Hematopoiesis

Hematopoietic Stem Cell (CD34+)

Myeloid Stem Cell

Erythroblasts RBCs

Myeloblasts

Neutrophils

Eosinophils

Basophils

Monoblasts Monocytes

Megakaryoblast Megakayrocytes

Lymphoid Stem Cell

B Lymphoblasts Naive B cells Plasma Cells

T Lymphoblasts Naive T cells

CD8+ T cells

CD4+ T cells

Leukemia: Myeloid or Lymphoid

AML

ALL/L

MPS

Sign and Symptoms of Lymphoid Leukemia

Mostly from malignant cells taking up BM space

-Anemia and fatigue

-Neutropenia and infections/fever

-Thrombocytopenia with petechiae/bruising

-Bone pain from expansion of BM

-CNS symptoms

Signs and Symptoms of Lymphoid Lymphomas

-Lymphadenopathy; may wax and wane from month

to years, grow over weeks or days.

-enlarged lymph nodes are usually painless and show

no signs of inflammation such as erythema or

discharge

-extranodal sites seen in ~1/3 of pts; BM, GI and skin

are most common signs

-B Symptoms (1) unexplained fever over 38C,

(2)drenching night sweats, (3)unexplained weight

loss greater than 10% if total body weight

Myeloid Neoplasms

Mye

loid

Neo

pla

sms

Acute

Acute Myeloid Leukemia (AML)

-inc blast >20%

-Cytopenia

-older ppl

-MPNs/MDS -> AML

-pancytopenia

-infiltrate in gingiva

-auer rods in cyto of myeloblasts!

Acute Promyelocytic Leukema

-Hypergranular promyelocytes w/ lots of auer rods in each

-DIC!

-t(15; 17) -> fusion protein whih blocks differentiations

-tx: All trans retinoic acid (ATRA)

Chronic

Myeloproliferative Neoplasm

(MPN)

- inc mature cells

-splenomegaly

-mutation in Tyr kinase -> MAPK constitutively active

Chronic Myelogenous Leukemia (CML)

-Neutrophilia with left shift, with absolute basophilia and eosinophilia

-bcr-abl +ve\

-Tx:Gleevec - blocks ATP binding to CML enzyme

Polycythemia Vera

-proliferation of erythrocytes

-Head Sx (headache, dizziness, visual disturbance, parasthesias)

-JAK is always on w/out it's ligand EPO

Essential Thrombocytosis

-sustained thrombocytosis

-TIAs. gangreen, Budd-Chiari

-platelets are high but normal

Primary Myelofibrosis (PMF)

-splenomegaly, thrombosis, leukocytosis

-extensive fibrosis in BM -> dry tap

-extramedullary hematopoiesis in spleen

-JAK-2 mutation but no bcr-abl mutation

Myelodysplastic Syndrome (MDS) - dec; disordered

maturation

-older ppl - 70yrs

inc cellularity but ineffective hematopoiesis so cytopenia

-Presents w/ normocytic or macrocytic anemia

-ringed sideroblasts

Lymphoid Neoplasms

Lymphoid Neoplasms

Acute/Precursors

Acute Lymphoblastic Leukemia

B-ALL

- Chd (85% in chd)

-"leukemic" presentation, B Sx

-Px favorable for chd (85% remission)

T-ALL

-late childhood, adolescence or YA;

- "lymphomic" presentation

-typically teen male with adenopathy or bulky mediastinal mass => SVC syndrome or

tracheal obstruction

-Generally worse Px

Mature

Mature B Cell

Non-Hodgkin's Lymphoma - See Below...

Hodgkins

- Aggressive, X'tic and predictable pattern, curable!

-from single or chain of LN -> spreads to neighboring nodes -> spleen and BM

-Young women, 32 yrs

-Histo: Scattered Reed-Steinberg cells (owl eyes) on a background of inflammatory cells

Mature T Cells

Mycosis Fungoides

-Most common T cell lymphoma, cutaneous, flat -> plaque -> tumor

-small cells with convoluted nuclei, invading skin and blood

-may -> Sezary Syndrome (blood and lymph node involvement and a rash

covering entire body)

...Mature B cell contd

Non-Hodgkin's B Lymphoma/

Mature B Cells

Indolent (months to years/ incurable or

chronic)

Chronic Lymphoctytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL)

-Most common leukemia in adults!

-sustained lymphocytosis >5000/L

-Immunodeficiency (as CLL lymphos are non-fxnal, auto-Ab against normal cells) -> infections, anemia

, thrombocytopenia -> DLBCL

-Good Px: Del 13q, 11q, trisomy 12

-Poor Px: del 17q (p53 gene)

Hairy Cell Leukemia

-cytopenias, monoctyopenias w/ neutropenia

-splenomegaly, "B" symptoms

-Hairy cells w/ abundant cyto, inc red pulp in spleen

-Mutation in BRAF gene, Tx:BRAF inhibitor

Follicular Lymphoma

-middle aged, indolent

-t (14; 18), bcl-2+ Ig H (upreg anti-apoptotic signal)

-follicular-looking nodules in nodes but no distinct parts of the node present

Extra nodal marginal zone lymphoma of mucosal assoc lymphoid tissue (MALToma)

-occurs in pts w/ chronic inflammation. ex. autoimmune, from polyclonal -> monoclonal B cell lymphoma

-Highly assoc with H. pylori (lymphoepithelial lesions)

Aggressive (weeks/tx urgently/curable)

Diffuse Large B cell (DLBCL)

-mean age 60yrs

-40% of all NHL

-aggressive symptomatic mass

-5yr Survival 60%

-Histo: sheets of lg lymphos

Immunodeficiency-assoc large B cell Lymphoma

-Acquired (HIV, post-transplant, inherited)

-oftern arise fromB-cells latently infected with EBV

-often involve the brain (esp HIV+ cases)

Highly Agressive (days/Tx

emergently/curable)

Burkitt's

-African (endemic), Sporadic (non endemic)

-t(8; 14), MYC (Promoter) + Ig promoter = v. rapid growth

-EBV (esp African)

-Starry sky appearance on histo, very chemo sensitive!

Hodgkins vs. Non-Hodgkins lymphoma

Genetic Alterations in Cancers

Hodgkin's lymphoma

Often Single lymph node or group of LN

Contiguous spread

Extra-nodal rare

Bimodal distribution: YA and >55yrs

B symptoms: high fever, drenching night sweats; weight loss >10%

Non-Hodgkin's Lymphoma

Multiple LN sites

Non-contiguous spread

Extranodal v. common

Peak age 20 - 40yrs

fewer signs/Sx

Genetic Alteration

Inc c-myc

Inc bcl-2

BCR-ABL

Others

Inc Her2/neu/ERB B2

Ras mutation

Loss of Rb

p53 mutation

dec TCG-beta

Cancer

Burkitt Lymphoma

Follicular Lymphoma

Chronic Myelogenous leukemia

Breast cancer

various

retinoblastoma

various

colon cancer

Genetic Mechanism

t (8, 14) translocation

t (14, 18) translocation

t (9; 22) translocation

Amplification

point mutation

deletion at 13q14 with loss of heterozygosity (LOH)

point mutation

point mutation