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Lymphocytes (B-, T-, NK-cells) stem from
Lymphoid stem cell
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All other blood cells stem from
myeloid stem cell
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myeloid stem cell gives rise to
- myeloblast (... baso-, eosino-, neutro-phils)
- immature monocyte (... monocyte ... macrophage)
- megakaryocyte (... platelet)
- pronormoblast (... erythrocyte)
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Lymphoid Organs
- Based on the Maturation of the Lymphocytes, can be divided into
- Primary Organs
- - Bone Marrow
- - Thymus
- Secondary Organs
- - Spleen
- - Lymph Nodes
- - MALT (Mucosa-Assoicated Lymphoid Tissue, eg. Peyer's patches, Waldeyer's ring - pharyngeal tonsils (or nasopharyngeal tonsils, "adenoids"), tubal tonsil, palatine tonsils ("the tonsils"), lingual tonsils)
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Lymph node
- Lymphoid follicle - B-cell zone
- Parafollicular cortex - T-cell zone
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Lymphoid follicle
- primary follicles
- secondary follicles
- - marginal zone - memory B cells
- - mantle zone - naïve B cells
- - germinal centers - maturation
- B cells proliferate here, undergo somatic hypermutation
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MALT
- The mucosa of the digestive, respiratory and urinary tracts often contains small aggregates of lymphocytes known as 'Mucosa associated lymphoid tissue' (MALT).
- - Tonsils (Waldeyer’s ring)
- - Peyer’s patches
- - Appendix
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Reactive proliferation of white blood cells
- Leukocytosis - in the blood
- Lymphadenitis - enlarged lymph nodes
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Leukocytosis
- neutrophilia: increase of granulocytes, neutrophils
- lymphocytosis: increase of nonneoplastic lymphocytes
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Reactive Neutrophilia
- Infections (especially bacterial).
- Medications (growth factors, steroids, lithium)
- Acute tissue necrosis (acute myocardial infarction, burns, trauma, goat).
- Inflammatory disorders (e.g. autoimmune disease).
- Tumor associated: e.g. CSF-producing carcinoma.
- Miscellaneous: stress, pregnancy, smoking, etc.
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Reactive Lymphocytosis
- Viral infection (e.g., hepatitis A, CMV, EBV)
- Bordetella pertussis infection
- Chronic immunological stimulation (e.g., tuberculosis, brucellosis)
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Nonspecific Lymphadenitis
- Acute
- - Nodes are enlarged and painful.
- - Microscopically, follicular hyperplasia, reactive germinal centers, macrophages (containing debris derived from dead bacteria or necrotic cells), neutrophils with necrosis and abscess formation (bacterial infections)
- Chronic
- - Nodes are nontender, because nodal enlargement occurs slowly over time.
- - Particularly common in inguinal and axillary nodes.
- - Microscopically, follicular hyperplasia, paracortical expansion, sinus histiocytosis.
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Neoplastic proliferation of white blood cells:
- Lymphoid Neoplasms
- Both leukemia and Non-Hodgkin lymphoma are among the top 10 of the new cancers and the top 10 leading causes of cancer deaths.
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Clinical Presentation of Lymphoma
- Fevers, night sweat, weight loss
- Lymphadenopathy, usually painless, often disseminated
- In non-Hodgkin lymphoma, extranodal sites are frequently involved (GI tract, skin, CNS)
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Evaluation of Lymphoma
- History
- Physical examination
- Radiology - CT Scan, PET Scan
- Lab - CBC, chemistries, LDH, HIV, Hep C, Hep B
- Pathology - Bone marrow aspiration and biopsy
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Diagnosis of Lymphoma
- Excisional lymph node biopsy:
- - Histology
- - Immunophenotyping (Immunohistochemistry and Flow cytometry)
- - Cytogenetic Studies
- - Molecular Genetic Studies (PCR, FISH, etc.)
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________ Staging System for Lymphomas:
- Ann Arbor
- Stage I: single site;
- stage II - multiple sites, not crossing diaphragm;
- stage III - multiple sites on both sides of diaphragm;
- stage IV - spread to extra-lymphatic organs or sites.
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Origin of lymphoid neoplasms
- Anything occurring in the precursors, can lead to acute lymphoblastic leukemia, or lymphoma, usually occurs in children
- Anything that occurs in the secondary organs are mature lymphomas, B or T cells
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2008 Classification of lymphoid neoplasms
- Precursor lymphoid neoplasms
- - B lymphoblastic leukemia/lymphoma
- - T lymphoblastic leukemia/lymphoma
- Mature B-cell neoplasms
- Mature T-and NK-cell neoplasms
- Hodgkin lymphoma - from a group of germinal center B cells
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Mature B-cell Lymphoma
- Diffuse large B-cell Lymphoma - worldwide most common
- Follicular lymphoma - Most common in the US
- CLL/SLL
- Burkitt
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Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
- Most common leukemia of adults in the western world.
- The median age at diagnosis is 65 years.
- Male predominance (male to famale ratio = 2 : 1).
- The two disorders are morphologically, phenotypically,
- and genotypically indistinguishable, differing by degree of peripheral blood lymphocytosis.
- Often asymptomatic or nonspecific symptoms at presentation - easy fatigability, weight loss, and anorexia.
- Lymphocytosis (lymphocytes > 5,000/uL).
- Generalized lymphadenopathy & hepatosplenomegaly
- (50-60% of the cases), anemia, thrombocytopenia.
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Peripheral blood smear and Lymph node/liver histology of CLL/SLL
- Small and round lymphocytes.
- certain larger cells, prolymphocytes, with a lot of chromatin, and prominent nucleolus, a white spot.
- Basket cells, larger, blurry, smudge cells.
- No follicles, invaded by the CLL process.
- The small lymphocytes also infiltrate the liver.
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Complications of CLL/SLL
- Autoimmune (autoimmune hemolytic anemia and thrombocytopenia).
- Hypogammaglobulinemia
- Transformation to high grade lymphoma:
- - Diffuse large B-cell lymphoma (Richter’s syndrome) (2-8%)
- - Hodgkin lymphoma (<1%)
- - Prolymphocytic leukemia (extremely rare)
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Follicular lymphoma
- Highest incidence in the US and Western Europe.
- Adults with median age: 6th decade, rare in adults <20, pediatric patients are mostly males.
- In adults, Male to female ratio 1:1.7
- Sites of involvement - predominantly Lymph nodes, but also spleen, BM (40-70%), peripheral blood and Waldeyer’s ring.
- May occasionally be primary in extranodal sites: skin, Waldeyer’s ring, GI tract, ocular adnexa, breast, testis, etc.
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Follicular Lymphoma - Histology
- Nodular pattern with closely packed follicles
- No polarity / light vs dark zone in germinal center - Centroblasts (make up the dark zone of normal germinal center) and centrocytes (make up the light zone of normal germinal center) are randomly distributed in the affected germinal center.
- "pin" cells
- No tangible-body macrophages.
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Grading of follicular lymophoma
- determined by number of centroblast, which should be the minority of cells under normal conditions
- grade 1 - <5
- grade 2 - 5-15
- grade 3 - >15
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Pathogenesis of Follicular Lymphoma
- The translocation between (14;18) is hallmark for follicular lymphoma (>85% of cases).
- t(14;18) fuses BCL2 (18) to IgH (14; strong promoter) resulting in overexpression of bcl2 gene, which antagonizes apoptosis and promotes tumor cell growth.
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Prognosis of Follicular Lymphoma
- Not curable, as most other relatively indolent lymphoid malignancies - not responsive to chemotherapy.
- Indolent wax and wane clinical course.
- Median survival, 7 to 9 years.
- 40% Transformation to higher grade lymphoma (usually Diffuse Large B-Cell Lymphoma, may be cured then?).
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Burkitt Lymphoma
- Affect mainly children and young adults.
- ~30% of childhood NHLs in the U.S.
- Aggressive, extremely short doubling time.
- Often presents in extranodal sites.
- Endemic in parts of Africa, sporadic in other areas.
- Most endemic cases and about 20% of sporadic cases are associated with EBV infection.
- Endemic tumors often manifest as maxillary or mandibular masses; sporadic tumors are more commonly abdominal tumors involving bowel, retroperitoneum, and ovaries.
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Morphology of Burkitt Lymphoma
- “Starry sky” - macrophages killing dead cell.
- c-myc involved, strong proliferating.
- lymphomas cells - Uniform medium-size, even shape.
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Pathogenesis of Burkitt Lymphoma
Translocations involving MYC (8) and (14, 2, or 22) (IGH, IGK, IGL); the hallmark.
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Treatment and prognosis of Burkitt Lymphoma
- Very aggressive chemotherapy cures majority;
- More responsive in children than in adult;
- Poor prognostic factors:
- - BM involvement
- - CNS involvement
- - Unresected tumor > 10 cm in diameter.
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Diffuse Large B-cell Lymphoma
- Mature B-cell neoplasm (from the germinal center)
- The most common type of lymphoma in adults, ~50% of adult NHLs.
- Several subtypes, all aggressive.
- Median age - 60 yo, but can occur at any age.
- Rapidly enlarging, symptomatic mass, easier to treat.
- Nodal or extranodal (40%; involving skin, thyroid, GI, etc.).
- Bone marrow involvement at diagnosis is not common.
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Morphology of Diffuse large B-cell lymphoma
snake-bite cells, with two prominent nucleoli, Open chromatin, large, prominent nuclei.
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Pathogenesis of Diffuse Large B-Cell Lymphoma
- Abnormalities of BCL-6 gene (3q27; up to 30%).
- t (14;18) involving BCL-2 gene (20-30%).
- Myc rearrangement (up to 10%) - usually with a complex karyotype pattern. Myc break partner: 60% IG gene, 40% non-IG gene.
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Treatment and Prognosis of Diffuse Large B-Cell Lymphoma
- Rapidly fatal if untreated.
- With Intensive combination chemotherapy:
- - Complete remission: 60-80%
- - Approximately 50% appear to be cured
- Limited disease is far better than widespread disease or a large bulky tumor mass.
- BM involvement - rare; poor prognosis independent of the IPI score (5-year overall survival, 10%).
- Rituximab has improved prognosis significantly.
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Multiple Myeloma
- Common plasma cell malignancies - go back to bone and releases Ab.
- Median age at diagnosis - 70.
- More in males and African descendants.
- Bone marrow and multiple lytic lesions throughout skeletal system. If only one lesion - plasmacytoma.
- Serum monoclonal immunoglobulin paraprotein (M protein), mostly IgG type, secreted by the neoplastic plasma cells.
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- Clinical features of Multiple Myeloma
- CRAB: (increased) Calcium, Renal dysfunction, Anemia, Bone lytic lesion.
- Bone lytic lesions – pathologic fracture & chronic pain. Plasma cells -> cytokines -> osteoclast -> bone resorb.
- Hypercalcemia – confusion, weekness, lethargy, constipation.
- Renal insufficiency – 2nd most common cause of death.
- - Bence Jones proteinuria, nephrotoxic.
- - Amyloid light chain Amyloidosis.
- Anemia.
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- Morphology of Multiple Myeloma
- Rouleaux - Peripheral Blood red blood cells stick together; “stack of coins”, results from high levels of serum M proteins.
- Neoplastic plasma cells - double nucleation, lobules containing immunoglobulin.
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5524
- Treatmenta and Prognosis of Multiple Myeloma
- Variable but generally poor.
- Median survival: 4-6 years.
- Treatment: chemotherapy
- Bone marrow transplant: longer remissions with patients < 50 year old.
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5615
- Extranodal NK/T cell lymphoma nasal type
- Asians and South Americans.
- Strongly associated with EBV infection.
- Adults (median age: 53 years).
- Male > female.
- Sites: nasal cavity, other regions of the upper aerodigestive tract, skin, GI tract, testis, soft tissue.
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5845
- Morphology of Extranodal NK/T cell lymphoma, nasal type
- Angiocentric and angioinvasive growth, involving blood vessels, very aggressive.
- Lymphocytes infiltrating blood vessel wall.
- Prominent ulceration and tissue necrosis. Also fibrin deposition.
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0215
- Hodgkin Lymphoma
- Relatively uncommon - ~8.5 : 65 NHL per year in U.S.
- Bimodal age distribution - 20’s and 50-60’s.
- Non-tender, rubbery neck mass (enlarged LN).
- Cervical lymph nodes involved (~80%).
- Axillaryor inguinal lymph nodes involved (10-20%).
- Spreads predictably to contiguous lymphoid groups.
- Pain in lymph nodes after alcohol ingestion
- “B Symptoms”
- - Fevers, weight loss, and/or drenching night sweats.
- -- correlate with more aggressive and extensive disease.
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- Classification of Hodgkin Lymphoma
- Nodular Lymphocyte Predominant Type - rare
- Classical Hodgkin lymphoma:
- - Nodular sclerosis Type
- - Mixed cellularity Type
- - Lymphocyte-depleted Type
- - Lymphocyte-rich Type
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- Morphology of Classical Hodgkin Lymphoma
- Reed-Sternberg cells secrete cytokines and induce a predominant background of reactive lymphocytes, eosinophils, histiocytes, and granulocytes.
- Immunophenotypically unique: Reed-Sternberg cells are CD15+ and CD30+.
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- Morphology of Classical Hodgkin Lymphoma:
- Reed-Sternberg cells:
- - Large (15-to-45 microns in diameter).
- - Binucleate or bilobed, with two halves often appearing as mirror images of each other.
- - Large, inclusion-like, owl-eyed nucleoli about the size of a small lymphocyte.
- - Nucleoli generally surrounded by a clear halo.
- - Abundant amphophilic cytoplasm.
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Nodular Sclerosis Type
- cellular nodules of RS cells
- Occur in young women
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1820
- Mixed Cellularity Type
- no fibrotic bands separating the cells
- Evenly distributed
- contains eosinophils, neutrophils, plasma cells
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1955
- Lymphocyte-Rich Type
- mostly lymphocytes
- RS cells visible
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2035
- Lymphocyte-Depleted Type
- Not many inflammatory cells; lots of irregular RS cells.
- HIV, immunodeficient patients can barely mount the inflammatory responses, in contrast to granuloma diseases like TB.
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2250
- Treatment of Classical Hodgkin Lymphoma
- Combination chemotherapy, ABVD (Adriamycin, Bleomycin, Vinblastine, and Dacarbazine; CHOP for non-Hodgkin lymphoma), plus involved-field radiation therapy - 95% long-term event-free survival.
- Autologous (self-donor) bone marrow transplantation (BMT), aka autologous hematopoietic stem Cell Transplantation (HSCT) - cure ~40% of patients with relapsed lymphoma.
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- Complications of Classical Hodgkin Lymphoma
- Chemotherapy and radiotherapy increase risk of secondary tumors:
- - Hematologic cancers (myelodysplastic syndromes, acute myelogenous leukemia, and non-Hodgkin lymphoma)
- - Solid cancers (lung, breast, stomach, skin, or soft tissues)
- Non-neoplastic complications of radiotherapy:
- - Pulmonary fibrosis
- - accelerated atherosclerosis
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- Prognosis of Classical Hodgkin Lymphoma
- Tumor burden (stage) rather than histologic type is the most important prognostic variable.
- Stages I and IIA: 5-year survival rate close to 90%, with many cured.
- Stages IVA and IVB: 5-year survival rate 60-70%.
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- Acute Myeloid Leukemia
- Neoplastic cells staying at early stage of myeloid cell development (blasts). They accumulate in the marrow (>20%) and frequently circulate in the peripheral blood.
- Diverse acquired mutations - abnormal transcriptional factors, interfering with myeloid differentiation.
- Blasts suppress remaining normal hematopoietic progenitor cells by physical replacement and other unknown mechanisms, which leads to anemia, thrombocytopenia, and neutropenia (pancytopenia).
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- Clinical Features of Acute Myeloid Leukemia
- Older adults median age: 50 yo; occurs in children too.
- Present within a few weeks or months.
- Symptoms: fatigue, pallor, fever, infections, and abnormal bleeding.
- Central nervous system - less common than in A.L.L.
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- Classifications of AML
- Class I. AML with recurrent chromosomal translocations
- Class II. AML with Multilineage Dysplasia
- Class III. AML, therapy-related (acquired after RT or CT)
- Class IV. AML, not otherwise classified (NOS)
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4218
- AML, not otherwise specified (NOS)
- With myeloid lineage
- - AML with minimally differentiation (FAB M0)
- - AML without maturation (FAB M1)
- - AML with maturation (FAB M2)
- Acute myelomonocytic leukemia (FAB M4) - myeloid and monocytes; tend to involve the tissue, have tissue implication
- Acute monoblastic and monocytic leukemia (FAB M5) - purely monocyte; tend to involve the tissue, have tissue implication
- Acute erythroid leukemia (FAB M6) - erythroid
- Acute megakaryocytic Leukemia (FAB M7) - megakaryocyte
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Myeloblasts
- Difficult to tell
- Auer rods – needle-shaped crystals; distinguishable.
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4731
Monoblasts and promonocytes
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4833
- Acute promyelocytic leukemia (APL)
- Association with DIC, a medical emergency.
- t(15;17) PML/RARA chimeric gene produces a PML/RARα fusion protein that blocks myeloid differentiation at the promyelocytic (before neutrophile) stage.
- Treatment: All-Trans Retinoic Acid (ATRA), an analogue of vitamin A, overcome this block and induce the neoplastic promyelocytes to rapidly differentiate into neutrophils.
- Favorable prognosis.
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Acute Myeloid Leukemia with monocytic differentiation
- Adults or young adults.
- Extramedullary masses, infiltration of the skin (leukemia cutis) and gingivae - swelling gums and necrotic papillae on the palatal side.
- Treatment: chemotherapy
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0004
- Acute Myeloid Leukemia, prognosis
- Fepending on the underlying molecular pathogenesis.
- ~60% achieve complete remission with chemotherapy, but only 15-30% remain free from disease for 5 years.
- AMLs with t(8;21), t(15;17) or inv (16) have good prognosis.
- Chemotherapy or MDS related AMLs have poor prognosis.
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0138
- Myeoproliferative Neoplasms Classification
- All mature, leukocytosis basically
- Chronic Myelogenous Leukemia (CML)
- Polycythemia Vera (PV)
- Essential Thrombocythemia (ET)
- Primary Myelofibrosis (PMF)
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0352
- Chronic Myelogenous Leukemia
- Median age ~ 50 years
- Non-specific symptoms: fatigue, weight loss, LUQ discomfort.
- Splenomegaly (~70%)
- Peripheral blood smear:
- - Marked leukocytosis.
- - Granulocytes in all stages of maturation (but < 20% blasts; above 20% is AML).
- - Basophilia.
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0621
- Pathogenesis of Chronic Myelogenous Leukemia
- Philadelphia chromosome, t(9;22)
- - Fusion of portions of BCR gene (22) and ABL gene (9).
- - Over production of protein with tyrosine kinase activity.
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948
- PERIPHERAL BLOOD SMEAR
- proliferation of blasts, which continue to mature.
- all stage of cells are shown.
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Clinical Course of Chronic Myelogenous Leukemia
- Chronic phase <2%
- Accelerated phase 15-20%
- Blast crisis:
- - Myeloid: 70%
- - Lymphoid: 30%
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Chronic Myelogenous Leukemia : Treatment
Tyrosine Kinase Inhibitor: Gleevac
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