Hematopathology Flashcards

Question

Folic acid deficiency

Answer 1

* Folate absorbed in jejunum * **Sx**: no neuro deficits * glossitis * **Dx:** * PB & BM both show megaloblastic anemia w macrocytic RBC and hypersegemented neutrophils * serology shows incr homocysteine & nl methylmalonic acid

Answer 2

Iron deficiency anemia Iron transport * plasma protein transferrin: 33% * normal serum iron: 100 to 120 ug/100ml * TIBC: 300 to 350 mg/ml Lab Dx: * CBC: decr. Hb, decr MCV, **incr RDW** * **Early stages of iron def. anemia = normocytic (Pathoma)** * PB: microcytic hypochromic anemia; severe cases -\> poikilocytosis w pencil and target cells * bigger central pallor; * most common cause in US is chronic blood loss from carcinoma or gastrectomy; impaired absorption (dumping syndrome, parasites) * Biochem: **decr ferritin**, **decr transferrin sat**, decr serum Fe, **incr TIBC, incr FEP (free erythrocyte protoporphyrin)** * Depletion of BM stores: Prussian blue- Other Dx * Koilonychia due iron deficiency anemia

Answer 3

Most common cause in hospitalised Pt * chronic infections: lung abscess, endocarditis * chronic immune diseases: rheumatoid arthritis * chronic malignancies Lab Dx: * PB: normochromic normocystic anemia but sometimes hypochromic and microcytic * Biochem: * **incr serum ferritin, decr serum Fe, decr TIBC, decr transferrin sat.** * **Hepcidin sequesters iron in storage sites (pathoma)** * nl or incr Fe stores in BM * EPO levels inappropriately low

Answer 4

**Aplastic anemia** * damage to HSC * Congenital: Fanconi's anemia (rare) * Acquired * Idiopathic (unknown cause): 65% * known causes: 35% of cases (see below) * Seen in teens & elderly Etiologies * drugs or chemicals: alkylating agents, CAT, chloropromazine, phenytoin & radiation * viral infections: hepatitis (non-A, B, C, D, G), CMV, EBV, HHV-1, 2 * autoimmune damage **Lab Dx:** * PB: **pancytopenia,** normocytic, normochromic, **low reticulocytes count (RC)** * BM: hypocellular; fat takes over, required to rule out leukemias and myelodysplastic syndrome); **dry tap** so BM biopsy required and **Spleen nl size** **Sx**: neutropenia -\> infections; thrombocytopenia -\> abnormal bleeding time Assoc with leukemia & PNH ( small percentage)

Answer 5

* Myelophthisic anemia: leukoerythroblastic blood picture (white & red cells precursors seen in PB) assoc with granulomatous inflammation and metastatic cancer * pathologic process that replaces BM, Ex. cancer (Pathoma from this point on) * Hematopoiesis impaired, resulting in pancytopenia. * Diffuse liver disease: BM hypofunction * Chronic renal failure: decr EPO

Answer 6

* PLT count: nl=1.5-4x10e5 * Bleeding time: incr. bleeding time indicates PLT defect * PT: extrinsic * PTT: common and intrinsic * Thrombin time: tests fibrinogen

Answer 7

* can be congenital or acquired * Acquired includes * NSAID * Uremia and chronic kidney failure

Answer 8

* spontaneous: 2 x 10e4 * trauma: 2 - 5 x 10e4 * 4 categories * decr PLT production * decr PLT lifetime * spleen sequestration * dilutional * General Sx of platelet disorders: small bleeds charactestic of platelet abnormalities ex. petechiae and superficial bleeds

Answer 9

* General BM defect * Aplastic anemia * Marrow infiltrates * Drug-indced * Infections * Megaloblastic anemia * MDS

Answer 10

* immune destruction * auto-immune: primary ITP or secondary (SLE, lymphoma) * iso-immune: post-transfusion, neonatal * drug-induced: heparin, septrin (antibiotic), quinidine * infection: HIV, CMV, infectious mono * non-immune destruction * DIC * TTP/HUS causing mucus plug * TTP: clinical syndrome of fever, thrombocytopenia, microangiopathic hemolytic anemia, transiet neuro deficits and renal failure -\> due to decr. ADAMSTS13, which nl cleaves vWF -\> large uncleaved vWF leads to abnormal paltelet ahesion (Pathoma) * **Schistocytes (helmets) **are hallmark (Pathoma) * HUS (hemolytic uremic syndrome): same same but less neuro deficits * **platelet microthrombi** due to **E. coli O157:H7 **-\> endothelial damage (Pathoma) * Giant hemangiomas * microangiopathic hemolytic anemias (mechanical destruction) **Dx labs (Pathoma):** * incr. bleed time * PT/PTT nl * anemia w schistocytes (helmet cells) * incr megakaryocytes on bm biopsy

Answer 11

* AUTOIMMUNE * Ab-bound platelets are consumed by splenic macrophages resulting in thrombocytopenia (ITP) * **acute** (uncommo): children, post-viral, abrupt onset, self-resolving * chronic: females 20 to 40 yo, insidious onset of skin +/- mucosal bleeding, rarely resolves spontaneously; may be primary or secondary (SLE) Chronic ITP lab Dx * decr platelets; PB smear may show they are mostly large PLT * incr bleeding time; BUT nl PT/PTT * auto-Ab against PLT membrane glycoproteins in 80% cases * incr megakaryocytes in BM biopsy: Megakaryocytic ITP = peripheral consumption and not BM problem Rx * immunosuppression (steroids) * IVIG (Pathoma) * splenectomy: will incr platelets but not to nl levels * eliminates source of Ab and site of destruction (Pathoma)

Answer 12

* commonest inherited disorder of bleeding * over 20 variants * type 1: reduced quantity of vWF; 70% of all cases, mild mucosal bleeding * type 3: severe deficiency of vWF, affects Factor VIII stability in plasma so Pt presents like hemophilia A * type 2: qualitative (functional) abnormality of vWF, 25% of vWF w mild to moderate bleeding **Dx labs:** * incr bleeding time due deficient platelet adhesion * incr PTT due to loss of FVIII stability, * nl PT * abnormal ristocetin test (Pathoma) * Rx: Desmopressin to stimualte WB to release vWF (Pathoma) **Sx** * Large bleeds: joint bleeds, abdominal bleeds

Answer 13

* X-linked R * Sx: massive bleeds after trauma or surgery (joint bleeds, abdominal bleeds), spontaneous hemorrhages following minimal trauma to joints and muscles. * Lab dx: * nl platelets, BT, PT * prolonged PTT -\> Factor VIII specific assay * Rx: recombinant FVIII

Answer 14

* HIV advanced infection * autoimmune * acute viral infection * drug-induced: cytotoxic chemotherapy, steroid therapy

Answer 15

Pathogenesis * decr or ineffective BM production * suppression of committed myeloid precursors: drug-induced * rare inherited disorders: Kostmann syndrome)suppression of myeloid stem cells: aplastic anemia, usually idiopathic * ineffective granulopoiesis: megaloblastic anemia, myelodysplastic syndromes * marrow infiltration: granulomatous inflammation, tumours * accelerated consumption/destruction * Peripheral loss: immune-related (idiopathic autoimmune disease, drugs), splenic sequestration (splenomegaly), incr consumption (overwhelming infection) Sx * agranulocytosis: severe neutropenia, prone to life-threatening infections (\<500 cells/ul) * severe neutropenia is most commonly drug-induced * signs and sx related to infections

Answer 16

* rarely reactive * indicates myeloproliferative neoplasm such as CML

Answer 17

* follicular hyperplasia -\> B cells * paracortical hyperplasia -\> T cells * sinus histiocytosis -\> dilated sinus

Answer 18

* NHL (60%) and all HL -\> non-tender LN enlargement * NHL (40%) -\> extranodal -\> site-related sx

Answer 19

* sx related to BM replacement -\> cytopenia

Answer 20

* bone destruction -\> bone pain

Answer 21

* Histology * PCR or Southern * IHC or flow cytometry for light chain restrictions

Answer 22

* middle age * painless lymphadenopathy * stage IV at dx w liver and spleen involvement * Tumour arises from GC B cells * 2 patterns: nodular or mixed nodular & diffuse * 2 types of cells: small & large * Diffuse and large -\> more aggressive * Immunophenotype: CD19, CD20, CD10+ * 90% cases have t(14;18) -\> results in overexpression of BCL-2, which inhibits apoptosis * indolent but incurable * some develop into more aggressive form DLBL Dx: distinguished from follicular hyperplasia by (Pathoma) * disruption of normal LN architecture * lack of tingible body macrophages in GC * expression of Bcl2 in follicle * monoclonality

Answer 23

* **Older people (60 yo)** * 60% in LN; 40% extranodal (ex. Waldeyer ring) * Primary (de novo) or 2o to transformation of a previous low grade follicular lymphoma * moderately aggressive tumour; responsive to treatment * Sx: B-sx -\> fever, night sweats, weight loss * Dx: Often stage I or II @ dx with -ve BM * CD19+ & CD10+ (Robbins)

Answer 24

* CLL is most common adult leukemia (aka Small lymphocytic lymphoma) * Sx: cytopenias, enlarged LN, liver or spleen * Dx: * PB: small, mature lymphocytes & **smudge cells** (2o to membrane fragility) * high WBC count * BM: interstitial nodules -\> diffuse replacement * Immunophenotype: CD19, CD5 & CD20 co-expression, CD23, CD43 +ve * C&C: * indolent and incurable * complication: * auto-immune hemolytic anemia * transformations to more aggressive neoplasm w larger cells: prolymphocytic leukemia (20%) & DLBL (10%) * hypogammaglobinemia -\> most common cause of death in CLL due to infections (Pathoma) * cause of death: pancytopenia -\> infections and bleeding

Answer 25

* neoplastic small B cells (CD20+) that expand mantle zone * expanding region immediately adjacent to follicle * clinically present in late adulthood w painless LAD **Etiopath** * driven by t(11,14) * cyclin D1 on chr11 translocates to Ig heavy chain locus on chr14 * overexpression of cyclin D1 promotes G1/S transition

Answer 26

* Indolent w mostly mature lymphocytes, extranodal * MALTS: tonsils, adenoids, Peyer’s patches, stomach * most common site for MALToma in stomach from H. pylori * other common sites are salivary gland and thyroid gland * assoc with chronic inflammatory states including Hashimoto, Sjorgren syndrome (autoimmune) * MZL can spread to other mucosal sites

Answer 27

Burkitt Lymphoma * aggressive B-cell lymphoma assoc w EBV Clinical scenarios * African (Endemic) Burkitt -\> 100% EBV * preferred sites: mandible, ovaries, kidneys, adrenal glands * Sporadic Burkitt -\> 15% EBV * **preferred site: ileocecal/abdomen -\> obstruction** * HIV-assoc Burkitt -\> 25% EBV Morphology * starry sky appearance from macrophages eating necrotic cell debris from all the cell proliferation. * normal looking lymphocytes, * Extranodal masses in form of neoplasm growing from mandible (right) * **t(8;14) -\> overexpression of MYC** * B sx: fever, night sweats, weight loss * Investigations: flow cytometry CD19+, CD20+, CD10+, and surface Ig+ C&C rapid growth but responsive to chemotherapy

Answer 28

Hairy cell leukemia Morphology * Right: Acid Phosphatase (TRAP) stain showing reticulin * Hairy cell in PB; fried egg in BM * BM with fibrosis so **dry tap** * Accumulates in **red pulp of spleen** -\> sequestration -\> Howell-Jolly bodies & beefy red appearance -\> **splenomegaly** * Dx * Flow: CD20, CD25, CD11c, 103 * biopsy -\> **TRAP stain** + (mostly for hairy cell leukemia) * Sx * Middle age males, pancytopenia due to being trapped in reticulin & splenomegaly * Rarely LN enlargement; asx or indolent; anemia

Answer 29

* Multiple myeloma -\> IgG * Walderstrom agammaglobinemia -\> IgM * Heavy chain disease -\> H chains * Primary amyloidosis -\> Light chains * MGUS

Answer 30

Multiple myeloma * Left: BM w abnormal plasma cells, excess clock face, golgi bodies secreting a lot of Ig * Right: Rouleaux formation due high production of Ig causing RBC to stick * Germinal centre B-cells acquired mutation -\> transformed -\> go to sites such as BM to proliferate -\> plasma cell neoplasm * middle age men w bone pains Etiopath * malignant proliferation of plasma cells in BM * high serum IL-6 (important GF for plasma cell) Sx: CRAB=Calcemia, Renal failure (2o to hypercalcemia, BJ proteins, amyloid), Anemia, Bone lesions * cytopenias due to BM replacement * organomegaly late in disease (liver, spleen, LN, lungs) * bacterial infections: 2o to neutropenia and hypogammaglobinemia (nl IgG low) * Dx * Serum analysis: * hypercalcemia, * M spike aka gamma Ig -\> monoclonal plasma cells * Urine analysis: light chains BJ proteins * AL amyloidosis -\> myeloma kidney -\> renal failure (Pathoma)

Answer 31

Hodgkin's lymphoma (HL) * Biopsy of LN * neoplastic Reed-Sternberg cells (altered germinal centre B-lymphocytes appearing as large B cell w multilobed nuclei) secreting cytokines drawing in reactive/inflammatory cells * Less tumour cells (Reed-Steenberg cells), more inflammatory cells * Owl eye cells -\> inclusion-like * Hodgkin lymphoma starts in single node and spread continuously (whereas non-Hodgkin spread is unpredictable) * Best prognosis is Hodgkin; younger age group * Stages: 1-4 * Stage I: single LN * Stage II: multipe LN involved on same side of diaphragm * Stage III: multiple LN involved on both sides of diaphragm * stage IV: multiple/disseminated involvement * Sx: Most lymphomas lead to hemolytic anemia * painless rubbery LN enlargement * pain in involved LN after drinking EtOH * fever, night sweats, weight loss * cutaneous anergy (itching) * Dx: HL divided into Classical or Variant HL according to immunophenotype * Classical: CD15+, CD30+, CD45- * Variant: CD20+, CD45, CD 15-, CD30- * Eosinophilia (Pathoma) * 2 groups of HL Types: * nodular sclerosis (most common) * mixed cellularity, * lymphocyte-rich, * lymphocyte-depleted * Variant: lymphocyte-predominant * Nodular sclerosis HL * mostly adolescents or young adults * mediastinal involvement * Stage I or II @ presentation (**mediastinal +/- neck LN)** * Large nodules, at least partly surrounded by thick fibrous collagen bands -\> fibrosis cuts nodules hence the name * Presence of Lacunar R-S cell (type of Reed-Sternberg cell) * Mixed cellularity HL * diffuse nodal replacement, frequent RS cells, often EBV+ * young adults & adults \>55 yo men * systemic sx and advanced stage (ab involvement) at presentation * assoc w eosinophilia (Pathoma) * Lymphocyte depleted HL * abundant RS cells that may be bizarre & very often EBV+, background of few lymphocytes and fibrosis * elderly of HIV+ w systemic sx and advanced stage IV @ presentation. * Variant HL * large nodules (but no collagen band fibrosis) * **L&H or popcorn cell** (a type of Reed-Sternberg) * Young men \< 35 yo * cervical or axillary nodes * indolent behaviour but tendency to recur * \<5% transform to a non-HL large B-cell lymphoma * Rx & Prognosis: * Radiation +/- multi-agent chemo depending on clinical stage. * stage is the most important prognostic indicator * 5YDFS * Stage I & II=90% * Stage IV=60 to 70% * C&C: long term survivors get 2o cancers including AML, lung cancers.

Answer 32

ALL * 85% ALL cases are pre-cursor B-cell types -\> Childhood * 15% ALL cases are T-cell neoplasms presenting as mediastinal masses -\> Adolescent males * Left image: Marked incr in lymphoblasts; mutations in genes involved in differentiation (TF) married w complementary mutations in genes involved in proliferation (MYC-ABL) * Right image: PAS stain to ddx ALL from AML. ALL will show clear (agranular) cytoplasm; no Auer rods, * Cytogenetics: 90% of ALL have hyperdiploidy (favourable prognosis) or translocation * Sx: Abrupt onset and severe (short history of sx) * bleeding problems -\> petechiae, bruising, epistaxis * cytopenias (and their sequelae), bone pain * generalised enlargement of LN, liver, spleen * thymic enlargement (T-ALL) * testicular enlargement (B-ALL) * CNS involvement (B-ALL): headaches, blurred vision, vomiting * Dx: tdt marker in nucleus (Pathoma) * B-ALL surface markers: CD10, CD19, CD20 * T-ALL surface markers: CD2 to CD8 (Blasts do no express CD10) * Rx: multi-agent chemotherapy w prophylactic chemo to scrotum and brain; Bone marrow transplant (BMT) for relapsed cases * Prognostic factors: see image Assoc diseases: Down syndrome after age of 5

Answer 33

AML * adults and old people (\>60 yo) * Sx: Acute onset (weeks-months), sx related to cytopenias * Tissue involvement can be a feature of AML w monocytic differentiatiion. * Ex. skin=funny rash; * mucosal=gum swelling * AML: FAB classification * Degree of maturation of granulocytic lineage of AML (M0 to M3) * Presence of additional lineages of blast cell (M4 to M7) * Chromosomal translocations * younger adults w de novo AML such as promylocytic leukemia: t(15:17) aka RXR mutation & AMLM3 * Complication: Auer rods & granules inducing DIC * most translocations -\> better prognosis except those having chr 11 * Deletions & monosomy on chr 5 & chr 7 * **Precursor syndrome: older people w AML w myelodysplasia (MDS)** or post-chemo/radiotherapy * Etiopath: * mutations similar to ALL * alkylating agents or radiotheraphy resulting in myelodysplastic disorder which can progress to AML * Sx: rapid onset of sx of cytopenias * anemia * neutropenia: fever, sepsis * thrombocytopenia: spontaneous mucosal, skin, intracranial bleeds * M4 & M5 complication: skin and mucosal manifestations -\> skin rashes, bleeding from gums (acute monoblastic leukemia), monocytes * extramedullary masses (uncommon) * hepataosplenomegaly: mild, if present * Lab Dx: * PM smear showing circulating blasts * occasionally, aleukemic leukemia * **MPO stain -\> aggregates called Auer rods** * **BM aspirate & biopsy (Gold standard) \> 20% blasts in BM** * **Flow cytometry: expression of myeloid markers** * **Cytogenetics** * Rx and Prognosis * In AML w t(15;17), the chimeric RARalphaPML -\> block of differentiation -\> so Trans-retinal to differentiate cells to neutrophils. * most AML given combination chemo * t(8;21) & inv 16 = better * t(15;7) = intermediate * del 5 or 7 = poor * BMT for high risk * C&C: Acute megarkyoblastic leukemia emergency due to risk of DIC (Pathoma)

Answer 34

* Clonal maturational defect leading to: * ineffective hematopoiesis * cytopenias * Clinical settings: * idiopathic: \>50 yo & gradual onset * therapy-related: 2 to 8 yo, post-chemo or radiation therapy * Outcome: transformation to AML (10 to 40% of cases), or death related to complication of cytopenias. * PB: macrocytic anemia, cytopenias, +/- blast cells * BM: usually hypercellularity but ineffective hematopoiesis * **abnormally shaped RBC**, granulocytic precursors, and **megakaryocytes.** * Course & complications: * in severe MDS, blast cells increased but by definition \<20% of total cells. * Dx: * cytopenias causing anemia (macrocytic & usually persistent and unexplained on presentation), neutropenia, thrombocytopenia * PB and BM morphology * cytogenetics * flow cytometry * 5q deletions marker for post-therapy myelodysplasia (Robbins) * Rx: * BMT for younger, supportive for older

Answer 35

1. CML 2. Polycythemia Vera 3. Essential Thrombocytosis (ET) 4. Primary Myelofibrosis (PM) -\> megakaryocytes Note: All have JAK2 mutations except CML which has the MYC-AB: translocation * Disorder to pluripotent progenitor cells, capable of uncontrolled proliferation w full differentiation. * Tumour cells circulate and home in on 2o sites of hematopoiesis in organs -\> spleen & liver organomegaly * PB smear image: * Myelocytes at numerous stages of differentiation * More granular mylocytes -\> megakaryocyte * Termination in a spent phase of progressive BM fibrosis and cytopenias (PV, ET, MF) or transformation to acute leukemia. * Sx: slow onset, organomegaly Complications (Pathoma): * incr risk of hyperuricemia (except in ET) * progression of marrow fibrosis * transformation to acute leukemia

Answer 36

CML (type of CMP): specific features * 100% of cases have t(9;22) ; Philadelphia chromosome acquired at stem cell stage. * mainly granulocytic * 25 to 60 yo men * PB smear image: * striking left shift of leukocytosis, mostly neutrophils, metamyelocytes, and myelocytes, and eosinophils and basophils (**basophilia)** * sometimes thrombocytosis * BM: mostly granulocyte precursors w incr megakaryoctyes * Sx: Gradual onset * tiredness, weakness, loss of weight and appetite * Enlarging spleen can lead to ab discomfort Dx (Pathoma) * DDx w infection which also show incr granulocytes * CML granulocytes are Leukocyte Alkaline Phosphatase (LAP) -ve, i.e. leukemoid reaction -ve * CML assoc w incr basophils * CML granuloctyes exhibit t(9,22) Course & complications: * Stable phase: 3 y w 50% progressing to accelerated * Accelerated: incr blasts, BM fibrosis, thrombocytopenia, and incr. cytogenetic abnormalities -\> transformation to acute leukemia * Blast crisis: looks like acute leukemia, left shift to stem cell stage, then 75% myeloid and 25% lymphoid stages Rx: * Imantinib (Gleevec) slows down TK activity of BCR-ABL translocation * IFn-alpha * Hydroxyurea: gentle chemo * BMT

Answer 37

Myelofibrosis * Left image: BM showing extensive reticular fibrosis * Dysplastic megakaryocytes in clusters * Distended marrow sinusoids, frequently containng intravascular hematopoiesis. * Right image: BM reticulin stain for collagen III * incr thickening of reticulin fibres; dense network of fibres * proliferation of fibroblasts & deposition of collage w/in BM * Image below: **leukoerythroblastosis** * **Tear-drop shape of dacryocyte**, characteristic of myelofibrosis. * Primary Myelofibrosis (aka Myeloid metaplasia): * type of myeloproliferative disorder. * hyperproliferation of neoplastic myeloid progenitors that retain capacity for terminal differentiation. * Leads to incr in one or more formed elements of PB * MPL or JAK kinase mutations (1o myelofibrosis) * A lot of megakaryocyte -\> secrete PDGF -\> fibroblasts laid down in BM * Sx: anemia, splenomegaly (extramedular hematopoiesis), leukoerythroblastic smear * Dx: Dry tap on BM aspirate * Course & complications: * incr risk of infection, thrombosis, bleeding hemorrhagic episodes * hyperurecemia, and gout due to rapid cell turnover

Answer 38

Infectious mono **Morphology** * Arrow is pointing to atypical large lymphocytes called Downey cells * Enlarged reactive CD8 T lymphocytes with increased cytoplasmic: nucleus ratio. Arrow is pointing to a phenomenon called “Dutch/Ballerina Skirt”. Nucleus of Lymphocytes in basophilic and peripherally located. **Etiopath** EBV spread via saliva→ virus invades and replicates inside epithelial cells of nasopharynx→ immune system response via CD8+ cells → symptoms (48wks after infec) **Sx** * Fever * lymphadenopathy (cervical, axillary and inguinal) * sore throat * hepatosplenomegaly (T cell hyperplasia) * Splenomegaly -\> periarterial lymphatic sheath (PALS); in white pulp (Pathoma) **Dx** * Serology: look for Ab against EBV/CMV, * **Heterophile-positive** (Monospot) test * Monospot test positive in EBV and negative in CMV * employs heterophile Ab -\>Latex agglutination assay -\> reactive to sheep and donkey sera) * lymph node biopsy find hyperplasia of paracortex (immature + mature T cells). **C&C** * incr risk of splenic rupture -\> avoid contact sports * rash if exposed to penicillin * dormancy of virus conferring increased risk of lymphoma ● Lymphocyte depleted hodgkin's lymphoma ● Burkitt’s Lymphoma (NHL) ● Nasopharyngeal carcinoma ● Oral hairy leukopenia

Answer 39

* Relative polycythemia: due to reduced plasma volume (usually 2o to dehydration). * Absolute polycythemia: * Primary – Polycythemia Vera (PRV), a chronic myeloproliferative neoplasm. * Secondary – (a) Appropriately high EPO levels – lung disease, cyanotic heart disease, living at high altitude. (b) Inappropriately high EPO levels – EPO secreting tumors (e.g. kidney & liver cancers) **Sx** * blurry vision and headache * incr risk of venous thrombosis -\> Budd-Chiari syndrome (hepative v. thrombosis) * flushed face due to congestion * itching after bathing from Mast cells releasing histamine