Researchers suggest CAD diagnosis system may need a revision
Genetic testing could aid in classifications, guide treatment decisions
Written by |
Some people with a diagnosis of cold agglutinin disease (CAD) secondary to another condition — when it’s then known as cold agglutinin syndrome, or CAS — may actually just have CAD.
That’s the hypothesis set forth in a small study, involving eight people with “clinically well-characterised CAD or CAS,” that challenges how the two conditions are now classified. The current classifications are set forth by the World Health Organization (WHO), in a system now in its fifth edition.
The researchers noted that two of the patients had bone marrow examinations suggesting features of lymphoma, a type of blood cancer — thus meeting the definition of CAS. However, these individuals instead carried certain genetic features typically seen in CAD.
According to the scientists, “most cases exhibited the established genetic hallmarks of CAD.”
The team says their findings suggest that combining genetic testing with standard bone marrow analysis could lead to more accurate diagnoses and, eventually, help guide treatment decisions for people with CAD regardless of their genetic signatures.
The study, “Cold Agglutinin Disease-Like Genetic Signatures in Lymphoplasmacytic Lymphoma-Like Cases Challenge the WHO Fifth Edition Classification,” was published in the journal AJHaem.
An autoimmune disease, CAD occurs when self-reactive antibodies known as cold agglutinins bind to red blood cells at low temperatures, causing the cells’ destruction. This leads to anemia, or a shortage of red blood cells, and other CAD symptoms. Cold agglutinins are produced by B-cells, the immune cells responsible for making antibodies.
World Health Organization sets classification system
The condition is classified as primary cold agglutinin disease — but known simply as CAD — when it occurs on its own. When it’s triggered by another underlying condition, such as infections, autoimmune diseases, or a blood cancer, it’s then classified as secondary cold agglutinin disease, or CAS.
Under the current World Health Organization (WHO) classification, CAD is recognized as a clonal B-cell lymphoproliferative disease (LPD) in the bone marrow, the spongy tissue in bones where blood cells, including immune cells, are made. Simply put, this means that a single B-cell multiplies excessively for an unknown reason.
CAD is defined as a distinct clonal B-cell LPD that does not meet the criteria for B-cell lymphoma, a blood cancer arising from B-cells. Cases associated with an overt B-cell lymphoma are instead classified as CAS.
“Nevertheless, a subset of cold agglutinin-associated cases encountered in routine practice remains difficult to classify according to current criteria,” the researchers wrote.
Some of these cases have bone marrow features that resemble a low-grade or slow-growing B-cell lymphoma, particularly lymphoplasmacytic lymphoma (LPL), despite lacking the genetic changes that define those cancers.
As a result, “such cases are inevitably classified as CAS, although whether this categorisation accurately reflects their underlying biology remains uncertain,” the researchers wrote.
2 patients with a CAS diagnosis fit CAD criteria
Because few studies have closely examined these “borderline cases,” as the researchers dubbed them, a team in Japan set out to investigate them in more detail. The researchers analyzed bone marrow samples and performed comprehensive genetic testing in eight people diagnosed with CAD at their institution between October 2021 and September 2025.
The group comprised six men and two women with a median age of 58. All had high levels of cold agglutinins, cold-induced symptoms, and anemia. However, none showed clinical or imaging evidence of an underlying LPD at the time of the diagnosis.
Subsequent bone marrow examination showed that five participants — slightly less than two-thirds — had the typical pattern of CAD-associated LPD, characterized by small clusters of B-cells surrounded by only a few plasma cells. Plasma cells are the mature B-cells that produce antibodies.
The remaining two patients, however, had bone marrow findings consistent with B-cell lymphoma, with multiple B-cell clusters occupying more than half of the bone marrow. However, plasma cells remained concentrated around the edges of these clusters — a feature typical of CAD. Both cases were initially diagnosed as LPL, and under the current WHO classification, they would be categorized as CAS.
These findings demonstrate that CAD-like genetic signatures can be present even in cases … that would currently be classified as CAS under the WHO criteria.
However, genetic testing painted a different picture, the researchers found. Neither patient carried mutations in the MYD88 or CXCR4 gene that are typically found in LPL, or mutations typically associated with other types of B-cell lymphoma.
Instead, both carried IGHV4-34, a gene segment that encodes for cold agglutinins, and one also harbored a mutation in the CARD11 gene, which has previously been linked to the disease.
“These findings demonstrate that CAD-like genetic signatures can be present even in cases with lymphoma-like [bone marrow features] that would currently be classified as CAS under the WHO criteria,” the researchers wrote, adding that the “results challenge the strict conceptual separation between CAD and CAS in the current WHO classification.”
Incorporating molecular testing alongside conventional bone marrow analysis into diagnostic evaluations could “better reflect the biological spectrum of cold agglutinin-associated disorders,” the team concluded.
The reserachers added that “further studies are warranted to refine disease definitions and to determine how molecular findings should inform future diagnostic classifications and clinical decision-making.”
Leave a comment
Fill in the required fields to post. Your email address will not be published.