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Pediatric Pathology QinshiPan Orange is stuff she said in class “know this, own this”

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1 Pediatric Pathology QinshiPan Orange is stuff she said in class “know this, own this”

2 Definitions Neonatal: 0-4 weeks after birth Perinatal: -5 to 1 month (morbidity/ mortality) Infancy: 1 st year Childhood: Birth – legal adult age Congenital Anomalies: morphological defects present at birth Malformations: intrinsically abnormal morphogenesis (anencephaly, heart defects) Disruptions: destruction of previously normal structure (amniotic bands) Deformations: extrinsic disturbance of development (leiomyomas/ oligohydramnios) Sequence: a pattern of cascade anomalies set off by one initiating aberration (Potter sequence) Malformation Syndrome: constellation of congential anomalies that are thought to be related but can’t be explained by single initiating event (viral infection) Agenesis:complete absence of an organ and primordium(renal agenesis) Aplasia: complete absence of an organ due to primordium development failure Atresia: absence of an opening usually in hollow organ (trachea/ intestine) Hyperplasia/Hypoplasia: increase/decrease in cell number (pulmonary hypoplasia) Hypertrophy/hypotrophy: increase/decrease in cell size Atrophy: decrease in size, wasting away, arrested development Dysplasia: abnormal organization of cells (omphalocele [big defect], gastroschisis [sticking out of hole])

3 Epidemiology Infant Mortality: lowest in Singapore, highest in Angola, lowish in US Under 1 year: Congenital abnormalities/ short gestation/low birth weight 1mo-1year: SIDS 1-24 years: accidents and adverse effects Causes of Congenital anomalies: unknown, multifactorial, chromosomal abberations, mendelian inheritance, maternal disease state, maternal infections Most common birth defects: Tri 21 (Down’s), Tri 13 (Patau), Tri 18 (Edwards), cleft palate/lip, tetrology of fallot, spinal bifida Potter Sequence: Oligohydramnios (usually from renal aplasia/ amniotic leak)  Potter Facies: Ocular hypertelorism Low-set ears Receding chin Flattening of the nose Deformed right foot (talipesequinovarus) Amnion Nodosum (nodules on fetal side of amniontic sac) Pulmonary hypoplasia Breech presentation

4 KaryotypicAbberations: usually during gametogenesis (not inherited) Trisomy 21: Down’s Simian Crease Mental Retardation Epitcanthic folds 40 4% from Robertsonian translocation Drugs and Chemicals: Retinoic Acid: Accutane, used in acne affects HOX Thalomide: used to prevent nausea. UpregulatesWNT(wingless) Antiepileptics:valproic acid disrupts HOX genes Smoking: low birth weight, prone to SIDS Fetal Alcohol Syndrome: dose-dependent, short palpebral fissures, maxillary hypoplasia, growth retardation, affects retinoic acid and SHH High in Native American Population MCC of mental retardation Phalates: PVC ) can cross placenta and pass into breast milk  testicular problems Radiation Single Gene Mutations: 90% autosomal and arise during gametogenesis SHH(Sonic Hedgehog Gene): Holoprosencephaly GL13 (downstream of SHH):Synpolydactyly Maternal Diabetes: hyperglycemic mom  hyperinsulinemic baby = GIANT BABY Multifactorial: Cleft lip/palate (alcohol, rubella, thalidomide) Neural tube defects (folic acid) Congenital dislocation of hip (shallow acetabulum = genetic, breech =environment) Congenital Anomalies: 3-9 weeks, peaks at 4-5 when all organ systems are developing PAX genes: DNA binding proteins PAX 2: Renal-coloboma (kidney, ears, eyes, brain) PAX 3: Waardenburg (pigment and deafness), alveolar rhabdomyosarcoma (PAX3/7) PAX 5: Leukemia (Non-hodgkins  B-cell) PAX6: Aniridia (no iris) PAX 7: Thyroid cancer (3 too) PAX8: thyroid cancer

5 APGAR: probability of survival (Done at 1 and 5 min following birth) Score 0-10, 0-2 for each category: appearance, pulse (100), grimace, activity, respiration 5min APGAR of 0-1 = 50% mortality in 1 st 28 days Birth Injuries: large babies (Maternal DM) in danger Caput succedaneum (scalp edema) Cephalohematoma (hematoma on scalp) Intracranial hemorrhages Skeletal fractures Nerve, liver, adrenal laceration Birth Weight AGA: appropriate (10-90 th %) SGA: small (<10 th %) LGL: large (>90 th %) Fetal Growth Restriction (FGR) 1.Symmetrical: chromosomal disorder, congenital anomaly, infection by a TORCH 2.Assymmetric: uteroplacental insufficiency (esp 3 rd tri) placenta, cord, insertion problems, Trisomy 7 mosaicism 1.Maternal Causes: preeclamsia, eclampsia, HTN, hypercoagulable states, alcohol, drugs, malnutrition Gestational Age: Premature: < 37 weeks Postmature: > 42 weeks Premature: 2 nd MCC of neonate death Risks: 1.Premature rupture of placental membranes (PPROM/PROM- TNF and metalloproteinases 1,8,9)TLR-4 upregulated in placentas with chorioamnionitis. Also LPS binding TLR-4 may trigger preterm labor (said in class for us to look it up. R factor moment) 2.Intrauterine infection: can cause or be caused by (P)PROM, increased IL-6 or maternal G-CSF  secretion of proteases and PGs (contractions) 3.Uterine, cervical, placental structural anomalies: fibroids, incomptent cervix that doesn’t stay close, placenta previa, placenta accreta 4.Multiple gestations Organs affected in preterm: Lungs (no surfactant) Kidneys (immature but OK) Liver (OK but too much bilirubin  kernicterus : treat with UV light) Brain: not developed, use temp/resp regulation to fix

6 Respiratory Distress in the newborn. Causes: Excessive maternal sedation Fetal head injury Blood/amniotic fluid aspiration Intrauterine hypoxia from nuchal cord MCC: Hyaline membrane disease Preterm/AGA, male, maternal DM, multiple gestation, C section before labor. Deficiency of pulmonary surfactant (normally lecithin, SP-B, SP-C) secreted by Type II pneumocytes to decrease surface tension in the lungs)  induced by labor Increased diffusion gradient  decreased O2  atelectesis, dilation of alvoili  thickened hyaline membranes Treatment: weeks: Antenatal treatment with steroids <26-28 weeks: Administer surfactant Therapy with O2= risk of retinopathy (increased VEGF b/c decreased O2 after stopping O2 treatment) and bronchopulmonarydysplasia) (O2 decreases maturation so lungs stop at saccular stage Necrotizing Enterocolitis: Occurs after ORAL feeding Intestinal ischemia  bacterial colonization /formula aggravates mucosal injury  inflammation  PAF = mucosal breakdown  invasion by bacteria S&S: Babies present with poor feeding. Complications: May perforate and lead to peritonitis, sepsis, shock therefore SURGICAL EMERGENCY PostNEC  strictures Germinal Matrix Hemorrhage: Preterm infants: subependymal (periventricular hemorrhage) then into ventricles

7 Transplacental Infections T:oxoplasma O:thers (T. Pallidum) R:ubella (Concep  16weeks) Cataracts, cardiac, CNS, deaf C:MV (MC 2 nd trimester) owl eye inclusion, mainly targets CNS, heptaosplenomegaly, myocarditis H: erpes simplex Parvo B19 (fifth disease) in mother occurs in 1-5% of pregnancies*** Transcervical Infections Group B Strep (worst), some HSV II PROM frequent with Preterm delivery Chorioamnionitis/funisitis Post delivery Early (0-7days): GBS: acquired at or shortly before birth  pneumonia, sepsis, meningitis Late (7-90 days): Listeria, Candida, require latent growth period ***Pathognomonic for Parvo B19: infected cells are larger with intranuclear inclusions and rim of chromatin. Infects RBC precursors so RBCs never mature

8 Fetal Hydrops *** Accumulation of edema in fetus during intrauterine growth Gross: generalized edema and cystic hygroma on neck Immune Hydrops:Rh incompatibility Pathophysiology: Rh+ child sensitizes Rh- mother late in pregnancy  IgM response (does not cross placenta)  2 nd Rh+ child  Mom makes IgG (does cross placenta and attacks fetal RBC)  anemia, jaundice, hydrops, kernicterus (fetal cord blood is Coombs+) - Anemia  extramedularyhematopoiesis and cardiac decompensation  hydrops - Hb degradation  excess bilirubin  Jaundice  Kernicterus Treatment: Rhogam for mothers at 28 weeks and within 72 hours after birth. If hemolysis occurs in utero, treat with low dose of in utero transfusion ABO Incompatibility Low incidence b/c: -Most maternal anti-A/B are IgM -Fetal cells express A and B poorly -Most other cells also express A/B so Igs are sopped up -No effective prophylaxis (like Rhogam) therefore ABO incompatibility = MCC of immune hemolysis in newborns Non immune Hydrops: CV defects, chromosome anomalies, twintwin transfusion, fetal non- immune anemia (alpha thalassemia, parvoB19 induced aplastic anemia)

9 Kernicterus: unconjucated (can cross BBB) bilirubin deposited in brain after birth >20mg/dL usually to basal ganglia, thalamus, cerebellum Inborn Errors of Metabolism Self-mutilationLesch-NyhamPurine Degradation Sweaty FeetIsovalericacidemiaIsovaleric acid CoAdehydrogenase Musty/mousy odorPKUPhenylalanine hydroxylase Maple syrup urineMaple syrup diseaseBranched ketoaciddehydrogena se. Accum: ILV Cherry Red maculaTay SachsHexominidase A Cherry Red macula + hepatosplenomegaly Nieman-PickSphingomyelinase Dislocated lens, marfanoidhabitus HomocysteinuriaCystathione beta synthase CF: CFTR (MC lethal genetic disease in caucasians. Abnormal CFTR. S&S: pancreatic insufficiency, steatorrhea, malnutrition, heptatic cirrhosis, intestinal obstruction, male infertility, recurrent pulmonary infections, chronic lung disease Sudden Infant Death Syndrome (SIDS): #1 cause of death 1mo-12mo. (esp 2-4mo) Diagnosis of exclusion (must have negative autopsy) Risks: paternal marijuana, maternal opiate, cocaine use; prone or side sleeping position, sleeping on soft surface, hyperthermia, co sleeping in 1 st 3 months, male, premature, poor Autopsy findings:petechiae over thumus, viscera, epicardium, parietal pleura; congestion of lungs and pulmonary edema; astrogliosis of brainstem and cerebellum, hypoplasia of arcuate nucleus in BS Sudden unexpected infant death: NOT SIDS Find something on autopsy Ex: petechie in conjuctiva and lips of intentional suffocation Pathogenesis (triple risk): 1.Vulnerable infant 2.Critical development in homeostatic control 3.Exogenous stressor (URT infection, soft bedding, sleeping prone) Hypothesis: delayed development of arousal and cardiorespiratory control

10 ALTE: apparent life threatening event (have been resuscitated)= increased risk of future respiratory death S&S: prolonged apnea, diminished responses to hypercarbia or hypoxia Protein-Energy Malnutrition (PEM): Marasmus: caloric deprivation (months) -Somatic compartment affected more -Normal/slightly reduced albumin -Loss of fat and muscle -Hypoplastic BM  anemia (hypochromicmicrocytic anemia) Kwashiorkor: protein deprivation (weeks) -Visceral compartment affected more -Low serum albumin, tranferrin, others -Generalized/dependent edema -Skin with zones of hyper/hypopigmentation and desquamation -Hair loss, large liver, lactase deficiency, anemia Secondary PEM: advanced cancer, malsoprtion, diet restrictions, infections

11 Pediatric tumors: difficult to differentiate between true neoplasms and tumor-like collections of cells present b/c of development (MC: benign) Heterotopia (ectopic) or choristoma: normal cells from a tissue type in the wrong place Hamartoma: overdevelopment of tissue normally present Benign Tumors: Hemangiomas: most common tumor of infancy, usually in skin, ass with von Hippel-Lindau and Sturgeweber, spontaneously regress Lymphangiomas: skin or deeper Fibrous tumor: Congenital infantile fibrosarcoma: t(12;15)(p13;q25)= ETV6-NTKR3 fusion transcript  TK that stimulates Ras (MapK: cell proliferation) and PI3K/AKT (PLC  blc- 2= inhibits apoptosis) Teratomas: most common germ cell tumor of children (75% benign, 13% intermediate (immature), 12% frankly malignant (malignancy arising in teratoma)) Peaks at 2yo and late adolescence, younger= benign Usually sacrococcygeal in females Malignant Tumors: -Tendency to regress or differentiate (more cures in children) -Small round blue cell tumors 0-4yo: MC: neuroblastoma  ALL(#1 death)  CNS 5-9: ALL still most common add in hepatocellular carcinoma, ewing sarcoma (t(11;22), lymphoma Neuroblastoma: N-myc amp, 17q gain, 1p del -Most common extracranial solid tumor of childhood, usually in SNS, brain or adrenal medulla -5 yo: 55%, median age 22 months Histo: Homer-Wright pseudorosettes, neurosecretory granules, neuron-specific enolase (not helpful), Schwann cells (favorable prognosis) S&S: abdominal mass, blueberry baby, catacholamine secretion (HTN less than pheo) Measure:VMA, HVA in urine Prognosis: same except 4S: to skin, liver, BM = good Retinoblastoma: MC malignant eye tumor Germline/somatic RB1 gene: white eye reflex and Flexner-Wintersteiner rosettes Nephroblastoma (Wilms Tumor): MC primary renal tumor (feel bump in baby’s back), Histo is triphasic: stroma, tubules, blastemal elements) Medulloblastoma (17p deletion)

12 WBC Qinshi Pan Cytogentics, CD markers, pathognomic/uber important, probably pretty impt.

13 CD Markers CD1: Langerhangs Cells CD3/5: Tc CD 4: helper Tc CD 8: cytotoxicTc CD 10: immature Bc, follicular lymphoma CD11c: granulocytes, monos, hairy cell leukemia CD 15: granulocytes and Reed-Sternberg (Hodgkins) CD 16: NK and granuloctyes CD 20/22: Mature Bc (Anti CD20= Rituxan) (Not in Hodgkin) CD 25: Increased in Adult T cell lymphoma (HTLV-1) CD 30: Reed-Sternberg Cell CD 34: immature lympho/myelo cells (disappears on promyelocyte) CD 38: Multiple Myeloma, CLL/SLL (bad) CD 45 all leukocytes (Not in Hodgkin)y CD 56: NK and some T CD 79a: Bc CD 103: Hairy Cell Leukemia sIg-: immature Bc sIg+: mature Bc

14 Stains: Romanovsky stains: eosin + methylene Wright Giemsa: Lymphocytes, segmented neutrophil Eosinophils WBC Differential: count 100 WBC and relative # of each type expressed as %  Red marrow in vertebral bodies Bone marrow aspirate: look at cytology and space occupying lesions BM cellularity: 100-age until 20% Formed elements: cellular elements of blood Leukemia: malignancy of BM Lymphoma: Tumors from lymphoid tissue

15 Left Shift: absolute increase in # of immature nps Hypersegmentation: PMNs have 5/6 lobes instead of ¾ Toxic Granulation: more purple granules (usually bact or G-CSF, reA change) Dohle bodies: blue patches of dilated ER (reA change) *Relative change in WBC doesn’t matter much, absolute count matter Neutropenia: too few np (MCC: infection, MCC sig: drugs) Agranulocytosis (severe neutropenia) Neutrophilia: 1.Increased release from marrow: acute infection/left shift 2.Increased circulation: epi, exercise 3.Decreased to tissue: cortisone 4.Increased # in marrow: chronic infection, CML Leukemoid Reaction: elevated WBC and immature precursor. LAP:(CML[low] vsleukemoid [high]) Eosinophila: allergies/parasites Basophilia: usually CML(9:22 philadelphia) Lymphopenia: usually HIV/SCID Lymphocytosis: chronic immunological stimulation, virus, pertussis Monocytosis: Chronic infections (Tb, SLE, UC) Atypical (Activated) Lymphocytes:mono Life Span of WBC Np: 1-48 hrs (small% circulating) Bc: hours-days Tc: days to years Eos: 1-48 hrs (small% circulating) Absolute counts: Np(seg/band): 1,700-7,000/uL Lympho: 1,400-3,500/uL Eos: 700/uL Multipotent SC  selective/commited cell (myeloid/lymphoid)  Colony forming cell  WBC/RBC/platelet **All of this depends on interaction with CK environment (GMCS: give to chemo ppl so they don’t get infections

16 Bone Marrow Transplant: eliminate own BM SC and replace with other SCs Source of SC support BM: Rich, difficult to harvest, may be tumor contaminated Peripheral blood: low counts, easy to harvest, mobilization with GFs Both: not done unless donor is really far away Cord blood: lots of SC, low volume, need multiple donors Autologous (own cells)Allogeneic (other’s cells) Source of SC- Bone marrow, -peripheral blood SC harvest - Identical twin (syngeneic) -HLA-matched sibling -Matched unrelated -Umbilical Cord (2/3 cords added but 1 will win) - Give higher doses of chemo for cancer (solid tumors, lymphoma, acute leukemia post remission esp if no donors or old) - Allows manipulation of SC (gene therapy) - Replaced damanged/depleted SC (aplastic anemia) - Replace defective SC (immunodeficiencies, Sickle,thalassemia, m0 storage disorder, myelodysplasia, acute/chronic leukemia) Complications 1. Host factors: Rejection (not enough CKs) 2. Donor: GVHD 3. Tumor factors: Relapse 4: Chemo factors: Organ damage 5. Immunosuppresion: infection 6: Other: sterility, 2ry malignancy, autoimmune disease

17 Bone Marrow Failure Syndromes: pancytopenia(all 3 lineages), bone marrow hypoproliferation (aplastic anemia), abnormal maturation (myelodysplasia) Acquired Idiopathic Aplastic Anemia: Patho: depletion of SCs, suppression of SCs by T cells (either Tc are whack or SCs are defective) Causes: idiopathic, toxins, drugs (chloramphenicol), viral (hepB/C, EBV) S&S: pancytopenia, normal physical, hypocellularmarrow replaced by fat and a few inflammatory cells (mimicked by post chemo) Therapy: Immunosupression with ATG/cyclosporin, BMT, remove inciting agent (limit exp to drugs and blood transfusion [don’t want to hyperA]) Myelodysplastic Syndromes:>60 bone marrow failure, comes in tired S&S: pancytopenia, pandysplasia(too many/few lobes, wrong shape), hypercellularity in BM Low grade: Low blast counts, ringed sideroblasts, refractory anemia High grade: excess blasts  AML Cytogenetics/Blast count to predict prognosis Treatment: supportive, targeted therapies, immunesuppression (low grade), chemo (high grade), allogenic SC transplantation Associated with cytogenetic abnormalites (mutations in SC) and can progress to AML Low platlets = bleeding Low RBC = fatigue Low WBC= infection

18 Acute Leukemias: malignant disorder of infiltration of marrow by blasts (these blasts secrete CKs that suppress normal SCs  problems) Clinical Feature: fatigue, fever, bleeding, bone and joint pain Physical Findings: B/Tc: splenomegaly, hepatomegaly, lymphadenopathy Other: gum swelling, skin nodules, sternal tenderness, petechiae Laboratory Findings: Blood: pancytopenia& circulating blasts Bone: hypercellular replaced by immature blasts Labs: elevated uric acid and LDH Characteristics: monoclone  clonalprogression  clonal dominance  extinction of normal clones  genetic instability Pathogenesis: Environmental Radiation Chemicals (benzenes) Chemo drugs Inherited disorders and DNA repair defects (Fanconi, Downs) Retroviruses (HTLV-1) Somatic Mutation (MCC): idiopathic Oncogenes: cause tumors when they are activated (TKs and GF-R) Tumor Supressors: cause tumors when they are deleted (p53) Cytogenetics: grow cells in culture with mitogens then look at chromosomes t (9:22):(Philadelphia chromosome) short= ALL; long=CML Bcr-abl tyrosine kinase: complete oncogene T (15:17): Acute promyelocytic leukemia PML-RARA (retinoic acid receptor): partial oncogene (need 2 hits) Mechanism: inhibits differentiation but promotes survival. High [Vit A] induces differentiation 11q23: AML, topo II inhibitor MLL: many different translocations with different cytologies Secondary to alkylating chemotherapy 5q: partial deletion

19 Classification of Acute Leukemia ALL (acute lymphoblastic leukemia): committed SC of B/T AML (acute myelogenous leukemia): multipotent/committed SC of myeloid lines (np, mono, RBC, megas) -Midadulthood, remission for 2 years, usually follows something else (ex. CML, toxins), AUER RODS - PML-RARA: good, Normal: intermediate, 5q/ 11q: poor Acute leukemias of mixed lineage: multipotent SC that expresses lymphoid and myeloid ALL/LBL (acute lymphoblastic leukemia/lymphoma): immature B/T cells (lymphoblasts) - Leukemic: ALL: B-cell, childhood (MC malignancy, good prognosis), BM/LN/spleen, peak in adults, poorer prognosis (Hyperdiploid: good (seen in kids), Normal: intermediate, translocation: poor) - Lymphoma: LBL: T-cell, adolescent males, presents as mediastinal mass, thymic -Highly aggressive w/CNS Diffuse chromatin, TdT, CD10, CD19, CD 22 markers Treatment: chemotherapy to kill leukemia & normal but spare SCs (SCs are spared b/c they are supressed from division by CKs from leukemia) CNS: chemo infused into CSF New: targeted therapies

20 Myeloproliferative Disorder (chronic leukemia): increase of 1 or more MATURE peripheral blood cell types Commited germ cell markers: CFU- GM, CFU-E, BFU-E SC Disorders: mutation in multipotent (mylodysplasia, aplastic anemia), mutation in commited (Acute leukemias, CML) CML:30-35yo Asymptomatic: early Chronic:splenomegaly, hypermetabolic rate. PB: Increased granulocytes, np, baso (WBC>100,000  sludge  decreased perfusion); more turnover= more LDH/uric acid BM: 100% hetergenous cellular (may go to fibrosis) Treat with oral chemo/ gleevec (imantinib) –I bcl-abl Acute:gains c-myc/ras  goes to AML/ALL PB: immature np, anemia BM: 100% homogenous cellular with blasts Cytogenetics: Philadelphia 9: c-abloncogene; 22: unknown bcl. Short=ALL long= CML P. Vera: yo PB: increased RBC, np, platelets BM: hypercellular and goes to fibrosis (looks like CML) Labs: less EPO, more LDH/uric acid) Cytogenetics: JAK2 mutation on many or both chromosomes Ddx: 1.P.vera: neoplastic 2.Hypoxia: reactive Relative. Stress in smokers: less plasma V but same RBC so looks like P. Vera Measure: 51Cr (RBC), CT/exam (spleen), leukocytosis, thrombocytosis, O2 sat. Essential Thrombocytosis: 20 yo female splenomegaly PB: more platlets BM: normal/hypercellular with megakaryocytes in clusters (usually single) Cytogenetics: JAK2 mutation on 1 chrom. Or small # of cells Idiopathic Myelofibrosis: Like P.Vera/ET w/o symptoms. PB: Nucleated RBCs and teardrop cells from squishing between fibrotic BM BM: thickenend, firbrosed. Increased reticulin and collagen Cytogenetics: JAK2 Chronic: heteroAcute: homo

21 Reactive and NeoplasticLymphoid Conditions Reactive Conditions: Normal: CD4>CD8; κ:λ 1:2 80% Tcells Infectious Mononucleosis: acute, MCC: EBV, rare: CMV EBV infects Bc  B/T response  CD8 kill Bc S&S: severe fatigue, lymphadenopathy, lymphocytosis (days-weeks) PB: Downey cells (ballerina skirt): lymphocytes surrounded by RBCs that push on PM Do Monospot test for heterophilIg test Lymphopenia: Look at PB for morphology. If Hemogram abnormality  BMBx and aspirate, if immune deficiency  flow and look for serum proteins MCC: Chemo/Radi/Cortisone/EPO/AIDS Acute Nonspecific lymphadenitis:PAINFUL, sudden, swollen nodes. Acute bacterial  cervical/ mesenteric Lymphadeopathy:PAINLESS (viral unless >4cm then malignant), sarcodoisis, mets (>60 yo) Chronic Nonspecific Lymphadenitis: PAINLESS - Bc: follicular hyperplasia (RA, toxo, early HIV) - Tc: paracortical hyperplasia (mono, viral, vacc, dilatin) Histo: difuse - LN Sinusoids: sinus histocytosis (macrophages), look for breast cancer LN: light zone is where B/T interact Neoplastic Conditions: SC Lymphoid (ALL) Myeloid (AML) Bc (CLL) B/T in LN (Lymphoma) PC (MM) Stuff (myeloproliferative disorders) Within lymphoid: Hodkin: classic or NLPHL Bcell: (im)mature Tcell: (im)mature

22 Lymphoma: Dx needs Bx, confirm with flow S&S: 2/3 NHL + Hodkin  enlarged nontender LN 1/3 NHL  extranodal symptoms (skin, stomach, brain) 1.Suppresion of normal hematopoeisi 2.Due to circulationg factors (PC  Ig, CK  B Symptoms : fever, night sweats, weight loss) Other: BMF, CNS infl, Immune dysregulation (AIHA/thromb), compression (SC, ureters), obstruction (bowel), pleural/pericardial effusions, ascities Epidemiology: Hodkin (stable) NHL (increasing) Indolent: CLL/SLL, MALT, follicular lymphoma Aggressive: Mantle Cell, diffuse large Bc Highly Aggressive: Burkitt, lymphoblastic Hodkin Lymphoma (30%): -Classic (CHL) (95%): 20s then later CD15/30+ CD 20/45- Nodes: cervical, mediastinal, axillary, paraaortic + Bsymp Histo: Reed-Sternberg cell (double owl eye, lacunar) -Nodular Lymphocytic Predominent (NLPHL) (5%): maleCD15/30-, CD20/45+ Nodes: cervical, axillary, inguinal + Bsymp Histo: large cell with folded/multilobulated nuclei (popcorn cell) NHL: Mature T cell Adult T cell: HTLV-1 provirus CD25+ <1 yr -endemic in Japan, W Africa, Carib. Histo: Cloverleaf nuclei Anaplastic Large Cell Lymphoma: 2p23 ALK (good) -Responds well to treatment Histo: embryo like nuclei Peripheral T Cell: lymphadenopathy, pruritis, fever, weight loss <1 yr Mycosis Fungoides:male, CD3/4+, CD7- Cutaneous: Patch  Plaque  tumor Sezary Syndrome: leukemic counterpart (general erythroderma) Pautriermicrabscess

23 NHL: Bc immature (ALL/LBL) Bc Mature: -Burkitts: 8:14 EBVc-myc  IgHCD10/19+ Endemic (EBV+, jaw) Sporadic (EBV-, ileo-cecal, bilat breast/ovary), HIV Histo: Starry Sky (macrophage eating Bcells) -Follicular Lymphoma: white adults, 14:18 Bcl-2 Active, CD10+ Generalized lymphadenopathy +BM, lots of nodules in spleen. 2 types: small/large Grade based on # of centroblasts -Mantle Cell: old man11:14 Bcl1(cyclin D)  IgH CD5+, CD10/23 -, aggressive, hard to cure -Diffuse Large B cell: CD19/20+ No BM 50% curable with chemo and Rituxan (Anti CD20), 1 tumor in spleen Subtypes (mediastinal, young female w/CNS, immune def w/EBV, body cavity w/KSHV/HHV8, 60-80% remission -MALT: extranodal inflammation (GI, skin, lung, cry and spit) 80% at 5yrs If gastic: ass w/H. Pylori therefore Abx sensitive -Lymphoplasmacytic: lymphadenopathy, hepatomegaly, splenomegaly, 50% with Waldenstrommacroglobulinemia(high IgM: cryoglobulinemia) Visual, dizzy, stupor, deaf, bleeding, NO LYTIC BONE LESIONS 4-5 yrs survival Histo: differing degrees of PC maturation

24 CLL (chronic lymphoid leukemia)/SLL (small lymphocytic lymphoma) CD5+(Tc Ag)/CD23+(Activation marker) western 65yo female SLL: CLL w/o leukemia Reactive fault. 40% Asymptomatic Lymphadenopathy (cervical/supraclav): discrete, movable, painless Splenohepatomegaly: tumor cell invades Infections (pneumonia &osteomyelitis): normal immune function disturbed B symptoms:esp when going to worse Ddx: Tb: PPD & Culture B. Pertussis: young w/ cough EBV: HeterophileIg and teenager Leukemic phase of NHL(FL): CD10+ Hairy Cell Leukemia: CD 103+ Lymphoplasmacytic Lymphoma: more IgM Large granular lymphocytic leukemia Labs: lymphocytosis, anemia (autoimmune = +direct coombs), thrombocytopenia, increased b2m and LDH PB: nucleated RBC (b/c severe anemia), Smudge cell(fragile tumor cell), clump chromatin pattern (CLL) like soccer ball. BM: >30% lymphocytes. Patterns: interstitial, nodular, mixed, diffuse (bad) LN: not organized (effacement) of small lymphocytes with round nuclei, clumped chromatin, scant cytoplasm Cytogenetics: -Del 13q (long survival 50%) -Del 11q (20%)bad -Tri 12bad -Del 17p (p53 locus) bad Two types of IgV genus % SHM of IgV (memory B) = better % no SHM of IgV (naive B)= bad Staging: BEST PREDICTOR of survival Binet: A15, B5(>2LN), C3 (

25 Other Chronic Lymphoid Leukemias Hairy Cell: CD103+, ∧ surface hypermutation S&S: infiltrate BM, liver, spleen  massive splenomegaly, pancytopenia, infections, leukocytosis Indolent, Sens. To chemo, long lasting remission Large Granular: Tγ lympoproliferative disease Tc (Indolent) NK (aggressive) Histo: Lymphocytes with blue cytoplasm/granules decreased np and RBC w/o BM Ass w/ Felty disorder (RA, spleno, np) Extranodal NK/Tcell Lymphoma= lethal midline granuloma EBV related, sinonasal lymphoma, MC in Asia, S/Central America Langerhangs Cell Histocytosis:S100+, CD1+, HLA-DR+, Birbeck Granules (tennis rackets) Multifocal Multisystem (Letterer- Siwe):<2yocutaneouslesion like seborrheicerruption, liver, spleen, pulm, bone lesions Chemo: 50% 5 year (w/o DIE) Unifocal:older children/adults, skeletal m, local excision/radiation Multifocal Unisystem: young children, multiple bony erosions, 50% have DI, spontaneous regression/chemo Hand-Scheuller-Christian: calvarial bone defect, DI, exophtalmos Pulmonary: 15-40yo, Bilateral interstitial, multiple fine nodules in upper/middle lung, regresses w/ stop smoking Other:Blasticplasmaytoid DC, highly agressive Plasma Cell: normal PC are perivascular PC Dyscrasia: Bc clone that secretes single homogenous Ig/fragments Bence Jones P: free light chains (in urine) M component: monoclonal Ig in blood Plasmacytoma: single mass Waldenstrom: more IgM Heavy(light): secretes free fragments Amyloid: free light  amyloid MGUS: M comp in blood no S&S Multiple Myeloma:14q32(IgH), CD38+, CD increases, then peak at 80-90, usually black male S&S: hypercalcemia, infections (MCC death), renal insufficiency (2 nd MCC), amyloids, BJP, path fractures, bone pain, Usually: IgG (60%) >IgA Untreated: 6-12mo, Chemo: <5yr Myeloma  IL-6  RANKL/OPG/MIP-1  Osteoclasts  resorption (BM: high cellular w/ sheets of PCs w/ER) Variants: Flame/Mott cell, Russell/Dutcher body

26 Spleen -Accessory common -Removes unwanted elements by phagocytosis, harbors 30-40% platlets, can also undergo extramedullaryhematopoisis -DCs in periarterial sheath trap Ag  show to Tc  T/B on edge of white pulp  PC in sinus of red pulp Splenomegaly -MCC: congestive -May rupture espw/mono, malaria, typhoid fever, lymphoid neoplasm  thrombocytopenia, anemia, leukopenia (treat with splenoctomy) -Mild: Acute infections, congestion, etc -Moderate: everything else -Massive: lymphoma, hairy cell, malaria, gaucher, primary spleen neoplasm Nonspecific Acute Splenitis: blood borne infe Congestive: block vv, cirrhosis Infarcts: block aa (sickle or emboli) Neos:lymphangiomas&hemangiomasγδTc Thymus -Medulla: 3 rd pharyngeal pouch (endo) -Cortex: pharyngeal cleft (ecto) -Increase in size till puberty then get smaller (replacd by fat) DiGeorge:Thymichypoplasia/aplasiaw/ parathyroid probs22q11(decreased cell mediated immunity) Thymic Cysts: uncommon, incidental finding. If symptomatic (look for lymphoma/thymoma) Hyperplasia: more Bc in thymus vs Myasthenia Thymomas: >40yo. Neo thymic epithelial cells, normal Tc. Minimal invasion = complete excision (90% 5yr) Benign encapsulated: CD5+ Malignant: - Type I: Invasive thymomaCyto OK aggressive - Type II: thymic carcinoma Cyto BAD Other Carciomas (CD5- so not Tc):MC(squamous), 2 nd (Lymphoepithelioma like w/50% EBV)

27 RBC Qinshi Pan

28 Hematopoiesis: SC  RBC/WBC/platlets -can increase 4-5 fold in 7-10 days -usually in BM, can also be in liver, spleen, LN RBCs in intravascular space (not stored) O 2 in kidney  EPO(peritubular caps)  SC (clusters of dark cells)  RBC  40% of blood RBC: transport O 2 and CO 2 for days Aging: smaller, less elastic, spherical (removed in spleen) 4 factos: 1.Normal vs impaired Hb 2.Acute vs Chronic loss 3.Extent of RBC volume loss 4.Indirect effects (Fe, spleen, etc) Clinical Measurements: Hematocrit: RBC mass as % of blood volume (high as baby, dips at few months then men: / female: ) Hemoglobin: Total Hb/ volume blood Hct/3=Hgb Red Cell Distribution (RDV): measure of anisocytosis Low Hb and Hct (amt of RBC)= anemia Low MCV (size)= microcytosis Low MCH (color)= hypochromia Hyperchromic does not exist Haptoglobin: protein that binds plasma circulating heme, in hemolysis taken out of circulation (acute phase reactant) therefore hemolysis= less haptoglobin Hemolysis: -Intravascular (sudden, catastrophic): destruction of RBCs in BVs  schistocytes, anemia, Hb goes up, Haptoglobin goes down, bilirubin increases, hemoglobinemia, hemoglobinuria  Renal failure, DIC -- Immunehemolytic RBC, C’ mediated, severe osmotic stress -Extravascular(slow): chronic, enhancement, amp, of normal physiologic removal of RBCs  anemia, elevated EPO, BM hyperplasia (rxn to decreased RBCs) Anemia:Hb or Hct<2.5 percentile after being adjusted for age, sex, machine, altitude [therefore clinical definition] 4 approaches: Etiology, RBC size/morphology, frequency of occurrence, practical (Fe/B12 shot)

29 Normal Anisocytosis (size) Poikilocytosis (Shape) Echinocytes: may be artifact from storing Teardrop Spherocytosis Elliptocytosis Stomacytosis Rouleux Basophilic Stippling: RNA Howell-Jolly: DNA Pappenheimer body: Iron Heinz body: Denatured hemoglobin

30 Etiology: Blood Loss - Acute: trauma (normal hgb/hct) 10-15% loss in <1hr: S&S from defect in vascular volume not lack of O 2 carrying capacity 20% loss in <1 hr: shock, postural hypoTN - Chronic: GI/Gyn: gradual b/c BM can increase production by 4-5 fold. S&S if Hb<7 Increased Destruction of RBCs - Intrinsic (Defective RBC): -Hereditary:spherocytosis, G6PD thalassemia, sickle cell anemia - Acquired: paroxysmal nocturnal hemoglobinuria - Extrinsic (Normal RBC): AIHA, mechanical trauma, Pb poisoning Impaired Red Cell production Intrinsic Defects Hereditary Spherocytosis (memH): usu AD Ankryn, can also be spectrin. Unstable membrane  shear stress in circulation  loss of fragments S&S: 6-9 Hb, spleno, cholelithiasis Dx: osmotic fragility test Rx: Splenonectomy Sequelae: parvo infection  aplastic crisis Paroxysmal Nocturnal Hemoglobinuria (memA): GPI anchor mut  less CD55/59/C8BP  C’ med chronic hemolysis WITHOUT severe hemoglobinuria  acute at night S&S:dark urine (morning), hemolysis and hemoglobinuria Ass: venous thrombosis, AML Peripheral BloodCongested Spleen

31 Sickle Cell Disorders (Qualitative): 6 position of beta Glu  Val(Hetero: trait, Homo:Disease) 5-6mo (no HbF)  Sickle crisis (severe bone/lung/liver/brain/penis pain)/ Autosplenectomy (esp with S pneumo and H. Flu), also see gallstones, skin ulcers 50% to 50yo Dx: Hb electrophoresis, DNA testing, HbS solubility Treat with hydroxyurea G6PD Deficiency (metabH): XR  can’t protect as well from free radicals GDPD A-: blacks, moderately reduced GDPD Mediterranean: Middle east, Fava bean  hemolytic episode Both protect against Malaria. Patho: oxidative stress  acute intravascular hemolysis  anemia, hemoglobinuria, hemoglobinemia  removed extravascularily PB: Heinz bodies and bite cells Episodes are self-limited if stress is removed Intrinsic Defects Thalassemia (Quantitative): 2 beta and 2 alpha globin make 1 Hb PB: anisocytosis, microcytosis, Crewcut radiograph Alpha: SE Asia Chrom 16 (a1-4): -/a a/a: silent carrier, asymptomatic -/- a/a or -/a -/a: asympt like Bminor -/- -/a: HbH disease, severe like Binter -/- -/-: HydrobsFetalis: die in utero Beta:mediterranian Chrom 11 (B1-2): B- (normal) B0/B+ (mutation) B0/B0 or B+/B+ or B0/B+: Major, Severe, transfuse Variable: Intermediate, severe but don’t need to transfuse B0/B-, B+/B-: Minor, asymptomatic Spleen cong. w/ sickle cells Sickle cell

32 Extrinsic Defects Chemical Toxicity (Pb): Patho: Pb  binds sulfhydryl groups in ferrochelatase  displaces iron amd makes zinc protoporphyrin/erytrocyteprotoporphyrin PB: hypochro, microcytic anemia, basophilic stippling Traumatic Hemolytic Anemia: Path: trauma  RBCs turn to fragments  intravascular hemolysis -Mechanical: prostethic cardiac valve -Microangiopathic: TTP/HUS/DIC Immunohemolytic: -Warm (IgG): idiopathic, SLE, drugs, CLL -Severe, life threatening extravascularhemolysis (hard to treat b/c no compatible blood) -Cold (IgM): -mycoplasma, mono (younger, abrupt, severe) - idiopathic, Waldenstrom, CLL, DLBCL, splenic lymphoma (older, mild, worse when cold) -Cold (IgG): Cold hemolysin Hemolytic Anemia  paroxysmal cold hemoclobinuria. RARE Anemia caused by impaired RBC production Decreased(Diminished) or Ineffective Erythropoiesis – Megaloblastic: B12 and folatedeficiency (nutritional) – Iron Deficiency (nutritional) – Anemia of Chronic Disease (inhibits hematopoeisis) – Aplastic anemia and pure red cell aplasia (destroy SCs) Marrow failure: replacement/displacement marrow space – Myelofibrosis, primary versus secondary – Space-occupying Hematologic malignancy Metastatic non-hematologic malignancy

33 Megaloblastic Anemia (B12 and Folate): B12 Deficiency: elevated homocysteine and methylmalonic acid (better sensitivity than decreased serum cobalamin) Pernicious Anemia: Patients have antiparietal cell Ig  No IF  no Bwe S&S: glossits, gastric atrophy, neurological (can occur before B12 goes too low) cortex/lateral columns Usually 60 Other causes: Nutritional, malsorption, competitive uptake by parasites, increased requirement (pregnancy/ hyperthyroidism) PB: hypersegmentednp with 6 lobes + leukopenia, severe macrocyticanemia, hyperbilirubinemia (extravascualrhemolysis) BM: ineffective erythropoiesis Dx: serum B12, MMA, homocysteine (also up in B9 deficiency), Schillings test, pernicious needs Ig test Folic Acid: common in alcoholics, pregnant, and those taking methotrexate. Does not present with neurological symptoms Iron Deficiency: -insufficient intake (diet, malsorption, celiac, removal of ileium (Chrons), secondary to systemic - excessive loss (blood loss, hemodialysis) - excessive use (growing children, pregnancy, lactation) S&S: smooth tongue, spoon nail PB:hypochromatic, microcytic RBC, low serum ferritin/iron/transferrin saturation/stores, increased iron- binding capacity Dx: Iron studies then look at reticulocytes to see if there’s BM problem BMBx:Prussian Blue stain for Iron Anemia of Chronic Disease: Decreased EPO or can’t move Fe to erythroid precursor, MCC in hospitalized patients besides post-surgical and acute hemorrhage -Chronic infections: osteomyelitis/endocarditis -Immune (RA, Chrons) -Malig: Hodkin, Carcinoma of lung/breast High serum ferritin (Fe def has low) Definitive: BM has prussian blue macrophage Aplastic Anemia: idiopathic, chemo (alkylatin), Chloramphenicol (ABX), Idiosyncratic, physical agents (Hep, CMV, VZ, fanconi, telomerase) FATTY BM- think back to WBC Myelophthsic Anemia: like aplastic but instead of messing with RBCs you have a mass in the bone

34 Polycythemia: RBC mass > 97.5 percentile (remember to adjust for altitude, age, sex) Erythrocytosis: Increased RBCs with no increase in WBC or platelets MCC: smoking, high alt., blue bloaters Polycythemiarubravera: see WBC notes (comes with increase in WBC and platlets) -- increased viscosity, CV complications, thrombosis, hemmorrhage Dx: phlebotomy Blood Testing ABO and RhD Hep B/C, HIV, HTLV, Syphilis Acute hemolytic Anemia: -Burning along vein, low back pain, chills, fever, shock, increase pulse rate, DIC -Lab: increased bilirubin and LDH Febrile, Nonhemolytic Reaction -Increase in temp by 1 degree, chills Allergic Reaction: -Urticaria, pruritis, facial/glottal edema Anaphylactic Reaction: -ANS dysregulation, dyspenea, pulmonary edema, bronchospasm, hypotension Transfusion Related Acute Lung Injury (TRALI) -Acute respiratory distress in 6 hrs with hypoxemia and bilateral pulmonary infiltrates ABO Compatibility: O can only get O (universal donor) AB can get every type (universal acceptor/ blood hogger) A can’t have B, B can’t have A Blood Products Platelets: replaces platlets  10,000/ml if stable, >20,000/ml if unstable or > 50,000/ml in bleeding or surgical patients Frozen Plasma: replace coagulation factors active bleeding or massive transfusions, emergency reversal warfarin effect, Cryoprecipitatedantihemophilic factor Replace fibrinogen and Factor XIII Replace factor VIII or vWF (if factor VIII and factor VIII/vWF Cellular Therapy Products White cells Stem cells from bone marrow, cord blood, or apheresis


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