MOLECULAR AND CLINICOPATHOLOGIC HETEROGENEITY OF IGM-NEGATIVE LYMPHOPLASMACYTIC LYMPHOMA: INSIGHTS FROM A PAKISTANI MULTICENTER STUDY
Main Article Content
Keywords
Lymphoplasmacytic lymphoma, Waldenström Macroglobulinemia, IgM-negative, MYD88, Pakistan, Clinicopathologic heterogeneity.
Abstract
: Lymphoplasmacytic lymphoma (LPL) is diagnostically and therapeutically defined by its association with Waldenström Macroglobulinemia (WM) and an IgM paraprotein. The IgM-negative LPL variant is a rare and poorly characterized entity, with limited data on its molecular drivers and clinical behavior, particularly in non-Western populations. Aims & Objectives: This study aimed to define the clinicopathologic and molecular profile of IgM-negative LPL and compare it with classic IgM-positive WM in a Pakistani multicenter cohort. Methodology: A total of 92 patients diagnosed between March 2024 and July 2025 were enrolled from across three major healthcare institutions in Pakistan: Sheikh Zayed Hospital, both campuses Lahore & Rahim Yar Khan; and Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore. 47 with IgM-negative LPL and 45 with WM. Clinicopathologic data were collected retrospectively and prospectively. Centralized pathological review and molecular analysis for MYD88 L265P (by allele-specific PCR and Sanger sequencing) and CXCR4 mutations (by Sanger sequencing) were performed. Results & Findings: The IgM-negative cohort exhibited a significantly more aggressive phenotype, with higher rates of splenomegaly (48.9% vs. 26.7%, p=0.025), lower platelet counts (median 165 vs. 212 x 10⁹/L, p=0.008), and higher serum creatinine (median 1.4 vs. 1.0 mg/dL, p=0.003). The MYD88 L265P mutation was significantly less prevalent in IgM-negative LPL (63.8%) compared to WM (95.6%, p<0.001). Within the IgM-negative group, MYD88 wild-type status was associated with worse cytopenias and renal impairment. With a median follow-up of 14 months, overall survival was significantly inferior for IgM-negative patients (12-month OS 85% vs. 98%, p=0.013). Conclusion: IgM-negative LPL represents a distinct, more aggressive subtype of LPL characterized by a high burden of extramedullary disease, cytopenias, renal impairment, a lower frequency of MYD88 mutations, and inferior survival. These findings advocate for the integration of immunoglobulin isotype and molecular profiling into the diagnostic and prognostic stratification of LPL to guide personalized therapy.
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Nabila akram
Assisstant Professor Pathology, Avicenna Medical College, Lahore, Pakistan.
Tooba Ammar
Consultant Haematologist & Head of Haematology Department, Bolan Medical College Quetta, Pakistan.
Saima Iram
Consultant Haematologist & Head of Haematology Department, Bolan Medical College Quetta, Pakistan.
Hussain Farooq
Department of Hematology, Shaikh Zayed Post Graduate Medical Institute Lahore, Pakistan.
Javaeria Abdullah
Department of Hematology, Shaikh Zayed Post Graduate Medical Institute Lahore, Pakistan.
Ujala Aymun
Assisstant Professor Pathology, Avicenna Medical College, Lahore, Pakistan.