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

Haem 5 - Lymphoma 1 Flashcards by Charis Eleftheriou

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

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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

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Key enzyme involved in class switch recombination and somatic hypermutation

Adenosine induced deaminase

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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

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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

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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

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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)

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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

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What type of lymphoma is Marginal zone lymphoma?

B cell NHL

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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)

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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)

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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

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Commonest type of lymphoma

B cell NHL (80-85%)

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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

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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

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Mantle cell lymphoma characteristics

cyclin D1 overexpression
CD5 +ve
t11;14

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Translocation 2;5 is found in which type of lymphoma?

Anaplastic large cell lymphoma

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Common B cell NHL

Indolent
High grade
Aggressive

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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

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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?

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Middle aged
Disseminated disease at presentation

Lymph nodes - lymphadenopathy
GIT - pt may present with extensive polyposis

Burkitt’s lymphoma buzzwords

clinical
histopathology
molecular
mx

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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?

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CD10

Diffuse large B cell lymphoma buzzwords

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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

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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

Haem 5 - Lymphoma 1 Flashcards

(43 cards)