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2nd MBBS Pathology - Respiratory System (MUHS Exam Notes)

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PART 1: LUNG ABSCESS

Definition

Etiology (IMPORTANT)

Key exam point: Anaerobic bacteria are present in almost ALL lung abscesses, and are the exclusive isolates in 1/3 to 2/3 of cases. Most common anaerobes: Prevotella, Fusobacterium, Bacteroides, Peptostreptococcus.

Morphology

• Abscesses range from few mm to 5-6 cm in diameter
• Location depends on cause:
  • Aspiration-related: More common on the right side (more vertical right main bronchus), usually single; posterior segment RUL and apical segment of RLL
  • Pneumonia/bronchiectasis-related: Multiple, basal, diffusely scattered
  • Septic emboli: Multiple, any region
• As abscess enlarges, it ruptures into airways → partial drainage → air-fluid level on X-ray (pathognomonic)
• Chronic cases: Fibrous wall formation (fibrous capsule)

• Suppurative (neutrophilic) destruction of lung parenchyma - central area of cavitation
• Central cavity filled with suppurative debris
• If communication with airway: air-containing cavity
• Superimposed saprophytic infections within necrotic debris
• Gangrene of the lung: Large, poorly demarcated, fetid, green-black, multilocular cavities
• Chronic abscess: Fibrous wall (fibroblastic proliferation)

Clinical Features

• Cough, fever, copious amounts of foul-smelling purulent/sanguineous sputum
• Chest pain, weight loss
• Clubbing of fingers and toes
• Diagnosis confirmed by radiology (air-fluid level on CXR/CT)
• Always rule out underlying carcinoma in older patients

Complications

1. Extension into pleural cavity (empyema)
2. Hemorrhage
3. Brain abscess or meningitis (septic emboli)
4. Secondary amyloidosis (type AA) - rare

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PART 2: LUNG CARCINOMA

Histologic Classification (WHO)

LUNG CARCINOMA
├── NON-SMALL CELL LUNG CARCINOMA (NSCLC) ~85%
│   ├── Adenocarcinoma (most common, ~40%)
│   ├── Squamous Cell Carcinoma (~25-30%)
│   └── Large Cell Carcinoma (~10-15%)
└── SMALL CELL LUNG CARCINOMA (SCLC) ~15%

Etiopathogenesis

1. Tobacco Smoking (most important): ~80% of lung cancers occur in active/recent smokers. Risk is 60 times greater in heavy smokers (2 packs/day x 20 years). Only 10-15% of smokers develop lung cancer - suggesting genetic susceptibility.
2. Industrial Hazards: Asbestos (synergistic with smoking), arsenic, chromium, uranium, nickel, vinyl chloride, mustard gas, ionizing radiation
3. Air Pollution: Radon gas (radioactive decay product of radium) - particularly important in miners
4. Molecular Pathogenesis:
   • Multiple genetic mutations required (multi-step carcinogenesis)
   • Proto-oncogenes: KRAS, EGFR, MYC, ALK
   • Tumor suppressor loss: TP53, RB, p16
   • High mutation burden from tobacco carcinogens → tumor neoantigens → responsive to immune checkpoint inhibitors (PD-1/PD-L1)
5. Squamous metaplasia → dysplasia → carcinoma in situ → invasive cancer (best documented pathway, especially for SCC)

Clinical Presentations

• Local effects: Cough, hemoptysis, chest pain, wheezing (endobronchial lesion)
• Obstructive pneumonitis (post-obstructive pneumonia)
• Superior vena cava syndrome - SVC obstruction → facial edema, arm swelling
• Pancoast tumor (superior sulcus) - shoulder pain, Horner syndrome (ptosis, miosis, anhidrosis)
• Pleural effusion (malignant)
• Hoarseness - recurrent laryngeal nerve involvement
• Paraneoplastic syndromes (IMPORTANT for exams):

Small Cell Carcinoma - Morphology

• Most aggressive lung cancer; almost always metastatic at presentation
• Arises centrally from bronchial mucosa

• Central/perihilar mass, often with bulky lymph node involvement at diagnosis
• White-tan, soft, friable tumor
• Frequently causes compression of bronchi and vascular structures

• Small cells (about the size of 2-3 lymphocytes)
• "Oat cell" appearance - scant cytoplasm, round-to-oval nuclei, finely granular chromatin ("salt and pepper"), absent/inconspicuous nucleoli
• Cells arranged in sheets, nests, ribbons
• Nuclear molding (nuclei indent each other)
• High mitotic rate, abundant necrosis, apoptotic debris ("nuclear streaming")
• Neuroendocrine differentiation - cells contain dense-core neurosecretory granules on electron microscopy
• IHC: Positive for CD56, synaptophysin, chromogranin, NSE (neuroendocrine markers)
• Strongly associated with TP53 and RB mutations

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PART 3: PATHOGENESIS OF EMPHYSEMA

Definition

Types (Exam Diagram)

                    TERMINAL BRONCHIOLE
                           |
              ┌────────────┴────────────┐
              │                         │
    RESPIRATORY BRONCHIOLE         ALVEOLAR DUCT
              │                         │
           ALVEOLI                   ALVEOLI

Centriacinar: Central/proximal part affected (respiratory bronchiole) - MOST COMMON
Panacinar: Entire acinus from respiratory bronchiole to alveolus - α1-AT deficiency
Paraseptal: Distal alveoli near pleura/septa - spontaneous pneumothorax in young
Irregular: Paracicatricial, near scars - clinically insignificant

Pathogenesis (PROTEASE-ANTIPROTEASE + OXIDATIVE STRESS)

1. Protease-Antiprotease Imbalance

• Tobacco smoke stimulates macrophages and neutrophils in alveoli
• These inflammatory cells release elastase and other proteases (MMPs, cathepsins)
• Proteases break down elastin, collagen in alveolar walls
• Normally, α1-antitrypsin (α1-AT) inhibits neutrophil elastase
• In smokers: Oxidants from smoke inactivate α1-AT → relative deficiency
• Hereditary α1-AT deficiency (Pi locus, chromosome 14, ZZ phenotype) - causes panacinar emphysema at younger age; affects lower lobes

2. Oxidative Stress

• Cigarette smoke contains reactive oxygen species (ROS)
• ROS also released from activated macrophages/neutrophils
• Causes direct tissue damage, endothelial dysfunction, inflammation
• Inactivates antiproteases → compounds protease-antiprotease imbalance
• NRF2 normally protects cells from oxidant damage; genetic variants in NRF2 increase susceptibility

3. Inflammatory Mediators

• Mediators released: LTB4, IL-8, TNF
• Attract more inflammatory cells (perpetuating cycle)
• Lead to T and B cell accumulation in affected lung

4. Infection

• Not initiating, but bacterial/viral infections cause acute exacerbations

Gross Features of Emphysema

Microscopic Features

• Destruction of alveolar walls without fibrosis - key distinguishing feature
• Enlarged air spaces
• Reduced number of alveolar capillaries
• Deformed terminal/respiratory bronchioles (loss of supporting septa)
• Bronchiolar inflammation and submucosal fibrosis in advanced disease
• "Pink Puffer" presentation: Barrel chest, pursed-lip breathing, hyperinflated lungs on CXR, relatively normal blood gases

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PART 4: BRONCHIECTASIS

Definition

Etiology/Pathogenesis

• Tumors, foreign bodies, mucus impaction

• Necrotizing/destructive infections: Bacterial (S. aureus, Klebsiella, anaerobes), TB, viral (adenovirus, influenza), fungal

• Cystic fibrosis (most common cause in Western countries)
• Kartagener syndrome (immotile cilia/Primary Ciliary Dyskinesia) - bronchiectasis + situs inversus + sinusitis
• Williams-Campbell syndrome (bronchial cartilage deficiency)
• Mounier-Kuhn syndrome (tracheobronchomegaly)

• Hypogammaglobulinemia, HIV, post-transplant

• Rheumatoid arthritis, IBD, allergic bronchopulmonary aspergillosis (ABPA)

Morphology

Gross Features

• Most commonly involves the lower lobes bilaterally (dependent portions where secretions pool)
• Bronchi are dilated (up to 4x normal diameter), extend to within 1-2 cm of pleural surface
• Three patterns:
  • Cylindrical (tubular) - uniform dilation, most common
  • Varicose - irregular, bead-like dilation
  • Saccular (cystic) - progressive cystic ballooning, most severe
• Cut surface: Dilated airways filled with purulent mucopurulent material
• Lung parenchyma around the bronchi shows fibrosis and consolidation
• Pleura may be thickened and adherent

Microscopic Features

• Inflammatory exudate in the bronchial lumen (neutrophils, pus)
• Destruction and replacement of all layers of bronchial wall with fibrous tissue
• Loss of bronchial mucous glands and cartilage
• Squamous metaplasia of bronchial epithelium
• Vascular changes: Enlargement of bronchial arteries, arteriovenous anastomoses (explains hemoptysis)
• Surrounding alveolar parenchyma: Fibrosis, organizing pneumonia
• Mucus gland hypertrophy

Clinical Features

• "Wet lung disease"
• Copious purulent sputum (3-layer if allowed to settle: frothy top, mucopurulent middle, pus sediment)
• Hemoptysis (due to enlarged bronchial vessels)
• Recurrent respiratory infections
• Dyspnea, cough
• Clubbing of fingers - classic finding

Complications

1. Cor pulmonale (right heart failure due to pulmonary hypertension from hypoxia)
2. Empyema and pyopneumothorax
3. Metastatic brain abscess and meningitis
4. Secondary amyloidosis (AA amyloidosis) - from chronic infection
5. Right-sided heart failure (cor pulmonale)
6. Respiratory failure

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PART 5: LOBAR PNEUMONIA

Definition

Etiopathogenesis

• Gram-positive diplococci
• Other causes: Klebsiella pneumoniae (alcoholics - "currant jelly sputum"), S. aureus, Legionella, H. influenzae

1. Organisms reach alveoli via inhalation or aspiration
2. Encounter alveolar macrophages (first defense)
3. If overwhelmed - organisms multiply in alveoli
4. Organism + complement activation → cytokine release (IL-1, TNF, IL-8)
5. Outpouring of edema fluid into alveoli (Stage 1 - Congestion)
6. Massive neutrophil influx (Stages 2 and 3)
7. Resolution (macrophage clearance) - Stage 4

Stages of Lobar Pneumonia - Classic Four Stages

Stage 1: Congestion (Days 1-2)

• Lung is heavy, wet, and red
• Increased weight, congested, boggy

• Vascular engorgement - dilated, engorged capillaries
• Intra-alveolar serous/watery edema fluid (protein-rich exudate)
• Few neutrophils
• Numerous bacteria (numerous cocci visible in alveoli)
• Alveolar septa intact

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Stage 2: Red Hepatization (Days 3-4)

• Lobe is red, firm, and airless
• Cut surface resembles liver (hepatization = liver-like consistency)
• Pleural surface may show fibrinous exudate

• Massive confluent exudation
• Alveoli packed with: Neutrophils + Red Blood Cells + Fibrin strands
• Fibrin strands pass through pores of Kohn between alveoli
• Alveolar capillaries compressed by exudate
• No air in alveoli

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Stage 3: Gray Hepatization (Days 5-7)

• Lobe is gray-brown, firm, dry (less congested than Stage 2)
• Still liver-like consistency but color changes to gray

• Progressive disintegration/lysis of RBCs (hence gray color - less hemoglobin)
• Fibrinopurulent exudate persists - alveoli filled with fibrin and pus (neutrophils undergoing degeneration)
• Macrophages begin to appear
• Fibrin strands prominent
• Capillaries still compressed

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Stage 4: Resolution (Days 7-10 onwards)

• Lung returns toward normal appearance
• Softening and granular texture as exudate liquefies

• Enzymatic digestion of the exudate by macrophages and enzymatic activity
• Production of granular, semifluid debris
• Debris is resorbed, ingested by macrophages, or expectorated
• Fibrinous exudate may be organized by fibroblasts (→ fibrous scar = "carnification" if resolution fails)
• Macrophages are the dominant cell

Key exam memory: "Congestion → Red → Gray → Resolution" (CGR mnemonic)

Clinical Features

• Abrupt onset of high fever, shaking chills
• Cough with rusty (rust-colored) sputum - characteristic of pneumococcal pneumonia (from RBC breakdown in alveoli)
• Pleuritic chest pain (pleuritis/friction rub when pneumonia reaches lung surface)
• Dyspnea, tachypnea
• Dullness to percussion over affected lobe
• Bronchial breathing, increased tactile fremitus
• Herpes labialis may appear
• Resolution with antibiotics in 8-10 days

Complications

1. Abscess formation (tissue destruction/necrosis)
2. Empyema - spread to pleural cavity (fibrinopurulent pleurisy)
3. Bacteremia/sepsis - spread to heart valves (endocarditis), brain (meningitis, brain abscess), joints (septic arthritis), kidneys (abscess), spleen
4. Organizing pneumonia (carnification) - failure of resolution → fibroblast invasion → fibrous scar in lung
5. Fibrous pleuritis - fibrous thickening or permanent pleural adhesions

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PART 6: LUNG TUMORS - WHO CLASSIFICATION & ETIOPATHOGENESIS

WHO Classification of Lung Tumors (2021)

MALIGNANT EPITHELIAL TUMORS
├── Adenocarcinoma
│   ├── Atypical Adenomatous Hyperplasia (AAH) - precursor
│   ├── Adenocarcinoma in Situ (AIS, ≤3cm)
│   ├── Minimally Invasive Adenocarcinoma (MIA)
│   └── Invasive Adenocarcinoma
│       ├── Lepidic predominant
│       ├── Acinar predominant
│       ├── Papillary predominant
│       ├── Micropapillary predominant
│       └── Solid predominant
├── Squamous Cell Carcinoma
│   ├── Keratinizing
│   ├── Non-keratinizing
│   └── Basaloid
├── Large Cell Carcinoma
├── Adenosquamous Carcinoma
├── Sarcomatoid Carcinomas
└── NEUROENDOCRINE TUMORS
    ├── Small Cell Carcinoma
    ├── Large Cell Neuroendocrine Carcinoma
    ├── Typical Carcinoid
    └── Atypical Carcinoid

Etiopathogenesis

• Most important carcinogen; ~80% of all lung cancers
• Risk: 60x higher in heavy smokers (2 packs/day x 20 years)
• Carcinogens in smoke include polycyclic hydrocarbons, nitrosamines, benzene
• Activated by P-450 monooxygenase system → reactive carcinogens → DNA damage
• Causes a stepwise progression: normal → basal cell hyperplasia → squamous metaplasia → dysplasia → CIS → invasive cancer

• Asbestos (especially + smoking = synergistic effect; also causes mesothelioma)
• Radon gas, arsenic, chromium, nickel, uranium

Morphology of Major Types

Adenocarcinoma

• Peripheral subpleural location (most common location for adenocarcinoma)
• Gross: Grayish-white mass, may show central scar (desmoplasia); mucin production gives gelatinous areas
• Micro: Glandular/acinar/papillary architecture; mucin-secreting columnar cells; lepidic pattern = tumor cells growing along alveolar walls without invasion
• Bronchioloalveolar (lepidic) pattern: Distinct - pneumonia-like consolidation on imaging

Squamous Cell Carcinoma

• Central location - arises at or near the hilus from main/lobar bronchi
• Gross: Gray-white hilar mass with cavitation (central necrosis is common), firm
• Micro: Sheets of polygonal cells with: intercellular bridges, keratin pearls, individual cell keratinization; marked pleomorphism; dysplastic changes in adjacent epithelium

Large Cell Carcinoma

• Undifferentiated (no squamous/glandular/NE features)
• Peripheral location
• Micro: Large cells with prominent nucleoli, abundant cytoplasm; no differentiation markers
• Diagnosis of exclusion

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SUMMARY TABLE - HIGH-YIELD EXAM POINTS

MUHS Exam Tip: For morphology questions, always describe both gross AND microscopic. For lobar pneumonia, draw a table of the 4 stages. For emphysema, draw the protease-antiprotease diagram. For lung carcinoma, memorize the paraneoplastic syndromes table.

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