Blood > Lymphomas > Flashcards

Lymphomas Flashcards

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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
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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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)
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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+)
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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
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14
Q

Classification of T cell NHLs

A
  • Adult T cell
  • Mycosis fungoides (sezary)
  • Peripheral T cell
  • Anaplastic large cell
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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
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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
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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
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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
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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)
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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)
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21
Q

FCC vs reactive hyperplasia

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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

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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)

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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)

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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
Burkitt lymphoma
- 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)
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Precursor T (acute T lymphoblastic lk/lymphoma)
- 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
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Mature T/NK lk/lymphomas
- 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
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Hodgkin Lymphoma (HL)
- 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
Classical HL
- 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
Nodular sclerosing HL
- 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
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Other types of classical HL
- 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
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Lymphocyte-predominant (LP) HL
- 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
Ag expression during B cell development
- 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
Origin of B cell lymphomas
- 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
Lymphocyte precursor surface markers
- PreB cells express CD34+, CD10+, CD19+, TdT+ (CD20 + or -) | - PreT cells express CD34+, CD2+, TdT+ (CD4/8-)
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ALL in children
- 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
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Rx of ALL
- 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
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Classification of NHL based on tumor behavior
- 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)
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Chromosomal translocations of B cells malignancies
- 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)
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Risk factors for NHL
- 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)
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Staging of NHL and HL
- 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
HL statistics
- 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
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Indolent lymphomas
- 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
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Prognosis of FCC stats
- 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
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Rituximab
- 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
Biology of CLL
- 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
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Indolent T cell lymphomas
-Cutaneous T cell lymphomas: mycosis fungoides, sezary syndrome
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Aggressive NHL
- 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
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Mantle cell lymphoma biology
- 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
Aggressive T cell lymphomas
- 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)
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Causes for anemia in lymphoproliferative diseases
- 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
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Mediastinal masses
- 4 T's - Substernal thyroid - Teratoma - Thymoma - Terrible lymphomas: T cell lymphoma/lk (young men), B cell lymphomas, NS HL (young women)
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