HC26: Malignant lymphomas

Principles of lymphoid differentiation

There are 2 types of malignant lymphomas:

• T-cell lymphoma/NK-cell lymphoma
• B-cell lymphoma

Pluripotent hematopoietic stem cells (HSC) differentiate into:

• Common lymphoid precursor cells (CLP) → differentiate into:
  • T-precursor cells → naïve T-cells → T-memory cells
  • B-precursor cells → B-memory cells or plasma cells
  • NK-cells
• Common myeloid precursor cells (CMP)

By morphology alone, CLPs cannot be distinguished from CMPs → additional tests are necessary. A plasma cell is recognizable thanks to its big Golgi system. This is the only type of cell which can be distinguished by cell morphology alone. The difference between T-cells and B-cells can be made by looking at cell type specific antigens which are present on the cell:

• T-cells: CD3
• B-cells: CD19, CD20, CD79
• NK-cells: CD16/56

Neoplasia:

The primary purpose of lymphocytes is to recognize an antigen receptor. Precursor cells, like blast cells, do not have antigen receptor (AgR) expression yet → they are AgR negative. Both AgR positive and negative cells can cause neoplasia:

• Precursor neoplasia: caused by AgR negative cells
  • Have a blast-like morphology
• Mature neoplasia: caused by mature (AgR positive) cells
  • Have a lymphocyte/plasma cell morphology

If mature cell receptors are destroyed, the cell goes into programmed apoptosis. This doesn’t happen in case of plasma cells, because they don’t have a receptor.

Physiological B-cell differentiation

There aren’t enough genes to code for the different type of receptors present in the adaptive immune system. This is solved by VDJ (IgH) and VJ (IgL) recombination:

1. A B-cell precursor starts to express a receptor to become a B-cell
2. The B-cell precursor starts to cut out parts of DNA to form a functional gene → multiple V and J sequences are put together
   • 18 different combinations can be made
3. More differentiation is possible by nibbling away some nucleotides on the open ends of DNA and adding random nucleotides
   • This happens by chance
4. A completely new functional gene with a completely unique receptor is made

Mechanism of B-cell lymphomas

Lymphomas are frequently caused by activation of proto-oncogenes in the course of antigen receptor formation:

• Chromosomal translocations
  • VDJ recombination
  • Class switch recombination
• Point mutations
  • Somatic hypermutation

This results in resistance to apoptosis and activation of signaling cascades.

B-cell maturation is a dangerous process because it contains double strand DNA breaks → risk of getting mutations. For instance, this can happen when VDJ-recombination activates a proto-oncogene:

1. During recombination an oncogene is translocated to an immunoglobulin heavy chain locus on the genome
2. The oncogene becomes irreversibly active
3. The B-cells containing oncogenes mature
4. In a lymph node, the mutated B-cell is exposed to an antigen for which its receptor is sensitive
5. The germinal center response takes place → the mutated B-cell develops from centroblast to centrocyte
   • Somatic hypermutation and class switch recombination takes place
6. The mutated B-cells have a higher affinity for the antigen
   • This is done by somatic hypermutation of the immunoglobulin receptor
     • This also is a random process

The chance of randomly changing the receptor and having more affinity for the antigen is pretty low. All cells which do not function properly are cells the immune system doesn’t need → usually go into apoptosis when they reach the germinal center of a lymph node. Only a few B-cells, which have a higher affinity for an antigen, are stimulated and positively selected. Because this mechanism only is present in B-cells, B-cell lymphomas are far more common than T-cell lymphomas.

Lymphomas can occur everywhere where lymphocytes are present. A lymphoma isn’t a lymph node cancer (a lymph node is a fibrous capsule), but cancer of B-cells or T-cells.

Symptoms of B-cell lymphomas

Symptoms of B-cell lymphomas are:

• Unexplained weight loss
• Night sweats
• Fever

The same disease can occur in different patterns, for example in case of precursor neoplasia:

• Leukemic precursor neoplasia is called acute lymphoblastic leukemia
• Nodal precursor neoplasia is called lymphoblastic lymphoma
• Extranodal precursor neoplasia sits in other tissues such as the brain

It still is the same disease and is treated the same way.

Mantle cell lymphoma:

Mantle cell lymphoma is comparable to a chameleon → it can occur in all 3 types of precursor lymphoma:

• Nodally
• Extranodally
• Leukemic

Hodgkin’s lymphoma:

Hodgkin’s lymphoma is caused by a B-cell which, during somatic hypermutation, has lost the expression of its receptor. Hodgkin lymphomas always are nodal. Normally, such B-cells die in the germinal center, but for some reason these B-cells can resist programmed apoptosis.

Classification of malignant lymphomas

The WHO has made a description and discrimination of “really existing” lymphoma entities under consideration of:

• Morphology
  • Histopathology
  • Cytopathology
• Immunophenotype
  • Immunohistochemistry
  • Flow cytometry
• Genetic aberrations
  • Cytogenetics
  • FISH
  • PCR
  • Microarrays
  • Immunohistology
• Clinical behavior of the lymphoma
  • History
  • Physical examination
  • Laboratory
  • Staging

The doctor has to integrate all this information and determines what kind of lymphoma it is.

Types of lymphoma

Acute lymphoblastic leukemia isn’t very frequent. 80-90% of lymphomas are B-cell lymphomas. The most common lymphoma by incidence is the diffuse large B-cell lymphoma, the most common lymphoma by prevalence is chronic lymphocytic leukemia.

Extranodal margical zone lymphoma of MALT-type:

An extranodal margical zone lymphoma of MALT-type typically occurs due to a chronic infection of the h. pylori bacteria:

1. H. pylori stimulates T-helper cells
2. T-helper cells make cytokines → stimulate mature B-cells
3. Oligo-clonal B-cell expansion, which is h. pylori dependent, occurs
   • Cytokines from T-helper cells are necessary for stimulation
4. An h. pylori dependent MALT-lymphoma is developed
5. During late stages of the disease, the lymphoma acquires genetic changes → becomes h. pylori independent
   • Typically, lymphomas are a cancer of the adaptive immune system → if the stimulus which causes the disease is taken away, everything becomes normal again
     • E.g. with antibiotics

Follicular lymphoma:

Follicular lymphomas grow in follicles. The follicles still keep some normal shapes → follicular lymphomas are not as malignant as some other types of cancers. Follicular lymphoma arises as follows:

1. Due to a translocation during VDJ/VJ recombination BCL2 is expressed
2. The cell acquires anti-apoptotic properties → resistance to apoptosis
   • This usually isn’t a problem → most people have B-cells with this mutation
3. When the B-cells reach the germinal center, they don’t die due to their BCL2 expressed apoptosis resistance
   • The cells don’t go away, but don’t grow very fast either → if the patient isn’t sick, nothing has to be done about it

Because the cells are equipped with an anti-apoptotic gene, the disease can never go away. It is an indolent lymphoma. Treatment can make the disease go into remission, but it will never fade entirely. Therapy consists of anti-CD20 antibodies (passive immunotherapy) in combination with light chemotherapy. After 10 years, 40-80% of patients are still alive.

Diffuse large B-cell lymphoma:

A diffuse large B-cell lymphoma is characterized by cells which look like fibroblasts diffusely growing through the lymph node structure. This forms a problem during somatic hypermutation in the germinal center → the cells acquire activating mutations in BCR signaling cascades and BCL6 activation.

Diffuse large B-cell lymphomas occur nodally and extra-nodally. The tumors are very aggressive. Treatment consists of 3 chemotherapies with rituximab (an anti-CD20 antibody) and prednisone.

Chronic lymphatic leukemia:

Chronic lymphatic leukemia is the second most frequently occurring lymphoma. It is typically leukemic and can come in nodal-type. It arises during VDJ/VJ recombination → the B-cell receptor gains properties than enable intracellular stimulation without there actually being an antigen on its receptor.

It is an indolent lymphoma. Treatment is only necessary when the patient is suffering and consists of rituximab and certain cytotoxic drugs.

Therapeutic options for malignant lymphomas

A malignant lymphoma is a systemic disease → surgery is not an option. Sometimes the lymphoma is present in a certain region. In that case, radiation therapy combined with medical therapy can be considered. Usually, only medical therapy is used:

• Classical medical therapy: targets proliferating cells with DNA damage
  • In case of Hodgkin lymphomas, T-lymphomas, B-lymphomas
    • Often combined with rituximab in case of B-lymphomas
• Passive immunotherapy: targets lymphocyte subsets
  • E.g. rituximab
• Targeted therapy: targets activated oncogenes
  • Venetoclax: very useful for BCL2 expressing cells
  • May be useful for MYC

If usual treatment isn’t an option, allogenic stem cell transplantation can be done. This is also known as active cellular immunotherapy.