Lungs - Patho

What is pulmonary hypoplasia, and what are its common causes?

A defect in lung development characterized by a decrease in lung size. It is caused by abnormalities that compress the lung or impede lung expansion in utero, such as Congenital Diaphragmatic Hernia (CDH) and Oligohydramnios.

Most common foregut cyst?

Bronchogenic cyst.

Describe foregut cysts – types, location, and clinical significance.

Origin: Abnormal detachment of primitive foregut.

Location: Hilum or middle mediastinum.

Types: Bronchogenic (most common), esophageal, enteric.

Clinical: Usually incidental; may cause symptoms from compression of nearby structures.

Extralobar vs. intralobar sequestration – typical presentation?

Extralobar → infant mass.

Intralobar → recurrent infections in older child.

Define pulmonary sequestration and differentiate the two types.

Definition: Discrete area of lung tissue not connected to airways, with abnormal blood supply.

Extralobar: Outside lung; often presents in infants as a mass lesion.

Intralobar: Within lung; presents in older children/adults with recurrent infections or bronchiectasis.

Atelectasis with mediastinal shift toward affected lung?

Resorption atelectasis (airway obstruction)

Atelectasis with mediastinal shift away from affected lung?

Compression atelectasis (pleural fluid/tumor/air).

List the three types of acquired atelectasis and their causes.

1. Resorption: Obstruction of airway → air resorbed distally → collapse; mediastinum shifts toward affected lung.

2. Compression: Accumulation of fluid, tumor, or air in pleural cavity compresses lung; mediastinum shifts away.

3. Contraction: Focal or generalized pulmonary/pleural fibrosis.

Cardiogenic pulmonary edema mechanism?

Increased hydrostatic pressure (left heart failure).

Non-cardiogenic pulmonary edema mechanism?

Microvascular injury → increased capillary permeability.

List all causes of pulmonary edema according to classification.

Hemodynamic Edema - Left-sided heart failure (common), volume overload, pulmonary vein obstruction, hypoalbuminemia, lymphatic obstruction

Edema due to alveolar wall injury - Infections, inhaled gases (O₂, smoke), aspiration, radiation, lung trauma; indirect: sepsis, burns, pancreatitis, transfusion, drugs/chemicals

Edema of undetermined origin - High altitude, neurogenic

Heart failure cells are?

Hemosiderin-laden macrophages.

“Brown induration” of lung is seen in?

Long-standing pulmonary congestion (e.g., mitral stenosis).

Describe the microscopic findings in cardiogenic pulmonary edema.

Engorged alveolar capillaries

Intra-alveolar exudates (finely granular pink material)

Alveolar microhemorrhages

Heart failure cells: hemosiderin-laden macrophages (abundant in chronic congestion)

Brown induration: fibrosis + thickening of alveolar walls → lungs become firm and brown.

Hallmark histology of ARDS (Acute Respiratory Distress Syndrome)?

Hyaline membranes.

What is ARDS (Acute Respiratory Distress Syndrome)?

Manifestation of severe acute lung injury; abrupt hypoxemia + bilateral pulmonary edema (non-cardiogenic).

Pathogenesis of ARDS

Injury to pneumocytes and pulmonary endothelium.

Endothelial activation (by mediators or via alveolar macrophages).

Neutrophil adhesion, extravasation → release of proteases, ROS, cytokines.

Leaky capillaries → interstitial and intra-alveolar edema, surfactant abnormalities → hyaline membrane formation.

Resolution (type II pneumocyte proliferation, endothelial regrowth) or progression.

Histologic stages of ARDS

Exudative: Hyaline membranes, edema, inflammation.

Proliferative/organizing: Type II pneumocyte proliferation, granulation tissue.

Note: Lesions unevenly distributed → V/Q mismatch. Worse prognosis in chronic alcoholics and smokers.

FEV1/FVC ratio in obstructive disease?

< 0.7

Most common form of emphysema?

Centriacinar (centrilobular).

Emphysema associated with α1-antitrypsin deficiency?

Panacinar (panlobular) – lower lobes.

Centriacinar (anatomic site, lobe predilection, association, feature, microscopic)

Central acinus (respiratory bronchioles)

Upper lobes

Heavy smoking (95% of cases)

Centriacinar

Both emphysematous and normal airspaces in same acinus

Panacinar (anatomic site, lobe predilection, association, feature, microscopic)

Entire acinus

Lower zones, anterior margins

α1-antitrypsin deficiency

Panacinar

Uniform enlargement from respiratory bronchiole to alveoli

Clinical definition of chronic bronchitis?

Cough with sputum ≥3 months in ≥2 consecutive years.

Reid index in chronic bronchitis?

Ratio of mucous gland thickness to wall thickness; normal ~0.4, increased in chronic bronchitis.

Describe the pathogenesis of chronic bronchitis

Initiating factor: inhaled irritants (tobacco, dust).

Early feature: mucus hypersecretion → submucosal gland enlargement, goblet cell hyperplasia.

Mediators: histamine, IL-13; acquired CFTR dysfunction → abnormal dehydrated mucus.

Inflammation and fibrosis of small airways lead to obstruction.

Infection does not initiate but maintains and causes exacerbations.

Describe the morphology of chronic bronchitis.

Gross: hyperemia, swelling, excessive mucinous/mucopurulent secretions.

Microscopic: chronic inflammation (lymphocytes, macrophages), goblet cell hyperplasia, mucous gland enlargement, peribronchial fibrosis.

Reid index: ratio of mucous gland layer thickness to total wall thickness (epithelium to cartilage). Normal 0.4; >0.4 indicates chronic bronchitis.

Complication: obliteration of lumen (bronchiolitis obliterans)

“Blue bloater” = ?

Chronic bronchitis (hypoxic, cor pulmonale, copious sputum).

“Pink puffer” = ?

Emphysema (dyspnea, scanty sputum, late hypoxia).

Asthma – most common form?

Atopic asthma (IgE-mediated, childhood onset).

Aspirin-sensitive asthma mechanism?

Inhibits cyclooxygenase → decreased PGE2.

Asthma – Curschmann spirals?

Spiral mucus plugs from bronchioles.

Asthma – Charcot-Leyden crystals?

Eosinophil-derived galectin-10.

Describe the pathogenesis of asthma.

Th2-mediated response to allergens.

IL-4 → IgE production; IL-5 → eosinophil activation; IL-13 → mucus secretion.

Early phase: bronchoconstriction, mucus, vasodilation.

Late phase: recruitment of eosinophils, neutrophils, T cells. o Genetic susceptibility: loci on 5q (IL13, IL4R), IL33, TSLP.

Describe the subtypes of asthma.

Atopic: IgE-mediated (Type I) hypersensitivity; childhood onset; positive family history; skin test positive; high IgE.

Non-atopic: No allergen sensitization; triggered by viruses, pollutants, cold, exercise.

Drug-induced: e.g., aspirin – inhibits cyclooxygenase → decreased PGE2 → asthma.

Occupational: Fumes, dust, gases after repeated exposure.

Describe the morphology of asthma

Gross: thick, tenacious mucus plugs. o

Microscopic: Curschmann spirals, Charcot-Leyden crystals, airway remodeling (sub-basement membrane fibrosis, goblet cell hyperplasia, smooth muscle hypertrophy, increased vascularity).

Bronchiectasis – common organisms in sputum?

H. influenzae, P. aeruginosa.

Define bronchiectasis

Permanent dilation of bronchi and bronchioles due to destruction of smooth muscle and elastic tissue from persistent/severe infection.

Causes of bronchiectasis

Congenital: cystic fibrosis, intralobar sequestration, immunodeficiency, primary ciliary dyskinesia, Kartagener syndrome.

Acquired: severe necrotizing pneumonia, bronchial obstruction (tumor, foreign body), immune disorders (RA, SLE, IBD).

Idiopathic: up to 50%.

Morphology of bronchiectasis

Gross: dilated airways (up to 4× normal), often lower lobes; cystic spaces f illed with mucopurulent secretions.

Microscopic: intense acute and chronic inflammation, desquamation, ulceration.

Clinical: severe persistent cough, foul-smelling sputum, hemoptysis, paroxysms on morning rising.

Restrictive pattern on PFTs (Pulmonary Function Tests)?

Decreased total lung capacity, normal FEV1/FVC.

End-stage lung appearance in chronic interstitial disease?

Honeycomb lung.

What are the categories of restrictive lung disease?

Chronic interstitial and infiltrative diseases (e.g., idiopathic pulmonary f ibrosis, pneumoconioses).

Chest wall disorders (neuromuscular diseases, severe obesity, pleural diseases, kyphoscoliosis).

What are the functional abnormalities of restrictive lung diseases?

Functional: Reduced total lung capacity; FEV1 and FVC decrease proportionally → FEV1/FVC ratio normal.

Clinical: Dyspnea, tachypnea, end-inspiratory crackles, cyanosis; chest X-ray shows nodules, lines, ground-glass shadows; advanced = honeycomb lung.

Most common source of pulmonary emboli?

Deep vein thrombosis (leg veins).

Saddle embolus lodges where?

Main pulmonary artery bifurcation.

Definitive diagnosis for PE?

CT pulmonary angiogram.

Describe the pathogenesis of pulmonary embolism.

Source: Thrombi from deep leg veins (90%).

Risk factors: Thrombophilia (Factor V Leiden, prothrombin mutation, antiphospholipid), immobilization, surgery, cancer, pregnancy, obesity, oral contraceptives.

Pathophysiology:

1. Respiratory compromise: non-perfused but ventilated segment → V/Q mismatch.

2. Hemodynamic compromise: increased pulmonary vascular resistance → acute right heart failure, sudden death.

Describe the morphology of pulmonary embolism.

Large emboli: lodge in main pulmonary artery or bifurcation (saddle).

Smaller: more peripheral → hemorrhagic infarct (red-blue, raised area; histology shows ischemic necrosis of alveolar walls).

Septic infarct: infected embolus with intense neutrophilic reaction.

Describe the clinical features of pulmonary embolism.

Large: sudden death, electromechanical dissociation.

Small: transient chest pain, cough; may be silent.

D-dimer screen; CT pulmonary angiogram definitive.

Recurrence rate 30%; prophylaxis: early ambulation, compression stockings, anticoagulation.

Chronic small emboli → pulmonary hypertension, cor pulmonale.

Pulmonary hypertension – definition?

Mean pulmonary artery pressure ≥25 mm Hg at rest.

Plexiform lesion is characteristic of which group?

Group 1 pulmonary arterial hypertension.

Most common genetic mutation in familial pulmonary hypertension?

BMPR2.

Classify pulmonary hypertension

1.Pulmonary arterial hypertension (idiopathic, autoimmune, drugs, HIV).

2. Pulmonary hypertension due to left heart disease.

3. Due to lung diseases/hypoxia (COPD, interstitial disease, sleep apnea).

4. Chronic thromboembolic pulmonary hypertension.

5. Multifactorial mechanisms.

describe the pathogenesis of pulmonary hypertension

Inactivating germline mutations in BMPR2 (75% familial, 25% sporadic).

Dysfunction and proliferation of endothelial cells and vascular smooth muscle.

Morphology of pulmonary hypertension

Medial hypertrophy of pulmonary arteries.

Right ventricular hypertrophy.

Plexiform lesions: tuft of capillary formations spanning lumen of small arteries; characteristic of group 1.

Goodpasture syndrome – antibody target?

Anti–basement membrane antibody (collagen IV, α3 chain).

List diffuse pulmonary hemorrhage syndromes and their features.

Idiopathic pulmonary hemosiderosis:

• Intermittent diffuse alveolar hemorrhage; mostly young children.

• Cause unknown; no anti-GBM antibodies. Treatment: prednisone, azathioprine.

Goodpasture syndrome:

• Anti-GBM antibody disease (collagen IV α3 chain) → glomerulonephritis + pulmonary hemorrhage.

• Microscopic: focal necrosis of alveolar walls, intra-alveolar hemorrhage, hemosiderin-laden macrophages.

• Treatment: plasmapheresis + immunosuppression.

Vasculitis-associated hemorrhage:

• Hypersensitivity angiitis, granulomatosis with polyangiitis (Wegener), SLE.

• Capillaritis, poorly formed granulomas (in GPA).

Most common cause of community-acquired bacterial pneumonia?

Streptococcus pneumoniae.

Lobar pneumonia stages in order?

Congestion → red hepatization → gray hepatization → resolution.

Bronchopneumonia pattern?

Patchy consolidation (usually lower lobes).

Describe the morphology of lobar pneumonia

Affects large portion or entire lobe.

Stages:

1. Congestion: heavy, boggy, red; vascular engorgement, bacteria, few neutrophils.

2. Red hepatization: red, firm, airless; massive confluent exudate with neutrophils, RBCs, fibrin.

3. Gray hepatization: gray-brown; RBC disintegration, persistent f ibrinosuppurative exudate.

4. Resolution: enzymatic digestion, resorption, or organization.

Describe the morphology of bronchopneumonia.

Patchy consolidation, often bilateral and lower lobes.

Suppurative exudate fills bronchi, bronchioles, adjacent alveoli.

Complications: abscess, empyema, bacteremic dissemination.

Klebsiella pneumoniae – classic association?

Alcoholics; thick, mucoid, blood-tinged sputum.

Legionella pneumophila – transmission?

Inhalation of aerosolized water or aspiration (cooling towers, plumbing).

List key features of important bacterial pneumonias.

• S. pneumoniae: most common CAP; vaccine available.

• H. influenzae: type B most virulent; vaccine reduced incidence; non-typeable causes otitis, sinusitis, bronchopneumonia; most common bacterial cause of COPD exacerbation.

• M. catarrhalis: second most common cause of COPD exacerbation; common in otitis media.

• S. aureus: secondary to viral illness; high complication rate (abscess, empyema); hospital-acquired, IV drug users.

• K. pneumoniae: alcoholics; thick mucoid sputum (capsule).

• P. aeruginosa: hospital-acquired; cystic fibrosis, neutropenic patients; invades vessels.

• Legionella pneumophila: Legionnaires’ disease; from water systems; diagnosis by PCR, urine antigen, culture.

Most common cause of viral pneumonia in adults?

Influenza virus.

Antigenic shift vs drift?

Shift = major change (pandemic)

Drift = minor changes (epidemic).

Describe viral pneumonia, focusing on influenza.

General: Viruses cause upper/lower respiratory infections; extension favored by extremes of age, malnutrition, immunosuppression.

Mechanism: Viral tropism → attachment to respiratory cells → replication → cytopathic effects → impaired mucociliary clearance → bacterial superinfection.

Influenza:

• Type A: major cause of epidemics/pandemics.

• Hemagglutinin (H) attaches to sialic acid; neuraminidase (N) releases virions.

• Genome: 8 single-stranded RNAs.

• Antigenic drift (mutations) → epidemics; shift (recombination) → pandemics.

• Host defense: α/β-interferon, NK cells, cytotoxic T cells, antibodies.

Human metapneumovirus: paramyxovirus; children, elderly, immunocompromised; PCR diagnosis.

Coronaviruses: SARS-CoV-2 binds ACE2 on alveolar epithelial cells.

Morphology: URTI: hyperemia, mononuclear infiltration, mucus. Lungs: patchy or lobar congestion, interstitial inflammatory reaction.

Most common organisms in healthcare-associated pneumonia?

MRSA, P. aeruginosa.

Aspiration pneumonia – frequent complication?

Lung abscess.

Most common location for aspiration abscess?

Right lung (more vertical right main bronchus).

What is a lung abscess?

Local suppurative necrosis of lung tissue.

Risk factors of Lung abscess

Aspiration of infective material (most common) – risk factors: suppressed cough reflex, alcohol, opioid use, coma, anesthesia, dysphagia, poor dental hygiene.

Postpneumonic: S. aureus, Klebsiella, pneumococcus.

Septic embolism (e.g., endocarditis).

Neoplasia (post-obstructive).

Direct extension, hematogenous seeding.

Primary cryptogenic (no discernible cause).

Complications and morphology of lung abscess

Morphology: Suppurative destruction; cavity diameter few mm to 5–6 cm; more common on right.

Clinical: Cough, fever, copious foul-smelling purulent/sanguineous sputum.

Complications: Extension, hemorrhage, brain abscess/meningitis from septic emboli, secondary amyloidosis (AA).

Pneumocystis jiroveci pneumonia – CD4 count threshold?

<200 cells/mm³

Pulmonary disease in HIV infection – correlation with CD4 count.

• CD4 >200: Bacterial and tubercular infections.

• CD4 <200: Pneumocystis jiroveci pneumonia.

• CD4 <50: CMV, fungal, Mycobacterium avium complex (MAC).

• Bacterial pneumonias are more common, severe, and bacteremic in HIV.

• Not all infiltrates are infectious; consider neoplasm.

Most common indication for lung transplant?

End-stage COPD.

Most common infection early post-transplant?

Bacterial infections.

Chronic lung allograft rejection histology?

Bronchiolitis obliterans.

What are the complications of lung transplantation?

Infections:

• Early (first weeks): bacterial.

• 3–12 months: CMV (ganciclovir prophylaxis), P. jiroveci (TMP-SMX), fungal (Aspergillus, Candida).

Acute rejection: Weeks to months; fever, cough, dyspnea, infiltrates; diagnosis by transbronchial biopsy.

Chronic rejection: 3–5 years; >50% of patients; irreversible decrease in lung function due to fibrosis; histology = bronchiolitis obliterans.

Most common cancer cause of death worldwide?

Lung cancer.

Most common lung cancer subtype in non-smokers?

Adenocarcinoma.

EGFR (Estimated Glomerular Filtration Rate) mutations most common in which population?

Non-smokers, women, adenocarcinoma.

List the genetic mutations associated with lung cancer subtypes.

• Adenocarcinoma (non-smokers): Gain-of-function in EGFR, ALK, ROS1, MET, RET, BRAF, PI3K, KRAS.

• Squamous cell carcinoma: Deletions involving 3p, 9p (CDKN2A), 17p (TP53); p53 overexpression; p16 mutation.

• Small cell carcinoma: TP53 and RB inactivation (always smoking-related).

• Precursor lesions: Atypical adenomatous hyperplasia, adenocarcinoma in situ, squamous dysplasia/carcinoma in situ, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.

Squamous cell carcinoma – typical location?

Central/hilar.

Squamous cell carcinoma – IHC markers?

p40, p63.

Adenocarcinoma – IHC markers?

TTF-1, napsin A.

Small cell carcinoma – genetic hallmark?

TP53 and RB inactivation.

Small cell carcinoma – cytologic features?

Small cells, scant cytoplasm, salt-and-pepper chromatin, nuclear molding.

Pancoast tumor causes?

Horner syndrome (ptosis, miosis, anhidrosis, enophthalmos).

Paraneoplastic hypercalcemia in lung cancer?

Squamous cell carcinoma (PTHrP).

Paraneoplastic SIADH?

Small cell carcinoma (ADH).

List local effects of lung tumor spread and paraneoplastic syndromes.

Local effects:

• Cough (central airway involvement)

• Hemoptysis

• Chest pain

• Pneumonia/abscess/lobar collapse from obstruction

• Pleural effusion

• Hoarseness (recurrent laryngeal n.)

• Dysphagia (esophageal invasion)

• Diaphragm paralysis (phrenic n.)

• SVC syndrome (SVC compression)

• Horner syndrome (sympathetic ganglia invasion)

Paraneoplastic syndromes:

• SIADH → hyponatremia (small cell)

• ACTH → Cushing syndrome (small cell)

• PTHrP → hypercalcemia (squamous)

• Calcitonin → hypocalcemia

• Gonadotropins → gynecomastia

• Serotonin/bradykinin → carcinoid syndrome

Carcinoid tumor – typical vs atypical mitoses?

Typical <2 per 10 HPF; atypical 2–10 per 10 HPF.

Describe pulmonary neuroendocrine tumors and hamartoma.

Typical carcinoid: Low grade; organoid/trabecular pattern; <2 mitoses/10 HPF; no necrosis; may cause carcinoid syndrome if metastatic.

Atypical carcinoid: Intermediate grade; 2–10 mitoses/10 HPF; foci of necrosis; more pleomorphic.

Pulmonary hamartoma: Benign; cartilage (most common), fat, smooth muscle; well-circumscribed “coin lesion”.

Lymphangioleiomyomatosis: Young women; proliferation of perivascular epithelioid cells (melanocyte/smooth muscle markers); cystic changes, pneumothorax; only cure is transplant.

Inflammatory myofibroblastic tumor: Children; spindle cells, lymphocytes, plasma cells.

Most common metastatic tumor to lung?

Lung is the most common site of metastasis from any primary.

Most common cause of hydrothorax?

Congestive heart failure.

Empyema is?

Purulent pleural effusion (pus).

Chylothorax fluid appearance?

Milky white (due to chyle)