Unusual Co-occurrence of Cold Agglutinin Disease in a Bladder Transitional Cell Carcinoma Patient with Unexplained Anemia and Cold-Related Symptoms
Anemia is a common clinical condition that can arise from a variety of underlying causes. While often straightforward to diagnose, some cases present significant challenges, particularly when multiple contributing factors are involved. This report details an unusual case of an elderly patient with a long history of bladder transitional cell carcinoma who was subsequently diagnosed with cold agglutinin disease (CAD), a rare form of autoimmune hemolytic anemia (AIHA). This case highlights the complexities of diagnosing and managing anemia in patients with concurrent malignancies and rare hematologic disorders.
The patient, an 86-year-old man, was referred to the hospital in 2017 due to symptoms of acrocyanosis triggered by cold exposure, as well as weakness, fatigue, and mild dyspnea that had persisted for five years. His medical history included a 15-year history of bladder carcinoma, with three previous local resections of bladder tumors in 2002, 2010, and 2012 due to tumor recurrence. The diagnosis of transitional cell carcinoma of the bladder was confirmed by post-operative pathology. Recently, the patient had developed hematuria, and imaging studies revealed a 2.4 cm × 2.5 cm × 3.1 cm lesion in the bladder, strongly suggesting tumor recurrence. Physical examination revealed an anemic appearance and a surgical scar on the lower abdomen, but no signs of jaundice, lymphadenopathy, hepatomegaly, or splenomegaly.
Initial blood tests revealed severe anemia, with a hemoglobin (HGB) level of 58 g/L, significantly below the normal reference range of 120–160 g/L. This degree of anemia raised concerns about the patient’s ability to tolerate further surgery for the bladder tumor. However, the extent of hematuria alone could not account for the severity of the anemia. The patient’s symptoms worsened after cold exposure, and blood drawn for testing exhibited agglutination, prompting further investigation into the underlying cause of the anemia.
Additional laboratory tests provided critical insights. The patient had elevated reticulocytes (RET%) at 3.2%, above the normal range of 0.8%–2% of red blood cells (RBCs), indicating increased RBC production in response to hemolysis. Lactic dehydrogenase (LDH) levels were elevated at 291 U/L (normal range: 135.0–215.0 U/L), and free hemoglobin (FHb) was 10.4 mg/dL (normal range: 0–5 mg/dL), both consistent with hemolysis. Complement C3 and C4 levels were reduced at 0.511 g/L and 0.048 g/L, respectively, compared to their normal ranges of 0.73–1.46 g/L and 0.1–0.4 g/L. The direct Coombs test was positive for anti-C3 (+++), while the indirect antiglobulin Coombs test was negative. Cold agglutinin (CA) tests were positive, with a titer of 1:512 at 4°C, 1:8 at 25°C, and no agglutination at 37°C. Other tests, including the autologous erythrocyte agglutination assay and elution test, were negative. Urine tests showed proteinuria and occult blood. Blood film examination revealed strong agglutination of RBCs, and bone marrow aspiration indicated erythroid hyperplasia with an inverted granulocyte-to-erythrocyte ratio of 0.85:1 (normal range: 1–5.2:1). Bone marrow biopsy showed increased hematopoietic tissue and a decreased granulocyte-to-erythrocyte ratio. Immunoglobulin levels (IgG, IgA, IgM) were within normal ranges, and tests for antinuclear antibodies and antineutrophil cytoplasmic antibodies were negative. Serum protein electrophoresis and serum immunofixation electrophoresis showed no abnormalities. Polymerase chain reaction (PCR) for clonal IgH rearrangement was negative, ruling out B-cell malignancies. Based on these findings, a diagnosis of CAD was made.
CAD is a rare form of AIHA caused by cold agglutinins, typically IgM antibodies, that agglutinate RBCs at low temperatures, leading to hemolysis through complement activation. The diagnosis of CAD requires evidence of chronic hemolysis (anemia, elevated RET%, LDH, and bilirubin), abnormal RBC agglutination in blood films, erythroid hyperplasia in bone marrow, a CA titer ≥1:64 at 4°C, and a positive direct Coombs test for complement protein C3d. In this case, all diagnostic criteria were met, confirming CAD as the primary cause of the patient’s anemia.
The patient’s CAD was likely secondary to his bladder carcinoma, a rare association given that CAD is more commonly linked to hematologic malignancies or autoimmune diseases. The pathogenesis of CAD secondary to non-hematologic malignancies is not well understood but may involve tumor-produced monoclonal antibodies or a generalized immunodeficiency state that disrupts immune regulation and neoplastic growth control. In this case, the onset of bladder carcinoma preceded the development of CAD, suggesting a possible causal relationship.
Treatment for CAD includes avoiding cold exposure and administering rituximab, a monoclonal antibody targeting CD20 on B cells. Splenectomy and corticosteroids are generally ineffective in CAD. In this patient, rituximab was administered at a dose of 375 mg/m² weekly for four weeks, along with precautions to minimize cold exposure. This treatment led to a partial response, with the patient’s HGB level increasing to 92 g/L, RET% decreasing to 2.89%, and FHb dropping to 4 mg/dL. The improvement in anemia allowed the patient to undergo successful transurethral resection of the bladder tumor, with pathology confirming tumor recurrence. The patient experienced no complications post-operatively and remained free of tumor recurrence or metastasis during a three-year follow-up period.
This case underscores the importance of considering rare hematologic disorders, such as CAD, in cancer patients presenting with unexplained anemia and cold-related symptoms. The association between CAD and non-hematologic malignancies, though rare, should not be overlooked, as it may have significant implications for diagnosis and treatment. Clinicians should maintain a high index of suspicion for CAD in such cases, particularly when anemia is severe and not fully explained by the underlying malignancy.
doi.org/10.1097/CM9.0000000000001277
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