Bladder Cancer Linked to CAD in Rare Case

Researchers have reported a very rare case of cold agglutinin disease (CAD) associated with urothelial carcinoma, the most common type of bladder cancer, in an 86-year-old man.

The acquired autoimmune disease has been associated with blood cancers, but cases of CAD secondary to solid tumors are rare. This case report highlights the need for clinicians to consider CAD in solid cancer patients with unexplained anemia and cold-induced symptoms, as well as the presence of unnoticeable solid cancers in people with CAD, the researchers noted.

The case study, “Unusual co-occurrence of cold agglutinin disease in a bladder transitional cell carcinoma patient with unexplained anemia and cold-related symptoms,” was published in the Chinese Medical Journal.

CAD is a form of autoimmune hemolytic anemias, a group of rare disorders in which the immune system abnormally produces autoantibodies — immune proteins that mistakenly target a person’s own tissues or organs — that lead to the destruction of red blood cells (hemolysis).

Autoantibodies in CAD, called cold agglutinins, bind to red blood cells when exposed to cold temperatures. This sparks the formation of clumps that trigger immune reactions leading to red blood cell rupture, or destruction, known as hemolysis.

Such hemolysis ultimately leads to hemolytic anemia — a blood disorder in which red blood cells are destroyed faster than they can be replaced — which is responsible for most CAD symptoms.

CAD can be classified as primary, when the underlying cause is unknown, or as secondary, when it is associated with other underlying conditions, such as blood cancers, infections, and other autoimmune diseases.

To date, very few studies have reported cases of CAD in association with solid tumors. The mechanisms behind this link remain largely unclear, but researchers hypothesize that it may be due to the release of tumor-associated molecules mimicking red blood cell-specific molecules and the production of autoantibodies by the tumor itself.

As such, tumor eradication, either through surgery or cancer treatment, may lessen or treat CAD in these patients.

Now, researchers in China have reported, presumably for the first time, a case of CAD secondary to bladder cancer.

The patient was admitted to their hospital in 2017, at age 86, with acrocyanosis triggered by slight cold exposure, as well as weakness, fatigue, and slight shortness of breath. The symptoms had been occurring for about five years. Acrocyanosis is characterized by skin discoloration due to poor blood circulation, especially in the fingers and toes, and can be caused by CAD.

The man had been living with urothelial carcinoma, the most common bladder cancer, for the previous 15 years, with a history of three surgeries to remove the tumor due to cancer relapse.

He also showed pale skin, suggestive of anemia, and reported the recent presence of blood in his urine (hematuria), which could be causing anemia. Further urogenital system examination showed a lesion in his bladder, which was highly indicative that his cancer had returned.

Notably, lab work revealed severe anemia, “which not only raised safety concern for further surgery targeting the bladder tumor but could also not be explained by the extent of his hematuria,” the researchers wrote.

A battery of tests was then conducted to identify the cause of his severe anemia. The results showed strong red blood cell clumping and the presence of antibodies that targeted red blood cells at low temperatures, leading to a CAD diagnosis.

Since CAD onset followed the occurrence of bladder cancer and there was no evidence of the presence of a blood cancer, the researchers considered the man “was more likely to [have] cold-agglutinin syndrome secondary to bladder carcinoma.”

To lessen CAD, and particularly his anemia, the man was given rituximab — a common treatment for CAD — for four weeks, and was asked to avoid exposure to cold temperatures.

He achieved a partial response to treatment, with an increase in levels of hemoglobin, the molecule in red blood cells that transports oxygen throughout the body, and a reduction in cold-induced symptoms. That allowed him to proceed with the planned surgery to remove the tumor.

The tumor was successfully removed and further analyses confirmed it was, indeed, cancer reocurrence. The patient was discharged after surgery and had no tumor relapse or spread to other parts of the body after three years of follow-up.

“This is the first case with CAD possibly secondary to transitional cell carcinoma of bladder,” the researchers wrote, adding that “clinicians should be aware of the unusual co-occurrence of CAD in cancer patients with unexplained anemia and cold-related symptoms.”