HLS Systemic Pathology Final Course PDF

0  HLS Lineage maturation of blood cells - Myeloblast  neutrophils, basophils, eosinophils,… - Megakaryocyte  platelets - Erythroblast  mature erythrocyte (RBC) Note: Prussian blue stain for iron content and abnormal sideroblas...

0  HLS Lineage maturation of blood cells - Myeloblast  neutrophils, basophils, eosinophils,… - Megakaryocyte  platelets - Erythroblast  mature erythrocyte (RBC) Note: Prussian blue stain for iron content and abnormal sideroblasts How do we diagnose anemia? - Clinical (headache, fatigue, shortness of breath) - Laboratory work-up: CBC (most important), Peripheral blood smear, Iron studies, Folate, vit.B12, bilirubin CBC A quantitative assessment of each of the blood`s cellular elements. Components: 1. Red Blood Cell Count (RBC): The number of red cells in a specified volume of blood [106/μL= M/μL] 2. Hemoglobin (HGB): The amount of hemoglobin in a specified volume of blood (g/dl) 3. Hematocrit HCT (aka Packed Cell Volume PCV): The ratio of the volume of red cells to the volume of whole blood (measured as a percentage %) 4. Mean corpuscular volume (MCV): The average volume per red cell o The most important RBC index o Directly measured using [fL] (femtoliter or 1015 liter) 5. Mean Corpuscular hemoglobin (MCH): Hemoglobin content per RBC o MCH correlates linearly with MCV 6. Mean Corpuscular Hemoglobin Concentration (MCHC): Concentration of Hb in a given volume of RBCs. Example of CBC test ‫االرقام ليست للحفظ‬ 7. Red cell Distribution Width (RDW): Measures the variation in size of RBCs o Normal range is 12-15% o Anisocytosis: abnormal variation in RBC size Difference in normal range Reticulocyte Count between males and females ‫االرقام‬ ‫ليست للحفظ‬  Reticulocyte is a newly released RBC (< 36 hours)  Normal reticulocyte count is less than 1.5%  High reticulocyte count: Hemolysis, Acute blood loss  Low reticulocyte count: Bone marrow disease, Temporary depression of bone marrow (by infection or cytotoxic drugs) Anemia  Definition: a reduction in the O2 carrying capacity of blood / Reduction in the volume of red blood cells hematocrit (packed cell volume) / reduction in hemoglobin concentration when compared to similar values from a reference population.  Bottom line: Hb < 13 g/dl (male), Hb < 12g/dl (female)  Anemia is not a diagnosis but a sign of disease 1 Classification of anemia: 1. Functional: Blood Loss, Hemolytic Anemia, Decrease Red cell production (Marrow aplasia, Defective DNA or Hemoglobin synthesis, Marrow Infiltration as seen in Myelophthisic anemia, Marrow replacement by primary neoplasm) 2. Morphologic: Microcytic (MCV < 80 fL), Normocytic (MCV 80-100 fL), Macrocytic (MCV >100 fL) Iron deficiency, Thalassemia, Acute blood loss, Hemolysis, Anemia of Megaloblastic Anemia: B12 and Anemia of Chronic Disease Chronic Disease (may be microcytic), folate deficiency , Drugs (usually normocytic) Hypersplenism, Bone Marrow Failure Non-Megaloblastic Anemias: Sideroblastic Anemias (Hereditary; Chemotherapy, Drugs/Toxins, Lead poisoning) Aplastic Anemia, Hypothyroidism, Sideroblastic Anemia (Acquired) Iron metabolism  The normal total body iron mass is about 2.5g for women and 3.5g for men.  Approximately 80% of functional body iron is present in hemoglobin, the remainder is found in myoglobin and iron-containing enzymes  The iron storage pool: hemosiderin and ferritin-bound iron (found in liver, spleen, bone marrow, and skeletal muscle) contains on average 15 % to 20 % of total body iron.  Serum ferritin level is a good measure of iron stores  Iron is transported in the plasma bound to the protein transferrin. o Transferrin is about 33% saturated with iron o The normal total iron binding capacity of serum is 300 to 350 μg/dL.  Iron studies: iron level, ferritin level, transferrin saturation, total iron binding capacity TIBC 1- Iron deficiency anemia Causes A. Poor nutritional intake (Most imp. cause in developing world) B. Blood loss (Most imp. cause in Western world): o Gastrointestinal (Peptic ulcer, colonic cancer, hemorrhoids) o Female genital tract (menorrhagia or cancer) o Urologic, pulmonary (hemoptysis) C. Increase demands (Pregnancy or infancy) D. Malabsorption (Celiac disease) Characteristics: Low serum Ferritin and Iron, Low Transferrin saturation, Increase in TIBC Peripheral blood findings: Hypochromic microcytic anemia, Anisocytosis and pokilocytosis, Low reticulocyte count 2- Megaloblastic anemia  Disorder related to reduction of DNA synthesis that impairs nuclear maturation.  Nuclear/cytoplasmic Asynchrony  Ineffective erythropoiesis: Megaloblasts undergo apoptosis in the bone marrow.  Granulocyte and platelet precursors are also affected  Hallmark: Cellular Gigantism. o RBCs: Egg-shape Macroovalocytes. o Neutrophils: Hypersegmented (Earliest change). o Platelets: Large platelets.  Bone marrow: Hypercellular, megaloblastic erythroid progenitor, Giant metamyelocytes, large megakaryocytes  Manifestations o GI: Atrophy of mucosal lining o CNS: Demyelination of posterior and lateral columns of the spinal cord (in vit.B12 deficiency only), severity not related to degree of anemia. 2 Causes of Vit.B12 deficiency  Pernicious anemia (Most Frequent cause): antiparietal cell/anti intrinsic factor antibody (Autoimmune)  Chronic Malabsorption: After gastrectomy, Crohn`s disease  Poor vitamin B12 intake Causes of Folate deficiency  Poor folic acid intake: Dietary lack  Malabsorption: Celiac disease, Tropical Sprue  Increased requirement: Hemolytic anemias, Pregnancy  Drugs: Phenytoin, Methotrexate 3- Anemia of Chronic disease  Most common form of anemia in hospitalized patients  Arises from the suppression of erythropoiesis by systemic inflammation o Pro inflammatory cytokines ( IL-6 ): increase liver hepcidin synthesis which lead to  Decrease in Iron Mobilization from stores  Increase iron stores o Chronic inflammation blunts erythropoietin synthesis by the kidney, lowering red cell production by the marrow Characteristics: low serum iron levels, elevated Serum ferritin, reduced TIBC, Increase storage of iron in the bone marrow 4- Aplastic Anemia  Bone marrow failure and Pancytopenia secondary to suppression of multipotent myeloid stem cells.  Acquired o Idiopathic o Exposure to myelotoxic agents: Drugs or chemicals (dose dependent or idiosyncratic) o After certain viral infections (hepatitis, Parvovirus B19, HIV)  Inherited: Defect in Telomerase, Inherited disorder of DNA repair (Fanconi Anemia)  Bone marrow: markedly hypocellular (Greater than 90% of the inter-trabecular space occupied by fat)  Clinical Course: o Slowly progressive anemia: weakness, pallor, and dyspnea. o Thrombocytopenia: petechiae and ecchymosis. o Leukocytopenia: frequent and persistent infections  No splenomegaly  Bone marrow transplantation often is curative 5- Myelophthisic Anemia Normal bone marrow Hypocellular Bone marrow (inter- trabecular space occupied by fat)  Extensive infiltration of the marrow by tumors or other lesions o Metastatic breast, lung, or prostate cancer o Advanced tuberculosis  Anemia and thrombocytopenia; usually white cell is less affected.  Peripheral blood: Immature granulocytic and erythrocytic precursors (leukoerythroblastosis) along with mild leukocytosis.  Management: Treatment of the underlying condition. Immature granulocytic and erythrocytic precursors + “tear drop” red cells (dacrocytes) 3  Mature lymphocyte neoplasm (Lymphoma) Introduction  Lymph Node Histology: Cortex (Follicle, Mantle Zone, Marginal Zone), Paracortex, Medulla o Cortex: B lymphocyte / Paracortex: T lymphocyte. o Lymphoid follicles in cortex: Primary follicle (inactive)  secondary Follicle has Germinal center (active follicle)  Lymph nodes distributed around body, and each group drain specific location of body. Lymphadenopathy: enlargement of LNs (localized vs generalized)  Lymphoma: Malignant tumors of lymphoid tissue (mature), characterized by abnormal proliferation of B or T cells in the lymphoid tissue. (B cell lymphoma is more common)  WHO Classification of Lymphoma into : Hodgkin & Non-Hodgkin o Non-Hodgkin (NHL) classified into: Low, intermediate (aggressive), high grade (very aggressive)  During maturation, Lymphocytes gain some Surface Antigen, and lose some of them (called Cluster Differentiation): o Helper T-cell: CD4, Cytotoxic T-cell: CD8 o Specific B-cell markers: CD19 (Pan B cell marker), CD20 (mature B lymphocyte marker; not found in blasts or plasma cells), CD5 (only in bone marrow then lost, but regained in some lymphoma) o Immature (primitive) markers: CD34  Lymphoma (malignant cell in lymphoid tissue), leukemia (malignant cells in bone marrow and peripheral blood) Non-Hodgkin Lymphoma NHL LOW GRADE NHL Small Lymphocytic Lymphoma (SLL)/ chronic lymphocytic leukemia (CLL)  Accounts for 5% of all NHL.  Diffuse growth pattern.  Cytologically: small cells (appear similar to normal lymphocytes)  Focal aggregates of prolymphocytes form so-called proliferation centers.  Rare Mitotic figures + minimal atypia  Neoplastic cells are monoclonal (either k or L light chains) B-cells that express: surface IgM, IgD, CD19, CD20, CD23, CD5.  Elderly patients with generalized lymphadenopathy  If involve lymph node  SLL , but if peripheral blood or BM is involved (40% cases) then called  CLL  Bone marrow invariably involved B-Cell Chronic Lymphocytic Leukemia (CLL)  Neoplasm of mature lymphocytes  Accumulation of mature B-lymphocytes in Bone marrow or Peripheral blood  Epidemiology: Most common leukemia in West, 30% of all leukemia, Older adults (median age 70 y)  Clinical features: Asymptomatic OR Anemia, Thrombocytopenia, Lymphadenopathy OR o Immunologic abnormalities: Autoimmune hemolytic anemia (positive Coomb’s test), Hypogammaglobinemia, Paraprotein (IgM) 4  Pathology o ‫ شرط التشخيص‬Peripheral blood: Lymphocytosis > 5,000 Or >30% bone marrow involvement o CD10-, CD19+, CD20+, CD23+, CD5+ o Bone marrow: Small lymphocytic infiltrate – nodular, diffuse, or interstitial o Spleen: Prominent white pulp o Lymph nodes: Diffuse effacement of architecture by small round lymphocytes  Course & Prognosis: Mean survival 6 y (range 2-30 y) o Prolymphocytoid transformation (10%) : when >10% prolymphocytes, increased splenomegaly o Richter transformation (5%): transform into Large cell lymphoma/Hodgkin Lymphoma, Mean survival 2 m Follicular lymphoma  Accounts for 45% of adult NHL.  Nodular growth pattern.  Two types of cells are seen: o Centrocytes: Majority are small with irregular nuclear contours and indentations and scant cytoplasm and low mitotic activity o Centroblasts: the second population is composed of large cells with open chromatin, multiple nucleoli and moderate cytoplasm  Immunologically, the cells are monoclonal B-cells that display restricted surface Ig, CD19, CD20, Bcl2 and often CD10.  Bone marrow is involved in 70% of the cases (paratrabecular).  85% of the cases have t(14;18) and positive for bcl-2 oncogene  Presentation o Elderly with generalized lymphadenopathy. o Extranodal sites are rare. o Slight female predominance. o The disease is incurable but follows indolent course (median survival 7-9 years). o Transformation (from low grade into high grade) occurs in 30%-50% of cases  Grading (more centroblasts  worse) o Grade 1 (follicular small cleaved): 0-5 centroblasts/HPF. o Grade 2 (follicular mixed): 6-15 centroblasts/HPF. o Grade 3 (follicular large cell): >15 centroblasts/HPF. Marginal Zone Lymphoma MZL  Types: Nodal marginal zone lymphoma, splenic marginal zone lymphoma, MALT-type lymphoma  MALT-type Lymphoma (Extranodal) o Lymphoma is preceded by and may be associated with chronic inflammation (H.pylori gastritis) or autoimmune disorder (Sjogren`s syndrome, Hashimoto thyroiditis) o Tendency to remain localized at the site of origin for prolonged time. o Cells are small and resemble marginal cells INTERMEDIATE GRADE B-CELL NHL Mantle cell lymphoma  5% of all NHL, Age: 40-50  Male predominance.  Neoplastic cells (monotonous small lymphocyte with round-cleft nuclei *centrocytes*) resemble normal mantle cells.  Nodular (cells surround atrophic B-cell follicles) or diffuse growth pattern.  Involvement: Majority have BM involvement / Intestinal involvement may produce lymphomatoid polyposis / 20-40% have peripheral blood involvement. 5   Neoplastic cells are monoclonal B-cells that express either k or L light chains, surface IgM, IgD, CD19, CD20, and CD5; but lack CD23.  More than 70% have t(11;14)  bcl-1  cyclin D1 G1 to S phase of the cell cycle.  Prognosis: o The disease is widely disseminated at presentation (similar to follicular lymphoma and SLL). o Not curable by conventional therapy (Median survival is 3-4 years). HIGH GRADE NHL Diffuse Large B Cell Lymphoma DLBCL (20% of all NHL) Burkitt Lymphoma Aggressive with Diffuse growth pattern. Tumor cells are monotonous with round nuclei and Large cell + High mitotic activity + significant atypia. multiple prominent nucleoli. Could rise: 1- de novo , 2- transformation of SLL or FL High proliferative rate: Bcl6 mutation (30%)  High: Mitotic activity + S-phase fraction BCL2 30% (FL transformation)  Ki-67 fraction (100%). Median age is 60 years; however, the age range is very wide, it Prominent cell death  macrophages engulfing debris  accounts for 25% of childhood lymphomas. starry sky appearance. Very responsive to chemotherapy. However, relapses are Usually, it involves one site. Extranodal origin is common. common. Bone marrow, liver and spleen involvement is rare early in the Three types: disease. 1- African (endemic): often involves the maxilla and Rapidly fatal if not treated. However, complete remission can be mandible. (EBV) achieved in 60-80% of the patients, and 50% are cured. 2- Western (non-endemic): mostly intra-abdominal/ovaries. Bad prognostic indicators: 3- Immunodeficiency associated. (EBV and HIV)  Presence of systemic symptoms. (Fever, weight loss,..) Neoplastic cells are peripheral B-lymphocytes that express  Bulky tumors. surface IgM, and CD10.  Advanced stages. t(8;14)  c-myc activation (all the cases)  Marked elevation of the serum lactic dehydrogenase. To sum up: Clinical Features  CLL/SLL, FL: indolent and incurable, observed until symptomatic  MALT: indolent, may be cured by localized radiotherapy and antibiotics (treat H.pylori  MALT regress)  MCL: aggressive , incurable, median survival of 3 years  DLBCL: aggressive lymphoma that could be cured by aggressive chemotherapy  Burkitt: very aggressive and needs aggressive chemotherapy Epidemiology:  Median age is 6th-7th decades except for mediastinal B-cell lymphoma (37 years)  Burkitt and large cell lymphoma occur in children  Most types have slight male predominance.  Mantle cell lymphoma has striking male predominance (74%)  Female predominance in follicular and mediastinal B-cell lymphomas (74% & 66%) Etiology  Viral agents o EBV (Burkitt) o Herpesvirus-8 (Primary effusion Lymphoma & Multicentric Castelman) o Hepatitis C (Lymphoplasmacytic Lymphoma with type II cryoglobulinemia)  Bacteria: H.pylori ( Gastric MALT lymphoma), B.Burgdoferi ( Cutaneous MALT) 6  Hodgkin lymphoma 30% of all lymphomas  Classified according to: Clinical features, Morphological and immunophenotypic findings (Differences of Reed Sternberg cells and Composition of cellular response)  WHO Classification: o Classical Hodgkin lymphoma (CHL): Nodular sclerosis (65-70%), Mixed cellularity (20-25%), Lymphocyte-rich ( 50 years of age o Early childhood peak in developing countries o Case clustering  High economic standards association with the young adult peak  Etiology: o Viral theory supported by: Case clustering, Occurrence of multiple cases in a single household, EBV has been found by serologic and epidemiologic studies, 20-80% of the cases have the EBV genome. o Genetic  Histopathology: The quality and the quantity of following component determines the subtype of Hodgkin disease. o Neoplastic cells: Reed-Sternberg cells  Morphologic Features: Large in size, Polylobated nucleus, Huge round inclusion like nucleoli o Immunologic reaction to tumor  Non-neoplastic reactive cells: Lymphocytes (CD4), Histiocytes, Eosinophils, Plasma cells, Neutrophils, Fibroblasts and fibrous tissue.  Variants of Reed Sternberg cells 1. Hodgkin cells (Mononuclear variant): Insufficient for diagnosis but can be used for diagnosing extra nodal sites in known cases. 2. Mummified cells: dark smudge degenerating cells with pyknotic nuclei and eosinophilic cytoplasm. 3. Lacunar cells: Large Polylobated nuclei surrounded by pale cytoplasm and contain inconspicuous nucleoli. 4. (LP) L&H cells: cells with hyperlobated nuclei, finely granular chromatin and inconspicuous small nucleoli  Immunophenotype o Classical HL (RS cells)  Positive for: CD 15, CD30, CD25 (IL-2 receptor) PAX 5 (weak), MUM1, CD71 (transferrin receptor), HLA-DR  Negative for: CD 45 (LCA), CD 20, CD 3 o NLPHL (L&H cells: CD 45+, CD 20+, CD 30-, CD 15-) 7  Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)  5% of all cases of HL and affect young males ( females eosinophils - HIV infection - B-symptoms are common. - Peripheral LN are typically - Granuloma-like clusters of Histiocytes or granulomas - Usually involves intra-abdominal involved may be seen. (immune-compromised patients) sites/retroperitoneal nodes. - Stage I or II disease - Abdominal involvement is seen in half of the patients. - Stages III&IV are usual. - HIV uncommon - Numerous easily identified Reed-Sternberg cells in the - Pancytopenia. - Bulky disease uncommon appropriate setting. - Prognosis is unfavorable. - Background cells: lymphocytes, eosinophils, macrophages, plasma cells, neutrophils. 4- Nodular Sclerosis - 70% of cases of HD - High incidence in females. - Patients present at an early stage (I&II). - Mediastinum is the most commonly involved site. - Excellent prognosis. - Histopathology Triad of:  Sclerosis: interconnecting collagenous tissue that circumscribe nodules of abnormal lymphoid tissue.  Lacunar cells.  Reed-Sternberg cells (rare).  Poor Prognostic Factors o B symptoms, Age> 45yr, Male gender o Stage IV, Histology (particularly the lymphocyte-depleted) o ESR (>50), Albumin level (