Lung-nontumor
Last revised 23 April 2009
Last major update November 2003
Copyright (c) 2003-2009, PathologyOutlines.com, Inc.
See also Lung-tumor, Mediastinum, Pleura, Trachea
Bold and underlined topics are hypertext links-may open a new window
Primary references, normal anatomy, normal histology, findings of no clinical significance, biopsy, patterns of injury
Cystic disease/congenital anomalies: general, bronchial atresia, bronchopulmonary dysplasia, cystic adenomatoid malformation, cystic fibrosis, cysts, emphysema due to alpha-1-antitrypsin deficiency, hypoplasia, lobar overinflation, mesenchymal cystic hamartoma, sequestrations
Chronic obstructive pulmonary disease: general, asthma, bronchiectasis, chronic bronchitis, emphysema
Infections: general, abscess, adenovirus, AIDS, Aspergillus, atypical mycobacteria, bacillary angiomatosis, Blastomyces, Candida, CMV, Coccidiodes, Cryptococcus, Cryptosporidium, Dirofiliaria, Echinococcus, hantavirus, Herpes simplex, Histoplasma, influenza, Legionella, malakoplakia, measles, mucor, Mycobacterium avium-intracellulare, Mycoplasma, Nocardia, organizing pneumonia, Paragonimus, Pneumocystic carinii, Pseudomonas, respiratory syncytial virus, Rhodococcus, SARS, Serratia, Staph aureus, Strongyloides, syphilis, Toxoplasma, tropical eosinophilia, tuberculosis, varicella
Granulomatous (non-infectious) inflammation: general, allergic, bronchocentric, hyalinizing granuloma, sarcoidosis, Wegener’s
Other interstitial pneumonitis/fibrosis: general, acute interstitial pneumonia, amiodarone, BOOP, bronchiolocentric interstitial pneumonitis, chronic eosinophilic pneumonia, chronic pneumonitis of infancy, DIP, diffuse panbronchiolitis, drug induced, eosinophilic, giant cell, honeycomb lung, lipoid, Loeffler’s syndrome, lymphoid interstitial pneumonia, nonspecific, obliterative bronchiolitis, PVP, respiratory bronchiolitis, UIP
Pneumoconiosis: general, aluminum, anthracosis, asbestos, asbestosis, berylliosis, coal workers’ pneumoconiosis, extrinsic allergic alveolitis, organic dust, siderosis, silicosis, silo-filler’s disease
Other non-neoplastic disease: alveolar proteinosis, amyloidosis, arteriovenous fistula, atelectasis, black spots, broncholithiasis, Crohn’s disease, crystal storing histiocytosis, diffuse alveolar damage, endometriosis, eosinophilic reactions, Goodpasture’s, hematoma, hemorrhage, idiopathic pulmonary hemosiderosis, infarct / pulmonary emboli, intravenous drug abusers, kayexalate, microlithiasis, muscular hyperplasia, polyarteritis nodosa, pulmonary edema, pulmonary hypertension, radiation, rheumatoid lung disease, rounded atelectasis, transplantation, veno-occlusive disease
Go to Lung tumors
AJCC Cancer Staging Manual (6th Ed)
American Journal of Surgical Pathology (AJSP), Jan 2002 to Nov 2003
Archives of Pathology and Laboratory Medicine (Archives), Jan 2002 to Nov 2003
Human Pathology (Hum Path), Jan 2002 to Sep 2003
Modern Pathology (Mod Path), Jan 2002 to Oct 2003
Rosai, J: Ackerman’s Surgical Pathology (8th Ed); Mosby-Year Book, Inc., 1996
Sternberg, S: Diagnostic Surgical Pathology (3rd Ed); Lippincott Williams & Wilkins, 1999
Websites: Loyola University-Stritch School of Medicine
Please refer to these primary references for more detailed discussions and photographs
Trachea divides into right and left mainstem bronchi
Each main bronchus divides into lobar bronchi, then into segmental bronchi
Lobar bronchi are usually called secondary bronchi and segmental bronchi are called tertiary bronchi, except in Japan, where they are called first order and second order, respectively.
Bronchioles lack cartilage and submucosal glands
Right lung has 3 lobes, left lung has 2 lobes plus lingula
Right bronchus more vertical than left, thus aspirated material tends to enter right lung
Lung has double arterial supply - pulmonary and bronchial
Lungs are surrounded by visceral pleural membrane; inner chest cavity is lined by parietal pleural membrane; these membranes define the pleural space, which normally has minimal volume
Regional lymph nodes: paratracheal, pre- and retrotracheal, aortic, subcarinal, periesophageal, inferior pulmonary ligament, hilar, peribronchial, intrapulmonary
Gross images: cross section #1, #2, lungs and bronchi
Lung parenchyma consists of airways (bronchi / bronchioles) and alveoli
Alveolar capillary basement membrane fuses with alveolar epithelium to form a single membrane for oxygen and carbon dioxide diffusion
Acinus / terminal respiratory unit contains 3-5 terminal bronchioles, alveolar ducts and alveoli
Alveoli are lined by respiratory epithelium (pseudostratified, columnar, ciliated)
Alveoli contain type I and II pneumocytes
Type I pneumocytes: 95%, flattened
Type II pneumocytes: 5%, produce surfactant (lamellar bodies on EM), involved in repair if type I destroyed
Bronchial-bronchiolaar epithelium contains goblet cells, neuroendocrine (Kultschitsky’s) cells, serous cells, basal cells, Clara cells and ciliated cells
Neuroendocrine cells: numerous in neonatal bronchial and bronchiolar epithelium; rare in adults except as clusters within epithelium of bronchi and bronchioles
Clara cells: increase towards terminal bronchiole; have secretory function; main progenitor cell after bronchiolar injury; have apical PAS+ diastase resistant secretory granules
Submucosal glands: contain serous and mucus cells with myoepithelial lining; may have oncocytic changes
Lymphatics: not present in alveolar walls
Pulmonary arteries: have internal and external elastic membrane, compared to a single elastic layer in pulmonary veins
Normal findings in alveoli: alveolar macrophages, corpora amylacea, blue bodies (calcium carbonate), megakaryocytes
Normal findings in interstitium: anthracotic pigment, scattered silica crystals
Pores of Kohn: perforations in alveolar walls; permit passage of bacteria and exudate between alveoli
Micro images: bronchus #1, #2, bronchiole
Virtual slides: fetal lung, lung-baby, normal lung
Histologic findings of no clinical significance
Apical caps: zones of fibrosis with chronic inflammatory infiltrate in lung apices
Ectopic tissue: skeletal muscle, pancreas, adrenal cortex, neuroglia
Intrapulmonary lymph nodes
Metaplastic bone: age related finding in bronchial cartilage; associated with bone marrow elements; also rarely associated with alveolar exudate
For non-neoplastic lesions, clinical correlation is essential
Evaluating biopsies: alveolar space, alveolar septal membrane, conducting airways, pulmonary arteries, other vessels and lymphatics
Tips of lingula and right middle lobe typically show more fibrosis than elsewhere
Frozen section is recommended for open biopsies so (a) tissue arrives fresh, not in preservative, (b) pathologist can tell surgeon if specimen is adequate and representative
Elastic and trichrome stains are often helpful for non-neoplastic tissue
Patterns of injury for non-neoplastic disease
Source: Sternberg, S: Diagnostic Surgical Pathology (3rd Ed); Lippincott Williams & Wilkins, 1999
Interstitial inflammation/fibrosis: DIP, UIP, diffuse alveolar damage, Langerhans cell histiocytosis, asbestosis, amyloidosis, sarcoidosis, extrinsic allergic alveolitis
Intraalveolar reaction: DIP, pulmonary alveolar proteinosis, infection, extrinsic allergic alveolitis, chronic eosinophilic pneumonia
Small-airway disease: bronchiolitis obliterans, respiratory bronchiolitis, mycoplasma infection, viral infection, extrinsic allergic alveolitis, eosinophilic pneumonia
Large-airway disease: allergic bronchopulmonary aspergillosis, bronchocentric granulomatosis, TB, fungi, Wegener’s
Granulomatous vasculitis: Wegener’s, sarcoidosis, Churg-Strauss, bronchocentric granulomatosis, fungi, TB
Small vessel disease: primary pulmonary hypertension, thromboembolism, polyarteritis nodosa, veno-occlusive disease, Churg-Strauss syndrome
Hemorrhage: Goodpasture’s, SLE, immune complex glomerulonephritis, idiopathic pulmonary hemosiderosis, Wegener’s
Lymphoid infiltrates: lymphocytic interstitial pneumonia, lymphoma, lymphoid aggregates, extrinsic allergic alveolitis
Eosinophils: chronic eosinophilic pneumonia, Churg-Strauss syndrome, bronchocentric granulomatosis, Langerhans cell histiocytosis
Cystic disease/congenital anomalies
Congenital or acquired:
Congenital: cysts, cystic adenomatoid malformation, lobar hyperinflation, sequestrations
Acquired: emphysema, healed abscess, honeycombing
Mixed: cystic fibrosis
Portion of bronchial tree with normal branching pattern, but without any demonstrable connection to the central bronchial tree
Complication of prematurity
Respiratory distress continues for months
Patients have limited pulmonary reserve, develop repeated infections, often have pulmonary hypertension and develop cor pulmonale
Micro: bronchiolar and interstitial fibrosis, compensatory emphysema of less damaged acini, inadequate alveolar development causes fewer but larger alveoli
Micro images: severe fibrosis, large alveoli
Virtual slides: respiratory distress syndrome & bronchopulmonary dysplasia
Cystic adenomatoid malformation
Rare hamartomatous disorder, 1 per 25,000 births
Variably sized cysts lined by “adenomatoid” columnar-type epithelium
Associated with stillbirth, neonatal distress and bronchial atresia; type I found in older children and adults
May develop with and be related to other congenital or acquired lung conditions (Archives 2002;126:934)
May regress spontaneously
Classification:
Type 0: 1-3%, small/firm lungs; formerly called acinar dysplasia; associated with other malformations, incompatible with life
Type I: 60-70%: large cysts up to 10 cm, lined by pseudostratified ciliated cells interspersed with mucus cells; may appear late; good prognosis since can resect; shows lepidic growth within cysts and adjacent lung, resembles bronchioalveolar carcinoma
Type II: 10-15%: small cysts up to 2 cm, resemble dilated bronchioles separated by normal alveoli; associated with other malformations; poor prognosis
Type III: 5%, solid gross appearance, excess bronchiolar structures separated by small air spaces with cuboidal epithelium resembling fetal lung; poor prognosis
Type IV: 15%, large cysts up to 10 cm, lined by flattened epithelium; good prognosis; similar to grade 1 pleuropulmonary blastoma although less cellular; sample generously to rule out blastoma
Case reports: Case of the Week #58
Treatment: close followup for asymptomatic infants, with elective surgery for persistent lesions within the first year of life (Arch Dis Child Fetal Neonatal Ed 2006;91:F26, Int J Gynaecol Obstet 2005;89:99)
Gross images: type I, type II, type II cut surface
Micro images: various examples, type I
type II: image #1; #2; #3; #4; #5; #6
Molecular: no karyotypic abnormalities, no p53 mutations (Pediatr Dev Pathol 2006;9:190)
References: AJSP 2003;27:1139
1 in 20 in US are carriers; most common mutation (seen in 70% in UK) is #508 (Eur J Hum Genet 2002;10:583)
Mutations cause reduced chloride ion in secretions, thicker respiratory secretions, upper respiratory infections, late pancreatic insufficiency
Mutations also cause defective cilia and infertility
Meconium ileus seen in 5-10% of patients; also intussusception
Gross: emphysema, bronchiectasis, abscess, fibrosis
Gross images: image1
DD: Kartegeners (defective cilia syndrome)
Cystic fibrosis associated infections
Burkholderia cepacia: unique to cystic fibrosis, seen in 20% of patients; causes rapid deterioration of pulmonary status and death; transmitted person to person, has marked social impact as those infected are excluded from social functions (camps) and ineligible for transplant; treat with Chloramphenicol, trimethoprim-sulfamethoxazole
Pseudomonas aeruginosa: bacteria produces alginate, a capsular protein that mediates adherence; mucoid phenotype is unique to cystic fibrosis; bacteria is never eradicated from lung; treat with ceftazidime
Staphylococcus aureus: infection persists despite treatment
Stenotrophomonus maltophilia: aerobic gram negative rod, multidrug resistant, smells like onions; treat with trimethoprim-sulfamethoxazole, resistant to imipenim
Abnormal detachment of a fragment of primitive foregut
Usually are bronchogenic cysts, adjacent to bronchi, may not connect with airways, filled with air/mucin; may become infected
Emphysema due to alpha-1-antitrypsin deficiency
Genetic deficiency
Alpha-1-antitrypsin (AAT) inhibits proteases, particularly elastase (which digests lung tissue), which is secreted by neutrophils during inflammation
PiMM: normal phenotype; 90% of population
PiZZ: associated with AAT deficiency; 80% develop symptomatic emphysema; occurs earlier and is more severe in smokers
Neutrophils are normally present in lung and alveolar space; when stimulated, neutrophils and macrophages increase in number and release elastase and oxygen free radicals, which causes emphysema unless counteracted by antiproteases such as AAT
Smokers have more neutrophils and macrophages in alveoli, tobacco use enhances release of elastase from neutrophils, enhances elastase activity, oxidants in tobacco smoke inhibit AAT
Lung weighs less than normal with fewer alveoli than expected for gestational age
Bilateral disease is fatal
Causes: oligohydramnios (renal agenesis, fetal membrane rupture), decreased intrathoracic space (renal cystic disease, diaphragmatic hernia), reduced breathing (anencephaly, musculoskeletal disorders)
Gross images: image1
Also called congenital lobar emphysema
Infants or young children
Perhaps due to hypoplasia of bronchial cartilage; associated with other cardiopulmonary anomalies
Affects left or right upper lobe or right middle lobe
May cause severe compression of other pulmonary lobes
Not emphysema since no tissue destruction
Micro: massive distention of alveolar spaces but no tissue destruction
Multifocal, bilateral cysts < 1 cm lined by normal or metaplastic respiratory epithelium resting on a cambium layer of mesenchymal cells
Sequestrations (intralobar and extrapulmonary lobar)
Lobes or segments of lung without a normal connection to the airway system
Extrapulmonary sequestrations: external to lung, covered with separate pleural lining, may be anywhere in thorax or mediastinum; usually infants, abnormal masses, 90% on left side, 20% have other congenital anomalies; associated with polyhydramnios and edema
Intralobar sequestrations: within the lung, usually lower lobe, segment is supplied by a large artery from aorta, not invested with its own pleura, associated with infections, bronchiectasis, chronic inflammation, fibrosis
Blood supply is from aortic branches, NOT pulmonary arteries
Chronic obstructive pulmonary disease (COPD)
Also called chronic obstructive lung disease (COLD)
Major cause of bed defining disability in US
Major symptom is dyspnea (shortness of breath)
Usually due to cigarette smoking
Site of disease: bronchi-chronic bronchitis, bronchiectasis, asthma; bronchioles-bronchiolitis, acini-emphysema
Obstructive airway disease: increase in resistance to airflow due to obstruction at any level; includes emphysema, chronic bronchitis, bronchiectasis, asthma, tumor, foreign body; reduced maximal airflow rates (FEV1)
Restrictive airway disease: reduced expansion of lung parenchyma with decrease in total lung capacity; normal FEV1; due to chest wall disorders (polio, obesity, pleural disease, kyphoscoliosis), interstitial / infiltrative diseases (ARDS, dust diseases, interstitial fibrosis)
Chronic relapsing inflammatory disorder characterized by hyperreactive airways, causing episodic, reversible bronchoconstriction
Usually associated with atopy, mediated by IgE
Has increased in Western hemisphere over past 30 years
Extrinsic: Type I hypersensitivity; either atopic (due to allergens), occupational or due to allergic bronchopulmonary aspergillosis
Intrinsic: nonimmune; due to aspirin ingestion, pneumonia, cold, stress, exercise
Status asthmaticus: unremitting attacks due to exposure to previously sensitized antigen; may be fatal
Gross: overdistended lungs, small areas of atelectasis, thick mucus plugs in proximal bronchi containing whorls of shed epithelium
Gross images: mucus plugs #1, #2, #3, thickened bronchial walls, status asthmaticus #1, #2, #3
Micro: Curschmann spirals, eosinophils contain Charcot-Leyden crystals (eosinophil membrane protein); increased mucosal goblet cells and submucosal glands, thickened basement membrane, bronchial smooth muscle hypertrophy, airway wall edema
Micro images: smooth muscle hypertrophy and inflammatory cells #1, #2, #3, goblet cells and inflammatory cells, Curschmann spiral, eosinophils and Charcot-Leyden crystals
DD: allergic bronchopulmonary aspergillosis, bronchocentric granulomatosis without the granulomatous inflammation
Atopic asthma
Begins in childhood, triggered by environmental allergens (dander, dust, pollen, food), often positive family history
Skin test causes wheel and flare reaction
Classic example of Type I IgE mediated hypersensitivity reaction
Initial sensitization affects T helper 2 cells, which release IL-4/5, which promote IgE release by B cells, mast cells and eosinophils
Reexposure to allergen leads to mediator release from mucosal mast cells
Acute/intermediate response is bronchoconstriction, edema, mucus secretion, hypotension
Late phase reaction, due to influx of other inflammatory cells, is release of major basic protein from eosinophils, which causes epithelial damage and airway constriction
Putative mediators: leukotrienes C4, D4, E4 and acetylcholine; minor mediators: histamine, prostaglandin D2
Associated with serum eosinophilia, sputum eosinophils
Occupational asthma
Due to repeated exposure to fumes, dusts, gases, chemicals, often in minute quantities
Drug induced asthma
Associated with aspirin use
Rare, associated with recurrent rhinitis and nasal polyps
Patients are sensitive to small doses of aspirin, get urticaria and asthma
May be due to direct effects of aspirin on cyclooxygenase pathway
Nonatopic asthma
Due to respiratory infection (rhinovirus, parainfluenza virus); usually not familial
Normal serum IgE, negative skin tests
Viral induced inflammation may lower threshold of subepithelial vagal receptors to irritants
Chronic necrotizing infection of bronchi and bronchioles associated with permanent dilation of these airways
Diagnosis is based on presence of infection (stasis occurs in dilated bronchi) and obstruction
Symptoms: cough, fever, copious amounts of foul-smelling, purulent sputum
Causes: bronchial obstruction (localized bronchiectasis), congenital bronchiectasis, cystic fibrosis, intralobar sequestration of lung, immunodeficiency states, immotile cilia / Kartegeners syndrome, Young’s syndrome, necrotizing pneumonia (staphylococcus, tuberculosis)
Obstruction (due to tumor, foreign body, inspissated mucus) causes resorption of air distal to obstruction, atelectasis, intraluminal secretions
Nonobstructive bronchiectasis is due to pneumonia and atelectasis, which increase negative intrapleural pressure, which exerts an external force on bronchial walls, causing them to dilate; usually left sided affecting lower lobes
Cystic fibrosis: obstruction due to mucus plugs, infection is due to decreased ciliary clearance of bacteria
Kartegeners syndrome: autosomal recessive condition with variable penetrance, due to absent or irregular dynein arms of cilia, which causes defective bacterial clearance (bronchiectasis, sinusitis), defective cell motility during embryogenesis (situs inversus), immotile sperm (infertility)
Young’s syndrome: infertility caused by azoospermia, but without ultrastructural ciliary abnormalities
Gross: markedly distended peripheral bronchi, usually in lower lobes, can trace to pleural surface; bronchial walls irregularly thickened
Gross images: image1, image2, image3, image4
Micro: chronic inflammation, ossification and ulceration of bronchial cartilage; variable inflammation and fibrosis of alveoli; thickened pleura
Micro images: image1
Virtual slides: bronchiectasis
Diagnosis: persistent cough with sputum for 3 months in 2 consecutive years
More infections, purulent sputum, hypercapnia, hypoxia than emphysema; clinically called “blue bloaters”
May cause secondary pulmonary vascular hypertension, cor pulmonale, congestive heart failure; death due to respiratory acidosis and coma, congestive heart failure, pneumothorax
Simple chronic bronchitis: cough but no physiologic evidence of airway obstruction
Chronic asthmatic bronchitis: hyperreactive airways with intermittent bronchospasm and wheezing
Obstructive bronchitis: often have associated emphysema
Causes: 4-10x more common in smokers, also chronic irritation, infections
Tobacco interferes with ciliary action, directly damages airway epithelium, inhibits ability of white blood cells to clear bacteria; infections maintain but do not initiate chronic bronchitis
Reid index: ratio of thickness of mucus gland layer to thickness of wall between epithelium and cartilage; normal is 0.4, increased in chronic bronchitis
Gross: boggy mucosa with excessive mucinous secretions, pus
Micro: early-hypersecretion of mucus in large airways with hypertrophy of submucosal glands in tracheobronchial tree
later-increase in goblet cells in small airways causes excessive mucus production and airway obstruction; increased Reid index; variable dysplasia, squamous metaplasia, bronchiolitis obliterans
Micro images: increased mucus glands
Diagram: Reid index
Abnormal permanent enlargement of air spaces distal to terminal bronchiole with wall destruction but without fibrosis
Differs from overinflation, which is not due to wall destruction (example: due to loss of opposite lung)
Acinar and airspace enlargement is usually due to tobacco related wall destruction
Centroacinar emphysema: 95% of emphysema cases, causes significant airflow obstruction, affects central part of acini, sparing distal alveoli; worse in upper lobes, particularly apices; walls are anthracotic with parabronchial inflammation; seen in heavy smokers, coal worker pneumoconiosis; clinically significant at age 40+ in smokers, although ventilatory deficits seen earlier
Gross images: entire lung, cut section #1, #2, bullae#1, #2, #3, smoking pattern
Micro images: dilated air spaces and loss of alveolar walls
Virtual slides: image1
Panacinar (panlobular) emphysema: 5% of cases, causes significant airflow obstruction; acini uniformly enlarged from respiratory bronchiole to terminal alveoli; usually lower lungs; associated with alpha-1-antitrypsin deficiency; lungs usually voluminous
Paraseptal (distal acinar) emphysema: minor clinically; distal acini only affected, emphysema is next to pleura, near areas of fibrosis, scarring or atelectasis; multiple continuous airspaces are affected; may be source of spontaneous pneumothorax in young adults
Irregular emphysema: minor clinically; invariably associated with scarring, irregular involvement of acini
Compensatory emphysema: response to loss of lung elsewhere, such as post-lobectomy
Senile emphysema: due to age-related alterations in internal geometry of alveoli leading to larger alveolar ducts, smaller alveoli, but no loss of elastic tissue or destruction of lung substance
Obstructive emphysema: due to tumor, foreign body or congenital lobar overinflation (infants, perhaps due to hypoplasia of bronchial cartilage; associated with other cardiopulmonary anomalies); due to ball-valve effect with inhalation via collaterals (pores of Kohn, canals of Lambert); may compress normal lung, may be life-threatening
Bullous emphysema: any form that produces blebs > 1 cm; often subpleural, near apex, associated with tuberculosis scarring; may rupture and cause pneumothorax, hemorrhage; called placental transmogrification if it resembles chorionic villi
Interstitial emphysema: air into connective tissue stroma of lung, mediastinum or subcutaneous tissue; due to alveolar tears, chest wounds, coughing, whooping cough
Pathogenesis: alteration in balance between proteases and antiproteases
Clinical: no symptoms until 1/3 of functional capacity is lost; get shortness of breath, coughing, wheezing, weight loss; barrel chest; breath through pursed lips (pink-puffer), which causes slowing of forced expiration
May cause secondary pulmonary vascular hypertension, cor pulmonale, congestive heart failure, death due to respiratory acidosis and coma, pneumothorax
Best to assess based on morphometry, not lung function data, Mod Path 2003;16:1
Infections
Lung is #1 site for infections that cause lost workdays
Pneumonia is due to impairment of normal defense mechanisms or lowered host resistance
Normal defense mechanisms: nasal clearance (sneezing, blowing, swallowing), tracheobronchial clearance (mucociliary action), alveolar clearance (alveolar macrophages)
Impairment due to suppression of cough reflex (drugs, virus), injury to mucociliary apparatus (smoking, virus, Kartegeners syndrome), injury to macrophages (tobacco, alcohol, anoxia), pulmonary congestion/edema, accumulation of secretions (cystic fibrosis)
Note: viral pneumonia predisposes to bacterial pneumonia
Common agents: Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenza, Pseudomonas aeruginosa, coliforms
Complications: abscess, empyema, organization, sepsis, meningitis
Consolidation: exudative solidification of lung
Symptoms of pneumonia: shortness of breath, fever, productive cough, malaise, friction rub (if fibrinous pleuritis)
Micro images: aspiration pneumonia
Virtual slides: early pneumonia, aspiration pneumonia-adult, aspiration pneumonia-infant, organizing pneumonia
Bronchopneumonia
Patchy consolidation of the lung centered on bronchi
Gross images: whole lung, cut surface, cut surface-close up #1, #2, patchy consolidation #1, #2
Micro: neutrophils in bronchi, bronchioles and adjacent alveolar spaces; lipid pneumonia if marked lipid laden macrophages
Micro images: bronchopneumonia with adjacent normal lung, patchy involvement, neutrophils in alveoli, destruction of lung tissue
Virtual slides: bronchopneumonia, with abscess #1, #2
Lobar pneumonia
Affects entire lung but now rare due to antibiotics; associated with increased virulence of organism or increased host vulnerability (infants, elderly); may be due to extension of existing bronchiolitis or bronchitis
Gross images: whole lung, cut surface #1, #2, red hepatization, gray hepatization #1, #2
Micro: initially congestion with bacteria and few neutrophils; then red hepatization (grossly resembles liver) with massive congestion, neutrophils, fibrin; then gray hepatization with fibrinopurulent exudate and organization; then resolution with resorption of exudate
Virtual slides: lobar pneumonia
Due to sinobronchial infections, dental sepsis, aspiration (due to alcoholism, coma, debilitation), primary bacterial infection (Staphylococcus aureus, Klebsiella pneumonia, Streptococcus pneumonia), fungi, bronchiectasis, post-transplant, septic emboli, neoplasia induced obstruction, idiopathic
Aspiration induced abscesses more common on right side (right sided bronchus is more vertical), usually single
Air fluid level present if there is communication with air passages
Symptoms: cough, fever, copious foul-smelling sputum, fever, chest pain, weight loss, clubbing of digits
10% of cases are associated with underlying carcinoma
May extend into pleural cavity, create septic emboli causing meningitis or brain abscess, serve as nidus for fungal overgrowth (Mucor, Aspergillus), spread elsewhere in lung
Treatment: lobectomy
Gross: thick fibrotic walls and surrounding pneumonia in chronic abscesses
Gross images: cut surface, abscess cavities #1, #2, abscess and bronchopneumonia
Micro images: early abscess #1, #2, with bacteria, chronic abscess
Cold agglutinins present in 20%
Micro: epithelial cells contain smudged nuclei with bricklike intranuclear inclusions; also necrosis of bronchial and alveolar epithelium and acute inflammation
Micro: interstitial inflammation (no inclusions identifiable)
Neonatal adenovirus infection of lung
More typical findings in liver and adrenal glands than in lung
Micro: glassy nuclei; severe necrotizing bronchiolitis extending into ducts and airways
Diagnose with bronchoalveolar lavage, transbronchial biopsy or open lung biopsy
Nonspecific features resemble DIP or lymphocytic interstitial pneumonia
Patients often have multiple infections
Open lung biopsies should routinely be stained for Pneumocystis, fungi, mycobacteria
Cavitary lesions: Staphylococcus, fungi (Candida, Aspergillus, Cryptococcus, Histoplasma, Blastomyces), Mycobacterium tuberculosis, Mycobacterium avium intracellulare, Rhodococcus equi
Patients also have infections from CMV, Pneumocystis carinii, toxoplasma, microsporidia
Associated with Kaposi’s sarcoma
Occurs as secondary colonization of lung abscess, aspergilloma, allergic bronchopulmonary aspergillosis or invasive aspergillosis in immunocompromised
Associated with renal transplant recipients
Gross images: abscess
Micro: dichotomous (into two nearly equal branches) branching, septate hyphae, often invade vessels
Micro images: fungus ball, hyphae, PAS, Diff-Quik stain
contributed by Professor Venna Maheshwar, Drs. Kiran Alam and Anshu Jain, J. N. Medical College, India - PAS stains - #1; #2
Virtual slides: aspergilloma (fungal ball)
Allergic bronchopulmonary aspergillosis
Bronchocentric granulomas in asthmatics that contain numerous eosinophils, and noninvasive Aspergillus organisms or other fungi
Also thick mucus plugs
Over time, bronchi become dilated, causing bronchiectasis
Associated with immunosuppression, chronic obstructive lung disease, prior TB, pneumoconiosis, bronchiectasis, lung carcinoma
Culture required for diagnosis
Positive stains: acid fast (bacilli are longer [20 microns], more coarsely beaded and more bent than M. tuberculosis bacilli)
Pseudoneoplastic vascular proliferation affecting lungs, bronchi, other sites
Treatment: antibiotics
Grossly resembles tuberculosis
Gross images: multiple caseating granulomas
Micro: mixed acute and granulomatous inflammation caused by large budding yeasts, with broad based buds
Virtual slides: blastomycosis
Pseudohyphae and budding yeasts
Usually immunocompromised patients
Associated with Pneumocystis and other infections
Xray: 2-4 cm peripheral nodules, miliary pattern, diffuse interstitial process
Micro: mononuclear infiltrate, edema and pneumocyte hyperplasia; enlarged cells have nuclear and basophilic cytoplasmic inclusions; hemorrhagic necrosis may be present; CMV usually infects endothelial and epithelial cells
Micro images: contributed by Drs. Michael P. Orejudos and Rosemarie Rodriguez, San Antonio Uniformed Services Health Education Consortium, San Antonio, Texas (USA) - #1; #2; #3; #4; #5
Positive stains: PAS, GMS, CMV
In Southwest US, Mexico, Central America and San Joaquin Valley (California) in soil
In vitro, may have hyphae which form arthrospores, very infectious, requires careful handling in lab
Gross: necrotic center surrounded by fibrous tissue with concentric lamination
Micro: granulomatous inflammation, large thick-walled spherules contain variable sized daughter cysts
Micro images: spherules within giant cell, spherule with endospores
Yeast found in pigeon droppings, may cause meningitis
Micro: somewhat pleomorphic round/oval 4-10 micron yeast, thick mucinous capsule stains bright red with mucicarmine; some are unencapsulated
Virtual slides: bronchial mucosal ulcer
Dog heartworm; may infect humans as secondary end-stage host, particularly in southern coastal states in US
Adult worms die in right ventricle, embolize in pulmonary arterial circulation, evoke necrotizing granulomatous response with vasculitis in lung tissue
Rarely see dead worms
Usually self limited in humans, but may cause lung infarct
Case report of solitary pulmonary nodule in 15 year old girl who had contact with dogs, Archives 2002;126:227
Chest Xray: solitary peripheral pulmonary nodule
Micro: rounded infarct with coagulative necrosis, well demarcated from surrounding normal lung by epithelioid histiocytes and fibrous connective tissue; focal calcifications and lymphoid aggregates; necrotic nematode has homogenous cuticle without external ridges, longitudinal muscle layer just internal to cuticle and internal cuticular ridges
Micro images: H&E and Movat stain (1C)
Also called hydatid cyst
Micro images contributed by Dr. Hanni Gulwani, New Delhi (India): image #1; #2; #3
Severe pulmonary disease, often in Southwest US
Causes interstitial pneumonitis with mononuclear infiltrate, edema, focal hyaline membranes
Gross: diffusely firm lungs with small yellow/red necrotic areas
Micro: interstitial pneumonia with necrosis of bronchial and alveolar epithelium and acute and chronic inflammatory infiltrate; occasional intranuclear viral inclusions present at edge of necrotic areas
Neonatal HSV pneumonia
More typical findings in liver or adrenal gland than in lung
Gross: normal
Micro: patchy necrosis; minimal inflammatory response; not bronchocentric
Gross: resembles tuberculosis, has “tree-bark” appearance
Micro: small budding yeasts, 3-5 microns, intracellular
Micro images contributed by Dr. Jamie Shutter, Florida: H&E #1; #2; GMS #1; #2
Negative stains: acid-fast
Variable changes from mild acute lung injury to necrotizing pneumonia to BOOP-like changes
Legionella pneumophila / Legionnaires’ disease
Initial awareness after epidemic in Philadelphia, Pennsylvania (US) convention of American Legion
Retrospective review disclosed sporadic cases since early 1900’s
Caused by short, gram-negative bacillus
Hilar lymph nodes infected in 50% of cases at autopsy, 25% have spread to other organs
Causes: initially infected water cooling systems; also corticosteroids in renal transplant patients, any potable water supplies
Treatment: erythromycin, other antibiotics, although high mortality in immunocompromised
Micro: extensive bronchopneumonia with intra-alveolar neutrophils, macrophages, fibrin, often with leukocytoclastic neutrophilic infiltrate, small vessel vasculitis and necrosis
Positive stains: Dieterle silver stain
Virtual slides: Legionella pneumonia
Very rare, usually in immunocompromised patients
70% of cases are due to Rhodococcus equi, an animal pathogen causing opportunistic infections
Treatment: antibiotics
Gross: nodular masses or infiltrates with cavitation
Micro: intraalveolar histiocytes with pink or foamy cytoplasm that fill and destroy alveoli, not interstitium; histiocytes contain PAS+ bacteria, also Michaelis-Gutmann bodies [round/oval structures, 5-20 microns, with laminated or targetoid appearance that stain deeply with H&E, iron and calcium stains]; also lymphocytes, plasma cells, neutrophils
DD: atypical mycobacteria (blue histiocytes, positive acid fast stain), Whipple’s disease, Gaucher’s disease
Micro: giant cells with viral inclusions; nuclei may contain single large Cowdry Type A inclusion
Virtual slides: measles pneumonia
Fungi common in patients with diabetes
Micro: large, non-septa hyphae with 90 degree angle branching and non-parallel walls
Mycobacterium avium-intracellulare
More common in AIDS patients with low CD4 counts or other immunosuppressed individuals
Micro: marked intraalveolar and parenchymal infiltration by foamy histiocytes or proteinaceous reaction
Positive stains: acid fast (high numbers of intracellular bacteria)
Mycoplasma pneumoniae pneumonia
Formerly called atypical pneumonia
Causes interstitial pneumonia (usually) or bronchopneumonia
Often asymptomatic
Diagnosis: cold agglutinins present in 50% of cases
Gross: red-blue, congested, patchy lungs, usually no pleuritis
Micro: bronchiolitis, interstitial and minimal intra-alveolar involvement with widened alveolar septa due to lymphoplasmacytic inflammatory cells; intra-alveolar proteinaceous material; neutrophilic infiltrate in bronchioles, bronchiolar metaplasia, lymphoplasmacytic infiltrate in bronchial wall, pneumocyte hyperplasia
DD of infectious interstitial pneumonia: respiratory syncytial virus, rhinovirus, rubeola, varicella, Chlamydia psittacosis, Coxiella burnetti (Q fever)
Opportunistic lung infection associated with transplantation, chemotherapy, immunosuppression, steroids
Gross images: abscess
Gram stain: slender, slightly beaded, branching, filamentous bacilli
Micro: focal bronchopneumonia with microabscesses, ill-defined granulomas
Micro images: acid fast stain, modified Fite stain
Positive stains: acid fast
Pneumonia may resolve or organize
Organizing pneumonia may simulate malignancy due to radiographic shadows and clinical cough, hemoptysis and weight loss; usually due to Streptococcus pneumoniae or Haemophilus influenza
Gross: sharply outlined, firm area, with preservation of lung pattern; extends to thickened pleura
Micro: exudate of fibrin and neutrophils, necrotizing changes in bronchi, alveolar macrophages
DD: BOOP, inflammatory pseudotumor
Paragonimus kellicotti
Due to ingestion of raw or undercooked crayfish infected with trematode Paragonimus (lung fluke)
Case report of 35 year old North American man with recurrent pneumothorax and cavitary lesion, AJSP 2003;27:1157
Micro: non-necrotizing granulomas with giant cells containing eggs with operculum; also lymphocytes, plasma cells, eosinophils
Pneumocystis carinii pneumonia
Opportunistic fungus present in bronchoalveolar lavage (BAL), sputum or biopsy
Most common pneumonia in AIDS patients, who are at high risk if CD4 < 200 or if protein-calorie malnutrition
Causes diffuse or patchy pneumonia; may have coexisting CMV or other infections
Diagnosis: bronchoalveolar lavage and imprints have high sensitivity
Treatment: pentamidine, folic acid inhibitors, anti-HIV drugs
Micro: alveolar spaces filled with pink, foamy, amorphous material composed of proliferating fungi and cell debris; fungi are 4-6 microns, cup/boat shaped cysts; also mild inflammatory reaction with fibrin exudate, hyaline membranes
Micro images: alveolar space with frothy material; cup shaped organisms (also Diff-Quik)
Positive stains: GMS, Warthin Starry, other silver stains, Gram-Weigert
DD: alveolar proteinosis (diffuse pulmonary opacification and intra-alveolar PAS-positive material and lipid; sputum contains gelatinous material; no inflammation; alveolar contents contain type II pneumocytes & necrotic alveolar macrophages)
DD: Goodpasture’s (necrotizing, hemorrhagic, interstitial pneumonitis; associated with rapidly proliferative glomerulonephritis, linear immunoglobulin deposits on basement membranes of alveolar septal walls; also intra-alveolar hemorrhage, septal thickening and hypertrophy, organization of blood in alveolar spaces)
DD: BOOP (bronchiolar and alveolar plugs of loose fibrous tissue)
Pseudomonas aeruginosa
Gram negative bacillus
Infants (below), patients with burns or on ventilators, immunocompromised, critically ill
Immunocompromised patients usually have paucicellular pattern below; immunocompetent have cellular pattern
Perivascular bacterial infiltration is somewhat specific for pseudomonas
Gross images: abscess
Micro: necrotizing pneumonia with 2 patterns - paucicellular coagulative confluent bronchopneumonia with perivascular bacillary infiltration or cellular pneumonia without evidence of perivascular organisms
Infants
Rare (0.3% of neonatal ICU admissions); usually low birth weight (1.2% of low birth weight admissions)
Mortality 32-87% with death within 1-2 days
Diagnosis made by culture
Rapidly progressive course in immunosuppressed individuals, who often have paucicellular bronchopneumonia and bacteremia
More protracted course if immunocompetent, associated with cellular pneumonia
Micro: necrotizing pneumonia with 2 patterns - paucicellular coagulative confluent bronchopneumonia with perivascular bacillary infiltration or rarely a cellular pneumonia without evidence of perivascular organisms
References: Hum Path 2003;34:929
Respiratory syncytial virus (RSV)
Often in children under 2 years old, may cause death in infants 1-6 months
Micro: giant cells with round, pink, intracytoplasmic inclusions
Micro images: giant cells
May cause malakoplakia in AIDS patients
Case report of cavitary lesion in 15 year old girl with congenital AIDS, Archives 2003;127:e315.
“Rhodo” since salmon-pink pigment in culture
Treated with antibiotics, but mortality is 50% in AIDS patients, 20% in other immunocompromised, 10% in immunocompetent
Micro: epithelioid macrophages containing gram positive, partially acid fast coccobacilli organisms; may produce malakoplakia
Micro images: 2/3: gram stain, 4:autopsy
Severe Acute Respiratory Syndrome
Caused by SARS-associated coronavirus, a new member of Coronaviridae
Outbreaks worldwide in 2002
Micro: diffuse alveolar damage (DAD) varying based on duration of illness; 10 or fewer days - acute phase DAD, airspace edema, bronchiolar fibrin, small airway injury; 11+ days - organizing phase DAD, type II pneumocyte hyperplasia and marked reactive atypia, squamous metaplasia, multinucleated giant cells, acute bronchopneumonia
Acute phase DAD: hyaline membranes lining alveolar walls, interstitial and airspace edema, interstitial infiltrates of inflammatory cells, and vascular congestion
Organizing-phase DAD: fibroblast proliferation in interstitium and air spaces
Small airway injury: loss of cilia, bronchiole epithelial denudation, deposition of fibrin within the lumen and on exposed basement membranes
References: Hum Path 2003;34:743
Gram negative rod
Micro images contributed by anonymous - elderly immunocompetent man with bronchial wash - #1; Pap stain; Diff-Quick
Case report of premature newborn with congenital syphilis, acute hyaline membrane disease and bilateral lung abscesses with spirochetes, Archives 2002;126:484
Gross/micro images: image1
Associated with AIDS, immunosuppression
Intracellular parasite that causes focal parenchymal necrosis, diffuse interstitial pneumonia
Micro: organisms present in histiocytes, alveolar lining cells, endothelial cells
Positive stains: GMS, Giemsa, Gram-Weigert
Due to microfilaria of Wuchereria bancrofti, which circulate in pulmonary capillaries and cause immediate type of eosinophilic hypersensitivity reaction
Restricted to tropical regions
Micro: microfilaria within pulmonary capillaries with marked eosinophilic infiltrate
Due to Mycobacteria tuberculosis
Lung involvement is the major cause of morbidity/mortality
Cases increasing due to AIDS and emergence of multiple-drug resistant strains; AIDS patients may lack granulomas
Rarely involves skin, oropharynx, lymphoid tissue
Initial focus of infection is Ghon complex, consisting of parenchymal subpleural lesion, near upper/lower lobe interlobar fissure (apex has high oxygen tension) with enlarged caseous lymph nodes; lesions usually undergo fibrosis, calcification and cause no symptoms
Rarely (infants, children, immunocompromised), get progressive spread with cavitation, TB pneumonia, miliary TB
Treatment: prolonged multi-agent antibiotics
Surgery: pulmonary resection indicated for open cavity after 4-6 months of drug therapy, residual caseous disease, irreversible destructive lesion (bronchiectasis, bronchial stenosis), recurrent hemorrhage, unexpandable lobe with associated TB empyema, suspected tumor; surgical success rate (inactive disease) is 80% after 2-5 years
Gross: inflamed, fibrotic, nonfunctioning lung parenchyma, may have bronchial strictures, bronchiectasis, cavitation, thickened pleura
Gross images: lung with scattered granulomas #1, #2, #3, #4, granulomas with caseous necrosis, cavitation, Ghon complex #1, #2, miliary TB #1, #2, apical lesions
Micro: caseating granulomas; cavities show approximation of walls, granulation tissue, fibrosis, stellate scar; may have metaplastic bone formation
Micro images: caseating granuloma
Virtual slides: caseating granuloma #1, #2
Secondary (reactivation) pulmonary TB
5-10% of cases of primary infection
Produces more damage than primary TB
Apical areas of consolidation with caseous necrosis in draining nodes
Usually get progressive fibrous encapsulation, which causes focal pleural adhesions, may contain anthracotic pigment
Tubercles coalesce over time, creating confluent area of consolidation
Diagnosis: appearance of bacteria with acid-fast stain, positive smears or cultures; 1 bacillus in a 1 cm3 granuloma indicates the presence of 2000 organisms
Micro: caseating granulomas with Langhans giant cells
Progressive pulmonary TB
Progression to cavitary disease, miliary TB or TB bronchopneumonia
Cavitary disease: drainage of caseous focus transforms it into a cavity, usually in apex and walled off; may spread to other parts of lung, producing endobronchial and endotracheal TB, laryngeal seeding, intestinal TB
Miliary TB: seeds bone marrow, liver, spleen, retina via blood or lymphatics; grossly see distinct, small, yellow-white areas of consolidation, central necrosis identifiable microscopically
TB bronchopneumonia: occurs in highly sensitized, highly susceptible people; also called “galloping consumption”; multi-agent treatment is effective unless resistant organisms, diabetes, AIDS, reactive amyloidosis
Tuberculomas
Due to reinfection; may rupture and cause widespread dissemination
Treatment: excision to rule out malignancy and destroy possible nidus for infectious spread
Gross: round, discrete, solitary, firm nodules, adjacent to pleura; may have concentric laminations, cavitation or calcification; may communicate with bronchus
Micro: persistent caseation surrounded by thick fibrous walls with Langhans giant cells, epithelioid histiocytes, lymphocytes; also subpleural fibrous thickening
Positive stains: acid-fast bacilli
Associated with necrosis of bronchial and alveolar epithelium and acute inflammation
Granulomatous inflammation (non-infectious)
Rosai recommends culture and stains for fungi and Mycobacteria in every case
Other disorders with granulomas: fungi (Actinomyces, Aspergillus, Blastomyces, Coccidiodes, Cryptococcus, Histoplasma, Mucor, Sporotrichosis), eosinophilic pneumonia, bronchial chondromalacia, inhalation of talc (drug abusers), metal dust from occupational exposure (berylliosis), extrinsic allergic alveolitis, prior alveolar hemorrhage (cholesterol granulomas), lipogranulomas (with diabetes)
Also called Churg-Strauss syndrome
Very rare
Systemic vasculitis resembling polyarteritis nodosa associated with asthma, peripheral eosinophilia, pulmonary involvement, fever
Rarely presents without pulmonary disease as fever of unknown origin
Treatment: steroids (effective, but patients may relapse)
Micro: lung and extrapulmonary sites (skin, heart, nervous system, GI) have prominent eosinophilic infiltrate, granulomatous reaction around necrotic foci with radially arranged histiocytes and pallisading giant cells near small arteries or arterioles, eosinophilic vasculitis; may have fibrin-rich edema, lymphocytes, sarcoid-like granulomas, focal fibrosis, eosinophilic microabscesses
DD: Wegener’s (also kidney involvement, no tissue or serum eosinophilia or asthma), rheumatoid nodules (no tissue or serum eosinophilia or asthma)
Granulomatous disease of lungs in which almost all granulomas are centered in bronchi or bronchioles, causing their destruction
Immunologic reaction related to chronic eosinophilic pneumonia and allergic bronchopulmonary aspergillosis
Usually adults, often with asthma history, limited to lungs, may be asymptomatic
Usually solitary lesions that appear on chest Xray as atelectasis or consolidation, not nodules
Favorable prognosis
Gross: viscous material in involved bronchi
Micro: large and medium bronchi infiltrated by neutrophils, eosinophils and necrotic debris surrounded by foreign body giant cells; fragmented elastic tissue (with elastic stain); also bronchiolitis obliterans; no fibrinoid necrosis of vessels
DD: Wegener’s (may also have bronchocentric granulomas), TB, fungi, cystic fibrosis, rheumatoid arthritis
Rare nodular lung lesion
Usually multiple, bilateral, cause unknown
Associated with sclerosing mediastinitis, retroperitoneal fibrosis, lymphoma
May be progressive but doesn’t cause death
Micro: central keloid-like collagen, arranged in whorls, surrounded by foreign body giant cells simulating nodular amyloidosis; may have plasma cells and lymphocytes between collagenous bands; usually no epithelioid granulomas, no necrosis
Negative stains: Congo red
Multisystemic disease of unknown origin that involves lung in 90% of cases
Presents as perihilar node involvement, diffuse pulmonary disease, pulmonary interstitial fibrosis, localized bronchial stenosis, distal bronchiectasis and atelectasis
Usually 20-40 years, F > M, 90% are black, rare in Chinese, Southeast Asians
80% have elevated serum angiotensin-converting enzyme (not specific); polyclonal serum hypergammaglobulinemia is common
65% recover without further problems; 20% have permanent pulmonary loss; 3% die of pulmonary fibrosis, congestive heart failure
Best prognosis: hilar lymphadenopathy alone
Worst prognosis: pulmonary disease without adenopathy
Treatment: steroids for severe symptoms, advanced disease
A diagnosis of exclusion, since there are no specific criteria for disease; should culture and use special stains
Lungs: either no gross lesion or 1-2 cm nodules; often in bronchial submucosa, so biopsies are helpful
Lymph nodes: hilar or mediastinal lymph nodes involved in almost all cases, tonsils involved in 25% of cases; nodes are enlarged, may be calcified
Liver/spleen: microscopic involvement in 75% of cases, gross disease in 20%
Bone: Xray changes in 20%, usually small bones of hands and feet
Skin: involved in 30-50% with erythema nodosum; also mucus membranes
Eye: iritis or iridocyclitis in 20-50%
Micro: non-caseating epithelioid granulomas with tightly packed epithelioid cells, Langhans giant cells, lymphocytes (T cells), usually in interstitium adjacent to bronchioles and around and within vessel walls, pleura, connective tissue septa; may also be hyalinization, diffuse interstitial fibrosis, fibrinoid necrosis and fibrosis within granulomas, intra- and extracellular inclusions; pleural involvement in 10%
Micro images: non-caseating granulomas #1, #2, granuloma-high power, lymphangitis distribution
Schaumann bodies: laminated concretions of calcium and protein
Asteroid bodies: stellate inclusions within giant cells, in 60% of granulomas
Neither is specific for sarcoid (also seen in berylliosis)
Virtual slides: sarcoidosis
DD: mycobacteria, fungi, berylliosis (need clinical history to differentiate), extrinsic allergic aspergillosis (loosely arranged epithelioid cells in granulomas)
Necrotizing sarcoid granulomatosis
May be localized or diffuse
Appears to be a variant of sarcoidosis
Usually women, often with mild or no symptoms
Excellent prognosis
Treatment: steroids and immunosuppressive drugs, surgery for localized lesions
Micro: extensive vascular noncaseating sarcoid-like granulomas invading pulmonary arteries and veins with diffuse necrosis of lung parenchyma
DD: tuberculosis, fungal infection
Triad of necrotizing angiitis, aseptic necrosis of upper respiratory tract and lungs, focal glomerulonephritis
May also involve temporal artery, cutaneous small vessels and cause extrapulmonary masses
All ages, but most common with ages 45+
Rarely associated with diffuse pulmonary hemorrhage
Should order special stains and cultures to rule out TB and fungi
Labs: c-ANCA positive in 90% with active generalized disease and 60% with limited disease (diffuse cytoplasmic staining, directed against neutrophil serine proteinase 3); can monitor course of disease with titers
p-ANCA (perinuclear staining, directed against myeloperoxidase) usually negative, positive in microscopic polyarteritis, inflammatory bowel disease, crescentic glomerulonephritis
Other causes of positive c-ANCA or p-ANCA: connective tissue disorders, chronic hypersensitivity pneumonia, postinfectious bronchitis, ulcerative colitis related lung disease, Mod Path 2002;15:197
Chest Xray: waxing and waning of pulmonary infiltrates and nodules is relatively specific
Diagnosis: biopsy of upper airway or skin showing inflammatory change is helpful
Treatment: cyclophosphamide, trimethoprim-sulfamethoxazole
Gross: well circumscribed lesion with necrotic appearance
Gross images: necrotizing lesions
Micro: liquefactive or coagulative necrosis in lungs with profuse eosinophils, multinucleated giant cells as part of poorly formed granulomas surrounded by pallisading histiocytes and giant cells with central necrosis; destructive leukocytic angiitis of arteries and veins outside of the necrotic granuloma by neutrophils, plasma cells and eosinophils; scanty lymphocytes and plasma cells; bronchial wall is rarely involved; fulminant subtype has predominance of exudative changes; fibrous scar subtype has marked collagenous stroma; small vessel variant involves alveolar septal capillaries instead of large arteries or veins (resembles SLE)
Micro images: image1, image2, image3, image4
Virtual slides: necrotizing vasculitis
DD pulmonary vasculitis: tuberculosis, fungi
Limited Wegener’s
Confined to lungs, no glomerulonephritis (or occurs many years later)
More protracted clinical course
Treatment: steroids, cytotoxic drugs
Gross: multiple, bilateral nodules, round or infarct-like, often in lower lobes
Micro: similar to classic type, but must have angiitis outside of granulomas and necrotic areas for diagnosis
Other interstitial pneumonitis / fibrosis
Clinical information is usually necessary to properly interpret biopsy
Also called Hamman-Rich syndrome
Rapidly progressive disease with no identifiable cause; death usually within 2 months
Young adults with influenza-like illness followed by shortness of breath
Micro: resembles diffuse alveolar damage with brisk interstitial fibroblastic proliferation
Amiodarone induced pulmonary toxicity
Case report of 68 year old man with amiodarone induced pulmonary toxicity, Archives 2002;126:745
Treatment: drug withdrawal or dose reduction
May have 50% mortality if diffuse alveolar damage present
Micro: intra-alveolar exudate of finely vacuolated foamy macrophages, also present within alveolar septa; may have diffuse alveolar damage or BOOP type changes
Micro / cytology / EM images: image1
Cytology: finely vacuolated, foamy macrophages; variable neutrophils
EM: membrane-bound cytoplasmic lamellar inclusions due to drug accumulation in the lungs
Bronchiolitis obliterans-organizing pneumonia (BOOP)
Common response to infectious or inflammatory injury to lungs
Also associated with drugs, collagen vascular disease, graft versus host disease in bone marrow transplant patients
Cause cannot be determined from biopsy - requires clinical history
Acute onset with cough, shortness of breath, fever and malaise
Excellent prognosis; steroid resistance may lead to death
Treatment: steroids
Micro: patchy fibroblastic plugs in bronchioles (bronchiolitis obliterans) and alveoli (organizing pneumonia); plugs formed by spindled fibroblasts in pale-staining matrix, with serpiginous or elongated shape; also foamy macrophages, rare neutrophils, thickened alveolar septa
Low power: evenly spaced nodules or plugs of organizing connective tissue and inflammation that obliterates terminal airways
Bronchiolocentric interstitial pneumonitis
May resemble hypersensitivity pneumonitis
80% women, ages 40-50 years
Xray: interstitial and restrictive lung disease
Poor prognosis - 33% dead after mean 4 years
Similar pattern seen with rheumatoid arthritis, Sjogren’s syndrome, scleroderma, methotrexate, amiodarone (5-10% of patients)
Micro: centrilobular inflammation with peribronchiolar fibrosis and inflammation radiating into interstitium of distal acinus in a patchy fashion; inflammatory process begins at bronchovascular bundle, accompanied by centrilobular fibrosis and metaplasia; periphery of lobule shows relative sparing; no granulomas, no honeycomb change
Micro images: low power #1, #2, #3, peribronchiolar fibrosis, mononuclear infiltrate
DD: hypersensitivity pneumonitis (specific cause usually identifiable, less centrilobular fibrosis, usually has granulomas), nonspecific interstitial pneumonia (by definition excludes bronchiolocentric interstitial injury)
References: Mod Path 2002;15:1148
Chronic eosinophilic pneumonia
Reaction to drugs, Aspergillus or other fungi
Prolonged (months) febrile illness with cough, weight loss, generalized fatigue, drenching night sweats
Associated with chronic asthma, peripheral eosinophilia
Xray: patchy infiltrates in peripheral lungs with central sparing
Treatment: steroids cause complete resolution
Gross: consolidation, mucus plugs in distal bronchi or bronchioles
Micro: patchy intraalveolar edema, interstitial inflammation with giant cells, eosinophils, chronic inflammatory cells; mucus plugs composed of inflammatory cells and cellular debris; often bronchiolitis obliterans; blood vessel infiltration by inflammatory cells is common, but no vascular necrosis; no diffuse alveolar damage
Micro images: Charcot-Leyden crystals
DD: DIP (if extensive intraalveolar macrophages), Langerhans cell histiocytosis (interstitial infiltrate, Langerhans cells), extrinsic allergic alveolitis (less edema, more interstitial inflammation), parasites, fungal allergies
References: Orphanet J Rare Dis 2006;1:11
Chronic pneumonitis of infancy
Rare
Micro: marked alveolar thickening, alveolar pneumocyte hyperplasia, alveolar exudate
Desquamative interstitial pneumonitis (DIP)
Usually adults with insidious onset of shortness of breath, progressing to respiratory insufficiency; also cough, cyanosis, clubbing
Cause unknown
Mean survival 12 years, mortality 28%
90% are current or past cigarette smokers
Associated with collagen vascular disease, positive ANA (similar to UIP)
Xray: bilateral, lower lobe, ground glass infiltrates
Treatment: steroids (respond better than UIP)
Micro: diffuse collections of intraalveolar macrophages containing lipid and PAS+ granules (originally thought to be desquamated pneumocytes); type II pneumocyte hyperplasia, acute and chronic inflammatory cells; may be focal interstitial fibrosis; no necrosis, no hyaline membranes, no fibrin
Micro images: low power
Virtual slides: DIP
Positive stains (macrophages): PAS after diastase, iron
EM: type II pneumocytes contain lamellar bodies (surfactant), may be phagocytosed by macrophages
DD: DIP reaction to Langerhans cell histiocytosis, extrinsic allergic alveolitis, asbestosis, respiratory bronchiolitis
Rare, usually Japanese and Asians
Associated with HLA BW54, Haemophilus influenza infection
Chronic and progressive disease course
Treatment: antibiotics
Micro: foamy macrophages in pulmonary interstitium, chronic inflammation in terminal bronchioles
Bleomycin, amiodarone (5-15% of patients) cause pneumonitis and fibrosis
Methotrexate, nitrofurantoin cause hypersensitivity pneumonitis
General term that includes all lung disease associated with eosinophils in alveolar and interstitial spaces, usually with peripheral eosinophilia, but excluding Langerhans cell histiocytosis
Causes: drug reactions (antibiotics, cytotoxic or anti-inflammatory drugs), immune disorders (Churg-Strauss syndrome, collagen vascular disease, asthma, hypereosinophilic syndrome, rheumatoid arthritis) infections (bacteria, Aspergillus, HIV, parasites-helminths, Dirofiliaria, filarial) or tobacco (flavored cigars-Chest 2007;131:1234, new onset of smoking-JAMA 2004;292:2997)
Idiopathic eosinophilic pneumonia is classified as simple, acute or chronic.
Simple eosinophilic pneumonia: see Loeffler’s syndrome
Acute eosinophilic pneumonia: onset in 1-4 days, accompanied by fever, cough, dyspnea and chest pain; prominent eosinophils in bronchoalveolar lavage fluid (Am J Respir Crit Care Med 2002;166:1235), diffuse alveolar damage at biopsy
Chronic eosinophilic pneumonia: see above
Symptoms: fever, weight loss, shortness of breath
Xray: peripheral infiltrate
Case reports: Case of the week #105
Treatment: steroids cause dramatic response to acute or chronic forms
Micro: acute form has diffuse alveolar damage; alveolar and interstitial infiltration by eosinophils, also plasma cells and histiocytes; may have Charcot-Leyden crystals; variable angiitis, granulomatosis, fibrosis, mucus plugging, bronchiolitis with necrosis
Micro images (acute): image #1; #2; #3
Giant cell interstitial pneumonia
Rare
Associated with industrial exposure to hard metals
Micro: intraalveolar multinucleated giant cells and other inflammatory cells; giant cells often phagocytose other histiocytes
Final common pathway of various processes causing chronic interstitial fibrosis
Progressive shortness of breath, severe interstitial fibrosis, diffuse cystic changes with blebs and subsequent pneumothorax, shrunken lungs (restrictive lung disease) with elevation of diaphragm
Gross: stiff, spongy, fibrotic lungs with cystic changes
Micro: dense interstitial and peribronchial fibrosis and smooth muscle; reduced alveolar capillaries; marked medial hyperplasia of pulmonary arteries and arterioles; cystically dilated alveoli; may have mucinous metaplasia of lining epithelium with atypia
Incidental post-mortem finding associated with debilitating disease
Exogenous (due to nasal sprays) or endogenous (bronchial obstruction)
Gross: well-circumscribed, firm, with prominent lymphatics on lung surface in exogenous type
Gross images: yellow cut surface
Micro: lipoid material (or empty spaces), inflammatory cells, young fibroblasts; reactive endarteritis, marked alveolar lining cell hyperplasia, lipid-laden foamy macrophages
Micro: aspiration pneumonia, foamy macrophages in alveolar spaces
Acute eosinophilic pneumonia
Transient diffuse pulmonary infiltrates and serum eosinophilia
Self limited - lasts up to 1 month
Lymphoid interstitial pneumonia (LIP)
1/3 associated with Sjogren’s syndrome; also associated with AIDS, pulmonary drug reactions
May occur in children with AIDS
May be EBV related, particularly in AIDS patients
Shortness of breath, cough, polyclonal gammopathy
Often progresses
Treatment: poor response to steroids or chemotherapy
Micro: lymphocytes with germinal centers, plasma cells, macrophages, epithelioid granulomas in lung interstitium; no effacement of alveolar architecture; no invasion of parietal pleura, although visceral pleura may have mild inflammation; late - diffuse interstitial fibrosis
Micro images: image
Molecular: polyclonal
DD: follicular bronchitis and bronchiolitis, nonspecific inflammatory reaction, SLL/CLL
Nonspecific interstitial pneumonia/fibrosis
Varying etiologies
Relatively good prognosis with good response to steroids
Micro: uniform thickening of alveolar septa and interstitial infiltrates of plasma cells and lymphocytes, minimal architectural destruction, occasional granulomas, mild interstitial fibrosis; may have fibrotic foci, bronchiolitis obliterans
Associated with bone marrow, heart, lung transplants, rheumatoid arthritis, penicillamine or gold therapy
Poor prognosis
Micro: lymphocytic infiltration of terminal bronchi and bronchioles, sloughing of epithelium, replacement of wall by fibrous tissue, leading to total fibrous obliteration; also distended alveoli
Micro images: follicular bronchiolitis that obliterates lumen
Crospovidone, a N-vinyl-2-pyrrolidone polymer, is used as a disintegrant in pharmaceutical tablets, may embolize to lung if injected IV
Micro: deeply basophilic, coral-like particles within pulmonary arteries and in extravascular foreign-body granulomas; associated with inflammatory cells
Positive stains: Movat pentachrome (orange-yellow)
Negative stains: Alcian blue
EM: irregular, electron dense, laminated, finely granular material
EM images: image1
References: Mod Path 2003;16:286
Common, almost always seen in cigarette smokers, may persist 5 years or more after quitting, AJSP 2002;26:647
May cause cough and dyspnea, which regresses after cigarette cessation
Micro: focal chronic inflammation of terminal bronchioles and alveolar ducts, with adjacent focal interstitial inflammation and fibrosis; histiocytes fill alveolar ducts and spaces, but are predominantly peribronchiolar; histiocyte cytoplasm contains brown-black-yellow granules (smoker’s granules)
DD: DIP (no pigmented macrophages)
Usual interstitial pneumonitis (UIP)
Also called chronic interstitial pneumonitis, cryptogenic fibrosing alveolitis
Most common pattern of idiopathic pulmonary fibrosis
Usually ages 50+
50% have unknown cause with insidious onset (exertional dyspnea) and chronic evolution; complications include secondary pulmonary hypertension, cor pulmonale, cardiac failure
Some cases may represent a form of immune-complex lung disease associated with collagen vascular diseases or autoimmune diseases (Sjogren’s, ulcerative colitis, rheumatoid disease, scleroderma, Raynaud’s disease, thyroid disease)
Most cases have circulating immune complexes; 30% have serum antinuclear antibodies (ANA)
May be associated with neurofibromatosis, pulmonary veno-occlusive disease or adenocarcinoma if atypical foci of acinar and squamous proliferation are present
May represent a common pathway for alveolar wall injury from various causes, followed by interstitial edema, alveolitis, type II pneumocyte hyperplasia, fibroblast proliferation and progressive fibrosis
Reduced diffusing capacity is mainly due to ventilation-perfusion mismatch from ventilation of lung tissue with capillary destruction and perfusion of underventilated alveoli; small component is reduced diffusion across fibrotic alveolar septa
Treatment: steroids (20% improve)
Mean survival 6 years, mortality 66%
Diagnosis: requires open lung biopsy; transbronchial biopsy specimen is inadequate
Prognostic factors: eosinophilia associated with poor response to steroids, more functional abnormalities, worse prognosis
Gross: shrunken lung with "hobnailed" pleura due to retraction by underlying fibrous scarring
Gross images: honeycomb pattern
Micro: marked regional variation in nature and degree of infiltrate on low power without transition (scant mononuclear infiltration, fibromyxoid connective tissue nodules, honeycomb fibrosis), fibroblast foci, architectural distortion, honeycomb change; interstitial injury is patchy, tends to be peripheral, subpleural and periseptal
Lymphoid nodules around bronchioles, bronchiolitis obliterans, fibrinous pleuritis associated with coexisting rheumatoid arthritis
Lymphoid nodules, mucinous hyperplasia, marked media thickening in pulmonary arteries associated with scleroderma
May have frequent areas of nonspecific interstitial pneumonitis or coexisting diffuse alveolar damage, BOOP
Early: firm lungs, pulmonary edema, hyaline membranes, mononuclear infiltration, type II pneumocyte hyperplasia
Later: fibrous tissue, fibrogenic foci (areas of active disease), thickened alveolar septa (solid and normal lung), hyperplastic smooth muscle, microcysts, loss of alveolar capillaries
End stage: spaces lined by cuboidal/columnar epithelium separated by fibrosis and forming honeycomb lung (particularly in the superior portion of lobes); also lymphoid hyperplasia, thickening of intima and media of pulmonary arteries
Micro images: fibroblast foci
EM: fibrosis due to migration of activated mesenchymal cells through defects in epithelial lining and its basement membrane from interstitial to intraluminal compartment, replacement of alveolar type I cells by hyperplastic alveolar type II cells
DD: pneumoconiosis, hypersensitivity pneumonitis, bronchiolitis obliterans organizing pneumonia, oxygen toxicity pneumonitis, scleroderma, radiation injury, nonspecific interstitial pneumonia (NSIP)
References: AJSP 2002;26:1567
Pneumoconiosis
Non-neoplastic disease due to inhalation of mineral dust, exclusive of asthma, bronchitis and emphysema
Amount of dust retained in lungs depends on particulate size (dangerous: 1-5 mm); particles are phagocytosed by macrophages, but they may be overwhelmed
Large particles resist dissolution, may evoking fibrosing collagenous pneumoconiosis (silicosis)
Quartz directly injures membranes by interacting with free radicals
Silica causes macrophages to release mediators which stimulate fibroblasts
Particles may also cause immune response (immune complex formation)
Chronic exposure to high concentrations of fumes during aluminum arc welding causes severe pneumoconiosis with diffuse pulmonary accumulation of aluminum metal and reduction in lung function
Case report of 2 aluminum welders who died of complications, Hum Path 2002;33:819
Gross: slate-gray metallic appearance in scarred areas and peribronchial lymph nodes
Micro: patchy pleural thickening, emphysematous blebs, pneumothorax, considerable fibrous replacement of lung tissue with aluminum containing macrophages
Presence of carbon particles in lung
Not a pathologic condition necessarily, often due to urban living
Carbon particles are relatively inert and usually don’t elicit reactive fibrosis
May cause coal workers’ pneumoconiosis (below)
Causes localized fibrous plaques, pleural effusions, parenchymal interstitial fibrosis (asbestosis), bronchogenic carcinoma, mesothelioma, laryngeal carcinoma, possibly colon carcinoma
Exists in serpentine/chrysotile (curly, flexible) and amphibole (straight, stiff, brittle) forms; most asbestos in industry is serpentine, but amphiboles are more pathogenic; link with mesothelioma is almost always with amphibole form
Chrysotiles usually are caught in upper respiratory passages, removed by mucociliary elevator; they are soluble and leached from tissue if they reach alveoli
Amphiboles (straight, stiff) go deeper into lungs; fibers > 8 mm and thinner than 0.5 mm are more injurious
Both types are fibrogenic; act as tumor initiator and promoter; toxic chemicals may also be adsorbed to asbestos fibers (tobacco smoke)
Asbestos may act by countering antioxidant effect of Vitamin C (ascorbic acid), Hum Path 2003;34:737
Relative risks compared to normal population: asbestos and bronchogenic carcinoma has RR of 5, with tobacco use, RR is 55
Asbestos and mesothelioma (pleural, pericardial, peritoneal) has RR of 1000; no increased risk with smoking
Note: asbestos related tumors have no special histologic features
EM images: asbestos fibers
Similar to other pneumoconiosis
Initial injury is at bifurcations of small airways and ducts; macrophages ingest fibers, release chemotactic factors and fibrogenic mediators, causing interstitial fibrosis
Begins around respiratory bronchioles and alveolar ducts, extends distally; eventually causes honeycomb lungs
Begins in lower lobes and subpleurally (in contrast to CWP and silicosis), progresses to middle and upper lobes
Visceral pleura becomes fibrotic, may bind lung to chest wall; may have associated Caplan syndrome
Symptoms: usually begin after 10 years of exposure, initially shortness of breath with exertion, later at rest; may progress to heart failure
Pleural plaques: well circumscribed plaques of dense collagen, often with calcium; on parietal pleura and dome of diaphragm; do not contain asbestos bodies, but rare if no asbestos history; may induce pleural effusions, usually no symptoms
Asbestos fiber detection: H&E, incineration, EM
Gross images: pleural plaque
Micro: early - interstitial pneumonia with desquamative features, hyperplastic alveolar cells with intracytoplasmic Mallory’s hyaline tissue; later - diffuse interstitial fibrosis with honeycombing (silicosis is nodular), asbestos bodies (golden brown, fusiform or beaded rods with translucent center; asbestos fibers coated with iron-containing proteinaceous material); iron from phagocyte ferritin
Asbestos fibers may have oxalate crystal deposition, Hum Path 2003;34:737
Ferruginous bodies: inorganic particulates coated with phagocyte ferritin
Micro images: asbestos fiber, ferruginous body #1, #2, pleural plaque
Due to heavy exposure to dusts or fumes of beryllium, more common in nuclear and aerospace industries
Acute disease has disappeared due to exposure standards
Low-dose exposure may cause granulomatous lesions that mimic sarcoidosis
Chronic berylliosis due to cell-mediated immunity; 2% of those exposed develop disease; delayed hypersensitivity leads to noncaseating granulomas in lungs, hilar nodes, become progressively fibrotic; no symptoms until late
Heavy beryllium exposure is linked to lung cancer
Coal workers’ pneumoconiosis /progressive massive fibrosis
Incidence declining due to dust reduction measures
Simple coal workers’ pneumoconiosis (CWP): patients have coal macules (1-2 mm collections of carbon-laden macrophages) and coal nodules (coal macules and fibrosis) scattered throughout lung, more in upper lobe and upper lower lobe, near respiratory bronchioles; usually minimal symptoms but 10% develop progressive massive fibrosis
Micro images: image1
Progressive massive fibrosis: also called complicated coal workers’ pneumoconiosis; intensely blackened scars > 2 cm, multiple, containing dense collagen and pigment; center of lesion may be necrotic due to ischemia
Associated with pulmonary hypertension and cor pulmonale
May progress even if dust exposure ceases
Due to any pneumoconiosis, although most common in CWP and silicosis
Associated with increased incidence of clinical tuberculosis, chronic bronchitis and emphysema, independent of smoking
Does not appear to increase the risk of lung cancer
Micro images: large scar
Caplan syndrome: rheumatoid arthritis and pneumoconiosis cause rapidly developing nodular pulmonary lesions, composed of central necrosis surrounded by collagen, fibroblasts and macrophages (similar to rheumatoid nodules); associated with exposure to coal, asbestosis, silica dust
Also called hypersensitivity pneumonitis
Spectrum of immunologically mediated, interstitial lung disorders caused by intense, often prolonged exposure to inhaled organic dusts and occupational antigens
Individuals have abnormal sensitivity or heightened reactivity to these antigens
Similar to asthma, but involves alveoli, not bronchi
Acute attacks occur 4-6 hours after inhalation; diffuse/nodular pulmonary infiltrates appear on chest Xray; chronic exposure causes shortness of breath, respiratory failure, cyanosis, decreased total lung capacity and compliance
Chronic low levels of exposure may cause diffuse interstitial lung disease with fibrosis and honeycomb lung
Good prognosis, responds well to steroids and withdrawal of offending antigen
Causes: spores of thermophilic bacteria, fungi, animal proteins, bacteria from hay, grain, sugar cane, bark, cheese, cork, animal feces; exposure results in early formation of type III immune complexes, then type IV delayed hypersensitivity
Air conditioner lung: due to thermophilic bacteria
Byssinosis: in textile workers due to fibers from cotton, linen, hemp; resembles asthma clinically; may not be immune mediated
Farmer’s lung: from moldy hay containing spores of thermophilic actinomycetes
Maple bark stripper’s lung: fungal spores
Pigeon breeder’s lung: also called bird fancier’s disease: proteins from serum, feathers, excreta
Treatment: remove environmental agent early
Micro: interstitial bronchiolocentric pneumonitis with lymphocytes, plasma cells, foamy macrophages also in alveolar space and terminal airways; interstitial fibrosis, obliterative bronchiolitis, poorly circumscribed epithelioid granulomas, intra-alveolar exudate; also nodules of organizing fibroblasts, histiocytes and other inflammatory cells
Micro images: giant cells
Due to direct toxic effect causing acute bronchopneumonia or diffuse alveolar damage
Not due to hypersensitivity
Associated with grain silos but different from silo-filler’s disease
Most patients recover completely
Associated with iron workers and welders
Silica: crystalline silicon dioxide
Most prevalent chronic occupational disease in the world, due to foundry work, sandblasting, stone cutting, coal mining
Decades of exposure usually required for symptoms
Causes a progressive, nodular, fibrosing pneumoconiosis
Acute silicosis: due to heavy exposure; similar to alveolar proteinosis with generalized accumulation of lipoproteinaceous material within alveoli
Crystalline forms of silica are more fibrogenic than amorphous forms; quartz is particularly fibrogenic, although quartz plus other minerals is less fibrogenic
Quartz causes directly injury to membranes via SiOH groups and by free radicals generated by crushing silica
Silica also causes macrophages to release mediators which stimulate fibroblasts, including tumor necrosis factor
Initial lesions are in upper lung zones, more fibrotic than with coal workers’ pneumoconiosis
Talc, vermiculite and mica are noncrystalline silicates that less commonly cause pneumoconiosis
Detect on routine chest Xray as a fine nodularity in upper lobes, but normal pulmonary function; no symptoms until progressive massive fibrosis, then disease progresses with impaired pulmonary function
Not associated with lung cancer
Gross: early, tiny, discrete pale to black (if coal dust present) nodules in upper zones of lungs, progressing to hard collagenous scars; nodules have stellate shape at the edges, may cavitate due to tuberculosis or ischemia; fibrosis present in hilar nodes and pleura; may see eggshell calcification in nodes on Xray
Micro: early lesions - small nodules of fibroblasts and histiocytes with abundant silica, that become less cellular and more hyalinized with time; with progressive massive fibrosis, see hyalinized and condensed collagen, needle-like spicules with pointed ends, 5 microns or less, birefringent with polarization, intra- or extracellular
Micro images: silicotic nodule #1, #2, silica crystals (polarized light)
Virtual slides: silicosis
A chemical pneumonitis due to inhalation of nitrogen dioxide produced by fermenting silage (green forage plants)
No granulomas
Other non-neoplastic disease
Diffuse pulmonary disease associated with silica dust, aluminum, fiberglass, chemicals, immunosuppression, leukemia / lymphoma
Considered a response to alveolar injury, not a specific entity
Usually adults, also children
Sputum contains chunks of gelatinous material; no inflammation
Usually does NOT progress to chronic fibrosis
May be due to dysfunction of alveolar macrophages causing surfactant accumulation
Associated with infection by Nocardia, Mycobacteria, Aspergillus
Xray: resembles pulmonary edema; diffuse pulmonary opacification
Treatment: whole lung lavage
Micro: alveoli contain amorphous, eosinophilic, PAS+ material in lumina consisting of type II pneumocytes, lamellar bodies and necrotic alveolar macrophages; variable fibrosis; mild/no lymphocytic infiltration
Virtual slides: alveolar proteinosis
EM: exudate contains lamellar bodies, lipid particles, cellular debris
Rare, presents as asymptomatic nodule, primary tracheobronchial involvement (below) or diffuse interstitial septal amyloidosis (below)
Usually in asymptomatic elderly with nodule on chest Xray but no evidence of systemic disease
Good prognosis; typically doesn't progress to lymphoproliferative disorders
May be a reaction to chronic inflammatory conditions (TB, HIV, connective tissue disorders)
Also associated with plasma cell dyscrasias and lymphoproliferative disorders
Micro: well circumscribed amyloid, often with lymphocytes (T cells) and plasma cells; granulomatous reaction to amyloid common, often calcification and ossification
Micro images: image1, image2, image3, image4, kappa & lambda stains
Positive stains: glassy, salmon-pink amorphous material with apple green birefringence with Congo Red stain and polarized microscopy; clonal restriction of plasma cells (kappa or lambda staining, not both)
EM: amyloid fibrils
EM images: fibrils
DD: primary pulmonary lymphomas with amyloid production (<1% of pulmonary lymphomas have amyloid deposits, usually age 70+, marginal zone or SLL/CLL subtypes, often with lymphatic tracking and reactive lymphoid follicles, even distribution of lymphocytes in nodule, invasion of pleura is specific for lymphomas)
DD: hyalinizing granuloma (history of exposure to Histoplasma or TB, collagen is Congo-red negative)
Tracheobronchial amyloidosis
Diffuse narrowing of airway or solitary / multiple nodules
Symptoms of hemoptysis, atelectasis, obstruction, asthma
15-40% die at mean 9 years after diagnosis from respiratory failure, pulmonary hemorrhage, pneumonia
Does not evolve into systemic amyloidosis
Case report in 49 year old man, Archives 2003;127:e420
Amyloid may be present in lymphocytic interstitial pneumonia, lymphoplasmacytic lymphomas, plasma cell dyscrasias, but morphology is different
Diagnosis: bronchial biopsy
Treatment: laser therapy or bronchoscopic removal of deposits, radiation therapy, lung transplant
Gross: focal to diffuse nodular thickening of trachea and proximal bronchial walls with patchy mural calcification; also extensive bronchial stenosis, postobstructive pneumonia, atelectasis
Gross/micro images: image1
Micro: extensive thickening of submucosa due to irregular nodular masses or sheets of amyloid, reduced submucosal glands, calcification or osseous metaplasia of larger airways; variable multinucleated, osteoclast-like giant cells and plasma cells within amyloid; also amyloid deposition within submucosal vessel walls
Positive stains: Congo Red (apple-green birefringence with polarized light)
DD: systemic amyloidosis, light chain deposition disease, pulmonary scar tissue, pulmonary lymphoproliferative disorders, tracheobronchopathia osteochondroplastica (submucosal bony and cartilaginous tissue projects into tracheobronchial lumen, no amyloid)
Diffuse interstitial septal amyloidosis
Similar symptoms as diffuse interstitial fibrosis
Diffuse interstitial deposits of amyloid involving alveolar septa; also involvement of pulmonary arteries
Associated with systemic amyloidosis, congestive heart failure, pulmonary edema
No effective treatment; poor prognosis
Detect by Xray
Often multiple lesions, most commonly in right lower and middle lobe
Probably congenital
Shunting of blood between arterial and venous circulations causes bruit, cyanosis, polycythemia, low arterial oxygen content
Treatment: excision
Gross: large vascular channels with arteriovenous connections
Micro: abnormal vessels with excess or deficiency of smooth muscle making it difficult to differentiate veins and arteries
Incomplete expansion of lung or collapse of previously inflated lung, due to obstruction/resorption, compression or contraction
Obstruction: resorption of oxygen causes collapse, mediastinal shift towards affected lung; due to mucus plugs, asthma, chronic
bronchitis, bronchiectasis, postoperative changes, foreign bodies, not usually due to tumors (cause subtotal obstruction)
Compression: due to fluid (congestive heart failure), air (pneumothorax), tumor, blood; mediastinal shift away from affected lung
Contraction: due to fibrosis (restrictive lung disease)
Patchy: due to loss of surfactant in acute respiratory distress syndrome
Common in urban dwellers on parietal pleura, usually near diaphragm, AJSP 2002;26:1198
May be related to structures responsible for lymphatic drainage of pleural cavity
Do not appear to be clinically significant
Any calcification that impinges on or distorts a bronchus
Due to food aspiration, bronchiectasis, TB, histoplasmosis or other granulomatous disease
Acute or chronic bronchiolitis with nonnecrotizing granulomas, bronchopneumonia, interstitial pneumonia, organizing pneumonia
May be due to mesalamine (anti-inflammatory component of sulfasalazine)
May have CMV or atypical mycobacteria infections
DD: sarcoidosis (lymphangitic distribution, no interstitial pneumonia, no chronic bronchiolitis), hypersensitivity pneumonia (different history), ulcerative colitis (necrobiotic parenchymal lung nodules)
References: AJSP 2003;27:213
Case report of recurrent lung mass in 54 year old woman, containing macrophages with numerous eosinophilic cytoplasmic crystals in alveoli and interstitium, Archives 1996;120:978
Associated with plasmacytoma
Negative stains: PAS
Also called adult respiratory distress syndrome
Rapid onset of severe, life-threatening respiratory insufficiency, cyanosis, severe arterial hypoxemia refractory to
oxygen therapy, usually severe pulmonary edema, with diffuse alveolar infiltration on Xray
Causes: sepsis, aspiration, diffuse pulmonary infections (viral, mycoplasma, Pneumocystis, tuberculosis), mechanical
trauma, surfactant deficiency in newborns, near drowning; also other injury, inhaled irritants, chemical injury, radiation, amiodarone, chemotherapy, acute pancreatitis, burns, uremia
Pathophysiology: due to final common pathway of diffuse damage to alveolar capillary walls in both lungs
Capillary defect in adults attracts white blood cells and cytokines which further damage endothelium; may be due to endotoxin
Treatment: nitric oxide (vasodilator) decreases pulmonary vascular resistance and reduces ventilation-perfusion mismatch
Mortality 60%; 150,000 cases and 90,000 deaths per year in US
Gross: heavy, firm, red, boggy lung
Gross images: congestive phase, fibrotic phase
Micro: congestion and hemorrhage, interstitial and intra-alveolar edema, fibrin deposition, hyaline membranes (composed of edema fluid and cellular debris), type II pneumocyte proliferation with atypia, mitotic activity, cytoplasmic hyaline bodies and intracytoplasmic lipid, intra-arterial thrombosis, bronchiolitis obliterans; minimal chronic inflammatory infiltrate; may have extensive squamous metaplasia with atypia simulating squamous cell carcinoma (Hum Path 2002;33:1052)
early phase is exudative, later phase is organizing with fibrin, intra-alveolar fibrosis; may have superimposed pneumonia
Micro images: in immature lung, hyaline membranes #1, #2
Virtual slides: diffuse alveolar damage-infant
DD: Pneumocystic carinii
Acute fibrinous and organizing pneumonia
May be a variant of diffuse alveolar damage, Archives 2002;126:1064
Associated with collagen vascular disease, occasionally with amiodarone, Haemophilus influenza, Acinetobacter, lymphoma, hairspray, construction work, coal mining, zoological work, idiopathic
50% mortality, 30% require mechanical ventilation; either death in months or subacute illness with recovery
Treatment: antibiotics, steroids
Micro: patchy intra-alveolar fibrin in dominant finding, organizes into balls within alveolar spaces; no classic hyaline membranes, no prominent eosinophils, no fibroblastic Masson bodies; alveolar walls have acute or chronic inflammatory infiltrate, type 2 pneumocyte hyperplasia
Micro images: prominent intra-alveolar fibrin
Hemoptysis associated with menstruation or asymptomatic nodules
Hypersensitivity reactions mediated by IgE and circulating immune complexes
Allergens are fungi, parasites, drugs, unknown
Includes Loeffler’s syndrome, chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, bronchocentric granulomatosis, tropical eosinophilia
Autoimmune disease affecting men > women, usually ages 15-29, with simultaneous (a) sometimes massive hemorrhagic interstitial pneumonitis and (b) rapidly progressive (crescentic) glomerulonephritis
Death common due to uremia
Due to IgG antibodies to basement membrane of alveoli and glomeruli
Treatment: plasma exchange (removes antibodies and chemical mediators), immunosuppressive therapy (prevents further antibody production)
Lungs: heavy, focal necrosis of alveolar wall, fibrous thickening of septa with mild hyperplasia of alveolar lining cells, organization of blood in alveolar space, hemosiderin laden macrophages; linear deposits of immunoglobulin along basement membrane
Kidney: focal proliferative to crescentic glomerulonephritis, with linear deposits of immunoglobulin and complement along basement membrane, similar to lung
DD: mitral stenosis, periarteritis nodosa, SLE, systemic vasculitis (all cause secondary pulmonary alveolar bleeding and hemosiderosis), immune complex glomerulonephritis (granular pattern of immunofluorescence), idiopathic pulmonary hemosiderosis (no antibodies)
Round mass that resembles a neoplasm on Xray
Usually due to blunt trauma to chest
Causes: Goodpasture’s, SLE, immune complex glomerulonephritis, idiopathic pulmonary hemosiderosis, Wegener’s, generalized bleeding disorder, pulmonary venous obstruction
Idiopathic pulmonary hemosiderosis
Rare, usually children or teenagers with hemoptysis and refractory anemia similar to Goodpasture’s disease, but no antibodies in serum or tissue, no renal disease
Usually fatal after several years
Diagnosis of exclusion
Micro: hemosiderin laden macrophages in alveolar lumina, shedding and hyperplasia of alveolar epithelial cells, marked alveolar capillary congestion; varying interstitial fibrosis, intra-alveolar hemorrhage
No necrosis, no vasculitis, no granulomas, no lymphoid follicles
DD: mitral stenosis, periarteritis nodosa, SLE (neutrophils in alveolar septal capillaries), systemic vasculitis (all cause secondary pulmonary alveolar bleeding and hemosiderosis)
Occlusions usually embolic, not thrombotic, as pulmonary vasculature is low pressure
95% of emboli are from deep leg veins; also indwelling central venous lines cause right atrial thrombi
50,000 deaths/year in US due to pulmonary emboli (major cause of death in 10% of adults dying acutely in hospitals)
Large emboli cause sudden death by (a) lodging in major branches of pulmonary arteries or at bifurcations, causing electromechanical dissociation with rhythm but no pulse or (b) acute cor pulmonale (dilation of right side of heart) due to local increased resistance to blood flow, pulmonary hypertension, right sided failure
Emboli originate from leg or pelvic veins, often in immobilized individuals; other risk factors are trauma, hypercoagulable state, carcinoma and Trousseau’s syndrome, protein C/S deficiency, oral contraceptives, heart failure, pregnancy, older age
Small infarcts usually have minimal symptoms, except if bronchial circulation is inadequate, then have shortness of breath, tachycardia, pain, fever, cough, hemoptysis, fibrinous pleuritis, friction rub
If cardiovascular function is adequate, bronchial artery may compensate for pulmonary emboli, leading to hemorrhage without infarction; lungs can recover from hemorrhage but not from infarction
Emboli cause infarction only when circulation is already inadequate, so rare in young
Tissue plasminogen activator (tPA) and plasminogen activator inhibitor-type 1 may be more sensitive / specific lab tests than D-dimer for ruling out pulmonary emboli, Archives 2003;127:310
Fat emboli: due to long bone fracture or CPR
Amniotic fluid emboli: rare pregnancy complication, with squames in vessels
Hypercoagulable states: primary (deficiency of antithrombin III or protein C, defective fibrinolysis, lupus anticoagulant) or secondary (obesity, surgery, cancer, estrogen, pregnancy)
Chest Xray: wedge shaped infarct after 12-36 hours; may simulate carcinoma
Nuclear scan: macroaggregates of labeled albumin with perfusion lung scanning; angiography most definitive diagnostic test
Gross: wedge shaped, hemorrhagic parenchyma, fibrinous pleural exudate; eventually scars
Gross
images: thromboemboli
in pulmonary artery #1, #2, #3, #4,
saddle
embolus, hemorrhagic
infarct #1, #2,
#3,
#4,
organizing
infarct , fibrous
band
Micro: neutrophils present if septic emboli
Micro images: thromboemboli #1, #2, small thromboemboli, with recanalization, fat emboli, amniotic fluid emboli
Virtual slides: infarct due to septic emboli, hemorrhagic infarct, thromboemboli
Lesions due to injection of insoluble fillers of oral mediation, which lodge in small pulmonary arteries
Usually incidental findings at autopsy or biopsy
Rarely cause pulmonary hypertension
Micro: fresh or organizing arterial thrombi with foreign material; perivascular foreign-body granulomas contain birefringent foreign material resembling starch, talc or other materials; may be associated with acute vasculitis, interstitial inflammation, fibrosis
Micro images: polarized light #1, #2
Sodium polystyrene sulfonate is cation exchange resin given enterally for hyperkalemia
Case reports of aspiration, Archives 1996;120:967
Micro: basophilic amorphous foreign material in airspaces
Rare, diffuse, bilateral microliths or calcospherites within alveoli of otherwise normal lung
May represent end stage of interstitial pneumonia
Gross: resembles cirrhotic liver
Micro: marked smooth muscle hyperplasia throughout lung parenchyma, fibrosis
Rarely causes clinical lung disease
Associated with asthma, serum eosinophilia, serious systemic disease
Micro: vasculitis of bronchial arteries with fibrinoid necrosis; also tissue eosinophils; no large granulomas
Due to hemodynamic disturbances (cardiogenic) or local microvascular injury
Hemodynamic disturbances: due to increased hydrostatic pressure from congestive heart failure; lungs are wet and heavy, fluid initially at base of lower lobes because hydrostatic pressure is greater here; congestion, fluid, hemosiderin laden macrophages (heart failure cells) are present; later fibrosis and thickening of alveolar walls (brown induration of lung)
Local microvascular injury: injury causes leakage of fluids and proteins into interstitial space, eventually into alveoli; when diffuse,
contributes to acute respiratory distress syndrome
Virtual slides: pulmonary edema
top
Defined as at least 25% of systemic pressure; normal is 10% of systemic, due to low resistance of pulmonary vasculature
Hypertension usually due to structural diseases causing increased pulmonary blood flow or pressure, increased pulmonary vascular resistance or left heart resistance
Note: pulmonary atherosclerosis implies there is pulmonary hypertension
Causes: emphysema (hypoxia and alveolar destruction reduce the number of capillaries, causing increased arterial resistance, causing hypertension), congenital and acquired heart disease such as mitral valve stenosis (elevated left atrial pressure, pulmonary venous and arterial pressure), recurrent thromboemboli (reduced cross sectional area of pulmonary vascular bed causes increased vascular resistance), idiopathic (rare), vasospasm, endothelial cell dysfunction, ingestion of bush tea (Crotalaria spectabilis), aminorex (appetite suppressant), adulterated olive oil, fenfluramine / phenterimine, interstitial fibrosis, chronic liver disease, pulmonary veno-occlusive disease
Idiopathic: may be due to decreased production of nitric oxide and prostacyclin and increased levels of endothelin, leading to endothelial cell activation and thrombogenesis; usually women ages 20-40; asymptomatic until late, then shortness of breath, fatigue, angina, progressing to right ventricular hypertrophy, cor pulmonale, pulmonary emboli, pneumonia
Treatment: vasodilators, calcium channel blockers, nitric oxide, antithrombotic medications
Disease reversible if arterial lesions restricted to medial hypertrophy, intimal thickening of longitudinal smooth muscle or cellular intimal proliferation
Irreversible if moderate/severe concentric laminar intimal fibrosis, fibrinoid necrosis, plexiform lesions
Micro: organizing thrombi (suggests recurrent pulmonary emboli); interstitial fibrosis if hypoxia; changes in major vessels / branches are similar to systemic atherosclerosis; small vessels have medial hypertrophy and intimal fibrosis which may narrow lumina to pinpoint; plexogenic arteriopathy: tuft of capillaries spanning lumina of arteries
Micro images: atherosclerosis
Primary plexogenic hypertension
Young women with progressive shortness of breath, angina, syncope and possibly sudden death
Associated with collagen vascular disease and positive ANA
Death usually within a few years; 5 year survival is only 35%
Micro: grade I (early) - muscularization and media hypertrophy (>7% of lumen) of pulmonary arteries
Grade II - intimal hyperplasia causing attenuation of vascular lumen
Grade III - subintimal fibrosis with onion-ring appearance; marked reduplication of internal elastic membrane; arteries and arterioles resemble pipes
Grade IV to V - dilation and plexiform lesions, aneurysmal dilation of small pulmonary arteries, plexiform and glomeruloid nodules; fibrin thrombi within plexiform lesion, old/new hemorrhage present
Grade VI - uncommon, acute necrotizing arteritis with fibrinoid necrosis and acute inflammation of vessel wall, similar to polyarteritis nodosa; associated with extreme pulmonary hypertension
Micro images: plexiform lesion #1, #2, #3, #4 (note: #2-#4 are actually from secondary hypertension)
DD: secondary pulmonary hypertension (similar histology, different history)
Thrombotic pulmonary hypertension
Also young women, also associated with collagen vascular disease
Micro: recent and organized intravascular thrombi; eccentric intimal fibrous plaques, bands and septa; recanalization may resemble a plexiform lesion; no marked intimal fibroplasia, no plexiform lesions, no arteritis
DD: plexogenic hypertension (may also have thromboemboli)
Multiple pulmonary emboli
Older men and women, emboli cause pulmonary hypertension
Radiation induced lung disease
top
Acute radiation pneumonitis: 1-6 months after therapy
Symptoms: fever, shortness of breath, radiologic infiltrates, diffuse alveolar damage, type II pneumocyte atypia
Treatment: steroids
Chronic radiation pneumonitis: interstitial fibrosis, epithelial atypia, foam cells in vessel walls
top
Chronic pleuritis with variable effusion, diffuse interstitial fibrosis, intrapulmonary rheumatoid nodules, rheumatoid nodules with pneumoconiosis (Caplan’s syndrome), pulmonary hypertension, bronchiolitis obliterans, pleural effusion, amyloidosis, vasculitis
Note: 30% with rheumatoid arthritis have abnormal pulmonary function
Rheumatoid nodules are associated with active joint disease and elevated titers of rheumatoid factor
Treatment: steroids (thus, must first rule out an infectious process)
Gross: pleural fibrosis, rheumatoid nodules, pneumonia
Gross images: rheumatoid nodules
Micro: rheumatoid granuloma usually in lung periphery near pleura; round with zone of pallisading histiocytes perpendicular to necrobiotic center; adjacent vasculitis; nodules have carbon and silica within the necrotic center in Caplan’s syndrome
Micro images: nodules with central necrosis and pallisading histiocytes, vasculitis #1, #2
DD: Wegener’s granulomatosis
Rounded atelectasis
top
Localized area of subpleural lung collapse with associated pleural fibrosis
Usually posterior portion of a lower lobe
Gross: lung shows ill defined atelectasis with deeply invaginated pleural folds which may disappear during grossing
Micro: pleural fibrosis and invagination (use elastic stains to highlight) and atelectasis
Lung transplantation is the only effective treatment for severe idiopathic pulmonary fibrosis, primary pulmonary hypertension, emphysema, cystic fibrosis
For cystic fibrosis, both lungs are removed, even if only one replaced, to minimize infectious complications
Recipient lung may be infected by CMV, Pneumocystis, fungi, bacteria, due to immunosuppression
Acute rejection: weeks to months after transplant, with fever, shortness of breath, cough, chest Xray abnormalities; diagnose via biopsy
Micro: chronic inflammatory infiltrate around small vessels or in submucosa of airways; treat with steroids
Chronic rejection: affects 25-50% of patients, 6-12 months after surgery, with shortness of breath, cough and bronchiolitis obliterans; no effective treatment
Post-transplantation injury in lung
Graft versus host disease and interstitial pneumonia cause most nonleukemic deaths after bone marrow transplant
Pneumonia typically is caused by CMV; pneumonitis is caused by chemotherapy, radiation injury
Post lung-transplant lymphoproliferative disorder (PTLD)
Incidence is 3%, with a median 7 months to development of disease, Mod Path 2002;15:647
B cell lineage, 78% were EBV+, all monoclonal, usually occurred in lung
Most died at a mean 5 months
Micro images: polymorphic PTLD, monomorphic PTLD, CD20, EBER in situ hybridization
top
Rare, usually children and adolescents, male and female; also after cancer chemotherapy
Causes pulmonary hypertension secondary to widespread thromboemboli of large and medium size branches of pulmonary vein; also diffuse occlusion of postcapillary venous beds by fibrous tissue
Usually recanalization and pseudoangiomatous changes, arterial thickening, hemosiderosis
Most patients die within 2 years of diagnosis; lung transplant may prolong lives
Case report in 6 year old girl with progressive dyspnea, Archives 2003;127:e393
Micro: eccentric intimal thickening of venules in lobular septa with some septal veins completely occluded, increased elastic fibers in venous media (highlighted with elastin stain); medial hypertrophy of arterioles but no plexiform lesions; intraalveolar hemorrhage and hemosiderosis; prominent alveolar septa due to congestion
Micro images: 3:septal veins, 4:elastin stain; images
DD: UIP (no increased elastic fibers)
End of Lung-nontumor chapter
Go to Lung-tumors