Clinicopathological features and prognostic analysis of non-Hodgkin's lymphoma with paraproteins: A single-center retrospective study

Abstract

Abstract Objective: In the 5th edition of the WHO Classification of Haematolymphoid Tumors (WHO-HAEM5), other diseases with paraproteins that are distinct from plasma cell neoplasms are included as a new entity. However, it does not include lymphoma (Lym) with aberrant immunoglobulin secretion. These lymphomas are mainly Non-Hodgkin's Lymphomas (NHL) and display a unique biological behavior. The aim is to investigate the incidence, clinicopathological features, molecular genetic alterations, and prognosis of Lym patients (excluding WM) with paraproteins, defining the clinical and biological behavior of this rare condition. Methods: We retrospectively screened 1001 patients with serum paraprotein registered at Bethune Hospital in Shanxi, China, between 2013.1-2023.12. Among them, there are 34 Lym patients, of whom 31 have NHL (excluding 2 WM) and 1 has HL. Another 31 NHL patients without serum accessory protein secretion, who were matched for gender, age, and pathological classification, were selected as the control group during the same period. Pathology diagnostic criteria follow WHO-HAEM5. Lym subtypes were confirmed via immunohistopathology or bone marrow biopsy/flow cytometry. The paraprotein type was identified by quantifying serum immunoglobulins and performing immunofixation electrophoresis. EB virus infection was confirmed by plasma viral nucleic acid testing. The treatment plan involved immunotherapy, implemented according to NCCN guidelines. Statistical analysis including frequencies, percentages, median survival, and the correlation of clinical features with prognosis was performed using SPSS 26.0. The Kaplan-Meier (K-M) curve was used for survival comparison, and univariate regression analysis was conducted to identify prognostic factors. Results:Incidence: Lym patients with paraproteins constitute 3.4% of all patients with serum paraproteins. The proportion of WM and plasmacytoma is 0.5% and 0.3%, respectively, while the others are patients with rheumatic and immune system diseases.Pathological Subtypes in NHL: Among 34 patients, B-cell NHL accounts for 22/32 (68.8%), T-cell NHL for 9/32 (28.1%), and HL for 1/32 (3.1%).In B-NHL, diffuse large B-cell lymphoma (DLBCL, 18.8%, n=6), marginal zone lymphoma (MZL, 18.8%, n=6), mucosa-associated lymphoid tissue lymphoma (MALT, 9.38%, n=3), small B-cell lymphoma (SLL, 9.38%, n=3), lymphoplasmacytic lymphoma (LPL, 6.25%, n=2), mantle cell lymphoma (MCL, 3.1%, n=1), and follicular lymphoma (FL, 3.1%, n=1).In T-cell lymphomas (9/32, 28.1%): Angioimmunoblastic T-cell lymphoma (AITL, 21.9%, n=7), peripheral T-cell lymphoma not otherwise specified (PTCL-NOS, 3.1%, n=1), and cutaneous T-cell lymphoma (3.1%, n=1).Paraprotein Types: IgM (56.25%, n=18), IgG (56.25%, n=18), IgA (18.75%, n=6), IgD (0%). Among these, five lymphoma cases exhibited the secretion of two different accessory proteins: one case with both IgM and IgG, two with both IgM and IgA, and two with both IgG and IgA.Clinical Features: 82.35% presented with advanced-stage (III-IV) disease. In addition to B symptoms with fever (32.35%), active manifestations included anemia (38.2%), thrombocytopenia (26.5%), and EBV infection (23.5%).Molecular Signature: NGS testing was performed on 4 NHL cases, with 75% (n=3) detecting the MYD88 L265P mutation.Prognosis: The median overall survival (OS) was only 6 months (range: 0-120 months) in lymphoma patients with paraproteins, which was significantly worse than in the control group (matched lymphoma patients without paraproteins) (p < 0.05).Bruton's tyrosine kinase inhibitor (BTKI) combined with chemotherapy improved effectiveness in the research. Combining regimens for Multiple Myeloma (MM) may also increase survival. Conclusions:Paraprotein secretion occurs in various NHL patients, with B-NHL accounting for the majority and T-NHL being relatively less common. T-NHL is notably seen in AITL, secondary in MZL, and third in DLBCL. The main types of paraproteins are IgM and IgG, with IgM being the most common. The clinicopathological features include advanced disease, cytopenia such as anemia and thrombocytopenia, EBV infection, and MYD88 mutations, which indicate aggressive tumor behavior. Paraprotein is an independent marker of poor prognosis in NHL and should be considered a high-risk factor in clinical management. Incorporating BTKI into first-line treatment regimens is a promising strategy to improve outcomes for B-NHL patients with paraproteins.