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Lung PathologyNORMALS FOR REFERENCE

1. Normal lung:A lung is bisected, revealingbranching conducting airways (bronchi) andspongy brown parenchyma.

2 and 3. Normal bronchus: The bronchial wallincludes the respiratory mucosa, smoothmuscle, submucosa with seromucinousglands, and cartilage. The epithelium ispseudostratified and columnar, and consists ofciliated cells, goblet cells and reserve cells.Neuroendocrine (Kulchitsky) cells cannot bedistinguished.

4. Normal alveolar parenchyma: Terminaland respiratory bronchioles (*), alveolarducts, alveolar sacs, and a small arteryare shown.

5. Normal alveolar parenchyma: Apulmonary macrophage (arrow) lies inthe central alveolus.

6. Normal interlobular septum withlymphatic: A lymphatic (*) coursesthrough an interlobular septum.

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ATELECTASIS

Definition: incomplete expansion of the lung, or collapse of previously inflated lungtissue

Atelectatic parenchyma is predisposed to infection

Depending upon the amount of lung tissue involved, oxygenation may bereduced

Usually reversible - parenchyma can be reexpanded unless scarring hasoccurred

Etiologies/Types of Atelectasis

1. Obstructive (absorptive) - complete airway obstruction----> absorption of air trapped distally ----> collapse(mediastinum may shift toward the collapsed lung)

Causes: Excessive bronchial secretions and mucusplugging (asthma, chronic bronchitis, postoperative)

Masses (aspirated foreign bodies, tumors)

2. Compressive - compression of the lung by a substance inthe pleural space [air (pneumothorax), blood (hemothorax),fluid (effusion)] or an abnormally elevated diaphragm (basal

atelectasis) associated with peritonitis or subdiaphragmaticabscess; mediastinum may shift away from the collapsedlung

3. Contraction - collapse of parenchyma around fibroticareas of lung or pleura.So-called round atelectasisis a type of contractionatelectasis: the visceral pleura develops a localized area offibrosis associated with an infolding of the pleura thatextends downward into the underlying lung tissue. Many

patients have a history of asbestos exposure. Significance:round atelectasis may look like a mass radiographically.

4. Patchy - with loss of or inadequate surfactant (ARDS,hyaline membrane disease of newborn)

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DISEASES OF VASCULAR ORIGIN

Pulmonary edema Lungs are heavy, with increased fluid particularly in the lower lobe bases

Histologically, there is eosinophilic fluid in alveoli, congested capillaries,

focal intraalveolar hemorrhages and hemosiderin-laden macrophages("heart failure cells")

Causes include hemodynamic alterations and microvascular injury

Hemodynamic causes: processes that alter the balance between forces movingfluid into and out of capillaries (Starlings law of capillary interstitial fluid exchange)

Increased hydrostatic pressure - left-sided heart failure, fluid overload,pulmonary venous obstruction

Decreased oncotic pressure - hypoalbuminemia (nephrotic syndrome,cirrhosis, protein-losing enteropathy)

Lymphatic obstruction - tumor blockage of lymphatics

Microvascular injury - injury to the alveolar capillary endothelium ----> fluids andproteins leak into the interstitium and then the alveoli; can be localized (ex: near apneumonia) or diffuse (see section on ARDS)

7. Pulmonary edema: Eosinophilic fluid fillsalveoli, and focal hemorrhages are alsopresent.

8. Chronic passive congestion:Hemosiderin-laden macrophages and

edema fluid occupy alveoli.

Chronic passive congestion With longstanding congestion of the lungs, such as is seen with mitral stenosis,

numerous hemosiderin-laden macrophages collect in alveoli and interstitialfibrosis develops; lungs look brown and feel firm (brown induration)

Pulmonary embolism, hemorrhage, and infarction

General facts:

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Pulmonary emboli cause about 50,000 deaths/yr. in the U.S.

Most (>95%) of the emboli arise in the large lower leg veins, and occasionallylarge pelvic veins or the right side of the heart are the source of the emboli

Increased incidence in patients with

o Primary hypercoagulable states: factor V Leiden, antithrombin III or protein

C deficiency, antiphospholipid syndrome, prothrombin 20210 A, otherso Secondary hypercoagulable states: chronic immobilization, late

pregnancy, oral contraceptive use, cancer, recent surgery

Embolism is much more common than thrombosis in pulmonary arteries;thrombosis usually requires a predisposing condition such as tumor or infection

Prevention: early ambulation of post-surgical and postpartum patients, elasticstockings and leg exercises for bedridden people, anticoagulation in high riskpeople, or use of a filter in the inferior vena cava

Emboli lead to respiratory compromise due to V/Q mismatch, and hemodynamiccompromise caused by increased resistance to blood flow induced by obstruction. Theclinical significance of an embolus depends on:

Extent of obstruction of pulmonary artery blood flow (size, # of vessels occluded)Collateral (bronchial) circulationUnderlying cardiorespiratory status of the patient

OUTCOME MECHANISM FREQ.

Nothing (clinically silent) 60-80%

Sudden death / Acute right heart failure /

Electromechanical dissociation

>60% of the pulmonary vasculature

is obstructed

5%

Infarction (visible on CXR 12 36 hours

after embolism occurs)

Inadequate collateral pulmonary

blood flow; often coexisting heart or

lung disease is present

10-15%

Hemorrhage Collateral blood flow is sufficient to

sustain viability of tissues

10-15%

Pulmonary hypertension Usually multiple emboli over time;

can cause R ventricular hypertrophy

2-3%

Morphology:

Embolus: red cells and fibrin fill arterial lumen, adhering to the endothelial surface ---->may lyse, contract, organize and/or recanalize

Hemorrhage: blood in alveoli and interstitium, with preservation of architecture

Infarct: usually wedge-shaped and peripheral, with embolus at apexacute - ischemic necrosis of the parenchyma with hemorrhage

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older - scar (fibrosis), often with hemosiderin-laden macrophages

9. Pulmonary embolus: Blood clot fills thelumen of the pulmonary artery.

10. Recent pulmonary infarct: The infarctlies in a typical location (subpleural) and hasthe typical wedge shape. The hemorrhagicappearance tells you that it is a recent (notold) infarct.

11-12. Organizing pulmonary embolus andinfarct: The lung tissue shows coagulativenecrosis and hemorrhage. A small artery isfilled by an organizing fibrin embolus.

Special types of emboli:

Embolic carcinomatosis - some carcinomas of the breast, stomach, and lung

massively invade blood vessels, widely disseminate and block pulmonary arteries Septic embolism - fragments of an infected (bacteria or fungi) venous thrombus

or tricuspid valve vegetation embolize, sometimes producing septic infarcts orthrombarteritis; microscopically - neutrophils and organisms

Fat embolism - from trauma, esp. fractures or extensive subcutaneous tissueinjury, or surgery involving bones

Air embolism - from trauma, surgery, intravenous injection, obstetricalprocedures; usually takes > 100 cc to have a clinical effect via occlusion of vessels

Bone marrow embolism - after CPR with chest massage leading to rib fractures

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Amniotic fluid embolism - around the time of delivery; can cause shock andARDS

Starch or talc particles - contained in drug solutions injected by addicts

Parasites - Dirofilaria immitis (dog heart worm)

13. Tumor emboli: A plug of metastaticcarcinoma and fibrin fills a small pulmonaryartery. The parenchyma at left is infarcted.

14. Intravenous talcosis: Abundant talc

(polarizable) is present adjacent to bloodvessels, in this lung from an intravenousdrug abuser.

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15. Dirofilaria immitis: Thebody of a dog heartworm iscurled in the lumen of a small

pulmonary artery (Massontrichrome stain).

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Pulmonary hypertension: mean pulmonary pressure >or = 1/4 X systemic bloodpressure (normally, pulmonary blood pressure is about one-eighth of systemic bloodpressure).

Most cases are secondary to structural cardiopulmonary conditions that increasepulmonary blood flow and/or pressure, pulmonary vascular resistance (PVR), or

left heart resistance to blood flow. A smaller number of cases are primary.

Simonneau G, Gali N, Rubin LJ, et al. Clinical classifi cation of pulmonary hypertension.J Am CollCardiol. 2004;43

(12 Suppl S):5S-12S

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SECONDARY CAUSES MECHANISMS

Chronic obstructive and

interstitial lung diseases

1. Chronic hypoxia ---> vasoconstriction ---> inc PVR

2. Decreased numbers of alveolar capillaries

Recurrent pulmonary emboli Decrease in cross-sectional area of open pulmonary vessels

Congenital heart diseaseswith left to right shunts

Increased pulmonary blood flow ---> inc PVR

Acquired heart diseases (ex:

mitral stenosis)

Increased left atrial pressure ---> increased pulmonary venous

pressure ----> increased pulmonary arterial pressure

Collagen vascular disorders Vascular inflammation and fibrosis

Pathogenesis:Endothelial cell injury resulting from mechanical forces (increasedblood flow and pressure), biochemical alterations (such as due to the fibrin in

thromboemboli), or unknown sources (idiopathic) produces changes in the chemicalmicroenvironment that initiate the vascular responses causing pulmonary hypertension:

Vasoconstriction Promoted by dec prostacyclin and nitric oxide, inc endothelin

Platelet adhesion and activation - Promoted by dec prostacyclin and nitric oxide

Fibrin formation and deposition

Migration and proliferation of vascular smooth muscle cells and production ofextracellular matrix

Vasospasm

Primary (idiopathic)pulmonary hypertension:

Many cases are linked to mutations in the bone morphogenetic protein receptortype 2 (BMPR2) signaling pathway

- BMPR2 locus in on chromosome 2q33; signaling is important for inhibitingvascular smooth muscle cell proliferation and favoring apoptosis

- Since the disease only occurs in 10-20% of people with BMPR2 mutations,other modifier genes and/or environmental triggers may be needed tocause clinical disease

Occasional familial cases (autosomal dominant)

Usually fatal within 2-5 yrs. from cor pulmonale, though vasodilators,antithrombotic medications and lung or heart-lung transplantation may prolong life

Morphology (pulmonary hypertensive disorders):

Medial hypertrophy, intimal proliferation and fibrosis in arterioles and smallarteries

Atheromatous deposits in main elastic arteries

Capillary tufts in lumina of arteries (plexiform lesions) - indicates severe andirreversible pulmonary hypertension; more common in primary pulmonaryhypertension and congenital heart disease with L-to-R shunts

Additional findings specific for a given etiology:- antecedent pulmonary emboli: may see organizing/ed emboli

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- coexisting diffuse pulmonary fibrosis, severe emphysema or chronic bronchitis

16. Pulmonary hypertension: This smallartery demonstrates medial hypertrophy.

17. Pulmonary hypertension: This plexiformlesion is an aggregate of small capillaries,and indicates the existence of severepulmonary hypertension.

Veno-occlusive disease:Small veins become occluded by fibroblasts andcollagen, leading to chronically impaired venous outflow and histologic changes ofchronic passive congestion. Chemotherapeutic agents or other toxins sometimes causethis disorder, but no etiology can be determined in a large number of cases. Occurs inchildren and young adults. Can be treated by lung transplantation.

18. Pulmonary veno-occlusive disease: Asmall vein is occluded by fibrous tissue, andthe surrounding lung shows changes ofchronic passive congestion

Disorders associated with diffuse pulmonary hemorrhage: With vasculitis:

o Goodpasture syndrome

o Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides

Wegeners granulomatosis

Microscopic polyangiitis

Churg-Strauss syndromeo Collagen vascular diseases

Systemic lupus erythematosus

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Otherso Behcet disease

Without vasculitis:o Idiopathic pulmonary hemosiderosis

o Associated with coagulopathy

o Associated with infections

o Associated with diffuse alveolar damageo Associated with chronic passive congestion

o Associated with arteriovenous malformation

Goodpasture Syndrome (Anti-glomerular basement membrane disease)

Necrotizing hemorrhagic interstitial pneumonitis and glomerulonephritis causedby antibodies to a glomerular basement membrane antigen (a component of thenoncollagenous domain of the alpha3 chain of collagen type IV) that cross-reactwith alveolar basement membranes

M > F, especially in second and third decades; present with hemoptysis,consolidation, renal failure

Cofactors - smoking, exposure to hydrocarbons (dry cleaning work), viralinfection; associated with HLA-DR2

Morphology: intraalveolar hemorrhage +/- hemosiderin-laden macrophages;immunofluorescence (IF) reveals linear deposits of IgG along basementmembranes of alveolar septa and glomeruli

Treatment - plasma exchange, immunosuppression

19. Goodpastures syndrome: IF staining forIgG reveals the diagnostic linear stainingalong the basement membrane.

Wegeners Granulomatosis

An autoimmune disease that classically involves the triad of the lungs, upperrespiratory tract and kidneys, but can involve almost any anatomic site

Associated with antineutrophil cytoplasmic antibodies (ANCA), which arebelieved to play a role in the pathogenesis of the disease

Pathologic findings include vasculitis (any size vessel), necrosis,granulomatous inflammation

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20. Wegeners granulomatosis small vesselvasculitis: The capillaries are densely infiltratedby neutrophils and there is a background ofpulmonary hemorrhage.

21. Wegeners granulomatosis granuloma:This small granuloma has a centralmicroabscess.

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Acute respiratory distress syndrome (ARDS)

Clinicalpresentation - a syndrome that manifests acutely, usually within hours of thetriggering event, with severe life-threatening respiratory insufficiency, cyanosis, andsevere hypoxemia that is refractory to oxygen therapy, and often leads to multiorganfailure; CXR - diffuse bilateral infiltrates ("white out")

mechanical ventilation is used to try to maintain oxygenation; often, highoxygen concentrations are needed, which may add to injury due to oxygen toxicity

mortality rate has been 40-60%, but there has been recent improvement

Triggers can be systemic inflammatory conditions or primary lung diseases or injuries, orcombinations. Etiologies include

Diffuse pulmonary infections***Inhalation of smoke, irritant gases

Aspiration of gastric contents***

Sepsis***Shock***Trauma***Massive air, fat, or amniotic fluid embolismDrugs - chemotherapeutic agents, narcotic (esp. heroin) overdose, occasionally other drugsRadiationDisseminated intravascular coagulation and other blood disordersHemodialysis and cardiopulmonary bypassUremia, diabetic ketoacidosis, and other metabolic disordersExtensive burns

Acute pancreatitisNear-drowningOxygen toxicityPulmonary contusions

*** most common

Pathogenesis: diffuse damage to the alveolar wall (capillary endothelium andalveolar epithelium) predictable series of physiologic and morphologic eventsthat are generally similar regardless of the initiating agent

Although endothelial and epithelial injury is directly caused by some of the initiatingagents, native inflammatory cells and mediators are usually central to the evolution of theprocess. Pulmonary intravascularneutrophil aggregation occurs in many of theconditions leading to ARDS and is responsible for damage to endothelial and epithelial

cells through release of toxic oxidants and proteases. ARDS, however, can also developin a setting of neutropenia.

Cytokine (TNF-, IL-1, IL-8) release from lung macrophages enhances endothelialexpression of adhesion molecules for leukocytes and promotes the inflammatoryresponse. NF-B is an important participant in transcriptional mechanisms that controlexpression of proinflammatory genes.Neutrophils oxygen-derived free radicals and proteasesMacrophages oxygen-derived free radicals, proteases, arachidonic acid metabolites,

platelet-activating factor

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Oxygen-derived free radicals endothelial and epithelial injury increasedvascular permeability and epithelial sloughing

Lysosomal enzymes (proteases) destroy structural proteins (collagen, elastin)Thromboxane vasoconstrictionMacrophage-derived factors transforming growth factor and platelet-derived

growth factor fibroblast proliferation, collagen deposition

Morphology: diffuse alveolar damage (DAD) is the pathologic lesion that occurs invictims of ARDS; it is divided into an acute (exudative) stage which occurs in the firstweek following injury, and an organizing (proliferative) stage, which begins about 7days post injury; hyaline membrane disease of the newborn has very similar morphology,but the pathogenesis is different (deficiency of surfactant)

Trigger

Acute

Stage

Variablerecovery of Organizingrespiratory Fibrosis and Stagefunction architectural remodeling

22. Diffuse alveolar damage/acuterespiratory distress syndrome: Hyalinemembranes line alveolar septa. Hyalinemembranes are composed of fibrin-richedema fluid mixed with cytoplasmicremnants from necrotic cells.

14

PMN,macrophage

activation

Endothelial

& epithelialinjury

Edema, pneumocyte

necrosis, hyaline

membranes, atelectasis

V/Q mismatch hypoxemia

Type II pneumocyteproliferation, interstitial

inflammation and fibroblast

proliferation

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BACTERIAL INFECTIONS OF THE LUNG

PREDISPOSING FACTORS

Impairment of pulmonary defense mechanisms or generalized lowering of host

resistance (chronic disease, immunocompromise, chemotherapy, previous severeinfection - particularly pneumonia) predispose to bacterial pneumonia.

Loss or suppression of the cough reflexmay lead to aspiration oforopharyngeal and/or gastric materials - ex: anesthesia, coma, drugs,neuromuscular disorders.

Mucociliary apparatus dysfunction leads to impaired bacterial clearance.Agents and disorders that can cause, or be associated with, mucociliary apparatusdysfunction include cigarette smoke, viral infections, immotile cilia syndrome,inhalation of toxic gases, aspiration of toxic substances.

Disturbance of the phagocytic or bactericidal actions of alveolar macrophagescan reduce bacterial clearance. Causes include cigarette smoke, alcohol, anoxia.

Hypogammaglobulinemia.

In addition,pulmonary edema and congestion (congestive heart failure) andaccumulated secretions (cystic fibrosis, bronchial obstruction) can foster bacterialgrowth.

HOW THESE INFECTIONS DEVELOP

Although inhalation of bacteria is the usual mode of infection, occasionallyhematogenous spread from other foci of infection can occur. Hematogenouspneumonia is a particular problem in hospitalized patients with intravenous lines. Theselines can become colonized by bacteria, especially Pseudomonas aeruginosaandStaphylococcus aureus, and the organisms can embolize to the lungs where theycause pneumonias and abscesses. Nosocomial pneumonias, developing via inhalationor hematogenous routes, are not uncommon, and can be difficult to treat due to thefrequency of antibiotic resistance in organisms dwelling within the hospital environment.Intubation also increases the likelihood of nosocomial infection. Bacterial contaminationof respirator apparatus may occur, leading to tracheobronchial colonization,

tracheobronchitis, and pneumonia.

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BACTERIAL PNEUMONIA

Symptoms: fever, chills, cough, expectoration, expiratory rales, shortness ofbreath, cyanosis (if decreased vital capacity), pleuritic chest pain

Course depends upon the virulence of the responsible agent, the extent ofpneumonic involvement, the patient's underlying condition, and the effectivenessand promptness of antibiotic therapy; mortality < 10%

Complications: lung abscess, empyema, suppurative pericarditis, bacteremiawith metastatic abscess formation, extensive pulmonary fibrosis

Bronchopneumonia:patchy consolidation of one or multiplelobes of the lung, usually representing extension of a bronchitis

Very common, esp. in older people with chronic illnesses

The usual organisms:oCommunity-acquired pneumonia: Streptococcus

pneumoniae, H. influenzae, Moraxella catarrhalis,Pseudomonas aeruginosa, Staphylococcus aureus,Klebsiella pneumoniae

oNosocomial pneumonia: Pseudomonas aeruginosa, Staphylococcus aureus,

Klebsiella pneumoniae, Serratia marcescens, E. coli

23. Acute bronchopneumonia: The tan-yellowspots centered around airways are foci of acutebronchopneumonia, and represent acuteinflammatory exudate in bronchi, bronchiolesand adjacent alveoli.

24-25. Acute bronchopneumonia: Neutrophilsfill a bronchiole and adjacent alveoli.

Morphology:

Gross: firm gray/red/yellow foci separated by more normal appearing parenchyma

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Microscopic:neutrophils fill bronchi, bronchioles, and adjacent alveolar spaces;necrosis may be present with more virulent organisms; with time, the exudate mayresolve, leaving little fibrosis behind, ororganize with variable fibrosis

Lobar Pneumonia: bacterial infection involving an entire lobe or a large portion of alobe

Less common than in the past, due to effective antibiotictherapy which can abort the pneumonia before it progressesto lobar consolidation

90-95% caused by Streptococcus pneumoniae - themucoid capsule of the bacteria protects them fromphagocytosis and favors their dissemination; other bacteriawhich cause lobar pneumonia include Klebsiella pneumoniae,staphylococci, other streptococci, H. influenzae,Pseudomonas, Proteus

26. Lobar pneumonia: The entire left upperlobe is pale and firm (consolidated),reflecting the acute inflammatory exudatefilling virtually all airspaces. There is focalabscess formation (box).

27. Empyema: Suppurative exudate coversthe pleural surfaces. This exudate mayorganize and form a pleural rind and pleuraladhesions that can impair lung expansion.

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General progression ofmorphology in lobar pneumonias:

Gross:

Red hepatization Gray hepatization

Time

Micro:

Legionnaire's Disease: pneumonia caused by Legionella pneumophila occurringprimarily in smokers, elderly, patients with chronic lung diseases, andimmunosuppressed patients; bacteria requires special media for culture, and a silverstain is needed for its detection in tissues

Bacteria are resistant to chlorine, may contaminate cooling systems in buildings

Aspiration Pneumonia

Aspiration is common in people with:

Alteration inmental status or level of consciousness producing a diminishedor absent gag reflex orcompromised epiglottic closure

Neuromuscular disorders (myasthenia gravis, laryngeal palsy)

Gastroesophageal reflux

The location of the aspiration pneumonia depends on the patient's position andgravity:

lying on back ---> apical segment of right lower lobelying on side ---> posterior regions of upper lobechronic ---> both lower lobes

Causative agents are usually gram negative enterics and anaerobes, butPseudomonas and S. aureus are important in hospitalized patients.

In addition to the usual changes of acute pneumonia, other pathologic presentations caninclude diffuse alveolar damage/ARDS (with aspiration of gastric acid), foreign body giantcell reaction to food particles, and lipoid pneumonia (see below).

Lipoid pneumonia (exogenous): an oily substance (ex: mineral oil, used by some folksas a laxative) is aspirated and phagocytosed by macrophages, whose cytoplasm thenappears foamy; fibrosis can also develop over time

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Red,swollen

Congestion,

edema, fewneutrophils,

bacteria

Red, firm, liver-like,often with overlying

pleuritis

Numerous PMN

and RBC inalveoli, bacteria

in PMN

Degenerating

PMN, fibrin

Gray-brown

Normal or

variablefibrosis

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Endogenous lipoid pneumonia is histologically similar to exogenous lipoidpneumonia, but is usually secondary to bronchial obstruction (not aspiration)

28. Lipoid pneumonia: In exogenous lipoidpneumonia, aspirated oily substances (ex:mineral oil) are phagocytized bymacrophages whose cytoplasm takes on a

foamy appearance. Large empty spaces (*)represent collections of fat that did notsurvive the processing steps involved inmaking a glass slide. The fat triggersfibrosis. Endogenous lipoid pneumonia isusually caused by bronchial obstruction by atumor or other process, and is histologicallysimilar to exogenous lipoid pneumonia,except that the large fat collections areabsent.

Bacterial causes of chronic pneumonias:

Nocardia asteroides:aerobic gram + bacteria that grows in branched chains andcauses opportunistic infections in immunocompromised people (defective T-cellmediated immune function due to HIV, prolonged steroid use, diabetes mellitus)

o Causes respiratory disease that often resembles TB (chronic cough, fever,

weight loss, pulmonary infiltrates), and also often infects the CNSo Stains with Fite acid fast stain (unlike Actinomyces)

Actinomyces israelii: gram + anaerobic filamentous bacteria that are commonlyfound in the mouth but can cause aspiration-related pneumonia or abscess

o Similar morphology to Nocardia sp., but form sulfur granules and do not

stain with the Fite stain (unlike Nocardia)

29. Nocardia asteroides: The bacteria formchains and are acid fast-positive.

30.Actinomyces israelii: A sulfur granuleformed by the bacteria is shown.

LUNG ABSCESS: localized suppurative process with necrosis of lungtissue

Most frequent in young adults

Mixed infections are common, and 60% are caused by anaerobic organismsnormally found in the oral cavity

Predisposing factors

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o Oropharyngeal surgeries, sinobronchial infections, CNS impairment

aspiration of oropharyngeal contents

o Preexisting pulmonary bacterial infection - pneumonia or bronchiectasis

caused by a virulent organism necrosis of lung tissue

o Neoplasm (present in 10-15% of abscesses) persistent airway infection

o Septic embolism from systemic veins or the right side of the heart Symptoms: cough, fever, copious foul-smelling purulent sputum, chest pain

CXR: cavitary mass with air-fluid level

Morphology:

Gross:necrotic, often cavitary, masses measuring from millimeters to 6 cm., whichmay be filled with purulent material, or if a communication exists with an airpassage, may contain air (drainage having occurred through the airway); whendue to aspiration, more common on the right (main bronchus is more vertical)

Microscopic: suppurative (neutrophilic) necrosis of lung parenchyma

31. Abscess: An abscess cavity (*) is formedby suppurative necrosis of lung tissue, in thiscase caused by a bacterial infection that wasprobably related to aspiration (note thelocation in the RLL). Next to the abscess,the lung parenchyma appears consolidated

(firm and tan) due to pneumonia. Two smallbronchi terminate in the abscess, passagesthrough which foul smelling purulent materialcan be coughed up.

32. Abscess: Neutrophils are mixed withnecrotic material. The giant cells raise thepossibility of aspirated material (though noneis seen in this view).

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ATYPICAL PNEUMONIAS

More common causes of atypical pneumonia:

AGENT USUAL PATIENT GROUP USUAL IMMUNE STATUS

Mycoplasma pneumoniae Adults Nonimmunocompromised

Chlamydia spp. (pneumoniae,psittaci, trachomatis)

Adult Nonimmunocompromised

Coxiella burnetti (Q fever) Adults Nonimmunocompromised

RNA viruses:

Respiratory syncytial virus,

Parainfluenza

Infants, children

Adults

Nonimmunocompromised

Immunocompromised

Human metapneumovirus Children and adults Nonimmunocompromised

Influenza Adults Nonimmunocompromised

DNA viruses:

AdenovirusChildren, military recruits

Adults

Nonimmunocompromised

Immunocompromised

Herpes simplex virus All Immunocompromised

Varicella-zoster virus Adults, esp. pregnant women Both

Cytomegalovirus All Immunocompromised

Viral Pneumonias: General Comments

Most of the respiratory viruses (RSV, parainfluenza, influenza, adenovirus, rhinovirus)can produce clinical illnesses ranging from trivial upper respiratory tract infections tosevere lower respiratory tract infections. Clinical severity is highly influenced byhost factors, particularly immune status. Malnutrition, alcoholism, and debilitatingillnesses also favor development of a more severe infection. Superimposed bacterialpneumonias are a major source of morbidity and mortality with some of the viralpneumonias, especially influenza A.

Viral pneumonias can be diffuse and bilateral, patchy, or localized. Depending upon thevirus, the primary site of infection can be the airways, the alveolar septa, or both.Common patterns of lung involvement by viruses are listed below. Identification ofone of these patterns should prompt a search for cytologic evidence of a specific virus.

Diffuse alveolar damage bilateral severe pneumonia pattern that is morecommon with immunocompromised patients

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Interstitial pneumonia - interstitial inflammation

Bronchitis/bronchiolitis/bronchopneumonia - inflammation in airways;acute bronchiolitis can lead to bronchiolitis obliterans (bronchiolar lumenalobliteration by fibrous tissue)

Hemorrhagic parenchymal nodules - foci of hemorrhage, inflammation,

necrosis

Respiratory syncytial virus (RSV)

Most common cause ofserious lower respiratory tract infection in children thrombosis andinfarction, hematogenous dissemination

58. Angioinvasive mucormycosis: Theentire left lung is infarcted, due toextensive vascular invasion bymucormycosis and subsequentpulmonary artery thrombosis. Vascularinvasion, thrombosis, and subsequentinfarction of the infected organ are

characteristic manifestations ofmucormycosis. Dissemination to othersites also occurs via vascular channels.This patient was markedlyimmunocompromised.

59-60. Angioinvasive mucormycosis (hematoxylin eosin

above, MSS-below): The top image shows a medium-sized blood vessel in the lung whose lumen is filled withnumerous intertwined fungal hyphae (*) admixed with recells. The MSS stain for fungus (lower image) highlightthe hyphae (black) that fill the vessel lumen and infiltratthe vessel wall. The hyphae are broad, irregularlybranching, and nonseptate, features of zygomycetes, thfamily of fungi which includes Mucor, Rhizopus, and

Absidia.

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Aspergillosis (Aspergillus fumigatus, niger, and other species)

Widely distributed in nature, found in dust raised during construction, andfrequently contaminate hospitals

Fungal morphology: thin septate hyphae with parallel walls and branching atapprox. 45 degree angles

Forms of Disease Usual Patients Pathology

Allergicbronchopulmonaryaspergillosis

Asthmatics Superficial colonization of the bronchialmucosa -----> inflammation andscarring of the airway, worsening ofsymptoms

Aspergilloma("fungus ball")

Have pre-existingcavity or

bronchiectasis

Cavity or ectatic bronchus becomesfilled with proliferating masses of

fungal hyphae; tissue invasion isabsent or minimal

Airway-invasiveaspergillosis

Slightly compromised Airway invasion by fungi, usuallyrelatively limited, often chronic

Chronic necrotizingaspergillosis

Slightly compromised Parenchymal invasion by fungi withslow growth, often contained ingranulomas

Invasive aspergillosis Immunocompromised Necrotizing pneumonia with tissue andvascular invasion by fungus,thrombosis and infarction

Disseminatedaspergillosis

Immunocompromised Systemic dissemination viahematogenous spread, withparenchymal invasion, vascularinvasion, thrombosis and infarction

61. Aspergillus infection (silvermethenamine stain): Aspergillus speciesdemonstrate thin septate hyphae with

approximate 45angle branching.

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62-63. Aspergilloma (fungus ball): A largeaggregate of aspergillus hyphae fills a pre-existing cavity in the lung apex (arrow and *).

64. Invasive aspergillosis: This lung from aseverely immunocompromised patient hasnumerous round colonies of fungus.

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DIFFUSE INTERSTITIAL DISEASES OF THELUNG

Diseases with recognized causes1. Occupational and environmental substances

Inorganic dust diseases (asbestosis, silicosis, coal workers pneumoconiosis,etc)

Numerous antigens (hypersensitivity pneumonitis)

Toxic inhalants (oxygen toxicity, sulfur dioxide, mustard gas, etc)2. Drugs, esp. chemotherapeutic agents3. Radiation pneumonitis4. Infections: viral, mycoplasmal, Pneumocystis, occasionally bacterial, fungal, viral

Diseases with undetermined causes1. Idiopathic interstitial pneumonias

Usual interstitial pneumonia

Desquamative interstitial pneumonia

Acute interstitial pneumonia

Nonspecific interstitial pneumonia

Cryptogenic organizing pneumonia

Respiratory bronchiolitis interstitial lung disease

Lymphoid interstitial pneumonia2. Sarcoidosis3. Langerhans cell histiocytosis (Histiocytosis X)

4. Lymphangiomyomatosis5. Alveolar proteinosis6. Idiopathic hemosiderosis7. Eosinophilic pneumonia, acute and chronic8. Goodpastures syndrome

Common characteristics of diffuse interstitial lung diseases

Diffuse, often bilateral, involvement of the lung with primary effects on theinterstitium in the alveolar walls

Symptoms - dyspnea, tachypnea, and ultimately hypoxemia and cyanosis

CXR - diffuse bilateral "ground glass" or interstitial nodular and irregular shadows

Restrictive functional alterations in pulmonary function: decreased oxygen-diffusing capacity, lung volumes, and compliance

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Some of the diseases may lead to "honeycomb lung" (endstage replacement ofalveoli by cystic spaces separated by thick fibrous bands with inflammatory cells)and right-sided heart failure secondary to pulmonary hypertension

65. Honeycomb lung: The air spaces areenlarged and separated by fibrous bands.This represents an end stage of severalinterstitial lung diseases.

In most of these diseases, lung injury is believed to result from an alveolitis, an

accumulation of inflammatory and immune effector cells in alveoli, with release oftheir secreted products, stimulated by a known or unknown trigger. Neutrophilsoften contribute to the injury by release of oxygen-derived free radicals and toxicenzymes. Macrophages release similar substances as well as fibroblast growthfactors that promote remodeling and scarring. Lymphocytes can cause injuryto endothelial cells and epithelial cells and secrete substances that attract andactivate macrophages and neutrophils, and cause granuloma formation in somediseases.

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SARCOIDOSIS

A systemic granulomatous disease of unknown etiology, which commonly(in over 90% of cases) involves the lung and/or hilar or mediastinal lymphnodes

Common, F > M, especially prevalent in the southeastern US

o Association with HLA-A1 and B8

o Increased frequency in African-Americans than American Caucasians

Causal agent isunknown but many have been suggested (mycobacteria, pinepollen, viruses); analysis for mycobacterial DNA has produced conflicting results

Immunologic abnormalities suggest a cell-mediated response to anundetermined antigen:

o Increased CD4+ T-cells in the lungs, with oligoclonal expansion of T-cell

subsets

o Increased Th1 cytokines (IL-1 and IFN-), leading to T-cell proliferation

and macrophage activation in the lungs

o Increases in other cytokines (IL-8, TNF, macrophage inflammatory protein

1, involved in the formation of granulomas

o Cutaneous anergy to Candida or PPD

o Polyclonal hypergammaglobulinemia, reflecting T-cell dysregulation

Labs - hypercalcemia, increased angiotensin converting enzyme

Course - variable; may be chronic, waxing/waning or spontaneously remitting,but usually corticosteroids produce improvement

Morphology:

Gross:

Lungs - may have small nodules or no visible abnormalities

Lymph nodes - hilar and mediastinal - enlarged ("potato nodes")

Microscopic: small nonnecrotizing granulomas with perigranulomatousand interstitial fibrosis; may have asteroid or Schaumann's bodies (notspecific for sarcoidosis)

Since mycobacterial and fungal infections, and berylliosis (a pneumoconiosiscaused by beryllium exposure) can produce similar granulomas, the diagnosisof sarcoidosis is one of exclusion (cultures and special stains reveal noorganisms, no history of beryllium exposure)

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66. Sarcoidosis: Compact non-necrotizinggranulomas are the hallmark of sarcoidosis.Mycobacterial and fungal infections must beruled out before making the diagnosis of

sarcoidosis (diagnosis of exclusion).

IDIOPATHIC PULMONARY FIBROSIS (IPF)(synonyms: usual interstitial

pneumonitis, cryptogenic fibrosing alveolitis, etc.)

Most patients are between 30 and 70 years old, M > F, and present with aninsidious onset of dyspnea; course is usually chronic and progressive withsurvival times after diagnosis usually less than 5 years

No effective therapy

Etiology is unknown

Current theory about pathogenesis is that repeated cycles ofacute lung injurymay lead to disadvantageous wound healing responses and scarring overtime

Immunologic mechanisms may have a role in pathogenesis

o Th2 responses are thought to be involved

o Activated macrophages attract neutrophils, leading to release of damaging

proteases and oxidants

o Activated macrophages and pneumocytes secrete fibrogenic and

chemotactic cytokines, leading to fibroblast proliferation and collagendeposition

o Histologically identical lung disease can develop in patients with

rheumatoid arthritis and other collagen vascular disease

o Immune complexes are increased in some patients

Morphology: marked variation in the nature and severity of fibrosis and inflammation inadjacent areas of lung, which probably reflects the repetitive occurrence of acute lunginjury over time (temporal heterogeneity of histologic changes), leading to airspaceremodeling

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Areas of relatively normal lung are found adjacent to abnormal areas, which haveinterstitial chronic inflammatory infiltrates (mostly lymphocytes with occasionalplasma cells and other inflammatory cells), interstitial fibroblast proliferation(fibroblast foci) and collagen deposition, hyperplastic type II pneumocytes,bronchiolar metaplasia

Honeycomb lung can develop with time

Destruction of the pulmonary capillary bed and hypoxemia pulmonary hypertension

Similar pathologic findings may be associated with many other entities (collagenvascular diseases, oxygen toxicity pneumonitis, irradiation and chemotherapy-inducedpneumonitis, pneumoconioses . . .), etiologies which must be excluded before makingthis diagnosis.

67. Usual interstitial pneumonia (idiopathicpulmonary fibrosis): The lung showsinterstitial fibrosis and lymphocytes, as wellas a fibroblast focus (arrow). 68. Usual interstitial pneumonia (idiopathic

pulmonary fibrosis): There is subpleuralinterstitial fibrosis with honeycomb change(airspace remodeling).

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COLLAGEN VASCULAR DISEASES

Lung and pleural involvement is common in patients with collagen vascular diseases.The spectrum of involvement includes pleuritis, interstitial pneumonia, vasculitis, andairway-centered lesions. In rheumatoid arthritis (forms of involvement below),

abnormal pulmonary function tests are found in 30-40% of patients.

Pleural lesions Chronic pleuritis with or without effusion

Rheumatoid nodules

Parenchymal lesions Usual interstitial pneumonia

Non-specific interstitial pneumonia

Bronchiolitis

Rheumatoid nodules

Vasculitis

Pulmonary hypertension

Amyloidosis

CRYPTOGENIC ORGANIZING PNEUMONIA (formerly known asbronchiolitis obliterans organizing pneumonia

Clinical: cough, dyspnea, often a recent history of respiratory tract infectionsymptoms (occult viral infection is suspected as an etiology, but has not beenproven)

CXR: patchy consolidation or interstitial infiltrates

Morphology: young connective tissue (fibroblasts with mucopolysaccharidesand usually little collagen) in bronchioles, interstitium, and alveolar spaces

Usually improves quickly withcorticosteroids

Similar histologic reactions can be associated with bacterial and viral infections,aspiration, collagen vascular diseases, drug reactions, inhaled toxins, etc., whichmust be excluded before diagnosing cryptogenic organizing pneumonia

69. Organizing pneumonia: The air spacesare filled with young connective tissue.

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HYPERSENSITIVITY PNEUMONITIS (EXTRINSIC ALLERGICALVEOLITIS)

An immunologically-mediated disease that develops when a patient withabnormal sensitivity to an antigen is exposed to the inhaled antigen (usually

an organic or occupational antigen, often spores of bacteria, fungi, animalproteins, etc)

Acute (fever, cough, dyspnea 4-6 hrs after exposure) and chronic (slowlyprogressive dyspnea, cyanosis) presentations

o Many patients have antibodies to the triggering agent in their serum, and

this can be helpful in pinpointing the cause

Treatment: stop exposure to the antigen, corticosteroids are often helpful

Pathogenesis: believed to represent a type III hypersensitivity reaction (early) type IV hypersensitivity reaction to produce granulomas

Morphology (chronic form): triad of a) interstitial pneumonitis (lymphocytes,plasma cells, macrophages) +/-- fibrosis, b) chronic or obliterative bronchiolitis,and c) granulomas or collections of giant cells

DISEASE ANTIGEN SOURCE

Farmers lung Bacteria - Micropolyspora Moldy hay, grain

Ventilation pneumonitis Bacteria - actinomycete Contaminated air conditioner

systems

Bagassosis Bacteria - actinomycete Moldy sugarcane

Bird fanciers, breeders or

handlers lung

Avian droppings, feathers,

serum, etc

Parakeets, pigeons, chickens,

turkeys, etc

Tobacco growers lung Tobacco plants

Coptic lung Cloth wrappings of mummies

Thatched roof lung Dead grasses and leaves

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PNEUMOCONIOSES : disorders caused by the inhalation of anydust or other aerosol

General characteristics

Usually slow and insidious in onset, appearing after decades of exposure, andcompatible with long life spans

Although safety regulations have reduced the frequency of mostpneumoconioses, the long time interval before they become clinically apparentmeans that they currently remain sources of morbidity and mortality

Often occupational diseases

For most substances capable of producing a pneumoconiosis, there is aspectrum of severity ranging from clinically insignificant depositions of materialwith little or no scarring to progressive, disabling and sometimes fatal scarring

[progressive massive fibrosis (PMF)] associated with larger depositions of theoffending agent

o Symptoms of dyspnea and cough are usual with more fibrosis

o PMF can lead to pulmonary hypertension and cor pulmonale

Factorsinfluencing the consequences of dust inhalation

Amount of dust retained in the lung and airways : determined by theconcentration of the dust in the air, duration of exposure, and effectiveness ofclearance mechanisms (diminished by smoking)

Size, shape and buoyancy of the particles:

- particles 1-5u diam. tend to settle in small airways and alveoli

- buoyant particles (ex: asbestos fibers) tend to stay in the center of a moving airstream, avoid clearance in the upper airways, and impact in the smaller airways

Particles' solubility and physicochemical reactivity:

- generally, smaller particles reach toxic levels more rapidly than larger particles;larger particles may persist and cause fibrosis

- some particles (ex: silica) can directly trigger macrophages to release

inflammatory mediators and fibrogenic substances

Possible effects ofother irritants (ex: carcinogens in cigarette smoke adsorbedon the surfaces of asbestos particles) may contribute to the synergy betweensmoking and heavy asbestos exposure in causing bronchogenic carcinoma

Pathogenesis: particles not removed by mucociliary clearance deposit in airways andare phagocytosed by macrophages -----> macrophages release toxic substances,

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inflammatory mediators, and substances promoting fibroblast proliferation and collagensynthesis

PNEUMOCONIOSES

AGENT DISEASE EXPOSURE

Mineral Dusts

Coal dustmacules, progressive massive

fibrosis, Caplan's syndromecoal mining

Silica silicosis, Caplan's syndromesandblasting, mining, stone

cutting, etc

Asbestos

asbestosis, pleural plaques, Caplan's

syndrome, mesothelioma, lungcancer

mining, milling, fabrication,

installation and removal ofinsulation

Beryllium acute and chronic berylliosis, cancer nuclear and aerospace industries

Iron oxide siderosis welding

Barium sulfate baritosismining

Tin oxide stannosis mining

Organic Dusts that Induce

Hypersensitivity Pneumonia

see section on hypersensitivity

pneumonia

Organic Dusts that Induce Asthma

Cotton, flax, hemp

Red cedar dust

byssinosis

asthma

textile manufacturing

lumbering, carpentry

Chemical Fumes and Vapors

Nitrous oxide, sulfur dioxide,ammonia, benzene, cyanate

insecticides, numerous others

bronchitis, asthma, pulmonary

edema, respiratory distresssyndrome, mucosal injury, fulminant

poisoning

occupational and accidentalexposure

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ASBESTOS: a generic term for a variety of naturally occurring fibrous silicates foundin the environment (air and water), sharing the properties of high tensile strength, highheat resistance, and resistance to chemical attack; everyones lungs contain somefibers

Heaviest exposures occur in industries dealing with the mining, fabrication, andinstallation of asbestos and asbestos-containing products (insulation, flooring,ceiling, roofing, sewer and water conduits, brake linings, clutch casings)

Types of asbestos fibers:

Serpentine(curly and flexible) fibers: tend to impact in the upper

tracheobronchial tree removed by the mucociliary apparatus; chrysotile is oftenused commercially and is a major air pollutant

Amphibole (brittle straight) fibers: may align with moving air and traveldeeper into the lungs; crocidolite, amosite, and tremolite are used commercially

ASBESTOS-RELATED PROBLEMS

a.Asbestosis = diffuse interstitial fibrosis + asbestos bodies in areas of fibrosis

Asbestos bodies: asbestos fibers phagocytized by macrophages and coatedwith iron-containing proteinaceous material; beaded, sometimes dumbbell-shaped; a type offerruginous body (particle with iron-protein coat)

Most fibers remain uncoated (not usually visible by light microscopy)

70. Asbestos bodies: Asbestos bodiesconsist of asbestos fibers coated with

hemosiderin-containing proteinaceousmaterial.

71. Asbestosis: There is interstitial fibrosisand asbestos bodies.

b. Pleural reactions: fibrocalcific parietal pleural plaques - most common sign ofasbestos exposure; visceral pleural fibrosis; effusions

c.Cancers: also see sections on "Tumors" and "Pleural Diseases"

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Bronchogenic carcinoma, especially adenocarcinoma, is the most commonmalignancy associated with asbestos exposure; 30-40% of people with asbestosisdevelop carcinoma.

Relative risks: nonexposed nonsmokers 1

asbestos-exposed nonsmokers 5nonexposed smokers 11asbestos-exposed smokers 55

Malignant mesotheliomas are rare tumors linked to amphibole exposure (>1000Xincrease in relative risk); families of heavily exposed workers also have an increasedincidence.

Also, laryngeal and other extrapulmonary neoplasms have been linked to asbestosexposure.

SILICOSIS:lung disease caused by inhalation of crystalline silica (SiO2)

Most prevalent chronic occupational disease in the world

Exposures: mining, sandblasting, quarrying, stone cutting, etc.

Pathogenesis: silica is ingested by macrophages, activates them, andcauses release of IL-1, TNF, fibronectin, oxygen-derived free radicals,fibrogenic cytokines, and other mediators; crystalline forms, including quartz,are more fibrogenic than amorphous forms

Tuberculosis occurs with increased frequency (10 - 30 X increased

incidence) in patients with silicosis International Agency for Research on Cancer stated that crystalline silicafrom occupational sources is carcinogenic in humans, but this is still acontroversial subject

Morphology:Gross: tiny collagenous nodules esp. in the upper zones -----> enlarge, coalesce-----> largerscars -----> honeycombing or massive fibrosis; draining lymphnodes also show collagenous nodules

Microscopic: hyalinized collagenous nodules with concentric laminationsseparated by cleftlike spaces containing needle-shaped crystals of silicates(birefringent with polarization) and silica (poorly polarizable)

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72. Silicosis: Younger, more cellular, andolder, more fibrotic, silicotic nodules lie sideby side.

COAL WORKERS PNEUMOCONIOSIS (CWP): lung disease caused byinhalation of coal dust

Anthracosis, simple CWP, and complicated CWP (PMF) are three sections of acontinuum of severity of carbon dust accumulation and fibrosis in the lung. Fewer than10% of people with simple CWP progress to PMF.

73. Coal workers pneumoconiosis: There is marked carbondeposition with scarring.

Anthracosis: smallclinically insignificant

accumulations of carbon

dust found in most of us,particularly in city

dwellers and smokers

Simple CWP: aggregates of

coal dust - containingmacrophages (macules), some

with associated fibrosis

(nodules), usually littlerespiratory impairment

Many years of

coal mining

(usually > 30

years)

Few people

Complicated CWP: heavy accumulations of coal dustin the lungs with fibrous scars 2-10 cm.; clinically

disabling dyspnea, chronic cough, blackened sputum

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OBSTRUCTIVE PULMONARY DISEASES

Obstructive lung diseases include emphysema, chronic bronchitis, asthma,bronchiectasis, and small airway diseases (bronchiolitis), which share the symptom

of dyspnea and the presence of chronic or recurrent obstruction to airflow in the lung.Chronic obstructive pulmonary disease (COPD) is a commonly used term that refersto emphysema and chronic bronchitis, two disorders which often coexist since theyshare the common etiologic factor of tobacco smoking. COPD is the fourth leadingcause of morbidity and mortality in the United States.

EMPHYSEMA

Definition

Disorder characterized by abnormal permanent enlargement of air spacesdistal to the terminal bronchiole, with destruction of their walls and withoutobvious fibrosis

Incidence

Estimated to affect 5-8% of the U.S. population

Primarily affects smokers and individuals with A1AT deficiency

Morbidity and Mortality

Can lead to pulmonary hypertension and cor pulmonale especially if concurrentchronic bronchitis exists

Can cause death from respiratory failure or rupture of bullae with tensionpneumothorax or hemorrhage

Gender and Age Distribution

Male predominance (male-to-female ratio 2:1)

Symptoms in smokers usually develop after age 50, but can occur earlier inA1AT deficiency, especially with concurrent smoking

ClinicalFeatures

Dyspnea is characteristic

If chronic bronchitis coexists, individuals will have a productive cough

Physical examination: barrel chest, decreased breath sounds, prolongedinspiration

Spirometry: decreased forced expiratory volume in 1 second (FEV1)

With advancing disease, hypoxemia develops

Radiologic Features

Hyperinflated lungs, tapering vascular shadows with hyperlucency, pushed

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down diaphragms, bullae

Prognosis and Therapy

Damage is irreversible

Smoking cessation is central to treatment plan, to avoid progression

A1AT deficiency is treated with A1AT replacement therapy

Surgical therapies include bullectomy, lung volume reduction therapy, and lungtransplantation

Pathologic Features

Gross Findings

o Enlarged and hyperinflated lungs

o Bullae (distended air spaces > 1 cm diameter) may be present, especially

in the apical regions in smokers, and may rupture and causepneumothorax

o Several types of emphysema, which can occur in combinations and withvarying severities:

Centriacinar (centrilobular): enlarged air spaces in centers oflobules (primarily at the level of the respiratory bronchiole), oftenwith blackened walls, surrounded by unaffected parenchyma; upperlobes affected more than lower lobes

Tobacco products are the usual cause

Panacinar (panlobular): air space enlargement throughout thelobule; in A1AT deficiency, lower lobes are affected more thanupper lobes

Paraseptal: enlarged air spaces along interlobular septae andpleura

Irregular: Localized air space enlargement adjacent to a focallesion, usually a scar

Microscopic Findings

o Alveolar wall destruction with free-floating portions of septa that

appear disconnected from other parenchymal structures, leading to airspace enlargement

Modified from Green L: Emphysema and diseases of large airways. In Zander DS,Farver CF: Pulmonary Pathology, Elsevier, 2008.

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74. Centriacinar emphysema: Air spacesare enlarged, primarily in the center of theupper lobe. The enlarged air spaces areassociated with deposits of carbonparticles, giving the parenchyma adarkened appearance. Particles intobacco smoke deposit primarily inrespiratory bronchioles, which lie at thecenters of lobules/acini. This initiates the

development of emphysema adjacent torespiratory bronchioles.

75. Centriacinar emphysema: This more severecase shows more extensive air space enlargement

primarily in the centers of lobules, associated withdeposits of carbon particles.

76. Centriacinar emphysema: Air spaces around therespiratory bronchiole are enlarged, due to destructionof alveolar septa. Note the presence of black carbondeposits near the enlarged air spaces.

TB

RB

RB

RB

ADAD

AD

Centriacinar

Paraseptal

End-stage centriacinar

or panacinar

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77. Panacinar emphysema: Theparenchyma has been extensivelydestroyed, with enlargement of airspacesfrom the level of the respiratory bronchioledistally (to involve the entire acinus).

78. Panacinar emphysema: The parenchymahas been extensively destroyed, withenlargement of airspacesthroughout the acinus.

Alveolar septa are fragmented and reduced innumber.

79. Bullous emphysema: Bullae are air-filledspaces measuring greater than 1 cm. in diam.They may be associated with any type ofemphysema. Complications arising from bullaeinclude pneumothorax (from rupture of a bulla),compression of adjacent lung, and infection.The bulla (*) shown measures ~ 12 cm.

Pathogenesis: Protease-antiprotease theory - imbalance between proteases (mainlyelastase) and antiproteases (mainly A1AT) in the lung leads to alveolar wall destruction

Alpha-1-antitrypsin (A1AT) is the major antielastase in serum and interstitialtissue. Neutrophils, and to a lesser extent macrophages, mast cells, andbacteria, are the main sources of elastase. When elastase is given intratracheally

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to experimental animals, emphysema results. Stimuli that increase the number ofneutrophils and macrophages in the lung, or promote release of elastase, willincrease tissue destruction, particularly if antiprotease activity is low (A1ATdeficiency).

A1AT deficiency: A1AT is transmitted codominantly and is specified by the proteinaseinhibitor (Pi) locus on chromosome 14. About 70 A1AT phenotypes exist. The normalphenotype (PiMM) occurs in 90% of the population. Several phenotypes are associatedwith A1AT deficiency. PiZZ is the most common of these, and leads to emphysema inover 80% of people with this phenotype. Smoking accelerates development ofemphysema in people with A1AT deficiency. The emphysema is believed to result fromchronic low grade proteolysis due to neutrophil passage through the lungs (greatest inlower lobes, which show the most severe involvement).

Cigarette smoking and centriacinar emphysema: Smokers have both increasedpulmonary elastase activity and decreased antielastase activity. They also develop

an imbalance between oxidants (increased) and antioxidants (decreased) in thelung. CD8+ T-cells may also contribute to emphysema by causing apoptosis of alveolarepithelial cells or through recruitment of macrophages.

Smoke particles impact in small bronchi and bronchioles, with the followingconsequences which lead to centriacinar emphysema:

neutrophils and macrophages accumulate in alveoli

elastase and other protease release from neutrophils is stimulated

macrophage elastase activity (not inhibited by A1AT) is enhanced

oxidants (reactive oxygen species) in smoke and released by neutrophilsproduce oxidative lung damage and inhibit A1AT

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CHRONIC BRONCHITIS

Definition

Clinically defined by a chronic productive or mucus-producing cough onmost days of the month for at least 3 months in at least 2 consecutiveyears, with no other identifiable cause

Incidence

Affects 4-5% of the U.S. population

Morbidity and Mortality

A component of COPD, which is the 4th leading cause of death in the UnitedStates and has a mortality rate of 50% at 10 years after diagnosis

Can lead to pulmonary hypertension and cor pulmonale

Can cause death from respiratory failure due to severe disease, often withsuperimposed respiratory tract infection

Age Distribution

Most affected individuals are more than 45 years of age

Clinical Features

Associated with smoking (more than 90%); exposure to dusts, fumes, ortoxins; airway infections; allergic airway injury

Symptoms include cough with excessive sputum production, dyspnea

Superimposed respiratory tract infections are common, and can beassociated with worsening respiratory symptoms, fever, chills

Spirometry: decreased forced expiratory volume in 1 second (FEV1)

With advancing disease, hypoxemia develops

Radiologic Features

Nonspecific but may show bronchial wall thickening

Therapy

Geared toward reducing bronchial irritation and treating infections: smokingcessation, antibiotics for infections, bronchodilators, supplemental oxygen

Pathologic Features

Gross Findings

Airways are filled with abundant mucus or mucopurulent secretions

Bronchial walls often appear thickened, and the mucosal surfaces hyperemic

Microscopic Findings

Abundant mucus in bronchial and bronchiolar lumens, with variable acuteinflammation depending upon the presence or absence of infection

Enlargement of the mucous glands in the bronchial wall

Increased bronchial goblet cells, goblet cell metaplasia of bronchioles

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Chronic inflammatory infiltrates in airway mucosa and submucosa

Increased bronchial-associated lymphoid tissue (BALT) in small airways

Submucosal and adventitial fibrosis in bronchi and bronchioles

Squamous metaplasia and reserve cell hyperplasia

Thickening of the bronchial basement membrane

Modified from Green L: Emphysema and diseases of large airways. In Zander DS,Farver CF: Pulmonary Pathology, Elsevier, 2008.

Pathogenesis:Inhaled substances (especially cigarette smoke but can also beallergens in people with asthma) cause chronic irritation of the tracheobronchial system.Infections help maintain and acutely exacerbate the inflammation and injury. Cigarettesmoking predisposes to infections by impairing ciliary function, damaging respiratoryepithelium, and interfering with the ability of leukocytes to clear bacteria.

Smoking, allergen(s), air pollutant(s) or other chronic irritant(s) respiratory bronchiolitis (small airways disease) with intraluminalpigmented macrophages, bronchiolar chronic inflammation and fibrosis increased size of submucosal glands and increased goblet cells

hypersecretion of mucus in large airways sputum overproduction, obstruction of small airways

variable epithelial changes (metaplasia, dysplasia)

80-82. Chronic bronchitis: Although chronicbronchitis is a clinically defined disorder,pathologic findings associated with it includean increase in the size of the bronchial

submucosal glands to occupy greater than40% of the thickness of the bronchialsubmucosa, increased mucus ormucopurulent secretions in bronchi andbronchioles, increased goblet cells,thickened basement membrane, chronicinflammation, and epithelial changes(metaplasia, dysplasia).

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ASTHMA

Definition

National Asthma Education and Prevention Program Expert Panel (1997): Asthma

is a chronic inflammatory disorder of the airways in which many cells andcellular elements play a role, in particular, mast cells, eosinophils, Tlymphocytes, neutrophils, and epithelial cells. In susceptible individuals, thisinflammation causes recurrent episodes of wheezing, breathlessness, chesttightness, and cough, particularly at night and in the early morning. Theseepisodes are usually associated with widespread but variable airflowobstruction that is often reversible either spontaneously or with treatment. Theinflammation also causes an associated increase in the existing bronchialhyperresponsiveness to a variety of stimuli.

Incidence

Affects 5-10% of the U.S. population, and is increasing

Morbidity and Mortality

Responsible for more than 11 million hospital visits per year

Accounts for > 5,000 deaths annually, and may contribute to more

Status asthmaticus is the most severe and potentially fatal form; attacks can last fordays

Gender and Age Distribution

Male predominance (M:F ratio 2:1) until puberty (M:F ratio 1:1)

Higher frequency in children, with 2/3 of individuals diagnosed before age 18

Clinical Features

Symptoms: wheezing, breathlessness, cough, chest tightness, sputumproduction

Typical acute episode lasts up to several hours and responds tobronchodilators

Some patients have persistence of mild symptoms between acute exacerbations

Symptoms may be triggered by exposure to allergens, respiratory tractinfections, exercise, medications, air pollution, cold, stress

Physical exam reveals an increased respiratory rate and end-respiratory wheezing

Spirometry shows a reduced FEV1/FVC ratio that improves with bronchodilators

Radiologic Features

Chest x-ray can appear normal or show hyperinflation or occasionally atelectasis

Symptoms often disappear as children become adults

Most patients with asthma can achieve symptomatic control and improvement oflifestyle through patient education, avoidance of potential triggers, and pharmacologic

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therapy with antiinflammatory agents and bronchodilators

Pathologic Features

Gross Findings

In fatal status asthmaticus, there are areas of overinflation and atelectasis, and

filling of bronchi and bronchioles with mucusMicroscopic Findings

Mixed inflammatory cell infiltrates (with eosinophils) in bronchi andbronchioles

Smooth muscle hypertrophy in airways

Goblet cell hyperplasia in bronchi, goblet cell metaplasia of bronchioles

Enlarged bronchial submucosal glands

Mucus plugging of airways with mixed inflammation including eosinophils andCharcot-Leyden crystals

Epithelial cell injury and loss, reserve cell hyperplasia, squamous Thickened bronchial basement membranes

Modified from Green L: Emphysema and diseases of large airways. In Zander DS,Farver CF: Pulmonary Pathology, Elsevier, 2008.

83. Asthma: Histologic findings in asthmaare those of chronic bronchitis, and inaddition, airway smooth muscle hypertrophyand bronchial eosinophil infiltration. Thisexample demonstrates a mixed eosinophiland chronic inflammatory infiltrate withoverlying squamous metaplasia.

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TYPES OF ASTHMA PRECIPITATING FACTORS MECHANISMS

Extrinsic:1. Atopic (allergic)2. Occupational3. Allergic bronchopulmonary

aspergillosis

specific allergenschemicals, fumes, dusts, gases

Aspergillus spores

type I hypersensitivity reactiontype I hypersensitivity reactiontype I and III hypersens.

reactions

Intrinsic:1. Nonatopic2. Drug-induced

respiratory infection, esp. viralaspirin

hyperreactive airwaysdec prostaglandins, incleukotrienes

Atopic

Most common type of asthma, usually beginning in childhood

Often have a family history of allergies

IgE is usually elevated; inciting antigen(s) will usually provoke a positive (wheal-and-flare) skin test

Type I hypersensitivity reaction: antigen reacts with sensitized mast cells onthe mucosal surfaces, provokes release of mediators (histamine, ECF, NCF,leukotrienes, PGD2, PAF, etc.), initiates a Th2 T-cell response, and directlystimulates subepithelial vagal receptors ----> bronchoconstriction, edema, mucussecretion, flushing, epithelial damage (due to the major basic protein ofeosinophils)

Release of growth factors (TGF-beta, IGF, PDGF) and other substances will

eventually cause airway fibrosis if the inflammatory reaction proceedsunchecked, so treatment is aimed at reducing inflammation as well asbronchoconstriction.

Nonatopic- inflammation of the respiratory mucosa may render subepithelial vagalreceptors more sensitive to irritants ----> bronchoconstriction

Allergic bronchopulmonary aspergillosis

Bronchial colonization by Aspergillus leads to development of IgE and IgGantibodies against the fungus

Exposure to spores leads to mast cell degranulation ----> bronchoconstrictionand increased vascular permeability

IgG antibodies form immune complexes with fungal antigens in bronchi ---->inflammation and fibrosis of bronchi

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Churg-Strauss Syndrome (Allergic Angiitis and Granulomatosis)This syndrome develops in a small subset of people with asthma (and rare peoplewithout asthma), and is a systemic vasculitis that often involves the lungs, heart, andperipheral nerves. Patients have peripheral eosinophilia > 10% of white blood cells.

Pathologic features: necrotizing vasculitis, tissue infiltration by eosinophils,extravascular granuloma

84. Churg-Strauss syndrome:Necrotizing vasculitis (arrow) withextravascular eosinophils (hard todiscern at this power) is present in anappendix from a patient with asthma,peripheral blood eosinophilia,migratory pulmonary infiltrates,sinusitis.

Manifestations: Pulmonary asthma, lung infiltration by eosinophils (chroniceosinophilic pneumonia), lung infiltrates caused bygranulomas and vasculitis

Cardiac heart failure, pericarditis, etc.

Peripheral nerves neuropathyGastrointestinal abdominal pain, diarrhea, etc.Renal insufficiencySkin nodules, purpura, urticaria, etc.

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BRONCHIECTASIS

Chronic necrotizing infection, usually with mixed flora, of bronchi andbronchioles, with abnormal airway dilatation

Pathogenesis:Airway obstruction and infection are commonly part of thepathogenesis. Severe, often longstanding inflammation permanently damagesbronchial wall components, which are eventually replaced with scar tissue.

Airway obstruction may predispose to infection or result from infection due toincreased luminal secretions and exudates, which also contribute to dilatation.

Associated with production of large amounts of purulent sputum particularly inthe morning, when patients arise and the purulent material drains

Associated conditions:

Bronchial obstruction (tumor, mucus impaction, foreign body) ----> usuallylocalized bronchiectasis, rarely diffuse (in atopic asthma or chronic bronchitis)

Necrotizing infectious pneumonias: bacterial, tuberculous, adenoviral,influenza-associated, Aspergillus (ABPA)

Congenital or hereditary conditions:

o Immotile cilia and Kartagener's syndromes (bronchiectasis, sinusitis, situs

inversus): structurally abnormal cilia, often with absent or irregular dyneinarms, defective motility

Poor bacterial clearance in lungs and sinuses ----> chronic

infections Abnormal cell motility during embryogenesis ----> situs inversus

o Cystic fibrosis and immunodeficiency states ----> chronic infections

Other chronic inflammatory conditions: lung transplant rejection, graft-versus-host disease, collagen vascular diseases

Morphology:

Gross: marked dilatation of airways, with airways visible to within 2-3 cm. of

pleuraMicroscopic: variable acute and chronic inflammation, ulceration, necrosis,abscess formation, squamous metaplasia, and fibrosis

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85. Bronchiectasis, localized:Bronchi (arrow) obstructed by atan tumor (center) are markedlydilated distal to the tumor.

86. Bronchiectasis, generalized: Allbronchi are markedly dilated.Bronchial mucosae are yellow-tan and

ragged, reflecting the presence of anongoing suppurative infection.Proximal bronchial walls are pale andfibrotic, due to longstanding infectionand subsequent scarring.

87. Bronchiectasis: The bronchialwall is markedly inflamed. Theepithelium may be intact, as it ishere, or it may be ulcerated.

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TUMORS OF THE LUNG

Lung Cancer Leading cause of cancer death in the U.S.

During the last 50 years, the number of deaths/yr. due to lung cancer increasedmarkedly in the U.S.: 18,000 in 1950 vs. 153,000 in 1994

The death rate for men has leveled off; for women, the rate continues to rise;changes trail behind decreases in the prevalence of cigarette smoking

Peak incidence in 50s and 60s; occurs most often between ages40 and 70

Etiology/Pathogenesis

Tobacco smoking

Statistical evidence from retrospective studies : association between thefrequency of lung cancer and the number of cigarettes smoked/day, duration ofsmoking, and the tendency to inhale

o 87% of lung cancers occur in smokers; smoking is also associated with

ENT cancers and cancers of the esophagus, bladder, pancreas

o Avg. smokers have 10X risk of nonsmokers, heavy (>40/day) >20X risk

o After approx. 10 - 15 years without cigarettes, risk approaches baseline for

light smokers (< 1 pack/day), but remains elevated (4X) for heavy smokers

o Cigar and pipe smoking increase risk, but not as high as cigarettes

Clinical evidence : increased atypical and hyperplastic changes in thetracheobronchial tree of smokers (96.7%) vs. controls (0.9%)

Experimental evidence :

o Of the more than 1200 substances present in cigarette smoke, many are

potential carcinogens - initiators (polycyclic aromatic hydrocarbons),promoters (phenol derivatives), radioactive elements, other (arsenic,nickel, molds, etc.)

o Benzopyrene, a component of cigarette smoke, causes DNA damage at

lung cancer mutational hotspots in p53

Industrial hazards numerous reported, including

Radiation - uranium miners have increased risk

Asbestos exposure - increases risk, especially in combination with smoking

Air pollution

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Small "urban factor" of increased risk

Radon is linked to lung cancer in miners exposed to high concentrations, but riskof lower concentrations is not clearly defined

Genetics Dominant oncogene mutations often involved in lung cancer: c-MYC (esp.

small cell ca), K-RAS (esp. non-small cell ca), EGFR, HER2neu

Commonly deleted or inactivated tumor suppressor genes include p53 (bothsmall cell and non-small cell carcinomas), RB (esp. small cell ca), p16 (esp. non-small cell ca), and multiple loci on chromosome 3p

Some oncogene mutations and deletions of tumor suppressor genes can also befound in morphologically benign lung epithelial cells, probably due to a fieldeffect

Occasional familial groupings; polymorphisms in cytochrome P450 geneCYP1A1 have been identified as markers for genetic susceptibility

Variable risk among smokers of developing lung cancer

Scarring- usually a desmoplastic reaction to a cancer, but occasionally precedes acancer (usually an adenocarcinoma); some diffuse fibrosing conditions (ex: asbestos,scleroderma, idiopathic pulmonary fibrosis) are associated with an increased risk ofbronchogenic carcinoma

Precursor Lesions (and their associated cancers) Squamous dysplasia and carcinoma in situ (squamous cell carcinoma)

Atypical adenomatous hyperplasia (bronchioloalveolar carcinoma)

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (carcinoid)

Note: These lesions can (but do not always!) lead to the associated cancer.

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Major Histologic Types of Malignant Epithelial Lung Tumors

Adenocarcinoma: 25-40% (most common)Squamous cell carcinoma: 25-40%

Small cell carcinoma: 20-25%Large cell carcinoma: 10-15%Carcinomas with sarcomatoid elementsCarcinoidCarcinomas of salivary gland typeOther tumors

Non-small cell carcinoma: this term is used to include squamous cell carcinoma,adenocarcinoma, and large cell carcinoma, as well as some less common types of lungcancer, but NOT small cell carcinomas.

Mixed types of carcinomas (e.g., adenosquamous carcinoma, combined small celland squamous cell carcinoma, etc) are not uncommon (~10%).

Staging: The TNM system is used to stage bronchogenic carcinomas. This systemincorporates the data for tumor size, extension to adjacent structures, nodalmetastases, and distant metastases, to arrive at a stage (I - IV). Prognosis generallyworsens with higher stages.

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Adenocarcinoma

Males and females equally affected

Less associated with smoking than squamous or small cell carcinomas, but mostpatients (>75%) have a history of smoking

Most common type of lung cancer in women and nonsmokers

Usually peripherally located; may be associated with a scar

Morphology:

o Gland formation is present, with complex glands, back-to-back glands,

cribriforming, papillary processes, solid areas; more well differentiatedtumors have more gland formation, and poorly differentiated tumors aremore solid

o Columnar or cuboidal cells with pleomorphic nuclei, often large nucleoli

o 80% contain mucin

EGFRmutations are found in some of these tumors, more often inbronchioloalveolar carcinomas

K-RASmutations are found in some of these tumors, more often in smokers(30%) than non-smokers (5%)

88. Adenocarcinoma: This type of neoplasmcharacteristically occurs in the periphery of the lung.

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89. Adenocarcinoma: Thistumor forms complex glandulararrangements. Glands arefocally back-to-back. Mucinoussecretions are present inglandular lumens.

90. Adenocarcinoma: As in this

example, tumor cells are oftencolumnar, with variablyhyperchromatic andpleomorphic nuclei andprominent nucleoli.

91. Adenocarcinoma: Thismucicarmine stain revealsintracellular mucin (red-pink),which indicates glandulardifferentiation and is a markerfor adenocarcinomas.

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Bronchioloalveolar Carcinoma

A subtype of adenocarcinoma, currently defined as an in situ adenocarcinoma

Accounts for 1-9% of lung cancers; increasing incidence for unclear reasons

Usually peripherally located, probably arise in terminal bronchioles or alveoli

Solitary or multiple nodules, or resembles pneumonia on CXR; believed tospread aerogenously

Overall 5 year survival rate is about 25%, better prognosis than othercommon types of lung cancer; surgically resectable solitary lesions have 5year survival rate of 50-75%; slower growing than other types of lung cancer

Morphology: tall columnar to cuboidal epithelial cells (differentiation along linesof mucin-secreting bronchiolar cells, Clara cells, and/or type II pneumocytes) thatline alveolar septa, may form papillary projections; most tumors are well-differentiated

92. Bronchioloalveolar carcinoma:Bronchioloalveolar carcinoma may presentas a single or multiple discrete nodules, oras in this slide, in a manner resemblingpneumonia.

93-94. Bronchioloalveolar carcinoma: Thistype of malignancy is defined by its patternof growth: it spreads along alveolar septawithout disrupting them, using them as itsstroma. Most of these tumors are welldifferentiated, and composed of columnar orcuboidal epithelial cells that can containmucin.

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Squamous Cell Carcinoma

Most common in men, highly associated with smoking

Most arise near the hilum, in the first-third order bronchi, and are oftenassociated with dysplasia and carcinoma in situ

Thickening and irregularity of the bronchial mucosa may be seen with abronchoscope

Well differentiated forms have prominent keratin production and intercellularbridges; poorly differentiated tumors may have only focal keratin, and look almostundifferentiated

Often have prominent necrosis and may cavitate

Tend to spread locally and metastasize laterthan other patterns, but growth rateis usually more rapid than other histologic types

Highest frequency ofp53 mutations among the lung cancers

95. Squamous cell carcinoma: This wartyexophytic tumor (box) originated in a proximalbronchus and has only a small invasivecomponent (not visible).

96. Squamous cell carcinoma: Thislarge tumor is cavitated, aconsequence of necrosis.

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97-98. Squamous cell carcinoma, welldifferentiated: Large nests of keratinizingepithelial cells with large hyperchromaticpleomorphic nuclei comprise this tumor. The

round aggregates of keratin are "keratin pearls".The stroma is desmoplastic, reflecting tumorinvasion.

99. Carcinoma in situ: Nuclearpleomorphism and hyperchromasia existthroughout the full thickness of theepithelium. Lack of epithelial maturationis evident. The process remainssuperficial to the basement membrane(in situ).

100. Squamous cell carcinoma withpost-obstructive pneumonia: Distal tothe tumor, the lung is pale and firm(consolidated), corresponding to anacute pneumonia.

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Small Cell Carcinoma

More common in men, strong association with smoking; most aggressive typeof lung cancer, demonstrates early and widespread metastasis

Usually centrally located (near hilum)

Small cells with high nuclear:cytoplasmic ratios, fine chromatin, small orabsent nucleoli, little cytoplasm; "crush artifact" often seen

Often show neuroendocrine differentiation by immunohistochemistry (+synaptophysin, chromogranin) and EM (dense core neurosecretory granules)

P53 and RB tumor suppressor genes are commonly mutated in these tumors

101. Small cell carcinoma with hilar lymph

node metastases: The tan tumor (withincurved line) arose from the contiguousbronchus and metastasized to multiple hilarlymph nodes (arrows).

102-103. Small cell carcinoma: Thetumor consists of small cells with smallnuclei and high nuclear:cytoplasmicratios (little cytoplasm). The chromatinhas a fine salt and pepperappearance, without nucleoli.

Large Cell Carcinoma Large cells with no light microscopic evidence of squamous or glandular

differentiation

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Clinical Course

Symptoms: cough, weight loss, chest pain, dyspnea

CXR: lung mass or infiltrate

Local metastasis to regional lymph nodes in about 50% of cases

Distant metastasis occurs via lymphatic or hematogenous routes; common sitesare the adrenals (>50% of cases), liver, brain, bone

~15% overall 5 year survival rate

Tumorstage is the most important factor in predicting survival; unfortunately,many cancers are discovered after they have become unresectable ormetastasized

Small cell carcinomas are not usually treated surgically, but are usuallysensitive to radiation and chemotherapy; 1 year mean survival after diagnosis

Non-small cell carcinomas are usually treated surgically, unless metastaseshave occurred or the tumor is unresectable; localized tumors < 4 cm. diametertreated surgically ----> 5 year survival rate of up to 40% for squamous cell ca andup to 30% for adenoca and large cell ca

Local Phenomena Associated with Lung Cancer

Bronchial obstructionbronchitis, pneumonia, bronchiectasis, abscess, lipoidpneumonia

Compression or invasion of the superior vena cava SVC syndrome

Extension through pleura or pericardium pleuritis, pericarditis, effusions

Extension into or around esophagus dysphagia

Extension into or around recurrent laryngeal nervehoarseness

Extension into or around phrenic nerve diaphragmatic paralysis

Extension into chest wall rib destruction

Some paraneoplastic syndromes

ADH SIADH; esp. small cell

ACTHCushing's syndrome; esp. small cell

Parathormone (PTH), PTH-related peptide, prostaglandin E hypercalcemia;esp. squamous cell

Serotonin carcinoid syndrome; esp. carcinoids or rarely small cell carcinoma

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Some systemic manifestations

Lambert-Eaton myasthenic syndrome - muscle weakness caused byautoantibodies reactive with the neuronal calcium channel

Hypertrophic pulmonary osteoarthropathy - finger clubbing

Venous thrombosis and embolism, nonbacterial thrombotic endocarditis - due tohypercoagulable tendency particularly associated with adenocarcinomas

Pancoast's tumors

Located in the apical region of the lung, in the superior pulmonary sulcus

May invade the cervical sympathetic plexus ----> Horner's syndrome(enopthalmos, ptosis, miosis, anhidrosis), and the brachial plexus ----> pain in thedistribution of the ulnar nerve

Carcinoid (not a type of pulmonary carcinoma)

~1-5% of lung tumors; most patients are < 40 years old

Not related to smoking or any other recognized environmental factors

Most < 4 cm. in diameter; most grow intraluminally in the major bronchi, and areassociated with pneumonia, bronchiectasis, emphysema, and atelectasis; someinvade the bronchial wall and fan out into the peribronchial tissues ("collarbutton")

5-10% metastasize to regional lymph nodes; 5 year survival rate is 90-95%

Occasionally secretory, and associated with the carcinoid syndrome -intermittent diarrhea, flushing, cyanosis

Occasionally found in patients with multiple endocrine neoplasia type I

Morphology

Cells have uniform round nuclei and infrequent (

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104. Carcinoid: A polypoid intraluminal mass(arrow) with a smooth surface, in a bronchus is acommon presentation.

105. Carcinoid: Tumor cells form nests, andtypically have uniform nuclei with littlepleomorphism, few mitoses, and a fibrovascularstroma. The presence of necrosis, increasedmitoses, and increased nuclear pleomorphismis associated with a worse prognosis (lowersurvival, higher frequency of metastasis).

106. Carcinoid: This chromogranin stain ispositive (brown), indicating neuroendocrinedifferentiation (as one would expect with thistumor). Chromogranins are located inneurosecretory granules.

Hamartomas (Benign Mesenchymomas,Fibrochondrolipomas)

Most common benign tumors of the lung

CXR and CT scans lung nodule, central or peripheral; may see low densityareas that correspond to fat; may have calcifications

Symptoms usually asymptomatic, but if central, can be polypoid and assoc