4. Lymphoma 1 Flashcards
What is a lymphoma?
neoplastic (malignant) tumour of lymphoid cells, usually found in:
- lymph nodes, BM, and/or blood (lymphatic system)
- lymphoid organs, spleen or GALT
- Skin (often T-cell disease e.g. Mycoses Fungoides)
- Rarely “anywhere” (CNS, ocular, testes, breast etc)
How can we split lymphomas
HL = 20%
NH = 80%
Types of lymphoid malignancies
ALL
NHL (B cell lineage)
NHL (T and NK cell lineage)
Hodgkin lymphoma
process of lymphoma (3)
Recombination of DNA
- = diversity in Ig (and Ig class switching) and TCR
- = unwanted point mutations
Rapid cell proliferation in germinal centres
- = rapid response to infection
- = replication errors
Apoptosis dependency (90% lymphocytes die in germinal centres)
- = antibody specific, elimination of self-reactive clones
- = apoptosis switched off in germinal centre, acquired DNA mutation in apoptosis-regulating genes
two stages of Ig and TCR gene recombination (the molecular basis of an adaptive immune response)
(1) VDJ recombination = creates a molecule that recognises an epitope
- occurs in BM
- enzymes RAG1 and RAG2
_(2) Class switch recombinatio_n → more important for lymphoma genesis
- somatic hypermutation in germinal centre (IgM to IgG)
- enzyme: adenosine induced deaminase (AID)
AID
- Ig promotor highly active in B cells to drive AB production
- recombination errors occur
- oncogenes brought close to the promotor
- oncogenes = anti-apoptotic or proliferative (Bcl2/7,C-MYC, CyclinD1)
2 specific risk factors and pathways to sub-type lymphomas
immune system diseases (constant antigenic stimulation)
loss of T cell function
Immune system diseases (constant antigenic stimulation)
Chronic bacterial infection/auto-immune disorders
B-cell NHL marginal zone lymphoma subtype (B-cell NHL, MZL)
- H. pylori → gastric MALT = MZL of stomach
- Sjoigren’s syndrome = MZL of salivary glands
- Hashimoto’s thyroiditis (lymphocytic destruction) = MZL of thyroid (thyroiditis = de Quervain’s [viral], Reiter’s [IgG4-related]
Enteropathy associated T-cell NHL (EATL)
coeliac disease = small intestine EATL
Viral infection (direct viral integration of lymphocytes)
HTLV1 retrovirus → adult T-cell leukaemia lymphoma (ATLL) = subtype of T cell NGL
- Caribbean, Japan endemic infection
Loss of T cell function (permitting EBV-driven B-cell lymphomas)/B cell lymphoproliferative disease
Background = EBV infection:
- EBV infects B-cells → stimulates proliferation → B-cells expresses EBV-associated antigens on cell surface → CTL attack EBV-expressing B-cells → carrier state for years…
- EBV switches on at later life and drives proliferation (normally CTL will control this but if you have a low CTL due to (1) HIV or (2) immunosuppression, the EBV can drive a lymphoma)
(1) Viral killing of T-cells (HIV) → low CTL
* HIV → B-cell NHL (60x increased incidence)
(2) Iatrogenic immunosuppression / after HSCT → low CTL
* Transplant immunosuppression → Post-Transplant Lymphoproliferative Disorder (PTLD)
3 types of tissue of the lymphoreticular system:
Generative LR tissue → generation/maturation of lymphoid cells
- Bone marrow and thymus
Reactive LR tissue → development of immune reaction
- Lymph nodes and spleen
Acquired LR tissue → development of local immune reaction
- Extra-nodal lymphoid tissue (e.g. skin, stomach, lung)
cells of the lymphoreticular system
Lymphocytes
- B lymphocytes = express surface Ig, antibody production
- T lymphocytes = surface TCR, regulation of B cells and macrophage function, cytotoxic function
Accessory Cells:
- Antigen-presenting cells
- Macrophages
- Connective tissue cells
lymph node histology
- Rounded areas = B cell follicles
- Between B cell follicles = T cell areas
- Central medulla = where mature B cells eventually end up
B cell histology
B-cell area [see picture]:
- Crescent shaped region is the mantle zone where naïve unstimulated B cells are located
- B-cells migrate into germinal centre where they encounter APCs and undergo activation and selection
There is a lot of cell turnover in this area, which is a predisposing factor for lymphoma
T cell area comprises of (3)
- T-cells
- APCs
- High endothelial vessels
Lymphoma CD markers often how classified:
- CD19, CD20 = B-cells
- CD3, CD5 = T-cells
WHO classification of lymphoma
HL – classical, lymphocyte predominant
NHL – two main cell lineages:
- B-cell (most common – 80%) = precursor B-cell neoplasms, peripheral B-cell neoplasms (high and low grade)
- T-cell = precursor T-cell neoplasms, peripheral T-cell neoplasms
Basic principles of lymphoma
- Neoplastic lymphoid cells circulate in the blood (often disseminated at presentation) → Hodgkin’s lymphoma is an exception because it tends to only affect one or two lymph node groups
- Lymphoid neoplasms can disrupt the normal immune system → patients may develop immunodeficiencies
Cytology and histology in lymphoma
Cytology (single cells aspirated from a lump)
Histology (tissues)
- Architecture (nodular, diffuse)
- Cells (small round, small cleaved, large (centroblastic, immunoblastic, plasmoblastic) – large cells are suggestive of a high-grade lymphoma)
two other investigation in lymphoma
Immunophenotyping → identify proteins on/in the cells – i.e. determine cell lineage:
- Cell types (CD markers)
- Cell distribution
- Loss of normal surface proteins
- Abnormal expression of proteins (e.g. cyclin D1 is suggestive of Mantle cell lymphoma)
- Clonality of B cells (light chain expression – normal clonal proliferation → even kappa and lambda)
Cytogenetics / molecular tools → identify genetics:
- FISH – identify chromosome translocations
- PCR – identify chromosome translocations, clonal T cell receptor or Ig gene rearrangement
- DIAGNOSTIC – i.e. t (11; 14) = Mantle Cell Lymphoma
- PROGNOSTIC – i.e. t (2; 5) = Anaplastic Large Cell Lymphoma
3 grades of common B cell NHL and examples of lymphomas in each
Low-grade:
- Follicular lymphoma
- Small lymphocytic lymphoma/chronic lymphocytic leukaemia (CLL)
- Marginal zone lymphoma (MALT)
High-grade:
- Diffuse large B cell lymphoma
- Mantle zone lymphoma
Aggressive:
- Burkitt’s lymphoma
Follicular lymphoma
S/S: lymphadenopathy in the middle-aged or elderly
FOLLICULAR PATTERN, NODULAR APPEAREANCE
Mx = watch and wait, rituximab, obinutuzumab + CVP
- mostly incurable, median survival 12-15 years
- INDOLENT
Histopathology:
Follicular pattern:
- Follicles are neoplastic, they are not normal
- Often these follicles spread out of the node into the adjacent tissues
Germinal centre cell origin:
- Demonstrated by showing positive staining for CD10 and bcl-6
Molecular:
- t (14;18) translocation involving bcl-2 gene (Immunohistochemistry can be used to show that these neoplastic follicles express bcl-2 whereas normal follicles do not)
- Usually indolent, but can transform into high grade lymphoma
Small cell lymphocytic lymphoma (CLL)
S/S: Middle-aged or elderly, detected in the lymph nodes or blood
Histopathology:
- Small lymphocytes
- Arises from naïve B cells or post-germinal centre memory B cells (CD5 and CD23 positive)
- They replace the entire lymph node so that you no longer see follicles or T cell areas
Molecular:
- Multiple genetic abnormalities
- Indolent, but can transform into a higher-grade lymphoma (Richter transformation)
Marginal Zone lymphoma (MALT)
Middle-aged
CHRONIC ANTIGEN STIMULATION
- H. pylori MALT lymphoma
- Sjogren’s syndrome PAROTID lymphoma
Indolent, but can transform into a high-grade lymphoma
Mx: Can treat low-grade disease by removing the antigen (i.e. by eradicating H. pylori via triple therapy + chemotherapy
Diffuse Large cell B-cell lymphoma (DLBC)
- S/S: middle-aged and elderly, lymphadenopathy
- Aggressive
- Richter’s transformation
- other lymphomas occur 2o to DLBCL
mx = rituximab-CHOP, auto-SCT for relapse
Histopathology:
- Arise from germinal centre or post-germinal centre B cells
- LARGE lymphoid cells = SHEETS OF LARGE LYMPHOID CELLS
- The lymph node is effaced so it is not possible to identify germinal centres and follicles
Prognosis:
- Having a germinal centre phenotype is associated with a GOOD prognosis
- p53 positive and high proliferation fraction is associated with a POOR prognosis
Mantle-cell lymphoma
S/S: middle-aged males, affects lymph nodes and the GI tract, disseminated disease
- M>F
- aggresisive
- disseminated at presentation
- median survival 3-5 years
- t(11;14) translocation
- Cyclin D1 deregulation
ANGULAR CLEFTED NUCLEI
Mx = rituximab-CHOP, auto-SCT for relapse
Histopathology:
- Located in the mantle zone of the lymph node
- Arise from pre-germinal centre cells
- Aberrant expression of CD5 and cyclin D1
Molecular
- t(11;14) translocation
- Cyclin D1 over-expression
- Prognosis = median survival: 3-5 years
Burkitt’s lymphoma
S/S: Jaw/abdominal mass in children/young adults; endemic, sporadic or immunodeficiency ± EBV
Histopathology:
- Arises from germinal centre cells
- Starry-sky appearance
- Molecular: = C-myc translocation (8;14, 2;8 or 8;22)
Prognosis = it is an AGGRESSIVE disease, fast-growing
Mx = rapidly responsive to rituximab chemotherapy (anti-CD20 found on B cells) + leukaemia protocol
3 types of burkitt’s lymphoma
Endemic
- most common malignancy in equatorial Africa
- EBV-associated
- characteristic JAW INVOLVEMENT and abdominal masses
Sporadic
- found outside AFRICA
- EBV-associated
- Jaw LESS commonly involved
Immunodeficiency
- Non-EBV-assoiciated
- HIV/post transplant patients
Features of T cell lymphomas
- Middle-aged and elderly
- Presenting with lymphadenopathy and extra-nodal sites
- Large T lymphocytes
- Often found with an associated reactive cell population (especially eosinophils)
- AGGRESSIVE
5 types of T cell lymphomas
- Anaplastic large cell lymphoma
- Peripheral T-cell lymphoma
- Adult T cell leukaemia lymphoma / ATLL (Caribbean and Japan; HTLV-1 infection)
- Enteropathy-associated T cell lymphoma / EATL (long-standing Coeliac disease)
- Cutaneous T cell lymphoma (i.e. mycosis fungoides)
Anaplastic large cell lymphoma
- children and young adults
- aggressive
- LARGE EPITHELIOID LYMPHOCYTES
- t(2;5)
- Alk-1 protein expression
Peripheral T-cell lymphoma
- middle-aged and elderly
- aggressive
- Large T-cells
Adult T cell leukaemia/lymphoma (ATLL)
- Caribbean and Japanese
- HTLV-1 infection, aggressive
Enteropathy-associated T cell lymphoma (EATL)
Associated with longstanding coeliac disease (antigenic stimulation with gluten/gliadin)
- abdominal pain, obstruction, perforation GI bleeding
- malabsorption
- systemic symptoms
AGGRESSIVE → not that responsive to treatment
mx: strict adherence to gluten-free diet
Cutaneous T cell lymphoma
Associated with mycosis fungoides
T cell lymphoma summary
alemtuzumab (anti-CD52) can be used in Rx
B cell lymphomas summary
B cell lymphomas summary
NHL classicifciation and presentation
Painless lymphadenopathy, often involving multiple site’s, constitutional symptoms
NO PAIN after alcohol
Staging as per Hodgkin’s
HL: Key differences from NHL (2)
- Hodgkin is more localised (usually only one nodal site)
- Hodgkin spreads contiguously to adjacent lymph nodes (NHL involves multiple sites and spreads sporadically)
Types of HL
Classical Hodgkin Lymphoma: subtypes are…
- Nodular sclerosing = GOOD prognosis
- Mixed cellularity = GOOD
- Lymphocyte rich (GOOD) /depleted (POOR)
Lymphocyte Predominant (disorder of the elderly, multiple recurrences)
- Some relationship to NHL
Classical HL
S/S: Young and middle-aged, single group of lymph nodes
Arises from the germinal centre or post-germinal centre cells
Associated with EBV
Histopathology
- Sclerosis
- Mixed cell population with Reed-Sternberg/Hodgkin cells (binucleate ‘owl’s’ eyes)
- Lymphoma cells are relatively few in number and tend to be scattered around
- Eosinophils
Prognosis:
- Moderately aggressive
- Diagnostic markers = CD30, CD15
Classical HL
S/S: Young and middle-aged, single group of lymph nodes
Arises from the germinal centre or post-germinal centre cells
Associated with EBV
Histopathology
- Sclerosis
- Mixed cell population with Reed-Sternberg/Hodgkin cells (binucleate ‘owl’s’ eyes)
- Lymphoma cells are relatively few in number and tend to be scattered around
- Eosinophils
Prognosis:
- Moderately aggressive
- Diagnostic markers = CD30, CD15
Nodular lymphocyte predominant lymphoma
- S/S: Isolated lymphadenopathy
- Arise from germinal centre B cells (will stain positive for some germinal centre B cell markers)
- NO association with EBV
Histopathology:
- B cell rich nodules
- Scattered around L&H cells
- The reactive population in the background will just be small lymphocytes
- You do NOT see eosinophils or macrophages like you would with classical Hodgkin
- Can transform to high grade B cell lymphoma (so it can transform into a non-Hodgkin lymphoma)
Key Markers:
- NEGATIVE for CD30 + CD15 (which is seen in classical Hodgkin)
- POSITIVE for CD20
Lymphoma summary
Clinical presentation of HL
Asymmetrical painless lymphadenopathy +/- obstructive/mass effect symptoms
B-symptoms:
- fever >38 = Pel-Ebstein fever (cyclical 1-2wk) seen in a minority
- Drenching sweats at night
- Weight loss >10% in 6 months unintentional
Pain in affected nodes after alcohol
Nodes tend to be mediastinal/cervical but not always
HL epidemiology
M>F; bimodal age incidence – 20-29 year olds and >60 year olds
EBV-associated
Spreads contiguously to adjacent lymph nodes; often involves single LN group
HL investigations
CT/PET.
Tissue diagnosis: LN or BM biopsy - cells stain with CD15 & CD30
Reed-Sternberg cell – bi-nucleate/multinucleate (‘owl eyed’) cell on a background of lymphocytes & reactive cells
Subtypes: nodular sclerosing (most common), mixed cellularity, lymphocyte rich, lymphocyte depleted, nodular lymphocyte predominant (not classical HL)
Ann-Arbor staging of HL
Ann-Arbor staging of HL
Treatment of HL
LT consequences of ABVD = pulmonary fibrosis, cardiomyopathy
Disadvantages of radiotherapy
- risk of damage to normal tissues (collateral damage)
- associated with increased risk of breast/lung/skin cancer, leukaemia/myelodusplasia
- chemo + radio carries greatest risk
2nd line relapse (salvage chemotherapy) = high-dose chemotherapy + autologous/self HSCT
3rd line relapse (post-salvage) = anti-CD30 (Brentuximab Vedotin) + anti-PD1 (nivolumab)
EVERYONE gets ABVD followed by PET CT to assess response and need for any radiotherapy
KEY: after ~5 years, patients are more likely to die of a secondary malignancy or cardiovascular complications
Treatment dilemma:
- HL is curable (~80%)
- Intensify therapy → more cures (>80%) but more secondary cancers (>10%)
- Reduce therapy → less secondary cancers (<10%) but less cures (<80%)
Nodular sclerosino HL subtype
- F > M (20-29yo)
- Neck nodes and a mediastinal mass; may have B symptoms
- Spreads contiguously
- Needs tissue diagnosis
Prognostic markers and important tests for NHL
Prognosis (i.e. IPI):
- LDH (marker of cell turnover)
- Performance status
Viral infections:
- HIV serology (if appropriate, HTLV1 serology) HIV may have predisposed to NHL
- Hepatitis B serology (many patients are asymptomatic carriers of hepatitis B)
- NHL patients may be given treatments that deplete B cells
- This may cure the lymphoma, but the patient might then present with fulminant liver failure because you have reactivated any asymptomatic hepatitis B
What is CLL?
PROLIFERATION OF MATURE B cells
CLL epidemiology
- Most common (UK = 4.2/100,000/year) leukaemia in West
- Tends to affect Caucasians
- Median age at presentation: 72 years (10% aged <55yo)
- Relatives have 7 x increased risk
Same as SLL
- CLL in BM
- SLL in LN
CLL: lab findings
- Lymphocytosis (5-300 x 109/L)
- Smear cells (weak cells so break when put on a slide)
- Normocytic normochromic anaemia
- Thrombocytopaenia
- Bone marrow lymphocytic replacement of normal marrow elements
as this is an indolent leukaemia, it is often only picked up during routine blood tests for other reasons
CLL immunophenotyping
Maturity of B cells can be determined from its antigen expression, identified through immunophenotyping– B-cells express different antigens as they progress through development – mature B-cells specifically express:
- sIg
- CD-19
- CD5+ (ONLY IN CLL)
Binet staging of CLL
Prognostic factors for CLL
Binet Stage C, IgH unmutated, 17p (TP53) DELETION, LDH raised, CD38 +ve, 11q23 deletion = bad
Hypermutated Ig gene, Low ZAP-70 expression, 13q14 deletion = good
Clinical features of CLL
May be asymptomatic, often diagnosed on routine bloods (80% cases)
Symmetrical painless lymphadenopathy
BM failure - anaemia & thrombocytopenia symptoms, recurrent infections (50% deaths)
B symptoms = Weight loss, low grade fever, night sweats
Hepatomegaly & splenomegaly (less prominent)
Associated with autoimmunity (Evan’s Syndrome) – AIHA, ITP
Can progress to a form of lymphoma (DLBC, see later) – Richter’s transformation
May be asymptomatic, often diagnosed on routine bloods (80% cases)
Symmetrical painless lymphadenopathy
BM failure - anaemia & thrombocytopenia symptoms, recurrent infections (50% deaths)
B symptoms = Weight loss, low grade fever, night sweats
Hepatomegaly & splenomegaly (less prominent)
Associated with autoimmunity (Evan’s Syndrome) – AIHA, ITP
Can progress to a form of lymphoma (DLBC) – Richter’s transformation
Treatment for CLL
Supportive (50% deaths from infections) + watchful waiting if asymptomatic with slowly progressing disease
- vaccination (flu, pneumococcus), no live vaccines (i.e. VZV)
- anti-infective prophylaxis and tx = acyclovir for viral infections, PCP prophylaxis for immunosuppressed, IVIG for those with hypogammaglobulinaemia and recurrent bacterial infections
High-grade (Richter) transformation → treat as high-grade lymphoma (R-CHOP)
Young patients = allogenic stem cell transplantation
if P53 deletion = alemtuzumab, ibrutinib/adalalisib + transplant
- otherwise = clinical trial or chlorambucil/dludarabine/rituximab
