Men1

This inherited tumour syndrome causes a variety of endocrine neoplasms, including gastrinomas. In patients with MEN-1 associated ZES (MEN-1/ZES), ECL-cell lesions are usually dysplastic or overtly carcinoid in nature {1779}. In the MEN-1 syndrome, the mutation or deletion of the suppressor MEN-1 oncogene in 11 q 13 may be involved {394} as an additional pathogenetic factor. In A-CAG, achlorhy-dria or associated mucosal changes may

Fig. 3.31 Chromogranin A immunostain demonstrates hyperplasia of endocrine cells at the base of glandular tubules.

contribute to tumourigenesis {1785}. Several growth factors, including transforming growth factor-a (TGFa) and basic fibroblast growth factor (bFGF) seem to be involved in tumour development and progression as well as stromal and vascular proliferation of ECL-cell carcinoids {171}.

Localization

Type I, II, and III ECL-cell carcinoids are all located in the mucosa of the body-fundus of the stomach, whereas the rare G-cell tumours are located in the antro-pyloric region. Small cell carcinomas prevail in the body/fundus, but some are located in the antrum {1590}.

Clinical features

The three distinct types of ECL-cell carcinoids are well differentiated growths but with variable and poorly predictable behaviour.

Type I ECL-cell carcinoids

These are associated with A-CAG involving the corpus and fundus mucosa. Clinical signs include achlorhydria and, less frequently, pernicious anemia. Hypergastrinaemia or evidence of antral gastrin-cell hyperplasia is observed in all cases of A-CAG. In patients with a carci-noid, ECL-cell hyperplastic changes are a constant feature and dysplastic growths are frequently observed {1590}. A-CAG associated carcinoids are typically small (usually less than 1 cm), mul tiple and multicentric. Of 152 cases studied by endoscopy, 57% had more than two growths {1561}.

Type II ECL-cell carcinoids

Hypertrophic, hypersecretory gastropa-thy and high levels of circulating gastrin are critical diagnostic findings. In all cases, ECL-cell hyperplasia and/or dysplasia were noted in the fundic peritu-moural mucosa {1590}. These gastric carcinoids are usually multiple and smaller than 1.5 cm in size in the majority of cases {1590}.

Type III (sporadic) ECL-cell carcinoids

These lesions are not associated with hypergastinaemia or A-CAG. They are generally solitary growths, and arise in the setting of gastric mucosa devoid of ECL-cell hyperplasia/dysplasia and of significant pathologic lesions except for gastritis (other than A-CAG). Rare multiple tumours have been observed {1590}. Clinically, type III tumours present (1) as a mass lesion with no evidence of endocrine symptoms (nonfunctioning carci-noid) and with clinical findings similar to those of adenocarcinoma, including gastric haemorrhage, obstruction and metastasis, or (2) with endocrine symptoms of an 'atypical carcinoid syndrome' with red cutaneous flushing and absence of diarrhoea, usually coupled with liver metastases and production of histamine and 5-hydroxytryptophan {1386, 1598}.

Non ECL-cell gastric carcinoids.

These uncommon tumours may present with ZES due to their gastrin production (which is more frequently found in duodenal gastrinomas) or with Cushing syndrome due to secretion of adrenocorti-cotrophic hormone (ACTH) {711, 1791}.

Macroscopy

Type I ECL-cell carcinoids are multiple in 57% of cases {1590}, usually appearing as small tan nodules or polyps that are circumscribed in the mucosa or, more often, to the submucosa. Most tumours (77%) are < 1 cm in maximum diameter and 97% of tumours are < 1.5 cm. The muscularis propria is involved in only a minority of cases (7%) {1590}. The stomachs with type II tumours are enlarged and show a thickened gastric wall (0.6-4.5 cm) due to severe hyper-trophic-hypersecretory gastropathy and multiple mucosal-submucosal nodules which, though larger than those of type I, are generally smaller than 1.5 cm in size in 75% of cases {1590}. Type III ECL-cell tumours are usually single and in 33% of the cases larger than 2 cm in diameter. Infiltration of the muscu-laris propria is found in 76%, and of the serosa in 53% of cases {1590}.

Histopathology

The histopathological categorization of endocrine tumours of the stomach described here, is a modification of the WHO classification of endocrine tumours {1784}.

Carcinoid tumour

A carcinoid is defined morphologically as a well differentiated neoplasm of the diffuse endocrine system.

ECL-cell carcinoid

The majority of type I and type II ECL-cell carcinoids are characterized by small, microlobular-trabecular aggregates formed by regularly distributed, often aligned cells (mosaic-like pattern), with regular, monomorphic nuclei, usually inapparent nucleoli, rather abundant, fairly eosinophilic cytoplasm, almost absent mitoses, and infrequent angioin-vasion.

Tumours with these features (grade 1 according to Rindi et al {1589}) are generally limited to mucosa or submucosa {1589} and can be considered as tumours with benign behaviour. The ECL nature of the tumours is confirmed by strong argyrophilia by Grimelius or Sevier Munger techniques and positive immunoreactivity for chromogranin A, in the absence of reactivity for the argentaffin or diazonium tests for serotonin, and no or only occasional immunoreactivity for hormonal products {1591}. Minor cell sub-populations expressing serotonin, gastrin, somato-statin, pancreatic polypeptide (PP), or a-hCG have been detected in a minority of tumours {1591}. A few ECL-cell tumours produce histamine and 5-hydroxy-tryptophan; these lesions, when they metastasize, can produce 'atypical' carcinoid syndrome {1591} Vesicular monoamine transporter type 2 (VMAT-2) is a suitable and specific marker for ECL-cell tumours {1592} while hista-mine or histidine decarboxylase immuno-histochemical analysis, although specific, is less suitable for routinely processed

Fig. 3.32 Sporadic (type III) ECL-cell carcinoid of the gastric body. The surrounding mucosa is normal.

specimens {1865}. The ECL-cell nature of argyrophil tumours is ultimately assessed by demonstrating ECL-type granules by electron microscopy {232, 1591}. Sporadic ECL-cell carcinoids are usually more aggressive than those associated with A-CAG or MEN-1. Histopathologi-cally, these tumours show a prevalence of solid cellular aggregates and large tra-beculae, crowding, and irregular distribution of round to spindle and polyhedral tumour cells, fairly large vesicular nuclei with prominent eosinophilic nucleoli, or smaller, hyperchromatic nuclei with irregular chromatin clumps and small nucle-oli, considerable mitotic activity, sometimes with atypical mitotic figures and scarce necrosis.

Tumours with these histological features or grade 2 features {1589} show a higher mitotic rate (mean of 9 per 10 HPF), a frequent expression of p53 (60%), a higher

Table 3.02.

Histological classification of endocrine neoplasms of the stomach1

1. Carcinoid -

well differentiated endocrine neoplasm

1.1 ECL-cell carcinoid

1.2 EC-cell, serotonin-producing carcinoid

1.3 G-cell, gastrin-producing tumour

1.4 Others

2. Small cell carcinoma -

poorly differentiated endocrine neoplasm

3. Tumour-like lesions

Hyperplasia Dysplasia

1 Benign behaviour of ECL-cell carcinoid is associated with the following: tumour confined to mucosa-sub-mucosa, nonangioinvasive, < 1cm in size, nonfunc-tioning; occurring in CAG or MEN-1/ ZES. Aggressive behaviour of ECL-cell carcinoid is associated with the following: tumour invades muscularis propria or beyond, > 1cm in size, angioinvasive, functioning, and sporadic occurrence.

Fig. 3.33 A Type I ECL-cell carcinoid in a patient with pernicious anaemia. B Type II ECL-cell carcinoid in a patient with MEN1 and ZES.

Fig. 3.33 A Type I ECL-cell carcinoid in a patient with pernicious anaemia. B Type II ECL-cell carcinoid in a patient with MEN1 and ZES.

Ki67 labelling index (above 1000 per 10 HPF) and more frequent lymphatic and vascular invasion than well differentiated ECL-cell carcinoids {1589}. In addition, deeply invasive tumours are associated with local and/or distant metastases in most cases.

EC-cell, serotonin-producing carcinoid

This is a very rare tumour in the stomach {1591}. It is formed by rounded nests of closely packed small tumour cells, often with peripheral palisading, reminiscent of the typical type A histologic pattern of the argentaffin EC-cell carcinoid of the midgut. The tumour cells are argentaffin, intensely argyrophilic and reactive with chromogranin A and anti-serotonin antibodies. Electron microscopic examination confirms the EC-cell nature by detecting characteristic pleomorphic, intensely osmiophilic granules similar to those of normal gastric EC-cells.

Gastrin-cell tumours

Most well differentiated gastrin-cell tumours are small mucosal-submucosal nodules, found incidentally at endoscopy or in a gastrectomy specimen. They may show a characteristic thin trabecular-gyriform pattern or a solid nest pattern. The cells are uniform with scanty cytoplasm and show predominant immunore-activity for gastrin.

Small cell carcinoma (poorly differentiated endocrine neoplasm)

These are identical to small cell carcinomas of the lung. They correspond to grade 3 tumours according to Rindi et al. {1589}, and are particularly aggressive, malignant tumours {1591}.

Large cell neuroendocrine carcinoma is a malignant neoplasm composed of large cells having organoid, nesting, trabecular, rosette-like and palisading patterns that suggest endocrine differentiation, and in which the last can be confirmed by immunohistochemistry and electron microscopy. In contrast to small cell carcinoma, cytoplasm is more abundant, nuclei are more vesicular and nucleoli are prominent {1954}. These tumours have not been well described in the gastrointestinal tract because of their apparent low frequency {1188}.

Fig. 3.34 ECL-cell carcinoid showing immunoexpression of chromogranin A.

Mixed exocrine-endocrine carcinomas

These consist of neoplastic endocrine cells composing more than 30% of the whole tumour cell population. They are relatively rare in the stomach, despite the frequent occurrence of minor endocrine components inside the ordinary adenocarcinoma. They should generally be classified as adenocarcinomas.

Precursor lesions

ECL-cell carcinoids arising in hypergas-trinaemic conditions (types I and II) develop through a sequence of hyperpla-sia-dysplasia-neoplasia that has been well documented in histopathological studies {1777}. The successive stages of hyperplasia are termed simple, linear, micronodular, and adenomatoid. Dysplasia is characterized by relatively atypical cells with features of enlarging or fusing micronodules, micro-invasion or newly formed stroma. When the nodules increase in size to > 0.5 mm or invade into the submucosa, the lesion is classified as a carcinoid. The entire spectrum of ECL-cell growth, from hyperplasia to dysplasia and neoplasia has been observed in MEN-1/ZES and autoimmune chronic atrophic gastritis (A-CAG). A similar sequence of lesions has been shown in experimental models of the disease, mostly based on hypergastrinaemia secondary to pharmacological inhibition of acid secretion in rodents {1896}.

Genetic susceptibility

ECL-cell carcinoids are integral components of the MEN-1 syndrome {1042}. In patients with familial MEN-1/ZES, type II gastric carcinoids arise in 13-30% of cases {854, 1042}. However, patients

Fig. 3.35 Sporadic (type III) ECL carcinoid. A Tumour extends from mucosa into submucosa with well delineated inferior border. B The carcinoid (left) has round, regular, isomorphic nuclei.

with sporadic ZES rarely develop gastric carcinoids despite serum gastrin levels, which persist 10 fold above normal for a prolonged time.

Diagnostic criteria of MEN-1

This rare dominantly inherited disorder is characterized by the synchronous or metachronous development of multiple endocrine tumours in different endocrine organs by the third decade of life. The parathyroid glands are involved in 90-97%, endocrine pancreas in 30-82%, duodenal gastrinomas in 25%, pituitary adenomas in more than 60%, and foregut carcinoids (stomach, lung, thymus) in 5-9% of cases {394}. Other, so-called non-classical MEN-1 tumours, such as cutaneous and visceral lipomas, thyroid and adrenal adenomas, and skin angiofi-bromas, may occur {394, 1444}.

MEN-1 gene

MEN-1 has been mapped to chromosome 11q13 {107, 1015}. It encodes for a 610 amino acid nuclear protein, termed 'menin', whose suppressor function involves direct binding to JunD and inhibition of JunD activated transcription {271, 18}. The tumour suppressor function of the gene has been proposed based on the results of combined tumour deletion and pedigree analysis {107, 271, 394}. High rates of loss of heterozygosity (LOH) at the MEN-1 gene locus have been reported in classic tumours of the MEN-1, such as endocrine pancreatic, pituitary and parathyroid neoplasms {1553, 1923}. LOH at 11q13 of type II gastric carcinoids was found in 9 of 10 MEN-1 patients investigated {123, 173, 219, 394}.

These findings support the concept that these gastric tumours are integral components of the MEN-1 phenotype, sharing with parathyroid and islet cell tumours the highest frequency of LOH at 11 q 13. In multiple carcinoids from the same stomach, the deletion size in the wild-type allele differed from one tumour to another, suggesting a multiclonal origin {394}. One of the type II tumours showing LOH at 11q13 was in a patient who had neither ZES nor hypergastri-naemia {173}, suggesting that inactiva-tion of the MEN-1gene alone is capable

Fig. 3.36 Gastrin cell tumour (gastrinoma) of the pylorus with trabecular growth pattern.

of causing ECL-cell tumours without requiring the promoting effect of hyper-gastrinaemia.

The role of MEN-1in non MEN-associated gastric carcinoids is more controversial. Analysing six type I gastric carcinoids, Debelenko et al. {394} found 11q13 LOH in one tumour while D'Adda et al. {363} detected 11q13 LOH in 12 out of 25 cases (48%). Large deletions in both the 11q13 and 11q14 regions were observed in two poorly differentiated endocrine carcinomas {363}.

Prognosis and predictive factors

The prognosis of carcinoids is highly variable, ranging from slowly growing benign lesions to malignant tumours with extensive metastatic spread. Benign behaviour of ECL-cell carcinoids is associated with the following: tumour confined to mucosa-submucosa, nonan-gioinvasive, < 1 cm in size, nonfunction-ing; occurring in CAG or MEN-1/ ZES. Type I, A-CAG associated tumours, have an excellent prognosis, as do most type II MEN-1/ZES tumours. Aggressive behaviour of ECL-cell carci-noid is associated with the following: tumour invades muscularis propria or beyond, is > 1 cm in size, angioinvasive, functioning, with high mitotic activity and sporadic occurrence {1591, 1590, 1589}. Metastasis. Lymph node metastases are detected in 5% of type I and 30% of type II cases, while distant (liver) metastases are found respectively in 2.5% and 10% of cases. No tumour-related or only exceptional death was observed among patients with type I carcinoid, while only 1/10 patients died of type II carcinoid. On

Fig. 3.37 Small cell carcinoma of the stomach.

the other hand, lymph node metastases are found in 71% and distant metastases in 69% of patients with type III tumours;

death from the tumour occurs in 27% of patients with a mean survival of 28 months {1590}.

Therapy

Polypoid type I carcinoids < 1cm, fewer than 3-5 in number, associated with A-CAG can be endoscopically excised and have an excellent prognosis. If larger than 1 cm or more than 3-5 lesions are present, antrectomy and local excision of all accessible fundic lesions is recommended.

In type II carcinoids the clinical evolution depends on the behaviour of associated pancreatic and duodenal gastrinomas more than on the behaviour of gastric tumours, although some aggressive ECL-cell carcinomas may be fatal {173}. In such patients, careful search for associated pancreatic, duodenal, parathyroid, or other tumours and family investigation for the MEN-1 gene mutation are needed. Type III (sporadic) ECL-cell carcinoids > 1 cm generally require surgical resection even when they are histologically well differentiated.

Lymphoma of the stomach

A. Wotherspoon A. Chott R.D. Gascoyne H.K. Müller-Hermelink

Definition

Primary gastric lymphomas are defined as lymphomas originating from the stomach and contiguous lymph nodes. Lymphomas at this site are considered primary if the main bulk of disease is located in the stomach. The majority of gastric lymphomas are high-grade B-cell lymphomas, some of which have developed through progression from low-grade lymphomas of mucosa associated lymphoid tissue (MALT). The low-grade lesions are almost exclusively B-cell MALT lymphomas.

Historical annotation

Classically, primary gastric lymphomas have been considered to be lymphomas that are confined to the stomach and the contiguous lymph nodes {378}. While this excludes cases of secondary involvement of the stomach by nodal-type lymphomas - which may occur in up to 25% of nodal lymphomas {508} -this definition is excessively restrictive and excludes more disseminated, higher stage lymphomas arising within the stomach as well as those with bone mar row involvement. Today, stomach lymphomas are considered primary if the main bulk of disease is present in the stomach. Recognition of morphological features characteristic of primary extra-nodal lymphomas of mucosa-associated lymphoid tissue-type helps in defining these lesions as primary to the stomach irrespective of the degree of dissemination.

Epidemiology

Approximately 40% of all non-Hodgkin lymphomas arise at extranodal sites {1438, 527}, with the gastrointestinal tract as the commonest extranodal site, accounting for about 4-18% of all non-Hodgkin lymphomas in Western countries and up to 25% of cases in the Middle East. Within the gastrointestinal tract, the stomach is the most frequent site of involvement in Western countries while the small intestine is most frequently affected in Middle Eastern countries. Lymphoma constitutes up to 10% of all gastric malignancies; its incidence appears to be increasing but this may, at least in part, be due to the recognition of the neoplastic nature of lesions previously termed 'pseudolymphoma' {677}. Gastric lymphoma has a worldwide distribution; somewhat higher incidences have been reported for some Western communities with a high prevalence of Helicobacter pylori infection {420}. Primary Hodgkin disease is very rare in the gastrointestinal tract.

Age and sex distribution

Incidence rates are similar in men and women. The age range is wide but the majority of patients are over 50 years at presentation.

Aetiology

Helicobacter pylori infection

Initial studies of low-grade MALT lymphoma suggested that the tumour was associated with H. pylori in 92-98% of cases {447, 2135}; subsequent studies have suggested an association in 62-77% {1316, 583, 2146, 890, 178}. H. pyloriinfection is seen less frequently in high-grade lymphomas with a low-grade component (52-71%) and in pure high-grade lymphomas (25-38%) {583,

890, 178}. The organism has been shown to be present in 90% of cases limited to the mucosa and submucosa, falling to 76% when deep submucosa is involved, and is present in only 48% of cases with extension beyond the submucosa {1316}. It has been shown that the infection by H. pyloriprecedes the development of lymphoma, both by sequential serological studies {1474} and by retrospective studies of archival gastric biopsy material {2211, 1314}. There is some controversy surrounding the role of the organism's genetic features and the risk of lymphoma development. Studies of the association between MALT lymphoma and cagA bearing H. pyloristrains have produced conflicting results, ranging from a lack of association between cagA and lymphoma {1492, 384} to a strong association {441}. One study claimed no association with low-grade lymphoma but a high frequency of cagA strains in high-grade lesions {1492}. Recently, a truncated form of an H. pylori associated protein, fldA, has been shown to be closely associated with gastric MALT lymphoma. All strains of H. pylori associated with MALT lymphoma showed a nucleotide G insertion at position 481 of the fldA gene, compared to 6/17 stains unassociated with lymphoma. This mutation causes a short truncation in the protein and antibodies to this truncated protein could be detected in 70% of the patients studied with MALT lymphoma, compared to 17% of control patients {274}.

Immunosuppression

Lymphomas may arise or involve the stomach in patients with both congenital and acquired immunodeficiencies. In general, the incidence, clinical features and the histology of the lesions is indistinguishable from those that develop outside the stomach. Up to 23% of gastrointestinal tract non-Hodgkin lymphomas arising in HIV infected patients occur in the stomach and the vast majority of these are large B-cell or Burkitt/Burkitt-like lymphomas, {122} although occasional low-grade MALT lymphomas are described {2132}.

Clinical features

Symptoms and signs Patients with low-grade lymphomas often present with a long history of non-specific symptoms, including dyspepsia, nau sea and vomiting. High-grade lesions may appear as a palpable mass in the epigastrium and can cause severe symptoms, including weight loss.

Imaging

Low-grade MALT lymphomas present as intragastric nodularity with preferential location in the antrum {2180}. A more precise assessment is obtained with spiral CT, particularly if this is used in conjunction with distension of the stomach by water. This technique can identify up to 88% of cases, most of which have nodularity or enlarged rugal folds, and it can assess the submucosal extent of the tumour {1493}. High-grade lymphomas are usually larger and more frequently associated with the presence of a mass and with ulceration. In some cases, the radiological features may mimic diffuse adenocarcinoma {1059}. Endoscopic ultrasound is emerging as the investigation of choice in the assessment of the extent of lymphoma infiltration through the gastric wall. Local lymph node involvement can also be assessed by this technique.

Endoscopy

Some cases show enlarged gastric folds, gastritis, superficial erosions or ulceration. In these cases the surrounding normal appearing gastric mucosa may harbour lymphoma, and accurate mapping of the lesion requires multiple biopsies from all sites including areas appearing macroscopically normal. In a proportion of cases, endoscopic examination shows very minor changes such as hyperaemia and in a few cases random biopsies of apparently entirely normal mucosa may reveal lymphoma. High-grade lymphoma is usually associated with more florid lesions, ulcers and masses. It is often impossible to distinguish lymphoma from carcinoma endoscopically.

MALT lymphomas

Pathogenesis

The normal gastric mucosa contains scattered lymphocytes and plasma cells but is devoid of organised lymphoid tissue. The initial step in the development of primary gastric lymphoma is the acquisition of organised lymphoid tissue from within which the lymphoma can develop. In most cases, this is associated with infection by H. pylori {572}, although it has also been seen following infection by

Fig. 3.38 Multifocal malignant lymphoma of the stomach. The two larger lesions are centrally ulcerated.

Helicobacter heilmannii {1842} and in association with coeliac disease {227}. This organised lymphoid tissue shows all the features of MALT, including the infiltration of the epithelium by B-lympho-cytes reminiscent of the lymphoepitheli-um seen in Peyer patches {2135}. The cellular basis of the interaction between H. pyloriand MALT lymphoma cells has been studied in detail. When unseparated cells isolated from low-grade gastric MALT lymphomas are incubated in vitro with heat treated whole cell preparations from H. pylori, the tumour cells proliferate while those cultured in the absence of the organism or stimulating chemical mitogen rapidly die {768}. The proliferative response appeared to be strain specific for individual tumours but varied between tumours from different patients {768}. When T-cells were removed from the culture system the pro-liferative response was not seen and this could not be induced if the T-cells were replaced by supernatant from other cultures containing unseparated tumour derived cells {769}. Together these studies show that the proliferation of the MALT lymphoma is driven by the presence of the H. pyloribut that this, rather than being a direct effect on the tumour

Fig. 3.39 Low-grade B-cell MALT lymphoma. Perifollicular distribution of centrocyte-like cells with a predominant monocytoid morphology.
Fig. 3.40 Low-grade B-cell MALT lymphoma. Small lymphoid cells form a diffuse infiltrate extending into the submucosa.

cells, is due to a mechanism mediated via T-cells and that this help is contact dependant. Further studies have shown that the T-cells responsible for the proliferative drive are specifically those found within the tumour and their function cannot be replaced by T-cells derived from elsewhere (e.g. the spleen) in the same patient {769}.

Histopathology

The organisation of the lymphoma mimics that of normal MALT and the cellular morphology and immunophenotype is essentially that of the marginal zone B-cell. The neoplastic cells infiltrate between pre-existing lymphoid follicles, initially loca-lised outside the follicular mantle zone in a marginal zone pattern. As the lesion progresses, the neoplastic cells erode, colonize and eventually overrun the lymphoid follicles resulting in a vague nodularity to an otherwise diffuse lymphomatous infiltrate {800}. The morphology of the neoplastic cell can be variable even within a single case. Characteristically, the cell is of intermediate size with pale cytoplasm and an irregular nucleus. The resemblance of these cells to the centrocyte of the follicle centre has led to the term 'centrocyte-like (CCL)' cell being applied to the neoplastic component of MALT lymphomas. In some cases, the CCL cell may be more reminiscent of a mature small B lymphocyte while in other cases, the cell may have a monocytoid appearance with more abundant, pale cytoplasm and a well defined cell border. Plasma cell differentiation is typical and may be very prominent. Dutcher bodies may be identified. The CCL cells infiltrate and destroy adjacent gastric glands to form lym-phoepithelial lesions. Lympho-epithelial lesions typical for MALT lymphoma are defined as infiltration of the glandular epithelium by clusters of neoplastic lym-phoid cells with associated destruction of gland architecture and morphological changes within the epithelial cells, including increased eosinophilia.

Immunohistochemistry

The immunophenotype of the CCL cell is similar to that of the marginal zone B-cell. There is expression of pan-B-cell antigens such as CD20 and CD79a and the more mature B-cell markers CD21 and CD35. The cells do not express CD10. They are usually positive for bcl-2 protein and may express CD43 but do not express CD5 or CD23. They express surface and, to a lesser extent, cytoplasmic immunoglobulin (usually IgM or IgA, rarely IgG) and show light chain restriction. Immunostaining with anti-cytoker-atin antibodies is useful in demonstrating lymphoepithelial lesions. Immunostaining with antibodies that highlight follicular dendritic cells (anti-CD21, anti-CD23 or anti-CD35) help to demonstrate underlying follicular dendritic cell networks in those cases in which the lymphoid follicles have been completely overrun by the lymphoma.

Differential diagnosis

The distinction between florid gastritis and low-grade MALT lymphoma may be difficult. In such cases it is essential to have sufficient biopsy material (up to eight biopsies from endoscopically suspicious areas) with good preservation of morphology and correct orientation of the biopsy specimen. For the distinction between reactive and neoplastic infiltrates, histological evaluation remains the gold standard, but accessory studies may be helpful. In both reactive and neo-plastic cases, lymphoid follicles are present and these may be associated with active inflammation, crypt abscesses and reactive epithelial changes. In gas tritis, the infiltrate surrounding the lym-phoid follicles in the lamina propria is plasma cell predominant while in MALT lymphoma the infiltrate contains a dominant population of lymphocytes with CCL cell morphology, infiltrating through the lamina propria and around glands. Prominent lymphoepithelial lesions, Dutcher bodies and moderate cytologi-cal atypia are associated only with lymphoma. All of these features may not be present in biopsy material from a single case. In some cases it is justifiable to make the diagnosis of low-grade MALT lymphoma in the absence of one or more of these features if the overall histological appearances are those of lymphoma. Rare or questionable lymphoepithelial lesions, dense lymphoid infiltration, mild cytological atypia and muscularis mucosae invasion are features more often associated with, but not limited to, lymphoma {2212}.

In some cases it will not be possible to make a definite distinction between reactive infiltrates and lymphoma and in these cases a diagnosis of 'atypical lym-phoid infiltrate of uncertain nature' is appropriate.

Effect of H. pylori eradication

The histological appearances of gastric biopsies from patients showing complete regression of lymphoma after H. pylori

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