Leukaemia and Lymphoma Flashcards
Where does normal B cell development start?
In the bone marrow
What is B cell production stimulated by?
Growth factor and cytokine production that initiates gene regulation commiting the common lymphocyte progenitor to B cell lineage
How does a progenitor B cell differentiate to a mature B cell?
- Rearrangement of Ig Heavy Chain Genes
2. Rearrangement of Ig Light Chain Genes
What chains are brought together to form the heavy chain?
Kappa and Lambda chains
What are most B cell lymphomas derived from?
Germinal Centre Cells
What are the 4 B cell lymphomas (most common to least common)?
- Diffuse Large B Cell Lymphoma
- Follicular Lymphoma
- Mantle Cell Lymphoma
- Burkitt’s Lymphoma
What is a germinal centre?
A site within secondary lymphoid organs (lymph nodes and the spleen) where mature B cells proliferate, differentiate
What surrounds the germinal centre?
Mantle zone
Where does mantle cell lymphoma arise from?
Naive B Cells in the mantle zone
What do BL, FL and DLBCL arise from?
Germinal centre B cells
What drives Burkitt Lymphoma?
Chromosomal translocation
What kinds of Burkitt Lymphoma can occur?
High grade amd low grade, Sporadic and Epidemic, Immunodeficieny associated
What is the name for the histological appearance classically seen with BL?
Starry Sky
How do lymphoma cells appear?
Large nucleus with very little cytoplasm. Vacuoles within the cytoplasm.
What are 2 examples of epidemic causes of Burkitt lymphoma?
- Epstein Barr Virus
- Malaria
How does EBV cause BL?
Attaches to and activates B-lymphocytes CD21 receptor
Where is sporadic BL more common?
In the western world
Which chromosomes are translocated in BL?
8 and 14 (t(8;14))
What does the 8:14 translocation cause?
MYC brought into the antibody heavy chain locus so increased expression influenced by antibody HC enhancer element
Where does the translocation tend to occur within the body in sporadic BL?
Later, within the germinal centre
Where does the translocation tend to occur within the body in epidemic BL?
Within the bone marrow
What happens in cells with increased deregulated cMYC expression?
Cell cycle progression factors increase, allowing cell transformation and persistence of cells with decreased affinity (instead of apoptosis) -> tumorigenesis -> cancer
What can help distinguish BL from other lymphomas?
FISH - get red and green probes mixing -> orange fusion signal on the translocated genes
What is Follicular lymphoma?
B cell lymphoma where abnormal lymphocytes build up in the lymph nodes
Is FL generally lower or higher grade?
Lower, with a slower clinical course
How does FL present often?
Painless swelling in neck, armpit or groin
What chromosomal translocation causes FL?
t(14;18)
What does the t(14;18) cause?
The antibody HC gene enhancer element is brought to the bcl-2 gene area and incresases the bcl-2 expression
What does Bcl-2 have an important role in?
Apoptosis
Which types of Bcl-2 genes are amplified in FL?
Anti-apoptotic subfamily
What do these anti-apoptotic Bcl-2 proteins do?
Help stabilise the outer mitochondrial membrane, and prevent pro-apoptotic Bcl-2 proteins from binding.
What is diffuse large b-cell lymphoma?
The most common type of high-grade (fast‑growing) non-Hodgkin lymphoma, where the B cells are abnormally large and spread diffusely.
What is the median age of diagnosis with DLBCL?
66
What translocation commonly causes DLBCL?
3q27 translocation affecting the BCL6 gene
How does the 3q27 translocation affect the BCL6 gene?
It amplifies it and deregulates it
What does BCL6 normally do?
It is a transcription repressor of other genes (oncogenes and TSGs) to allow rapid B cell differentiation, especially in response to antigen-presentation
Where is BCL 6 normally only active?
Within the germinal centre
How does this BCL6 amplification/deregulation cause DLBCL?
Overexpressed BCL6 still represses tumour suppressor genes but mutated oncogenes escape regulation causeing aggressive lymphoma
How is LBCL classified?
Based on expression of 3 genes
What are the 3 genes?
- CD10
- BCL6
- MUM1
What TSG is frequently disrupted in LBCL?
BLIMP1
Which viruses are indirectly involved in lymphoma?
- HCV
- HIV
- EBV
Which viruses are directly involved in lymphoma?
- HHV8/KSHV
- HTLV1
What is primary effusion lymphoma?
A rare NHL associated with HHV8
When is primary effusion seen?
In immunosuppressed patients (either HHV8 infected AIDS pts or transplant recipients recieving high doses of immunosuppression)
What is always present with primary effusion lymphoma?
HHV8-genome positive
What else can HHV8 cause apart from primary effusion lymphoma?
- Multi-centric Castleman’s Disease
- Kaposi’s Sarcoma
How does a HHV8 infection lead to PEL?
- Latent infection of B lymphocyte pool
- Immune Supression
- Cellular genetic changes -> PEL
How does a HHV8 infection lead to Multi-centric Castleman’s disease?
- Latent infection of B lymphocyte pool
- Immune suppression
- Additional Co-factors -> Multicentric Castleman’s disease
How does a HHV8 infection lead to Kaposi’s Sarcoma?
HHV8 aka KSHV:
- Replicative infection of endothelial cells
- Rare latent infection in cells failing to replicate virus
- Immune suppression -> KS
How does HHV8 affect signalling?
Causes the insertion of an HHV8 GPCR into the B cell membrane. This causes a signalling cascade that increases nuclear transcription.
What is Adult T-cell Leukaemia Lymphoma?
A rare and aggressive lymphoma, found in the blood (leukemia), lymph nodes (lymphoma), skin, or multiple areas of the body.
Where is Adult T-cell Leukaemia Lymphoma prevalent?
Southern Japan, Equitorial Africa, Malaysia, the Caribbean, South America, and the southern United States
What is Adult T-cell Leukaemia Lymphoma caused by?
HTLV-1
What % of people with HTLV-1 will develop Adult T cell lymphoma/leukaemia?
Less than 5%
What is the most common route of spread of HTLV-1 infection?
Mother to baby via breast milk
When does Adult T cell lymphoma/leukaemia manifest?
Latent period ie several decades after initial infection
What promotes growth in the HTLV-1 infected cells?
Tax and other viral genes
How is this growth normally suppressed?
Cytotoxic T cells work against Tax.
Tax expression suppressed by Rex, HBZ, and p30
What occurs along the path of clonal proliferation?
Somatic alterations eg transcriptional changes
What do mature ATL cells have?
- Frequently loss of Tax expression
- Continuous expression of HBZ gene
How is Primary Effusion Lymphoma unique clinically?
In presentation - usually arises in body cavities
How is PEL treated?
Combination chemotherapy
What combination chemotherapy is used on PEL?
Cyclophosphamide, doxorubicin, vincristine, and prednisolone
What else is used if the Pt is HIV positive?
Anti-retroviral therapy
What is the prognosis for PEL?
Poor - 6 month median survival
How does the HHV8 genome exist in PEL cells?
As mono- or oligoclonal episomes
How does HHV8 lead to PEL?
Infected cells undergo clonal expansion -> neoplastic transformation
What commonly is seen in a blood test at presentation?
Lowered CD4+ count
What do a significant proportion of PEL patients already have?
Kaposi’s sarcoma or MCD
How do patients with PEL present?
Symptoms of malignant effusion e.g. dyspnoea (pericardial/pleural), abdominal distention
Does PEL commonly metastasise?
Yes
What causes death in PEL patients?
- Opportunistic infections
- HIV related complications
- Progression of lymphoma
How is PEL diagnosed?
Following virological, morphological, immunophenotypical and molecular criteria
How do PEL neoplastic cells look morphologically?
Large, have round irregular nuclei, prominant nucleoli
What is serology used for in PEL diagnosis?
HHV8 detection
How is PEL evaluated?
Full blood count, including a serum lactate dehydrogenase (elevated serum lactate dehydrogenase associated with better prognosis)
How is PEL staged?
All cases are Stage IV so Ann Arbor not used
What should all PEL pts be encouraged to do?
Get involved in well-designed clinical trials if possible
What is associated with better prognosis in PEL?
Use of HAART
What is used to combat opportunistic infections?
Use of growth factors to avoid prolonged neutropenia associated with chemotherapy
What is Burkitt Lymphoma associated with in immunosuppressed pts in non-endemic areas?
HIV infection
What can intensive chemotherapy achieve in BL pts?
Excellent outcomes in children
Poor prognosis in adults/elderly
What has shown promise in BL therapy?
Adjuvant monoclonal antiody therapy with rituximab
Who is immunodeficiency BL typically seen in?
Pts with HIV
When in HIV infection does BL most commonly occur?
In the early stages when CD4+ count is high (more than 200/microlitre)
What does EBV do to B cells in culture?
Induces immortalisation
What can EBV do to cells to promote BL?
Promote instability, disregulate telomere function, and induce DNA damage
What is the suggested pathogenic mechanism for BL developing in HIV infected pts?
Chronic antigenic stimulation (as occurs in pts with high T cell count)
How does sporadic BL commony present?
Abdominally - abdo pain, distention, N&V, GI bleeding
Next most commonly -H&N
What are the symptoms of BL presenting in the H&N?
Lymphadenopathy, involvement of the naso- or oro-pharynx, tonsils or sinuses
What % of BL patients get bone marrow infiltrated?
~20%
How does epidemic BL commony present?
Jaw or periorbital swellings, or abdo involvement
What do BL B cells contain?
Coarse chromatin and prominent basophilic nuclei
Do chromosomal break points differ between different types of BL?
Yes, but some overlap can occur
Where do epidemic BL breakpoints tend to occur?
Upstream of Myc. They occur within the Ig gene loci
Where do sporadic BL breakpoints tend to occur?
Closer to Myc
How is BL confirmed in a lab?
Microscopy and Immunocytological analysis of sample from superficial lymph node/malignant pleural fluid (most often)
Which method of biopsy is prefered and why?
Excision, as fine-needle aspirate doesn’t collect enough tissue
If BL is suspected, what tests should be performed?
- FBC (differential and film)
- ESR
- Urea and electrolytes
- LFTs
- Serum LDH
- Urate
- EBV status
- Chest imaging
What chest imaging should be done?
CT - shows disease extent
What common co-infections can be found with epidemic BL?
Malaria, Helminth infections
What should happen before chemotherapy?
These co-infections should be treated
What staging system is used for BL?
St. Jude’s / Murphy Classification
What can be used to monitor BL throughout treatment?
The signal BL gives off with fluorodeoxyglucose PET
How is BL initially managed? (cytoreduction)
With cyclophosphamide, prednisolone, and vincristine
What follows inital management of BL?
Intensive chemotherapy in varying combinations
How many cycles of moderately intensive chemo do children with completely surgically removed localised disease need?
2
How many cycles of intensive chemo do children with residual or stage 3 disease need?
At least 4
How many cycles of intensive chemo do children with CNS or bone marrow involvement need?
Up to 8 cycles
What is the cure rate of sporadic BL in high income countries?
~90%
What important side effects are there to the treatment of BL?
- Long periods of haematological toxic effects
- Mucositis
- High risk of severe infection
How do pts with Adult BL present?
With rapidly developing disease - common in the abdomen, weight loss, night sweats, unexplained fevers
