B-Cell Non-Hodgkin Lymphomas & CLL

Overview: Sorting B-Cell Lymphomas

Growth pattern. About 85% of non-Hodgkin lymphomas are B-cell neoplasms, each resembling a normal B cell at a particular stage. Indolent lymphomas (CLL/SLL, follicular, marginal zone, hairy cell, lymphoplasmacytic) have few dividing cells, are often widespread at diagnosis, and are rarely cured, yet patients may live for many years; asymptomatic disease is often simply observed. Aggressive lymphomas (DLBCL, Burkitt, primary CNS lymphoma) grow quickly but are often curable with intensive chemoimmunotherapy. Mantle cell lymphoma behaves aggressively yet is rarely cured.

Marker logic. CD19 and CD20 mark B cells. CD5 and CD10 then sort the small B-cell lymphomas, and TdT appears only in precursor (lymphoblastic) neoplasms, never in these mature lymphomas.

Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

Definition. CLL is the most common adult leukemia in Western countries, with a median age near 70. It requires at least 5,000/μL monoclonal B cells: small, mature lymphocytes that are CD19+, dimly CD20+, CD5+, and CD23+ with dim surface immunoglobulin. Small lymphocytic lymphoma is the same disease centered in lymph nodes rather than blood.

Findings. Fragile CLL cells burst on the slide, leaving smudge cells. Many patients are asymptomatic and diagnosed from a routine CBC; others have painless lymphadenopathy and hepatosplenomegaly. Progressive marrow infiltration causes anemia and thrombocytopenia, the basis of Rai and Binet staging. Del(13q) is the most common and most favorable cytogenetic change, whereas del(17p) or TP53 mutation predicts resistance to chemotherapy.

Immune dysfunction. The malignant B cells do not make useful antibody, so hypogammaglobulinemia leads to recurrent sinopulmonary infections with encapsulated bacteria, the leading cause of death. Immune dysregulation also produces warm (IgG) autoimmune hemolytic anemia with spherocytes and a positive direct antiglobulin test, and immune thrombocytopenia.

Richter transformation. In about 2–10% of patients, a rapidly enlarging node, new B symptoms, and a rising LDH signal transformation, usually to DLBCL, with a poor prognosis.

Treatment. Early, asymptomatic CLL is observed. Symptomatic disease is treated with BTK inhibitors (ibrutinib, acalabrutinib), which can cause atrial fibrillation and bleeding, or the BCL-2 inhibitor venetoclax, which can trigger tumor lysis and is started with a slow dose ramp-up; an anti-CD20 antibody is often added.

Other Indolent B-Cell Lymphomas

Follicular lymphoma. The most common indolent NHL. The t(14;18) translocation places BCL2 next to the immunoglobulin heavy-chain enhancer, and excess BCL-2 blocks mitochondrial (cytochrome c–mediated) apoptosis, so germinal-center cells that should die survive. Middle-aged and older adults have painless generalized lymphadenopathy that waxes and wanes, usually widespread (often including marrow) at diagnosis. Nodes are effaced by crowded, back-to-back follicles of centrocytes and centroblasts that lack tingible-body macrophages and have thin or absent mantle zones. The neoplastic follicles are CD10+, BCL6+, CD5−, and BCL-2+, unlike reactive germinal centers, which are BCL-2−. Management ranges from watchful waiting to rituximab-based therapy, and some cases transform to DLBCL.

Marginal zone and MALT lymphoma. Extranodal marginal zone lymphoma arises in lymphoid tissue created by chronic antigen stimulation: the stomach (H. pylori), salivary glands (Sjögren syndrome), and thyroid (Hashimoto thyroiditis). Other links include Chlamydia psittaci (ocular adnexa), Borrelia (skin), Campylobacter jejuni (small intestine), and hepatitis C (splenic marginal zone lymphoma). The CD20+, CD5−, CD10− cells invade glandular epithelium, forming lymphoepithelial lesions. The most common translocation, t(11;18), creates an API2::MALT1 fusion that activates NF-κB.

Early gastric MALT lymphoma depends on H. pylori–driven T-cell help and regresses in most patients after eradication therapy. Tumors with t(11;18) grow independently of the bacterium and need radiation or rituximab.

Hairy cell leukemia. Middle-aged men develop mature B cells with fine hair-like cytoplasmic projections that express CD11c, CD25, CD103, and annexin A1, stain for tartrate-resistant acid phosphatase (TRAP), and carry BRAF V600E in nearly all classic cases. Cells fill the splenic red pulp and marrow, causing massive splenomegaly and pancytopenia with monocytopenia, usually without lymphadenopathy. Marrow reticulin fibrosis makes aspiration a dry tap, and patients are prone to atypical mycobacterial infections. Cladribine, a purine analog resistant to adenosine deaminase, produces long remissions.

Lymphoplasmacytic lymphoma. Small lymphocytes, plasmacytoid lymphocytes, and plasma cells in the marrow secrete monoclonal IgM, producing Waldenström macroglobulinemia. Large IgM pentamers cause hyperviscosity (blurred vision, sausage-like retinal veins, headache, mucosal bleeding), and the IgM may act as a cold agglutinin or cryoglobulin or cause neuropathy. MYD88 L265P is present in more than 90%, and Dutcher bodies (PAS+ intranuclear immunoglobulin inclusions) are a histologic clue. Unlike myeloma, there are no lytic bone lesions or hypercalcemia. Plasmapheresis rapidly relieves hyperviscosity.

Aggressive B-Cell Lymphomas

Diffuse large B-cell lymphoma. The most common NHL in adults consists of diffuse sheets of large CD20+ B cells. Older adults present with a rapidly enlarging nodal or extranodal mass (GI tract, bone, CNS), often with B symptoms and a high LDH. DLBCL arises de novo or transforms from CLL or follicular lymphoma. BCL6 rearrangement is the most common translocation, with BCL2 or MYC rearranged in others; double-hit lymphoma, with MYC plus BCL2 rearrangement, has a poor prognosis. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) cures roughly 60–70%. Key toxicities are hepatitis B reactivation with rituximab (screen first), hemorrhagic cystitis with cyclophosphamide, cardiomyopathy with doxorubicin, and peripheral neuropathy with vincristine. Anti-CD19 CAR-T cells treat relapsed disease.

Mantle cell lymphoma. The t(11;14) translocation joins CCND1 to the heavy-chain enhancer, and excess cyclin D1 activates CDK4/6, which phosphorylates Rb and pushes cells from G1 into S phase. Older men present with widespread lymphadenopathy, splenomegaly, marrow involvement, and GI lesions (lymphomatous polyposis). Cells are CD5+, CD23−, cyclin D1+, and SOX11+. It is aggressive and rarely cured, and BTK inhibitors are active.

Burkitt lymphoma. The t(8;14) translocation, or less often t(2;8) or t(8;22) involving light-chain genes, drives MYC transcription and relentless proliferation, with Ki-67 near 100%. Sheets of medium-sized CD10+, BCL6+, BCL-2−, TdT− B cells are dotted with tingible-body macrophages that have engulfed apoptotic tumor cells, producing the starry-sky pattern. Endemic Burkitt (equatorial Africa, with malaria as a cofactor) presents in children as a jaw or facial mass and is nearly always EBV-positive. Sporadic Burkitt presents as an ileocecal or abdominal mass in children and young adults and is EBV-positive in a minority; a third form accompanies HIV. Tumor lysis risk is extreme, but intensive short-course chemotherapy cures most patients.

Primary CNS lymphoma. An aggressive DLBCL confined to the brain, eyes, or CSF. In AIDS with CD4 counts below 50/μL, it is EBV-driven and usually appears as a single, often periventricular, ring-enhancing lesion. Toxoplasmosis instead produces multiple ring-enhancing lesions, often in the basal ganglia, with positive Toxoplasma IgG and improvement on pyrimethamine-sulfadiazine. EBV DNA in CSF supports lymphoma. Corticosteroids are withheld before biopsy because they kill lymphoma cells and can make the lesion vanish. High-dose methotrexate is the backbone of therapy.