Expression of adhesion molecules in primary B-cell gastric lymphoma and lymphoid follicles

To determine whether primary B-cell gastric lymphoma (GL) is one entity, we examined the expression of three adhesion molecules in the microvasculature of lymphomas. Stromal cells, including vascular endothelial cells, within lymphoid follicles of the gastric mucosa were also investigated. Twenty-two surgical specimens of GL were classified into low-grade malignant lymphoma arising from mucosa-associated lymphoid tissue (low-grade lymphoma, n=9), and high-grade malignant lymphoma with (secondary high-grade lymphoma, n=6) or without (primary high-grade lymphoma, n=7) a low-grade component. The proportion of venules positive for ELAM-1 or VCAM-1 was significantly higher (P<0.001) in primary high-grade lymphoma than in low-grade and secondary high-grade lymphomas. In gastric lymphoid follicles, the stromal cells of the germinal centre (GC) were positive for ICAM-1, ELAM-1, and VCAM-1, but the stromal cells of the marginal zone (MZ) were positive only for ICAM-1. We found two patterns of adhesion molecule expression in gastric lymphoid follicles, the MZ pattern and the GC pattern. Low-grade and secondary high-grade lymphomas, which had the MZ pattern, might be of MZ-cell lineage, but most primary high-grade lymphomas, which had the GC pattern, might be of follicular centre cell lineage.     

Monoclonal antibody 4C7 recognizes an endothelial basement membrane component that is selectively expressed in capillaries of lymphoid follicles

In order to define compartment-related structures within the extracellular matrix of human lymphoid organs, monoclonal antibodies (MAbs) were generated by immunizing mice with stromal fragments of human tonsils. One MAb (4C7) was selected which recognized an endothelial basal membrane component that is selectively expressed in capillaries of lymphoid follicles. The epitope was also present in follicles within chronically inflamed synovial membrane and in a hyperplastic thymus of a patient with myasthenia gravis. B-cell non-Hodgkin's lymphomas with a follicular growth pattern expressed the antigen in neoplastic follicles, whereas diffuse growing lymphomas lacked the antigen. The restricted distribution pattern suggests involvement of the 4C7-defined antigen in the organization of the follicular compartment within human lymphoid tissue.     

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-FDC1P. 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.     

Expression of glucocorticoid receptors in non-neoplastic lymphoid follicles and B cell type malignant lymphomas

OBJECTIVE: To evaluate the expression of human glucocorticoid receptors (hGRs), such as hGR (4H2), hGR-alpha, and hGR-beta, in non-neoplastic lymphoid follicles and B cell type malignant lymphomas. METHODS: The expression of hGRs in non-neoplastic lymphoid follicles and malignant lymphomas, including diffuse large cell lymphoma, mantle cell lymphoma, and follicular lymphoma, was examined immunohistochemically. HGR (4H2) expression was confirmed by double immunostaining of tissues and in isolated cells from tonsillar germinal centres, and by immunoelectronmicroscopy. RESULTS: In secondary lymphoid follicles of any non-neoplastic diseases--such as chronic tonsillitis, reactive lymphadenitis, and Kimura's disease--the germinal centre cells often expressed hGR (4H2) and hGR-alpha. Double immunocytochemical staining of isolated germinal centre cells showed that the majority of hGR (4H2) positive cells were CD20 positive B cells, and that follicular dendritic cells also expressed hGR. Immunoelectronmicroscopy revealed the presence of nuclear hGR (4H2) in the binucleated follicular dendritic cells and germinal centre cells. The frequency of hGR (4H2) expression in diffuse large B cell lymphoma was higher, that in mantle cell lymphoma was lower, and that in follicular lymphoma was intermediate among the types of malignant lymphoma. The hGR (4H2) expression was less frequent in cases of grade I follicular lymphoma. CONCLUSIONS: There are differences in hGR expression between the germinal centre and the mantle zone in non-neoplastic lymphoid follicles, and differences of hGR (4H2) expression among the types of malignant lymphoma and grades of follicular lymphoma, which probably contribute to the different steroid sensitivities.     

A quantitative study of the size of benign and malignant lymphoid follicles.

The mean areas of lymphoid follicles have been determined in 20 specimens of malignant follicular (centrocytic-centroblastic) lymphoma, 15 specimens of reactive follicular hyperplasia and 10 palatine tonsils. In all of the benign specimens and whenever possible for those showing malignancy, the areas of both the whole follicles (including the "mantle" zones) and of the follicle centres were measured; this procedure was facilitated by means of the Reichert-Jung (Kontron) MOP-AMO3 image-analyser. Reactive lymph nodes were found to have larger mean follicle areas than centrocytic-centroblastic lymphomas; the areas of reactive follicles also show greater variation than do those of their malignant counterparts. In addition, the "mantle" zone is usually absent from malignant follicles but may account for up to 65.5% of the mean total follicle size in reactive lymph nodes and tonsils.     

Natural killer (Leu 7+) cells in reactive lymphoid tissues and malignant lymphomas

Leu 7 (HNK-1) is a monoclonal antibody reported to identify human natural killer/killer cells. The frequency and distribution of Leu 7+ cells in 14 reactive lymphoid tissues and 47 malignant lymphomas were studied using the frozen section immunoperoxidase technic. In reactive lymphoid tissues, Leu 7+ cells were concentrated in the pale zone of germinal centers and usually were relatively scarce in the interfollicular areas. Of the malignant lymphomas, follicular lymphomas most consistently had numerous admixed Leu 7+ cells and lymphoblastic lymphomas the least. The authors' findings suggest that Leu 7+ cell accumulation in normal and neoplastic lymphoid tissue is associated at least in part with something shared by the pale zone of the normal germinal centers and the presence of neoplastic germinal centers. This association does not appear to be a simple response to lymphoid proliferation.     

Tenascin in reactive lymph nodes and in malignant lymphomas.

Tenascin is an extracellular matrix protein which accumulates in the stroma of various malignant and some benign neoplasms. This has been verified in several immunohistochemical studies. The distribution of tenascin immunoreactivity in lymphatic tissues and neoplasias, however, has not been thoroughly studied. In this investigation we analyzed tenascin immunoreactivity in several benign and malignant lymphatic lesions, including both Hodgkin's and non-Hodgkin's lymphomas. In benign lymph nodes, faint reticular immunoreactivity could be observed in the lymphatic tissue. In benign reactive hyperplasias, a stronger reticular pattern of tenascin immunoreactivity was observed in the interfollicular and medullary areas, while the lymphoid follicles contained only a few positive fibers. A similar immunoreactivity was observed in malignant follicular lymphomas. In diffuse lymphomas, a diffuse meshwork of positively stained fibers was seen. This was also the case for the three cases of Hodgkin's disease of the lymphocyte-predominance nodular subtype. There was no difference in the intensity of the immunoreactivity between benign and malignant disorders. However, in Hodgkin's disease of the nodular sclerosis and lymphocyte-depletion subtypes, a much more pronounced immunoreactivity could be observed in the fibrous septa and the cords. This suggests that the tumor cells are possibly capable of synthesizing growth factors which stimulate fibroblasts to synthesize tenascin. The results indicate that tenascin does not accumulate in the stroma of malignant lymphoid neoplasms with the exclusion of some subtypes of Hodgkin's disease. The distribution of tenascin immunoreactivity in lymphatic tissue is similar to that of the reticular fibers suggesting that the molecules are associated with these structures.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cellular composition of follicles of follicle centre cell lymphomas in relation to germinal centres of reactive lymph nodes. A morphometrical electromicroscopical study

The cell spectrum of neoplastic and benign reactive germinal centres was determined ultrastructurally. The degree in which the cell composition found in reactive germinal centres is maintained in analogous structures of follicular lymphomas was investigated by pattern recognition methods and discriminant analysis based on the frequencies of the various lymphoid and non-lymphoid cell types. The follicular lymphomas included lymphomas with predominantly centrocytes (FCCL, Cb-cc) and lymphomas with predominantly centroblasts (FCCL, Cb). Pattern analysis of FCCL Cb, FCCL Cb-cc and reactive germinal centres indicates that FCCL Cb follicles resemble reactive germinal centres in more aspects than follicles of FCCL Cb-cc. Clear statistical differences were encountered between the frequencies of the lymphoid cell types and of the follicular dendritic and histiocytic reticulum cells in follicles of FCCL Cb-cc and FCCL Cb and reactive germinal centres. Application of a discriminant analysis using a combination of the frequency of centrocytes and follicular dendritic cells demonstrated that both types of neoplastic follicles and reactive germinal centres were correctly classified on the basis of their cell spectrum. For the three groups the most potent discriminator was the centrocyte, whereas the small and large centroblast were of less value. For discrimination between Cb-cc follicles and reactive germinal centres again the centrocyte was the most potent discriminator. Discrimination between FCCL Cb follicles and reactive germinal centres of FCCL Cb-cc follicles can be easily achieved using the frequencies of small centroblasts or centrocytes on their own. These findings indicate that (1) follicles of both FCCL Cb and FCCl Cb-cc differ greatly in the cellular composition and not only with respect to their content of centroblasts but also in their content of follicular dendritic cells and (2) they may be considered as neoplasms representing different developmental phases of germinal centres.     

Localization of beta 1 integrins and their extracellular ligands in human lymphoid tissues.

In this study, we describe the immunocytochemical distribution of the beta 1 integrins (alpha 1 to alpha 6) and their extracellular matrix ligands in human peripheral lymphoid tissues. The results show that within these tissues individual beta 1 integrins are differentially expressed by (sub)populations of stromal cells, including reticular cells, endothelial cells, epithelial cells, and sinus lining cells. The extracellular matrix components studied, eg, collagen I, III, and VI, fibronectin, laminin, and vitronectin, were predominantly associated with the stroma of the lymphoid tissues, and a unique distribution pattern was observed for each of them. Except for alpha 4 (and beta 1), low or no expression of the beta 1 integrins was found on lymphocytes, macrophages, interdigitating cells, and follicular dendritic cells. The results suggest that cell-matrix interactions play a major role in the maintenance of the complex spatial organization of the lymphoid tissue.     

Helicobacter pylori gastritis and primary gastric non-Hodgkin's lymphomas.

AIMS--To evaluate further the relation between gastric malignant lymphoma of the mucosa associated lymphoid tissue (MALT) and Helicobacter pylori. METHODS--One hundred and sixty two surgical specimens of MALT lymphoma were retrospectively investigated to determine tumour type and inflammatory patterns. In 121 cases biopsy specimens obtained before surgery were available and stained with haematoxylin and eosin, periodic acid Schiff, Giemsa and Warthin-Starry stains. RESULTS--Residual lymphoid follicles were found less often in high grade malignant than in low grade malignant MALT lymphomas. Chronic active gastritis was shown within the mucosa at some distance from the tumours in 143 of 146 specimens. In all the cases for which biopsy specimens could be evaluated, colonisation of the mucosa by H pylori had occurred. Lymphoid follicles and lymphoid aggregates were detected in 82.7% of the antral, and in 85% of the body mucosa specimens. CONCLUSIONS--These data support the hypothesis that H pylori has an important role in the development of MALT lymphomas. Furthermore, the chronic inflammation preceding malignant transformation might enhance the probability of malignant transformation via chronic stimulation of the lymphoid tissue. This might in part indicate why MALT lymphomas occur most often in the stomach.     

EXTRACELLULAR MATRIX AND β1 INTEGRIN EXPRESSION IN NODAL AND EXTRANODAL T-CELL LYMPHOMAS

Since non-Hodgkin's lymphoma (NHL) cells interact with surrounding structures similarly to their normal counterparts, micro-environmental changes and the aberrant expression of adhesion molecules are considered to be of importance in lymphomagenesis. In this immunohistochemical study, the composition of several extracellular matrix (ECM) components and the expression of their β1 integrin receptors were examined in nodal and extranodal T-cell NHLs. Except for the T-lymphoblastic NHLs, almost all T-NHLs displayed abundant deposition of matrix and considerable expression of the α4 and β1 integrin chains. This is in contrast to B-cell NHLs, which show ECM patterns comparable to those in reactive lymphoid tissue or, in cases of high-grade malignancy, active matrix degradation and very low expression or absence of β1 integrins, as previously described. This difference is probably based on distinct cytokine production in B- and T-cell malignancies. As in B-NHL, nodal and extranodal T-NHLs of the same morphological subtype exhibit identical ECM patterns, which suggests that malignant lymphoid cells of both B and T origin create at least part of their own specific micro-environment.     

Nodal and extranodal lymphoproliferative disorders in Sjogren's syndrome: a clinical and immunopathologic study

Sjogren's syndrome (SS) is frequently associated with both reactive and neoplastic lymphoproliferative disease. Over a 12-year period beginning in 1970, 21 of 138 patients with SS followed at two tertiary university medical centers had biopsies taken of enlarged lymph nodes (18) or extranodal lymphoid infiltrates (8). Many had immunologic studies performed on fresh tissue and all had paraffin-embedded tissue available for histochemical and immunoperoxidase studies. Eight of our patients had malignant lymphomas which were chiefly B cell neoplasms including two lymphoplasmacytic lymphomas and two follicular center cell lymphomas. The remaining 13 patients had either reactive adenitis (usually with follicular hyperplasia) or atypical lymphoid hyperplasia which failed to meet both histopathologic and immunopathologic criteria for malignancy. None of the nine patients with reactive hyperplasia has yet progressed to lymphoma, while one of four patients with atypical lymphoid hyperplasia progressed to overt lymphoma. Clinical features such as age, duration of disease, extent of lymphadenopathy, splenomegaly, or parotid swelling failed to identify those subsets of patients with lymphadenopathy at increased risk for lymphoma. Recognition of lymphoma in two patients was greatly facilitated by tissue immunologic studies demonstrating focal areas of monotypic B cell proliferation. In one patient in whom the histopathologic diagnosis was immunoblastic sarcoma of B cells, tumor cells were L26-negative and strongly UCHL1-positive suggesting T cell differentiation. In three patients with relatively homogeneous extranodal lymphoid infiltrates, B cell polyclonality on tissue immunoperoxidase studies, and the absence of cytologic atypia, precluded a diagnosis of malignant lymphoma; none of these three patients has progressed to overt lymphoma. Our results indicate that (1) patients with SS develop a variety of B cell lymphomas and other lymphoproliferative disorders, and (2) the nature of the lymphoproliferative disorder is best determined by multiparameter analysis including immunologic phenotyping.     

Relevance of Ki-67 expression in the classification of non-Hodgkin''s lymphomas: a morphometric and double-immunostaining study

The proliferation of reactive and neoplastic cells was retrospectively assessed in 92 cases of non-Hodgkin's lymphoma by morphometry using a double-immunoenzymatic technique including surface markers and the monoclonal antibody Ki-67. The findings were compared with the histological diagnosis. The overall Ki-67 positivity is not always a good measure of the corresponding corrected values and therefore we recommend that a correction should be made for the total number of complementary lymphocytes in the tumour. Taking the macrophages and the Ki-67 positivity of the reactive cells into account does not generally add any information. There was no difference in reactive cell content between follicular (counted within follicles) and diffuse lymphomas within the tumour areas. The value of the group mean for low-grade follicular (nodular) lymphomas was significantly higher than that of diffuse low-grade lymphomas, but not significantly different from that of intermediate-grade lymphomas. High-grade lymphomas exhibited significantly greater Ki-67 positivity than those of intermediate grade. In 76% of the cases there was significant agreement between malignancy grade (low/intermediate malignant versus high malignant) at 45% corrected Ki-67 counts.     

Follicular colonization of nodal marginal-zone B-cell lymphoma resembling follicular lymphoma: report of 6 cases

The formation of neoplastic B-cell follicles is accepted as a diagnostic criterion of follicular lymphoma. However, extranodal marginal-zone B-cell lymphomas (MZBLs) of mucosa-associated lymphoid tissue (MALT) type also sometimes contain numerous lymphoid follicles and may even have a predominantly follicular growth pattern. However, morphologic, immunohistochemical, and genotypic findings suggest that lymphoid follicles in extranodal MZBLs are neoplastic follicles formed as the result of colonization of previously reactive follicles by tumor cells (centrocyte-like cells). We present here 6 cases of nodal MZBL demonstrating a follicular growth pattern. Immunohistochemical study demonstrated that the tumor cells were CD10-, CD20+, CD79a+,CD138-, Bcl-2+, Bcl-6- and IRF4+. Residual nonneoplastic follicular center cells were CD10+, CD20+, CD79a+, Bcl-2-, and Bcl-6+. CD21/CD23 immunostain demonstrated a disrupted follicular dendritic cell pattern characteristic of follicular colonization in extranodal MZBL of MALT type. Taken in conjunction with the morphologic findings, nodal MZBL may also show a follicular growth pattern similar to extranodal MZBL of MALT type. The marginal-zone nature is most recognizable on immunohistochemistry, although the histologic appearance alone may cause some diagnostic problems. It is important for pathologists to consider this type of lesion in diagnostic practice.     

Production of a monoclonal antibody reactive with human dendritic reticulum cells and its use in the immunohistological analysis of lymphoid tissue.

A murine monoclonal antibody (designated R4/23) which reacts strongly with human dendritic reticulum cells (DRC) is described. Immunoperoxidase staining of tissue cryostat sections revealed that this antibody reacts strongly with DRC in lymphoid follicles (both primary and secondary), and also weakly with marginal zone splenic B cells and with some peripheral follicular mantle B lymphocytes in lymph node cortical follicles. The value of antibody R4/23 is that it allows the distribution of DRC in reactive and neoplastic lymphoid tissue to be clearly delineated. Of particular interest is the fact that all cases of follicular lymphoma of germinal centre cell origin are consistently accompanied by a proliferation of DRC, even when the neoplasm is present in non-lymphoid tissue--for example, in the kidney. In contrast, DRC in B cell lymphomas of non-germinal centre origin are partially or totally obliterated.     

Follicular colonization in thyroid lymphoma.

The presence of neoplastic (light chain restricted) B-cell follicles in low-grade B-cell gastrointestinal (GI) lymphoma of mucosa-associated lymphoid tissue (MALT) has been explained on the basis of specific colonization of reactive follicles by centrocyte-like (CCL) cells. Low-grade B-cell thyroid lymphomas have been included in the category of MALT lymphoma, but the frequent presence of a follicular pattern in these tumors has contributed to the view that they are follicle center cell (FCC) tumors. We have reviewed the histology and investigated the phenotype and genotype of nine cases of primary low-grade B-cell lymphoma of the thyroid, all of which were distinguished by a predominantly follicular pattern. All cases also demonstrated features of MALT lymphoma, including CCL cells and lymphoepithelial lesions. The appearances and immunohistology of the follicles were those of follicular colonization as described in GI MALT lymphoma rather than FCC follicular lymphoma. The predominant pattern of follicular colonization was replacement of the follicle center by slightly enlarged CCL cells that showed a strikingly high proliferation rate. No evidence of the t(14;18) translocation was found in any case, using the polymerase chain reaction (PCR) on DNA extracted from fresh (n = 1) or paraffin-embedded (n = 9) tissue. These findings argue against a FCC lineage for primary thyroid lymphomas and support their inclusion in the MALT category.     

Extra medullary Plasmacytoma of the Thyroid, Associated with Follicular Colonization and Stromal Deposition of Polytypic Immunoglobulins and Major Histocompatibility Antigens Possible Categorization in MALT Lymphoma

A 78 year old woman complaining of a neck mass underwent right hemithyroidectomy. The 7×6 cm thyroid tumor consisted predominantly of mildly atypical, epithelial membrane antigen-positive plasma cells and scattered lymphoid follicles. Features of follicular colonization (plasma cell infiltration into germinal centers) were noted. Numerous CD45RO-positive reactive T cells and a smaller number of CD2O-positive blast-like B cells were also distributed among the plasma cell infiltrate. IgG, x-type mono-clonality with J-chain reactivity was identifled in the plasma cells, including those in the lymphoid follicles. The association of pre-existing lymphocytic thyroiditis was confirmed histologically in the non-tumorous thyroid tissue. The tumor exhibited deposition of reticulin flber-rich, amorphous eosinophilic substances, provoking pronounced foreign body reactions. The deposit, polytypically im-munoreactive for immunoglobulin γ-,μ-, ϰ- and Λ chains, β₂-microglobulin and HLA-DR, was scarcely reactive upon amyloid staining, and consisted ultrastructurally of electron-dense, non-fibrillar material and entrapped collagen fibers. Multiple myeloma was ruled out by laboratory, histologic and clinical examinations. The possible categorization of this extramedullary plasmacytoma of the thyroid within low-grade B cell lymphoma of the mucosa associated lymphoid tissue (MALT) is discussed. Acta Pathol Jpn 42: 672–683, 1992.     

Distribution of T-cell subsets in follicular and diffuse lymphomas of B-cell type.

The authors examined the number and distribution of cells reacting with monoclonal antibodies to T-cell subsets in frozen tissue sections of B-cell lymphomas (30 follicular and 17 diffuse lymphomas). In five diffuse lymphomas (two lymphocytic, three small cleaved cell) the neoplastic B-lymphocytes reacted with the monoclonal antibody anti-T1. In all other cases, the monoclonal antibodies to T-cell subsets reacted only with small lymphocytes concentrated between the follicles of follicular lymphomas and distributed randomly in diffuse lymphomas. The distribution of T cells and the T4+/T8+ ratio in follicular small cleaved and mixed lymphomas was similar, although not identical, to that seen in hyperplastic lymphoid follicles. Fewer T cells and a decrease in the T4+/T8+ ratio were seen in follicular large cell lymphoma and in diffuse large cell lymphomas. The number and distribution of T cells in follicular lymphomas is consistent with the hypothesis that there is a functional interaction between neoplastic B cells and benign T cells. No tumors were found in which the neoplastic B cells reacted with anti-T3, anti-T4, or anti-T8.     

反应性淋巴组织和滤泡性淋巴瘤中T细胞的分布及其生物学意义

应用6种抗体的免疫组织化学及形态学定量方法,对19例反应性淋巴组织及11例滤泡性淋巴瘤组织中T细胞的分布及其生物学意义进行探讨,结果表明:在反应性淋巴滤泡中的了细胞90％以上分布于核分裂象较少的明区,而在核分裂象较多的暗区,T细胞仅占10％。在滤泡性淋巴瘤组织中,T细胞失去上述极性分布特点。组织学观察发现与肿瘤细胞的增殖相对应,T细胞呈弥漫型、边缘优势型、边缘型、部分边缘型、散在型等5种分布样式。根据上述结果推论T细胞主要介入正常及肿瘤性B细胞的分化过程。     

Platelet integrins and immunoreceptors

Summary:  Stable platelet adhesion to extracellular matrices and the formation of a hemostatic or pathological thrombus are dependent on integrin αIIbβ3, also known as GPIIb–IIIa. However, maximal platelet responses to vascular injury may involve the participation of other integrins expressed in platelets (αVβ3, α2β1, α5β1, and α6β1). Platelet membrane 'immunoreceptors' contain at least one subunit with an extracellular immunoglobulin superfamily domain and/or an intracellular stimulatory immunoreceptor tyrosine-based activation motif (ITAM) or immunoreceptor tyrosine-based inhibitory motif (ITIM). Platelet ITAM receptors, such as FcγRIIA and the GPVI–FcRγ complex, promote activation of integrins, while ITIM receptors, such as platelet–endothelial cell adhesion molecule-1, may promote their inhibition. This review summarizes the structure and function of platelet integrins and immunoreceptors, the emerging functional relationships between these receptor classes, and the consequences of their interaction for platelet function in hemostasis and thrombosis.