Pathology of the Lung
Dr. Dexter MD FRC Path Undercover Professor
Dept. of Pathology St.George's University
Objectives
Define and use in proper context the following terms
adult respiratory distress syndrome (ARDS) alveolar-capillary membrane Asteroid body Asthma Atelectasis Barrel chest Bleb blue bloater bronchial cyst Bulla chronic bronchitisBronchiectasis bronchiolitis obliterans bronchogenic carcinoma chronic obstructive pulmonary disease (COPD) coin lesion Consolidation cor pulmonale diffuse alveolar damage (DAD) Emphysema empyema extrinsic allergic alveolitis (EAA) Ghon complex Goodpasture syndrome Hemothorax heart failure cell Hemoptysis Honeycomb lung Horner syndrome
Hyaline membrane Hydrothorax Hypertrophic pulmonary osteoarthropathy Idiopathic interstitial pneumonia Idiopathic pulmonary fibrosis (IPF) Non-small cell lung cancer (NSCLC) Obstructive lung disease Organizing pneumonia Pancoast tumor Paraneoplastic syndrome Pink puffer Plexiform lesion Pneumothorax Pulmonary edema Pulmonary embolism Pulmonary veno-occlusive disease (PVOD) Rales Reid index Restrictive lung disease Rhonchi Saddle embolus Schaumann body Severe acute respiratory syndrome (SARS) Small airways disease Status asthmaticus Tension pneumothorax
Clinical
The student should be able to Enlist the steps in clinical examination
of the respiratory system, usual related investigations performed (listed) and normal results of spirometry and arterial blood gases.
Explain the pathogenesis of common symptoms related to respiratory illnesses (listed).
Pain Cough dyspnea sputum production cyanosis clubbing of fingers
hypertrophic pulmonaryosteoarthropathy
secondary polycythemia hemoptysis cor pulmonale
Define atelectasis, classify and explainthe pathogenesis
Infections Explain the normal defense mechanisms against
infections in lung. Distinguish the settings for primary versus
secondary pneumonias. Derive the clinical featuresof pneumonias based on the common structural andfunctional alterations in lungs.
Identify the common cause of pneumonias in thefollowing clinical settings- community acquired,immunodeficiency, neutropenia, hospital acquired,alcoholics, post viral infection, COPD, malnutrion,preexisting cardiac conditions, diabetes, aspiration
Explain the concepts of airspace pneumonia and interstitialpneumonias , indicate the common category of organismsresponsible for each.
Distinguish grossly and microscopically lobar and bronchopneumonias and identify commonly responsible organisms foreach.
Outline the usual investigations and the course of illness. Explain steps in the evolution of histopathology of pneumonias
(4 listed), the usual settings and outcomes for the followingpneumonias - Strep. pneumonia, legionella pneumophilia,klebsiella, staph. Aureus, pseudomonas and aspiration.
Distinguish Interstitial Pneumonias as agroup and derive their clinical features,pathology and common agentsresponsible,
Explain the pathogenesis of lungabscesses and characterize thefeatures of that secondary toaspiration.
Recapitulate the lung lesions causedby tuberculosis, CMV, pneumocystiscarinii, cryptococcus, histoplasma,actinomycosis and nocardia. ( notincluded in the exam)
Vascular and hemodynamicdiseases
List the causes of passive and activepulmonary edema (listed)
Explain the pathogenesis of adultrespiratory distress syndrome (ARDS)and mention the clinical settings(listed)
Derive the pathologic features andclinical features and the course ofARDS.
Explain the common settings for thedevelopment of pulmonary embolism;differentiate the effects of large,medium and small emboli.
Describe the gross and microscopicappearances of pulmonary infarcts andcorrelate them with clinical features.
Classify pulmonary hypertension intoprimary, secondary and list the causesfor secondary type.
Describe the vascular changes inpulmonary hypertension.
Distinguish lesions of Goodpasturessyndrome from idiopathic pulmonaryhemosiderosis by morphology andetiology.
Restrictive lung disease
Explain the meaning of restrictive lungdisease and why it leads to respiratorydifficulty.
Explain the pathogenesis of AdultRespiratory Distress Syndrome (ARDS)and name at least 3 common causes.
Explain the pathogenesis of idiopathicpulmonary fibrosis (Hamman Rich
Syndrome) and derive the clinicalfeatures.
Differentiate desquamative interstitialpneumonia, pulmonary alveolarproteinosis and lymphocytic interstitialpneumonia theoretically.
Explain the pathology, pathogenesisand clinical features of sarcoidosis anddistinguish it from tuberculosis onhistology.
Give three examples of hypersensitivitypneumonitis (listed) and highlight themain pathogenetic mechanism.
Mention the salient clinical andpathologic features of Goodpasturessyndrome and explain thepathogenesis.
Distinguish idiopathic pulmonaryhemosiderosis from Goodpasturessyndrome theoretically.
Recapitulate( not included in the exam)the pathology and pathogenesis ofcommon pneumoconiosis likeanthracosis, silicosis, asbestosis andberylliosis and recognize that they areincluded in the spectrum of restrictivelung disease.
Chronic obstructive pulmonary disease (COPD)
Explain the concept of COPD and mention the common diseases included in the category (listed).
Define emphysema, classify into centriacinar, panacinar and septal, explain the pathogenesis, and derive the clinical features.
Define chronic bronchitis, classify into simple, mucopurulent , asthmatic and obstructive types, explain the pathogenesis and derive the clinical features.
Distinguish pink puffers from blue bloaters theoretically.
Define bronchial asthma, classify into intrinsic and extrinsic, explain the pathogenesis, pathology and derive the clinical features. Define status asthmaticus.
Define bronchiectasis, identify the components (destruction, fibrosis, dilatation), etiology, pathologic and clinical features.
Name the components of Kartagenerssyndrome and identify the basic defect.
Derive the complications of bronchiectasis (listed).
Explain the role of exercise therapy in COPD
Neoplasms/ tumors
Classify the lung tumors (histologically) and indicate relative frequencies.
Distinguish hilar and peripheral tumors with examples and clinical features. Explain what is occult lung cancer.
Intelligently analyze data on relationship of smoking and lung cancer (statistics, clinical, experimental, histological subtypes)
Identify oncogenes related to lung cancer
List the predominant clinical features, growth pattern, spread and prognosis of Squamous cell carcinoma, Adenocarcinoma, Bronchioloalveolarcarcinoma, Small cell carcinoma, bronchial carcinoids and
Mesotheliomas.
Highlight the peculiarities of Bronchioloalveolar carcinoma -(resemblance to pneumonia, X-ray, histology).
Describe the different modes of Spread of lung cancer
Explain Horners Syndrome, Pancoastsyndrome, Carcinoid Syndrome.
Identify usual sites of metastasis of lung cancer.
Explain the importance of Virchows lymph node; coin lesion on X-ray
Define paraneoplastic syndromes, enlist those associated with bronchogenic carcinoma, identify any specific relationship to histologicsubtypes.
Explain why liver metastasis is not a prerequisite to manifest Carcinoidsyndrome in bronchial carcinoids as compared to gut carcinoids.
Concerning Mesotheliomas, identify etiology, special feature of histology and mode of spread.
Concerning nasopharyngeal carcinoma, analyze the relationship with EBV and discuss the term Lymphoepithelioma.
Outline the investigations that can be performed for diagnosis of lung cancer -Sputum, X-ray, pleural tap, pleural biopsy, bronchoscopy, bronchoscopicbiopsy, bronchoscopic cytology, bronchioalveolar lavage,
ultra sound/ CT guided FNAC, Lymph node or Liver FNAC, open lung biopsy, hormonal assay.
Normal lung, signs and symptoms,investigations, atelectasis and
infections
Lung-1
Clinical features of lung diseases Infections of lung
Clinical symptoms of lung disease
Dyspnea - aware, obstruction, pain
Cyanosis - >5-gm / dl reduced Hb
Clinical symptoms of lung disease
Dyspnea - aware, obstruction, pain
Cyanosis - >5-gm / dl reduced Hb Chest pain- parietal pleura
Chest pain
Cardiovascular Gastrointestinal Respiratory Chest wall
Clinical symptoms
Cough - dry, productive Sputum - purulent, frothy Hemoptysis - Tb, Carcinoma, Left
heart failure
Clinical signs of lung disease
Physical Examination of Chest: movement - symmetry accessory muscles of respiration palpation percussion auscultation
Investigations:
Examination of sputum: microbes malignant cells RBCs
Imaging:
Chest X- ray CT scan MRI Bronchography Arteriography
Investigations
Bronchoscopy: visualize, cytology biopsy broncho alveolar lavage
Investigations
Ventilation scanPerfusion scan
Investigations
FNAC Open lung biopsy Pleural tap - exudate, neoplastic
cells, microbes Pleural biopsy
Tests of pulmonary function
Arterial blood gases (increased pCo2, decreased pO2)
Spirometry - Ventilatory function Total Lung Capacity Vital Capacity Residual Volume
Tests of pulmonary function
Forced Vital Capacity - FVC Forced Expiratory Volume in first
second - FEV1 FEV1 : FVC ratio (normal > 75%)
Respiratory failure
Fall in pO 2 Rise in pCO 2
Atelectasis
Incomplete expansion or collapse of previously inflated
lung Newborn
Atelectasis
Adult------- Obstruction (resorption)-
asthma, chronic bronchitis,aspiration
Compression- pleural fluid, air(pneumothorax)
Contraction- fibrosis of lung Microatelectasis
Pneumonia
Acute infection of lung Fever, cough, dyspnea, chest pain
Lung- defense mechanisms
Mucociliary reflex, cough reflex,alveolar macrophages
Non immune opsonins - surfactant,fibronectin
Lung- defense mechanisms
Immune opsonins (alveolarmacrophages)
C3b, IgA, IgG T lymphocytes normally in airspaces Neutrophils (not normal), easily
recruited
Pneumonia-classifications
Primary, Secondary Mode of infection- community,
hospital, aspiration Site of action- alveolar space
(typical), alveolar wall (atypical) Microorganism- Bacterial, Viral,
Chlamydia, Fungi etc
Pneumonia
Primary, Secondary
Primary pneumonia
Healthy personVirulent organism
e.g. Strep. pneumonia, L. pneumophilia
Secondary pneumonia
Underlying abnormality predisposes Postoperative (ventilation reduced) Smoking (mucociliary reflex, aspiration
due to loss of cough and swallowingreflex, pmn, macrophage, chemotaxis)
Preexisting lung disease - viral infection,emphysema,bronchiectasis
Immunosuppression
Secondary pneumonia contd.
Bronchial obstruction- tumor, foreignbodies
Coma - cough reflex lost Alcoholics, diabetes
Pneumonia
Community acquired Hospital acquired
Community acquired pneumonias
Healthy individual Acute pneumonia- sudden illness-
Strep. pneum, H. influenza, Moraxella catarrhalis, Legionella
Atypical pneumonia- mycoplasma, chlamydia, viral (influenza), rickettsiae
Hospital acquired pneumonias
Nosocomial Gram negative-Klebsiella, E.coli,
Pseudomonas, Staph Immunosuppression, antibiotics,
catheters, ventilators
Aspiration pneumonias
Acid Organisms Mixed nature of organisms
Immune abnormality and type of organisms
CMI viral, mycobacteria, low virulence -
Pneumocystis Innate
pmn, complement and humoralimmunity -- pyogenic organisms
Pneumonia
Site of action- alveolar space (typical)- airspace alveolar wall (atypical)- interstitial
Airspace pneumonia
Types of pneumonia
Airspace pneumonia- Bacteria
Interstitial pneumonia -Virus
Bacterial pneumonias
Multiply extracellularly in alveoli Inflammatory exudate in alveoli -
airless (consolidated)
Air space pneumonia Lobar Pneumonia:
Large confluent areas of consolidation
Almost whole lobe Bronchi not involved Spread through pores of Kohn Usually virulent organism- Strep.
pneumonia
Bronchopneumonia:
bronchi + surrounding alveoli Patchy Usually less virulent organisms
Bronchopneumonia
lesions are patchy, confluent bronchi, bronchioles also damaged intervening areas normal less chances of pleuritis
Pneumonia: stages
Both lobar and broncho pneumonia go through 4 stages if untreated
Antibiotics halt the process
Acute Congestion heavy red boggy lungs
bacteria multiply in alveoli, dilated alveolar capillaries, early fluid exudation
early PMNs + early red cells
Red Hepatization consistency liver like
lining alveolar cells lost
PMNs, fibrin, red cells Pleuritis
infection controlled
Gray hepatization dry, gray, firm
exudation and hyperemia stop
red cells depleted
Resolution
Removal of exudate complete resolution can occur because
structure of alveoli not damaged in lobar pneumonia
Bronchopneumonia has structural damage
Complications of pneumonia
Complications
Abscess (Staph.aureus, gm -vebacilli, type 3 pneumococci)
Empyema Organization - scar tissue Bacteremia - menigitis, arthritis,
endocarditis Recurrent pneumonias , bronchiolitis
obliterans
Clinical - pneumonia
Abrupt high fever, cough, rusty purulent sputum
Chest pain, pleural rub (if there is pleuritis)
air entry, consolidation, X- ray Microbe - sputum, blood
Pneumococcal pneumonia Settings- usually nil, viral infection,
CHF, COPD, immune deficiency, splenectomy (auto)
Sputum - gram positive diplococci- normal flora, look for intracellular in pmn
Blood culture - more specific Vaccines
H. Influenzae pneumonia
COPD, cystic fibrosis, bronchiectasis Common cause of acute exacerbation
of COPD
Moraxella catarrhalis
Elderly individuals Second most common cause of
pneumonia in COPD
Klebsiella Pneumonia
Most frequent gram negative pneumonia
Debilitated and malnourished Chronic alcoholics Thick gelatinous sputum ( viscid
capsular material) Extensive destruction
Staph. aureus pneumonia:
After viral respiratory illness -secondary
Hospitalized patients - primary Abscess formation, empyema i/v drug abusers- endocarditis Penicillin resistance
Psuedomonas aeroginosa Progressive necrotizing pneumonia Nosocomial, neutropenic patients,
burns Vasculitis and vascular spread Extensive destruction, abscess
formation Empyema Cystic fibrosis
Legionella pneumonia
Sporadic, epidemic Artificial water pools- tubing, cooling
towers In chronically ill patients, post
transplant High fatality Culture- best for diagnosis, others-
sputum, urine
Quiz 10 questions 2 friends sitting together 9 correct each but one gets 9
other 8 points Answer to Q.5- I dont know Neither do I
Types of pneumonia
Airspace pneumonia- Bacteria
Interstitial pneumonia -Virus
Interstitial pneumonia
Interstitial Pneumonias (Atypical)
Infection by obligate intracellularpathogens
Mostly community acquired Sporadic - Mycoplasma pneumonia
(children, young adults), chlamydiae, rickettsiae
Endemic Influenza Immune Compromised - Herpes,CMV
AIDS - Pneumocystis
Usual Interstitial Pneumonia
Patchy lung involvement Alveolar septa involved
Pathology interstitial pneumonia
Tracheo bronchitis ( nose to alveoli) Attach to alveolar epithelial cells, kill
them, inflame alveolar septa Alveolar septa - edema, hyperemia,
lymphocytes, plasma cells Alveolar cells - necrosis, inclusions,
multinucleation
Pathology interstitial pneumonia
Hyaline membrane Alveolar lumen clear (except in
pneumocystis cariini - frothy exudate rich in organisms)
Prone for secondary bacterial infection
Severe acute respiratory distress syndrome-SARS
Mar 2003- China- Avian flu Pathology similar More necrosis and hyaline
membranes in fatal cases (ARDS) Corona virus
Clinical interstitial pneumonias
Variable Mild illness usually Fever, cough- nonproductive, dyspnea
(sometimes out of proportion to chest signs and radiology)
Very few clinical signs Reticular shadows on chest X- ray
Clinical interstitial pneumonias
Organisms difficult to demonstrate, check antibody titers
Treat with Erythromycin - covers Chlamydia, mycoplasma which are
the common offenders Complications: Secondary bacterial
pneumonia
Mycoplasma pneumoniae
Children, young adults Endemic Diagnosis- Mycoplasma Ag or PCR for
Mycoplasma DNA Rising titers of antibodies - takes
time to demonstrate
Lung infections
Lung abscess
Lung abscess
Chronic Lung Abscess
1. Sequela of acute suppurativepneumonia (Staph. Aureus, Klebsiella, Pseudomonas)
2. Bronchial obstruction - foreign body (inhalation, aspiration), tumor
Lung abscess
3. Bronchiectasis4. Secondary infection on tuberculous
cavity5. Septic embolus from infective
endocarditis right heart
Abscess single vs multiple
Aspiration of infected material Single , right side Apical portion of lower lobe or
subapical, axillary portion of upper lobe
Secondary to pneumonia or septicemia or bronchiectasis - multiple
-
Lung Abscess - Clinical
Copious, foul sputum, hemoptysis, fever, malaise
Complications bronchopleuralfistula, empyema, septicemia, amyloidosis
Treat with antibiotics, drainage
Pneumonia not responding to treatment
Bronchiectasis, lung abscess Lung tumor- hilar obstruction,
bronchioloalveolar carcinoma Vasculitis
LungVascular and hemodynamic
pathology
Pulmonary edema- Passive
Left ventricular failure Excess IV fluids Severe hypoproteinemia Lymphatic obstruction (carcinoma)
Pulmonary edema--Active
Damage to vascular endothelium (ARDS)
Capillaries and venules Exudate into interstitium and lumen,
hyperemia
Direct injury
Infections Toxic gases Corrosive liquids (aspiration) Drugs like cancer chemotherapy,
heroin, cocaine Oxygen toxicity, noxious fumes,
weed killers - paraqat poisoning
Indirect injury
Severe trauma (hemorrhage, shock), septic shock (endotoxemia)
Severe burns Acute pancreatitis, post surgery
(abdominal)
Adult ( Acute)RespiratoryDistress Syndrome (ARDS)
Syn. Shock Lung Syndrome, Acute lung injury, Diffuse alveolar damage (DAD), Acute lung injury (ALI)
(cf. RDS in neonates due to deficiency of surfactant)
Shock lung Endothelial damage, damage to type
1 pneumonocytes Exudate, impaired gas exchange Hyaline membrane (necrotic debris
from epithelial cells plus edema fluid coagulate)
Type II pneumonocyte necrosis- loss of surfactant- microatelectasis
Mechanism of damage Imbalance between pro and anti
inflammatory cytokines Macrophages -> IL8 -> pmn chemotaxis and
activation IL-1,TNF -> pulmonary vascular
sequestration of pmn and exude into septa and lumen
PMNs, macrophages -with leukotrine B4
Mechanism of damage
Alternate pathway of complement, tumor necrosis factor (TNF) tissue thromboplastin
If hyperbaric oxygen -> further damage TGF-,PGDF -> promote fibrosis
Clinical features Respiratory difficulty- acute Gasping for breath Severe hypoxemia, cyanosis Bilateral infiltrates on chest X-ray Absence of clinical features of LVF Predisposes to infections High mortality
Nitric oxide- NO- inhalation reduces PA pressure and resistance
Healing may result in diffuse interstitial fibrosis
Phases of ARDS
Exudation- 0-7 days Proliferation - 1-3 weeks
macrophages phagocytose dead cells and hyaline membrane, type II pneumonocytes proliferate mature in to type I cells
Fibrosis- TGF-, PDGF
SARS
Acute respiratory distress syndrome due to infection
Corona virus China, Hongkong, Singapore, Canada
Pulmonary embolism 95% from deep leg veins Sick, bedridden patients with
pulmonary, cardiovascular disease BIG -> bifurcation of PA, sudden
death from acute right heart failure - no time to develop any changes in lungs
Pulmonary embolism
MEDIUM -> hemorrhage, infarction only if circulatory status already compromized
SMALL -> usually no infarct because of dual supply, resolve ( lysis),
if recurrent- pulmonary hypertension
Infarction
Clinically resembles myocardial infarction - chest pain, dyspnea, shock
Gross: Wedge shaped, hemorrhagic infarct, may be multiple
Micro: coagulation necrosis
Pulmonary hypertension
Primary- Rare, young women,recurrent dyspnea
,syncope Reynauds phenomenon (vasopasm
of peripheral vessels) ? Neurohormonal hyperactivity ? Vasotropic virus- HSV 8
Pulmonary hypertension
Secondary COPD - Chronic bronchitis,
emphysema, diffuse fibrosis Congenital shunts- VSD Recurrent pulmonary
thromboembolism in small sized vessels
Morphology of pulmonary hypertension
Changes in medium sized arteries Medical thickening Intimal hyperplasia / fibrosis Reduplication of elastica,
Morphology of pulmonary hypertension
Plexogenic changes in severe varieties only (primary)
Necrosis of wall (fibrinoid) Thrombosis Rupture, bleed Dilation lesions, angiomatoid
lesions Hemosiderin
Primary pulmonary hypertension-clinical
Symptoms appear late Fatigue, dyspnoea Syncope on exercise Chest pain Respiratory insufficiency, cyanosis Cor pulmonale
Goodpasture syndrome
Hemoptysis, oliguria, hematuria Pulmonary alveolar hemorrhages,
hemosiderin Rapidly progressive
glomerulonephritis- linear immunofluorescence
Antibodies targeted against collagen IV- basement membrane
LungRestrictive lung disease
Extrinsic
Chest wall injury,deformity ( kyphoscoliosis)
Severe obesity Neuromuscular (Guillain Barre
Syndrome)
Intrinsic
Acute - ARDS Chronic- Idiopathic Pulmonary Fibrosis ( IPF ) Bronchiolitis obliterans Pneumoconiosis Sarcoidosis Hypersensitivity pneumonitis
Restrictive lung disease
Introduction
Lung stiff, hard, difficult to expand Diffusion across blood air barrier is
difficult Referred to as interstitial lung disease
Restrictive lung disease
Acute - Adult respiratory distress syndrome (vascular)
Chronic - many entities FEV1 , FVC , FEV1: FVC ratio
normal
Restrictive lung disease Idiopathic- pulmonary fibrosis-IPF Occupational- inorganic-
pneumoconiosis, organic-hypersensitivity pneumonitis
Drug- chemotherapy, radiation, oxygen therapy
Immunological- autoimmune diseases, sarcoidosis
Idiopathic pulmonary fibrosis
(Hamman Rich Syndrome) (Honey comb Lung)
Cause not known Diffuse fibrosis in alveolar septa M > F > 60 years age
Idiopathic pulmonary fibrosis
Immunological damage (responds to steroids)
Probably starts as alveolitis damage to type I epithelial cells Proliferation of type II cells - attract T
cells, macrophages
Idiopathic pulmonary fibrosis
Type II cells- Replace type I cellls Secrete chemotactic factors for
macrophages, T cells Contribute to fibrosis by secreting
PDGF and TGF-
Pathology - IPF Early - edema, hyaline membrane,
mononuclear cells in septa necrosis of type I cells Later - type II cells - cuboidal cell
hyperplasia Lymphocytes, plasma cells, macrophages Septal fibrosis Honey comb lung
Clinical IPF Progressive dyspnea, hypoxia,
cyanosis, pulmonary hypertension Bilateral basal lesions CT- early detection of IPF, exclude
other causes of pulmonary fibrosissubpleural wedge biopsy- image guided
Clinical IPF
Cor pulmonale- JVP, edema Progression- variable Death in 2-4 years Similar end result in many ->
rheumatoid arthritis, systemic sclerosis, SLE etc.
Variants
Unusual interstitial pneumonia Desquamative interstitial pneumonia
(DIP) (Alveolar macrophages aggregate)
Lymphocytic interstitial pneumonia (LIP)
(Psuedo lymphoma)
Bronchiolitis
Idiopathic Organizing fibrosis in bronchioles Cigarette smoke settling on respiratory
bronchioles and setting up inflammation and fibrosis
If lumen obliterated- obstructive features also- bronchiolitis obliterans
Sarcoidosis - In the lung - restrictive disease Multisystem involvement,
noncaseating epitheloidgranulomas
Differentiate from Tb, berylliosis, fungal infections
Cell mediated hypersensitivity to some unidentified antigen
Sarcoidosis
Lymph nodes, lungs, skin, eye, spleen, liver etc
Asteroid bodies, Schaumann bodies - suggestive but not diagnostic
Sarcoidosis
May be associated with hypercalcemia (activation of vit. D by epitheloid cells)
Raised serum angiotensinconverting enzyme (ACE) - 60%
Sarcoidosis
Mikulicz Syndrome - Parotid, sublingual, submaxillary, Uveal
Bilateral uniform enlargement Sarcoid, lymphoma-leukemia,
Sjogrens syndrome
Hypersensitivity pneumonitis
Allergic alveolitis (not bronchioles) Granulomas in alveolar walls, less
fibrosis Acute (type III) or Chronic (type IV) Irritation, complement, immune
complex damage Farmers lung (hay), Bagassosis
(sugar cane), Pegion breeders lung etc.
Hypersensitivity lesions
Size of particles Hay fever (type I) Bronchitis / asthma Bronchiolitis obliterans Pneumonitis (type III,IV)
Diffuse pulmonary hemorrhage
(Good Pastures Syndrome) Lung hemorrhage + acute
glomerulonephritis Antibody to basement membrane
(linear immunofluoroscence)- type II Hemoptysis + nephritic illness Triad- hemoptysis, anemia, diffuse
pulmonary infiltrates
Goodpastures syndrome
Oliguria, hematuria, hypertension Progressive dyspnea, right heart
failure Treat by plasmapheresis,
immunosuppression
Idiopathic pulmonary hemosiderosis
Younger patients Cause not known - no antibodies, no
renal involvement Recurrent hemorrhage, fibrosis
Pneumoconiosis
(Revise environmental pathology) Anthracosis, silicosis, asbestosis,
berylliosis -> Restrictive lung disease
Other causes of interstitial fibrosis
Anticancer drugs- busulfan, methotrexate, cyclophosphamide
Paraquat (herbicide) Radiation pneumonitis Toxic gases Intravenous heroin (contaminants)
Other causes of Interstitial fibrosis
Autimmune disorders- SLE, rheumatoid arthritis, scleroderma
Wegener's granulomatsis- pulmonary angiitis and granulomatosis-sinusitis, lung involvement, kidney
involvement, c-ANCA
LungChronic obstructive pulmonary
disease (COPD, COAD)
COPD
Common disease There is chronic obstruction to flow
of air.
COPDChronic obstruction to flow of air
Common disease; 4th leading cause of deaths in the US; 3rd most common cause of death worldwide by 2020
Once principally a disease of men, it now affects men and women equally
In 2000, COPD was responsible for 8 million physician office visits, 1.5 million emergency department visits, and 726,000 hospitalizations (about 13% of total hospitalizations)
Second only to coronary heart disease as a reason for payment of Social Security disability benefits.
NEJM March 2009Case Vignette
A 61-year-old woman is referred for pulmonary consultation.
She smoked one pack of cigarettes a day for 45 years but quit a year ago.
For 2 years she has noted progressive exertional dyspnea,with breathlessness occurring when she is walking up one flight of stairs or hurrying on level ground.
A diagnosis of chronic obstructive pulmonary disease (COPD) was made a year ago, and she was treated with inhaled medications.
Casaburi R, ZuWallack R. N Engl J Med 2009;360:1329-1335
She is sedentary and recently gained 15 lb (6.8 kg); her only frequent social activity is playing cards.
Her physical examination is normal except for a weight of 195 lb (88.5 kg) (body-mass index [the weight in kilograms divided by the square of the height in meters], 32) and for decreased breath sounds and prolonged expiration on chest auscultation.
Spirometry reveals moderate airway obstruction; an echocardiogram is normal.
Obstructive lung disease
Reversible- Bronchial asthma Irreversible- Chronic bronchitis,
emphysema, bronchiectasis
Obstructive lung disease
Total lung capacity (TLC)- increased Forced vital capacity(FVC)- Normal or
decreased FEV-1 reduced So FEV1 : FVC ratio reduced (
Emphysema
Permanent dilation of terminal air spaces with destruction of their wall.
Elasticity lost, cannot recoil to expel air
( Inspiration is active, expiration is passive).
Emphysema
Elderly males with dyspnea (after significant damage). No organic obstruction - only failure of recoil.
May develop chronic bronchitis in addition.
Types of emphysema
Normal
Septal
Centriacinar
Panacinar
Emphysema-Types
1 Centriacinar ( Centrilobular) 2 Panacinar ( Panlobular)
Distinction possible in early stages and not in late stages.
Centrilobular emphysema
Damage is at respiratory bronchioles(central and proximal part of acinus)
Distal alveoli spared, Common in upper lobes (apex)
Panacinar emphysema
Uniform enlargement from respiratory bronchioles, alveolar ducts and alveoli,
Common in lower lobes.
Pathogenesis of emphysema
Excessive protease (Elastase) + less anti protease
1. Alpha -1- antitrypsin deficiency (2% of all emphysema)
Polymorphic Pi ; Pi MM normal, PiZZworst
2. Neutrophils release elastase(e.g. cigarette smoking)
Cigarette smoking
Cigarette smoke particles lodge at bifurcation of respiratory bronchioles
Engulfed by macrophages which release elastase
This elastase is not inhibited byA1AT and can digest the A1AT
Cigarette smoking
Cigarette smoke also contains oxidantsThese oxidants along with free oxy
radicals released by pmn.s inhibit A1AT
Pathology of emphysema
Panacinar - Large, pale,voluminous lungs, cover the heart
Centriacinar - no gross changes
Micro: alveoli large, wall thin, destroyed
Pathology of emphysema
terminal and respiratory bronchioles deformed
loss of tethering by surrounding alveoli leads to obstruction in expiration
Emphysema- Clinical Symptoms appear late Barrel chest, dyspnea, prolonged
expiration X- ray flat domes of diaphragm Hyperventilation blood gases normal till
late Pink Puffers, Late stage - hypoxia, respiratory acidosis
Emphysema
Usually the patients are weak and skinny
Weight loss because of excess puffing and panting due to hyper ventilation
Emphysema- Clinical
Hypoxia and hypercapnia Pulmonary vasoconstriction, compensatory polycythemia
Loss of pulmonary capillary surface area from alveolar destruction
Pulmonary hypertension Cor pulmonale ( RVH, RVD,RVF )
Death in emphysema
Respiratory failure - acidosis, hypoxia, coma
or Cor pulmonale
Other types of emphysema
Compensatory : eg. Pneumoconiosis Senile Obstructive overinflation : tumor,
foreign body-- danger of collapse of rest of lung, pneumothorax due to rupture
Mediastinal emphysema
Air escapes in to the connective tissue of lung stroma, mediastinum and subcutaneous tissue
Sudden increase in intra alveolar pressure
violent cough, vomiting, whooping cough, trauma usually with some obstruction to the bronchial passage- eg mucus plug
tear in the interstitium
Mediastinal emphysema
Patient bloats suddenly like a balloon including chest head and neck
Crackling crepitations over chest wall
Recovers spontaneously after the defect is sealed
Chronic bronchitis
Cigarette smokers, smoke in city Persistent productive cough for at
least 3 consecutive months in at least 2 consecutive years.
Types: Simple , mucopurulent , asthmatic ,obstructive
Pathogenesis
Irritation Excess secretion by mucus glands hypertrophy of glands Metaplastic goblet cells in surface epithelium, secondary bacterial infection.
Inflammation and fibrosis obstruction of small airways
Superimposed emphysema.
Pathology
Externally lungs appear normal Large airways - hyperemia, edema,
mucous secretion
Chronic bronchitis - bronchi
hypertrophy and hyperplasia of mucous glands
(Reid Index > 0.5) Goblet cells in the surface epithelium Squamous metaplasia
Chronic bronchitis - bronchioles
Goblet cell metaplasia Inflammation fibrosis (collapse in expiration) smooth muscle hyperplasia
Chronic bronchitis - Clinical
Definition Eventually small airways obstruction pO2, pCO2, Cyanosis Blue bloaters (edema due to heart
failure) Pulmonary hypertension, Cor
pulmonale Secondary infections
Chronic bronchitis
Persistent hypercapnia makes respiratory centers insensitive to pCO2 stimulus
Respiration is now driven by low O2 If you administer oxygen the drive
is lost and they die of CO2narcosis
Exercise intolerance resulting from dyspneaor fatigue is often the chief symptom reported by patients with COPD.
The degree of exercise intolerance roughly parallels the severity of the disease, but exercise intolerance is also distinctly presentin patients with only mild disease.
The extent to which quality of life is impaired is reflected in patients' symptoms, decreasedfunctional status, and frequency of exacerbations.
Pathophysiology
Extrapulmonary effects Skeletal muscle dysfunction (legs) Low type 1 fibres; early onset of lactic
acidosis Fatigue leads to decreased ambulation
rather than dyspnea
Effects of therapy
Pulmonary rehab doesnt improve lungs Optimizes function of the rest of the body Effect of lung dysfunction on the rest of the
body is minimized Decreased lactic acidosis, decreased
ventilatory demand
Bronchial asthma
Sudden attacks of respiratory distress Expiratory dyspnea Wheezing / Rhonchi Episodic Relieved spontaneously or by
bronchodilators Thick sputum
Bronchial Asthma Hypersensitivity of tracheobronchial
tree Bronchiolar smooth muscle spasm Bronchial inflammation precipitates
the hyper reaction of bronchial tree
Bronchial inflammation is now considered the important feature
Types of asthma
Intrinsic Extrinsic
Final mechanism of damage similar and hence the distinction may not be that relevant
Types of asthma - extrinsic
3 types Atopic Occupational Allergic bronchopulmonary
aspergillosis
Intrinsic asthma (nonallergic)
Precipitated by Cold Aspiration Viral infection Psychological Exercise induced
Extrinsic (Atopy)
(Type I hypersensitivity) Childhood, familial, serum IgE,
sensitivity to many antigens Raised eosinophils in blood
Older patients serum IgE normal
Genesis
CD4 cells of Th2 subtype release IL 4,5,13
These favor synthesis of IgE, growth of mast cells and growth and activation of eosinophils
Genesis early phase
Early Phase starts in 30-60 minutes of exposure and lasts up to 4-6 hours
Antigen + IgE on mast cells in mucosa Release Histamine, bradykinin,
Leukotreines, Prostaglandins, platelet activating factors
Bronchoconstriction, acute inflammation, thick mucus
Genesis early phase
Epithelial damage Opens the intercellular junctions Antigens get in Sensitize mast cells in submucosa Aggravation of reaction Stimulation of submucosal vagal
fibers leads to reflex smooth muscle contraction
Eosinophils
Eosinophils attracted by IL5, PAF (mast cells), eotaxin (epithelial cells)
Amplify and sustain the reaction. Recruitment of pmn.s, basophils,
eosinophils, CD4 cells
Eosinophils
Have granules like mast cells The granules contain eosinophil
cationic protein and myelobasicprotein which are toxic to epithelial cells
Late phase
Epithelial cells secrete- endothelin and Eotaxin
Lead to smooth muscle contraction
Late phase
Eosinophils produce LeukotreinesC4,PAF activate mast cells
Cytokines activate myofibroblasts to lay down more collagen in the basement membrane
Genesis
Microenvironment of brochial tree-altered due to genetic mutations in metalloproteinases- ADAM-33
This precedes the development of asthmatic attacks and may predispose to it
Effects of Asthma
Obstruction, more in expiration (wheeze)
FEV-I < 30%, hyperventilation Hypoxia, hypercapnia, respiratory
acidosis
Asthma - lungs
Occlusion of bronchi, bronchioles by thick tenacious mucus
Overinflated lungs
Asthma lungs- micro
Eosinophils, mucus plugs in lumen Inflammation- eosinophils, mast
cells, basophils, macrophages, CD4 lymphocytes, neutrophils
Edema
Asthma lungs- micro
Thick basement membrane Patchy necrosis and shedding of
epithelial cells Hypertrophy of submucosal glands and
increase in goblet cells in bronchial lining
Hypertrophy of smooth muscle
Asthma - Clinical
Short, acute attacks - Expiratory dyspnea, wheeze, dry cough
Thick stringy mucus, casts, (Curschmans spirals)
Charcot Leyden crystals
Asthma - Clinical
Respond to bronchodilators Skin tests - desensitize Status asthmaticus (severe,
prolonged)
Asthma - management
Acute attacks- bronchodilators Steroid inhalers (anti-inflammatory) Antihistamines Leucotrine blockers ( Accolate)
Prevention , Desensitization
Bronchiectasis
Permanent, abnormal, irreversible dilatation of bronchial tree proximal to terminal bronchioles
Result of chronic infection destruction, fibrosis, dilatation.
Causes
Obstruction - tumors, foreign bodies Mucoviscidosis (cystic fibrosis) Necrotizing bronchopneumonia
(Sequela to measles,Whooping cough) Kartageners syndrome
Kartageners syndrome
ciliary abnormality of microtubules1/3 also have dextrocardia called
Kartageners syndrome upper respiratory Infections + sterility
in male + Dextrocardia (loss of ciliary action during embryogenesis)
Pathology of bronchiectasis
Localized or generalized Cylindrical, fusiform or saccular Bronchi reach up to pleura Walls inflamed, fibrosed, ulcerated,
purulent Lung abscess
Bronchiectasis - Clinical
Productive cough Large amount foul sputum Episodic fever Clubbing of fingers Pulmonary hypertension, Cor
pulmonale Amyloidosis
LUNG -Neoplasms
Lung tumors
Secondary Primary
Lung tumors
Secondary multiple (Cannon balls) peripheral rarely lymphangitis carcinomatosa,
peribronchial, (perivascular, lymphatics)
restrictive lung disease
Primary
Bronchial epithelium - 95% 5% Carcinoid, mesotheliomas,
bronchial gland, mesenchyme, lymphoma
Hamartomas (coin lesion, cartilage, fat, blood vessels)
Bronchogenic carcinoma
No. 1 cause of cancer deaths in the U.S.
No. 1 cause of cancer deaths in females also
Cigarettes smoking : 10 times more common in smokers, 40 - 70 years age group
Classification
1. NSCLC - Non Small Cell Lung Carcinoma (70-75%)
Squamous Cell Carcinoma (25- 30%) Adeno Carcinoma (30- 35%) Large Cell Carcinoma (10-15%)
2. SCLC - Small Cell Lung Carcinoma (20-25%)
3. Combined Patterns
Etiopathogenesis
SCLC myc amplification, p53, Rb deletion short arm of chr 3 (3p 14-25)
(tumor suppressor genes) NSCLC = K- ras Field of exposure - metaplasia,
atypical hyperplasia, dysplasia, Carcinoma insitu, invasive carcinoma
Smoking and lung cancer evidences
STATISTICAL - Pack years - Heavy Smokers vs Nonsmokers- 20
times 15 years after stopping smoking - risk
normal Passive smoking (x2)
Smoking
CLINICAL - Epithelial changes in sequence
EXPERIMENTAL - Missing link
Smoking
Why all exposed to smoking do not develop cancer?
Genetic predisposition. (P-450 mono-oxygenase systems for activation of mutagens)
What is it in smoking? Polycyclic hydrocarbons?
Others ( > 1200 elements identified)
Other etiologies
Asbestos - (x55) Radioactive ore mining Arsenic, Uranium
General features
Majority HILAR Smoking - special relation to
Squamous cell, Small cell Aggressive infiltration Metastasis: Liver, Adrenal,
brain,bones,kidneys Paraneoplastic Syndrome (specially
SCLC)
Squamous cell carcinoma
Male > female Central (hilar) location Hilar lymph nodes Cumulative pre cancerous histologic
changes Obstruction, atelectasis, infection
Adenocarcinoma
Younger age < 40 years Women, Non smokers Peripheral (coin lesion) May relate to scars (infarct,
granuloma, TB, diffuse fibrosis) Scar carcinomachronic scarring leading to carcinoma
Adenocarcinoma
AAH- atypical adenomatoushyperplasia
? Precursor of adenocarcinoma Is there a spectrum from AAH-
bronchoalveolar carcinoma to frank adenocarcinoma?
Distinguish from scar caused by cancer
Slow growth Early metastasis Types= Glandular (mucin) and
Bronchioloalveolar (papillary)
Bronchiolo alveolar carcinoma
Multiple coalescing nodules -pneumonia like, alveolar growth pattern
Tall columnar cells with mucin Arise from surfactant producing type
II pneumonocytes (South African sheep - infection -
Jagziekte shows similar features)
Large Cell Carcinomas Squamous or Adeno
with no differentiation Poor prognosis, early
metastasis
Small Cell Carcinomas
Male > females Related to Smoking Hilar location Cells resemble lymphocytes (oat
cells) Frequent mitosis
Oat cell carcinoma
Frequent vascular invasion Infiltrate and metastasize widely Not resectable Responsive to chemotherapy Neuro endocrine origins
(Paraneoplastic Syndromes)
Oat cell carcinoma
Neuron Specific Enolase, Neurosecretory granules
Neurofilaments, PolypeptidieHormones
ACTH, Calcitonin, Gastrin Releasing Polypeptide etc.
Spread of lung cancer
Infiltration lung, pleura, pericardium, Superior venacava (SVC), Sympathetic plexus,
Lymph nodes (Carina , Mediastinal,Scalene, Supra clavicular)
Virchows LN
Spread of lung cancer
Vascular - liver, adrenal, brain, bones TNM classification
Clinical features
Peripheral- may be clinically silent Hilar (Central)-
Obstruction- partial or total Infection- pneumonia, abscess,
bronchiectasis Atelectasis
Clinical features
Cough, weight loss, hemoptysis, dyspnea
Pulmonary osteoarthropathy -(clubbing)
Hoarseness, chest pain Pericardial and pleural effusion
Clinical features
Persistent atelectasis, pneumonitis(obstruction)
Suprior vena cava (SVC) syndrome due to obstruction
Horners Syndrome: Cervical sympathetic plexus damaged
Ipsilateral enophthalmos, ptosis, meiosis, anhidrosis
Clinical features
Pancoasts syndrome (apical neoplasm) T1T2 destruction
wasting of hand muscles, pain in arms
Recurrent laryngeal nerve paralysis Esophagus involvement- dysphagia Thoracic duct obstruction-
chylothorax
Clinical features- metastasis
LN mets most common Adrenal (50%)-very rarely
Addisons (insufficiency) Liver (30-50%) hepatomegaly Brain (20%) mental, neurologic Bone (15-20%) Pain, fracture Kidney- (15%)
Prognosis in lung cancer
SCLC carries worst prognosis Usually metastasis by the time of
detection Median survival l year Chemotherapy for SCLC Lobectomy or pneumonectomy for
NSCLC if localized
Paraneoplastic syndromes
10% of all lung cancers(SCLC) Hypercalcemia (PTH)- more with
squamous cell carcinomas Cushings (ACTH) bilateral adrenal
hyperplasia Syndrome of inappropriate
ADHsecretion Hyponatremia Gonadotropins - gynecomastia
Paraneoplastic syndromes
Neuropathy, myopathy Clubbed fingers, hypertrophic
pulmonary osteoarthropathy Migratory thrombophlebitis DIC, nonbacterial thrombotic
endocarditis ( NBTE) more common with adenocarcinoma
Carcinoid tumor
Cells look like carcinoma cells but are not truly carcinoma cells because they do not arise from epithelial cells
Arise from Neuroendocrine(Kulchitsky) cells
Carcinoid tumor Belong to the APUD cells system (Amine
Precursor Uptake Deamination)
Part of a widespread system Neuro secretory granules seen in the
cytoplasm ? Precursor lesion in the form of local or
diffuse neuroendocrine hyperplasia ? Carcinoid tumor is a precursor for Small
cell carcinoma
Carcinoid tumor
Usually localized Located in the main bronchi (Hilar) Resectable Age group of 40 years
Carcinoid tumor
Growth Polypoid,may grow in and out of bronchial wall- collar button
Micro:- uniform round cells in nests, no pleomorphism or mitosis
Nuclei not hyperchromatic
Carcinoid tumor- death
Pneumonia Lung abscess Bleeding
Carcinoid tumor - clinical
Obstruction - cough, hemoptysis, infections (Hilar location)
May be incidentally detected Carcinoid Syndrome may be
produced Good Prognosis- usually benign Rare metastasis
Carcinoid syndrome
1% of all Carcinoid tumor patientsshow carcinoid syndrome
Symptoms due to high 5HT, 5HIAA in blood and urine (produced by the tumor cells)
Others may be histamine, bradykinin, prostaglandins
Carcinoid tumor
Lung carcinoids secrete into systemic circulation (produce symptoms of the syndrome)
Carcinoid tumors occur in the gut also
Carcinoid syndrome
Gut carcinoids secrete into portal circulation Liver metabolizes the
secretions (no symptoms) If metastasis to liver from gut
carcinoids - secretions from the tumor cells in the liver get into circulation - carcinoid syndrome produced
Systemic fibrosis
Heart involvement gut carcinoids - right ventricle
endocardium, pulmonary and tricuspid valve ;
bronchial carcinoids -Left ventricle
Retroperitoneal fibrosis
Hamartoma - Lung
Made up of cartilage, blood vessels, fat, spaces lined by bronchial epithelium
Silent clinically, picked up incidentally by X- ray
Peripheral location- Coin lesion Resection cures it
Coin Lesions
Peripheral nodular lesion picked by byX-ray chest
peripheral adenocarcinoma hamartoma inflammation FNAC to make a diagnosis
Mesothelioma
Asbestos (shipyards, miners, insulators)
25 - 40 years Asbestos + Smoking Increased
bronchogenic carcinoma not increased risk for mesothelioma
Amphibole variety not serpentine
Mesothelioma
Fibers stay in the body for life Preceded by - Extensive pleural
fibrosis, plaque formation Pleural effusion, spread along pleura Yellowish firm gelatinous encasement Obliterates pleural space
Mesothelioma
Metastasis rare but infiltrates lungs and thoracic wall
Micro: Combination of epithelial (adenocarcinoma) and connective tissue (sarcoma) elements
Nasopharyngeal carcinoma
Common in Chinese (? Genetic) EBV - genome in all of them Occult primary-usually presents as
metastatic lymph nodes in the neck
Nasopharyngeal carcinoma
Squamous cell carcinoma Poorly differentiated carcinoma
(EBV) Lympho epitheliomas
radiosensitive
Carcinoma larynx
M: F 7:1 Smoking, alcohol, asbestos Squamous cell carcinoma Intrinsic, Extrinsic (extended outside
larynx)
Carcinoma larynx
Clinical: Hoarseness, pain, dysphagia, hemoptysis
Infection of lung 60% localized resect
Investigations for lung cancer
Sputum (can detect overt and occultcancer)
X-ray, CT Pleural fluid tap Pleural biopsy
Investigations for lung cancer
Bronchoscopy Bronchoscopic cytology, biopsy Bronchoalveolar lavage
Investigations for lung cancer
Ultrasound / CT guided FNAC Open lung biopsy Lymph node, liver FNAC Hormonal assay- ( paraneoplastic
syndrome )