What is lymphoproliferative disease?

What is Lymphoproliferative Disease?

Lymphoproliferative disease (LPD) is a heterogeneous group of disorders characterized by the uncontrolled neoplastic proliferation of lymphoid or plasmacytic cells, ranging from benign reactive processes to malignant lymphomas. 1, 2

Core Definition and Pathophysiology

Lymphoproliferative disorders encompass a wide spectrum of abnormalities that can be broadly classified based on their cellular clonality and clinical behavior 2:

• Reactive (benign) proliferations - polyclonal expansions of lymphocytes in response to infections, autoimmune conditions, or other triggers 1
• Malignant diseases - clonal proliferations including various lymphomas and leukemias 2, 3

The fundamental pathologic process involves disruption of normal lymphocyte homeostasis, leading to accumulation of proliferating lymphoid cells that can infiltrate lymph nodes, spleen, bone marrow, and other organs 1

Major Categories of Lymphoproliferative Disease

Post-Transplant Lymphoproliferative Disorders (PTLD)

PTLD represents uncontrolled neoplastic proliferation of lymphoid or plasmacytic cells occurring after solid organ or hematopoietic stem cell transplantation. 1

• After allogeneic HSCT, PTLD is almost exclusively EBV-related (>90% of cases), whereas rare non-EBV cases exist 1
• Historically carried 84.6% mortality before 2000, though outcomes have improved with rituximab and EBV monitoring to approximately 33% mortality 1
• Risk factors include EBV infection, recipient age, transplanted organ type, intensity of immunosuppression, and genetic factors 4

The WHO classification recognizes four PTLD categories 1, 4:

• Early polyclonal lesions
• Polymorphic PTLD
• Monomorphic PTLD (B-cell or T/NK-cell types)
• Classical Hodgkin lymphoma-type PTLD

Autoimmune Lymphoproliferative Syndrome (ALPS)

ALPS is a genetic disorder caused by defective lymphocyte apoptosis, most commonly due to FAS gene mutations, resulting in accumulation of proliferating lymphocytes. 1

Clinical features include 1:

• Chronic (≥6 months) nonmalignant, noninfectious lymphadenopathy and/or splenomegaly
• Elevated CD3+ TCR+ CD4- CD8- double-negative T cells (≥1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes)
• Multilineage cytopenias secondary to autoimmune destruction and sequestration
• Increased risk of B-cell lymphoma

Most patients harbor heterozygous germline FAS mutations inherited in autosomal dominant fashion, though somatic FAS mutations are the second most common cause 1

Chronic Lymphoproliferative Disorders

This category includes a heterogeneous group of diseases with highly variable clinical courses 3:

• B-cell chronic lymphocytic leukemia (CLL) - the most frequent type and model for studying these disorders 3
• Mantle cell lymphoma - characterized by overexpression of Prad1/CCND1 gene, can occasionally be CD5-negative 5, 3
• Waldenström's macroglobulinemia - requires IgM monoclonal protein with surface IgM+, CD19+, CD20+, CD23- immunophenotype and ≥10% bone marrow lymphoplasmacytic infiltration 1, 5
• Hairy cell leukemia - treated preferentially with cladribine monotherapy 5
• Lymphoproliferative disease of granular lymphocytes (LDGL) - characterized by >2000 granular lymphocytes/mm³ in peripheral blood with heterogeneous clinical course 6

Clinical Manifestations

Common presenting features across LPD types include 1:

• Lymphadenopathy - chronic, nonmalignant enlargement of lymph nodes
• Splenomegaly and/or hepatomegaly - organ infiltration by proliferating lymphocytes
• Cytopenias - anemia, thrombocytopenia, neutropenia from autoimmune destruction or sequestration
• Constitutional symptoms - fever, night sweats, weight loss (B symptoms)
• Autoimmune manifestations - autoimmune hemolytic anemia, immune thrombocytopenia

Diagnostic Approach

Diagnosis requires integration of clinical, laboratory, immunophenotypic, and histopathologic findings. 1

Key diagnostic elements include 1:

• Flow cytometry or immunohistochemistry - to characterize cell surface markers and identify clonality
• Tissue biopsy with histopathology - demonstrating disruption of cellular architecture and monoclonal/oligoclonal populations
• Detection of viral markers - particularly EBV-encoded RNA by in situ hybridization (EBER-ISH) for PTLD, which has high sensitivity and specificity 1
• Molecular and cytogenetic studies - FISH for del(17p), del(11q), t(11;14), and other prognostic markers 5
• Functional assays - defective lymphocyte apoptosis testing for ALPS 1

A critical pitfall is that detection of EBV DNA in blood alone is insufficient for PTLD diagnosis - tissue confirmation with EBV detection is required for proven disease 1

Prognosis and Clinical Behavior

The clinical course varies dramatically 2, 3, 6:

• Some LPDs are indolent with spontaneous regression or stable disease requiring only observation 5, 3, 6
• Others are aggressive malignancies requiring immediate intensive treatment 1, 4, 3
• PTLD mortality remains approximately 33% despite modern therapies 1
• LDGL shows heterogeneous outcomes with about 25% asymptomatic at diagnosis, while others experience fatal progression 6

Poor prognostic features in LDGL include fever at diagnosis, low percentage of HNK-1-positive cells (≤15%), and relatively low granular lymphocyte count (≤3000/mm³) 6

Treatment Principles

Management strategies depend on the specific LPD subtype 1, 5, 4:

For PTLD 1, 4:

• Reduction of immunosuppression as first-line
• Rituximab (anti-CD20 monoclonal antibody)
• EBV-specific cytotoxic T-cell therapy
• Chemotherapy for refractory cases

For chronic lymphoproliferative disorders 5, 3:

• Observation ("watch and wait") for asymptomatic early-stage disease with monitoring every 3-12 months
• Treatment initiation only when meeting specific criteria: advanced stage disease, progressive/symptomatic organomegaly, constitutional symptoms, rapidly progressive disease, or autoimmune cytopenias unresponsive to corticosteroids
• Chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) for fit patients requiring treatment

A common pitfall is initiating treatment based solely on elevated lymphocyte count or minimal lymphadenopathy without meeting established treatment criteria. 5