Lymphoma: Multidisciplinary Flashcards
What systems are part of the lymphoreticular system (3)
Generative LR tissue
Reactive LR tissue
Acquired LR tissue
What forms the generative lymphoreticular system (2)
Bone marrow and thymus
Function of generative LR tissue
Generation/maturation of lymphoid cells
Components of reactive LR tissue (2)
Lymph node
spleen
Function reactive LR tissue
Development of immune reaction
Components acquired LR tissue
Extranodal lymphoid tissue (skin, stomach, lung)
Function LR tissue
Development of local immune reaction
Cells of LR system (2)
Lymphocytes
Accessory cells
How are lymphocytes classified
B lymphocytes
T lymphocytes
Characteristics of B lymphocytes (2)
Express surface immunoglobulin
Antibody production
Characteristics of T lymphocytes (3)
Express surface T cell receptor
Regulation of B cell and macrophge function
Cytotoxic function
Some accessory cells (3)
Antigen presenting cells
Macrophages
Connective tissue cells
What comprises the B cell area in the lymph node (2)
Paracortical T cell zone Lymphoid follicle (mantle zone, germinal centre)
What are the components of the lymphoid follicle (2)
Mantle zone - naive unstimulated B cells
Germinal centre - B cells, antigen presenting cells
What is significant about the germinal centre
This is where B cells which bind antigen epitopes are selected and activated
What is significant about the T cell area
This is where T cells which bind antigen epitopes are selected and activated
Components of the T cell area (3)
T cells
Antigen presenting cells
High endothelial vessels
How are lymphocyte subtypes identified
Identify lymphocyte subtypes and different stages of development by the different types of cell surface receptors expressed by the cells (CD markers)
Detected in tissue sampling by immunohistochemistry
Definition of lymphoma
Neoplastic proliferation of lymphoid cells forming discrete tissue masses
Where do lymphomas arise
Arise in and involve lymphoid tissues (including acquired lymphoid tissue - extranodal lymphomas)
Classification of lymphomas (2)
Hodgkin lymphoma
Non-Hodgkin lymphoma (B cell type most common, T cell type)
What predisposes to lymphoma
Immunosuppression predisposes to development of lymphoma (infection, loss of surveillance)
What is the pathogenesis of lymphoma (2)
Neoplastic proliferation of lymphoid cells - clonal
Mutation in genes to allow uncontrolled cell growth
Causes of mutations leading to lymphoma (5)
Normal lymphocytes undergo controlled genomic “instability” of lymphoid cells - mistakes in this process produce neoplastic mutations
Inherited disorders – inherited disorder resulting in increased/abnormal genomic instability
Viral agents – EBV, HTLV-1
Environmental agents – mutagens, chronic immune stimulation (e.g H pylori)
Iatrogenic causes – radiotherapy, chemotherapy
WHO classification of lymphoma
Hodgkin: Classical, lymphocyte predominant
Non-Hodgkin lymphoma: B cell (precursor B cell, peripheral B cell), T cell (precursor T cell, peripheral T cell)
Most common form of lymphoma
B cell Non-Hodgkin lymphomas (80-85%)
When do lymphomas arise
Can arise at different stages of lymphocyte development and activation
Therefore in certain lymphomas the neoplastic lymphoid cell resembles a normal counterpoint both in morphology and in the pattern of CD markers expressed
Where are the neoplastic lymphoid cells present
Circulate in the blood
Hence often disseminated at presentation - exception is Hodgkin lymphoma and some very early NHL
What effect do lymphomas have on the immune system
They may disrupt normal immune system - therefore patients may develop immunodeficiencies
Lymphomas arising from germinal centre (4)
Follicular lymphoma
Burkitt lymphoma
Diffuse large B cell lymphoma
Hodgkin lymphoma
Lymphomas arising from post germinal centre (4)
Diffuse large B cell lymphoma
marginal zone lymphoma
Small lymphocytic lymphoma
Chronic lymphocytic leukaemia
What are the diagnostic tools for lymphoma (2)
Cytology: look at single cells aspirated from a lump
Histology: look at tissue sections
What do you look at histologically in lymphoma (2)
Architecture (nodular, diffuse)
Cells (small round, small cleaved, large (centroblastic, immunoblastic, plasmoblastic))
What is immunohistochemistry used for
Used to identify proteins on/in cells in tissue sections
How does immunohistochemistry work
Use labelled antibody to cell surface receptor
Dye label is visible under light microscope in tissue sections
What can you determine with immunopheontyping (5)
Cell type (T = CD3, CD5, B = CD20)
Cell distribution
Loss of normal surface proteins (e.g. neoplastic T cells)
Abnormal expression of proteins (often secondary to specific chromosomal/gene abnormalities e.g. cyclin D1)
Clonality of B cells - light chain expression
What molecular tools are available for lymphoma analysis (2)
FISH - identify chromosome translocations
PCR - identify chromosome translocations and clonal T cell receptor or immunoglobulin gene rearrangement
How can PCR be used in lymphoma (2)
Diagnostic - e.g. 11;14 mantle cell lymphoma
Prognostic - e.g. 2;5 Anaplastic large cell lymphoma
Low grade Non-Hodgkin lymphomas (4)
Follicular lymphoma
Small lymphocytic lymphoma/chronic lymphocytic leukaemia
Marginal zone lymphoma
Mantle zone lymphoma
High grade Non-Hodgkin lymphoma
Diffuse large B cell lymphoma
Intermediate grade Non-Hodgkin lymphoma
Burkitt’s lymphoma
Clinical presentation of follicular lymphoma (2)
Lymphadenopathy
MA/elderly
Histopathology follicular lymphoma (2)
Follicular pattern
Germinal centre cell origin CD10, bcl-6+
Molecular pattern follicular lymphoma
14;18 translocation involving bcl-2 gene
Typical grade of follicular lymphoma
Indolent but can transform to high grade lymphoma
Immunohistochemistry in follicular lymophoma
Detection of bcl-2 expression by neopalstic B cells in follicles
Clinical presentation small lymphocytic lymphoma/CLL (2)
MA/elderly
Nodes or blood
Histopathology small lymphocytic lymphoma/CLL
Small lymphocytes
Naive or post-germinal centre memory B cell
CD5, CD23
Molecular pattern small lymphocytic lymphoma/CLL
Multiple genetic abnormalities
Typical grade for small lymphocytic lymphoma/CLL
Indolent, but can transform to high grade lymphoma (richter transformation)
Cause of marginal zone lymphoma/MALT
Thought to arise in response to chronic antigen stimulation (e.g. by Helicobacter in stomach)
Site of origin for marginal zone lymphoma/MALT
Arise mainly at extranodal sites (many sites e.g. gut, lung, spleen)
Post germinal centre memory B cell
Typical grade marginal zone lymphoma/MALT
Indolent but can transform to high grade lymphoma
Treatment of low grade marginal zone lymphoma/MALT
Can treat low grade disease with non-chemotherapeutic modalities - i.e. remove antigen
Clinical features mantle cell lymphoma (3)
MA male predominence
Lymph nodes, GI tract
Disseminated disease at presentation
What is the histopathology of mantle cell lymphoma (3)
Located in mantle zone
Pre-germinal centre cell
Aberrant CD5, cyclin D1 expression
What are the molecular features of mantle cell lymphoma (2)
11;14 translocation
Cyclin D1 over expression
What is the median survival rate for mantle cell lymphoma
3-5 years
Clinical features of Burkitt’s lymphoma (3)
Jaw or abdominal mass in children and young adults (endemic, sporadic, immunodeficiency)
EBV associated
Aggressive disease
Histopathology of burkitt’s lymphoma (2)
Germinal centre cell origin
Starry sky appearance
Molecular features of burkitt’s lymphoma
c-myc translocation (8;14, 2;8, 8;22)
Clinical features of diffuse large B cell lymphoma (2)
MA/elderly
Lymphadenopathy
Histopathology of diffuse large B cell lymphoma (4)
Germinal center or post-germinal center B cell
Sheets of large lymphoid cells
Germinal center phenotype = good prognosis
p53 positive, high proliferation fraction = poor prognosis
Features of T cell lymphoma (5)
MA/elderly Lymphadenopathy and extranodal sites Large T lymphocytes Often with associated reactive cell population, esp eosinophils Aggressive
Special forms of T cell lymphoma (4)
Adult T cell leukaemia/lymphoma
Enteropathy associated T cell lymphoma
Cutaneous T cell lymphoma
Anaplastic large cell lymphoma
What are the associations with adult T cell leukaemia/lymphoma (2)
Caribbean and Japan
HTLV1 infection
What is associated with enteropathy associated T cell lymphoma
Some patients with long standing coeliac disease
Clinical features of anaplastic large cell lymphoma (3)
Children/young adults
Lymphadenopathy
Agressive
Histopathology anaplastic large cell lymphoma (2)
Large epithelioid lymphocytes
T cell or null phenotype
Molecular features of anaplastic large cell lymphopma (2)
2;5 translocation
Alk-1 protein expression - better prognosis
Features of Hodgkin lymphoma (5)
More often localised to a single nodal site
Spreads contiguously to adjacent lymph nodes
Classical, with several subtypes
Lymphocyte predominent
Moderately agressive
Features of Non-Hodgkin lymphoma (2)
More often involves multiple lymph node sites
Spreads discontinuously
Subtypes of classical Hodgkin’s lymphoma (3)
Nodular sclerosing
Mixed cellularity
Lymphocyte rich and lymphocyte depleted
Clinical features of classical HL (2)
Young and MA
Often involves just a single lymph node group
Origin of classical HL
Germinal centre/post-germinal centre B cell origin
Associations of classical HL
EBV
Histopathology of classical HL
Sclerosis, mixed cell population in which scattered Reed-Sternberg and Hodgkin cells with eosinophils
Clinical features of nodular HL (4)
Isolated LN
Lymphadenopathy
Indolent
Can transform to high grade B cell lymphoma
Origin of nodular HL
Germinal centre B cell (positive for some germinal centre B cell markers)
Nodular HL associations
No associations, not associated with EBV
Histopathology of nodular HL
B cell rich nodules with scattered L&H cells
What is involved in haemato-oncological diagnosis (4)
Morphology
Immunophenotyping
Cytogenetics
Molecular genetics
What is meant by morphology of a tumour (3)
Architecture of the tumour
Cytology
Cytochemistry
What is involved in immunopheonotype (2)
Flow cytometry
Immunohistochemistry
What is involved in cytogenetics (2)
Conventional karyotyping
FISH
What is involved in molecular genetics (4)
Mutation detection
PCR analysis
Gene expression profile
Whole genome sequencing
What is lymphoma
It is a neoplasm of lymphoid cells
Where do lymphomas occur (4)
Lymph nodes, bone marrow and/or blood (lymphatics)
Lymphoid organs (spleen, GALT)
Skin (often T cell disease)
Rarely, anywhere (CNS, occular, testes, brest, etc…)
What is the incidence of lymphoma
10,000 new cases/year in the UK
NHL - 80%
HL - 20%
Why are cancers of the immune system so dangerous (3)
Rapid proliferation - increases risk of DNA replication error.
Normal cells are dependent on apoptosis - apoptosis is switched off in the geminal centre, acquired DNA mutation in pro apoptotic genes
Great potential for recombination errors and new point mutations
What immunoglobulin gene recombinations are involved in lymphoma (2)
VDJ recombination. Occurs in bone marrow, Key enzymes RAG1+2, TdT
Class switch recombination. Somatic hypermutation. Key enzymes: adenosine induced deaminase.
What chromosomal translocations are involved in lymphoma
t(8;14)
Lymphoma/recombination associated translocations involve the Ig locus. Ig promoter is highly active in B cells, bring intact oncogenes close to the Ig promoter. Oncogenes may be anti-apoptotic, proliferative (bcl2, bcl6, Myc, cyclinD1)
Risk factors for lymphoma (4)
Majority of cases no identifiable risk factor.
Constant antigenic stimulation
Infection (direct viral infection of lymphocytes)
Loss of T cell function
Give examples of antigenic stimulation that may lead to lymphoma (3)
H.Pylori : Gastric MALT (mucosa associated lymphoid tissue) Marginal Zone NHL of stomach
Sjogren syndrome : Marginal Zone NHL of Parotid lymphoma
Coeliac disease: small bowel T cell lymphoma EATL (enteropathy associated T-Cell Non Hodgkin lymphoma)
What infections are associated with lymphoma (2)
HTLV1 infection of T cells
Immunosuppression and EBV infection (e.g. HIV, PTLD - post transplant lymphoproliferative disorder)
Reed Sternberg cells
Classical Hodgkin Lymphoma
B cell lymphomas (2)
Precursor B lymphoblastic leukaemia or lymphoma
Mature B cell neoplasm: DLBCL, Follicular, NHL, CLL
T/NK cell lymphoma (2)
Precursor T lymphoblastic leukaemia or lymphoma
Mature T and NK neoplasm: PTCL, anaplastic, cutaneous
Features of HL
HL is more common in males than females.
Bimodal age incidence: Most common age 20-29, young women NS subtype; Second smaller peak affecting elderly >60 years old
Painless enlargement of lymph node/nodes.
May cause obstructive symptoms/signs
Constitutional symptoms; fever, night sweats weight loss (the B symptoms) and pruritis may be present. Rarely alcohol induced pain present.
Classical HL subtypes (4)
Nodular sclerosing 80%- Good prognosis (causes the peak incidence in young women)
Mixed cellularity 17% - Good prognosis
Lymphocyte rich (rare)- Good prognosis
Lymphocyte depleted (rare)- Poor Prognosis
How are HL staged
FDG-PET/CT scan
Consider biopsy of other site if possibly infiltrated e.g. liver
Staging in lymphoma
Stage 1 - one group of nodes
Stage 2 - >1 group of nodes on same side f diaphragm
Stage 3 - nodes above and below the diaphragm
Stage 4 - extra nodal spread
Suffix A if none of below, B if any of below:
Fever
Unexplained weight loss >10% in 6 months
Night sweats
How does chemotherapy work for lymphoma
Given as a combination of drugs which affect the malignant cells in different way s
How does radiotherapy work in lymphoma
HL is highly responsive to radiotherapy, can be given at end of chemo as an Involved field a small area only targeting diseased nodes (less toxicity to normal tissue)
Chemotherapy for HL (4)
ABVD - given at 4 weekly intervals (2-6 cycles) Adriamycin Bleomycin Vinbalstine DTIC
Effective treatment
Preserves fertility
Can cause pulmonary fibrosis and cardiomyopathy (long term)
What are the risks of radiotherapy for lymphoma treatment (3)
Ca breast (risk 1:4 after 25 years)
Leukaemia/mds (3%@10years)
Lung or skin cancer
How is radiotherapy given for lymphoma
Modern practice involved field only
What is the risk of combined chemotherapy and radiotherapy treatment for lymphoma
Greatest risk of secondary malignancy
Treatment of lymphoma
Chemotherapy for all cases (ABVD 2-6 cycles)
+/- Radiotherapy
PET CT scanning
Relapse - high dose salvage chemotherapy, autologous PB stem cell transplant as salvage.
HL prognosis
Older patients generally do less well as do those with lymphocyte depleted histology
Prognosis depends on stage
Cure rates range from 50-90% (over 80% of patients with stage 1 or 2 disease are cured, only 50% of stage 4 patients are cured)
Arguments for and against reduced therapy
Reduced therapy - chemotherapy only, reduce risk of secondary malignancy, increased HL relapse
Intensify therapy - chemo +/- radiotherapy. Decrease HL relapse, increase secondary malignancy after 10 years.
