TUBERCULOSIS (TBC)
TUBERCULOSIS (TBC)
General features
• Caused by Mycobacterium tuberculosis,
transmitted person to person as an aerosol.
• Very common infectious cause of death in
developing countries
• In developed countries, tbc is the disease of the
elderly, the urban poor, and the
immunosuppressed individual.
Primary pulmonary tuberculosis
• First exposure in an immunocompetent
infant/child:
• The inhaled bacteria implant close to the pleura.
The microbes are resistant to the killing
mechanisms of alveolar macrophages, and
multiple within these cells and alveoli, plus are
carried to the hilar lymph node.
• Dendritic cells in lymph nodes present
mycobacterial antigens to CD4+ T cells; CD4
TH1 lymphocytes produce IFN-γ which activate
macrophages.
Primary pulmonary tuberculosis
• 3 weeks after infection, a delayed
hypersensitivity response develops → caseating
granulomatous inflammation surrounds the
microbes. Caseous necrosis prevents the O2
supply of bacteria → their multiplication is
stopped, and the giant cells of Langhans type
phagocytose and kill the bacteria.
• Subpleural and lymph node caseating
granulomas (Ghon complex) heal with fibrosis
and secondary calcification.
Ranke - Ghon primary complex:
JCE Undervood:General and Systematic Pathology,Third edition, 2000.
Morphology of primary tuberculosis
Ranke - Ghon primary complex
hilar
lymphadenitis
supleural focus
of tuberculosis
Caseating granuloma in the lung
Central caseation, Langhans-type giant cell
Primary pulmonary tuberculosis
• Primary tbc induces hypersensitivity and
resistance;
• however, the foci of scarring may harbor viable
bacilli, and are the nidus for reactivation at a
later time.
Primary pulmonary tuberculosis
• In malnourished children, progressive pulmonary
tbc can develop.
• In developed countries, BCG-vaccination of
neonates achieves hypersensitivity and inhaled
bacteria are rapidly eliminated via generation of
microscopic foci of caseating granulomas.
Secondary pulmonary tuberculosis
(reactivation tbc)
• Host resistance is weakened; the primary
lesions reactivate or exogeneous reinfection
occurs, localized to the apex of one or both
upper lobes;
• LM: foci of consolidation with central caseation
and peripheral fibrosis (fibrocaseous tbc)
• May heal with fibrosis
Secondary pulmonary tuberculosis
bilateral apical lesions
JCE Undervood:General and Systematic Pathology,Third edition, 2000.
Bilateral caseating tuberculotic foci in the upper
lobes
Secondary pulmonary tuberculosis
(reactivation tbc)
• May transform into progressive pulmonary
tbc → the area of caseation expands →
dissemination via bronchi, blood
vessels, lymphatic vessels, and direct
extension to the pleura
Secondary pulmonary tuberculosis
(reactivation tbc)
• Erosion of bronchi → evacuates the
caseous center → cavities several cm in
diameter, termed cavernas develop: →
cavernous fibrocaseous tbc
• With coughing, the infective material
causes endobronchial, endotracheal,
laryngeal tuberculosis; within the lung,
• the bronchial dissemination is apicocaudal
Apical lung cavernas in tuberculosis,
drained by bronchus
Caseous necrosis affects the the wall of bronchi, drainage of the
caseous debris results in cavity (caverna) formation.
Sputum (infective!!!!)
Secondary pulmonary tuberculosis
(reactivation tbc)
• Erosion of pulmonary arteries →hematogeneous
dissemination in the lungs
• Erosion of pulmonary veins
→ usually small number of bacteria enter into the
systemic circulation: isolated-organ tuberculosis: renal
tuberculosis, genitary tuberculosis, tuberculous
meningitis, tuberculous osteomyelitis, etc.
→ If great number of bacteria enter into the systemic
circulation: miliary tuberculosis: small, visible (2 mm)
foci of caseating granulomas in meninges, parenchymal
organs, bones, etc.
Miliary tuberculosis, lung
JCE Undervood:General and Systematic Pathology,Third edition, 2000.
Miliary tuberculosis in lung
Cut surface of formaldehyde fixed specimen:
numerous small gray-white granulomas in the lung.
Miliary tuberculosis:
Numerous small
caseous granulomas
in the lung.
Secondary pulmonary tuberculosis
(reactivation tbc)
• Lymphatic spread: tuberculous
lymphadenitis in hilar nodes → venous
blood → right side of the heart →
pulmonary arteries → isolated miliary
tuberculosis of the lungs
• Tuberculous pleurisy in the vicinity of
cavernous fibrocaseous tbc
Clinical features of reactivation tbc
• Insidious onset; cytokine release: low grade
fever, malaise, anorexia, weight loss
• Increasing amount of sputum (infective!!!!) +
haemoptysis
• Pleuritic pain
• + symptoms of extrapulmonary manifestations
• Life-threatining forms: tuberculous meningitis,
miliary tbc
• Dg: demonstration of bacteria in sputum by acidfast stains or culture or PCR method; or in
tissues with Ziehl-Neelsen staining
Acid fast mycobacteria, Ziehl-Neelsen staining
CHRONIC INTERSTITIAL LUNG
DISEASES
Chronic interstitial lung diseases
Clinical:
• Chronic restrictive lung disease
• Dyspnoe
• Decreased lung volume
• Decreased lung compliance
Radiology: diffuse infiltrates
Chronic interstitial lung diseases
Pathology:
• Involves the alveolar epithelium and interstitium
• Chronic round cell inflammation, lymphocyte,
plasma cell, macrophages → interstitial fibrosis
• Advanced stage: parenchymal destruction and
scarring → end-stage socalled “honeycomb
“lung
with progression:
• Respiratory failure
• Pulmonary hypertension
• Chr cor pulmonale
Chronic interstitial lung diseases
Main Groups:
• Fibrosing diseases
• Granulomatous diseases
• Smoking-Related diseases
• Diffuse alveolary hemorrhage syndromes
Chronic interstitial lung diseases
Fibrosing diseases:
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Idiopathic pulmonary fibrosis
Nonspecific interstitial pneumonia
Cryptogenic organizing pneumonia
Pulm. involvement in connective tissue diseases
Pneumoconiosis
Idiopathic pulmonary fibrosis
• Idiopathic pulmonary fibrosis is a disorder of
unknown cause characterized by progressive
pulmonary interstitial fibrosis.
• Repeated cycles of epithelial activation/injury
→ abnormal repair resulting in excessive
fibroblast and myofibroblast proliferation; →
continuing deposition of collagen and ECM.
TGF-β1 is the likely driver by inducing fibrosis.
Idiopathic pulmonary fibrosis
Morphology
• Usual interstitial pneumonia (UIP): there is
heterogeneity of the histologic changes; new,
cellular fibroblastic foci with moderate
inflammation coexist with older, more densely
fibrotic areas.
• Destruction of the alveolar architecture leads to
honeycomb lung with dense fibrosis and cystic
spaces lined by hyperplastic type II
pneumocytes or bronchiolar epithelium
Idiopathic pulmonary fibrosis:
The wall of alveoli is lined by type II pneumocytes cuboid in shape.
Idiopathic pulmonary fibrosis
Clinical Course
• The disease typically has an insidious onset
• Between ages 40 and 70 years
• marked by dyspnoea on exertion and a dry
cough.
• Most have a gradual deterioration despite
therapies.
• Mean survival is 3 years or less; lung
transplantation is the only definitive therapy.
Nonspecific interstitial pneumonia
• Nonspecifc interstitial pneumonia (NSIP) is a
diffusely fibrosing disease of unknown etiology,
manifesting with chronic dyspnea and cough.
• The histologic pattern shows either cellular
pattern with moderate interstitial inflammation or
fibrosing pattern with diffuse patchy interstitial
fibrosis without the temporal heterogeneity seen
in UIP.
• The prognosis for NSIP is better than for UIP.
Cryptogenic organizing pneumonia
• Formerly called bronchiolitis obliterans
organizing pneumonia (BOOP)
• Histologically, there are loose fibrous tissue
plugs within bronchioles, alveolar ducts, and
alveoli, but there is no interstitial fibrosis or
honeycombing.
• Patients can spontaneously recover, although
most require steroid therapy.
Cryptogenic organizing pneumonia
loose fibrous plug fills the lumen of bronchiole and alveoli
Cryptogenic organizing pneumonia
loose fibrous plug fills the lumen of bronchiole
fibrous plug within bronchioles
Pulmonary involvement in connective tissue diseases
• Pulmonary involvement in connective tissue
diseases (e.g., systemic lupus erythematosus,
rheumatoid arthritis, and scleroderma) is
common;
• Patterns include NSIP, UIP, vascular sclerosis,
organizing pneumonia, and bronchiolitis.
Pneumoconiosis
Lung injury caused by inhaled mineral or
organic dusts, fumes
• Factors determining the health effect:
» Amount of dust retained
» Size and shape of particles, 1-5 micrometer is pathogenic
» Physicochemical properties
• Pulmonary alveolar macrophages play a central
role in the pathogenesis of lung injury by
promoting inflammationand producing reactive
oxygen species and fibrogenic cytokines.
Pneumoconiosis
Consequence:
• Tissue injury → interstitial fibrosis → chronic cor
pulmonale
• Tobacco smoking worsens the effects of all
inhaled mineral dusts, more so with asbestos than
with any other particle.
Pneumoconiosis
Coal workers pneumoconiosis (CWP)
• Inhalation of coal pigement
• Anthracosis; common, mild, asymptomatic
in urban inhabitants, tobacco smokers morphology:
small, harmless coal dust laden macrophages along
lymphatics and lymph nodes
Consequences: depends on duration and magnitude
of exposure
progressive massive fibrosis → pulmonary hypertension
→ chr cor pulmonale
Anthracosis
Coal dust laden macrophages outline the lymphatic chanels in black.
Anthracosis
Black coal dust laden macrophages.
Silicosis
• The most common pneumoconiosis in the world
• Occupational disease, sandblasting and hardrock mining
• Crystalline form: most toxic and fibrogenic
• It is associated with an increased susceptibility
to tuberculosis
Silicosis
Gross: small fibrotic nodules, dense scars
Silicosis
• Histology: whorls of acellular collagen with
birefringent silica particles under polarized light,
focal dystrophic calcification
Asbestosis
• Asbestos is a family of fibrous silicates.
Asbestos body.
golden brown fusiform rod
Chong S et al. Radiographics 2006;26:59-77
Asbestosis
Injuries caused by asbestos exposition:
• Parenchymal interstitial fibrosis (asbestosis)
• Localized pleural plaques and effusions, rarely,
diffuse pleural fibrosis
• Lung carcinoma, cigarette smoking increases
the risk, even family members of workers are at
increased risk
• Malignant mesothelioma
• Laryngeal carcinoma
Smoking-related interstitial diseases
• Respiratory bronchiolitis: macrophages
containg brown pigment in
bronchiolocentric” distribution
• Desquamative interstitial pneumonia:
intraalveolar collection of dusty brown
macrophages + patchy interstitial fibrosis
Desquamative interstitial pneumonia
Intraalveolar collection of dusty brown macrophages
+ patchy interstitial fibrosis
Diffuse alveolary hemorrhage syndromes
• Goodpasture syndrome
• Idiopathic pulmonary hemosiderosis
• Vasculitis-associated hemorrhage
Wegener granulomatosis
microscopic polyangiitis
SLE
Goodpasture syndrome. Severe lung hemorrhage.
Lung hemorrhage
Goodpasture syndrome.
Crescentic glomerulonephritis.
Punctuated hemorrhage
in the kidney.
Fibrin in a crescent.
Fibrin a félholdban.
Linear IgG along the GBM.
Granulomatous diseases
Hypersensitivity pneumonitis
• Immunologically mediated response to an
extrinsic antigen that involves both immune
complex and delayed-type hypersensitivity
reactions.
• Acute and chronic forms.
• Farmer's lung: Actinomycete spores in hay
• Pigeon breeder's lung: proteins from bird
feathers or excreta
• Humidifier or air-conditioner lung: bacteria in
heated water reservoirs
Granulomatous diseases
Hypersensitivity pneumonitis
Pathology:
• Patchy bronchiolocentric mononuclear cell
infiltrates in the pulmonary interstitium
• Interstitial noncaseating granulomas in more
than two thirds of cases
• In chronic cases, diffuse interstitial fibrosis
• Early cessation of exposure prevents the
development of fibrosis!
Hypersensitivity pneumonitis, farmer’s lung
small granulomas in the lung
Granulomatous diseases
Boeck sarcoidosis
General features:
• Multisystemic disease of unknown etiology
• Noncaseating epitheloid cell granulomas in
various tissues, organs
• 90% of cases involve hilar lymph nodes or lung
• Adults, younger than 40 years
• Women are involved more frequently than men
• Higher prevalence among nonsmokers
• American blacks 1Ox more often than whites
Granulomatous diseases
Boeck sarcoidosis
• Pathomechanism: disease of disordered
immune regulation in genetically predisposed
persons exposed to certain environmental
agents
• Several immunologic abnormalities in
sarcoidosis suggest the development of a cellmediated response to an unidentified antigen.
The process is driven by CD4+ helper T cells.
Granulomatous diseases
Boeck sarcoidosis
Dg:
• Characteristic chest x-ray: bilateral hilar
lymphadenopathy
• Lymph node or liver biopsy demonstrating
noncaseating granulomas
• Tbc and other granulomatous diseases
should be excluded!
Granulomatous diseases
Boeck sarcoidosis
Histology:
• Noncaseating epitheloid cell granulomas:
epitheloid cells, multinucleated giant cells,
CD4+ lymphocytes and depending on the
age of lesion fibrosis
• Schaumann bodies: laminated calcified
proteinaceous concreations
• Asteroid bodies: stellate inclusions within giant
cells
Boeck sarcoidosis, lymph node
noncaseating epitheloid cell granulomas
Boeck sarcoidosis
Asteroid body: stellate inclusion within giant cell
Granulomatous diseases
Boeck sarcoidosis
Organ involvement:
• Lymph nodes: most commonly in the hilar
region, bilateral hilar lymphadenopathy
• Lungs: diffuse scattered granulomas in the
interstitium, heal with hyalinized small scars
• Spleen and liver
• Skin, eye, parotis, bone marrow
Granulomatous diseases
Boeck sarcoidosis
clinical outcome:
• 7O% no or minimal residual manifestations
• 2O% permanent lung or ocular dysfunction
• 1O% die due to pulmonary fibrosis and cor
pulmonale, chr cardiac failure
OTHER UPPER AIRWAY
DISEASES
Rhinitis
Acute rhinitis ("common cold")
• Caused by adeno-, echo-, and rhinoviruses
• Produces erythematous and edematous nasal
mucosa with profuse catarrhal discharge
• May extend, producing a concomitant
pharyngotonsillitis
• Bacterial superinfection can induce
mucopurulent exudates
Rhinitis
Allergic rhinitis ("hay fever")
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•
•
Affects 20% of individuals
It is an IgE-mediated immune reaction
Mucosal edema and erythema, and
eosinophil-rich infiltrates
Nasal polyps
Nasal polyps „inflammatory pseudopolyps”
• Occur after recurrent rhinitis attacks
• Edematous mucosa infiltrated by neutrophils,
eosinophils, and plasma cells
• When multiple or large, they obstruct the airway
and impair sinus drainage, necessitating removal
Nasal polyps „inflammatory pseudopolyps”
Edematous mucosa infiltrated predominantly by eosinophyls.
Rhinitis
Chronic rhinitis
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Is a sequel to repeated attacks of acute rhinitis
May be microbial or allergic in origin
Deviated nasal septum or nasal polyps predispose
to infection
Frequently there is superficial desquamation or
ulceration of the mucosal epithelium
Variable cellular infiltrate of neutrophyls,
lymphocytes and plasma cells may be present
Suppurative infections sometimes extend into the
sinuses
Sinusitis
•
Commonly preceded by acute or chronic
rhinitis
•
Maxillary sinusitis can occur by extension of a
periapical tooth infection through the sinus floor
•
Offending organisms are normal oral
commensals (commonly mixed microbial flora)
Sinusitis
• Diabetics can develop severe chronic
sinusitis due to fungi (e.g.,mucormycosis)
• In Kartagener syndrome, (congenitally
defective cilia) is part of the triad:
sinusitis
bronchiectasis
situs inversus
Chronic sinusitis
Heavy mononuclear cell infiltrate. Eosinophils are
also present.
Nasopharynx Inflammation
Pharyngitis and tonsillitis
• Are frequent concomitants of viral upper
respiratory infections
• There is mucosal edema and erythema with
reactive lymphoid hyperplasia
• Bacterial superinfection exacerbates the
process, particularly in immunocompromised
individuals or children without protective
immunity
Nasopharynx Inflammation
Acut pharyngitis és tonsillitis
More severe forms of inflammation:
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•
Pseudomembranous nasopharingitis
Follicular tonsillitis
enlarged reddened tonsils due to reactive
lymphoid hyperplasia and dotted
pinpoints of exudate emanating from
tonsillar crypts
Nasopharynx Inflammation
Acut pharyngitis és tonsillitis
• Streptococcal „sore throats”
• caused β -haemolyticus streptoccus
Major significance: late sequela
Rheumatic fever
Acute poststreptococcal glomerulonephritis
Necrotizing Lesions of the Nose and Upper
Airways
1. Spreading fungal infections
2. Wegener granulomatosis
3. Lethal midline granulomas; an
angiocentric non-Hodgkin lymphoma
called nasal T cell lymphoma
WEGENER GRANULOMATOSIS
Oral mucosa: necrotising granulomatous
inflammation with vasculitis
A
cANCA
C
B
Lung: necrotising granulomatous
inflammation
D
Kidney: crescentic glomerulonephritis
Tumors of the Nose, Sinuses, and
Nasopharynx:
Nasopharyngeal angiofibroma
• Highly vascularized benign tumor
• Occurres in adolescent boys
• Serious bleeding can complicate surgical resection
Inverted papilloma
• Benign but locally aggressive neoplasm of squamous
epithelium
Olfactory neuroblastomas
• Uncommon, highly malignant tumors
• Composed of neuroendocrine cells
Nasopharyngeal carcinomas: as discussed before
Larynx, inflammations
Laryngitis
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•
Can be caused by allergic, viral, bacterial, or
chemical injury
Most common causes are nonspecific infection or
heavy tobacco smoke exposure
In children, Haemophilus infiuenzae laryngitis
Can be life threatening due to airway obstruction
from rapid onset severe mucosal edema
Larynx, inflammations
Rare forms of laryngitis
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•
tuberculotic
diphteric
LARYNGEAL TUMORS
Vocal cord nodules (polyp)
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Singers nodules
Inflammatory in origin
Often on true vocal cords
Fibrous tissue covered by stratified squamous
epithelium
Vocal cord nodule
Fibrous tissue covered by stratified squamous epithelium
Laryngeal papilloma
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Benign tumor
True vocal cords
Soft raspberry-like tumor less than 1 cm
Multiple fingerlike projections supported by a
fibrovascular core covered by stratified squamous
epithelium
• Trauma may cause hemoptysis
• Single in adults
• Multiple: juvenile laryngeal papillomatosis,
HPV 6 and 11, spontaneously regress
Laringeal papilloma
Multiple fingerlike projections supported by a fibrovascular core
covered by stratified squamous epithelium
Carcinoma of Larynx
• After the age of 4O.
• Male:female, 7:1
• Smoking, alcohol, asbestos exposure
Carcinoma of Larynx
Localization:
• Vocal cord carcinoma (60%-75%)
• Supraglottic carcinoma (25-40%)
• Subglottic carcinoma (5%)
Types:
1. Intrinsic: confined to the larynx
2. Extrinsic: arise or extends outside larynx
Carcinoma of Larynx
Gross:
• Early lesion cc in situ, later pearly gray, wrinkled
plaque on the mucosal surface
• With progression ulceration and fungation follows
Histology:
• 95% sqamous cell cc, rarely adenocarcinoma
• The surrounding epithelium may show dysplasia or
cc in situ
Carcinoma of larynx
Carcinoma of Larynx
• Prognosis: depends on location
• Vocal cord: better
- Immobility, symptoms early
- Sparse lymphatic supply
- spread beyond the larynx is rare
• Suppraglottic: bad
- Rich in lymphatics
- 1/3 already regional cervical lymph node
metastasis at the time of diagnosis
• Subglottic: worse, silent for longer period of time,
presents as advanced disease
Carcinoma of Larynx
Clinical features
• Symptoms: persistent hoarseness, pain,
dysphagia, hemoptysis
• Cause of death in one third of cases: infection,
metastasis, cachexia
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