| Disease | Epidemiology | Path | diagnsosis | Histo | Gross | Tx | ||
| Achondroplasia | 1) major cause of dwarfism, 2) most common disease of growth plate, 3) AD w/ 80% spontaneous | MECH: 1) FGFR3 mutattion = constant activation = suppressed growth (decrease chondrocyte proliferation in growth plate) | CLIN: 1) short extremities, 2) normal trunk, 3) enlarged head and depressed root of nose, 4) normal lifespan, intelligence, reproductive status | |||||
| Osteogenesis Imperfecta | 1) 4 subtypes, 2) variable inheritance (AD most common, AR), 3) variable prognosis (lethal in utero, survival to adult), 4) JEEST (joints, eyes, ears, skin, teeth) also affected | MECH: 1) mutations in alpha chain of collagen 1, 2) either decrease collagen production or abnormal helix (severe from); CLIN: 1) marked cortical thinning, 2) attenuation of trabeculae, 3) extreme skeletal fragility | 1) Variable features: blue sclerae (dec. collagen), joint laxity, hearing impairment (sensorineural & mid/inner ear bone abnormality) | |||||
| Osteopetrosis | 1) Petra = stone (fracture like chalk), 2) rare, rare, rare!, 2) fragility and fractures | MECH: 1) Decreased carbonic anhydrase II = defective hydrogen secretion = osteoclast resorption malfunction | Either die at birth or have cranial nerve problems, repeated fractures and infections (decreased hematopoeisis from reduced marrow space), and extramedullary hematopoiesis (hepatospleenomegaly) | Bone marrow transplant (provide osteoprogenitor cells for osteoclast) | ||||
| Osteoporosis | 1) very common, 2) age related bone loss equal in sexes but higher in whites than blacks, 3) peak bone mass in 30-40s (resistance exercise, diet, vitD receptor influence) | MECH: 1) Primary: postmenopausal (dec E = inc cytokines =osteoclast stimulation via increase RANK/L and decreased OPG; high turnover rate), senile (dec. osteoblast activity; low tunrover rate), 2) Secondary: endocrine disorder (hyper-PTH, hypo/hyperthyroid), immobilization (force magnitude dependent) | 1) Dual energy absorptiometry, 2) quantitative CT | CLIN: 1) Vertebral fractures (trabeculae thinning), 2) pelvic/femoral neck fracture (PE and Pneumonia) | 1) Resistance exercise, 2) Bisphosphonates, 3) PTH (teripara+G10tide), 4) estrogen, 5) calcium and V-D | |||
| Paget Disease | 1) common, 2) most asymptomatic, 3) 5-11% whites, 3) begins in early adulthood with increased incidence in advancing age, 4) hereditary component (abnormal osteoclast RF) | MECH: 1) Paramyxovirus; STAGES: 1) Osteolytic stage (rapid resorption), 2) Mixed phase (disordered unsound bone formation), 3) Osteosclerotic phase (diminished activity) | CLIN: 1) Pain (microfractures or nerve compression due to overgrowth), 2) secondary osteoarthritis, 3) Fractures (osterosclerotic phase), 4) Giant cell tumor and bone sarcoma, 5) extraosseous hmeatopoesis (diminished marrow space), 6) calor (hypervascularization) | Abnormally laiden bone seen well in polarized light | the FLAME | calcitonin and bisphosphonates (etidronate-oral, Pamidronate-IV) | ||
| Hyperparathyroidism | Multinucleated osteoclasts resorbing lamelar bone | |||||||
| Renal osteodystrophy | MECH: 1) chronic renal failure = hyperphosphatemia = hyperPTH = inc osteoclast activity, 2) CRF = metabolic acidosis = increased resorption and HAP release, 3) damaged kidneys = dec 1,25-[OH]D3 (renal hydroxylase inhibition) = hypocalcemia = osteomalacia (softening) | |||||||
| Osteonecrosis (Avascular necrosis) | 1) 10% joint replacements | MECH: 1) Ischemia (may be due to a fracture (vascular interruption), corticosteroids, thrombosis/embolism, or idiopathic) | CLIN: 1) pain initially associated with activity, followed by chronic pain due to subchondral necrosis and collapse, leading to OA | femoral head with subchondral necrosis and resultant microfractures resulting in collapse of bone. Flap of articular cartilage. | ||||
| Pyogenic Osteomyelitis | 1) most from hematogenous spread to long bones or vertebral bodies, 2) Staph (80-90%), 3) GU/drug abuser = EC, Pseudo, Kleb, 4) Neonate = HI, Strep B, 5) Sick cell = SA > salmonella | Majority acute but 5-25% chronic (acute spontaneous flare-up after years of dormancy). Rarely SSC arise in sinus tract | 1) XRAY - may mimic malignancy | |||||
| Tuberculosis osteomyelitis | 1)1-3% TB have osseous involvement, 2) 3rd world = adolescents, 3) US = older immunosuppressed | 1) Pott Disease (thoracic and lumbar vertebrae) = more destructive and resistant than pyogenic | ||||||
| Osteoarthritis | 1) Most common joint disease, 2) Oligoarticular, 3) Primary = idiopathic or aging (50s); oligoarticualar (hip, knee, vertebrae, DIPs), 4) Secondary = predisposed joints (trauma, DM, deformity, obesity, hemochromatosis) | MECH: 1) Aging and mechanical effects, 2) Genetics (Hand & hip); DISEASE PROGRESSION: 1) Cartilage deterioration, 2) IL-1, TNF, and NO = Dec proteoglycans, type II collagen breakdown, apoptosis, 3) chondrocyte prolif (futile), 4) bone eburnation, subchondral cyst (synovial fluid impaction) | SX: 1) deep achy pain, 2) morning stiffness, 3) pain with use, 4) Crepitus (friction), 5) dec ROM, 6) Osteophytes (Heberden nodes = DIP; Bouchard = PIP) | XRAY: medial joint space narrowing | ||||
| Rheumatoid arthritis | 1) 1 % world population, 2) 3:1 F:M, 3) 40-70yo, 4) initiates w/ malaise and MS pain followed by progressive course w/ fluctuations causing greatest damage first 5yrs, 5) small joints, 6) Polyarthritis | Inflammory synovitis progressing to articular cartilage destruction and ankylosis w/ possible systemic vasculitis; MECH: 1) autoimmune rxn (unknown antigen = CD4 T cell activation = TNF & IL-1 , 2) Genetic susceptibility (Class II HLA locus) | CLIN: (4 criteria) 1) AM stiffness, 2) polyarthropathy (>2), 3) PIP, MCP, IP, 4) symmetric, 5) rheumatoid nodules (pressure sites = elbow, ect.; fibrinoid necorsis w/ inflammatory cell periphery), 6) Rh factor, 7) Xray changes (ulnar deviation of fingers, radial wrist, marginal eroisions, swan neck finger) | Synovitis | histo: Pannus | Radiograph: 1) MCP narrowing, 2) PIP marginal erosion | ||
| Juvenille Rheumatoid Athritis | 1) RA before 16yo, 2) Large joints, 3) Oligoarthritis, 4) ANA+ , 5) 75% enter long remission w/ little disability | Autoimmune dx affecting large joints first w/ common systemic involvement (spiking fever, rash, hepatosplenomegaly, serositis) and extra-articular manifestations (pericarditis, myocarditis, pulmonary fibrosis, GN, uveitis, GR) | ||||||
| Ankylosing spondyloarthritis | 1) M>F, 2) 90% HLA-B27 | DEF: Chronic inflammatory joint disease of axial skeleton (sarcroiliac, vertebrae) | CLIN: 1) Progressive, 2) Sever spinal immobility, COMPLICATIONS: 1) Fracture, 2) Uveitis, 3) Aortitis, 4) amyloidosis | |||||
| Reactive Arthritis | 1) Commonly following GU or GI infection (but non-infectious), 2) Appendicular skeleton, 3) 80% HLA-B27, 4) HIV | MECH: autoimmune | CLIN: similar to akylosing spondylitis | |||||
| Psoriatic arthritis | 1) 10% of px w/ psoriasis, 2) 30-50yo, | MECH: 1) Complication of psoriasis (sensitized T cells secreting IL-1 and TNF), 2) | CLIN: 1) Sausage finger (distal tendon sheet), 2) Stiffness improves w/ mobility, 3) AM stiffness, 4) assymetric, 5) nail pitting, 6) Axial skeleton | |||||
| Suppurative Arthritis | 1) Single joint, 2) Axial spine in drug addicts | MECH: 1) Gonococcus (adolescence), 2) Staph aureus (older children & adults), 3) Strep, 4) H. influenza (children < 2), 4) Salmonella (sickle cell) | CLIN: 1) acute painful, hot, swollen joint w/ restricted ROM, 2) systemic fever and leukocytosis, 3) rapid joint destruction if untreated | |||||
| Gout | RF: 1) older, 2) EtOHic, 3) Obesity, 4) thiazides, 5) lead toxicity | MECH: 1) uric acid is end product of purine metabolism, 2) Purines synthesized de novo or salvaged (HGPRT) from diet, 3) 90% Primary hyperuricemia (90% unknown enzyme defects, 10% HGPRT def = inc purine synth = inc uric acid), | CLIN: 1) chronic disease w/ acute relapses, 2) 12yrs = bone erosion in joint, 3) renal failure (20%), 4) Tophi (masses of urates + inflammatory reaction) | 1) Allopurinol (Xanthine oxidase inhibitor = inh uric acid synthesis), 2) Colchine (acute gout; inhibit granulocyte), 3) Probenacid & sulfinpyrazone (inhibit renal reabsorption) | ||||
| Pseudogout | 1) >50yo, 2) Site: knees, wrists, elvows, shoulders, ankles | MECH: Calcium pyrophosphate deposition; 3 types; 1) Sporadic (idiopathic), 2) Hereditary (AD), 3) Secondary (joint damage, hyperPTH, hemochromatosis, DM, hypothyroid) | CLIN: 1) variable presentation, 2) 50% w/ significant joint injury (no tx) | |||||
| BONE TUMORS | ||||||||
| Osteochondroma | 1) Age: late adolescence to early adult, 2) Benign | SITE: Long tubular bones (femur, tibia) near growth plate | Xray: osteochondroma (outgrowth from epiphyseal cartilage with benign hyaline cartilage cap) | Histo | ||||
| Chondroblastoma | 1) Age: Teens, 2) Prog: non-destructive local recurrence | SITE: Epiphysis of long bones (knee) | Xray: lytic lesion in epiphysis of humerus | Histo: Cartilaginous matrix (bluish color). Each cell of similar size | ||||
| Enchondroma | 1) Age: 20-50yo, 2) Prog: low risk of recurrence (benign) | SITE: 1) Metaphysis of long tubular bones, 2) short tubular bones in hands and feet; MECH: 1) Neoplastic chondrocytes in a hyaline matrix with peripheral enchondral ossification | Xray: white cloud in medullary bone | Histo: hyaline matrix w/ neoplastic chondrocytes in lacunea | ||||
| Conventional chondrosarcoma | 1) Older (>40yo) | SITE: 1) Central skeleton (pelvis, ribs, shoulder) | Xray: hyaline and mixoid cartilage tissue mass | histo | ||||
| De-differentiated Chondrosarcoma | Conventional has de-differentiated into something worse | histo | ||||||
| Clear cell and Mesenchymal Chondrosarcoma | 1) Age: 20-30s, 2) high grade sarcomas with recurrence and mets | Differentiate b/w enchondroma via SITE by X-ray | Histo: small round blue cell tumor with islands of cartilage | |||||
| Osteoma | 1) Age: middle aged, 2) Gardners | SITE: 1) Skull and facial bones | Xray: skull radiodensities | Histo: Identical to dense bone | ||||
| Osteoid Osteoma / Osteoblastoma | 1) Age: 75% < 25yo, 2) Prog: Nidus removal = cure, 3) Nocturnal leg pain relieved by aspirin (PGE2 from osteoblasts) | SITE: Cortex of any bone (femur, tibia, vertebrae) | Xray: Nidus = small round lucency with central mineralization | Histo: haphazardly woven bone w/ interconnecting trabeculae rimmed by osteoblasts | ||||
| Osteosarcoma | 1) Age: 75% < 20 yo + Elderly, 2) Prog: Low grade (recurring potential), High grade (recurrence, lung metastasis) | SITE: 1) Metaphysis of long bones (<20yo), 2) Flat bones (elderly) | Xray: Destroying cortex and eroding into soft tissue (HIGH GRADE) | Histo: HIGH GRADEchondroblastic osteosarcoma- coarse lacelike pattern of neoplastic bone with anaplastic malignant tumor cells (mitotic figures) and OSTEOID | Distinuish chondroblastic osteosarcoma from chondrosarcoma by AGE and SITE | |||
| Non-ossifying Fibroma (Fibrous cortical defect) | 1) Age: childhood and adolescense, 2) Prog: usually regress spontaneously but large lesions r fracture risk (treat) | SITE: 1) Metaphysis and cortical long bones | Xray: Lytic lesion with smooth boundary | Histo: mixture of fibroblasts and multinucleated osteoclasts (look like giant cells) | ||||
| Monostotic Fibrous Dysplasia | 1) Age: early adolescense, 2) Prog: minimal symptoms unless fracture, 3) 70% of fibrous dysplasias | SITE: Ribs, femur, tibia, jawbones, calvaria | Xray: Soap bubbles filling up entire bone | Histo: Irregular curved branching islands of woven bone in a bed of fibroblasts | ||||
| Polyostotic Fibrous Dysplasia | 1) Age: early adolescense, 2) Prog: Progressive w/ fractures and deformities (Shepard's crook) rarely transforming into osteosarcoma | SITE: Craniofacial; CLIN: McCune Albright syndrome = polyostotic fibrous dysplasia + café au lait spots + endocrinopathy | ||||||
| Fibrosarcoma (Malignant Fibrous Histiocytoma) | 1) Age: Middle aged and elderly, 2) Prog: recurrence and mets | SITE: long bone Metaphysis and flat bones; MORPH: identical to soft tissue counterparts | ||||||
| Ewing/PNET | 1) Age: young | SITE: Diaphysis (femur) or pelvis; GEN: EWS translocations | Xray: Destructive bone lestion in diaphysis | Histo: small round blue cell | Histo: CD99 stain | Distinguish Ewing & osteosarcoma w/ biopsy | ||
| Giant Cell Tumor of bone (osteoclastoma) | 1) Age: Skeletally mature (20-40yo), 2) Prog: Benign but locally aggressive w/ local recurrence rate (40-60%) and rare lung mets (seed during resection, not mets) | SITE: Long bone Epiphysis & Metaphysis, MECH: Mononuclear cell fusion = osteoclast-like giant cells | Xray: lytic lesion in epiphysis | Histo: giant cells admixed with mononuclear sromal cells | Epiphyseal tumor? Distinguish b/w chondroblastoma and giant cell w/ biopsy | |||
| Metastatic Carcinoma | 1) Most common skeletal malignancy in adults, 2) Age: older | MECH: 1) Prostate adenocarcinoma, 2) Renal cell carcinoma, 3) Breast adenocarcinoma | ||||||
| Bone Tumor Syndroms | Ollier = multiple enchondromas | Maffucci = enchondroma + hemangiomas | McCune-Albright = Polyostotic fibrous dysplasia + endocrinopathy + Café au Lait spots | Gardner syndrome = Osteomas + Deep fibromatosis + Adenomatous polyposis | ||||
| SOFT TISSUE TUMORS | ||||||||
| Lipoma | 1) Age: mid-adulthood, 2) Most common soft tissue tumor | SITE: Superficial, mobile, painless mass | Histo: Lipoma = adipocytes (look like normal fat) | Histo: Intramuscular lipoma | ||||
| Atypical lipomatous tumor (well differentiated liposarcoma) | 1) Most common adult sarcoma, 2) Age: adults (>40yo), 3) Prog: High recurrence rate in retroperitoneum (resection difficulty) | SITE: Deep soft tissue | Histo: Smudge cell (multilobulated cell w/ dense chromatin) is dianostic | Histo: Lipoblast | De-differntiation (progression from WDL to high grade sarcoma) | |||
| WDL < Myxoid (indolent, low mets) < Round cell (mets) = Pleomorphic liposarcoma | 1) MLS progresses to high-grade round cel sarcoma, 2) round cell is typically surrounded by periphery of myxoid | Mixoid histo: blue mixoid background w/ small capillary and signet ring-like multivacuolated cells | Histo: Pleomorphic Liposarcoma (arrow = pleomorphic lipoblast) | Histo: Myxoid vs. Round cell | ||||
| Leiomyoma | 1) Benign, 2) Prog: low recurrence risk | SITE: 1) Skin (Dermis or sucutis; adolescent to early adult), 2) Uterus (reproductive age) | histo: pink cells growing in fascicles | |||||
| Leiomyosarcoma | 1) Malignant, 2) Adults, 3) Prog: local recurrence w/ mets potential | SITE: Skin, deep soft tissue, retroperitoneum, uterus | Histo: pleomorphic cell w/ irregular clumpy chromatin (diagnostic) | |||||
| Embryonal Rhabdomyosarcoma | 1) Most common rhabdomyosarcoma (66%), 2) Age: <10yrs, 3) Prog: cured w/ chemo, 4) Allelic loss | SITE: Head and Neck | ||||||
| Botryoid Embryonal Rhabdomyosarcoma | SITE: Bladder | Histo: Cambium layer | ||||||
| Spindle Cell Embryonal Rhabdomyosarcoma | SITE: Scrotal/Paratesticular | |||||||
| Alveolar Rhabdomyosarcoma | 1) Age: 10-20 yo, 2) Prognosis: worse than embryonal, more aggressive = aggressive therapy | SITE: Extremities and trunk; MECH: PAX3-FKHR translocation (muscle differentiation dysregualtion) | Histo: Round nested like space look like alveoli in lungs. Cell cling to surface of fibrous septae | |||||
| Pleomorphic Rhabdomyosarcoma | 1) Adults, 2) Poor prognosis | SITE: Deep soft tissue | Histo: Desmin (muscle diff) and Myogenin (skeletal muscle specific) | |||||
| Nodular Fasciitis | 1) Age: 20-40yo, 2) Prog: self-limited | SITE: superficial extremities; MECH: trauma induced proliferation | ||||||
| Superficial fibromatosis | 1) Age: >30yo, 2) Prog: non-aggressive w/ local recurrence | SITE: 1) Dupuytren contracture (palm w/ finger malfnct), 2) Ledderhose disease (Plantar) | Histo: Sweeping fascicles in same direction w/ no pleomorphic cells | |||||
| Deep Fibromatosis (desmoid) | 1) Prog: Benign but fatal if in delicate area (carotids) | |||||||
| Fibrosarcoma | 1) Age: adult, 2) Prognosis: local recurrence w/ mets | Histo: malignant spindle cells arranged in herringbone pattern | ||||||
| Benign Fibrous Histioctoma (Dermatofibroma) | 1) Age: 30-50yo, 2) Prognosis: non-destructive recurrence (small risk) | SITE: Dermis or subcutis, slow growing, painless, firm/mobile | Histo: LM | Histo: HM | ||||
| Malignant Fibrous Histiocytoma | 1) Age: adult, 2) Prog: Aggressive recurrence w/ mets, 3) Most common post irradiation sarcoma | SITE: Deep soft tissue | Histo: bizarre multinulceate cells | |||||
| Synovial Sarcoma | 1) Age: 15-35 yo, 2) Prog: aggressive high grade sarcoma | SITE: >80% ins deep soft tissue of extremities: GEN: SYT-SSX translocation | Histo: malignant spindle cells arranged in herringbone pattern | Histo: Biphasic (glands b/w spindle cells) | Cytokeratin stain = epithelial component | |||
| ANEMIIAS | ||||||||
| Hemolytic anemia | CLASSIFICATION: 1) Intravascular hemolysis (hemoglobinemia, hemoglobinuria, jaundice), 2) Extravascular hemolysis (commonly in spleen; rendered foreign and phagocytized; no hemoglobinemia or hemoglobinuria but may be jaundiced. MECH: 1) intrinsic defects (herediatry spherocytosis, G-6-PH def, sick cell, thalassemias, Paroxismal nocturanal hymolysis), 2) extrinsic (trauma, antibody mediated lysis) | 1) elevated reticulocyte count (elevated erthropoietin), 2) decreaseed hematocrit and hemoglobin, 3) elevated unconjugated bilirubin, 4) elevated LDH (enzyme rich in RBC), 5) decreased haptoglobin (binds heme and excreted) | 1) Wright-Giemsa stain for reticuocytes, 2) New Methylene blue stain (reticulin fibers) | |||||
| Hereditary spherocytosis | 1) Northern Europe highest prevalence, 2) AD (75%) & AR (25%), 3) AR more severe | MECH: 1) Intrinsic defects in membrane = spheroidal with decreased deformability = splenic sequestration and destruction (extravascular hemolysis), 2) Band 3 (primary anion transporter) and ankynin mutations = defective intracellular scaffolding | CLIN: 1) anemia, splenomegaly, jaundice, 2) mild to mod hemolytic anemia w/ viral induced aplastic for hemolytic crisis, 3) FH, 4) positive osmotic hemolytic test | 1) Spleen packed with RBC b/c they are having difficulty extravasating and reentering vasculature | peripheral blood smear | |||
| Hereditary Elliptocytosis | camels are normally elliptic | MECH: 1) 4.1 protein defect in scaffolding = elliptic RBC | ||||||
| Sickle Cell | 1) African american | MECH: 1) two abnormal beta chains (glutamic acid becomes a valine, with diff charge), 2) oxygenated state is normal, 3) Deoxygenated HbA molecules (incr hemoglobin conc, low pH = reduced O2 aff) aggregate and form polymers stretching the cell occluding vessels and extravascular hemolysis | CLIN: 1) Spleenic autoinfarction due to vascular occlusion, 2) end-organ damage other organs, 3) infections, 4) acute pain episodes, DIAG: 1) hemoglobin electrophoresis | Spleening infarction | blood smear | |||
| Mechanical Hemolysis | 1) Cardiac valve prostheses, 2) narrowing or vascular obstruction | Disease associations: DIC, TTP, HUS, SLE, and malignant HTN | Microangiopathic hemolytic anemia | schistocytes (fragmented RBC) = mechanical injury | ||||
| Megaloblastic anemias | 1) vitamin B12, 2) 2-3ug daily requirement | MECH: 1) B12 & folate deficiency (diet, gastrectomy, ileal resection, D. latum) = impaired thymidine synthesis = delay or block in cell division, 2) RNA and protein synthesis unaffected (uracil instead of thymidine) | CLIN: 1) pancytpenia (all derived from myeloid stem cells), 2) MCV increase, 3) decreased reticulocyte count, 4) hypersegmented PMN, 5) marrow hyperplasia (not maturing and released normally) and hemolysis (precursor apoptosis) | A (proerthryblast with immature DNA), B (nucleus is too large and too heterchromatinized) | Histo: megaloblastic hyperchromic anemia | PMN | Tx: must identify cause. Folate improved anemia but not B12 neuopathy | |
| Pernicous anemia | 1) older | MECH: 1) autoimmune (Tcell mediated) destruction of parietal cell in gastric mucosa = decreaed intrinsic factor = dec B12 absorption, 2) Type 1 (block B12 and IF binding; 75%), Type 2 (block B12-IF complex binding to Ileal receptors), Type 3 (bind parietal cells) | CLIN: 1) elevated homocystein/methyl malonic acid, 2) megaloblastic anemia, 3) leukopenia w/ hypersegmented PMN, 4) thrombocytpenia, 5) achlorhydria (parietal cell destruction) | 1) Bone marrow: megaloblastic, 2) GI: glossitis, atrophic gastritis, cancer, 3) CNS: degeneration of dorsolateral spinal tracts (malonyl CoA accum and insert into myelin) | ||||
| Folate deficiency (megaloblastic anemia) | 1) reserves last for a few months | MECH: 1) decreased intake (diet, absorption), inc requirement (preg, infant), impaired use (methotrexate = DHFR inhibition = FH4 reduction) | 1) Must analyze seurm folate | Folic acid replacement (followed by brisk retic response in 5 days) | ||||
| Iron deficiency Anmia | 1) toddlers, adolescent girls, women childbearing age, 2) 2-4mg intake w/ 1-2 mg daily loss, 3) Women have lower strage capacity, 4) No mech for excretion (toxicity) | MECH: Iron deficiency - 1) dietary lack, 2) impaired absoprtion, 3) chronic blood loss (GI), PHYS: 1) need Fe for normal epithelial growth | CLIN: 1) Koilonychia (concave fingernails), 2) alopecia, 3) atrophic glossitis, 4) Plummer-Vinson Syndrome (microcytic hypochromic anemia, atrophic glossitis, esophageal webs); LAB: 1) decreased hemoglobin, hematocrit, MCHC, serum iron, and ferritin, 2) increased total iron binding capacity (TIBC) = transferrring saturation < 15% (nl = 33%) | Fe Regulation: 1) Hepcidin (dec Fe = dec hepcidin = inc duodenal absorption and mac release), 2) HFE(positive regulation; mutation = inc Fe abs = hemochromatosis) | Microcytic hypochromic anemia | |||
| Anemia of Chronic disease | 1) ASSN: chronic infections (osteomyelitis), autoimmune (AR), malignancies | MECH: Decreased erythroid proliferation and imparied iron utilization | LAB: 1) normocytic normochromic, 2) dec serum Fe = inc serum ferritin, 3) dec TIBC | |||||
| Aplastic anemia | 1) 65% idiopathic, 2) 35% exposure to toxic agent (benzene, chlorampheicol, irradiation, hepaititis, CMV, EBV) | MECH: multipotent progenitor disappearance = pancytopenia; 1) stem cell abnormality = dec. prolif, 2) immune mediated marrow suppression (IL-1, TNF, IF-g = dec eerythropoetin + inc hepcidin (dec Fe abs) | CLIN: 1) pancytopenia (myeloid progenitor cells disappearance), 2) insdious onset, 3) thrombocytopenia (petechiae, ecchymoses), 4) neutropenia (infections), 5) anemia (weakness, pallor, dyspnea), 6) normocytic normochromic | 1) very few cells,mostly fat | 1) immunosuppression, 2) BM transplant | |||
| Coagulopathy | ||||||||
| Series of platelet events | 1) Plateletes adhere to ECM at sites of endothelial injury and are activated | 2) On activation, they change conformation and secrete granules (e.g. ADP) and synthesize TxA2 | 3) Platelets expose phospholipid complexes for activation of intrinsic pathway (localize to site of injury) | 4) Injured or activated endothelial cells exposed membrane bound tissue factor activating extrinsic pathway | 5) Released ADP stimulated formation of a primary plug (GpIIb-IIIa conformational change), which is eventually converted (via ADP, thrombin, and TxA2) to a secondary plut | 6) Fibrin deposition stabilizes and anchors aggregated platelets | ||
| Important regulators of coagulation | Antithrombin III - Activated by heparin-like endothelial molecule inhibiting thrombin and factors IX-XII (action of heparin) | Thrombomodulin - Surface decoy receptor for thrombin on normal endothelial cells activates viatmin K dependent protein C and S (inactivates Va and VIIIa) | Tissue type plasminogen activator - Converts plasminogen to plasmin wich breaks down fibrin (Fibrin split polymers = D-dimer) and interferes w/ polymerization | |||||
| Lab Tests | Bleeding Time - Skin puncture to assess platelets ability to form primary plug (nl = 2-9min) | Platelet count - nl = 150-300 E 3/ul; | Prothrombin time - (PT ET 7 = prothrombin time + Extrinsic + thromboplastin + factor VII); Admister tissue thromboplastin and Ca2+ to extrinsic and common pathway | Partial Prothrombin Time (PTT) - Administer Kaolin (activates hageman XII), Cephalin (phospholipid substitue) and Ca to test intrinsic and common pathway | ||||
| Vessel Wall Abnormalities | MECH: 1) Infections (DIC or microvascular damage; ricketssioses, septicemia, meningococcemia), 2) Drug rxns (anti-wall Ab), 3) Abnormal collagen (scurvy or Ehlers-Danlos), 4) Henoch-Schonlein Purpura (Immune complexes = purpuric rash + colicky ab pain + polyarthralgia + Acute GN), 5) Hereditary hemorrhagic telangiectasia (AD, dilated thin turtuous vessels in mucous membranes), 6) Amyloid deposition (plasma cell dyscrasias) | CLIN: 1) Petechia, purpura, 2) More severe bleeding (joints, muscles, nose, GI) LAB: 1) normal platelet count, bleeding time, PT, and PTT (no platelet or coagulation abnormality) | ||||||
| Thrombocytopenia | 1) nl = 150,000 - 300,000/ul, 2) Spontaneous bleeding < 20,000 (mucuos mem, intracranial), 3) Post-traumatic bleeding (20,000 - 50,000) | MECH: 1) Decreased production (e.g. marrow dx, B12/folate def), 2) Dec platelet survival (auto/all-Ab, mech injury), 3) Sequestration (spleenomegaly), 4) Dilutional (tranfusions)[1] | LAB: 1) Normal PT & PTT (normal coagulation), 2) Prolonged bleeding time | |||||
| Chronic Immune Thrombocytopenic Purpura | 1) Primary ITP (idiopathic and either acute or chronic), 2) Secondary ITP (SLE, viral, drug induced or HIT, HIV), 3) Women < 40yo w/ history of bleeding disorder | MECH: 1) Chronic primary ITP (IgG anti-Iib-IIIa or anti-Ib-IX = platelete opsonization and phagocytosis in spleen), 2) Acute ITP (childhood, usually viral w/ 2wk post-inf purpura, resolves in 6mo) | CLIN: 1) Petechia, ecchymoses, 2) melena, hematuria, excessive menstrual flow, 3) NO hepatospleenomegaly, normal CBC, normal bone marrow; LAB: 1) Low platelet count, 2) megathrombocytes (elevated thrombopoetin), 3) Prolonged bleeding time, 4) Normal PT & PTT | Note: secondary can mimic primary, so must rule out possible underlying cause of dx before primary diagnosis | 1) Glucocorticoids, 2) Spleenectomy (75-80% remarkabe improvement) | |||
| Heparin Induced Thrombocytopenia (HIT) | 1) 5% px on heparin develop thrombocytopenia | MECH: Ab to heparin and platelet factor 4 = platelete activation = thrombosis & thrombocytopenia | CLIN: 1) Type I thrombocytopenia (rapid onset, modest severity, insignificant), 2) Type II (1-2wk post therapy w/ life threatening thrombosis) | 1) Type 1 (insignificant), 2) Type 2 (discontinue heparin) | ||||
| HIV Associated Thrombocytopenia | MECH: 1) CD4 on megakaryocytes = infection = apoptosis, 2) B cell dysregulation and hyperplasia = autoantibodies | |||||||
| Thrombotic Thrombocytopenic Purpura | MECH: 1) Deficient ADAMTS 13 vWF metalloprotease = vWF accumulation = thrombosis, 2) Either autoantibody or mutation (rare) | CLIN: Pentad - 1) Fever, 2) Thrombocytopenia, 3) microangiopathic hemolytic anemia, 4) transient neurological defects, 5) renal failure; LAB: Normal PT & PTT | 1) Plasma transfer (replace enzyme) | |||||
| Hemolytic Uremic Syndrome | MECH: 1) E. coli O157:H7 shiga-like toxin = endothelial damage = platelet activation (child and elderly), 2) Drug/Radiation induced injury (Adults) | CLIN: Distinguish b/w TTP by NO neuro defects and acute renal failure; LAB: Normal PT & PTT | ||||||
| Bernard-Soulier | MECH: Defect in GpIb (complexed w/ V and IX) a receptor for subendothelial vWF | CLIN: 1) abnormal bleeding | ||||||
| Glazmann thrombasthenia | 1) AR | MECH: Defective GpIIb-IIIa complex = defective fibrinogen receptor = defective platelet crosslinking/aggregation | CLIN: 1) abnormal bleeding | |||||
| Von Willebrand Disease | 1) 1% population frequency, 2) Common inherited bleeding disorders, 3) 70% are mild type 1, 4) 25% are mild to moderate type 2, 5) AD most common | Type 1: Moderate reduced circulating vWF (AD); Type 3: Severely reduced circulating vWF w/ resulting VIII instability (AR); Type 2A: Defective multimer assembly (quality); Type 2B: GOF mutation = spontaneous platelet binding w/ rapid platelet clearance and HMW mulimers (thrombocytopenia) | CLIN: 1) vWF dx has prolonged bleeding w/ normal platelet count, 2) Type 1 & 3 = Prolonged PT & PTT (secondary VIII decrease)[2] | LAB: Ristocetin agglutination test (promotes vWF-Ib interaction & aggregation of formalin fixed platelets) | Type 1: Desmopressin (release endothelium vWF stores); Type 3: vWF concentrate (no stores); Type 2A: vWF concentrate; Type 2B: vWF concentrate, Desmopressing contra b/c released abnormal vWF | |||
| Hemophilia A | 1) A sounds like 8, 2) X-linked recessive, 3) 30% px w/ neg FH | MECH: 1) Reduced factor VIII (cofactor for activation of IX and X) = inadequate coagulation and inappropriate fibrinolysis (thrombin required to activate fibrinolysis inhibitor), 2) Severity proportional to VIII activity | CLIN: 1) Easy bruising, 2) massive hemorrhage post trauma/surgery, 3) hemarthroses, 4) Petechia absent | LAB: 1) Normal bleeding time, 2) Normal platelet count, 3) normal PT, 4) abnormal PTT, 5) Diagnosis = Factor VIII specific assay | 1) Recombinant VIII infusion (may develop anti-VIII Ab), 2) Bypass inhibitors w/ factor IX or VIIa | |||
| Hemophilia B | 1) X-linked recessive, 2) 14% factor IX not functional | Factor IX deficiency | CLIN: idenitcal to hemophilia A | DIAGNOSIS: factor assay | Recombinant factor IX | |||
| Diffuse Intravascular Coagulation | 1) 50% obstetrics (deliver fetus), 2) Most commonly obstetrics, malignant neoplasia, sepsis, and trauma | MECH: 1) Release of tissue factor (G- sepsis = IL-1 & TNF = tissue factor and thrombomodulin expression = hemorrhagic diathesis) or thromboplastic substances (placenta or AML granules or mucin from adenocarcinoma which activates factor X), 2) Widespread endothelial injury (septic shock = TNF mediated endothelial injury | CLIN: 1) thrombotic complications (brain>heart>lungs>kidneys>adrenals>spleen>liver, 2) bleeding diathesis (obstetrics or trauma), 3) microangiopathic hemolytic anemia (fibrin deposition = RBC shear); LAB: 1) Dec HCT (hemolytic anemia), 2) increased liver fnct tests (bilirubin, LDH), 3) thrombocytopenia, 4) Prolonged PT & PTT, 5) Elevated d-dimer | DIC in brain: fibrin deposition and thrombosis | DIC in glomerulus | 1) treat underlying cause | Waterhouse-Friderichsen Syndrome = meningococcemia induced adrenal hemorrhage due to microthrombi | |
| Lymphoid Neoplasms | ||||||||
| BONE MARROW | Acute Lymphoblastic Leukemia (Pre-B cells) | Young white males: 1) 4yo = highes incidence, 2) Whites (2X more common), 3) M>F, 4) 90% complete remission and 2/3 cured, 5) Unfavorable prognosis (philadelphia chromosome t(9;22), <2yo or adult, blast count > 100,000 | MECH: 1) Chromosomal aberations (90%) = dysregulation of TF = arrested development = accumulation of immature progenitors; CYTOGENETICS: 1) Hyperploidy (>50 chromosomes) most common, 2) Philadelphia chromosome t(9;22) = poor prog, 3) t(12:21) & t(4;11) | CLIN: 1) abrupt stormy onset, 2) pancytopenia (infection, bleeding), 3) bone pain (marrow expansion, periosteum infiltrate), 4) lymphadenopathy, hepatospleenomegaly (infiltrate), 5) CNS (HA, palsies) | LAB: 1) terminal deoxynucleotydil transferase (tDT) = specialized DNApol in pre-B/T blasts, 2) CD 10, 3) CD 19 & 22, 4) NOTE: Tx dependent on diff b/w AML | HISTO: 1) agranular w/ small nucleoli and condensed chromatin | 1) Aggressive chemotherapy, 2) Allogeneic bone marrow transplant | |
| Acute Lymphoblastic Lymphoma (Pre-T cells) | 1) peak incidence = adolescence, 2) Thymic masses, 3) Lymphomatous presentation | MECH: same as pre-B | CLIN: Mediastinal thymic stemming with lymphadenopathy and spleenomegaly | LAB: 1) CD 1, 2, 3, 4, 5, 7, 8, 2) TdT | ||||
| Chronic Lymphocytic Leukemia (CLL)/ Small Lymphocytic Lymphoma (SLL) | 1) CLL is most comon leukemia of adults in western world, 2) SLL ~4% of NHL, 3) Older Males (> 50yo;med=60), 4) M:F = 2:1 | MECH: 1) Deletion (11q, 13q, 17p) or trisomy 12q | CLIN: 1) often asymptomatic, 2) Nonspecific (fatigue, weight loss, anorexia), 3) lymphadenopathy & hepatosplenomegaly, 4) autoimmune hemolytic anemia & thrombocytopenia, 5) hypogammaglobulinemia (infection) | LAB: 1) CD 19, 20, 23, 2) CD 5 (Tcell marker), 3) low level surface Ig heavy chain | Histo (peripheral): 1) Smudge cells, 2) spherocytes (hyperchromatic round RBC), 3) nucleated erythroid cells (anemia) | Histo (biopsy): 1) Diffuse effacement of lymph node, 2) Pro-lymphocyte (form proliferation center = pathognomonic) | ||
| Lymphoplasmacytic Lymphoma | 1) older adults (60-70yo) | MECH: Deletion in 6q = plasma cell neoplasm = monoclonal IgM = Waldenstrom macroglobulinemia (blood hyperviscocity | CLIN: 1) Visual impairment (venous tortuosity and distension; hemorrhages, exudates), 2) Neuro Sx (sluggish blood flow), 3) Bleeding (Ab-CF interactions), 4) Cryoglobulinemia (low temp precipitation = raynauds) | Lymphoid cells w/ various degrees of plasma cell differentiation. | ||||
| Multiple Myeloma | 1) Older Males (50-60yo), 2) 2) African, 3) 1% of cancer deaths | MECH: 1) Plasma cell neoplasia (IL-6 dependent proliferation and survival) = monoclonal IgG & kappa light chain + bone resorption (MIP1a + NF-kB = osteoclast activation), 2) | CLIN: 1) Multifocal destructive bone tumors = fractures and bone pain , 2) Bone resorption = hypercalcemia = Neuro sx (lethargy, confusion, weakness, constipation), 3) Recurrent infections, 4) Renal insufficiency (kappa light chain renal tubular toxicity), 5) hyperviscocity | LAB: 1) M protein (monoclonal IgG), 2) kappa light chain (Bence Jones proteinuria) | Histo: 1) Plasma cell predominance, 2) Prominent nucleoli, 3) cytoplasmic droplets = immunoglobulin, 4) Bizzare cell (not shown) | |||
| MANTLE | Mantle Cell Lymphoma | 1) 3% of NHL, 2) Older Males (50-60yo) | MECH: t(11:14) = IgH locus and Cyclin D juxtaposition = Cyclin D overexpression = unregulated G1 to S phase progression | CLIN: 1) painless lymphadenopathy, 2) spleenomegaly, 3) GI involvement (lymphomatoid polyposis), 4) death due to organ infiltratio and dysfnct; LAB: 1) cyclin D1, 2) sIg | Histo: Absent prolymphocytes, centrocyte, and centroblasts | 1) Palliative w/ 3-4 yr median survival | ||
| GERMINAL CENTER | Follicular Lymphoma | 1) Middle aged, 2) Most common NHL in US (45%), 3) rare in asian | MECH: 1) t(14;18) = IgH locus and BCL2 juxtaposition = BCL2 overexpression = apoptosis antagonism = follicular survival | CLIN: painless generalized lymphadenopathy; LAB: 1) CD 19, 20, 10, 2) BCL2(mantle zone normally produced, proliferation center in FL), 3) BCL6 | Histo: 1) Nodular aggregate, 2) Centrocytes (small, condensed chromatin, cleaved nuclaear outlines), 3) centroblasts (large, central nucleoli) | 1) Palliative (no cure) w/ median survival of 7-9yrs | ||
| Diffuse large B cell lymphoma | 1) Large age range (med 60yr), 2) 20% of all NHL, 3) Rapidly fatal is not treated (good chemo response) | MECH: 1) BCL6 (zink finger TF) overexpression = Germinal center proliferation, 2) Subtypes: Immunodeficiency-associated LBCL (EBV infected B-cells w/ severe T-cell def), Body cavity large cell lymphoma (ascitic effusion, HIV assoc, KSHV/HHV8 infected tumor cells) | CLIN: 1) Rapidly enlarging destructive mass (spleen, liver) | LAB: 1) CD 19, 20, 10, 2) BCL 6, 3) sIg | 0 | 0 | ||
| Burkitt Lymphoma | 1) Endemic and sporadic: children to young adults presenting with mandibular (endemic) or abdominal mass (sporadic), 2) Endemic = 100% EBV, 3) Sporadic = 20% EBV | MECH: 1) EBV induced translocation of c-MYC (chromosome 8) to either IgH locus (ch 14), kappa chain (ch 2), or lambda light chain (ch 22) locus , 2) Mature B cell lineage | LAB: 1) CD 19, 20, 10, 2) BCL6, 3) sIg | Histo: 1) LM = "Starry Sky", 2) HM = Tingible body macs | ||||
| MARGINAL ZONE | Hairy Cell Leukemia | 1) Middle aged caucasians | CLIN: 1) Splenomegaly (massive), 2) Pancytopenia (marrow failture and splenic sequestration), 3) Rarely hepatomegaly and lymphadenopathy | LAB: 1) CD 19, 20, 11c, 22, 25, 103, 2) sIgH | 1) hair-like cells, 2) Phase contract can see them really well | |||
| Diffuse Large B cell lymphoma | 1) Large age range (med 60yr), 2) 20% of all NHL, 3) Rapidly fatal is not treated (good chemo response) | MECH: 1) BCL6 (zink finger TF) overexpression = Germinal center proliferation, 2) Subtypes: Immunodeficiency-associated LBCL (EBV infected B-cells w/ severe T-cell def), Body cavity large cell lymphoma (ascitic effusion, HIV assoc, KSHV/HHV8 infected tumor cells) | CLIN: 1) Rapidly enlarging destructive mass (spleen, liver) | LAB: 1) CD 19, 20, 10, 2) BCL 6, 3) sIg | ||||
| Extranodal Marginal Zone Lympoma (MALT) | 1) No spread till late in dx, 2) Eradiation of agent may cause regression | MECH: 1) Chronic inflamatory disorders (Sjogren, H. pylori, Hashimoto thyroiditis) = polyclonal prolif = translocation = T-helper dependent neoplasm = progression to B lymphoma | ||||||
| PERIPHERAL | Large Granular Lympohocytic Leukemia (LGL) | 1) Rare | 2 types: 1) T-cell (indolent), 2) NK-cell (aggressive) | CLIN: 1) T-cell (lymphocytosis, splenomegaly), 2) NK (mild), 3) Felty syndrome incidence increase (RA, splenomegaly, neutropenia) | Histo: abundant blue cytoplasm w/ scattered course azurphilic granules | |||
| Adult T-cell Leukemia/Lymphooma | 1) Endemic regions (Japan, West Africa, Carribean basin) | MECH: 1) HTLV-1 = CD4+ T helper cell neoplasm | CLIN: 1) Skin lesions, 2) generalized lymphadenopathy, 3) Hepatosplenomegaly, 4) PB lymphocytosis, 5) hypercalcemia, 6) Fatal w/in 1 yr | LAB: 1) CD 3, 4, 5, 2) CD7 negative | Histo: | |||
| Anaplastic Large Cell Lymphoma | 1) Children, 2) Good prognosis | MECH: ALK translocation = chimeric ALK fusion proteins = constititive tyrosin kinase activity = T cell neoplasm | CLIN: 1) Cluster around venules and infiltrate lymphoid sinuses (mimic mets), 2) soft tissue involvement | LAB: ALK (anaplastic large cell lymphoma kinase) immunohistochemistry | Histo: Horseshoe or embryo-like nuclei | |||
| Mycosis fungoides/Sezary Syndrome | MECH: CD 4+ T-h cells | CLIN: 1) Mycosis funoides (progresses from inflammatory to skin patches and plaque to tumor phase),2) Sezary syndrome (exfoliative erythroderma, gen lymphad, w/o tumor development) | LAB: 1) CD 3, 4, 5, 2) CD7 negative | Histo: 1) MF (epidermal and upper dermal tumor infiltration), 2) SS (cerebriform nuclei) | Gross: 1) MF (erythematous plaques), 2) SS (generalized exfoliative erythroderma) | |||
| Peripheral T-cell Lymphoma, Uspecified | WASTEBASKET | |||||||
| Extranodal NK/T-cell Lymphoma | 1) Rare in US and Europe, 2) 3% of NHLs in Asia | MECH: 1) EBV infected NK-cell = cKIT proto-oncogene and p73 tumor suppressor gene mutation = aggressive & poorly responsive tumor | CLIN: 1) Destructive midline mass involving nasopharynx, 2) small vessel invasion = ischemic necrosis; LAB: 1) cCD3, CD56 | |||||
| HODGKINS LYMPHOMA | ||||||||
| NODULAR | Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) | 1) 5% of HL, 2) Young males, 3) Rarely transforms to large B-cell lymphoma | Prog: Least favorable HL (others are excellent) | CLIN: Lymphadenopathy (cervical, axillary, mediastinal); LAB: 1) CD 20 & 45, 2) BCL6 (germinal center specific TF on LH cells) | 1) Rare Reed-Sternberg cells, 2) Characteristic Lympho-histiocytic variants (L&H cells) = "popcorn cells" | 1) ORIGIN: Germinal center B-cells, 2) MECH: EBV infection = LMP-1 expression = lymphocyte activation = accumulation of reactive cells = cytokine support for tumor growth and survival, 3) HL SPREAD: nodal disease --> splenic & hepatic disease --> marrow and extranodal dx, 4) STAGING: Stage I (single lymph node region), Stage II (2+ lymph node regions, same side diaphragm), Stage III (both sides diaphragm), Stage IV (extranodal); 5) CLIN: presents w/ painless lymphadenopathy | ||
| CLASSICAL | Nodular Sclerosis Hodgkin Lymphoma (NSHL) | 1) 70% of HL, 2) Young adults | CLIN: 1) Mediastinum lymphadenopathy; LAB: 1) CD15 & 30, 2) Negative for CD45 and CD20 | Histo: 1) Lacunar cells (multilobate nucleus w/ abundant pale cytoplasm; often disrupted during cutting = empty hole (lacuna), 2) collagen bands divide lymphoid tissue into nodules, 3) mummified cell = pyknotic death | ||||
| Mixed Cellularity Hodgkin Lymphoma (MCHL) | 1) 20% HL, 2) Biphasic (young adults and >55yo) | MECH: 1) EBV (70%) | CLIN: LAB: 1) CD 15 & 30, 2) Negative for CD45 & 20 | Histo: 1) Diffuse effacement of lymph nodes (lymph, eos, plasma, macs), 2) Plentiful Reed-Sternberg cells | ||||
| Lymphocyte Rich Classical Hodgkin Lymphoma (LRCHL) | 1) 5% of HL | MECH: 1) EBV (40%) | CLIN: LAB: 1) CD 15 & 30, 2) Negative for CD45 & 20 | Histo: 1) reactive lymphocytes make up vast majority of cellular infiltrate, 3) Frequent mononuclear, 4) Reed-Sternberg cells | ||||
| Lymphocyte -depleted Hodgkin lymphoma (LDHL) | 1) Very rare, 2) older px, 3) HIV | MECH: 1) EBV (most) | CLIN: LAB: 1) CD 15 & 30, 2) Negative for CD45 & 20 | Histo: 1) Reed-Sternberg abundance | ||||
| Myeloid Neoplasms | ||||||||
| Acute Myeloid Leukemia | EPIDEMIOLOGY: 1) 15-39 yo; CLASSIFICATION: MO) Minimally differentiated AML, M1) AML without Differentiation, M2) AML with maturation (t(8:21), auer rods), M3) Acute promyelocytic leukemia (t(15;17), hypergranular promyelocytes, auer rods, DIC), M4) Acute myelomonocytic leukemia (15-20%, inv(16), nonspecific esterase), M5) Acute monocytic leukemia (older px, organomegaly, lymphad, tissue infiltrate), M6) Acute erythroleukemia, M7) Acute megakaryocytic leukemia | MECH: 1) t(8:21) and inv(16) = chimeric CBF1a/ETO and CBF1b/MYH11 fusion = CB1Fa/CB1Fb heterodimer interferance = terminal myeloid differentiation block = marrow suppression = pancytopenia, 2) t(15:17) = RARa/PML fusion = constitutive tryosine kinase = cellular proliferation and survival Must have 20% blast cells | CLIN: 1) Pancytopenia (fatigue, bleeding, infection), 2) Organomegaly and mild lymphadenopathy, 3) Leukemia cutis (mono skin infiltrate) and gingiva infiltrate (M4/5) | HISTO: Acute Promyelocytic Leukemia (Auer rods and bilobed nuclei) | Histo: 1) Myeloblasts w/ azurophilic granules | TX: 1) Retinoic acid (APL); PROG: 1) 60% complete remission w/ only 15-30% dx free at 5 yr, 2) AML related to therapy (alkylating agent) or has accompanying dysplasia has a very poor prognosis | ||
| Myeloblastic Syndromes | EPI: 1) older (>60yo); PROG: 1) Primary MDS (median = 9-29 months, good pronosis groups up to 5yr), 2) t-MDS (4-8mo median survival), 3) 5q deletion = good prognosis | MECH: 1) Unknown, 2) Deletions of 5q, 7q, & 20q, 3) Trisomy 8 TYPES: 1) Idiopathic/Primary MDS (>50yo, insidious onset, 10-40% progress to AML), 2) Therapy-related MDS (post-genotoxic or radiation therapy, 2-8yrs post therapy, rapid AML progression) | CLIN: 1) Pancytopenia (weakness, infetions, hemorrhage) | Histo: Ring Sideroblast (Iron deposition in erythroid precursors) | ||||
| Chronic Myeloproliferative Disroders | Chronic Myelogenous Leukemia | 1) Adults (25-60yo, peak 45), 2) PROG: slow progression w/ 3yr survival | MECH: 1) Philadelphia chromosome (t(9;22) = BRC-ABL fusion = constitutive tyrosine kinase = unregulated myeloproliferation (pluripotent stem cell) w/ no terminal diff. inhibition | CLIN: 1) Anemia (fatigue, weak, weight loss, anorexia), 2) Spleenomegaly (extramedullary hematopoesis), 3) Insidous onset (3yrs) --> accelerated phase --> blast crisis --> death | 1) Granulocytosis (PMN, myelocyte, metamyelocyte) | Marrow will be 100% cellular (nl = 50%) | 1) Gleevec = BRC-ABL tyrosine kinase inhibitors (90% hematologic remission), 2) Allogenic bone marrow transplantation (young, 75% cured) | |
| Polycythemia Vera | 1) late middle aged (med = 60yo), 2) AML progression (2-15%), 3) Death via thrombotic event w/in months of diagnosis w/o tx | MECH: 1) Unknown, 2) Decreased erythropoetin requirements and serum levels | CLIN: 1) Increased RBC mass (hg = 14-28) and HCT (60%) = abnormal blood flow (venous pooling) = thrombotic events (MI, DVT, stroke, ect.), cyanosis, HTN, GI sx, 2) Histamine release from basophils = pruritis & peptic ulcers, 3) Cell turnover = hyperuricemia = gout, 4) Spent phase (10yrs) = primary myelofibrosis = spleomegaly (extramed hematopoeisis) | 1) Bone marrow: hypercellular (erythroid progenitors), 2) Peripheral blood (basophilia, large platelets,) | 1) Phlebotomy (TOC, 10yr survival), 2) Chemo (increases AML progression) | |||
| Essential Thrombocytosis | 1) Older (>60yo) | MECH: 1) Unknown, 2) Rapid and abnormal megakaryocyte growth = thrombocytosis = thrombotic events (qualitative and quantitative abnormalities) | 1) Bone Marrow: 100% cellular w/ megakaryocytes (numerous nuclei) and platelets | CLIN: 1) thrombotic events, 2) Erythromelalgia (pain in hands and feet due to vasoocclusion) | PROG: 12-15yr median survival | myelosuppressive alkylating agents (lower platelet counts) | ||
| Primary (Idiopathic) Myelofibrosis | 1) Older (>60yo) | MECH: 1) Neoplastic megakaryocytes = fibrogenic factors (TGF-b & PDGF) = fibroblast mitogen & fibrosis/angiogenesis promotion = medullary collagen deposition = extramedullar hematopoeisis (liver, spleen, lymph nodes) | CLIN: 1) Spleenomegaly, 2) B-symptoms (increased metabolism for spreading hematopoiesis), 3) infections, thrombotic events, & bleeding | LAB: 1) Peripheral blood (normocytic normochromic anemia w/ "tear drop" dacrocytes and leukoerythroblastosis (erythroid and granulocyatic precursors) | ||||
| Langerhans Cell Histiocytosis | 1) Letterer Siwe: mostly <2yo, 2) Adult smokers = polyclonal reactive dx (resolves w/ cessation) | MECH: 1) Monoclonla proliferation of immature DC, or Langerhans cells = marrow infiltration | CLIN: Letterer-Siwe Disease: 1) anemica, thrombocytopenia, infection (marrow infiltration), 2) Hepatosplenomegaly, lymphadenopathy, osteolytic bone lesion, 3) cutaneous lesions (LC trunk and scalp infiltrate); Eosinophilic granulomas: 1) bone erosion; Hand-Schuller-Christian triad: 1) Calvarial bone defects, 2) Diabetes insipidus (pituitary), 3) Exophthalmos | LAB: 1) S-100 (neural crest markder), 2) HLA-DR (activation marker), 3) CD1a | Histo: Birbeck granule | |||
| THYMUS | ||||||||
| DiGeorge Syndrome | Thymic hypoplasia | 22q11 deletion | ||||||
| Thymic hyperplasia | MECH: Assiated w/ autoimmune dx, especially myasthenia gravis (65-75%) | |||||||
| Thymomas | 1) Adults (>40yo) | MECH: Thymic epithelial cell tumors; 1) Benign encapsulated, 2) Malignant: Type I (invasive but not morphologically neoplastic) and Type II (thymic carcinoma, cytologically malignant) | CLIN: Mediastinal impingement (SVC = blood enters but doesn't leave = blue head) | |||||