What does CD56 (Cluster of Differentiation 56) expression on a bone marrow biopsy indicate in terms of hematological malignancy?

CD56 Expression on Bone Marrow Biopsy: Clinical Significance

CD56 expression on bone marrow biopsy most commonly indicates one of three hematologic malignancies: blastic plasmacytoid dendritic cell neoplasm (BPDCN), multiple myeloma, or a subset of acute myeloid leukemia (AML), with the specific diagnosis determined by the complete immunophenotypic profile and clinical context.

Primary Diagnostic Considerations

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

• BPDCN is the most specific diagnosis when CD56 is co-expressed with CD4, CD123, BDCA-2/CD303, TCL1, and CLA 1
• This is a clinically aggressive myeloid-related neoplasm typically presenting with skin lesions and regional lymphadenopathy, with frequent progression to peripheral blood and bone marrow involvement 1
• The blasts characteristically lack myeloperoxidase and nonspecific esterase expression 1
• CD7 and CD33 may be co-expressed in some cases, and TdT is positive in approximately 30% 1
• CD34 and CD117 are consistently negative, which helps distinguish BPDCN from other entities 1

Multiple Myeloma

• CD56 is expressed by most neoplastic plasma cells in multiple myeloma 2
• The absence of CD56 in myeloma patients is associated with significantly worse prognosis (median OS: 24 vs. 60 months for CD56+ disease, p=0.0050) 3
• CD56 expression helps distinguish abnormal from normal plasma cells when evaluated alongside CD19 expression patterns 3

Acute Myeloid Leukemia (AML)

• CD56 expression occurs in approximately 10-13% of de novo AML cases overall 2
• The highest frequency is in AML M5 (monocytic leukemia) at 38%, which is statistically significant (p=0.003) 2
• Other AML subtypes show lower frequencies: AML M1 (33%), AML M0 (13%), AML M2 (7%), and AML M4 (8%) 2
• In acute promyelocytic leukemia (APL), CD56 positivity is associated with significantly higher relapse rates at 3 years (71.4% vs. 12% in CD56-negative cases, p=0.005) 4
• In AML M2 with t(8;21), CD56 expression is consistently associated with unfavorable prognosis 4

Critical Diagnostic Algorithm

Step 1: Evaluate Complete Immunophenotype

• If CD56+ with CD4+, CD123+, BDCA-2+, TCL1+, and absence of CD34/CD117 → diagnose BPDCN 1
• If CD56+ with plasma cell markers (CD138+, CD38+) → diagnose multiple myeloma 2, 3
• If CD56+ with myeloid markers (CD13+, CD33+, MPO+) → diagnose AML and determine FAB subtype 2, 4

Step 2: Assess Clinical Context

• Skin lesions with lymphadenopathy strongly suggest BPDCN 1
• Lytic bone lesions, hypercalcemia, and monoclonal protein suggest multiple myeloma 3
• Circulating blasts with cytopenias suggest acute leukemia 2, 4

Step 3: Perform Cytogenetic and Molecular Studies

• For suspected AML, evaluate for t(8;21), t(15;17), and other recurrent genetic abnormalities 1
• For multiple myeloma, assess CD49e expression to determine maturity subtype and guide therapy selection 3
• BRAF V600E mutation testing may be relevant if histiocytic neoplasm is considered 5

Important Caveats and Pitfalls

Physiologic CD56 Expression

• CD56 can be expressed in normal immature granulocytes in regenerative bone marrow, particularly after allogeneic hematopoietic stem cell transplantation 6
• CD56 positivity in immature granulocytes can reach up to 73.1% in post-transplant regenerative marrow 6
• This physiologic expression occurs at variable levels (mean 24.3 ± 16.7%) and should not be misinterpreted as malignancy 6

Lineage-Specific Considerations

• Acute lymphoblastic leukemia (ALL) is consistently CD56-negative, which helps exclude this diagnosis 2
• Biphenotypic leukemias are also CD56-negative 2
• CD56 expression in B-cell non-Hodgkin lymphomas is extremely rare, with only isolated case reports of diffuse large B-cell lymphoma expressing CD56 7

Prognostic Implications Require Context

• While CD56 expression indicates poor prognosis in APL and AML M2 with t(8;21), its prognostic role remains uncertain in other AML subtypes 4
• The median percentage of CD56+ blasts when positive is typically 56% (range 21-99%) 4
• Close molecular monitoring is mandatory for CD56-positive APL patients due to high relapse risk 4

Recommended Diagnostic Workup

• Multiparameter flow cytometry using minimum six colors following established protocols (e.g., European LeukemiaNet criteria) is required 1
• Immunohistochemistry on bone marrow biopsy sections provides complementary information, particularly in hypocellular or fibrotic specimens 1
• Cytogenetic analysis of at least 20 metaphases is mandatory, as genetic aberrations override immunophenotypic findings 1
• Molecular studies for FLT3, NPM1, CEBPA, and other relevant mutations should be performed when AML is diagnosed 1