the hematopoietic and lymphoid systems. hematopathology blood lymphoid organs –central: bone...

the hematopoietic and the hematopoietic and lymphoid systemslymphoid systems

hematopathology

•blood• lymphoid organs

– central:•bone marrow•thymus

– peripheral:•lymph nodes•MALT (Waldeyer´s ring, intestine...)

•splenic white pulp

hematopathology

• leukaemia = neoplastic cells in peripheral blood

• lymphoma = tumour of the lymph node

• hemoblastosis – primary bone marrow– leukaemia + tumoriform

• lymphomas– primary lymph nodes– lymphoma + leukemic phase

bone marrow

bone marrow• weight cca 1,5kg• red (hematopoietic) x yellow (adipose)• structure:

– hematopoietic cells: granulopoiesis peritrabecular, erytropoiesis a megakaryocytes intertrabecular and perisinusoidal

– corroborative elements: makrophages, fibroblasts, mastocytes, plazmocytes, lymfocytes

– blood sinuses– bone trabeculas

diminished hematopoiesis

A) total diminutionaplastic anemia (panmyelophtisis)• hereditary:

– Fanconi anemia• AR• death because of infectious and bleeding

complications• +/- turn into AML

• acquired:– infectious, irradiation, use of some drugs

diminished hematopoiesis

B) selective• one or more of hematopoietic lineages

critical is peripheral blood – marrow could be hypercelular = „ineffective hematopoiesis“

diminished hematopoiesis...anemia

1) anemia• ↓ total circulating RBC volume, +/-

↓Hb and ↓O2• hypoxia of tissues = clinical

symptoms

anemia...loss of RBC

a) hemorrhage: blood loss anemia• hypovolemia → normocytic

normochromic anemia → ↑ erytropoiesis (bone marrow) → reticulocytosis, hypochromic anemia

anemia...hemolytic

b) increased rate of RBC destruction: the hemolytic anemias

• anemia + reactive hyperplastic erytropoiesis

• bm: ↑erytropoiesis/myelopoiesis, gaucheroid cells

• +/- extramedullary hematopoiesis• Hb -emia, -uria

anemias..hemolytic..intrinsic

I) intrinsic (intracorpuscular) abnormalities of RBC

hereditary: 1) disorders of RBC membrane cytoskeleton

spherocytosis– erythrocytes spheroidal, less deformable

and vulnerable to splenic sequestration and destruction

– AD– anemia, splenomegalia a hemolytic icterus


2) RBC enzyme deficiencies3) disorders of Hb synthesis: hem+globin

deficient globin synthesis: thalassemia syndromes– lack of or decreased synthesis of globin chains:

α chains = α thalassemia β chains = β thalassemia

– ↓ synthesis of Hb → anemia (microcytic hypochromic) + excess of α chains in β thalassemia → insoluble aggregats → damage RBC membrane → reduction of plasticity → phagocytosis, inefective erytropoiesis

– heterozygous = thalassemia minor homozygous = thalassemia major


structurally abnormal globin synthesis (hemoglobinopathies): sickle cell anemia– structurally abnormal Hb S – on

deoxygenation polymerization = gelation or crystallization → microvascular obstruction → ischemic tissue damage + ↑ removing in the spleen = „autosplenectomy“


acquiredmembrane defect: paroxysmal

nocturnal hemoglobinuria)– ↓resistance against C3– granulocytes and plateles affected too →

hemolysis, +/- trombotic complications and ↑ susceptibility to infections

anemias..hemolytic..extrinsic

II) extrinsic (extracorpuscular) abnormalities

1) antibody mediated isohemagglutininserythroblastosis fetalis

– Rh (mother Rh-, father and child Rh+)– antibodies against fetal RBC– hydrops fetus universalis, mental

retardation, ↑extramedulary hematopoiesis


autoantibodies– idiopathic (primary), drug associated,

SLE– Coombs tests


2) mechanical trauma to RBCs mikroangiopathic hemolytic anemias

– DIC, TTP mechanic traumatization of

erythrocytes– dialysis, valves prosthesis

3) infections (malaria)

anemia...impaired RBC production

c) diminished erythropoiesis1) combination with the others in

aplastic anemia 2) pure „erytroblastophtisis“

Blackfan-Diamond syndrom• children• + thymomas and T-CLL

3) myelophtisic anemia• extensive replacement of the marrow by

tumours or other lesions → extramedullary hematopoiesis, leukoerythroblastosis


4) iron deficiency anemia• most common• mikrocytar hypochromic• ↓low intake (diets, malabsorptions) x

↑ demands (pregnancy, infancy, chronic blood loss)

• gross: hypoxic myocardial steatosis • marrow normal or hyperplastic

erythropoiesis, decline in serrum ferritin and depletion of stainable iron in the bone marrow


5) megaloblastic anemia• disturbance of proliferation and

differentiation of erythroblasts → megaloblasts, megakaryocytes

• nuclear-cytoplasmic asynchrony• giant metamyelocytes →

hypersegmented neutrophils• ineffektive erythropoiesis folate (folic acid) deficiency anemia• tetrahydrofolate• neurologic abnormalities do not occur


pernicious anemia• vitamin B12 (cobalamin) deficiency• diet, ↓intrinsic faktor (parietal

gastric cells), terminal ileum• gross: atrophic glossitis, gastritis,

demyelinization


6) lack of erythropoietin• kidney failure, parvovirosis (B19)

diminished hematopoiesis... leukopenia

2) leukopeniaa) lymfopenia• hereditary immunity disorders,

infections(viral), chronical diseases, steroid therapy

leukopeniab) neutropenia (granulocytopenia)• increased susceptibility to infections• marrow failure (aplastic anemia) →

agranulocytosis• inadequate or ineffective granulopoiesis:

certain drugs: benzen, purin and pyrimidin analogs, anthracyklin x idiosyncrastic reaction (chloramfenikol, chlorpromazin, fenylbutazon)

• accelerated removal or destruction of neutrophils: hypersplenism, certain drugs

• bm: depend on the underlying basis: ↑ or ↓ granulopoiesis and +/- reaction to infection

increased hematopoiesis

• transitory increasing of hematopoiesis1) ↑erythropoiesis = polycythemia• increased erythropoietin levels:

– appropriate: lung disease, high-altitude living, cyanotic heart disease

– inappropriate: erythropoietin-secreting tumours, „doping“

• bm hypercellular, inappropriate increasing of erythropoiesis

• no extramedullary hematopoiesis!

increased hematopoiesis

2) leukocytosisa) lymfocytosis: chronical infections (IM)b) granulocytosis: acute bacterial

infections (pyogenic organisms), sterile inflammation (tissue necrosis, burns) → leukemoid reaction (like in CML)

c) eosinophilia: allergic disorders, parasitic infestation, drug reaction, certain mlg

3) thrombocytosis: infections, chronical bleeding, tumours, iron deficiency

myelodysplastic syndromes

• heterogeneous group of disorders• some evidence of bone marrow failure

and dysplasia in one or more myeloid cell lineages

• may evolve to AML• chromosomal aberrations• primary x secondary (radiotherapy,

alkylating agent therapy) • bm hypercellular, ↑ erythropoiesis,

morphological changes, +/- fibrosis

myelodysplastic syndromes...histological

classification refractory anemia (RA) refractory anemia with ring

sideroblasts (RARS) refractory cytopenia with multilineage

dysplasia refractory anemia with excess blasts

(RAEB) MDS, unclassifiable

chronic myeloproliferative diseases

• CMPDs: clonal haematopoietic stem cell disorders characterised by proliferation in the bone marrow of one or more of the myeloid (i.e. granulocytic, erythroid and megakaryocytic) lineages

CMPDA) chronic myelogenous leukaemia• most common• adults, 30-60eyars• neutrophilic leukocytosis in peripheral

blood• Ph+ = t(9;22) = Philadelphia chr.• bm: hypercellular (↑granulopoiesis,

↑megakaryocytes), +/- fibrosis• extramedullary leukaemic infiltration:

spleen, liver• → accelerated phase → blast phase

CMPD

B) polycythaemia vera (polycythaemia rubra vera, m. Vaquez-Osler)

• ↑ erythropoiesis• hypertension, thrombosis,

haemorrhage• bm:

– initial phase: hypercellular, with increased erythropoiesis + extramedullar infiltration → hepatosplenomegaly

– +/- blast phase or „spent“ phase

CMPD

C) essential thrombocythaemia• proliferation primarly magakaryocytic

lineage• sustained thrombocytosis in the blood• bm: large, mature megakaryocytesD) chronic idiopathic myelofibrosis• proliferation of mainly

megakaryocytes, associated with reactive deposition of bone marrow connective tissue and extramedullary hematopoiesis

acute leukaemias• causes:

– complication of certain chromosomal diseases (m. Down, Fanconi anemia, Klinefelter´s syndroma...)

– radiation– chemicals (benzen, alkylating agents, drugs)– viruses (HTLV-1)

• AML, ALL• symptoms: combination of aplastic anemia

and agranulocytosis• bm: leukaemic infiltration, +/- extramedullar

infiltration (liver, spleen, kidney, CNS)• myelosarcoma („chloroma“)

acute myeloid leukaemias... histological

classification M0...acute myeloblastic l. minimally

differentiated M1 ...acute myeloblastic l. without

maturation M2...acute myeloblastic l. with

maturation M3...acute promyelocytic l. M4...acute myelomonocytic l. M5...acute monocytic l. M6...acute erythroid l. M7...acute megakaryoblastic l.

acute lymphoblastic leukaemias... histological

classification precursor B- and T- cell lymphoblastic

leukaemia/lymphoblastic lymphoma

proliferation of macrophages, histiocytosis

A) reactive proliferation of macrophages

• bone marrow, many causes (hemosiderosis, aiha, viral infections)

• lysosomal storage diseases (m. Gaucher, Niemann-Pick...)


B) hemofagocytic syndroma• ↑ proliferation of macrophages or

histiocytic precursores → haemofagocytosis → cytopenia

• + hepatosplenomegaly, fever• proliferating macrophages: clonal (mlg

histiocytosis) x reaction (infection, Kawasaki, T lymphomas)

• fatal haemofagocytosis


C) histiocytosis X (Langerhans cells histiocytosis)

1) solitary eosinophilic granuloma– bng– bones (unifocal lytic lesion), skin, lymph

nodes, lungs– Langerhans cells (Birbeck granules) +

eosinophils, +/- plasma cells and lymphocytes

2) m. Hand-Schüler-Christian– trias: multifocal lytic lesions of bone +

exophtalamus + diabetes insipidus


3) m. Abt-Letterer-Siwe– mlg – children before 2 years of age– cutaneous lesions resembling seborrheic

skin eruptions + hepatosplenomegaly, lymphadenopathy, pulmonary lesions, osteolytic bone lesions → anemia and thrombocytopenia, reccurent infections

metastasis

• osteolytic x osteoplastic• prostate, breast, stomach, lung

cancer

bone marrow necrosis

• ischemia: – vascular collaps in hypercellular marrow– metastatic obstruction– sickle cell disease, DIC...

• symptoms: pain, fever, hematopoietic precursors in peripheral blood

transplantation

• transplantation: bone marrow, peripheral stem cells

• autologous x allogenneous (relatives, non-relatives)

• indications:– hematological: tumours,

immunodeficiency, anemias, b.m. aplasia– non-hematological: tumour metastasis

transplantation

• bone marrow suppression → graft • hypocellularity → proliferation• immunosuppression!• GvHD acute x chronic:

– skin, intestine, liver

Bleeding disorders

• cause:• defect in the vessel wall• platelet deficiency or dysfunction• coagulation factors disorder

bleeding disorders...vascular

A) defects in the vessel wall 1) hereditarya) m. Osler-Rendu-Weber (hereditary

hemorhagic teleangiektasias)– capillary aneurysms in the skin and

mucous membranes

b) connective tissue disorders m. Ehlers-Danlos Marfan´s syndrome

bleeding disorders...vascular

2) acquireda) avitaminosis C, ↑ corticosteroids

– cutaneous, intramuscular, mucosal bleeding

b) purpura Henoch-Schönlein– circulating IC → skin, kidney

bleeding disorders...plateles

B) plateles deficiency or dysfunction

1) thrombocytopeniaa) decresed production aplastic anemia hereditary disorders (sy Bernard-

Soulier, grey-plateles sy, m. Wiskott-Aldrich)


b) increased destruction splenomegaly, arteficial valves,...DIC (disseminated intravascular

coagulation)– activation of the coagulation sequence,

leading to formation of thrombi throughout the microcirculation → consumption of plateles and coagulation factors and secondarily activation of fibrinolysis


thrombotic thrombocytopenic purpura (TTP)– thrombocytopenia, fever, microvessel

obstruction symptoms– → microangiopathic hemolytic anemia– hyaline thrombi in the microcirculation

hemolytic-uremic syndrome (HUS)– E.coli– kidney cortex necrosis, intestinal bleeding


idiopathic thrombocytopenic purpura (ITP)– autoimmune origin– destruction in the spleen → splenectomy– bm +/- increased megakaryopoiesis


2) platelet dysfunction adhesion disorder (Bernard-Soulier, m.

von Willebrand) aggregation disorder (thrombasthenia

Glanzmann) secretion disorder: tromboxan A2

inhibition (aspirin)

bleeding disorders...coagulation factors

C) coagulation disorders1) hereditary deficienciesa) hemophilia A (classic hemophilia)

– f VIII (severe = activity < 1%!)– X chromosoma (new mutation x familiar)– easy bruising and massive hemorrhage

after trauma or operative procedures, „spontaneous“ hemorrhages – joints (hemarthroses) → progressive deformities

b) hemophilia B (Christmas disease)– f IX

bleeding disorders...coagulation factors

2) acquireda) DICb) liver diseases• synthesis of coagulation factors

(fibrinogen, prothrombin, fV, VII, IX-XI) + anticoagulation and fibrinolytic factors

c) vitamin K• food, synthesis in the large intestine

(bacterias) d) anticoagulation therapy

lymph vessels and nodes

lymphatic vessels

A) lymphoedema • lymph is protein-rich → lymphostasis

leads to fibroproduction, +/- infectious and ulcerative complications

1) hereditary = Milroy´s disease• valvular disorder2) acquired lymphoedema• lymphoedema praecox• secondary lymphoedema: obstruction

and lymphostasis (mlg, inflammatory changes)

lymphatic vessels

B) lymphangiectasia• focal extension of lymphatic vessels • skin, small intestine (chylangiectasia)• → lymforhea (chylothorax...)

lymphatic vessels

C) lymphangiitis• lymph vessels draining the primary

(infectious) focus• β hemolytic streptococci• + regional lymphadenitis• clinical: red subcutaneous line• histology:

– lymphangiitis simplex– lymphangiitis purulenta: pus + fibrin →

spreading → abscesses, trombophlebitis

lymfatic nodes...structure

• cells: lymphocytes, dendritic cells (FDRC, IDRC), macrophages with apoptotic bodies, NK cells

• follicles = B zone– lymphocytes from the bm → primary

follicle → immunity stimulation → germinal centres = secondary follicle, immunity answer → polarization of germinal centres

– germinal centres: B cells augmentation, selection Ag high affinity clones → plasma cells differentiation → migration into medulla, waiting to secondary immunity answer

lymph nodes...structure

• medulla– lymphatic tissue between medullar sinuses– small lymphocytes, plasma cells

• paracortex = T zone– mainly CD4 T cells, small venules – T lymphocytes 70% of lymphocytes in

lymph node and 80-90% in blood

• sinuses– incoming lymph vessels → subcapsular

(marginal) sinus → interfollicular → medulla → outgoing vessels

lymph nodes...regressive changes

A) regressive changes and circulatory disorders

1) infarction• vasculitis• tumorous infiltration vascular transformation of sinuses2) atrophy• lipomatous• hyalin3) pigmentation4) amyloidosis5) storage diseases

lymph nodes...inflammation

B) lymphadenitis1) acute nonspecific• inflammation of regional lymph node• clinicaly: enlarged, erythematous

lymph nodes• histology: ↑ follicles, mitoses, sinuses

filled with granulocytes, histiocytes• +/- healing with fibrous scarse


2) chronic nonspecific lymphadenitis• etiology:a) follicular hyperplasia• etio: tonsillitis, respiratory infections,

RA, syphilis, AIDS• histology: ↑ germinal centers,

fanciful shapes, many mitoses, blastic forms of cells – could be misinterpreted like mlg lymphoma!


progressive transformation of germinal centres– connection with HD (paragranuloma)

m. Castleman (angiofollicular hyperplasia)– „lolly pops“ follicles – unifocal bng x multifocal fatal


b) paracortical hyperplasia• etio: viruses (IM, HSV), inoculation,

some drugs• histology: enlarged paracortex, with

many IDRC, small follicles in the periphery of the lymph node, T imunoblasts

c) reactive sinusoidal histiocytosis • etio: reactive (different Ag)• histology: dilated sinuses filled with

histiocytes


m. Rosai-Dorfman (masive sinusoidal histiocytoses)– intrasinusoidal macrophages with

emperipolesis

d) mixed reactive hyperplasia• etio: toxoplasmosis (epitheloid

granulomas)


3) granulomatus purulent• epitheloid granulomas with central

necrosis with accumulation of neutrophils

cat scratch diseaseveneric lymphogranuloma

(Chl.trachomatis)mesenterial lymphadenitis

(Y.enterocolitica)ulcus molle (H. ducreyi)


4) granulomatous necrotictularemia (Fr. tularensis)plague (Y. pestis)anthrax (B. antracis)5) granulomatous• tuberculoid granulomas without central

necrosis sarcoidosis, m. Crohn...6) TBC lymphadenitis• miliary x caseous productive


7) granulomatous reaction to lipid materials

m. Whipple – lipid vacuoles, around epitheloid

histiocytes, intracytoplasmic PAS+ material

8) granulomatous reaction to foreign bodies

• silicic material in prosthesis

lymph nodes...neoplasms

lymph nodes...neoplasms

C) neoplasms, malignant lymphomas1) m. Hodgkin (HD)• group of disesases• presence of distinctive neoplastic giant

cells: Reed-Sternberg cells, Hodgkin cells, admixed with a variable infiltrate of reactive, nonmalignant inflammatory cells

• young people

lymph nodes...neoplasms...HD

• classification: nodular lymphocytic predominance

Hodgkin lymphoma• „classic“: lymphocyte rich HL (LR-CHL) nodular sclerosis (NS-CHL) mixed cellularity (MC-CHL) lymfocyte depleted (LD-CHL)

lymp nodes...neoplasms...NHL2) non Hodgkin lymphomas• predominance of neoplastic cells• elder patients • B and T cells

lymph nodes...neoplasms...B-NHL

a) B-NHL chronic lymphocytic leukaemia/small

lymphocytic lymphoma (CLL/SLL) follicular lymphoma (FCL) mantle cell lymphoma (MCL) marginal zone lymphoma (MZL): SMZL,

ENMZL=MALT, NMZL hairy cell leukaemia (HCL) diffuse large B-cell lymphoma (DLBCL) Burkitt lymphoma

chronic lymphocytic leukaemia/small lymphocytic

lymphoma (CLL/SLL)

• elderly patients• naive lymphocytes• indolent type of lymphoma

follicular lymphoma (FCL)

• middle aged patients• centrocytes and centroblasts• indolent course but rellapsing!

mantle cell lymphoma (MCL)

• „diffuse centrocytoma“• agressive type of lymphoma• t(11;14) – cyklin D1

marginal zone lymphoma (MZL)

• mucosa associated lymphoid tissue (MALT) – GIT, bronchi…

• association with chronic inflammation

diffuse large B-cell lymphoma (DLBCL)

• „waste basket“• transformation of small cell

lymphomas• aggresive course x good reaction

to therapy

Burkitt lymphoma

• endemic x sporadic• younger patients• association with EBV infection

lymph nodes...neoplasms...B-NHL

• plasma cell neoplasms: monoclonal gammopathy of

undetermined significance (MGUS) lymphoplasmacytic lymphoma (LPL),

m. Waldenström plasmacytoma multiple myeloma

lymph nodes...neoplasms...T-NHL

b) T-NHL peripheral T cell lymphoma (PTL) anaplastic large T cell lymphoma

(ALCL) angioimmunoblastic T cell lymphoma

(AILT) adult T cell leukaemia mycosis fungoides/Sezary syndrom

anaplastic large T cell lymphoma (ALCL)

• young patients• typical translocation t(2;5)

mycosis fungoides/Sezary syndrom

• primary skin lymphoma → generalisation = Sezary syndrom

spleen

spleen

• structure:– white pulp: lymphoid tissue– red pulp: venous sinuses → hilus

• splenomegaly: venosthasis, inflammation, neoplasms

• hypersplenism = increased function → cytopenia

• hyposplenism → susceptibility to certain bacterial infections

spleen...regressive changes, circulatory disorders

A) inborn anomalies• accessory spleens = spleniculiB) regressive changes and

circulatory disorders1) amyloidosis• secondary (AA)• +/- hyposplenism

spleen...regressive changes, circulatory

disorders2) storage diseases3) hemolytic anemias• ↑ splenic function → splenomegaly• hereditary spherocytosis4) chronic perisplenitis5) splenic infarction• white (embolization, vasculitis)• red (thrombosis of lienal vein)

spleen...regressive changes, circulatory

disorders6) chronic venosthasis7) splenic rupture, bleeding• traumatic

spleen...inflammation

A) inflammation1) acute septic tumour• reaction to general infection x

tumour lysis• clinically: tense capsula, soft tissue• histology: red pulp cellular, small

abscesses (central pyemia)

spleen...inflammation

2) chronic inflammatory tumour• chronic infections (IE)• histology: red pulp hyperemia,

reactive hyperplasia of the white pulp

• malaria• TBC, histoplasmosis, leishmaniosis,

trypanosomiasis• AIDS

spleen...tumoursD) tumours and pseudotumours1) cystic formations• posttraumatic pseudocysts• parasitary cysts2) hamartoma (splenoma)• nodule• histology: chaotic sinuses a fibrous tissue

= incorrect arrangement of the red pulp• +/- hypersplenism

spleen...tumours

3) hemangioma• histology: cavernous blood spaces,

thrombosis4) littoral cell angioma• phagocytosis → pancytopenia5) inflammatory pseudotumour• histology: inflammatory cells +

fibroproduction

spleen...tumours

6) malignant lymphomas• primary: SMZL• secondary:• more often• secondary infiltration by NHL, HD, CML,

HCL7) epithelial metastasis• microscopically

thymus

thymus...structure

• structure:• lobulus• cortex and medulla mixture of T

lymphocytes and a epithelial cells = lymphoepithelial organ

• cortex: mainly T lymphocytes• lymphatic follicles without germinal

centres• medulla: thymocytes, Hassal bodies

thymus...function

• function:– production of small lymphocytes with

cellular immunity– TdT a CD1 → maturation → CD4 a CD8 →

postthymic lymfocytes in medulla: CD4 (helpers/inducers), CD8 (suppressor/cytotoxic), loss of TdT a CD1 → blood, peripheral lymphatic organs

• main role intrauterine and in childhood

thymus...dysgenesis

A) thymic dysgenesis• primary immunodeficiency syndromes

(diGeorge, Nezelof...)

thymus...regressive changes

B) regressive changes1) lipomatous atrophy (involution)• puberty – involution with increase of

adipous tissue = ↓ thymocytes, calcification of Hassal bodies...

2) acute (accidental) involution• etio: corticosteroids – stress• histology: fragmentation of cortical

thymocytes, cystic transformation of Hassal bodies, lymfocytes disappeared, in cortex only spindle epithelial cells

thymus...hyperplasia

C) thymic hyperplasiaprimary hyperplasiamyasthenia gravis• histology: lymphoid hyperplasia,

lymphatic follicles with germinal centres

• Ab anti acetylcholin-receptors

thymus...neoplasms

D) neoplasms1) thymomas• epithelial thymic cells + lymphocytes• local manifestation• association with myasthenia gravis

2) neuroendocrinne tumors3) germinal cells tumours (teratoma,

seminoma)• bng, cystic4) malignant lymphoma

the hematopoietic and lymphoid systems. hematopathology blood lymphoid organs –central: bone...

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