street, London WC1 E 6JJ, UK. Correspondence to Prof P. G. Isaacson

Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma.

Although lymphoid tissue is absent in normal gastric mucosa, primary lymphomas arise in the stomach and most of these recapitulate the features of muc...
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