Far Eastern University Nicanor Reyes Medical Foundation Congenital Anomalies

Pathology B Lungs Developmental anomalies are rare, more common are:

Humphrey Bitun M.D.
Pulmonary Hypoplasia
Lungs are constructed to carry out their cardinal function, the Defective development of one or both lungs.
exchange of gases between inspired air and blood. Caused by abnormalities that compresses the lungs or impedes
Developmentally, it comes from an outgrowth from the ventral normal lung expansion in utero (e.g. congenital diaphragmatic
wall of the foregut; the midline trachea develops 2 lateral hernia or oligohydramnios).
outpocketings called lung buds, 3 on the right and 2 on the left Severe hypoplasia is fatal.
which eventually divide into lobar bronchi.
The lobar bronchi have firm cartilaginous walls that provide Foregut Cysts
mechanical support and are lined with columnar ciliated Arise from abnormal detachments of primitive foregut.
epithelium with abundant sub epithelial glands that produce Most often located in the hilum or middle mediastinum.
mucus that impede entry of foreign bodies. Depending on the wall structure these are classified as:
Aspirated foreign material tends to enter the right lung more Bronchogenic (most common)
often than the left lung.
Esophageal
The lobar bronchi branch dichotomously giving rise to Enteric
progressively smaller airways.
Bronchogenic is rarely connected to the tracheobronchial tree.
The branching is accompanied by the double arterial supply
The cyst is lined by ciliated pseudostratified columnar epithelium
of the lungs (pulmonary artery & bronchial artery).
Contains bronchial glands, cartilage, and smooth muscle.
Progressive branching forms bronchioles, which are
distinguished from bronchi by the absence of cartilage and
Pulmonary Sequestration
submucosal glands.
Discrete area of lung tissue that:
Further branching leads to terminal bronchioles < 2mm in
Lacks any connection to the airway system
diameter; part of the lungs distal to the terminal bronchiole is
Abnormal blood supply arising from the aorta or its branches
called the acinus, roughly spherical, 7 mm in diameter.
Extralobar sequestrations are external to the lungs in infants as
Each acinus is composed of respiratory bronchiole (each gives
mass lesions, associated with congenital anomalies.
off several alveoli from its sides), alveolar ducts and sacs.
Intralobar sequestrations occur within the lung, present in older
A cluster of 3-5 terminal bronchioles is a pulmonary lobule.
children often due to recurrent infection or bronchiectasis
Except for the vocal cord, the whole respiratory tree is lined by
pseudostratified, tall, columnar, ciliated epithelium.
Other less common congenital abnormalities:
The bronchial mucosa contains neuroendocrine cells that
Tracheal and Bronchial anomalies (Atresia, Fistula, Stenosis)
have neurosecretory granules (serotonin, calcitonin,
Vascular Anomalies
bombesin),
Congenital Pulmonary airway malformation
Congenital lobar over inflation (Emphysema)
MICROSCOPIC STRUCTURE OF THE ALVEOLAR WALLS

Atelectasis

Network of anastomosing capillaries lined by endothelium.

Basement membrane and surrounding interstitial tissue that
separates the endothelial cells from alveolar lining epithelia.
Atelectasis refers either to incomplete expansion of the lungs
Alveolar epithelium, a continuous layer composed of type I
(neonatal atelectasis) or the collapse of previously inflated lungs,
pneumocytes (95%) and type II pneumocytes (5%) that
producing areas of relatively airless lung parenchyma.
synthesize surfactants and are involved in the repair of damaged
epithelium, can give rise to type I cells. Main types encountered in adults:
Alveolar macrophages, loosely attached to epithelial cells or Resorption Atelectasis
lying free within the alveolar spaces. Compression Atelectasis
Contraction Atelectasis

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Resorption Atelectasis
Stems from complete obstruction of the airways, which can be
due to excessive secretions, exudates in smaller bronchi (e.g.
bronchial asthma, chronic bronchitis, bronchiectasis, post-op)
Air is resorbed from the dependent alveoli, which collapses.
Lung volume is diminished, mediastinum shifts ipsilateral or
towards to the atelectatic lung.
Compression Atelectasis
Results whenever a significant volume of fluid (blood,
transudate, and exudate), tumor, or air (pneumothorax)
accumulates within the pleural cavity.
Mediastinum shifts contralateral / away from the collapsed lung.
Contraction Atelectasis
Occurs when focal or generalized pulmonary fibrosis prevents
full lung expansion.
Atelectasis reduces oxygenation and predisposes to infection.
Except to that caused by contraction, atelectasis is reversible.
Pulmonary Edema
Leakage of excessive interstitial fluid which accumulates in the
alveolar spaces, can result from:
Hemodynamic disturbances (increased capillary pressure,
decreased oncotic pressure, lymphatic obstruction)
Direct increased capillary permeability (microvascular injury)
1.) Hemodynamic Pulmonary Edema
Due to increased hydrostatic pressure, as occurs most
commonly in left-sided heart failure.
Fluid accumulates initially in the basal regions of the lower lobes
where hydrostatic pressure is greatest (dependent edema).
Histologically, capillaries are engorged, and an intra-alveolar
transudate appears as finely granular pink material.
Alveolar micro-hemorrhages and hemosiderophages (heart
failure cells) are present in long standing cases (e.g. Mitral
Stenosis).
Fibrosis and thickening of the alveolar walls cause lungs to
become firm and brown (brown induration).
Heavy and wet lungs
Predisposes to infection, impair normal respiratory function.
2.) Microvascular Injury Edema
Injury to the alveolar septa.
Primary injury to the vascular endothelium or damage to
alveolar epithelial cells produces inflammatory exudate that
leaks into the interstitial space.
In most forms of pneumonia, the edema remains localized and
overshadowed by the manifestations of infection.
When diffuse, alveolar edema is an important contributor to a
serious, fatal condition: Acute Respiratory Distress Syndrome
(ARDS).
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Acute Lung Injury and Acute Respiratory Distress Syndrome
Acute Lung Injury (ALI), also called non-cardiogenic pulmonary
edema, is characterized by abrupt onset of significant hypoxemia
and bilateral pulmonary infiltrates without cardiac failure.
Acute Respiratory Syndrome (ARDS) is a manifestation of severe ALI.
Both are associated with inflammation, which increases
pulmonary vascular permeability, edema, and epithelial death.
Histologically, these manifest diffuse alveolar damage (DAD).
Pathogenesis
Initiated by injury of pneumocytes and pulmonary endothelium.
Endothelial Activation
Secondary to pneumocyte injury sensed by macrophages.
Macrophages then secrete mediators (TNF).
Circulating mediators can activate pulmonary endothelium
increasing expression of adhesion molecules, procoagulant
proteinsm and chemokines.
Adhesion and Extravasation of Neutrophils
Neutrophils degranulate in the interstitium and the alveoli.
They secrete inflammatory mediators (TNF, ROS, Cytokines).
Increased recruitment and adhesion of leukocytes, more
endothelial injury, and local thrombosis.
Accumulation of intra-alveolar fluid and formation of hyaline
membrane
Leaks from the pulmonary capillary results to edema.
Damage and necrosis of Type II cells lead to surfactant
deficiency, further compromising gas exchange.
Protein-rich edema fluid organizes to hyaline membrane.
Resolution of Injury
Impeded in ALI/ARDS due to epithelial necrosis and
inflammatory damage that impairs the ability of remaining
cells to assist with edema resorption.
Lessening of the inflammation results to release of fibrogenic
cytokines (TGF-B, PDGF) that stimulates fibrosis of the
alveolar walls.
Bronchial stem cells replace pneumocytes.
Morphology
Acute Stage
Lungs are heavy, firm, red, and boggy.
Exhibits congestion, interstitial, and intra-alveolar edema
Inflammation, fibrin deposition, DAD.
Alveolar walls become lined with waxy hyaline membrane.
Organizing Stage
Type II pneumocytes proliferation.
Granulation tissue forms in the alveolar walls.
Fibrotic thickening (scarring) may ensue.
Often have superimposed bronchopneumonia.
Clinical Course
Profound dyspnea and tachypnea, initially normal CXR.
Increased cyanosis and hypoxemia, respiratory failure, and
appearance of diffuse bilateral infiltrates on CXR.
 Hypoxemia may be refractory to oxygen therapy due to
ventilation perfusion mismatching and respiratory acidosis
develops.
Lungs become stiff due to loss of functional surfactant.
Ventilation-perfusion mismatch poorly aerated regions
continue to be perfused.
Acute Interstitial Pneumonia
A term used to describe widespread ALI of unknown etiology
with a rapidly progressive clinical course.
An uncommon disorder that occurs at a mean age of 59 years
with no sex predilection.
Patient presents with acute respiratory failure often following an
illness of less than 3 weeks that resembles URTI.
CXR are same those of the organizing stage of ALI.
Diffuse Pulmonary Diseases
1.) Obstructive Lung (Airway) Disease
Increase in resistance to airflow.
Due to a partial or complete obstruction at any level from the
trachea and larger bronchi to the terminal and respiratory
bronchioles.
Pulmonary function tests show decreased maximal airflow rates
during forced expiration, usually expressed as FEV1/FVC ratio, a
ratio of less than 0.7 generally indicates airway obstruction.
Disorders associated with airflow obstruction:
1. Bronchial Asthma
2. Emphysema
3. Chronic Bronchitis
4. Bronchiectasis
Causes of death in COPD:
Respiratory acidosis and coma
Right-sided heart failure
Massive collapse of lungs secondary to pneumothorax
2.) Restrictive Lung Diseases
Reduced expansion of the lung parenchyma and decreased total
lung capacity.
Expiratory rate is normal or proportionately reduced.
Occurs in two broad conditions:
1. Chest wall disorders (e.g. severe obesity, pleural diseases,
kyphoscoliosis, and neuromuscular diseases such as polio)
2. Chronic Interstitial and Infiltrative diseases (e.g.
pneumoconiosis and interstitial fibrosis)
Obstructive Lung Diseases
A.) BRONCHIAL ASTHMA
A chronic disorder of the conducting airways, usually caused by
an immunologic reaction, which is marked by episodic
bronchoconstriction due to increased airway sensitivity.
Inflammation of bronchial walls and increased mucus secretion.
Recurrent episodes of wheezing, breathlessness, chest tightness,
and cough particularly at night and/or early morning.
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Extrinsic Asthma is typically a Type I hypersensitivity reaction
induced by exposure to an extrinsic antigen.
Intrinsic Asthma is triggered by non-immune ingestion of aspirin,
pulmonary infections, cold, inhaled irritants, stress, & exercise.
A state of unremitting attacks called acute severe asthma,
formerly called status asthmaticus, may prove fatal; usually such
patients have long history of asthma.
Asthma can be classified as:
1. Atopic Asthma evidence of allergen sensitization and
immune activation, often in allergic rhinitis or eczema.
2. Non-Atopic Asthma no evidence of allergen sensitization
Early-onset allergic asthma is associated with TH2 helper T cell
inflammation, which responds well to corticosteroid treatment.
Pathogenesis
Exaggerated TH2 response to normally harmless antigens.
TH2 secretes cytokines that promote inflammation and stimulate
B cells to produce IgE and other antibodies:
IL-4 stimulates production of IgE
IL-5 activates locally recruited eosinophils
IL-13 stimulate mucus secretion from bronchial submucosal
glands and also promote IgE production by B cells.
IgE binds to the Fc receptors on submucosal mast cells, and
repeat exposure to the allergen triggers the mast cells to release
granule contents and produce cytokines and other mediators.
TH1 produces interferon gamma and IL-2 which initiate killing of
viruses and intracellular organisms.
Cytokines from TH1 inhibit TH2 cells and vice versa any
imbalance leads to ASTHMA. (from PPT)
Airway Remodeling hypetrophy of bronchial smooth
muscles and deposition of subepithelial collagen.
ADAM33 belongs to MMPs or collagenases accelerate
proliferation of bronchial smooth muscle and fibroblasts
bronchial hyperreactivity and subepithelial fibrosis.
Atopic Asthma
Most common type
Usually begins in childhood and is triggered by allergens.
Skin test in (+) family history shows wheal-and-flare reaction.
Exposure of pre-sensitized IgE coated mast cells to allergen
causes release of chemical mediators leading to direct simulation
of subepithelial vagal receptors promoting bronchoconstriction.
Early-phase or immediate hypersensitivity and late-phase rxn
Early phase/Acute Phase:
Mediators: LTC4, D4, E4, PGD2, E2, F2, Histamine, PAF,
Mast cell tryptase.
Dominated by bronchoconstriction, increased mucus
production, vasodilation, edema, hypotension.
Late phase:
Starts 4-8 hours, persists for 12-24 hours or more
Mediators: Eosino- & neutrophilic chemotactic factors, LTB4,
IL4, IL5, PAF, TNF
Dominated by leukocytes (eosinophils) and more T cells.
 Mediators produced by leukocytes and epithelial cells can be
ranked based on the clinical efficacy of drug intervention:
1. Clearly supported by efficacy of pharmacologic intervention:
Leukotrienes C4, D4, E4 play a role in bronchospasm,
prolonged bronchoconstriction, increased vascular
permeability and mucus secretion.
Acetylcholine from intrapulmonary motor nerves cause
airway constriction by direct muscarinic stimulation
2. Present in allergy but the role seems minor on basis of lack of
efficacy of potent antagonists:
Histamine potent bronchoconstrictor
Prostaglandin D2 bronchoconstrictor and vasodilator
Platelet-activating factor aggregation and serotonin
3. Suspects for asthma but drug has not been produced:
IL-13/IL-4 on-going development of IL-3 monoclonal
antibodies and IL-4 receptor antagonists.
TNF, IL-6, Chemokines, Eotaxin (CCL11), Nitric Oxide,
Bradykinin, Endothelin.
Non-Atopic Asthma
Do not have evidence of allergen sensitization, skin test (-).
Positive family history is less common.
Most frequent triggers are respiratory tract infections due to
viruses (rhino, parainfluenza, & respiratory syncytial virus)
IgE levels are normal.
No associated allergies.
May be triggered by innocuous events such as exposure to cold
or even exercise.
Drug-Induced Asthma
Aspirin-sensitive asthma is an uncommon type.
Occurring in individuals with recurrent rhinitis and nasal polyps.
They experience asthma attacks with urticaria.
Aspirin inhibits cyclooxygenase pathway of arachidonic acid
metabolism without affecting the lipoxygenase route.
Declining PGE2 levels will occur.
PGE2 inhibits enzymes that generate proinflammatory
mediators such as leukotrienes (LTB4, C4, D4, E4).
Occupational Asthma
Form of asthma may be triggered by:
Fumes (Epoxy, Resins, Plastics)
Organic and Chemical Dusts (Wood, Cotton, Platinum)
Gases (Toluene)
Others (Formalin, Penicillin).
Only minute amount are required to induce attack, which usually
occur after repeated exposure.
Morphology
Lungs are distended by overinflation
Contain small areas of atelectasis
Most striking gross finding is occlusion of the bronchi and
bronchioles by thick, tenacious mucus plugs often contain shed
epithelium.
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Curschmann spirals in sputum or lavage which may result from
extrusion of mucus plugs from subepithelial mucus gland ducts
or bronchioles.
Eosinophilia
Charcot-Leyden crystals composed of eosinophilic protein
called galectin-10.
Airway remodeling characterized by:
Thickening of basement membrane of bronchial epithelium
Edema and inflammation of bronchial walls (eosinophilia)
Increase in size of submucosal glands
Hypertrophy and hyperplasia of bronchi wall smooth muscle
B.) EMPHYSEMA
Irreversible enlargement of airspaces distal to the terminal
bronchioles, accompanied by destruction of their walls without
obvious fibrosis.
Classified according to its anatomic distribution within the lobule
Centriacinar
Panacinar
Paraseptal
Irregular
Pathogenesis
Factors affecting emphysema:
Inflammatory mediators and leukocytes (LTB4, IL8, TNF)
Protease-antiprotease imbalance
Oxidative Stress
Infection
Protease-antiprotease imbalance is abetted by the oxidant-
antioxidant imbalance.
Elastase primarily derived from neutrophils.
Anti-elastase 1-antitrypsin, leukoprotease inhibitor, 1-
macroglobulin
Destructive effect of high protease activity in subjects with low
anti-protease activity.
Patients with 1-antitrypsin deficiency have a markedly
enhanced tendency to develop pulmonary emphysema which is
compounded by smoking.
Nicotine is chemoattractant to neutrophils and macrophages,
compounded by oxidant-antioxidant imbalance
PMN Proteases (Neutrophil elastase, Proteinase 3, Cathepsin G)
and Macrophage elastase and matrix metalloproteinases
TISSUE DAMAGE
Clinical Features
Symptoms do not appear until at least 1/3 of the functioning
pulmonary parenchyma is damaged.
Dyspnea usually appears first insidiously progressing steadily.
Cough or wheezing is the chief complaint, confused with asthma
Weight Loss is common and is severe to consider occult cancer.
Classically, they are:
Barrel Chested and dyspneic
Obviously prolonged expiration
Sits forward in a hunched-over position
Breathes through pursed lips
In severe emphysema:
Cough is often slight
Overdistention is severe
Diffusion capacity is low
Blood gas values are normal at rest.
May overinflate and remain well oxygenated pink puffers.
Development of cor pulmonale, eventually congestive heart
failure related to secondary pulmonary hypertension.
Death in most emphysema patients is due to:
Coronary artery disease
Respiratory Failure
Right Sided Heart Failure
Massive lung collapse secondary to pneumothorax
Anatomic Distributions of Emphysema
1.) Centriacinar (Centrilobular) emphysema
Central or proximal parts of the acini, formed by respiratory
bronchioles are affected.
Distal alveoli are spared.
Both emphysematous and normal airspaces exist in the same
acini or lobule.
More common and severe in the upper lobes (apical segments).
Inflammation around bronchi and bronchioles are common.
Occurs predominantly in heavy smokers, associated with chronic
bronchitis (COPD).
2.) Distal Acinar (Paraseptal) emphysema
The proximal portion of the acini is normal; the distal part is
predominantly involved.
More striking adjacent to the pleura, along the lobular
connective tissue septa, and at the margins of the lobules.
Occurs adjacent to areas of fibrosis, scarring, or atelectasis, most
severe in the upper half of the lungs.
Multiple, continuous, enlarged airspaces from <0.5 to more than
2.0 cm in diameter, sometimes forming cyst-like structures.
Underlies many cases of spontaneous pneumothorax in adults.
3.) Panacinar (Panlobular) emphysema
Acini are uniformly enlarged from the level of the respiratory
bronchioles to the terminal blind alveoli.
Tends to occur more in the lower zones and anterior margins of
the lungs, most severe at the bases of the lungs.
Associated with 1-antitrypsin deficiency.
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4.) Irregular emphysema
Airspace enlargement with fibrosis.
Acinus is irregularly involved, almost invariably associated with
scarring.
Occurs in small foci, clinically insignificant.
Other types of Emphysema
1.) Compensatory hyperinflation
Used to designate dilation of alveoli without destruction of the
septal walls in response to loss of lungs substance elsewhere.
Exemplified by hyperinflation of residual lung parenchyma
followed by surgical removal of a diseased lung or lobe.
2.) Obstructive overinflation
Lung expands because air is trapped within it.
Commonly caused by subtotal obstruction of the airways by a
tumor or a foreign object.
Congenital Lobar Overinflation in infants result from hypoplasia
of bronchial cartilage sometimes associated with cardiac and
lung congenital anomalies.
Causes:
Ball-valve effect allowing air to enter on inspiration and
preventing its exit on expiration.
Collaterals bring in air behind the obstruction, consists of
pores of Kohn and other accessory bronchiolo-alveolar
connections (canals of Lambert).
A life-threatening emergency, since the affected portion distends
sufficiently to compress the remaining lung.
3.) Bullous emphysema
Large subpleural blebs or bullae (spaces >1cm in diameter) that
can occur in any form of emphysema.
Occur near the apex, near old tuberculous scarring.
Rupture of bullae may lead to pneumothorax
4.) Interstitial Emphysema
Entrance of air into the connective tissue stroma due to:
Alveolar tears caused by rapid increases in pressure in
alveolar sacs (coughing + bronchial obstruction)
Chest wounds
Fractured ribs puncturing the lungs
Premature children on positive pressure ventilation and
artificially ventilated adults are most at risk.
Morphology
Produces voluminous lungs, often overlapping the heart and
hiding it when the anterior chest wall is removed.
Upper 2/3 of lungs are more severely affected.
Large alveoli can be easily seen on cut surface of fixed lung.
Microscopically, abnormally large alveoli are separated by thin
septa with only focal centriacinar fibrosis.
Loss of attachments of the alveoli to the outer wall
Pores of Kohn are so large, the septa appears floating or
protrude blindly with a club-shaped end
 Alveolar wall destruction results to decreased capillary bed area
Due to blebs or bullae, there is compression of the respiratory
bronchioles and vasculature of the lungs.

C.) CHRONIC BRONCHITIS

A persistent cough with sputum production for at least 3 months
in at least 2 consecutive years, in the absence of any other
identifiable cause.
Common in habitual smokers, smog-laden areas.
One end of spectrum in COPD, together with emphysema.
Simple chronic bronchitis
Chronic asthmatic bronchitis
Obstructive chronic bronchitis
D.) BRONCHIECTASIS
Pathogenesis A disorder in which destruction of smooth muscle and elastic
Initiating factor is exposure to noxious or irritating inhaled tissue by chronic necrotizing infections lead to permanent
substance (e.g. tobacco smoke, dusts, silica) dilation of bronchi and bronchioles.
Mucus Hypersecretion Associated with variety of conditions:
Earliest feature is hypersecretion of mucus in large airways. Congenital or hereditary conditions cystic fibrosis,
Associated with hypertrophy of submucosal glands. intralobar sequestration, immunodeficiency, primary ciliary
dyskinesia and Kartagener syndrome.
Hypersecretion mechanism involves inflammatory mediators
such as histamine and IL-13. Infections necrotizing pneumonia (single or recurrent)
Inflammation Bronchial Obstruction tumor, foreign bodies, or mucus
impaction.
Inhalants cause cellular damage, eliciting both acute and
chronic inflammation involving neutrophils, lymphocytes, Other conditions RA, SLE, IBD, COPD, Post-transplant
and macrophages. (Chronic GVHD after bone marrow transplant).
Long standing inflammation and fibrosis lead to chronic - of cases are idiopathic, lacking associations.
airway obstruction.
Pathogenesis
Infection
Obstruction and infection are the major conditions associated.
Does not initiate but significant in maintaining it.
Normal clearing mechanisms are impaired.
Morphology Cystic Fibrosis defective mucocilliary action and thick viscid
Grossly, there is hyperemia, swelling, and edema of the mucous secretions that obstruct the airway
membranes, w/ excessive mucinous or mucopurulent excretions. Primary Ciliary Dyskinesia an autosomal recessive syndrome
Mild chronic inflammation and enlargement of mucus glands. with dysfunction in ciliary action due to shortened or absent
dynein arms.
Numbers of goblet cells increase, major change is in the size.
Associated with Kartageners Syndrome marked by situs
Increase in size of mucous glands can be assessed by Reid Index,
inversus or partial lateralizing abnormality associated with
normally 0.4, is increased in chronic bronchitis.
bronchiectasis and sinusitis.
Epithelium may exhibit squamous metaplasia or dysplasia.
Allergic Bronchopulmonary Aspergillosis occurs in asthma and
Narrowing of bronchioles due to mucous plugging.
cystic fibrosis patients, results from hypersensitivity of
Most severe cases, lumen can obliterate due to fibrosis known as
Aspergillus fumigatus leading to activation of TH2 helper cells
bronchiolitis obliterans.
recruiting eosinophils, clinically have high IgE levels.

Clinical Features
Morphology
Cardinal symptom is persistent cough productive of sparse
Usually affects the lower lobes bilaterally.
sputum for many years.
Most severe in the more distal bronchi and bronchioles.
Dyspnea on exertion eventually develops.
Airways are dilated, sometimes 4x the normal size.
With passage of time and continued smoking, other elements of
Histologic finding vary with activity and chronicity of the disease
COPD may appear
Intense acute and chronic inflammatory exudation within the
Hypercapnia
walls of the bronchi or bronchioles
Hypoxemia
Desquamation of the epithelium
Mild Cyanosis (Blue Bloaters)
Necrosis destroys bronchial walls and forms abscess leading to
Many patients with COPD have both bronchitis and emphysema
fibrosis in chronic cases leading to subtotal or total obliteration.
Long standing leads to cor pulmonale and heart failure

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 Variety of bacteria can be found:
Staphylococci, Streptococci, Pneumococci, Enteric organisms,
aerobic, and microaerophilic bacteria.
Haemophilus influenzae (particularly in children) and
Pseudomonas aeruginosa
Clinical Course
Severe, persistent cough with expectoration of foul smelling,
sometimes bloody sputum.
Dyspnea and orthopnea in severe cases with hemoptysis.
Symptoms are episodic and precipitated by URTI with fever.
Restrictive Lung Diseases (Diffuse Interstitial, Infiltrative)
Heterogeneous group of disorders characterized predominantly
by inflammation and fibrosis of the pulmonary interstitium.
Patients have dyspnea, tachypnea, end-inspiratory crackles, and
cyanosis without wheezing or other evidence of obstruction.
Classic functional abnormalities are reduction in diffusion
capacity (carbon monoxide), lung compliance, and lung volume.
On CXR, there is bilateral diffuse infiltration by small nodules,
irregular lines, or ground-glass appearance.
Secondary pulmonary hypertension and right-sided heart failure.
Grossly referred to as end-stage lung or honeycomb lung.
Major Categories of Chronic Interstitial Lung Diseases
1.) Fibrosing Idiopathic Pulmonary Fibrosis
Non-specific Interstitial Pneumonia
Cryptogenic Organizing Pneumonia
Connective tissue disease-associated
Pneumoconiosis
Drug Reactions
Radiation pneumonitis
2.) Granulomatous Sarcoidosis
Hypersensitivity pneumonitis
3.) Eosinophilic
4.) Smoking-related Desquamative interstitial pneumonia
Respiratory bronchiolitis-associated
5.) Others Langerhans cell histiocytosis
Pulmonary alveolar proteinosis
Lymphoid Interstitial pneumonia
A.) FIBROSING DISEASES
1.) Idiopathic Pulmonary Fibrosis (IPF)
Marked by progressive interstitial fibrosis and respiratory failure.
Histologic pattern of fibrosis is referred to as usual interstitial
pneumonia (UIP), hallmark is patchy interstitial fibrosis.
Pathogenesis
Unknown, fibrosis arises in genetically predisposed individuals
who are prone to aberrant repair of recurrent injuries caused by
environmental exposure:
Environmental factors most important is smoking
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Genetic factors loss-of-function mutations in TERT & TERC,
encoding for genes for telomerase, others have mutations in
surfactant genes having misfolded proteins.
Age Rarely appears before the age of 50.
Morphology
Earliest lesion is fibroblastic foci.
Microscopic hallmark is patchy interstitial fibrosis.
Grossly, pleural surface is cobblestoned as a result of scar
retraction, cut sections show firm, rubbery white areas of
fibrosis primarily in the lower lobes (subpleural region along the
interlobular septa).
Fibrosis cause collapse of alveolar walls and formation of cystic
spaces lined by hyperplastic type II pneumocytes or bronchial
epithelium (honeycomb fibrosis).
Mild to moderate acute & chronic inflammation within fibrosis.
Foci of squamous metaplasia and smooth muscle hyperplasia.
Clinical Course
Begins insidiously w/ gradually increasing dyspnea on exertion
Dry cough
Most patients are 55-75 years old.
Late cyanosis, clubbing, and hypoxemia.
2.) Non-specific Interstitial Pneumonia (NSIP)
Diffuse interstitial disease of unknown etiology.
These patients have much better prognosis than with usual.
May be idiopathic or associated with connective tissue diseases.
Morphology
Divided into:
Cellular Pattern primarily of mild to moderate chronic
interstitial inflammation w/ lymphocytes and few plasma
cells, in a uniform or patchy distribution.
Fibrosing Pattern Diffuse or patchy interstitial fibrosis.
Fibroblastic foci, honeycombing, hyaline membrane, granulomas
are all ABSENT.
Clinical Course
Dyspnea and cough of several months duration.
th
More likely female, non-smokers in 6 decade of life.
On CT, bilateral, symmetric, lower lobe reticular opacities.
Patients w/ cellular pattern are younger & have better prognosis.
3.) Cyptogenic Organizing Pneumonia (COP)
Synonymous with bronchiolitis obliterans organizing pneumonia
Unknown etiology.
Presents with cough and dyspnea with patchy subpleural or peri-
bronchial areas of airspace consolidation in CXR.
Histologically, there are polypoid plugs of loose organizing
tissues (Masson bodies) w/in alveolar ducts, alveoli, bronchioles.
No interstitial fibrosis or honeycombing.
It is important to recognize that organizing pneumonia with intra-
alveolar fibrosis is most often seen as a response to infections or
inflammation of the lungs, including viral, bacterial pneumonia,
inhaled toxins, connective tissue diseases, GVHD.
4.) Pulmonary involvement in Autoimmune Vascular Diseases
Systemic Lupus Erythematosus (SLE)
Patchy transient parenchymal infiltrates
Rheumatoid Arthritis pulmonary involvement in 30-40% of px
Chronic pleuritis w/ or w/o effusion
Diffuse interstitial pneumonitis and fibrosis
Intrapulmonary rheumatoid nodules
Follicular Bronchiolitis
Pulmonary Hypertension
Systemic Sclerosis
Diffuse interstitial fibrosis (non-specific)
Pleural Involvement
5.) Pneumoconioses
Non-neoplastic lung reaction to inhalation of mineral dusts, now
includes organic, inorganic particulate, fumes, and vapors.
Pathogenesis
Development of pneumoconiosis depends on:
1. Amount of dust retained in the lungs and airways
2. Size, Shape, and Buoyancy of the particle
3. Particle solubility and physicochemical reactivity
4. Possible additional effects of other irritants (smokers)
Coal Workers Pneumoconiosis (CWP)
Inhalation of coal particles and other admixed forms of dust.
Spectrum of lung findings in coal workers is wide:
1. Asymptomatic Anthracosis
2. Single CWP with little or no pulmonary dysfunction
3. Complicated CWP or progressive massive fibrosis
Contaminating silica can favor progressive disease.
Carbon dust itself is the major culprit.
May also develop emphysema and chronic bronchitis.
Morphology
Anthracosis is the most innocuous lesion.
Inhaled carbon pigment is engulfed by alveolar macrophages,
which accumulate in connective tissue along lymphatics.
Simple CWP characterized by coal macules (1-2mm) which are
carbon laden macrophages and coal nodules which are delicate
network of collagen fibers.
Upper lobes and upper zones of lower lobes are heavily
involved, adjacent to respiratory bronchioles.
Sometimes give rise to centrilobular emphysema
Complicated CWP (progressive massive fibrosis) is characterized
by intensely blackened scars 1 cm to 10 cm usually multiple.
Microscopically consist of dense collagen and pigment with
necrotic central portion most likely due to ischemia.
Page 8 of 20
Clinical Course
Usually benign, little decrement in lung function.
Less than 10% of cases leads to progressive massive fibrosis and
may manifest pulmonary dysfunction, pulmonary hypertension,
and cor pulmonale.
Silicosis
Caused by inhalation of proinflammatory crystalline silicon
dioxide (silica), manifests after decades of exposure as slowly
progressing, nodular, fibrosing pneumoconiosis.
Pathogenesis
Crystalline forms (Quartz, Crystobalite, Tridymite) are more
fibrogenic than the amorphous forms.
Amorphous forms are biologically less active.
The particles are phagocytosed and activate the inflammasome
leading to activation and release of following factors:
- IL-1, IL-18 - TNF - Fibronectin
- Lipid Mediators - O2-derived free radicals - Fibrogenic cytokines
Morphology
Grossly, in early stages, tiny, barely palpable, discrete pale to
blackened nodule in the hilar lymph nodes and upper zones.
The nodules coalesce into hard collagenous scars.
Some nodules may undergo central softening and cavitation due
to superimposed tuberculosis or ischemia.
Thin sheets of calcification occur in hilar lymph nodes with
eggshell calcification in CXR.
Expansion and coalescence of lesions may produce progressive
mass fibrosis.
Microscopically, there are concentric layers of hyalinized
collagen surrounded by dense capsule of more condensed ones.
On polarized microscopy, there are bifringent particles.
Clinical Course
CXR show fine nodularity in upper zones of lungs.
Pulmonary functions are normal or moderately affected, most
do not develop shortness of breath until massive fibrosis
Slow to kill, with impaired pulmonary function.
Increased susceptibility to tuberculosis.
Asebestos-related diseases
Asbestos is family of pro-inflammatory crystalline hydrated
silicates associated with:
Localized fibrous plaques, or rarely, diffuse pleural fibrosis.
Pleural effusions, recurrent
Parenchymal Interstitial Fibrosis (Asbestosis)
Lung Carcinoma
Mesotheliomas
Laryngeal, extrapulmonary neoplasms (colon carcinoma)
Pathogenesis
Occurs in two geometric forms: Serpentine and Amphibole.
Amphiboles (crocidolite, amosite, tremolite, anthophyllite,
actinolyte) are more pathogenic w/ induction of mesothelioma.
 Greater pathogenicity of amphiboles is related to their
aerodynamic properties and solubility.
Asbestos can act as a tumor initiator or tumor promoter,
mediated by free radicals.
Same pathophysiology with silica upon macrophage ingestion.
Morphology
Diffuse pulmonary interstitial fibrosis with presence of Asbestos
Bodies, which are golden brown, fusiform or beaded rods, with a
translucent center and consists of asbestos fibers coated with an
iron coating proteinaceous material.
Arise when phages phagocytose asbestos, iron is from the
phages own ferritin.
Ferruginous bodies other inorganic particulates that became
coated with similar iron-protein complex.
Begins as fibrosis around respiratory bronchioles and alveolar
ducts and extends to adjacent alveolar sacs.
Fibrous tissue distorts the architecture creating enlarged
airspaces enclosed with thick fibrous walls, eventually becomes
honeycombed.
Usually begins in the Lower lobes and Subpleurally.
The middle and upper lobes of the lungs become affected as
fibrosis progress
Scarring may trap and narrow pulmonary arteries causing
pulmonary hypertension and cor pulmonale.
Pleural Plaques, most common manifestation of asbestosis, are
well-circumscribed plaques of dense collagen often calcified.
Most frequently on anterior and posterolateral aspects of the
parietal pleura and diaphragm.
Risk of developing lung CA (5x risk), mesothelioma (1,000x)
6.) Drug Induced Lung Diseases
Cytotoxic drugs
Bleomycin pneumonitis and fibrosis
Methotrexate hypersensitivity pneumonitis
Amiodarone pneumonitis and fibrosis
Nitrofurantoin hypersensitivity pneumonitis
Aspirin and beta-agonists - bronchospasm
7.) Radiation-Induced Lung Diseases
Acute Radiation Pneumonitis occurs 1-6 months after therapy,
presents with fever, dyspnea, pleural effusion, radiologic
infiltrates.
Chronic Radiation Pneumonitis is a progressed form of acute
radiation pneumonitis manifested as pulmonary fibrosis.
B.) GRANULOMATOUS DISEASES
1.) Sarcoidosis
A systemic disease of unknown cause, may involve many organs.
Most common is bilateral hilar lymphadenopathy and lung
involvement.
Eye and skin lesions are next common.
Produces non-caseating granuloma.
Page 9 of 20
Pathogenesis
Etiology remains unknown but evidences suggest a disease of
disordered immune regulation in genetically predisposed
individual.
Immunologic Factors
Intra-alveolar and interstitial accumulation of CD4+ T cells
resulting in CD4:CD8 ratio from 5:1 to 15:1, suggesting there
is oligoclonal expansion of T cell subsets.
Increased levels of TH1 cytokines (IL-2, IFN-Y).
Increased levels of cytokines in the local environment (IL-8,
TNF, MIP-1) favors recruitment of T-cells & monocytes.
Impaired in dendritic cell functions.
Systemic Immunologic Abnormalities
Anergy to common skin test antigens such as Candida or PPD.
Polyclonal hypergammaglobulinemia.
Genetic Factors
Include familial and racial clustering cases.
Association with certain HLA genotypes (Class I HLA-A1 & B8).
Environmental Factors
Proposed putative microbes: Mycobacteria, Propionibacterium
acnes, Rickettsia sp.
No unequivocal evidence to suggest that sarcoidosis is caused
by infectious agent.
Morphology
Tissue contain well-formed non-necrotizing granulomas
composed of aggregates of tightly clustered epitheloid
macrophages, often giant cells
Central necrosis is unusual.
Chronicity may become enclosed within fibrous rims or may be
replaced by hyaline fibrous scars.
Giant cells are composed of Schaumann bodies that are
laminated concretions composed of calcium and proteins and
stellate asteroid inclusion bodies.
Lungs:
No demonstrable alteration.
Small nodes, 1-2cm, non-caseating, non-cavitated granulomas
Distributed along lymphatics around bronchi and vessels.
Alveolar lesions may be seen.
BLA: CD4/CD8 ratio of >2.5 and CD3/CD4 ratio <0.31
Lymph Nodes:
Particularly the hilar and mediastinal nodes.
Enlarged, discrete, and calcified.
Spleen is enlarged with granulomas
Liver is slightly enlarged with scattered granulomas
Bone marrow: the most common involvement are the
phalangeal bones of the feet and hand.
Skin lesions include discrete subcutaneous nodules, focal slightly
elated, erythematous plaques or flat lesions.
Eye involvement produces iritis and iridocyclitis
Bilateral sarcoidosis of the salivary glands constitutes combined
uveoparotid involvement is designated as Mikulicz Syndrome.
Muscle involvement is underdiagnosed, may be asymptomatic.
Clinical Course
Have an unpredictable course:
65%-70% recover with minimal or no residual manifestations.
20% have permanent loss of lung function or some permanent
visual impairment.
10-15% have cardiac or CNS damage, may succumb to
progressive pulmonary fibrosis and cor pulmonale.
2.) Hypersensitivity Pneumonitis
Immunologically mediated, predominantly interstitial lung
disorders caused by intense, often prolonged exposure to
inhaled organic antigens.
Immune complex & delayed type hypersensitivity (Type 2 and 4)
Abnormal sensitivity or heightened reactivity to causative
antigens primarily involving the alveolar walls thus also called
extrinsic allergic alveolitis.
Results from inhalation of organic dusts containing antigens
made up of spores of bacteria, fungi, etc.
Involves primarily the alveoli, progressing to chronic fibrotic lung
diseases.
Described depending on occupation or exposure:
Farmers Lung dusts from hay with spores of Actinomyces.
Pigeon Breeders Lung (Bird Franciers) provoked by
proteins from serum, excreta or feathers of birds.
Humidifier / Airconditioner Lung caused by thermophilic
bacteria in heated water.
Evidences suggest it is an immunologic disease:
Bronchoalveolar lavage from acute phase shows pro-
inflammatory markes such as MIP-1 alpha and IL-8.
BAL consistently with increased T cells, both CD4 and CD8.
Presence of specific antibodies in serum (Type II
hypersensitivity).
Complement and Immunoglobulins are present in the vessel
walls (Type III).
2/3 have non caseating granuloma (Type IV).
Morphology
Characteristically centered on bronchioles.
Interstitial pneumonitis consisting primarily of lymphocytes,
plasma cells & macrophages.
Non-caseating granulomas in 2/3 patients.
Interstitial fibrosis & obliterative bronchiolitis
More then of patients have (+) intra-alveolar infiltrates.
Clinical Features
Acute attacks consist of recurring episodes of fever, dyspnea,
cough, and leukocytosis.
Micronodular infiltrates in CXR and pulmonary test shows acute
restrictive disorders.
If exposure is continuous & protracted:
Progressive respiratory failure, dyspnea and cyanosis.
Decrease in total lung capacity and compliance, similar to
chronic interstitial disease.
Symptoms usually appear 4-6 hours, may last 12 hours to days.
Page 10 of 20
C.) PULMONARY EOSINOPHILIA
Characterized by infiltration of eosinophils, recruited in part by
elevated alveolar levels of eosinophil attractants (IL-5).
Divided into the following categories:
Acute eosinophilic pneumonia with respiratory failure
Acute illness of unknown cause
Rapid onset fever, dyspnea and hypoxemic respiratory failure
CXR: diffuse infiltrates
Lavage contains >25% eosinophils
Microscopic findings: diffuse alveolar damage and many
eosinophils
Prompt response to corticosteroids
Secondary Eosinophilia
Parasitic, fungal or bacterial infection
Hypersensitivity pneumonitis
Drug allergies
Associated with asthma, allergic bronchopulmonary
aspergillosis, or vasculitis (Churg Strauss Syndrome).
Idiopathic Chronic Eosinophilic Pneumonia
Focal areas of cellular consolidation distributed chiefly on the
lung periphery.
Heavy aggregates of lymphocytes and eosinophils within
both the septal walls and the alveolar spaces.
Interstitial and organizing pneumonia often present.
Clinical manifestations: high fever, night sweats, dyspnea
responsive to corticosteroid therapy
D.) SMOKING-RELATED INTERSTITIAL DISEASES
1.) Desquamative Interstital Pneumonia
Characterized by large collection of macrophages in the
airspaces in a current or former smoker.
Most striking feature: large number of macrophages with
abundant cytoplasm containing dusty brown pigments
(smokers macrophages)
Some macrophages contain lamellar bodies composed of lung
surfactants with phagocytic vacuoles, derived necrotic type II
pneumocyte
Thickened alveolar septa with sparse lymphocytes and plasma
cells.
Interstitial fibrosis and emphysema may be present
40-50 years old, men > women with 4:1 ratio
Cigarette smokers
Clinical manifestations: insidious onset of dyspnea and dry
cough over weeks or months often associated with clubbing of
digits
Good prognosis and excellent response to steroid
2.) Respiratory Bronchiolitis Associated Interstitial Lung Disease
Pigmented dusty brown intraluminal macrophages within the
first and second order respiratory bronchioles
Changes are patchy with bronchiolocentric distribution
Submucosal and peribronchiolar fibrosis
Centrilobular emphysema
E.) OTHER RESTRICTIVE DISEASES
1.) Pulmonary Langerhan Cells Histiocytosis
A rare disease characterized by focal collections of Langerhans
cells (accompanied by eosinophils).
Scarring occurs leading to airway destruction and alveolar
damage resulting in appearance of irregular cystic spaces.
CXR shows cystic and nodular abnormalities.
Langherhan cells are immature dendritic cells with grooved,
indented nuclei and abundant cytoplasm.
2.) Pulmonary Alveolar Proteinosis (PAP)
Rare disease caused by defects to granulocyte-macrophage
stimulating factor (GM-CSF) or pulmonary macrophage
dysfunction.
Accumulation of surfactant in the intra-alveolar and bronchiolar
spaces.
Radiologically, it shows bilateral patchy asymmetrical pulmonary
opacifications.
Non-specific respiratory difficulty of insidious onset, cough, and
abundant sputum often with chunks of gelatinous material.
Three distinct classes:
1.) Autoimmune / Acquired PAP
90% of cases, unknown etiology without any familial
predisposition.
Caused by circulating neutralizing antibodies specific for
GM-CSF
Anti-GM-CSF inhibits the activity of endogenous GM-CSF
leading to a state of function GM-CSF deficiency.
2.) Secondary PAP
Uncommon, associated with diverse diseases:
Caused by hematopoietic disorders, malignancies,
immunodeficiency disorders, lysinuric metabolism, silicosis.
3.) Congenital PAP
Hereditary PAP is extremely rare.
Occurs in neonates caused by mutations that disrupt genes
involved in GM-CSF signaling.
Immediate onset neonatal respiratory distress on a full term
with death ensuing at 3-6 mos.
Mutations in 3 genes:
Surfactant B protein homozygositiy for a frameshift
mutation in SF-B gene.
GM-CSF
GM receptor (GM/IL3/IL5) beta chain
Morphology
Characterized by a peculiar homogeneous, granular precipitate
containing surfactant proteins within the alveoli.
Focal to confluent consolidation of large areas of the lungs with
minimal inflammatory reaction.
On cut surface: Turbid fluid exudes with marked increase in size
and weight of lungs.
Alveolar precipitate is PA positive.
Immunologic stains is + for SP-A and SP-C.
Page 11 of 20
Alveolar precipitate is periodic acid-Schiff positive, contains
cholesterol clefts and surfactant proteins.
Surfactant lamellae in type II pneumocytes are normal.
3.) Surfactant Dysfunction Disorder
Disease caused by mutations in genes encoding proteins
involved in surfactant trafficking or secretion:
ATP-binding cassette protein member 3 (ABCA3)
Most frequently mutated gene
Autosomal recessive.
Rapidly progressive respiratory failure follower by death.
Surfactant Protein C
Second most commonly mutated gene in surfactant
dysfunction.
Autosomal dominant.
Surfactant Protein B
Least common mutated gene.
Autosomal recessive.
Infant is full term, rapidly develops progressive distress
shortly after birth, death w/in 3-6 months.
Morphology
Variable amount of pink granular material, type II pneumocyte
hyperplasia, interstitial fibrosis and alveolar simplification.
Immunohistochemical stain show lack of surfactant proteins B
and C.
Lamellar bodies are present in all.
Diseases of Vascular Origin
Pulmonary Embolism and Infarction
Important in patients who are bedridden, but also in a
hypercoagulable state.
Blood clots occlude the large pulmonary arteries, almost always
embolic in origin, 95% arise from thrombi within large deep
veins of lower legs.
Risk factors: Cardiac diseases, cancer, immobilization,
hypercoagulable states.
Pathophysiology
Occurs in patient with predisposing condition that produces
increased tendency to clot (thrombophilia).
Pathophysiologic response and clinical significance depends on:
Extent to which pulmonary artery is obstructed.
Size of occluded vessels.
Number of emboli
Overall status of CVS.
Release of vasoactive factors like TXA2.
2 main pathologic consequences:
Respiratory Compromise owing to the non-perfused,
although ventilated segment.
Hemodaynamic Compromise owing to increased
resistance to pulmonary blood flow that leads to
pulmonary hypertension and acute cor pulmonale.
 Pulmonary infarct is classicaly hemorrhagic and appears as
raised, red-blue area in early stages.
Fibrous replacement begins at the margins as a gray-white
peripheral zone and eventually converts the infarct into a
contracted scar.
If the infarct is caused by an infected embolus, the neutrophilic
inflammatory reaction can be intense, referred to as septic
infarcts.
Clinical Course
Patient is frequently is said to have electromechanical
dissociation, in which ECG has a rhythm but no pulses are
palpated.
Findings on CXR are variable, usually 12-36 hours after it has
occurred.
Multiple small emboli may lead to hypertension and chronic cor
pulmonale.
Pulmonary Hypertension
Mean pulmonary pressure is greater than or equal to 25 mmHg
at rest.
(from PPT), when mean pulmonary pressure reaches of
systemic levels is most frequently secondary to structural
cardiopulmonary conditions
Obstruction of vasculature caused by proliferation of
endothelial, smooth muscle and intimal cells accompanied by
concentric laminar intimal fibrosis.
Classification by WHO:
1. Pulmonary arterial hypertension, diverse collection of
disorders that all primarily impact small pulmonary arteries.
2. Pulmonary hypertension secondary to left-heart failure.
3. Pulmonary hypertension stemming from lung parenchymal
disease or hypoxemia.
4. Chronic thromboembolic pulmonary hypertension.
5. Pulmonary hypertension of multifactorial basis
Pathogenesis
Most frequently associated with structural cardiopulmonary
conditions that increase pulmonary blood flow, pulmonary
vascular resistance, or left heart resistance.
Common causes:
Chronic obstructive or Interstitial lung diseases (Group 3)
these diseases obliterate alveolar capillaries increasing
pulmonary resistance to blood flow secondarily pulmonary
blood pressure.
Antecedent congenital or Acquired heart disease (Group 2)
Mitral stenosis wherein an increase left atrial pressure.
Recurrent thromboemboli (Group 4) reduction in the
functional cross sectional area of the ascular bed.
Autoimmune disorders (Group 1) most notable in
systemic sclerosis.
Obstructive sleep apnea (Group 3) common disorder that
is associated with obesity and hypoxemia.
Page 12 of 20
Primary Pulmonary Hypertension
All known causes of increased pulmonary pressure are excluded.
Mutation in bone morphogenetic protein receptor type 2
(BMPR2) signaling pathway.
Inactivating BMPR 2 causes smooth muscle proliferation
BMPR2 is down regulated in lungs from some idiopathic
pulmonary arterial hypertension without gene mutation.
Secondary Pulmonary Hypertension
Endothelial dysfunction.
Increased shear and mechanical injury in left to right shunts or
biochemical injury produced by fibrin in thromboembolism
Decrease prostacyclin and nitric oxide, increase endothelin
Endothelial activation makes cell thrombogenic and promote
persistence of fibrin
Growth and factors and cytokines induce migration and
proliferation of smooth muscle and elaborate extracellular
matrix.
Morphology
Associated with:
Atherosclerosis
Medial hypertrophy, Intimal Fibrosis
Plexogenic pulmonary arteriopathy tuft of capillary
formation present producing a network of web that
spans the lumen of dilated thin walled, small arteries.
Right Ventricular Hypertrophy
Plexiform lesions are most prominent in:
Idiopathic and familial pulmonary HTN (Group 1)
Unrepaired congenital heart disease with left-to-right
shunts (Group 2)
Pulmonary HTN associated with HIV
Drugs (Group 1)
Clinical Course
Symptoms become evident in advanced arterial disease.
Idiopathic pulmonary HTN is most common in women are 20-40
years old.
Presenting symptoms are usually dyspnea and fatigue, but some
have angina type of chest pain.
Over time, respiratory distress, cyanosis, and right ventricular
hypertrophy occur, and death from decompensated cor
pulmonale with superimposed thromboembolism pneumonia
usually w/ 2-5 years in 80% of patients.
Diffuse Pulmonary Hemorrhage Syndrome
1.) Goodpasture Syndrome
Autoimmune disease characterized by presence of circulating
autoantibodies against the non-collagenous domain of alpha-3
chain of collagen IV.
Antibody initiates an inflammatory destruction of the basement
membrane in kidney glomeruli and lung alveoli.
Gives rise to rapidly progressive glomerulonephritis and
necrotizing hemorrhagic interstitial pneumonitis.
Pathogenesis
Production of antibodies against basement membranes.
Antibodies initiate an inflammatory destruction of the basement
membrane in glomeruli and alveoli.
Morphology
Lungs are heavy with areas of red-brown consolidation.
Focal necrosis of the alveolar walls associated with intra-alveolar
hemorrhages containing hemosiderophages.
Fibrous thickening of septa, hypertrophy of type II pneumocytes.
Organization of blood in alveolar spaces.
Clinical Features
Begin clinically as respiratory symptoms, primarily hemoptysis.
CXR evidence of focal pulmonary consolidation.
Soon manifests as glomerulonephritis.
Most common cause of death is uremia.
2.) Idiopathic Pulmonary Hemosiderosis
Rare disorder characterized by intermittent, diffuse alveolar
hemorrhage, same with Goodpasteur syndrome.
Usually present with insidious onset of hemoptysis and anemia.
Cause is unknown, no anti-basement membrane antibodies.
3.) Vasculitis-Associated Hemorrhage
Wegener Granulomatosis (Polyangiitis w/ granulomatosis)
Hypersensitivity Angiitis
Systemic Lupus Erythematosus.
Pulmonary Infections
Respiratory tract infections are more frequent than infections
of any other organs, vast majority are URTI caused by viruses.
Factors that compromise local defense mechanism of lungs:
Loss/Suppression of cough reflex coma, anesthesia,
neuromuscular disorders, drugs, chest pain (aspiration).
Injury to mucocilliary apparatus impairment of ciliary
function or destruction of epithelium due to giarette
smoke, corrosive gases, viral diseases, or genetics.
Accumulation of secretions cystic fibrosis
Interference with phagocytotic/bactericidal actions of
alveolar macrophages alcohol, smoke, anoxia.
Pulmonary congestion and edema
Defects in innate and humoral immunity lead to increased
incidence of pyogenic bacterial infections.
Mutations in MyD88 are associated with destructive
bacterial pneumonia.
Cell-mediated defects lead to increased mycobacterial and
herpes viruses, even low virulent Pneumocystis jiroveci.
Community-Acquired Bacterial Pneumonia
Lung infection in otherwise healthy individuals that is acquired
from the normal environment.
Often, bacterial infection follows an URT viral infection.
Page 13 of 20
Bacterial invasion of the parenchyma causes the alveoli to be
filled with inflammatory exudate, thus causing consolidation or
solidification of pulmonary tissue.
1.) Streptococcus pneumoniae
Most common cause of CAP.
Part of endogenous flora, gram-positive lancet-shaped diplococci
Pneumococcal vaccines contain capsular polysaccharides from
common serotypes.
2.) Haemophilus influenzae
Pleomorphic, gram negative occurs in encapsulated and non-
encapsulated forms.
6 serotypes of encapsulated, B type being most virulent.
May follow viral respiratory infection, is a pediatric emergency
and has a high mortality rate.
Descending laryngotracheobronchitis causes airway obstruction
as smaller bronchi are plugged by dense, fibrin-rich exudates.
3.) Moraxella catarrhalis
Pneumonia in elderly.
Second most common bacterial cause of acute COPD
exacerbation.
Along with S. pneumoniae and H. influenzae causes 3 most
common causes of otitis media in children.
4.) Staphylococcus aureus
Important cause of secondary bacterial pneumonia in children
and young adults following viral respiratory illness.
Associated with lung abscess and empyema.
IV drug users are high risk of development of staphylococcal
pneumonia with endocarditis.
Important cause of hospital acquired pneumonia
5.) Klebsiella pneumoniae
Most frequent cause of gram-negative bacterial pneumonia
Commonly affects debilitated, malnourished, and alcoholics
Thick mucoid blood-tinged sputum is characteristic often
described as currant jelly in appearance.
6.) Pseudomonas aeruginosa
Most commonly cause of hospital-acquired infections.
Occurrence in cystic fibrosis and immunocompromised patients
Common in neutropenic and propensity to invade blood vessels
with consequent extrapulmonary spread.
7.) Legionella pneumophila
Causative agent of Legionnaires disease
Pontiac fever self-limited URTI w/o pneumonic symptoms.
Flourishes in artificial aquatic environments.
Anatomic Patterns of Bacterial Pneumonia
Two Patterns of anatomic distribution:
1.) Lobar Bronchopneumonia patchy lung consolidation with
acute suppurative inflammation. Lesions are slightly elevated,
dry, granular, gray-red to yellow, and poorly delimited.
2.) Lobar Pneumonia fibrinosuppurative consolidation of a
large portion of a lobe or the entire lobe.
LOBAR PNEUMONIA
Four stages of the inflammatory response:
1.) Congestion
Lung is heavy, boddy, and red, with vascular engorgement.
Intra-alveolar fluid with few neutrophils and many bacteria.
2.) Red Hepatization
Massive confluent exudation, as neutrophils, red cells, and fibrin
fill the alveolar spaces.
Lobe is red, firm, and airless, with a liver-like consistency.
3.) Gray Hepatization
Marked by progressive disintegration of red cells.
Persistence of fibrinosuppurative exudate.
Grayish brown, dry surface, liver-like consistency.
4.) Resolution
Exudate within the alveolar spaces is broken down by enzymatic
digestion. It produces granular, semi-fluid debris, that is
reabsorbed, ingested by macrophages, expectorated, or
organized by fibroblasts.
Complications of Pneumonia
1.) Tissue destruction and necrosis leading to abscess formation
2.) Spread of infection to the pleural cavity, causing intrapleural
fibrinosuppurative reaction known as empyema.
3.) Organization of exudates
4.) Bacteremic Dissemination causing metastatic abscesses.
Community-Acquired Atypical Pneumonia
Atypical means moderate amount of sputum, no physical
findings of consolidation, only moderate leukocytosis, and lack of
alveolar exudate.
1.) Mycoplasma pneumoniae most common
2.) Viruses
3.) Chlamydia pneumanie
4.) Coxiella burnettii (Q Fever)
Morphology
Patchy pneumonic involvement may or may not involve whole
lobes bilaterally or unilaterally.
Microscopically:
Interstitial nature of inflammatory reaction.
Widened and edematous alveolar septa
Mononuclear inflammatory infiltrates
Pink hyaline membrane surrounding alveolar walls.
Page 14 of 20
1.) Influenza Infections
Influenza Type A is the major cause of pandemics and epidemics.
Most important viral virulence in lipid bilayer envelope:
Hemagglutinin 3 subtype (H1,H2,H3), attaches the virus to
its target via sialic acid residues.
Neuraminidase 2 subtypes (N1, N2), facilitates release of
newly formed virions budding from infected cells.
Spontaneous mutations that alter the hemagglutinin and
neuraminidase proteins:
Antigenic Drift causes new viral strains that elde a part of
the anti-influenza antibodies causing epidemics.
Antigenic Shift Both the proteins are replaced through
recombination w/ other influenza viruses causing pandemics.
ssRNA bound by nucleoproteins that determine the type (A,B,C).
Two mechanism of clearance of primary viral infections:
Cytotoxic T Cells Kills virus infected cells.
Mx1 Intracellular anti-influenza protein, encodes for a
GTPase that interferes with influenza gene transcription.
2.) Human Metapneumovirus (MPV)
Discovered in 2001, found worldwide associated with URTI/LRTI.
Commonly seen in children, elderly and immunocompromised
Can cause severe bronchiolitis and pneumonia.
3.) Severe Acute Respiratory Syndrome (SARS)
Caused by coronaviruses, it differs from other coronaviruses in
that it infected the LRT and spread throughout the body.
Incubation period of 2-10 days.
Clinical Manifestations:
Varies, masquerade as severe URTI or as chest colds.
Dry cough, malaise, fever and chills.
May improve and resolve or progress to severe respiratory
distress.
Mechanism of Transmission:
First transmitted to humans via contact with wild masked
palm civets and was spread from person to person via
respiratory secretions and some via stool.
Diagnosis is via PCR (viral detection) or detection of antibodies.
Health Care-Associated Pneumonia
Hospitalization of at least 2 days, presentation from nursing
home or long-term care facility.
Hospital or hemodialysis clinic.
Intravenous antibiotic therapy, chemotherapy, or wound care.
Most common are MRSA and Pseudomonas aeruginosa.
Hospital-Acquired Pneumonia
Acquired in the course of a hospital stay.
Common in patient with immunosuppression, prolonged
antibiotic therapy or invasive access devices.
Patients on mechanical ventilation are high risk.
Gram (+) cocci S. aureus, S. pneumoniae and Gram (-) bacilli
Enterobacteriaceae, Pseudomonas, are the most common.
Gram negative bacilli are more common.
Aspiration Pneumonia
Occurs markedly in debilitated patients or those who aspirate
gastric contents wither while unconscious or during repeated
vomiting.
Patients have abnormal gag and swallowing reflex.
Resultant pneumonia is partly chemical and bacterial.
More than one organism is recovered in cluture.
Often necrotizing, pursues a fulminant clinical course, lung
abscess is common in those who survive.
Microaspiration, occurs in almost all people, especially people
with GERD.
Results in non-necrotizing granuloma with multinucleated
foreign body giant cell reaction.
Lung Abscess
Pulmonary abscess describes a local suppurative process that
produces necrosis of lung tissue.
Etiology/Pathogenesis
Aerobic and anaerobic streptococci, S. aureus, and gram
negative organisms.
Anerobic organisms: Bacteroides, Fusobacterium, and
Peptococcus are present in 60% of cass.
Can be introduced via:
Aspiration of infective material most frequent cause.
Antecedent primary lung infection postpneumonic abscess
formations associated with S. aureus, K. pneumoniae, Type 3
pneumococcus.
Septic Embolism
Neoplasia
Miscellaneous direct penetration trauma
Morphology
Varies in diameter, few mm to large cavities 5-6vm.
May affect any part of the lungs, may be multiple or single.
Pulmonary abscess due to aspiration are more common on the
right due to vertical right main bronchi and more often single.
Cardinal histologic change is suppurative destruction of the lung
parenchyma within the central area of cavitation
Clinical Course
Cough, fever, copious amount of foul smelling purulent or
sanguineous sputum.
Complications:
Extension to the pleural cavity
Brain abscess or meningitis from septic emboli.
Secondary amyloidosis (Type AA)
Chronic Pneumonia
Most often localized lesion in immunocompromised patients, w/
or w/o lymph node involvement.
Typically inflammatory reaction is granulomatous caused by
bacteria or fungi.
Page 15 of 20
1.) Histoplasmosis
Caused by inhalation of dust particles from soil contaminated
with bird or bat drooping that contain microconidia of
Histoplasma capsulatum.
H. capsulatum is an intracellular pathogen found mainly in
phagocytes, clinical presentation resembles tuberculosis:
A self-limited and often latent primary pulmonary
involvement, coin lesions on CXR.
Chronic, Progressive, secondary lung disease localized to the
lung apices (fever, cough, night sweats).
Spread to extrapulmonary sites
Widely disseminated in immunocompromised
It produces granulomas which usually undergo caseation
necrosis and coalesce to produce large areas of consolidation,
but may also liquefy to form cavities (COPD patients).
Requires identification of 3-5m thin walled yeast forms.
Chronic histoplasmosis gray white granulomas in the lung
apices with pleural thickening and retraction and in hilar nodes.
Fulminant disseminated histoplasmosis occurs in
immunosuppressed individuals, no granuloma formation.
Diagnosis is established on culture or identification.
2.) Blastomycosis
Blastomyces dermatitidis a dimorphic fungi with 3 clinical forms:
a.) Pulmonary Blastomycosis
b.) Disseminated Blastomycosis
c.) Rare Cutaneous Infections
Pulmonary Blastomycosis
Most often presents as abrupt illness with productive cough,
headache, chest pain, weight loss, fever, abdominal pain,
nightsweats, chills, and anorexia.
CXR revelas lobar consolidation, multilobar and perihilar
infiltrates, multiple nodules, or miliary infiltrates.
Upper lobes are most frequently involved.
Lung lesions are suppurative granulomas, persistence of yeast
cells recruit neutrophils.
B. dermatitidis is a 5-10m yeast cell.
3.) Coccidioidomycosis
Develops type IV hypersensitivity upon spore inhalation.
C. immitis infective arthroconidia, when ingested by
macrophages, block fusion of phagosome and lysosome, and so
resists intracellular killing
Asymptomatic, but 10% develop lung lesions, accompanied by
erythema nodosum or multiforme.
Lung lesions are same to granulomatous lesions of Histoplasma.
Pneumonia in Immunocompromised Hosts Asbestos
Smoker 50 to 90x greater risk
Non-smoker 5x greater risk
Air Pollution
Radon
Molecular Genetics
Oncogenes: c-MYC, K-RAS, EGFR and HER-2/neu
Deleted or inactivated tumor suppressor genes: p53, RB
INK4a
p16 , multiple loci of chromosome 3p
CYP141

Precursor Lesions of Lung Cancer

1. Squamous dysplasia and carcinoma in situ
2. Atypical adenomatous hyperplasia
3. Adenocarcinoma in situ
4. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
Lung Transplantation
Indications include almost all non-neoplastic terminal lung WHO Histological Classification of Malignant Epithelial Lung Tumors
diseases, provided the patient has no other serious disease.
Most common indications are end-stage emphysema, idiopathic
pulmonary fibrosis, cystic fibrosis, pulmonary arterial
hypertension.
Complications of transfusion:
Pulmonary Infections bacterial infections are most
common in early post-transplant period.
Acute Rejections
Chronic Rejection associated with bronchiolitis obliterans

Tumors of the Lungs

Carcinomas (90-95%)
Bronchial Carcinoids (5%)
Mesenchymal & Miscellaneous neoplasms (2-5%) Squamous Cell Carcinoma (32% & 25%) - 20%
Small Cell Carcinoma (14% & 18%) - 14%
Risk Factors for Lung CA Adenocarcinoma (37% & 47%) - 38%
Tobacco smoking greater than 1200 substances Large cell carcinoma (18% and 10%) - 3%
80% of lung cancers occur in active smokers who stopped Others - 25%
recently
Initiators : polycyclic aromatic hydrocarbons As To Clinical Use: Two Groups of Lung Cancer
Promoters : phenol derivatives Small cell carcinoma
Radioactive elements : Po-210, C-14, K-40 Most often metastatic
Contaminants : arsenic, nickel, molds & additives High initial response to chemotherapy
Amount of daily smoking Non-small cell carcinoma
Average smokers 10x greater risk and heavy smokers (more Less often metastatic
than 40 cigars/day for several years) have 60 fold greater risk Less responsive
Tendency to inhale smoke Lung Carcinomas
Duration of smoking habit Most patients are in the 50s with symptoms of several months
Cessation of smoking for 10 years reduces risk but never to duration
control levels Cough (75%) Chest pain (40%)
Industrial Hazards Weight Loss (40%) Dyspnea (20%)
High dose ionizing radiation Most often found in the:
Uranium Periphery of the lungs more often adenocarcinoma
Cancer rates among nonsmoking uranium miners are 4x Central/Hilar region more often squamous cell carcinoma
higher than those in the general population, and among Periphery from the alveolar septal cells or terminal bronchioles
smoking miners, about 10x higher

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 Grossly appears as:
Irregular warty excrescence
Intraluminal mass
Cauliflower-like intra-parenchymal mass
Direct extensions are the pleural cavity and pericardium
Spread widely through the body at early stage except squamous
cell carcinoma
Distant spread: occurs through both lymphatic and
hematogenous pathways
Adrenals (50%) Brain (20%)
Liver (30-50%) Bone (20%)
Atypical Adenomatous Hyperplasia
Small lesion (<5 mm) characterized by dysplastic pneumocytes
lining the alveolar walls that are mildly fibrotic.
Can be single, multiple, can be in the lung adjacent to invasive
tumor or away from it.
Adenocarcinoma in situ
Formerly called bronchioloalveolar carcinoma
Less than 3 cm composed of entirely dysplastic cells growing
along pre-existing alveolar septae.
Mucinous or non-mucinous.
Adenocarcinoma
Most common type in women and non-smokers.
EFGR (15%), K-RAS mutation (30%)
p53, RB and p16 mutation and inactivation.
Microscopic findings:
Glandular differentiation
Patterns: nonmucinous, mucinous, lepidic, acinar, papillary,
solid, mucinous adenocarcinoma
Usually more peripherally located and tend to be smaller.
Grows more slowly than squamous cell carcinoma but tends to
metastasize widely and earlier.
Majority express thyroid transcription factor-1 (TTF-1)
Tumors <3 cm with a small invasive component <5mm is
associated with peripheral scarring and peripheral growth
pattern called microinvasive carcinoma.
At the periphery of the tumor, there is often a lepidic pattern
spread, in which tumor cells crawl along normal alveolar septa.
Grossly:
Peripheral portion
Single nodule or more often multiple diffuse nodules
(pneumonia like consolidation)
Nodules have mucinous, gray translucence when secretion
Squamous Cell Carcinoma
Most commonly found in men and smokers.
Often antedated by squamous metaplasia or dysplasia in
bronchial epithelium, then transforms to carcinoma in situ which
may last for years undetected and asymptomatic.
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Microscopic findings:
Keratinization and/or intercellular bridges in the form of
squamous pearls or individual cells with markedly
eosinophilic dense cytoplasm
Mitotic activity is higher in poorly differentiated tumors.
Most arise centrally from segmental/sub-segmental bronchi
Many genetic abberations are chromosome deletions.
Involves 3p, 9p (CDKN2A gene), and 17p (TP53 gene)
Highest frequency of TP53 mutations.
Loss of protein expression of the tumor suppressor gene RB
INK4
Inactivated CDK-inhibitor p16
Small Cell Carcinoma
Highly malignant, strongly related to smoking.
May arise in bronchi or lung periphery.
No known pre-invasive phase, most aggressive of lung tumors.
Most common pattern is associated with ectopic hormone production
Microscopic findings:
Small epithelial cells with scant cytoplasm, ill-defined cell
borders, salt and pepper pattern of chromatic, absent or
inconspicuous nucleoli.
Cells are round, ovoid or spindly and nuclear molding is prominent
High mitotic count
Exhibits neither glandular or squamous organization
Necrosis is common and often extensive.
Azzopardi effect, basophilic staining of vascular walls due to
encrustation by DNA, is often present.
Single variant: combined small cell carcinoma
Believed to arise from neuroendocrine progenitor cells of
bronchial epithelium
Secrete polypeptide hormones, parathyroid hormone like
and other hormonally active products
Neurosecretory granules (EM)
Presence of neuroendocrine markers such as
Chromogranin, synapthophysin and Leu-7 (75%)
Mutation: p53 (50-80%) and RB gene (80-100%)
Intense expression of BCL2 (90%) and low frequency of BAX
Large Cell Carcinoma
Undifferentiated malignant epithelial tumor that lacks cytologic
features of other lung cancer forms.
Large nuclei, prominent nucleoli, moderate cytoplasm amt.
LCC is a diagnosis of exclusion since it expresses none of the
markers associated with adenocarcinoma (TTF-1, Napsin A) and
squamous cell carcinoma (p63, p40),
Histological variant: Large Cell Neuroendocrine Carcinoma
Molecular features similar to small cell carcinoma.
Organoid nesting, trabecular, rosette & palisading patterns
Combined Carcinoma
Comprises 10% of cases
Combined histological features two or more patterns
Local Effects of Lung Tumor Spread Other systemic manifestations:
Pneumonia, abscess, lobar collapse Diaphragm paralysis Lambert Eaton Myasthenic Syndrome muscle weakness due to
Lipid pneumonia Rib destruction auto-antibodies directed to neuronal calcium channels.
Pleural effusion SVC syndrome Peripheral neuropathy purely sensory
Hoarseness Horner syndrome Acanthosis nigricans
Dysphagia Pericarditis, tamponade
Leukemoid reactions
Trosseau Syndrome hypercoagulable state (Migratory DVT)
New International Staging System for Lung Cancer (TNM Staging)
Hypertrophic pulmonary osteoarthropathy
T1 - <3cm without pleural or main stem bronchus involvement
Pancoast tumor tumor of the lung apices causing compression
T2 - >3cm or involvement of main stem bronchus 2cm from
of structures resulting to Horners Syndrome.
carina, visceral pleural involvement or lobar atelectasis
T3 involvement of chest wall (including superior sulcus
Neuroendocrine Proliferations and Tumors
tumors), diaphragm, mediastinal pleura, pericardium, main stem
Benign Tumorlets
bronchi 2cm from carina, or entire lung atelectasis
Hyperplasitc neuroendocirine cells seen in areas of scarring or
T4 invasion of mediastinum, heart, great vessels, trachea,
chronic inflammation
esophagus, vertebral body or carina with a malignant pleural
effusion
Carcinoid Tumors
N0 no demonstrable metastasis on regional lymph nodes 1-5% of all lung tumors, patients are younger than 40 y/o with
no sexual predilection, 20-40% are non-smokers.
N1 ipsilateral hilar or peribronchial node involvement
Low grade malignant epithelial neoplasm
N2 ipsilateral mediastinal or subcarinal lymph node metastasis
N3 metastasis to contralateral mediastinal or hilar nodes,
Clinical manifestation:
ipsilateral or contralateral scalene or supraclavicular nodes
Persistent cough, hemoptysis, impairment of drainage of
respiratory passages with secondary infections, bronchiectasis,
M0 no (known) distant metastasis
emphysema and atelectasis
M1 distant metastasis present
Classic Carcinoid Syndrome - intermittent attacks of diarrhea,
flushing, cyanosis.
Stage Grouping
Stage Ia: T1 N0 M0
Morphology
Stage Ib: T2 N0 M0
Central 3-4cm finger-like or spherical polypoid masses projecting
Stage IIa: T1 N1 M0
into the lumen of the bronchus covered by intact mucosa, collar
Stage IIb: T2 N1 M0 / T3 N0 M0
button lesion
Stage IIIa: T1-3 N2 N0 / T3 N1 M0
Peripherally it is solid and nodular
Stage IIIb: Any T N3 M0 / T3 N2 / M0 / T4 Any N M0
Organoid, trabecular, palisading, ribbon or rosette-like
Stage IV: Any T Any N M1
arrangement of cells separated by delicate fibrovascular stroma
Individual cells are regular with uniform round nuclei and
Overall 5 year survival rate: 15%
moderate amount of eosinophilic cytoplasm.
Bronchioalveolar CA non-invasive tumor, doesnt metastasize
Overall, do not have secretory activity, do not metastasize,
AdenoCA and SCCA - remain localize longer and slightly better
follow benign course and amenable to resectio
prognosis than undifferentiated CA
EM: dense core granules
Small cell CA sensitive to radio-chemotherapy and surgical
IHC: serotonin, neuron-specific enolase, bombesin, calcitonin
resection is ineffective
Subclassification:
Untreated cases survival rate: 6-17 weeks
Typical: <2 mitosis / 10HPF
With treatment survival rate: about 1 year
Atypical:
2-10 mitosis / 10 HPF and or foci of necrosis
Paraneoplastic Syndromes
More cellular atypia, increased cellularity, prominent
Lung CA can be assocaiated with these hormones, some of which
nucleoli, lymphatic invasion, disorganized architecture
may antedate the development of detectable lesion.
Survival rates:
ADH Hyponatremia due to SIADH
5 Years 10 Years
ACTH Cushing Syndrome
Typical 87% 87%
PTH, PTHRP, PGE2 Hypercalcemia
Calcitonin Hypocalcemia Atypical 56% 35%
Gonadotropin Gynecomastia Large Cell NE CA 27% 9%
5-HT and Bradykinin Carcinoid Syndrome Small cell CA 9% 5%

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Miscellaneous Tumors Pleura
Hamartoma Pleural involvement is most often secondary, important primary
<3 to 4cm in diameter with Coin lesion on CXR disorders include:
Chromosome aberration 6p21 or 12q14-15 Primary intrapleural bacterial infection
Nodules of connective tissue intersected by epithelial clefts Primary neoplasm (mesothelioma)
Epithelial clefts lined by ciliated or non-ciliated columnar epith.
Pleural effusion
Lymphangioleiomyomatosis No more than 15 ml of serous, relatively acellular, clear fluid
Affects young woman of childbearing age. lubricates the pleural surface. Accumulation occurs during:
Characterized by proliferation of perivascular epitheloid cells Increased hydrostatic pressure
that express markers for both melanocytes and smooth muscles. Increased vascular permeability
Proliferation distorts the involved lung, leading to cystic, Decreased osmotic pressure
emphysema-like dilation of terminal airspaces. Increased intrapleural negative pressure
Thickening of interstitium and obstruction of lymphatics. Decreased lymphatic drainage
Loss-of-function mutation of TSC2 gene.
Inflammatory Pleural Effusions
Inflammatory Myofibroblastic Tumor Serofibrinous pleuritis associated w/ inflammation of adjacent
Common in children, equal male to female ratio lung (e.g. Tuberculosis) or collagen vascular disease
Manifests as fever, cough, chest pain, hemoptysis Suppurative pleuritis (empyema) bacterial or mycotic seeding
Single (rarely multiple) round, well defined, usually peripheral Hemorrhagic pleuritic found in diastheses, rickettsia, tumors.
mass with calcium deposits on CXR.
Grossly appears as 3-10cm, grayish white, firm Non inflammatory Pleural Effusions
Histologically, proliferation of spindle shaped fibroblasts and Hydrothorax non-inflammatory collection of serous fluid in the
myofibroblasts, lymphocytes, plasma cells and peripheral fibrosis pleural cavity, most common cause is congestive heart failure.
Hemothorax escape of blood into the pleural cavity, a fatal
Mediastinal Tumors complication of aortic aneurysm or vascular trauma
Anterior Mediastinum Middle Mediastinum Chylothorax accumulation of milky fluid, usually of lympatic
Thymoma Bronchogenic cyst origin due to malignancies that obstruct the major lymph ducts.
Teratoma Pericardial cyst
Lymphoma Lymphoma Pneumothorax
Thyroid lesion
Refers to air or gas in the pleural cavities most commonly
Parathyroid tumor
Superior Mediastinum Posterior Mediastinum associated with emphysema, asthma and tuberculosis
Lymphoma Neurogenic tumor May be spontaneous, traumatic, or therapeutic.
Thymoma Lymphoma Spontaneous complicates any form of pulmonary disease
Thyroid lesions Gastroenteric hernia that causes rupture of an alveolus.
Metastatic carcinoma Traumatic caused by perforating injury.
Parathyroid tumors
Spontaneous idiopathic encountered in young people, due to
rupture of small, peripheral, apical subpleural blebs.
Metastatic Tumors
Tension pneumothorax permits entry but not the exit of air,
Lungs is the most common site of metastatic neoplasm. may compress mediastinal structures and the other lung.
Both carcinomas and sarcomas arising elsewhere may spread to
the lungs via blood or lymphatics.
Pleural Tumors
Growth of contiguous tumors in the lungs occurs most often
Most frequent metastatic malignancies originating from the
with esophageal carcinomas and mediastinal lymphomas.
lungs and breast

Morphology
Solitary (localized) fibrous tumor
Typical is multiple discrete nodules (cannonball lesion) scattered
Tumor is often attached to by a pedicle, may be small (1-2cm) or
throughout the lobes
may be large but remains confined to the lung surface.
Diffuse intralymphatic dissemination dispersed throughout the
Dense fibrous tissue with occasional cysts filled with viscid fluid
peribronchial and perivascular channels
Whorls of reticulin and collagen fibers among which are
interspersed spindle cells
Malignant variant: with pleomorphism, mitotic activity, necrosis,
large size (>10cm), CD34 (+) and keratin (-)

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Malignant mesothelioma
Rare, increased incidence among people exposed to asbestos.
Arise from either visceral or parietal pleura.
Asbestos bodies and asbestos plaques are present.
Cytogenetic studies show deletion in chromosome 1p, 3p, 6q, 9p
or 22q - 60 to 80%, low frequency of p53 mutation, SV40 viral
DNA sequences demonstrated in 60-80%.
Increased incidence among people with asbestos exposure
Lifetime risk: 7-10%, Long latent period: 25-45 years

Clinical manifestations
Chest pain, dyspnea, recurrent pleural effusions
Lung is invaded directly with metastatic spread to hilar lymph
nodes and eventually to liver and distant organs
50% die within 12months of diagnosis and few survive longer
than 2 years

Morphology
Lung is ensheated by a thick layer of soft, gelatinous, grayish pink
tumor tissues.
Two types of cells:
Epithelium like lining cells
Mesenchymal stromal cells
Epitheliod type mesothelioma (60%)
Cuboidal, columnar or flattened cells forming tubular or
papillary structures resembling adenocarcinoma.
(+) acid mucopolysaccharide
(-) CEA & other epithelial glycoprotein antigens
Strong (+) keratin with accentuation of perinuclear rather
than peripheral staining
(+) calretinin, Wilms tumor 1 susceptibility gene product,
cytokeratin 5/6, mesothelin, thrombomodulin
Long microvilli and abundant tonofilaments but absent
microvillous rootlets and lamellar bodies in electron
microscopy (golden standard for diagnosis)
Sarcomatoid type mesothemioma (20%)
Appears as Spindle Cell Sarcoma, resembling Fibrosarcoma.
Tend to have lower expression of many markers.
Mixed type mesothelioma (Biphasic type) (20%)
Contains both epitheloid and sarcomatoid pattern

The night is dark and full of terrors.

(Bantis zbrie issa se ossngnoti ldys.)

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