Diagnosis of primary CAD difficult with standard criteria: Study
Autoimmune disorder tough to distinguish from certain blood cancers
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Primary cold agglutinin disease (CAD) is not a single, uniform disease and can be difficult to distinguish from certain blood cancers, making it challenging to diagnose using standard criteria, a study in Japan suggests.
Researchers found that, even after excluding cases linked to underlying conditions — known as cold agglutinin syndrome (CAS) — establishing a diagnosis of primary CAD remained challenging.
Bone marrow features, which are often used for diagnosis, varied between patients and, in some cases, overlapped with those seen in certain blood cancers. Further analyses were ultimately needed to refine and confirm a diagnosis.
“These findings highlight the diagnostic challenges of primary CAD, even after exclusion of CAS-associated underlying conditions by standard clinical evaluation, and demonstrate that primary CAD encompasses” a spectrum of variable clinical features, researchers wrote. “Our results suggest that further refinement of the current diagnostic criteria for primary CAD may be warranted.”
The study, “Clinicopathological features of primary cold agglutinin disease in the Japanese population: Heterogeneous characteristics and diagnostic challenges,” was published in the Journal of Clinical and Experimental Hematopathology.
CAD is classified as primary when its cause is unknown
CAD is caused by self-reactive antibodies, called cold agglutinins, that bind to red blood cells at cold temperatures. This causes the cells to clump together and be marked for destruction — a process known as hemolysis — leading to circulatory problems and anemia (a shortage of red blood cells), which drive CAD symptoms.
The disease is classified as primary when its cause is unknown, or secondary, also called CAS, when it occurs due to other underlying conditions, such as infections, autoimmune diseases, or cancer.
Primary CAD is recognized as a clonal B-cell lymphoproliferative disease in the bone marrow. Simply put, this means that a single B-cell multiplies excessively for an unknown reason. B-cells are immune cells responsible for producing antibodies.
Because this type of clonal B-cell growth is also seen in certain slow-growing blood cancers, such as B-cell lymphomas, distinguishing between these conditions can be difficult.
“Moreover, most available studies have been conducted in Western countries, and … studies of CAD in Japan are scarce,” the researchers wrote. “As a result, the current status of CAD in Japan remains insufficiently characterized.”
Study sought better understanding of how disease presents in Japan
To better understand how the disease presents in Japan, researchers analyzed the clinical characteristics of 21 people diagnosed with CAD between April 2013 and March 2024 at three hospitals in Nagano Prefecture, a relatively cold region of the country.
Most participants were men (86%), and ages ranged from 31 to 89. More than one-third (38%) had underlying conditions, including blood cancers, infections, lung cancer, and other blood-related disorders, and were classified as having CAS.
The remaining 13 patients (62%) were considered suspected primary CAD cases. Based on features in the bone marrow, where all blood cells are produced, these patients were classified into three groups.
The first group included four cases (31%) with bone marrow findings typical of primary CAD, showing small clusters of mature B-cells, often surrounded by a more specialized form of antibody-producing B-cells, called plasma cells, and no features suggesting B-cell lymphoma.
The second group included six cases (46%) with atypical or overlapping features, in which B-cells showed bone marrow patterns also seen in B-cell cancers, making the diagnosis uncertain without further testing. The third group consisted of three cases (23%) with very low levels of B-cells in the bone marrow and no evidence of a tumor.
Through this analysis, we encountered a subset of patients in whom distinction between primary CAD and other [slow-growing] B-cell lymphomas, as well as confirmation of clonal B-cell [growth], remained challenging.
Additional testing, including detailed analyses of bone marrow tissue and genetic tests, was then performed to clarify the diagnosis. These analyses looked for specific cell markers and genetic changes commonly used to distinguish CAD from related blood cancers.
Using this combined approach, primary CAD was confirmed in all four cases in the first group, four of the six patients in the second group, and one of the three cases in the third group, for a total of nine confirmed cases.
“Through this analysis, we encountered a subset of patients in whom distinction between primary CAD and other [slow-growing] B-cell lymphomas, as well as confirmation of clonal B-cell [growth], remained challenging,” the researchers wrote.
As a result, they said that certain cases “may continue to require a diagnosis by exclusion under the current diagnostic framework,” meaning the condition is identified by ruling out other diseases rather than by clearly defined features.
Overall, the findings suggest that primary CAD encompasses a group of related conditions rather than a single disease, the team concluded. They added that collecting more patient data and conducting “comprehensive molecular analyses” will be essential “to refine diagnostic criteria and to better define the biological boundaries of this disease.”
