GRANULOMATOUS INFLAMMATION :

Tuberculosis, SyphilisTuberculosis, Syphilis

Dr. Deepak K Gupta

Syllabus

• Granulomations inflammation.• Tuberculosis

– Epidemiology– Pathogenesis (Formation of tubercle)– Pathological features of Primary and secondary TB– Complications and Fate– Complications and Fate

• Syphilis– Epidemiology – Types and stages of syphilis– Pathological features – Diagnostic criterias– Oral lesions

Introduction

• It is a distinctive pattern of chronic inflammation characterized by aggregates of activated macrophages that assume an epithelioidappearance.appearance.

• Certain specific pathologic states

• “Walls off”- offending agent • Tuberculosis is the

prototype of a granulomatous disease.

Granulomatous Disease

Disease Cause

Tuberculosis Mycobacterium tuberculosis

Leprosy Mycobacterium leprae

Syphilis Treponema pallidumSyphilis Treponema pallidum

Cat Scratch Disease Gram (–) bacillus

Sarcoidosis Unknown etiology

Crohn’ Disease Immune reaction against intestinal bacterial, self antigen

PATHOGENESIS OF GRANULOMA

Engulfment by

Macrophages

• Unable to eat MCO like M. tubercle

• Undergo morphologic changes to epithelioid cells.

• When macrophage fails to kill MCO

CD4+ T cells

• When macrophage fails to kill MCO

• It presents it to CD4+ cells.

Cytokines

• IL-1 and IL-2, Interferon-γ, TNF-α

• Fibroblast proliferation

Histological features• The following three layer structure of the inflammatory

granulation tissue is common• Resorption zone

– Innermost – borders directly on the necrotic material and primarily consists

of phagocytic histiocytes.– store the poorly soluble fat in lysosomal vacuoles - foam cells– store the poorly soluble fat in lysosomal vacuoles - foam cells

• Granulation zone– granulation tissue rich in capillaries and fibroblasts.– Resorptive and reparative function

• Mature connective tissue zone– oldest and outermost layer of tissue - highly fibrous connective

tissue

Histological features

Histological features

COMPOSITION OF GRANULOMA

• Following structural components

– Epitheloid cells

– Multinucleate giant – Multinucleate giant cells

– Lymphoid cells - cell mediated immune reaction

– Necrosis & Fibrosis.

Epithelioid cells

• epithelial cell-like appearance

• modified macrophages/histiocytes

• abundant cytoplasm with hazy outlines

• cell membrane of adjacent epithelioid cells is • cell membrane of adjacent epithelioid cells is closely apposed

• Epithelioid cells are weakly phagocytic

Multinucleate giant cells

• fusion of adjacent epithelioidcells

• 20 or more nuclei• Langhans’ giant cells - nuclei

may be arranged may be arranged – Periphery– Horseshoe– Ring– Clustered at the two poles.

• Foreign body giant cells –centrally placed nuclei

• Weakly phagocytic

Multinucleate giant cells

Necrosis & Fibrosis

• Necrosis may be a feature of some granulomatousconditions– Central caseation– Central caseation

necrosis of tuberculosis

• Fibrosis - healing by proliferating fibroblasts at the periphery of granuloma. Ex: Rheumatoid Arthritis

Mycobacteria

• Slender rods with lipid-rich cell walls• Cell walls are unusual– 60 percent lipid– Long–chain (75 to 90 carbons), β-hydroxylated fatty

acids (mycolic acids)acids (mycolic acids)– This complexes with variety of polysaccharides and

peptides– waxy cell surface - strongly hydrophobic, impervious

and acid fast staining

• Resistant to drying but not to heat or ultraviolet irradiation

Mycobacteria• They are grouped in

three groups

– Tuberculosis causing Mycobacterium.

– Atypical Bacteria.

– Lepra group.

Tubercle bacillus

• Robert Koch in 1882• Organism is a strict aerobe • Grows best in tissues with high oxygen tension

such as in the apex of the lung– M. tuberculosis hominis (human strain) – most – M. tuberculosis hominis (human strain) – most

commonly found– M. tuberculosis bovis (bovine strain) - unpasteurised

milk– M. africanum - isolated from patients from parts of

Africa)– M. microti, M. pinnipedii and M. canettii

M. tuberculosis hominis

• neutral on Gram staining

• demonstrated by the following methods– Acid fast (Ziehl-Neelsen) staining

– Fluorescent dye methods– Fluorescent dye methods

– Culture of the organism from sputum in Lowenstein Jensen (L.J.) medium for 6 weeks

– Guinea pig inoculation -subcutaneous injection

– Molecular methods - PCR

Atypical Mycobacterium

• Other than M. tuberculosis complex and M. leprae.

• Environmental mycobacteria – widely distributed in the environment

• Occasionally cause human tuberculosis - atypical • Occasionally cause human tuberculosis - atypical mycobacteriosis

• Resistant to usual antitubercular drugs.

• Classified on the basis of colour of colony produced in culture and the speed of growth in media (solid)

Atypical Mycobacterium

• Speed of growth

– Rapid growers - within 7 days

• Ex: M. abscessus, M.fortuitum, M. chelonae

• Slow growers - 2-3 weeks

– Ex: M. avium-intracellulare, M. kansasii, M. ulcerans– Ex: M. avium-intracellulare, M. kansasii, M. ulcerans

• Color of colony formed

– Photochromogens - yellow pigment in the presence of light

– Scotochromogens – produces pigments in the absence of light

– Non-chromogen - no pigmentation

Atypical Mycobacterium

• Acquired directly from the environment

• lesions - granulomas, nodular collection of foamy cells, or acute inflammation

• Less virulent• Less virulent

Mycobacterium leprae

• damage to the skin and the peripheral nervous system.

• Hansen’s disease

• transmitted from human to human - through prolonged human - through prolonged contact

• exudates of a leprosy patient’s skin lesions and the abraded skin of another individual

• Low virulence

Mycobacterium leprae

• Long incubation period -develop years or even decades after initial contact with the organism.contact with the organism.

• Two clinical extremes: tuberculoid and lepromatous leprosy

Mycobacterium leprae : tuberculoidleprosy

• lesions occur as large maculae (spots) in cooler body tissues, such as

• skin (especially the nose, outer ears, and testicles),• superficial nerve endings.

– Neuritis - patches of anesthesia in the skin. – Neuritis - patches of anesthesia in the skin. – Lesions are heavily infiltrated by lymphocytes and

giant and epithelioid cells, but caseation does not occur.

– a strong cell-mediated immune response and develops delayed hypersensitivitY - skin test with lepromin, a tuberculin-like extract of lepromatoustissue.

– There are few bacteria in the lesions (paucibacillary).

Initial lesion of Leprosy

Mycobacterium leprae : lepromatousleprosy

– slow but progressive

– Large numbers of organisms - present in the lesions and the lesions and reticuloendothelialsystem (multibacillary),

– Severely depressed immune system.

– No well-formed granulomas emerge

Tuberculosis

Introduction

• Communicable chronic granulomatous disease caused by Mycobacterium tuberculosis

• It usually involves the lungs but may affect any organ or tissue in the body.organ or tissue in the body.

• Typically, the centers of tubercular granulomasundergo caseous necrosis

Epidemiology

• one of the oldest diseases known to affect humans

• major cause of death worldwide

• one third of the world’s population is infected with M. tuberculosis

• one third of the world’s population is infected with M. tuberculosis

• If untreated, the disease may be fatal within 5 years in 50–65% of cases

• 50 percent of the HIV-infected population is coinfected with M. tuberculosis.

Etiology

• M. tuberculosis hominis is responsible for most cases of tuberculosis

• reservoir of infection is usually found in humans with active pulmonary disease

• Transmission is usually direct• Transmission is usually direct– Inhalation : fresh cough droplets or in dried sputum from

infected person– Ingestion : tonsillar or intestinal tuberculosis, self-

swallowing of infected sputum– Inoculation – infected postmortem tissue– Transplacental route – congenital tuberculosis in foetus

from infected mother and is a rare mode

Pathogenesis• No demonstrable toxins• Virulence mycobacteria reach the

alveoli• Macrophage – initiates

phagocytosis, but unable to do so– bacterial sulfolipids inhibit the fusion

of phagocytic vesicles with of phagocytic vesicles with lysosomes

• multiply in the pulmonary epithelium or macrophages

• 2 to 4 weeks - destroyed by the immune system, but some survive and are spread by the blood to extrapulmonary sites

• Ability to survive and grow within host cells

Types of Tuberculosis

• Tubercle bacilli is of 2 main types

– Primary tuberculosis

– Secondary tuberculosis.

Primary tuberculosis

• Individual - not been previously infected or immunised.

• Ghon’s complex or childhood tuberculosis.

• begins with a primary subpleural focus (Ghon• begins with a primary subpleural focus (Ghoncomplex) in the central parenchyma of the lung.

• Incidence of primary infection is high in immuno-compromised patients

Lung Anatomy

Ghon’s complex

• lungs consists of 3 components• Pulmonary component

– 1-2 cm solitary area– located peripherally under a patch of

pleurisy– in any part of the lung but more often in

subpleural focus in the upper part of lower lobe.subpleural focus in the upper part of lower lobe.

• Lymphatic vessel component– lymphatics draining the lung lesion

contain phagocytes containing bacilli

• Lymph node component– enlarged hilar and tracheo-bronchial

lymph nodes in the area drained by lymph

– lymph nodes are matted and show caseation necrosis

Ghon’s complex

Tuberculous peritonitis• Small primary focus in intestine

• Enlarged mesenteric lymph nodes producing tabes mesenterica.

• When it enlarges - rupture into peritoneal cavity and cause tuberculous peritonitiscavity and cause tuberculous peritonitis

FATE OF PRIMARY TUBERCULOSIS

1. Heals by fibrosis or calcification and even ossification

2. Progressive primary tuberculosis : Spreads to other parts of Lungs

3. Primary miliary tuberculosis : bacilli may enter 3. Primary miliary tuberculosis : bacilli may enter the circulation through erosion in a blood vessel and spread to various tissues and organs. Ex: liver, spleen, kidney, brain and bone marrow

4. Progressive secondary tuberculosis : bacilli lying dormant in acellular caseous material gets activated

Secondary Tuberculosis

Secondary Tuberculosis

• The infection of an individual who has been previously infected or sensitised is called secondary, or post-primary or reinfection, or chronic tuberculosis

• The infection may be acquired from– Endogenous source : reactivation of dormant primary – Endogenous source : reactivation of dormant primary

complex

– Exogenous source : fresh dose of reinfection by the tubercle bacilli

• Most commonly in lungs in the region of apex

• Other sites like tonsils, pharynx, larynx, small intestine and skin

Secondary Tuberculosis

Secondary Pulmonary Tuberculosis

• begin as 1-2 cm apical area of consolidation of the lung

• With time develop a small area of central caseation necrosis and peripheral fibrosiscaseation necrosis and peripheral fibrosis

• This occurs by haematogenous spread from the site of primary complex

• oxygen tension is high and favourable forgrowth of aerobic tubercle bacilli

Secondary Pulmonary Tuberculosis

• Microscopically, it represents tuberculousgranulomas with caseationnecrosis

• HIV patientsIf previously exposed will – If previously exposed will have more incidence of reactivation

– involvement of hilar lymph nodes rather than cavitaryand apical lesions in the lung

– M. avium-intracellulare –more common

FATE OF SECONDARY PULMONARY TUBERCULOSIS

• Either of the following– lesions may heal with fibrous scarring and

calcification.

– lesions may coalesce together to form larger area of tuberculous pneumoniaof tuberculous pneumonia

– Or produce progressive secondary pulmonary tuberculosis • Fibrocaseous tuberculosis

• Tuberculous caseous pneumonia

• Miliary tuberculosis

FIBROCASEOUS TUBERCULOSIS

• Massive central caseation necrosis, which may either form

– Cavitary lesion : break into a bronchus from a cavity. Also known as open tuberculosis may cause cavity. Also known as open tuberculosis may cause endobronchial, endotracheal, laryngeal andintestinal tuberculosis

– Non-cavitary : Remain as a soft caseous lesion without drainage into a bronchus or bronchiole

FIBROCASEOUS TUBERCULOSIS

1. The external surface shows thickened pleura

3. The cavity is lined by yellowish caseous necrotic yellowish caseous necrotic material. The lung tissue around the cavity is consolidated. The hilumshows a few enlarged and matted lymph nodes

FIBROCASEOUS TUBERCULOSIS

Sectioned surface of the lung shows a cavity in the apex of the lung

Morphological Features

• Gross– cavity is spherical with thick fibrous wall– lined by yellowish, caseous, necrotic material– lumen is traversed by thrombosed blood vessels– consolidation are seen around the wall of cavity– consolidation are seen around the wall of cavity– The overlying pleura may also be thickened

• Microscopic– shows eosinophilic, granular, caseous material– foci of dystrophic calcification– Coalesced tuberculous granulomas composed of epithelioid

cells, Langhans’ giant cells and peripheral mantle of lymphocytes

– outer wall of cavity shows fibrosis

Morphological Features

Complications of cavitary secondary tuberculosis

• Aneurysms of patent arteries crossing the cavity – haemoptysis

• Extension to pleura producing bronchopleuralfistulafistula

• Tuberculous empyema - deposition of caseous material on the pleural surface

• Thickened pleura - adhesions of parietal pleura

TUBERCULOUS CASEOUS PNEUMONIA

• high degree of hypersensitivity -spreadto rest of the lung producing caseouspneumoniaproducing caseouspneumonia

• Microscopically it shows – exudative formations

containing tubercle bacilli

– oedema, fibrin, polymorphs and monocytes

MILIARY TUBERCULOSIS• Lymphohaematogenous

spread of tuberculousinfection from primary focus or later stages of tuberculosis - systemic organs or isolated organorgans or isolated organ

• Infection into– Pulmonary vein :

disseminated or isolated organ lesion

– Pulmonary artery : restricting the development of lesions within the lung

MILIARY TUBERCULOSIS

The pleural (1) as well as sectioned surface as sectioned surface shows presence of minute (about pin-head sized) yellowish nodules with central necrosis called miliarytubercles (2)

MILIARY TUBERCULOSIS

• Lesions are millet seed-sized (1 mm diameter)

• Yellowish, firm areas • Yellowish, firm areas without grossly visible caseation necrosis

• Structure of tubercles with minute areas of caseation necrosis

MILIARY TUBERCULOSIS

Milliary TB of Spleen

References

• Robbinson's basic pathology 8 ed

• Harsh Mohan - Textbook of Pathology 6th Ed.

• Color atlas of pathology

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