Lung

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


Introduction

Lung stiff, hard, difficult to expand Diffusion across blood air barrier is

difficult Referred to as interstitial 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


Immunological damage (responds to steroids)

Probably starts as alveolitis damage to type I epithelial cells Proliferation of type II cells - attract T

cells, macrophages


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


Bronchoscopy Bronchoscopic cytology, biopsy Bronchoalveolar lavage


Ultrasound / CT guided FNAC Open lung biopsy Lymph node, liver FNAC Hormonal assay- ( paraneoplastic

syndrome )

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