Lymphoid Neoplasms Flashcards
1
Q
What are the three types of lymphoid neoplasms
A
B-cell, T-cell, and NK-cell origin
2
Q
Major difference between leukemia and lymphoma
A
Leukemia: bone marrow and peripheral blood (ex: acute lymphoblastic leukemia, chronic lymphocytic leukemia)
Lymphoma: discrete tissue masses
- lymph node (ex. diffuse large B-cell lymphoma
- extranodal (ex. MALT lymphoma of stomach)
Note: in reality, theres so much overlap (i.e. lymphomas can spill into the blood “leukemic phase”)
3
Q
Site of origin for lymphoid tissue neoplasms (4)
A
- lymph node
- spleen
- thymus
- bone marrow
(and other sites)
4
Q
What are the four things you must integrate for a diagnosis, according to WHO classification
A
- morphologic
- immunophenotypic
- genetic
- clinical
5
Q
WHO classifications of lymphoi neoplasms (5)
- Precursor B-cell neoplasm
- Peripheral B-cell neoplasm
- Precursor T-cell neoplasm
- Peripheral T-cell neoplasm
- Hodgkin lymphoma
A
6
Q
Two most frequent lymphoma types
A
DLBCL (30%)
Follicular Lymphoma (20%)
7
Q
6 main etiologies and pathogenesis of lymphoma
A
- acquired genetic abnormalities (chromosomal translocations, other mutations)
- inherited genetic abnormalities
- viruses
- chronic inflammation
- iatrogenic factors (from medical treatment)
- smoking
8
Q
Abnormal monoclonal (neoplastic)
antigen receptor gene rearrangement
A
express same antigen receptor
IgH, TCR
9
Q
4 diagnostic tools
A
- Morphology (light microscopy)
- Immunophenotyping
- cytogenetics/FISH
- molecular diagnostics (PCR)
10
Q
What are the two subsets of morphology (light microscopy) as a diagnostic tool?
A
- Patterns
- follicular/architecture (e.g. follicular lymphoma)
- diffuse patterns (eg. diffuse large B cell lymphoma)
- Cytology
- small cells (eg. CLL/SLL)
- large cells (eg. DLBCL)
11
Q
2 subsets of immunophenotyping
A
1) immunohistochemistry
2) flow cytometry
12
Q
lymphoid progenitor markers (3)
A
Tdt
CD34
HLA-Dr
13
Q
Pre-B markers (6)
A
CD19
CD20
CD10
Dr
Tdt
cig
14
Q
mature B cell markers (3)
A
CD19
CD20
slg
15
Q
plasma cell makers (2)
A
CD138
CD38
16
Q
Important T cell markers (before differentiating into mature cytotoxic and helper T cells)
A
CD1-CD8
17
Q
Mature Cytotoxic T cell marker
Mature Helpter T cell marker
A
cytotoxic: CD8
helper: CD4
18
Q
Which is the most common cancer in children
A
Acute Lymphoblastic Leukemia (ALL)
19
Q
ALL has symptoms similar to AML. What are 4 exceptions?
A
In ALL:
- lymphadenopathy/organomegaly is more common
- Sanctuary site involvement
- Can sometimes present like a lymphoma (for example: T-ALL tends to present as a mediastinal mass)
- CNS involvement
20
Q
Origin of ALL (Acute Lymphoblastic Leukemia)
A
hematopoietic stem cell
21
Q
Genetic abnormalities in ALL-general concepts (3)
A
- multiple mutations (not just 1 single mutation can produce ALL)
- These varied mutations deregulate transcription factors needed for differentiations aka block normal maturation
- Ph chromosome 190 kDA (as opposed to the typical 210kDa we see in CML)
22
Q
90% ALL cases have numerical or structural chromosomal abnormalities. List the 3
A
- hyperdiploidy (most common)
- hypodiploidy
- balanced translocations
23
Q
What is the key difference between a meyloblast and a lymphoblast?
A
myeloblast tend to be bigger and have moderate cytoplasm
lymphoblasts are a little smaller, can barely see cytoplasm, and have immature chromatin
when you see a slide collection, you can narrow it doen to ACUTE leukemia, but can’t commit to lymphoid or meyloid. Need to do flow cytometry to determine the lineage
24
Q
What are prognostic factors for ALL? (3)
Overall, what is the prognosis?
A
- Age (worse if under 2 or over 10
- WBC (>100,00/ul), poor prognostic feature
-
Karyotype
- good: hyerdiploidy, trisomy 4, 7, 10, t(12;21)
- Philadlephia chromsome t(9;22): good thing about Ph is we have targeted treatment (imatinib/gleevec)
Overall, good prognosis! 78-85% children cured
25
What is the problem in Non-Hodgkin Lymphomas?
What type of cell (at what stage) does the problem arise?
- Arrest at maturation OR over-proliferation at a particular stage of development
- arises from mature lymphocytes
26
Increase in LDH--what is it, what does it mean?
- clinical feature of lymphoma
- indicates you're dealing with high grade
27
"B symptoms"
Fever, night sweat, weight loss
associated with lymphomas
28
Mature B Cell Neoplasms (B-NHL)
Pre germinal center:
Mantle cell lymphoma
29
Mature B Cell Neoplasms (B-NHL)
Germinal center: (3)
- follicular lymphoma
- burkitt lymphoma
- DLBCL
\*also see hodgkins occur at germinal center, but we're talking here specifically about non-hodgkins\*
30
Mature B Cell Neoplasms (B-NHL)
Post germinal center: (4)
- CLL
- Marginal zone lymphomas
- Waldenstrom macroglobulinemia
- Multiple Myeloma
31
Lymphomagenesis: two important general mechanisms
1. activation of **proto-oncogenes**
2. inactivation of **tumor suppressor genes**
32
What are the two main types of proto-oncogene activations that occur in lymphomas?
- translocation (usually involves immunoglobulin heavy chain gene)
- point mutation
33
Most common inactivation of tumor suppressor gene in lymphoma development. What is the requirement of this type of inactivation?
p53 is most common example
- you NEED bi-allelic inactivation
- one allele deleted and one mutated
34
t(14;18)
- type of lymphoma
- result of the translocation
Follicular lymphoma
Bcl2 over expression (blocks apoptosis)
35
t(11;14)
lymphoma
gene affected
Mantle cell lymphoma
BCL1 / Cyclin D1
36
t(8;14)
t(8;2)
t(8;22)
- lymphoma
- gene affected
Burkitt's lymphoma
MYC
37
Besides activation of proto-oncogenes, and inactivation of tumor suppressor genes, what are 3 other mechanisms of lymphomagenesis?
**1. INFECTIONS by oncogenic viruses**
- HHV-8 (primary effusion lymphooma)
- EBV
**2. Antigenic stimulation**
- H. pylori infection
- MALT lymphoma of the stomach
**3. Host immunodeficiency**
- HIV
- immunosuppressive theraoy
38
Memory B-cells are associated with what two types of lymphomas?
1) Chronic Lymphocytic leukemia
2) MALT lymphomas
39
In terms of lymphoma grading, explain the major differences between "low" grade and "high" grade. What are examples of each? (2)
_Low grade:_
indolent, long survival but not curable, disseminated at presentation (follicular lymphoma, CLL/SLL)
_High grade:_
short survival if untreated, curable (50%) if aggressively treated (DLBCL, Burkitt lymphoma)
40
Ann Arbor Classification / Lymphoma staging
What does "A" "B" and "E" mean?
A = no symptoms (think A for **A**bsent)
B = presence of **B** symptoms
E = **E**xtranodal site contiguous to a nodal site
41
Lymphoma Staging / Ann Arbor Classifications
Briefly describe Stages I-IV
I: single lymph node region
II: two lymph node regions on _same side of diaphragm _
III: lymph node regions or structures on _both sides of diaphgram_
IV: involvement of an _extranodal site (beyond E),_ usually bone marrow or liver
42
two major differences between Non-Hodkin and Hodgkin lymphoma
NHL: spreads in less predictable fashion, widespread growth
HL: spreads in predictable fashion, contiguous growth
43
most common leukemia
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
44
How do most patients look with CLL/SLL?
What are two possible fates of CLL?
_many pts are asymptomatic_
CLL can transform to _more aggresive lymphoid neoplasms:_
- prolymphocytic transformation (prolymphocytes are large lymphoid cells)
- Richter's transformation to large B-cell lymphoma
45
4 types of Genetics involved in CLL pathogenesis
- deletions (11q, 13q, 17p)
- trisomy 12
- Somatic hypermutated vs Non-mutated Ig variable genes (hypermutated have better prognosis)
- Notch1 receptor
\*\*unlike most other lymphoid malignancies, **translocations are rare in CLL/SLL**\*\*
46
Describe CLL morphology on a peripheral blood smear
small round lymphocytes with mature chromatin and round nuclei
pattern: clubbed, dark chromatin
47
What exactly is Small lymphocytic lymphoma
CLL in a lymph node
basically CLL can present as a leukemia in blood or lymphoma in lymph node, or both.
48
Classic immunophenotype of CLL (3)
**CD20+** (B-cell)
**CD5** (T cell marker, but just so happens to be expressed on CLL, also see in mantle cell lymphoma)
**CD23**
In addition you'd see: **CD45** (general leukocyte marker), **CD19, CD20** (B-cell marker), **kappa or lambda light chain restriction **(monoclonality)
49
what does follicular lymphoma typically present with
lymphadenopathy
50
Classic immunophenotype of Follicular Lymphoma
**CD20+**
**CD10+**
**BCL2+, BCL6+**
(recall that CLL is CD10 negative. CD10 is also see in Burkitt)
also see CD45, CD19
51
follicular pattern
what type of cells do you see
nodular pattern
small cell centrocytes
large cell centroblasts
52
does DLBCL have good response to chemo?
YES. Good response to intensive combination chemotherapy:
60-80% complete remission
40-50% cured
This goes to show that aggressive (high grade) lymphomas such as DLBCl that may be nodal and/or extranodal can have good response to chemo. In fact, low grade lymphomas are TOUGHER to treat with chemo.
53
DLBCL subtypes (4)
- T-cell/Histiocyte-rich large B-cell lymphoma
- Primary DLBCl of CNS
- Primary cutaneous DLBCL, leg type
- EBV positive DLBCL of the elderly
54
Diffuse Large B-cell Lymphomas are molecularly heterogenous. What are 3 main genes that can be affected?
1) BCL6 (translocations with breakpoint in chromosome 3q27; mutations in BCL6 promoter regions
2) BCL2 t(14;18)
3) MYC
55
What is Marginal Zone Lymphoma associated with?
Chronic inflammation or infection
56
Lymphoma associated with memory B cells
Marginal zone Lymphoma-post germinal center B-cell deviation
57
Marginal Zone lymphoma is comprised of what type of cells? What are the 3 main locations?
B-cell lymphocytes comprised of small cells
1) **MALT** lymphoma (extranodal sites i.e. stomach, thyroid)
2) **Nodal** marginal zone lymphoma (arising in lymph nodes)
3) **splenic** marginal zone lymphoma
58
role of persistent antigen stimulation and chronic inflammation
polyclonal--\> monoclonal
59
Gastric MALT lymphoma:
- translocations
- upregulation
- TF activation
- effect
- t(11;18), t(14;18), t(1;14)
- upregulate **BCL10** and/or **MALT1**
- MALT1/BCL10 complex part of signaling pathway that activates the transcription factor **NF-kB**
- NF-kB promotes B-cell proliferation
60
CD10+
Follicular Lymphoma, Burkitt Lymphoma
61
Burkitt lymphoma
- type of cell and marker
- lymphoma grade, who it occurs in
- high grade, children and young adults
- MATUREB cells, CD10+
62
Two types of Burkitt lymphoma
Endemic:
- associated with EBV
- jaw (African)/abdomen(sporadic), visceral mass
Non-endemic:
-ileo-cecal or peritoneal mass
63
What do plasma cell neoplasms secrete?
Almost always secrete an antibody or antibody fragment (e.g. light chain)
64
What are the 5 main types of plasma cell neoplasms?
1) Plasma cell myeloma (Multiple Myeloma)
2) Waldenstrom Macroglobulinemia
3) Heavy chain disease
4) Amyloidosis (primary)
5) monoclonal gammopathy of undetermined significance (MGUS)
65
What can the M component B in monoclonal plasma cells? (3)
- complete antibody
- heavy chains
- light chains (urine: Bence Jones proteins)
66
M-spikes
-since neoplastic plasma cells produce immunoglobulin, M spike is seen most commonly due to monoclonal IgG or IgA
present in plasma cell myeloma (Multiple Myeloma) and occasionally found in asymptomatic patients (MGUS)
67
Proliferation and survival of neoplastic plasma cells depends on: (2)
- IL-6
- bone marrow stromal cells
68
Myeloma cells upregulate pathways. Provide one important example
activate osteoclasts--\> increased bone resorption --\> hypercalcemia
69
Diagnosis of plasma cell myeloma: 3 main signs
1) increased # of plasma cells
2) Monoclonal (M spike)
ex. IgG/Kappa, SPEP/UPEP/IFE, increase in serum free light chains
3) end organ damage "CRAB"
- hypercalcemia, renal failure, anemia, lytic bone lesions/back pain
70
Hodkins Lymphoma: 4 clinical and laboratory features
- HL starts in ONE lymph node or chain of nodes, and typically spread to anatomically **contiguous lymph nodes**
- lymphadenopathy, splenomegaly, hepatomegaly, bone marrow, other tissues
- B symptoms (fever, night sweats, weight loss)
- Anemia, increased ESR (how much inflammation in the body), eosinophilia
- Cell mediated immune defects
71
Hodgkin Lymphoma pathogenesis
* Hodgkin Reed Sternberg cells (HRS): most often derive from germinal center B cells
* cells have somatic hypermutation
* loss of B-cell genes, reprogrammed gene expression
* Activation of NF-kB
* multiple signaling pathways and TF are deregulated
* activation of NF-kB by EBV
* NF-kB activated: promote lymphocyte survival and prolifreation
* rescue crippled germinal center B-cells
72
In general, what do HRS cells attract?
INFLAMMATORY cells into the tissue (inflammatory cells can make up to 90% of the tumor: HRS are the minority)
73
List the 4 main cytokines/chemokines HRS stimulate and their effects
1. GM-CSF --\> increased WBC and monocyte/macrophage activation
2. IL-5 --\> eosinophilia --\> TGF-beta --\> Fibrosis
3. TGF-beta --\> fibrosis
4. TNF --\> fever, malaise, cachexia, acute/chronic phase proteins
74
Under classical Hodgkin Lymphoma, what are the 4 WHO classifications?
1. nodular sclerosis
2. lymphocyte rich
3. lymphocyte depeletion
4. Mixed cellularity
75
Classical Hodgkin Lymphoma markers (2)
**CD30+ CD15+**
CD20-, CD45-
76
targeted therapy for Hodgkin lymphoma
anti-CD30 antibodies
77
early stage HL can be treated with \_\_\_\_
B symptoms require \_\_\_\_\_
early stage (IA, IIA): radiation therapy
B symptoms (and Stage III and IV): chemotherapy
78
