Lymphoma Of Mucosa-associated Lymphoid Tissue Type Research Articles

Salivary gland lymphoid infiltrates associated with lymphoepithelial lesions: A clinicopathologic, immunophenotypic, and genotypic study

The criteria for distinguishing benign lymphoepithelial lesions (BLEL) from low grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type in salivary glands and the significance of genotypically documented clonality in this setting are controversial. In addition, the clinical implications of a neoplastic diagnosis are unclear. The histopathologic features of 68 specimens from 49 patients with at least one salivary gland biopsy with LEL together with available clinical data were, therefore, reviewed. Paraffin section immunohistochemical (IHC) stains for κ, λ, CD3, CD20, and CD43; in situ hybridization (ISH) for κ and λ; and polymerase chain reaction (PCR) for immunoglobulin (Ig) HC rearrangement were performed. The 61 salivary gland specimens were classified as BLEL-13, BLEL with monocytoid B-cell (MBC) halos (BLEL-halo-8), low grade B-cell lymphoma of MALT type with confluent zones of MBC or other atypical lymphocytes (ML-MALT-24), low grade B-cell lymphoma of MALT type with monoclonal plasma cells (ML-MALT-PC-12), and high grade B-cell lymphoma of MALT type (MALT-high grade-4). Soft tissue and perineural invasion was not observed in BLEL and was most common in the MALT lymphomas. Lymph node involvement was identified in six patients at the time of their salivary gland MALT lymphomas but in none with BLEL. CD43+ B cells were seen most commonly in ML-MALT but were present in all other categories except MALT-high grade. Clonal B cells were identified by PCR in 5 of 12 BLEL, 5 of 8 BLEL-halo, 17 of 22 ML-MALT, 6 of 10 ML-MALT-PC, and 3 of 3 MALT-high grade biopsies. All ML-MALT-PC were clonal by ISH or IHC. Repeat biopsies in 14 patients most commonly showed a BLEL/ML-MALT lesion in an ipsilateral or contralateral salivary gland with one transformation to a MALT-high grade. Although only a few patients are known to have received chemoradiation or radiation therapy, most patients with low-grade lesions have pursued an indolent course. These data show the presence of two types of borderline lesions within the spectrum of lymphoid proliferations associated with salivary gland LEL. One has clonal B cells without histological features of neoplasia and the other nonconfluent MBC extending beyond the confines of LEL (“halos”). They share some features with the infrequent nonneoplastic BLEL and others with the more common low-grade B-cell lymphomas of MALT. A few high-grade B-cell lymphomas of MALT were also identified including a rare example of transformation from a low- to high-grade lesion. The optimal therapeutic approach for the borderline and low-grade lesions and the reason why so many of the lymphoproliferative lesions associated with LEL remain localized to the neck remain to be defined.

Marginal Zone B-Cell Lymphomas Including Mucosa-Associated Lymphoid Tissue Type Lymphoma (MALT), Monocytoid B-Cell Lymphoma and Splenic Marginal Zone Cell Lymphoma and Their Relation to the Reactive Marginal Zone

The marginal zone of the B follicle represents a well-defined compartment of the B area. Its cellular composition is distinct from that of the follicle centre, from which it also differs in its functional role in the immune response. Several newly identified lymphoma entities, e.g. extranodal MALT type lymphoma, nodal monocytoid B-cell lymphoma and splenic marginal zone B-cell lymphoma, display in common a very peculiar organoid growth pattern reminiscent of the marginal zone. Moreover, their neoplastic components share morphologic and phe-notypic similarities to the cellular components of the marginal zone. The clinical characteristics of these various marginal zone cell lymphomas may differ depending of the organ which is involved. Nevertheless, they all share common cytogenetic abnormalities suggesting a common pathogenesis.

Biased VH family usage in primary gastric B cell lymphoma of mucosa‐associated lymphoid tissue‐type and the selected Vβ expression of T cells infiltrating into the lymphoma cells

Seven cases of primary gastric low-grade B cell lymphoma of mucosa-associated lymphoid tissue (MALT) type, two cases of high-grade B cell lymphoma with a low-grade component and three cases of pure high-grade lymphoma were selected for the current study. The Ig VH gene use of lymphoma cells and the V beta repertoires of infiltrating T cells were investigated. The VH gene analysis showed multiple VH family usage in 12 cases, but the MALT-type lymphoma cell usage was found to be biased for the families that have a low number of VH genes (VHIV and V). Another analysis of lymphoma-infiltrating T cells showed restricted expressions of the V beta repertoire in all seven low-grade cases and three high-grade cases. In those 10 cases, a considerable number of CD4-positive T cells infiltrated into lymphoma cells and RAG-1 was also prominently expressed. Based on these findings, it was thus assumed that the normal counterpart of gastric B cell lymphoma of MALT type is different from the conventional B cell lymphoma, and the restricted expression of V beta repertoires is therefore considered to be a characteristic finding in low-grade B cell lymphomas of MALT type as well as in a proportion of high-grade lymphomas (the so called 'high-grade lymphoma of MALT type').

Marginal Zone Lymphoma (Low-grade B-cell Lymphoma of Mucosa-associated Lymphoid Tissue Type) of Skin and Subcutaneous Tissue

Extranodal low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type occurs in the gastrointestinal tract, salivary gland, thyroid, orbit, lung, and breast. We report 15 patients with MALT-type lymphomas involving skin and subcutaneous tissue. All patients had tumors with histologic features of low-grade B-cell lymphoma of MALT type, including marginal zone cells (15 of 15 cases), plasmacytic differentiation (10 of 15 cases), Dutcher bodies (three of 15 cases), and reactive germinal centers (10 of 15 cases). All expressed pan B-cell antigens and monotypic immunoglobulin. Seven patients (five women, two men) aged 29 to 86 years (median, 53 years) had primary MALT-type lymphoma of skin (6) or subcutaneous tissue (1). One patient had persistent disease, and four patients had relapses involving skin, subcutaneous tissue, breast, orbit, and lymph node. At last follow-up (11-121 months; median, 36 months), one patient was alive with disease, and six patients had no evidence of disease. Three patients (two women, one man) aged 36 to 67 years (median, 57 years) had concurrent MALT-type lymphoma involving both subcutaneous tissue and extracutaneous sites at primary diagnosis, including lung, breast, orbit, lymph node, and bone marrow. One patient responded to treatment but relapsed with lymphoma of the skin and breast. The other two patients had persistent disease despite treatment. One patient died of disease at 25 months, and, at last follow-up (7 and 46 months), two patients were alive with disease. Five patients (four women and one man) aged 29 to 72 years (median, 63 years) had secondary skin or subcutaneous involvement by MALT-type lymphoma with primary tumors of ocular adnexa (3) or parotid gland (2). All five patients had relapses, which involved skin or subcutaneous tissue, parotid gland, lacrimal gland, breast, and lymph node. At last follow-up (61-137 months), two patients were alive with disease and three were alive with no evidence of disease. Low-grade B-cell lymphomas of MALT type may arise in or secondarily involve the skin and subcutaneous tissue and have a tendency to affect middle-aged to older women. These tumors are characterized by multiple extranodal relapses and are associated with long patient survival. Patients with primary MALT-type lymphoma of skin or subcutaneous tissue without extracutaneous involvement at diagnosis were more likely to experience prolonged disease-free survival than patients with extracutaneous spread at presentation (p < 0.03).

Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue.

Previous studies have shown that tumour cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue (MALT) type proliferate in vitro in response to heat-killed whole cell preparations of Helicobacter pylori, but only in the presence of tumour-infiltrating T cells. This response is strain-specific in that the tumours studied responded optimally to different strains of H. pylori. It was unclear from these studies, however, whether the ability to recognize the specific stimulating strains of H. pylori was a property of the tumour cells or the tumour-infiltrating T cells. This study shows that whereas the tumour cells do not respond to H. pylori, both freshly isolated tumour-infiltrating T cells and a T cell line derived from these cells proliferate in response to stimulating strains of H. pylori. T cells from the spleen of one of the patients do not share this property. These results suggest that B-cell proliferation in cases of low-grade gastric lymphoma of MALT type in vitro in response to H. pylori is due to recognition of H. pylori by tumour-infiltrating T cells, which in turn provide help for tumour cell proliferation. The observations provide an explanation for properties of gastric MALT-type lymphoma, such as regression following eradication of H. pylori and the tendency of the tumour to remain localized to the primary site.

Bronchoalveolar lavage in the diagnosis of low-grade, MALT type, B-cell lymphoma in the lung

Low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type represents one of the most frequent primary lymphomas in the lung. This study demonstrates the value of bronchoalveolar lavage (BAL) in the diagnosis of this entity. Three patients with biopsy proven MALT lymphoma in the lung were submitted to bronchoscopy. BAL fluid analysis showed an increased cellularity and a striking lymphocytosis. Cytological features consistent with a low-grade malignant lymphoma were present in two cases (medium sized lymphoid cells with an evident lymphoplasmocytoid differentiation, and irregular nuclear borders). In all cases, flow cytometry analysis showed a high percentage of cells expressing a B phenotype (52, 40 and 28%, respectively). In two cases, there was a striking monotypic expression of surface light-chain immunoglobulin (Kappa/Lambda ratio = 38 and 0.04, respectively). Bronchoalveolar lavage appears to be a valuable procedure in the diagnosis of low-grade B-cell lymphoma of MALT type in the lung.

Early detection of lymphomas in Sjögren's syndrome by in situ hybridisation for kappa and lambda light chain mRNA in labial salivary glands.

Sjögren's syndrome (SS) is an autoimmune disease characterised by a generalised lymphoproliferation. Patients have an increased risk of developing lymphomas which are usually of the type associated with mucosa-associated lymphoid tissue (MALT). Histological examination of the minor salivary glands of the lower lip is a common and useful diagnostic test for SS but has not been able to provide information with regard to potential malignant change. In this study, a sensitive in situ hybridisation technique for the detection of kappa and lambda immunoglobulin light-chain mRNA was applied to labial salivary glands of 14 patients with SS. 7 cases showed light chain restriction, in 5 cases this was kappa(kappa:lambda ratio > 8.0) and in 2 it was lambda(kappa:lambda ratio < 0.6). Of these 7, 5 developed lymphomas--4 were low grade lymphomas of MALT type and the fifth patient died of disseminated lymphoma. The finding of light chain restriction in lip minor salivary glands is strong evidence of a monoclonal population of B-cells at this site. It is concluded that in patients with SS who develop lymphomas, dissemination of malignant cells may result in detectable disease in the minor salivary glands. Determination of kappa:lambda ratios in labial minor salivary glands may thus provide important prognostic information.

Low-grade B-cell lymphoma of mucosa-associated lymphoid tissue type in Waldeyer's ring.

Amongst a total of 329 cases of low-grade B-cell lymphoma of Waldeyer's ring, we identified 12 cases that corresponded histomorphologically to low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type. These lymphomas are characterized by an extrafollicular growth pattern, often with a marginal zone-like arrangement, and by the centrocyte-like morphology of the tumour cells. They have not been described previously in this location. They predominantly affected the palatine tonsil. Ten cases were primary lymphomas of Waldeyer's ring. In two cases there was a simultaneous high-grade component. Two cases showed regional spread to cervical lymph nodes, but there was no widespread nodal involvement at the time of diagnosis. Immunohistochemically, all cases displayed B-cell markers and light chain restriction. Tropism of tumour cells for the epithelium was a consistent finding. In two cases involvement of Waldeyer's ring was secondary; in one of them the primary tumour was a gastric low-grade B-cell lymphoma of MALT type and in the other a high-grade B-cell non-Hodgkin's lymphoma of the stomach. These findings indicate that low-grade B-cell lymphomas of MALT type occurring in Waldeyer's ring should be included amongst the tumours of the MALT system. We surmise that in Waldeyer's ring such tumours are derived from the marginal zone, as has already been postulated for similar gastric tumours.

Follicular dendritic cells in extranodal non-Hodgkin lymphomas of MALT and non-MALT type

Extranodal lymphomas of the thyroid (n = 19), kidney (n = 15) and testis (n = 30) were investigated histologically and immunohistochemically for follicular dendritic cell pattern using the monoclonal antibody Ki-FDClP. This recognizes follicular dendritic cells in paraffin sections. Follicular dendritic cells were most predominant in lymphomas of the thyroid. These thyroid lymphomas showed the morphological features of mucosa-associated lymphoid tissue (MALT) type lymphomas in 18 of 19 cases and were classified as high-grade malignant lymphoma of MALT type with evidence of a low-grade malignant component (n = 18). Ten of these cases contained destroyed reactive follicles of follicular dendritic cells. In 6 of these 10 cases follicular dendritic cells occurred in a pattern of tumour-associated abortive follicle type. The remaining lymphoma of the thyroid was an immunoblastic lymphoma of B-cell type showing no detectable follicular dendritic cells. In extranodal lymphomas of non-MALT type follicular dendritic cells occurred in only two cases where immunocytoma involved the kidney. Malignant lymphomas of the kidney (chronic lymphocytic leukaemia, n = 2; immunocytoma, n = 4; centroblastic lymphoma, n = 9) and of the testis (immunocytoma, n = 2; centroblastic lymphoma, n = 27; immunoblastic lymphoma of B-cell type, n = 1) revealed no characteristics of MALT type lymphoma, cytologically or with respect to follicular dendritic cells. Classical lymphoepithelial lesions formed by centrocyte-like cells, a hallmark of MALT, occurred exclusively in thyroid lymphomas of MALT type. Although occurrence of classical lymphoepithelial lesions formed by centrocyte-like cells was limited to thyroid lymphomas of MALT type, a growth pattern of lymphoid blasts, with formation of lesions mimicking lymphoepithelial lesions superficially, was found in 6 of 27 testicular centroblastic lymphomas. Follicular dendritic cells in non-Hodgkin's lymphomas of MALT type show distinct follicular patterns not found in other extranodal lymphomas such as those found in the kidney and testis.

Malignant lymphoma of the breast. Immunologic type and association with lymphocytic mastopathy.

Clinical and pathologic findings in 19 cases of primary non-Hodgkin's lymphoma of the breast collected from several hospitals in Japan were reviewed. All patients were women (median age, 45 years) and they usually had breast masses that had recently become enlarged. The sites of the lesions were the right breast in eight cases, the left breast in eight, and both breasts in one. The locations of two masses were unknown. Lymphoma recurred in the opposite breast in three cases 14, 23, and 23 months after surgery. Histologically, diffuse large cell lymphoma was the most common form of disease (63%). One lesion was a follicular lymphoma. The so-called lymphoepithelial lesion, a characteristic finding for mucosa-associated lymphoid tissue type lymphomas, was observed in eight cases (42%). Immunohistochemical analysis revealed that all but two tumors were of B-cell type; such findings confirmed morphologically based conclusions. Histologic and immunohistochemical evidence of lymphocytic mastopathy, a recently described autoimmune disease of the breast, was found in most of the cases. Formation of lymphoid follicles in or around the tumors was found in five cases (26%). Based on these findings, it is suggested that most mammary lymphomas are B-cell tumors and they may be associated with coexisting or antecedent lymphocytic mastopathy.

Monocytoid B‐cell lymphoma: morphological variants and relationship to low‐grade B‐cell lymphoma of the mucosa‐associated lymphoid tissue

Twenty-eight cases of monocytoid B-cell lymphoma of lymph nodes and 16 lymph node metastases of primary gastric lymphomas, mostly low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type were investigated morphologically and immunohistochemically. Both groups showed the same morphological and immunohistochemical features: diagnostically important sites of infiltration were the sinuses and the marginal zones. The tumour cells were either medium-sized or small. The cytoplasm stained grey with Giemsa and was sometimes rather pale. In imprints the grey colour of the cytoplasm was a characteristic feature. The medium-sized cell type was more frequent; in one third of the cases it was combined with a prominent lymphoplasmacytic component from the same clone, and it resembled the monocytoid B-cells of the sinuses. The small cell type was less common, was not combined with a lymphoplasmacytic component and more closely resembled marginal zone cells. The difference was underlined by the negative reaction with the monoclonal antibody Ki-B3 in the small cell type, which, conversely, was positive in the medium-sized cell type and in the monocytoid B-cell reaction of the sinuses. Both of these cell types, however, showed a granular reaction with the new monoclonal antibody Ki-Mlp. The morphological and immunohistochemical parallels are arguments in favour of the assumption that monocytoid B-cell lymphoma is the nodal equivalent of low-grade B-cell lymphoma of MALT type. This is further supported by the fact that in nine of our 28 cases of monocytoid B-cell lymphoma, lymphomas were found simultaneously or subsequently in organs of the MALT. Monocytoid B-cell lymphoma must be differentiated from an infiltration that occurs in the form of clusters of monocytoid B-cells in other low-grade B-cell lymphomas, especially in immunocytoma with a high content of epithelioid cells.