Abstract
Introduction
The chromosomal translocation t(11;14)(q13;q32), which juxtaposes the cyclin D1 (CCND1) and the immunoglobulin heavy chain genes, is the most common cytogenetic abnormality in systemic immunoglobulin light chain (AL) amyloidosis, occurring in ~50% of patients. Its presence has important prognostic and therapeutic implications. Fluorescence in situ hybridization (FISH) remains the gold standard for detecting t(11;14), but the accuracy of this method relies on a high-quality bone marrow aspirate with sufficient clonal plasma cells. This can be a particular challenge in AL amyloidosis where the bone marrow plasma cell (BMPC) burden is often low; up to 20% of patients have fewer than 5% clonal plasma cells.
The t(11;14) translocation leads to downstream overexpression of CCND1, which can be detected in bone marrow biopsy specimens using immunohistochemistry (IHC). IHC is a widely accessible, cost-effective technique that does not require specialized sample processing, making it particularly valuable in resource-limited settings.
The sensitivity and specificity of CCND1 IHC for identifying t(11;14) in AL amyloidosis have yet to be defined. Therefore, we investigated the correlation between CCND1 expression detected by IHC and t(11;14) status determined by FISH, aiming to evaluate the utility of CCND1 IHC as a diagnostic surrogate.
Methods
We conducted a single-center, retrospective study of patients with AL amyloidosis evaluated at the Boston University Amyloidosis Center between January 2020 and January 2025. Patients who underwent a bone marrow biopsy and had morphologic evidence of a plasma cell dyscrasia were included if they had both FISH testing for t(11;14) and IHC staining for CCND1. Dual IHC staining for CD138 and CCND1 was performed on formalin-fixed, paraffin-embedded bone marrow core biopsy specimens to assess CCND1 expression specifically in plasma cells.
Results
A total of 131 patients met the inclusion criteria, including 57 (44%) with newly diagnosed untreated AL amyloidosis. Among these 131 patients, 69 (53%) were t(11;14)-positive by FISH. Concordant positive results—defined as CCND1 expression by IHC and t(11;14) positivity by FISH—were observed in 66 patients (50%). Concordant negative results—defined as negative CCND1 expression by IHC and t(11;14) by FISH—were observed in 55 patients (42%). Discordance with CCND1 expression by IHC but negative t(11;14) by FISH occurred in 7 patients (5%). Notably, all patients in this discordant group had low BMPC burden, defined as ≤5%. One patient in this group had +11q. Three patients (2%) had a positive t(11;14) by FISH but lacked CCND1 expression by IHC.
Overall, CCND1 IHC demonstrated a sensitivity of 96% (66/69), specificity of 89% (55/62), positive predictive value of 90% (66/73), and negative predictive value of 95% (55/58) for detecting t(11;14) as determined by FISH. The correlation between CCND1 expression and BMPC percentage was modest, with a Pearson's correlation coefficient of r = 0.34 (p < 0.001) and a Spearman's rank correlation coefficient of ρ = 0.43 (p < 0.001).
Conclusion
CCND1 expression by IHC demonstrates high sensitivity and negative predictive value for detecting t(11;14) in AL amyloidosis, supporting its potential use as a screening tool, particularly when FISH is unavailable or BMPC burden is low. The high sensitivity minimizes the risk of missing patients who may benefit from targeted therapies such as venetoclax, while the high negative predictive value allows for confident exclusion of t(11;14) when CCND1 expression is absent. Notably, CCND1 expression was still detectable by IHC even in cases with low BMPC burden, where FISH may be limited due to insufficient clonal cell enrichment. However, CCND1 expression can also result from other genetic alterations, such as 11q gain or trisomy 11. Conversely, some t(11;14)-positive cases may lack CCND1 expression by IHC for unclear reasons. Therefore, while CCND1 IHC is a useful triage tool, confirmatory testing with FISH or molecular assays remains essential for definitive detection of t(11;14).
