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Disease Categories > Oncologic Disease

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Lung Cancer

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

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

Indications for Ordering

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
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, Malignancy8280005 Method: Routine Cytopathologic Evaluation	May be used as initial screening test		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 May be used as an initial screening test	Immunohistochemistry for EGFR is standard testing to use for prediction of prognosis	Bronchial brushings, washings, tissue biopsy (transbronchial and open lung) from site of lung involved
Cytokeratin 19 Fragment (CYFRA 21-1), Serum 0081344 Method: Chemiluminescent Immunoassay	Predict prognosis in early and late stages of NSCLC
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 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

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 (Link to NGC)

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 (Link to NGC)

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. (Link to PubMed)

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. (Link to PubMed)

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

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. (Link to PubMed)

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. (Link to PubMed)

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. (Link to PubMed)

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

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

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

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. (Link to PubMed)

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

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. (Link to PubMed)

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;-. (Link to PubMed)

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. (Link to PubMed)

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. (Link to PubMed)

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. (Link to PubMed)

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. (Link to PubMed)

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. (Link to PubMed)

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. (Link to PubMed)

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. (Link to PubMed)

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

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. (Link to PubMed)

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

References from the ARUP Institute for Clinical and Experimental Pathology®

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. (Link to PubMed)

Reviewed by

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