Low-grade B cell lymphoma in the perirenal space of the left kidney associated with high titer cold agglutinin disease.

Am J Blood Res 2023;13(3):104-109 www.AJBlood.us /ISSN:2160-1992/AJBR0149214 Case Report Low-grade B cell lymphoma in the perirenal space of the left kidney associated with high titer cold agglutinin disease Takashi Miyoshi1, Tomoya Masada2, Fumihiko Kono3, Shinsaku Imashuku1,4 Division of Hematology, Uji-Tokushukai Medical Center, Uji, Kyoto 611-0041, Japan; 2Department of Radiology, Uji-Tokushukai Medical Center, Uji, Kyoto 611-0041, Japan; 3Department of Diagnostic Pathology, Uji-Tokushukai Medical Center, Uji, Kyoto 611-0041, Japan; 4Department of Laboratory Medicine, Uji-Tokushukai Medical Center, Uji, Kyoto 611-0041, Japan 1 Received January 17, 2023; Accepted May 22, 2023; Epub June 15, 2023; Published June 30, 2023 Abstract: Cold agglutinin disease (CAD) is a subgroup of autoimmune hemolytic anemia caused by monoclonal cold agglutinins produced by clonally expanded B lymphocytes. In primary CAD, lymphoproliferative bone marrow disorder is noted, while as one of the secondary cold agglutinin syndromes (CAS), the initial manifestation of CAD is followed by development of lymphoma. Here, we report a case of low-grade B cell lymphoma developed 3 months after an initial CAD diagnosis. The patient had an extremely high serum cold agglutinin titer (1:16,384) and slightly elevated serum IgM (452 mg/dL; reference, 31-200) with positive monoclonal IgM-kappa chain. After diagnosis of lymphoma-associated CAS, he was managed successfully with six cycles of a BR (bendamustine and rituximab) regimen. Cold agglutinin titers fell rapidly to 1:2048 at 5 months and to 1:512 at 10 months after chemotherapy, and the patient has been in a complete remission for 34 months. Keywords: Cold agglutinin disease, low-grade lymphoma, perirenal lymphoma, IgM-kappa Introduction Cold agglutinin disease (CAD) is a subgroup of autoimmune hemolytic anemia triggered by cold reactive immunoglobulins against red blood cells (RBC) surface antigens in the pathogenesis. CAD can be divided into two categories: primary CAD and secondary cold agglutinin syndrome (CAS) [1]. The major cold autoantibody in CAD/CAS is directed against the I antigen of RBC and can cause peripheral RBC agglutination and acrocyanosis, resulting in hemolysis via activation of the classical complement cascade [2]. As symptoms/signs, patients present with hemolytic anemia (increased lactate dehydrogenase, bilirubin, and reticulocytes, along with decreased haptoglobin) and/or acrocyanosis, which is occasionally associated with peripheral gangrene following exposure to cold. Primary CAD is a clonal B cell disorder characterized by clonally expanded B cells in the bone marrow [3, 4]. By contrast, CAS shows a similar picture of cold-hemolytic anemia, but occurs secondary to hematological malignancies (lymphomas, leukemias) [5-13] or infectious diseases (particularly Mycoplasma pneumoniae and Epstein-Barr virus infections) [14, 15]. In the majority of patients with primary CAD, monoclonal IgM-kappa antibodies are noted while lymphoma-associated CAS shows IgM-lambda type [3, 5]. In addition, some of primary CAD and lymphoma-associated CAS may show chromosomal abnormalities [16-18]. In lymphoma-associated CAS, symptoms/signs of CAD are noted as initial manifestation of disease before lymphoma can be identified. In terms of treatment/outcome of CAD/CAS, for primary CAD, B-cell directed therapies against the clonal B-lymphocytes have been employed including anti-CD20 antibody rituximab, as well as complement modulation with use of a novel agent sutimlimab [19, 20]. On the other hand, for lymphoma-associated CAS, anti-lymphoma chemotherapy for specific types is required. In terms of outcome of CAD/CAS, in the past, sur- CAD-associated lymphoma vival time was shorter in lymphoma-associated CAS than primary CAD [5]. Here, we report a case of low-grade B cell lymphoma with IgMkappa chain diagnosed during the search for the cause(s) of CAD in an adult patient with cold-related circulatory symptoms showing a significantly high cold agglutinin titer. Case report The patient was a 59-year-old male who received percutaneous catheter myocardial ablation for the treatment of persistent atrial fibrillation. During this procedure, a blood smear revealed Rouleaux formation. His cold agglutinin titer was extremely high at 1:16,384 (reference: <1:64). It remained unknown for how long the patient had CAD; however, he developed cold-related circulatory symptoms (such as Raynaud phenomenon) at least 6 months earlier. On referral to our hematology clinic, examination revealed that he was 176 cm tall and weighed 82.9 kg. His blood pressure was 128/81 mmHg and his heart rate was 93/min. He was neither anemic nor icteric, with normal hepatic function and slightly exacerbated renal function. Laboratory data were as follows: white blood cell count (WBC), 6,700/µL (no abnormal cells on the smear); Hb, 14.5 g/ dL; mean corpuscular volume (MCV), 107 fL; platelet count, 235 K/µL; reticulocyte count, 1.7%; haptoglobin, 95 mg/dL; C-reactive protein, 0.30 mg/dL; aspartate aminotransferase (AST), 25 U/L; alanine aminotransferase (ALT), 23 U/L; lactate dehydrogenase (LDH), 338 U/L; total bilirubin, 0.51 mg/dL; total protein, 7.6 g/ dL; albumin, 4.2 g/dL; blood urea nitrogen, 15.3 mg/dL; creatinine, 1.23 mg/dL; uric acid, 6.8 mg/dL. Thus, hemolytic anemia was not significant. Immunological studies revealed the following: serum IgG, 1,366 (reference value; 820-1740) mg/dL; IgA, 237 (90-400) mg/dL; and IgM, 452 (31-200) mg/dL with positive monoclonal IgM-kappa protein. Complement was normal. He was negative for anti-nuclearantibody and other autoimmune antibody levels were within normal. Serum soluble IL-2 receptor (sIL-2R) was elevated at 1,831 (122496) U/L, with a high free kappa/lambda ratio of 2.18 (0.26-1.65). There was no evidence of active Epstein-Barr virus or cytomegalovirus infection. Since he had compensated hemolysis [1], he was put on non-pharmacological management with thermal protection alone. A bone marrow aspirate showed a few (<5% of 105 nuclear cell counts) moderately large lymphoblastoid cells with a high N/C ratio, which characterization was not possible. There were no clusters of lymphoblastoid cells as those in lymphoplasmacytic lymphoma (data not shown) and the karyotype of the bone marrow was normal, which ruled out primary CAD. We thus searched for cause(s) of CAD in this case. Three months later, a contrast-enhanced computed tomography (CT) scan of the abdomen revealed a soft tissue mass at the perirenal space of the left kidney, which was associated with swelling of neighboring lymph nodes (Figure 1A). A repeat assay of cold agglutinin at this point revealed the same high (1:16,384) titer. A CT-guided needle (18-gauge TEMNO) biopsy of this region (Figure 1B) was performed, which obtained a lympho-proliferative tissue (Figure 1C). Histopathology showed lymphoma tissue (Figure 2A), immunostaining analyses of which revealed tumor cells were pos (...truncated)