Phenotypic and Immunohistochemical Features Distinguishing PMBCL from DLBCL-NOS
Primary mediastinal large B-cell lymphoma (PMBCL) can be reliably distinguished from diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS) by the combined presence of nuclear c-Rel and cytoplasmic TRAF1 expression (specificity 98%), along with characteristic expression of CD23, MAL protein, and PD-L1/PD-L2 amplification. 1, 2
Core Immunohistochemical Panel
PMBCL-Specific Markers
Nuclear c-Rel is present in 65% of PMBCL cases versus only 18% of DLBCL-NOS, reflecting activation of the NF-κB signaling pathway that characterizes PMBCL. 2
Cytoplasmic TRAF1 expression occurs in 62% of PMBCL but only 12% of DLBCL-NOS, making it a highly discriminatory marker. 2
The combination of nuclear c-Rel AND TRAF1 expression is seen in 53% of PMBCL but only 2% of DLBCL-NOS, providing 98% specificity for PMBCL diagnosis. 2
CD23 positivity is characteristic of PMBCL and helps distinguish it from typical DLBCL-NOS. 3
MAL (myelin and lymphocyte) protein shows weak to positive staining in PMBCL but is typically negative in DLBCL-NOS. 3
CD30 expression is frequently positive in PMBCL due to increased TNFRSF8 gene expression. 3
Molecular Signatures
9p24.1 amplification (PD-L1/PD-L2 locus) is a disease-specific structural alteration in PMBCL, with increased CD274 gene expression encoding PD-L1 protein. 1, 3, 4
PMBCL shows higher PD-L2 expression in B-cells, lower PD-1 expression in T-cells, and higher CTLA-4 expression in T-cells compared to DLBCL-NOS. 5
JAK-STAT and NF-κB pathway dysregulation distinguishes PMBCL from DLBCL-NOS at the molecular level. 1
Standard B-Cell Markers
Both PMBCL and DLBCL-NOS are CD20+, CD79a+, and PAX5+ as mature B-cell lymphomas. 3
CD10 expression is variable in both entities: DLBCL-NOS shows CD10 positivity in germinal center type, while PMBCL is typically CD10-negative. 6
BCL6 is positive in both, though expression patterns may differ. 6
MUM1/IRF4 positivity in PMBCL is associated with better survival, whereas its significance differs in DLBCL-NOS. 3, 5
Proliferation Index
Ki-67 proliferation index is high in PMBCL and serves as a prognostic marker—higher Ki-67 at diagnosis correlates with poorer survival. 5
Ki-67 is variable in DLBCL-NOS and does not have the same prognostic weight. 7
Morphologic Features
PMBCL often exhibits compartmentalizing fibrosis and "clear cells" due to abundant pale cytoplasm, features not typically seen in DLBCL-NOS. 1
DLBCL-NOS shows diffuse growth pattern without compartmentalizing fibrosis, with variable nuclear contours and scant to moderately abundant cytoplasm. 7, 1
Critical Diagnostic Pitfall
PMBCL shares molecular features with nodular-sclerosing Hodgkin lymphoma, creating the intermediate entity "mediastinal gray-zone lymphoma" where cases may resemble classical Hodgkin lymphoma but express CD20, CD45, and B-cell transcription factors, or resemble PMBCL but contain Reed-Sternberg-like cells with aberrant phenotype (CD20-, CD15-/+, CD45+, CD30+, Pax5+). 1, 8
Recommended Diagnostic Algorithm
Perform comprehensive IHC panel: CD20, CD79a, PAX5, CD23, CD30, MUM1, MAL, c-Rel (nuclear), TRAF1 (cytoplasmic), Ki-67. 3, 2
If nuclear c-Rel + cytoplasmic TRAF1 both present: Highly specific for PMBCL (98% specificity). 2
Confirm with molecular testing: FISH for 9p24.1 amplification (PD-L1/PD-L2), next-generation sequencing showing increased TNFRSF8 and CD274 gene expression. 3, 4
Correlate with clinical presentation: PMBCL requires bulky anterior mediastinal mass in young adult (median age 30-35 years) with female predominance, whereas DLBCL-NOS typically occurs in older adults (median age 60-70 years) without gender predilection. 1
Excisional or mediastinal core biopsy is mandatory—clinical-pathologic correlation is essential as molecular testing is paramount given PMBCL's distinctive immunophenotype. 1, 3