Bronchogenic Carcinoma Etiopathogenesis

• 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

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

• 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

• Behave similar to adenocarcinomas but the lesions formed tend to be somewhat larger

• 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

• Cancer induced lipolysis and proteolysis leads to loss of adipose and skeletal muscle. Protein synthesis is also reduced via a number of mechanisms.

• Tumour in the central airway
• Blood vessels resulting from tumour-induced angiogenesis are leaky and tortuous, predisposing them to easy rupture and causing hemoptysis

• Extrinsic or intraluminal airway obstruction
• Activation of mechanoreceptors and chemoreceptors in lungs due to cachexia or hypoxemia/acidosis
• Also due to mediastinal involvement

• Tumour involving pleural surface causing pleuritic chest pain
• Also due to mediastinal involvement

• 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)

• Infiltrate into the pericardium or press on the heart causing pericardial effusion
• Tamponade, arrhythmias or cardiac failure

• Benign: lymphatic obstruction, post-obstructive pneumonitis, or atelectasis
• Malignant: malignant cells in pleural fluid

• Middle 1/3rd esophageal compression by enlarged subcarinal lymph nodes

• 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

• Direct extension to chest wall

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

• 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

• 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

• 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.

1. Symmetrical proximal muscle weakness
2. Muscle biopsy evidence of myositis (muscle necrosis, perifascicular atrophy, lymphocytic infiltration)
3. Elevation in serum skeletal muscle enzymes (CK, aldolase, SGOT, SGPT, LDH)
4. Characteristic EMG pattern (Myopathic pattern)
5. 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)

• 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

• 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