4. Lymphoma 1 Flashcards
(60 cards)
1
Q
What is a lymphoma?
A
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)
2
Q
How can we split lymphomas
A
HL = 20%
NH = 80%
3
Q
Types of lymphoid malignancies
A
ALL
NHL (B cell lineage)
NHL (T and NK cell lineage)
Hodgkin lymphoma
4
Q
process of lymphoma (3)
A
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
5
Q
two stages of Ig and TCR gene recombination (the molecular basis of an adaptive immune response)
A
(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)
6
Q
2 specific risk factors and pathways to sub-type lymphomas
A
immune system diseases (constant antigenic stimulation)
loss of T cell function
7
Q
Immune system diseases (constant antigenic stimulation)
A
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
8
Q
Loss of T cell function (permitting EBV-driven B-cell lymphomas)/B cell lymphoproliferative disease
A
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)
9
Q
3 types of tissue of the lymphoreticular system:
A
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)
10
Q
cells of the lymphoreticular system
A
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
11
Q
lymph node histology
A
- Rounded areas = B cell follicles
- Between B cell follicles = T cell areas
- Central medulla = where mature B cells eventually end up
12
Q
B cell histology
A
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
13
Q
T cell area comprises of (3)
A
- T-cells
- APCs
- High endothelial vessels
14
Q
Lymphoma CD markers often how classified:
A
- CD19, CD20 = B-cells
- CD3, CD5 = T-cells
15
Q
WHO classification of lymphoma
A
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
16
Q
Basic principles of lymphoma
A
- 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
17
Q
Cytology and histology in lymphoma
A
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)
18
Q
two other investigation in lymphoma
A
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
19
Q
3 grades of common B cell NHL and examples of lymphomas in each
A
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
20
Q
Follicular lymphoma
A
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
21
Q
Small cell lymphocytic lymphoma (CLL)
A
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)
22
Q
Marginal Zone lymphoma (MALT)
A
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
23
Q
Diffuse Large cell B-cell lymphoma (DLBC)
A
- 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
24
Q
Mantle-cell lymphoma
A
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
25
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
26
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**
27
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**
28
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)
29
Anaplastic large cell lymphoma
* children and young adults
* aggressive
* LARGE EPITHELIOID LYMPHOCYTES
* t(2;5)
* Alk-1 protein expression
30
Peripheral T-cell lymphoma
* middle-aged and elderly
* aggressive
* Large T-cells
31
Adult T cell leukaemia/lymphoma (ATLL)
* Caribbean and Japanese
* **HTLV-1 infection,** aggressive
32
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
33
Cutaneous T cell lymphoma
Associated with **mycosis fungoides**
34
T cell lymphoma summary
alemtuzumab (anti-CD52) can be used in Rx
35
B cell lymphomas summary
36
B cell lymphomas summary
37
NHL classicifciation and presentation
**Painless lymphadenopathy,** often involving multiple site's, constitutional symptoms
**NO PAIN after alcohol**
Staging as per Hodgkin's
38
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)
39
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
40
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**
41
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**
42
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**
43
Lymphoma summary
44
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
45
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**
46
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)
47
Ann-Arbor staging of HL
48
Ann-Arbor staging of HL
49
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%)
50
Nodular sclerosino HL subtype
* **F** \> M **(20-29yo)**
* Neck nodes and a _mediastinal mass_; may have B symptoms
* Spreads contiguously
* Needs tissue diagnosis
51
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
52
What is CLL?
PROLIFERATION OF **MATURE B cells**
53
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
54
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
55
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)
56
Binet staging of CLL
57
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**
57
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
58
**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**
59
Treatment for CLL
**Supportive** (50% deaths from infections) + **watchful waiting i**f 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
