Chapter 15 – The Lung The Lung 3.

Vascular anomalies
4. Congenital lobar overinflation (emphysema)
1. Congenital Anomalies  Developmentally: outgrowth from the ventral wall of
5. Foregut cysts
the foregut
2. Atelectasis (Collapse) o Arise from an abnormal detachment of primitive
 Trachea develops two lateral outpocketings – the lung
foregut
3. Pulmonary Edema buds
o Most often located in the hilum or middle
 R lung = 3 lobes
4. Acute Lung Injury and Acute Respiratory Distress mediastinum
 L lung = 2 lobes
Syndrome (Diffuse Alveolar Damage) o Classified as bronchogenic (most common),
 Aspirated foreign materials tend to enter the right lung
esophageal, or enteric
a. ACUTE INTERSTITIAL PNEUMONIA  R main stem bronchus is more vertical and more
o LE: columnar epithelium with squamous
directly in line with the trachea
5. Obstructive versus Restrictive Pulmonary Diseases  Bronchial mucosa – contains neurosecretory-type
metaplasia
6. Congenital pulmonary airway malformation
6. Obstructive Pulmonary Diseases granules [serotonin, calcitonin, and gastrin-releasing
7. Pulmonary sequestrations
a. EMPHYSEMA peptide (bombesin)]
o Def: Presence of a discrete mass of lung tissue
 The entire respiratory tree (larynx, trachea, and
b. CHRONIC BRONCHITIS without normal connection to the airway system
bronchioles)  lined by pseudostratified, tall, columnar,
c. ASTHMA o Blood supply: aorta or its branches
ciliated epithelial cells
o Extralobar sequestrations  external to the
d. BRONCHIECTASIS  Microscopic structure of the alveolar walls
lung and may be located anywhere in the thorax
7. Chronic Diffuse Interstitial (Restrictive) Diseases o Capillary endothelium
or mediastinum
o Basement membrane and surrounding
a. FIBROSING DISEASES o Intralobar sequestrations  within the lung,
interstitial tissue
b. PULMONARY EOSINOPHILIA usually in older children and are often
o Alveolar epithelium
associated with recurrent localized infection or
c. SMOKING-RELATED INTERSTITIAL DISEASES o Alveolar macrophages
bronchiectasis
d. PULMONARY ALVEOLAR PROTEINOSIS
Alveolar epithelium
8. Diseases of Vascular Origin  A continuous layer of 2 cell types
a. PULMONARY EMBOLISM, HEMORRHAGE, AND  Type I pneumocytes - covering 95% of the alveolar 2. Atelectasis (Collapse)
INFARCTION surface  D/t incomplete expansion of the lungs (neonatal
b. PULMONARY HYPERTENSION  Type II pneumocytes atelectasis) or to the collapse of previously inflated
o Synthesize surfactant lung  producing airless pulmonary parenchyma
c. DIFFUSE PULMONARY HEMORRHAGE o Contained in osmiophilic lamellar bodies  May be divided into:
SYNDROMES o Involved in the repair of alveolar epithelium o Resorption (or obstruction)
9. Pulmonary Infections through their ability to give rise to type I cells o Compression
a. COMMUNITY-ACQUIRED ACUTE PNEUMONIAS o Contraction atelectasis
*Pores of Kohn - permit the passage of bacteria and
b. COMMUNITY-ACQUIRED ATYPICAL (VIRAL AND exudate between adjacent alveoli
Resorption atelectasis
MYCOPLASMAL) PNEUMONIAS  Consequence of complete airway obstruction
c. HOSPITAL-ACQUIRED PNEUMONIA
d. ASPIRATION PNEUMONIA 1. Congenital Anomalies  Leads to resorption of the oxygen trapped in the
dependent alveoli, without impairment of blood flow
Developmental defects of the lung include the following: through the affected alveolar walls
e. LUNG ABSCESS
1. Agenesis or hypoplasia of both lungs, one lung, or  Mediastinum shifts toward the atelectatic lung
f. CHRONIC PNEUMONIA single lobes  Caused principally by excessive secretions
g. PNEUMONIA IN THE IMMUNOCOMPROMISED o Decreased weight, volume, & acini  Most often found in: bronchial asthma, chronic
HOST disproportional to the body weight and bronchitis, bronchiectasis, postoperative states,
gestational age aspiration of foreign bodies, or bronchial neoplasm
h. PULMONARY DISEASE IN HUMAN
o Etiology: abnormalities that compress the
IMMUNODEFICIENCY VIRUS INFECTION lung(s) or impede normal lung expansion in Compression atelectasis
10. Lung Transplantation utero (congenital diaphragmatic hernia and  The pleural cavity is partially or completely filled by fluid
oligohydramnions) exudate, tumor, blood, tension pneumothorax
11. Tumors 2. Tracheal & bronchial anomalies (atresia, stenosis,  Mediastinum shifts away from the affected lung
12. Pleura tracheoesophageal fistula)

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Contraction atelectasis
 Occurs when local or generalized fibrotic changes in
the lung or pleura prevent full expansion
*Note: atelectasis is a reversible disorder (except that
caused by contraction)
Hemodynamic Pulmonary Edema
 *Increased hydrostatic pressure (Left sided heart failure)
- most common hemodynamic cause
 Gross: Heavy, wet lungs
o Fluid accumulates initially in the basal regions
of the lower lobes because hydrostatic pressure
is greater in these sites (dependent edema)
 Microscopic

3. Pulmonary Edema o
o
Engorged alveolar capillaries
(+) Intra-alveolar granular pink precipitate
 Result from hemodynamic disturbances or from direct o (+) Alveolar microhemorrhages and
increases in capillary permeability (microvascular hemosiderin-laden macrophages (“heart
injury) failure” cells)
 Long-standing cases (seen in mitral stenosis):
TABLE 15-1 -- Classification and Causes of Pulmonary o Abundant hemosiderin-laden macrophages
Edema o Fibrosis and thickening of the alveolar walls
o Soggy lungs becomes firm and brown (“brown
induration”)
 Predisposes to infection

Edema Caused by Microvascular Injury

 *Results from primary injury to the vascular endothelium
or damage to alveolar epithelial cells
 Direct increases in capillary permeability
 Leakage of fluids and proteins first into the interstitial
space & alveoli
 Edema is localized and overshadowed by the
manifestations of infection
 Contributor to ARDS
4. Acute Lung Injury and ARDS
(Diffuse Alveolar Damage)
 ALI – AKA: noncardiogenic pulmonary edema
 Abrupt onset of significant hypoxemia & diffuse
pulmonary infiltrates in the absence of cardiac failure
 ARDS – refers to severe ALI
 Both (ALI & ARDS) have inflammation-associated
increase in pulmonary vascular permeability
 Histologic feature: diffuse alveolar damage (DAD)
 Most etiologic factor: Sepsis
 Complication: Direct injuries to the lungs and systemic
disorders ( Table 15-2 )
TABLE 15-2 -- Conditions Associated with Development
of Acute Respiratory Distress Syndrome
Pathogenesis:
 Alveolar capillary membrane is formed by two separate
barriers: microvascular endothelium and the alveolar
epithelium
 In ARDS - lung injury is caused by an imbalance of pro-
inflammatory and anti-inflammatory mediators
o Nuclear factor κB (NF-κB) – has pro-
inflammatory effect
o IL-8, IL-1 and TNF - leads to:
 Endothelial activation
 Pulmonary microvascular sequestration
 Activation of neutrophils (*impt. role in
pathogenesis of ARDS)
 How is Neutrophil sequestered?
o Activated by IL-8
o TNF upregulate the expression of adhesion
molecules that allow them to bind to their
ligands on activated endothelial cells
o Activated neutrophils become “stiff” and less
deformable and thus get trapped in the narrow
capillary beds of the lung
o Activated neutrophils release a variety of
products (e.g., oxidants, proteases, platelet

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 activating factor, and leukotrienes) that cause
damage to the alveolar epithelium 5. Obstructive vs. 6. Obstructive Pulmonary
 Dysregulation of the coagulation system - also a feature
of ARDS
Restrictive Pulmonary Diseases Diseases
o *coagulation pathway is a powerful pro- Obstructive diseases: Restrictive diseases:
inflammatory signal - Increase in resistance to - Reduced expansion of lung
airflow due to partial or parenchyma and decreased
Morphology: complete obstruction at any total lung capacity
 ACUTE STAGE level  from the trachea
o GROSS: Heavy, firm, red & boggy and larger bronchi to the
o MICROSCOPIC: terminal and respiratory
 Congestion, interstitial & and intra-alveolar bronchioles
edema, inflammation, fibrin deposition, and ↓ forced expiratory volume ↓ total lung capacity
DAD at 1 second ↓/Normal expiratory flow
 Alveolar walls become lined with waxy rate
hyaline membrane
 ORGANIZING STAGE Restrictive defects occur in two general conditions:
o MICROSCOPIC: (1) Chest wall disorders
 Type II pneumocytes undergo proliferation  Poliomyelitis, severe obesity, pleural diseases, and
 (+) granulation tissue kyphoscoliosis
 Fibrotic thickening of alveolar septa - (2) Chronic interstitial & infiltrative diseases
caused by proliferation of interstitial cells  Pneumoconioses and interstitial fibrosis of unknown
and deposition of collagen etiology

Clinical Course FIGURE 15-5: Schematic representation of overlap between chronic

obstructive lung diseases.
 Clinical manifestations: Profound dyspnea and
tachypnea herald ALI, followed by increasing cyanosis
and hypoxemia, respiratory failure, and the appearance 1. EMPHYSEMA
of diffuse bilateral infiltrates on radiographic  Def: irreversible enlargement of the airspaces distal to
examination the terminal bronchiole, w/ destruction of their walls &
 Functional abnormalities in ALI are not evenly distributed without fibrosis
throughout the lungs  Incidence: heavy cigarette smoking, women and
 Majority of deaths are attributable to sepsis or multi- African Americans
organ failure and, in some cases, direct lung injury  Four major types:
o (1) centriacinar – 95% of cases
ACUTE INTERSTITIAL PNEUMONIA o (2) panacinar
o (3) paraseptal
 Term that is used to describe widespread ALI associated
o (4) irregular
with a rapidly progressive clinical course that is of
unknown etiology; AKA: idiopathic ALI-DAD
Clinical Course:
 Mean age of 50 years with no sex predilection
 C/M: Respiratory failure often following an illness of less  Manifestations appear until at least 1/3 of the
than 3 weeks' duration that resembles an URTI functioning pulmonary parenchyma is damaged
 Mortality rate: from 33-74%  Dyspnea is usually the first symptom
 Most deaths occurring within 1-2 months  Cough or wheezing is the chief complaint
 Weight loss is common and can be severe suggesting a
hidden malignant tumor
 Barrel-chested and dyspneic - sits forward in a
hunched-over position
 Severe emphysema may overventilate and remain well
oxygenated – called pink puffers

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1.] Centriacinar (Centrilobular) Emphysema
 Central or proximal parts of the acini, formed by
respiratory bronchioles, are affected & distal alveoli are
spared/normal
 More common & severe in the upper lobes (apical
segments)
 Occurs predominantly in heavy smokers, often in
association with chronic bronchitis
2.] Panacinar (Panlobular) Emphysema
 Acini are uniformly enlarged from the level of the
respiratory bronchiole to the terminal blind alveoli
 “pan” refers to the entire acinus but not to the entire
lung
 More common in the lower zones and in the anterior
margins of the lung
 Most severe at the bases
 Associated with α1-antitrypsin (α1-AT) deficiency
3.] Distal Acinar (Paraseptal) Emphysema
 The proximal portion of the acinus is normal, and 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
 More severe in the upper half of the lungs
 Findings: multiple, continuous, enlarged airspaces from
less than 0.5 cm to more than 2.0 cm in diameter
 Most cases of spontaneous pneumothorax in young
adults
4.] Airspace Enlargement w/ Fibrosis
(Irregular Emphysema)
 Associated with scarring
 Asymptomatic and clinically insignificant
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Pathogenesis: (+) Inflammation throughout the airways
Hypothesis: Destruction of alveolar walls is d/t the
protease antiprotease mechanism, aided and abetted by
imbalance of oxidants and antioxidants
 Protease – derived from neutrophils
 Anti protease (protective) - α1-antitrypsin (principal),
leukoprotease inhibitor & alpha-1 macroglobulin
 Thus, result from the destructive effect of high protease
activity in subjects with low antiprotease activity
Sequence:
1. Neutrophils (the principal source of cellular proteases)
are normally sequestered in peripheral capillaries,
including those in the lung, and gain access to the
alveolar spaces
2. Any stimulus that increases either the number of
leukocytes (neutrophils and macrophages) in the lung
or the release of their protease-containing granules
increases proteolytic activity
3. With low levels of serum α1-antitrypsin, elastic tissue
destruction is not checked and emphysema results
Protease-antiprotease imbalance:
Direct chemoattactant effect of nicotine to neutrophils and
macrophages that accumulate in alveoli
↓
Accumulated neutrophils are activated & release their
granules and smoking enhances elastase activity in
macrophages
↓ of septal walls
Proteases (neutrophil elastase, proteinase 3, and cathepsin
G, macrophage elastase, matrix metalloproteinases)
↓
TISSUE DAMAGE
Oxidant-antioxidant imbalance:
 Normally, the lung contains a healthy complement of
antioxidants (superoxide dismutase, glutathione)
that keep oxidative damage to a minimum
 Tobacco smoke contains abundant reactive oxygen
species (free radicals), which deplete antioxidant
mechanisms  tissue damage
o Oxidative injury causes inactivation of native
antiproteases  resulting in “functional” α1-
antitrypsin deficiency
Respiratory bronchioles to collapse during expiration –
causing airflow obstruction d/t:
 ↓ elastase: loss of elastic tissue in the walls of alveoli
(recoil)
 Inflammation on bronchioles < 2 mm in diameter are
seen in the ff. changes:
1. Goblet cell metaplasia with mucus plug
2. Inflammatory infiltration of the walls with
neutrophils, macrophages, B cells, CD4 and
CD8+ T cells
3. Thickening of the bronchiolar wall - due to
smooth muscle hypertrophy and peribronchial
fibrosis
Morphology:
 Large alveoli separated by thin septa
 Destruction of alveolar walls
 Respiratory bronchioles & vasculature are deformed &
compressed
Cause of Deaths:
(1) Respiratory acidosis & coma
(2) Right-sided heart failure
(3) Massive collapse of the lungs
Treatment:
 Bronchodilators, steroids, bullectomy & in some lung
volume reduction surgery & transplantation
Other forms of Emphysema:
Compensatory Hyperinflation (Emphysema)
 Used to designate dilation of alveoli but not destruction
 Lung parenchymal hyperexpansion that follows surgical
removal of a diseased lung or lobe
Obstructive Overinflation
 Lung expands because air is trapped within it
 Ex: tumor or foreign object, congenital lobar
overinflation
Bullous Emphysema*
 A large subpleural blebs or bullae (spaces >1 cm in
diameter)
 Most often subpleural & occur near the apex,
sometimes in relation to old tuberculous scarring
 May give rise to pneumothorax
Interstitial Emphysema
 Refers to the entrance of air into the connective tissue
stroma of the lung, mediastinum, or subcutaneous tissue
  Cigarette smoke predisposes to infection in different
ways:
o Interferes with ciliary action of the respiratory
epithelium
o Cause direct damage to airway epithelium
o Inhibits the ability of bronchial and alveolar
leukocytes to clear bacteria
Morphology:
 Gross: hyperemia, swelling, and edema of the mucous
membranes
 Microscopic:
o Chronic inflammation of the airways
(predominantly lymphocytes) and enlargement
of the mucus-secreting glands of the trachea
and bronchi
o Hyperplasia of mucus secreting glands – can be
assessed thru Reid index (normally 0.4)
o Bronchial epithelium exhibit squamous
metaplasia and dysplasia
2. CHRONIC BRONCHITIS o Bronchiolitis obliterans - narrowing of
 Persistent cough with sputum production for at least 3 bronchioles caused by mucus plugging,
months in at least 2 consecutive years, in the absence of inflammation, and fibrosis
any other identifiable cause
 When persistent for years, it may: Clinical Features:
(1) Progress to COPD  Cardinal symptom: persistent productive cough w/
(2) Lead to cor pulmonale and heart failure sputum
(3) Cause atypical metaplasia and dysplasia of the  Hypercapnia, Hypoxemia, and Mild cyanosis (“blue
respiratory epithelium, providing a rich soil for cancerous bloaters”)
transformation  Longstanding severe chronic bronchitis commonly leads
to cor pulmonale with cardiac failure
Pathogenesis:  Death may also result from further impairment of
 Initiating factor: long-standing irritation by inhaled respiratory function due to superimposed acute
substances such as tobacco smoke (90%), and dust infections
from grain, cotton, and silica
3. ASTHMA
 Hypersecretion of mucus in  Also a marked  Def: Chronic inflammatory disorder of the airways that
the large airways increase in causes recurrent episodes of wheezing, breathlessness,
Proteases from neutrophils goblet cells of chest tightness, and cough, particularly at night and/or
(neutrophil elastase, cathepsin, small airways in the early morning
and matrix metalloproteinases)  Hallmarks of the disease are:
stimulate mucus hypersecretion o Increased airway responsiveness
↓ o Episodic bronchoconstriction
Causing Hypertrophy of submucosal gland o Inflammation of the bronchial walls
 A protective reactions o Increased mucus secretion
↓  Status asthmaticus
Mucus secretion = sputum overproduction o State of unremitting attacks
o Fatal, usually in patients have had a long history
 Secondary role of infection - significant in maintaining it of asthma
and may be critical in producing acute exacerbations o Asymptomatic
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 Asthma is categorized into:
o Atopic (evidence of allergen sensitization, often
in a patient with a history of allergic rhinitis,
eczema)
o Non-atopic (without evidence of allergen
sensitization)
Atopic Asthma
 A classic example of type I IgE-mediated
hypersensitivity reaction
 Begins in childhood and is triggered by environmental
allergens
 Family history of asthma is common
 Skin test with the offending antigen in these patients
results in an immediate wheal-and-flare reaction
*Non-Atopic Asthma
 No evidence of allergen sensitization
 Skin test results are usually negative
 Family history of asthma is less common
 Respiratory infections due to viruses are common
triggers
 Lowers the threshold of the subepithelial vagal receptors
to irritants
Drug-Induced Asthma: Aspirin-sensitive asthma
 Are exquisitely sensitive to small doses of aspirin as well
as other nonsteroidal anti-inflammatory medications
 Also experience urticarial
 Inhibiting the cyclooxygenase pathway of arachidonic
acid metabolism  favoring bronchoconstrictor
leukotrienes
Pathogenesis:
 Initial sensitization to inhaled allergens stimulate
induction of TH2 cells which secrete cytokines that
promote allergic inflammation and stimulate B cells to
produce IgE and other antibodies that includes:
o IL-4 - stimulates the production of IgE
o IL-5 - activates locally recruited eosinophils
o IL-13 - stimulates mucus secretion and
promotes IgE production by B cells
 IgE coats submucosal mast cells and repeat exposure to
the allergen triggers the mast cells to release granule,
cytokines & other mediators
 Induce the early-phase (immediate hypersensitivity)
reaction
o Early phase mediators – Leukotrienes
C4,D4,E4, Prostaglandin D2, E2, F2-alpha,
Histamine, PAF, Mast cell trptase)
 o Dominated by bronchoconstriction, increased
mucus production, and variable degrees of
vasodilation with increased vascular
permeability
 Late-phase reaction - inflammation with recruitment of
leukocytes (eosinophils, neutrophils, & more T cells)
 Leukocyte recruitment is stimulated by chemokines
produced by mast cells, epithelial cells, T cells, and other
cytokines
o Ex: eotaxin, produced by airway epithelial cells,
a potent chemoattractant and activator of
eosinophils; “the major basic protein of
eosinophils”
Chemical Mediators:
Putative mediators – role in bronchospasm
 Leukotrienes C4,D4,E4: bronchoconstriction, increase
vascular permeability & mucus secretion
 Acetylcholine: from intrapulmonary motor nerves
causes airway smooth muscle constriction directly by
stimulating muscarinic receptors
Mediators at the “scene of crime” – role in acute asthma
effects
 Histamine: potent bronchoconstrictor
 PGD2: bronchoconstriction & vasodilation
 PAF: aggregation of platelets & release of histamine &
serotonin from their granules
“Suspects” – not studied yet
 IL-1, TNF, IL, chemokines (e.g., eotaxin), neuropeptides,
nitric oxide, bradykinin, and endothelins
“Airway remodeling” - repeated bouts of allergen
exposure result in structural changes in the bronchial wall:
 Hypertrophy & Hyperplasia of bronchial smooth muscle
 Epithelial injury
 Increased airway vascularity
 Increased subepithelial mucus gland
hypertrophy/hyperplasia
 Deposition of subepithelial collagen
Genetics of Asthma:
Multiple susceptibility genes interact with environmental
factors:
 Chr 5 polymorphism in the IL13 gene - strongest
and most consistent associations with asthma or allergic
disease
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 Class II HLA - tendency to produce IgE antibodies
against some (pollen) antigens
 ADAM-33 polymorphism - accelerate proliferation of
bronchial smooth muscle cells and fibroblasts, thus
contributing to bronchial hyperreactivity & fibrosis
 β2-adrenergic receptor gene - maps to 5q associated
with airway hyper-responsiveness
 IL-4 receptor gene - associated with atopy, elevated
total serum IgE, and asthma
 Chitinases are enzymes that cleave chitin
o acidic mammalian chitinase (w/ enzymatic
activity) - is up-regulated in and contributes to
TH2 inflammation
o YKL-40 (w/o enzymatic activity) - is associated
with severity of asthma
Morphology:
 Curschmann spirals - result either from mucus
plugging in subepithelial mucous gland ducts
 Eosinophils (neumerous)
 Charcot-Leyden crystals - collections of crystalloid
made up of an eosinophil lysophospholipase binding
protein called galectin-10
Clinical Course:
 Classic acute asthmatic attack lasts up to several hours
 Severe form – Status asthmaticus may lead to death
 With appropriate therapy, most patients are able to
maintain a productive life
4. BRONCHIECTASIS
 Def: Permanent dilation of bronchi and bronchioles
caused by destruction of the muscle and elastic tissue,
resulting from or associated with chronic necrotizing
infections
 Bronchiectasis develops in association with the
conditions:
o Congenital or hereditary conditions: cystic
fibrosis, intralobar sequestration of the lung,
immunodeficiency states and primary ciliary
dyskinesia and Kartagener syndromes
o Postinfectious conditions: necrotizing
pneumonia caused by bacteria (Mycobacterium
tuberculosis, Staphylococcus aureus,
Haemophilus influenzae, Pseudomonas), viruses
(adenovirus, influenza virus, human
immunodeficiency virus [HIV]), and fungi
(Aspergillus species)
o Bronchial obstruction
o Other conditions: RA, SLE, inflammatory
bowel disease, and post-transplantation
Morphology:
 Affects the lower lobes bilaterally
 Most severe in the more distal bronchi and bronchioles
 Airways are dilated, sometimes up to 4x the normal size
Histologic findings vary with the activity and chronicity of the
disease:
 There is an intense acute and chronic inflammatory
exudation within the walls of the bronchi and bronchioles
 With desquamation of the lining epithelium and
extensive areas of necrotizing ulceration
 Necrotizing ulceration  lead to lung abscess
 Develop fibrosis
Etiology and Pathogenesis:
 Infection and Obstruction - conditions associated with
bronchiectasis; seen in cystic fibrosis
 OBSTRUCTION - accumulation of thick viscid secretions
that obstruct the airways
 INFECTION – increase susceptibility
 Destruction of supporting smooth muscle and elastic
tissue, fibrosis, and further dilatation of bronchi.
 The smaller bronchioles become progressively
obliterated as a result of fibrosis (bronchiolitis obliterans)
Other conditions:
 Primary ciliary dyskinesia – AR; poorly functioning
cilia contribute to the retention of secretions; absence or
shortening of the dynein arms that are responsible for
the coordinated bending of the cilia
o ½ have Kartagener syndrome (bronchiectasis,
sinusitis, & situs inversus or partial lateralizing
abnormality)
o Males – tend to be infertile
 Allergic bronchopulmonary aspergillosis - high
serum IgE levels
Clinical course:
 Severe, persistent cough; Expectoration of foul-smelling,
sometimes bloody sputum
 Dyspnea and Orthopnea; Hemoptysis; Fever
 Symptoms often precipitated by URTI
 Obstructive respiratory insufficiency can lead to
marked dyspnea and cyanosis
 Complications: Cor pulmonale, brain abscesses, and
amyloidosis
7. Chronic Diffuse Interstitial
(Restrictive) Diseases
 Characterized predominantly by inflammation and
fibrosis of the pulmonary connective tissue, principally
the most peripheral and delicate interstitium in the
alveolar walls
 Reduced expansion of lung parenchyma & decreased
total lung capacity
 C/M: dyspnea, tachypnea, end-inspiratory crackles, and
eventual cyanosis, without wheezing
 CXR: bilateral infiltrative lesions in the form of small
nodules, irregular lines, or ground-glass shadows, hence
the term infiltrative
 Eventually, secondary pulmonary hypertension and
right-sided heart failure with cor pulmonale may result
 Advanced forms: scarring and gross destruction of the
lung  referred to as end-stage lung or honeycomb lung
Restrictive Diseases – 2 general conditions:
 Chest wall disorders
o Neuromuscular diseases like poliomyelitis
o Severe obesity
o Pleural diseases
o Kyphoscoliosis
 Chronic interstitial & infiltrative diseases
A.] FIBROSING DISEASES:
1. Pulmonary Fibrosis (IPF)
 AKA: cryptogenic fibrosing alveolitis
 Histologic pattern: usual interstitial pneumonia (UIP)
Pathogenesis:
 The current concept is that IPF is caused by “repeated
cycles” of epithelial activation/injury by some
unidentified agent
 There is inflammation and induction of T H2 cell,
characterized by the presence of eosinophils, mast cells,
IL-4 and IL-13
 Abnormal epithelial repair gives rise to exuberant
fibroblastic/myofibroblastic proliferation, leading to the
“fibroblastic foci” particularly TGF-β1 as the driver of the
process
o TGF-β1 is known to be fibrogenic and is released
from injured type I alveolar epithelial cells
o TGF-β1 negatively regulates telomerase activity,
thus facilitating epithelial cell apoptosis and the
cycle of death and repair
o Another molecule regulated by TGF-β1 is
caveolin-1
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 Caveolin-1 acts as an endogenous
inhibitor of pulmonary fibrosis by

limiting TGF-β1
Caveolin-1 is decreased in IPF, which
inhibits collagen deposition
Morphology:
 The hallmark of UIP is patchy interstitial fibrosis
 Fibrosis causes the destruction of alveolar architecture
and formation of cystic spaces lined by hyperplastic type
II pneumocytes or bronchiolar epithelium (honeycomb
fibrosis)
 Mild to moderate inflammation within the fibrotic areas,
consisting: lymphocytes (mostly), and a few plasma
cells, neutrophils, eosinophils, mast cells
 Foci of squamous metaplasia and smooth muscle
hyperplasia
 Pulmonary arterial hypertensive changes (intimal fibrosis
and medial thickening)
Clinical Course:
 Increasing dyspnea on exertion and dry cough
 40 to 70 years old at the time of presentation
 Late course: Hypoxemia, cyanosis, and clubbing
 Mean survival: <3 years
2. Nonspecific Interstitial Pneumonia (NSIP)
 Dyspnea and cough of several months' duration
 Between 46-55 years of age
 Diffuse interstitial lung disease of unknown etiology
 Better prognosis than UIP
Morphology:
 Cellular pattern - mild to moderate chronic interstitial
inflammation in a uniform or patchy distribution
 Fibrosing pattern - diffuse or patchy interstitial fibrosis
without the temporal heterogeneity that is characteristic
of UIP
 (-) fibroblastic foci and honeycombing
3. Cryptogenic Organizing Pneumonia
 Def: with cough and dyspnea and have subpleural or
peribronchial patchy areas of airspace consolidation
radiographically
 Histologically:
o (+) polypoid plugs of loose organizing
connective tissue (Masson bodies) within
alveolar ducts, alveoli & bronchioles
o (-) interstitial fibrosis or honeycomb lung
4. Pulmonary Involvement in Connective Tissue
Diseases
 Rheumatoid arthritis: pulmonary involvement may
occur in 30% to 40% of patients as
o (1) chronic pleuritis, with or without effusion;
o (2) diffuse interstitial pneumonitis and fibrosis;
o (3) intrapulmonary rheumatoid nodules;
o (4) pulmonary hypertension
 Systemic sclerosis (scleroderma): diffuse interstitial
fibrosis
 Lupus erythematosus: patchy, transient parenchymal
infiltrates
5. Pneumoconioses
 Def: A non-neoplastic lung reaction to inhalation of
mineral dusts encountered in the workplace, especially in
urban areas
Pathogenesis: development of pneumoconiosis depends on
(1) Amount of dust retained in the lung and airways;
(2) Size, shape, and therefore buoyancy of the particles;
(3) Particle solubility and physiochemical reactivity;
(4) Additional effects of other irritants (tobacco smoking)
 The most dangerous particles range from 1 to 5 μm in  Within the macrophages silica causes activation and
diameter because they may reach the terminal small release of mediators (IL-1, TNF, fibronectin, lipid
airways and air sacs and settle in their linings mediators, oxygen-derived free radicals, and fibrogenic
 Solubility and Cytotoxicity of particles - modify the cytokines)
nature of the pulmonary response
o The smaller the particle, the more likely it is to Morphology
appear in the pulmonary fluids and reach toxic Gross:
levels rapidly  Early stage: tiny, barely palpable, discrete pale to
 Some Lung Diseases Caused by Air Pollutants: blackened nodules which coalesce into hard, collagenous
1. Coal Workers' Pneumoconiosis scars
2. Silicosis  Central softening & cavitation – d/t superimposed TB or
3. Asbestos-Related Diseases ischemia
 Fibrotic lesions in the hilar lymph nodes and pleura –
with eggshell calcification visible on X-ray
5.1. Coal Workers' Pneumoconiosis (CWP)  expansion and coalescence of lesions may produce
Spectrum of lung findings:
progressive massive fibrosis
(1) Asymptomatic anthracosis
(2) Simple CWP with little or no pulmonary dysfunction
Microscopic features:
(3) Complicated CWP, or progressive massive fibrosis (PMF)
 layers of hyalinized collagen surrounded by a dense
capsule of more condensed collagen
Morphology
 On polarized microscopy: a birefringent silica particles
 Anthracosis - most innocuous coal-induced pulmonary
lesion
Clinical Course
 Simple CWP - upper lobes and upper zones of the lower
 Slow to kill, with impaired pulmonary function
lobes are more heavily involved; primarily adjacent to
 Increased susceptibility to TB
respiratory bronchioles; characterized by:
o coal macules (1 to 2 mm in diameter) -
consists of carbon-laden macrophages 5.3. Asbestos-Related Diseases
Occupational exposure to asbestos is linked to:
o coal nodules - consists collagen fibers
 Localized fibrous plaques or, rarely, diffuse pleural
o centrilobular emphysema - dilation of
fibrosis
adjacent alveoli
 Pleural effusions
 Complicated CWP (progressive massive fibrosis)
 Parenchymal interstitial fibrosis (asbestosis)
o Multiple intensely blackened scars (2-10 cm)
o Microscopic: lesions consist of dense collagen  Lung carcinoma
and pigment; center of the lesion is often  Mesotheliomas
 Laryngeal & other extrapulmonary neoplasms, including
necrotic, most likely due to local ischemia
colon carcinomas
5.2. Silicosis
 Inhalation of crystalline silicon dioxide (silica)
Pathogenesis:
 Silicosis usually presents after decades of exposure as a
slowly progressing, nodular, fibrosing pneumoconiosis  2 distinct forms: serpentine and amphibole
 Acute silicosis - a disorder characterized by the Serpentine chrysotile - Amphiboles - more
chemical form accounts for pathogenic in induction of
accumulation of abundant lipoproteinaceous material
within alveoli most of the asbestos used malignant pleural tumors
(mesotheliomas)
more flexible, curled pathogenicity of amphiboles
Pathogenesis
structure, are likely to is apparently related to their
 Silica occurs in both crystalline and amorphous forms,
become impacted in the aerodynamic properties and
but crystalline forms (including quartz, crystobalite, and
upper respiratory passages solubility
tridymite) are much more fibrogenic
and removed by the
o quartz is most commonly implicated in silicosis
mucociliary elevator
 After inhalation, the particles interact with epithelial cells
More soluble Align themselves in the
and macrophages
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airstream to be delivered
deeper into the lungs
Both are fibrogenic, and increasing doses are associated with
a higher incidence
 Also act as a tumor initiator and promoter mediated by
reactive free radicals
Morphology
 Marked by diffuse pulmonary interstitial fibrosis
 Presence of multiple asbestos bodies
o Appear as golden brown, fusiform or beaded
rods with a translucent center and consist of
asbestos fibers coated with an iron-containing
proteinaceous material
 Ferruginous bodies
 Begins as fibrosis around respiratory bronchioles and
alveolar ducts
 (+) honeycombed
 Begins in the lower lobes and subpleurally
 Middle and upper lobes of the lungs become affected as
fibrosis progresses
 The scarring may trap and narrow pulmonary arteries
and arterioles, causing pulmonary HPN and cor
pulmonale
 Pleural plaques - most common manifestation of
asbestos exposure
o well-circumscribed plaques of dense collagen
often calcium
o develop most frequently on the anterior and
posterolateral aspects of the parietal pleura
and diaphragm
 Both lung carcinomas and mesotheliomas (pleural and
peritoneal) develop in workers exposed to asbestos
o lung carcinoma (5x risk) & mesotheliomas
(1000x)
o smoking increase risk of carcinoma but NOT
mesotheliomas
Drug-Induced Lung Diseases
Radiation-Induced Lung Diseases
 Acute Radiation Pneumonitis
o 1-6 months after therapy
o C/M: Fever, dyspnea, pleural effusion, radiologic
infiltrates
 Chronic Radiation Pneumonitis
o AKA: Pulmonary fibrosis
o a consequence of the repair of injured
endothelial and epithelial cells within the
radiation portal

B.] GRANULOMATOUS DISEASES
1. Sarcoidosis
 Systemic disease of UNKNOWN cause
 NONCASEATING granulomas
 C/M:
o Bilateral hilar lymphadenopathy or lung
involvement
o Eye & skin lesions
Etiology and Pathogenesis:
Immunological Factors
 Intra-alveolar and interstitial accumulation of CD4+ T
cells, resulting in CD4/CD8 T-cell ratios ranging from 5 :
1 to 15 : 1
 Increased levels of T cell–derived T H1 cytokines such as
IL-2 and IFN-γ
 Increased levels of several cytokines in the local
environment (IL-8, TNF, macrophage inflammatory
protein 1α) that favor recruitment of additional T cells
and monocytes
Systemic immunological abnormalities
 Anergy to common skin test antigens such as Candida or
tuberculosis purified protein derivative (PPD)
 Polyclonal hypergammaglobulinemia, another
manifestation of helper T-cell dysregulation
Genetic Factors
 Familial and racial clustering of cases
 Association with certain HLA genotypes
o (class I HLA-A1 and HLA-B8)
Environmental Factors
 Proposed putative microbes: Mycobacteria,
Propionibacterium acnes & Rickettsia species
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 There is no unequivocal evidence that sarcoidosis is 2. Hypersensitivity Pneumonitis (HP)
caused by an infectious agent  Def: immunologically mediated predominantly
interstitial, lung disorders in response to intrinsic Ag-
Morphology: immune complex & delayed type of hypersensitivity.
Lungs  common site  Caused by intense, prolonged exposure to inhaled
 Gross: NO demonstrable abnormality or small nodules organic antigens (made up of spores of thermophilic
(1-2cm), noncaseating, noncavitated granulomas bacteria, true fungi, animal proteins, or bacterial
 Microscopic: lesions are distributed primarily along the products)
lymphatics, around bronchi & vessels, although alveolar  Involves primarily the alveoli – progressing to chronic
lesions may be seen FIBROTIC lung disease
 Bronchial lavage: CD4/CD8 ration (>2.5) & CD3/CD4
ration (<0.31) Types of Hypersensitivity Pneumonitis
 Farmer’s Lung: dusts from hay with spores of
Lymph nodes actinomycetes
 Involved in almost all cases specifically hilar &  Pigeon breeder's lung (bird fancier's disease): caused
mediastinal lymph nodes by proteins from serum, excreta, or feathers of birds
 Humidifier or air-conditioner lung: caused by
Others: thermophilic bacteria in heated water reservoirs
 Spleen
 Liver HP is an immunologically mediated disease
 Bone Marrow  Bronchoalveolar lavage (BAL) in acute phase - show
 Skin increased levels of proinflammatory chemokines such as
 Eyes (iritis, iridiocystitis) & salivary glands macrophage inflammatory protein 1α and IL-8
 Muscle involvement  BAL consistently demonstrate increased numbers of T
lymphocytes of both CD4+ and CD8+
NON CASEATING granulomas  Most patients have specific antibodies in their serum, a
 Aggregate of tightly clustered epitheliod cells, often with feature that is suggestive of type III (immune complex)
Langhans or Foreign body type giant cells with unusual hypersensitivity
central necrosis  Complement and Ig present within vessel walls by
 Granulomas may become enclosed by fibrous rims or immunofluorescence indicating a type III
replaced by hyaline fibrous scars hypersensitivity
 Schaumann bodies - laminated concretions composed  2/3 of noncaseating granulomas - suggests the
of calcium and proteins development of a T cell–mediated (type IV)
 Asteroid bodies - stellate inclusions enclosed within
giant cells Morphology (centered on bronchioles)
 interstitial pneumonitis consisting primarily of
Clinical Course: lymphocytes, plasma cells, and macrophages
Follows an unpredictable course  noncaseating granulomas in 2/3 of patients
 65% - 70% of affected patients recover with minimal  interstitial fibrosis, honeycombing, and obliterative
or no residual manifestations bronchiolitis (in late stages)
 20% - have permanent loss of some lung function or  >1/2 patients have intra-alveolar infiltrates
some permanent visual impairment
 10% - 15%, some die of cardiac or central nervous Clinical Features:
system damage, but most succumb to progressive  Symptoms usually appear 4 to 6 hours after exposure
pulmonary fibrosis and cor pulmonale  Acute attacks: consist of recurring episodes of fever,
dyspnea, cough, and leukocytosis
 If exposure is continuous and protracted:
o progressive respiratory failure, dyspnea, and
cyanosis
o decrease in total lung capacity and compliance
C.] PULMONARY EOSINOPHILIA
 Eosinophils - recruited by IL-5
 Divided into the following categories:
Acute eosinophilic pneumonia with respiratory failure
 acute illness of unknown cause
 has a rapid onset with fever, dyspnea, and hypoxemic
respiratory failure
 CXR: diffuse infiltrates
 BAL fluid contains > 25% eosinophils
Simple pulmonary eosinophilia or Löffler syndrome
 transient pulmonary lesions, eosinophilia in the blood,
and a benign clinical course
 CXR: shadows of varying size and shape in any of the
lobes
 Microscopic: alveolar septa are thickened by an infiltrate
composed of eosinophils and occasional interspersed
giant cells
o NO vasculitis, fibrosis, or necrosis
Secondary eosinophilia - occurs in a:
 number of parasitic, fungal, and bacterial infections
 hypersensitivity pneumonitis
 drug allergies
 in association with asthma, allergic bronchopulmonary
aspergillosis, or vasculitis
Chronic eosinophilic pneumonia/ Idiopathic
 focal areas of cellular consolidation of the lung substance
distributed chiefly in the periphery of the lung fields
 heavy aggregates of lymphocytes and eosinophils within
both the septal walls and the alveolar spaces
 C/M: high fever, night sweats, and dyspnea which
respond to corticosteroid therapy
Tropical eosinophilia
 caused by infection with microfilariae
D.] SMOKING-RELATED INTERSTITIAL DSES.
 Grouped into: obstructive diseases and restrictive or
interstitial diseases
 2 ends of smoking-associated interstitial lung diseases:
1. Desquamative interstitial pneumonia (DIP)
2. Respiratory bronchiolitis-associated interstitial
lung disease
1. Desquamative Interstitial Pneumonia (DIP)
 40-50 y/o, Men > women: 4 : 1 ratio
 Found in Cigarette smokers
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 C/M: insidious onset of dyspnea and dry cough over
weeks or months, often associated with clubbing of digits
 good prognosis & excellent response to steroid
Morphology:
 Most striking histologic finding: accumulation of a large
number of macrophages with abundant cytoplasm
containing dusty brown pigment (smokers'
macrophages)
 Some of the macrophages contain lamellar bodies
(composed of surfactant)
o Derived from necrotic type II pneumocytes
 Thickened alveolar septa with sparse inflammatory
infiltrate of lymphocytes & plasma cells
o Septa lined by cuboidal pneumocytes
 Interstitial fibrosis & emphysema may be present
2. Respiratory Bronchiolitis-Associated Interstitial
Lung Disease
 Found in cigarette smokers
 Presence of pigmented intraluminal macrophages within
first- and second-order respiratory bronchioles
 Dyspnea and cough at 40-50 y/o over 30 pack-years of
cigarette smoking
 2 : 1 male predominance?
Morphology:
 Changes are patchy at low magnification and have a
bronchiolocentric distribution
 contain aggregates of dusty brown macrophages
(smokers' macrophages)
 patchy submucosal and peribronchiolar infiltrate of
lymphocytes and histiocytes
 Centrilobular emphysema - common but NOT severe
E.] PULMONARY ALVEOLAR PROTEINOSIS
 Bilateral patchy asymmetric pulmonary opacifications
 & accumulation of acellular surfactant in the intra-
alveolar and bronchiolar spaces
Acquired PAP
 90% of all cases, unknown etiology without any familial
predisposition
 Considered as autoimmune disorder
 Anti–GM-CSF antibody is responsible for the
development of the disease - antibodies inhibit the
activity of endogenous GM-CSF, leading to a state of
functional GM-CSF deficiency
o Normally, GM-CSF – involves in surfactant
clearance by alveolar macrophage
Congenital PAP
 Rare cause of immediate-onset neonatal respiratory
distress on a full term with death ensuing at 3-6 months
 Associated with mutations in the multiple genes:
o ATP-binding cassette protein member A3
(ABCA3)
o Surfactant protein B (SP-B) – transmitted AR d/t
homozygosity for a frameshift mutation in the
SP-B gene
o Surfactant protein C (SP-C)
o GM-CSF
o GM receptor (GM-CSF/IL-3/IL-5) β chain
Secondary PAP
 Is uncommon
 Causes: hematopoietic disorders, malignancies,
immunodeficiency disorders, lysinuric protein
intolerance, and acute silicosis and other inhalational
syndromes
Morphology:
 Characterized by a peculiar homogeneous, granular
precipitate within the alveoli
 Causing a focal-to-confluent consolidation of large areas
of the lungs with minimal inflammatory reaction
 Cut surface: turbid fluid exudes with marked increase in
the size and weight of the lung
 Alveolar precipitate is PAS positive and also contains
cholesterol clefts
 Immunohistochemical stains: show the presence of
surfactant proteins A and C
 Abnormalities in lamellar bodies in type II pneumocytes
can be seen in mutations of SP-B, SP-C, and ABCA3
8. Diseases of Vascular Origin
A.] PULMONARY EMBOLISM, HEMORRHAGE, &
INFARCTION
 Almost always EMBOLIC in origin – >95% arise from
thrombi within the large deep veins of the lower legs
 Risk factors:
o Cardiac disease, Cancer, Immobilization,
Hypercoagulable states
 Pathophysiologic response and clinical significance of
pulmonary embolism depends on:
1. extent to which the pulmonary artery blood flow
is obstructed
2. size of the occluded vessel(s)
 3. number of emboli
4. overall status of the cardiovascular system
5. the release of vasoactive factors like
thromboxane A2 from platelets
 Emboli result in 2 main pathophysiologic consequences:
o Respiratory compromise due to the
nonperfused although ventilated segment
o Hemodynamic compromise due to increased
resistance to pulmonary blood flow w/c leads to
pulmonary HPN & R-sided HF
2.] PULMONARY HYPERTENSION (PH)
 Def: occurs when mean pulmonary pressure reaches ¼
of systemic levels – most frequently secondary to
structural cardiopulmonary conditions that increase
pulmonary blood flow or pressure resistance; These
include the following:
 Obstruction of vasculature caused by proliferation of
endothelial S.M., muscle cell & intimal cells accompanied
by concentric laminar intimal fibrosis
Chronic obstructive or interstitial lung diseases:
 Have hypoxia, destruction of lung parenchyma & fewer
alveolar capillaries. This causes increased pulmonary
arterial resistance & elevated pressure
Antecedent congenital or acquired heart disease:
 Occurs w/ mitral stenosis, because of an increase in left
atrial pressure that ↑ pulmonary venous pressure and
pulmonary artery pressure
Autoimmune disorders:
 Due to a reduction in the functional cross-sectional area
of the pulmonary vascular bed brought about by the
obstructing emboli
Connective tissue diseases:
 Most notably systemic sclerosis
Obstructive sleep apnea:
 Associated with obesity
PRIMARY PULMONARY HPN - encountered sporadically in
patients in whom all known causes of increased pulmonary
pressure are excluded
 Mutation in bone morphogenic protein receptor type 2
(BMPR2) signaling pathway
o In vascular s.m. cells BMPR2 signaling causes
inhibition of proliferation and favors apoptosis
 Inactivating BMPR2 causes smooth muscle proliferation
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SECONDARY PULMONARY HPN causes:
 Endothelial cell dysfunction
 Increased shear and mechanical injury associated with
left-to-right shunts or the biochemical injury produced
by fibrin in thromboembolism
 ↓ prostacyclin & nitric oxide + ↑ endothelin =
vasoconstriction
 Endothelial activation makes endothelial cells
thrombogenic and promotes the persistence of fibrin
 Release of GF & cytokines induce the migration &
replication of vascular smooth muscle cells & elaboration
of extracellular matrix
Other causes of pulmonary arterial HPN:
 Crotalaria spectabilis - used medicinally in bush tea
 Aminorex - appetite depressant
 Adulterated olive oil
 Fenfluramine and phentermine - anti-obesity drugs
Morphology:
 The vessel changes can involve the entire arterial tree,
from the main pulmonary arteries down to the arterioles
o Atherosclerosis
o Medial hypertrophy & intimal fibrosis*
o Plexogenic pulmonary arteriopathy – tuft of
capillary formation is present producing a
network of web that spans the lumen of dilated
thin, walled, small arteries
Clinical Course:
 Idiopathic PH - most common in women 20-40 y/o
 Clinical signs and symptoms of all forms of hypertension
become evident only with advanced disease
 Initially, the presenting features: dyspnea and fatigue,
chest pain
 Over time, severe respiratory distress, cyanosis, and
right ventricular hypertrophy occur, and death from
decompensated cor pulmonale, often with superimposed
thromboembolism and pneumonia, within 2 to 5 years in
80% of patients
C.] DIFFUSE PULMONARY HEMORRHAGE
SYNDROMES
Includes:
 Goodpasture syndrome
 Idiopathic pulmonary hemosiderosis
 Vasculitis-associated hemorrhage, found in:
o Hypersensitivity angiitis
o Wegener granulomatosis
o SLE
1. Goodpasture Syndrome
 autoimmune disease of kidney and lung injury
 caused by circulating autoantibodies against the
noncollagenous domain of the α3 chain of collagen IV
 antibodies initiate inflammatory destruction of the
basement membrane in renal glomeruli and pulmonary
alveoli
 occur in the teens or 20s; male preponderance
 Pathogenesis: genetic predisposition is associated with
certain HLA subtypes (e.g., HLA-DRB1*1501 and *1502)
Morphology:
 proliferative, usually rapidly progressive
glomerulonephritis and a necrotizing hemorrhagic
interstitial pneumonitis
 Characteristic findings in kidney:
o Early: focal proliferative glomerulonephritis
o Progeressive: crescentic glomerulonephritis
 reveal linear deposits of immunoglobulins along the
basement membranes of the septal walls
Clinical Features:
 Uremia - most common cause of death
 Prognosis for this disease - improved by intensive
plasmapheresis
2. Idiopathic Pulmonary Hemosiderosis
 characterized by intermittent, diffuse alveolar
hemorrhage
 usually presents with an insidious onset of productive
cough, hemoptysis, anemia, and weight loss
 no anti–basement membrane antibodies
 *Cardinal histologic feature: hemorrhage into the
alveolar spaces & hemosisderosis
3. Wegener Granulomatosis
 most often involves the upper respiratory tract
 transbronchial lung biopsy - provide the only tissue
available for diagnosis
 (-) necrosis and granulomatous vasculitis
 *Important features: capillaritis and scattered,
poorly formed granulomas (unlike those of
sarcoidosis, which are rounded and well-defined)
Pulmonary Infections o Typically, the encapsulated form dominates the lobular lobar pneumonia
unencapsulated forms by secreting an antibiotic bronchopneumonia
1) COMMUNITY-ACQUIRED ACUTE PNEUMONIAS called haemocin that kills the unencapsulated H. -Patchy consolidation of the - fibrinosuppurative
2) COMMUNITY-ACQUIRED ATYPICAL (VIRAL AND influenza lung consolidation of a large
MYCOPLASMAL) PNEUMONIAS  *Type b (encapsulated) - has a polyribosephosphate - lobe with focal opacities portion of a lobe or of an
3) HOSPITAL-ACQUIRED PNEUMONIA capsule, used to be the most frequent cause of severe -4 stages of inflammatory entire lobe
invasive disease response: congestion, red - lobe is radiopaque
4) ASPIRATION PNEUMONIA  Nonencapsulated/ nontypeable forms – spreads in hepatization, gray
5) LUNG ABSCESS URT & produce otitis media (infection of the middle ear), hepatization, and resolution
6) CHRONIC PNEUMONIA sinusitis, and bronchopneumonia
7) PNEUMONIA IN THE IMMUNOCOMPROMISED HOST 4 stages of the inflammatory response:
3. Moraxella catarrhalis 1. Congestion: 1-2 days
8) PULMONARY DISEASE IN HUMAN IMMUNODEFICIENCY
 *2nd most common bacterial cause of acute exacerbation  Gross: lung is heavy, boggy, and red
VIRUS INFECTION of COPD  Microscopic: vascular engorgement, intra-alveolar fluid
 constitutes one of the three most common causes of with few neutrophils, and often the presence of
9. Pulmonary Infections otitis media in children numerous bacteria
2. Red hepatization: 2-4 days
 Pneumonia - broadly defined as any infection of the lung 4. Staphylococcus aureus  Gross: Lungs – red, firm & airless with liver-like
parenchyma  important cause of secondary bacterial pneumonia in consistency
 Pneumonia can result whenever these local defense children and healthy adults following viral respiratory  Microscopic: massive confluent exudation with
mechanisms are impaired or the systemic resistance of illnesses neutrophils, red cells, and fibrin filling the alveolar
the host is lowered  associated with a high incidence of complications: lung spaces
abscess and empyema 3. Gray hepatization: 4-6 days
Local defense mechanisms of the lung can be interfered  *Intravenous drug abusers are at high risk of  Gross: grayish brown, dry surface with liver-like
with: developing staphylococcal pneumonia in association with consistency
 Loss or suppression of the cough reflex (coma, endocarditis  Microscopic: progressive disintegration of red cells and
anesthesia, neuromuscular disorders, drugs, or chest
the persistence of a fibrinosuppurative exudate
pain) 5. Klebsiella pneumonia 4. Resolution: 8-9 days
 Injury to the mucociliary apparatus  *Most frequent cause of gram-negative bacterial  Microscopic: Consolidated exudate within the alveolar
 Accumulation of secretions (cystic fibrosis and bronchial pneumonia; afflicts debilitated and malnourished people, spaces undergoes progressive enzymatic digestion to
obstruction) particularly chronic alcoholics produce granular, semifluid debris that is resorbed,
 Interference with the phagocytic or bactericidal action of  Thick and gelatinous sputum is characteristic ingested by macrophages, expectorated, or organized by
alveolar macrophages
fibroblasts growing into it
 Pulmonary congestion and edema 6. Pseudomonas aeruginosa
 *Most commonly causes hospital-acquired infections Complications:
COMMUNITY-ACQUIRED ACUTE PNEUMONIAS  Common in patients who are neutropenic with a (1) tissue destruction and necrosis, causing abscess
1. Streptococcus pneumonia or pneumococcus propensity to invade blood vessels with consequent formation (type 3 pneumococci or Klebsiella infections)
 *Most common cause of community-acquired acute extrapulmonary spread (2) spread of infection to the pleural cavity, causing the
pneumonia
intrapleural fibrinosuppurative reaction known as empyema
 Gm (+), lancet-shaped diplococcic 7. Legionella pneumophila (3) bacteremic dissemination causing metastatic
 part of the endogenous flora in 20% of adults  Causes: Legionnaires' disease & Pontiac fever abscesses, endocarditis, meningitis, or suppurative arthritis
 vaccines containing capsular polysaccharides - used in  Flourishes in aquatic environments (ie. water-cooling (4) organization of exudates
patients at high risk towers & tubing system)
 Organ transplant recipients are particularly susceptible
2. Haemophilus influenza COMMUNITY-ACQUIRED ATYPICAL (VIRAL
 Gm (-), major cause of life-threatening acute lower Morphology:
AND MYCOPLASMAL) PNEUMONIAS
respiratory tract infections and meningitis in young  Atypical - applied to an acute febrile respiratory disease
 Bacterial pneumonia has two patterns of anatomic
children o *Denotes moderate amount of sputum, no
distribution: lobular bronchopneumonia and lobar
 A ubiquitous colonizer of the pharynx, where it exists in physical findings of consolidation, only moderate
pneumonia
two forms: encapsulated (5%) and unencapsulated elevation of white cell count, and lack of alveolar
(95%) exudate

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 Characterized by patchy inflammatory changes in the
lungs, largely confined to the alveolar septa and
pulmonary interstitium
 Caused by a variety of organisms:
o Mycoplasma pneumonia – most common
o Viruses
o Chlamydia pneumonia
o Coxiella burnetii (Q fever)
Pathogenesis:
 attachment of the organisms to the upper respiratory
tract epithelium followed by necrosis
Morphology:
 Lung involvement may be quite patchy or may involve
whole lobes bilaterally or unilaterally
 Histologic:
o interstitial nature of the inflammatory reaction
o widened and edematous alveolar septa
o mononuclear inflammatory infiltrates
o pink hyaline membranes lining the alveolar walls
Influenza Infections
 genome of influenza virus is composed of eight helices of
single-stranded RNA
 each encoding a single gene bound by a nucleoprotein
that determines the type (A,B,C) of virus
 Rarely causes interstitial myocarditis or after aspirin
therapy – d/t Reye syndrome
 w/ lipid bilayer (envelope) containing the viral
hemagglutinin & neuramidase which determines the
subtype of virus (H1 to H3; N1 to N2)
*Influenza B&C – do NOT show antigenic drift or shift, infects
mostly children
Influenza A
 Major cause of pandemic and epidemic influenza
infection because of antigenic shift or drift
 ANTIGENIC DRIFT – mutations of the hemagglutinin
and neuraminidase that allow the virus to escape most
host antibodies; give rise to the EPIDEMICS of
influenza
 ANTIGENIC SHIFT - occur when both the
hemagglutinin and the neuraminidase are replaced
through recombination of RNA segments with those of
animal viruses, making all individuals susceptible to the
new influenza virus; give rise to the PANDEMICS of
influenza
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Avian influenza (antigenic type H5N1)
 lethal in humans (approximately 60%)
 severity of the disease results from the ability of the
virus to cause widespread infection in the human body,
instead of infection being limited to the lung
 The tissue tropism of H5N1 influenza is increased due to
the unusual structure of its hemagglutinin protein
Human Metapneumovirus (MPV)
 a paramyxovirus & associated with upper and lower
respiratory tract infections
 most commonly in young children, elderly subjects, and
immunocompromised patients
 *cause severe infections: bronchiolitis & pneumonia
 No commercial treatments yet, but
o Ribavirin – shows activity both in vitro and in
animal models
Severe Acute Respiratory Syndrome (SARS)
 appeared in November 2002 in the Guangdong Province
of China
 Etiologic agent: coronavirus
 incubation period: 2 to 10 days
 C/M: dry cough, malaise, myalgias, fever, and chills w/c
may improve and resolve the infection or progress to
severe respiratory disease
 MOT: first transmitted to humans through contact with
wild masked palm civets & subsequently spread person-
to-person infected respiratory secretions, some cases
may have been contracted from stool
 Diagnosed by:
o Detection of virus – PCR
o Detection of antibodies to the virus
 Patients who have died of SARS the lungs show diffuse
alveolar damage and multinucleated giant cells
HOSPITAL-ACQUIRED PNEUMONIA
 Hospital acquired pulmonary infections
 the most common isolates: Gram-negative rods
(Enterobacteriaceae and Pseudomonas species) & S.
aureus
ASPIRATION PNEUMONIA
 occurs in markedly debilitated patients or those who
aspirate gastric contents either while unconscious (e.g.,
after a stroke) or during repeated vomiting
 patients have abnormal gag and swallowing reflexes
 In those who survive, lung abscess is a common
complication
LUNG ABSCESS
 A local suppurative process within the lung,
characterized by necrosis of lung tissue
Etiology and Pathogenesis
 aerobic and anaerobic streptococci, S. aureus, and a
host of gram-negative organisms
 Anaerobic organisms: Bacteroides, Fusobacterium, and
Peptococcus species - are the exclusive isolates in about
60% of cases
 The causative organisms are introduced by the following
mechanisms:
o Aspiration of infective material (the most
frequent cause) - acute alcoholism, coma,
anesthesia, sinusitis, gingivodental sepsis,&
depressed cough reflex
o Antecedent primary lung infection - Post-
pneumonic abscess formations are usually
associated with S. aureus, K. pneumoniae, and
the type 3 pneumococcus
o Septic embolism
o Neoplasia
*primary cryptogenic lung abscesses – unknown cause
Morphology:
 Gross: few millimeters to large cavities of 5 to 6 cm
 Pulmonary abscesses due to aspiration are more
common on the right (because of the more vertical right
main bronchus) and are most often single
 Microscopic: cardinal histologic change suppurative
destruction of the lung parenchyma within the central
area of cavitation
o In chronic cases - fibroblastic proliferation
produces a fibrous wall
Clinical Course:
 C/M (same w/ bronchiectasis): cough, fever, and copious
amounts of foul-smelling purulent or sanguineous
sputum
 Complications:
o extension of the infection into the pleural cavity
o hemorrhage
o development of brain abscesses or meningitis
from septic emboli
o rarely, secondary amyloidosis (type AA)
CHRONIC PNEUMONIA
 Def: localized lesion in the immunocompetent patient,
with or without regional lymph node involvement
 the inflammatory reaction is granulomatous
 Etiologic agent:
o bacteria (e.g., M. tuberculosis)
o *fungi (e.g., Histoplasma capsulatum,
Blastomyces, Coccidioides)
1.] Histoplasmosis
 Def: Acquired by inhalation of dust particles from soil
contaminated with bird or bat droppings that contain
small spores (microconidia), the infectious form of the
fungus
 An intracellular parasite of macrophages
 Clinical presentations and morphologic lesions includes:
1) Self-limited & often latent primary pulmonary
involvement that result in coin lesions on CXR;
2) Chronic, progressive, secondary lung disease,
which is localized to the lung apices and causes
cough, fever, and night sweats;
3) Localized lesions in extrapulmonary sites,
including mediastinum, adrenals, liver, or
meninges
4) A widely disseminated disease in
immunocompromised patients
 Macrophages are the major target of infection
 Histoplasma infections are controlled by helper T cells
that recognize fungal cell wall antigens and heat-shock
proteins and subsequently secrete IFN-γ, which
activates macrophages to secrete TNF & kill intracellular
yeasts
 Antigen detection in body fluids is most useful in the
early stages, because antibodies are formed 2 to 6
weeks after infection
Morphology:
 Produce epithelioid cell granulomas that usually undergo
caseation necrosis & coalesce to produce large areas of
consolidation & liquefy to form cavities (seen in patients
with COPD)
 lesions undergo fibrosis and concentric calcification
(tree-bark appearance)
 In fulminant disseminated histoplasmosis that
occurs in immunosuppressed individuals, epithelioid cell
granulomas are NOT formed; instead, there are focal
accumulations of mononuclear phagocytes filled with
fungal yeasts
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2.] Blastomycosis
 A soil-inhabiting, dimorphic fungus, caused by B.
dermatitidis
 There are three clinical forms:
o Pulmonary blastomycosis,
o Disseminated blastomycosis,
o Primary cutaneous form (rare) - results from
direct inoculation of organisms into the skin
 CXR: lobar consolidation, multilobar infiltrates, perihilar
infiltrates, multiple nodules, or miliary infiltrates
 Upper lobes - most frequently involved
Morphology:
 Lung lesions – are suppurative granulomas
 Macrophages have a limited ability to ingest and kill B.
dermatitidis, and the persistence of the yeast cells leads
to continued recruitment of neutrophils
 Skin and larynx is associated with marked epithelial
hyperplasia
3.] Coccidioidomycosis
 Etiologic agent: Coccidioides immitis
PULMONARY DISEASE IN HUMAN
 Most of the primary infections with C. immitis are
asymptomatic IMMUNODEFICIENCY VIRUS INFECTION
 10% of people have lung lesions, fever, cough, and  Pulmonary disease continues to be the leading cause of
pleuritic pains, accompanied by erythema nodosum or morbidity and mortality in HIV-infected individuals
erythema multiforme (the San Joaquin Valley fever
complex) General principles of HIV-associated pulmonary
disease:
Morphology:  Bacterial pneumonias in HIV-infected persons are more
 Primary and secondary lung lesions – are granulomatous common, more severe, & more often associated with
(same w/Histoplasma) bacteremia than in those without HIV infection
o Organisms include: S. pneumoniae, S. aureus,
H. influenzae, & gram-negative rods
 Not all pulmonary infiltrates in HIV-infected individuals
PNEUMONIA IN THE IMMUNOCOMPROMISED
are infectious in etiology
HOST Noninfectious diseases: Kaposi sarcoma,
o
 Appearance of a pulmonary infiltrate, with or without primary lung cancer
signs of infection - one of the most common and serious
 The CD4+ T-cell count can define the risk of infection
complications in patients whose immune defenses are with specific organisms
suppressed caused by infection in normal hosts
o Bacterial & Tubercular infections – have
higher CD4+ counts (>200 cells/mm)
o Pneumocystis pneumonia - usually strikes at
CD4+ counts below 200 cells/mm3
o Cytomegalovirus & Mycobacterium avium
complex infections - are uncommon until the
very late stages of immunosuppression (CD4+
counts <50 cells/mm)
SUMMARY of Pulmonary Infections: Morphology:
 The transplanted lung is subject to two major
complications: infection & rejection

1] Pulmonary infections
 bacterial infections are most common
 Most infections occur in the 3rd -12th month after
transplantation

2] Rejections

Acute rejection Chronic rejection

□ Occurs during the early □ By 3 to 5 years
weeks to months or years □ C/M: cough, dyspnea, and
later an irreversible decrease in
□ C/M: fever, dyspnea, lung function tests
cough, and radiologic □ Major morphologic: assoc.
infiltrates with bronchiolitis
□ Morphologic features: obliterans - partial or
inflammatory infiltrates complete occlusion of small
(lymphocytes, plasma cells, airways by fibrosis, with or
and few neutrophils and without active inflammation
eosinophils), either around
small vessels, in the
submucosa of airways, or
both
 Acute cellular airway rejection is generally responsive to
therapy, but the treatment of established bronchiolitis
obliterans has been disappointing
 Survival rates:
o 1 year – 78%
o 5 years – 50%
o 10 years – 26%

11. Tumors
 90-95% are carcinomas
 5% are bronchial carcinoids
10. Lung Transplantation  2-5% are mesenchymal & other neoplasms
 The most common indications are: (FICE*)
o idiopathic/Familial pulmonary arterial CARCINOMAS:
hypertension  Lung cancer - the most frequently diagnosed major
o Idiopathic pulmonary fibrosis cancer in the world
o Cystic fibrosis
o End-stage emphysema Etiology and Pathogenesis:
 When bilateral chronic infection is present (e.g., cystic 1] Tobacco Smoking
fibrosis, bronchiectasis), both lungs of the recipient must  87% of lung carcinomas occur in active smokers or those
be replaced to remove the reservoir of infection who stopped recently

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 Statistical association between the frequency of lung
cancer and…
o (1) the amount of daily smoking,
 average smokers of cigarettes have a
10x risk of developing lung cancer
 heavy smokers (more than 40
cigarettes per day for several years)
have a 60x greater risk
o (2) the tendency to inhale, and
o (3) the duration of the smoking habit
 Cessation of smoking for 10 years
reduces risk but never to control levels
 Only 11% of heavy smokers develop lung cancer in their
lifetime
 Lung tumors of smokers frequently contain a typical,
though not specific, molecular fingerprint in the form of
G : C > T : A mutations in the p53 gene that are
probably caused by benzo[a]pyrene, one of the many
carcinogens in tobacco smoke
 Experimental work: More than 1200 substances of
cigarettes are potential carcinogens w/c contains:
o Initiators: polycyclic aromatic hydrocarbons
such as benzo[a]pyrene
o Promoters: phenol derivatives
o Radioactive elements:
 polonium-210,
 carbon-14, and
 potassium-40
o Other contaminants:
 arsenic, nickel, molds, & additives
 The few cancers that have developed have been
bronchioloalveolar carcinomas, a type of tumor that
is not strongly associated with smoking in humans
2] Industrial Hazards
 High-dose ionizing radiation is carcinogenic
 Uranium - a weak radioactive, but lung cancer rates
among
o nonsmoking uranium miners are 4x higher
o smoking miners are about 10x higher
 Asbestos
o Asbestos workers who do not smoke have a 5x
greater risk of developing lung cancer
o Smoker – 50-90x greater risk
3] Air Pollution
 Attention has been drawn to the potential problem of
indoor air pollution, especially by radon
 Radon is a ubiquitous radioactive gas
4] Molecular Genetics
 It has been estimated that 10 to 20 genetic mutations
have occurred by the time the tumor is clinically
apparent
 Lung cancers can be divided into two clinical subgroups:
small cell carcinoma and non-small cell carcinoma
 The dominant oncogenes that are frequently involved
in lung cancer include c-MYC, KRAS, EGFR, c-MET, and
c-KIT
 The commonly deleted or inactivated tumor
suppressor genes include: p53, RB1, p16(INK4a), and
multiple loci on chromosome 3p
 Small cell lung carcinoma is associated with:
o C-KIT (40–70%), MYCN and MYCL (20–30%),
p53 (90%), 3p (100%), RB (90%), and BCL2
(75–90%)
 Non-small cell lung carcinoma is associated with:
o EGFR (25%), KRAS (10–15%), p53 (50%), p16
INK4a (70%)
 Telomerase activity is increased in over 80% of lung
tumor tissues
 People with certain alleles of CYP1A1* have an
Morphology:
increased capacity to metabolize procarcinogens derived
from cigarette smoke and, conceivably, incur the  Lung carcinomas arise most often in hilus of the lung
greatest risk of developing lung cancer  Carcinomas of the lung arise in the periphery of the lung
from the alveolar septal cells or terminal bronchioles
5] Precursor Lesions  Gross:
(1) Squamous dysplasia and carcinoma in situ o Irregular warty excrescence
(2) Atypical adenomatous hyperplasia o produce an intraluminal mass
(3) Diffuse idiopathic pulmonary neuroendocrine cell o cauliflower-like intraparenchymal mass
hyperplasia o neoplastic tissue is gray-white and firm to hard
 Distant spread of lung carcinoma occurs through both
*World Health Organization Histologic Classification lymphatic and hematogenous pathways
o Adrenals (50%)
of Malignant Epithelial Lung Tumors o Liver (30-50%)
 Adenocarcinoma (males 37%, females 47%) o Brain (20%)
 Squamous cell carcinoma (males 32%, females 25%) o Bone (20%)
 Small cell carcinoma (males 14%, females 18%)  Tumors often spread early throughout the body
 Large cell carcinoma (males 18%, females 10%) EXCEPT for squamous cell carcinoma, which
metastasizes outside the thorax
Clinical use:  Direct extension: pleural cavity, pericardium
 *Various histologic types of lung cancer can be clustered
into 2 groups on the basis of likelihood of metastases & Clinical Course:
response to available therapies:  *Most patients are in 50s with symptoms of several
o Small cell carcinomas (almost always months durations
metastatic, high initial response to o Cough (75%)
chemotherapy) o Weight loss (40%)
o Non-small cell carcinomas (less often o Chest pain (40%)
metastatic, less responsive) o Dyspnea (20%)
 With strong relationship to smoking is:
o Squamous cell & Small cell carcinoma

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 Bronchioloalveolar carcinomas  are noninvasive tumors Nonmucinous Mucinous  A single variant of small cell carcinoma is recognized
and do not metastasize; unless resected, they kill by >Consist of a peripheral >Tend to spread aerogenously,  Believed to arise from neuroendocrine progenitor cells of
suffocation lung nodule with only forming satellite tumors the lining bronchial epithelium
rare aerogenous spread >Has distinctive, tall, columnar o Secrete polypeptide hormones &
1.] Adenocarcinoma – 25-40% >Has columnar, peg- cells with cytoplasmic and intra- parathormone-like and other hormonally
 A malignant epithelial tumor with glandular shaped, or cuboidal cells alveolar mucin, growing along active products
differentiation or mucin production by the tumor >Amenable to surgical the alveolar septa o Presence of neuroendocrine markers:
cells resection with an >Resembling lobar pneumonia & chromogranin, synaptophysin, Leu-7 (in 75% of
 Grow in various patterns: acinar, papillary, excellent 5-year survival are less likely to be cured by cases)
bronchioloalveolar, and solid with mucin formation surgery o Neurosecretory granules
o Only pure bronchioloalveolar carcinoma has  Mutations:
distinct gross, microscopic, and clinical features 2.] Squamous Cell Carcinoma – 25-40% o P53 (50-80%)
 Most common type of lung cancer in women and o RB tumor suppressor genes (80-100%)
 Most commonly found in men and is closely correlated
nonsmokers  High levels of the anti-apoptotic protein BCL2 (in 90%
with a smoking history
 Lesions are usually more peripherally located, and tend of tumors) with a low frequency of pro-apoptotic
 With p53 mutations: highest frequency compared to
to be smaller protein BAX
other histologic type
 Grow more slowly than squamous cell carcinomas but  Loss of protein expression of the tumor suppressor gene
tend to metastasize widely and earlier RB1 4.] Large Cell Carcinoma – 10-15%
 Associated with scarring  Inactivated cyclin-dependent kinase:  *Def: undifferentiated malignant epithelial tumor that
 Less frequently associated with a history of smoking o CDK-inhibitor p16(INK4a) lacks the cytologic features of small-cell carcinoma and
(still, greater than 75% in smokers) than are squamous glandular or squamous differentiation
or small cell carcinomas (>98% in smokers) Microscopic findings:  One histologic variant: Large cell neuroendocrine
 Mutations:  Presence of keratinization and/or intercellular bridges carcinoma
o KRAS mutations  Keratinization may take the form of squamous pearls or o Recognized by such features:
o p53, RB1, p16 mutations and inactivation individual cells with markedly eosinophilic dense  Trabecular,
have the same frequency in adenocarcinoma as cytoplasm  Organoid nesting,
in squamous cell carcinoma  Higher mitotic activity  Rosette-like,
o epidermal growth factor receptor gene (EGFR)  Palisading patterns
o c-MET o *These features suggest neuroendocrine
3.] Small Cell Carcinoma – 20-25% differentiation
 Def: Highly malignant tumor has a distinctive cell type
Bronchioloalveolar Carcinoma
 Most common pattern associated with ectopic hormone
 Occurs in the pulmonary parenchyma in the terminal
production
Combined Carcinoma
bronchioloalveolar regions  Approximately 10% of all lung carcinomas
 Strong relationship with SMOKING
 Occurs in 1-9% of all lung cancers  Have a combined histology, including two or more of the
 Occur both in major bronchi & periphery of the lung
 There is NO known preinvasive phase or carcinoma in above types
Gross (always occurs in):
situ
 Peripheral portions Prognosis of LUNG CANCER:
 Single nodule or multiple diffuse nodules - sometimes Microscopic findings:  Overall 5-year survival rate is only 15%
coalesce to produce a pneumonia-like consolidation  In general, the adenocarcinoma and squamous cell
 Small epithelial cells, with scant cytoplasm, ill-defined
 Have a mucinous, gray translucence when secretion is patterns tend to remain localized longer and have a
cell borders, finely granular nuclear chromatin (“salt
present slightly better prognosis than do the undifferentiated
and pepper pattern”), and absent or inconspicuous
cancers, which are usually advanced by the time they
nucleoli
Microscopic findings: are discovered
 Cells are round, oval, or spindle-shaped, and nuclear
o Pure bronchioloalveolar growth pattern with no evidence  Small cell CA – sensitive to radiochemo therapy &
molding is prominent
of stromal, vascular, or pleural invasion surgical resection is ineffective
 The mitotic count is high
o Key feature: “lepidic” – carcinoma grow along o Untreated cases survival rate – 6-17 wks
 Cells grow in clusters that exhibit neither glandular nor
preexisting structures without destruction of alveolar o With treatment survival rate – about 1 year
squamous organization
architecture  Necrosis is common and often extensive
*Have two subtypes: o Necrotic tumor cells (Azzopardi effect) is
frequently present

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Paraneoplastic Syndromes
Lung carcinoma can be associated with several
paraneoplastic syndromes:
 ADH def. – hyponatremia (small cell CA)
 ACTH – Cushing syndrome (small cell CA)
 Parathormone, Parathyroid hormone related peptide,
prostaglanding E & some cytokines – hyperkalemia
(SCCA)
 Calcitonin – hypocalcemia
 Gonadotropins – gynecomastia
 Serotonin & Bradykinin – associated with carcinoid
syndrome
 ACTH and ADH are predominantly small cell carcinomas,
whereas those that produce hypercalcemia are mostly
squamous cell tumors
Other systemic manifestations of lung carcinoma:
 Lambert-Eaton myasthenic syndrome - muscle
weakness is caused by auto-antibodies (possibly elicited
by tumor ionic channels) directed to the neuronal
calcium channel
 Peripheral neuropathy - usually purely sensory
 Acanthosis nigricans
 Leukemoid reactions
 Hypertrophic pulmonary osteoarthropathy -
associated with clubbing of the fingers
 Pancoast tumors
o Apical lung cancers in the superior pulmonary
~egbii~
sulcus that invade the neural structures around
the trachea, including the cervical sympathetic
plexus
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o C/M:
 severe pain in the distribution of the
ulnar nerve
 Horner syndrome (enophthalmos,
ptosis, miosis, and anhidrosis)
NEUROENDOCRINE PROLIFERATIONS & TUMORS
 Normal lung contains neuroendocrine cells within the
epithelium as single cells or as clusters, the
neuroepithelial bodies
 Neoplasms of neuroendocrine cells in the lung include:
1. Benign tumorlets
 small, inconsequential, hyperplastic nests of
neuroendocrine cells seen in areas of scarring or chronic
inflammation
2. Carcinoids tumors
 highly aggressive small cell carcinoma and large cell
neuroendocrine carcinoma of the lung
 represent 1% to 5% of all lung tumors
 younger than 40 years of age
 incidence is equal for both sexes
 20% to 40% of patients are nonsmokers
 Carcinoid tumors are low-grade malignant epithelial
neoplasms that are subclassified into typical and atypical
carcinoids
o Typical carcinoids have no p53 mutations or
abnormalities of BCL2 and BAX expression, while
atypical carcinoids show these changes
Morphology:
 may arise centrally or may be peripheral
 GROSS:
o central tumors grow as finger-like or spherical
polypoid masses that commonly project into the
lumen of the bronchus and are usually covered
by an intact mucosa; exceed 3 to 4 cm in
diameter; produce little intraluminal mass but
instead penetrate the bronchial wall to fan out in
the peribronchial tissue – called button lesion
o Peripheral tumors are solid and nodular
 Histologically:
o the tumor is composed of organoid, trabecular,
palisading, ribbon, or rosette-like arrangements
of cells separated by a delicate fibrovascular
stroma
o individual cells are quite regular and have
uniform round nuclei and a moderate amount of
eosinophilic cytoplasm
 Typical carcinoids
o have fewer than 2 mitoses/ 10 high-power fields
 Grossly, the lesion is firm, 3 to 10 cm in diameter, and
grayish white
and lack necrosis  Microscopically, there is proliferation of spindle-shaped
 Atypical carcinoids fibroblasts and myofibroblasts, lymphocytes, plasma
o have between 2 -10 mitoses/ 10 high-power cells, and peripheral fibrosis
fields and/or foci of necrosis  anaplastic lymphoma kinase (ALK) gene, located on
o show increased pleomorphism, have more 2p23, has been implicated in the pathogenesis of this
prominent nucleoli, and are more likely to grow tumor
in a disorganized fashion and invade lymphatics
3. Tumors in the mediastinum
On electron microscopy  arise in mediastinal structures or may be metastatic
 the cells exhibit the dense-core granules characteristic of from the lung or other organs
other neuroendocrine tumors  may also invade or compress the lungs
Immunohistochemistry
 Table 15-13 lists the most common tumors in the
 found to contain serotonin, neuron-specific enolase, various compartments of the mediastinum
bombesin, calcitonin, or other peptides
SUPERIOR ANTERIOR
Clinical Features: A] Lymphoma A] Thymoma
 cough, hemoptysis, impairment of drainage of B] Thymoma B] Teratoma
respiratory passages with secondary infections, C] Thyroid lesions C] Lymphoma
bronchiectasis, emphysema, and atelectasis D] Metastatic carcinoma D] Thyroid lesions
 Classic carcinoid syndrome: intermittent attacks of
E] Parathyroid tumors E] Parathyroid tumors
diarrhea, flushing, and cyanosis MIDDLE POSTERIOR
 Most bronchial carcinoids…
A] Bronchogenic cyst A] Neurogenic tumors
o Do not have secretory activity and do not B] Pericardial cyst (schwannoma, neurofibroma)
metastasize to distant sites but follow a
C] Lymphoma B] Lymphoma
relatively benign course for long periods, C] Gastroenteric hernia
o and are therefore amenable to resection
METASTATIC TUMORS
MISCELLANEOUS TUMORS  Lung - the most common site of metastatic neoplasms
1. Lung hamartoma  spread to the lungs via the blood or lymphatics or by
 usually discovered as an incidental, rounded focus of direct continuity
radio-opacity (coin lesion) on a routine chest film  Growth of contiguous tumors into the lungs occurs most
 less than 3 to 4 cm in diameter often with esophageal carcinomas and mediastinal
 chromosomal aberrations involving either 6p21 or lymphomas
12q14–q15
 Microscopic findings Morphology:
o Consists of nodules of connective tissue  Gross: multiple discrete nodules (cannonball lesions) are
intersected by epithelial clefts scattered throughout all lobes
o Epithelial clefts are lined by ciliated columnar  Microscopic findings:
epithelium or nonciliated epithelium o Confined to peribronchial or perivascular spaces
o Subpleural lymphatics may contain the tumor
2. Inflammatory myofibroblastic tumor o Diffuse intralymphatic dissemination dispersed
 more common in children; equal male-to-female ratio throughout the peribronchial & perivascular
 Presenting symptoms : fever, cough, chest pain, and channels
hemoptysis o Microscopic tumor emboli may be present
 Imaging studies show a single (rarely multiple) round,
well-defined, usually peripheral mass with calcium
deposits
12. Pleura
A] PLEURAL EFFUSION
 A common manifestation of both primary and secondary
pleural diseases, which may be inflammatory or
noninflammatory
 Normally, no more than 15 mL of serous, relatively
acellular, clear fluid lubricates the pleural surface
 Accumulation of pleural fluid occurs in the following
settings:
o ↑ hydrostatic pressure (CHF)
o ↑ vascular permeability (pneumonia)
o ↑ intrapleural negative pressure (atelectasis)
o ↓ osmotic pressure (nephrotic syndrome)
o ↓ lymphatic drainage (mediastinal
carcinomatosis)
Inflammatory Pleural Effusions
 Serofibrinous pleuritis
o Inflammation in adjacent lung
o Collagen vascular disease
 Suppurative pleuritis (empyema)
o Results from bacterial or mycotic seeding of the
pleural space
o Empyema is characterized by loculated, yellow-
green, creamy pus composed of masses of
neutrophils admixed with other leukocytes
 Hemorrhagic pleuritis
o Manifested by sanguineous inflammatory
exudates
o Found in hemorrhagic diatheses, rickettsial
diseases, and neoplastic involvement of the
pleural cavity
Noninflammatory Pleural Effusions
 Hydrothorax
o Noninflammatory collections of serous fluid
within the pleural cavities
o fluid is clear and straw colored
o The most common cause of hydrothorax is
cardiac failure*
 Hemothorax
o Rscape of blood into the pleural cavity
o D/t: ruptured aortic aneurysm & trauma
 Chylothorax
o An accumulation of milky fluid, usually of
lymphatic origin, in the pleural cavity

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 o Chyle is milky white because it contains finely
emulsified fats.
o Most often caused by thoracic duct trauma or
obstruction that secondarily causes rupture of
major lymphatic ducts
B] PNEUMOTHORAX
 Def: refers to air or gas in the pleural cavities and may
be spontaneous, traumatic, or therapeutic
 Spontaneous pneumothorax may complicate any
form of pulmonary disease that causes rupture of an
alveolus
o Mostly associated with: emphysema, asthma,
and tuberculosis
o Idiopathic form: young people, rupture of small,
peripheral, usually apical subpleural blebs &
subsides spontaneously
 Traumatic pneumothorax is usually caused by some
perforating injury to the chest wall, but sometimes the
trauma pierces the lung and thus provides two avenues
for the accumulation of air within the pleural spaces
 When the defect acts as a flap valve and permits the
entrance of air during inspiration but fails to permit its
escape during expiration, it effectively acts as a pump
that creates the progressively increasing pressures of
tension pneumothorax, which may be sufficient to
compress the vital mediastinal structures and the
contralateral lung
C] PLEURAL TUMORS
 The most frequent metastatic malignancies arise from
primary neoplasms of the lung & breast.
Solitary Fibrous Tumor
 No relationship to asbestos
Gross:
 Small (1-2 cm) or large
 Attached to the pleural surface by a pedicle
 Dence fibrous tissue w/ occasional cysts filled with viscid
fluid
Microscopic findings:
 Whorls of reticulum & collagen fibers among which are
interspersed spindle cells
 MALIGNANT variant: with pleomorphism, mitotic activity,
necrosis, large size (>10 cm)
 IHC: (+) CD34+ & (-) keratin  useful in differentiating
from malignant mesothelioma w/c show opposite results
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Malignant Mesothelioma 1. Epithelioid type
 Arise from either the visceral or the parietal pleura  consists of cuboidal, columnar, or flattened cells forming
 Also arise in peritoneum, pericardium, tunica vaginalis & tubular or papillary structures resembling
genital tract adenocarcinoma
 Peritoneal mesotheliomas – particularly related to
heavy asbestos exposure 2. Mesothelioma include:
o 50% of patients have pulmonary fibrosis 1) (+) staining for acid mucopolysaccharide, which is
o Assoc. w/ intestinal obstruction inhibited by previous digestion by hyaluronidase
2) Lack of staining for carcinoembryonic antigen & other
C/M: epithelial glycoprotein antigens, markers that are
 Chest pain, dyspnea, recurrent pleural effusions generally expressed by adenocarcinoma
 Lung is invaded directly with metastatic spread to hilar 3) Strong staining for keratin proteins, with accentuation of
lymph nodes & eventually to liver & distant organs perinuclear rather than peripheral staining
 50% die within 12 months of Dx & few survive longer 4) (+) staining for calretinin, Wilms tumor 1 (WT-1),
than 2 years cytokeratin 5/6, & D2–40
5) On electron microscopy: the presence of long microvilli
and abundant tonofilaments but absent microvillous
Cytogenic studies:
rootlets and lamellar bodies
 60-80% have deletions in chromosomes 1p, 3p, 6q, 9p,
or 22q
**The mesenchymal type of mesothelioma appears as:
 31% have p16 mutations
o A spindle cell sarcoma, resembling fibrosarcoma
 With low frequency of p53 mutations
(sarcomatoid type).
 presence of SV40 (simian virus 40) viral DNA sequences
***The mixed type of mesothelioma contains both
in 60% to 80% of pleural malignant mesotheliomas
epithelioid and sarcomatoid patterns
Morphology:
 Spreads widely in the pleural space and is usually
associated with extensive pleural effusion and direct
invasion of thoracic structures
 Increased incidence among people with asbestos
exposure
o Lifetime risk: 7-10%
o Long latent period: 25-45 years
 Gross:
o Lungs is ensheathed by a layer of soft,
gelatinous, grayish pink tumor tissue
 Microscopic findings:
o 2 types of cells:
1. Epithelium-like lining cells
2. Mesenchymal stromal cells