Small B-cell lymphomas are a group of tumors composed mainly of medium and small B lymphocytes as opposed to diffuse large B-cell lymphomas (DLBCL). Small B-cell lymphomas account for 46.3% of non-Hodgkin’s lymphomas (NHL) and 56.7% of B-cell lymphomas (BCL) and include: follicular lymphoma (FL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), marginal zone B-cell lymphoma of lymph nodes (NMZL), marginal zone B-cell lymphoma of extrajunctional mucosa-associated lymphoid tissue (MALToma The 2008 WHO classification of malignant lymphomas classifies these lymphomas as separate diseases with their own clinical manifestations, morphology, immunophenotype, and genetic characteristics. The diagnosis of various types of small B-cell lymphoma is often difficult in clinical practice, and the correct diagnosis is directly related to the timing of treatment, the choice of treatment plan and the assessment of prognosis. This article summarizes the clinical manifestations, cell morphology, immunophenotype, and genetic characteristics of various small B-cell lymphomas. Xu Wei, Department of Hematology, The First Affiliated Hospital of Nanjing Medical University I. Common features of small B-cell lymphoma The common features of small B-cell lymphoma are that it is common in middle-aged and elderly people, with slow clinical progression and inert clinical course (except MCL), but it can transform into aggressive lymphoma, which can be remitted after treatment, but is difficult to be cured. Morphology is dominated by small mature lymphocytes, some of which may appear as medium-sized lymphocytes. The immunophenotype is characterized by the expression of mature B cell-associated antigens (CD19, CD20, CD22) and a single light chain (k or l) of surface immunoglobulin (sIg). Both have immunoglobulin heavy chain (IgH) or/and light chain (IgL) gene rearrangements. Second, FL FL is a more common type of inert NHL that originates from the germinal centers of lymph nodes, with a median age of onset of approximately 60 years and rare under 20 years of age. Most patients are in advanced stage (III/IV) at diagnosis, mainly invading lymph nodes, spleen and bone marrow, occasionally involving peripheral blood, and rarely involving extra-nodal organs such as gastrointestinal tract and skin. FL cell morphology is characterized by proliferation of follicular centroblasts and centroblasts, mostly in a follicle-like growth pattern, but also in diffuse areas, often with sclerosis. Depending on the number of follicles, they can be classified as follicle-dominant (follicles >75%), follicular and diffuse (follicles 25%-75%), and diffuse (follicles 25%). The central cells are small to medium in size, accompanied by cleft nuclei; the central mother cells are larger, with round nuclei, several nucleoli close to and under the touch, little cytoplasm and basophilic. most FL are predominantly central cells, with a small number of central mother cells present. According to the number of mother cells (including follicular mother, germinating mother and immunoblast), FL was divided into 3 grades: grade 1 was 0-5 central mother cells per high magnification field; grade 2 was 6-15 central mother cells; grade 3 was more than 15 central mother cells. The FL3 grade can be further divided into 3a and 3b, and 3b shows a lamellar distribution of centroblasts and the absence of centroblasts (based on standard objective). FL cells express the mature B cell-associated antigens CD19, CD20, CD22, CD79a or PAX5, and are positive for the germinal center antigens CD10, BCL2 and BCL6. The combination of CD5-negative and CD10-positive can be distinguished from SLL; CD5 and cyclin D1-negative and CD10-positive can be distinguished from MCL. BCL-2 can only be used to distinguish tumorigenic follicles from reactive follicles (reactive follicles BCL-2-negative), but not to distinguish FL from other small B-cell lymphomas. The major cytogenetic abnormality in FL is t(14;18)(q32; q21) or variant t(2;18) and t(18,22) [detectable by fluorescence in situ hybridization (FISH)], and the resulting Bcl-2/IgH fusion gene, which causes overexpression of BCL-2 protein, is seen in 85% to 90% of FL. but another 10% of FL even with BCL6 is a transcriptional repressor, and its high expression in FL can be distinguished from reactive lymphocytes and other small B-cell lymphomas, and BCL6 is also the most meaningful marker for FL. Third, MCL MCL is mostly aggressive and has a poor prognosis. The median age of onset is about 60 years, male s female = 2-4 s.1 Most patients are in advanced stage (III/IV) at the time of diagnosis, most of them present with generalized lymph node enlargement and extra-nodal dissemination is common (oropharyngeal ring, gastrointestinal tract, bone marrow, peripheral blood). MCL cells consist of morphologically homogeneous small to medium-sized lymphocytes with distinctly irregular or tangential nuclear margins, resembling the central cells of a germinal center, with dense chromatin, inconspicuous nucleoli, and low cytoplasm. MCL lacks cytoplasmic basophilic transformed macrophages and proliferation centers composed of juvenile lymphocytes and paramyocytes, and is not associated with plasma cell differentiation. A few morphologic subtypes resemble primitive cells (maternal cell variants with large cell size, scattered chromatin, small nucleoli, and little cytoplasm) or pleomorphic cells. Very few morphologically resemble SLL cells, even with an immunophenotype that is CD5-positive and CD23-positive, so cyclin D1-positive or t(11;14)(q13; q32) is essential. The MCL immunophenotype expresses mature B cell-associated antigens CD19, CD20, CD22, CD79a, or PAX5, with expression of both CD5 and cyclin D1, and is often negative for CD10, CD23 (25% weakly positive), CD11c, and BCL6. CD20, CD79b, and sIg are more strongly expressed than SLL, and are negative or weakly positive for CD23, and CD11c negative, could be distinguished from SLL. FISH is the ideal technique for detecting t(11;14) (sensitivity 80%-100%), while conventional cytogenetic detection of t(11;14) has a sensitivity of 50%-75% and PCR has a sensitivity of only 30%-50%. Very few patients are t(11;14)(q13;q32) negative. t(11;14)(q13;q32) translocation leads to overexpression of cyclin D1 mRNA, i.e. protein, and consequently abnormal cell cycle function and high cell proliferation activity, so MCL is clinically more aggressive. Mutations in the p53 gene can be present in maternal cell variant MCL, suggesting a poor prognosis. About 5% of cyclin D1 negative MCL, do not express cyclin D1, but express cyclin D2 or cyclin D3, and the diagnosis can be FISH for fusion genes involving cyclin D2, cyclin D3, etc. MCL cell nuclei express SOX11 (SOX11-C1 monoclonal antibody) as a major complement to cyclin D1, especially valuable for the diagnosis of cyclin D1-negative MCL patients. In addition, clinically inert MCL (iMCL) [different from in situ MCL (no dilated, scattered distribution of t(11;14) lymphocytes in the nucleus of the nucleus)] often presents with mild lymphocytosis (leukemic manifestations) and mild splenomegaly, no significant enlargement of lymph nodes, Ki-67 below 30%, SUVmax <6 on PET-CT, 70%-90% immunoglobulin There are mutations in the heavy chain variable region ( IGVH) gene, no p53 mutation, and no or low expression of SOX11. There is no uniform standard on how to identify iMCL. IV. SLL SLL is a clonal proliferative tumor of mature B lymphocytes. Most patients present with bone marrow and peripheral blood involvement with the histomorphologic and immunophenotypic features of chronic lymphocytic leukemia (CLL), as defined by the International Working Group on CLL (IWCLL): enlarged lymph nodes, hemocytopenia due to bone marrow infiltration without lymphoma cells and peripheral blood B cells <5×109/L. The median age of onset of SLL is 60-75 years, male s female = 2s1. SLL is mainly composed of small and medium-sized B cells and can manifest as a diffuse neoplastic small lymphocytic infiltrate with scattered areas of focal paucity composed of young lymphocytes and paramyocytes, i.e. proliferation centers. SLL cells are similar to or slightly larger than normal small lymphocytes, with clumpy chromatin and round or occasionally irregular nuclei. Small nucleoli may be seen. Juvenile lymphocytes are medium-sized, with round nuclei, toxic chromatin clumping, a single nucleolus, and a medium, bland cytoplasm. SLL may be associated with plasma cell differentiation and highly malignant transformed cells such as immunoblast-like cells, centroblast-like cells, and R-S-like cells. Typical immunophenotype of SLL: sIg+ (M+/-D) weakly expressed, CD5+, CD20 weakly expressed, CD23+, CD43+, bcl-6-, CD10-, cyclinD1-. Some SLL exhibit an atypical immunophenotype: CD5 negative or CD23 negative, sIg or CD20 strongly positive. cd43 is useful to distinguish SLL from FL, which is often negative, but MCL also often expresses CD43. mCL expresses CD5 like SLL, but is CD23 negative. cd200 is highly expressed in SLL cells, while in other small B-cell lymphomas it is Negative or low expression. Because SLL cells are relatively mature lymphocytes with poor dividing ability, conventional karyotyping is difficult to obtain the mid-phase division phase. CpG-stimulated karyotyping of chromosomes is technically demanding, although it can increase the detection rate of chromosomal abnormalities to nearly 80%. Interphase FISH is not affected by whether the cells divide or not, and is the most commonly used cytogenetic detection technique at home and abroad. Using FISH with a set of probes can detect cytogenetic abnormalities in about 80% of SLL patients, and common genetic abnormalities include: del(13q14), +12, del(11q22.3), del(17p13), del( 6q23), etc. Patients with SLL with simple del(13q) are generally considered to have a better prognosis, chromosomally normal and +12 have an intermediate prognosis, while patients with SLL with del(11q) (ATM gene deletion) or del(17p) (p53 gene deletion) have a significantly worse prognosis than those with chromosomally normal or simple del(13q). V. Marginal zone lymphoma (MZL) includes NMZL, MALToma and SMZL. NMZL develops at a relatively young age, is more common in women, and presents with local or generalized lymph node enlargement, and is prone to invade the bone marrow and peripheral blood, often without extra-nodal sites and spleen involvement, and some patients may convert to aggressive lymphoma. Extra-nodal MALToma accounts for approximately 5% of NHL cases, with a median age of onset of approximately 60 years and a slightly higher incidence in women than in men. The disease often involves the mucosal tissues of the gastrointestinal tract, lung, ocular appendages, parotid gland, breast, thyroid gland, etc. Most of the clinical cases are stage I-II, with limited lesions that can be cured by local treatment. SMZL is more common in patients over 50 years of age, and there is no difference in the incidence between men and women. The most distinctive features of SMZL are splenomegaly, frequent involvement of the splenic hilar lymph nodes, and the absence of superficial lymph nodes and extra-nodal tissues, and peripheral blood and bone marrow involvement in most SMZL patients. 1/3 of patients have monoclonal immunoglobulins. SMZL should be considered in B-cell chronic lymphoproliferative disease (B-CLPD) that is difficult to classify as CD5-negative, especially in patients with marked splenomegaly without lymph node enlargement. MZL is mainly composed of marginal zone cells (similar to central cells but with richer, lighter-stained cytoplasm), monocyte-like B cells, small lymphocytes, plasma cells, and transformed macrophages. The morphologic features of MALToma are lymphoepithelial lesions (marginal zone cells infiltrating the epithelium), reactive follicles i.e. follicular implantation (marginal zone or monocyte-like B cells invading the reactive follicles), marginal zone cells and/or monocyte-like B cells, small lymphocytes, plasma cells and scattered transformed macrophages. NMZL cells are predominantly monocyte-like B cells, medium in size with round or slightly depressed nuclei. SMZL often involves the marginal zone of the splenic white marrow, mostly with residual germinal centers and nuclei, and SMZL cells are mature small lymphocytes without nucleoli. Almost all patients with SMZL have peripheral blood and bone marrow involvement with characteristic polar villi. A nodular interstitial infiltrate is seen on bone marrow biopsy, a feature that helps to exclude hairy cell leukemia (HCL). The minimum criteria for the diagnosis of SMZL are: (i) splenic histology + CLL immunophenotype score ≤ 2; or (ii) typical blood and bone marrow morphology + immunophenotype + sinusoidal CD20 positive cell infiltration if splenic histology is not available. That is, in patients with splenomegaly, typical blood and bone marrow manifestations are diagnostic if splenic histology is not available. The immunophenotype of MZL is the expression of mature B cell-associated antigens CD19, CD20, CD22, CD79a or PAX5 without specific antigen expression. negative for CD5, CD23, CD10 and CD38, negative for CD5 and CD23 can be distinguished from SLL; negative for cyclin D1 and CD5 can be distinguished from MCL; negative for CD10 and BCL6 can be distinguished from FL. The antibody DBA44 is mostly positive in paraffin-embedded samples of SMZL and splenic lymphoma with villous lymphocytes (SLVL). patients with SLVL express CD11c and DBA44, but are CD25 and CD103 negative and are identified with HCL. There are no specific genetic abnormalities in MZL. common genetic abnormalities in NMZL and MALToma include +3, +18 and t(11;18)(q21;q21)/API2-MALT1. common genetic abnormalities in SMZL include 7q21-32 deletion in more than 40% and +3 in 17%, involving 7q and 17p abnormalities suggesting poor prognosis; with IGHV1-2 (31%), IGHV4-34 (13%), IGHV3-23 (8%) are common; NOTCH2 mutation is a more characteristic abnormality with a higher incidence (23.1%). LPL is a plasma cell-like lymphoproliferative disorder. The typical tumor consists of small B cells, lymphoplasmacytic lymphocytes and plasma cells, mostly involving the bone marrow, lymph nodes and spleen, but rarely involving other extra-nodal sites and peripheral blood. The median age of onset is approximately 60 years. It often involves the bone marrow, lymph nodes and spleen and presents with complete cytopenia and enlarged lymph nodes and spleen. Most patients have an associated monoclonal immunoglobulin increase, mostly IgM, at which point the diagnosis of Wartsein's macroglobulinemia (WM) with hyperviscosity syndrome (HVS) is made. LPL consists of small lymphocytes, lymphoplasmacyte-like lymphocytes (cytoplasmic, basophilic, plasma-like cells with lymphocyte-like nuclei) and plasma cells. LPL cells can be diffusely distributed (without proliferation centers) or parafollicular and sinusoidal. PAS-positive spherical inclusion bodies in the cytoplasm (Russell vesicles) or nucleus (Dutcher vesicles) of some cells and a small number of immunoblasts are also seen. LPL expresses mature B-cell associated antigens CD19, CD20, CD22, CD79a or PAX5, and is positive for CD38 and CD138. Most patients do not express CD5, CD10 and CD23, but 10%-20% of patients do. There is no specific genetic abnormality in LPL. 6q21-q23 deletion is the most common structural abnormality, occurring in 30%-50% of patients, but is not a characteristic change in LPL patients. Other genetic abnormalities include 13q- (10%-13%), +18 (11%-17%), +4 (10%-20%), 17p- ( 7-10%). Recently, the incidence of MYD88L265P mutation in LPL patients has been reported in the literature as high as 90% or more, which may have important value for the diagnosis and differential diagnosis of LPL. The immunophenotypic and genetic characteristics of various small B-cell lymphomas are shown in Table 1, and the diagnosis and differential diagnosis of most small B-cell lymphomas can be made through systematic conventional pathological and immunophenotypic analysis, combined with cytogenetic and molecular biological tests. The biological behavior of these patients and their treatment need to be further studied. Based on the importance of traditional cell morphology, the diagnosis of small B-cell lymphoma advocates a comprehensive diagnostic model combining immunophenotype, cytogenetics, molecular biology and clinical features of the disease, while with the emergence of high-throughput technologies such as second-generation sequencing and microarrays, the diagnosis system of small B-cell lymphoma will be further improved and enriched.