Lymphoreactive Diseases 1 Overview of the lymphoid immune

Lymphoreactive Diseases 1

Overview of the lymphoid immune system Lymphocytes evolve from pluripotent stem cells located in the bone marrow, and differentiate into two major functional cell types: 1. B lymphocytes, comprising the humoral immune system, whose ultimate function is the production of antibodies 2. T lymphocytes, comprising the cellular immune system, whose functions include a. Direct killing of foreign or intracellularly infected cells, cytotoxic T cells b. Fine control of the immune response through the secretion of cytokines, helper and suppressor T cells. n 2

The anatomical organization of the lymphoid immune system can also be divided into two major functional groups: 1. The primary immune organs, which are the sites of initial maturation from immature precursors into immune competent cells: n a. B cells- bone marrow n b. T cells- thymus 2. The secondary immune organs, which are the sites of antigen driven replication and differentiation into committed effector cells n a. Lymph nodes n b. Spleen n c. Mucosal Associated Lymphoid System (MALT)lymphoid cells lining the respiratory and gastrointestinal tracts n d. Everywhere else 3

The lymph nodes, in their totality, are the largest of the secondary immune organs, and the site of the majority of lymphoid pathology. 4

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Small lymphocytes a. Small round dark blue dots. Round nucleus, clumped chromatin, small or absent nucleolus. b. The monotonous looking cells hiding the greatest level of functional heterogeneity. Can be T or B cell, virgin (unexposed to antigen) or differentiated effector/memory cell. Most likely lineage guessed by location within the node, but lineage and state of differentiation must be confirmed by immunologic/molecular techniques c. Locations: (1) B cells- primary follicles, mantle zone of secondary follicles, medullary cords (2) T cells- paracortex, minor population within germinal center. d. Kinetically, clumped chromatin tells us that the cell is nonproliferating- not activated to enter the cell cycle and replicate 7

§ § The lymph node is thus a dynamic organ, composed of transient B and T lymphocytes, antigen processing and presenting cells, replicating B and T lymphocytes (in response to antigen), persistent and transient final effector cells. Some of these functional subgroups are cytologically unique, and others are cytologically indistinguishable. The ultimate microscopic impression, with practice, is one of cytologic heterogeneity, and histologic organization. 8

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Follicular (germinal) center cells (replicating and post-replicating B cells) 12

A. Infections Pathology of lymph nodes 1. Bacterial 2. Fungal, mycobacterial B. Reactive hyperplasias 1. Exaggerations of normal histology. Expansion of all regions or selective expansion of one. Some types characteristic of certain diseases, but most not 2. Follicular hyperplasia increase in number and size of germinal centers, spread into paracortex, medullary areas a. Collagen vascular diseases, b. Systemic toxoplasmosis, c. Syphillis 3. Interfollicular hyperplasia- paracortexa. Skin diseases b. Viral infections c. Drug reactions 4. Sinus histiocytosis- expansion of the medullary sinus histiocytesa. Adjacent cancer b. Infections C. Sarcoidosis D. Metastatic tumors E. Malignant lymphomas (Non-Hodgkins' lymphomas-NHLs) and Hodgkin's lymphoma 13

Reactive lymphoid hyperplasias 1. Exaggerations of normal histology. Expansion of all regions or selective expansion of one. Some types characteristic of certain diseases, but most not 2. Follicular hyperplasia increase in number and size of germinal centers, spread into paracortex, medullary areas a. Collagen vascular diseases, b. Systemic toxoplasmosis, c. Syphillis 3. Interfollicular hyperplasia- paracortexa. Skin diseases b. Viral infections c. Drug reactions 4. Sinus histiocytosis- expansion of the medullary sinus histiocytesa. Adjacent cancer b. Infections 14

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A: Follicular center B: Mantle zone C: Marginal zone 16

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Reactive Lymphadenitis Non-specific lymph node enlargement (Lymphadenopathy usually secondary to bacterial or viral infection) Acute non-specific lymphadenitis (Often due to local bacterial infection) Chronic non-specific lymphadenitis (viral, Romatoid arthritis, others. . . ) 18

Some Specific Definitions: • Acute lymphadenitis is the hyperplasia in a reactive node. • Acute lymphadenitis, since it comes up suddenly and stretches the capsule, is likely to make the node tender. • Localized lymphadenitis is most often due to a bacterial infection in the area drained by the lymph node. • Generalized lymphadenitis suggests a systemic viral infection. • "Mesenteric adenitis", often indistinguishable from acute appendicitis, is caused by Yersinia enterocolitica. 19

Patterns of Reactive Lymphadenitis (Response to Chronic Antigen Exposure) Reactive States with follicular hyperplasia B cell antigens Reactive states with interfollicular hyperplasia Reactive states causing diffuse effacement of the lymph node Paracortical hyperplasia T-cell antigens Interfollicular Sinus histiocytosis Histiocytic proliferation 20

Reactive states with follicular hyperplasia Romatoid Arthritis Toxoplasmosis Syphilis HIV infection Inflammatory pseudotumor Kimura’s disease Sjögren’s syndrome SLE Cat-Scratch disease Angiofollicular hyperplasia (Castleman’s disease) Dilantin reaction 21

n n n Reactive states with interfollicular hyperplasia Whipple’s disease Viral adenitis Virus associated hemophagocytic syndrome Dermatopathic lymphadenopathy Sinus histiocytosis with massive adenopathy Histiyocytosis-X 22

n n n Reactive States Causing Diffuse Architectural Effacement of Lymph Node Immunoblastic lymphadenopathy Angioimmunoblastic lymphadenopathy Drug reactions Sarcoidosis Infarction Vasoproliferative lesions 23

Follicular hyperplasia • Lots and lots of large follicles • Longstanding contact with organisms or "other causative agents" that stimulate the B-cells. Examples: Toxoplasmosis (mini-granulomas touching the germinal centers at their edges, this is supposedly pathognomonic; some of these are groups of macrophages; some are big "monocytoid B-cells" especially in the medulla) Rheumatoid arthritis (lots of plasma cells) Syphilis (plasma cells, mini-granulomas, spirochetes) AIDS-related complex / persistent generalized lymphadenopathy of HIV infection common variable immunodeficiency (ineffective B-cell activation) 24

Reactive Lymphadenitis (Follicular Hyperplasia) 25

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Paracortical lymphoid hyperplasia n n n Lots and lots of lymphocytes in the T-cell regions of the cortex longstanding contact with organisms or "other things" that stimulate the T-cells. Examples: n weird reactions to a vaccine n infectious mononucleosis family (those angry T-killers) 30

Sinus histiocytosis n Sinusoids with swollen endothelial cells and lots of histiocytes. Examples: n nodes draining a cancer n nodes injected with permanent radiology contrast medium ("lymphangiogram dye") n Castleman's giant angiofollicular lymphoid hyperplasia n hemolysis n Coombs-positive, n macrophages rendered hungry by infection "erythrophagocytic reticulosis" n Rosai-Dorfman disease : sinus histiocytosis with massive lymphadenopathy. Lymphocytes in those histiocytes. Benign (virus? ) 31

Sinus histiocytosis 32

Special types of lymphadenitis n n Dermatopathic lymphadenitis: Melanin and sebum-laden nodes draining chronically inflamed skin. mistaken for malignant lymphoma. Mixed granulomatous-suppurative lymphadenitis (1) lymphogranuloma venereum, (2) cat scratch fever, (3) brucellosis, (4) plague, (5) tularemia, (6) glanders-melioidosis, (7) miscellaneous yersinia infections. 33

Granulomas with suppuration • With pus in their centers, • stellate microabscesses. • Bacterial diseases with a propensity to involve lymph nodes: – – – – – lymphogranuloma venereum, cat scratch fever, brucellosis, plague, tularemia, glanders-melioidosis, listeria, camphylobacter, yersinia infection. 34

Cat Scratch Disease n n n Self limited lymphadenitis Caused by Bartonella henselae Axillary LAP Usually secondary to feline scratch Necrotizing lymphadenitis Bacteria visualized with silver stain. 35

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Cat Scratch Disease B. Henselae bacteria 38

• • • Angioimmunoblastic lymphadenopathy Proliferation of vessels and B- or Timmunoblasts. Patients have systemic signs and often go on to die of immunoblastic lymphoma; Causes: HIV, herpes 8. Kikuchi-Fujimoto necrotizing histiocytic lymphadenitis Proliferation of histiocytes and lymphocytes with necrosis Cause: viral infections. 39

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Granulomatous Lymphadenopathy with caseification n n n Tuberculosis Histological examination shows evidence of a delayed hypersensitivity reaction Classical appearance is of caeseating necrosis Tuberculous follicle consists of central caseaous necrosis Surrounded by lymphocytes, multi-nucleate giant cells and epitheloid macrophages Organisms may be identified within the macrophages 41

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Langhans GIANT Cell 43

Acid Fast Stain (+) 44

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Infectious mononucleosis n n Major alterations in: n blood, n lymph nodes, n spleen, n liver, n CNS. Hyperplasia in lymph nodes n Lymphadenomegaly (posterior cervical, axillary, and inguinal) Splenomegaly n Spleen: infiltrated with activated T-cells 47

n n n Benign atypical lymphocytes are activated cells (B- or T-) seen typically in the blood (lymphocytosis) Occasionally, cells resembling Reed-Sternberg cells. The syndrome results from first meeting one of these four micro-organisms: (1) (2) (3) (4) Epstein Barr virus; Cytomegalovirus; Toxoplasmosis; HIV. 48

Reactive Lymphocytes in Infectious Mononucleosis 49

leukophagocytic macrophages in a lymph node in EBV EBER ISH 50