Histopathology of mucosa-associated lymphoid tissue

Mucosa-associated lymphoid tissue (MALT) is a generalized term incorporating a disseminated collection of lymphoid tissues in multiple sites throughout the body. MALT sites that have been/are primarily studied include bronchus-associated lymphoid tissue (BALT), gut-associated lymphoid tissue (GALT), and nasopharynx-associated lymphoid tissue (NALT). Since MALT sites are often under-sampled in conventional toxicity studies, MALT lesions have not been extensively documented in these lymphoid effector sites. Lesions of the nasopharyngeal lymphoid tissue and Peyer's patches include degeneration, inflammation, and both primary and metastatic neoplasia.     

Malignant lymphoma of mucosa-associated lymphoid tissue

Lymphomas of the gastrointestinal tract, salivary glands, lung and thyroid are grouped together as tumours arising in mucosa-associated lymphoid tissue. The great majority of them are of B-cell origin but distinctive T-cell lymphomas are also recognized in the gastrointestinal tract. These lymphomas tend to remain localized for prolonged periods but, whereas the B-cell group respond favourably to local therapy, the T-cell group are associated with severe morbidity and their overall prognosis is extremely poor. Accepted histological classifications of non-Hodgkin's lymphomas are difficult to apply to these tumours. In this paper their morphological features are reviewed; recent findings based on immunohistochemistry and DNA analysis are presented; and the biological behaviour of these tumours is discussed insofar as they offer insight into mucosal immunological mechanisms.     

Ability of intestinal Escherichia coli to survive within mesenteric lymph nodes.

Identification of mesenteric lymph node (MLN) bacteria showed that indigenous streptomycin-sensitive Escherichia coli could be recovered from MLN at least 48 h after this organism had been essentially eliminated from the cecal flora by antibiotics and replaced with exogenous streptomycin-sensitive E. coli JK. Additional experiments with antibiotic-treated rats also showed that indigenous streptomycin-sensitive E. coli could be recovered from the MLN 4 days after elimination of this organism from the cecal flora. These findings suggest that the time of bacterial translocation to MLN may be kinetically different from the time of recovery of bacteria from MLN and that the MLN may be a focus of infection with intestinal bacteria.     

Terminology: nomenclature of mucosa-associated lymphoid tissue

Stimulation of mucosal immunity has great potential in vaccinology and immunotherapy. However, the mucosal immune system is more complex than the systemic counterpart, both in terms of anatomy (inductive and effector tissues) and effectors (cells and molecules). Therefore, immunologists entering this field need a precise terminology as a crucial means of communication. Abbreviations for mucosal immune-function molecules related to the secretory immunoglobulin A system were defined by the Society for Mucosal Immunolgy Nomenclature Committee in 1997, and are briefly recapitulated in this article. In addition, we recommend and justify standard nomenclature and abbreviations for discrete mucosal immune-cell compartments, belonging to, and beyond, mucosa-associated lymphoid tissue.     

Epitheliotropism in high-grade lymphomas of mucosa-associated lymphoid tissue

Low-grade lymphomas of mucosa-associated lymphoid tissue (MALT) characteristically show centrocyte-like cells, plasmacytic differentiation, follicular colonization and lymphoepithelial lesions (epitheliotropism). High-grade lymphomas of MALT are thought to lack these features and can only be identified as MALT lymphomas with confidence if they are admixed with residual low-grade tumours. We studied 23 cases of MALT lymphoma of the thyroid. Six were predominantly low-grade, 12 were predominantly high-grade, and five contained both low- and high-grade areas. All cases were stained for cytokeratin, epithelial membrane antigen and laminin using an immunoperoxidase technique. The low-grade lymphomas all contained lymphoepithelial lesions, generally in the form of clusters of intra-acinar centrocyte-like cells. Eleven of the 12 high-grade MALT lymphomas of the thyroid also showed lymphoepithelial lesions. These appeared in three forms: follicles or clusters of epithelial cells infiltrated by groups of centrocyte-like cells, intra-acinar clusters of blast cells, or irregular invasion of islands of epithelial cells by blast cells. The first pattern presumably represented residual low-grade tumour over-run by high-grade lymphoma. The second two patterns indicated that the factors that result in epitheliotropism in low-grade MALT lymphomas are also prsent in high-grade tumours. Following this study we identified epitheliotropism in single examples of high-grade MALT lymphomas of the bronchus and small intestine. Previous failure to recognize epitheliotropism in high-grade MALT lymphomas of the gastrointestinal tract may be due to loss of the affected epithelium. The localization and relatively good prognosis of high-grade MALT lymphomas may be related to retention of MALT characteristics including epitheliotropism.     

Intraoperative cytology of lymph nodes and lymphoid lesions

Cytologic preparations from lymph nodes and lymphoid lesions in other tissues permit accurate intraoperative diagnosis of a number of lesions that are not commonly identifiable with certainty in conventional frozen sections. The clarity of cytologic detail in smears or imprints allows recognition of Hodgkin's and non-Hodgkin's lymphomas, certain metastatic tumors such as melanoma or oat cell carcinoma, and some nonneoplastic disorders, all of which must be diagnosed on the basis of cellular alterations. The characteristic cytologic features of these disorders are presented. Cytologic preparations also have proved valuable in evaluating lesions that usually can be diagnosed with frozen sections. For these lesions, the ability to see cytologic details provides greater diagnostic certainty. For some necrotic, calcified, or fatty specimens, smears or imprints are the only preparations possible. With alcohol fixation and rapid hematoxylin and eosin or Papanicolaou staining, the preparations are ready for examination within 2 minutes after the specimens are received. The cytologic presentations are essentially identical to those of aspiration biopsies. Use of each type of preparation helps develop and maintain the diagnostic skills needed for the other.     

Ischaemic changes in human mesenteric lymph nodes

Lymph node lesions attributable to ischaemia are described in the mesenteric nodes from 10 patients with volvulus of the small and large bowel. Frank infarction, the microanatomy of which differs from that seen in superficial lymph nodes, is one of the nodal lesions evoked by ischaemia. Two others in the form of lymphocyte depletion and capsular hypervascularity also appear to result from vascular occlusion. These three lesions were also found in nodes associated with 'primary' venous and arterial infarction of the bowel mucosa, but not in non-vascular diseases of the small bowel or colon. The enhanced frequency of infarction in volvulus with mucosal necrosis, as opposed to cases with 'primary' vascular thromboses suggest that ischaemic lymph node changes are more frequent when several sets of vessels are occluded. Distension of lymph node sinuses, erythrocyte extravasation, and dilatation of small intranodal vessels were not restricted to vascular cases, and appear to be less specific reactions to ischaemia. The range of ischaemia-induced reactions is wider than has hitherto been recognized in human lymph nodes.     

The mononuclear cells of human mesenteric blood, intestinal mucosa and mesenteric lymph nodes: compartmentalization of NK cells.

The proportions of T cell subsets and Leu 7+ cells and the spontaneous cell-mediated cytotoxicity (SCMC) of isolated mononuclear cells have been determined across the mesenteric vascular bed and along the intestinal mucosal-mesenteric lymph node (MLN) axis in patients undergoing abdominal surgery. Whereas the proportion of T4+ and T8+ cells were similar in simultaneously taken PVB and mesenteric venous blood (MVB), the proportion of Leu 7+ cells was higher in MVB in 16 of 17 studies (15.4 +/- 6.8%, 10.8 +/- 5.1%). Additional studies showed that the proportions of lymphocyte subsets in peripheral arterial blood are the same as those in PVB. Thus, an enrichment of Leu 7+ cells occurs across the mesenteric vascular bed. Isolated intestinal and MLN mononuclear cells contained similarly high proportions of T4+ and T8+ cells as in PVB but Leu 7+ cells made up a minority subpopulation in intestinal (1.3 +/- 0.8%) and MLN mononuclear cells (1.0 +/- 0.9%). The SCMC of intestinal and MLN mononuclear cells was low and paralleled the proportion of Leu 7+ cells. Despite the higher proportions of Leu 7+ cells in MVB, the SCMC was less than that of PVB in eight patients with inflamed intestine and not significantly different from PVB in seven patients with normal intestines. These paradoxical findings were at least in part due to inhibitory factors in mesenteric plasma. In conclusion, NK cells appear to be largely confined within the vascular system and the enrichment of Leu 7+ cells across the mesenteric vascular bed suggests that this compartmentalization may be due to differences in the traffic of lymphocyte subpopulations through the intestinal mucosa and MLN.     

干燥综合征与粘膜相关型淋巴瘤临床病理分析

目的：探讨干燥综合征（ＳＳ）病理分析对诊断ＳＳ的意义、Ｍｉｋｕｌｉｃｚ病与粘膜相关淋巴组织（ＭＡＬＴ）型淋巴瘤的关系。方法：回顾性分析１５９例经病理证实的ＳＳ,对疑为ＭＡＬＴ型淋巴瘤的６例用免疫组化ＡＢＣ法标记,使用抗体ＬＣＡＬ－１、Ｌ２６及免疫球蛋白ＩｇＧ、ＩｇＡ、ＩｇＭ、ＩｇＤ、ＩｇＥ和к、λ。结果：６例可疑病例中有４例发生ＭＡＬＴ型淋巴组化ＬＣＡ、Ｌ２６、ｂｃｌ－２、ＩｇＭ、к和ＩｇＭ、λ呈     

Ocular adnexal marginal zone lymphoma of mucosa-associated lymphoid tissue

Ocular adnexal lymphomas are a group of heterogeneous neoplasms representing approximately 1–2% of non-Hodgkin lymphomas and 8% of extranodal lymphomas. The incidence of primary ocular adnexal lymphoid tumors has raised over the last decades, and this could be probably attributed to the more sophisticated diagnostic techniques. Due to the wide spectrum of clinical manifestations, ocular tissue biopsy is important in order to set a precise diagnosis based on histological, immunophenotypical and, in some cases, molecular findings. The most common subtype, which may account for up to 80% of primary ocular adnexal lymphomas, is extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue. This lymphoma is usually asymptomatic in the early phase of the disease causing a delay in the final diagnosis and prompt therapy. The pathogenesis of a proportion of these tumors has been linked to chronic inflammatory stimulation from specific infectious factors (e.g., Chlamydia psittaci) or to autoimmunity. The further improvement in diagnostic methods and the further understanding of the pathogenesis of ocular adnexal EMZL may contribute to the establishment of a more successful multidisciplinary therapeutic planning.     

Primary hepatic B-cell lymphoma of mucosa-associated lymphoid tissue.

Mucosa-associated lymphoid tissue (MALT) lymphomas are low-grade B-cell lymphomas that occur in a variety of extranodal sites but rarely as a primary hepatic lymphoma. We describe the histological findings, immunophenotype, and immunohistochemistry of one such lymphoma found incidentally in a 69-year-old woman. The lymphoid infiltrate invaded the liver in a serpiginous configuration with entrapment of nodules of normal liver. Reactive follicles were surrounded by intermediate-sized lymphoid cells with slightly irregular nuclei and pale cytoplasm. Only a few scattered lymphoepithelial lesions were identified since most of the bile ducts were destroyed. The immunophenotype determined by flow cytometry identified the lymphoid cells as being CD19, CD20 positive and exhibiting lambda light chain restriction. CD5, CD10, and CD23 were negative. Immunohistochemistry showed the neoplastic cells to be positive for CD20 (L-26) and bcl-2. The reactive follicles were negative for bcl-2. CD3 showed only a few scattered T cells. Cyclin D1 did not stain the neoplastic cells. Cytokeratin (AE1/AE3) highlighted the lymphoepithelial lesions and residual bile ducts. MALT lymphomas need to be recognized and distinguished from other B-cell lymphomas, particularly mantle cell lymphomas, because of the difference in behavior and treatment.     

Proliferation and differentiation of tumour cells from B-cell lymphoma of mucosa-associated lymphoid tissue in vitro

Several characteristics of lymphomas of mucosa-associated lymphoid tissue (MALT type) suggest that they are antigen-dependent and that their growth parodies a normal immune response. We have previously shown that three cases of low-grade B-cell MALT-type lymphoma recognize autoantigens. In this study, we investigated the response of three low-grade and one high-grade case of MALT-type lymphoma to anti-idiotypic antibody as a model of antigen binding either alone or as a co-stimulus with B-cell mitogens. We also studied the response of tumour cells to interleukin-6 (IL-6), which induces differentiation to immunoglobulin-producing cells in many systems. Of the four cases studied, one low-grade case showed markedly enhanced proliferation in response to anti-idiotype alone. This could not be increased by the addition of mitogens. In the remaining two low-grade cases, mitogen responsiveness was observed which was affected by anti-idiotype either by an enhancement or by a reduction in the proliferative response. The high-grade case failed to respond to the stimuli studied. No response to IL-6 was observed. This study supports the suggestion that antigen may affect the pathogenesis of low-grade tumours of MALT type.     

Intranasal immunization with polymer-grafted microparticles activates the nasal-associated lymphoid tissue and draining lymph nodes.

Waldeyer's ring is located at the juncture of the respiratory and alimentary tracts, where it is bombarded by inhaled and ingested antigens. However, knowledge of its exact function or consequences of its removal is incomplete. Recently, the murine nasal-associated lymphoid tissue (NALT) has been reported to have functional similarities to Waldeyer's ring and, thus, might be a suitable model to examine the function of oronasopharyngeal lymphoid tissues. To explore the capability of NALT to incite local mucosal and systemic immunity, we immunized mice intranasally (i.n.) with 3-(triethoxysilyl)-propyl-terminated polydimethylsiloxane (TS-PDMS)-grafted microparticles (MP), an inoculant previously shown to induce robust systemic and mucosal humoral immunity following intragastric (i.g.) administration. We demonstrated that i.n. immunization with low doses of microentrapped, but not soluble, human serum albumin (HSA) evoked robust circulating IgG responses (P < 0.05). Additionally, NALT cells isolated from MP-treated mice proliferated in vitro when restimulated with HSA (P < 0.05), suggesting that i.n. immunization with HSA-containing MP incited specific immunity via NALT cell activation. Coinciding with these observations, after i.n. MP administration HSA-specific spot-forming cells (SFC) were observed in NALT, and later posterior cervical lymph nodes (pCLN) and spleen (SPL), suggesting that the observed MP-induced specific systemic antibody responses emanated from the NALT. We also showed that i.n. immunization with HSA-containing TS-PDMS-grafted MP stimulated interleukin-4 (IL-4)-secreting lymphocytes in the NALT. This cytokine microenvironment was probably responsible for driving the IgG1 sera response observed after i.n. MP administration, via the migration of NALT-derived IgG1-committed B cells. Interestingly, unlike i.g. MP administration, i.n. immunization with HSA-containing MP did not evoke detectable specific IgA in any lymphoid tissue examined, or in nasal secretions, probably reflecting differences between NALT and other mucosae-associated lymphoid tissues (MALT).     

Tumour cell trapping in rat mesenteric lymph nodes

We describe a new experimental model of mesenteric lymph node metastasis in the rat, involving afferent mesenteric lymphatic inoculation of tumour cell suspensions via glass microcannulae. This model has been used to perform a series of experiments to investigate whether the rat mesenteric lymph node trapped tumour cells. Afferent mesenteric lymphatic inoculation of suspensions of transplantable sarcoma cells in inbred hooded Lister rats resulted in tumour growth in the inoculated lymph node in 100% of rats, with no tumour growth at any other site. The same procedure performed on rats which had previously undergone mesenteric lymphadenectomy resulted in growth of tumour in the lungs. Using 125Iododeoxyuridine (IDUR) labelled sarcoma cells we have shown that although radioactivity decreased significantly in the mesenteric lymph node up to 24 h following afferent lymphatic inoculation, there was no evidence that tumour cells reached thoracic duct lymph. We conclude that the rat mesenteric lymph node trapped sarcoma cells.     

CCR6 identifies lymphoid tissue inducer cells within cryptopatches

The chemokine receptor CCR6 is expressed by dendritic cells, B and T cells predominantly within the organized structures of the gut‐associated lymphatic tissue. Its ligand CCL20 is synthesized by the follicle‐associated epithelium and is crucial for the development of M cells within Peyer's patches. In addition, lineage‐negative c‐kit positive lymphocytes within cryptopatches (CP) express CCR6. CCR6‐deficient mice exhibit an altered intestinal immune system containing increased amounts of intraepithelial lymphocytes and show smaller Peyer's patches, while progression of cryptopatches to mature isolated lymphoid follicles (ILF) is inhibited. In this report, we show that lin^‐ c‐kit⁺ lymphocytes express a variety of different chemokine receptors and that CCR6 identifies those cells located within CP. In contrast, cells found outside CP are positive for CXCR3 and exhibit a different surface marker profile, suggesting that at least two different populations of lin^‐ c‐kit⁺ cells are present. The presence of CCR6 does not influence the expression of Notch molecules on lin^‐ c‐kit⁺ cells, nor does it influence Notch ligand expression on bone marrow‐derived dendritic cells. In the human gut, CCR6 identifies clusters of lymphocytes resembling murine CP. CCR6 seems to have an important role for lin^‐ c‐kit⁺ cells inside CP, is expressed in a regulated manner and identifies potential human CP.