A 38-year-old Indian woman presents with a 2-month history of progressive right upper quadrant pain and abdominal distension. On examination, she has hepatomegaly (4 cm below costal margin) and mild splenomegaly. Ultrasound abdomen shows multiple hypoechoic lesions in the liver and mesenteric lymphadenopathy. Laboratory investigations reveal hemoglobin 10.5 g/dL, WBC 7,200/µL (normal differential), LDH 450 U/L (elevated), and normal platelet count. Liver biopsy shows infiltration by small cleaved lymphocytes arranged in a follicular pattern with preserved nodal architecture. Immunohistochemistry shows CD20+, CD10+, BCL2+, and BCL6+ cells. What is the most likely diagnosis?

Explanation

## Diagnosis: Follicular Lymphoma (FL) ### Clinical Presentation This patient presents with the typical indolent presentation of follicular lymphoma: 1. **Insidious onset** — 2-month progressive course 2. **Extranodal involvement** — hepatic and mesenteric lymph node involvement 3. **Preserved performance status** — no constitutional symptoms (fever, night sweats, weight loss) 4. **Mild cytopenias** — anemia present, but WBC and platelets normal ### Morphologic Features — The Gold Standard **Key Point:** The **follicular pattern with small cleaved (centrocytic) lymphocytes** is the hallmark of follicular lymphoma. The preserved nodal architecture (no effacement) indicates a low-grade lymphoma. ### Immunophenotype — Diagnostic Constellation | Marker | Follicular | CLL/SLL | Burkitt | DLBCL | |--------|-----------|---------|---------|-------| | CD20 | **Positive** | Positive | Positive | Positive | | CD10 | **Positive** | Negative | Negative | Negative | | BCL2 | **Positive** | Negative | Negative | Variable | | BCL6 | **Positive** | Negative | Negative | Positive | | CD5 | Negative | Positive | Negative | Negative | | CD23 | Negative | Positive | Negative | Negative | | Ki-67 | Low (10–30%) | Low | Very high (>90%) | High (>40%) | **High-Yield:** The **CD10+BCL2+BCL6+ phenotype** is virtually diagnostic of follicular lymphoma. This immunophenotype reflects the germinal center B-cell origin of FL. ### Cytogenetics **t(14;18)(q32;q21)** — **BCL2/IGH translocation** is present in ~90% of follicular lymphomas. This translocation results in constitutive BCL2 expression, leading to resistance to apoptosis and the indolent clinical course. ### Why NOT the Other Options? #### Diffuse Large B-Cell Lymphoma (DLBCL) - DLBCL presents with **rapid progression**, constitutional symptoms, and higher LDH - Morphology shows large cells with high mitotic rate, not small cleaved cells - Ki-67 is high (>40%); here it would be low - CD10 may be positive in germinal center subtype, but the **follicular architecture** and **small cell size** rule out DLBCL #### Burkitt Lymphoma - Burkitt lymphoma presents with **rapid onset** and **constitutional symptoms** - Morphology shows medium-sized cells with high mitotic rate ("starry sky" pattern) - Immunophenotype: CD20+, CD10+, but **BCL2− and BCL6−** - **t(8;14)(q24;q32)** — MYC/IGH translocation (not BCL2) - Ki-67 is extremely high (>90%) - LDH is markedly elevated; here it is only mildly elevated #### Nodal Marginal Zone Lymphoma - Nodal marginal zone lymphoma is rare and typically presents with lymphadenopathy, not hepatic involvement - Immunophenotype: CD20+, but **CD10− and BCL2−** - Does not have the characteristic follicular architecture ### Clinical Pearl **Follicular lymphoma is the second most common NHL worldwide and the most common indolent lymphoma.** It has an excellent initial response to treatment but is generally **incurable** with conventional therapy; patients often have a relapsing-remitting course over 10–15 years. The t(14;18) translocation is present at diagnosis in ~90% of cases and can be detected in peripheral blood of healthy individuals, suggesting a long latency period before clinical manifestation. ### Grading (WHO/BNLI) - **Grade 1–2 (Low-grade):** 0–15 centroblasts per hpf — indolent course - **Grade 3a (Intermediate):** 16–60 centroblasts per hpf - **Grade 3b (High-grade):** >60 centroblasts per hpf or sheets of centroblasts — behaves like DLBCL This patient's biopsy shows small cleaved cells, consistent with Grade 1–2 FL. ### Staging & Prognosis This patient likely has **Stage III–IV disease** (extranodal involvement). The **FLIPI (Follicular Lymphoma International Prognostic Index)** score incorporates age, LDH, hemoglobin, stage, and nodal involvement to stratify risk. **Mnemonic for FL features:** **FOLLICLE** — **F**ollicular architecture, **O**ldindolent course, **L**ow-grade morphology, **L**ow Ki-67, **I**mmunophenotype CD10+BCL2+, **C**entrocytes (small cleaved cells), **L**ow LDH, **E**xcellent initial response