In a patient with smoldering multiple myeloma, is Congo‑red staining of a tissue specimen required to diagnose AL (amyloid light-chain) cardiac amyloidosis?

Diagnosis of AL Cardiac Amyloidosis in Smoldering Myeloma

Yes, Congo red staining of tissue is absolutely required to diagnose AL cardiac amyloidosis, even in a patient with known smoldering myeloma. The diagnosis of AL amyloidosis mandates both demonstration of tissue amyloid deposits by Congo red staining AND evidence of a plasma cell dyscrasia—you cannot diagnose AL cardiac amyloidosis based solely on the presence of smoldering myeloma. 1

Why Tissue Confirmation Is Mandatory

Unlike ATTR cardiac amyloidosis (which can be diagnosed non-invasively with bone scintigraphy when no monoclonal protein is present), AL amyloidosis requires histologic proof of amyloid deposition. 1 The 2023 ACC Expert Consensus explicitly states that diagnosis of AL amyloidosis requires both: (1) demonstration of tissue amyloid deposits, and (2) evidence of a plasma cell dyscrasia. 1

Critical Reasoning

• Smoldering myeloma alone does not equal AL amyloidosis. Approximately 5% of individuals over 70 years have monoclonal gammopathy of undetermined significance (MGUS), and over 10% of patients with a monoclonal gammopathy can actually harbor ATTR deposits rather than AL amyloid. 1, 2

• Misdiagnosis has devastating consequences. Assuming AL amyloidosis without tissue typing can lead to inappropriate chemotherapy when the patient actually has ATTR amyloidosis, or vice versa—treatments for these two entities are completely different. 2

• Concomitant disease occurs. Patients can have both ATTR and AL amyloidosis simultaneously, particularly when MGUS or smoldering myeloma coexists with abnormal nuclear scintigraphy. 1

Optimal Biopsy Strategy in Your Patient

First-Line Approach: Surrogate Site Biopsy

• Abdominal fat pad aspiration is a simple, office-based procedure with 84% sensitivity for AL cardiac amyloidosis. 1, 2

• Bone marrow biopsy (which may already be performed for smoldering myeloma surveillance) has 69% sensitivity for systemic AL amyloidosis. 1, 2

When to Proceed to Cardiac Biopsy

• If fat pad and bone marrow biopsies are negative for Congo red staining but clinical suspicion for cardiac amyloidosis remains high (restrictive cardiomyopathy, elevated NT-proBNP ≥332 ng/L, typical echocardiographic features), proceed directly to endomyocardial biopsy to definitively exclude or confirm AL cardiac amyloidosis. 1

• Endomyocardial biopsy provides approximately 100% sensitivity and specificity for detecting cardiac amyloid deposits. 2

Essential Steps After Positive Congo Red Staining

Amyloid Typing Is Mandatory

• Mass spectrometry (LC-MS/MS) is the gold standard for identifying the precursor protein, with 88% sensitivity and 96% specificity. 1, 2, 3, 4

• Do not rely on immunohistochemistry alone—it is less reliable than mass spectrometry. 1, 2

• If LC-MS/MS is not immediately available, send the Congo red-positive tissue to an experienced reference laboratory for definitive typing. 1, 2

Why Typing Cannot Be Skipped

• Treatment hinges entirely on amyloid type. AL amyloidosis requires chemotherapy/immunotherapy targeting plasma cells (daratumumab-based regimens), whereas ATTR amyloidosis requires TTR stabilizers or silencers. 2, 3, 4

• Over 10% of patients with monoclonal gammopathy have ATTR deposits in bone marrow, not AL deposits. 1, 2

Common Pitfalls to Avoid

• Never assume AL amyloidosis based solely on smoldering myeloma. Tissue proof is non-negotiable. 1, 2

• Do not skip comprehensive monoclonal protein screening (serum free light chains, serum and urine immunofixation) even though your patient has known smoldering myeloma—the pattern and degree of abnormality guide prognosis and treatment intensity. 1, 2

• Avoid plastic coverslips on Congo red slides—they interfere with polarized light examination and can cause false-negative results. 5

• Use a proper polarizing microscope with strain-free optics; standard clinical microscopes may miss subtle amyloid deposits. 5

• Examine Congo red slides under both standard light and polarized light with fluorescence microscopy (Texas red filter) to maximize sensitivity—fluorescence microscopy detects amyloid missed by polarized light alone in up to 46% of cases. 6

Algorithmic Summary

1. Perform comprehensive monoclonal protein assessment (serum free light chains, serum and urine immunofixation) even though smoldering myeloma is known. 1, 2

2. Obtain tissue biopsy: Start with abdominal fat pad aspiration and/or bone marrow biopsy. 1, 2

3. If surrogate sites are Congo red negative but cardiac amyloidosis is strongly suspected, proceed to endomyocardial biopsy. 1

4. Once Congo red staining confirms amyloid deposits, send tissue for mass spectrometry (LC-MS/MS) to identify the precursor protein. 1, 2, 3, 4

5. Collaborate with hematology to exclude progression to active multiple myeloma and to guide AL-specific therapy if confirmed. 1, 2