A 62-year-old man with a 4-year history of untreated, asymptomatic, low-grade follicular l… — USMLE Step 3

A $62$ -year-old man with a $4$ -year history of untreated, asymptomatic, low-grade follicular lymphoma presents with rapid enlargement of a right cervical lymph node, new-onset fevers, and a $10\%$ body weight loss over the past $6$ weeks. An excisional biopsy of the rapidly enlarging node is performed.

Histopathologic and molecular evaluation reveals the following:
- Complete architectural effacement by a diffuse infiltrate of large lymphoid cells.
- The atypical cells display vesicular chromatin, prominent nucleoli, and moderate basophilic cytoplasm.
- No residual nodular or follicular architecture is identified.
- Immunohistochemistry: The large cells are strongly positive for $CD20$ , $CD10$ , $BCL-2$ , and $BCL-6$ .
- The Ki-67 proliferation index is estimated at $85\%$ .
- Fluorescence in situ hybridization (FISH) confirms the persistence of a $t(14;18)(q32;q21)$ translocation and identifies a newly acquired $MYC$ gene rearrangement at $8q24$ .

Which of the following is the most accurate diagnostic interpretation of this lymph node biopsy?

Histologic transformation to a high-grade B-cell lymphoma with MYC and BCL2 rearrangementsAnswer
B
Progression to follicular lymphoma, grade 3B, characterized by a diffuse growth pattern of centroblasts
C
Development of a secondary, independent Burkitt lymphoma driven by the newly acquired MYC rearrangement
D
Blastoid variant of mantle cell lymphoma, indicated by the aggressive clinical presentation and high proliferation index
E
Reactive blastoid hyperplasia secondary to an acute infectious process superimposed on the underlying indolent lymphoma

Answer

The correct diagnosis is histologic transformation to a high-grade B-cell lymphoma with MYC and BCL2 rearrangements (commonly referred to as 'double-hit' lymphoma).

This patient's biopsy demonstrates a diffuse proliferation of large B-cells that harbor both a BCL2 rearrangement (evidenced by the t(14;18) translocation typical of his original follicular lymphoma) and a newly acquired MYC rearrangement. According to the WHO classification of lymphoid neoplasms, a diffuse large B-cell lymphoma or high-grade B-cell lymphoma that concurrently harbors rearrangements of MYC and BCL2 (and/or BCL6) is classified as a 'High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements', colloquially known as a 'double-hit' lymphoma. This pathologic interpretation is critical because double-hit lymphomas are highly aggressive and generally respond poorly to standard R-CHOP chemotherapy, requiring more intensive treatment regimens. The complete loss of follicular architecture and the acquisition of large cell morphology with a high Ki-67 index histologically confirm the transformation from his previously indolent disease.

Step-by-Step Solution

Analyze the clinical history and morphologic changes.

The patient has a history of indolent follicular lymphoma but now presents with rapidly growing lymphadenopathy, systemic B-symptoms, and a biopsy showing complete architectural effacement by large lymphoid cells.

To recognize that the clinical and morphologic picture strongly indicates histologic transformation to an aggressive large cell lymphoma.

Interpret the immunohistochemistry (IHC) profile.

The large cells are positive for CD20, CD10, BCL-2, and BCL-6.

To establish that the transformed cells maintain a germinal center B-cell phenotype, consistent with an origin from the pre-existing follicular lymphoma.

Synthesize the molecular and cytogenetic data with the morphology.

FISH demonstrates both a t(14;18) (BCL2) rearrangement and a newly acquired MYC rearrangement in a diffuse large B-cell proliferation.

To apply the specific WHO classification criteria, which require this exact combination of genetic hits to diagnose a high-grade B-cell lymphoma with MYC and BCL2 rearrangements.

Key Concept

Diagnosis of high-grade B-cell lymphoma with MYC and BCL2 rearrangements ('double-hit' lymphoma) through the synthesis of morphology, immunophenotype, and FISH cytogenetics.

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