A 22-year-old male presents with fever, weight loss, and cervical lymphadenopathy for 3 weeks. Lymph node biopsy shows large pleomorphic cells with horseshoe-shaped nuclei, strong CD30 positivity, and both cytoplasmic and nuclear ALK immunostaining. Interphase FISH confirms the translocation marked **B** in the diagram. Which of the following best describes the molecular consequence of this translocation?

Question

Accepted Answer

D. Constitutively active tyrosine kinase driving STAT3, PI3K-AKT, and RAS-MAPK signaling pathways. ## Why "Constitutively active tyrosine kinase driving STAT3, PI3K-AKT, and RAS-MAPK signaling pathways" is right

The translocation marked **B**, t(2;5)(p23;q35), fuses the NPM1 gene on chromosome 5q35 to the ALK gene on chromosome 2p23, creating the NPM1-ALK fusion protein. This fusion protein is a constitutively active tyrosine kinase that drives oncogenic signaling through STAT3, PI3K-AKT, and RAS-MAPK pathways—the defining molecular hallmark of ALK-positive anaplastic large cell lymphoma. The cytoplasmic and nuclear ALK staining pattern (due to NPM1's nuclear shuttling function) is pathognomonic for this translocation. (Robbins Basic Pathology 11e; WHO Classification 5e)

## Why each distractor is wrong

- **Loss of tumor suppressor function through BCL2 anti-apoptotic overexpression**: This describes t(14;18), the translocation in follicular lymphoma (marked **C**), not t(2;5).
- **MYC oncogene dysregulation leading to uncontrolled cell proliferation**: This describes t(8;14), the translocation in Burkitt lymphoma (marked **A**), not t(2;5).
- **CCND1-driven G1/S cell cycle checkpoint disruption**: This describes t(11;14), the translocation in mantle cell lymphoma (marked **D**), not t(2;5).

**High-Yield:** ALK-positive ALCL = t(2;5) NPM1-ALK fusion = constitutively active tyrosine kinase + cytoplasmic/nuclear ALK staining + young patient + CD30+ + favorable prognosis (70–90% 5-year survival).

[cite: Robbins Basic Pathology 11e (Hematopoietic Neoplasms); WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues 5e]

Answer

A. MYC oncogene dysregulation leading to uncontrolled cell proliferation

Answer

B. Loss of tumor suppressor function through BCL2 anti-apoptotic overexpression

Answer

C. CCND1-driven G1/S cell cycle checkpoint disruption

Explanation

Why "Constitutively active tyrosine kinase driving STAT3, PI3K-AKT, and RAS-MAPK signaling pathways" is right

Why each distractor is wrong

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