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T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) should be distinguished from the following entities.

Reactive Lymphoid Hyperplasia (RLH): RLH is unlikely to show scattered large solitary cells in a background of small lymphocytes. In RLH, the large lymphoid cells usually occur in aggregates, show transition to plasmablasts and plasma cells, stain heterogenously with CD20, and are not light chain restricted.

Classical Hodgkin Lymphoma: The lymphocyte-rich and mixed cellularity types of Hodgkin lymphomas can simulate THRLBCL. However, the Reed-Sternberg cells are either negative for pan B-cell markers or show heterogenous positivity. They are usually positive for CD30 and CD15 - both markers would be negative in the large B-cells of THRLBCL. EBV is frequently positive in Hodgkin lymphoma (40% cases) and negative in THRLBCL.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL): NLPHL with diffuse areas are indistinguishable from THRLBCL on morphologic grounds. The two entities also share some cytogenetic and molecular abnormalities. Features favoring NLPHL over THRLBCL include: young age (4th-5th decades), nodal location, early stage at presentation (80%-95% are stage I or II), at least focal nodular pattern, presence of follicular T-cell rosettes (CD57+, PD-1+) around neoplastic cells, and infrequent expression of cytotoxic marker TIA-1 in the small lymphocytes.

Peripheral T-cell Lymphoma (PTCL): PTCL can show lymphoid cells of various sizes with cytologic atypia. The larger cells do not stand out as prominently as in THRLBCL. Moreover, the larger atypical cells in PTCL express pan T-cell markers rather than pan B-cell markers. The presence of reactive large B-cells (EBV-driven) in some peripheral T-cell lymphomas can cause confusion. In challenging cases, genotyping is useful. THRLBCL will show rearranged immunoglobulin genes and germline T-cell receptor genes. PTCL will have the reverse profile.

Lymphomatoid Granulomatosis (LG): LG resembles THRLBCL and shows large atypical B-cells in a background of reactive T-cells. However, it is always extranodal and is most commonly seen in the lungs and skin. It usually positive for EBV, unlike THRLBCL.

The image shows scattered large atypical lymphoid cells (B-cells) in a background of abundant small lymphocytes (T-cells).

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