Introduction to lymphomas and CLL

Introduction to lymphomas and CLL

1. Hodgkin lymphoma

   • WHO classes
     • Nodular, lymphocytic predominance (20%)
     • Classic (80%)
       • Nodular sclerosis
       • (these 3 are classified according to relative proportion of Reed-Sternberg cells)
         • Mixed cellularity
         • Lymphocytic rich
         • Lymphocyte depletion
   • Neoplastic cells are by far the minority of cells you find in lymph nodes
     • With a storm of signals they favor the accumulation of non-neoplastic cells around them
     • Final diagnosis cannot be obtained if you don't find the neoplastic cells

2. CLL

   • Characterized by lymphocytosis
   • 3 steps required to produce a CLL
     • Transformation
     • Accumulation
     • Autonomous growth
   • Clonal B cell malignancy (most often CD+ B lymphocytes)
   • Epidemiology
     • Most common in adults >50 years
   • Many patients have comorbidities
   • Etiology
     • Unkown
     • No established viral etiology
     • Genetic factors
       • Nearly 9% of patients have a familial history of CLL
     • Increased incidence in farmers, rubber manufactory workers and asbestos workers
     • Cytogenetics
       • 50% have clonal chromosomal abnormalities
       • Patients with an abnormal karyotype have a worse prognosis
     • Development of CLL is strangely linked to monoclonal B cell-lymphocytosis (MBL)
       • In MBL there is a 2-5% risk to develop CLL
         • Risk depends on the degree of lymphocytosis
           • If B cell count <5000/µl, risk is <2%
           • If B cell count >5000µl, risk is >5%
   • Molecular features
   • Clinical features
   • Signs
     • Lymphadenopathy
     • Splenomegaly
     • Hepatomegaly
     • Other organs
     • Paraneoplastic phenomenon
   • Investigations
     • Pretreatment studies
       • CBC
         • Lymphocytosis (>5000/µl)
         • Cytopenias
           • Anemia
           • Thrombocytopenia
           • Neutropenia
       • Peripheral blood smear
       • Reticulocyte count
       • Coomb's test
       • Renal and liver function tests
       • Serum protein electrophoresis
       • Immunoglobulin level
         • Hypogammaglobulinemia, observed in 80% of patients
       • Autoimmune disorders
       • Plasma beta2 microglobulin test
     • Immunophenotyping if available
       • Immunophenotype of CLL is: CD5+, CD20+, CD23+
       • CD38 is a prognostic factor
         • CD38-: less aggressive behavior
         • CD38+: aggressive behavior
     • Histopathology
       • Bone marrow biopsy
         • It can show a nodular pattern or a diffuse pattern
       • Lymph node: typically completely infiltrated by the disease
   • Differential diagnosis
     • Infection
     • Malignant causes
       • T cell CLL (<1% cases)
       • B cell
         • Leukemic phase of NHL
         • Hairy cell leukemia
         • Waldenstrom macroglobulinemia
   • Staging systems
     • Ray staging system
     • Binet staging system
   • Prognostic markers
     • Features suggestive of poor prognosis
     • 17p deletion: bad prognosis
     • Ig mutations: better prognosis
   • Transformation
     • Diffuse large B cell lymphoma (Richter syndrome) accounts for almost 80% of cases of transformation
       • Pro-lymphocytic leukemia (20%)
       • Hodgkin disease
       • Multiple myeloma
       • Acute leukemia
   • Treatment
     • Cure is not the goal (not a curable disorder)
     • Reserved for patients with low or intermediate risk disease who are asymptomatic or have a progressive disease
     • Indications to start treatment
   • Follow-up: evaluation
     • Lymphocytosis
     • Lymphocyte doubling time
     • Anemia and thrombocytopenia
   • Evaluating response to treatment
     • Complete response, defined as:
       • Free of the clinical problems for which the treatment was initiated
       • No constitutional symptoms
       • Normal blood counts and Hb
       • No organomegaly
       • No bone marrow infiltration by lymphocyte nodules and marrow lymphocytosis <30%
     • Minimal residual disease (MRD)
     • Progressive disease
       • 50% increase in lymphocyte count
       • Transformation to aggressive histology
       • Increase in spleen or lymph node size
       • Appearance of new lymph nodes
   • Treatment strategy
     • Alkylating agents
       • Chlorambucil
       • Cyclophosphamide
       • Bendamustine
     • Nucleoside analogues
     • Combination
     • CHOP regimen
     • Monoclonal antibodies
       • Rituximab, Alentuzumab
     • Immunomodulators (lenalidomide)
     • Drugs acting on the signaling pathways of BCR
       • p3K inhibitor
       • BTK inhibitors

3. To recognize a particular stage of development we need

   • Morphology
     • Tissue architecture
       • Relationship with capsule
       • Growth pattern
     • Cytological properties (cell size, nuclear/cytoplasmic ratio, nuclear irregularity...)
   • Immunophenotypes
     • B vs T
     • Maturation stage level markers
     • Immunohistoshemistry cannot be used as 1st method for classification, first you need morphology

4. Frequency of WHO histotypes

   • 50% by 2 entities
     • Diffuse large B cell lymphomas (30%)
     • Follicular lymphomas (22%)
   • The remaining are fragmented in many entities

5. Concepts specific for lymphomas

   • Concept of dysplasia is not part of the spectrum of these malignancies
   • Grading is not reliable
     • Only exception is follicular lymphoma
   • Spreading of the tumor through the body is called "localization", not metastasis
   • Sometimes the definition between lymphoma and leukemia is quantitative

6. Steps in the classification of lymphomas

   • 1966: Henry Rappaport's AFIP Classification
   • Kiel classification (1974)
   • Working formulation (1982)
   • Updated Kiel classification (1988)
     • For the first time lymphomas were classified not only by morphology but also by immunohistochemistry
   • Revised European American Lymphoma (REAL) Classification

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