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 Table of Contents  
Year : 2020  |  Volume : 11  |  Issue : 3  |  Page : 137-140

Intestinal diffuse large B-cell lymphoma preceding cold agglutinin disease

Department of Internal Medicine, Maulana Azad Medical College, New Delhi, India

Date of Submission12-Apr-2020
Date of Decision16-Apr-2020
Date of Acceptance08-May-2020
Date of Web Publication16-Sep-2020

Correspondence Address:
Dr. Roopa Sharma
Sultanpur, District Chamba - 176 314, Himachal Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/joah.joah_39_20

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Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia, which shows IgM antibodies in the serum of the patient against red blood cell antigens, showing maximal reactivity at 4°C. CAD can be idiopathic or secondary to infections such as mycoplasma, Epstein–Barr virus, cytomegalovirus, lymphoma, and plasma cell dyscrasia. It can present either as hemolytic anemia or acrocyanosis. We are reporting a case of CAD presenting with acrocyanosis, which initially did not show any secondary etiology despite extensive work-up. However, after a gap of 1½ years, the patient presented with intestinal obstruction, which was diagnosed to be due to malignant stricture secondary to intestinal diffuse large B-cell lymphoma. This association makes it important to follow-up cases of CAD without secondary etiology for the development of lymphoma in future.

Keywords: Cold agglutinin disease, diffuse large B-cell lymphoma, intestinal lymphoma, non-Hodgkin's lymphoma

How to cite this article:
Goyal K, Sharma R, Garg S. Intestinal diffuse large B-cell lymphoma preceding cold agglutinin disease. J Appl Hematol 2020;11:137-40

How to cite this URL:
Goyal K, Sharma R, Garg S. Intestinal diffuse large B-cell lymphoma preceding cold agglutinin disease. J Appl Hematol [serial online] 2020 [cited 2020 Oct 22];11:137-40. Available from: https://www.jahjournal.org/text.asp?2020/11/3/137/295121

  Introduction Top

Cold agglutinin disease (CAD) is a rare cause of autoimmune hemolytic anemia. Patients of CAD have antibodies specific to I/i antigen of red blood cells (RBC) and agglutinate maximally at 4°C. CAD can be primary or secondary to infections or malignancy. Non-Hodgkin's lymphoma (NHL) is the most common etiology in secondary cases of CAD. Most of the NHL cases associated with CAD are low-grade lymphoplasmacytic lymphoma.[1] We are reporting a case of CAD preceding intestinal diffuse large B-cell lymphoma (DLBCL). The association of CAD with intestinal DLBCL is very rare, and there is a lack of literature for the appearance of CAD ahead of lymphoma.

  Case Report Top

A 50-year-old male patient presented to medicine department of our institution with complaints of painful bluish-purple discoloration of toes and fingers with cold exposure for 2 months. There was no history of any chronic medical condition, similar complaints in the past, or in the family. Physical examination did not reveal any lymphadenopathy or splenomegaly. His primary work-up revealed normal complete blood counts and hemoglobin of 12.5 mg/dl, normal RBC indices, and reticulocyte count. Ethylenediaminetetraacetic acid (EDTA) vial shows granular deposits enhanced on cold incubation and disappear on warm incubation. Peripheral blood smear showed RBC clumping. His kidney function test, liver function test, lactate dehydrogenase, and other biochemical parameters were also normal. Autoimmune markers, serum C3 component and C4 component of complement were also normal. No cryofibrinogenemia or cryoglobulinemia was detected. Further work-up revealed a negative direct Coombs test and positive indirect Coombs test (ICT) at 4°C with antibody titer of 1:1024. Patient's extended blood grouping was found to be B Rh positive at 37°C. ICT has done at 37°C Coombs phase as well as the saline phase at 4°C showed a dual positive (4+) reaction. The patient's antibodies were shown to be IgM type with anti-I and anti-i specificity. Hence, the diagnosis of CAD was made. HIV, hepatitis B surface antigen, hepatitis C serology, mycoplasma serology, Epstein–Barr virus, and cytomegalovirus serology were negative. Serum electrophoresis did not show any M band. Serum immunofixation showed faint bands in both kappa and lambda region. The serum-free light chain assay showed a normal ratio of kappa and lambda chains. Bone marrow biopsy was done to rule out lymphoproliferative disorder. Bone marrow biopsy did not show any lymphoproliferative disease even after immunohistochemical and flow cytometric analysis. Positron emission tomography scan did not show any metabolic hyperactive lymph node or any extranodal mass. The patient was started on conservative nonpharmacological managements such as avoidance of cold exposure and warm clothing. His symptoms improve partially.

After 20 months, the patient presented to the surgical emergency of our institution with complaints of abdominal pain, distension, and vomiting. The diagnosis of small bowel obstruction was made after appropriate radiographical investigations. Urgent laparotomy was done. Intraoperative findings showed a large growth 7–8 cm in length present in distal ileum about 15 cm proximal to ileocecal junction and a nonpassable stricture 5 cm proximal to ileocecal junction [Figure 1]. Resection of the involved segment of ileum was done, and primary anastomosis was done to maintain ileal continuity.
Figure 1: Gross resection specimen showing Ileal stricture of the patient

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Histopathological examination of surgical specimens showed sheaths of atypical lymphoid cells splaying muscle fibers and reaching up to serosa [Figure 2]. On immunohistochemistry, these cells were found to be common leukocyte antigen, PAX5, and CD20 positive. Hence, the diagnosis of DLBCL of the small intestine was made.
Figure 2: (a and b) ×40 and ×100 magnified view of hematoxylin and eosin stain of the ileal specimen showing atypical lymphoid cells, respectively (c) CD20 staining of the histopathological image of the ileal specimen showing a positive reaction

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Staging work-up of lymphoma established it to be Ann Arbor stage 2(E) lymphoma with international prognostic score of 2. Patient was given CHOP chemotherapy (cyclophosphamide 750 mg/m2 IV, doxorubicin 50MG/m2 IV, vincristine 1.4 mg/m2 IV, and prednisone 40 mg/m2 PO) along with rituximab (375 mg/m2) for six cycles. The patient tolerated chemotherapy without any adverse event. The patient's symptoms of acrocyanosis improved completely with improvements in clumping in peripheral smear [Figure 3]. Repeat ICT showed negative results.
Figure 3: Peripheral smear before and after two cycles of chemotherapy showing improvement in red blood cells clumping

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  Discussion Top

CAD has been associated with underlying B-cell lymphoproliferative disease in up to 75% of patients.[2] Based on a study done by Economopoulos et al., only 1.1% of NHL patients develop CAD.[3] DLBCL presenting with CAD is a rare entity, and extranodal DLBCL with cold agglutinins is even rarer. Only a few cases have been reported with DLBCL presenting with CAD. NíÁinle et al. have reported a case of DLBCL isolated to bone marrow presenting with secondary CAD.[4] Bachmeyer et al. have reported a case of Raynaud's phenomenon due to CAD secondary to T-cell lymphoma.[5] Airaghi et al. have described a case of a patient with DLBCL with extranodal (adrenal and renal) involvement presenting with CAD.[6] There is only one reported case, in which primary gastrointestinal DLBCL was found during the work-up for CAD.[7]

Our case is a rare case of CAD, which developed intestinal DLBCL after a gap of more than 1½ years. After chemotherapy, the patient showed improvement in acrocyanosis, clumping of RBCs in EDTA vial and peripheral smear on cold incubation improved. Patient's ICT also became negative. Thus, we were able to ascribe the association of CAD to the development of intestinal DLBCL.

Most cases of lymphoma which develop CAD presents at the time of diagnosis or later during the course of the disease. In our case, after the nonresolution of symptoms, repeating diagnostic tests for hematological malignancies at regular intervals could have helped to diagnose the intestinal DLBCL early. However, performing such investigations without significant literature evidence to support limited us from doing so. To our knowledge, this case is the first reported case of CAD preceding intestinal DLBCL. A close follow-up is recommended to diagnose any evolving lymphoma in cases of CAD without any secondary causes, as early diagnosis can improve the prognosis of the patient.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published, and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood 2013;122:1114-21.  Back to cited text no. 1
Michel M. Classification and therapeutic approaches in autoimmune hemolytic anemia: An update. Expert Rev Hematol 2011;4:607-18.  Back to cited text no. 2
Economopoulos T, Stathakis N, Constantinidou M, Papageorgiou E, Anastassiou C, Raptis S. Cold agglutinin disease in non-Hodgkin's lymphoma. Eur J Haematoly 1995;55:69-7.  Back to cited text no. 3
Níáinle F, Hamnvik OP, Gulmann C, Bermingham C, Kelly J, Mc Evoy P, et al. Diffuse large B-cell lymphoma with isolated bone marrow involvement presenting with secondary cold agglutinin disease. Int J Lab Hematol 2008;30:444-5.  Back to cited text no. 4
Bachmeyer C, Blum L, Chesneau AM, Richecoeur J, Testard F, Benchaa B, et al. Raynaud's phenomenon with necrosis of the extremities induced by cold agglutinin disease secondary to a T-cell lymphoma. Acta Derm Venereol 2003;83:374-5.  Back to cited text no. 5
Airaghi L, Greco I, Carrabba M, Barcella M, Baldini IM, Bonara P, et al. Unusual presentation of large B cell lymphoma: A case report and review of the literature. Clin Lab Haematol 2006;28:338-42.  Back to cited text no. 6
Eskazan A, Akmurad H, Ongoren S, Ozer O, Ferhanoglu B. Primary gastrointestinal diffuse large B cell lymphoma presenting with cold agglutinin disease. Case Rep Gastroenterol 2011;5:262-6.  Back to cited text no. 7


  [Figure 1], [Figure 2], [Figure 3]


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