Haem 5 - Lymphoma 1 Flashcards
Type of cell giving rise to
Hodgkin’s lymphoma - HL
Non-Hodgkin’s lymphoma - NHL
HL - B cell
NHL - B cell or T cell or NK cell
Lymphoma RF
Most lymphoma subtypes/cases are sporadic with no known RF
Some lymphoma subtypes have specific risk factors
- immune diseases acquired or iatrogenic
- Associated specific infections or inflammation
Key enzyme involved in class switch recombination and somatic hypermutation
Adenosine induced deaminase
What problem can arise as a result of a mutation during class switch recombination? Give examples
- Normal recombination Ig/immunoglobulin molecules brought under the promotor => promotor drives AB production
- Problem mutation occurs oncogene brought under the promotor
• Oncogenes = anti-apoptotic or proliferative o Bcl2 o Bcl3 o (C-)MYC o CyclinD1
Which types of lymphomas can be caused by chronic bacterial infection or auto-immune diseases causing chronic antigenic stimulation?
Mechanism
Give examples
Treatment
chronic antigenic stimulation –> over production of lymphocytes –> emergence of autonomous subclones that give rise to particular types of lymphomas
–> B cell NHL Marginal zone subtype (Marginal zone lymphoma)
Arises mainly at extranodal sites
o H. pylori – gastric MALT = MZL of the stomach
o Sjogren’s syndrome = MZL of salivary glands
o Hashimoto’s thyroiditis (lymphocytic destruction) = MZL of thyroid
–> Enteropathy associated T cell NHL
o Coeliac disease – small intestine EATL
• Can treat low grade disease with non-chemotherapeutic modalities
o i.e. remove antigen e.g. helicobacter eradication by abx treatment
Which virus can give rise to a lymphoma? What type of lymphoma?
HTLV1 virus - retrovirus
Infects T cells by vertical transmission
Stimulates lymphomagenesis
ATLL = Adult T cell leukaemia lymphoma
Sub-type of NHL
How can EBV drive a lymphoma?
• EBV infects B-cells EBV driven proliferation of B cells B-cells express EBV-associated antigens on cell surface proliferating B cells targeted and killed by EBV specific CTL response
- EBV switches on at later life + drives proliferation
- Low CTL due to (1) HIV or (2) immunosuppression –> EBV can drive a lymphoma (loss of CTL function = failure to eliminate EBV driven proliferation of B cells)
Rare NHL subtypes have specific risk factors:
Three main groups/mechanisms.
- Constant antigenic stimulation
Bacteria infection (chronic)
Auto immune disorders
e.g. B cell NHL marginal zone subtype or enteropathy associated T cell NHL - Viral Infection (direct viral integration of lymphocytes) e.. HTLV1 causing ATLL
- Loss of T cell function and EBV infection (EBV driven B cell lymphomas) due to
Loss of T cells (HIV)
Iatrogenic immunosuppression
What type of lymphoma is Marginal zone lymphoma?
B cell NHL
Describe the 3 tissues in the lymphoreticular system
o Generative LR tissue – generation/maturation of lymphoid cells
BM and thymus
o Reactive LR tissue – development of immune reaction
Lymph nodes and spleen
o Acquired LR tissue – development of local immune reaction
Extra-nodal lymphoid tissue (e.g. skin, stomach, lung)
Within the lymph node
where are naive B cells B cells + APC Mature B cells CD4/CD8 T cells + APC
located?
Naive B cells - mantle zone of B cell follicles located in the outer part/cortex of the lymph node
B cells + APC - germinal centres of B cell follicles
• B cell follicles = darker outer mantle zone and a paler central germinal centre
Mature B cells = medulla of lymph node
CD4/CD8 T cells + APC cells - paracortical areas of the lymph node around follicles (after they mature + leave the thymus)
Markers
Mature T helper cell Mature T killer cell T cells B lineage activated B cell Plasma cell T regulatory cells NK cells
Mature t helper cell markers --> CD3 CD4 Mature T killer cell --> CD3 CD8 T cells --> CD3, CD5 B lineage --> CD19*, CD20 activated B cell --> CD19 CD25, CD30 plasma cell --> CD138 T regulatory cells --> CD25, Foxp3 NK cells --> CD3 neg, CD56+ CD16+
All B cells express CD19 except plasma cells
https://www.abcam.com/primary-antibodies/b-cells-basic-immunophenotyping
Commonest type of lymphoma
B cell NHL (80-85%)
How does HL - hodgkin’s lymphoma spread?
tends to only affect 1 or 2 lymph node – spreads in a contiguous fashion involving contiguous lymph node groups
Follicular lymphoma characteristics
epidemiology symptom architecture cells translocation markers management prognosis
middle aged, elderly
Lymphadenopathy
Architecture - follicular
+ nodular pattern
cells - small cleaved
FISH - t14;18
over-expression of bcl-2 (an anti-apoptotic protein)
14 Ig locus
18 BCL2 locus (an anti-apoptotic protein
CD10, BCL-6+
detection of bcl-2 expression by neoplastic B cells in follicles (normal germinal centre in follicle is negative for bcl-2)
FLIPI score (follicular lymphoma international prognostic index - Similar to IPI used in diffuse large B cell NHL)
o Treatment At presentation • Watch and wait • Only treat if clinically indicated o Compression due to nodes (e.g. bowel, bile duct, ureter, vena cava) o Massive painful nodes o Recurrent infections o Treatment
Combination immuno-chemotherapy R-COP or R-CHOP (Rituximab, Cyclophosphamide, Adriamycin (H), Vincristine (O), Prednisolone)
Conventional treatment is not curative, may require 2nd or 3rd line
Prognosis
Incurable
12-15 years median survival
Mantle cell lymphoma characteristics
cyclin D1 overexpression
CD5 +ve
t11;14
Translocation 2;5 is found in which type of lymphoma?
Anaplastic large cell lymphoma
Common B cell NHL
Indolent
High grade
Aggressive
Indolent
- Follicular cell lymphoma (germinal centre origin)
- Marginal zone lymphoma (post germinal centre B cell)
- CLL (chronic lymphocytic leukaemia) / Small lymphocytic lymphoma* (naive or post germinal centre B cell)
High grade
- Burkitt’s lymphoma (germinal centre cell origin) (very aggressive)
- Diffuse large B cell lymphoma (germinal centre or post germinal centre origin)
Aggressive
- Mantle cell lymphoma (pre-germinal centre cell)
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are the same disease, but in CLL cancer cells are found mostly in the blood and bone marrow. In SLL cancer cells are found mostly in the lymph nodes.
CLL/ small lymphocytic leukaemia histopathology + risk
Small lymphocytes with granular chromatic pattern
naive or post germinal centre memory B cells
CLL- smear cells
CD5 CD23 +ve cells
risk of Richter transformation =
development of an aggressive large-cell lymphoma in the setting of underlying chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
How might mantle cell lymphoma present?
Middle aged
Disseminated disease at presentation
Lymph nodes - lymphadenopathy
GIT - pt may present with extensive polyposis
Burkitt’s lymphoma buzzwords
clinical
histopathology
molecular
mx
clinical
o jaw or abdominal mass in children/young adults
o EBV associated
o highly aggressive
histopathological
o “starry-sky” appearance
Stars – white macrophages
Sky – lymphoma cells – dark nuclei with prominent nucleoli
molecular c-myc translocation 8:14 8:22 2:8
mx
urgent admission
treat as acute leukaemia
Which marker indicated germinal centre origin?
CD10
Diffuse large B cell lymphoma buzzwords
clinical
middle aged, elderly
lymphadenopathy
sheets of large b cells
CD10 - good prognosis (indicates germinal centre phenotype + germinal centre phenotype - good prognosis)
p53 - bad prognosis (high proliferating fraction
Histopathology of T cell lymphomas vs B cell lymphomas
o More heterogenous picture compared to B cell NHL
o We don’t only have the abnormal neoplastic B cells which are medium sized/large in appearance with variable nuclei sizes
o We often see an accompanying infiltrate of reactive small lymphocytes – eosinophils, macrophages
T cell lymphomas characteristics
- Rarer types of NHL
- Middle aged
- Elderly
- Lymphadenopathy and extranodal sites
- Large T lymphocytes
- Often associated reactive cell population esp. eosinophils, macrophages
- Aggressive
Commonest form of cutaenous T cell lymphoma?
Mycosis fungoides
Types of T cell NHL
• Adult T cell leukaemia/lymphoma
o Caribbean and Japan
o Associated with HTLV-1 infection
o Has acute and chronic forms
• Enteropathy associated T cell lymphoma
o Some patients with long standing coeliac disease
o Affects small bowel and mesenteric lymph nodes
• Cutaneous T cell lymphomas
o E.g. mycosis fungoides (commonest form)
o CD4 T cells infiltrating the epidermis forming patches and plaques
• Anaplastic large cell lymphoma
Anaplastic large cell lymphoma buzzwords
clinical
histopathology
molecular
• Clinical
o Children/young adults
o Lymphadenopathy
• Histopathology o Large “epithelioid” lymphocytes o T cell or null phenotype o Large variability in cell + nuclei shape and size o Abundant cytoplasm
• Molecular
o 2;5 translocation
o Alk-1 protein expression
Alk-1 positive better prognosis
• Aggressive
Hodgkin’s lymphoma - HL
Non-Hodgkin’s lymphoma - NHL
Location
Spread
Hodgkin’s lymphoma - HL
- More often localised to a single nodal site
- Spreads contiguously to adjacent lymph nodes
Non-Hodgkin’s lymphoma - NHL
- More often involves multiple lymph node sites
- Spreads discontinuously
Diagnostic markers for classical HL hodgkin’s lymphoma
Positive for
CD15
CD30
Negative for CD20
Hodgkin lymphoma subtypes
- Classical HL (proportion of these associated with EBV) Nodular sclerosing mixed cellulariy lymphocyte rich lymphocyte depleted
- Nodular Lymphocyte predominant (no association with EBV)
Classical Hodgkin’s lymphoma histopathology
o Arises from the germinal centre or post-germinal centre cells
o Sclerosis
o Mixed population with Reed-Sternberg/Hodgkin cells (binucleate “OWL’S” eyes, large prominent nuclei) – originate from B cells
o Lymphoma cells are relatively few in number and tend to be scattered around
o Most of the cells are reactive lymphocytes (macrophages, plasma cells)
o Eosinophils
CD15, CD30 positive
CD20 negative
What is classical HL associated with
proportion of classical HL are associated with EBV
What risk is there with nodular lymphocyte predominant lymphoma
• Can transform to high grade B cell lymphoma – sheets of atypical large B cells that are much more progressive
i.e. can transform into a non-Hodgkin lymphoma
Diagnostic markers for nodular lymphocyte predominant lymphoma
Negative for
CD15
CD30
Positive for CD20
(i.e. exact opposite of classical HL)
how to differentiate between classical HL and nodular lymphocyte predominant lymphoma
classical HL
+ve for CD15, CD30
-ve for CD20
o most of the cells are reactive lymphocytes (macrophages, plasma cells) + eosinophils
o Lymphoma cells are large + relatively few in number and tend to be scattered around
nodular lymphocyte predominant lymphoma -ve for CD15, CD30 \+ve for CD20 o No oesinophils or macrophages o The reactive population in the background will just be small lymphocytes
Nodular Lymphocyte predominant Lymphoma histolpathology (NLPHL)
o Hodgkin cells scattered around infiltrate mostly composed of small lymphocytes
o Arise form germinal centre B cells – will stain positive from some germinal centre B cell markers
o B cell rich nodules
o L+H cells (lymphocytic and/or histiocytic)
Reed-Sternberg cell variants
Typical feature of NLPHL
Also known as POPCORN cells – multilobulated nucleus
What is IPI?
Where is it used?
International prognostic index Age Stage III or IV (Ann Arbor) LDH Extra-nodal disease sites ECOG performance status 2-4
used to determine the prognosis and treatment of diffuse large B cell NHL
Diffuse large B cell NHL mx
R-CHOP (6-8 cycles)
Rituximab (anti-CD10 monoclonal antibody) Cyclophosphamide Adriamycin Vincristine Prednisolone
Relapse –> autologous SCT
Alemtuzumab (anti-CD52) can be used in the management of…
The following T cell lymphomas
Anaplastic large cell lymphoma Peripheral T cell lymphoma Adult T cell leukaemia lymphoma Enteropathy associated T cell lymphoma(EATL) Cutaneous T cell lymphoma
What is Cutaneous T cell lymphoma associated with?
Mycosis fungoides
Anaplastic large cell lymphoma buzzwords
children and young adults aggressive large epithelioid lymphocytes t2;5 Alk-1 protein expression
Peripheral T cell lymphoma buzzwordss
middle aged
aggressive
large t cells
