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B cell lymphoma is a solid tumor arising from B cells. It includes Hodgkin lymphoma and non-Hodgkin lymphoma. There are many subtypes, with classic Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma now considered tumors originating from B cells. The five most common types of B cell non-Hodgkin lymphoma are diffuse large B cell lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma (MALT), small lymphocytic lymphoma/chronic lymphocytic leukemia, and mantle cell lymphoma (MCL), accounting for three-quarters of non-Hodgkin lymphoma. The prognosis and treatment of B cell lymphoma depend on the specific type and staging of the lymphoma.
Disease Classification
B Cell Hodgkin Lymphoma Classification
Hodgkin lymphoma includes classic Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma, which are now considered tumors originating from B cells.
B Cell Non-Hodgkin Lymphoma Classification
B cell non-Hodgkin lymphoma WHO classification in 2008:
Precursor lymphoid tumors
1. B lymphoblastic leukemia/lymphoma, not otherwise specified
2. B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
B lymphoblastic leukemia/lymphoma with t(9:22) (q34;q11.2); BCR/ABL
B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged (ETV6-RUNX1), B lymphoblastic leukemia/lymphoma with hyperdiploidy
B lymphoblastic leukemia/lymphoma with hypodiploidy
B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32)(IL3-IGH)
B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); E2A-PBX1; TCF3/PBX1)
Mature B cell tumors
1. Chronic lymphocytic leukemia/small lymphocytic lymphoma
2. B-precursor lymphoblastic leukemia
3. Splenic marginal zone lymphoma
4. Hairy cell leukemia
5. Splenic lymphoma/leukemia, unclassifiable
6. Lymphoplasmacytic lymphoma
7. Heavy chain disease
8. Plasma cell myeloma/plasmacytoma
9. Extranodal marginal zone B cell lymphoma (MALT lymphoma)
10. Primary cutaneous follicle center lymphoma
11. Follicular lymphoma
– Gastrointestinal follicular lymphoma
– Pediatric follicular lymphoma
– “In situ” follicular lymphoma
12. Intranasal marginal zone B cell lymphoma
13. Mantle cell lymphoma
14. Diffuse large B cell lymphoma
– Diffuse large B cell lymphoma, not otherwise specified
T cell/histiocyte-rich large B cell lymphoma
EBV-positive diffuse large B cell lymphoma in the elderly
Chronic inflammation-associated diffuse large B cell lymphoma
– Empyema-associated lymphoma
– Chronic osteomyelitis-associated lymphoma
– Implant-associated lymphoma
Primary central nervous system diffuse large B cell lymphoma
– Lymphoma-like granuloma
– Primary mediastinal (thymic) large B cell lymphoma
– Intravascular large B cell lymphoma
– Primary cutaneous large B cell lymphoma, leg type
– Plasmablastic lymphoma
– Primary effusion lymphoma
– ALK-positive diffuse large B cell lymphoma
– Large B cell lymphoma arising in HHV8-positive multicentric Castleman disease
15. Burkitt lymphoma
16. B cell lymphoma unclassifiable, with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma
17. B cell lymphoma unclassifiable, with features between diffuse large B cell lymphoma and classical Hodgkin lymphoma
The following are the five most common B cell NHLs, accounting for three-quarters of non-Hodgkin lymphoma:
1. Diffuse large B cell lymphoma
2. Follicular lymphoma
3. Mucosa-associated lymphoid tissue lymphoma (MALT)
4. Small lymphocytic lymphoma/chronic lymphocytic leukemia
5. Mantle cell lymphoma (MCL)[1-2]
Disease Prognosis
Based on clinical behavior, B cell lymphoma is classified into indolent lymphoma and aggressive lymphoma. Indolent lymphomas typically progress slowly, maintaining stable disease for many years and long-term survival, but are not curable. Aggressive lymphomas usually require more intense treatment but have a chance of cure. The prognosis and treatment of B cell lymphoma depend on the specific type and staging of the lymphoma.
In 1993, Shipp et al. proposed the International Prognostic Index (IPI) for NHL, classifying NHL prognosis into four categories: low-risk, low-intermediate-risk, high-intermediate-risk, and high-risk, with expected 5-year overall survival rates of 73%, 51%, 43%, and 26%, respectively. Age over 60, stage III or IV, more than one extranodal site, requiring bed rest or assistance with daily living, and elevated serum LDH are five adverse prognostic factors in the IPI, which can be used to assess NHL prognosis based on the number of adverse IPI factors present in the patient.
Discussion of B Cell Lymphoma
Diffuse Large B Cell Lymphoma
Diffuse large B cell lymphoma (DLBCL) is the most common NHL, accounting for approximately 30% to 40% of all adult NHL cases, with a higher incidence in China. DLBCL exhibits significant heterogeneity in morphology, biological behavior, and clinical presentation, and the 2008 WHO classification further divides it into non-specific (NOS), specific subtypes, and independent diseases.
Typical immunomarkers: tumor cells positive for CD45, positive for all B cell markers (CD19, CD20, CD22), positive for CD79a, positive for membrane and/or cytoplasmic immunoglobulin (IgM>IgG>IgA), and expression of immunoglobulin light chain restriction (κ-/λ+ or κ+/λ-).
1.1 DLBCL, NOS
This is a group of DLBCL that cannot be classified into specific subtypes or independent diseases, with the vast majority of DLBCL cases falling into this category. Based on the morphology of tumor cells, it can be divided into three common variants: centroblasts (CB), immunoblasts (IB), and anaplastic forms, along with some rare variants (myxoid stroma, fibrous stroma, pseudo-germinal center formation, spindle cells, or Reed-Sternberg-like cells).
Based on gene expression profiling (GEP) analysis, DLBCL can be divided into germinal center B cell (GCB)-like and activated B cell (ABC)-like molecular subgroups, with GCB-like accounting for 45% to 50% of cases, but in China, GCB-like DLBCL only accounts for 20% to 30% of cases. Many studies show that the GCB-like subgroup has a better prognosis than the ABC-like subtype, while various morphological variants cannot reliably predict the molecular subgroup.
As GEP classification is not yet widely available, the WHO classification recommends dividing DLBCL based on immunophenotype into two subtypes: (1) GCB-like: CD10+, Bcl-6+/- , MUM1+/- or CD10-, Bcl-6+, MUM1+/-; (2) Non-GCB-like: CD10-, Bcl-6+/- , MUM1+ or CD10-, Bcl-6-, MUM1+/- . The prognosis of the GCB-like subgroup is better than that of the non-GCB-like subtype. The relationship between immunohistochemical grouping and molecular grouping largely overlaps but with some differences.
The WHO classification also lists the CD5+ DLBCL immunophenotype, which generally does not express CD23 or cyclin D1, distinguishing it from small B cell lymphoma, mantle cell lymphoma, etc. This subgroup accounts for about 10% of all DLBCL cases, most of which are primary DLBCL of the non-GCB-like subgroup, with a poorer prognosis.
1.2 DLBCL Subtypes
1.2.1 T cell/histiocyte-rich large B cell lymphoma (THRLBCL)
Account for less than 10% of all DLBCL, the tumor primarily involves lymph nodes, with tumor cells always dispersed among a large number of reactive T lymphocytes (CD3+, CD45RO+) and varying numbers of histiocytes (CD68+). When tumor cells cluster into sheets, exceeding 10% of the cell population or are EBV+, they should not be diagnosed as THRLBCL.
1.2.2 Primary central nervous system diffuse large B cell lymphoma (CNS DLBCL)
Refers to all LBCL originating in the brain or eyes, excluding those occurring in the meninges, intravascular, secondary, and immunodeficiency-related LBCL. Tumor cells are mostly similar to CB, growing along perivascular spaces, invading brain parenchyma, with tumor cells showing CD10+(10%–20%), Bcl-6+(60%–80%), MUM1+(90%), suggesting most originate from non-GCB cells, with a poor prognosis.
1.2.3 Primary cutaneous DLBCL, leg type
Common in elderly females on the lower leg, the tumor is composed of relatively homogeneous CB and IB infiltrating the skin, but not involving the epidermis. The tumor can often disseminate outside the skin, with GEP and immunohistochemistry showing tumor cells as ABC-like DLBCL, with a poor prognosis and a 5-year survival rate of approximately 50%.
1.2.4 EBV-positive diffuse large B cell lymphoma in the elderly
The new classification lists this type as provisional, being a clonal proliferation of large B cells positive for EBV in individuals over 50 years old (median age 71), without immunodeficiency or previous lymphoma history. Diagnosis requires exclusion of other EBV-related diseases and lymphomas. About 2/3 of cases occur extranodally, with large or pleomorphic tumor cells, which may exhibit IB or plasmacytic (PB) characteristics, often with geographic necrosis within the tumor. The immunophenotype is usually CD10-, Bcl-6-, MUM1+, LMP1+, EBER+. The clinical course is rapid, with a poor prognosis and a median survival of about 2 years.
1.3 DLBCL Independent Diseases
1.3.1 Primary mediastinal (thymic) large B cell lymphoma (PMBL)
PMBL originates from thymic medullary B cells, commonly found in young females, presenting clinically as a large mass in the anterior mediastinum, often involving the kidneys, adrenal glands, liver, CNS, and ovaries upon dissemination. Tumor cells are large, with abundant cytoplasm, transparent or lightly stained, often surrounded by collagen fibers, with the immunophenotype usually being CD30+/-, CD3+, MAL+, MUM1+, Ig-. The tumor responds well to aggressive chemotherapy and radiotherapy.
1.3.2 Intravascular large B cell lymphoma (IVLBCL)
IVLBCL commonly occurs in elderly males, primarily affecting the skin and CNS, often invading the kidneys, lungs, adrenal glands, gastrointestinal tract, and soft tissues, rarely involving lymph nodes. The tumor consists of large cells (CB and IB) located mainly within the lumina of small and medium blood vessels in various organs, usually without obvious masses. The 2008 WHO classification describes the Asian type of IVLBCL, with tumors involving the sinusoidal spaces of the liver, spleen, and bone marrow, presenting as hepatosplenomegaly, hemophagocytic syndrome, and multiple organ failure. Tumor cells show CD10-, MUM1+/- . Patients progress rapidly, respond poorly to treatment, and have a poor prognosis.
1.3.3 DLBCL associated with chronic inflammation
The tumor arises on the basis of long-term chronic inflammation (e.g., empyema, osteomyelitis, metal implants, or skin ulcers), combined with EBV infection, leading to B cell transformation, proliferation, and evasion of the immune surveillance system, ultimately progressing to DLBCL. The tumor commonly occurs in elderly males, with tumor cells exhibiting CB and IB morphology, often accompanied by extensive necrosis and angioinvasive growth. If there is significant plasmacytic differentiation, then CD20-, CD138+, MUM1+. EBV’s LMP1+, EBER+, with genetic abnormalities such as IF I27 gene expression. The tumor is highly aggressive, with a 5-year survival rate of only 25% to 30% for empyema-associated lymphoma.
1.3.4 Lymphomatoid granulomatosis (LYG)
LYG is a proliferative disease of vascular centers and vascular destructive lymphoid tissue composed of EBV-positive B cells mixed with varying numbers of reactive T cells. The tumor commonly occurs in adult males, with the vast majority (>90%) of patients having pulmonary involvement. Based on the number of EBV-positive B cells and the polymorphic background components, LYG is classified into three grades: Grade 1: few atypical large cells, many inflammatory components, focal necrosis, EBV+ cells < 5/HPF; Grade 2: more atypical large cells, fewer inflammatory components, necrosis more common, EBV+ cells 5-20/HPF; Grade 3: sheets of atypical large cells, inflammatory components not obvious, often with extensive necrosis, EBV+ cells > 20/HPF, potentially reaching hundreds. Grade 3 and some Grade 2 LYG have Ig gene rearrangement. Early LYG responds to treatment with INFα2b, but when it progresses to Grade 3 (EBV+DLBCL), the prognosis is poor; however, recent use of aggressive chemotherapy combined with rituximab has shown some efficacy.
1.3.5 ALK-positive large B cell lymphoma (ALK+ LBCL)
The tumor commonly occurs in middle-aged males, primarily affecting lymph nodes and mediastinum. The tumor cells are large and singular, resembling IB and PB, often growing along the lymphatic sinuses within lymph nodes. Tumor cells express ALK, with positive reactions localized in the cytoplasm, granular. The typical immunophenotype of DLBCL with ALK expression is CD45+, EMA+, VS38c+, CD4+, CD57+, ALK+, with all B markers negative (CD20-), CD138+, MUM1+, cIg+ (IgA>IgG), CD30-. The genetic abnormality is t(2;17). The tumor progresses rapidly, is resistant to rituximab treatment, and has a poor prognosis, with a median survival time of only 11 months in stage III-IV patients.
1.3.6 Plasmablastic lymphoma (PBL)
The tumor commonly occurs in middle-aged males, with most patients having a history of HIV or other causes of immunodeficiency. The tumor is most commonly located in the oral cavity but can also occur in other extranodal sites. Tumor cells exhibit plasmablastic (PB) morphology, CD20-, CD138+, MUM1+, cIg+ (mostly IgG), EBER+, but LMP1-. The oral mucosal type of PBL is usually CD56-, and if CD56 is expressed, it should raise suspicion of possible plasma cell myeloma. PBL has a very poor prognosis, with most patients dying within a year of diagnosis.
1.3.7 Large B cell lymphoma arising in HHV8-associated multicentric Castleman disease
This is a clonal proliferation of large B cells expressing IgM and exhibiting PB morphological characteristics, arising from multicentric Castleman disease (MCD) with additional HHV8 infection. Patients often have a background of HIV infection, clinically associated with HHV8 MCD, often involving lymph nodes and spleen, and may accompany Kaposi’s sarcoma. Tumor cells express HHV8 latent nuclear antigen 1 (LANA1), cIgM+, λ+, CD20+/-, CD79α-, CD138-, EBER+. This disease has a high level of malignancy, with a median survival time of only a few months.
1.3.8 Primary effusion lymphoma (PEL)
PEL is a type of diffuse large B cell lymphoma characterized by the presence of tumor cells in the effusions of the pleural cavity, pericardial cavity, and abdominal cavity without obvious masses, associated with HHV8 infection, mostly occurring in AIDS patients, often with concurrent monoclonal EBV infection. The tumor commonly occurs in young and middle-aged males. After centrifugation of the effusion, atypical IB and PB can be observed, with tumor cells being CD20-, CD79α-, Ig-, CD138+, EMA+, LANA1+, EBER+, LMP1-. PEL has a very poor prognosis, with a median survival time of only 6 months. A recently recognized form of lymphoma that morphologically and immunophenotypically resembles PEL is called extramedullary PEL, which primarily affects the gastrointestinal tract, skin, CNS, lungs, or lymph nodes.
Follicular Lymphoma
Follicular lymphoma (FL) is classified into grades 1, 2, and 3 based on the number of centroblasts (CB) per high-power field (HPF) within the neoplastic follicles: 0-5, 6-15, and >15, respectively. Since grades 1 and 2 can transform into each other, both are classified as indolent in the 2008 WHO classification and combined as FL grades 1-2, while grade 3 is still classified based on the presence of centrocytes (CC) in the neoplastic follicles as FL 3A (with CC) and FL 3B (without CC). If FL grade 3 areas appear in grades 1-2, a separate diagnosis of FL grade 3 should be made, and the proportion of each grade should be estimated. In grade 3 FL, if diffuse large B cell areas appear, it should be diagnosed as (1) diffuse large B cell lymphoma (-%), (2) FL 3A or 3B (-%). When grade 3 FL or diffuse large cell areas appear, they should be treated according to the more aggressive DLBCL protocol.
The 2008 WHO classification also listed several variants of FL: (1) pediatric FL: common in males under 20 years old, often involving cervical lymph nodes and oropharynx, with localized lesions. The neoplastic follicles vary in size and shape, often being expansively large follicles, with the surrounding area preserved. Tumor cells are primarily CB, Bcl2-, with no t(14;18), but Ig gene rearrangement, with an excellent prognosis; (2) primary gastrointestinal FL: common in the duodenum, presenting as multiple small polyps, most patients are clinically stage I E or II E, with morphological, immunophenotypic, and genetic characteristics similar to nodal FL, with an excellent prognosis, even without treatment, patients can survive long-term; (3) intrafollicular neoplasia/”in situ” FL: when one or more follicles with Bcl-2 overexpression are found in structurally normal lymph nodes or other lymphoid tissues, it is referred to as “in situ” FL. These patients may appear FL in other locations simultaneously, or before or after, but some patients have no evidence of FL upon long-term follow-up. “In situ” FL must be diagnosed based on Bcl-2 immunohistochemical staining, its significance remains unclear, but clinical follow-up should be conducted to check for FL in other locations, and patients without FL should be monitored closely.
Typical immunophenotype: tumor cells express membrane immunoglobulin (IgM+/-IgD, IgG, IgA), all B cell markers (CD19, CD20, CD22), CD79a, CD10, BCL6, and do not express CD5, CD23, cyclin D1. The vast majority of FL cases express BCL2 (skin FL is generally BCL2 negative), which aids in distinguishing it from reactive lymphoid follicle hyperplasia.
Primary Cutaneous Follicle Centre Lymphoma
Primary cutaneous follicle centre lymphoma (PCFCT) originates from mature B cells in the germinal center and is more common in middle-aged individuals, with a male-to-female ratio of 115:1. Clinically, it presents as solitary or localized plaques, nodules, or tumors on the upper trunk (especially the head and chest). The tumor consists of moderate to large CC and varying numbers of CB, exhibiting follicular and/or diffuse growth patterns, infiltrating around blood vessels and skin appendages, without involving the epidermis. The immunophenotype is similar to nodal FL, but usually negative for Bcl-2 and Ig expression, with no t(14;18) in genetics. PCFCT has an excellent prognosis, with a 5-year survival rate of >95%.
Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) has been more precisely described regarding its etiology, precursors, and genetics in the 2008 WHO classification. In terms of etiology, Helicobacter pylori infection is closely related to gastric MALT lymphoma; Chlamydia psittaci, Campylobacter jejuni, and Borrelia burgdorferi are associated with ocular adnexal MALT lymphoma, immunoproliferative small intestinal disease (IPSID), and skin MALT lymphoma, respectively; autoimmune diseases such as Sjögren’s syndrome and Hashimoto’s thyroiditis are related to MALT lymphoma of the salivary glands and thyroid, respectively. Known genetic abnormalities associated with MALT lymphoma include t(11;18), t(14;18), t(3;14), and t(1;14), with t(11;18) primarily seen in lung and gastrointestinal MALT lymphoma, t(14;18) mainly in ocular adnexal and salivary gland MALT lymphoma, and t(3;14) mostly in thyroid, ocular adnexal, and skin MALT lymphoma. Additionally, +3 and +18 are common, but these changes lack specificity.
Early gastric MALT lymphoma and IPSID can regress with antibiotic treatment, and even achieve complete cure, but gastric MALT lymphoma with t(11;18) is ineffective with anti-Helicobacter pylori treatment and requires chemotherapy, and gastric MALT lymphoma with t(11;18) generally does not transform into diffuse large B cell lymphoma.
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) defines the diagnostic criteria for CLL as when it involves extramedullary tissue, with a monoclonal lymphocyte of CLL phenotype (CD5+ CD23+) ≥5 × 10^9 /L in peripheral blood. If oligoclonal cells with CLL phenotype appear in the peripheral blood of healthy individuals at levels <5 × 10^9 /L, it is called monoclonal B lymphocytosis (MBL), which requires no special treatment but should be monitored. The diagnostic criteria for SLL are the presence of CLL morphology and immunophenotype in extramedullary tissue (usually lymph nodes) without leukemic manifestations.
Typical immunomarkers: tumor cells express membrane IgM or IgM+IgD, all B cell markers (CD19, CD20, CD22), CD79a, CD5, CD23, CD43, CD11c (weak), and do not express CD10, cyclin D1.
Studies show that only 40% to 50% of CLL cases have unmutated IgH V genes, while 50% to 60% have undergone somatic hypermutation. Unmutated CLL often expresses ZAP70 and CD38, which are associated with poor prognosis; mutated CLL usually does not express ZAP70 and CD38. Therefore, immunohistochemical detection of ZAP70 and CD38 can indirectly reflect the mutation status of CLL’s IgH V genes and assist in prognostic assessment.
Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) mentions the existence of “in situ” MCL that only involves the inner mantle zone in the 2008 WHO classification. Among the morphological variants, “blastoid” and “pleomorphic” are classified as aggressive variants of MCL; “small cell” and “marginal zone-like” are classified as other variants of MCL. The 2008 WHO also describes changes in cell cycle and DNA damage repair pathways in MCL and proposes molecular mechanisms for the occurrence, development, and progression of MCL. When naive B lymphocytes that have not been stimulated by antigens undergo t(11;14) chromosomal translocation, they can evolve into early MCL, followed by abnormalities in ATM and CHK2 genes leading to increased genetic instability and development of typical MCL, some of which may progress to blastoid MCL due to deletions or mutations in genes such as p16/CDK4/Rb and ARF/Mdm2/p53.
The poor prognosis of MCL is related to high mitotic counts (>10–37.5/15 HPF, >50mm2), high Ki67 index (>40% or >60%), blastoid/pleomorphic variants, as well as genetic changes such as +12, complex karyotype, TP53 mutations/overexpression/deletion, +3q, -9q, and clinical features of lymphadenopathy with significant peripheral blood involvement.
Hairy Cell Leukemia
Hairy cell leukemia (HCL) and its related diseases are now thought to originate from activated late memory B cells. The tumor cells of HCL are small to medium in size, with abundant, pale-staining cytoplasm, and clear cell borders, showing numerous long projections under electron microscopy. Tumor cells demonstrate positive reactions for tartrate-resistant acid phosphatase (TRAP), and the immunophenotype expresses not only CD19, CD20, and CD22 but also CD103, CD123, DBA.44, FMC7, and annexin A1 (a membrane-associated protein), with annexin A1 expressed only in HCL and not in any other B cell lymphomas.
Splenic B cell lymphoma/leukemia, unclassifiable (splenic B cell lymphoma/leukemia, unclassifiable). The 2008 WHO classification designates some small B cell lymphomas of the spleen, for which there is currently insufficient evidence to classify them as independent diseases, as splenic B cell lymphoma/leukemia, unclassifiable. In this group of tumors, two tumors are defined and described: one is splenic diffuse red pulp small B cell lymphoma, composed of small, solitary B cells diffusely infiltrating the splenic red pulp (including cords and sinuses), which can also involve the sinusoidal spaces of the bone marrow and peripheral blood. The tumor cells have short, small, villous projections, with an immunophenotype of CD20+, DBA.44+, IgG+/IgD-, while CD25, CD103, CD123, annexin A1, CD10, and CD23 are all negative. After excluding CLL, PLL, SMZL, HCL, and LPL based on clinical, morphological, and immunophenotypic features, it can be diagnosed as splenic diffuse red pulp small B cell lymphoma. The other is hairy cell leukemia variant (HCLv), which has characteristics of both typical HCL and lymphoblastic leukemia (PLL) in morphology, with some features typical of HCL in immunophenotype, such as DBA.44+, FMC7+, and CD103+, but negative for CD25, annexin A1, and TRAP. Reports indicate that HCL2v has a higher incidence among Asians than typical HCL, and responds poorly to standard HCL treatment.
Lymphoplasmacytic Lymphoma
Lymphoplasmacytic lymphoma (LPL) can involve only lymph nodes, but many patients can detect monoclonal IgM in serum. When LPL patients have bone marrow involvement and IgM monoclonal disease, it is referred to as Waldenström macroglobulinemia (WM), which is an important variant of LPL; secondly, it was previously thought that 50% of LPL cases had t(9;14), but this is actually very rare, and some cases (especially WM) often have -6q, but without specificity; thirdly, gamma heavy chain disease (γHCD) is a type of heavy chain disease characterized by the secretion of truncated γ heavy chains but lacking light chain binding sites, usually associated with lymphoma consistent with LPL morphology.
Plasma Cell Tumors
Plasma cell tumors are tumors composed of terminal B cells that secrete monoclonal Ig (M protein), including monoclonal gammopathy of undetermined significance (MGUS), plasma cell myeloma, plasmacytoma, and immunoglobulin deposition disease. The 2001 classification included heavy chain disease in plasma cell tumors, but the 2008 WHO classification lists HCD separately due to its ability to secrete Ig, similar to LPL (including WM), but the tumor is not composed solely of plasma cells but also of lymphocytes and plasma cells.
In the 2008 WHO classification, it is proposed that myeloma should be classified based on serum and urinary M protein, bone marrow clonal plasma cells or plasmacytoma, and related organ or tissue damage (hypercalcemia, renal failure, anemia, and bone lesions) into symptomatic and asymptomatic myeloma, with the most important criterion being the presence of end-organ damage. Clinically, it can also be classified into three stages based on serum β2-microglobulin and albumin levels: Stage I with β2-microglobulin <3.5mg/L and albumin >3.5g/dL; Stage II with β2-microglobulin <3.5mg/L and albumin <3.5g/dL or β2-microglobulin 3.5-5.5mg/L regardless of albumin levels; Stage III with β2-microglobulin >5.5mg/L. The median survival for these three groups is 62 months, 44 months, and 29 months, respectively. Prognosis for plasma cell myeloma can be predicted based on cyclin D and translocations, with D1 (11q13) or D3 (6p21) groups having a good prognosis, and D2 (4p16) or D1+D2 groups having a poor prognosis. Additionally, cytogenetic abnormalities such as -13 or aneuploidy, t(4;14) or t(4;16) or t(14;20), -17p13, and hypodiploid plasma cell myeloma have poor prognoses, while hyperdiploid t(11;14) or t(6;14) plasma cell myeloma have good prognoses.
Nodal Marginal Zone Lymphoma
Nodal marginal zone lymphoma (NMZL) describes a provisional type in the 2008 WHO classification with an immunophenotype similar to adult NMZL, commonly occurring in males (male-to-female ratio of 20:1) in the head and neck lymph nodes, often asymptomatic, with 90% of children being stage I. Histologically, it is similar to adult NMZL but often shows progressive transformation of germinal centers, with the outer edges of follicles breaking and being infiltrated by tumor cells. Pediatric NMZL has a good prognosis, with long-term survival after treatment and rarely relapses.
Burkitt Lymphoma
Burkitt lymphoma (BL) has stricter definitions in the 2008 WHO classification, primarily affecting extranodal sites or presenting as acute leukemia. Tumor cells are uniform, medium-sized, with extremely short doubling times and very high proliferative activity, Ki67+ (~100%); the immunophenotype shows CD20+, CD10+, Bcl-6+, Bcl-2-, sIgM+; genetic abnormalities include t(8;14), t(2;8), or t(8;22). BL is a highly aggressive tumor but can be cured, with early patients achieving a cure rate of up to 90% with intensive combination chemotherapy, while late-stage patients can achieve a cure rate of 60%-80%.
Typical immunomarkers: tumor cells express membrane IgM and all B cell antigens (CD19, CD20, CD22) CD10, BCL6, CD38, CD77, CD43, usually BCL2-, TdT-, with almost 100% of cells being Ki-67 positive.
B Cell Lymphoma
Unclassifiable, with intermediate features between DLBCL and BL (B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma), this is a B cell lymphoma with morphological and genetic characteristics that are intermediate between DLBCL and BL, making it difficult to clearly classify as any one type. The 2008 WHO classification refers to this as a borderline lesion, also known as grey zone lymphoma (GZL). This disease mainly occurs in adults and can involve lymph nodes and many extranodal sites. Tumor cells are medium to large; the immunophenotype shows CD20+, CD10+, Bcl-6+, Bcl-2+/- , Ki67+(50%-100%); genetic abnormalities show complex karyotypes, often involving chromosomal translocations of MYC and BCL-2 genes. The tumor is highly invasive, with a short survival time for patients.
B Cell Lymphoma
Unclassifiable, with features between DLBCL and classical Hodgkin lymphoma (CHL) (B cell lymphoma, unclassifiable, with features between diffuse large B cell lymphoma and classical Hodgkin lymphoma), the tumor exhibits intermediate characteristics of DLBCL (especially PMBL) and CHL in clinical, morphological, and/or immunophenotypic features, but cannot be classified into any one type. The tumor commonly occurs in young males aged 20-40, mostly presenting as a large mass in the anterior mediastinum. The tumor consists of sheets of pleomorphic tumor cells, resembling HL’s lacunar cells and H cells, with some areas resembling CHL and others resembling DLBCL, with a stroma showing diffuse or focal fibrosis, and the inflammatory background is usually not obvious, with necrosis being common. The immunophenotype shows CD20+, CD30+, CD79α+/- , CD15+/- , Bcl-6+/- , CD10-, PAX5+, OCT2+, BOB.1+; genetic abnormalities include +2p and +9q, with GEP analysis showing a close relationship between the tumor and CHL and PMBL. Clinically, the tumor exhibits strong invasiveness, with a prognosis worse than CHL or PMBL.
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