What does a CD138 (Cluster of Differentiation 138) positive result in immunohistochemistry (IHC) indicate?

CD138 Positive in Immunohistochemistry

CD138 positivity in IHC primarily identifies plasma cells (both normal and neoplastic), making it the gold standard marker for detecting plasma cell disorders, particularly multiple myeloma, though certain epithelial malignancies can also express this marker. 1, 2

Primary Diagnostic Significance

Plasma Cell Identification

• CD138 is the definitive marker for plasma cell identification in bone marrow and tissue specimens, showing virtually 100% sensitivity for both normal and neoplastic plasma cells 2
• The marker demonstrates excellent membrane localization on plasma cells, enabling precise enumeration and characterization 2
• CD138 expression is mandatory for flow cytometry-based plasma cell gating, used in combination with CD38 and CD45 for optimal detection 3, 1

Multiple Myeloma and Related Disorders

• All cases of multiple myeloma (100%) express CD138, including plasmablastic and leukemic variants 2
• CD138 enables differential diagnosis between neoplastic plasma cell disorders and reactive plasmacytosis when combined with additional markers 3, 1
• The marker facilitates detection of minimal residual disease and treatment monitoring in myeloma patients 1
• CD138 immunostaining significantly increases plasma cell detection compared to routine morphology alone, identifying focal involvement that may be missed on standard bone marrow examination 4

Critical Diagnostic Pitfalls

Non-Plasma Cell Malignancies

• CD138 positivity does NOT definitively establish plasma cell origin unless hematolymphoid derivation has been confirmed through other means 5
• Multiple carcinomas express CD138, including:
  • Hepatocellular carcinoma 6
  • Prostate, colon, and renal cell carcinomas 6
  • Various epithelial tumors (30/33 cases in one series) 5
  • Mesenchymal and melanocytic tumors 5
• Metastatic carcinoma to bone marrow can mimic multiple myeloma when CD138-positive, requiring careful morphologic correlation 6, 5

Treatment-Related Loss of Expression

• Proteasome inhibitor therapy can cause CD138 downregulation on neoplastic plasma cells, potentially leading to false-negative results 7
• Daratumumab (anti-CD38 antibody) treatment can result in double CD138-/CD38- negative myeloma, rendering both standard and CD138-independent detection strategies ineffective 7
• This phenomenon necessitates awareness of treatment history when interpreting negative results 7

Optimal Diagnostic Approach

Technical Recommendations

• CD138 should be assessed alongside CD38 and CD45 in at least one tube for flow cytometry, with primary gating based on CD38 vs. CD138 expression 3, 1
• For immunohistochemistry on bone marrow biopsies, CD138 provides superior plasma cell enumeration compared to morphology alone 4
• Manual counting on CD138-stained sections correlates well with image analysis and is significantly more accurate than aspirate counts 4

Confirmatory Panel

• A minimal confirmatory panel should include CD19 and CD56 to distinguish abnormal from normal plasma cells 1, 8
• Abnormal plasma cells typically show CD19-/CD56+ phenotype (in 95% and 75% of myeloma cases, respectively) 8
• Light chain restriction (kappa:lambda ratios >4:1 or <1:2) confirms clonality 8, 4
• A preferred extended panel includes CD20, CD117, CD28, and CD27 for comprehensive characterization 1

Avoiding Misdiagnosis

• Always correlate CD138 positivity with morphologic features and clinical context before concluding plasma cell origin 6, 5
• In cases with atypical morphology or unexpected clinical presentation, consider non-plasma cell malignancies that may aberrantly express CD138 6, 5
• Stromal CD138 reactivity can occur in both myeloma and metastatic carcinoma, requiring careful distinction from true cellular expression 5
• B-cell lymphomas, including those with secretory features (lymphoplasmacytoid, immunoblastic), are uniformly CD138-negative, helping exclude these diagnoses 2