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 yearly in the U.S.
Age of peak incidence
- 55-65 years
Gender - males > females
- Female prevalence has increased, while male prevalence has stabilized

Risk Factors

Tobacco use (13-fold increase in risk)
Radon/uranium exposure
Asbestos exposure
- Most common malignancy is mesothelioma
- Cumulative risk if patient smokes
Previous chest irradiation
Genetic - family history combined with tobacco use increases the risk

Pathophysiology

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

Clinical Presentation

20% of patients are identified incidentally when asymptomatic
Related to:
- Local tumor growth
- Invasion and obstruction of adjacent structures
- Distant metastasis
- Tumor product secretion
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
  - 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 symdrome
- Distant metastases
  - Superior vena caval syndrome
  - Pericardial tamponade
  - Pleural effusions
  - Pathologic bone fractures
  - Adrenal - rare cause of adrenal insufficiency
- 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 small cell
      - Syndrome of inappropriate secretion of ADH
      - Hyponatremia
    - Adrenocorticotropic hormone (ACTH)
      - Usually small cell
      - Usually not Cushingoid
      - Hypokalemia
  - Skeletal/connective tissue syndromes
    - Clubbing
      - 30% incidence
      - Usually Non Small Cell Lung Cancer (NSCLC)
    - Hypertrophic pulmonary osteoarthropathy
      - Usually adenocarcinoma
  - Neurologic/myopathic syndromes
    - Eaton Lambert
      - Myasthenia gravis symptoms
      - Usually small cell
    - Retinal blindness
      - Usually small cell
    - Peripheral neuropathy
    - Subacute cerebellar degeneration
    - Cortical degeneration
    - Polymyositis
    - Hematologic syndromes
      - Migratory thrombophlebitis - Trousseau’s 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

See Also

Carcinoid Tumors

Head and Neck Cancer - Squamous Cell Carcinoma

Mesothelioma

Nicotine & Metabolites

Paraneoplastic Neurological Syndromes

Diagnosis

Serum laboratory testing is not helpful in diagnosing lung cancer
Tissue diagnosis necessary
- Bronchoscopic biopsy
- Mediastinal node sampling
- Fine needle aspiration using CT guidance
- Open lung biopsy
Solitary pulmonary nodule
- Usually found on chest radiograph incidentally
- 35% are malignant
- Histologic diagnosis required if:
  - Patient is 35 or older
  - >1 cm diameter
  - Growth of lesion
  - Lack of calcification
  - Adenopathy
  - Positive PET scan

Disease Monitoring

Many markers have been evaluated without much evidence to suggest they are helpful in diagnosis or prognosis
- p53 - SCLC, squamous
- Pro CRP - SCLC
- CA 125 - NSCLC
- LKB1/STK11 - adenocarcinoma
- P4RAS - adenocarcinoma
- HER-2 - NSCLC
- TU M2-PK - all types
- BCL-2 - SCLC
- Chromogranin A - SCLC
- CEA - NSCLC
- Squamous cell antigen - squamous
EGFR (epidermal growth factor receptor) mutations and amplifications
- Holds the most promise as a marker
- When used in conjunction with cytology, it can improve the rate of detection of lung cancer (either bronchial brushings or washings are suitable specimens)
  - FISH is actually more sensitive in early detection than cytology
- Majority have adenocarcinoma (bronchoalveolar pathology predominated)
- High incidence in Asian lung cancer populations
- Majority are nonsmokers or modest tobacco users
- Marker usefulness not well described yet
  - 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 have same effect 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 the value has not been validated in a high-level evidence study

Disease Screening

No proven benefit in detection rate or survival
Screening (sputum cytology and chest radiography) of patients ages 45 and older who have a history of tobacco use does not improve survival rates
- Screened patients are more likely to be asymptomatic than non-screened, yet survival is not different between the groups
Recent studies using CT scanning in at risk group demonstrate improved survival for stage I

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Cytology, Pulmonary

ARUP #: 8209702

Methodology: Routine Cytopathologic Evaluation

Use:

May be used as initial screening test

Limitations:

Negative screening does not mean cancer is not present

Follow-up:

Bronchial brushings, washings, tissue biopsy (transbronchial and open lung) from site of lung involved

Test name: Cytology, Bronchoalveolar Lavage, Malignancy

ARUP #: 8280005

Methodology: Routine Cytopathologic Evaluation

Use:

May be used as initial screening test

Limitations:

Follow-up:

Bronchial brushings, washings, tissue biopsy (transbronchial and open lung) from site of lung involved

Test name: EGFR by FISH

ARUP #: 0049234

Methodology: Fluorescence in situ Hybridization

Use:

Predict prognosis

May be used as an initial screening test

Limitations:

Immunohistochemistry for EGFR is standard testing to use for prediction of prognosis

Follow-up:

Bronchial brushings, washings, tissue biopsy (transbronchial and open lung) from site of lung involved

Test name: Cytokeratin 19 Fragment (CYFRA 21-1), Serum

ARUP #: 0081344

Methodology: Chemiluminescent Immunoassay

Use:

Predict prognosis in early and late stages of NSCLC

Test name: Neuron Specific Enolase

ARUP #: 0098198

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

May be useful to monitor tumor recurrence in SCLC

Limitations:

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

Follow-up:

Test name: Immunohistochemistry Stain Offering

ARUP #: arup005

Methodology: Immunohistochemistry

Use:

For fixed tissue samples, consultative services as well as immunohistochemical staining for Ber-Ep4, CD57 (Leu7), CK5/6, CK7, Calretinin, Chromogranin A, EGFR, EGFR (H-11), EMA, ERA (moc-31), Keratin 903 (HMW), p16, p21, p27, p53, Placental alkaline phosphatase (PLAP), PGP9.5, Synaptophysin, Villin, ACTH and NSE are available

References

Guidelines

Initial diagnosis of lung cancer: ACCP evidence-based clinical practice guidelines. (2nd Edition) American College of Chest Physicians - Medical Specialty Society. 2003 Jan (revised 2007 Sep). 18 pages. NGC:005930

Screening for lung cancer: ACCP evidence-based clinical practice guidelines. (2nd Edition) American College of Chest Physicians - Medical Specialty Society. 2003 Jan (revised 2007 Sep). 9 pages. NGC:005926

Zhu CQ, Shih W, Ling CH, Tsao MS. Immunohistochemical markers of prognosis in non-small cell lung cancer: a review and proposal for a multiphase approach to marker evaluation. J Clin Pathol. 2006;59(8):790-800.

General References

Alberg AJ, Ford JG, Samet JM. Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):29S-55S.

Arenberg D. Bronchioloalveolar lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):306S-313S.

Bach PB, Silvestri GA, Hanger M, Jett JR. Screening for lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):69S-77S.

Bharti A, Ma PC, Salgia R. Biomarker discovery in lung cancer--promises and challenges of clinical proteomics. Mass Spectrom Rev. 2007;26(3):451-466.

Cappuzzo F, Toschi L, Finocchiaro G, Ligorio C, Santoro A. Surrogate predictive biomarkers for response to anti-EGFR agents: state of the art and challenges. Int J Biol Markers. 2007;22(1 Suppl 4):S10-S23.

Crino L, Foglietta J, Hamzaj A. Lung cancer. J Thorac Oncol. 2007;2(5 Suppl):S24-S26.

Dubey S, Powell CA. Update in lung cancer 2006. Am J Respir Crit Care Med. 2007;175(9):868-874.

Gabrielson E. Worldwide trends in lung cancer pathology. Respirology. 2006;11(5):533-538.

Gould MK, Fletcher J, Iannettoni MD, Lynch WR, Midthun DE, Naidich DP, Ost DE. Evaluation of patients with pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):108S-130S.

Greenberg AK, Lee MS. Biomarkers for lung cancer: clinical uses. Curr Opin Pulm Med. 2007;13(4):249-255.

Henschke CI, Yankelevitz DF, Libby DM, Pasmantier MW, Smith JP, Miettinen OS. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med. 2006;355(17):1763-1771.

Infante M, Lutman FR, Cavuto S, Brambilla G, Chiesa G, Passera E, Angeli E, Chiarenza M, Aranzulla G, Cariboni U, Alloisio M, Incarbone M, Testori A, Destro A, Cappuzzo F, Roncalli M, Santoro A, Ravasi G. Lung cancer screening with spiral CT Baseline results of the randomized DANTE trial. Lung Cancer. 2007;:-.

McCrory DC, Lewis SZ, Heitzer J, Colice G, Alberts WM. Methodology for lung cancer evidence review and guideline development: ACCP evidence-based clinical practice guidelines (2nd Edition). Chest. 2007;132(3 Suppl):23S-28S.

Rosell R, Cuello M, Cecere F, Santarpia M, Reguart N, Felip E, Taron M. Usefulness of predictive tests for cancer treatment. Bull Cancer. 2006;93(8):E101-E108.

Rubins J, Unger M, Colice GL. Follow-up and surveillance of the lung cancer patient following curative intent therapy: ACCP evidence-based clinical practice guideline (2nd edition). Chest. 2007;132(3 Suppl):355S-367S.

Samson DJ, Seidenfeld J, Simon GR, Turrisi AT III, Bonnell C, Ziegler KM, Aronson N. Evidence for management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):314S-323S.

Shen KR, Meyers BF, Larner JM, Jones DR. Special treatment issues in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):290S-305S.

Sienel W, Dango S, Ehrhardt P, Eggeling S, Kirschbaum A, Passlick B. The future in diagnosis and staging of lung cancer. Molecular techniques. Respiration. 2006;73(5):575-580.

Simon GR, Turrisi A. Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):324S-339S.

Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers--a different disease. Nat Rev Cancer. 2007;7(10):778-790.

Wahidi MM, Govert JA, Goudar RK, Gould MK, McCrory DC. Evidence for the treatment of patients with pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):94S-107S.

Yau G, Lock M, Rodrigues G. Systematic review of baseline low-dose CT lung cancer screening. Lung Cancer. 2007;58(2):161-170.

References from the ARUP Institute for Clinical and Experimental Pathology Research®

Willmore-Payne C, Holden JA, Layfield LJ. Detection of epidermal growth factor receptor and human epidermal growth factor receptor 2 activating mutations in lung adenocarcinoma by high-resolution melting amplicon analysis: correlation with gene copy number, protein expression, and hormone receptor expression. Hum Pathol. 2006;37(6):755-763.

Medical Reviewers

Bentz, Joel S., M.D., M.S. Associate Professor, Pathology, University of Utah

Grenache, David G., Ph.D. Medical Director, Special Chemistry at ARUP Laboratories; Assistant Professor, Clinical Pathology, University of Utah

Layfield, Lester , M.D. Fine-Needle Aspiration Services and Molecular Diagnostics at ARUP Laboratories; Professor and Division Head, Anatomic Pathology, University of Utah

Perkins, Sherrie L. , M.D., Ph.D. Medical Director, Hematopathology at ARUP Laboratories; Professor, Anatomic Pathology, University of Utah

Comprehensive Review: January 2008
Last Update: May 2008