Leucocyte Disorders PDF

Leukocytic disorders DR ZZT (2025) C Disorders of White Cells 5 types Dr Zin Zin Thu UNIT OF PATHOLOGY FACULTY OF MEDICINE...

Leukocytic disorders DR ZZT (2025) C Disorders of White Cells 5 types Dr Zin Zin Thu UNIT OF PATHOLOGY FACULTY OF MEDICINE 1  Objectives To discuss leukocytosis, agranulocytosis, leucopenia, leukemoid reactions, lymphadenitis and aetiology and the classification of lymphoid neoplasms. Topic outcomes DR ZZT (2025) At the end of the lecture, students should be able to 1. Identify the causes of Leukocytosis, Leucopenia, and Agranulocytosis. 2. Interpret Leukemoid reaction and relate it to the underlying causes. 3. Diagnose Acute and Chronic nonspecific lymphadenitis by relating it to the clinical presentation, common causes and morphology. 4. Explain the etiologic and pathogenetic factors in White cell neoplasia. 5. Differentiate the types of Lymphoid neoplasms based on the world health organisation classification (WHO) of lymphoid neoplasms. 2  Hematopoiesis Haematopoiesis from Ancient Greek (haîma) 'blood' (poieîn) 'to make' The components of the hematopoietic system divided into 1. Myeloid Tissues Bone Marrow DR ZZT (2025) cells derived from it (Red Cells, Platelets, Granulocytes, Monocytes) Bone Marrow → source of all lymphoid progenitors 2. Lymphoid Tissues consisting of Thymus, Lymph Nodes, Spleen. The Component of blood Red Cells Granulocytes c Neutrophil (no colour) , Basophil (granule blue) , Eosinophil (granulea Monocytes 3 Platelets Lymphocytes  Hematopoiesis Stem Cells Committed precursors DR ZZT (2025) Late precursors And Mature form 4 Lymphocytes RBC CFU, Colony forming unit; LIN−, negative for lineage-specific markers; NK, natural killer.  Hematopoiesis Hematopoietic Stem Cells HSCs two essential properties → required for the maintenance of hematopoiesis: 1. Pluripotency 2. Capacity for self-renewal Pluripotency Single HSC → Ability to generate All mature blood DR ZZT (2025) cells. Capacity for self-renewal HSC divides → one daughter cell → self renew to avoid stem cell depletion Pluripotent stem cell → form any cell type in the body Multipotent stem cell and Unipotent stem cell → form a limited selection of cell types 5 Self renewal → automatic refill. proliferation.  Hematopoiesis Many diseases → alter the production of blood cells. The Marrow source of → most cells of the innate and adaptive immune system responds to → infectious or inflammatory challenges by increasing its output of granulocytes under the direction of specific growth factors and cytokines DR ZZT (2025) Many disorders → are associated with defects in hematopoiesis lead to deficiencies of one or more types of blood cells. Primary tumors of hematopoietic cells Genetic Diseases Infections Toxins interfere with marrow function Nutritional Deficiencies Chronic Inflammation from any cause 6 decrease the production of blood cells by marrow  Disorders of White Cells Disorders of white blood cells can be classified into (2) categories: 1. Proliferative disorders Expansion of leukocytes (increase) 2. Leukopenias Deficiency of leukocytes (decrease) DR ZZT (2025) Proliferations of White Cells I. Reactive II. Neoplastic. Type of Leukemia Acute myeloid Reactive proliferations Leukemia common lymphoid chronic leukemia Infections or Inflammatory processes large numbers of Leukocytes → needed for an Effective Host Response Neoplastic disorders 7 less frequent more important clinically  LEUKOPENIA The number of circulating white cells → decreased In a variety of disorders. D An abnormally low white cell count (leukopenia) results from 1. reduced numbers of Neutrophils Neutropenia Granulocytopenia DR ZZT (2025) 2. reduced numbers of Lymphocyte Lymphopenia 8  LEUKOPENIA Causes of Lymphopenia - 1. Congenital Immunodeficiency Diseases - 2. Advanced Human Immunodeficiency Virus (HIV) Infection - 3. Therapy with - Glucocorticoids Or Cytotoxic Drugs 4. Autoimmune Disorders DR ZZT (2025) 5. Malnutrition 6. Certain Acute Viral Infections Reason & Virus → cell death → lymphopenia Virus → lymphoid organ damage → lymphopenia 9 Cytokine lymphopoiesis suppression → lymphopenia malnutrition during childhood affects thymic development  LEUKOPENIA Neutropenia reduction in the number of neutrophils in the blood Agranulocytosis DR ZZT (2025) marked reduction in neutrophils C severe neutropenia 10  LEUKOPENIA BM > Neutrophil Causes of Neutropenia Problem in Bm & Neutrophil (1) Inadequate or ineffective Granulopoiesis : i. Suppression of HSCs a. Aplastic anemia (deficiency of all blood cell types due to infection, drugs, etc b. Infiltrative marrow disorders (e.g., tumors, granulomatous disease) ii. Suppression of committed granulocytic precursors (by certain drugs) iii. Disease states associated with ineffective hematopoiesis a) Megaloblastic Anemia DR ZZT (2025) b) Myelodysplastic syndrome (defective precursors die in the marrow.) iv. Rare congenital conditions (e.g., Kostmann syndrome), inherited defects ( specific genes impair granulocytic differentiation) (2) Accelerated destruction or sequestration of neutrophils occurs with: i. Immunologically mediated injury to neutrophils idiopathic immunologic disorder (e.g., systemic lupus erythematosus) exposure to drugs ii. Splenomegaly (splenic enlargement ) 11 destruction of neutrophils in the spleen iii. Increased peripheral utilization Bacterial, Fungal infections  LEUKOPENIA Causes of Agranulocytosis I. Drug toxicity. 1. Alkylating agents and antimetabolites used in cancer treatment cause a generalized suppression of hematopoiesis 2. Antibiotic 3. Anticonvulsants 4. Anti inflammatory drugs 5. Antipsychotic agents  toxic effect on granulocytic precursors in bone DR ZZT (2025) 6. Diuretics marrow 7. Sulfonamides  antibody-mediated destruction of neutrophils II. Acquired idiopathic neutropenia (attack Autoantibodies directed against neutrophil-specific antigens (+) III. Large Granular Lymphocytes ( LGL) Leukemia Suppression of granulocytic progenitors by neoplastic cell 12 IV. Serious Bacterial and Fungal Infections  Leukocytosis Increase in the number of White Cells in the blood. common reaction to a variety of Inflammatory States. D The peripheral blood leukocyte count is influenced by several factors, 1. The size of the myeloid and lymphoid precursor storage cell pools in the bone marrow, thymus, circulation, peripheral tissues. (Increased Marrow Production) 2. The rate of release of cells from the storage pools into the circulation. (Increased DR ZZT (2025) Release From Marrow Stores) 3. The proportion of cells that are adherent to blood vessel walls (Decreased Margination) 4. The↓rate of extravasation of cells from the blood into tissues. 13 Ref,https://www.ncbi.nlm.nih.gov/books/ NBK66050.1/figure  Leukocytosis Leukocyte Homeostasis maintained by 1. cytokines effects on 2. growth factors the proliferation, differentiation, and extravasation 3. adhesion molecules of leukocytes and their progenitors In acute infection rapid increase of mature granulocytes from the bone marrow pool DR ZZT (2025) mediated by effects of tumor necrosis factor (TNF) and interleukin-1 (IL-1). Infection or an inflammatory process IL-1, TNF, and inflammatory mediators stimulate macrophages, bone marrow stromal cells, and T cells to produce increased amounts of hematopoietic growth factors. increase the proliferation and differentiation of granulocytic progenitors 14 increase in neutrophil production.  & Causes of Leukocytosis > - Trauma also can Increased Marrow Production 1. Chronic infection or inflammation (growth factor–dependent) 2. Paraneoplastic (e.g., Hodgkin lymphoma; growth factor–dependent) 3. Myeloproliferative neoplasms (e.g., chronic myeloid leukemia; growth factor–independent) immature neutrophil appear in PBS ↓ & Increased Release From Marrow Stores left shift 1. Acute inflammation 2. Chronic inflammation DR ZZT (2025) Decreased Margination 1. Exercise 2. Catecholamines (Adrenaline , Noradrenaline, Dopamine) Decreased Extravasation Into Tissues 1. Glucocorticoids (steroid hormones) 15  Causes of Leukocytosis (bacterial Neutrophilic Leukocytosis 1. Acute bacterial infections (Pyogenic organisms) 2. Sterile inflammation caused by tissue necrosis myocardial infarction burns < parasitic ( Eosinophilic Leukocytosis (Eosinophilia) DR ZZT (2025) D1. Allergic disorders such as asthma, hay fever, parasitic infestations 2. Drug reactions 3. Malignancies Hodgkin and some non-Hodgkin lymphomas 4. Autoimmune disorders pemphigus, dermatitis herpetiformis 5. Atheroembolic disease (viral 16 Basophilic Leukocytosis (Basophilia) Myeloproliferative Neoplasm (Chronic Myeloid Leukemia)  Causes of Leukocytosis Monocytosis 1. Chronic infections Tuberculosis Bacterial Endocarditis Rickettsiosis Malaria 2. Autoimmune disorders Systemic Lupus Erythematosus DR ZZT (2025) 3. Inflammatory bowel diseases Ulcerative Colitis Lymphocytosis 1. Chronic Immunologic stimulation Tuberculosis Brucellosis 2. Viral infections 17 Hepatitis A Cytomegalovirus Epstein-barr virus Leukemoid reaction and underlying causes. DR ZZT (2025) 18  7 Leukocytosis increase in the number of white cells in the blood. Leukocyte Count → 15 or 20 (×103/μL) severe condition ofLeukocytosis ~ severely ↑ amount of WB Leukemoid reactions < I Leukocyte Count → 40 to 100 (×103/μL) by infection Extreme Elevations → Leukemoid Reactions similar white cell counts observed in leukemia Leukocytosis accelerated release of granulocytes from the bone marrow ( by cytokines, TNF IL-1) DR ZZT (2025) rise in both mature and immature neutrophils in blood → shift to the left. PBS of Chronic myeloid leukemia = Leukemoid reaction Prolonged infection → induces proliferation of precursors in the bone marrow caused by → increased production of colony-stimulating factors (CSFs) mainly from → activated macrophages and marrow stromal cells. 19 increase in the bone marrow output of leukocytes → compensates for the loss of cells in the inflammatory reaction.  Causes Of Leukemoid Reactions 1. Severe hemorrhage (retroperitoneal hemorrhage) 2. Drugs i. Sulfa drugs ii. Dapsone iii. Glucocorticoids iv. G-CSF or related growth factors v. All-trans retinoic acid (ATRA) 3. Infections i. Clostridium difficile DR ZZT (2025) ii. Tuberculosis iii. Pertussis iv. Infectious mononucleosis (lymphocyte predominant) v. Visceral larva migrans (eosinophil predominant) 4. Asplenia (absence of spleen) 5. Diabetic ketoacidosis 6. Organ necrosis i. Hepatic necrosis ii. Ischemic colitis 7. As a feature of trisomy 21 in infancy (incidence of ~10%) 20 DKA → lack of insulin, inflammatory processes activity, secretion of adrenaline Acute and Chronic nonspecific Lymphadenitis DR ZZT (2025) 21  Lymphadenitis (inflammation of lymph node) Infection/Inflammation in Lymph Nodes Primary Lymphoid Organs (Central ) 1. Bone marrow for B cells (lymphocytes) 2. Thymus for T cells (lymphocytes) Secondary Lymphoid Tissues (Peripheral) 1. Lymph nodes 2. Spleen DR ZZT (2025) 3. Tonsils 4. Adenoids (lymph nodes located in back of the throat behind the nose.) 5. Peyer patches (lymphoid follicles found in the intestine, Ileum) Lymph nodes Examined For Diagnostic Purposes most widely distributed ,easily accessible discrete encapsulated structures contain separate B-cell and T-cell zones phagocytes and antigen-presenting cells 22  Lymphocytes circulate through the blood  under the influence of specific cytokines and chemokines  LYMPH NODE - NORMAL HISTOLOGY v B(ei) rTall DR ZZT (2025) Cortex –Lymphoid follicle B cells Paracortex - T cells Medulla – macrophages and plasma cells 23 https://medicine.nus.edu.sg/pathweb/normal-histology/lymph-node/  Lymphadenitis Infections and inflammatory → stimulate Immune Reactions within Lymph Nodes. Activation of resident Immune Cells → morphologic changes in Lymph Nodes. Within several days of Antigenic stimulation Primary Follicles (B cells ) → enlarge and develop pale-staining germinal centers DR ZZT (2025) B cells → to make high-affinity antibodies against specific antigens. Paracortical (T-cell) zones → Hyperplasia Patterns of Lymph Node Reaction 1. Acute Nonspecific Lymphadenitis 2. Chronic Nonspecific Lymphadenitis 24  Acute Nonspecific Lymphadenitis CAUSES 1. Acute lymphadenitis in the cervical region microbes or microbial products from infections of the Teeth Or Tonsils 2. Axillary or inguinal regions infections in the Extremities. 3. Mesenteric lymph nodes Acute Appendicitis DR ZZT (2025) other inflammatory conditions involving the Gut 4. Acute Generalized Lymphadenopathy Systemic Viral Infections (particularly in children) Bacteremia 25  Acute Nonspecific Lymphadenitis MORPHOLOGY (GROSS) Lymph nodes → Swollen, Gray-red, Enlarged (Microscopically) Germinal centers → Large Reactive containing numerous mitotic figures. Macrophages → contain particulate debris ; from dead bacteria or necrotic cells. pyogenic organisms are the cause neutrophils → prominent DR ZZT (2025) centers of the follicles → necrosis entire node → converted to pus 26  Acute Nonspecific Lymphadenitis Clinical Presentation 1. Lymph Nodes - swollen and painful. 2. Abscess formation 3. overlying skin → red. 4. Suppurative Infections penetrate through the capsule of the node DR ZZT (2025) track to the skin → draining sinuses 5. Healing of lesions → associated with scarring. 27  Chronic Nonspecific Lymphadenitis Chronic immunologic stimuli may produce nonspecific lymphadenitis. Several different patterns of morphologic change are seen, often within the same lymph node. 1. Follicular hyperplasia 2. Paracortical hyperplasia 3. Sinus histiocytosis DR ZZT (2025) 28  Chronic Nonspecific Lymphadenitis Follicular hyperplasia CAUSES is caused by Activate Humoral Immune Responses. 1. Rheumatoid Arthritis 2. Toxoplasmosis DR ZZT (2025) 3. early HIV infection 29  Chronic Nonspecific Lymphadenitis Follicular hyperplasia MORPHOLOGY Features of reactive (nonneoplastic) hyperplasia include (1) preservation of the lymph node architecture (2) marked variation in the shape and size of the follicles (3) presence of frequent mitotic figures phagocytic macrophages recognizable light and dark zones. DR ZZT (2025) absent from neoplastic follicles Follicles presence of large germinal centers surrounded by a collar of small resting naive B cells (the mantle zone) Germinal centers consisting of two distinct regions: (1) dark zone - proliferating blast-like B cells (centroblasts) (2) light zone - B cells with irregular or cleaved nuclear contours (centrocytes) 30 follicular dendritic cells and macrophages (tingible-body macrophages) → contain nuclear debris of B cells  Chronic Nonspecific Lymphadenitis DR ZZT (2025) Follicular hyperplasia. (A) Low-power view reactive follicle and surrounding mantle zone. (B) High-power view dark zone shows several mitotic figures and numerous macrophages containing phagocytosed apoptotic cells (tingible bodies). Centroblasts – 3 - 4 times larger than lymphocytes and show narrow rim of basophilic cytoplasm and large, round to oval vesicular nuclei with 1 - 3 prominent peripheral nucleoli Centrocytes – 31 smaller lymphocytes with scant cytoplasm, cleaved nuclei, clumped chromatin and small or absent nucleoli  Chronic Nonspecific Lymphadenitis Paracortical hyperplasia CAUSES T-cell–mediated immune responses, such as acute viral infections (e.g., infectious mononucleosis). MORPHOLOGY T-cell regions typically contain The expanded T-cell zones DR ZZT (2025) efface the B-cell follicles Immunoblasts → numerous Immunoblasts Activated T cells three to four times the size of resting lymphocytes round nuclei, open chromatin, several prominent nucleoli, moderate amounts of pale cytoplasm. 32 sinusoidal and vascular endothelial cells → Hypertrophy Macrophages And Eosinophils → infiltrating  Chronic Nonspecific Lymphadenitis Sinus Histiocytosis (also called reticular hyperplasia) CAUSES prominent in lymph nodes draining cancers such as carcinoma of the breast. DR ZZT (2025) MORPHOLOGY Endothelial cells (line lymphatic sinusoids) → increase in number and size Intra sinusoidal Macrophages → increased numbers Sinusoids → expand and distort medullary sinuses (or sinusoids) are vessel-like spaces 33  Chronic Nonspecific Lymphadenitis Clinical Presentation 1. Lymph nodes Non tender; enlargement (occurs slowly) acute inflammation with associated tissue damage → absent 2. Chronic lymphadenitis common in inguinal and axillary nodes, stimulated by Immune reactions to Minor Injuries DR ZZT (2025) Infections of the Extremities 3. Collections of immune cells in non- lymphoid tissues by Chronic immune reactions → called tertiary lymphoid organs. (E.g ) Rheumatoid arthritis B-cell follicles → appear in the inflamed synovium. 34 Etiologic and Pathogenetic factors in White cell neoplasia Leukemia, Lymphoma DR ZZT (2025) 35  NEOPLASTIC PROLIFERATIONS OF WHITE CELLS Malignancies of white cells fall into (3) broad categories: D (1) Lymphoid neoplasms I. Tumors of B-cell II. Tumors of T-cell III. Tumors of NK-cell & (2) Myeloid neoplasms (3) categories of myeloid neoplasia are recognized: I. Acute myeloid leukemias (AMLs) DR ZZT (2025) immature progenitor cells accumulate in the bone marrow II. Myelodysplastic syndromes (MDSs) associated with → ineffective hematopoiesis peripheral blood cytopenias III. Myeloproliferative neoplasms increased production of differentiated myeloid elements (granulocytes) - leads to elevated peripheral blood counts. (3) The Histiocytoses (macrophage, dendritic cell, monocyte-derived cells) 36 uncommon proliferative lesions → of macrophages and dendritic cells. Langerhans cell histiocytoses. Neoplastic Disorders → immature dendritic cell, Langerhans cell & Etiologic and Pathogenetic Factors in White Cell Neoplasia Development of white blood cell neoplasms involves mutation-> development of Lockemia 1. Chromosomal Translocations and Other Acquired Mutations. 2. Inherited Genetic Factors 3. Viruses. & RMB name of virus 4. Chronic Inflammation DR ZZT (2025) 5. Iatrogenic Factors 6. Smoking. 37  Etiologic and Pathogenetic Factors in White Cell Neoplasia (1) Chromosomal Translocations and Other Acquired Mutations Translocations → Most commonly present in majority of white cell neoplasms. Abnormal mutation Abnormal Protein (1.A) Recurrently affected genes are often those that play crucial roles (in the development, growth, or survival of the normal counterpart) of the malignant cell. Mutations in certain genes are so strongly associated with DR ZZT (2025) specific tumor types required for particular diagnoses. Mutations produce a 1. a loss of function (“dominant negative” protein → inhibits with a normal function 2. a gain of function increase in some normal activity 38  Etiologic and Pathogenetic Factors in White Cell Neoplasia (1) Chromosomal Translocations and Other Acquired Mutations (1.B) Oncoproteins created by genomic aberrations (variation) often block normal maturation, turn on pro-growth signaling pathways, (Or) protect cells from apoptotic cell death. 1. (Block normal maturation) Oncoproteins → cause an arrest in differentiation Undifferentiated cells → proliferating rapidly. DR ZZT (2025) E.g,. Acute leukemias oncogenic mutations → interfere with stages of myeloid cell differentiation. 2. (turn on pro-growth signaling pathways) Mutations in transcriptional regulators → increase self-renewal of tumors cells (giving them stem cell–like properties) → tumors cell growth 3. (protect cells from apoptotic cell death ) Mutations → inhibit apoptosis 39 Oncoproteins → proteins encoded by oncogenes, involved in the regulation or synthesis of proteins related to growth of cancer cells  Etiologic and Pathogenetic Factors in White Cell Neoplasia (1) Chromosomal Translocations and Other Acquired Mutations 1.C. Proto-oncogenes are often activated in lymphoid cells by errors that occur during attempted antigen receptor gene diversification proto-oncogene c-MYC regulating cellular functions, including DR ZZT (2025) proliferation, growth, apoptosis. Dysregulation of c-MYC → B-cell lymphomas Genetic diversity - number of genetic characteristics proto-oncogene - normal gene that could become an oncogene due to mutations 40 oncogene - gene that has the potential to cause cancer  Etiologic and Pathogenetic Factors in White Cell Neoplasia (2) Inherited Genetic Factors. individuals with genetic diseases → promote genomic instability → increased risk of acute leukemia such as i. Bloom syndrome ii. Fanconi anemia iii. Ataxia telangiectasia Down syndrome (trisomy 21) → increased incidence of childhood leukemia. DR ZZT (2025) (3) Viruses. Lymphotropic viruses → causative agents in Lymphomas & i. HTLV-1 → associated with adult T-cell leukemia/lymphoma. ii. EBV → subset of Burkitt lymphoma Hodgkin lymphoma (HL) B-cell lymphomas rare NK-cell lymphomas. 41 iii. Human herpesvirus-8 (HHV-8 ) → associated with B-cell lymphoma (Kaposi sarcoma )  Etiologic and Pathogenetic Factors in White Cell Neoplasia B (4) Chronic Inflammation predispose to lymphoid neoplasia arises within the inflamed tissue. Examples; 1. H. pylori infection → Gastric B-cell lymphomas 2. Gluten-sensitive enteropathy → Intestinal T-cell lymphomas 3. Breast implants → T-cell lymphoma. 4. HIV infection DR ZZT (2025) increased risk of B-cell lymphomas B cells -associated with germinal center B-cell lymphomas. 5. EBV and KSHV/ HHV-8. → risk for B-cell lymphomas (5) Iatrogenic Factors ( state of ill health or adverse effect caused by medical treatment) Ironically, Radiation Therapy ,Chemotherapy used to treat cancer increase the risk of myeloid and lymphoid neoplasms. (mutagenic effects on hematolymphoid progenitor cells ) 42 (6) Smoking incidence of AML is increased 1.3- to 2-fold in smokers exposure to carcinogens, (benzene, in tobacco smoke). Types of lymphoid neoplasms based on the world health organisation (WHO) classification of lymphoid neoplasms DR ZZT (2025) 43  LYMPHOID NEOPLASMS Definitions Leukemias Neoplasms that present with widespread involvement of the bone marrow and (usually, but not always) the peripheral blood. Lymphomas Proliferations of white cells, typically lymphocytes, that usually present as DR ZZT (2025) discrete tissue masses. LYMPHOMAS, 1. Hodgkin lymphoma 2. non- Hodgkin lymphomas (NHLs). 44  LYMPHOID NEOPLASMS The current World Health Organization (WHO) classification scheme uses Morphologic Immunophenotypic Genotypic Clinical features & Lymphoid neoplasms into (5) broad categories, separated according to the cell of origin: DR ZZT (2025) I. Precursor B-cell neoplasms (neoplasms of immature B cells) II.Peripheral B-cell neoplasms (neoplasms of mature B cells) III. Precursor T-cell neoplasms (neoplasms of immature T cells) IV.Peripheral T-cell and NK-cell neoplasms (neoplasms of mature T cells and NK cells) V. Hodgkin lymphomas (neoplasms of Reed-Sternberg cells and variants) 45  Table ; World Health Organization Classification of Lymphoid Neoplasms I. Precursor B-Cell Neoplasms IV. Peripheral T-Cell and NK-Cell B-cell acute lymphoblastic leukemia/lymphoma (B-ALL) Neoplasms T-cell prolymphocytic leukemia II. Peripheral B-Cell Neoplasms Large granular lymphocytic leukemia Chronic lymphocytic leukemia/small lymphocytic Mycosis fungoides/Sézary syndrome lymphoma Peripheral T-cell lymphoma, B-cell prolymphocytic leukemia unspecified Lymphoplasmacytic lymphoma Anaplastic large-cell lymphoma Splenic and nodal marginal zone lymphomas Angioimmunoblastic T-cell lymphoma Extranodal marginal zone lymphoma Enteropathy-associated T-cell Mantle cell lymphoma lymphoma DR ZZT (2025) Follicular lymphoma Panniculitis-like T-cell lymphoma Marginal zone lymphoma Hepatosplenic γδ T-cell lymphoma Hairy cell leukemia Adult T-cell leukemia/lymphoma Plasmacytoma/plasma cell myeloma Extranodal NK/T-cell lymphoma Diffuse large B-cell lymphoma NK-cell leukemia Burkitt lymphoma V. Hodgkin Lymphoma Classic subtypes III. Precursor T-Cell Neoplasms Nodular sclerosis T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) Mixed cellularity Lymphocyte-rich Lymphocyte depletion 46 Nodular lymphocyte predominant NK, Natural killer.  Robbins and Cotran References Pathologic basis of Disease (Tenth edition) DR ZZT (2025) 47 Any Question ? THANK YOU. DR ZZT (2025) 48