Lung cancer

• Carcinomas constitute 90-95% of lung tumours
• They are the most common cause of cancer death for both men and women
• Peak incidence is in the 50’s and 60’s

 

Aetiology and Pathogenesis

• Arises from stepwise accumulation of genetic abnormalities that transform benign bronchial epithelium to neoplastic tumour
• Causes;

 

• Tobacco smoke
  • Frequency of lung cancer depends on;
  • The amount of daily smoking
  • The tendency to inhale
  • The duration of the smoking habit
  • Compared with nonsmokers, average smokers have a 10 fold greater risk, this increased to 60 fold in heavy smokers (>40/day)
  • Women are more susceptible to smoking carcinogens than men
  • Clinical evidence shows there is a correlation between intensity of cigarette smoke and epithelial changes beginning with squamous metaplasia, dysplasia, carcinoma in situ and invasive carcinoma
  • Experimentally a number of cigarette smoke carcinogens e.g polycyclic aromatic hydrocarbons, are known although bronchogenic carcinomas are nor readily inducible by inhalation in experimental animals

 

• Industrial hazards
  • Includes high dose ionising radiation – increased incidence in survivors of Hiroshima and Nagasaki
  • Asbestos – asbestos workers have a five times greater risk of developing lung cancer, this increases to 50-90 times if they smoke

 

• Air pollution
  • Radon gas and particulates

 

• Molecular genetics
  • It is estimated that 10 to 20 genetic mutations have occurred by the time the tumour becomes clinically apparent
  • Mutations involved include;
  • Dominant oncogenes e.g. c-MYC. K-RAS, EGFR and HER-2/neu
  • TSG e.g. p53, RB, p16^INK4a and multiple loci on chromosome 3p
  • Risk of lung cancer with a family history is 2.5 times

 

Precursor lesions

• Three types of precursor epithelial lesion are recognised;
  • Squamous dysplasia and carcinoma in situ
  • Atypical adenomatous hyperplasia
  • Diffuse iodiopathic pulmonary neuroendocrine dysplasia (precursor lesion for carcinoid tumours)
• Not all precursor lesions will develop into carcinoma

 

• The major types of bronchial carcinoma are;
  • Squamous cell carcinoma (25-40%)
  • Adenocarcinoma (25-40%)
  • Small cell carcinoma (20-25%)
  • Large cell carcinoma (10-15%)
• Histological heterogeneity is seen in at least 30% of lung cancers

 

Investigations

• CXR
• Lung function tests – if poor, not a good candidate for radical therapy
• CT scan
• PET scan or CT-PET scan
• Bronchoscopy
  • Fibreoptic with washings, brushings and biopsies
  • Fluorescence bronchoscopy
• CT guided fine needle aspiration biopsy
• Mediastinoscopy
• Endotracheal/endoscopic ultrasound guided aspiration (EBUS/EUS)
• VATS biopsy

 

Morphology

 

Squamous cell carcinoma

• Commonly found in men and is closely associated with smoking
• Most arise in or around the lung hilum but incidence in the periphery is increasing
• Macroscopically they are grey/white and firm and there may be central areas of haemorrhage and cavitation
• Histologically there is keratisation in intracellular bridge formation
• Squamous metapasia, epithelilal dysplasia and carcinoma in situ may be seen adjacent to the tumour mass
• Have a higher frequency of p53 mutation then other histological types
• Stage by stage, survival is better for SSC than adenocarcinoma

 

Adenocarcinoma

• Increase in incidence
• Mostly peripheral in location
• Shows glandular differentiation or mucus production
• Shows variation in growth patterns either pure or mixed. The patterns include;
• Acinar
• Papillary
• Bronchioloalveolar
• Solid with mucus production
• Adenocarcinomas grow more slowly than SSC but tend to metastasis widely and earlier
• They stain for surfactant apoproteins and thyroid transcription factor – 1

 

Bronchioloalveolar carcinoma

• Uncommon form of adenocarcinoma arising in the terminal brochioloalveolar regions
• Grossly there may be single or multiple nodules or a diffuse, pneumonia like tumour consolidation
• Grow along pre-existing structures without destruction of the alveolar architecture
• They consist of tall, columnar, often mucin producing tumour cells
• May be bilateral
• Shows a ground glass shadow on CXR/CT
• Not usually associated with smoking
• Can be ressected if solitary nodules but not if diffuse disease
• Non invasive and therefore don’t metastasise but they kill by suffocation

 

Small cell carcinoma

• Most malignant of lung cancers
• Generally arises in or near the hilum
• Strongly associated with cigarette smoking
• There is no known preinvasive or carcinoma in situ phase
• Characteristic microscopic appearance includes nests or clusters of small, oatlike cells with little cytoplasm and without squamous or glandular differentiation
• Ultrastructurally the cancer cells can exhibit neurosecretory granules and immunohistochemical stains can demonstrate neuroendocrine markers
• They often produce paraneoplastic syndrome
• Tendency for widespread dissemination at presentation (liver, bone, brain metastases)
• Sensitive to chemotherapy

 

Large cell carcinoma

• Probably represents poorly differentiated squamous cell carcinomas and adenocarcinomas
• Undifferentiated, lacks cytoplasmic features of small cell carcinoma and glandular or squamous differentiation
• The cells generally have large nuclei, prominent nucleoli and a moderate amount of cytoplasm
• 3% show neuroendocrine differentiation and are termed neuroendocrine carcinoma

 

• Approximately 10% of all lung carcinomas have a combined pathology

 

Metastases

• Commonly involve the adrenals, liver, brain and bone

 

Clinical course

• Major presenting complaint are, cough, weight loss, chest pain, dyspneoa
• Local effects may be cough, haemoptysis, pneumonia, SOB
• Intrathoracic spread may result in hoarseness and SVC obstruction
• Extrathoracic spread may result in abdominal or bone pain or neurological involvement
• Paraneoplastic syndromes – particularly associated with small cell carcinoma, however squamous cell can result in hypercalcaemia;
  • ADH – inducing hyponatraemia
  • ACTH – producing Cushing syndrome
  • Parathyroid hormone related peptide and prostaglandin E – hypercalcaemia
  • Calcitonin – hypocalcaemia
  • Gonadotrophins –gynaecomastia
  • Serotonin and brandykinin – associated with carcinoid syndrome

 

• Other systemic manifestations of lung cancer are;
  • Lambert –Eaton myasthenic syndrome causing muscle weakness
  • Peripheral neuropathy
  • Acanthosis nigricans
  • Hypertrophic pulmonary osteoarthropathy associated with clubbing of the fingers

 

• Overall 5 year survival is between 5 and 15%
• Surgical resection of solitary non-small cell tumours has a better survival rate of 48%
• Small cell carcinoma has almost always metastased by the time of diagnosis precluding surgical intervention. It responds to chemotherapy but ultimately recurs

 

Metastatic lung tumours

 

• The lung is the most common site of mets
• Carcinomas and sarcomas arising anywhere in the body may spread to the lungs via the blood, lymphatics or direct continuity e.g. oesophageal carcinomas and mediastinal lymphomas
• The pattern of metastatic growth is quite variable, in the usual case there is multiple discrete lesions (cannonball lesions) throughout all the lobes
• When the tumour extends to the lungs via the lymphatics, the tumour is generally confined to the peribronchiolar and perivascular tissue spaces
• The subpleural lymphatics may be outlined by the contained tumour, producing a gross appearance known as lymphangitis carcinomatosa
• Rarely microscopic tumour emboli fill the small pulmonary vessels and may result in life threatening pulmonary hypertension or haemorrhage

 

Malignant mesothelioma

 

• Arises from either the visceral or parietal pleural
• It is associated with occupational exposure to asbestos in 90% of cases
• The lifetime risk in heavily exposed individuals is 7-10% with a latency period between exposure and development of 25-45 years
• There is no increased risk of mesothelioma in asbestos workers who smoke
• Asbestos bodies and asbestos plaques are found in increased numbers in patients with mesothelioma

 

Morphology

• Tumour spreads diffusely over the lung surface and fissures forming an encasing sheath
• Microscopically they can be classified as;
  • Epithelioid (70%)
  • Sarcomatoid (20%)
  • Mixed (10%)
• Epithelioid tumours show epithelial cells forming tubules and papillary projections, resembling adenocarcinomas
• Sarcomatoid pattern shows malignant spindle shaped cells resembling fibrosarcoma

 

Clinical

• Presenting features are chest pain, dyspneoa and recurrent pleural effusions
• The lung is invaded directly and there is often metastatic spread to the hilar lymph nodes and eventually the liver and distant organs

50% die within a year of diagnosis and few survive longer than