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 Table of Contents  
Year : 2022  |  Volume : 24  |  Issue : 3  |  Page : 97-100

Immunoglobulin G Kappa Lymphoplasmacytic Lymphoma with Associated Al Amyloidosis: A Rare Combination!

1 Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Laboratory Medicine, Command Hospital Airforce, Bengaluru, Karnataka, India

Date of Submission02-Dec-2020
Date of Acceptance09-Mar-2021
Date of Web Publication21-Jan-2022

Correspondence Address:
(Dr) Preeti Tripathi
Department of Laboratory Medicine, Command Hospital Airforce, Room No 21, Second Floor, Bengaluru - 560 007, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmms.jmms_178_20

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Lymphoplasmacytic lymphoma (LPL) is a low-grade B-cell neoplasm, composed of small B-lymphocytes, plasmacytoid lymphocytes, and plasma cells involving bone marrow and sometimes lymph nodes or spleen and forms 1% of all non-Hodgkin lymphomas. LPL with bone marrow involvement and an Immunoglobulin M (IgM) monoclonal gammopathy of any concentration is designated as Waldenström macroglobulinemia (WM). Due to their frequent co-occurrence, the terms LPL and WM are often used interchangeably in clinical practice. However, although the clinical diagnosis of WM is restricted to cases with an IgM monoclonal protein, the World Health Organization recognizes that LPL can rarely present with paraproteins of immunoglobulin G (IgG) or immunoglobulin A (IgA). LPL associated with non IgM gammopathies are extremely rare and form >5% of all LPLs. We hereby present the case of a 65-year-old female with no previous co morbidities who presented with nonspecific complaints of weight loss, easy fatigability, and night sweats. Examination was within the normal limits except for the presence of subcentimetric axillary lymphadenopathy. She was found to have anemia with an altered A/G ratio M spike of 2.10 g/which was IgG kappa on immunofixation electrophoresis. The bone marrow revealed a mixture of lymphocytes, lymphoplasmacytoid cells, and plasma cells along with the presence of amyloid deposits. MYD88 L265P mutation done on peripheral blood was positive, and based on these, she was diagnosed with a case of IgG Kappa LPL with associated amyloidosis.

Keywords: Amyloidosis, immunoglobulin G kappa, lymphoplasmacytic lymphoma, MYD88 L265P

How to cite this article:
Kaur G, Tripathi P, Pati HP, Tyagi S. Immunoglobulin G Kappa Lymphoplasmacytic Lymphoma with Associated Al Amyloidosis: A Rare Combination!. J Mar Med Soc 2022;24, Suppl S1:97-100

How to cite this URL:
Kaur G, Tripathi P, Pati HP, Tyagi S. Immunoglobulin G Kappa Lymphoplasmacytic Lymphoma with Associated Al Amyloidosis: A Rare Combination!. J Mar Med Soc [serial online] 2022 [cited 2022 Dec 1];24, Suppl S1:97-100. Available from: https://www.marinemedicalsociety.in/text.asp?2022/24/3/97/336188

  Introduction Top

Lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) is a rare disease, with an annual incidence of 3–4 cases per million people, most commonly affecting older, white men in the seventh decade of life.[1] The World Health Organization recognizes that LPL can rarely present with paraproteins of immunoglobulin G (IgG) or immunoglobulin A (IgA). These are rare and form >5% of all LPLS.[1],[2] Clinical presentation is highly variable, with symptoms usually related to the cytopenias (mainly anemia) due to bone marrow infiltration. Due to the paucity of literature describing the clinicopathologic features of LPL associated with non-Immunoglobulin M (IgM) paraproteinemia, as well as the challenging nature of the diagnosis, the relationship of such cases to WM remains unclear. Recently, whole-genome sequencing studies have identified mutations in the MYD88 gene (MYD88 L265P) in 90%–95% of WM cases. Differential diagnosis for these cases should include multiple myeloma (MM), chronic lymphocytic leukemia, and other non-Hodgkin lymphomas (NHL) such as splenic or nodal marginal zone lymphomas (NMZL), as different treatment approaches are recommended for each of these.

  Case Report Top

A 65-year-old female presented with easy fatigability of 3 months, significant weight loss of 20 kg over 3 months and night sweats. There was pallor and axillary lymphadenopathy 0.5 cm along the anterior axillary group, nonmatted, and nontender. The spleen was just palpable. There was normocytic normochromic anemia, Hb-6 gm% and Rouleaux formation. TLC-12,3500 cu.mm, with lymphocytosis (47%) occasional lymphoplasmacytoid cells seen and total protein of 8.15 g/dl (6.4–8.1), albumin of 3.24 g/dl (3.6–5.4), and gamma globulin of 2.65 g/dl (0.70–1.50). There was reversal of A: G ratio (0.66) with M spike-2.10 g/which was IgG kappa on immunofixationelectrophoresis. Serum calcium was 8.66 mg/dl. C-reactive protein and erythrocyte sedimentation rate were 10.74 mg/dl and 120 mm/h. Serum free light chain assay-kappa free light chain 1500 mg/L (3.30–19.40), Lambda free light chain 40.40 mg/L (5.71–26.30), Kappa/Lambda ratio 37.129 (0.26–1.65). Bence Jones Proteins, ANA, viral markers, and tuberculosis gold interferon gamma release assay were all negative. Imaging showed mild hepatosplenomegaly with subcentimetric axillary, paratreahceal, and paraarotic lymph nodes, no lytic bony lesions were seen. Bone marrow aspirate (BMA) had monomorphic mature lymphocytes, lymphoplasmacytoid cells, and plasma cells [Figure 1]. Biopsy revealed a normal cellularity with these cells infiltrating the interstitium with amyloid deposits which were confirmed by Congo red staining under polarizing microscopy. On immunohistochemistry (IHC), these cells were positive for CD138 [Figure 2] and CD 20 and were negative for CD 23, CD 5, CD3, and Cyclin D1. Multiparametric flow cytometry on BMA aspirate had 23.0% lymphoid cells, CD19, CD20, FMC-7, κ light chain positive, heterogeneous CD38, and negative for CD5, CD10, CD23, CD56, CD103, and CD11c.
Figure 1: The bone marrow aspirate reveals three distinct populations of cells lymphocyte (orange arrow) plasmacytoid lymphocytes( green arrow) and plasma cells( red arrow). Majority of these cells have slightly eccentrically located round to oval nuclei, condensed chromatin, inconspicuous nucleoli and a certain amount of amphophilic cytoplasm. Scattered plasma cells are identified associated with few reactive mast cells. (Leishman Giemsa)

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Figure 2: (a) The bone marrow core biopsy showed diffuse infiltrate of small mature lymphoid cells intermingled with scattered plasma cells and surrounding areas of homogeneous acellular waxy eosinophilic amyloid( red arrow) which was confirmed on polarizing microscopy (H&E) (b) Immunohistochemical staining (IHC) study confirmed the neoplastic lymphoid cells to be focally positive for plasma cell marker CD138

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The beta 2 microglobulin-7943 ng/ml (609.00–2366.00) NT-pro BNP was 969.6 pg/ml (<301) placing the pt in Stage III of the Mayo classification. MYD 88 L265P mutation on BMA was positive. The karyotype was essentially normal fluorescence in situ hybridization (FISH) analyses for t(4:14) IGH/FGRF3, t(11:14) IGH/CCN, t(14:16) IGH/MAF,13q14.3, TP53 (17p13.1) for FISH myeloma panel were all was negative. Based on this, she was diagnosed with IgG kappa LPL with amyloidosis and because of her age and co-existing B-symptoms; it was decided to start her on chemotherapy. However, the patient wanted to be treated at her hometown and was therefore lost to follow-up.

  Discussion Top

The diagnosis of low-grade B-cell neoplasms is challenging because of overlapping histopathologic and immunophenotype findings. Differential diagnosis should include MM, chronic lymphocytic leukemia, and other NHL such as splenic or NMZL, as these differ considerably in their treatment approaches. Although most cases of LPL will fit into the diagnosis of WM, there are exceptions including lymphoplasmacytic B-cell proliferations associated with IgA or IgG gammopathies as in our case and primary, lymph node-based presentations of LPL.[1],[2]

Etiology of LPL is poorly understood, association with Hepatitis C virus and familial predisposition is known. Although indolent, LPL can transform into an aggressive immunoblastic variant or other high-grade lymphomas. Because of the frequent involvement of bone marrow, most LPL patients present with weakness and/or fatigue related to anemia. Some patients may present with the involvement of spleen, liver, and other extra nodal sites, including skin, stomach, and bowel.[3]

Peripheral blood counts reveal lymphocytosis with circulating plasmacytoid lymphocytes can be also seen. BMA reveals three distinct populations of cells lymphocytes, plasmacytoid lymphocytes, and plasma cells. The infiltrate is usually diffuse, interstitial, or focal nonparatrabecular, mast cells may be seen and favor the diagnosis of an LPL. Amyloid deposition as in our case and crystal storing histiocytosis may sometimes be seen. Nodal involvement is usually paratrabecular. The typical immunophenotype of LPL demonstrates expression of CD19, CD20, CD22, FMC7, BCL2, CD38, and CD79a with monotypic surface light chain with negative CD5, CD10, and CD23 is usually absent. Both small lymphocytes and plasma cells demonstrate light chain restriction on IHC.[4]

MYD88 L265P mutation is present in about 90% of WM associated with adverse prognosis and a lower response to Ibrutinib. In non-IgM LPL, the mutation is less common (40%). MYD88 L265P mutation is also seen in some nongerminal center subtype diffuse large B-cell lymphoma (DLBCL) NOS, primary cutaneous DLBCL, leg type, and primary CNS and testicular DLBCL cases.

Thirty percent patients harbour the truncating CXCR4 mutation associated with more active disease ARID1A mutations are seen in approximately 17% of patients TP53, CD79B, KMT2D mutations may also been seen though less common. Deletion in 6q is seen in 50% of bone marrow-based cases and is worse prognosis.[1]

Treatment of LPL/WM is generally expectant in asymptomatic patients. Patients with advanced disease consisting of bulky disease, profound cytopenias, constitutional symptoms, and hyperviscosity syndrome are typically treated with a regimen of rituximab, cyclophosphamide, and dexamethasone.[5]

While comparing IgM LPL and non IgM LPL [Table 1], more patients with nonIgM LPL reportedly exhibited extramedullary involvement (87.5%) as per a Korean study[6] which was also seen in a study from Italy by Varettoni et al.[9] Cao et al.[7] at MD Anderson Cancer Center (MDACC) reported the clinicopathologic features of 17 patients with non-IgM LPL as compared to those of patients with IgM LPL/WM. They had a high rate extramedullary involvement (52.9%), including the kidneys, nasopharynx, dura, and central nervous system and a lower rate of MYD88 mutation (40%). They found no significant differences between the pathological features. Similarly, a Mayo series found that 10/23 (43%) patients with non-IgM LPL harbored the MYD88 mutation, but there was no association between MYD88 status and morphology or phenotype features on the BM. The Korean Asian Medical Center and MDACC groups both reported that nonIgM LPL had poorer survival than IgM LPL/WM[6],[7]
Table 1: Comparison of patient data in previous studies on non-IgM lymphoplasmacytic lymphoma

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In conclusion, as a rule, the diagnosis of LPL lymphoma should be considered in elderly individuals with unexplained weakness, visual difficulties neurological deficits, neuropathies, and bleeding symptoms. The lack of MM features, such as bone lytic lesions or hypercalcemia, the specific immunophenotype along with MYD88 L265P mutation favors LPL.[8],[9] Treatment of LPL/WM is generally expectant in patients who have no symptoms. As compared to IgM LPL, nonIgM LPL commonly has an extramedullary masses and a low incidence of MYD88 mutation due to its heterogeneous nature.[10]

Declaration of patient consent

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

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375-90.  Back to cited text no. 1
Yun S, Johnson AC, Okolo ON, Arnold SJ, McBride A, Zhang L, et al. Waldenström macroglobulinemia: Review of pathogenesis and management. Clin Lymphoma Myeloma Leuk 2017;17:252-62.  Back to cited text no. 2
Lin P, Bueso-Ramos C, Wilson CS, et al. Waldenstrom macroglobulinemia involving extramedullary sites: Morphologic and immunophenotypic findings in 44 patients. Am J Surg Pathol 2003;27:1104-13.  Back to cited text no. 3
Cesana C, Barbarano L, Miqueleiz S, et al. Clinical characteristics and outcome of immunoglobulin M-related disorders. Clin Lymphoma 2005;5:261-4.  Back to cited text no. 4
Leblond V, Kastritis E, Advani R, Ansell SM, Buske C, Castillo JJ, et al. Treatment recommendations from the Eighth International Workshop on Waldenström's Macroglobulinemia. Blood 2016;128:1321-8.  Back to cited text no. 5
Kang J, Hong JY, Suh C. Clinical features and survival outcomes of patients with lymphoplasmacytic lymphoma, including non-IgM type, in Korea: A single-center experience. Blood Res 2018;53:189-97.  Back to cited text no. 6
Cao X, Medeiros LJ, Xia Y, Wang X, Thomas SK, Loghavi S, et al. Clinicopathologic features and outcomes of lymphoplasmacytic lymphoma patients with monoclonal IgG or IgA paraprotein expression. Leuk Lymphoma 2016;57:1104-13.  Back to cited text no. 7
King RL, Gonsalves WI, Ansell SM, Greipp PT, Frederick LA, Viswanatha DS, et al. Lymphoplasmacytic lymphoma with a non-IgM paraprotein shows clinical and pathologic heterogeneity and may harbor MYD88 L265P mutations. Am J Clin Pathol 2016;145:843-51.  Back to cited text no. 8
Varettoni M, Boveri E, Zibellini S, Tedeschi A, Candido C, Ferretti VV, et al. Lymphoplasmacytic lymphoma not associated with an IgM monoclonal paraprotein has distinctive clinical and biological features and a similar outcome as compared with Waldenstrom's macroglobulinemia: Multicentric study of the rete ematologica lombarda. Blood 2017;130 Supp l: 4045.  Back to cited text no. 9
Itchaki G, Dubeau T, Keezer A, Meid K, Xu L, Yang G, et al. Non-IgM secreting lymphoplasmacytic lymphoma - Experience of a reference center for Waldenstrom macroglobulinemia. Blood 2018;132 Supp l: 2886.  Back to cited text no. 10


  [Figure 1], [Figure 2]

  [Table 1]


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