Lung Cancer

Clinical Background

Lung cancer is the leading cause of cancer death in the U.S.

Epidemiology

  • Incidence
    • More than 150,000 new cases annually in the U.S.
  • Age – peak incidence is 55-65 years
  • Sex – M>F
    • Female prevalence has increased; male prevalence has stabilized

Risk Factors

  • Tobacco use
    • 13-fold increase in risk for primary user
    • Secondhand exposure – 1.14 to 5.20 relative risk for people who live/lived with smokers
  • Radon/uranium exposure
  • Asbestos exposure – cumulative risk if patient smokes
  • Previous chest irradiation
  • Genetic – positive family history combined with tobacco use increases the risk

Pathophysiology

  • Any tumor arising from respiratory epithelium or pneumocytes
  • 4 main tumor types (account for 85-90% of all lung cancers)
    • Non-small cell lung cancer (NSCLC) account for 85-90% of all lung cancers
      • Squamous (epidermoid) cell carcinoma (SCC)
      • Adenocarcinoma (includes bronchioloalveolar)
      • Large cell (large cell anaplastic)
    • Small cell lung cancer (SCLC)
  • Remainder of tumors
    • Undifferentiated, carcinoid, bronchial gland tumors, sarcomas
    • Other tumors rare
  • Recent rates of adenocarcinoma are equivalent to squamous cell carcinoma
    • Postulated reasons for change in distribution are the change in tobacco components (less tar in current tobacco products, leading to less squamous cell)

Clinical Presentation

  • 20% of patients are incidentally identified while asymptomatic by a chest x-ray for other reasons
  • Symptoms are related to the following:
    • Local tumor growth
    • Invasion and obstruction of adjacent structures
    • Distant metastases
    • Tumor product secretion
  • Symptoms based on area of tumor growth
    • Central – cough, wheeze, hemoptysis, stridor, dyspnea, postobstructive pneumonia
    • Peripheral – pleural/chest wall pain, cough, dyspnea
    • Invasion and obstruction of adjacent structures
      • Tracheal obstruction – dyspnea, wheezing
      • Esophageal compression – dysphagia
      • Recurrent laryngeal nerve invasion – hoarseness
      • Phrenic nerve invasion – diaphragmatic paralysis
      • Sympathetic nerve invasion – Horner syndrome
        • Ptosis
        • Miosis
        • Enophthalmos
        • Unilateral loss of sweating
      • Invasion of lung apex – pancoast tumor, superior vena caval syndrome
    • Distant metastases
      • Superior vena caval syndrome
      • Pericardial tamponade
      • Pleural effusions
      • Pathologic bone fractures
      • Adrenal insufficiency (rare) 
    • Paraneoplastic syndromes
      • Common; may be first presenting symptoms of lung cancer
      • Endocrine syndromes
        • Ectopic parathyroid hormone
          • Usually squamous cell
          • Hypercalcemia, hypophosphatemia
        • Antidiuretic hormone (ADH)
          • Usually SCLC
          • Syndrome of inappropriate secretion of ADH
          • Hyponatremia
        • Adrenocorticotropic hormone (ACTH)
          • Usually SCLC
          • Usually not Cushingoid in appearance
          • Hypokalemia
      • Skeletal/connective tissue syndromes
        • Clubbing
          • 30% incidence
          • Usually NSCLC
        • Hypertrophic pulmonary osteoarthropathy
          • Usually adenocarcinoma
      • Neurologic/myopathic syndromes
        • Eaton-Lambert syndrome
          • Usually SCLC
          • Myasthenia gravis symptoms
        • Retinal blindness
          • Usually SCLC
        • Peripheral neuropathy
        • Subacute cerebellar degeneration
        • Cortical degeneration
      • Polymyositis
      • Hematologic syndromes
        • Migratory thrombophlebitis – Trousseau sign
        • Nonbacterial endocarditis – marantic endocarditis
        • Disseminated intravascular coagulation
      • Dermatologic syndromes
        • Uncommon
        • Dermatomyositis
        • Acanthosis nigricans
      • Systemic syndromes
        • Unknown etiology
        • Cachexia, anorexia, fever, weight loss, suppressed immunity

Diagnosis

Indications for Testing

  • New pulmonary mass

Laboratory Testing

  • Serum testing is not helpful in diagnosing lung cancer; however, baseline testing (eg, CBC with differential, liver function) may be performed as a general screen for metastases
  • Immunohistochemistry (Beasley recommendations, 2008)
    • Should be used as adjunct and interpreted in clinical context
    • Primary adenocarcinoma and bronchioalveolar carcinoma
      • CK7 positive, CK20 negative, thyroid transcription factor-1 (TTF-1) positive
      • Primary mucinous adenocarcinoma – positive CK7 and CK20, negative TTF-1
    • SCC
      • Usually negative CK7, CK20, TTF-1
      • Does not typically require immunohistochemical staining for diagnosis
    • SCLC and neuroendocrine carcinomas
      • Typically negative CK7, CK20
      • Positive for neuroendocrine markers such as chromogranin, CD56, synaptophysin
      • Differentiating poorly differentiated SCC from SCLC
        • P63 and CK5/6 positive and TTF-1 negative supports SCC

Imaging Studies

  • Chest x-ray, CT scan, MRI provide basis for initial testing

Histology

  • Invasive testing to obtain tissue necessary for diagnosis
    • Bronchoscopic biopsy
    • Mediastinal node sampling
    • Fine needle aspiration using CT guidance
    • Open lung biopsy
    • Endobronchial ultrasound

Solitary Pulmonary Nodule (SPN)

  • Usually found incidentally on chest radiograph
  • 35% are malignant
  • Histologic diagnosis required in the following situations:
    • Patient is ≥35 years
    • Nodule is >1 cm diameter
    • Growth of lesion
    • Lack of calcification
    • Adenopathy
    • Positive PET scan
    • No previous imaging to review in order to determine if nodule has changed in size

Differential Diagnosis

  • SPN
    • Granuloma
      • Tuberculosis
      • Coccidiomycosis
      • Histoplasma
      • Cryptococcus
      • Aspergillus
    • Hamartoma
    • Round pneumonia
    • Bronchogenic cyst
    • Pulmonary infarction
    • Focal hemorrhage
    • Arteriovenous malformation
  • Mass
    • Pneumonia
    • Metastatic tumor
    • Fibrotic lung disease

Screening

  • No proven benefit in detection rate or survival – not recommended by U.S. Preventative Services Task Force, American Cancer Society (ACS)
  • Screening (sputum cytology and chest radiography) of patients ≥45 years who have a history of tobacco use does not improve survival rates
    • Screened patients are more likely to be asymptomatic than those not screened; however, survival rates do not differ between the groups
  • Recent studies using CT scanning in at-risk group demonstrate improved survival for stage I (International Early Lung Cancer Action Program – IELCAP)
    • Absence of control arm in study
    • Unclear whether screening merely identified more early-stage cancers but did not change the number of advanced cancers or lung cancer mortality
    • Recent Mayo Clinic study (Screening for Lung Cancer, ACCP, rev. 2007) found no meaningful reduction in deaths from lung cancer
  • Ongoing trials evaluating screening

Monitoring

  • Recommended monitoring (post-curative approach)
    • History and physical, chest x-ray, CBC and chemistries every 3-6 months for first 2 years (National Comprehensive Cancer Network [NCCN] recommends CT every 6 months in NSCLC)
  • Many markers have been evaluated without much evidence to suggest helpfulness in diagnosis or prognosis
    • p53 (available as immunohistochemical stain) – SCLC, SCC
    • Pro CRP – SCLC
    • CA-125 (available as immunohistochemical stain) – NSCLC
    • LKB1/STK11 – adenocarcinoma
    • P4RAS – adenocarcinoma
    • HER-2 – NSCLC
    • TU M2-PK – all types
    • BCL-2 (available as immunohistochemical stain) – SCLC
    • Chromogranin A (available as immunohistochemical stain) – SCLC
    • CEA (available as immunohistochemical stain) – NSCLC (especially adenocarcinoma and large cell carcinoma)
    • Squamous cell antigen – SCC
  • EGFR (epidermal growth factor receptor) mutations and amplifications
    • Holds the most promise as a marker and predictor of prognosis
    • Can improve the rate of detection of lung cancer when used in conjunction with cytology (either bronchial brushings or washings are suitable specimens)
    • Majority have adenocarcinoma
      • Should not be used in tumors of pure squamous origin or small cell
    • High incidence in Asian lung cancer populations
    • Majority are nonsmokers or modest tobacco users
    • Marker usefulness not yet well described
      • Current clinical trials assessing EGFR antagonists for therapy in patients who are EGFR positive
  • Cytokeratin-19 fragment (CYFRA 21-1)
    • The most sensitive tumor marker for NSCLC (particularly squamous)
      • May also be elevated in urological, gastrointestinal and gynecological tumors
    • Potential role as an independent prognostic factor in both early and late stages of NSCLC
      • May serve same role in SCLC
    • Potential role for monitoring therapy in advanced NSCLC and prediction of response to therapy
  • Markers that hold promise
    • Neuron specific enolase
      • High specificity for SCLC
      • May be useful in assessing prognosis in both SCLC and NSCLC
      • Currently in clinical use, but value has not been validated in a high-level evidence study

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
CBC with Platelet Count & Automated Differential 0040003
Method: Automated Cell Count with Flow Cell Differential

General screening for metastases

Recommended for disease followup

    
Hepatic Function Panel 0020416
Method: Refer to individual components.

General screening for metastases

    
Cytology, Pulmonary 8209702
Method: Routine Cytopathologic Evaluation

May be used as initial screening test

Negative screening does not mean cancer is not present

Bronchial brushings, washings, tissue biopsy (transbronchial and open lung) from site of lung involved
Cytology, Bronchoalveolar Lavage, Malignancy 8280005
Method: Routine Cytopathologic Evaluation

May be used as initial screening test

Negative screening does not mean cancer is not present

Bronchial brushings, washings, tissue biopsy (transbronchial and open lung) from site of lung involved
EGFR by FISH 0049234
Method: Fluorescence in situ Hybridization

Predict prognosis in lung cancer

May be inferior to mutation analysis for prediction of response to EGFR antagonists

Bronchial brushings, washings, tissue biopsy (transbronchial and open lung) from site of lung involved
EGFR Mutation Detection by PCR and Fragment Analysis 2002440
Method: Polymerase Chain Reaction/Fragment Analysis

Predict prognosis in lung cancer and response to therapy

    
Cytokeratin 19 Fragment (CYFRA 21-1), Serum 0081344
Method: Enzyme-linked Immunosorbent Assay

Predict prognosis in early and late stages of NSCLC

Not sensitive or specific enough to use in screening

Results obtained with different methods or kits cannot be used interchangeably

Assay values should not be interpreted as absolute evidence of the presence or absence of malignant disease

  
Neuron Specific Enolase 0098198
Method: Enzyme-Linked Immunosorbent Assay
 May be useful to monitor tumor recurrence in SCLC Not sensitive or specific enough to use in screening; moderate levels found in benign diseases and other cancers

Results obtained with different methods or kits cannot be used interchangeably

Assay values should not be interpreted as absolute evidence of the presence or absence of malignant disease

  
Immunohistochemistry Stain Offering arup005
Method: Immunohistochemistry

For fixed tissue samples, consultative services as well as immunohistochemical staining for ACTH, Ber-Ep4, BCL-2, CA-125, CD57 (Leu7), CD56, CK5/6, CK7, CK20, TTF-1, CDX2, CEA, D2-40, calretinin, chromogranin A, EGFR, EGFR (H-11), EMA, ERA (moc-31), keratin 903 (HMW), NSE, p16, p21, p27, p53, placental alkaline phosphatase (PLAP), PGP9.5, synaptophysin, and villin are available