Non Small Cell Ca

Anatomy

  • Oblique fissure→from the lung surface to the hilum
    • upper and lower lobes
  • Right lung → 3 lobes(horizontal fissure→ from the anterior margin into the oblique fissure ⇒ separates the middle lobe from the upper lobe )
  • Left lung→ 2 lobes
    • Upper lobe
    • Lower lobe
  • lingular portion of the left upper lobe corresponds to the middle lobe on the right.
  • Lungs are coated by the visceral pleura→extends into the fissures separating the lobes
  • Trachea→bifurcates approximately at T5
  • Hila of the lungs ( ناف ریه )
    • the bronchi
    • pulmonary arteries
    • pulmonary veins
    • bronchial arteries
    • bronchial veins
    • lymphatics
    • Intrapulmonary lymph nodes
      • along secondary bronchi
      • bronchopulmonary lymph nodes
        • Hilar LN
          • Along the lower portions of the main bronchi
        • Interlobar LN
          • At the bifurcations of the main bronchi into lobar bronchi
        • Including → the hilar nodes
        • From a radiotherapeutic viewpoint.
    • The mediastinal lymph nodes ( and then to supraclav. )
      • Superior, located above the bifurcation of the trachea (carina)
        • upper paratracheal( station 1 )
        • pretracheal( station 2 )
        • retrotracheal ; prevascular( station 3; ant & post )
        • lower paratracheal nodes (azygos nodes- station 4; left & right)
        • aortic window ( station 5 )
      • Inferior, situated in the subcarinal region
        • inferior mediastinum
          • subcarinal ( station 7 )
        • Paraesophageal ( station 8 )
        • pulmonary ligament nodes ( station 9 )
    • Right Upper Lobe → Same side; Hilar → SupraClav
    • Left Upper Lobe →
    • venous angle of the same side
    • venous angle of the opposite superior mediastinum
    • Right Lower Lobe lymphatics → subcarinal nodes( station 7) → Right superior mediastinum ( station 1,2 )
    • Left Lower Lobe lymphatics → subcarinal nodes ( station 7) → Right superior mediastinum ( station 1,2 )
      • Also to left sup as well

Molecular Biology

  • You know BCR-ABL is such pathognomonic for CML… There is not such a thing for lung ca.
  • EGFR and ALK mutations predominate in adenocarcinomas in nonsmokers
    • EGFR
      • ~50% of non-smokers
      • ~10% of non-smokers
      • Axon 19 deletion
      • EGFR ==> improved response rate and PFS with EGFR inhibitors
  • KRAS and BRAF mutations are more common in smokers or former smokers.

RAS FAMILY of GENES
MYC GENE

  • Overexpression and amplification seen in SCLC
  • Chemoresistant
  • Rare in NSCLC

p53
RB1
GASTRIN RELATED PEPTIDE

  • Usually expressed in neuro-endocrine calls in CNS, gut, fetal lung
  • In Lung if chronic damage such as smoking ⇒ overexpression
  • Most SCLC
  • Rare in NSCLC

KIT

  • 15% of SCLC
  • Overexpression
  • IMATINIB
    • GLEEVEC in GI stromal tumors
  • Unfortunately little evidence of activity in SCLC

Early detection and screening

Screening

  • Sputum cytology
  • Chest X-ray
  • CT-SCAN
    • ⇒ increase in detection of lung ca in earlier stage
    • Decreased death in heavy smokers from lung Ca
    • Now in NCCN guideline

Based on the following study:

  • 53,454 pts high risk for lung cancer
  • Low-dose CT vs CXR
  • Positive screening tests —>
    • 24% in CT and 7% in CXR
      • False positive:
        • 96 in CT
        • 94% in CXR
  • More lung ca detected in CT group:
    • (CT)645 vs (CXR)572 cases per 100,000 person-years
  • Less death from lung ca:
    • (CT)247 vs (CXR)309 deaths from lung cancer per 100,000 person-years
  • Relative reduction in mortality from lung cancer —> 20%
  • Relative reduction in rate of death from any cause —> 7%

Prevention

  • Low intake of retinoid and carotinoid
    • ⇒ squamous metaplasia in animal models
    • A randomized trial
      • Head and Neck Ca
      • 13-cis-retionic acid vs placebo
      • → no change of recurrence rate of initial lesion
      • →treated group had less second primary ca
        • Lung
        • Esophagus
        • H & N
    • BUT Confirmatory trials → No difference!
    • Trials using beta – Carotene ⇒ increased rate of Ca!!!
      • Two large randomized trial
        • FINLAND
          • Placebo vs beta-carotene vs alpha-tocopherol vs both
          • Increased death rate in beta-carotene
          • They were ACTIVE SMOKERS
        • UNITED STATES (CARET TRIAL)
          • Beta-carotene
          • Increased death from lung Ca!!!
  • SELENIUM
    • Selenium deficiency in animals → premalignant lesions
    • Randomised trial → selenium vs placebo in patients with skin Ca
      • No reduction in skin Ca but half of lung Ca seen in selenium group
      • Requires confirmatory trial

Epidemiology

  • The most common
  • The most fatal
  • More people in the US die of lung cancer than of the next three causes of cancer-related death—combined:
    • prostate cancer
    • breast cancer
    • colorectal cancer
  • Survival at 5 years : 15%.
  • Risk of second cancer:
    • 2% per year (non-pulmunary)
    • 1% per year (pulmunary)
      • ~30% of Lung Ca Stage I after resection develop second primary.
  • Risk Factors:
    • Smoking
      • filter cigarettes⇒ allowing smaller carcinogens to be deposited in the lung periphery
      • larger puffs and retain smoke longer to compensate for the lower nicotine yield
    • Asbestos
    • Coal tar fumes
    • Nickel
    • Chromium
    • Arsenic
    • Air pollution
      • Diesel exhaust
    • Indoor radon
    • Radioactive materials
  • Adenocarcinoma surpassed squamous cell carcinoma as the most common subtype of lung cancer in both men and women in the mid-1980s

Natural History

  • Adenocarcinoma has the slowest doubling time
  • Small cell carcinoma has the fastest

Patterns of Spread

  • Local (intrathoracic)
  • Regional (lymphatic)
  • Distant (hematogenous)
  • Higher in undifferentiated
  • Higher in small cell
  • In NSCLC
    • AdenoCa → higher risk for DM
  • Right lung tumors→ lower paratracheal nodes (station 4)→ subcarinal nodes (station 7)
  • Left upper lobe lesions→ the subaortic nodes (station 5)→ subcarinal nodes ( station 7 )
  • Lingular and left lower lobe lesions→ subcarinal (station 7)
  • Scalene (supraclavicular) nodal involvement → 2% to 37%
    • Predominantly from ipsilateral upper lobes
  • Adrenal metastasis 27.4%-50%

Clinical Presentation

  • Local tumour growth
    • Depending on the location and size of the tumour
      • Centrally located
        • Cough
        • A localized wheeze
        • Hemoptysis
        • Airway obstruction
        • Postobstructive pneumonitis
        • Dyspnea
        • Fever
        • Productive cough
      • Peripheral tumors
        • Asymptomatic when they are small and confined within the lung
        • Occasionally: cough and pleuritic chest pain
      • Apical tumors
        • Classic Pancoast's syndrome
          • Lower brachial plexopathy
            • Shoulder pain because of invasion of
              • C8 and T1 nerve roots
              • Satellite ganglion
              • Chest wall
          • Horner's syndrome (Invasion into sympathetic trunk)
            • Ptosis
            • Miosis
            • Anhydrosis
          • CXR→Asymmetric apical cap or an apical mass
          • Most superior sulcus tumors are squamous cell carcinomas, → may be adenocarcinomas or even SCLC(1% to 2%)
    • Regional and Intrathoracic spread
      • Mediastinal invasion
        • vague, poorly localized chest pain
        • Entrapment of the recurrent laryngeal nerve
          • Left more likely because of its longer course
          • Hoarseness
          • Dysphagia for both solids and liquids⇒ recurrent aspiration
          • Compression of the esophagus⇒ dysphagia
          • Tracheoesophageal or bronchoesophageal fistula(0.16%)
        • Involvement of the phrenic nerve⇒ hiccups⇒paralysis and elevation of the hemidiaphragm ⇒ dyspnea
        • Superior vena cava (SVC) obstruction syndrome
          • External compression or by intraluminal thrombosis
          • Lung cancer accounts for 65% to 90% of all cases of SVC
          • 85% of these cases the primary lung tumor is on the right
            • Right upper lobe or right mainstem bronchus
          • By cell type, small cell lung cancer (SCLC) predominates followed by squamous cell carcinoma.
    • Pleural involvement at initial presentation(15%)
      • 50% of patients will develop pleural effusion
      • asymptomatic when small
      • Dyspnea
      • Cough
      • Chest pain
    • Pericardial involvement
      • from direct extension of the tumour
      • retrograde spread through mediastinal and epicardial lymphatics
      • Lung cancer is the single most frequent source of pericardial metastases
        • 37% of cases
    • Distant metastases
    • Nonspecific systemic symptoms
    • Paraneoplastic syndromes.
    • Symptoms Due to Distant Metastasis
      • 60% of SCLC and 30% - 40% of NSCLC present with DM
      • Virtually any organ
      • Most common sites of hematogenous spread
        • CNS
          • Nonspecific headache
          • Mental status change
          • Focal or generalized seizures
          • Localized weakness
        • Bones
          • Bone pain
        • Liver
          • RUQ pain
          • Nausea
          • Weight loss
          • Anemia
        • Adrenal glands
          • Asymptomatic
          • Unilateral pain in the ank, abdomen, or costovertebral angle
        • Epidural and intramedullary spinal cord metastases may be the sole neurologic manifestations of lung cancer
      • Nonspecific Systemic Symptoms and Paraneoplastic Syndromes
        • Common
        • Anorexia(30%)
        • Underreported?
        • Weight loss (50%)
        • Generalized weakness (30%)
        • Anemia
        • Fever
        • postobstructive pneumonia
        • liver metastases.
      • Paraneoplastic syndromes
        • Endocrine
        • Neurologic
        • Cutaneous
        • Musculoskeletal
        • Cardiovascular
        • Hematological

Diagnostic and Staging Work-Up

  • History, physical examination
  • Routine Blood work ( CBC, LFT, KFT )
  • Chest x-ray
  • Chest CT scan with contrast
    • For mediastinal LN:
      • Sensitivity: 50%
      • Specificity: 80%
    • Should extend inferiorly to include upper abdomen and adrenal glands
  • Bone scans
  • CT/MRI of the brain
  • Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy
  • Fluorodeoxyglucose positron emission tomography (FDG-PET)
    • If PET scan is performed, bone scan is not necessary.
    • PET-CT is the standard choice
    • Comparing PET vs CT alone
      • Using PET in CT planning may avoid radical CRT for stage IV (15% of patients)
  • Sputum cytology
    • positive predictive value that can approach 100%
    • Sensitivity rate of only 10% to 15%

Radiologic Examination

  • Chest x-ray → simplest method
    • Lesions >5 mm
    • Atelectasis
    • Postobstructive pneumonitis
    • Abscess
    • Bronchiolitis
    • Pleural reaction
    • Rib erosion
    • Pleural effusion
    • Bulky mediastinal lymphadenopathy
  • CT scan
    • sensitivity ranging from 51% to 95%
    • Lymph node size of 1 cm or more
    • Better than MRI because:
      • better spatial resolution
      • greater freedom from motion
    • 8% to 15% false negative
    • PET scanning can detect lesions >5 to 8 mm
    • False-positive←benign inflammatory disease ( ~20%)
      • Abscesses
      • Active granulomatous diseases
      • Hypoxic conditions
        • After RT
      • Treatment induced hypermetabolic inflammation
    • False Negative ( ~20%)
      • Tumors with low glucose metabolism
        • Carcinoid
        • BAC
      • Negative FDG-PET scanning does not preclude biopsy of radiographically enlarged mediastinal lymph nodes
        • ⇒ Mediastinoscopy is necessary
  • Fiberoptic bronchoscopy
    • for determining the endobronchial extent of disease
    • measuring tumor proximity to the carina and various bronchi
    • identifying unsuspected occult lesions that indicate multiplicity of disease.
    • Peripheral lesions
      • Not visible endoscopically
      • Cytologic studies of brushings and bronchioloalveolar lavage
  • CT-guided transthoracic percutaneous fine-needle aspiration biopsy

Mediastinal Staging

  • PET is more sensitive but not perfect.
  • For mediastinal staging:
    • Sensitivity: 75%
    • Specificity: 85%
  • If negative medistinum in PET then primary tumour shall have good uptake otherwise needs pathologic confirmation
    • BAC doesn't have a good uptake sometimes
  • Mediastinoscopy
    • Best method to evaluate the upper, middle peritracheal, and subcarinal lymph nodes
    • Accuracy: 80% to 90%
    • False-negative: 10% to 12%
    • Station most commonly missampled→ subcarinal region ( station 7 )
    • Difficult to access
    • Subaortic and aortopulmonary window→ inaccessible by standard cervical mediastinoscopy
      • “Anterior mediastinotomy” = Chamberlain
        • through the second, third, or fourth anterior interspace
        • On the left side to evaluate disease in the subaortic and lateral aortic regions and the aortopulmonary window
  • Video-assisted thoracoscopy

Other Investigations:

  • Cardiopulmonary evaluation
    • If history of CAD
      • Stress test
      • Stress radionuclide angiography
  • Pulmonary function evaluation
    • Lung volumes
    • Flow rates
    • Diffusing capacity
    • Arterial blood gas analysis
PFT.png

Staging

Primary tumor (T)

  • TX No tumor seen in images. Only presence of malignant cells in sputum or bronchial washes
  • T0 No evidence of primary tumour
  • Tis Carcinoma in situ
  • T1 Tumor ≤3 cm and not in the main bronchus
    • T1a → ≤ 2cm
    • T1b → 2cm < T ≤ 3cm

The uncommon superficial tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, also is classified T1.

  • T2 3cm < T ≤ 7cm
    • T2a → 3cm < T ≤ 5cm
    • T2b → 5cm < T ≤ 7cm
    • Also → Involvement of
      • main bronchus ( But AT LEAST 2cm far from Carina )
        • if closer will be T3
        • if Carina involved will be T4
      • visceral pleura
    • Also → if associated with atelectasis or obstructive pneumonitis
      • OK if extends to the hilar region
      • BUT does not involve the entire lung
  • T3
    • T > 7cm OR
    • Invasion of
      • Chest wall (including superior sulcus tumours)
      • Diaphragm
      • Mediastinal pleura
      • Parietal pericardium
      • Main bronchus but <2 cm distal to the carina
        • NO involvement of the carina
      • Associated atelectasis or obstructive pneumonitis of the entire lung
  • T4
    • Invasion of
      • Mediastinum
      • Heart
      • Great vessels
      • Trachea
      • Esophagus
      • Vertebral body
      • Carina
    • Existence of Malignant pleural or pericardial effusion
    • Satellite tumor nodule(s) within the ipsilateral primary tumor lobe of the lung

Regional lymph nodes (N)

  • NX
    • Cannot be assessed
  • N0
    • No LN
  • N1
    • Ipsilateral
      • Peribronchial
      • Hilar
      • Intrapulmonary nodes involved by direct extension of the primary tumour
  • N2
    • Ipsilateral
      • Mediastinal
      • Subcarinal
  • N3
    • Contralateral (all)
    • Supraclavicular

Distant metastasis (M)

  • MX
    • Cannot be assessed
  • M0
    • None
  • M1
    • M1a
      • Separate tumor nodule in a any other lobe
      • Pleural nodules
      • Malignant pleural effusion
    • M1b
      • ALL OTHER
lung.png

Pathologic Classification

Brief on Lung Histology

  • Bronchus
    • Columnar epithelium ( سلول های پوششی استوانه ای )
    • Goblet Cells
    • Ciliated
  • Bronchioles
    • Cuboidal epithelium ( سلول های پوششی مکعبی )
    • No Goblet Cell
  • Alveoli
    • Flat type I thin epithelium
    • If cuboidal = Type II hyperplasia

Pre-malignant lesions

  • Before becoming invasive, lung epithelium may undergo morphological changes that include the following:
  • Hyperplasia.
  • Metaplasia.
  • Dysplasia.
  • Carcinoma in situ.

Dysplasia and carcinoma in situ are considered the principal premalignant lesions because they are more likely to progress to invasive cancer and less likely to spontaneously regress.

After resection of a lung cancer, there is a 1% to 2% risk per patient per year that a second lung cancer will occur.

Neoplastic Lung

Usually defined based on best-differentiated region of the tumor and graded by its most poorly differentiated portion

  • AdenoCa(50%)>SCC(35%)>Large cell(5%)
  • Non Small Cell Lung Ca
    • Squamous cell carcinoma
      • Arises from squamous metaplasia
      • Presence of keratin pearl formation and intercellular bridges would be classified as a squamous cell carcinoma.
        • If most of the cells of the remaining tumor did not show such features —> poorly differentiated squamous cell tumor.
      • Usually in major bronchi
        • ==> so tumours are centrel
      • keratin pearl formation and intercellular bridges
      • pink, dense cytoplasm
      • keratin whorls ( Keratin pearl formation )
    • Adenocarcinoma
      • Gland formation or mucin production —> it is almost certainly adenocarcinoma
        • then one must decide if it is primary or metastatic.
      • Arises from multiple cell types ==> vary in morphology
      • Patterns
        • Acinar, tubular, papillary, and solid
      • ALSO
        • Mucinous or nonmucinous
      • Bronchioloalveolar carcinoma (BAC) = in situ form of adenocarcinoma
        • Better prognosis
        • Still behaves like carcinoma
        • Mucinous (arising from goblet cell metaplasia)
        • Nonmucinous
          • Better prognosis
          • More often solitary.
        • Morphology
          • Columnar
          • Eosinophilic cells growing along the bronchial and alveolar walls
            • Outlining the structure of the airspaces
          • NO evidence of stromal invasion
        • Can be found at periphery of invasive Ca
  • Large cell carcinoma
    • Arises when adenocarcinoma dedifferentiates into a very ugly tumor with no recognizable glandular features
    • Pleomorphic or giant cell features
  • Other Lesions
    • Hamartoma
      • Tumor-like mass composed of a disorganized mixture of the normal elements found in that organ. It is not clonal and therefore not really a neoplasm.
      • In the lung —> masses of cartilage, fat, smooth muscle, and epithelium.
    • Salivary neoplasms
      • Seromucinous glands around the bronchi can give rise to any of the traditional salivary gland neoplasms.
    • Carcinosarcoma
      • Biphasic malignant lesion
        • Recognizable epithelial component (carcinoma)
        • A separate recognized form of sarcoma like:
          • Osteosarcoma
          • Chondrosarcoma.
          • Different from the sarcomatous carcinoma
            • Sarcomatous Carcinoma is a pure carcinoma that has acquired spindle cell morphology.
  • Small cell undifferentiated carcinoma

Incidences of the various histologic types:

  • Squamous cell carcinoma was the most common type
    • Recently years it has decreased
  • Adenocarcinoma has increased
    • MOST COMMON (49%)
    • In Europe, squamous cell carcinoma is still the most common type.

Prognostic Factors

  • Patient factors
    • Performance status
    • Stage
    • Weight loss
  • Tumor factors
    • Histology
      • Epidermoid carcinoma has the best prognosis, followed by adenocarcinoma and undifferentiated large cell carcinoma
      • Undifferentiated small cell carcinoma had the poorest prognosis
    • Molecular markers
  • Negative prognostic factors for NSCLC
    • K-RAS oncogene
    • Deletion of tumor-suppressor genes (e.g., p53)
    • NCAM (neural cell adhesion molecule) expression
    • Elevated serum levels of neuron-specific enolase
    • Overexpression of genes from the ErbB family
      • ErbB-1 (epidermal growth factor receptor)
      • ErbB-2 (Her2/neu)
    • Elevation of proliferative markers
      • Ki-67
      • Cyclin D1
      • P16 loss
      • Cyclin E
      • Cyclin B1
    • Elevated angiogenesis markers
      • Microvessel density
      • Vascular endothelial growth factor receptors ( VEGF R )
      • Matrix metalloproteinases)
    • Decreased apoptotic markers
      • Apoptotic index
      • Caspase-3
  • Treatment-specific variables

Management of NSCLCA