Pathology of COPD

The pathology encompasses various lesions in:

• Airways
• Lung parenchyma
• Pulmonary vasculature

These lesions are correlated with changes in:

• Pulmonary function tests
• Clinical appearances

Airflow obstruction is largely due to:

• Marked increase in airway resistance
• Structural abnormalities in various airway compartments

Emphysema

Defining Emphysema

A major problem in describing emphysema has been the lack of a generally accepted and easy-to-apply definition.

Early Definition (1959)

In 1959, a Ciba Guest Symposium defined emphysema in anatomical terms:

"A condition of the lung characterized by an increase beyond the normal of airspaces, distal to the terminal bronchiole, either from dilatation or from destruction of their walls."

Later Definitions

required destruction of respiratory tissue:

"Emphysema is a condition of the lung characterized by abnormal, permanent enlargement of the airspaces distal to the terminal bronchiole, accompanied by destruction of their walls."

This differentiates emphysema from "overinflation" (enlarged airspaces without destruction).

Defining Destruction

Destruction has been difficult to define unambiguously:

"Destruction is present when there is nonuniformity in the pattern of respiratory airspace enlargement, disturbing the orderly appearance of the acinus and its components."

Strict definitions
may eliminate airspace enlargement due to:

• Overinflation
• Failure of septation

However, these definitions wouldn't exclude changes due to reorganization of the airspaces such as is found in honeycomb lung.

CLASSIFICATION OF EMPHYSEMA

Emphysema is classified in terms of lung structure

The Acinus

Is the unit of lung structure distal to the terminal bronchiole, consisting of:

• Respiratory bronchioles
• Alveolar ducts
• Alveolar sacs
• Alveoli

Alveolar Ducts & Sacs

Alveolar ducts are entirely alveolated and contain smooth muscle around the mouths of their alveoli.

The walls of alveolar sacs are formed entirely by alveoli, without muscle.

Alveolar Pores of Kohn

Pores of Kohn, or alveolar vents, are normal components of adult alveoli, facilitating collateral ventilation.

They may also be an initial site of destruction, particularly in centriacinar emphysema.

Secondary Lobule of Miller

The acinus cannot be easily identified by gross examination. What can be seen instead is the secondary lobule of Miller

Defined as the tissue bounded on four sides by interlobular septa or pleura, generally 2–4 cm in size and containing 3-5 acini.

The terminal bronchiole and subtending respiratory bronchioles tend to be situated in the center of the lobule.

For this reason, “centrilobular” emphysema (CLE) and “panlobular” emphysema (PLE) are reasonable and widely used approximations for the more accurate “centriacinar” and “panacinar” emphysema

Emphysema Patterns

There are four recognized patterns of emphysema, depending on the involvement of the acini:

• Panacinar (or Panlobular) Emphysema
• Centriacinar (or Centrilobular) Emphysema
• Distal Acinar (or Paraseptal) Emphysema
• Irregular (or Paracicatricial) Emphysema

Panacinar (Panlobular) Emphysema

The acinus (and lobule) may be more or less uniformly involved.

Normally, the lung has a characteristic appearance under a microscope:

• Multifaceted alveoli contrast with larger, cylindrical conducting structures (alveolar ducts and respiratory bronchioles).

Loss of Distinction in PLE

In panlobular emphysema, the distinction between alveolar ducts and alveoli is lost as:

• Alveoli enlarge and lose their sharp angles.
• Alveoli and ducts lose contrast in size and shape.
• Results in a simplification of lung architecture, forming small box-like structures.

Progressive Changes in PLE

As the process worsens:

• The lung’s architecture becomes more deranged.
• Effacement and loss of the orderly arrangement of lung tissue occurs.
• Remaining structures are mainly the supporting framework of vessels, septa, and bronchi.

Unlike centrilobular emphysema, panlobular emphysema is usually more severe in the:

• Lower lobes of the lung.

Histological Features of PLE

The pattern is again:

• Simplification of the lung structure with diminishing contrast between alveoli and alveolar ducts.
• Pores of Kohn are more uniform and inconspicuous compared to centrilobular emphysema.

Associated Conditions

• α1-antitrypsin deficiency
Panlobular emphysema is the characteristic lung lesion
• Obliterative bronchiolitis or constrictive bronchiolitis.
may also occur as a consequence of permanent obliteration of airways

Parenchymal Changes After Obliteration

When airways are obliterated, the distal lung parenchyma may:

• Most often, Collapse with dilatation of proximal bronchi (as in postinfective bronchiectasis).
• In some instances, Remain expanded or become emphysematous if there is collateral ventilation.

depends on the amount of collateral ventilation between adjacent airspaces distal to unobstructed airways.

Centrilobular (Centriacinar) Emphysema

The proximal portion of the acinus (center of the lobule) may be dominantly involved.

This destructive lesion affects the respiratory bronchioles and characterized by:

• Enlarged, destroyed respiratory bronchioles coalesce in series and parallel.
• Forming sharply demarcated emphysematous spaces
• Separated from the acinar periphery by intact alveolar ducts and sacs.
• Walls contain variable amounts of black pigment.

• Irregular involvement of lobules.
• More common and severe in the upper zones of the lung.
• Most affected are the upper lobe (posterior and apical segments) and superior segment of the lower lobe.
• In severe CLE, destruction progresses toward the periphery of the lobule, blurring the distinction between CLE and panlobular emphysema (PLE).

Distal Acinar (Paraseptal) Emphysema

Alternately, the proximal portion of the acinus may be normal, and the distal part (alveolar sacs and ducts) may be dominantly involved.

Anatomic Distribution

Emphysema most striking:

• Adjacent to the pleura
  (Superficial / Mantel emphysema)
• Along lobular septa
  (Paraseptal emphysema)
• At margins of lobules and acini
  (Periacinar emphysema)
• Along vessels and airways
  → Linear pattern when cut longitudinally

Typical Distribution in the Lung

• Usually limited in extent
• Most common locations:
• Anterior & posterior parts of the upper lobe
• Posterior surface of the lower lobe
• When extensive → more severe in the upper half of the lung

Associated Pathologic Features

• Frequently associated with fibrosis between enlarged airspaces
• Often coexists with centriacinar emphysema
• Strong association with spontaneous pneumothorax
• Particularly in young, thin adults

Irregular Emphysema

Definition

Irregular emphysema is named due to the irregular involvement of the acinus.

Synonyms

• Scar emphysema
• Paracicatricial emphysema

Pathologic Features

Irregular emphysema is typically found adjacent to a scar.

• Most scars within the lung are small.
• Emphysema is usually limited in extent.

Severity and Distribution

• The severity depends on the extent of damage to the lung tissue.
• Multiple scars may lead to multiple foci of irregular emphysema.

Differential Diagnosis of Emphysema

Key Distinctions

Conditions characterized by gas trapping, non-emphysematous airspace enlargement, honeycomb lung, and combined emphysema and fibrosis need to be differentiated from emphysema.

Gas Trapping

Gas trapping may occur in several conditions, not all related to COPD.

Examples of Conditions with Gas Trapping

• Acute Asthma Attacks:
  • which lead to patient death
  • Lungs remain inflated with focal areas of atelectasis
• Long-standing Asthma:
  • Focal areas of atelectasis
  • Focal bronchiectasis, particularly in the anterior segment of the upper lobe
• Hypersensitivity Pneumonitis
• Connective Tissue Disease:
  • when it involves the small airways.

Important Diagnostic Notes

• Asthma does not cause parenchymal destruction.
• In asthma, gross, microscopic, and morphometric analyses will be normal.

Nonemphysematous Airspace Enlargement

In Infancy

Although not part of the COPD differential diagnosis,nonemphysematous airspace enlargement also occurs in infancy.

• Congenital Lobar Hyperinflation (Emphysema):
  • Lobes are overinflated, not emphysematous
  • Can be polyalveolar in some cases
• Genetic Abnormalities:
  • Enlarged airspaces due to failure of septation
  • Leads to simplified, not destroyed, alveolar framework

Senile Emphysema

The term senile emphysema was once used to describe airspace enlargement in the elderly.

• Lungs round out with increasing age.
• Post-59 years: only anteroposterior diameter increases, rounding lung dimensions (Ductectasia).
• No evidence of lung destruction, so not classified as emphysema.

Ductectasia

Aging results in an increase in alveolar duct air volume with shallower and flatter alveoli.

• Process termed ductectasia—a non-destructive lung change.

Compensatory Overinflation

When part of the lung collapses or is removed, the remaining lung can expand in a process called compensatory overinflation.

• No tissue destruction occurs, so this is not emphysema.
• Extent of expansion is thought to be modest, with equal expansion of all acinar parts.

Obstructive Overinflation

In adults, obstructive overinflation can occur with two possible mechanisms:

• Ball valve obstruction: Air enters on inspiration but doesn't leave on expiration.
• Complete bronchial obstruction: Air trapped behind collateral ventilation channels.

In both cases, the affected lung part expands significantly, but no tissue destruction occurs.

Honeycomb Lung

Overview

Honeycomb lung can occur in conditions like cryptogenic fibrosing alveolitis (usual interstitial pneumonia - UIP) and other fibrotic lung diseases.

It may be confused with emphysema, but has distinct characteristics.

Airspace Enlargement

While honeycomb spaces are enlarged airspaces, their cause is different from emphysema.

• Result from parenchymal remodeling
• Involves formation of new airspaces, not destruction of normal ones.

Wall Characteristics

Honeycomb spaces have thickened and irregular walls, which are very different from the acinar structure seen in emphysema.

• Walls are lined by bronchiolar epithelium.
• Often contain mucus.
• Well-collagenized connective tissue with varying amounts of muscle, fat, or even bone.

Interstitial Inflammation

Honeycomb lung often exhibits interstitial inflammation:

• Lymphocytic infiltration
• Plasma cell infiltration

Combined Emphysema and Fibrosis

Overview

The combination of emphysema and fibrosis (e.g., UIP) has been reevaluated in terms of its clinical, radiologic, and pathologic significance.

Although the definition of emphysema typically limits fibrosis, mixtures of both are commonly seen in smokers.

Smoking and Associated Conditions

Smokers are at higher risk for developing:

• Respiratory bronchiolitis-interstitial lung disease (RB-ILD)
• Idiopathic interstitial fibrosis (UIP)

The combination of these conditions with emphysema is not uncommon.

Clinical Impact

When emphysema is combined with UIP:

• Lung volumes may be preserved
• Diffusing capacity is markedly decreased
• Pulmonary hypertension develops, with a significantly negative prognosis

Radiologic Findings

CT scans show:

• Centrilobular or mixed centrilobular and paraseptal emphysema in the upper lobes
• Increased reticular markings and honeycomb remodeling in the lower lobes

Pathologic Findings

Pathology reveals:

• Gross and microscopic emphysema
• Interstitial fibrosis with fibroblast foci in areas of active fibrosis

Unresolved Question

It's still uncertain whether combined pulmonary fibrosis and emphysema represents a distinct entity or a mere clustering of two smoking-related conditions.

Lesions of the Large Airways in COPD

Overview

Most studies focus on lesions found when the clinical signs and symptoms of chronic bronchitis are present.

Gross Findings

The gross lesions in large airways are few and subtle:

• Bronchial Pits:
  • Dilated openings of mucus glands into the epithelium.
  • Located along the margins of cartilaginous rings and at airway bifurcations.

In Chronic Bronchitis

In chronic bronchitis, bronchial pits may become distended with mucus:

• Mucus may protrude into the lumen of the bronchus, visible grossly.
• These are not true diverticula, as
  • protrusions of normal ducts
  • they do not extend through all muscle coats of the bronchial wall.

Lesions of the Small Airways in COPD

Small airways in COPD refer to those with an internal diameter of 2 mm or less. Key features of small airway lesions in COPD include:

Intraluminal Mucus and Goblet Cell Metaplasia

- Intraluminal mucus is common in the small airways in COPD.

• Goblet cell metaplasia: Rare in normal small airways but frequent in COPD.
• There is a relationship between the degree of mucus occlusion and FEV1.

Wall Alterations in Small Airways

Small airway walls show significant alterations, including:

• Increased wall thickness in various compartments: epithelium, submucosa, smooth muscle, adventitia.
• Decreased diameter and airway deformity.
• These changes result in early airway obliteration.

Airway Obliteration

Airway obliteration occurs early, resulting in:

• Reduction in airways.
• Loss of alveolar attachments to the airway wall, leading to collapse during expiration.

Lesions of the Vessels in COPD

Alterations in Large Elastic Pulmonary Arteries

- No consistent alterations are found in the large elastic pulmonary arteries of subjects with COPD.

- Atheromata may be present, but only in the presence of pulmonary hypertension do these changes become more common. The incidence is comparable to a matched population without COPD.

Small Arteriole Changes in Smokers

- Cigarette smokers, with or without pulmonary hypertension, exhibit:

• Increased arterial muscle media thickness
• Intimal fibrosis in muscular arteries
• Progressive muscularization of small arterioles