Variable workup calls for guideline development for type 2A hereditary haemochromatosis.

BACKGROUND: Type 2A hereditary haemochromatosis (type 2A HH) is a rare iron-loading disorder caused by mutations in the HFE2 gene, which encodes the HJV protein. We present characteristics, treatment and follow-up of subjects diagnosed with type 2A HH in the Netherlands to increase awareness of the disease and its treatment, and to define knowledge gaps. METHODS: We collected clinical, biochemical and genetic data from seven patients (two female; five probands) from six families genetically diagnosed with type 2A HH at the Expertise Center for Iron Disorders, Radboud University Medical Centre between 2006 and 2016. RESULTS: The five probands presented with heterogeneous complaints between the ages of 19 and 39. One of two patients with delayed clinical diagnosis developed hypogonadism and Y. enterocolitica sepsis. Diagnostic workup and follow-up varied. When assessed, elevated transferrin saturation (79-98%), ferritin (1400-6200 µg/l) and severely elevated liver iron levels were found, and in all subjects, phlebotomies were initiated. One subject was switched to erythrocytapheresis. Target ferritin levels varied. Despite long-term iron depletion, two subjects developed clinical complications. Sanger sequencing revealed two pathogenic HFE2 variants (homozygous or compound heterozygous) for the five families of Dutch descent and one new pathogenic variant in the family of non-Dutch descent. CONCLUSION: Three genetic variants caused type 2A HH in six families. Clinical diagnosis was delayed in two subjects. We observed variance in presentation, workup, follow-up and treatment. We found new complications in long-term iron-depleted patients. We recommend research and guidelines for optimal workup, follow-up and treatment of type 2A HH.

Concurrent Whipple's disease and Giardia lamblia infection in a patient presenting with weight loss.

Whipple's disease is an uncommon systemic disease caused by the recently cultured Tropheryma whippelii, classically presenting with gastrointestinal symptoms. We report a patient with weight loss and malabsorption in which Whipple's disease and concurrent Giardia lamblia infection were diagnosed. Moreover, multiple small bowel polyps were present. The relationship between concurrent Whipple's disease and Giardia lamblia infection is discussed.

Expression of CD10, CD75 and CD43 in MALT lymphoma and their usefulness in discriminating MALT lymphoma from follicular lymphoma and chronic gastritis.

AIMS: While it may be difficult to discriminate between chronic gastritis, MALT lymphoma and a gastric location of a nodal lymphoma using histology of small endoscopic biopsies alone, additional markers like CD10, CD75 and CD43 and proliferative activity may be of value. We assessed the expression of these antigens in MALT lymphoma and their usefulness in discriminating MALT lymphoma from follicular lymphoma and from gastritis. METHODS AND RESULTS: Tissue samples of 38 patients with gastric MALT lymphoma were immunohistochemically stained for expression of CD10, CD75 and/or CD43. Proliferation index was scored using MIB-1 staining. Ten cases of nodal follicle centre B-cell lymphomas (n = 11) and 18 cases of high-grade MALT lymphoma (n = 22) showed moderate to high CD75 expression (25-100% positive cells). All tested low-grade MALT lymphomas (n = 9) and chronic gastritis (n = 6) were negative (0-25%) for CD75. All MALT lymphomas (n = 25) were negative for CD10. High-grade lymphomas show significantly higher proliferation indices (67% vs. 16%) than low-grade lymphomas. Only four of 26 MALT lymphomas were slightly positive for CD43. All gastritis biopsies (n = 4) were negative for CD43. CONCLUSIONS: These data suggest that combining both CD10 and CD75 may be useful in discriminating between low-grade MALT, high-grade MALT lymphoma and extranodal location of follicular lymphoma. However, CD43 expression cannot in the majority of cases be used to distinguish between low-grade MALT lymphoma and gastritis.

Gastric low-grade MALT lymphoma, high-grade MALT lymphoma and diffuse large B cell lymphoma show different frequencies of trisomy.

Gastric MALT lymphoma is a distinct entity related to Helicobacter pylori gastritis. Some studies suggest a role for trisomy 3 in the genesis of these lymphomas, but they mainly focused on low-grade MALT lymphoma. Gastric MALT lymphoma, however, comprises a spectrum from low- to high-grade cases. Furthermore, its exact relation to primary diffuse large B cell lymphoma (DLBCL) of the stomach is not clear. We applied in situ hybridisation (ISH) with centromeric probes on 43 samples of 39 patients with primary gastric lymphoma (13 samples with low-grade MALT lymphoma, 25 with high-grade MALT lymphoma and five with DLBCL) to detect numerical aberrations of 10 chromosomes. ISH was performed immunohistochemically on nuclei isolated from paraffin-embedded resection tissue and on whole paraffin sections using immunofluorescence. In six of 13 low-grade MALT lymphomas trisomy was detected (46%) and mostly involved chromosome 3 (33%). In high-grade MALT lymphomas, trisomies were found in 16 of 25 cases (64%), mainly involving chromosomes 12 and 18. Trisomy 3 was present in only 13% of these cases. Of five DLBCL, only one showed trisomy. Nine of the 16 aberrant high-grade MALT lymphomas (56%) showed trisomy of more than one chromosome per case vs two of six for low-grade cases. In lymphomas with separate low- and high-grade tumour components some trisomies were detected in both components, whereas others occurred only in the high-grade tumour cells. This supports the hypothesis that high-grade MALT lymphomas can develop from a low-grade type and that this progression is accompanied by the acquisition of more genetic aberrations. However, trisomy 3 probably does not play a major role in this progression.

Cell turnover parameters in small and large cell varieties of primary intestinal non-Hodgkin's lymphoma.

BACKGROUND: In contrast to primary gastric lymphoma, primary intestinal lymphoma is an uncommon condition with a poorer outcome, perhaps due to differences in its pathogenesis. In this study, the authors analyzed the roles of proliferation and apoptosis in the pathogenesis of intestinal lymphoma. METHODS: Fifty-one cases of intestinal non-Hodgkin's lymphoma (NHL) (10 small B-cell mucosa-associated lymphoid tissue [MALT] NHLs, 12 large B-cell MALT NHLs, 18 large B-cell NHLs, 2 small T-cell NHLs, 7 large T-cell NHLs, and 2 mantle cell NHLs) were studied for the immunohistochemical expression of MIB-1 and the TUNEL assay as well as the expression of bcl-2 and p53, both of which are regulatory gene products involved in apoptosis. RESULTS: The median proliferation index (PI) was 37.3%, and the median apoptotic index (AI) was 1.10%. The respective values of PI and AI were 5.8% and 0.06% in small B-cell MALT lymphoma, 52.8% and 0.24% in large B-cell MALT lymphoma, 58.85% and 1.36% in large B-cell lymphoma, 30.9% and 1.93% in mantle cell lymphoma, 18.13% and 1.25% in small T-cell lymphoma, and 43.4% and 1.93% in large T-cell lymphoma. In an analysis of B-cell NHL only (with mantle cell NHL excluded), proliferative and apoptotic indices were positively correlated (correlation coefficient=0.563, P < 0.001). Furthermore, high bcl-2 expression was inversely correlated with both PI and AI. Expression of p53 was observed in 8 cases (1 small cell lymphoma and 7 large cell lymphomas). CONCLUSIONS: Small cell lymphomas had low AI and PI values, whereas large cell lymphomas had high AI and PI values. Apoptosis and proliferation were positively correlated, and higher expression of bcl-2 was associated with lower rates of apoptosis.

Proliferation and apoptosis in primary gastric B-cell non-Hodgkin's lymphoma.

To elucidate the role of cell turnover in primary gastric B-cell non-Hodgkin's lymphomas we studied tissue samples of 72 patients-26 small cell (25 MALT lymphomas) and 46 large cell (31 MALT lymphomas). Proliferation indices and apoptotic indices were measured by Mib-1 expression and terminal deoxynucleotidyltransferase (TdT)-mediated nick end labelling, respectively. Furthermore, expression of the apoptosis related gene-products bcl-2 and p53 was studied. Large cell lymphomas showed significantly higher proliferation indices (59.1% vs. 15.4%) and apoptotic indices (3.2% vs.0.7%) than small cell lymphomas. Proliferation and apoptotic indices were positively correlated (r = 0.371, P = 0.03). Expression of the bcl-2 protein was significantly higher in the small cell lymphomas. Furthermore, cases with a high bcl-2 expression showed both a significantly decreased proliferation (P < 0.0001) and apoptotic index (P = 0.0096) compared to bcl-2 negative cases. Expression of the mutant p53 protein was present in 8.0% of small cell and in 18.2% of large cell lymphomas. p53 positive cases showed significantly higher proliferation indices, but showed no correlation with apoptotic index. These data suggest that impaired apoptosis by bcl-2 may be more prominent than proliferation in the genesis of small cell lymphomas, whereas a high cell turnover characterizes large cell primary gastric lymphomas.

Specific detection of Helicobacter pylori and non-Helicobacter pylori flora in small- and large-cell primary gastric B-cell non-Hodgkin's lymphoma.

BACKGROUND: Primary gastric non-Hodgkin's lymphomas possibly develop in response to local infection by Helicobacter pylori (H. pylori). We investigated the presence of H. pylori and non-H. pylori flora histologically in small- and large-cell primary gastric lymphoma using a specific staining method. MATERIALS AND METHODS: Specimens of 52 cases of primary gastric lymphoma (17 small cell, 35 large cell) were stained with modified Giemsa (MG) and immunohistochemically using a polyclonal antibody against H. pylori (IHC). RESULTS: Thirty-two cases (61.5%) (small cell 76% versus large cell 53%, P > 0.05) showed immunoreactivity for H. pylori in the mucosa surrounding the tumor. Remarkably, there was localization of H. pylori in the neck of the gastric glands in 3 cases. Non-H. pylori flora was seen in 35 cases (76.3%) (small cell 53% versus large cell 74%, P > 0.05). In 20 cases, this non-H. pylori flora was mixed with H. pylori. Five cases showed no bacterial flora at all. CONCLUSIONS: (1) Using immunohistochemistry, the prevalence of gastric lymphoma cases with H. pylori (61.5%) approximates that of H. pylori in the normal population. (2) No statistical difference was found between the occurrence of H. pylori and non-H. pylori bacterial flora in small- versus large-cell lymphoma. (3) Our results suggest that H. pylori may not be the only etiologic factor in primary gastric lymphoma.