What is the diagnosis and management approach for a patient with mature B cell abnormalities?

Mature B-Cell Neoplasms: Diagnosis and Management

Diagnostic Approach Using Immunophenotyping

The diagnosis of mature B-cell neoplasms requires systematic immunophenotyping starting with confirmation of B-cell lineage (CD19, CD20, CD79a, PAX5 positivity), followed by algorithmic assessment of cell size, CD5, CD10, and additional markers to distinguish specific entities. 1

Initial B-Cell Lineage Confirmation

• All mature B-cell neoplasms express pan-B-cell antigens: CD19, CD20, CD79a, and PAX5 1, 2
• CD19 is the hallmark marker expressed consistently across all B-cell developmental stages 2
• Surface immunoglobulin expression confirms mature B-cell status (distinguishes from precursor B-cell ALL which is TdT+) 1, 2

Algorithmic Classification by Cell Size

Small Cell Mature B-Cell Neoplasms

The differential diagnosis includes: CLL/SLL, mantle cell lymphoma, splenic marginal zone lymphoma, hairy cell leukemia, lymphoplasmacytic lymphoma, MALT lymphoma, nodal marginal zone lymphoma, and follicular lymphoma 1

CD5-Positive Small Cell Neoplasms:

• If Cyclin D1+: Mantle cell lymphoma (classic variant) 1, 3
• If Cyclin D1-: CLL/SLL (requires CD23+ for diagnosis; CD5+/CD23- excludes CLL) 3

CD5-Negative Small Cell Neoplasms:

• Flow cytometry on blood or bone marrow is essential if hairy cell leukemia is suspected 1
• If CD10+, BCL2+, t(14;18)+: Follicular lymphoma (85% will be BCL2+ or have t(14;18) translocation) 1
• If CD10-: Consider marginal zone lymphomas, lymphoplasmacytic lymphoma, or hairy cell leukemia based on clinical presentation 1

Medium Cell Mature B-Cell Neoplasms

CD5-Positive Medium Cells:

• If Cyclin D1+: Blastoid mantle cell lymphoma 1
• If Cyclin D1-, BCL6+/-, MYC+: CD5+ DLBCL 1

CD5-Negative, CD10-Positive Medium Cells:

• Panel: CD5, CD10, BCL2, BCL6, cyclin D1, Ki67 1
• If BCL2-, BCL6-, MYC+, Ki67 >90%: Burkitt lymphoma 1
• If BCL2+, BCL6+, MYC+: Perform FISH for MYC, BCL2, BCL6 to check for "double hit" or "triple hit" lymphoma (unclassifiable B-cell lymphoma intermediate between DLBCL and BL) 1

CD5-Negative, CD10-Negative Medium Cells:

• If Ki67 60-90%, BCL2+, BCL6+/-: U-DLBCL/BL; FISH for MYC, BCL2, BCL6 required 1

Large Cell Mature B-Cell Neoplasms

CD5-Positive Large Cells:

• If Cyclin D1+: Pleomorphic mantle cell lymphoma 1
• If Cyclin D1-, BCL6+/-: CD5+ DLBCL or U-DLBCL/CHL 1

CD5-Negative, CD10-Positive Large Cells:

• DLBCL, NOS germinal center B-cell-like (GCB) type (typically BCL6+) 1

CD5-Negative, CD10-Negative Large Cells:

• Panel: CD5, CD10, BCL6, IRF4/MUM1 1
• If BCL6+, IRF4/MUM1-: DLBCL, NOS GCB type 1
• If BCL6-, IRF4/MUM1+: DLBCL, NOS post-GCB (non-GCB) type 1
• Extended panel (CD20, PAX5, CD138, ALK1, CD30, CD15, EBV-EBER, HHV8, Ig light and heavy chains) required for specific subtypes 1

Special Large Cell Subtypes:

• If CD30+, CD15-, EBER-: Primary mediastinal B-cell lymphoma (may be BCL6+, REL+) or anaplastic large cell lymphoma 1
• If CD30+, CD15+: U-DLBCL/CHL 1
• If EBER+, elderly/immunosuppressed: EBV+ DLBCL 1
• If HHV8+: LBCL in HHV8+ multicentric Castleman disease (IgM lambda+) 1
• If CD20-, CD138+/-, PAX5-: Consider plasmablastic lymphoma (EBV+/-), primary effusion lymphoma (HHV8+), ALK+ DLBCL, or myeloma/plasmacytoma 1

Pediatric-Specific Considerations

For pediatric patients (≤18 years) and AYA patients treated in pediatric settings:

• Burkitt lymphoma and DLBCL are the most common aggressive mature B-cell lymphomas 1
• Burkitt lymphoma immunophenotype: CD20+, CD10+, BCL6+, BCL2-, Ki-67 ≥95%, surface immunoglobulin+, TdT- 1
• DLBCL immunophenotype: CD20+, variable CD10, variable BCL2/BCL6/Ki-67 expression 1
• Cytogenetics essential: MYC translocation with immunoglobulin gene (typically simple karyotype) confirms Burkitt lymphoma 1
• Double-hit and triple-hit lymphomas (MYC + BCL2 and/or BCL6 rearrangements) are rare in pediatric populations but more common in AYA patients 1
• EBV testing (EBV-EBER by in situ hybridization) indicated if immunodeficiency suspected or to distinguish sporadic from endemic forms 1

Management Principles

Workup Requirements

Essential diagnostic procedures:

• Excisional biopsy of most accessible site preferred; fresh tissue sent in saline 1
• Touch preparation for cytologic examination 1
• Morphologic and immunohistochemistry review 1
• Flow cytometry (minimum methodology for diagnosis, especially if patient critically ill) 1
• FISH for MYC, BCL2, BCL6 rearrangements 1

For dual B-cell and plasma cell disorders:

• Comprehensive serum and urine protein evaluation: SPEP with immunofixation, serum free light chain assay with kappa:lambda ratio, 24-hour urine UPEP with immunofixation, quantitative immunoglobulins 3
• Immediate renal function assessment: serum creatinine, eGFR, electrolytes, urinalysis 3
• Complete blood count with differential 3
• Bone marrow aspirate and biopsy with plasma cell quantification, flow cytometry, FISH 3
• CT chest/abdomen/pelvis/cervical regions for lymphadenopathy, splenomegaly, hepatomegaly 3

Treatment Approach by Entity

HIV-Associated Lymphomas:

• Antiretrovirals mandatory for all patients 1
• CODOX-M/IVAC, dose-adjusted EPOCH, or CDE ± rituximab (rituximab added for favorable presentations) 1
• GCSF for all patients 1
• Intrathecal therapy required 1
• Add rituximab if CD20+ 1

Castleman Disease-Associated Lymphoma:

• Dose-adjusted EPOCH, CDE, CHOP, or CDOP regimens 1
• Rituximab monotherapy first-line for HHV-8-associated multicentric Castleman disease 4
• Add etoposide for severe cases or cytotoxic chemotherapy if concurrent Kaposi sarcoma 4
• Antiretroviral therapy always administered in HIV+ patients 4

Pediatric Burkitt Lymphoma and DLBCL:

• Treatment is highly aggressive but curable; must occur at centers with expertise 1
• Premedication: acetaminophen and H1 antihistamine 30-60 minutes before rituximab infusion 5
• Prednisone administered as part of chemotherapy regimen prior to rituximab during induction 5
• PCP prophylaxis during treatment and up to 12 months following treatment 5
• Double-hit and triple-hit lymphomas treated with same regimens as other pediatric BL/DLBCL 1

Rituximab Administration (for CD20+ neoplasms):

• Premedicate with antihistamine and acetaminophen 5
• Dilute to 1-4 mg/mL in 0.9% NaCl or 5% dextrose 5
• Monitor closely for infusion reactions (urticaria, hypotension, angioedema, bronchospasm); institute medical management as needed 5
• Screen all patients for HBV (HBsAg and anti-HBc) before initiating treatment 5
• For HBsAg+ or anti-HBc+ patients, consult hepatology for HBV antiviral therapy consideration 5

Critical Pitfalls to Avoid

• Do not diagnose CLL without CD5+ and CD23+; absence of both excludes this diagnosis 3
• Do not diagnose mantle cell lymphoma without cyclin D1+ or t(11;14) on FISH 3
• Do not diagnose follicular lymphoma without CD10+ expression 3
• Always perform FISH for MYC, BCL2, BCL6 in medium/large cells with high Ki-67 to identify double/triple-hit lymphomas requiring aggressive therapy 1
• Never delay treatment in critically ill patients waiting for complete immunophenotyping; morphology and flow cytometry are sufficient to begin therapy 1
• Do not use adult DLBCL regimens for pediatric patients; pediatric protocols have superior outcomes 1
• Screen for HBV reactivation risk before rituximab; failure to do so can result in fulminant hepatitis and death 5
• Evaluate for monoclonal gammopathy of renal significance (MGRS) when lambda-restricted plasma cells with atypical immunophenotype are present, as renal dysfunction from light chains takes treatment precedence 3