1. Lymphoreactive Diseases

2. 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.

3. 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

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

7. 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

8. 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.

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

13. Pathology of lymph nodes
A. 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

14. 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

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

18. 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...)

19. 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.

20. 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

21. 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

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

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

24. 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)

25. Reactive Lymphadenitis (Follicular Hyperplasia)

30. 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)

31. 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?)

32. Sinus histiocytosis

33. 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.

34. 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.

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

38. Cat Scratch Disease B. Henselae bacteria

39. 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.

41. Granulomatous Lymphadenopathy with 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

43. Langhans GIANT Cell

44. Acid Fast Stain (+)

47. 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

48. Occasionally, cells resembling Reed-Sternberg cells.
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.

49. Reactive Lymphocytes in Infectious Mononucleosis

50. leukophagocytic macrophages in a lymph node in EBV
EBER ISH