patoloji-ders-notlari

Title

Serdar Balcı

Chronic Interstitial Lung Diseases

Serdar BALCI, MD

Chronic Interstitial Lung Diseases

Chronic Interstitial (Restrictive, Infiltrative) Lung Diseases

Heterogeneous group of disorders

Bilateral, often patchy, usually chronic

Involvement of the pulmonary connective tissue

Most peripheral and delicate interstitium in the alveolar walls

• Reduced compliance
  • More pressure is required to expand the lungs
  • They are stiff
• Increased effort of breathing (dyspnea)
• Abnormalities in the ventilation–perfusion ratio → Hypoxia
• Respiratory failure, pulmonary hypertension, cor pulmonale
• Advanced forms
  • Scarring and gross destruction of the lung
  • End-stage or “honeycomb” lung

Robbins Basic Pathology

FIBROSING DISEASES

IDIOPATHIC PULMONARY FIBROSIS

Idiopathic Pulmonary Fibrosis

• Cryptogenic fibrosing alveolitis
• Unknown etiology
• Patchy, progressive, bilateral interstitial fibrosis
• Males are affected more often than females
• 2/3 of patients >60 years at presentation
• Usual interstitial pneumonia
  • Radiologic and histologic pattern of fibrosis
• Progressive disease
  • Die in 3 yrs
  • Lung transplantation
• Caused by
  • Repeated cycles of epithelial activation/injury
  • Some unidentified agent
• Histopathologic features
  • Inflammation
  • TH2 response with eosinophils, mast cells, IL-4, and IL-13
  • Alternatively activated macrophages
  • Abnormal epithelial repair at the sites of damage and inflammation
  • Exuberant fibroblastic or myofibroblastic proliferation
  • Fibroblastic foci

from injured type I pneumocytes

Robbins Basic Pathology

• Retraction of scars along the interlobular septa → cobblestones
• Fibrosis
  • Lower lobe predominance
  • Subpleural regions and along the interlobular septa
• Usual interstitial pneumonia
  • Patchy interstitial fibrosis
  • Varies in intensity

Early stages

Alternating areas of light-colored fibrosis and normal lung

Autopsy Pathology: A Manual and Atlas

the degree of fibrosis increases and small subpleural cysts appear

Autopsy Pathology: A Manual and Atlas

visceral pleural surface becomes progressively more irregular

Autopsy Pathology: A Manual and Atlas

Late stage progressive cyst formation Honeycomb lung

Autopsy Pathology: A Manual and Atlas

**Usual interstitial pneumonia. The fibrosis is more pronounced in the subpleural region. **

Usual interstitial pneumonia. Fibrosis in the subpleural region.

Robbins Basic Pathology

Fibroblastic focus with fibers running parallel to surface and bluish myxoid extracellular matrix. Honeycombing is present to the left.

Robbins Basic Pathology

• Early lesions

  • Exuberant fibroblastic proliferation
  • Fibroblastic foci

• Over time

  • More collagenous
  • Less cellular

• Existence of both early and late lesions → temporal heterogeneity

• Dense fibrosis → collapse of alveolar walls → formation of cystic spaces

  • Honeycomb fibrosis

• Interstitial inflammation

  • Patchy
  • Lymphocytes and occasional plasma cells, mast cells, and eosinophils

• Secondary pulmonary hypertensive changes

  • Intimal fibrosis, medial thickening of pulmonary arteries

NONSPECIFIC INTERSTITIAL PNEUMONIA

Nonspecific Interstitial Pneumonia

Chronic bilateral interstitial lung disease

Unknown etiology

Distinct clinical, radiologic, and histologic features

Much better prognosis than that for IPF

• Histologic appearance
• Cellular pattern
  • Mild-to-moderate chronic interstitial inflammation
  • A uniform or patchy distribution
  • Better outcome than those with the fibrosing pattern and UIP
• Fibrosing pattern
  • Diffuse or patchy interstitial fibrosis
  • Without the temporal heterogeneity
• Fibroblastic foci and honeycombing –> in both variants

CRYPTOGENIC ORGANIZING PNEUMONIA

Cryptogenic Organizing Pneumonia

Bronchiolitis obliterans organizing pneumonia (BOOP)

Unknown etiology

Cough and dyspnea

Subpleural or peribronchial patchy areas of air space consolidation

• Histologic examination
  • Polypoid plugs of loose organizing connective tissue within alveolar ducts, alveoli, and often bronchioles
  • Connective tissue is all of the same age
  • Underlying lung architecture is normal

Cryptogenic organizing pneumonia

Alveolar spaces are filled with balls of fibroblasts (Masson bodies)

Adjacent alveoli are relatively normal, compressed

Robbins Basic Pathology

PULMONARY INVOLVEMENT IN COLLAGEN VASCULAR DISEASES

Pulmonary Involvement inCollagen Vascular Diseases

• Systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, dermatomyositis-polymyositis
• Several histologic variants can be seen
  • NSIP, UIP pattern, vascular sclerosis, organizing pneumonia, bronchiolitis
• Pleural involvement
  • Pleuritis, pleural nodules, and pleural effusion

PNEUMOCONIOSES

Pneumoconioses

• Non-neoplastic lung reaction to inhalation of mineral dusts
  • coal dust, silica, asbestos
• Diseases induced by organic as well as inorganic particulates
• Chemical fume- and vapor-induced non-neoplastic lung diseases

Robbins Basic Pathology

• Size, shape, solubility, and reactivity of the particles
  • >5-10 µm are unlikely to reach distal airways
  • <0.5 µm move into and out of alveoli, often without substantial deposition and injury
  • 1-5 µm in diameter are the most dangerous
    • Get lodged at the bifurcation of the distal airways
• Coal dust
  • Relatively inert
  • Large amounts required for clinically detectable disease
• Silica, asbestos, and beryllium
  • More reactive than coal dust
  • Fibrotic reactions at lower concentrations
• Dust is entrapped in the mucus blanket
  • Rapidly removed by ciliary movement
• Particles become impacted at alveolar duct bifurcations
  • Macrophages accumulate and engulf the trapped particulates
  • Particles activate the inflammasome and induce IL-1 production
• Inflammatory response, fibroblast proliferation, collagen deposition
• When particles enter lymphatics → amplification and extension of the local reaction
• Tobacco smoking worsens the effects of all inhaled dusts
  • espescially with asbestos

Coal Worker’s Pneumoconiosis

• Pulmonary anthracosis
  • Most innocuous coal-induced pulmonary lesion in coal miners
  • Commonly seen in all urban dwellers and tobacco smokers
  • Carbon pigment engulfed by alveolar or interstitial macrophages
  • Accumulate in the connective tissue along the lymphatics
  • Including the pleural lymphatics, in lymph nodes
• Simple CWP
  • Coal macules
  • Larger coal nodule
• Coal macule
  • Dust-laden macrophages
  • Small amounts of collagen fibers arrayed in a delicate network
  • Upper lobes and upper zones of the lower lobes
  • Centrilobular emphysema can occur
• Complicated CWP
  • Progressive Massive Fibrosis on a background of simple CWP
  • Coalescence of coal nodules
  • Years to develop
  • Multiple, intensely blackened scars
  • Larger than 2 cm, up to 10 cm
  • Consist of dense collagen and pigment

Progressive massive fibrosis in a coal worker

Large amount of black pigment is associated with fibrosis

Robbins Basic Pathology

Progressive massive fibrosis superimposed on coal workers’ pneumoconiosis

• 10% of cases of simple CWP progress to PMF
• If smoking-related risk has been taken into account
  • No increased frequency of lung carcinoma in coal miners
    • Different from silica and asbestos exposures

Silicosis

• Most prevalent chronic occupational disease in the world
• Inhalation of crystalline silica, in occupational settings
• Silica
  • Crystalline
    • Quartz, cristobalite, and tridymite
      • When mixed with other minerals, quartz has a reduced fibrogenic effect
        • Iron-containing hematite provides a protective effect
    • Most toxic and fibrogenic
  • Amorphous forms
• Particles interact with epithelial cells and macrophages
• Pulmonary macrophages
  • IL-1
  • TNF
  • Fibronectin
  • Lipid mediators
  • Oxygen-derived free radicals
  • Fibrogenic cytokines
• Anti-TNF monoclonal antibodies can block lung fibrosis in mice

Silicotic nodules

Early stages

Tiny, barely palpable, discrete, pale-to-blackened nodules

Upper zones of the lungs

Advanced silicosis

Scarring contracted the upper lobe into a small dark mass

Dense pleural thickening

Robbins Basic Pathology

Concentrically arranged hyalinized collagen fibers

Surrounding an amorphous center

Whorled appearance of the collagen fibers is distinctive for silicosis

Robbins Basic Pathology

• Polarized microscopy
  • Weakly birefringent silica particles in the center of the nodules
• Disease progresses
• Individual nodules may coalesce into hard, collagenous scars
• Progression to progressive massive fibrosis
• Lung parenchyma may be compressed or overexpanded
• Honeycomb pattern may develop
• Fibrotic lesions occur in the hilar lymph nodes and pleura
• Thin sheets of calcification occur in the lymph nodes
  • Radiographically as “eggshell” calcification
  • Calcium surrounding a zone lacking calcification
• End stage lung and heart diseases
• Silicosis is associated with an increased susceptibility to tuberculosis
  • Depression of cell-mediated immunity
  • Crystalline silica may inhibit the ability of pulmonary macrophages to kill phagocytosed mycobacteria
• Crystalline silica from occupational sources is carcinogenic in humans
  • The relationship between silica exposure and subsequent lung cancer is controversial

Asbestosis andAsbestos-Related Diseases

Occupational exposure to asbestos

Parenchymal interstitial fibrosis (asbestosis )

Localized fibrous plaques or, rarely, diffuse fibrosis in the pleura

Pleural effusions

Lung carcinomas

Malignant pleural and peritoneal mesotheliomas

Laryngeal carcinoma

**an asbestos body, revealing the typical beading and knobbed ends **

Robbins Basic Pathology

**an asbestos body, revealing the typical beading and knobbed ends **

Robbins Basic Pathology

Asbestos

Concentration, size, shape, and solubility of the different forms of asbestos affect pathogenesis

Two distinct forms of asbestos

Serpentine

Amphibole

Both are pathogenic for all diseases

Serpentine

Fiber is curly and flexible

Serpentine chrysotile accounts for most of the asbestos used in industry

Impacted in the upper respiratory passages and removed by the mucociliary elevator

**Those that are trapped in the lungs are gradually leached from the tissues, because they are more soluble than amphiboles **

Amphibole

Fiber is straight, stiff, and brittle

More pathogenic than the serpentine chrysotile

Align themselves in the airstream → delivered deeper into the lungs → penetrate epithelial cells to reach the interstitium

Both forms cause disease

• Increasing exposure to either form
  • associated with a higher incidence of all asbestos-related diseases
• Interaction of particulates with lung macrophages → fibrosis
• Functions as both a tumor initiator and a promoter
  • Reactive free radicals generated by asbestos fibers → mesothelial tumors
  • Potentially toxic chemicals adsorbed onto the asbestos fibers
    • Tobacco smoking

Asbestosis

Diffuse pulmonary interstitial fibrosis

Indistinguishable from UIP

Except for the presence of asbestos bodies

Asbestos Bodies

• Golden brown, fusiform or beaded rods with a translucent center
• Coated with an iron-containing proteinaceous material
• Formed when macrophages attempt to phagocytose asbestos fibers
  • The iron is derived from phagocyte ferritin
• Can be found in the lungs of normal persons
  • Much lower concentrations and without an accompanying interstitial fibrosis.

Robbins Basic Pathology

Asbestosis

• Begins in the lower lobes and subpleurally
  • In contrast with CWP and silicosis
• Middle and upper lobes of the lungs become affected as fibrosis progresses
• Contraction of the fibrous tissue
  • Distorts the normal architecture
  • Creating enlarged air spaces enclosed within thick fibrous walls
  • Affected regions become honeycombed
• Fibrosis develops in the visceral pleura
  • Adhesions between the lungs and the chest wall
• Scarring trap and narrow pulmonary arteries and arterioles
  • Pulmonary hypertension and cor pulmonale

Asbestosis

Markedly thickened visceral pleura covers the lateral and diaphragmatic surface

Severe interstitial fibrosis diffusely affecting the lower lobe

Robbins Basic Pathology

Pleural plaques

Most common manifestation of asbestos exposure

Well-circumscribed plaques of dense collagen

Often contain calcium

Most frequently on the anterior and posterolateral aspects of the parietal pleura and over the domes of the diaphragm

Do not contain asbestos bodies

**Rarely occur in persons with no history or evidence of asbestos exposure **

Uncommonly, asbestos exposure induces pleural effusion or diffuse pleural fibrosis.

Robbins Basic Pathology

Asbestosis

End stage lung and heart diseases

The risk of lung carcinoma is increased 5x

Mesothelioma risk 1000x

Concomitant cigarette smoking greatly increases the risk of lung carcinoma but not that of mesothelioma

DRUG- AND RADIATION-INDUCED PULMONARY DISEASES

Bleomycin

Anticancer agent

Pneumonitis and interstitial fibrosis

Direct toxicity of the drug

Stimulating the influx of inflammatory cells into the alveoli

Amiodarone

An antiarrhythmic agent

Associated with risk for pneumonitis and fibrosis

Radiation pneumonitis

• Complication of therapeutic irradiation of pulmonary and other thoracic tumors
• Acute radiation pneumonitis
  • 1-6 months after therapy
  • in as many as 20% of the patients
  • Fever, dyspnea out of proportion to the volume of irradiated lung, pleural effusion, and development of pulmonary infiltrates corresponding to the area of radiation
  • May resolve with corticosteroid therapy or progress
• Chronic radiation pneumonitis
  • Progress from acute form
  • Associated with pulmonary fibrosis

GRANULOMATOUS DISEASES

SARCOIDOSIS

Sarcoidosis

• A multisystem disease

• Unknown etiology

• Characterized by noncaseating granulomas in many tissues and organs

• Other diseases sometimes also produce noncaseating granulomas

  • mycobacterial or fungal infections and berylliosis

• Diagnosis of sarcoidosis is one of exclusion

• Bilateral hilar lymphadenopathy

• Lung involvement

  • Visible on chest radiographs

• Eye and skin involvement, 25% of cases

• Adults <40 year

• Danish and Swedish populations, African Americans (10x whites)

• Higher prevalence among nonsmokers

• Development of a cell-mediated response to an unidentified antigen

• Intra-alveolar and interstitial accumulation of CD4+ T H 1 cells

• Oligoclonal expansion of T cell subsets

• Increases in T cell–derived T H 1 cytokines

  • IL-2 and IFN-γ

• T cell expansion and macrophage activation

• Increases in several cytokines in the local environment

  • IL-8, TNF, macrophage inflammatory protein-1α

• Recruitment of additional T cells and monocytes

• Formation of granulomas

• Anergy to common skin test antigens

  • Candida or purified protein derivative (PPD)
  • Result from pulmonary recruitment of CD4+ T cells
  • Peripheral depletion

• Polyclonal hypergammaglobulinemia

• Association with HLA-A1 and HLA-B8

• After lung transplantation, sarcoidosis recurs in the new lungs in 75%

• Putative antigens have been proposed

  • Viruses, mycobacteria, Borrelia, pollen
  • No proof

Histopathologic feature of sarcoidosis

• Noncaseating epithelioid granuloma, irrespective of the organ involved
• Discrete, compact collection of epithelioid cells
• Rimmed by an outer zone of largely CD4+ T cells
• Epithelioid cells are derived from macrophages and are characterized by abundant eosinophilic cytoplasm and vesicular nuclei
• Intermixed multinucleate giant cells formed by fusion of macrophages
• A thin layer of laminated fibroblasts is present peripheral to the granuloma
• Over time
  • Entire granuloma with a hyalinized scar

Sarcoid

Characteristic peribronchial noncaseating granulomas with many giant cells

Robbins Basic Pathology

• Schaumann bodies
  • Laminated concretions composed of calcium and proteins
• Asteroid bodies
  • Stellate inclusions enclosed within giant cells
• They are not specific

Sarcoidosis

• Skin
  • Erythema nodosum
• Eye
  • Iritis or iridocyclitis
  • Corneal opacities, glaucoma, total loss of vision
  • Choroiditis, retinitis, and optic nerve involvement
• Lacrimal glands
  • Sicca syndrome
• Parotitis
  • Mikulicz syndrome
• Liver
• Spleen
• **Bone marrow **
• Hypercalcemia and hypercalciuria
  • production of active vitamin D by the mononuclear phagocytes in the granulomas

HYPERSENSITIVITY PNEUMONITIS

Hypersensitivity Pneumonitis

Allergic alveolitis

Occupational disease

Heightened sensitivity to inhaled antigens such as in moldy hay

The damage at the level of alveoli

Robbins Basic Pathology

• Bronchoalveolar lavage specimens
  • increased numbers of T lymphocytes of both CD4+ and CD8+ phenotype.
• Type III hypersensitivity
  • Specific precipitating antibodies in serum,
  • Complement and immunoglobulins within vessel walls by immunofluorescence
• Type IV hypersensitivity
  • Presence of noncaseating granulomas in 2/3 of patients
• Patchy mononuclear cell infiltrates in the pulmonary interstitium
• Characteristic peribronchiolar accentuation
• Lymphocytes predominate
• Plasma cells and epithelioid cells also are present
• Acute forms of the disease, neutrophils may be seen
• Interstitial noncaseating granulomas
  • peribronchiolar location
• Advanced chronic cases
  • Diffuse interstitial fibrosis occurs.

Hypersensitivity pneumonitis

Loosely formed interstitial granulomas and chronic inflammation are characteristic

Robbins Basic Pathology

PULMONARY EOSINOPHILIA

Pulmonary Eosinphilia

Infiltration and activation of eosinophils

Elevated levels of alveolar IL-5

Diverse diseases of immunologic origin

Acute eosinophilic pneumonia with respiratory failure

Rapid onset of fever, dyspnea, hypoxia

Diffuse pulmonary infiltrates on chest radiographs

Bronchoalveolar lavage fluid typically contains more than 25% eosinophils Prompt response to corticosteroids

Simple pulmonary eosinophilia

Loeffler syndrome

Transient pulmonary lesions

Eosinophilia in the blood

Alveolar septa are thickened by an infiltrate containing eosinophils and occasional giant cells

• Tropical eosinophilia
  • Infection with microfilariae and helminthic parasites
• Secondary eosinophilia
  • Association with asthma
  • Drug allergies
  • Vasculitis

Idiopathic chronic eosinophilic pneumonia

Aggregates of lymphocytes and eosinophils within the septal walls and the alveolar spaces

Periphery of the lung fields

SMOKING-RELATED INTERSTITIAL DISEASES

Smoking-Related Interstitial Diseases

• Obstructive pulmonary disease
  • Emphysema
  • Chronic bronchitis
• Restrictive or interstitial lung diseases
  • Desquamative interstitial pneumonia (DIP)
  • Respiratory bronchiolitis

Desquamative interstitial pneumonia

Accumulation of large numbers of macrophages

Abundant cytoplasm containing dusty-brown pigment

Smoker’s macrophages

Desquamative interstitial pneumonia

**Accumulation of large numbers of macrophages within the alveolar spaces, **

Slight fibrous thickening of the alveolar walls

Robbins Basic Pathology

• Alveolar septa are thickened
  • Sparse inflammatory infiltrate
    • Lymphocytes
  • Interstitial fibrosis
    • Mild
• Good prognosis with excellent response to steroid therapy and smoking cessation

Respiratory bronchiolitis

Pigmented intraluminal macrophages similar to DIP

Bronchiolocentric distribution

Mild peribronchiolar fibrosis