Pegg

Respiratory Pathology
Atelectasis
 A state in which the entire lung or part of the lung is collapsed or without air
 Loss of lung volume secondary to alveolar collapse leading to decreased
oxygenation, which results in V/Q mismatch (ventilation perfusion
imbalance)
 Hypoxemia
 Collapsed lung leaves room for superimposed infection
 Resorption atelectasis
o Consequence of complete airway obstruction in the bronchi,
subsegmental bronchi or bronchioles (bronchial obstruction)
 Prevents air from reaching the alveoli
 Resorption of air trapped in distal airspaces through the pores
of Kohn
 Pores of Kohn: holes in the wall of alveolar septi that
connect adjacent alveoli
o Causes of obstruction
 Mucus plug following surgery
 Aspiration of foreign material (right bronchus in children)
 Bronchial asthma, chronic bronchitis, bronchiectasis
(obstructive lung disease)
 Bronchial neoplasms (total obstruction)
o Reduction in size and volume of the lung followed by lung collapse
o Reversible
o “child younger than 2 years old playing with small toys”
o Clinical findings
 Fever and dyspnea within 24 – 36 hours of collapse
 Resorption atelectasis is the most common cause of fever
24 – 36 hours following surgery)
 Ipsilateral deviation of trachea (deviation towards the area of
obstruction)
 Ipsilateral diaphragmatic elevation
 Absent breath sounds and absent vocal vibratory sensation
(tactile fremitus)
 Collapsed lung does not expand on inspiration
 Compression atelectasis
o Air or fluid accumulates in the pleural cavity, leading to increased
pressure that collapses the underlying lung
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o Reversible
o Examples
 Tension pneumothorax: arises with penetrating chest wall
injury
 Medical emergency treated with insertion of a chest tube
 Pushes the trachea to the opposite side
 Pleural effusion
o Trachea and mediastinum shift away from the atelectatic lung
o Pancoast tumor can obstruct the thoracic duct, leading to chylothorax
and then compression atelectasis
 Contraction atelectasis
o Occurs when local or diffuse fibrosis affecting the lung or the pleura
hamper lung expansion
o Irreversible (fibrosis)
o caused by restrictive lung diseases (sarcoidosis, IPF, Loeffler’s,
asbestosis, silicosis, CWP, byssinosis, drugs)
 Neonatal atelectasis (Immune Neonatal ARDS)
o Loss of surfactant
 Surfactant: phosphatidylcholine (lecithin),
phosphatidylglycerol, proteins
 SP A and D: innate immunity
 SP B and C: reduction of surface tension at air liquid
barrier in alveoli
 Synthesized by type II pneumocytes during the 28th week
of gestation
 Stored in lamellar bodies
o Any child born before this time has a high risk for neonatal atelectasis
o Surfactant reduces surface tension in small airways and prevents
collapse on expiration
o Synthesis of surfactant is modulated by different hormones
 Cortisol and thyroxine increase surfactant production
 Insulin decreases surfactant production
o Respiratory distress syndrome (ARDS) in newborns
o Causes
 Prematurity (surfactant synthesis starts at 28 weeks)
 Maternal diabetes (insulin inhibits surfactant production)
 Fetal hyperglycemia stimulates insulin release
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 C-section (decreased vaginal stress leads to decreased cortisol

stimulation)
o Complications
 Intraventricular hemorrhage in the brain (fragile, premature
blood vessels in the brain)
 PDA due to persistent hypoxemia
 Necrotizing enterocolitis due to intestinal ischemia
 Hypoglycemia due to excessive insulin release
 Cataracts
 Supplemental oxygen increases the risk for free radical injury
and bronchopulmonary dysplasia
o Collapsed alveoli are lined by hyaline membranes which impairs gas
exchange
o Clinical findings
 Respiratory distress within a few hours of birth
 Hypoxemia and respiratory acidosis
 “ground glass” appearance on chest x-ray

Acute lung injury/ARDS

 Also called “shock lung syndrome”, “acute lung injury”, and “diffuse
alveolar damage”
 Diffuse damage to alveolar – capillary interface (diffuse alveolar damage)
and leakage of protein-rich fluid leads to edema and formation of hyaline
membranes in the alveoli
 Formation of hyaline membranes diffusely in the lungs
 Causes
o Direct causes
 Pneumonia
 Gastric aspiration
 Near-drowning
 Embolism
 Smoke inhalation
o Indirect causes
 Sepsis
 Hypovolemic shock
 Acute pancreatitis
 Uremia following renal failure
 Severe burns
o Trauma
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o DIC
o Hypersensitivity reactions
o Drugs
 Clinical features
o Hypoxemia and cyanosis with respiratory distress
o “white-out” on chest x-ray
o Rapid onset (within one week)
o Bilateral pulmonary infiltrates
o Refractory to oxygen therapy
 Secondary to both direct and indirect lung injury (may have the same
findings as left ventricular heart failure)
o Direct lung injury: pneumonia, aspiration, emboli, inhalation injury,
drowning, oxygen toxicity
o Indirect lung injury: sepsis, trauma with shock, acute pancreatitis,
severe burns, transfusion of blood products, uremia, drugs
 Increased vascular permeability, loss of diffusion, and surfactant deficiency
(type II pneumocyte damage)
 Thickened diffusion barrier for the exchange of gases, so patients will not be
able to exchange gas very well and as a result, they develop hypoxemia and
cyanosis
 Normal pulmonary capillary wedge pressure
 Hyaline membranes are sticky and will increase the surface tension of the
alveolar air sac, creating a pressure on the air sac to collapse
 Air sacs are lined by dense, pink, hyaline membranes
 Acute lung injury: endothelial or epithelial injury initiated by numerous
factors
o Non-heritable and heritable
o Mediators: cytokines, oxidants, TNF, IL-1, IL-6, IL-10, TGF-
o Manifestations: pulmonary edema (non-cardiogenic), diffuse alveolar
damage (ARDS)
 Diffuse alveolar damage is the histologic correlate of ARDS
o Acute (exudative) phase
 0 – 4 days
 Heavy and firm lungs
 Interstitial and intra-alveolar edema/hemorrhage
 Necrosis and sloughing of alveolar epithelial cells
 Hyaline membranes
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 Necrotic debris and fibrin produce a diffusion barrier in

which O2 cannot exit and CO2 cannot leave, leading to
cyanosis
 Hypoxemia refractory to O2 therapy
o Organizing (proliferative) phase
 4 days – 3 weeks
 Proliferation of type II pneumocytes
 Organization of fibrin exudates to fibrosis
 Alveolar septal thickening
 May become restrictive
 In ARDS, distal lungs show pink hyaline membranes, thickened interstitium,
and many macrophages, but few neutrophils
 Clinical features of ARDS/DAD
o 40% mortality rate
o Supportive therapy
o Poor prognosis for elderly and patients with bacteremia/sepsis
o May progress to multisystem organ failure
o Normal function can return after 6 – 12 months in alveoli that have no
undergone fibrosis
o Cyanosis refractory to O2 therapy due to hyaline membranes
 Edema occurs 1 day after injury, hyaline membranes occur roughly 2-6 days
after injury, interstitial inflammation and interstitial fibrosis occur a week
after injury
 Treatment: PEEP (positive end-expiratory pressure)

Obstructive lung diseases (COPD)

 Airway disorder (trachea to terminal bronchiole)
 Increased resistance to airflow and limited expiratory rates on forced
expiration
 Reduced FEV1:FVC ratio
 Increased TLC
 Normal/decreased FVC
o FVC: the amount of air you can blow out when you breathe all the
way in and blow out as much as you can (maximal expiration)
 “blow out candles on a birthday cake”
 Reduced FEV1
o FEV1: amount of volume you can get out in a one second period
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 Obstruction secondary to limitation of airflow

 4th leading cause of death in the US (very common)
 Affects men and women equally
 Air trapping due to a problem with airflow
 Obstruction during expiration
 Progressive and irreversible (except for asthma, which is a reversible,
episodic condition)
o Know how to differentiate between emphysema and asthma based
on past medical history
 COPD: emphysema
o Largest risk factor is smoking
o Loss of elastic recoil
o Expiratory obstruction secondary to collapse
o Irreversible destruction and dilation of airways without fibrosis
 No fibrosis because there is decreased TGF- expression
o Abnormal permanent airspace enlargement
o Distal to the terminal bronchioles (alveoli and respiratory bronchioles)
o Destruction of airspace walls (alveolar walls)
o No fibrosis
o Occurs due to imbalance of proteases and anti-proteases (1-
antitrypsin)
o Destruction of alveolar air sacs and loss of elastic reoil and collapse of
small airways, leading to air trapping
o In emphysematous lungs, compliance increases, DLCO decreases, and
elastic recoil decreases
o Centrilobular (centriacinar) emphysema
 Respiratory bronchiole is affected (distal alveoli are spared)
 Most common
 Emphysematous areas and adjacent normal alveoli
 Caused by smoking (“C for cigarette and central”)
 Upper lobes (“smoke rises upwards”)
 Can find diseased and normal airspaces in the same lobule
 > 50 years old (still make normal levels of 1-antitrypsin)
 Elastase overwhelms 1-antitrypsin
 Macrophages make MMP9 and MMP12 that destroy the
ECM
o Panlobular (panacinar) emphysema
 Respiratory bronchiole to the terminal alveoli are affected
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 Diffuse involvement of the lung

 Emphysematous changes are all over the lung
 Due to 1-antitrypsin deficiency (normal function is to inhibit
neutrophil proteases)
 Protein is not in the blood, but the liver is still making the
misfolded protein, so the protein accumulates in the ER
of hepatocytes and leads to liver cirrhosis/chronic liver
disease
 1-antitrypsin globules are PAS positive
 Disease severity is based on the degree of 1-antitrypsin
deficiency (point mutation in the Pi gene on chromosome
14)
o PiMM: normal allele
o PiZZ: mutation resulting in misfolding of proteins
and misfolded proteins accumulate in the ER
o PiMZ heterozygotes: usually asymptomatic with
decreased circulating levels of 1-antitrypsin;
significant risk for emphysema with smoking;
treatment with smoking cessation
 Lower lobes
o Paraseptal (distal acinar) emphysema
 Very rare
 Upper lobes
 May form bullae (subpleural bullae)
 May lead to pneumothorax
 Next to atelectasis, along septa, margins of lobes
 Subpleural
o Irregular (paracicatricial) emphysema
 Surrounds scar
 Asymptomatic
o Pathogenesis
 Imbalance in the protease/antiprotease mechanism
 Proteases: neutrophilic enzymes that break down
proteins
o Ex: elastase
 Proteases destroy lung tissue
 Antiproteases such as 1-antitrypsin inhibit these proteases and
play a protective role
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 Any increase in neutrophils in the lung tissue or any decrease in

antiprotease activity can lead to destruction of the alveolar
parenchyma
o Genetic factors
 1-antitrypsin deficiency
 TGFB gene polymorphisms (decreased TGFB signaling causes
inadequate repair of elastin injury)
 Matrix metalloproteinase (MMP) polymorphisms (increased
MMP 9 & 12)
o Example question: “non-smoker comes in with lower lobe
emphysema, what else would you expect to see? Liver issue”
o Example question: “patient who is a non-smoker comes in with
emphysema and liver problems, what is the cause? 1-antitrypsin
deficiency”
o Hyperinflated lungs with/without bullae formation
o Parenchyma has a “moth-eaten” appearance
o Histology
 Large alveolar spaces
 Destruction of alveolar septa without fibrosis (free floating
alveolar septa in air spaces)
 Destruction of elastin within small airways that causes airway
collapse during expiration (functional obstruction)
o Clinical features
 Late onset of symptoms (earlier if patient also has chronic
bronchitis)
 Insidious and progressive dyspnea
 Productive cough with minimal sputum
 Weight loss due to hyperventilation, excessive puffing, and
panting
 Labored breathing requires “exercise”
 “pink puffers”
 Barrel chest: increased AP diameter of the chest
 Prolonged expiration and pursed lips (“pink puffer”)
 Decreased elastic recoil of the lung
 Increased functional residual capacity (FRC)
 Sitting in a forward hunched position
o Late complications
 Hypoxemia
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 Polycythemia (kidney makes erythropoietin in chronic hypoxia,

leading to hyperviscosity and cerebral thrombosis)
 Pulmonary hypertension (leading to cor pulmonale)
 Cor pulmonale
o Lab investigations
 Pulmonary function tests: increased lung volumes, decreased
FVC, decreased FEV1, decreased FEV1:FVC ratio, decreased
DLCO
 Chest x-ray: increased air trapping, flat domes of diaphragm
 Blood gases: normal until late stages in which there is hypoxia,
hypercapnia, and respiratory acidosis
 COPD: chronic bronchitis
o Chronic productive cough lasting at least 3 months over a minimum
of 2 years
o Largest risk factor is smoking
o Common among smokers and urban dwellers
 Inhaled irritants: cigarette smoke, SO2, NO2
o Loss of elastic recoil
o Affects bronchioles and bronchi with mucus plugs
o Goblet cell hyperplasia and hypertrophy of seromucinous glands
o Expiratory obstruction secondary to collapse
o Irreversible
o Cyanosis
o Increased PaCO2 and decreased PaO2
o Increased risk of infection and cor pulmonale
 Note: any time you have a tube and you block it, you are going
to have an infection behind that tube
o Hypertrophy of the bronchial mucosal glands
 Increased thickness of mucus glands relative to overall
bronchial wall thickness
 Reid index > 40% (over 40% of the bronchial wall is mucinous
glands)
o Pathogenesis
 Submucosal gland hypertrophy leads to hypersecretion of
mucus
 Goblet cell metaplasia in bronchioles
 Eventual smooth muscle hyperplasia and peribronchiolar
fibrosis (small airway obstruction distal to the fibrosis)
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 Inflammation (infiltration of CD8+ T cells, macrophages, and

neutrophils)
 Example question: “inflammation with no eosinophils is
chronic bronchitis, inflammation with eosinophils is
asthma”
o Hyperemia and edema of mucous membranes
o Excessive mucinous or mucopurulent secretions
o MUCUS
o Histology
 Thickening of the mucus gland layer (increased Reid index)
 Goblet cell metaplasia, smooth muscle hyperplasia,
peribronchiolar fibrosis
 Squamous metaplasia (due to irritant)
 5 changes in the bronchi (large airway disease)
 Squamous metaplasia
 Goblet cell hyperplasia
 Basement membrane thickening
 Hypertrophy of bronchial smooth muscles
 Hypertrophy of seromucinous glands (Reid index > 50%)
 4 changes in the bronchioles (small airway disease)
 Goblet cell metaplasia
 Smooth muscle hyperplasia
 Acute and chronic inflammatory cells (no eosinophils)
 Fibrosis of bronchial alveolar walls
o Clinical features
 Persistent cough productive of mucoid sputum
 Progresses to dyspnea on exertion
 Cyanosis (“blue bloaters”)
 Hypoxia
 Persistent hypercapnia
 Not specific to chronic bronchitis
 Respiratory centers insensitivity to PCO2 so respiratory
drive is driven by low pO2 (caution when giving patients
oxygen)
 Cells will adapt and CO2 is not the driving force
anymore; instead the hypoxia (decreased O2) is the
driving force
 Cyanosis
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o Complications
 Secondary infections (no cilia to clear mucus plugs)
 Resorption atelectasis due to obstruction
 Bronchiectasis
 Over time, pulmonary hypertension and cor pulmonale will
occur
 Asthma
o Reversible airway bronchoconstriction
o Most often due to allergic stimuli (type I hypersensitivity reaction)
o Bronchiole hyperreactivity
o Episodic, reversible bronchoconstriction
o Recurrent wheezing, breathlessness, chest tightness, and cough
o Increased mucus secretion
o Anatomic narrowing of airways
o Presents in childhood and is most often associated with allergic
rhinitis, eczema, and a family history of atopy
o Reversible
o Example question: “inflammation with no eosinophils is chronic
bronchitis, inflammation with eosinophils is asthma”
o Clinical features
 Dyspnea and wheezing
 Productive cough
o Curschmann spirals and Charcot-Leyden crystals
o Severe, unrelenting attack can result in status asthmaticus and death
o Allergens induce TH2 phenotype in CD4+ T cells of genetically
susceptible individuals
 TH2 cells secrete IL-4, IL-5, IL-10
 IL-4: allow plasma cells to class-switch to IgE
 IL-5: calls in eosinophils
 IL-10: inhibit production of TH1 cells and induce the production
of TH2 cells (promotes reaction)
o Re-exposure to allergen
 IgE-mediated activation of mast cells leading to
bronchoconstriction (early stage)
 Inflammation (ex: major basic protein) perpetuates
bronchoconstriction (late phase)
 Mast cells have a 2nd phase by which they perpetuate
inflammation by production of leukotrienes C4, D4, E4 causing
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vasoconstriction, increased vascular permeability by

constricting pericytes, and bronchoconstriction
 See inflammation lecture
 Allergen cross-links surface IgE, activating mast cells
 When the mast cell is activated, it dumps pre-formed histamine
granules (1st thing) resulting in histamine-induced vasodilation
and histamine-induced vascular permeability
 Histamine-induced vasodilation occurs at arterioles and leaking
of fluid occurs in the post-capillary venule
o In an acute asthmatic episode, there can be an outpouring of mucus
which, along with dehydration, can lead to the formation of mucus
plugs. These atopic asthmatic episodes in children are usually initiated
by a type I hypersensitivity reaction, typically with exposure to an
allergen, such as pollen
o Classification of asthma
 Based on prior sensitization to allergen
 Atopic: patient is sensitized
o Type I hypersensitivity (IgE)
o Trigger: environmental (dust, pollen, dander,
foods)
o Begins in childhood
o Family history of asthma
o Immediate wheal and flare
o Past history of allergic rhinitis or eczema
 Non-atopic: patient is not sensitized
o Bronchial hyperirritability
o Viral respiratory infections, SO2, NO2
 Non-allergic causes of asthma
 Drug-induced (ex: aspirin-intolerant asthma)
 Occupational
 Seasonal
 Exercise-induced
 Viral infection
o Atopic asthma: type I IgE-mediated hypersensitivity reaction
 Inhaled allergen elicits a TH2 response in genetically
predisposed individuals
 TH2 cells secrete cytokines
 IL-4: stimulates IgE production (elevated IgE)
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 IL-5: activates eosinophils

 IL-13: stimulates mucus production and promotes IgE
production by B cells
 IgE coats mast cells which degranulate with antigen exposure,
leading to symptom presentation
 Subsequent exposure: mast cell degranulation has 2 waves of
reactions
 Early phase: minutes
o Bronchoconstriction
o Increased mucus
o Vasodilation and increased permeability
o Further recruitment of leukocytes causes the late
phase
 Late phase: 4 – 24 hours
o Activation of eosinophils, neutrophils, and T cells
o Epithelial cells are activated and recruit more TH2
cells and eosinophils
 Management is the same, regardless of whether the
patient is in the early or late phase
 Presentation
 Rhinitis (hay fever)
 Eczema (atopic dermatitis)
 Arterial-blood gas levels: initially shows compensation leading
to alkalosis due to hyperventilation (increased pH and
decreased CO2) and as they decompensate within a few hours,
they retain CO2 and become acidotic (decreased pH and
increased CO2)
 Immediate wheal and flare
 Sputum analysis: mucus plugs (IL-13), Charcot-Leyden crystals
(MCP and eosinophilic cationic protein), Curschmann spirals
 Complications: status asthmaticus
o Non-atopic asthma
 No evidence of sensitization (serum IgE is normal)
 Secondary viral infections or inhaled SO2, NO2, and O3
 Virus induced mucosal damage lowers the threshold of
subepithelial vagal receptors to irritants
 Most common cause is influenza virus (viral infection of
the upper respiratory tract)
 Pathogenesis
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 Direct damage by viruses to bronchial mucosa, which

lowers the threshold of vagal receptors and upregulates
parasympathetic response in airways, leading to more
reactive airways
 Wheezing, cough
 Mostly CD8+ T cells
 NO eczema or rhinitis
o Drug-induced asthma (aspirin-induced asthma)
 Aspirin inhibits COX, leading to excessive LOX, and
bronchoconstriction
 Results in recurrent rhinitis, nasal polyps, urticaria, and
bronchospasm (question stem)
o Occupational asthma
 Asthma stimulated by fumes, organic dusts, chemical dusts, and
gases
 Epoxy resins, plastics, wood, cotton, platinum, toluene
 Asthma attacks following repeated exposure
 Easy to diagnose: patient goes to work and has asthma, but
comes home and is fine
o Occlusion of airways by thick mucus
o Hyperinflation of lungs (occurs with all obstructive conditions)
o Histology
 Edema
 Patchy epithelial necrosis
 Bronchial lumen shows mucus plugs with Curschmann spirals,
Charcot-Leyden crystals and eosinophils
 Curschmann spirals: whorls of shed epithelium
 Charcot-Leyden crystals: collections of crystalloids
from eosinophils
 Inflammation with eosinophils
 Increase in goblet cells
 Bronchial smooth muscle hypertrophy and hyperplasia
 Basement membrane thickening
o Clinical features
 Recurrent sudden attacks of dyspnea, chest tightness,
wheeze/ronchi, cough with thick sputum
 Progressive hyperinflation of lungs with air trapped distal to
mucus packed bronchi
 Episodic (nights and early mornings)
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 Attacks last a couple of hours and subside spontaneously or

with therapy
 Status asthmaticus (severe, prolonged, unresponsive to therapy)
needs emergency management
 Obstruction (more during expiration, leading to wheezing)
 Tachypnea
 Eosinophilia
 Hypoxia
 Hypercapnia
 Respiratory acidosis
o No pulmonary hypertension or cor pulmonale
 Eosinophilic granuloma
o NOTHING TO DO WITH EOSINOPHILS
o Also called “pulmonary histiocytosis X” or “pulmonary Langerhan
cell histiocytosis (PLCH)”
o Pulmonary disease in adults that exclusively involves smokers
o Treatment centers on smoking cessation
o Dyspnea and cough
o Interstitial nodular and fibrocystic disease
o Obstructive and restrictive changes on spirometry
o Langerhans cells contain Birbeck granules
 Bronchiectasis
o Permanent dilation of bronchioles and bronchi
o Loss of airway tone results in air trapping
o Destruction of supporting tissue
o Due to or associated with chronic necrotizing inflammation with
damage to airway walls
 Obstruction (tumor, foreign body) can lead to localized
bronchiectasis
 Congenital/hereditary conditions (cystic fibrosis,
immunodeficiency, Kartagener syndrome)
 Cystic fibrosis: thick secretions cause mucus plugging
that increases the risk of infection and infection damages
the airway
o Most common cause of bronchiectasis
 Kartagener syndrome: defect in dynein arm of cilia,
preventing ciliary movement and causing sinusitis,
infertility, situs inversus, or lung infection
 Necrotizing infection
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 Allergic bronchopulmonary aspergillosis: hypersensitivity

reaction of large airways due to aspergillus seen in asthmatics
and patients with cystic fibrosis
o Loss of elastic recoil
o Expiratory obstruction secondary to collapse
o Irreversible
o Proximal to terminal bronchioles
o Obstruction hampers clearance so pooling leads to a secondary
infection, leading to damaged/weakened bronchial walls, resulting in
bronchiectasis
o Tram-track appearance on CT/x-ray due to fibrosis and dilation of
bronchial walls
o Markedly dilated bronchi filled with purulent mucus (pus)
 Large, dilated circular air spaces at the edge of the lungs
 Normally, when you cut the lung, you shouldn’t be able to see
the bronchi near the lung borders
 If bronchi are extending to the border, it is abnormal
o Histology
 Intense acute and chronic inflammatory exudate in bronchial
walls (inflammation)
 Necrotizing ulceration
 Squamous metaplasia of the bronchial epithelium
 Lung abscesses may be present (pus-filled cysts)
 Fibrosis of bronchial walls leading to bronchiolitis obliterans
 Positive cultures
o Clinical features
 Cough up mucus due to mucus trapping
 Dyspnea
 Foul-smelling sputum (loaded with inflammatory junk that has
been sitting and rotting in the lungs)
 Hemoptysis
 Finger clubbing (emphysema and obstructive lung diseases
generally do NOT cause finger clubbing or foul-smelling
sputum)
 Cyanosis
 Cachexia (due to TNF, IL-1, and IL-6)
o Complications
 Hypoxemia with cor pulmonale
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 Secondary amyloidosis: chronic inflammation produces acute-

phase reactant SAA
 Lung abscesses
 Septicemia (metastatic abscess)
o Kartagener syndrome
 Primary ciliary dyskinesia
 Autosomal recessive disorder of ciliary microtubules (normally,
clear out secretions, and without this, there is pooling of
secretions, leading to infection and bronchiectasis)
 Decreased mobility of spermatozoa lead to sterility
 Bronchiectasis, sinusitis, and sinus inversus (organs on the
opposite side)

Restrictive lung diseases (interstitial lung diseases)

 Parenchymal disorder (respiratory bronchiole, alveoli, and alveolar ducts)
 Decreased expansion with reduced total lung capacity, decreased O2
capacity, reduced lung volumes, and reduced compliance
 Restricted from filling the lung (problem with filling the lung)
 Normal/increased FEV1:FVC ratio
 Decreased TLC
 Decreased FVC
 Decreased diffusion capacity (decreased DLCO)
 Decreased FEV1
 Decreased expansion of the parenchyma
 Heterogenous group of lung parenchymal disorders
 Most commonly occurs due to interstitial disease (fibrosis of the
interstitium)
o Fibrosis of the interstitium thickens the gas exchange barrier of the
alveoli, prohibiting the ability to exchange gases well and prevents
filling of the lung because it will be hard to open the fibroses alveoli
when you want to fill the lung
o Infiltrative lung disease: infiltration of cellular and non-cellular
elements within alveolar septa and alveoli
o Restrictive lung disease: characterized by reduced total lung capacity
in the presence of a normal or reduced expiratory flow rate
o Diffuse parenchymal lung disease (DPLD)
 Not a problem with air flow
 “alveolitis”: damage to pneumocytes and endothelial cells
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 Leads to leukocytes releasing cytokines that mediate and stimulate

interstitial fibrosis
 Decreased lung compliance
o Decreased lung expansion during inspiration and increased work to
breathe (need more energy/work in order to fill the lungs)
 Clinical features
o FIBROSIS
o Dyspnea
o Hypoxia
o Tachypnea
o Cyanosis
 Chest x-ray shows bilateral infiltration that can be nodular/reticular (“dots
and lines”) or infiltrative (“ground-glass”)
 Complications
o Progression to respiratory failure with pulmonary hypertension and
cor pulmonale (right heart failure due to lung disease)
 Damage to interstitium lead to V/Q mismatch, resulting in the hypoxia,
which leads to tachypnea and cyanosis
 4 major categories of restrictive diseases
o Fibrosing
 Usual interstitial pneumonia (UIP)
 See below
 Non-specific interstitial pneumonia (NSIP)
 Unknown etiology
 Better prognosis as it is able to be treated with steroids
 Younger demographic
 Histology shows uniform fibrosing process (“chicken-
wire”)
o 2 variants: cellular variant (lymphocytic infiltrate),
or fibrosing variant, or both
 Lacks honeycomb change and fibroblast foci
 Cryptogenic organizing pneumonia (COP)
 Also called “bronchiolitis obliterans organizing
pneumonia” (BOOP)
 Unknown etiology
 Presents with cough and dyspnea
 Patchy peribronchial or subpleural consolidation on
radiography
 Pegg

 Histology
o Alveolar structure is not destroyed
o Masson bodies: polypoid plugs of loose
fibroblastic tissue filling alveolar spaces
 Can be seen following infectious pneumonia, lung or
bone marrow transplants, or collagen vascular diseases
o Collagen vascular disease can manifest as lupus,
rheumatoid arthritis, systemic sclerosis, or
dermatomyositis-polymyositis
 Spontaneous recovery or recovery with steroids
 Acute interstitial pneumonia (AIP)
 Presents as an ARDS patient
 Hamman-Rich syndrome
 Very aggressive form of interstitial lung disease
 May also occur as an acute phase of acceleration of IPF
 Presents with diffuse alveolar damage and hyaline
membranes, similar to those founding ARDS/DAD
 Lymphoid interstitial pneumonia (LIP)
 Expansion of the interstitium by groups and sheets of
lymphoid cells (many lymphocytes)
 Occurs in association with connective tissue diseases,
autoimmune diseases, or HIV
 In a small number of cases, LIP may transform to
lymphoma
 Pneumoconiosis
 See below
o Granulomatous
 Sarcoidosis
 See below
 Hypersensitivity pneumonia (HP)/extrinsic allergic alveolitis
(EAA)
 Inhaled organic antigen produces granulomatous
interstitial pneumonitis (extrinsic allergic alveolitis)
 Associated with inhaled organic antigens often related to
occupational exposures
 Farmer’s lung: moldy hay, thermophilic actinomycetes
bacteria, saccharopolyspora rectivirgula
 Pegg

 Silo fillers’ disease: inhalation of gases from plant

material (nitrogen oxides)
 Byssinosis: cotton, linen, or hemp in textile factory
workers (“Monday morning blues”)
 Presents with fever, cough, and dyspnea hours after the
exposure, and resolves with removal of the exposure
 Chronic exposure leads to interstitial fibrosis
 Pathogenesis
o Immunologically-mediated response to an extrinsic
antigen
o Type III hypersensitivity reaction
 1st exposure: IgG antibodies in serum
 2nd exposure: antibodies combine with
inhaled antigens to form immune complexes
and lead to an inflammatory response in the
lung (interstitial)
 Chronic exposure: granuloma formation
(Type IV hypersensitivity)
o Type III and type IV hypersensitivity reactions
may occur at the same time
o Eosinophilic
 Leoffler syndrome
 Drug/allergy – related
 Chronic eosinophilic pneumonia
o Smoking-related
 Desquamativie interstitial PNA (DIP)
 Alveolar macrophages accumulate within the alveolar
spaces (macrophages in alveolar spaces)
 Minimal interstitial fibrosis (no/little fibrosis)
 Respiratory bronchiolitis, interstitial lung disease (RBILD)
 Macrophages accumulate within the lumen of the
respiratory bronchioles (macrophages in bronchioles)
 Associated peribronchiolar fibrosis (fibrosis)
 Responds to steroids and smoking cessation
 Pulmonary Langerhans cell histiocytosis (eosinophilic
granuloma)
 Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP)
o Unknown etiology, but related to cyclical lung injury with cyclical
healing
 Pegg

 One of the mediators of healing is TGF-, which is released

from injured pneumocytes to induce fibrosis
 Secondary causes: drugs (ex: bleomycin, amiodarone) and
radiation therapy
o IPF is the diagnosis the physician gives
o UIP is the radiographic and pathologic correlate
o Decreased lung compliance
o Males are affected more than females
o 2/3 of patients are > 60 years of age (mean age is 40-70 years old)
o Clinical features
 Insidious onset of progressive dyspnea and cough
 Fibrosis on lung CT
 Fibrosis initially begins in the subpleural region right
underneath the pleura of the lung and eventually will
progress to the entire lung
 Finger clubbing
 Honeycomb lung: diffuse fibrosis throughout the entire
lung (fibrosis retracts and creates spaces)
 Increased interstitial “markings” (fibrosis) in bilateral
lower zones
 Gross appearance shows a “cobblestoned” pleural surface
 Firm, fibrotic parenchyma with lower lobe and
subpleural accentuation
 Honeycomb cysts: cystic spaces are lined by type II
pneumocytes or respiratory epithelium and the dense
fibrosis will destroy the architecture of the parenchyma,
creating cysts
 Temporal and geographic heterogeneity
 Temporal: different stages of fibrosis are seen
simultaneously (mature fibrosis and lung fibroblast foci)
 Geographic: some parts of the lung are fibrosed, and
some parts are fine
 Physical examination may show crackles on inspiration
 Late stages: cyanosis, cor pulmonale, and finger clubbing
o Progressive bilateral interstitial fibrosis, leading to severe hypoxia and
cyanosis
o Relentless progression (once fibrosis appears, it keeps getting worse)
with poor prognosis
 Pegg

o Lung transplant is the only treatment option

 Sarcoidosis
o Diagnosis of exclusion
o Idiopathic systemic disease (multi-system disease)
 Unknown etiology, but most likely due to CD4+ helper T cell
response to an unknown antigen
 Other commonly involved tissues: uvea (uretitis), skin
(cutaneous nodules or erythema nodosum), parotid glands
(bilateral parotitis), salivary and lacrimal glands (mimics
Sjogren’s syndrome)
 Almost any tissue can be involved!
o Non-necrotizing epithelioid granulomata
 Granulomas most commonly involve the hilar lymph nodes and
lungs, creating an interstitial problem, resulting in restrictive
lung disease
 Lung becomes less compliant due to all of the granulomas
present in the interstitium
 Non-caseating: all of the cells of the granuloma are alive and
there is no necrosis
o Young adults < 40 years old
o Affects people of Danish, Swedish, and African American descent
 Classically seen in African American females
o Occurs more often in non-smokers
o Pathogenesis
 Cell-mediated (Type IV) hypersensitivity reaction to an
unidentified antigen
 CD4+ helper T cell driven process
 Intra-alveolar and interstitial accumulation of CD4 TH1
cells that secrete cytokines (IFN- and IL-2)
o IL-2: causes granuloma formation
 Peripheral depletion
 Anergy to skin tests with candida antigen/PPD
o PPD: purified protein derivative
 May lead to end-stage lung disease
o Clinical presentation
 Most of the time, is asymptomatic
 Gradual development of respiratory symptoms in 90% of
patients
 Shortness of breath, dry cough, vague discomfort
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 Constitutional symptoms: fever, fatigue, weight loss, night

sweats
 Severe impairment with CNS, cardiac, ocular, or cutaneous
involvement (panhypopituitarism due to destruction of pituitary
glands and Bell’s facial nerve palsy)
 Sicca syndrome: dry eyes and dry mouth due to parotid glands
and lacrimal glands
 Restrictive cardiomyopathy (heart failure, cardiac arrhythmias,
AV blocks)
 Kidney stones (calcium stones leading to hydronephrosis and
pyelonephritis)
 Liver cirrhosis
 Spleen susceptible to encapsulated bacteria
 Pancytopenia due to bone marrow failure
 Erythema nodosum
o Lab investigations
 Elevated serum ACE
 Hypercalcemia
 Granulomas have 1-hydroxylase activity which
activates Vitamin D
 Note: in any disease in which patients have a ton of non-
caseating granulomas, there will be excess activity of the
1-hydroxylase enzyme, resulting in hypercalcemia
 Chest x-ray shows bilateral hilar lymphadenopathy (incidental
finding), parenchymal infiltrates, or fibrosis (reticular nodules)
o Histology
 Non-necrotizing epithelioid granulomata in a lymphangitic
distribution
 Over time, collagen replaces the granuloma, yielding a
hyalinized scar
 5 – 15% progress to diffuse interstitial fibrosis and honeycomb
lung
 Schaumann bodies: laminated concretions of calcium and
protein deposited in concentric circles
 Asteroid bodies: stellate inclusions in the giant cells
 Note: Schaumann bodies and asteroid bodies will be present in
any disorder in which there is granuloma formation within the
lungs
o Diagnosis of exclusion
 Pegg

 Need to exclude infectious processes before even considering

sarcoidosis
o Treatment usually involves steroids or spontaneous resolution
 Following a lung transplant, sarcoidosis recurs in 35% of
patients
 Most common outcome is remission
 Most common cause of death is recurrent infections
 Pneumoconioses
o Interstitial fibrosis due to occupational exposure
o Requires chronic exposure to small, fibrogenic particles
o Interstitial fibrosis is mediated by alveolar macrophages
 Alveolar macrophages are the only thing in the distal lung for
defense, so they consume the particles and freak out and induce
fibrosis all over the lung to try to wall off the garbage, and as it
induces fibrosis, that is what results in interstitial fibrosis
o Non-neoplastic lung diseases secondary to inhalation of mineral dusts,
organic/inorganic particulates, and vapors
o Asbestosis
 Exposure to asbestos fibers
 Seen in construction workers, milling workers, insulators,
demolitions workers, plumbers, and shipyard workers
 “fibrosis of the lung, fibrosis of the pleura, cancer of the lung,
cancer of the pleura”
 Mesothelioma: cancer of the pleura
 Lung carcinomas are more common than mesothelioma
 Lesions may contain long, golden-brown fibers with associated
iron
 Asbestos body: long, rod-shaped particle with little
brown beads of iron (ferruginous body)
 Fibrogenic
 Pro-inflammatory
 Diffuse interstitial fibrosis
 Pathogenesis
 Exposure to asbestos fibers leads to asbestos
phagocytosis by alveolar macrophages, activation of the
inflammasome and release of proinflammatory factors
and fibrogenic mediators, and ultimately diffuse
interstitial fibrosis due to long-term exposure (persistent
release of mediators)
 Pegg

 Pleural plaques: usually develop over the domes of the

diaphragm and contain dense collagen and calcification, but NO
asbestos bodies
 Incidental finding
o Silicosis
 Exposure to silica (silicon dioxide)
 Seen in sandblasters, miners, demolition workers, stonecutters,
grinders, foundry workers, ceramic workers, and silica miners
 Fibrotic nodules in the upper lobes of the lung
 Increased risk for TB because silica impairs phagolysosome
formation by macrophages
 Inhibits the ability of pulmonary macrophages to kill
phagocytosed mycobacteria
 Fibrogenic
 Pathogenesis
 Activate inflammasome, leading to release of
inflammatory mediates IL-1 and IL-8, leading to fibrosis
 Collagenous nodule/scar usually in the hilar lymph nodes and
upper lung field
 Eggshell calcification: sheets of calcification in the periphery
of lymph nodes; radiographic finding
 Progressive massive fibrosis
 Histology
 Central area of whorled collagen fibers with dust-laden
macrophages
 Weakly birefringent under polarized microscopy
 Slow progression
o Coal workers pneumoconiosis (CWP)
 Exposure to carbon dust
 Coal miners
 Massive exposure leads to diffuse fibrosis and “black lung”
 Associated with rheumatoid arthritis (Caplan syndrome)
 Mild exposure to carbon (ex: pollution) results in anthracosis
 Anthracosis: collections of carbon-laden macrophages
due to accumulation of carbon pigment in peri lymphatic
regions and lymph nodes
o Asymptomatic
 Morphological changes in chronological order
 Anthracosis
 Pegg

 Simple CWP
o Macules and nodules composed of aggregates of
dust-laden macrophages
 Coal macules: coal dust-laden macrophages
with reticular fibers (type III collagen)
 Coal modules: aggregates of macules along
with type I collagen
o Minimal or absent fibrosis
o Little or no pulmonary dysfunction
o < 10% progress to complicated
 Complicated CWP (progressive massive fibrosis)
o Coalescence of nodules into fibrous scars
o Impaired pulmonary function
 No risk for cancer or TB
 Risk of cor pulmonale
o Berylliosis
 Exposure to beryllium
 Seen in beryllium miners and workers in the aerospace industry
 Non-caseating granulomas in the lung, hilar lymph nodes, and
systemic organs
 Sounds exactly like sarcoidosis, except it is driven by
beryllium!
 Increased risk for lung cancer
 Example: “patient works for NASA or recently designed a jet”
 Acute restrictive disease (ARDS)
 Chronic restrictive diseases (interstitial fibrosis, pneumoconiosis,
granulomatous)
 May also arise with chest wall diseases/deformities
o Obesity
o Pleural diseases
o kyphoscoliosis
 Neuromuscular (ex: Gullian-Barré)

Pneumonia: any infection of lung parenchyma

 Can arise from bacteria, viruses, mycoplasma, or fungi
 Can be acute or chronic
 Fever, cough, dyspnea, chest pain
 “pneumonia” is also used for interstitial lung diseases that are non-infectious
 Pegg

Vascular diseases
 Pulmonary edema
o Accumulation of fluid in alveolar spaces, leading to decreased
diffusing capacity, hypoxemia, and shortness of breath
o See hemodynamics slide 7
o Cardiogenic: left heart failure
o Non-cardiogenic: ARDS, high altitude, neurogenic (head trauma,
SAH/ICH, ECT, intracranial surgery, seizure), pulmonary embolism
 Pulmonary thromboembolism
o Blood clot travels to the lungs, lodging within a pulmonary artery or
downstream branch
o Originates in larger, deeper veins of the legs/pelvis
o Risk factors: immobility (airplane, bed rest), orthopedic surgery,
severe trauma (burns, fractures), congestive heart failure, birth control
pills (elevated estrogen), disseminated malignancy, hypercoagulability
disorders (factor V Leiden, protein C deficiency, protein S deficiency,
antithrombin III deficiency, lupus anticoagulant)
o Virchow’s triad
o Effect of the pulmonary embolism is dependent on the size of the
embolus and the cardiopulmonary status of the patient
o Consequences of pulmonary arterial occlusion
 Increased pulmonary artery pressure with or without vasospasm
and release of mediators (TXA2, 5-HT)
 Ischemia of pulmonary parenchyma
o Acute increase in pressure on the right heart
o Hypoxia secondary to…
 Atelectasis: reduced surfactant production in the ischemic areas
 Some blood flow is redirected to the normally hypoventilated
areas of the lung
 Right-to-left shunt through a patent foramen ovale
o Saddle embolus: large embolus lodges in the main pulmonary artery
bifurcation
 Sudden death from hypoxia or acute right heart failure
o Ischemic necrosis/infarct is rare and occurs when combined with
compromised cardiovascular status (hemorrhagic, wedge-shaped,
peripheral)
 Pegg

o 60 – 80% are asymptomatic

o 10 – 15% result in infarction
 End artery occlusion and cardiovascular compromise
 Dyspnea
o 5% result in sudden death, acute cor pulmonale, and shock
 60% of total pulmonary vasculature obstructed by a large
embolus or multiple simultaneously small emboli
o < 3% result in pulmonary hypertension and chronic cor pulmonale
secondary to recurrent emboli
o Non-thrombotic pulmonary embolism: air, fat, amniotic fluid, IV
drugs, bone marrow
o Hemorrhage
o Infarction
o CT pulmonary angiogram
o Fat embolism
 1-3 days after broken bones
 Free fatty acids damage the endothelium, leading to
thrombocytopenia and petechiae, leading to DIC
 Stains: osmium tetroxide, oil red O, Sudan black
 Pulmonary hypertension
o High pressure in the pulmonary circuit
o Normal pressure in the pulmonary circuit is low (10 mmHg)
o Pressure in the pulmonary artery is at least 25 mmHg at rest
o Primary
 Sporadic
 6% familial (autosomal dominant)
 TGF-: mediator of smooth muscle proliferation
 50% of familial cases have germline mutations in BMPR
type 2 (bone morphogenetic protein receptor)
 Normal BMPR type 2 binds to various TGF- pathway
ligands and inhibits smooth muscle proliferation
 Familial forms are related to inactivating mutations of
BMPR2, leading to proliferation of vascular smooth
muscle
o Secondary
 Due to decreased cross-sectional area of blood flow due to
COPD or interstitial lung disease, recurrent pulmonary emboli,
or heart disease (mitral stenosis, left-to-right shunt)
 Pegg

 Endothelial cell dysfunction due to an underlying disorder

 Decreased vasodilatory agents
 Increased vasoconstrictive agents
 Growth factor production
 Occurs due to hypoxemia (ex: COPD, interstitial lung disease)
or increased volume in the pulmonary circuit (ex: congenital
heart disease)
 During hypoxemia, vessels in the lung constrict in an
effort to shunt blood to other lung areas
 May also arise with a recurrent pulmonary embolism
 Asymptomatic, because the lung has a dual circulation
and most pulmonary emboli are relatively small
 May get pulmonary infarction or sudden death due to
saddle emboli
 Chronic, long-standing pulmonary embolism that gets
reorganized, resulting in thickening of the vascular wall,
resulting in pulmonary hypertension
o Loud P2: sound of pulmonary valve closing under pressure
o Clinical features
 Primary pulmonary hypertension
 Young women
 Fatigue, syncope, dyspnea on exertion, chest pain
 Severe respiratory insufficiency, cyanosis
 Death from right heart failure 2-5 years from the
diagnosis
 Treatment: vasodilators, anti-thrombotic agents, and lung
transplant
 Secondary pulmonary hypertension
 Any age
 Reflects underlying disease (pulmonary or
cardiovascular)
 Respiratory insufficiency and right heart strain
o Leads to right ventricular hypertrophy and cor pulmonale
 Presents with exertional dyspnea or right-sided heart failure
 Example: “young woman with exertional dyspnea”
o Atherosclerosis of the pulmonary trunk
o Smooth muscle hypertrophy of the pulmonary arteries
o Intimal fibrosis
 Pegg

o Plexiform lesions in severe, long-standing pulmonary hypertension

o Morphological changes
 Main elastic arteries: atheromas
 Medium-sized muscular arteries: intimal cell and smooth
muscle cell proliferation (wall thickening)
 Small arteries/arterioles: thickening, medial hypertrophy,
reduplication of the internal and external elastic lamina
 Plexiform lesions: multiple lumina within a small artery at a
branch point from a larger artery; tuft of capillaries that arise as
a result of long-standing
 Right ventricular hypertrophy (chronic)
 Vasculitis
o See last modules lectures
 Diffuse alveolar hemorrhage syndromes
o Primary immune-mediated diseases which manifest as a triad of
hemoptysis, anemia, and diffuse pulmonary infiltrates
o Bleeding into alveolar spaces
o Goodpasture syndrome
 Immunofluorescence: linear deposition of IgG (anti-basement
membrane antibody)
 Antibody against collagen in the glomerular and alveolar
basement membranes
 Antibodies target the 3-chain of type IV collagen
 Hematuria and hemoptysis
 Young, adult males who are active smokers
 RPGN: nephritic syndrome that progresses to renal failure in
weeks to months; characterized by crescents in Bowman’s
space that are comprised of fibrin and macrophages
 Heavy lungs with red-brown consolidation
 Abundant hemosiderin due to earlier episodes of
hemorrhage
 Histology
 Intra-alveolar hemorrhage (Prussian blue stain picks up
iron)
 Patchy necrosis of alveolar walls
 Intra-alveolar hemosiderin
 Septal thickening and reactive hypertrophy of type II
pneumocytes in later stages
 Chest x-ray shows focal consolidations
 Pegg

 Clinical findings
 Hemoptysis
 Anemia
 Pulmonary infiltrates
 RPGN: hematuria, edema, uremia
 Treatment
 Plasmapheresis: filter out antibodies
 Immunosuppressive therapy
 Kidney transplant
 “1, 2, 3, 4 of Goodpasture’s”
 Type 1 RPGN
 Type II hypersensitivity
 3 chain
 Type IV collagen
o Idiopathic hemosiderosis
 Rare
 More common in children
 Histopathology similar to Goodpasture’s
 Not associated with renal disease
 No anti-basement membrane antibodies
 Treatment: steroids and immunosuppression
o Wegener granulomatosis (polyangiitis with granulomatosis)
 Immunofluorescence: negative (pauci-immune)
 C-ANCA (PR3-ANCA)
 Autoimmune disease
 Granulomas in the lung/upper respiratory tract
 Cavities can become organizing and cause fibrosis
 Vasculitis of small-medium sized vessels
 RPGN
 Middle-aged men
 Clinical features
 Pneumonitis with nodules and cavitary lesions
 Chronic sinusitis
 Mucosal ulcerations of the nasopharynx
 RPGN: hematuria, proteinuria
 Rashes
 Myalgias
 Fever
 Pegg

 Articular involvement
 Neuritis
 Histology
 Patchy necrosis (geographic)
 Neutrophilic micro-abscesses
 Necrotizing granulomas
o Palisaded: elongated nuclei, “fence-like”
appearance
o Free giant cells
 Vasculitis (necrotizing capillaritis)
 Necrotizing/crescentic RPGN
 Treatment: steroids, cyclophosphamide, anti-TNF, rituximab

Neoplasia of the Lung

 Note: “when the tumor starts with an ‘S’, then it is going to be highly
associated with Smoking, it is going to be Central, and it will be associated
with paraneoplastic Syndromes”
o Squamous cell carcinoma
o Small cell carcinoma
 General features of carcinomas of the lung
o Bronchogenic carcinoma makes up 90-95% of all lung tumors
o Single most important cause of cancer in 1st world countries
o All involve a 3p deletion
o Risk factors: cigarette smoke, radon, asbestos
o Presentation
 Non-specific symptoms: cough, weight loss, hemoptysis, post-
obstructive pneumonia, etc.
 Imaging shows a solitary nodule/coin lesion about 2-5 cm in
diameter
 Question: “what is the next step after finding a solitary
nodule?”
 “Go back and compare against a prior x-ray. If the coin
lesion hasn’t changed over time, it is more likely to be
something benign. However, if it is new or growing, that
would raise concern and prompt a biopsy”
 Biopsy is necessary for cancer diagnosis
 Pegg

o Asbestos exposure + smoking causes a 55x risk for cancer due to

synergy
o Peripheral tumors may be clinically silent (ex: adenocarcinomas)
o Central (hilar) tumors may lead to obstruction, infection, or atelectasis
o Local complications
 Pleural involvement (adenocarcinoma)
 Obstruction of the superior vena cava (SVC syndrome)
 Involvement of the recurrent laryngeal or phrenic nerve
 Compression of the sympathetic chain leading to ptosis,
pinpoint pupils, and anhidrosis (Horner syndrome) (Pancoast
tumor at the apex of the lung)
o Clinical features
 Cough
 Weight loss (cachexia)
 Hemoptysis
 Dyspnea
 Chest pain
 Finger clubbing (pulmonary osteoarthropathy)
o Lymph node metastasis most common, followed by adrenal metastasis
 Pancoast tumor
o Any tumor present at the apex of the lung
o Apical neoplasm (T1T2 destruction)
o Wasting of hand muscles and pain in arms due to ulnar nerve damage
within the brachial plexus
o Horner syndrome: compression of the sympathetic cervical plexus
o Compression of blood vessels leads to edema
o Recurrent laryngeal nerve paralysis
o Dysphagia (if esophagus is involved)
o Chylothorax (due to thoracic duct obstruction)
 Small cell (oat cell) carcinoma
o Poorly differentiated small cells
 Significant degree of mitotic activity
o Histology
 Round cells with scant cytoplasm and fine, granular chromatin
(“salt and pepper” appearance)
 Fragile
 “Crush artifacts” (Azzopardi effect)
 Nuclear molding
 Extensive necrosis (eosinophilic and no nuclei)
 Pegg

 Mitotically active (hyperchromatic nuclei and high

nuclear:cytoplasmic ratio)
 Inconspicuous nucleoli
 Many sheets of cells that are 3x the size of resting lymphocytes
o Arises from neuroendocrine cells
 Chromogranin positive
 Synaptophysin
 Neuron-specific amylase
o Male smokers
o Centrally located
o Paraneoplastic syndromes: Cushing’s (ACTH), SIADH (ADH),
Lambert-Eaton syndrome (antibodies against pre-synaptic Ca2+
channels), gastrin-releasing peptide, calcitonin
o Presents as metastatic
 Early metastasis to mediastinal lymph nodes
 Frequent vascular invasion
o Genetic components: myc amplification, p53, RB, 3p deletion
o Not amenable to surgery! (“cells of small cell carcinoma are so small
that the surgeon cannot see them”)
o Treatment: chemotherapy
 Squamous cell carcinoma
o Keratin pearls: eosinophilic aggregates of keratin surrounded by
neoplastic squamous cells
o Intercellular bridges: tight junctions between adjoining neoplastic
squamous cells
o Most common tumor in male smokers
o Arsenic in cigarettes increases the risk for squamous cell carcinoma
o Spreads to hilar lymph nodes
o May cause obstruction, atelectasis, and infection
o Central necrosis from tumors outgrowing the blood supply may lead
to cavitation
o May lead to “endogenous lipid pneumonia” (alveoli filled with foamy
macrophages)
o Genetic components: 3p deletion, p16/CDKN2a
o Centrally located
o Paraneoplastic syndrome: produce parathyroid-hormone related
peptide (PTHrP), resulting in hypercalcemia
 Pegg

o Do NOT use bevacizumab in these patients, because it can lead to

life-threatening hemorrhage
o Patients are also less like to respond to pemetrexed
o Order of metastases
 “LA Lakers Brought Back Kobe”
 Lymph nodes to adrenal gland, to liver, to brain, to bone, to
kidney
 Adenocarcinoma in-situ (bronchioloalveolar carcinoma)
o Columnar cells that grow along pre-existing bronchioles and alveoli
o Arises from Clara cells
o Genetic components: 3p deletion, p16/CDKN2a
o Peripherally located
o May present with pneumonia-like consolidation on imaging
o Excellent prognosis
o Dysplastic cells grow along pre-existing septae
o Walls of alveolar air sacs are replaced by tall, columnar cells
o Hyperchromatic cells along septa
o Cells are plump with mucin
o Lipidic pattern of growth
o “butterfly on a fence” appearance
o No invasion of the basement membrane
o Clinical features
 Cough
 Pneumonia-like presentation
 However, patient does NOT respond to antibiotics!
 “ground glass” appearance on x-ray
 Adenocarcinoma
o Glands or mucin
o Slow growing
o May invade pleural cavity and cause pleural effusion
o Metastasis widely at an early stage
o May be associated with scarring
o Most common tumor in non-smokers and female smokers
o Patients are younger than 45 years old
o Most common primary lung tumor
o Peripherally located
o Genetic components: 3p deletion, p16/CDKN2a, KRAS, EGFR, ALK
(signet-ring adenocarcinoma)
 Pegg

o Signet-ring adenocarcinoma: “large, hyperchromatic peripheral

nuclei”
o Classification in order of increasing malignancy
 Atypical adenomatous hyperplasia (AAH)
 Most benign
 Proliferation of slightly atypical pneumocytes along
alveolar septa
 Alveolar septa lined by dysplastic cells that have not
invaded the basement membrane
 Adenocarcinoma in-situ
 Lacks invasive disease
 Minimally invasive adenocarcinoma
 Invasive histologic types (>5 mm)
 Most malignant
o Histology
 Morphological differentiation: gland formation
 Functional differentiation: mucin production
 Thyroid transcription factor I stain
o Paraneoplastic syndrome: Trousseau’s syndrome
o Grading: ratio of glands to solid elements
 G1: well-differentiated
 G2: moderately-differentiated
 G3: poorly-differentiated
o Staging: status of invasion
o Patients with advanced lung adenocarcinoma who are positive for the
EGFR mutation are more likely to respond to treatment with tyrosine
kinase inhibitors such as gefitinib or erlotinib
o Patients with adenocarcinoma or unspecified non-squamous cell large
cell carcinoma are more likely to respond to pemetrexed
o Cirzotinib is a protein kinase inhibitor drug that inhibits the active
EML4/ALK fusion protein found in 45% of NSCLC patients
o KRAS mutations have poor response to EGFR inhibitor
treatment
 Large cell carcinoma
o Poorly differentiated large cells with no keratin pearls, no intercellular
bridges, no glands, and no mucin
 Diagnosis of exclusion
 Lack of squamous or glandular differentiation
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 Pleomorphic and “bizarre” cells (cells of different shapes and

sizes with large nuclei and fine, granular chromatin)
o Anaplasia with tumor giant cells
o Ki67 positive
o Immunohistochemical stain: cytokeratin (epithelial), vimentin
(connective tissue), desmin (muscle)
o Associated with smoking
o Genetic components: 3p deletion, p16/CDKN2a
o Can be centrally or peripherally located
o Poor prognosis due to early metastasis
 Carcinoid tumor
o Well-differentiated neuroendocrine cells
 Chromogranin positive
 Nests of cells that are not mitotically active and do not show
necrosis
 Arises from Kulchitsky cells (neuroendocrine cells present in
the epithelial lining of the bronchus)
 “salt and pepper” chromatin
 Fine, granular cytoplasm
 Uniform appearance
o Not related to smoking
o Most common in people who are 40 years old
o Can be centrally or peripherally located
 Classically forms a polyp-like mass in the bronchus
 Polypoid growth/finger-like projection
o Clinical features
 Obstruction
 Cough
 Hemoptysis
 Infection
o Low-grade malignancy
 Good prognosis
 Resectable
o May cause carcinoid syndrome
 Neuropeptides are secreted into the systemic circulation to lead
to symptoms
 Mostly serotonin, but may include histamine, bradykinin, and
prostaglandins
 Episodic attacks
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 Vasomotor disturbances: flushes, cyanosis

 GI hypermotility: diarrhea, cramps, vomiting
 Asthma attacks
 Malignant mesothelioma
o Primary malignancy of the pleura, peritoneum, or pericardium
o Strongly associated with asbestos
o Clinical features
 Chest pain
 Dyspnea
 Cough
 Fatigue
o Imaging shows moderate to large unilateral pleural effusion, nodular
pleural thickening (PET scan)
o 3 primary histological patterns
 Epithelioid
 Sarcomatoid
 Mixed (biphasic)
o Differential diagnosis considerations
 Metastases from other primary sites (ex: breast, lung, stomach,
kidney, pancreas, ovary, etc.)
 Primary pleural tumors (ex: angiosarcoma, epithelioid
hemangioendothelioma, synovial sarcoma, etc.)
 Lymphoma, leukemia (CLL), melanoma
o Poor prognosis, clinical course is usually progressive and fatal
 Pulmonary hamartoma
o Nodules of connective tissue (cartilage/fibrous tissue/fat) along with
epithelial clefts
o Bronchial hamartoma is often calcified
o Benign mass comprised of tissue that normally belongs in that
location, however, it is disorganized
o Contains lung tissue and cartilage
 Others
o Lymphoma
o Lymphamatoid granulomatosis
o Sclerosing hemangioma
o Clear cell tumor
o Germ cell tumors
o Pulmonary Langerhan cell histiocytosis (PLCH)
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o Metastatic tumors (secondary)

 Most common sources are breast and colon carcinomas
 Multiple “cannon-ball” nodules on imaging
 More common than primary tumors

Pulmonary causes of finger clubbing

 Bronchiectasis
 Lung abscess
 Emphysema
 Lung cancer
 IPF/UIP
 Mesothelioma

Loeffler’s: hyper-eosinophila in response to Ascaries (nematodes)

 Abnormal granulation of eosinophils leads to release of MBP (abnormal
degranulation)
 Damages the heart (restrictive cardiomyopathy) and lungs (restrictive lung
disease)

Infectious pneumonias
 Community-acquired pneumonias
o Productive cough due to exudate within alveolar spaces
o Lobar pneumonia
 Entire lobe is consolidated
 Spreads via pores of Kohn
 No destruction of alveolar walls
 No involvement of bronchi
o Bronchopneumonia
 Begins in the bronchus (structural damage to bronchus and
bronchioles)
 Patchy consolidation within the lungs
o Organisms
 S. pneumonia (most common)
 Klebsiella (alcoholics, post-surgery, diabetics)
 S. aureus (post-viral)
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 COPD patient: S. pneumoniae, H. influenzae, Moraxella

catarrhalis
 Cystic fibrosis/severe burns: pseudomonas
 Also associated with neutropenia
 Atypical pneumonia
o Dry cough
o Involves alveolar septa (alveolar spaces are empty)
o Inflammatory response (mononuclear as organisms are obligate
intracellular)
o Organisms
 Mycoplasma (most common)
 Hemolytic anemia (cold agglutinins) due to hemolysis in
extremities
 Rash over trunk and extremities (erythema multiform)
 Coxiella
 Farmers or veterinarians (cattle and sheep)
 Within placental products of sheep and cattle
 Q fever: ring granuloma in the liver and causes hepatitis
 Viruses: influenza, rhinovirus, adenovirus
 Chlamydia psittacci: inhalation of parrot feces (psitacossis)
 Chlamydia pneumoniae
o Mild symptoms: dry cough, fatigue, headaches
 Hospital-acquired pneumonia
o Gram negative organisms
 Pseudomonas
 Klebsiella
 E. coli
o Risk factors
 Ventilation (most common)
 Central lines in ICU patients
 Broad spectrum antibiotics
 Immunocompromised patients (especially organ transplant and
AIDS patients)
 Pre-existing lung diseases
 Aspiration pneumonia
o Goes to right lung
o Usually a mixed flora (mostly anaerobes)
o Productive cough with foul-smelling sputum
o Fever
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o Dyspnea
o Risk factors
 Alcoholics (decreased cough and gag reflex)
 Strokes
 Seizures
 Comatose patients
 Bed-ridden patients/Alzheimer’s (number one cause of death
in patients with Alzheimer’s)
 Infection-related pneumonia
o Burns, cystic fibrosis, neutropenia, ventilators, HAP: Pseudomonas
o AC units, water fountains (LUA, SIADH, liver, renal, GI
disturbances): Legionella
o Alcoholics, diabetics, HAP: Klebsiella
o Veterinarians, farmers: Coxiella
o Post-viral pneumonia: S. aureus (otherwise, strep pneumoniae)
o Parrot droppings: Chlamydia psittacci
o Bird/bat droppings with RES involvement in Ohio/Mississippi:
Histoplasma
o COPD patients: S. pneumoniae, H. influenza, Moraxella catarrhalis
o Healthy young adult with lobar consolidation: S. pneumoniae
o Healthy adult with dry cough, dyspnea on exertion, rash on trunk and
limbs, cold AIHA (IgM): Mycoplasma
o Arizona construction worker with erythema nodosum, arthralgia,
Valley Fever: coccidiodes
o Broad budding yeast with bone lesions: Blastomyces
o AIDS patient with interstitial infiltrate: P. jirovecii
o Immigrant with night sweats, weight loss, fever, hemoptysis, and
sputum positive for acid-fast bacilli: tuberculosis
o Recurrent productive cough, dyspnea with high serum IgE and
eosinophilia, and acute angle branching fungi with septate hyphae:
aspergillis
o History of recurrent pneumonia in a sickle cell patient/auto-
splenectomy due to encapsulated bacteria: S. pneumoniae, H.
influenza

Lung Abscess
 Liquefactive necrosis (cavity filled with pus)
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 Risk factors
o Aspiration
o Bronchial obstruction (cystic fibrosis, Kartagener’s, lung tumors)
o Bacterial endocarditis with septic embolization
 IV drug users (tricuspid valve)
o Septicemia
o Infection of TB cavities
o Wegener’s granulomatosis
o Churg-Strauss
o Complications of necrotizing bacterial pneumonia
 Angio-invasive bacteria: Klebsiella and Pseudomonas
 cause necrosis
 Pathogenesis
o Enzymatic degradation of lung parenchyma (enzymes made by
neutrophils and macrophages lead to liquefactive necrosis)
 Presentation
o Productive cough with foul-smelling sputum
o Halitosis
o Spiking fever
o Finger clubbing
o Cachexia
 Chest x-ray shows air and pus within air cavity
 Complications
o Emphysema leading to compression atelectasis (most common)
o Bronchopleural fistula
o Septicemia leading to meningitis and brain abscess
o Amyloidosis (AA/systemic)
o Fungal ball (aspergilloma)
o Cavity may become organizing and become a fibrous scar