When and how should a CD38 (CD438) flow‑cytometry assay be used in the work‑up and management of suspected T‑cell lymphoma?

CD38 Flow Cytometry in T-Cell Lymphoma Workup

CD38 is not a standard diagnostic marker for T-cell lymphoma and is not included in the recommended immunophenotyping panels for peripheral T-cell lymphoma (PTCL) workup, though it may have emerging utility in specific contexts.

Standard Immunophenotyping Panel for T-Cell Lymphoma

The NCCN guidelines specify a comprehensive panel for T-cell lymphoma evaluation that does not include CD38 as a routine marker 1:

Recommended Flow Cytometry Markers

• Core T-cell markers: CD45, CD3, CD5, CD2, CD7 1
• Subset markers: CD4, CD8 1
• Additional markers: CD19, CD10, CD20, CD30 1
• T-cell receptor markers: TCRalpha, TCRbeta, TCRgamma 1

Immunohistochemistry Panel

The IHC panel for PTCL includes CD20, CD3, CD10, BCL6, Ki-67, CD5, CD30, CD2, CD4, CD8, CD7, CD56, CD21, CD23, TCRbeta, TCRdelta, PD1/CD279, ALK, and TP63—notably CD38 is absent from this list 1.

When CD38 Testing May Be Relevant

T-Cell Acute Lymphoblastic Leukemia (T-ALL)

CD38 has demonstrated robust expression in T-ALL with potential therapeutic implications 2:

• 97.9% of diagnostic T-ALL samples express CD38 2
• Median CD38-positive blast percentage: 85.9% at diagnosis 2
• Expression remains relatively stable through chemotherapy (88.7% in MRD samples, 82.9% at relapse) 2
• Clinical utility: Identifies candidates for anti-CD38 immunotherapy (daratumumab) 2, 3

Differential Diagnosis Considerations

CD38 is primarily used for plasma cell identification in multiple myeloma workup, not T-cell lymphomas 4, 5:

• CD38 combined with CD138 serves as the primary gating strategy for plasma cells 4, 5
• This helps distinguish plasma cell disorders from lymphomas 4

Practical Algorithm for CD38 Testing in Suspected T-Cell Malignancies

Step 1: Determine the suspected diagnosis

• If PTCL suspected: Use standard NCCN panel (CD3, CD5, CD2, CD7, CD4, CD8, CD30, TCR markers) 1
• If T-ALL suspected: Include CD38 in the flow panel for both diagnostic and therapeutic planning purposes 2

Step 2: If CD38 is included and shows bright expression

• Consider T-ALL over PTCL 2
• Evaluate for anti-CD38 immunotherapy eligibility 2, 3
• Note that CD38 expression intensity (MFI) remains stable through treatment 2

Step 3: If plasma cell involvement is suspected

• Use CD38 with CD138 and CD45 for plasma cell gating 4, 5
• This distinguishes concurrent plasma cell disorders from T-cell lymphoma 4

Critical Pitfalls to Avoid

• Do not rely on CD38 alone for T-cell lymphoma diagnosis—it is not part of standard diagnostic criteria 1
• Do not confuse CD38 utility between plasma cell disorders (where it's essential) and T-cell lymphomas (where it's not standard) 4, 5
• Do not assume CD38 negativity excludes T-ALL—while 97.9% are positive, 2.1% may be negative 2
• CD38 expression in memory B cells can cause confusion; proper gating with T-cell markers is essential 6

Emerging Therapeutic Context

CD38-targeted therapy is expanding beyond multiple myeloma 3:

• Anti-CD38 CAR T cells show activity against CD38-high lymphoid malignancies including T-ALL and NK/T-cell lymphoma 3
• All-trans retinoic acid (ATRA) can upregulate CD38 expression in CD38-low tumors, potentially expanding treatment eligibility 3
• Clinical implication: Document CD38 expression levels in T-ALL for future therapeutic stratification 2, 3