Non-Neoplastic Conditions
Congenital Pulmonary Airway Malformation
Clinical Features
- •
Uncommon developmental anomaly predominantly seen in infants that has features of both immaturity and malformation of the airways and distal lung parenchyma (formerly congenital cystic adenomatoid malformation [CCAM])
- •
Often detected by antenatal ultrasound during the second trimester
- •
Reported incidence ranges from 1 in 25,000 to 35,000 pregnancies
- •
About 60% of lesions show variable, spontaneous regression during gestation
- •
Postnatal diagnosis of congenital pulmonary airway malformation (CPAM)
- •
About 66% present in the neonatal period either as an infant with respiratory distress (cyanosis, grunting, tachypnea) or as a stillborn infant with anasarca
- •
The remaining patients present later during childhood with recurrent pneumonia, cough, dyspnea, or cyanosis
- •
Unclear risk of development of malignancy in CPAM type 1
- •
Gross Pathology
- •
Masses of maldeveloped lung tissue composed of cystic or adenomatous overgrowth of terminal bronchioles and air spaces
- •
CPAM makes direct communication with the tracheobronchial tree through abnormal connecting bronchi
Histopathology
CPAM Type 0—Incompatible with Extrauterine Life
- •
Small lungs with finely nodular surface in infants who are often less than 50% of expected weight for gestational age; lesions appear solid grossly
- •
Disorganized proximal airways form the bulk of the lesion; distal components of the normal tracheobronchial tree are rarely present
- •
Mesenchymal cells and collagen—along with thick-walled arteries, large vascular channels, collections of basophilic debris, and foci of extramedullary hematopoiesis—form the prominent intervening tissue
CPAM Type 1
- •
Medium and large interconnecting cysts (1 to 10 cm) usually limited to one lobe
- •
Cyst walls composed of bronchial epithelium, often with clusters of mucous cells and smooth muscle bands with vascular connective tissue
CPAM Type 2
- •
Back-to-back, dilated bronchiolar-like cysts (0.5 to 2 cm) that blend with normal parenchyma
- •
Cysts separated by alveolar ductlike structures and small arterioles and venules and sometimes skeletal muscle ( Figure 4.1 )
Figure 4.1
Congenital pulmonary airway malformation.
Intermediate-power photomicrograph of H&E-stained section shows cysts lined by a single layer of ciliated columnar epithelial cells. The stroma contains cells with skeletal muscle differentiation (congenital pulmonary airway malformation, type 2).
- •
Associated with other severe anomalies in 50% of cases (sirenomelia, renal agenesis or dysgenesis, diaphragmatic hernia, and cardiovascular anomalies)
CPAM Type 3
- •
Original type of CPAM described in 1949 that occurs almost exclusively in males and is associated with maternal polyhydramnios in 80% of cases
- •
Lesion that forms a solid mass involving the lobe or even entire lung resulting in mediastinal shift and compression with subsequent hypoplasia of adjacent lung
- •
Composed of randomly arranged glandlike structures, less than 0.2 cm, resembling bronchioalveolar ducts lined with low cuboidal epithelium
CPAM Type 4
- •
Variable sized cysts are distributed peripherally and can involve more than one lobe
- •
Walls of larger cysts can be thick (0.1 to 0.3 cm) with muscular arteries
- •
Lined by single layer of pneumocytes with no immature cells in submucosa
- •
Overlapping features with regressed cystic pleuropulmonary blastoma
Special Stains and Immunohistochemistry
- •
Thyroid transcription factor-1 (TTF-1) and surfactant protein A and B label the epithelial lining of CPAM type 4 lesions
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
Pulmonary Sequestration
- •
Pulmonary sequestration has a systemic rather than a pulmonic blood supply and does not communicate with the tracheobronchial tree
- •
CPAM type 2 is seen within up to 50% of extralobar pulmonary sequestrations
Pleuropulmonary Blastoma
- •
CPAM type 1 does not have a subepithelial or septal mesenchymal spindle cell component (with or without cartilage)
- •
CPAM type 4 is lined by type 2 alveolar cells instead of the cuboidal or columnar cells seen in pleuropulmonary blastoma (PPB)
Consider congenital diaphragmatic hernia, bronchogenic cyst, congenital lobar emphysema.
- •
Diagnosis of CPAM cannot be made in the presence of chronic inflammation and fibrosis
- •
CPAM is reported to be rarely associated with the development of adenocarcinoma and rhabdomyosarcoma (RMS) in adolescent or adult patients
- •
Presence of mucinous epithelium and completeness of resection should be assessed to assist with follow-up
Selected References
Dehner L.P., Stocker J.T., Mani H., et. al.: The respiratory tract.Husain A.N.Stocker J.T.Dehner L.P.Stocker and Dehner’s Pediatric Pathology.2016.Lippincott Williams & WilkinsPhiladelphia:pp. 444-523.
Leblanc C., Baron M., Desselas E., et. al.: Congenital pulmonary airway malformation: state-of-the-art review for pediatrician’s use. Eur J Pediatr 2017; 176: pp. 1559-1571.
Stocker J.T.: Cystic lung disease in infants and children. Fetal Pediatr Pathol 2009; 28: pp. 155-184.
Bronchopulmonary Sequestration
Clinical Features
- •
Rare congenital malformation involving a segment of lung with no connection to the normal tracheobronchial tree and with anomalous systemic blood supply
- •
Two types: intralobar sequestration (ILS) and extralobar sequestration (ELS)
Gross Pathology
Intralobar Sequestration
- •
About 98% are within the lower lobe, and may be sharply demarcated from adjacent lung parenchyma
- •
Numerous cysts of variable size
Extralobar Sequestration
- •
Most common on left side; may be subdiaphragmatic, oval or pyramidal, circumscribed, pink to gray-white mass (0.5 to 15 cm)
- •
Covered with visceral pleura and separate from the normal lung
Histopathology
Intralobar Sequestration
- •
Similar to ELS
- •
May have marked chronic inflammation with mucus accumulation and microcyst formation when presenting in older children
Extralobar Sequestration
- •
Irregular, enlarged (2 to 5 times) bronchi, bronchioles, and alveoli ( Figure 4.2 )
Figure 4.2
Bronchopulmonary sequestration.
In this extralobar sequestration, there are too many dilated bronchioles (congenital pulmonary airway malformation) and normal-appearing lung. No cartilage was identified within the lesion.
- •
If present, bronchial structures range from normal to irregular lumens lined with pseudostratified columnar epithelium
- •
No significant inflammatory or fibrotic component is present
- •
Dilated subpleural lymphatics may be severe
- •
Areas of CPAM type 2 are present in up to half the cases
Special Stains and Immunohistochemistry
- •
Noncontributory
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
- •
CPAM: communicates with the tracheobronchial tree and has normal pulmonary arterial supply
- •
Consider bronchogenic cyst, congenital lobar emphysema, primary lung abscess
- •
ELS is frequently associated with CPAM type 2
- •
ELS is associated with other congenital anomalies, which determine the prognosis
- •
Ultrasound-detected lesions can partially or completely resolve
Selected References
Correia-Pinto J., Gonzaga S., Huang Y., et. al.: Congenital lung lesions—underlying molecular mechanisms. Semin Pediatr Surg 2010; 19: pp. 171-179.
Wong K.K.Y., Flake A.W., Tibboel D., et. al.: Congenital pulmonary airway malformation: advances and controversies. Lancet Child Adolesc Health 2018; 2: pp. 290-297.
Bronchogenic Cyst
Clinical Features
- •
Cystic lesion arising from anomalous budding of the tracheobronchial anlage of the primitive foregut during development
- •
Mostly located within the mediastinum, or less frequently at any point along tracheobronchial tree, but does not communicate with it
- •
Occasionally found peripherally in the lung parenchyma or within the cervical, intrapleural, or suprasternal cutaneous regions or occasionally below the diaphragm or pericardium
Gross Pathology
- •
Round to oval mass that molds around adjacent structures on radiograph
- •
Smooth-walled, unilocular or multilocular cystic lesion containing viscous fluid that may form an air-fluid level
- •
Cysts range from 1 to 10 cm ( Figure 4.3A )
Figure 4.3
Bronchogenic cyst.
A, Gross picture of a bronchogenic cyst that is smooth walled and unilocular. B, Microscopic picture of a 6-cm mediastinal cystic mass demonstrates respiratory epithelial lining, seromucinous glands, and cartilage.
Histopathology
- •
Thin-walled cyst lined by ciliated pseudostratified columnar epithelium ( Figure 4.3B )
- •
Wall composed of smooth muscle fascicles mixed with cartilage islands and seromucinous glands similar to the normal bronchus, without alveoli
- •
Squamous metaplasia or chronic inflammation commonly present
Special Stains and Immunohistochemistry
- •
Noncontributory
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
- •
CPAM: alveolar tissue can be present
- •
Mediastinal cysts: esophageal cyst (absence of cartilage, double muscular wall layer), enteric cyst (lined by gastric mucosa), thymic cyst, cystic teratoma, pericardial cyst
- •
Consider pulmonary sequestration, abscess, cystic bronchiectasis, postinfarction cyst, interstitial emphysema, pleuropulmonary blastoma
- •
Inflamed cysts may be difficult to definitively diagnose
- •
Malignant degeneration occurs very rarely in cystic lesions
Selected References
Chang Y.C., Chang Y.L., Chen S.Y., et. al.: Intrapulmonary bronchogenic cysts: computed tomography, clinical and histopathologic correlations. J Formos Med Assoc 2007; 106: pp. 8-15.
Correia-Pinto J., Gonzaga S., Huang Y., et. al.: Congenital lung lesions—underlying molecular mechanisms. Semin Pediatr Surg 2010; 19: pp. 171-179.
Maurin S., Hery G., Bourliere B., et. al.: Bronchogenic cyst: clinical course from antenatal diagnosis to postnatal thorascopic resection. J Minim Access Surg 2013; 9: pp. 25-28.
Congenital Lobar Emphysema
Clinical Features
- •
Hyperinflation of one or more lobes of the lung, often diagnosed on computed tomography (CT)
- •
Rare, with estimated prevalence of 1 in 20,000 to 30,000
- •
Males affected more than females (3:1)
- •
Most patients present within first 6 months of life with tachypnea, cyanosis, wheezing, and increased labor of breathing
- •
Recurrent pneumonia and failure to thrive can occur
Gross Pathology
- •
Hyperinflated lobe leads to compression of adjacent normal lung and mediastinal shift
- •
Upper lobes are involved in virtually all cases, with the left upper lobe being affected more commonly
- •
Enlarged lobe maintains appropriate shape
Histopathology
- •
Overinflation of the lobe with alveolar distention without fibrosis
Special Stains and Immunohistochemistry
- •
Noncontributory
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
- •
Pneumothorax: radiologically lacks the linear bronchovascular and alveolar markings of congenital lobar emphysema (CLE); treatments aimed at pneumothorax can worsen patient’s actual CLE
- •
Consider localized interstitial emphysema, CPAM, pulmonary sequestration, bronchogenic cyst, congenital diaphragmatic hernia
- •
Most cases are idiopathic
- •
Either intrinsic or extrinsic obstruction of the bronchus supplying the developing lobe is seen in 25% of CLE patients, leading to air trapping within the affected lobe
- •
Intrinsic obstruction is often secondary to defects in bronchial wall (e.g., decreased bronchial cartilage), whereas extrinsic obstruction is often caused by vascular malformations or intrathoracic masses (tumor, cyst)
- •
Cardiovascular anomalies are present in 14% of CLE patients
Selected References
Guidry C., McGahren E.D.: Pediatric chest I: developmental and physiologic conditions for the surgeon. Surg Clin North Am 2012; 92: pp. 615-643.
Shanti C.M., Klein M.D.: Cystic lung disease. Semin Pediatr Surg 2008; 17: pp. 2-8.
Obstructive Lung Diseases
Chronic Obstructive Pulmonary Disease
- •
Emphysema and chronic bronchitis share extensive overlap clinically and are often referred to as chronic obstructive pulmonary disease (COPD) which affects 3% to 5% of the US population
Emphysema
Clinical Features
- •
Emphysema is often present in patients with moderate or severe COPD, often with chronic bronchitis; less commonly, some patients have asthma associated with these disorders
- •
Onset typically occurs during midlife years with slowly progressive shortness of breath in patients with a long smoking history
Gross Pathology
- •
Proximal acinar or centrilobular emphysema is most often seen in cigarette smokers
- •
Panacinar or panlobular emphysema is seen in patients with α 1 -antitrypsin deficiency
- •
Distal acinar or paraseptal emphysema is characteristically found in the subpleural areas of the upper lobes and posterior aspects of the lower lobes, and it may be related to bullous disease or idiopathic spontaneous pneumothorax
- •
Irregular or scar emphysema is found at the periphery of scars, adjacent to healed granulomas, or in association with interstitial lung disease
Histopathology
- •
Emphysema is a pathologic term used to describe abnormal, permanent enlargement of air spaces distal to the terminal bronchioles due to destruction of the walls without fibrosis
- •
All forms of emphysema have a similar underlying histologic pattern of large, dilated alveoli, many with club-shaped septa projecting into the air spaces ( Figure 4.4 )
Figure 4.4
Emphysema.
The alveolar spaces are markedly enlarged with only minimal interstitial fibrosis. Note anthracosis and the club-shaped alveolar walls projecting into the spaces.
- •
No interstitial fibrosis is present, except for some peribronchial fibrosis associated with pigmented macrophages and chronic inflammation seen in smokers
- •
Secondary hypertensive changes are commonly present
Special Stains and Immunohistochemistry
- •
Noncontributory
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
Interstitial Emphysema
- •
Air dissects out of the alveolar spaces and into the loose connective tissue of the interlobular septa, the subpleural region, and around bronchovascular bundles forming clear cystic spaces
- •
There is too much air for the amount of lung parenchyma, even in atelectatic areas
- •
Inflating emphysematous lungs with formalin before taking histologic sections is recommended
Chronic Bronchitis
Clinical Features
- •
Clinically defined as a productive cough of unknown cause occurring on most days for 3 or more months for at least 2 successive years
- •
Most common in cigarette smokers and those exposed to dust or irritating fumes
Gross Pathology
- •
Increased mucus in the airways due to mucus hypersecretion
- •
Thickened bronchial wall due to mucous gland enlargement
Histopathology
- •
Mucus hypersecretion due to increased submucosal glands and goblet cell hyperplasia
- •
Enlargement and dilation of gland ducts
- •
Reid index is the ratio of gland thickness to bronchial wall thickness; Reid index greater than 0.5 is consistent with chronic bronchitis
- •
Chronic inflammation is mild and does not correlate with mucous gland enlargement
- •
Respiratory bronchiolitis is typically present in cigarette smokers
Special Stains and Immunohistochemistry
- •
Noncontributory
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
- •
Asthma: associated with eosinophils and sub-basement membrane fibrosis
- •
Diagnosis of chronic bronchitis requires exclusion of other causes of chronic cough, including lung carcinoma, bronchiectasis, cystic fibrosis (CF), congestive heart failure, and tuberculosis
Selected Reference
Travis W.D.: Non-neoplastic disorders of the lower respiratory tract.Atlas of Non-tumor Pathology. First Series, Fascicle 2.2002.American Registry of Pathology: Armed Forces Institute of Pathology; Universities Associated for Research and Education in PathologyWashington, DC:
Asthma
Clinical Features
- •
Chronic inflammatory disorder of the airways in which mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells play a pathophysiologic role
- •
Clinical diagnosis: episodic symptoms of airflow obstruction that is at least partially reversible, and alternative diagnoses ruled out
- •
Status asthmaticus is acute respiratory failure due to refractory bronchospasms with inflammation of the airway, mucus plugging, and edema, which may lead to death if untreated
Gross Pathology
- •
Plugging of bronchioles and medium and small bronchi with thick, tenacious mucus
- •
Hyperinflated lungs and secondary saccular bronchiectasis
Histopathology
- •
Mucus plugging of bronchi and bronchioles mixed with eosinophils, epithelial cells, and Charcot-Leyden crystals
- •
Curschmann spirals (mucus plugs) and creola bodies (whorls of desquamated epithelial cells) seen in sputum cytology
- •
Sub-basement membrane fibrosis with patchy desquamated or denuded epithelium ( Figure 4.5 )
Figure 4.5
Asthma.
A, This endobronchial biopsy from a treated asthmatic patient shows sub-basement membrane fibrosis and prominent smooth muscle bundles. B, High-power photomicrograph shows submucosal eosinophils and chronic inflammation.
- •
Goblet cell hyperplasia and occasional squamous metaplasia
- •
Thickened airway walls due to edema, smooth muscle hyperplasia, and submucosal gland hyperplasia
- •
Eosinophilic infiltration of medium and small bronchi—may be decreased or absent if patient is treated
Special Stains and Immunohistochemistry
- •
Noncontributory
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
- •
Chronic bronchitis: histologically similar but has few or no eosinophils
- •
Atopy is the strongest predisposing factor to developing asthma
- •
Eosinophilic inflammation is the hallmark of asthma but paucicellular asthma also occurs
- •
Can be complicated by allergic bronchopulmonary aspergillosis
Selected References
Gordon I.O., Husain A.N., Charbeneau J., et. al.: Endobronchial biopsy: a guide for asthma therapy selection in the era of bronchial thermoplasty. J Asthma 2013; 50: pp. 634-641.
Husain A.N.: The lung.Kumar V.Abbas A.K.Aster J.C.Robbins and Cotran Pathologic Basis of Disease.2020.SaundersPhiladelphia:
Bronchiectasis
Clinical Features
- •
Historically, most cases of bronchiectasis were secondary to infection; antibiotic therapy has led to a marked decrease in the incidence of abnormal irreversible bronchial dilation
- •
Causes of bronchiectasis include cystic fibrosis, primary ciliary dyskinesia, immunodeficiency, rheumatoid arthritis, inflammatory bowel disease, and graft-versus-host disease; 30% are idiopathic
- •
Patients present with persistent cough and large amounts of foul-smelling sputum
- •
High-resolution CT is the procedure of choice for noninvasive diagnosis
- •
Disease is radiologically classified into cylindrical, varicose, and saccular or cystic bronchiectasis
Gross Pathology
- •
Slightly less than 50% of cases are bilateral
- •
By definition, bronchiectasis is present when the diameter of the bronchus exceeds the diameter of the accompanying bronchial artery, ranging from mild to massive dilation
- •
Dilated bronchi are filled with yellow-green mucopurulent secretions
- •
Grossly dilated bronchi can extend out to the pleural surface
Histopathology
- •
Dilated bronchi filled with mucopurulent exudate or necrotic debris
- •
Mucosa shows varying degrees of necrosis or sloughing, inflammation, and reparative or metaplastic changes
- •
Chronic inflammation of bronchial wall with fibrosis is seen
- •
Follicular bronchiectasis describes cases with lymphoid hyperplasia
- •
Secondary pneumonia and constrictive bronchiolitis are often associated
Special Stains and Immunohistochemistry
- •
Noncontributory
Other Techniques for Diagnosis
- •
Screen for known causes of bronchiectasis, such as CF, immotile cilia syndrome
Differential Diagnosis
Postinfectious Bronchial Damage
- •
Commonly associated organisms: Pseudomonas aeruginosa, Mycobacterium avium-intracellulare, gram-negative bacilli, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, β-hemolytic streptococcus
Cystic Fibrosis
- •
CF is the most common cause of bronchiectasis in children and is invariably present among bronchiectasis patients older than 6 months
- •
Widespread bronchiectasis with mucus plugging of large and small airways, pleural adhesions or fibrosis, abscess, and cystic changes ( Figure 4.6 )
Figure 4.6
Cystic fibrosis.
A, Gross picture of the cut surface of the explanted lung shows dilated bronchi throughout. B, The dilated bronchi are thick walled and filled with green-yellow mucoid material.
Primary Cilia Dyskinesis
- •
Immotile cilia, Kartagener syndrome, Young syndrome, secondary cilia dyskinesis
- •
About 1.5% of patients with bronchiectasis have primary cilia dyskinesia
- •
Ultrastructural abnormalities affect virtually all cilia and are characterized by loss of dynein arms, absence of radial spokes, microtubule transposition, absence of microtubules, compound cilia, or disorientated cilia
Middle Lobe Syndrome
- •
Recurrent or permanent atelectasis of right middle lobe or lingula, with chronic inflammation
- •
Strong association with lymphadenopathy and malig-nancy
- •
Predisposing factors for the development of bronchiectasis include bronchopulmonary infection, bronchopulmonary obstruction, congenital anatomic defect, immunodeficiency states, hereditary abnormalities, and other rare miscellaneous factors
- •
Antibiotic therapy and prophylaxis for pediatric infections has resulted in a steep decline in the number of cases of bronchiectasis, with many cases in developed countries now due to an underlying disorder
- •
Can be complicated by allergic bronchopulmonary aspergillosis
Selected Reference
Barbareschi M., Cavazza A.: Non-neoplastic pathology of the large and small airways.Leslie K.O.Wick M.R.Practical Pulmonary Pathology: A Diagnostic Approach.2017.ElsevierPhiladelphia: 229–234
Small Airway Diseases
- •
See Table 4.1
TABLE 4.1
Clinical and Pathologic Features of Small Airway Diseases
Constrictive Bronchiolitis
Acute Bronchiolitis
Diffuse Bronchiolitis
Respiratory Bronchiolitis
Mineral Dust Bronchiolitis
Follicular Bronchiolitis
General features
Mainly involves terminal conducting airway
Associated with obstructive airway disease
Children and infants with wheezing and associated viral infection
Rare form affecting Asian adults, particularly Japanese
Common in cigarette smokers
Restrictive lung disease due to parenchymal fibrosis (pneumoconiosis)
Obstructive lesions due to external compression of the bronchioles
Histopathology
Peribronchiolar and submucosal fibrosis
Incomplete or complete luminal obliteration
Intense acute and chronic inflammation of small bronchioles
Infiltration of lymphocytes, plasma cells, and foamy macrophages
Prominent intraluminal neutrophils
Inflammatory infiltrate within respiratory bronchiole interstitium and adjacent alveoli
Deposits of inhaled dust primarily around respiratory bronchioles
Increased fibrosis
1- to 2-mm peribronchial nodules
Lymphoid hyperplasia and reactive germinal centers
Chronic inflammation
Epithelial metaplasia
Smooth muscle hyperplasia
Associated epithelial necrosis and sloughing
Edema
Inflammatory exudate in bronchiole lumen
Organization of exudate with polypoid plugs
Smooth muscle hypertrophy
Mild fibrosis
Prominent pigmented alveolar macrophages
Luminal narrowing
Hyperplasia of bronchus-associated lymphoid tissue (BALT)
Associated conditions
CVD
Infection (viral)
Inhalation injury
CHP
Drugs
Organ transplantation
IBD
Viral infection
Bacterial infection
Associated with human leukocyte antigen Bw54
Increased cold agglutinins, ESR, and leukocytosis
Inhalation of asbestos, iron oxide, aluminum oxide, talc, mica, silica, silicate, coal
N/A
CVD (rheumatoid arthritis, Sjögren syndrome)
Immunodeficiency (AIDS)
Infection (mycoplasma, tuberculosis)
Neuroendocrine cell hyperplasia
Multiple carcinoid tumorlets
Hypersensitivity reaction
Cystic fibrosis
Bronchiectasis
Chronic aspiration
CHP , Chronic hypersensitivity pneumonia; CVD , collagen vascular disease; ESR , erythrocyte sedimentation rate; IBD , inflammatory bowel disease.
Selected Reference
Barbareschi M., Cavazza A.: Non-neoplastic pathology of the large and small airways.Leslie K.O.Wick M.R.Practical Pulmonary Pathology: A Diagnostic Approach.2017.ElsevierPhiladelphia: 299–334
Restrictive And Interstitial Lung Diseases
Interstitial Pneumonias
Diffuse alveolar damage (DAD), acute respiratory distress syndrome (ARDS), acute interstitial pneumonia (AIP), and acute fibrinous and organizing pneumonia (AFOP)
Clinical Features
- •
Acute lung injury (ALI): form of lung injury which varies from noncardiogenic pulmonary edema to ARDS, caused by sepsis, shock, hypoxia, direct damage by inhalants, other organs not involved
- •
ARDS: clinical syndrome of severe fulminant form of ALI often with multiorgan involvement
- •
AIP: lung injury with no known etiology
- •
DAD: pathologic correlate of ARDS and AIP ( Table 4.2 )
TABLE 4.2
Clinical, Radiologic, and Prognostic Features of Idiopathic Interstitial Pneumonias
Clinical Diagnosis
Histologic Pattern
Duration of Illness
Distribution and Typical Computed Tomography Findings
Prognosis
IPF
UIP
Chronic (>12 months)
Subpleural predominance
Honeycombing
Reticular opacities
Traction bronchiectasis
Ground-glass opacities
5-year survival, 20% (2- to 3-year mean)
NSIP
NSIP
Subacute to chronic (months to years)
Subpleural, basal, symmetrical peribronchovascular ground-glass opacities
Reticular opacities
Lower lobe volume loss
Rare honeycombing
Cellular NSIP: 10-year survival, >90%
Fibrotic NSIP: 5-year survival, 90%; 10-year survival, 35%
COP
OP
Subacute (<3 months)
Subpleural, peribronchial patchy consolidation, nodularity
5-year survival, >95%
ARDS, ALI, AIP
DAD
Acute (1–2 weeks)
Lower zone, peripheral consolidation
Ground-glass opacities with lobular sparing
40%–60% mortality rate in <6 months
DIP
DIP
Subacute (weeks to months)
Subpleural predominance
Ground-glass opacities
Thin-walled cysts
Reticular opacities
Rare honeycombing
5-year survival, >95%
RB-ILD
RB
Subacute (weeks to months)
Diffuse bronchial wall thickening
Centrilobular nodules
Patchy ground-glass opacity
No deaths reported
AIP , Acute interstitial pneumonia; ALI , acute lung injury; ARDS , acute respiratory distress syndrome; COP , cryptogenic organizing pneumonia; DAD , diffuse alveolar damage; DIP , desquamative interstitial pneumonia; IPF , idiopathic pulmonary fibrosis; NSIP , nonspecific interstitial pneumonia; OP , organizing pneumonia; RB , respiratory bronchiolitis; RB-ILD , respiratory bronchiolitis–associated interstitial lung disease; UIP , usual interstitial pneumonia.
- •
AFOP: similar to DAD, but typical hyaline membranes lacking; organization of hyaline material into round balls that fill the alveoli
- •
Possibly related to DAD and often reported in connective tissue diseases
Gross Pathology
- •
Rigid, heavy, hemorrhagic lungs in exudative phase
- •
Firm, consolidated, pale-gray lungs in proliferative phase
- •
Spongy, cystic, pale-gray lungs in fibrotic phase
Histopathology
- •
DAD is bilateral and patchy ( diffuse refers to the whole alveolus, not the whole lung) with an early or exudative phase followed by a proliferative or organizing phase (but combinations can be seen) and a late fibrotic phase (in a minority of patients)
Exudative Phase (First Week after Injury)
- •
Type 1 pneumocyte necrosis, inflammatory exudate, hyaline membranes, partial alveolar collapse with interstitial edema ( Figure 4.7 )
Figure 4.7
Acute interstitial pneumonia.
This photomicrograph of the exudative phase shows patchy widening of interstitium due to hyaline membranes, edema, and a sparse inflammatory infiltrate in the lobule seen in the lower part of the picture, whereas the upper lobule is spared.
- •
Endothelial injury with congestion, neutrophil aggregates, and minimal microthrombi
Proliferative Phase (Second Week after Injury)
- •
Florid fibroblastic and myofibroblastic proliferation within interstitium and alveolar air spaces with type 2 pneumocyte proliferation
- •
Remnants of hyaline membranes occasionally seen within air spaces or incorporated into the interstitium
- •
Occasional squamous metaplasia with atypia
- •
Intimal proliferation, medial hypertrophy, and thrombi in small pulmonary arteries
Fibrotic Phase (Late)
- •
Thick interstitial fibrosis and microcyst formation
Special Stains and Immunohistochemistry
- •
Noncontributory
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
Infection
- •
Granulomas, viral inclusions (e.g., cytomegalovirus [CMV]), foci of necrosis, neutrophil aggregates, or microabscess formation
Usual Interstitial Pneumonia or Accelerated Usual Interstitial Pneumonia
- •
Fibrotic areas show temporal heterogeneity in UIP, whereas histopathologic changes in DAD are relatively uniform from field to field
- •
Fibrosis encountered in DAD contains more fibroblasts and myofibroblasts, more edematous stroma, and less collagen deposition
Diffuse Alveolar Damage in Patients with Collagen Vascular Disease
- •
Dermatomyositis, polymyositis, scleroderma, and rheumatoid arthritis may present with DAD pattern
- •
Acute lupus pneumonitis, Takayasu arteritis, polyarteritis nodosa, Behçet syndrome, and microscopic polyarteritis can present with an AIP-like clinical picture
- •
Hyaline membranes are a histologic hallmark of DAD and are seen in ARDS/AIP but are not present in UIP, nonspecific interstitial pneumonia (NSIP), or cryptogenic organizing pneumonia (COP)
- •
Diagnosis of AIP is considered in patients presenting with severe community-acquired pneumonia who fail to respond to appropriate antibiotic therapy and in whom no other causative etiology is identified
- •
The clinical course of AIP is rapidly progressive, with more than 78% (range, 60% to 100%) of patients dying within 6 months due to respiratory failure and right heart failure
- •
Most patients who recover from ALI/ARDS have near-normal lung function
Selected References
Beasley M.B., Franks T.J., Galvin J.R., et. al.: Acute fibrinous and organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage. Arch Pathol Lab Med 2002; 126: pp. 1064-1070.
Beasley M.B.: The pathologist’s approach to acute lung injury. Arch Pathol Lab Med 2010; 134: pp. 719-727.
Mukhopadhyay S., Parambil J.G.: Acute interstitial pneumonia (AIP): relationship to Hamman-Rich syndrome, diffuse alveolar damage (DAD), and acute respiratory distress syndrome (ARDS). Semin Respir Crit Care Med 2012; 33: pp. 476-485.
Obadina E.T., Torrealba J.M., Kanne J.P.: Acute pulmonary injury: high-resolution CT and histopathological spectrum. Br J Radiol 2013; 86: pp. 20120614. Epub 2013 May 9
Organizing Pneumonia
Clinical Features
- •
Organizing pneumonia (OP) can be observed in a variety of lung conditions including infections, drug reactions, inhalation, aspiration, adjacent to tumor or infarction, or as a component of interstitial lung disease
- •
If idiopathic, OP may represent clinical condition termed cryptogenic organizing pneumonia COP
- •
Prior terminology of bronchiolitis obliterans organizing pneumonia (BOOP) is now restricted to the post-transplant setting
- •
If COP, most patients recover after steroid therapy; however, there is a significant relapse rate 1 to 3 months after cessation of therapy
Gross Pathology
- •
See Table 4.2
Histopathology
- •
Intraluminal plugs (Masson bodies) composed of fibroblasts and myofibroblasts embedded in loose connective tissue that invariably occlude alveoli, alveolar ducts, and less frequently the bronchioles (bronchiolar component may be minor or absent) ( Figure 4.8 )
Figure 4.8
Organizing pneumonia.
A, Lower-power photomicrograph shows nodules of myxoid loose fibrous tissue filling alveolar spaces and streaming from one space to another. B, Nodules of young fibrous tissue (Masson bodies) are seen distending some alveolar spaces. The adjacent lung parenchyma is compressed and the alveolar walls are relatively normal.
- •
Patchy, bronchiolocentric distribution of Masson bodies, with extension into adjacent alveoli through the intra-alveolar pores of Kohn, giving a butterfly pattern
- •
Within the intraluminal plugs are small clusters of lymphocytes, plasma cells, histiocytes, and endothelial proliferation, resembling granulation tissue
- •
Mild chronic interstitial inflammation with foci of foamy macrophages
- •
Pertinent negatives: honeycombing, dense interstitial fibrosis, granulomas, neutrophils or abscess formation, necrosis, hyaline membranes or air space fibrin, predominant eosinophilic infiltrates, and vasculitis
Special Stains and Immunohistochemistry
- •
Loose connective tissue stains green with the Movat stain compared with the yellow staining pattern characteristic of dense fibrosis
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
Usual Interstitial Pneumonia
- •
Chronic clinical course
- •
Extensive, temporally heterogeneous pattern of fibrosis with dense scarring, honeycombing, and architectural destruction
- •
Fibroblastic foci of usual interstitial pneumonia (UIP) adjacent to areas of dense fibrosis, in contrast to the polypoid intraluminal location of connective tissue seen in OP
Nonspecific Interstitial Pneumonia
- •
Mild to moderate chronic interstitial inflammation or fibrosis without Masson bodies
Desquamative Interstitial Pneumonia
- •
Intra-alveolar finely pigmented smoker’s macrophages without Masson bodies
Acute Respiratory Distress Syndrome/Diffuse Alveolar Damage
- •
Patients are acutely ill
- •
Depending on time of biopsy, there is interstitial edema, hyaline membranes, type 2 pneumocyte hyperplasia, and organized fibrosis within alveolar walls and, occasionally, alveolar spaces
- •
COP is a distinct clinicopathologic diagnosis of exclusion employed when all other underlying causes of organizing pneumonia are excluded
Selected References
Cottin V., Cordier J.F.: Cryptogenic organizing pneumonia. Semin Respir Crit Care Med 2012; 33: pp. 462-475.
Roberton B.J., Hansell D.M.: Organizing pneumonia: a kaleidoscope of concepts and morphologies. Eur Radiol 2011; 21: pp. 2244-2254.
Usual Interstitial Pneumonia
Clinical Features
- •
UIP is a histologic pattern of lung disease that occurs in a variety of clinical settings; when no underlying disease is identified, the clinical diagnosis of idiopathic pulmonary fibrosis (IPF) is made
- •
Patients with IPF present with progressive, chronic exertional dyspnea associated with nonproductive cough
- •
Incidence of 7.4 to 10.7 cases per 100,000 and prevalence of 13 to 20 per 100,000 make IPF the most common type of idiopathic interstitial pneumonia (47% to 62%)
- •
Average age of onset is 67 years, with median survival of 3 years without therapy
- •
More common in males and smokers
- •
Other clinical conditions in which UIP pattern is seen include collagen vascular disease, drug toxicity, chronic hypersensitivity pneumonia, asbestosis, familial IPF, and Hermansky-Pudlak syndrome
Gross Pathology
- •
See Table 4.2
Histopathology of Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis
- •
Patchy fibrosis with subpleural and paraseptal distribution ( Figure 4.9 )
Figure 4.9
Usual interstitial pneumonia (UIP).
A, Patchy fibrosis is seen in the subpleural region, which is extending into deeper lung parenchyma, whereas some alveolar walls are not involved (variation in intensity). B, Fibroblastic focus is present in the submucosa of a small bronchiole (center right) in an area of honeycombing (fibrosis causing destruction of alveolar architecture with remaining air spaces lined by bronchiolar epithelium). C, Very large fibroblastic foci are seen here. Fibroblastic focus is a subepithelial area of young fibrosis with abundant myxoid intercellular matrix and fibroblasts running parallel to the airspace. Older (pink) collagen is seen adjacent to the fibroblastic foci (variation in time). D, Bronchiolar metaplasia and foci of acute and chronic inflammation, as seen here, are common in UIP.
- •
Areas of fibrosis adjacent to normal-appearing lung parenchyma creating a variegated appearance on low power (variation in intensity)
- •
Dense, pink fibrosis, which represents chronic scarring adjacent to pale, light blue, myxoid fibroblastic foci, which represent acute or active wound repair (temporal heterogeneity)
- •
Fibroblastic foci composed of parallel palisades of fibroblasts and connective tissue beneath hyperplastic type 2 pneumocytes or bronchiolar epithelium
- •
Minimal inflammation away from areas of fibrosis
- •
Microscopic honeycomb change (destruction of alveolar architecture with bronchiolar metaplasia) is present 90% of the time and is an important diagnostic feature
- •
Cystically dilated bronchioles lined by ciliated columnar respiratory epithelium within areas of fibrosis that replace normal alveoli
- •
Secondary traction bronchiectasis and peribronchiolar fibrosis with associated epithelial hyperplasia (peribronchiolar metaplasia) can also occur
- •
Lower lobes are most severely affected
Special Stains and Immunohistochemistry
- •
Noncontributory
Other Techniques for Diagnosis
- •
High-resolution CT scans often diagnostic in the appropriate clinical setting
Differential Diagnosis
Chronic Hypersensitivity Pneumonia with Fibrosis
- •
Predominantly bronchocentric and mostly involves upper lobes
- •
Poorly formed granulomas or scattered giant cells in addition to UIP pattern
- •
More cellular, less subpleural fibrosis, and less honeycomb change
Langerhans Cell Histiocytosis
- •
Stellate configuration and bronchiolocentric distribution of nodules
- •
Emphysematous changes prominent in longstanding cases
- •
Fibroblastic foci are rare
Organizing Pneumonia
- •
Lack of fibrosis or interstitial pneumonia away from intraluminal fibrosis
- •
Little or no architectural distortion
- •
Diagnosis of IPF/UIP is confounded by inadequate sampling, microscopic findings resembling other conditions (e.g., desquamative interstitial pneumonia [DIP]-like areas), and the fact that UIP-like fibrosis occurs in other conditions
- •
American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines define IPF as a distinct type of chronic fibrosing interstitial pneumonia of unknown cause limited to the lungs and associated with a surgical specimen showing a histologic UIP pattern
- •
If in addition to UIP, other histologic patterns of other interstitial lung disease are present (e.g., NSIP), the final diagnosis should be UIP associated with NSIP. This combination is suggestive of underlying connective tissue disease
- •
Clinician should identify cases of UIP associated with an underlying connective tissue disease because of the markedly better clinical course
- •
Cigarette smoking confers a 1.6- to 2.3-fold increased risk for developing UIP
- •
Fibroblastic foci are not specific to UIP but are always present in UIP and are a key feature for diagnosis
- •
Combined findings of UIP and DAD, capillaritis, infection, or organizing pneumonia with extensive fibroblastic proliferation are associated with an accelerated or acute phase of IPF and often represent the terminal phase of the illness
Selected References
Cipriani N.A., Strek M., Noth I., et. al.: Pathologic quantification of connective tissue disease-associated versus idiopathic usual interstitial pneumonia. Arch Pathol Lab Med 2012; 136: pp. 1253-1258.
Lynch D.A., Sverzellati N., Travis W.D., et. al.: Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society white paper. Lancet Respir Med 2018; 6: pp. 138-153.
Popper H.H.: Interstitial lung diseases-can pathologists arrive at an etiology-based diagnosis? A critical update. Virchows Arch 2013; 462: pp. 1-26.
Raghu G., Remy-Jardin M., Myers J.L., et. al.: Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 2018; 198: pp. e44-e68.
Takemura T., Akashi T., Kamiya H., et. al.: Pathological differentiation of chronic hypersensitivity pneumonitis from idiopathic pulmonary fibrosis/usual interstitial pneumonia. Histopathology 2012; 61: pp. 1026-1035.
Nonspecific Interstitial Pneumonia
Clinical Features
- •
Characterized by varying degrees of interstitial fibrosis and inflammation (cellular and fibrotic subtypes) and does not meet the criteria for other forms of idiopathic interstitial pneumonia
- •
Second most common subtype of idiopathic interstitial pneumonia that accounts for 14% to 36% of all idiopathic interstitial pneumonia
- •
Commonly recognized pattern in patients with connective tissue disease, hypersensitivity pneumonia, drug toxicity, and immunodeficiency
- •
Patients present with a subacute illness with dyspnea, cough, or fever and typically have a history of cigarette smoking
- •
Often steroid responsive
- •
5- and 10-year survivals near 80% and 70%, respectively; prognosis similar between idiopathic NSIP and NSIP secondary to connective tissue disease
Gross Pathology
- •
See Table 4.2
Histopathology
- •
Pertinent negatives: dense fibrosis, honeycombing, fibroblastic foci, granulomas, eosinophils, neutrophils, organisms, necrosis
Cellular Nonspecific Interstitial Pneumonia
- •
Diffuse interstitial lymphoplasmacytic infiltrate with no significant fibrosis and preservation of lung architecture
- •
Type 2 pneumocyte hyperplasia
- •
Minor features: focal organizing pneumonia, lymphoid aggregates, alveolar macrophages
Fibrotic Nonspecific Interstitial Pneumonia
- •
Mild to moderate amount of patchy loose to dense interstitial fibrosis causing uniform thickening of alveolar walls with preservation of lung architecture ( Figure 4.10 )
Figure 4.10
Nonspecific interstitial pneumonia.
The alveolar walls are uniformly thickened by mild fibrosis and mature small lymphocytes.
- •
Fibrosis lacks temporal heterogeneity of UIP (fibroblastic foci are inconspicuous or insignificant in number) and no honeycombing
- •
Mild to moderate chronic inflammation
- •
Minor features: organizing pneumonia, lymphoid aggregates, alveolar macrophages, bronchial metaplasia, metaplastic calcifications, or bone formation
Special Stains and Immunohistochemistry
- •
Noncontributory
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
Usual Interstitial Pneumonia Versus Nonspecific Interstitial Pneumonia
- •
Underlying lung architecture is preserved in NSIP
- •
Fibrosis is heterogenous in UIP and relatively more homogeneous in NSIP (fibrotic type)
- •
Fibroblastic foci and honeycomb fibrosis are rare or inconspicuous in NSIP
- •
Inflammation is relatively more abundant in NSIP (cellular type)
Hypersensitivity Pneumonitis
- •
Scattered, poorly formed granulomas and intraluminal fibrosis, which is bronchiolocentric in hypersensitivity pneumonitis
- •
NSIP pattern present in addition to granulomas
Lymphoid Interstitial Pneumonia
- •
Extensive, chronic alveolar septal inflammation with architectural distortion in lymphoid interstitial pneumonia versus mild, patchy inflammation in NSIP (cellular type)
Organizing Pneumonia
- •
Intraluminal plugs of fibrotic tissue within distal airways and alveoli
- •
NSIP is a diagnosis of exclusion; it lacks the features of UIP, DIP, COP, and DAD
- •
NSIP is the most common histologic pattern of lung damage observed in patients with collagen vascular disease
- •
Extensive lymphoid follicles or plasmacytic differentiation within interstitial infiltrates is suggestive of associated collagen vascular disease
Selected References
Belloli E.A., Beckford R., Hadley R., et. al.: Idiopathic non-specific interstitial pneumonia. Respirology 2016; 21: pp. 259-268.
Husain A.N.: Nonspecific interstitial pneumonia.Thoracic Pathology.2012.ElsevierPhiladelphia:pp. 69-70.
Desquamative Interstitial Pneumonia
Clinical Features
- •
Uncommon disease, which along with respiratory bronchiolitis–associated interstitial lung disease (RB-ILD), accounts for 10% to 17% of all interstitial pneumonias
- •
More than 90% of patients report current or past history of cigarette smoking
- •
DIP and RB-ILD likely represent different spectra of a single smoking-related interstitial lung disease
- •
Average age of onset is 46 years, with a male-to-female ratio of 2:1
- •
Subacute illness lasting weeks to months with dyspnea, cough, or chest pain; often resolves with cessation of smoking
Gross Pathology
- •
See Table 4.2
Histopathology
- •
Even, uniform filling of distal air spaces by cohesive clusters of pigmented alveolar macrophages with finely granular brown pigment within abundant cytoplasm ( Figure 4.11 )
Figure 4.11
Desquamative interstitial pneumonitis.
The alveolar spaces are filled with finely pigmented macrophages in a patient who also has emphysema (enlarged alveoli).
- •
Subtle to mild uniform interstitial fibrosis with hyperplasia of type 2 pneumocytes
- •
Scattered lymphoid aggregates, often with germinal centers
- •
Medial and intimal thickening of vascular structures
- •
Mild bronchiolar fibrosis with minimal inflammation
- •
Pleural inflammation and fibrosis sometimes present along with dilated pleural lymphatics
- •
Negative findings: architectural remodeling, dense fibrosis, honeycombing, fibroblastic foci
Special Stains and Immunohistochemistry
- •
Prussian blue stain for iron demonstrates finely granular pigment within macrophages that contrasts with coarse brown hemosiderin granules associated with pulmonary hemorrhage
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
Respiratory Bronchiolitis–Associated Interstitial Lung Disease
- •
Bronchiolocentric accumulation of macrophages with sparing of distal air spaces in RB-ILD, whereas DIP has more extensive and diffuse changes
- •
RB-ILD associated with more benign clinical course
Usual Interstitial Pneumonia
- •
DIP lacks the architectural distortion and honeycombing seen in UIP
- •
Fibrous component of DIP (if present) is mild and without fibroblastic foci
Nonspecific Interstitial Pneumonia
- •
Cellular NSIP: increased interstitial inflammation, few alveolar macrophages
- •
Fibrosing NSIP: interstitial fibrosis, few alveolar macrophages
Focal, Nonspecific Desquamative Interstitial Pneumonia-Like Reactions
- •
Likely represent RB-ILD and often seen around scar, tumor, or infarction
- •
DIP-like condition described in infants with mutations in the SP-C gene coding for surfactant protein C
- •
DIP and RB-ILD lesions can persist for long periods of time after smoking cessation
- •
Reported association of DIP with sirolimus therapy
- •
DIP pattern can be identified, focally, in numerous other types of ILD
- •
Significant overlap between smoking-related ILD processes
Selected References
Godbert B., Wissler M.P., Vignaud J.M.: Desquamative interstitial pneumonia: an analytic review with an emphasis on aetiology. Eur Respir Rev 2013; 22: pp. 117-123.
Konopka K.E., Meyers J.L.: A review of smoking-related interstitial fibrosis, respiratory bronchiolitis, and desquamative interstitial pneumonia: overlapping histology and confusing terminology. Arch Pathol Lab Med 2018; 142: pp. 1177-1181.
Lymphoid Interstitial Pneumonia
Clinical Features
- •
True idiopathic LIP is extremely rare
- •
Historically, most cases previously diagnosed as LIP were likely low-grade B-cell lymphomas, typically marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type (discussed later)
- •
In children, LIP is a common manifestation of HIV infection and establishes the diagnosis of AIDS
- •
In adults, LIP can be associated with HIV, AIDS, or other immunocompromised states
- •
Clinical presentation in children includes recurrent bacterial and viral infections, failure to thrive, parotiditis, and occasionally respiratory failure
Gross Pathology
- •
Scattered nodular solid areas
Histopathology
- •
Extensive diffuse interstitial chronic inflammation, comprised of mainly mature lymphocytes, plasma cells, and histiocytes ( Figure 4.12 )
Figure 4.12
Lymphoid interstitial pneumonia.
There is a marked mononuclear cell infiltrate in the alveolar septa and around blood vessels and airways partially obliterating lung architecture in this 5-year-old with AIDS.
- •
Minimal to mild interstitial fibrosis and germinal centers may be present
Special Stains and Immunohistochemistry
- •
Not monoclonal; stains for fungi and bacteria are negative
Other Techniques for Diagnosis
- •
Epstein-Barr virus (EBV) can be detected in most cases by in situ hybridization
Differential Diagnosis
- •
Viral pneumonitis: may need to be determined by serologic testing
- •
Pathogenesis of LIP is unknown and presumably caused by the direct effects of HIV on the lung tissue
- •
EBV plays a cofactor in triggering the lymphoproliferative response; however, EBV is not isolated from all patients with the disease
- •
LIP does not progress to interstitial fibrosis of the lung in children or adults
Selected References
Panchabhai T.S., Farver C., Highland K.B.: Lymphocytic interstitial pneumonia. Clin Chest Med 2016; 37: pp. 463-474.
Tian X., Yi E.S., Ryu J.H.: Lymphocytic interstitial pneumonia and other benign lymphoid disorders. Semin Respir Crit Care Med 2012; 33: pp. 450-461.
Hypersensitivity Pneumonitis
Clinical Features
- •
Bilateral, interstitial granulomatous lung disease representing an immune-mediated reaction to inhaled organic antigens or chemicals, with upper lobe predominance
- •
More than 200 different organic antigens are associated with HP, with thermophilic actinomycetes and avian proteins responsible for most cases
- •
Prevalence ranges from 5% to 15% of the population exposed to known inciting antigens
- •
Acute HP: onset within 4 to 8 hours of exposure to high levels of antigen and resolves within 24 to 48 hours
- •
Subacute HP: continuous or intermittent exposure to low levels of antigen; symptoms can resolve following steroid treatment and removal of offending antigen
- •
Chronic HP: similar to subacute HP, but fibrosis is present, and long-term prognosis is worse
Gross Pathology
- •
Patchy to diffuse ground-glass opacities on CT
- •
Poorly defined centrilobular nodules corresponding to cellular bronchiolitis, organizing pneumonia, or peribronchiolar interstitial pneumonitis
Histopathology
- •
Acute phase: biopsy rarely done, but can show patterns of acute lung injury, organizing pneumonia, or granuloma formation
- •
Subacute phase
- •
Small, poorly formed, nonnecrotizing granulomas with occasional multinucleated giant cells and a patchy mononuclear cell infiltration consisting of lymphocytes and plasma cells adjacent to respiratory or terminal bronchioles ( Figure 4.13 )
Figure 4.13
Hypersensitivity pneumonitis.
A, Poorly formed granulomas with multinucleated giant cells are seen in centrilobular location (adjacent to small arteries) in this patient with subacute HP. There are macrophages and lymphocytes but, typically, no eosinophils. B, Chronic HP shows the typical UIP pattern with fibrosis, fibroblastic foci, and honeycombing.
- •
Large histiocytes with foamy cytoplasm present in the alveoli and the interstitium
- •
Chronic phase: HP has three distinct histologic patterns
- •
UIP-like pattern: subpleural, patchy, pauci-cellular fibrosis and architectural distortion; fibroblastic foci; focal areas of subacute HP pattern
- •
Fibrotic NSIP-like pattern: homogeneous, linear fibrosis with preservation of lung architecture
- •
Irregular peribronchiolar pattern: peribronchiolar fibrosis; additional UIP-like pattern of subpleural fibrosis
Special Stains and Immunohistochemistry
- •
Negative fungal and acid-fast bacilli (AFB) stains
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
Nonspecific Interstitial Pneumonia
- •
Granulomas and giant cells are not features of NSIP
- •
NSIP may be the sole histologic lesion of HP, and careful exposure history potentially is the best method to distinguish NSIP from HP in these cases
Usual Interstitial Pneumonia
- •
Giant cells and granulomas are not features of UIP
- •
Peribronchiolar fibrosis and upper lobe predominance favor HP
UIP is most severe in lower lobes with subpleural distribution
Lymphoid Interstitial Pneumonia
- •
More prominent interstitial lymphoid infiltrate with extensive alveolar septal involvement
- •
Granulomas and intraluminal fibrosis are less common in LIP (5% in LIP versus 67% in HP)
Sarcoidosis
- •
Granulomas are well-formed, tightly packed, and sharply delineated with a hyalinized rim and are distributed along bronchovascular bundles and pleura
- •
Intraluminal fibrosis and UIP-like or NSIP-like component absent in sarcoidosis
- •
Best diagnosed by wedge biopsy
- •
The chronic form of HP is the type that will eventually be biopsied
- •
Chronic hypersensitivity pneumonitis has a fibrotic component that resembles UIP
- •
Presence of fibrosis on lung biopsy is an important poor prognostic factor
- •
If a known history of exposure exists, but the biopsy shows only NSIP-like or UIP-like fibrosis, the possibility of chronic HP should be considered
- •
About 95% of HP cases occur in nonsmokers
Selected References
Myers J.L.: Hypersensitivity pneumonia: the role of lung biopsy in diagnosis and management. Mod Pathol 2012; 25: pp. S58-S67.
Selman M., Pardo A., King T.E.: Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am J Respir Crit Care Med 2012; 186: pp. 314-324.
Spagnolo P., Rossi G., Cavazza A., et. al.: Hypersensitivity pneumonitis: a comprehensive review. J Investig Allergol Clin Immunol 2015; 25: pp. 237-250.
Eosinophilic Lung Diseases
Clinical Features
- •
Eosinophilic lung diseases are classified into three major categories
- •
Eosinophilic lung disease of unknown etiology
- •
Simple pulmonary eosinophilia/Löffler syndrome (SEP)
- •
Acute eosinophilic pneumonia (AEP), onset <1 month
- •
Chronic eosinophilic pneumonia (CEP), onset >1 month
- •
Eosinophilic lung disease of determined cause
- •
Allergic bronchopulmonary aspergillosis (ABPA)
- •
Bronchocentric granulomatosis (BCG)
- •
Parasitic infections
- •
Drug reaction
- •
Eosinophilic vasculitis
- •
Allergic angiitis
- •
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
Acute Eosinophilic Pneumonia
- •
Acute onset of respiratory distress in an otherwise healthy person, mimicking infectious pneumonia
- •
Diagnostic criteria include high eosinophil percentage on bronchoalveolar lavage (BAL) (>25%), but peripheral blood eosinophil percentages usually normal at time of presentation (rises in a few days)
- •
Associated with cigarette smoke (in two thirds) and dust exposure
- •
Bilateral patchy areas of ground-glass opacities with interstitial thickening on CT
- •
Histologic appearance similar to acute phase of diffuse alveolar damage but with alveolar and interstitial eosinophilic infiltrates ( Figure 4.14 )
Figure 4.14
Eosinophilic pneumonia.
Marked eosinophilic infiltration is seen both in the interstitium and in the alveolar spaces with eosinophilic abscess, fibrinous exudate, and reactive type 2 pneumocytes. The presence of occasional giant cells raises the differential of Langerhans cell histiocytosis.
- •
Hypertrophic, detached type 2 pneumocytes without disruption of the basal lamina
- •
Prompt and complete clinical response to corticosteroid therapy
Chronic Eosinophilic Pneumonia
- •
Peripheral eosinophilia ranging from mild to severe
- •
Elevated IgE in 7% of patients
- •
Peripheral consolidation, most commonly involving the middle and lower zones (reversed pulmonary edema pattern on CT)
- •
Eosinophils, lymphocytes, and deeply eosinophilic macrophages (forming pseudogranulomas) in the intra-alveolar air spaces and interstitium; eosinophilic microabscesses
- •
Damage to the basal lamina with subsequent interstitial and intra-alveolar fibrosis in 50% of patients
Special Stains and Immunohistochemistry
- •
Noncontributory
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
- •
Asthma, drug reaction, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
- •
Some fungal infections (e.g., aspergillosis, coccidioidomycosis)
- •
Parasite infestation
- •
Allergic reaction: Entamoeba, Toxocara species; Clonorchis sinensis
- •
Direct invasion: Ascaris lumbricoides infection (strong association with SEP), schistosomiasis, Paragonimus westermani, Ancylostoma duodenale infection
- •
Others: dirofilariasis, Strongyloides stercoralis, Wuchereria bancrofti, and Brugia malayi infection
- •
The diagnosis of eosinophilic lung disease can be made if any of the following are present: pulmonary opacities with peripheral eosinophilia, biopsy-proven tissue eosinophilia, or increased eosinophils in BAL
- •
CEP can be histologically differentiated from AEP based on the greater extent of interstitial and alveolar fibrosis and fewer eosinophils in chronic disease
- •
White blood cell differential count is a crucial aspect of the evaluation because most eosinophilic lung diseases manifest with peripheral eosinophilia
- •
Charcot-Leyden crystals are bipyramidal crystals that may be present in sputum or tissue and are a hallmark of eosinophil-related disease
Selected References
Akuthota P., Weller P.F.: Eosinophilic pneumonias. Clin Microbiol Rev 2012; 25: pp. 649-660.
Cottin V.: Eosinophilic lung disease. Clin Chest Med 2016; 37: pp. 535-556.
Leslie K.O., Gruden J.F., Parish J.M., et. al.: Transbronchial biopsy interpretation in the patient with diffuse parenchymal lung disease. Arch Pathol Lab Med 2007; 131: pp. 407-423.
Sarcoidosis
Clinical Features
- •
Chronic, multisystem granulomatous disorder of unknown etiology
- •
Occurs most commonly in young adults (20 to 40 years old) with slight female predominance
- •
In United States, higher incidence in African Americans; also common in Scandinavians and Irish
- •
The lung is involved in 90% to 95% of patients
- •
Patients present with either an abrupt, acute illness showing a better prognosis or with a chronic, insidious illness and a persistent, progressive disease course
- •
Angiotensin-converting enzyme (ACE) serum levels can be elevated during active phases
Gross Pathology
- •
Irregular, well-circumscribed nodules (2 to 5 mm) have a perilymphatic distribution and are most numerous along the bronchi and pulmonary vessels
- •
Late-stage sarcoidosis shows interstitial fibrosis and cavitary lesions
- •
About 5% of cases have a single or multiple large nodules (nodular sarcoidosis)
Histopathology
- •
Interstitial nonnecrotizing granulomas distributed along lymphatic routes: pleura, interlobular septa, and bronchovascular bundles ( Figure 4.15 )
Figure 4.15
Sarcoidosis.
A, Gross photograph of the cut surface of lung in end-stage sarcoidosis shows marked fibrosis and distortion of lung architecture (honeycombing). B, Low-power photomicrograph shows characteristic well-formed non-necrotizing granulomas in this transbronchial biopsy. C, The sarcoid granuloma is formed by histiocytes and few lymphocytes. Langerhans-type giant cells, with peripheral horseshoe arrangement of nuclei, are present. Note submucosal location of the granuloma. D, Various inclusions (asteroid body in the lower left and Schumann body in the upper right) can be seen within the cytoplasm of the giant cells, which are characteristic, but not diagnostic, for sarcoidosis.
- •
Granulomas composed of epithelioid histiocytes with or without multinucleated giant cells
- •
Granulomas are tightly clustered, well-formed, and often surrounded by concentric fibrosis, which over time becomes hyalinized with a lamellar appearance
- •
Necrosis is usually absent; however, a minority of cases demonstrate small, punctate foci of necrosis
- •
Granulomas directly involve vessels (67% of cases) and pleura (10% of cases)
- •
Variety of inclusions, some of which may be confused for microorganisms
- •
Asteroid bodies (2% to 9%)
- •
Schaumann bodies, conchoidal bodies (70%)
- •
Hamazaki-Wesenberg bodies (GMS stain positive, Ziehl-Neelsen acid fast, misinterpreted for fungi)
- •
Microcalcifications, birefringent calcium oxalate, and calcium carbonate (mistaken for fungi or Pneumocystis jiroveci )
- •
Small number of patients progress to end-stage fibrosis and honeycombing, with an associated risk for cavitation, Aspergillus species infection, and subsequent hemoptysis
Special Stains and Immunohistochemistry
- •
GMS, periodic acid–Schiff (PAS), AFB stains negative for microorganisms
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
Infection
- •
Special stains to exclude fungal (e.g., histoplasmosis) and mycobacterial infection
- •
Mycobacterium avium-intracellulare: granulomas are distributed around airways (bronchocentric) and may fill bronchiolar lumen, along with a granulomatous vasculitis component
Hypersensitivity Pneumonitis
- •
Granulomas are not as well formed or as sharply delineated
- •
More prominent interstitial chronic inflammation
Reaction to Inhaled Substances (e.g., Talc, Aluminum, Beryllium)
- •
Consider exposure history and beryllium lymphocyte stimulation test
Conditions Associated with Sarcoid-Like Disorders
- •
Malignancies (lymphoma, lung carcinoma, carcinoid tumors, testicular germ cell tumors)
- •
Collagen vascular disease (systemic lupus erythematosus [SLE], Sjögren syndrome, primary biliary cirrhosis)
- •
Sarcoidosis is a clinical diagnosis, and the pathologic diagnosis of non-necrotizing (or noncaseating) granulomatous inflammation, etiology undetermined, with comments regarding the negative results of special stains for microorganisms is appropriate
- •
Hemoptysis suggests the presence of mycetoma
Selected References
El-Zammar O.A., Katzenstein A.L.: Pathological diagnosis of granulomatous lung disease: a review. Histopathology 2007; 50: pp. 289-310.
Leslie K.O., Gruden J.F., Parish J.M., et. al.: Transbronchial biopsy interpretation in the patient with diffuse parenchymal lung disease. Arch Pathol Lab Med 2007; 131: pp. 407-423.
Mukhopadhyay S., Gal A.A.: Granulomatous lung disease: an approach to the differential diagnosis. Arch Pathol Lab Med 2010; 134: pp. 667-690.
Hemorrhagic Diseases
Idiopathic Pulmonary Hemosiderosis
Clinical Features
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Recurrent, diffuse alveolar hemorrhage with no known etiology
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Mostly in children (80% of cases) and adolescents with an equal sex distribution
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Patients present with an insidious onset of productive cough, hemoptysis, iron deficiency anemia, and weight loss
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Spontaneous remissions and exacerbations are common
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Coexists with several other diseases: IgA nephropathy, celiac disease, and dermatitis herpetiformis
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Radiographic studies reveal bilateral alveolar and reticulonodular infiltrates
Gross Pathology
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Marked increase in lung weight with areas of red-brown consolidation
Histopathology
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Dense aggregates of hemosiderin-laden macrophages with mild septal fibrosis to severe intra-alveolar hemorrhage ( Figure 4.16 )
Figure 4.16
Idiopathic pulmonary hemosiderosis.
Prussian blue staining is positive for iron within intra-alveolar macrophages containing hemosiderin.
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Degeneration, sloughing, and hyperplasia of alveolar epithelial cells
Special Stains and Immunohistochemistry
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Prussian blue positive
Other Techniques for Diagnosis
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Noncontributory
Differential Diagnosis
Other Pulmonary Hemorrhagic Syndromes
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Goodpasture syndrome (anti-glomerular basement membrane disease with pulmonary involvement): circulating antibasement membrane antibodies
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Vasculitis-associated angiitis, granulomatosis with polyangiitis (Wegener granulomatosis), and SLE
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Biopsy specimens should be assessed for immune complex or immunoglobulin deposition using immunofluorescence or immunohistochemistry because these findings are inconsistent with idiopathic pulmonary hemosiderosis (IPH)
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Biopsies should not demonstrate any specific pathologic findings such as granulomas, vasculitis or capillaritis, pulmonary infarction, or infection
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Outcome has improved dramatically after implementation of immunosuppressive therapy, leading to the presumption that this is an immune-mediated disease
Selected References
Nuesslein T.G., Teig N., Rieger C.H.: Pulmonary haemosiderosis in infants and children. Paediatr Respir Rev 2006; 7: pp. 45-48.
Poggi V., Lo Vecchio A., Menna F., et. al.: Idiopathic pulmonary hemosiderosis: a rare cause of iron-deficiency anemia in childhood. J Pediatr Hematol Oncol 2011; 33: pp. e160-e162.
Goodpasture Syndrome (Anti-Glomerular Basement Membrane Disease with Pulmonary Involvement)
Clinical Features
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Autoimmune disorder caused by antibodies that react with glomerular and pulmonary basement membranes
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Rare disease with an incidence of 0.9 per million persons per year
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Typically affects young white males or elderly women with renal disease
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Younger patients frequently present with pulmonary symptoms (e.g., hemoptysis) before manifesting renal symptoms, whereas older patients develop glomerulonephritis and renal failure before the onset of pulmonary problems
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Hemoptysis ranges from mild to life threatening
Gross Pathology
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Diffusely consolidated lungs with areas of red-brown consolidation
Histopathology
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Lung biopsy is useful in cases with limited renal involvement
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Extensive intra-alveolar hemorrhage and numerous hemosiderin-laden macrophages ( Figure 4.17 )
Figure 4.17
Goodpasture syndrome.
H&E-stained section shows recent hemorrhage and hemosiderin-laden intra-alveolar macrophages, indicating old hemorrhage as well as a mild interstitial chronic inflammation.
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Fibrous thickening of alveolar septa with pneumocyte hyperplasia
Special Stains and Immunohistochemistry
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Immunofluorescence studies: linear staining of basement membrane along alveolar septa for IgG, IgM, or IgA and complement
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Circulating autoantibodies can be detected by serology
Other Techniques for Diagnosis
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Electron microscopy: widened gaps between endothelial cells and fragmentation of capillary basement membranes
Differential Diagnosis
Idiopathic Pulmonary Hemosiderosis
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No renal involvement
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Antibasement membrane antibodies are not identified
Granulomatosis with polyangiitis (Wegener Granulomatosis)
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PR3-ANCA (c-ANCA) in serum
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Necrotizing capillaritis and granulomas are prominent features
Systemic Lupus Erythematosus
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Antinuclear antibody (ANA) positive
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Necrotizing capillaritis is a prominent feature
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One third of patients have positive serum c-ANCA or p-ANCA in addition to ABMABD
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Antibodies of ABMABD target the noncollagenous domain of the α 3 chain of type IV collagen, and antibody titer correlates with disease severity
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About 90% of patients have HLA-DR2
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Diagnosis is often established from kidney biopsy specimens
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