Pathoma

leukopenia and leucocytosis Haematopoetic stem cell CD34+ Has ability to produc myeloid or lymphoid stem cell Lymphoid can produce B or T lymphoblast nave B or T cells which go to plasma or CD8/4+ T cells respectively Myeloid stem cell can produce RBC, myeloblast (neutrophil, basophil, eosinophil), monocyte, megakaryocyte Low WBC count is leukopenia High WBC count is leukocytosis Usually either of these are due to one cell type Neutropenia low number of circulating neutrophils Seen with drug toxicity ie chemotherapy Severe infection Treat with GSCF or GMCSF granulocyte monocyte colony stimulating factors Lymphopenia low number of lymphocytes Another example of low WBC count Immunodeficiency ie Digeorge syndrome underdeveloped thymus and hence T cells High cortisol state which induce apoptosis of lymphocytes, ie in cushing syndrome Autoimmune destruction lupus produce anitbodies against blood cells like RBCS, WBCs or platelets Whole body radiation Neutrophil leucocytosis increase in WBCs via high neutrophils Bacterial infection driving inflammation and hence neutrophils Tissue necrosis also drives inflammation High cortisol rate Monocytosis high monocytes Chronic inflammatory states Malignancy Eosinophilia high eosinophils Allergic reactions Parasitic infections Hodgkin lymphoma*** because of IL5 production Basophilia high basophil count CML** classic association

Lymphocytic leucocytosis high WBC count due to lymphocytes Viral infections fought and handled by CD8+ T cells Bordetella pertussis produces lymphocytosis promoting factor blocking lymphocytes from leaving blood to enter LNs Infectious mononucleosis EBV infection that results in a lymphocytic leucocytosis compromised of reactive CD8+ T cells o Transmitted by saliva o Affects oropharynx, liver (hepatitis), B cells o EBV leads to hyperplasia of paracortex of lymph nodes as this is where T cells are o In response to infection get CD8+ T cell response giving Generalised LAD - paracortex Splenomegaly specifically the perarterial lymphatic sheath PALS red and white pulp (where there are b and t cell areas, t cell area will be expanded) o High WBC with atypical lymphocytes Are atypical due to large nucleus (normally lymphocyte nucleus is RBC size) + abundant blue cytoplasm CMV is a less common cause Monospot testing is used for screening o Detects IgM heterophile antibodies (other loving antibodies, antibodies that have an affinity to bind RBCs from another animal) o Usually turns positive within 1 week after infection o Negative tests suggests CMV is the cause Complications o Increased risk for splenic rupture** due to splenomegaly o Rash if exposed to PCN o Dormancy of virus in B cells Acute leukemia Hematopoesis review Begins with HSC developing into myeloid or lymphoid blast/stem cell Myeloid blast eventually produces multiple myeloid lineages leading to RBCS, monocytes, granulocytes, megakaryocytes Acute leukemia disruption in ability of cells to mature*** leading to increase in myeloid or lymphoid blast Acute leukemia is a neoplastic proliferation of blasts Defined as accumulation of >20% blasts in the bone marrow Blasts crowd out normal hematopoiesis o Results in acute presentation with anemia, thrombocytopenia or neutropenia from loss of normal RBCs, platelets and neutrophils Blasts usually enter the blood resulting in high WBC o Blasts are large, immature cells often with punched out nucleoli on blood smear

 Subdivided into ALL and AML Based on phenotype of the blast Accumulation of myeloid blasts = AML Accumulation of lymphoid blasts = ALL Blasts on bone marrow aspirate or blood smear Hallmark marker for lymphoid blast is positivity for TDT in nucleus Classic marker for myeloid blast is presence of myeloperoxidase MPO o MPO can crystallise to form an AUER ROD** ALL Neoplastic accumulation of lymphoblasts Positive nuclear staining for TdT (DNA polymerase present in nucleus) TdT is absent in myeloid blasts and mature lymphocytes Most commonly in children** and is associated with Downs syndrome (AFTER THE AGE OF 5) Can be sub classified into B-ALL and T-ALL Based on surface markers Both have TdT positivity allowing it to be ALL B-ALL o Most common type of ALL o Expresses CD10, CD19, CD20 surface markers o Has excellent response to chemo o Has generally good prognosis based on cytogenic abnormalities T(12:21) has a good prognosis more commonly in kids T(9:22) has a poor prognosis more commonly in adults = Philidelphia chromosome + ALL T-ALL o Lymphoblastst that express markers ranging from CD2-CD8 o Blasts do not express CD10 o Presents as thymic mass, in mediastinum and in teenagers ** TTT o As it is a thymic mass rather than presenting in blood we call it acute lymphoblastic LYMPHOMA (meaning it forms a mass) AML Is a neoplastic accumulation of myeloblasts Characterised by staining for myeloperoxidase MPO o Crystal aggregates of MPO seen as Auer rods** in blastic cell o See an actual rod in cell Most commonly in odler adults around 55 years Subclassified in 3 ways: o Cytogenic abnormalities o Lineage of myeloblasts o Surface markers Classic type is acute promyelocytic leukemia characterised by t(15:17)

o Larger than RBCs, doesnt have much cytoplasm, has like paler hole in the middle of nucleus = nucleolus

o Results in RAR (retinoic acid receptor) receptor disruption, promyelocytes accumulate o Prevents cell maturation ability o Promyelocytes contain numerous Auer rods which can activate the coagulation cascade o Risk for DIC o ATRA - all trans retinoic acid derivative of vitamin A causes the blasts to mature and become neutrophils Side note: Acute monocytic leukaemia o Proliferation of monoblasts that infiltrate the gums o Lack MPO and hence no Auer rods Side note: Acute megaryoblastic leukaemia o Proliferation of megakaryoblasts lack MPO o Association with down syndrome before the age of 5 Also possible to get AML from pre existing dysplasia from alkylating agents like chemo or radio exposure

Chronic leukemia Neoplastic proliferation of mature circulating lymphocytes Characterised by high WBC count Usually insidious (slow and asymptomatic) in onset and seen in older adults CLL Neoplastic proliferation of nave B cells just born from bone marrow Cells co express CD5 (normally on T cells) and CD20 = characteristic finding Increased lymphocytes and smudge cells seen on blood smear Smudge cells - splattered cell classic of CLL Involvement of lymph nodes Causes genrealised LAD Called small lymphocytic lymphoma now that they involve lymph node and are now producing a mass Complications Develop hypogammaglobulinemia o Neoplastic B cells which normally become plasma cells and secrete IG o These cells dont produce immunoglobulins and hence get low immungoglobulin level in blood o Infection most common cause of death Autoimmune haemolytic anemia o These cells wont make much immunoglobulin but if they do they do a bad job and they produce antibody against the patients own red blood cells Transformation to diffuse large B cell lymphoma

 Hairy cell leukaemia Another chronic leukaemia Neoplastic proliferation of mature b cells Characterised by hairy cytoplasmic processes Cells are positive for TRAP See images in text book Features o Splenomegaly red pulp Usually in CLL cells affect white pulp so this is unusually o Dry tap with bone marrow aspiration as the bone marrow is often fibrosed in these patients o LAD is usually absent o Cells get TRAPped in red pulp and bone marrow and are positive for TRAP and as they are TRAPped in these places they dont get to LN and hence LAD is absent** Excellent response to drug called 2-CDA ATLL adult T cell leukemia lymphoma Neoplastic proliferation of CD4+ T cells Associated with HTLV1 human t cell leukemia virus 1 Presents with rash* (helps differentiate from multiple myeloma) Genrealised LAD with hepanosplenomegaly Lytic bone lesion with hypercalcemia** o Usually think multiple myeloma so need to remember this as well MYELOPROLIFERATIVE DISORDERS AML immature myeloid lineage

o Enlarging lymph node or spleen

Myeloproliferative disorder Get neoplastic proliferation of ALL of the myeloid mature cells But its named based on the PREDOMINANT cell accumulating Neoplastic proliferation of mature cells of myeloid lineage Disease in late adulthood Results in high WBC count with hypercellular marrow o Due to increased production of granulocytes Cells of all myeloid lineages wil be increased and classified based on dominant myeloid cell produced Complications o Increased risk for hyperuricemia and gout As youre developing many of these cells youre also turning over a tonne of these cells Its the break down of these cells that leads to these two things o Progression to marrow fibrosis o Transformation to acute leukaemia Chronic myeloid leukaemia Neoplastic proliferation of mature myeloid cells, especially granulocytes Basophils are characteristically increased o Basophilia is highly associated with CML Driven by t(9:22) Fusion between BCR-ABL leading to increased tyrosine kinase activity which drives overproduction of neoplastic cell First line of treatment is imatinib which blocks TRK activity Clinically o Splenomegaly is common suggests accelerated phase of disease, transformation to acute leukaemia usually follows shortly after Transformation to acute leukaemia can be either AML (66%) or ALL (33%) The mutation is at the HSC line (not at myeloid line)** hence why they can develop transformation to either myeloid or lymphoid leukaemia*** CML distinguished from leukemoid reaction Smear looks like acute infection (= over production of granulocytes high WBC count) or CMLwhich is it? CML granulocytes are LAP negative CML is associated with increased basophils CML granulocytes exhibit t(9:22)

ALL immature lymphoid lineage CL mature lymphoid lineage Myeloproliferative mature myeloid lineage then split up according to cell type.. o I.e RBC overproduction = polcythemia vera

Polcythemia vera Neoplastic proliferation of mature myeloid cells especially RBCs Granulocytes and platelets are also up raising the WBC Associated with JAK2 kinase mutation*** Clinically Symptoms of hyperviscosity o Blood loaded with RBC and becomes very thick o Blurry vision and headache o Increased risk of venous thrombosis o Flushed face due to congestion o Itching after bathing Treatment o Decrease RBC mass o Phlebotomy + hydroxyurea Essential thrombocythemia Neoplastic proliferation of mature myeloid cells, especially platelets RBC and granulocytes are also increased Associated with JAK2 kinase mutation Many small platelets on smear Looks similar to iron deficiency anemia also many platelets Symptoms o Increased risk of bleeding or thrombosis o Platelet not functioning or over functioning o Rarely progress to marrow fibrosis or acute leukemia unlike other myeloproliferative disorders Myelofibrosis Neoplastic proliferation of mature myeloid cells especially megakaryocytes Driven by JAK2 kinase mutation Produces excess platelet derived growth factor leading to fibrosis Clinical o Splenomegaly due to extra medullary haematopoiesis as it can no longer occur in the marrow due to fibrosis o Leukoerythroblastic smear o Increased risk of infection, thrombosis and bleeding PLASMA CELL DISORDERS Multiple myeloma Malignant proliferation of plasma cells in bone marrow Most common primary malignancy of bone High serum IL6 is sometimes present important growth factor for plasma cells

Bone pain with hypercalcemia Neoplastic plasma cells activate RANK receptor on osteoclasts Produce osteoclast activating factor they then eat away at bone Lytic punched out lesions seen on x ray especially in vertebrae and skull Leads to bone pain and hypercalcemia as calcium will be pushed into serum Increased risk of fracture Elevated serum protein Neoplastic plasma cells of multiple myeloma produce immunoglobulin M spike is present on SPEP (serum protein electrophoresis), most commonly due to IgG or can be IgA Large albumin band, alpha 1,2 band, beta band, then gamma band o Gamma band peak is usually wide and not as high as albumin normally o Gamma globulins include IgG, IgA, IgM o Myeloma patients have tumour of plasma cells that overproduce IG, hence get sharp spike in gamma region o This spike is called an M spike** o Indicates monoclonal immunoglobulin** Increased risk for infection Monoclonal antibody lacks antigenic diversity They all produce the exact same antibody from the one type of mother cell Infection is most common cause of death Rouleauzx formation on blood smear Increased serum protein decreases charge between RBCs Instead of blood cells distributing evenly they start piling up on each other Primary AL amyloidosis Malignany plasma cells overproduce light chain IG formed from heavy and light chain Normally plasma cell produces equal amounts of heavy and light chain to produce IG Overproduction of light chain leads to free light chain that circulates in serum and deposit in tissues and this leads to amyloidosis Proteinuria Free light chain is excreted in urine as bence jones proteins Free light chain can also deposit in kidney tubules leading to risk of renal failure (myeloma kidney) Summary The plasma cells are overproducing various substances

Osteoclast activating factor punching out bone marrow = bone pain and fracture and hypercalcemia Immunoglobulin high serum protein with M spike on SPEP Lack antigenic diversity leading to increased infection Over produce light chain goes into blood and deposit in tissue as amyloid, urine as bence jones protein and deposit in kidney as myeloma kidney

MGUS Increased serum protein with M spike on SPEP Other features are absent no lytic lesions, hypercalcemia, AL amyloid or bence jones proteinuria Isolated M spike with no other myeloma findings: Monoclonal gammopathy of undetermined significance = MGUS Common in elderly 5% over age of 70 have it, 1% of these go on to develop myeloma Waldenstrom macroglobulinemia B cell lymphoma with monoclonal IgM production IGM is large hence macroglobulinema As its lymphoma you get LAD, no lytic bone lesions Increased serum protein with M spike but due to IGM not IGG or IGA Visual neurological deficits retinal haemorrhage or stroke due to hyperviscosity of blood Bleeding due to defective platelet aggregation from hyperviscosity Treat with plasmapheresis remove blood, use machine to pull out IGM and decrease complication risk