Bronchogenic Carcinoma Etiopathogenesis

INCIDENCE

Male > Female
Age group: 50-75 years
Second highest cancer in both sexes after prostate (male) and breast (female)
Smokers > Non-smokers

ETIOLOGY OF LUNG CANCER

A. Cigarette smoking:

Smoking is the single most important risk factor for lung cancer, which can cause all types of lung cancer but is more strongly linked with Small cell carcinoma and Squamous-cell carcinoma.

Risk of cancer increases with: duration, intensity and depth of smoke inhalation

Type of tobacco smoking: Cigarette smoking (fine particles reaching distal airways) > Pipe and cigar smoking (large particles that only reaches upper airway)

Association: Active smoking > Passive smoking

Important carcinogens:

Polycyclic Aromatic Hydrocarbons (PAH): e.g. benzopyrene produces p53 mutation (G to T transversion)
N-nitroso compounds
Phenol derivatives

Chronic irritation: Leads to squamous metaplasia

Nicotine: Causes addiction and also promotes carcinogenesis

Sympathetic/Parasympathetic activation: nicotine binds to nicotinic cholinergic receptors, located on both sympathetic and parasympathetic postganglionic neurons – stimulates both sympathetic (increased heart rate and blood pressure) and parasympathetic (intestinal motility, relaxation) systems.
Addiction: dopamine release from nucleus accumbens, mediating reward and addiction
Carcinogen: nicotine does not initiate carcinogenesis, but it does promote initiated cells by nicotinic cholinergic receptor signalling in the lungs. Nicotine has been shown to inhibit apoptosis, proliferate cells, and cause angiogenesis in lung tumours.

Smoking cessation: Risk decreases but never returns to non-smoker (never smoker) level

Smoking initiates carcinogenesis early-on (3-p deletion, p53 mutation)
20-25 years required between smoking onset and cancer onset
Even after smoking cessation, existing initiated cells may progress if another carcinogen carries on process

B. Never-smokers:

Definition: <100 cigarettes in life-time

Accounts for 25% of lung cancers and is distinctly associated with: female cases, east-asian populations, positive family history, adenocarcinoma type, EGFR mutation, and better prognosis

C. Environmental exposures:

a. Occupational exposures: asbestos, tar, soot, metals (arsenic, chromium, and nickel)

b. Atmospheric air pollution

c. Radiation exposure:

Thoracic radiation therapy
Indoor radon-222 (radioactive gas that percolates up soil and becomes concentrated inside buildings)

D. Genetics:

Familial predisposition: Increased risk among first degree relatives

Identified gene: CYP1A1 (of Cytochrome P-450 family) – codes for aryl hydrocarbon hydroxylase

Increased metabolic activation of pro-carcinogens derived from cigarette smoking

E. Precursor lesions:

Squamous dysplasia: Squamous cell carcinoma

Adenomatous hyperplasia: Bronchioalveolar carcinoma (BAC) – a form of adenocarcinoma

Idiopathic pulmonary neuroendocrine cell hyperplasia: Pulmonary carcinoids

COPD, Idiopathic pulmonary fibrosis and tuberculosis are associated with increased risk of lung cancer.

PATHOLOGY OF LUNG CANCER

Major types of lung cancer: Broadly Small cell and non-small carcinoma with different cells of origin, different pathogenic processes and different genetic mutations

Small cell (oat cell) carcinoma
- mutations in MYC, BCL-2, c-KIT, p53, and RB
Non small cell carcinoma: mutations in EGFR, KRAS, CD44, and p16
- Squamous cell (epidermoid) carcinoma
- Adenocarcinoma (including Bronchoalveolar carcinoma)
- Large-cell carcinoma

Squamous cell and Small-cell carcinomas are generally centrally (hilar) placed tumors while large cell and adenocarcinoma are peripherally placed.

Neuroendocrine tumors arise from Kulchitsky cells of bronchial mucosa and comprise typical carcinoid, atypical carcinoid and small-cell lung cancer.

CLASSIFICATION OF LUNG CANCER

Lung cancer type	Location in the lung	Features
Adenocarcinoma (40%)	Peripheral	Commonest cancer in non-smoker Female > Male Arises from small airway epithelial and type II alveolar cells Should test for EGFR mutation for possible targeted therapy May appear at site of scarring Tend to form glands and secrete mucin
Squamous cell carcinoma (30%)	⅔ central ⅓ peripheral	Associated with cigarette smoking Arises from large (proximal) airway epithelial cells Tend to create obstruction and cause distal atelectasis Intrathoracic spread rather than distant metastasis; therefore, best prognosis
Small-cell lung carcinoma (SCLC) (15%)	Central (endobronchial) Kulchitsky cells are located at bifurcation of small airways	Strongest smoking association Arises from neuroendocrine (Kulchitsky) cells Causes paraneoplastic syndrome: commonly secrete ADH (SIADH) or ACTH (ectopic Cushing syndrome) Rapid growth and early distant metastasis (brain, liver, bone), leading to the worst prognosis
Large cell carcinoma(10%)	Peripheral	Behave similar to adenocarcinomas but the lesions formed tend to be somewhat larger

PATHOPHYSIOLOGY AND CLINICAL FEATURES OF LUNG CANCER

Symptoms	Mechanism and pathophysiology
*Primary lung lesion symptoms*
Cough (50-70%)	Presence of a mass irritates the cough receptors in the airway More common in central (hilar) tumors (more receptors) Obstruction from central airway could also lead to post-obstructive pneumonia and distal atelectasis
Weight loss (45%)	Cancer induced lipolysis and proteolysis leads to loss of adipose and skeletal muscle. Protein synthesis is also reduced via a number of mechanisms.
Hemoptysis (25-50%)	Tumour in the central airway Blood vessels resulting from tumour-induced angiogenesis are leaky and tortuous, predisposing them to easy rupture and causing hemoptysis
Dyspnea (25%)	Extrinsic or intraluminal airway obstruction Activation of mechanoreceptors and chemoreceptors in lungs due to cachexia or hypoxemia/acidosis Also due to mediastinal involvement
Chest pain (20%) – common in peripheral tumor	Tumour involving pleural surface causing pleuritic chest pain Also due to mediastinal involvement
*Mediastinal involvement*
Superior vena cava syndrome (Obstruction of SVC by tumor; more commin in SCLCl 2-4%)	Impaired venous return (causing edema) from: Arms: limb edema Periorbital area: periorbital edema Ocular mucosal membranes: chemosis (visual disturbance) Pharynx and larynx: stridor and hoarseness Walls of GI tract: dysphagia Cerebral veins/Cerebral edema: headache, confusion Neck veins: distended, non-pulsatile neck veins Reduction of cardiac output (inadequate compensation): pre-syncope, syncope Post-azygous obstruction = Features of pre-azygous obstruction + Dilation of veins over abdomen (retrograde flow through azygous via collaterals to IVC)
Pericardial effusion and cardiac involvement	Infiltrate into the pericardium or press on the heart causing pericardial effusion Tamponade, arrhythmias or cardiac failure
Pleural effusion (Chest pain and Dyspnea)	Benign: lymphatic obstruction, post-obstructive pneumonitis, or atelectasis Malignant: malignant cells in pleural fluid
Dysphagia	Middle 1/3rd esophageal compression by enlarged subcarinal lymph nodes
Pancoast tumour or Pancoast-Tobias tumor (superior sulcus tumour) – superior sulcus or costovertebral gutter extends from 1st rib to diaphragm	Tumour originates in the apical portion of the lung Occurs in 5% of non-small cell lung cancer Involves C8 and T1 Brachial plexus involvement: Motor and sensory complaints in ipsilateral arm Sympathetic chain involvement: Horner’s syndrome Phrenic nerve involvement: Unilateral diaphragm paralysis Recurrent pharyngeal nerve involvement: Hoarseness
Rib pain, pathological fractures and intercostal neuralgia	Direct extension to chest wall
*Paraneoplastic syndromes:* symptoms in cancer patients not attributable to tumour compression or invasion (usually result from peptide hormone secretion by tumor) – common with small cell cancer
Ectopic Cushing syndrome (most common paraneoplastic syndrome) 1. Rule out pseudo-cushing’s: alcohol excess, major depressive illness, primary obesity 2. Initial tests to diagnose Cushing syndrome: Late-night salivary cortisol level (between 11 PM to midnight) 1 mg overnight 11 PM dexamethasone suppression test (positive if morning 8 AM cortisol >1.8 mcg/dl) 24 hour urinary cortisol (>50 mcg/24 hr) 48 hr 2 mg/low dose dexamethasone suppresion test (0.5 mg 6 hrly started at 9 AM and measured at 9 AM of 3rd day) – 24 hr urine collected from 2nd day and plasma for 3rd day 3. Tests to establish cause: Morning plasma ACTH level(>80 ng/l – ectopic ACTH syndrome or pituitary dependent disease; <10 ng/l – adrenal source) 48 hr High dose 8 mg dexamethasone suppression test (2 mg 6 hrly – positive if cortisol suppression <50% of baseline) – positive in pituitary diseases and negative in ectopic ACTH and adrenal tumors MRI head and Inferior petrosal sinus sampling (Pituitary) CXR, CT chest, Tumor markers (Ectopic ACTH syndrome)	Ectopic secretion of adrenocorticotrophic hormone (ACTH) → adrenal cortisol secretion → Cushingoid features (Mnemonic: CUSHINGOID) Cataracts (posterior subcapsular cataract) – abberant differentiation and migration of epithelial cells; hyperglycemia; G6PD inhibition leading to decreased NADH and glutathione resulting in inhibition of Na/K ATPase pump Ulcers (Increased gastric acid secretion and decreased prostaglandin production) Skin (plethora, stria, bruising) – thinning of skin due to catabolic effects in epidermis and underlying connective tissue Acne: androgen and gluco-corticoid excess Hypertension and Hypokalemia – upregulation of RAAS and action on mineralocorticoid receptors resuling in Na+ retention and K+ loss Hirsutism – androgen excess by ACTH stimulation Hyperglycemia (Diabetic symptoms) – Insulin resistance leading to increased gluconeogenesis, decreased glucose uptake and glycogenesis Acanthosis nigricans: Insulin resistance leads to hyperinsulinemia which in turn stimulates proliferation of keratinocytes (containing melanin) and fibroblasts Hypercalciuria (Renal stones) – decreased intestinal and tubular reabsorption of calcium Hyperlipidemia – Increased lipolysis, VLDL synthesis, fatty accumulation in liver and peripheral insulin resistance Hypercoagulability – increased synthesis of fibrinogen and plasminogen activator inhibitor type-1 Infections of skin (Tinea versicolor) Necrosis (avascular) of femoral head – Fat embolization or as a coronary disease of hip (arteriosclerosis) Glycosuria – blood glucose exceeds renal threshold (~180 mg/dl) Gonadal dysfunction (oligomenorrhea, amenorrhea, impotence) – Inhibition of GnRH, FSH and LH release Osteoporosis – Increased RANKL (increases osteoclastogenesis) and decreased osteoprotegrin (decoy receptor for RANKL acting to decrease osteoclast differentiation); Impaired osteoblast differentiation and increased apoptosis; also due to suppresion of gonadotropin and growth hormone, muscle weakness and hypercalciuria Proximal myopathy: loss of protein in muscle (negative nitrogen balance) and hypokalemia Obesity – Insulin resistance and hyperphagia Central obesity (intra-abdominal visceral fat rather than subcutaneous fat): omental fat are able to convert inactive cortisone to cortisol via enzyme (11B-HSD1) Moon facies (bitemporal fat deposition) Buffalo hump (cervicodorsal fat deposition) – between scapula and neck Supraclavicular fat pads Immunosuppression (Opportunistic infection) – decreases lymphocyte and monocyte function and production; decreased complement level Dernaged mental function (Emotional lability, euphoria, depression, psychosis) – stimulation of mineralocorticoid receptors in limbic system
Syndrome of inappropriate antidiuretic hormone production (SIADH) Hyponatremia (Na <135 mEq/L) Hyp0-osmotic plasma (Plasma osmolality <280 mOsm/kg) Hyperosmotic urine (Urine osmolality >500 mOsm/kg) Hypernatremic urine (Urinary Na >20 mEq/L)	Ectopic secretion of ADH → retain free water in collecting ducts Euvolemic hyponatremia and concentrated urine Mild symptoms (>120 mEq/L): headache, nausea, vomiting Moderate symptoms (120-110 mEq/L): restless, irritability, confusion, cramps Severe symptoms: include altered mental status, seizures, respiratory depression, and death Common in SCLC
Hypercalcemia (>11 mg/dl) and hypophosphatemia	Increased secretion of PTHrP → acts like parathyroid hormone to increase bone resorption and renal calcium reabsorption → hypercalcemia Associated with squamous cell carcinoma Clinical features: Stones, Bones, Groans, Moans, Psychic overtones Stones – renal stones and nephrocalcinosis; polyuria or polydipsia; impairment of renal function Bones – bone pain and fractures; chondrocalcinosis Groans – anorexia, constipation, nausea and vomiting, peptic ulcers (calcium increases acidity) Moans – fatigue, myalgia, proximal muscle weaness, hypertension (calcified arterial walls), corneal calcification (slit-lamp) Psychic overtones – depression, lethargy, memory loss, confusion, coma ECG: shortened QT interval, prolonged PR and QRS, AV block
Hypertrophic osteoarthropathy and digital clubbing	Associated with NSCLC, especially the adenocarcinoma type Periosteal proliferation of the tubular bones characterized by (i) painful symmetrical arthritis of the ankles, knees, wrists and elbows, and (ii) digital clubbing.
Dermatomyositis and Polymyositis (Dermatomyositis or polymyositis associated with neoplasia fall under Group III; Others: Group I and II – Idiopathic polymyositis and dermatomyositis respectively; Group IV – Vasculitis associated; Group V – Collagen vascular disease associated)	Symmetrical proximal muscle weakness Muscle biopsy evidence of myositis (muscle necrosis, perifascicular atrophy, lymphocytic infiltration) Elevation in serum skeletal muscle enzymes (CK, aldolase, SGOT, SGPT, LDH) Characteristic EMG pattern (Myopathic pattern) Typical rash of dermatomyositis (Liliac colored Heliotrope rash over upper eyelids) Definite polymyositis: All of 1-4; Definite Dermatomyositis: 5 + any 3 of 1-4 Other pathognomic cutaneous manifestations: Gottron’s papules (violaceous papules over DIP or MCP areas, elbow or knee), Periungual telangiectasis; Shawl or V sign (erythematous macules distributed in a “shawl” pattern over shoulders, upper chest and neck); Mechanic’s hand (fissured, scaly and hyperkeratotic)
Other	Neuro-myopathic: Lamber-eaton syndrome (pre-synaptic voltage gated calcium channel antibodies; SOX protein antibody; SCLC associated; treated with 3,4-diaminopyridine), Peripheral neuropathy, Subacute cerebellar degeneration, Cortical degeneration Hematological: Trosseau’s syndrome (Migratory thrombophlebitis), Marantic endocarditis, DIC, Anemia, Granulocytosis, Leukoerythroblastosis Cutaneous: Acanthosis nigricans Renal: Nephrotic syndrome (Minimal change disease – benefitted by early use of steroid), Glomerulonephritis
Distant metastasis
Metastatic sites include brain, bone, liver and adrenal glands	Brain: headache, vomiting, neurologic deficits, seizures and confusion Bone: pain, pathologic fractures, raised ALP Bone marrow: cytopenias or leukoerythroblastosis Liver: biochemical liver dysfunction, anorexia, biliary obstruction, pain Lymph node: supraclavicular (scalene node) Epidural and bone: spinal cord compression syndromes