A 38-year-old Indian woman presents with a 2-month history of painless left inguinal lymphadenopathy and intermittent fever. Physical examination reveals a 4 cm firm, matted lymph node in the left groin and no hepatosplenomegaly. Laboratory investigations show hemoglobin 11.5 g/dL, WBC 7,200/μL, and platelets 180,000/μL. Excisional lymph node biopsy shows effacement of normal architecture with a nodular growth pattern. Histology reveals small lymphocytes and scattered large cells with clear cytoplasm and prominent nucleoli. Immunohistochemistry shows CD20+, CD10+, BCL2+, and BCL6+ large cells. What is the most likely diagnosis?

Explanation

## Diagnosis: Follicular Lymphoma (Grade I–II) ### Clinical Presentation The patient presents with: - Painless lymphadenopathy (inguinal node) - Systemic symptoms (fever) - No hepatosplenomegaly - Normal blood counts - Young to middle-aged woman **Key Point:** Follicular lymphoma is the second most common B-cell lymphoma worldwide. It typically presents with nodal disease, often in advanced stage (stage III–IV), but with preserved performance status and normal cytopenias. ### Histopathology — The Diagnostic Hallmark **Nodular growth pattern** with: - **Neoplastic germinal centers** composed of: - **Centrocytes** (small cleaved cells with irregular nuclei) - **Centroblasts** (large cells with vesicular nuclei and prominent nucleoli) - **Preserved mantle zone** at periphery - **Small lymphocytes** in interfollicular areas **High-Yield:** The **nodular pattern** of follicular lymphoma is distinct from the diffuse infiltration seen in other lymphomas. The presence of both small centrocytes and larger centroblasts within germinal center-like structures is pathognomonic. ### Immunophenotype — B-Cell Germinal Center Signature | Feature | Follicular | DLBCL | Burkitt | Primary Mediastinal | | --- | --- | --- | --- | --- | | **CD20** | Positive | Positive | Positive | Positive | | **CD10** | **Positive** | Negative (except GCB type) | Negative | Negative | | **BCL2** | **Positive** | Negative (usually) | Negative | Negative | | **BCL6** | Positive | Positive (GCB type) | Negative | Negative | | **CD5** | Negative | Negative | Negative | Negative | | **MYC translocation** | Negative | Negative (usually) | **t(8;14)** | Negative | | **t(14;18)** | **Present (85%)** | Absent | Absent | Absent | **Mnemonic:** **Follicular = CD10 + BCL2 + t(14;18)** — "**F**ollicular has **F**our features: germinal center origin (CD10+), anti-apoptosis (BCL2+), and the **t(14;18)** translocation." ### Molecular Hallmark **t(14;18)(q32;q21)** juxtaposes **BCL2** (chromosome 18) to the **immunoglobulin heavy chain (IGH)** locus (chromosome 14), resulting in constitutive BCL2 expression and resistance to apoptosis. This translocation is present in ~85% of follicular lymphomas and is virtually absent in other lymphomas. **Clinical Pearl:** The presence of BCL2+ large cells (centroblasts) in a nodular pattern with CD10+ and BCL6+ phenotype is virtually diagnostic of follicular lymphoma. The t(14;18) translocation can be detected by fluorescence in situ hybridization (FISH) or PCR. ### Grading Follicular lymphomas are graded by the number of centroblasts per high-power field (hpf): - **Grade I:** 0–5 centroblasts/hpf - **Grade II:** 6–15 centroblasts/hpf - **Grade III:** >15 centroblasts/hpf (subdivided into IIIA and IIIB) This case, with scattered large cells and preserved nodular architecture, suggests **Grade I–II** follicular lymphoma. ### Why This Is Follicular Lymphoma and Not Other Lymphomas **Diffuse large B-cell lymphoma (DLBCL)** would show: - **Diffuse infiltration** (not nodular) - Predominantly large cells (>50% of cellularity) - CD10+ only in germinal center B-cell (GCB) subtype; BCL2 usually negative - Often presents with B symptoms and rapid progression - Higher grade, more aggressive course **Burkitt lymphoma** would show: - **Diffuse infiltration** with monomorphous medium-sized blasts - **Starry-sky pattern** (macrophages with tingible bodies) - CD10+, but BCL2− (no t(14;18)) - **t(8;14)** translocation (MYC rearrangement) - Extremely aggressive, presents with high tumor burden - Young patients, often with extranodal disease **Primary mediastinal B-cell lymphoma** would show: - **Mediastinal mass** (not peripheral lymph node) - Sclerotic fibrosis and compartmentalization - CD20+, but CD10−, BCL2− - Often presents with chest symptoms or superior vena cava syndrome - Young women typically affected **High-Yield:** The **nodular pattern + CD10+ + BCL2+ + t(14;18)** triad is diagnostic of follicular lymphoma and excludes all other options. ### Clinical Course & Prognosis - **Indolent course** with median overall survival of 8–10 years (without treatment) - Often presents in advanced stage (III–IV) but with good performance status - Risk of **Richter transformation** to DLBCL (~3–5% per year) - Incurable with conventional chemotherapy; watch-and-wait is often appropriate for asymptomatic patients - Newer agents (anti-CD20, PI3K inhibitors, BTK inhibitors) improve outcomes **Clinical Pearl:** Follicular lymphoma is a "watch-and-wait" disease in asymptomatic patients. Treatment is indicated for symptomatic disease, cytopenias, or rapid progression.