Hematologic disorders, allergic and immunologic diseases. Markéta Hermanová RAS (recurrent aphthous ulcerations; canker sores) nPrimary immunodysregulation -In ulcerative stage: decreased ratio of CD4/CD8 T lymphocytes (about 1:10); increased TCRγδ+, increased TNF-α → increased activity of T cell subpopulations that mediate cytotoxic damage -Antibody-dependent cellular cytotoxicity, T-cell mediated cytotoxicity to oral epithelial cells (Ag unknown)??? cross reactivity between Ag shared by oral streptococci and oral epithelial cells??? -Patients with cyclic neutropenia n nDecrease of mucosal barrier n nIncrease in antigenic exposure n n Potential etiopathogenetic factors of aphthous stomatitis nAllergies nGenetic predisposition (HLA-B12, B51, Cw7) nNutritional abnormalities (B12, folate and iron deficiences) nHaematological disorders (anemia) nGastrointestinal diseases (avitaminosis B12 – atrophic oral mucosae, MAS, coeliac disease, ulcerative colitis, m. Crohn,…, nHormonal influences (pregnancy, luteal phase of MC,…) nInfectious agents (L form of streptococci, HSV, VZV, CMV,…) nTrauma nStress nSystemic disorders n n HSV infection 00756+ 00100+ Systemic diseases associated with recurrent aphthous stomatitis nBehcet´s syndrome (aphtous ulcers, genital ulcers, uveitis) nCeliac disease (gluten intolerance) nCyclic neutropenia (AD, ELA2 gene - neutrophil elastase) nNutritional deficiencies nIgA deficiency nImmunocompromised conditions, incl. HIV nInflammatory bowel disease (ulcerative colitis, Crohn´s disease) nMAGIC syndrome (mouth and genital ulcers with inflamed cartilage) nPFAPA syndrome (periodic fever, aphtous stomatitis, pharyngitis, cervical adenitis) nReiter´s syndrome (arthritis, urethritis, conjunctivitis and skin lesions) n n Clinical variation of aphthous stomatitis nMinor (80 %) nMajor (10 %) nHerpetiform n nHistopathology: ulcerative lesion covered with fibrinopurulent membrane, mixed inflammatory infiltration; spongiosis of the epithelium Aphtous stomatitis n n Zobrazit obrázek v plné velikosti Zobrazit obrázek v plné velikosti Behcet´s disease (syndrome) nRecurrent oral ulceration (minor, major or herpetiform aphthae) n n+ two of the following: -Recurrent genital ulcerations -Eye lesions (uveitis, retinal vasculitis,…) -Skin lesions (erythema nodosum, pseudofolliculitis or papulopustular lesions, acneiform nodules,…) n+ arthritis, CNS involvement, cardiovascular , GIT, hematologic, pulmonary, muscular, renal systems involvement n -HLA-B51 -Immunosuppresive treatment Sarcoidosis nMultisystem granulomatous disorder of unknown cause nInappropriate defense response to mycobacterial infectious agents + immunodysregulation nLungs, lymph nodes, skin, eyes, salivary glands,…. nAny oral mucosal sites can be affected (normal in color, brownish-red, violaceous, hyperkeratotic – submucosal mass) nNon-necrotising granulomas (accumulation of epitheloid histiocytes, Langhans´or foreign body-type giant cells, Schaumann bodies – basophilic calcifications, asteroid bodies – stellate inclusions) nDiagnosis: clinical and radiographic presentations, biopsy-histopathology, laboratory abnormalities, Kveim test (intradermal injection of human sarcoid tissue – development of papulonodular lesion) nTreatment: corticosteroids n n Other granulomatous disorders nOrofacial granulomatosis -Melkersson-Rosenthal syndrome (cheilitis granulomatosa+facial paralysis+fissured tongue) n nWegener´s granulomatosis nCrohn´s disease nTuberculosis nSarcoidosis nForeign body reaction, allergy n Granuloma in Crohn´s disease 100x Sarcoidosis granulomat la2 TBC 200x Foreign body reaction granulom cizí těleso Granulomatosis with polyangitis (Wegener´s granulomatosis) nNecrotizing granulomatous lesions of the respiratory tract n nNecrotizing glomerulonephritis n nSystemic vasculitis Granulomatosis with polyangitis (Wegener´s granulomatosis) nClassic nLimited (no rapidly progressive renal lesion) nSuperficial (skin and mucosa affected) n nOral lesions: strawberry gingivitis (hemorrhagic and friable), oral ulcerations, facial paralysis, labial mucosal nodules, oral-antral fistulae, poorly healing extraction sites, palatal ulcerations,….. n cANCA autoantibodies nCyclophosphamide + prednisone n n S146239940500921Xsup008 Granulomatosis with polyangitis (Wegener´s granulomatosis) Allergic mucosal reactions to systemic drug administration (stomatitis medicamentosa) nAnaphylactic stomatitis (penicillin, sulfa drugs,…): symtoms of anafylaxis (e.g. hoarseness, respiratory distress, vomiting), erytema and aphthous-like ulcerations in oral mucosa nIntraoral fixed drug reactions (erythema, edema, vesiculoerosive lesions on labial mucosa) nLichenoid drug reactions nLupus-erythematosus-like eruptions nPemphigus-like reactions n (resemble their namesakes clinically, histopathologically and imunologically; typically posterior buccal mucosa and the lateral borders of the tongue) nNonspecific vesiculoulcerative lesions Allergic contact stomatitis (stomatitis venenata) nFoods, food aditives, chewing gums, candies, ……topical anesthetics, restorative metals, acrylic denture materials,…cinnamon, amalgam n nAcute (burning, erythema, edema, visicles,erosions, ulcers,…) n nChronic (erythematous or white and hyperkeratotic) nPerioral dermatits n (papules, papulopustules periorally; F>M; cosmetics, tooth-paste,…) n nContact stomatitis from artificial cinnamon flavoring n (tooth-paste, candies, chewing gums,…; mucosal enlargement, edema, erythema, circumoral dermatitis, exfoliative cheilitis,…in chronic cases a thickening of the surface epithelium) n nChronic oral mucosal contact reactions to dental amalgam n (mercury in amalgam responsible for the allergic reaction; acute or chronic; histologically and clinically resemble lichen planus – contact lichenoid reaction; posterior buccal mucosa,ventral surface of the lateral borders of the tongue affected) n nAngioedema (angioneurotic edema, Quinke´s disease) -IgE-mediated hypersensitivity reactions caused by drugs (ACE inhibitors), foods, plants, dust, inhalants,… -mast cell degranulation caused by physical stimuli (heat, cold, exercise, emotional stress, solar exposure) -contact allergies -activation of complement pathway (hereditary or acquired (in lymphoproliferative diseases or in patients who develop specific antibodies)) -Tissue swelling, itching, erythema (face, lips, tongue, pharynx, larynx, dermatologic involvement); involvement of GIT and respiratory tract, perioral and periorbital involvement -Treated by oral antihistamines, corticosteroids; in laryngeal involvement – intubation and tracheostomy - n Perioral dermatitis perioral_dermatitis Angioedema traumatic_angioedema_side Hematologic disorders nLymphoid hyperplasia nHemophilia nAnemia, sickle cell anemia, aplastic anemia nThalassemia nNeutropenia, agranulocytosis, cyclic neutropenia, thrombocytopenia nLeukemia, polycythemia vera nHodgkin and non-Hodgkin lymphomas nLangerhans cell histiocytosis n n Lymphoid hyperplasia – follicular hyperplasia folik -Affect lymph nodes, lymphoid tissue of Waldeyer´s ring, oral cavity aggregates of lymphoid tissue -Reactive, non-neoplastic lesion: in acute infection, chronic inflammatory conditions, in HIV - Type Defect Inheritance Findings Hemophilia A (classic) Factor VIII X-linked recessive Abnormal PTT (partial tromboplastin time) Hemophilia B (Christmas d.) Factor IX X-linked recessive Abnormal PTT von Willebrand disease Abnormal von Willebrand factor, abnormal platelets AD Abnormal BT (bleeding time), abnormal PTT Inherited bleeding disorders (bleeding diatheses, specific clotting factor deficiency) - small oral lacerations (after minimal trauma) with significant blood loss, eccchymoses, - deep hemorhage after normal activities (muscles, joints, soft tissues) Anemia nDecrease in the volume of red blood cells (hematocrit) or in the concentration of hemoglobin n nReduced oxygen-carrying capacity of the blood n nClinical features: -Tiredness, headache, lightheadedness -Pallor of mucous membranes (oral mucosa) -Pallor of palpebral conjuctiva Causes of anemia nAnemias with disturbed iron metabolism -Iron deficiency -Sideroblastic anemias n nMegaloblastic anemias -Pernicious anemia (avitaminosis B12) -Folic acid deficiency - nAnemia associated with chronic disorders -in chronic infections -in inflammatory connective tissue disorders -in malignancy (secondary to chronic bleeding, myelophthisic anemia) -of uremia, of liver disease, of endocrine failure n - Causes of anemia nHemolytic anemias •Extrinsic causes -Splenomegaly -Red cell antibodies -Trauma in the circulation -Direct toxin effects •Membrane abnormalities n (paroxysmal nocturnal hemoglobinuria, hereditary spherocytosis, hereditary ellipsocytosis) •Disorders of the interior of the red cells Causes of anemia n nDisorders of hemoglobin -sickle cell anemia (hemoglobinopathy, hereditary, abnormal shape and adherence properties of erythrocytes, fragile erythrocytes, blockage of capillaries; abnormal gene persists in human race – some degree of resistance to malarian organism) -Thalassemias (hereditary disorders of hemoglobin synthesis; Thalassemia minor and major) n nAplastic anemia -life-threatening hematologic disorder; failure of hematopoietic precursor cells in the bone marrow -exposure to some environmental factors, drugs, certain viruses,…. -hereditary – Fanconi´s anemia -symptoms related to erythrocytes, plateles and leukocytes deficiency -oral lesions, gingical hemorrhages, petechiae, purpura, ecchymoses, ulcerations - nNeutropenia -decreased number of circulating neutrophils -congenital, hereditary; acquired (leukemia, metabolic diseases, drugs, infections,…) -bacterial infections, oral lesions n nAgranulocytosis -neutrophils absent -decreased production, increased destruction, idiopathic (some drugs?), congenital -malaise, sore throat, swelling, fever, oral lesions – necrotizing ulcerative gingivitis n nCyclic neutropenia -Idiopathic (some AD (ELA2 gene - neutrophil elastase), ?defect in hematopoietic stem cells in the bone marrow?) -Recurrent episodes of fever, anorexia, cervical lymphadenopathy, oral mucosal ulcerations, pharyngitis n nThrombocytopenia -Decreased number of circulating blood platelets; petechiae, ecchymoses, hematomas -Reduced production -Increased destruction (immunologic reaction (ITP, TTP); consuption -Splenomegaly n - n Hematooncology nLeukaemias nNeoplastic proliferation of white blood cell precursors n nDiffuse replacement of normal BM by leukaemic cells with their subsequent variable accumulation in peripheral blood (=leukaemization) n nInfiltration of peripheral organs by leukaemic cells (liver, spleen, lymph nodes, meninges, gonads,….) n nConsequence, particularly in acute leukaemias: bone marrow failure with anaemia, neutropenia and thrombocytopenia n nLymphomas nNeoplastic/lymphoma cells form tumor/neoplastic mass (primary nodal and/or extranodal) n nLymphomas may also present by leukaemic infiltrates and leukaemias also form solid neoplastic massess See the pathology lecture……. Hematooncology •Mutations that inhibit normal differentiation and maturation of progenitor cells, or mutations disrupting the regulation of progenitor and precursor cells by growth factors n Þunregulated clonal expansion of immature hematopoietic cells → inhibition of normal hemopoiesis → release of immature blast into circulation, infiltration of peripheral organs n Hematooncology nMyeloid neoplasms -from stem cells that normally give rise to the formed blood elements (granulocytes, red cells, platelets) -3 categories n → acute myelogenous leukemias n → myeloproliferative disorders n → myelodysplastic syndromes n n Lymphoid neoplasms/lymphomas n→ non-Hodgkin lymphomas n(incl. lymphocytic leukemias and plasma cell dyskrasias) n→ Hodgkin lymphomas n n Histiocytic neoplasms n Clinical features of leukemia nAcute myeloid leukemia -adults, broader age range, also children n nChronic myeloid leukemia -peak incidence during the 3rd and 4th decade - nAcute lymphoblastic leukemia -children, most common childhood malignancy - nChronic lymphocytic leukemia -elderly adults - Clinical features of leukemia nMyelophthisic anemia -marked reduction of normal white and red blood cells – crowding out of the normal hematopoietic stem cells by leukemic cells in bone marrow - -fatigue, easy tiring, dyspnoe, mild exertion - -lymphadenopathy, hepatomegaly, splenomegaly - -easy bruising and bleeding (due to thrombocytopenia), incl. gingival bleeding - - - - n Clinical features of leukemia -Infections (G-, bacteria, G+ cocci, Candida albicans, HSV), fever n -Ulcerations of oral mucosa (due to impaired ability of the host to combat the normal microbial flora); neutropenic ulcers (deep, punched-out lesions with necrotic base) n -Infiltration of the oral soft tissues by leukemic cells (diffuse, boggy, nontender swelling, also ulcerated, also diffuse gingival enlargement or tumorlike growth) - -Infiltration of the periapical tissues - - - n WHO classification of lymphomas nB-cell neoplasms 1.precursor B-cell neoplasms 2.peripheral B-cell neoplasms n nT-cell neoplasms 1.precursor T-cell neoplasms 2.peripheral T-cell neoplasms n nHodgkin lymphomas 1.Classical subtypes 2.Lymphocyte predominance Neoplasms of immature B and T cells (precursor B and T cell neoplasms) 1.Precursor -B-cell acute lymphoblastic leukemia/lymphoma -bone marrow precursor B-cell expressing TdT and lacking surface Ig -children (peak at age 4), highly aggressive/chemosensitive, leukemic presentation (80 %) -infiltration of bone marrow, LN, liver, spleen,… -diverse chromosomal translocation (t(12;21) n 2.Precursor-T-cell acute lymphoblastic leukemia/lymphoma -precursor T-cell (often of thymic origin) expressing TdT -diverse chromosomal translocations (TCR loci) -Adolescent males, thymic mass, variable splenic, hepatic, and bone marrow involvement; aggressive -B-ALL>>>T-ALL - Neoplasms of mature B-cells (peripheral B cells neoplasms) 1.B-chronic lymphocytic leukemia/small lymphocytic lymphoma -naive B-cell or postgerminal center memory B-cell (CD5+) -trisomy 12, deletions 11q, 13q, 17p -adults; bone marrow, lymph nodes, spleen, liver; indolent; transformation into high grade lymphoma – Richter´s syndrome - 2.Mantle cell lymphoma n- naive B-cell of mantles (CD5+, cyclinD1+(promotesG1 to S phase progression) -t(11;14); cyclinD1 locus/IgH locus -older males, often extranodal (lymphomatous polyposis); moderately aggressive – resistent to therapy - 3.Follicular lymphoma -germinal center B-cell (CD10+, bcl-2+, bcl-6+): centrocytes; centroblasts and immunoblasts -t(14;18); bcl-2/IgH (bcl-2 (inhibitor of apoptosis) overexpression – promotion of the survival of follicular lymphoma cells -adults; primary nodal, later disseminated; indolent - n Spleen, follicular lymphoma Follicular lymphoma Centrocytes, centroblasts Centroblasts Nodular infiltration Loss of polarity of germinal centers 4.Diffuse large B-cell lymphoma -germinal center or postgerminal center B-cell (centroblasts and immunoblasts) -diverse chromosomal translocations (bcl-6 rearrangement) -all ages, usually adults; 40 % extranodal; aggressive - 5.Burkitt lymphoma n (African endemic (jaws); sporadic (intestinal); HIV+ related) -germinal center B-cell (CD10+)?; „starry sky“ pattern; high mitotic rate, high apoptotic rate -t(8;14) (c-myc/IgH), t(2;8) (c-myc/kappa light chains), t(8;22) (c-myc/lambda light chains) -adolescents, young adults; aggressive, often association with EBV - 6.Extranodal marginal zone lymphoma (MALT lymphomas) -postgerminal center memory B-cell -extranodal in adults with chronic infalmmation (Helicobacter pylori gastritis, Sjogren´s syndrome, chronic lymphocytic autoimmune thyreoiditis,…); indolent, possible transformation into high grade lymphoma -+ nodal marginal zone B-cell lymphoma; + splenic marginal zone B-cell lymphoma - - - n Diffuse large B cell lymphoma DLBCL high2 DLBCL high imunoblasts centroblasts Burkitt lymphoma Burkitt - reprint Burkitt Ki 67 Ki67 7.Hairy cell leukemia -postgerminal center memory B-cell (no known the physiological equivalent; hairlike projections) -no specific chromosomal abnormality -older males; pancytopenia, infections, bone marrow, liver and spleen infiltration, no lymph nodes involvement; indolent - 8.Multiple (plasma cell) myeloma/plasmacytoma -plasma cell derived from a postgerminal center B-cell; neoplastic cell synthesizes and secretes a single homogeneous immunoglobulin or its fragments (monoclonal neoplastic proliferation of plasma cells) -diverse reaarangements involving IgH; -Myeloma: older adults; lytic lesions of bones, primary amyloidosis, renal failure. -Plasmacytoma: neoplastic plasma cell masses in bone or soft tissues -+ monoclonal gammapathy of undetermined significance; + heavy chain disease; +extraosseal plasmacytoma; +primary or immunocyte-associated amyloidosis - 9.Lymphoplasmacytic lymphoma -peripheral CD5- post-germinal center memory B-cell with activated plasma cell differentiation program ; neoplastic cells with PAS+ inclusions containing Ig (cytoplasmic Russell bodies and nuclear Dutcher bodies) -lymph nodes, bone marrow and spleen involvement -Waldenstrom macroglobulinemia (excess of IgM, hyperviscosity syndrome) -Indolent - - Multiple myeloma MYelom RTG myelom -kost Osteolytic lesions Infiltration by neoplastic plasma cells Neoplasms of mature B-cells B-CLL HCL MM MALT MALT Neoplasms of mature T-cells (peripheral T cells neoplasms) 1.Adult T-cell leukemia/lymphoma -helper T-cell (CD25+; IL-2 receptor) -HTLV-1 provirus in neoplastic cells -lymph nodes, bone marrow, hypercalcemia, osteolysis; aggressive - 2.Anaplastic large cell lymphoma T or null cell -cytotoxic T cell -rearangements of ALK -children, young adults, lymph nodes, soft tissues, skin; aggressive - n3. Extranodal NK/T cell lymphoma, nasal and nasal typ n- NK cells, cytotoxic T cells (before WHO classification: angiocentric lymphoma) -nasal (lethal midline granuloma), lung (lymphomatoid granulomatosis), CNS, skin -aggressive, accompanied with hemophagocytic syndrome - 4.Enteropathy-type-T-cell lymphoma -IEL (intraepithelial T cell; CD3+, CD4-, CD8+/-) -clonal reaarangement of TCR -often associated with CS (ulcerative jejunitis, therapy refractory sprue) -aggressive n n n5. Peripheral T-cell lymphoma (unspecified) n6. Mycosis fungoides/Sezary syndrome (leukemic) - helper cells - no specific chromosomal abnormality - skin involvement (patches, plaques, nodules n or generalized erythema); oral involvement - 25 cases described n7. T-chronic prolymphocytic leukemia - splenomegaly, leukemia - More aggressive than B-CLL n8. T-cell granular lymphocytic leukemia - CD8+ T cells or CD56+ NK cells (Asia, EBV) - splenomegaly, neutropenia, associated with autoimmune diseases – n reumatoid arthritis - indolent (CD8+); aggressive (CD56+) - n+ angioimmunoblastic T-cell lymphoma, panniculitis-like T-cell lymphoma, hepatosplenic γδ T-cell lymphoma n - n n Differences between HL and NHL Hodgkin lymphoma Non-Hodgkin Lymphoma Usually localized to a single axial group of LN (cervical, mediastinal, para-aortic) Involvement of multiple peripheral LN Contiguous spreading Non-contiguous spreading Mesenteric LN and Waldeyer ring rarely involved …… commonly involved Extranodal rare Extranodal common Diagnostic (neoplastic) cells admixed with reactive non-malignant inflammatory cells Neoplastic/lymphoma cells dominate B-cell origin B- or T-cell origin Hodgkin lymphoma nneoplastic cells (diagnostic cells) – minor fraction (germinal or post-germinal B-cells) nreactive lymphocytes, macrophages, granulocytes – major fraction of tumor mass n n nClassical HL: nNodular sclerosis nLymphocyte-rich nMixed cellularity nLymphocyte depletion n n+ Lymphocyte predominance/nodular n(diagnostic cells – the L&H (pop corn) cells- B phenotype) Hodgkin lymphoma nClinical picture nPainless enlargement of lymph nodes (cervical, mediastinal, para-aortic: often localized to single axial group with spread by contiguity); mesenteric nodes and Waldeyer ring rarely involved, extranodal involvement uncommon nYoung patients nNight sweats, weight loss n nNeoplastic cells in classical HL nDiagnostic Reed-Sternberg and Hodgkin cells (multiple or single nucleus) nLacunar cells n n n n n n Diagnostic cells – HL, classical NSHD-RS cell MCHD-Hodgkin cell NSHD-lacunar cell NSHD - Sternberg cell Lacunar cells R-S cell S-cell H-cell Myeloid neoplasms nNeoplasms originated from hematopoietic progenitor/stem cells capable of giving rise to differentiated cells of myeloid series nCells of the myeloid series n (erythrocytes, granulocytes, monocytes, platelets) nPrimary involvement of bone marrow n (secondary spleen, liver and lymph nodes) n3 categories: 1.Acute myelogenous leukemias 2.Myelodysplastic syndromes 3.Chronic myeloproliferative disorders n Acute myeloid leukeamia (AML) nAssociated with diverse aquired mutations that lead to abnormal expression of transcription factors, which interfere with myeloid differentiation; often assoc. with mutations in genes encoding GFR signaling pathways components or regulators of the epigenome n nReplacement of normal bone marrow elements by immature myeloid blasts n nHiatus leukemicus n nImmature myeloid lineage blasts released into peripheral blood n nLeukaemic infiltrates in bone marrow, liver, spleen, lymph nodes…. nClinical signs of bone marrow failure n → anemia (fatigue, palor) → trombocytopenia (abnormal bleeding) n → granulocytopenia (bacterial infections - fever) n nPeak incidence 15-39 years nGenerally poor prognosis (60 % remision; 15-30 % disease free for 5 years) n Myelodysplastic syndromes (MDS) n Clonal stem/progenitor cell disorder characterized by maturation defects (=ineffective maturation of myeloid progenitors) associated with ineffective hematopoiesis and an increased risk of development of AML. n de novo or following genotoxic exposures; frequently harbor mutations in splicing factors, epigenetic regulators, and transcription factors n nPrimary/idiopathic (six categories based on morphological and cytogenetic features in the WHO classification) nSecondary/therapy-related n n nPredominantly in older adults n nClinically: weakness, infections, hemorrhages due to pancytopenia n nTreatment: allogeneic HSC transplantation (in younger patients), supportive treatment with ATB and blood products transfusion, thalidomide-like drugs and DNA methylation inhibitors in some patients n nBone marrow: hypercellular or normocellular or (hypocellular) nDysplastic differentiation of erythroid, granulocytic, monocytic and megakaryocytic lineages to various degree nPeripheral blood: cytopenia of one or more cell lines nRisk of transformation into AML n(abnormal stem cell clone genetically unstable→additional mutations→AML Chronic myeloproliferative disorders - presence of mutated constitutively activated tyrosine kinases or other aberrations in signaling pathways that lead to growth factors independence nChronic myeloid leukaemia, BCR-ABL1-positive n Polycythaemia vera n Essential thrombocythaemia n Primary myelofibrosis n nChronic neutrophilic leukaemia nChronic eosinophilic leukaemia nMyeloid leukaemia, unclassifiable n Chronic myeloid leukaemia (CML) npresence of aquired genetic abnormality: t(9;22); BCR-ABL fusion gene: fusion protein with tyrosinkinase activity; Philadelphia chromosome; n nBCR-ABL preferentially drives the proliferation of granulocytic and megakaryocytic progenitors, abnormal release of immature granulocytes from the marrow into blood n nadults, peak incidence in 5th and 6th decade n nClinical features: n- anemia, hypermetabolism due to increased cell turnover: fatigability, n weakness, weight loss, anorexia n- slow progression-accelerated phase-blast crisis (AML-like) n nTherapy: n- transplantation of bone marrow n- imatinib mesylate (inhibitor of the BCR-ABL tyrosine kinase) Chronic myeloid leukaemia (CML) nElevated leukocyte count (>100,000 cells μ/l) n nHypercellular bone marrow n (hyperplasia of granulocytic and megakaryocytic precursors) n nCirculating cells: predominantly neutrofils, metamyelocytes and myelocytes, myeloblasts <5 % n nExtreme hepatosplenomegaly, spleen up to 20 kg n nExtramedullary hematopoiesis n Polycythemia vera §the transformed progenitor cells have markedly decreased requirements for erythropoietin and other hematopoietic growth factors due to activating mutations in the tyrosine kinase JAK2 § §increased marrow production of red cells, granulocytes and platelets (panmyelosis) § §symptoms related to the increased red cell mass and hematocrit: plethora, cyanosis owing stangnation and deoxygenation, headache, dizziness, hypertension, GIT symptoms, hyperuricemia due to increased cell turnover, abnormal blood flow and platelet function lead to increased risk of major bleeding and thrombosis § §transition into myelofibrosis, accompanied by increased extramedullary haematopoiesis § §transformation to AML in 2 % of patients Histiocytic and dendritic cell neoplasms n nLangerhans cell histiocytosis (histiocytosis X) nImmunophenotype: CD1a+, langerin+, S100+; ultrastructurally cytoplasmic tennis–racket shape Birbeck granules) n- monoostotic (solitary osteolytic lesion (eosinophilic granuloma), involvement of adjacent soft tissues) n- polyostotic (multifocal osteolytic lesion (Hand-Schüller-Christian d.), involvement of adjacent soft tissues) n- disseminated and multisystem (Letterer-Siwe disease; skin, bones, liver, spleen and bone marrow affected) nPulmonary Langerhans cell histiocytosis – special category, in smokers, reactive?, neoplastic? (BRAF mutated in some lesions) n nOral pathology in Langerhans cell histiocytosis: -osteolytic lesions, alco mandible or maxila affected -ulcerative and proliferative mucosal lesions, proliferative gingival mass, involvement of oral soft tissues -derived from mononuclear phagocytes (macrophages and dendritic cells (antigen presenting cells) or histiocytes -rare tumours, <1% of tumours presenting in lymph nodes and soft tissues Histiocytic and dendritic cell neoplasms nLangerhans cell sarcoma n(high grade malignancy, skin and soft tissue involvement, multisystem) n nHistiocytic sarcoma n nDendritic cell sarcomas n(follicular DCS, interdigitating DCS, other rare forms….) n nErdheim Chester disease n- rare clonal systemic proliferation of histiocytes, with foamy component and containg giant Touton cells n- involvement of different organs (bones, retroperitoneum, CNS,……), multisystem disease and CNS involvement with worse prognosis n Thank you for your attention …