Relapse of low-grade gastric MALT lymphoma after Helicobacter pylori eradication: true relapse or persistence? Long-term post-treatment follow-up of a multicenter trial in the north-east of Italy and evaluation of the diagnostic protocol's adequacy.

The effect of eradication of Helicobacter pylori on early stage gastric low-grade MALT lymphoma in 76 patients with follow-up of at least 1 year (12-63 months, mean 28) is reported. No regression was found in five cases after 12-48 months. In one case surgical resection detected the involvement of perigastric lymph nodes overlooked by endoscopic ultrasonography (EUS). Neither progression of the disease nor a high-grade component was documented by repeated gastric mappings, EUS and complete stagings in the other four cases. After histological remission five relapses of low-grade and one relapse of high-grade MALT lymphoma were found 12-48 months after eradication. Subsequent histological remission, without any additional therapy, was found in three relapsed cases. A rapid and persistent histological remission was obtained in 56 patients (73%). A late remission was observed in six cases. Monoclonal remission was found in half of the patients and was frequently delayed. Persistent monoclonality was associated with histological remission in the vast majority of patients. Our data confirm H. pylori eradication as the first choice therapy for early stage gastric low-grade MALT lymphoma and recommend extensive bioptic mapping and endoscopic sonography both in the local staging and in the regression evaluation. The rare cases of late remission encourage us to wait for at least 1 year after eradication of H. pylori. Longer follow-up studies will clarify the meaning of histological relapse/persistence and late remission. The study of non-responder cases could show us a step in lymphomagenesis.

Antigenic mimicry between Helicobacter pylori and gastric mucosa in the pathogenesis of body atrophic gastritis.

BACKGROUND & AIMS: The majority of patients with Helicobacter pylori infection have autoantibodies cross-reacting with gastric antigens. In this study, the relation between autoantibody status, histopathology of body mucosa, and antigenic profile of H. pylori was investigated. METHODS: One hundred patients were examined for H. pylori infection, body gastritis, and gastric autoantibodies. Balb/c mice were analyzed for serum autoantibodies after immunization with H. pylori from patients with and without atrophic gastritis. RESULTS: Immunoglobulin G autoantibodies were detected in 57 of the 87 infected patients (65.5%) but in none of the 13 patients without infection and gastritis. The autoreaction involved mainly the luminal surface of glandular cells and secretory canaliculi of parietal cells. The autoantibody status correlated with the presence and degree of inflammation and atrophy of the glands. H. pylori from patients with atrophic gastritis showed a higher capacity to induce autoantibodies than H. pylori from patients with a minimal superficial gastritis. Monoclonal antibodies showed differences in the bacterial expression of cross-reacting determinants. CONCLUSIONS: H. pylori-mediated autoimmunity is involved in the pathogenesis of chronic atrophic gastritis. The grade of antigenic mimicry of the infecting H. pylori strain plays a role in the progression of chronic gastritis to atrophy.

Carcinoma-like signet-ring cells in gastric mucosa-associated lymphoid tissue (MALT) lymphoma.

We noticed the presence of epithelial signet-ring cells (SRCs) in a proportion of primary gastric B-cell lymphomas, and in some endoscopic biopsies we found it difficult to decide whether they represented an associated carcinoma. To evaluate the frequency and nature of this phenomenon, we reviewed 108 stomachs resected for primary lymphoma, including 70 mucosa-associated lymphoid tissue (MALT) and 38 non-MALT lymphomas. We found SRCs, either isolated or grouped in clusters, in 26 of 70 MALT lymphomas. The SRCs were always localized in the superficial portion of the lamina propria and associated exclusively with lymphomatous areas. Isolated and scarce SRCs were also found in four of 22 cases of polyclonal atypical lymphoid hyperplasia. Our data suggests that SRCs occurring in gastric MALT lymphomas represent a particular type of LEL in which the foveolar cells disaggregated by the lymphomatous infiltration acquire a globoid, signet-ring appearance. These "foveolar" LELs are found in 37% of MALT lymphomas and are usually associated with the more classic and constant "neck" LELs, which are localized between the foveolae and mucopeptic glands. An awareness of the existence of the foveolar LEL may help avoid overdiagnosis of SRC carcinoma on gastric endoscopic biopsies.

Diagnosis and posttreatment follow-up of Helicobacter pylori-positive gastric lymphoma of mucosa-associated lymphoid tissue: histology, polymerase chain reaction, or both?

The differential diagnosis between Helicobacter pylori (H pylori-associated chronic gastritis and low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue (MALT) and the assessment of endoscopic biopsy specimens after treatment of lymphoma can be problematic. Although immunocytochemistry can be used to identify clonal B-cell populations, which are characteristic of MALT lymphoma, its application to small biopsy specimens and the subsequent interpretation can be difficult. The polymerase chain reaction (PCR) can detect clonal B-cell populations by analysis of the Ig heavy chain gene in routinely fixed paraffin-embedded material and might provide a useful tool in the assessment of these specimens. We have investigated the value of histology and PCR in the diagnosis of lymphoma and its followup in formalin-fixed paraffin-embedded gastric endoscopy biopsy specimens from 69 sequential patients selected on the basis of a dense mucosal lymphoid infiltrate associated with H pylori infection. Histologic evidence of MALT lymphoma was identified in 13 cases, 9 of which showed PCR-detected monoclonality. In 12 of 13 cases, H pylori was eradicated, and in 11 of 12 cases, histologic regression of the lymphoma followed. PCR evidence of monoclonality disappeared in 6 of 9 originally monoclonal cases. This was synchronous with histologic remission in 1 case, but lagged in the remaining 5 cases by up to 28 months. Two of the 3 of the 9 cases originally monoclonal by PCR that have not shown molecular regression have monoclonal-amplified products 17 and 24 months after negative histology. In 3 cases, the histology of the biopsies was considered indeterminate or discordant. In 1 of these cases, the histologic features were obscured by crush artefact. In a second case, there was molecular evidence of monoclonality in the absence of histologic features suggestive of lymphoma; this persisted after H pylori eradication. An additional single case originally diagnosed as reactive developed a PCR detectable clonal population 29 months after original evaluation in the absence of histologic features of lymphoma but in the presence of persistent H pylori infection. These findings suggest that the histologic assessment of gastric biopsies remains the method of choice for the diagnosis of lymphoma in gastric endoscopic biopsies with a dense mucosal lymphoid infiltrate. PCR provides a useful technique to support the diagnosis if clonal amplification products are found. The significance of PCR detected clonality in the absence of histologic evidence of lymphoma in uncertain but may represent a stage of tumor progression/regression when the clonal population is insufficient to be detected by conventional histology. This is supported by the evidence that PCR-detectable monoclonality can persist after treatment and the disappearance of histologically detectable lymphoma.

Routine application of polymerase chain reaction in the diagnosis of monoclonality of B-cell lymphoid proliferations.

We evaluated four polymerase chain reaction (PCR) methods for their efficiency in detecting monoclonality in a well-characterized panel of frozen and paraffin-embedded B-cell lymphoid proliferations. These approaches (referred to as FR3, FR3A, FR2, and FR1) are based on amplification of rearranged immunoglobulin heavy chain genes, using primers recognizing framework regions I, II, or III. FR3, FR3A and FR2 approaches reproducibly detected monoclonality in 51%, 72%, and 67% of DNAs from frozen lymphomas, respectively. No false-positives were observed. The combination of FR2 and FR3A methods raised the figure to 85%. Comparable results were obtained using paraffin-embedded lymphomas. Reproducibility of FR1 approach was unsatisfactory. The efficiency of all PCR approaches varied depending on lymphoma type. The highest detection rate was in small/intermediate cell and the lowest in centro-follicular lymphomas. Limiting dilution assays showed that PCR methods were able to detect monoclonal B-cell DNA representing 5% of nonlymphoid and 20% of polyclonal B-cell DNA. A diagnostic protocol may include quick and cost-effective PCR screening, particularly in cases of undetermined small cell lymphoid proliferations observed in fine needle aspirates or endoscopic biopsies. This would also reduce call-up of patients to obtain unfixed biopsies.

Pancreatic (acinar) metaplasia of the gastric mucosa. Histology, ultrastructure, immunocytochemistry, and clinicopathologic correlations of 101 cases.

The occasional finding within the gastric mucosa of unidentified epithelial cells with morphological features closely resembling those of pancreatic acinar cells has prompted us to investigate a retrospective series of 8,430 consecutive gastric biopsies and of 126 surgical specimens of gastric resection and total gastrectomy. The aims of the study were to morphologically and immunocytochemically characterize these cells, to define their actual prevalence in a large series of unselected cases, and to assess the clinicopathologic correlates of their occurrence. Pancreatic acinar-like cells characterized by abundant cytoplasm, which was acidophilic and finely granular in the apical and middle portions and basophilic in the basal compartment, have been identified in 101 cases (84 gastric biopsies and 17 gastrectomies). These cells, arranged in nests or in variably sized lobules among the gastric glands, were morphologically indistinguishable from pancreatic acinar cells, both by light and by electron microscopy. Furthermore, they were consistently immunoreactive for pancreatic lipase and trypsinogen and, in 75% of the cases, for pancreatic alpha-amylase. The appearance of these cells within the gastric mucosa was correlated significantly with chronic gastritis (p = 0.032) and with the simultaneous occurrence of intestinal and pyloric types of gastric metaplasia (p = 0.021). The findings indicate that this is a previously unrecognized pancreatic (acinar) metaplasia of the gastric mucosa, clinically and morphologically distinct from pancreatic heterotopia.

Gastric carcinoids and their precursor lesions. A histologic and immunohistochemical study of 23 cases.

A histologic and immunohistochemical study was carried out in 23 unselected nonantral gastric carcinoids and their precursor lesions classified according to Solcia et al. None of the patients showed Zollinger-Ellison syndrome. Two variants of carcinoids showing distinctive pathologic and pathogenetic characteristics were identified on the basis of presence or absence of associated chronic atrophic gastritis type A (A-CAG). Chronic atrophic gastritis type A was found in 19 cases showing either single or multiple neoplasms, tumor extension limited to the mucosa or submucosa, consistent endocrine cell precursor changes in extratumoral mucosa, and consistent hypergastrinemia and/or G cell hyperplasia. Associated precursor lesions were only hyperplastic in all but two cases with single carcinoids whereas they were also dysplastic in all but one case with multiple carcinoids. The four tumors arising in nonatrophic mucosa were all single, more aggressive, and not associated with extratumoral endocrine cell proliferations or with signs of gastrin hypersecretion. Tumor cells were diffusely immunoreactive for chromogranin A and synaptophysin but usually negative for chromogranin B or HISL-19. Scattered serotonin cells were found in ten carcinoids. They were more frequent in infiltrating than in intramucosal tumors as were the less represented pancreatic polypeptide cells whereas the reverse was found for alpha-subunit-containing cells. These results are of relevance for tumor pathogenesis and may provide the rationale for a less aggressive therapeutic approach in the patients.

Small-cell neuroendocrine carcinoma of the ampullary region. A clinicopathologic, immunohistochemical, and ultrastructural study of three cases.

We report the clinicopathologic, immunohistochemical, and ultrastructural features of three small-cell neuroendocrine carcinomas of the ampullary region of the duodenum. All patients were men; their ages were 51, 62, and 66 years. The therapy consisted of pancreatoduodenectomy. All patients died of the disease; median survival was 10 months from the diagnosis. The histological appearance was identical to pulmonary and extrapulmonary small-cell carcinoma. The neuroendocrine differentiation was demonstrated ultrastructurally by the presence of dense-core granules, and by the positive immunoreaction for neuron-specific enolase and Leu-7 in each case. One case expressed a focal positivity for chromogranin A (PHE-5) and argyrophilic granules. The same case showed the presence of neurofilaments on frozen material. Neurofilament proteins could not be demonstrated in any case in paraffin sections. Neoplastic cells exhibited cytoplasmic immunostaining for cytokeratins (CAM 5.2) in all cases. In one case, a large number of neoplastic cells (60-70%) exhibited nuclear Ki-67 positivity. We postulate that the disease's histogenesis was from epithelial stem cell expressing both epithelial and neuroendocrine characteristics. The clinical behavior of small-cell neuroendocrine carcinomas of the ampullary region appears to be extremely aggressive, with early metastases and fatal outcome.

Nodular hyperplasia of Brunner's glands.

A clinical, endoscopic, and histological study of 206 cases of nodular hyperplasia of Brunner's glands was carried out. Firm nodules with a reddened surface due to hyperplastic Brunner's glands were limited mainly to the first part of the duodenum and affected almost exclusively male patients. Gastric acid secretion after pentagastrin stimulation was significantly increased compared to normal. In most cases, biopsies of the nodule center revealed spreading of Brunner's glands from within the lamina propria to the surface epithelium, whereas in biopsies performed between nodules, Brunner's glands were limited to the deeper part of the mucosa. Thirty-six nodules completely removed by diathermy were composed almost entirely of Brunner's glands. The frequent association with duodenal ulcer, chronic gastric erosions, and cobblestone pattern of the gastric body mucosa, as well as the significant hypersecretory state, suggest that hyperacidity plays a role in the pathogenesis of nodular hyperplasia of Brunner's glands.

Polypoid lesions associated with diverticular disease of the sigmoid colon.

Colonscopy performed in five patients because of narrowing of the sigmoid colon with intramural diverticula revealed several bright red, slightly elevated patches. In three patients, some bright red polypoid structures 1 cm in size and hemispherical in shape were also present. On light microscopy the polyps showed the features of transitional mucosa but revealed a different pattern of mucus secretion.

Gastritis cystica polyposa: a possible precancerous lesion.

Twenty polypoid lesions at gastroenterostomy stomas (the so-called gastritis cystica polyposa-GCP) were endoscopically removed from gastroenterostomy stomas of 16 male and two female patients previously operated for benign lesions. The interval from surgery ranged from 3 to 40 years (mean: 16.2 years). At light microscopy GCP showed 2 histologic patterns: a) with cystic glands limited to the mucosal layer (gastritis cystica superficialis); b) with cystic glands also spreading into the submucosa (gastritis cystica profunda). Atrophy of specific gastric glands, intestinal metaplasia and dysplastic changes also occurred. Local chronic ischemia and inflammatory reaction as a consequence of gastric surgery and suture at gastroenterostomy together with bile reflux were considered responsible for the development of GCP. The sites and the histologic features of GCP resembled those of experimental stomal polyps preceeding carcinoma in rats after partial gastrectomy. The sites of formation, the sex incidence, the interval from previous operation as well as the histologic findings suggest that GCP is a possible precancerous lesion.

Prevalence of gastroduodenal lesions in uremic patients undergoing dialysis and after renal transplantation.

Upper gastrointestinal endoscopic examination showed lesions in 28 of 112 dialysis uremic patients and in 19 of 52 after renal transplantation. Most patients with and without lesions were symptom free. A significant increase in gastric acid secretion was found in patients with transplant as compared with dialysis uremic patients. The prevalence of ulcer in the dialysis group was not increased compared with the general population, whereas it was increased in the group with transplantation. An increase of duodenal and a decrease of gastric lesions (ulcers and erosions) in the group with transplantation compared with the dialysis group was found. The importance of a systematic upper gastrointestinal endoscopic survey in hemodialyzed and transplanted patients is stressed.

Chronic erosions of the stomach--a clinical, endoscopic and histological evaluation.

A clinical, endoscopic and histological study was performed in 300 patients with chronic gastric erosions. The male-female ratio was 4:1. The antrum was the preferential site of erosions. Chronic erosions were classified into two categories: "active" (with a dark clot or whitish coat of fibrin) and "inactive" (covered by a normal pink mucosa). All the lesions showed foveolar hyperplasia, partial obliteration of the lamina propria by fibrous and smooth muscle bundles, a greatly thickened muscularis mucosae and an increased number of submucosal thick-walled vessels. In the "active" stage the central umbilicated area was covered by a collection of granulocytes, while in some of the "inactive" erosions the central depression showed the presence of a channel-like structure penetrating into the lamina propria. In two cases the lesion mimicked a gastric adenomyoma. Gastric acid secretion was significantly increased in the tested patients as compared with normal. The similarity of the histological findings with those in ischemic conditions of the gastro-intestinal tract suggests that both hypersecretion and localized ischemia may play a role in the pathogenesis of chronic erosions.

Mucin secretion and morphological changes of the mucosa in non-neoplastic diseases of the colon.

Changes in mucin secretion and increase in height of the colonic mucosa adjacent to colorectal carcinoma (transitional mucosa) have been considered pre-malignant. In this study similar changes (both morphological and histochemical) have been found in some cases of ulcerative colitis and ischaemic colitis, as well as in juvenile, inflammatory and hyperplastic (metaplastic) polyps. 'Transitional' patterns of mucin secretion also occur in some other cases of ulcerative colitis, colostomies and Crohn's disease of the colon in which the mucosa has a normal height, suggesting the changes in mucin secretion are independent of mucosal morphology. In all these pathological conditions, hyperplastic (metaplastic) mucosa also coexisted. These findings seem to suggest that: (1) 'transitional' changes more likely represent a secondary regenerative phenomenon rather than a premalignant one; (2) the pattern of mucin secretion is not selective enough to serve as a premalignant marker; therefore is not a valid prognostic indicator in colonic biopsies; (3) hyperplastic (metaplastic) changes might derive from 'transitional' mucosa as a result of a more mature phase of this exaggerated regenerative phenomenon. However, in some patients longstanding 'transitional' mucosa may lead to dysplasia under the influence of environmental and genetic factors.

Juvenile and inflammatory polyps of the colon--a histological and histochemical study.

A light microscopy and histochemical study of 24 juvenile and 27 inflammatory polyps showed that both may derive from inflammatory processes. Granulation tissue, secondary to spontaneous local inflammation or due to surgical procedures may subsequently be covered by regenerating epithelium which lines haemorrhagic cavities and mucus lakes to form irregular, elongated and cystic glands, which are characteristic of juvenile polyps. Both juvenile and inflammatory polyps showed cystic, metaplastic and 'transitional-type' glands. The mucin distribution was identical in both types of polyps. All these findings suggest a common origin of the polyps. The presence of 'transitional-type' glands seems to confirm these as a secondary regenerative phenomenon rather than pre-neoplastic, although dysplastic changes in juvenile polyps have been described. It is suggested that both the juvenile and inflammatory polyps may undergo dysplasia only in genetically predisposed subjects. However, this event seems to be very rare.