This presentation mainly deals with granuloma formation and various factors involved in it. It describes the examples of granulomatous disorders and gives a details on how to seperate them on histopathology.It also describes type 4 hypersensitivty reaction concisely

1. GRANULOMATOUS
INFLAMMATION
MODERATOR: DR. SHARMILA
P.S
PRESENTER: DR.
SPOORTHY

2. • Inflammation is a response of vascularised tissue to
infections and damaged tissues
• It brings out cells and molecules of host defence
from the circulation to the sites where they are
needed
• To eliminate the offending agent

3. ACUTE
INFLAMMATION• Onset is sudden and the course of the disease is short
• CLINICALLY:
• Classical signs of inflammation are present with associated constitutional
symptoms
• MICROSCOPY :
• Vascular changes
• Exudation of fibrous fluid
• Presence of large number of neutrophils
• Cells like Fibroblasts, Histiocytes and Plasma cells are present at the stage
of repair

4. CHRONIC
INFLAMMATION
• It is a response of prolonged duration
• In which inflammation, tissue injury and attempts to
repair co exist in varying combinations
• CAUSES:
1. Persistent infections
2. Hypersensitivity diseases
3. Prolonged exposure to toxic agents

5. • MACROSCOPIC APPEARENCES
1. Chronic ulcer:
• Chronic peptic ulcer of stomach
2. Chronic Abscess cavity:
• Osteomyelitis
3. Thickening of wall of a hollow viscus:
• Crohns disease, chronic cholecystitis
4. Granulomatous inflammation
5. Fibrosis

6. • MICROSCOPY:
• Characterised by the proliferation of connective
tissue and blood vessels
• Presence of lymphocytes,plasma cells and
macrophages
• In many cases small areas of necrosis may be
present along with process of repair marked by
fibrosis
• Neutrophils are scarce

7. GRANULOMATOUS
INFLAMMATION

8. • Granuloma formation is a protective response to chronic
infection or presence of foreign material.
• It isolates a persistent offending agent, prevents it from
dissemination and restricting the inflammation
• This protects the host

9. • Granuloma is defined as a circumscribed lesion of
about 1mm in diameter composed predominantly
• Modified macrophages
• Rimmed at the periphery by lymphoid cells
• With a collar of fibroblast proliferation

10. Granulomatous
Diseases
• BACTERIAL
• Tuberculosis
• Leprosy
• Brucellosis
• Salmonellosis
• Listeriosis
• Syphilis
• Q fever

11. • FUNGAL
• Histoplasmosis
• Blastomycosis
• Coccidiomycosis
• Hypersensitivity Pneumonitis

12. • HELMINTHIC
• Schistosomiasis
• Trichinosis
• FOREIGN BODY TYPES
• Silica granulomatosis
• Foreign body pneumonitis

13. • VIRAL, CHLAMYDIAL
• Cat-scratch disease
• Lymphogranuloma venerum
• METAL INDUCED
• Berylliosis
• Zirconium Granulomatosis

14. • UNKNOWN CAUSES
• Sarcoidosis
• Crohns disease
• Wegeners granulomatosis
• Giant cell arteritis
• Rheumatoid arthritis

15. FORMATION OF
GRANULOMA

16. Cell injury
Failure to digest agent
Weak acute inflammatory response
Engulfment by macrophages
Persistence of injurious agents
T cell mediated response Poorly digestible agent
Activation of CD4 T cells
Monocyte chemotactic factor
Macrophages are activated by IFN-Y
Accumulation of tissue macrophages
Epitheloid giant cells Fibroblastic proliferating
cytokines
GRANULOMA

17. • CYTOKINES:
• Cytokines are formed by activated CD4 T cells and
also by activated macrophages
• IL-1 and IL-2: proliferation of T cells
• Interferon Y: activation of macrophages
• TNF-alfa: fibroblast proliferation, activates
endothelium
• Growth factors: TGF

18. COMPOSITION OF
GRANULOMA

20. EPITHELOID CELLS
• Macrophages become large and polygonal with pale, oval nuclei
and abundantly cloudy eosinophilic cytoplasm
• Called epitheloid cells due to resemblance to epithelial cells
• Apposing cell membranes of epitheloid cells exhibit a high degree
of inter digitation
• Macrophages become epitheloid cells:
1. No phagocytosis
2. Completely phagocytosed the material
3. Extruded phagocytosed material by exocytosis

22. GIANT CELLS
• When macrophages encounter insoluble material they coalesce to form
giant cells
• Mostly non proliferating macrophages fuse in this manner
• FOREIGN BODY:
• Large number of nuclei: 50-100
• Regular in size
• Scattered in the cytoplasm
• Site of : Suture
• Haemorrhage
• Atheroma

23. • LANGHANS TYPE:
• The nucleus are arranged around the periphery like a
horse shoe
• EXAMPLES: Tuberculosis
• Leprosy
• Syphilis
• TOUTON GIANT CELLS:
• The cytoplasm has a foamy or vacoulated appearance
• Typically seen in Xanthomas

24. • Osteoclastic giant cells
• Aschoff cells
• Tumour giant cells
• Virugenic giant cells

28. • LYMPHOID CELLS
• Cell mediated immunity reaction to antigen
• Lymphocytes are an integral composition of granuloma
• Plasma cells are indicative of accelerated immune response
• NECROSIS:
• Feature of some granulomatous conditions
• FIBROSIS:
• Feature of healing by proliferating fibroblasts at periphery of
granuloma

29. TYPES OF
GRANULOMAS

30. FOREIGN BODY Talc, Suture material
NECROTISING GRANULOMAS
Mycobacterium Tuberculosis,
Histoplasma Capsulatum,
Granuloma Annulare
NON NECROTISING
GRANULOMAS
M.Leprae, Sarcoidosis, SLE,
SUPPURATIVE GRANULOMAS
Actinomyces, Chlamydia
Trachomatis
HISTIOCYTIC RESPONSE, NO
GRANULOMAS
Listeria Monocytogenes,Mycosis
Fungoides

31. • FOREIGN BODY GRANULOMA:
• Relatively inert foreign bodies
• Absence of T cell mediated immune response
• Found around materials such as Talc, Sutures etc
• They do not incite any specific inflammation or immune
response
• Foreign material can be identified in the centre of
granuloma
• Viewed with polarised light- REFRACTILE

34. • IMMUNE GRANULOMAS
• Variety of agents inducing persistent T cell
mediated immune response
• It is usually seen when the inciting agent is difficult
to eradicate

36. TUBERCULOSIS

37. • Mycobacterium Tuberculosis
• Slender rod like bacillus
• Grows in straight or branching chains
• Gram positive and Acid fast
• Strict Aerobe
• 0.5um-3um

38. • VISUALIZED BY
1. Z-N staining
2. Fluorescent methods
3. Culture
4. Guinea pig inoculation
5. Molecular methods
6. Immunohistochemical stains

41. PATHOGENESIS
• Hypersensitivity and Immunity play a major role in
development of lesions
• TB bacillus does not produce any toxins
• Tissue changes seen are due to host response to the
organism
• Type 4 hypersensitivity reaction
• Host responses are due to several lipids present in
the organism

42. • MYCOSIDES:
• Cord factor which is essential for the growth and
virulence of the organism in animals
• GLYCOLIPIDS:
• Present in the bacterial cell wall
• Adjuvant along with tubercular proteins

43. TUBERCLE
FORMATION

45. PRIMARY
TUBERCULOSIS

46. • This is a form of disease which develops in
previously unexposed and therefore unsensitised
persons
• The source of organism is exogenous
• Also called as Primary tuberculosis or GHON’S
COMPLEX
• Lesions are produced in the tissue of the portal of
entry
• With foci in the draining lymph nodes and vessels

47. • Primary complex:
• Mostly seen in the Lungs or Hilar lymph nodes
• Ingested bacilli: Small intestine and Mesenteric
lymph nodes

48. GHON’S COMPLEX
• PULMONARY COMPONENT
• Inhaled bacilli implant in the distal air spaces of the
lower part of the upper lobe or the upper part of the
lower lobe
• Close to the pleura
• 1-1.5 cms area of gray-white inflammation with
consolidation emerges- GHON’S FOCUS

49. • LYMPHATIC VESSEL COMPONENT
• Lymphatics draining the lung lesion contain
phagocytes containing bacilli
• LYMPH NODE COMPONENT
• This consists of enlarged hilar and tracheo- bronchial
lymph nodes in the area drained
• Affected lymph nodes are matted and show caseous
necrosis
• Nodal lesions are potential source of re-infection later

51. • This combination of parenchymal lung lesion and
nodal involvement is referred to as GOHN'S
COMPLEX
• Most of the cases development of cell mediated
immunity controls the infection
• Gohn’s complex undergoes progressive fibrosis
• Followed by radiologically detectable calcification-
RANKE COMPLEX
• Despite seeding in other organs no lesions develop

52. • Primary tuberculosis of alimentary tract is due to
ingestion of the tubercle bacilli
• A small primary focus is seen in the intestine with
enlarged mesenteric lymph nodes
• TABES MESENTERICA
• Enlarged and caseous lymph nodes may rupture
into the peritoneal cavity
• Tuberculosis Peritonitis

53. • MICROSCOPY:
• Site of active involvement are marked by characteristic
granulomatous inflammation
• Both caseating and non-caseating tubercles
• Granulomas are enclosed by a fibroblastic rim punctuated by
lymphocytes
• Multinucleated giant cells are present
• Immunocompromised people do not form characteristic
granulomas
• Their macrophages contain many bacilli

55. FATE OF PRIMARY
TUBERCULOSIS

56. • PROGRESSIVE PULMONARY TUBERCULOSIS
• Older adults and immune suppressed people
• Apical lesion expands into the adjacent lung and
erodes into the bronchi and vessels
• Erosion of blood vessels results in Haemoptysis
• With adequate treatment the process may be arrested
• If treatment is inadequate or hosts defences are
impaired infection may spread via airways, lymphatic
channels or vascular system

57. • MILIARY TUBERCULOSIS
• Bacilli may enter the circulation through erosion and
spread by haematogenous route
• Individual lesions are small, 2mm, visible foci of
yellow white consolidation
• Most prominent in liver, bone marrow, kidney,
spleen, meninges

58. • MICROSCOPY:
• Resemble tb granuloma with absence or little
amount of caseous necrosis
• Few lymphocytes at the periphery
• Lesion heals fibrosis which begins around
granulomata till it becomes a tiny scar

60. SECONDARY
TUBERCULOSIS
• Infection of an individual who has been previously
infected or sensitised is called secondary or post
primary or reinfection
• Occurs most commonly in the lungs
• The lesions in secondary TB begins as 1-2 cm apical
consolidation of lung
• Develop small central necrosis and peripheral fibrosis
• Spread of infection is from primary complex to the apex
of affected lung- oxygen tension is high

61. • The lesions may heal with fibrous scarring and
calcification
• Lesions may coalesce together to form larger areas
of
• Fibrocaseous tuberculosis
• Tubercular caseous pneumonia
• Miliary tuberculosis
• Tuberculous empyema

65. EXTRA PULMONARY
TUBERCULOSIS

66. • Caseous abscess in one or both kidneys
• Abscess may develop in epididymis or prostate
• Fallopian tube may distend with creamy pus and
granulomata
• Walls of the tubes are scarred and lumen is
obliterated
• Granulomata may develop in endometrium

69. • A primary lesion in the tonsil causes enlargement of
the lymph nodes in the neck
• Tuberculosis of cervical lymph nodes is called
SCROFULA
• TB bone causes slow erosion of one or more
vertebrae in the lower thoracic or lumbar region
• Kyphosis or compression of spinal cord

74. SYPHILIS

75. • Treponema Pallidum
• Gram Negative Spirochete
• Slender cork screw shaped bacteria

77. • PATHOGENESIS:
• Proliferating end arteritis affecting small vessels
• Surrounding plasma cell infiltrate
• Pathology- Ischaemia produced by the vascular lesions
• Pathogenesis of end arteritis is unknown- Luetic Vasculitis

78. PRIMARY STAGE
• GROSS:
• Characterised by a primary sore: 3 weeks of infection
• Single, firm, non tender, raised red lesion- CHANCRE
• Site of treponemal invasion
• Penis, Labia, Anal region and Cervix
• Regional Lymphadenitis
• Heals with or without Therapy

80. • MICROSCOPY:
• Chronic inflammatory granulomas with typical syphilitic
arteritis in small vessels
• Dense infiltrate of plasma cells with scattered
macrophages and lymphocytes and proliferative end
arteritis
• Endothelial cell activation and proliferation and
progression to intimal fibrosis
• Lymph node: Plasma cell rich infiltrate or granulomas

81. SECONDARY STAGE
• Starts 6-10 weeks after development of chancre
• Generalised symptoms
• Earliest skin eruptions: Roseolar Rash
• Macular Syphilides
• Papulo Squamous Syphilides
• Pustules

82. • The rash is Symmetrical, Polymorphic and may
show 2 or more different types lesions in the body
at the same time
• The papule enlarge to produce flat, wart like
lesions called CONDYLOMA LATA
• Seen in moist areas such as genitilia, axilla and
underlying breast

85. • MICROSCOPY:
• Typical peri vascular infiltrate of lymphocytes and
plasma cells: PERI VASCULAR CUFFING
• Resemble primary lesions but are smaller, more diffuse
and milder in character
• Lesions contain many spirochetes: highly infectious
• CONDYLOMA: thickening of the epidermis and serous
discharge swarms with organisms

87. TERTIARY STAGE
• Affects about one- third of the untreated cases
• Lesions: GUMMAS- Benign tertiary syphilis
• Cardio vascular syphilis accounts for majority of the
deaths
• Destruction of the tissues:
1. FOCAL GRANULOMA: with tendency to central
necrosis called GUMMA
2. Diffuse inflammation with fibrosis of organs

88. • GUMMA:
• White-grey and rubbery
• Singly or Multiple and vary in size
• Occur in most of the organs but particularly in skin
and sub cutaneous tissue, bone and joints

90. • GROSS:
• Developing granuloma with central part of coagulative necrosis and
fibrosis in the surrounding tissue
• Necrosis is due to Syphilitc end arteritis
• Necrosis- produces gummy substance in exudate
• MICROSCOPY:
• Zone of central necrosis surrounded by fibrous tissue
• Walls of the vessels are thickened by end arteritis obliterans
• Surrounded by infiltration of lymphocytes, plasma cells and
occasional giant cells

92. • SKIN:
• Forms gummatous ulcers
• Round or oval with punched out edges
• Gumma on the palate causes perforation
• LIVER:
• Lesions causes destruction of the liver parenchyma
into irregular masses: HEPAR LOBATUM

93. • TESTIS:
• Testis is enlarged, feels stony hard due to thickened
fibrous tissue
• Painless on pressure
• BONE:
• Sclerosis and Gumma
• Affects Tibia, Sternum, Skull
• Skull: worm eaten bones i.e rarefaction surrounded by
sclerosis

94. • SYPHILITIC AORTITIS
• Slow progressive end arteritis obliterates of vasa
vasorum
• Necrosis of aortic media- wearing and stretching of
aortic wall
• Syphiltic aneurysm is saccular and involves
ascending aorta

95. • INTIMA: rough and shows irregular fibrosis and
thickening
• Bark of tree appearance
• MEDIA: replaced by scar tissue
• Aorta looses strength and resilience
• Stretches to a point of rupture
• Massive haemorrhage and sudden death

98. • NEURO SYPHILIS
• Slow progressive infection damages meninges,
cerebral cortex, spinal cord, cranial nerves and
eyes
1. Meningo vascular syphilis
2. Tabes dorsalis
3. General paresis

100. SARCOIDOSIS

101. • Systemic disease of unknown etiology
• Characterised by hard tubercle like granulomas in
various organs
• Clinically simulates Hodgkins disease
• Lesions: Regional and Mediastinal lymph nodes
• Lungs and Spleen
• Liver, Eyes, Parotid, Skin and Bones
• Mediastinal lymph nodes are involved in 75% of the
cases

102. PATHOGENESIS
Exogenous or Autologous antigen
Exaggerated helper T cell response
T cells accumulate in the affected organs
Secrete Lymphokines
Recruit Macrophages
Non caseating granuloma

103. • In appearance the sarcoid tissue is pearly grey in
colour
• Forms discrete and confluent masses in lungs
• mostly at mid zones and bases
• BONES: Small cysts are seen
• CUTANEOUS: Lupus Perino
• Soft, infiltrated, violaceous papule
• HERRFORDT’S SYNDROME

106. • MICROSCOPY:
• Discrete granulomas with plump endothelial cells
and few langhans giant cells are seen
• Few giant cells contain star shaped acidophilic
bodies or asteroides- LIPO PROTEINS
• SCHAUMANN BODIES
• Non specific end products of active metabolism and
secretion that take place in the cells

108. LEPROSY

109. • Slow progressive infection
• Mycobacterium leprae
• Mainly affects skin and nerves
• Source of infection and route of transmission is not
known
• Human respiratory secretions are likely causes
• Cannot be cultured artificially
• Mouse foot pads

110. • Leprae are taken up by
macrophages
• Disseminates in the blood
• Proliferates in relatively
cool tissues
• Secretes no toxins and its
virulence is based on the
properties of cell wall

111. TH1 RESPONSE
Strong TH1 response Weak TH1 response
Production of IF-Y Weak CMI
Macrophages Inability to control
bacteria
Microbial burden is low Can be visualised in tissue
sections

112. • FULL SPECTRUM OF LEPROSY:
• TT- Tuberculoid Polar ( high resistance)
• BT- Boderline Tuberculoid
• BB- Boderline
• BL- Boderline Lepromatous
• LL- Lepromatous Polar ( low resistance)

113. TUBERCULOID
• Individuals with relatively high immunity
• Localised flat, red skin lesions that enlarge and develop with
irregular shapes
• Elevated hyperpigmented margins and depressed pale centres
( central healing)
• Neuronal involvement dominates
• Nerves become enclosed in granulomatous inflammation and
are destroyed
• Causes skin anaesthesia with skin and muscle atrophy

115. • Liable to trauma of affected parts
• Leads to chronic ulcers, contractures, paralysis and
auto amputation of fingers and toes
• MICROSCOPY:
• All sites involved have granulomatous lesions
• Strong host defence bacteria are almost never
found
• PAUCI BACILLARY LEPROSY

117. LEPROMATOUS
• Involves: skin, peripheral nerves, upper airways, testis, hand
and feet
• Includes symmetric skin thickening and nodules
• Wide spread invasion of mycobacteria into Schwann cells
and endoneural and perineurial macrophages damage PNS
• Macular, papular or nodular lesions form on face, ears, wrists,
elbows and knees
• They coalesce to yield a distinctive Leonine Facies
• Diffuse involvement of nerves- Symmetric peripheral neuritis

118. • Nasal mucosa is also infiltrated by bacteria laden
macrophages
• Causes destruction of nasal bones which leads to
characteristic collapse of bridge of nose
• MICROSCOPY:
• Large Lipid laden macrophages: LEPRA CELLS
• Filled with masses( GLOBI) of acid fast bacilli
• Abundant bacteria- MULTI BACILLARY LEPROSY

120. CROHN’S DISEASE

121. • Inflammatory bowel disease which may occur in any
area of GI tract
• Mostly involves Terminal ileum, Ileo caecal valve,
Caecum.
• MORPHOLOGY
• Multiple, separate, sharply delineated areas of disease:
SKIP LESIONS
• Earliest lesion: APTHOUS ULCER
• Progress and coalesce into serpentine ulcers along the
axis of the bowel

122. • Odema and loss of normal mucosal texture
• Sparing of interspersed mucosa due to patchy
distribution of the disease: COBBLESTONE
APPEARENCE
• Fissures frequently develop between mucosal folds
and extend to form fistulas
• In extensive transmural disease mesenteric fat
frequently extends around the serosal
surface:CREEPING FAT

124. • MICROSCOPY
• Non caseating granulomas are a hallmark of crohn’s
disease
• Granulomas may also be present in mesenteric lymph
nodes
• Cutaneous granulomas form nodules- Metastatic crohns
disease
• ACTIVE DISEASE:
• Abundant neutrophils that infiltrate and damage crypt
epithelium
• CRYPT ABSCESS: clusters of neutrophils within the crypt
• Epithelial Metaplasia: consequence of relapsing injury

127. HISTOPLASMOSIS

128. • Histoplasma capsulatum
• Dimorphic fungus
• Small oval yeast cell: 1-4 um
• Surrounded by a thin capsule- Mucoid material
• Found in soil particularly in bird droppings
• Inhalation of contaminated dust

129. • Primary- Pulmonary
• Transient infection with Hilar node involvement
• Rapid healing with residual calcification
• Organisms in blood stream- small metastatic lesions in
spleen, liver and other organs
• DISSEMINATED INFECTION:
• Leads to involvement of many organs with high mono
nuclear phagocytic content
• Chronic pulmonary Histoplasmosis- resembles TB

131. • MICROSCOPY:
• Necrotising granulomas in lungs, mediastinal lymph
nodes, spleen and liver
• Early stages: caseous necrosis is surrounded by
macrophages, langhans giant cells, lymphocytes and
plasma cells
• Yeast forms can be demonstrated in the macrophages
• Eventually the cellular components of granulomas
largely disappear with caseous material
• Calcifies and finally forms FibroCaseous Nodule

133. RHINOSPORIDIOSIS

134. • Rhino sporidium seeberi
• Mucus membranes of the nose, cheek, uvula ,
lacrymal sac
• Characterised by polypoidal growth
• MICROSCOPY:
• Polyp consists of vascular, myxomatous connective
tissue
• Sporangia are seen often with empty chitinous
shells
• Seen are granulomas with foreign body giant cell
reaction

137. RHINOSCLEROMA

139. REFERENCES
• Robbins and Cotran: Pathological basis of diseases
9 edition
• Walter and Israel: General pathology 7 edition
• Boyd’s textbook of pathology: 10 edition
• General and Systemic pathology: J.C.E Underwood

140. THANK YOU