Hematopathology PDF

Hematopathology Kingsley Kamvuma MSc.. Mulungushi University Outline Leukopenia/Neutropenia Leukocytosis Lymphadenitis/Lymphadenopathy (Malignant) Lymphoma NON-Hodgkins Lymphoma Hodgkins Lymphoma (Hodgkins Disease) ALL/CLL (Acute/Chronic Lymphocytic...

Hematopathology Kingsley Kamvuma MSc.. Mulungushi University Outline Leukopenia/Neutropenia Leukocytosis Lymphadenitis/Lymphadenopathy (Malignant) Lymphoma NON-Hodgkins Lymphoma Hodgkins Lymphoma (Hodgkins Disease) ALL/CLL (Acute/Chronic Lymphocytic Leukemia) Multiple Myelom Myeloproliferative Disorder CML Splenomegaly Thymoma Overview hematopoietic system – myeloid tissue & lymphoid tissues Bone marrow --- Red cells, platelets, granulocytes & monocytes Lymphoid tissues -- thymus, lymph nodes, spleen myeloid leukemias originate from the bone marrow – spleen & lesser extend lymph node Immunohemolytic anemia Development and Maintenance of Hematopoietic Tissues Blood cell progenitors – York sac (third week) Source of long lived microglial cells & Kupffer cells Definitive hematopoietic stem cells (HSCs) – Mesoderm of AGM Third month HSCs migrate to the liver Chief site of blood formation until shortly b4 birth fetal placenta Fourth month – bone marrow By birth, marrow becomes hematopoietically active Hepatic hematopoiesis dwindles Until puberty – hemopoiesis throughout skeleton --- axial skeleton (adult) NEUTROPHILS Normal TOTAL WBC count 6-11 K Neutrophils usually 2/3 of total normal Myeloblast—Promyelocyte – Myelocyte – Metamyelocyte -- Band (stab) -- Mature Neutrophil (Poly, PMN, Neutrophilic Granulocyte) Produced in red (hematopoetic) marrow, sequester (pool) in spleen, live in peripheral blood, migrate OUT of vascular compartment PRN, live a couple days normally NEUTROPHIL MATURATION DISORDERS OF WHITE CELLS Can either be proliferative disorders or leukopenia Proliferations – reactive (infection or infla)/neoplastic PELGER-HUET ANOMALY Genetic: Autosomal Dominant) Sometimes ACQUIRED (Pseudo-PELGER-HUET) All neutrophils look like BANDS NOT serious, mostly a cute incidental finding CHEDIAK-HIGASHI SYNDROME Also genetic: Autosomal Recessive Abnormal LARGE irregular neutrophil granules Impaired lysosomal digestion of bacteria Associated with pigment and bleeding disorders CAN be serious, especially in kids LEUKOPENIA Due to a variety of disoders Usually due to neutropenia (granulopenia) Less commonly lymphopenia – HIV, congenital, glucocorticoids, viral infe, autoimm, maln Neutropenia, Agranulocytosis Reduction in neutrophil numbers Agranulocytosis clinically significant reduction in number of neutron Higly susceptible to bacterial/fungi, mainly due to drug toxicity Pathogenesis Inadequate or ineffective granulopoiesis, Suppression of HSCs – Aplastic anemia/infiltrative disoders (assoc anemia/thrombocypenia) Suppression of committed granulocytic precursors – some drugs Ineffective hematopoiesis– Megaloblastic anemias & myelodysplastic syndromes Rare congenital conditions (e.g., Kostmann syndrome) Increased destruction or sequestration in the periphery Immunologically mediated injury – idiopathic, assc SLE, certain drugs Splenomegaly (pooling), with anemia/thrombocytopenia Increased utilization-- bacterial, fungal, or rickettsial infections Morphology Bone Marrow Excessive destruction – hypercellular Also seen in ineffective granulopoiesis e.g. magaloblastic anemia/MDS Sx Agranulocytosis – assoc with a hypocellular bone marrow (cytotoxicity) Highly susceptible to infections Ulcerating necrotizing lesions of the gingiva, floor of the mouth, buccal mucosa, pharynx, or elsewhere in the oral cavity (agranulocytic angina) are quite characteristic skin, vagina, anus, or gastrointestinal tract Severe infections can occur in Lungs, urinary tract, and kidneys Neutropenic pts high risk for fungal infec e.g. Candida & Aspergillus Clinical features Neutropenia --- related to infection, Malaise, chills, fever, marked weakness & fatigability Agranulocytosis Infections is severe may cause death within hours to days Serious infections likely when Neut 2 cm) chemokines. Other 1/3 - extranodal sites E.g.skin, stomach, or brain) Lymphocytic leukemias --- suppress normal hematopoiesis Plasma cell neoplasm- MM -bony WHO classification scheme Uses morphologic, immunophenotypic, Important points about lymphoid genotypic, and clinical features neoplasms Precursor B-cell neoplasms Hx examination required (neoplasms of immature B cells) Similar to recognizable stage of B- or T- Peripheral B-cell neoplasms cell differentiation (neoplasms of mature B cells) Antigen receptor gene rearrangement Precursor T-cell neoplasms precedes Malignant transformation (neoplasms of immature T cells) Assoc immune abnormalities-- Peripheral T-cell and NK-cell Increased susceptibility/autoimmunity neoplasms (neoplasm mature T cells are seen and NK cells) Similar to the behavior of their normal Hodgkin lymphoma (RS cell and counterparts variants) HL spreads orderly fashion, NHL spread widely early (less predictable fashion) Precursor B- and T-Cell Neoplasms Acute Lymphoblastic Leukemia/Lymphoma Immature B (pre-B) or T (pre-T) cells (lymphoblasts) 85% are B-ALLs (childhood acute leukemias) T cells adolescent males (thymic lymphomas) ALL is the most common cancer of children (under 15), 3X whites than blacks, Hispanics Pathogenesis Dysregulate the function of transcription factors required for normal B- and T-cell development. Multistep origin of cancer (less than 10 mutation sufficient) 70% of T-ALLs have gain-of-function mutations in NOTCH1 Loss of fxn -- PAX5, E2A, and EBF, or t(12;21) invol genes ETV6 and RUNX1 (requi in the early hematopoietic prec) Disturb the differentiation of lymphoid precursors and promote maturation arrest Induce increased self-renewal 90% of ALLs have numerical or structural chromosomal changes MORPHOLOGY Hypercellular BM (lymphoblasts) mitosis Mediastenal thymic masses --50% “starry sky” appearance to 70% of T-ALLs Compared myeloblasts, Assoc Lymphadenopathy and splenomegaly lymphoblasts have more condensed chromatin, less Scanty basophilic with nuclei conspicuous nucleoli, and larger than small lymph smaller amounts of cytoplasm Nuclear chromatin is delicate and that usually lacks granules finely stippled, nucleoli small with Lymphoblasts are condensed chromatin myeloperoxidase neg/Periodic Aggressive clin.. behavior –high acid-Schiff–positive Immunophenotype TdT--pre-B and pre-T T-ALLs are arrested at various lymphoblasts (95% cases) stages Pan B-cell marker CD19 Positive for CD1, CD2, CD5, and CD7 More immature tumors negative for andtranscription factor PAX5, surface CD3, CD4, and CD8 but Pos in CD10 late pre T-cells Very immature B-ALLs, CD10 is negative Late pre-B” ALLs express CD10, CD19, CD20, and cytoplasmic IgM heavy chain Clinical Features Similar with AML Bone pain, lymphadenopathy, splenomegaly, hepatomegaly; In both, the accumulation of testicular enlargement neoplastic “blasts” in the BM suppresses hematopoiesis by physical Central nervous system crowding, competition for GFs manifestations Abrupt stormy onset within days to headache, vomiting, and nerve a few weeks palsies– meningeal spread Sx related to depression of marrow function Fatigue, fever; and bleeding Mass effects caused by neoplastic infiltration (More common in ALL) Peripheral B-Cell Neoplasms Chronic Lymphocytic Mean age diag 60 Leukemia/Small years & 2 : 1 male Lymphocytic predominance Lymphoma In contrast, SLL constitutes only 4% of Differ only in degree NHLs of peripheral blood lymphocytosis Absolute lymphocyte count > 5000 per mm3 – in most pts Most common leukemia in adults Pathogenesis Chromosomal abnormalities are rare Proliferation centers Deletions of 13q14.3, 11q, and 17p, Blood --small round lymphocytes with and trisomy 12q scant cytoplasm Chromosome 13 has implicated two Smudge cells microRNAs, miR-15a and miR-16-1 Involve BM, splenic white and red pulp (TSGs) and the hepatic portal tracts NOTCH1 receptor in 10% to 18% of IMMUNOPHENOTYPE tumors Pan B-cell markers CD19 and CD20, as MORPHOLOGY well as CD23 and CD5 Lymph nodes- diffusely effaced Low-level expression of surface Ig (IgM Infiltrate of small lymphocy 6-12 μm or IgM and IgD) with round - irregular nuclei, condensed chromatin, and scant cytoplasm Variable # of activated lymphocytes Clinical Features Asymptomatic at diagnosis, when present are nonspecific Easy fatigability, weight loss, and anorexia Lymphadenopathy & hepatosplenomegaly are present in 50%- 60% Sx pts Leukopenia can be seen in individuals with SLL counts in excess of 200,000/mm3 are sometimes seen in CLL patients A small monoclonal Ig “spike” in some pts CLL/SLL disrupts normal immune function through uncertain mechanisms Hypogammaglobulinemia (common) – infections Hemolytic anemia or thrombocytopenia due to autoantibodies (nonneoplastic B cells) Median survival is 4-6years, 10 years in pts with minimal tumor burdens Prognosis The presence of deletions of 11q and 17p, A lack of somatic hypermutation The expression of ZAP-70 The presence of NOTCH1 mutations Transformation to diffuse large B-cell lymphoma-- Richter syndrome Assoc with rapidly enlarging mass within a lymph node or the spleen 10 – 15% pts , survival is less than 1year  Follicular lymphoma Most common indolent NHL, Morphology Middle age, F=M Nodular/nodular and diffuse growth pattern in lymph node Centrocytes (majority), Centroblasts Pathogenesis Lymphocytosis (20,000 cells/mm3)- Arises from germinal center B cells, 10% chromosomal translocations in BCL2 Bone marrow involvement- 85% t(14:18) (90%), juxtaposes the IGH Involv.. splenic white pulp & hepatic locus 14, BCL2 18 (antiapoptosis) portal triads No apoptotic cells MLL gene mutations also identified (90%) (histone methyltransferase)  Follicular lymphoma Immunophenotype Resemble normal germinal center B Clinical features cells Painless, general.. lymphadenopathy CD19, CD20, CD10, surface Ig, and ExtraN--GIT, CNS, or testis uncommon BCL6, No CD5 indolent waxing and waning course bt BCL2 (90%), Normal (BCL2 Neg) incurable Low -dose chemo or immunotherapy (anti-CD20 Ab) – Sx pts, Palliative Hx transformation (30%-50%) DLBL, BL (MYC) Median survival is 90% point mutations serine/threonine kinase (BRAF) Morphology Fine hair like projections Immunophenotype Pan Bcell marker CD19, CD20, Surface Ig (IgG), Distinctive --CD11c, CD25, CD103, annexin A1 Clinical features – Good prognosis Infiltration of bone, liver, spleen.. Pancytopenia (1/2), infections Mycobacteria infection- Monocytopenia, Treated with gentle chemo, BRAF inhibitors Peripheral T-cell/NK cell Neoplasm 5-10% of NHLs bt more common in the far east Peripheral T cells Lymphoma, Unspecific Not easily categorized/diagnosed– waste basket Efface lymph nodes diffusely/pleomorphic mixture of variably sized malignant Tcell Reactive cells – eosinophil, Mϴ, angiogenesis Clinical –Lymphadenopathy, esinophilia, fever, pruiritis, wt loss-- Poor prog Anaplastic Large cell Lymphoma (ALK positive) Rearrangements in the ALK gene on chrom 2p23 Large anaplastic cells –horseshoe nuclei/voluminous cyto, cluster around venules ALK not expressed in normal lymph Children/young adults, good prognosis (cure in 75-80%) Adult T cell leukemia/Lymphoma CD4+ Tcells neoplasm– Human Tcell leukemia retrovirus type1 (HTLV-1) Common findings skins lesions, Generalised lymphadenopathy, Hepato-splenomegaly, Peripheral blood lymphocytosis, Hypercalcemia Tumor cells vary in morphology but cells with multilobed nuclei – Cloverleaf or flower (frequent) Encodes pr Tax – activates NF-kB --- Lymphocyte growth & Survival Most pts it’s a rapidly progressive disease – months to 1 yr (even-- aggressive chemo) HTLV-1 can give rise to demyelinating dz of CVS/Spinal cord. Mycosis Fungoides/ Sezary Syndrome Tumor of CD4+ cell that colonise the skin Mycosis fungoides Skin lesion progress in three stages Premycotic phase A plague phase A tumor phase Hx- T cells infiltrate the epidermis/upper dermis– Cerbriform appearance (infolding of the nuclear membrane) Late stages may spread to lymph nodes/BM Sezary Syndrome Skin – Generalised exfoliative erythroederma, Associated with leukemia of Sezary Sx Hodgkins Lymphoma(HL) Neoplastic giant cells– Reed Averg age of diagns– 32 yrs, common young adults/adolescents, Sternberg cells From Germinal centre/Postgerminal centre Bcell Curable (radiation/chemo) Lymphoid neoplasm differ from Classification Classical forms– Similar immunophenotype NHL. Lymphocyte predominance Localised (cervical, mediasternum, Para aortic) Orderly spread Pathogenesis Rarely involve waldeyer ring/mesen Majority of RS cells –Ig genes have undergone VDJ recombination/Somatic hypermutation Extranodal involvmt rare Fail express to Bcell specific genes Assoc with reactive lymph, Mϴ, granulo--- Activate NF-kB in classical HL (90% tumor cellularity) EBV infection EBV+ tumor cell LMP-1 Morphology RS/Variants– required for diagnosis Reed sturnberg cell Large cells (45um), Multiple nuclei, or single nucleus with multiple nuclear lobes Large nucleus abt the size of a small lymp Variants– mononuclear, Lacunar cells Lymphohistiocytic variant – Polypiod nuclei, inconspicuous nucleoli, Moderately abundant cytoplasm Diagn – RS/nonNeoplastic inflammatory cells Nodular sclerosis Most common (65-70%), Lacunar variant RS/collagen band divide lymph node into nodules Fibrosis scant/absent, Background – Eosino, Tcells, Plasma, Macro Immuno– PAX5, CD15, CD30, -ve Bcell/Tcell/CD45 Can involve- liver, spleen, BM with irregular nodules Uncommonly assoc with EBV, M=F, Involv.. Lower cervical, Supraclavicular, Mediasternal lymph nodes. Good prognosis Mixed cellularity 20-25% cases Lymph node – Tcell, eosin, plasma, Macro, RS RS/Mononuclear variants are plentiful EBV+ 70% cases Immuno– Similar NS type Male predominance, older age, night sweats/wt loss Prognosis very good Hodgkins Lymphoma Lymphocyte rich Uncommon, reactive lympho predominate Different from lymphocyte predominance EBV+ 40% cases, Excellent prognosis Lymphocyte depletion Least common (5%), paucity of lymph, Abundant RS/variants Immuno – similar to classical HL (excld Large cell NHLs) EBV 90% cases, older adults, HIV+ , Advanced stage/Systemic Sx are frequent– less favourable outcome Lymphocyte predominance type Uncommon (nonclassical), 5%. Infiltrate of small lymph/variable # Macro RS very rare, but Lymphohistiocytic variant (popcorn cell) Eosino, Plasm maybe absent Immuno- L&H variants Bcell markers (germinal center) CD20,BCL6, -ve for CD15/CD30 Clinical features Painless lymphadenopathy NS/LP– stage I or II, No systemic manifestation Disseminated dz (MC/LD)– fever, wt loss, Night sweats Factor from RS suppress the T cell immunity Orderly spread Nodal first, then splenic, hepatic, & BM and other tissues Stage rather than Hx is the most important prognostic stages I/IIA is close to 90% (cure) Even Stages IVA/IVB), survival at 5 ys is 60% to 70% Radiotherapy complications-- lung cancer, melanoma, and breast cancer Alkylating agent –AML Anti-CD30 Abs--- excellent responses Myeloid Neoplasms originate from hematopoietic progenitor cells Primarily involve the BM but liver, spleen and lymph nodes Sx related to altered hematopoiesis Three broad categories Acute myeloid leukemias (BM blasts) Myelodysplastic Sx –defective maturation -- ineffective hemopoiesis Myeloproliferative disorders-- increased production of one or more blood cells Acute Myeloid Leukemia Tumor of hematopoietic progenitors, all ages.. Peak -60yrs Acquired oncogenic mutations that impede differentiation Immature myeloid blasts in BM BM failure--- anemia, thrombocytopenia, and neutropenia Classification AML with recurrent genetic aberrations AML with MDS like features AML, therapy related AML, Not otherwise specitfied Pathogenesis of AML Disruption of genes encoding TFs Morphology (normal myeloid differentiation) Diagnosis – 20% myeloblasts in Common chrom rearrangements, BM t(8;21) and inv(16) Disrupt the RUNX1 and CBFB genes Myeloblasts- Delicate nuclear chromatin, 2-4 nucleoli, abundant cyto, Interfere with the fxn RUNX1/ CBF1β and block the maturation of myeloid Peroxidase positive azurophilic cells granules, Auer rods esp t(15:17) Mutations in GF signaling with TFs APL aberrations – AML Monoblasts -- folded/lobulated Epigenetic alterations important in nuclei, lack Auer rods AML Blasts maybe absent in blood (aleukemic leukemia) -- Pancytopenia # of leukemic cells is variable M0 M3 M4 M5 M6 M7 Cytogenetic of AML Central role in classification Karyotypic aberrations are detected in 50% to 70% of cases 90% of cases using special high-resolution banding AMLs assoc MDS/DNA damaging factors (chemo/radia Deletions or monosomies chrom 5 &7, No translocation Except topoisomerase II inhibitors MLL gene (11q23) De novo AMLs (younger adults) –balanced translocations t(8;21), inv(16), and t(15;17)  Clinical features of AML Weeks/Months— Anemia, neutropenia, and thrombocytopenia fatigue, fever, and spontaneous mucosal and cutaneous bleeding. Thrombocytopenia -- bleeding diathesis Cutaneous petechiae and ecchymoses, serosal hemorrhages into the linings of the body cavities and viscera, and mucosal hemorrhages into the gingivae and urinary tract are common Procoagulants and fibrinolytic factors exacerbate bleeding tendancies, t(15;17) Infections-- oral cavity, skin, lungs, kidneys, urinary bladder, and colon Oportun -- fungi, Pseudomonas, and commensals Sx related to involvmt of other tissues are less dramatic than ALL Prognosis of AMLs Difficult to treat 60% remission, only 15-30% free of dz after 5yrs, depends on subtypes All-trans retinoic acid and arsenic salts t(15:17) best prognosis (80% cure) AMLs t(8;21) or inv(16) w/t KIT – Good prog AMLs that follow MDS or genotoxic therapy/Adults– Poor prognosis High risk/relapsed AMLs ---- stem cell transplantation Myelodysplastic Syndromes Clonal stem cell disd Cytogenetic analysis Maturation defects, ineffective Pathogenesis hematopoiesis high rist tranf to AML Poorly understood but deep Neoplastic multipotent stem cell sequencing has identified mutated with capacity to differentiate in an genes ineffective & disordered fashion Epigenetic factors within BM– Cytopenias RNA Splicing 1st (idiopathic) or 2nd Transcriptiona factors genotoxic/radiat therapy (t-MDS) Mutations in TSGs (TP53)-10% (2-8yr) Chromosomal abnormalities t-MDS rapid transf to AML Mono-5,7, del-5q, 7q,20q, tris- 8. Diagnosis – Morphology + Myelodysplastic Syndrome MORPHOLOGY BM usually hypercellular at diagnosis Disordered (dysplastic) diff– erythroid, granulocytic, monocytic, Magakaryo Erythroid – ring Sideroblasts, erythroblast with perinuclear granules, Megablastoid Maturation (like B12), Nuclear budding abnormalities Neut – decreased granules, toxic granulations & Dohle bodies, Pseudo Pelger Huet cells or lack of Segmentation Pawn Ball Megakryocytes Myeloblasts- Maybe increased bt 100 x 10^9/L Neutrophils, bands, metamyelocytes, Myelocytes, eosinophils, basophils 10% blasts, Markedly increased platelets Spleen –enlarged (extensive extramedullary hematopoiesis) Mild hepatomegaly/Lymphadenopathy Clinical features Usually affects adults, Peak (50- (anemia, thrombocytopenia, 60yrs) basophilia) Blast crisis (6-12m), 50% this occurs Onset is insidious, mild anemia/ w/t accelerated phase Hypermetabolism 70% crises are Myeloid, other are Lymphoid (Pluripotent origin) Dragging sensation & acute onset Additn chrom abno–-- tri-8, isochr- left upper quadrant pain 17q, dupli-(Ph), Diff for othe MPDs – BCR-ABL fusion Treatm gene BCR-ABL inhibitors (remission 90%) Slow progression, Median survival Mutatn in BCR-ABL (50)%-- Resistance (3 years) Accelerated/blast crisis –Poor gnosis After 3yers – accelerated phase Polycythemia Vera Point Mutations in tyrosine kinase viscosity/sludging JAK2 Hyperviscosity+thrombocytosis/abnor mal plt fxn -- Thrombosis/Bleeding Panmyelosis –RBC, granulo, Plts Morphology RBCs assoc clinical Sx Pathogenesis BM is hypercellular Rbc progenitor increase is subtle with JAK2 involved in JAK/STAT granulocytic/Megakaryocytic increase pathway Late stage – Extensive BM fibrosis Extramedullary hematopoiesis Trasnformed progenitors– require (spleen,Liver) less erythropoietin/GFs Transformation to AML(1%) High haematocrit – increase Clinical feature Uncommon, insidious (adults) Hemorrhages Plethoric/cyanotic Minor (Epistaxis, gum bleeding), Life threatening hemorrhages– 5-10% Headaches, dizziness, HT, GI Sx Iron deficiency- Intense Pruritis, Peptic ulcer Hb– 14-28 mmg/dL, HCT –60% Thrombotic episodes WBCs: 120-500, Plt: 5000 (giant) MI,DVT,stroke (25%) w/t treamt -bleeding/thrombosis Hepatic vein thrombo (Budd chiary Sx), Phlebotomy, Port/Mesenteric veins (bowel spent form (15-20%)- after 10Yr infarc) 2% transform to AML Essential Thrombocytosis Assoc activating point mutations in JAK2 (50%) or MPL(5-10%)/ calreticulin ET -- elevated platelet counts Absence of polycythemia & marrow fibrosis w/t TK mutations other causes – inflammatory disoders, iron def should be exld Constitutive JAK2 or MPL signalling–projenitor thrombopoietin independent BM moder increased – Megaka markedly increased/large forms/leucocytosis Extramedullary hemo– mild organomegaly(50%), Uncommon-spent phase/transf to AML Thrombosis/Hemorrhage Like PCV– DVT, Port/hepatic vein thrombosis, MI, Erythromalalgia Primary Myelofibrosis Obliterative marrow fibrosis (Hallmarck) Causing Cytopenias/Extensive extramedullary hemo (disordered RBCs) Extensive collagen depositions by non-neoplastic fibroblast- Marrow failure JAK2 mutations (50-60%), MPL mutations (1-5%), calreticulin Fibrogenic factors (PDGF & TGF-beta) -- Megakaryo Morphology Early– BM hyperce, megaka (large, dysplastic, abnor clusters) Intermed– hypocell, diffusely fibrotic Very late– fibrotic marrow converted to bone- Osteosclerosis Extensive extramedullary hematopoiesis –esp in spleen Premature nucleated erythroid/early granulo progenitors (blood)  Clinical Features Less comm thn-ET,PCV, 60yrs WBCs nomal, mild reduced/elevated Plts –Normal/elevated, sometimes Clini attn.-- Progressive low anemia/splenomegaly (sensation of BM Biopsy essential for diagnosis fullness) Nonspecific Sx --fatigue, weight loss, Treatmt & night sweats Difficult to treat, Survival 3-5yrs Threats to life - infections, thrombosis, Hyperuricemia and 2ndly gout bleeding and transf to AML (5-20%) Laboratory findings JAK2 inhibitors, HSCs transplant Moder to sev normochromic normocytic anemia with leukoerythroblastosis  Langerhans Cell Histiocytosis Proliferative disord- dendritic cells/macrophages Rare “histiocytic” lymphomas (malignant) Reactive proliferations of macrophages in lymph nodes (Benign) In btn -Langerhans cell histiocytoses (immature dentritic cells) Valine-glutamate sub-residue 600 in BRAF (Hair cell Leuk)-55-60% Others TP53, RAS, and the tyrosine kinase MET– Proves neoplastic origin Clinico-pathological correlations Multifocal multisystem Langerhans cell histiocytosis (Letterer-Siwe disease) Unifocal and multifocal unisystem Langerhans cell histiocytosis (eosinophilic granuloma) Pulmonary Langerhans cell histiocytosis SPLEEN SPLEEN Spleen Functions Phagocytosis of blood cells and particulate matter Antibody production Hematopoiesis Sequestration of formed blood elements. Splenomegaly Assoc Dragging sensation Left upper quadrant/pressure stomach, discomfort after eating Enlargement can cause– Hyperspleenism anemia, leukopenia, thrombocytopenia (alone or in combination) Increased sequestration/phagocytosis by the splenic macrophages Nonspecific Acute Splenitis Enlargement of the spleen can occur in any blood-borne infection Due to microbiologic agents themselves and by cytokines Enlarged (200 to 400 gm) and soft Micros--acute congestion (red pulp), Neuts, plasma cells, & occasi eosino Congestive Splenomegaly Chronic venous outflow obstruction Maybe due to intrahepatic disorder/extrahepatic disorders May result in port or splenic vein hypertension Systemic, or central, venous congestion RSHF, tricus or pulmonic valvular dz, chronic cor pulmonale, or LSHF Rarely exceed 500 gm in wt Cirrhosis of the liver (important cause) Fibrosis of schistosomiasis, Alcohol, pigment Obstruction (thrombosis) of portal vein or splenic vein Pylephlebitis infiltrating tumors--carcinomas of the stomach or pancreas