Chapter 21. Leukocytic disorders O 수의 증감: leukocytosis, leukopenia (blood 1ul당 leukocyte number를 절대적으로 산출) 질적이상: 기능이상, 종양 이상백혈구 증식 (leukemia) 01. Leukocytosis (백혈구증가증) O leukocyte가 정상치보다 증가하는 경우 (11,000/ul이상: 8,000) O leukocyte: 성인보다 소아가 높은 수치

1. neutrophilia O 8,000/ul 이상 (원래 WBC의 70%): band, mature neutrophil 증가 O bacterial infection (viral infection: lymphocytosis) - 핵의 좌방이행, leukemoid reaction(유사백혈병반응) - endotoxin: 골수에서 말초혈액으로 호중구 유출 자극 - 장티푸스: 호중구 감소 (장티푸스 내독소: 중성구 파괴) O malignant tumor - tissue necrosis, infection, tumor cell (호중구 생성자극인자 생성) O chronic myeloproliferative disorders (fully differentiation) - chronic myelogenous leukemia (CML) - polycythemia vera - essential thrombocytosis - myelofibrosis with myeloid metaplasia (MMM) O drugs - Adrenal cortex hormone: 골수에서 말초혈액으로 호중구 유출 자극 - Epinephrine: marginal pool -> circulating pool - Heavy metal poisoning (lead, mercury) O 생리적 증가: exercise, epinephrine, pregnancy, newborn O acute hemolysis: 수혈부적합, 급성용혈성 질환 O acute hemorrhage: 내출혈 시

2. Eosinophilia O 450/ul 이상 O allergy reaction: 천식, 기생충감염 chronic myelogenous leukemia (CML) 3. basophilia O chronic myeloproliferative disorders polycythemia vera O allergy 4. monocytosis O 600/ul 이상 O tuberculosis, subacute endocarditis O sepsis, syphilis, brucellosis, neutropnea 5. lymphocytosis O 3,500/ul 이상 (유아기에는 WBC의 55% 차지) O virus infection, infectious mononucleosis O 이형림프구 (virocyte, Turk cell, reactive lymphocyte, Downey cell)

6. Myelofibrosis (with myeloid metaplasia) O fibrosis in bone marrow O extramedullary hematopoiesis (tumor-like) (hepatomegaly, splenomegaly) O chronic myeloproliferative disorders O PBS anemia: normochromic normocytic, tear drop cell (dacrocyte) leukocytosis (leukemoid reaction, alkaline phosphatase 활성증가) leukoerythroblastosis platelet: large, bizarre shape O bone marrow: myelophthisis (척수황폐증), dry tap (aspiration), fibrosis (biopsy), 거핵구 증가 7. Leukemoid reaction(백혈병모양반응) O 백혈병과 유사, 반응성 유사 상태 (백혈병과의 감별이 중요) O LAP (leukocyte alkaline phosphatase) score: increase O 골수백혈병모양 반응 악성종양말기, 중증 감염증, myelofibrosis CML과의 감별: basophilia, LAP감소, Ph chromosome O 림프백혈병모양 반응 virus infection, infectious mononucleosis (EBV)

8. Infectious mononucleosis (전염단핵구증) O cause: Epstein Barr virus (Ab specific for EBV) O reactive lymphocyte: increase, fever O PBS: RBC count: normal, WBC count: 초기감소, 1주일 후 증가 lymphocytosis (atypical lymphocyte), thrombocytopnea O EBV -> B cell infection -> proliferation (heterophil anti-sheep RBC Ab) -> cytotoxic T cell (atypical lymphocyte)

02. Leukopenia O leukocyte count가 정상치 이하로 감소된 상태

1. neutropenia O 2,000/ul 이하 O infection 장티푸스, viral infection O agranulocytosis drug: cross-reactive Ab (과립구 응집시험, 과립구 상해시험) neutrophil production defects in the marrow O acute leukemia, multiple myeloma: tumor in bone marrow O anemia (pancytopenia): aplastic anemia, megaloblastic anemia, paroxysmal nocturnal hemoglobinuria O 비장기능항진증 간경변, Banti syndrome(특발성 문맥압항진증) -> blood cell destruction in spleen O 면역성 호중구 감소증 동종항체성 태아호중구감소증 (Human Leukocyte Antigen) systemic lupus erythematosus(SLE), 자가면역성 호중구 감소 O drug: 골수저형성 ionizing radiation, benzene,

2. Eosinopenia O 장티푸스 초기 O Cushing’s syndrome, adrenal cortex hormone, stress pituitary gland, ACTH, cortisol increase 3. lymphocytopenia O 1,000/ul 이하 O 악성 림프종 등의 악성종양, adrenal cortex hormone, 항암제 O 면역결핍을 동반한 감염증 4. pancytopenia

03. 선천 과립백혈구 기능이상 O congenital, abnormal function (migration, phagocytosis, batericidal activity dysfunction-> infection) 1. Chronic granulomatous disease (만성육아종병) O defects in microbicidal activity (defects in enzymes responsible for ROS) 2. Myeloperoxidase deficiency (골수세포과산화효소 결핍증) O H2O2 생성 X -> 살균능 저하 O peroxidase staining: negative 3. Alder-Reilly anomaly O Alder-Reilly granule: lilac (연보라색), azurophilic granule peroxidase negative, PAS positive O bone disease, Hurler’s syndrome, Hunter’s syndrome O toxic granule과 혼동 쉬움 4. May-Hegglin anomaly O RNA+ribosome (Dohle body와 유사) O peroxidase and PAS negative O thrombocytopenia, large platelet -> 혈병수축시간연장, 혈소판수명단축 모세혈관저항시험 양성

5. Chediak-Higashi (-steinbrink) syndrome O lysosome aggregate: peroxidase and PAS and acid phosphatase positive O bactericidal activity and migration -> decrease (degranulation 장애) O anemia, neutropnea, thrombocytopenia O albinism, 어릴 때 증세 나타남 6. Pelger-Huet anomaly O hyposegmentation: peanut, dumb-bell, band form 7. Lazy leukocyte syndrome O defect in migration -> 골수에서 말초혈액으로 유입 저하 -> 과립구감소 8. Philadelphia chromosome O chronic myelogenous leukemia (CML) acute lymphoblastic leukemia (ALL) O translocation 9, 22 BCR/ABL

O leukemia vs lymphoma O Bone marrow disorder 1. systemic diseases (secondarily affect the bone marrow) 2. disorders of hematopoietic production or function (other than neoplasm) 3. clonal hematopoietic disorders (neoplasm) (1) chronic myeloproliferative disorders (HPS/CMP, differentiation O) - chronic myelogenous leukemia (CML) - polycythemia vera - essenctial thrombocytosis - myelofibrosis with myeloid metaplasia (MMM) (2) myelodysplastic syndromes (HPS/CMP, differentiation X) (3) acute leukemia (CMP: erythro, mono/CLP, differentiation X)

04. leukemia O 골수에서 증식하는 백혈구가 악성종양성 증식을 하는 질환 말초혈액중에 백혈병세포 출현 (cf. aleukemic leukemia) normal matured RBC, WBC, platelet: decrease O cause: hereditary vs acquired O classification -acute vs chronic (분화, 성숙능에 따라 구분) acute: immature leukocyte chronic: mature leukocyte -lymphoid vs myeloid -Acute lymphoblastic leukemia (ALL) chronic lymphocytic leukemia (CLL) acute myeloid (myelogenous) leukemia (AML) chronic myeloid (myelogenous) leukemia (CML)

1. Acute leukemia O transformed hematopoietic progenitor cells O self renewal O, terminal differentiation X O bone marrow failure -> pancytopenia (anemia, bleeding, infection, fever) -> bone pain, leukostasis (leukocytosis:immature) O AML (adult, age) vs ALL (childhood, mainly B cell type:70%) O cause: irradiation, benzene, chemotherapy, Down syndrome (trisomy 21) chromosome breakage disorder (Fanconi anemia) myeloproliferative disorder, myelodysplastic syndromes O blasts must account for more than 20% of the nucleated cells O histochemical method - Meloperoxidase: in primary granules of granulocytic precursor (AML blast) - Nonspecific esterase: monocytic differentiation - TdT (terminal deoxynucleotidyl transferase): Lymphoblast O specific marker CD34 (stem cell), CD14 (M4,5), glycophorin A (M6), vWF/CD41(GPIIb-IIIa) (M7)

O cytogenetic abnormality - Acute Promyelocytic Leukemia (M3) t(15;17) -> PML gene/RARalpha gene fusion - Mature B cell ALL, Burkitt’s lymphoma t(8:14), t(2;8), t(8;22) -> c-myc gene/Ig heavy or light chain gene enhancer - AML (5%), ALL (30%) t(9;22) -> philadelphia chromosome BCR(22)/ABL(9) fusion (1) Acute lymphoblastic leukemia (ALL) O young, B-cell type O lymphoblast 증가 in BM and PB O philadelphia chromosom t(9,22) -> 30% ALL t(8:14), t(2;8), t(8;22) -> Mature B cell ALL O classification L1: microlymphoblast L2: large and undifferentiated lymphoblast L3: Burkitt’s cell (large, cytoplasm: dark blue, vacuole)

(2) Acute myelogenous leukemia (AML) O acute non-lymphoblastic leukemia (ANLL) O PB: blast form 증가 O good prognosis: t(8:21), inv(16), t(15:17) poor prognosis: 5,7 deletion, monosomy O LAP score: low O MPO, SBB, Specific esterase stain: positive O classification (FAB) M0: myeloblastic leukemia without differentiation cytoplasmic budding, CD13 CD33 MPO, Sudan Black B: 양성률 3%이하 M1: meyloblastic leukemia without maturation Auer body MPO, Sudan Black B: 양성률 3%이상 myeloblast(대부분), promyelocyte(3%이하), mature granulocyte myelocyte, metamyelocyte: 관찰안됨 (hiatus leukemicus) -> CML과 구별점 백혈병성열공

M2: meyleoblastic leukemia with maturation myeloblast(30%이상), promyelocyte(3-20%), myelocyte, metamyelocyte, PMN 위양성 Pelger-Huet 핵이상 (PMN), Auer rods MPO, Sudan Black B: strong positive LAP score: decrease (1/3) specific esterase staining: positive non specific esterase staining: negative t(8;21): 50% 이상 M3: acute promyelocytic leukemia (APL) promyelocyte (30%) -> 세포크기가 정상보다 크다 M3a: azurophilic granule 많음, M3b: azurophilic granule 적음 DIC 수반 -> bleeding Auer rods -> faggot cell, bilobed nucleus t(15;17) -> PML gene/RARalpha gene fusion 80% M4: acute myelomonocytic leukemia (AMML) myeloblast, promyelocyte, monoblast/promonocyte (20% 이상) extramedullary acute leukemia (gingival hypertrophy, leukemia cutis, meningeal leukemia) chloroacetate esterase staining: - (monocytic), + (myelocytic) non specific esterase staining: positive M4E type: abnormal eosinophil, inv(16)(p13q22)

M5: monocytic leukemia (AMoL) alpha naphtyl acetate esterase: + M5a: monoblast, granule X, vacuole Peroxidase, Sudan Black B: negative M5b: promonocyte, monocyte, Peroxidase, Sudan Black B: positive CD64, CD68, CD11b, CD14: positive t(9:11) serum muramidase (lysozyme) activity: increase M6: erythroleukemia erythroid cells (50% 이상) megaloblastoid cell, 핵이 2개 이상인 세포 iron staining: ringed sideroblast M7: megakaryoblastic (AMML) megakaryocyte (골수 유핵세포의 30%이상) myelofibrosis CD41 (GPIIb/IIIa): positive

2. Myelodysplastic syndroms (MDS, 골수형성이상증후군) O refractory anemia, preleukemia로도 불림 O defects in HSC, CMP -> abnormalities in maturation, premature cell destruction O deletion of 5q or 7q O bone marrow failure O pancytopenia: anemia, neutropenia (infection), thrombocytopenia (purpura) O Acute myelogenous leukemia (AML)로 진행됨 O PBS and BMS: dysplastic characteristics 거대적혈구, 적혈구부동증, 변형적혈구증가증, 거대혈소판

O classification (FAB) - refactory anemia (RA) PB: myeloblast 1%이하, BM: myeloblast 5%이하 - RA with ringed sideroblast (RARS) PB: myeloblast 1%이하, BM: myeloblast 5%이하, ringed sideroblast (15%이상) - RA with excess of blasts (RAEB) RAEB-1: PB: 혈구감소, myeloblast 5%이하, monocyte: 1,000/ul이하, Auer body X, BM: myeloblast 5-9% RAEB-2: PB: 혈구감소, myeloblast 5-19%, monocyte: 1,000/ul이하, Auer body O, BM: myeloblast 10-19% - chronic myelomonocytic leukemia (CMML) PB: monocytosis (1,000/ul이상), myeloblast 5% BM: myeloblast 5-20%, 단구전구세포증가 - RAEB in transformation (RAEB-T) PB: myeloblast 5%이상, Auer body O, BM: myeloblast 20-30% Page. 313

3. Chronic myelogenous leukemia (만성골수성백혈병) O chronic myeloproliferative disorders O defects in HSC, CMP -> normal maturation O Philadelphia (Ph) chromosome: t(9;22) bcr (breakpoint cluster region)/ abl (abelson leukemia) gene fusion -> enhanced tyrosine kinase activity O CML의 급성전환: acute transformation blastic crisis O PB: leukocytosis -> 각 성숙단계의 호중구계세포 관찰 (cf. M1) basophilia, neutrophil의 LAP score: decrease O BM: hyperplasia 4. Chronic lymphocytic leukemia (만성림프구성백혈병) O old age O 주로 B cell type -> immunodeficiency -> infectious disease O PB: leukocytosis (lymphocytosis: small matured lymphocyte), smudged(basket) cell O BM: lymphocytosis

5. Adult T cell leukemia O helper T cell (CD4) leukemia -> 면역능 저하 O HTLV-1 (human T-cell lymphotropic virus-1): retrovirus O cutaneous infiltration O PB: flower cell (핵이 분절하여 분엽상의 모양을 함) O 백혈병세포: CD4, serum: anti-HTLV-1 Ab 6. Hairy cell leukemia O B cell origin (a kind of CLL) O hairy cell: 세포질: 다수의 모발상 돌기 O spelnomegaly, PB: pancytopenia, BM: fibrosis O tartrate-resistant acid phosphatase (TRAP) staining: positive

7. Malignant lymphoma (악성림프종) O lymphoma or vs lymphoid leukemia O malignant lymphoid cell tumor in lymphoid tissue O non Hodgkin’s lymphoma (mainly B-cell lymphoma) (follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma) * Burkitt lymphoma: B cell, EBV infection, t (8;14): c-myc/Ig gene enhancer O Hodgkin’s lymphoma spread in contiguous fashion inflammatory reaction in infiltrates Reed-Sternberg cell: large, bilobed nuclei, large nucleolus -> owl’s eye appearance O Ann arbor staging (I-IV stage) - I: one lymph node - II: more than two lymph node, same side of diaphragm - III: both sides of diaphragm - IV: diffused or disseminated involvement of bone marrow,liver,lung,skin 8. Plasma cell leukemia O B cell type – plasma cell (most abundant in bone marrow) O PB: 2,000/ul이상, WBC의 20%이상

05. M proteinemia O M (monoclonal) protein (non functional): 증가 -> M proteinemia paraproteinemia, dysproteinemia, monoclonal immunoglobulinemia O benign: benign monoclonal gammopathy O malignant: multiple myeloma, macroglobulinemia (Ig M), 1. Multiple myeloma (다발성골수종) O 골수 중에 이상형질세포가 다발성으로 종루를 만드는 것을 특징으로 함 O cause: unknown O symptom: M proteinemia, headache (hyperviscosity syndrome), bone: pain, destruction (hypercalcemia), anemia, bleeding, renal failure O PB: pancytopenia, rouleaux formation, abnormal plasma cell출현 O BM: plasma cell: increase -> myeloma cell이라 명명 O urine: Bence Jones protein (excretion of light chain) O myeloma cell: immature, chromatin: fine, nucleolus, mutinuclear, Russell body

O immunoserologic -M spike (monoclonal immunoglobulin) in serum EP: increase -Bence-Jones protein (only light chain) and non-secretion type: 다른 Ig 감소 -Erythrocyte Sedimentation Rate (적혈구침강속도): increase 2. Waldenstrom macroglobulinemia O M protein: IgM O symptom: multiple myeloma와 유사, bone fracture X O PB: rouleaux formation O BM: lymphocytic plasma cell (림프구성 형질세포): 림프구와 형질세포 중간형

06. immunodeficiency (면역결핍) O acquired immune deficiency syndrome (AIDS) - human immunodeficiency virus (HIV) - helper T cell (CD4) O immunodeficiency 검사소견 - 체액성면역부전: B cell감소, serum EP: gamma-globulin감소, serum Ig감소 세포성면역부전: T cell감소, PTH lymphoblast화 반응: 저하, Tuberculin반응: 음성

07. Systemic lupus erythematosus: SLE (전신성홍반루프스) O cause: unknown (failure to maintain self-tolerance) O female preponderance: (9:1) O collagen disorder (교원병): autoimmune disease O autoAb and immune complex joint (arthritis), skin, kidney (nephritis), heart damage bone marrow, blood cell damage -> pancytopenia O diagnostic test: LE cell, antinuclear Ab (ANA): Ab to dsDNA, snRNP (Sm Ag) serum complement level: low O anti-phopholipid antibody (lupus anticoagulants) Ab against blood cells 08. Lysosomal storage disease O lysosomal enzyme deficiency O sphingolipid, mucopolysaccharides accumulation (accumulation of partially degraded insoluble metabolites) O autosomal recessive, affect infants and young children hepatosplenomegaly, neuronal damage, cellular dysfunction by macrophage activation and release of cytokines

8.3 Polar lipid - amphiphilic; they have both nonpolar and polar structural features - construction of biological membranes

1. Gaucher disease O beta-glucocerebrosidase deficiency (cleave glucose from ceramide) -> glucocerebroside accumulation O Gaucher’s cell: histiocyte (tissue macrophage) cytoplasm -> wrinkled tissue paper (fine folding) O PAS, Sudan Black B, acid phosphatase staining: positive O serum acid phosphatase: increase

2. Niemann-Pick disease O spingomyelinase deficiency -> spingomyelin (phosphocholine + ceramide) accumulation O Niemann-Pick’s cell (lipid droplet, foamy cell), neuron O classification -type A: neurologic defect O, sphingomyelinase defect, -type B: neurologic defect X, sphingomyelinase defect, -type C: neurologic defect O, defect in lipid transport accumulation of cholesterol, ganglioside 3. Tay-Sachs disease (GM2 gangliosidosis) O hexosaminidase A (alpha subunit) deficiency -> GM2 ganglioside accumulation O CNS (brain), eye (retina) O foam cell, vacuolated histiocyte O whorled configuration within lysosome 4. Mucopolysaccharidoses (MPSs) O MPS degradative enzyme deficiency -> MPS accumulation O coarse facial feature, clouding of cornea, joint stiffness, cardiac complication, mental retardation O Hunter’s syndrome, Hurler’s syndrome