Lymphoma Flashcards
What is lymphoma?
Neoplastic proliferation of lymphoid cells forming discrete tissue masses.
Where are lymphomas usually found?
LN +/- blood (Lymphatic system)
Lymphoid organs: spleen or gut associated lymphoid tissue
Skin (Often T cell disease)
Where can lymphomas rarely occur? (5)
CNS
Eyes
Testes
Breast
Kidney
What are the 2 classes of lymphoma and their prevalence?
Non-Hodgkin’s 80%
Hodgkin’s 20%
Describe the aetiology of lymphoma
Mostly sporadic with no known RFs
Some a/w specific infections/ immune disorders
How does immunoglobulin configuration occur? What are the benefits and risks?
Ig + TCR genes cut + recombined, then subjected to deliberate DNA mutagenesis
Generates diversity + Ig class switching
Potential for recombination errors + harmful point mutations
What are the benefits and risks of rapid cell proliferation in the germinal centre?
Allows rapid response to infection
Rapid multiple cell divisions = increase chance of DNA replication errors
What are the benefits and risks of immune response dependancy on apoptosis?
Eliminates self-reactive clones or ineffective Ig clones
Apoptosis is “switched off” in germinal centre
Consequences of mutations in apoptosis regulating genes
What are the 3 mechanisms of risk factors for certain non Hodgkin’s lymphoma subtypes?
- Constant antigenic stimulation
- Viral infection (direct viral integration of lymphocytes)
- EBV infection in a scenario of loss of T cell function
Give 3 examples of chronic/ AI antigenic stimulation causing B cell Non Hodgkin Lymphoma marginal zone subtype?
H. Pylori: Gastric MALT- mucosa associated lymphoid tissue. MZL of stomach
Sjogren syndrome: MZL of parotid gland
Hashimoto’s Thyroiditis: MZL of thyroid
What chronic antigenic stimulation causes enteropathy associated T-cell non Hodgkin’s lymphoma (EATL)?
Poorly controlled coeliac disease:
Small intestine EATL
How does H. pylori cause gastric MALT?
Chronic bacterial infection stimulates + irritates gut mucosa
Leads to lymphocytic infiltration
In chronic polyclonal reactive response, may lead to clones being produced
Increasingly malignant
Leads to MZL
Give an example of a direct viral integration causing non Hodgkin lymphoma.
In which populations is this more common?
HTLV1 retrovirus infects T cells by vertical transmission
Caribbean, Japanese endemic
Risk of adult T cell leukaemia lymphoma is 2.5% at 70y (ATLL)
How does EBV and loss of T cell function result in B non-hodgkins lymphoma?
- EBV infects B lymphocytes. Healthy carrier state post glandular fever. EBV driven proliferation a/w surface EBV antigens- targeted by EBV specific cytotoxic T cell response
- Loss of T cell function e.g. HIV, transplant immunosuppression
- Failure to eliminate EBV driven proliferation of B cells due to absence of cytotoxic T cells
What are almost all lymphomas due to?
immunoglobulin mutations (often heavy chain rearrangement)
BCL2
BCL6
Myc
Cyclin D1
Give 3 features of lymphoma presentation
Painless progressive lymphadenopathy
Recurrent infections
Constitutional Sx
How can lymphomas cause presentation with other system involvement?
Extrinsic compression of any “tube”: ureter, bile duct, large blood vessel, bowel, trachea, oesophagus
Infiltrate/ impair any organ system
Give examples of symptoms caused by lymphoma infiltration in the brain, eyes and skin
Brain: Stroke, memory problems
Eyes: blindness in 1 eye
Skin: Rash, inflammation, plaques, nodules
In which type of Lymphoma are Reed Sternberg cells seen?
Hodgkin’s Lymphoma
What are the subtypes of B cell non-hodgkins lymphoma?
Precursor: B lymphoblastic leukaemia or lymphoma
Mature: B cell neoplasm, DLBCL, Follicular NHL, CLL
What are the subtypes of T or NK cell lymphoma?
Precursor: T lymphoblastic leukaemia or lymphoma
Mature: T + NK neoplasm, PTCL, Anaplastic, Cutaneous
Give 3 epidemiological facts about Hodgkin’s lymphoma
1% of all cancer
M > F
Bimodal:
Most common 20-29
2nd smaller peak >60s
List the 3 classic B symptoms seen in Hodgkins lymphoma and 2 other less common symptoms
B: Fever, Night sweats, Weight loss
Pruritis
Alcohol induced pain in nodes
Which subtype of Hodgkins lymphoma has a peak of incidence in young women more than men?
Nodular sclerosing
What are the 4 types of classic Hodgkin’s lymphoma? What is the prevalence of each? What is the prognosis in each?
Nodular sclerosing 80%: good
Mixed cellularity 17%: good
Lymphocyte rich (rare): good
Lymphocyte depleted (rare): poor
What investigations are used to stage Hodgkin’s lymphoma?
FDG-PET/ CT scan
Biopsy of other sites if infiltrated e.g. liver
How do non Hodgkin’s and Hodgkins lymphoma differ in the way they spread?
H: Spreads through lymphatic system
NHL: Spreads through circulation
What is the staging system and what are the stages of Hodgkin’s lymphoma?
Ann-Arbor
I: 1 group of nodes (can inc. spleen)
II: >1 group of nodes SAME side of diaphragm
III: nodes above + below diaphragm
IV: extra-nodal spread
Suffix A if none of below, B if any of below:
Fever, unexplained weight loss >10% in 6m, night sweats
How may nodular sclerosing Hodgkin’s lymphoma present?
Neck nodes + mediastinal mass (may be massive + compress SVC or trachea)
What is the chemotherapy regime for Hodgkins lymphoma?
ABVD
Adriamycin
Bleomycin
Vinblastine
DTIC
Give 2 benefits of ABVD
Effective- curative
Preserves fertility (unlike original MOPP regime)
Give 2 potential complications of ABVD in the long term
Pulmonary fibrosis
Cardiomyopathy
Describe the chemotherapy regime for Hodgkins lymphoma
4w intervals, 2-6 cycles
PET CT after 2 cycles, response assessment + at end of tx
+/- radiotherapy
Describe salvage chemotherapy in cases of relapsed Hodgkin’s lymphoma
High dose chemo
Autologous PB stem cell transplant
Why is radiotherapy not used in all Hodgkin’s lymphoma patients?
ABVD alone can be curative
Radiotherapy increases risk of secondary cancer, so in young try to avoid
(secondary: Breast, Leukaemia, Lung, Skin)
What is the prognosis in Hodgkins lymphoma?
80% cured
10% die from relapse of HL in 10y
10% die from tx related complications after 10y
Which patients generally do less well despite treatment in Hodgkin’s lymphoma?
Elderly
Lymphocyte depleted
What investigations are used for staging non Hodgkins lymphoma?
CT
PET scan (in aggressive lymphomas)
+/- BM biopsy
LP (if CNS involvement)
List 4 prognostic markers/ important tests to perform in non Hodgkins lymphoma
LDH (rapid cell turnover)
Performance status
HIV serology
Hep B serology (risk of reactivation if B cell depleting therapy given)
Which subtypes of non Hodgkin lymphoma are considered very aggressive? What is the median survival without tx and response to chemo?
Burkitt’s lymphoma
T or B cell lymphoblastic leukaemia/ lymphoma
2-5w survival if no Tx
Curable
Which subtypes of non Hodgkin lymphoma are considered aggressive? What is the median survival without tx and response to chemo?
Diffuse Large B cell 30-40% of NHL
Mantle cell
3-12m survival without Tx
Moderately curable
Which subtypes of non Hodgkin lymphoma are considered indolent? What is the median survival without tx and response to chemo?
Follicular
Small lymphocytic/ CLL
Mucosa associated (MALT)
10-15y survival without Tx
Incurable (long remission)
How are very aggressive non Hodgkins lymphoma treated?
Treated like acute leukaemias
What is prognosis and treatment determined by in diffuse large B cell NHL?
IPI (International Prognostic Index):
Age
Stage (Ann Arbor)
LDH
Extra-nodal disease sites
ECOG performance status
What is the chemotherapy regime for diffuse large B cell NHL?
6-8 cycles of R-CHOP
Rituximab: anti-CD20 monoclonal antibody
Cyclophosphamide
Adriamycin
Vincristine
Prednisolone
Give 4 features of the course of follicular NHL
Indolent
35% of NHL
Incurable, median survival 12-15y
May require 2-3 different chemotherapy schedules over the 12-15y
What translocation is follicular NHL associated with?
t(14:18) which results in over expression of bcl2 an anti-apoptosis protein
What is the initial treatment for follicular NHL?
Watch + wait
Treat only if clinically indicated e.g. nodal extrinsic compression, massive painful nodes or recurrent infections
What combination immunotherapy regime can be used in follicular NHL?
R-COP
or
R-CHOP
Tx not curative
Give 5 features of extra nodal marginal zone lymphomas
Involve extra-nodal lymphoid tissue e.g. gastric mucosa, parotids
8% of NHL
Chronic antigen stimulation
Median age 55-60y
H. pylori eradication may cure 75%
What is the most common presentation of marginal zone lymphoma?
Epigastric pain
Ulceration
Bleeding into the gut
Usually present at Stage I
B Sx uncommon
What is enteropathy associated T cell lymphoma?
T cell NHL in patients with coeliac due to chronic antigen stimulation (gluten)
Mature T cells
Involves jejunum + ileum
Aggressive
Give 6 ways in which enteropathy associated T cell lymphoma may present
Abdo pain
Obstruction
Perforation
GI bleeding
Malabsorption
Systemic Sx
What is the prognosis in enteropathy associated T cell lymphoma?
Generally fatal
Responds poorly to chemo
Aim to prevent with strict GF diet
What is chronic lymphocytic leukaemia? Give 3 epidemiological facts
Proliferation of mature B lymphocytes, predominantly involves BM + blood
Commonest leukaemia in western world
RF: Caucasian, FH
Median age 72 (10% <55)
Give 5 laboratory findings in CLL
Lymphocytosis 5-300 x10^9
Normocytic normochromic anaemia
Thrombocytopenia
BM lymphocytic replacement of normal marrow elements
Smear cells
What technique is used to diagnose CLL?
Immunophenotype by flow cytometry of peripheral blood
CD5 +ve B cells in peripheral blood (should only be transiently expressed in immature)
What is the common clinical course of CLL?
5-10y good health until progression to 2-3y rapid phase to death
Do all CLL patients progress?
1/3 never progress
1/3 progress, respond to tx, die from unrelated disorder
1/3 progress, require multiple lines of Rx, refractory disease, die from CLL
Give 3 cell based prognostic factors in CLL
IgHV mutation status
CLL FISH cytogenetic panel
TP53 mutation status (Chr17p deletion +/- TP53 point mutation)
Describe the normal development of B cells
Start with germline immunoglobulin gene configuration
Pass into germinal center
Undergo recombination, generating antibody diversity
How does immunoglobulin heavy chain status affect prognosis in CLL?
If IGHV are mutated (post GC) = better prognosis as cells have undergone somatic hypermutation, thus differ from germline
What staging systems are used for CLL?
Binet
or
Rai
What are the clinical issues in CLL? What are these caused by?
Increased infection risk (population of malignant non functional mature B cells + hypogammaglobinaemia)
BM failure (proliferation in BM)
Lymphadenopathy +/- splenomegaly, lymphocytosis (circulates to nodes, spleen, blood)
AI complications e.g. AIHA (disease of immune cells)
How can acquiring further mutations complicate CLL?
Transform to high grade lymphoma (Richter transformation)
What supportive care is given to prevent Sino-pulmonary infections in CLL?
Early tx with abx
Pneumocystis prophylaxis +/- zoster prophylaxis
Recurrent infection + IgG< 5g/l give IVIG replacement therapy
What vaccines are given to CLL patients?
Pneumococcal
SARS COV 2
Seasonal flu
(AVOID live vaccines)
In which 5 circumstances do you not watch and wait in CLL?
Progressive lymphocytosis
Progressive marrow failure
Massive/ progressive lymphadenopathy/ splenomegaly
Systemic Sx (B Sx)
AI cytopenias (treat with immunosuppression not chemo)
Give 3 options for therapy in CLL
Combination immune-chemotherapy
Targeted: BTK inhibitor or BCL2 inhibitor
Cellular: Allogenic SCT, CAR-T therapy
Give an example of a BCR kinase and BCL2 inhibitor
BCR: Ibrutinib PO
BCL2: Venetoclax PO
What do the targeted therapies for CLL affect?
Constant signalling through B cell receptor to promote survival (we maintain memory B cells for protective immunity)
BCR signalling requires BCR + downstream signalling proteins e.g. BTK
Prevent cells dying by increasing presence of anti-apoptotic proteins e.g. BCL2
What is the main risk of Venetoclax?
Tumour lysis syndrome
