Pathology of Interstitial Lung Diseases

Lung Structure

Airspace Compartment – respiratory bronchioles, alveolar ducts and alveoli

Interstitial Compartment – intervening supportive framework; contains alveolar septa, perivascular and peribronchial connective tissue

connective tissue is composed of reticulin and elastin fibrils and coarser collagen fibers Þ most prominent around large bronchovascular structures

Cells within the interstitium – fibroblasts, mast cells, tissue macrophages, lymphocytes

Type I Pneumocyte – flat and region of gaseous diffusion; vulnerable to injury
Type II Pneumocyte – polygonal and site of surfactant synthesis; can proliferate and reform alveolar epithelial surface

Barrier to gas exchange – alveolar epithelial cell, fused alveolar and capillary basement membrane and capillary endothelial cells

Pathogenesis of Interstitial Fibrosis – fibrous widening of interstitium is hallmark of chronic interstitial lung disease

Two Mechanisms

(1) Primary interstitial widening – edema and fibrosis formation directly within the interstitial compartment

examples: interstitial edema, sarcoidosis (thickening of interstitium initially by granuloma formation)

(2) Accretion – organization of exudate within the alveolar space that is converted to fibrous connective tissue and is incorporated into the interstitium; in some cases the exudate is cleared Þ resolution

examples: organizing pneumonia

End Stage Lung Disease – loss of characteristic feature of acute or subacute stages and see nonspecific fibrosis

Patterns (both can be present):

(1) Diffusely fibrotic

(2) Honeycomb – porous network of fibrous walled cysts that resembles a beehive or a sponge

if fibrosis involves pre-existent emphysematous areas, larger cysts may result

bullous panlobular emphysema has ß tissue consistency; more tissue consistency in honeycomb lung

abnormal cystic airspaces are lined by bronchiolar or alveolar epithelium

Characteristics Common to both patterns

alveolar destruction, bronchiectasis, bronchiolectasis and formation of fibrous septa between widely separated airspaces

clearance of intrapulmonary secretions is impaired leading to mucus stasis and secondary infection Þ Ý fibrosis

ß pulmonary capillaries Þ pulmonary HTN

vascular intimal sclerosis due to surrounding inflammation and morphological changes induced by hypoxia and HTN

right ventricle hypertrophy and cor pulmonale result from prolonged pulmonary HTN

Specific Types of Interstitial Lung Disease

(1) Diffuse Alveolar Damage (DAD) – acute interstitial injury

seen in Adult respiratory Distress Syndrome (ARDS) or called Shock Lung or Post-traumatic lung

sudden onset of respiratory failure with hypoxemia, Ý capillary permeability and diffuse alveolar infiltrates of CXR

pts require Ý inspired oxygen concentrations and ventilatory pressures

Etiology:

Primary Þ direct lung injury such as chest trauma/ viral pneumonia; acid aspiration or microemboli

Secondary Þ hypovolemic hemorrhagic or septic shock

Pathology: uniform regardless of cause indicating a stereotyped response of the lung to injury

Histology: three phases Þ exudative, proliferative and fibrotic

Exudative Phase: < 7 Days

Edema of the interstitial and intra-alveolar spaces
hyaline membrane and fibrinous exudate fill alveoli and alveolar ducts
necrosis of endothelial cell and type I pneumocyte

Proliferative Phase Days 7-20

hyperplasia of type II pneumocytes in an attempt to reconstitute the alveolar epithelial surface
influx of fibroblasts and inflammatory cells into the interstitium and into the intra-alveolar fibrinous exudate
collagen deposition by fibroblasts and alveolar exudate is converted to fibrous tissue and incorporated by accretion into the interstitium

Fibrotic Phase > 20 Days

organized fibrous tissue in a diffuse or interstitial pattern; honeycombing may be present
vascular remodeling

Pathogenesis - complex and not completely understood

injury leading to leukocyte chemoattraction by activated complement, platelet activating factor and thromboxane A2

leukocyte toxins contribute to lung injury

neutrophil proteases and O₂ metabolites (superoxide, hydrogen peroxide and hydroxyl radicals) injure lung tissue

leukocytes cause arachidonic acid metabolism; Leukotrienes are potent vasoconstrictors Þ Ý vasc. permeability

diffuse vascular injury is important in the pathogenesis and pathophysiology of ARDS Þ microthrombi and macrothorombi occur secondary to endothelial injury

platelet aggregation and activation Þ Ý serotonin Þ potent vasoconstriction

intimal fibrosis and medial muscle hypertrophy of the pulmonary arteries

(2) Chronic Interstitial Pneumonitis

Etiology – often unknown; often termed idiopathic interstitial pneumonitis or fibrosing alveolitis

viral pneumonia, autoimmune disorders (rheumatoid arthritis, scleroderma and dermatomyositis) pneumoconiosis (particularly asbestosis) or a drug reaction

Clinical Course – chronic; interstitial fibrosis and honeycombing develop in months or years

Histologic Features – similar to those seen in proliferative and fibrotic stages of DAD and include interstitial edema, type II cell hyperplasia and focal fibrosis

organizing intra-alveolar fibrin is usually less conspicuous in UIP than in DAD
microgranulomas or eosinophils in addition to the typical cellular infiltrate suggest the possibility of a hypersensitivity reaction
multifocal lung involvement by lesions of different ages; DAD involves the lung in a more uniform fashion

(a) Usual Interstitial Pneumonitis (UIP) – interstitial inflammatory infiltrate composed predominantly of lymphocytes and plasma cells

(b) Desquamative Interstitial Pneumonitis (DIP) – characterized by numbers of pigmented macrophages within alveolar spaces in addition to a usually mild chronic interstitial infiltrate

may be more responsive to steroids

(c) Lymphoid Interstitial Pneumonitis (LIP) – lymphocytes and plasma cells dominate the cellular infiltrate and rare much more numerous than in UIP

often associated with Sjogrens’s syndrome and dysglobulinemias
often difficult to distinguish between LIP and lymphoma involving the lung; LIP can progress to lymphoma

Pathology – not fully understood

may be related to immune complexes deposited in the alveolar walls causing complement activation and initiation of an inflammatory response

(3) Radiation Pneumonitis

follows irradiation of lung usually for a primary pulmonary neoplasm or cancer involving the mediastinum or chest wall

Clinical Course – insidious onset of respiratory symptoms, often delayed for 2-3 months from initial exposure

symptoms temporarily subside only to be followed by pulmonary fibrosis

Histology and Pathology – Acute or Chronic

Acute – initial onset of symptoms Þ resembles the early stages of DAD in ARDS in which fibrinous edema, hyaline membranes and epithelial hyperplasia are present

alveolar and bronchiolar epithelial cells become dysplastic, multinucleated and bizarre

endothelial cell injury is sever and blood vessels are nearly occluded by swollen endothelial cells

dense scar tissue and hyalinized vessels

Pathophysiology – formation of ion pairs by absorbed x-rays

ion pairs generate free radicals Þ break chemical bonds

radiation injury is intensified by hyperoxia Þ formation of irreversible organic peroxides

(4) Sarcoidosis

chronic, noncaseating granulomatous disease, with predilection to involve lung and lymph nodes

Etiology – unknown; may be a delayed hypersensitivity reaction

Histology – interstitial noncaseating granulomas distributed preferentially along lymphatic and bronchovascular pathways

granulomas composed of epithelioid histiocytes and Langhan’s giant cells which may contain intra-cytoplasmic asteroid or Schaumann bodies

granulomas become less cellular and more fibrotic as they age
chronic interstitial pneumonitis characterized by lymphocytic and plasma cell infiltrate

Clinical – may be diagnosed by transbronchial biopsy

granulomas may protrude into the airways causing obstruction
may lead to end stage lung

Differential Diagnosis – sarcoidosis is a diagnosis of exclusion; TB (usually caseating granulomas), fungi, berylliosis and hypersensitivity pneumonitis must be considered

(5) Organizing Pneumonitis (example: Pneumococcal pneumonia)

Etiology – bacterial infection, viral infection, inhalation of toxic fumes, drug reactions and collagen vascular disease

cause often remains unknown

Pathologic Progression – Resolution or Organization

(a) Resolution – complete clearing of the inflammatory exudate with restoration of lung architecture to normal

(b) Organization – conversion of the inflammatory exudate to fibrous tissue

also indicates subacute lung injury characterized by interstitial inflammation with lymphocytes and plasma cells and abundant exuberant organizing granulation tissue within alveolar lumens, alveolar ducts and respiratory bronchioles Þ intraluminal plugs of fibrous tissue are called Masson Bodies

bronchiolitis obliterans Þ fibrous tissue occlusion of respiratory bronchioles

Histology – similar to proliferative phase of DAD, but inflammation is often more intense, inta-alveolar granulation tissue is more prominent, and type II cell hyperplasia is less conspicuous

tends to be patchy; DAD is usually uniform throughout the lung

Clinical course – prolonged with a lesser degree of ventilatory impairment than patients with DAD

Prognosis – responds to corticosteroids; (UIP does not respond well to corticosteroids)

Note: Diffuse alveolar damage (DAD), organizing pneumonia and usual interstitial pneumonitis (UIP) have similar histological appearances reflective of the stereotyped response of the lung to a variety of insults. Remember that these three histological patterns reflect a injury to the alveolar–capillary unit and pulmonary interstitium and will progress to interstitial fibrosis.

Glossary of Terms of Interstitial Pneumonitis

Adult Respiratory Distress Syndrome (ARDS): A clinical term describing fulminant respiratory failure, often in previously healthy individuals, due to any one of a long list of causes.

(Synonyms: shock lung, respirator lung, post-traumatic pulmonary insufficiency)

Desquamative Interstitial Pneumonitis (DIP): A histopathologic term describing interstitial pneumonitis in which are seen numerous macrophages within alveolar spaces. DIP occasionally is the histologic pattern in patients with idiopathic pulmonary fibrosis.

Diffuse Alveolar Damage (DAD): A histopathologic term describing the pattern of lung injury in patients who clinically have the Adult Respiratory Distress Syndrome.

End-stage Lung: Fibrotic lung showing either diffuse fibrosis or honeycomb pattern. A non-specific response to a variety of inflammatory processes.

Extrinsic Allergic Alveolitis: An immune mediated process secondary to the inhalation of a variety of airborne organic dusts. Characterized histologically by chronic interstitial pneumonitis and non-caseating granulomas. (Synonyms: hypersensitivity pneumonitis, farmer's lung, etc.)

Hamman-Rich Syndrome (Idiopathic Pulmonary Fibrosis): Clinical term depicting the rapid evolution of interstitial pneumonitis and fibrosis, usually ending in death in weeks to months.

Honeycomb Lung: End-stage interstitial fibrosis in which contiguous cyst-like airspaces impart a honeycomb or sponge-like appearance to the lung.

Idiopathic Pulmonary Fibrosis (IPF): Interstitial pneumonitis and fibrosis of unknown etiology. Progresses to end-stage lung over a period of years. (Synonyms: cryptogenic fibrosing alveolitis, chronic interstitial pneumonitis, idiopathic interstitial pneumonitis and fibrosis.)

Lymphocytic Interstitial Pneumonitis (LIP): A histopathologic term describing a pattern of interstitial inflammation dominated by numerous lymphocytes and plasma cells. Considered to be a prelymphomatous condition.

Organizing Pneumonia: A histopathologic term describing a process characterized by intense interstitial inflammation associated with masses of granulation tissue (Masson bodies) in alveoli, alveolar ducts and respiratory bronchioles. Causes include partially treated bacterial pneumonia, toxic fume inhalation and viral injury. The histology overlaps that seen in the proliferative phase of DAD.

Usual Interstitial Pneumonitis (UIP): A histopathologic term describing the pattern of interstitial pneumonitis in patients with idiopathic pulmonary fibrosis, as well as a variety of other clinical disorders such as rheumatoid arthritis, asbestosis, viral pneumonia, etc. Occasionally, the term UIP is used incorrectly as a synonym for the clinical condition of Idiopathic Pulmonary Fibrosis.