A 35-year-old man from Mumbai with a 10-year history of recurrent bacterial infections (Streptococcus pneumoniae, Haemophilus influenzae) presents with generalized lymphadenopathy and hepatosplenomegaly. Serum protein electrophoresis shows a monoclonal spike in the gamma region. Flow cytometry reveals CD5+ B cells (CD19+/CD5+) comprising 60% of lymphocytes (normal <5%), with markedly reduced CD4+ T cells (15%, normal 40–60%). Serum IgM is elevated at 850 mg/dL (normal 40–230). Bone marrow biopsy shows infiltration by small lymphocytes. What is the most likely diagnosis?

Explanation

## Clinical and Laboratory Synthesis ### Key Clinical Features **High-Yield:** The combination of: 1. **CD5+ B cell lymphocytosis** (60% of lymphocytes) — CD5 is a T cell marker aberrantly expressed on B cells 2. **Monoclonal IgM spike** on serum protein electrophoresis 3. **Elevated serum IgM** (850 mg/dL, markedly elevated) 4. **Lymphadenopathy + hepatosplenomegaly** 5. **Reduced CD4+ T cells** (15%) 6. **Bone marrow infiltration** by small lymphocytes is pathognomonic for **Waldenström macroglobulinemia (WM)**. ## Differential Diagnosis Table | Feature | CLL | Lymphoplasmacytic Lymphoma | Waldenström Macroglobulinemia | Follicular Lymphoma | |---------|-----|---------------------------|-------------------------------|---------------------| | **CD5+ B cells** | Yes (>50%) | No | Yes (>50%) | No | | **Monoclonal protein** | Rare | IgM or IgG | IgM (>90%) | IgG/IgA | | **IgM level** | Normal/low | Elevated | Markedly elevated (>3 g/dL) | Normal | | **Bone marrow** | Infiltration common | Variable | Infiltration common | Nodular | | **Lymphadenopathy** | Common | Common | Common | Common | | **Hyperviscosity** | Rare | Rare | Common | Rare | ## Waldenström Macroglobulinemia: Pathophysiology ```mermaid flowchart TD A[MYD88 L265P mutation<br/>or WHIM syndrome]:::outcome --> B[Aberrant NF-κB activation]:::action B --> C[Clonal expansion of CD5+ B cells]:::action C --> D[Differentiation to plasma cells]:::action D --> E[Monoclonal IgM production]:::outcome E --> F[Hyperviscosity syndrome<br/>Cryoglobulinemia<br/>Immune complex disease]:::urgent C --> G[Reduced normal B cell function]:::action G --> H[Recurrent infections]:::outcome ``` **Key Point:** WM is a **lymphoplasmacytic lymphoma** with monoclonal IgM production. The CD5+ B cell population is the neoplastic clone, and plasma cells secrete the monoclonal IgM. ## Why This Is Waldenström, Not CLL **Clinical Pearl:** Although both CLL and WM present with CD5+ B lymphocytosis, WM is distinguished by: - **Monoclonal IgM spike** (CLL rarely produces monoclonal protein) - **Markedly elevated serum IgM** (CLL has normal/low immunoglobulins) - **Bone marrow infiltration pattern** (WM shows lymphoplasmacytic infiltrate; CLL shows interstitial pattern) - **Hyperviscosity risk** (WM; CLL does not) **Mnemonic:** **"WM = IgM + CD5 + Lymphoplasmacytic"** — remember that WM is the IgM-secreting cousin of CLL.