Introduction to lymphomas and CLL

Hodgkin lymphoma
1. WHO classes
  1. Nodular, lymphocytic predominance (20%)
  2. Classic (80%)
    1. Nodular sclerosis
    2. (these 3 are classified according to relative proportion of Reed-Sternberg cells)
      1. Mixed cellularity
      2. Lymphocytic rich
      3. Lymphocyte depletion
2. Neoplastic cells are by far the minority of cells you find in lymph nodes
  1. With a storm of signals they favor the accumulation of non-neoplastic cells around them
  2. Final diagnosis cannot be obtained if you don't find the neoplastic cells
CLL
1. Characterized by lymphocytosis
2. 3 steps required to produce a CLL
  1. Transformation
  2. Accumulation
  3. Autonomous growth
3. Clonal B cell malignancy (most often CD+ B lymphocytes)
4. Epidemiology
  1. Most common in adults >50 years
5. Many patients have comorbidities
6. Etiology
  1. Unkown
  2. No established viral etiology
  3. Genetic factors
    1. Nearly 9% of patients have a familial history of CLL
  4. Increased incidence in farmers, rubber manufactory workers and asbestos workers
  5. Cytogenetics
    1. 50% have clonal chromosomal abnormalities
    2. Patients with an abnormal karyotype have a worse prognosis
  6. Development of CLL is strangely linked to monoclonal B cell-lymphocytosis (MBL)
    1. In MBL there is a 2-5% risk to develop CLL
      1. Risk depends on the degree of lymphocytosis
        If B cell count <5000/µl, risk is <2%
        If B cell count >5000µl, risk is >5%
7. Molecular features
8. Clinical features
9. Signs
  1. Lymphadenopathy
  2. Splenomegaly
  3. Hepatomegaly
  4. Other organs
  5. Paraneoplastic phenomenon
10. Investigations
  1. Pretreatment studies
    1. CBC
      1. Lymphocytosis (>5000/µl)
      2. Cytopenias
        Anemia
        Thrombocytopenia
        Neutropenia
    2. Peripheral blood smear
    3. Reticulocyte count
    4. Coomb's test
    5. Renal and liver function tests
    6. Serum protein electrophoresis
    7. Immunoglobulin level
      1. Hypogammaglobulinemia, observed in 80% of patients
    8. Autoimmune disorders
    9. Plasma beta2 microglobulin test
  2. Immunophenotyping if available
    1. Immunophenotype of CLL is: CD5+, CD20+, CD23+
    2. CD38 is a prognostic factor
      1. CD38-: less aggressive behavior
      2. CD38+: aggressive behavior
  3. Histopathology
    1. Bone marrow biopsy
      1. It can show a nodular pattern or a diffuse pattern
    2. Lymph node: typically completely infiltrated by the disease
11. Differential diagnosis
  1. Infection
  2. Malignant causes
    1. T cell CLL (<1% cases)
    2. B cell
      1. Leukemic phase of NHL
      2. Hairy cell leukemia
      3. Waldenstrom macroglobulinemia
12. Staging systems
  1. Ray staging system
  2. Binet staging system
13. Prognostic markers
  1. Features suggestive of poor prognosis
  2. 17p deletion: bad prognosis
  3. Ig mutations: better prognosis
14. Transformation
  1. Diffuse large B cell lymphoma (Richter syndrome) accounts for almost 80% of cases of transformation
    1. Pro-lymphocytic leukemia (20%)
    2. Hodgkin disease
    3. Multiple myeloma
    4. Acute leukemia
15. Treatment
  1. Cure is not the goal (not a curable disorder)
  2. Reserved for patients with low or intermediate risk disease who are asymptomatic or have a progressive disease
  3. Indications to start treatment
16. Follow-up: evaluation
  1. Lymphocytosis
  2. Lymphocyte doubling time
  3. Anemia and thrombocytopenia
17. Evaluating response to treatment
  1. Complete response, defined as:
    1. Free of the clinical problems for which the treatment was initiated
    2. No constitutional symptoms
    3. Normal blood counts and Hb
    4. No organomegaly
    5. No bone marrow infiltration by lymphocyte nodules and marrow lymphocytosis <30%
  2. Minimal residual disease (MRD)
  3. Progressive disease
    1. 50% increase in lymphocyte count
    2. Transformation to aggressive histology
    3. Increase in spleen or lymph node size
    4. Appearance of new lymph nodes
18. Treatment strategy
  1. Alkylating agents
    1. Chlorambucil
    2. Cyclophosphamide
    3. Bendamustine
  2. Nucleoside analogues
  3. Combination
  4. CHOP regimen
  5. Monoclonal antibodies
    1. Rituximab, Alentuzumab
  6. Immunomodulators (lenalidomide)
  7. Drugs acting on the signaling pathways of BCR
    1. p3K inhibitor
    2. BTK inhibitors
To recognize a particular stage of development we need
1. Morphology
  1. Tissue architecture
    1. Relationship with capsule
    2. Growth pattern
  2. Cytological properties (cell size, nuclear/cytoplasmic ratio, nuclear irregularity...)
2. Immunophenotypes
  1. B vs T
  2. Maturation stage level markers
  3. Immunohistoshemistry cannot be used as 1st method for classification, first you need morphology
Frequency of WHO histotypes
1. 50% by 2 entities
  1. Diffuse large B cell lymphomas (30%)
  2. Follicular lymphomas (22%)
2. The remaining are fragmented in many entities
Concepts specific for lymphomas
1. Concept of dysplasia is not part of the spectrum of these malignancies
2. Grading is not reliable
  1. Only exception is follicular lymphoma
3. Spreading of the tumor through the body is called "localization", not metastasis
4. Sometimes the definition between lymphoma and leukemia is quantitative
Steps in the classification of lymphomas
1. 1966: Henry Rappaport's AFIP Classification
2. Kiel classification (1974)
3. Working formulation (1982)
4. Updated Kiel classification (1988)
  1. For the first time lymphomas were classified not only by morphology but also by immunohistochemistry
5. Revised European American Lymphoma (REAL) Classification

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Introduction to lymphomas and CLL

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