Lymphomas Flashcards
1
Q
Lymphadenopathy (LAD)
A
- In young people most are not malignant, but rather a reactive hyperplasia (local or systemic) to an infection
- In DDx for lymphomas you should include: reactive hyperplasia, primary neoplasm (lymphoma) and neoplastic metastasis
- Chances that LAD is lymphoma increase w/ age
- LAD unlikely to be malignant if it lasts >2wks w/o other symptoms, or over 1 yr w/o growing
2
Q
Malignant lymphomas
A
- The malignant lymphocytes in lymphomas circulate in blood to a degree
- Lymphomas can also occur in spleen, GALT, MALT, skin, and BM
- When the neoplastic cells are also found in large amounts in blood the disease is a lymphocytic leukemia
- Lymphomas can be B cell (large or small, diffuse or follicular), and T cell (diffuse only) in origin
- Account for 10% of all cancer deaths
3
Q
Methods to analyze lymphomas
A
- Morphology in biopsy
- Immunohistochemistry
- Flow cytometry (FC) to see wham markers are expressed
- FISH to see what translocations present
- Molecular changes to identify mutations
4
Q
Incidence for various lymphomas
A
- Hodgkin’s lymphoma (HL): 15% in adults, rare in kids
- Non-hodkin’s lymphoma (NHL): many types
- Follicular B cell: 30% in adults, rare in kids
- Burkitt’s: 30-50% of child lymphomas
- DLBCL: 30% in adults, rare in kids
- T cell lymphoblastic (TCLL): 40% of child lymphomas
- Burkitt’s and T lymphoblastic resembles embryonic origin cell types, the rest are adult cell types
5
Q
Etiology of lymphomas
A
- Multiple hits occur, a sustained immune response increases the hit rates (most are translocation events)
- Translocations often involve chromosomes 2, 22 (both for Ig light chain), and chrom 14 (Ig heavy chain)
- Other agents include viruses such as HTLV1 (human T leukemia virus) causing TCLL and EBV causing Burkitt’s
- Autoimmune and immunodeficiency disease show increased incidence (abnormal sustained stimulation)
6
Q
Chromosomal markers for lymphoma
A
- Burkitt’s shows a t(8;14), which moves c-myc (8) next to Ig heavy chain (IgH, 14). This up regulates c-myc, converting it to an oncogene and and increasing cellular proliferation
- Follicular center B cell (FCC) shows a t(14;18) that moves the bcl2 (18) gene next to IgH (14). Leads to over expression of bcl2, which inhibits apoptosis. This prevents cell death and the cells accumulate
- Mantle cell lymphoma shows a t(11;14) w/ up regulation of bcl1 (coding for cyclin D, 11) by moving it next to IgH (14). The up regulation of cyclin D leads to increased proliferation
7
Q
Dx for lymphomas
A
- Almost all monoclonal lymphocytic proliferations are considered as malignant lymphomas or lymphocytic leukemias
- There is a difference in how aggressive they are
- The gold standard for Dx is to biopsy the lymph node by removing the entire thing (morphologic classification)
- Other methods include CD markers, monoclonality (based on K/L light chains or heavy chains, TCR rearrangement, translocations)
- Also the size of the cell: large, intermediate, small
8
Q
Morphology of lymphomas
A
- Loss of normal LN architecture (cortex-> paracortex-> medulla from out to in), w/ or w/o follicles, mantle, marginal zones
- Cell size as compared to RBC (normal sized lymphocyte is around 10um)
- Presence of reed-sturnberg cells (RSCs) to divide HL from NHL (HL has RSCs)
- Diffuse (B or T) or follicular pattern (B only)
- Small cells are more mature, slower growing (well-behaved, seen in CLLs, FCC, mantle, marginal)
- Intermediate cells (burkitt’s) are usually rapidly dividing cells
- Large cells (DLBCL) are rapidly dividing and aggressive
9
Q
Characteristic phenotyping
A
- Based on pattern of CD markers, determined by IHC on sections or FC on live cells
- B cell markers: 19,20,21,22,79 (most around 20)
- T cell markers (≥8): 2,3,4,8
10
Q
Monoclonality
A
- Can also be distinguished by FC and IHC
- Presence of monoclonal light or heavy Ig chain
- Clonal Ig gene rearrangement
- Clonal TCR gene rearrangement
- Translocations/other genetic markers
11
Q
Classification of precursor lymphomas
A
- Can be B cells (B lymphoblastic leukemia/lymphoma, BALL) or T cells (T lymphoblastic leukemia/lymphoma, TALL)
- Both subsets are TdT+, CD34+ (stem cell marker)
12
Q
Classification of HLs
A
- Only B cell (RSC is the malignant cell)
- Nodular sclerosis (CD20-, CD15/30+)
- Lymphocyte predominant (CD20+, CD15/30-)
- Mixed cellularity (CD20-, CD15/30+)
- Lymphocyte depleted (CD20-, CD15/30+)
13
Q
Classification of B cell NHLs
A
- Small cell (CLL)
- Lymphoplasmacytic (waldenstrom’s)
- Multiple myeloma (MM)
- Marginal zone
- Follicular center cell (FCC)
- Mantle cell
- DLBCL
- Burkitt
14
Q
Classification of T cell NHLs
A
- Adult T cell
- Mycosis fungoides (sezary)
- Peripheral T cell
- Anaplastic large cell
15
Q
Precursor B (acute lymphoblastic lk/lymphoma)
A
- A type of B cell ALL, some may merge w/ Burkitt’s
- Cells resemble lymphoblasts, particularly occurs in childhood
- Display early CD markers, CD19,20 and CD10, as well as TdT+
- All B cell lymphomas (mature and lymphoblastic) show Ig gene rearrangement
16
Q
Mature B cell types
A
- Constitute lymphomas in adults, cells resemble mature lymphocyte phenotypes
- All (except plasmacytic) display CD19, 20, and 79 as the common B cell phenotypic markers
- All are monoclonal, some produce monoclonal Ig (especially plasmacytic)
- All B and T cell lymphomas besides ALL are mature cell type lymphomas
17
Q
B small cell lymphocytic lymphoma
A
- The same as CLL
- Diffuse proliferation of uniform, small lymphocytes, no histeocytes (no cells are dying)
- Disease of accumulation; long survival even untreated, difficult to cure
- Lymphoma is the tissue involvement of CLL, involves multiple nodes, spleen
- Has polymorphocytic varieties; some are larger cells and may be more aggressive
- t(11;19) bcl3 upregulated-> more NFkB
- Bad prognosis: presence of ZAP70
- Prognosis also depends on IgH mutations and CD38 expression
18
Q
Lymphoplasmacytic lymphoma (waldenstrom’s)
A
- Similar to small lymphocytic lymphoma but shows plasmacytoid differentiation, slow growing
- IgM monoclonal Ab (spike) common in serum, may produce hyperviscosity
- May have t(9;14) of pax5 (9) to IgH, up regulating pax5
- Pax5 encodes B cell specific activating protein
19
Q
Mantle cell lymphoma
A
- Comprised of mantle zone cells (at periphery of follicles), small B cells
- Aggressive and requires different Rx from other small B cell lymphomas
- Associated w/ t(11;14) which moves bcl1 (encoding cyclin D1) on chrom 11 onto IgH (14) and up regulates it
- More cyclin D leads to increased proliferation (induces G1->S phase transition)
20
Q
Follicular center cell (FCC) lymphoma
A
- One of the most common forms of NHL, predominantly small FCC lymphocytes (centrocytes)
- Can also have subtype that has a higher proportion of larger dividing (transformed type) cells (centroblasts)
- The more centroblasts, the more aggressive
- Most are due to t(14;18), where blc2 (18) is moved next to IgH thus increasing bcl2
- Bcl2 inhibits apoptosis thus cells accumulate
- Display all usual B cell markers plus CD 10
- Can be grade 1, 2, or 3 based on how many large cells there are
- Can complicate by progressing to DLBCL (if a single LAD LN grows even more)
21
Q
FCC vs reactive hyperplasia
A
- In FCC there will be loss of LN architecture; everything will be follicles (follicles extend to paracortex and medulla)
- In reactive hyperplasia the follicles simple grow in size and number but stay in the cortex
- In reactive hyperplasia (RH) there are tingible body macrophages (histeocytes) in the germinal centers (GC), which eat up the dead B cells from apoptosis (proliferate in response to infection but most die)
- In FCC there are no histoecytes, because the proliferating lymphocytes aren’t dying from apoptosis
- Can also stain for bcl2 in follicles
- Use FC to determine monoclonality (K/L ratio not 2:1)
22
Q
Marginal zone lymphoma
A
- Can be nodal, splenic, or extra-nodal, in GI is MALToma
- MALToma in stomach can be due to H pylori infection (disappears w/ antibio Rx)
- Due to proliferation of small B cells that expand in the marginal zone
- MALTomas often also contain many plasma cells and blur w/ lymphoplasmacytic lymphoma
- MALTomas can be formed during chronic inflammatory states
- Enlargement of marginal zone from post-GC B cells
- t(11;18)
23
Q
Multiple myeloma (MM)
A
- Neoplastic plasma cells in BM causing multiple lytic lesions (not usually in LNs)
- Typically shows monoclonal Ig (IgG or IgA, never IgM) spike
- Always starts as MGUS (monoclonal gammopathy of unknown significance)
24
Q
Diffuse large B cell lymphoma (DLBCL)
A
- Large B cells containing prominent nucleoli and abundant cytoplasm (CD20+)
- Poor prognosis but many respond to CRx
- Many show abnormalities of bcl6 gene, t(3;14)
- Others show t(14;18), and are thought to be a progression of an FCC lymphoma to large cell type (worse prognosis)
- Common (30% of adult lymphomas)
- Can present as mediastinal masses
25
Q
Burkitt lymphoma
A
- Aggressive and very common in children, associated w/ EBV
- Cells are CD20+, TdT- (not precursor cells)
- Due to t(8;14) moving c-myc (8) next to IgH (14) and up regulating myc, leads to very rapid cell proliferation
- Often presents on jaw (african form) or abdomen (sporadic form)
- Cells divide so fast that they die and histeocytes are recruited to clean up, forming the starry sky (stars are histeocytes against a see of blue neoplastic lymphocytes)
26
Q
Precursor T (acute T lymphoblastic lk/lymphoma)
A
- Children and young adults (especially males)
- Commonly presents as mediastinal mass, then becomes leukemic (mediastinal masses in females usually due to NS HL)
- Diffuse proliferation of primitive cells resembling embryonic T lymphoblasts
- High mitotic rate, aggressive
- Variable genetic abnormalities
- Expresses TdT and variably express T markers (CD1,2,3,4,5,7,8)
- All T cell lymphomas show TCR gene rearrangement
27
Q
Mature T/NK lk/lymphomas
A
- Most express CD3, other T markers variably present
- Much rarer than B cell lymphomas except in some asian countries
- Peripheral T cell lymphoma: resembles DLBCL but has CD3+ and CD20-
- Cutaneous T cell lymphomas (mycosis fungicides): small cells w/ folded (cerebriform) nuclei, frequently composed of CD4+ helper T cells (related condition is sezary syndrome)
- Adult T cell lymphoma/lk: uncommon but due to HTLV1
- Anaplastic large cell lymphoma (ALCL): characterized by CD30+ but may also show T cell CD markers, have t(2;5) translocation involving npm/alk, cutaneous is less aggressive than nodal form
28
Q
Hodgkin Lymphoma (HL)
A
- Characterized by presence of the malignant reed-sternberg cell (RSC) which is binucleate (large nuclei, mirror image, owl-eyes), a deranged B lymphocyte
- Bimodal age incidence w/ a peak in early adulthood and another in old age
- Cause is not known, some evidence it is due to infective agent (EBV found inside RSCs)
- Various phases of Ig gene rearrangement
- Hodgkin’s cells are mononuclear RSCs
- The few RSCs are surrounded by normal cells (lymphocytes, plasma cells, histeocytes, ect) which were recruited by release of cytokines by the RSCs (tumor is mostly normal cells)
- Often present w/ B symptoms: night sweats, fever, weight loss (due to cytokines) and this has lower prognosis
- Patients are often immunodeficient (can get OIs) due to T cell derangement from decreased IL2 secretion, increased TGFB (up regulates Threg), decreased T cell #, and functional impairment
29
Q
Classical HL
A
- 4 subtypes, all have RSCs that express CD15 and CD30 (most have incomplete Ig gene rearrangement), in contrast to lymphocyte-predominant which shows CD20, CD45
- The FC of HL looks much like reactive hyperplasia (normal FC) b/c majority of cells are normal (except lymphocyte-depleted)
- CD68+ macrophages present is associated w/ poor prognosis (tumor promoting)
- CD68- mac’s are anti-tumor and have better prognosis
30
Q
Nodular sclerosing HL
A
- Most common form of HL (70%)
- Broad bands of collagen circumscribing nodules of neoplastic tissue
- RSCs often sit in big open spaces (lacunar cells)
- Often present in cervical node, or in a young female presents as mediastinal mass
- Usually presents early stages and has slow progression
31
Q
Other types of classical HL
A
- Lymphocyte rich: best prognosis, numerous lymphocytes w/ few RSCs
- Mixed cellularity: intermediate prognosis, associated w/ abundant eosinophils (due to IL5 release) and other blood cells
- Lymphocyte depleted: very many RSCs and few lymphocytes, has worst prognosis (usually presents at stage III or IV) and is usually seen in elderly and HIV pts
32
Q
Lymphocyte-predominant (LP) HL
A
- Characterized by numerous lymphocytes and a few RSCs (good prognosis)
- Usually occurs in nodular form, presents as stage I and progresses slowly
- Contains polyploid variants of RSCs w/ lobulated nuclei (popcorn cells)
- RSCs express CD45 and CD20 (not CD15 or 30), and are positive for Ig gene rearrangement
- Now considered a form of B cell lymphoma
33
Q
Ag expression during B cell development
A
- CD10 and CD20 are the best markers to look for to determine if a B cell is immature (blast) or mature (cyte)
- CD10 is expressed on blasts in the BM (neoplasms lead to ALL)
- CD 20 is expressed on mature B cells (in BM and in periphery)
34
Q
Origin of B cell lymphomas
A
- Many of them arise in the germinal centers
- This includes: FCC, Burkitt’s, DLBCL (can also be activated B cell type), lymphocyte-predominant HL, classical HL
- BCLL can be from memory cells or marginal cells (either from pre or post-GC B cells), MALTomas from marginal cells (in setting of infection the lymphoid tissue will develop de-novo)
- Mantle cell lymphoma from mantle cells
- Multiple myeloma from plasma cells
- Waldenstrom’s from plasmablasts
- B cells more likely to be malignant b/c they have gene rearrangement more often
35
Q
Lymphocyte precursor surface markers
A
- PreB cells express CD34+, CD10+, CD19+, TdT+ (CD20 + or -)
- PreT cells express CD34+, CD2+, TdT+ (CD4/8-)
36
Q
ALL in children
A
- High risk: male, mediastinal mass (T cell), high WBC
- Increasing age a risk factor
- Presence of Ph+ chrom t(9;22) bcd-abl is poor prognosis (5% in children, 25% in adults)
- Childhood ALL has 85% cure rate
- In adults 60-80% enter remission from ALL after induction, 35-40% still in remission at 2 yrs
37
Q
Rx of ALL
A
- DVAP and L-asparaginase for induction, CNS prophylaxis, maintenance
- Rotating chemo for consolidation
- Tyr kinase inhibitors (imantinib) added if Ph+ (bcr-abl+)
- High risk pts get HSC Tx
38
Q
Classification of NHL based on tumor behavior
A
- Indolent NHL: low grade associated w/ slow disease progression, usually incurable by standard Rx (FCC)
- Aggressive NHL: intermediate and high grade, can be fatal in mos if untreated but can be cured w/ intense RX (DLBCL)
39
Q
Chromosomal translocations of B cells malignancies
A
- Mantle cell lymphoma: t(11;14) of oncogene bcl1 up regulating cyclin D1 protein (G1/S inducer)
- FCC lymphoma: t(14;18) of oncogene bcl2 upregulating BCL2 protein (antiapoptotic)
- CLL: t(11;19) of oncogene bcl3 up regulating protein NF-KB inhibitor
- Burkitt’s: t(8;14) of oncogene c-myc upregulating c-myc and inducing proliferation
- DLBCL: t(3;14) of oncogene bcl6
- Marginal zone: t(11;18)
40
Q
Risk factors for NHL
A
- Pesticides, chemicals, radiation, CRx
- Viruses: EBV for burkitt’s/HL (LMP1, latent membrane protein 1, from EBV has malignant transformation capacity), HTLV1 for T cell
- Other infections: H. pylori (MALToma), HepC (DLBCL)
- Immunosuppression: HIV, Tx pts, AID (HL)
41
Q
Staging of NHL and HL
A
- Stage 1: Involvement of a single LN
- Stage 2: involvement of ≥2 LNs but all on one side of the diaphragm
- Stage 3: involvement of ≥2 LNs but on both sides of the diaphragm
- Stage 4: extra-nodal involvement (other organs)
42
Q
HL statistics
A
- Bimodal age distribution: one peak btwn 2nd and 3rd decade of life, other peak btwn 5th and 6th decade of life
- M:F is 2:1 early in life, equal later in life
- Mixed cellularity is more common at younger ages
- more common in immune deficiency
- 50% of RSCs contain EBV genomes
- B symptoms in 20% of pts
43
Q
Indolent lymphomas
A
- FCC, small B cell, MALT, waldenstrom’s
- Together account for 30-40% of NHLs
- Often asymptomatic until stage 3 or 4
- Long median survival (10 years), w/ 30% chance of transformation to aggressive lymphoma over those 10 yrs
- Advanced disease rarely curable w/ conventional Rxs
44
Q
Prognosis of FCC stats
A
- Based on NoLASH: # of LNs involved, elevated LDH, age ≥60, stage3/4, Hb<12
- 0-1 of the above is low risk, 2 of the above is intermediate, 3-5 of the above is high risk
- Low risk prognosis is 90% for 5 yrs and 70% for 10
- Intermediate prognosis is 78% for 5 yrs and 50% for 10
- High risk prognosis is 52% for 5 yrs and 36% for 10
45
Q
Rituximab
A
- Chimeric Ab made of half mouse and half human (Fc portion) that binds to CD20
- Activates complement (CDC), causes ADCC, apoptosis, and interacts w/ Fc receptors on macs for phagocytosis, increases cytotoxicity of other chemo agents
- Apoptosis of CD20 cells bound by Rituximab due to cross-linking of the CD20s, which down regulates BCL2 and allows for apoptosis in FCC tumors
46
Q
Biology of CLL
A
- Inhibition of apoptosis and low proliferation index results in accumulation of CLL cells (BCL2 often is over expressed)
- t(11;19) of oncogene bcl3 up regulating protein NF-KB inhibitor
- Cells either from pre or post GC B cells
- Most common type of adult leukemia, many are asymptomatic
- Symptoms include: B symptoms, HSM, LAD, ID, AID
- Can transform in to DLBCL or prolymphocytic leukemia
47
Q
Indolent T cell lymphomas
A
-Cutaneous T cell lymphomas: mycosis fungoides, sezary syndrome
48
Q
Aggressive NHL
A
- Most common forms: DLBCL, mantle cell lymphoma (MCL), and mediastinal large B cell lymphoma
- Often symptomatic, short median survival if unRxed, curable in many cases
- DLBCL is most common form of NHL, but >50% can be cured w/ conventional Rx (CRx and rituximab)
- DLBCL: t(3;14) of oncogene bcl6
49
Q
Mantle cell lymphoma biology
A
- Diffuse pattern of intermediate sized cells
- Have the t(11;14) that over expresses cyclinD1
- Responsive to CRx but relapse usually at 18 mo, only Rx after that is HSC Tx
- Grows fast (high response to induction), but tends to relapse
50
Q
Aggressive T cell lymphomas
A
- Peripheral T lymphoma, anaplastic T lymphoma, T cell lymphoblastic lymphoma
- Often involved skin (like MF and SS), but w/ systemic disease and frequent extra nodal involvement of organs like liver
- Malignant T cells often have indented or convoluted nuclei, diffuse pattern in nodes
- Respond to CRx but overall survival worse than B cell lymphomas (except anaplastic)
51
Q
Causes for anemia in lymphoproliferative diseases
A
- Decreased RBC production due to BM involvement
- Decreased RBC production due to ACD
- Acute bleeding loss if GI involvement or other bleeding
- If bleeding exists possibly Fe deficient
- Hemolytic anemia: can happen in any lymphoproliferative disorder
52
Q
Mediastinal masses
A
- 4 T’s
- Substernal thyroid
- Teratoma
- Thymoma
- Terrible lymphomas: T cell lymphoma/lk (young men), B cell lymphomas, NS HL (young women)
