Lung Cancer

Primary Authors: Samowitz, Wade S., MD. Vaughn, Cecily P., MS. Wallander, Michelle L., PhD.

  • Key Points
  • Diagnosis
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Content

Molecular Markers in Lung Cancer

The presence of molecular markers in non-small cell lung cancer (NSCLC) is associated with responsiveness to targeted therapies (eg, tyrosine kinase inhibitors, monoclonal antibodies) for patients with adenocarcinoma or mixed-adenocarcinoma histology. Simultaneous ordering of EGFR, ALK, ROS1 with consideration of other mutations (eg, KRAS, RET, BRAF) is recommended for advanced stage adenocarcinoma or mixed adenocarcinoma subtypes. Mutational testing may be considered on small samples even in the absence of adenocarcinoma as sampling bias may occur and mixed adenocarcinoma tumors could otherwise be missed. Minimum testing should include EGFR mutation and ALK rearrangement detection (ASCO/CAP/IASLC/AMP, 2014). Guidelines strongly recommend using multiplex or next generation sequencing (NGS), which detects both common and rare mutations to optimize patient therapy (NCCN, 2015).

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 metastasis
  • Other testing
    • Neuron-specific enolase (NSE), serum – may have diagnostic value for small cell lung cancer (SCLC)

Imaging Studies

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

Histology

  • Invasive testing to obtain tissue is necessary for diagnosis
    • Bronchoscopic biopsy
    • Mediastinal node sampling
    • Fine needle aspiration using CT guidance
    • Open lung biopsy
    • Fine needle aspiration using endobronchial ultrasound (EBUS)
  • Immunohistochemistry
    • Should be used adjunctly and interpreted in clinical context
    • Squamous cell carcinoma (SCC)
      • Usually negative for CK 7, CK 20, TTF-1
      • Does not typically require immunohistochemical staining for diagnosis
    • Primary adenocarcinoma and bronchioalveolar carcinoma
      • Positive for CK 7, napsin A, and thyroid transcription factor-1 (TTF-1); negative for CK 20
      • Primary mucinous adenocarcinoma – positive for CK 7 and CK 20, negative for TTF-1
    • SCLC and neuroendocrine carcinomas
      • Typically negative for CK 7, CK 20
      • Typically positive for keratin epithelial membrane antigen and TTF-1
      • Positive for neuroendocrine markers such as chromogranin A, CD56 (NCAM), synaptophysin, NSE
    • Dysregulation in tumor progression, therapeutic target – c-MET
  • Molecular markers
    • Most useful for therapy planning in advanced stages of adenocarcinoma and mixed adenocarcinoma subtypes (ASCO/CAP/IASLC/AMP 2014) – see Key Points

Solitary Pulmonary Nodule

  • Usually found incidentally on chest x-ray (0.09-0.2% of all x-rays)
    • 35% are malignant
  • Histologic diagnosis required in the following situations
    • Patient is ≥35 years
    • Nodule is >10 mm 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

Prognosis

  • Markers
    • Mutations in genes – AKT1, ALK, BRAF, EGFR, ERBB2, ERBB4, KRAS, NRAS, PIK3CA
    •  Gene fusions that result in translocations – ALK, RET, ROS1
      • Refer to Key Points section
      • Used to establish eligibility for therapies such as tyrosine kinase and ALK inhibitors
  • Promising markers
    • Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1)
      • Control T-cell coinhibitory receptor and ligand function as immune checkpoint
        • PD-L1 is ligand for PD-1
        • PD-L1 expression facilitates immune system evasion by inhibiting T-cell activation
        • PD-1 and PD-L1 are expressed by a variety of solid tumors, including NSCLC
        • Detection of PD-1 and PD-L1 expression by immunohistochemistry may predict response to immunotherapy with monoclonal antibodies
    • Cytokeratin-19 fragment (CYFRA 21-1)
      • Most sensitive tumor marker for NSCLC (particularly squamous)
      • Uses
        • Prognostication
          • Elevated pretreatment level – associated with unfavorable prognosis
        • Monitoring
          • Decreasing levels predict objective response to treatment
    • Neuron-specific enolase (NSE)
      • High specificity for SCLC
      • May be useful in assessing prognosis in NSCLC and SCLC
      • Currently in clinical use, but prognostic value has not been validated in high-level study
    • p53 – tumor suppressor protein
      • Presence in patients with NSCLC is prognostic of short survival time and potential benefit from adjuvant chemotherapy
    • Pro GRP – SCLC
    • CA-125 (available as an immunohistochemical stain) – NSCLC
    • STK11 – adenocarcinoma
    • Tumor M2-PK (TU M2-PK) – all types
    • BCL-2 (available as an immunohistochemical stain) – SCLC
    • ERCC1 expression – high level
    • RRM1 expression – high level

Differential Diagnosis

  • Recommended monitoring (postcurative 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 non-small cell lung cancer [NSCLC])
  • Small-cell lung cancer (SCLC)
    • Serial neuron-specific enolase (NSE) testing may be useful for monitoring tumor recurrence in SCLC
  • NSCLC
    • CK 19 – potential role for monitoring therapy in advanced NSCLC

Lung cancer is the leading cause of cancer-related mortality in the U.S. and worldwide.

Epidemiology

  • Incidence – 62.5/100,000
    • Leading cause of cancer in the U.S. (NCCN, 2015)
  • Age – peak incidence is 65-74 years; median is 71 years
  • Sex – M>F, minimal
    • Female prevalence has increased; male prevalence has stabilized
  • Ethnicity – highest incidence in African American males

Risk Factors

  • Tobacco use – 85-90% of all lung cancers attributed to tobacco use
    • 13-fold increase in risk for primary user
    • Secondhand smoke exposure – 20-30% increased risk for those who live/ have lived with smokers
  • Radon exposure – likely main cause of lung cancer in nonsmokers
  • Asbestos exposure – cumulative risk; estimated to cause 3-4% of cases
    • Risk increased if patient also smokes
  • Occupational exposure to carcinogens (eg, bis(chloromethyl)ether, polycyclic aromatic hydrocarbons, chromium, nickel, organic arsenic)
  • Previous chest irradiation
  • Genetic – positive family history combined with tobacco use increases the risk

Pathophysiology

  • Any tumor arising from respiratory epithelium or pneumocytes
  • Two main types
    • Non-small cell lung cancer (NSCLC) – ~85% of all lung cancers
      • Adenocarcinoma (non-squamous cell) – most common
        • Occurs in glandular tissue of lung lining
      • Squamous (epidermoid) cell carcinoma (SCC)
      • Large cell (large cell anaplastic), other types
    • Small cell lung cancer (SCLC) – ~15% of all lung cancers
      • Epithelial tumor of small cells
        • 95% arise in lung; may also arise from extrapulmonary sites (eg, nasopharynx, gastrointestinal tract, genitourinary tract)
      • Nearly all cases result from smoking
      • Two subtypes
        • Small cell carcinoma (oat cell)
        • Combined small cell carcinoma
  • Other tumors (rare)
  • Undifferentiated bronchial-gland tumors, sarcomasneuroendocrine tumors

Clinical Presentation

  • 20% of cases incidentally identified by chest x-ray for other reasons (patients are typically asymptomatic)
  • Symptoms based on area of tumor growth
    • Central lesion – cough, wheeze, hemoptysis, stridor, dyspnea, postobstructive pneumonia
    • Peripheral lesion – 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 metastasis
      • 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 (SCLC in particular)
      • Endocrine syndromes
        • Ectopic parathyroid hormone
        • Antidiuretic hormone (ADH)
          • Usually SCLC
          • Syndrome of inappropriate secretion of ADH
          • Hyponatremia
        • Adrenocorticotropic hormone (ACTH)
      • Skeletal/connective tissue syndromes
        • Clubbing
          • 30% incidence
          • Usually NSCLC
        • Hypertrophic pulmonary osteoarthropathy
          • Usually adenocarcinoma
      • Neurologic/myopathic syndromes
        • Eaton-Lambert syndrome
        • Retinal blindness
          • Usually SCLC
        • Peripheral neuropathy
        • Subacute cerebellar degeneration
        • Cortical degeneration
        • Polymyositis
      • Hematologic syndromes
      • Dermatologic syndromes
      • Systemic syndromes
        • Unknown etiology
        • Cachexia, anorexia, fever, weight loss, suppressed immunity

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

Lung Cancer Comprehensive Mutation and Translocation Panel by Next Generation Sequencing 2011612
Method: Massively Parallel Sequencing

Limitations

Results of this test should be interpreted within the context of clinical findings

Not intended to detect minimal residual disease

Lung Cancer Panel 2008894
Method: Polymerase Chain Reaction/Pyrosequencing/Immunohistochemistry

Limitations

Results must be interpreted in the context of morphological and other relevant data

Tests should not be used alone to diagnose malignancy

Results may be compromised if the recommended tissue fixation procedures are not followed

Not intended to detect minimal residual disease

Lung Cancer Panel with KRAS 2008895
Method: Polymerase Chain Reaction/Pyrosequencing/Immunohistochemistry

Limitations

Results must be interpreted in the context of clinical findings and morphological and other relevant data

Tests should not be used alone to diagnose malignancy

Results may be compromised if the recommended tissue fixation procedures are not followed

Not intended to detect minimal residual disease

MET Gene Amplification by FISH 2013082
Method: Fluorescence in situ Hybridization

Limitations

Results must be interpreted in the context of morphological and other relevant data

Results may be compromised if the recommended tissue fixation procedures are not followed

c-MET by Immunohistochemistry 2008652
Method: Immunohistochemistry

EGFR T790M Mutation Detection in Circulating Cell-Free DNA by Digital Droplet PCR 2012868
Method: Polymerase Chain Reaction

Limitations

Limit of detection – based upon amplifiable DNA, the limit of detection ranges from 0.5% to <0.01% mutant alleles

Optimal clinical testing intervals are unknown

Mutations other than EGFR T790M are not detected

Presence or absence of EGFR T790M does not guarantee a response to EGFR T790M-specific drug therapy

PD-1 and PD-L1 by Immunohistochemistry with Interpretation 2012918
Method: Immunohistochemistry

KRAS Mutation Detection 0040248
Method: Polymerase Chain Reaction/Pyrosequencing

EGFR Mutation Detection by Pyrosequencing 2002440
Method: Polymerase Chain Reaction/Pyrosequencing

ALK (D5F3) by Immunohistochemistry with Reflex to ALK Gene Rearrangements by FISH 2011431
Method: Immunohistochemistry/ Fluorescence in situ Hybridization

ALK (D5F3) with Interpretation by Immunohistochemistry 2007324
Method: Immunohistochemistry

ALK Gene Rearrangements by FISH, Lung 2006102
Method: Fluorescence in situ Hybridization

ROS1 with Interpretation by Immunohistochemistry with Reflex to FISH if Equivocal 2008414
Method: Immunohistochemistry

ROS1 by FISH 2008418
Method: Fluorescence in situ Hybridization

EGFR Gene Amplification by FISH 2008605
Method: Fluorescence in situ Hybridization

Limitations

Not recommended for lung cancer mutation screening

Aids in prognostication and therapeutic decisions for neoplasms where amplification has been demonstrated

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

Limitations

Do not use for screening

Results obtained with different methods or kits cannot be used interchangeably

Test interference – hemolyzed specimens; icteric specimens; lipemic specimens; interfering antibodies in specimen (human anti-mouse or heterophile antibodies)

CYFRA 21-1 may be elevated in benign respiratory disease and other cancers  (eg, urologic, gastrointestinal, gynecological)

Neuron Specific Enolase 0098198
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Limitations

Do not use for screening

Results obtained with different methods or kits cannot be used interchangeably

Cytokeratin 7 (CK 7) by Immunohistochemistry 2003854
Method: Immunohistochemistry

Cytokeratin 20 (CK 20) by Immunohistochemistry 2003848
Method: Immunohistochemistry

Thyroid Transcription Factor (TTF-1) by Immunohistochemistry 2004166
Method: Immunohistochemistry

Chromogranin A by Immunohistochemistry 2003830
Method: Immunohistochemistry

CD56 (NCAM) by Immunohistochemistry 2003589
Method: Immunohistochemistry

Synaptophysin by Immunohistochemistry 2004139
Method: Immunohistochemistry

p63 by Immunohistochemistry 2004073
Method: Immunohistochemistry

Cytokeratin 5,6  (CK 5,6) by Immunohistochemistry 2003851
Method: Immunohistochemistry

Carcinoembryonic Antigen, Polyclonal (CEA P) by Immunohistochemistry 2003827
Method: Immunohistochemistry

Breast Carcinoma b72.3 by Immunohistochemistry 2003445
Method: Immunohistochemistry

Anti-Human Epithelial Antigen, Ber-EP4 by Immunohistochemistry 2003463
Method: Immunohistochemistry

Epithelial-Related Antigen, MOC-31 by Immunohistochemistry 2003875
Method: Immunohistochemistry

Neuron Specific Enolase, Polyclonal (NSE P) by Immunohistochemistry 2004052
Method: Immunohistochemistry

CDX2 by Immunohistochemistry 2003821
Method: Immunohistochemistry

Napsin A by Immunohistochemistry 2008716
Method: Immunohistochemistry

P40 by Immunohistochemistry 2010142
Method: Immunohistochemistry

PD-1 by Immunohistochemistry 2004085
Method: Immunohistochemistry

Additional Tests Available

Solid Tumor Mutation Panel by Next Generation Sequencing 2007991
Method: Massively Parallel Sequencing

Comments

Useful for prognosis and/or treatment of individuals with solid tumor cancer at initial diagnosis or in the presence of refractory disease

Analytic sensitivity – 5% mutant alleles

Simultaneously evaluates mutations in multiple genes, including EGFRKRASNRAS, and BRAF

For a full list of the targeted regions of the above genes, click here

BRAF Codon 600 Mutation Detection by Pyrosequencing 2002498
Method: Polymerase Chain Reaction/Pyrosequencing

Comments

Single gene assay

Detects activating BRAF mutations (codon 600) associated with anti-EGFR therapy resistance

Use prior to BRAF V600E inhibitor initiation

PD-L1 by Immunohistochemistry with Interpretation 2012105
Method: Immunohistochemistry

Comments

Screening test for monoclonal antibody therapy

Includes interpretation

PD-L1 tests are NOT the FDA-approved companion tests

PD-1 by Immunohistochemistry with Interpretation 2012912
Method: Immunohistochemistry

Comments

Screening test for monoclonal antibody therapy

Includes interpretation

PD-L1 tests are NOT the FDA-approved companion tests

Carcinoembryonic Antigen 0080080
Method: Quantitative Electrochemiluminescent Immunoassay

Comments

Prognostication and monitoring in lung cancer

Squamous Cell Carcinoma Antigen, Serum 0081054
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Comments

Prognostication and monitoring in lung cancer

Guidelines

ACR Appropriateness Criteria® solitary pulmonary nodule. American College of Radiology-Medical Specialty Society. 1995 (Revised 2012 ). NGC: 009227

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Jaklitsch M, Jacobson F, Austin J, Field J, Jett J, Keshavjee S, MacMahon H, Mulshine J, Munden R, Salgia R, Strauss G, Swanson S, Travis W, Sugarbaker D. The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups. J Thorac Cardiovasc Surg. 2012; 144(1): 33-8. PubMed

Leighl N, Rekhtman N, Biermann W, Huang J, Mino-Kenudson M, Ramalingam S, West H, Whitlock S, Somerfield M. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/Internat J Clin Oncol. 2014; 32(32): 3673-9. PubMed

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NCCN Clinical Practice Guidelines in Oncology, Non-Small Cell Lung Cancer. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jun 2015]

NCCN Clinical Practice Guidelines in Oncology, Small Cell Lung Cancer. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jun 2015]

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Rivera P, Mehta A, American College of Chest Physicians. Initial diagnosis of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007; 132(3 Suppl): 131S-148S. PubMed

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Schwartz A, Rezaei K. Diagnostic surgical pathology in lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013; 143(5 Suppl): e251S-62S. PubMed

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Wahidi M, Govert J, Goudar R, Gould M, McCrory D, American College of Chest Physicians. 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. PubMed

Wender R, Fontham E, Barrera E, Colditz G, Church T, Ettinger D, Etzioni R, Flowers C, Gazelle S, Kelsey D, LaMonte S, Michaelson J, Oeffinger K, Shih Y, Sullivan D, Travis W, Walter L, Wolf A, Brawley O, Smith R. American Cancer Society lung cancer screening guidelines. CA Cancer J Clin. 2013; 63(2): 107-17. PubMed

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General References

Albert R, Russell J. Evaluation of the solitary pulmonary nodule. Am Fam Physician. 2009; 80(8): 827-31. PubMed

Bach P, Mirkin J, Oliver T, Azzoli C, Berry D, Brawley O, Byers T, Colditz G, Gould M, Jett J, Sabichi A, Smith-Bindman R, Wood D, Qaseem A, Detterbeck F. Benefits and harms of CT screening for lung cancer: a systematic review. JAMA. 2012; 307(22): 2418-29. PubMed

Beasley M. Immunohistochemistry of pulmonary and pleural neoplasia. Arch Pathol Lab Med. 2008; 132(7): 1062-72. PubMed

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Bos M, Gardizi M, Schildhaus H, Buettner R, Wolf J. Activated RET and ROS: two new driver mutations in lung adenocarcinoma. Transl Lung Cancer Res. 2013; 2(2): 112-21. PubMed

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References from the ARUP Institute for Clinical and Experimental Pathology®

Medical Reviewers

Last Update: January 2016