Lymphoreactive Diseases

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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.

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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:

a. B cells- bone marrow b. T cells- thymus 2. The secondary immune organs, which are the

sites of antigen driven replication and differentiation into committed effector cells

a. Lymph nodes b. Spleen c. Mucosal Associated Lymphoid System

(MALT)-lymphoid cells lining the respiratory and gastrointestinal tracts

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.

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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.

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Follicular (germinal) center cells

(replicating and post-replicating B cells)

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Pathology of lymph nodesA. Infections

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- paracortex- a. Skin diseases b. Viral infections c. Drug reactions

4. Sinus histiocytosis- expansion of the medullary sinus histiocytes-

a. 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- paracortex- a. Skin diseases b. Viral infections c. Drug reactions

4. Sinus histiocytosis- expansion of the medullary sinus histiocytes-

a. Adjacent cancer b. Infections 14

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A: Follicular centerB: Mantle zoneC: Marginal zone

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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...)

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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.

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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

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Reactive states with follicular hyperplasiaRomatoid ArthritisToxoplasmosisSyphilisHIV infectionInflammatory pseudotumorKimura’s diseaseSjögren’s syndromeSLECat-Scratch diseaseAngiofollicular hyperplasia (Castleman’s

disease)Dilantin reaction 21

Reactive states with interfollicular hyperplasia

Whipple’s disease Viral adenitis Virus associated hemophagocytic

syndrome Dermatopathic lymphadenopathy Sinus histiocytosis with massive

adenopathy Histiyocytosis-X

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Reactive States Causing Diffuse Architectural Effacement of

Lymph Node Immunoblastic lymphadenopathy Angioimmunoblastic

lymphadenopathy Drug reactions Sarcoidosis Infarction Vasoproliferative lesions

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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)

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Paracortical lymphoid hyperplasia

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: weird reactions to a vaccine infectious mononucleosis family

(those angry T-killers)

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Sinus histiocytosis

Sinusoids with swollen endothelial cells and lots of histiocytes. Examples: nodes draining a cancer nodes injected with permanent radiology contrast

medium ("lymphangiogram dye") Castleman's giant angiofollicular lymphoid hyperplasia hemolysis

Coombs-positive, macrophages rendered hungry by infection

"erythrophagocytic reticulosis" Rosai-Dorfman disease : sinus histiocytosis with

massive lymphadenopathy. Lymphocytes in those histiocytes. Benign (virus?)

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Sinus histiocytosis

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Special types of lymphadenitis

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.

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Cat Scratch Disease

Self limited lymphadenitis Caused by Bartonella henselae Axillary LAP Usually secondary to feline scratch Necrotizing lymphadenitis Bacteria visualized with silver

stain.

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Cat Scratch Disease B. Henselae bacteria

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Angioimmunoblastic lymphadenopathy

• Proliferation of vessels and B- or T-immunoblasts.

• 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 Lymphadenopathywith caseification

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

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Langhans GIANT Cell43

Acid Fast Stain (+) 44

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Infectious mononucleosis

Major alterations in: blood, lymph nodes, spleen, liver, CNS.

Hyperplasia in lymph nodes Lymphadenomegaly (posterior cervical, axillary, and

inguinal) Splenomegaly

Spleen: infiltrated with activated T-cells

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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) Epstein Barr virus; (2) Cytomegalovirus; (3) Toxoplasmosis; (4) HIV. 48

Reactive Lymphocytes in Infectious Mononucleosis

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leukophagocytic macrophages in a lymph node in EBV EBER ISH 50