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 Topics
  • Videos

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, 2014; IASLC/AMP, 2013). 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 therapeutic decisions in patients with advanced stages of adenocarcinoma and mixed adenocarcinoma subtypes (ASCO/CAP, 2014; IASLC/AMP 2013) – see Key Points

Solitary Pulmonary Nodule

  • Definition – single, well-circumscribed opacity measuring up to 3 cm in diameter and completely surrounded by aerated wing
  • Usually found incidentally on chest x-ray (0.09-0.2% of all x-rays)
    • Incidence of cancer ranges from 10-70% (Kikano, 2015)
  • Histologic diagnosis may be necessary in the following 
    • Patient is ≥35 years
    • Nodule is ≥8 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) (Cho, 2007)
      • 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

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-L1 22C3 pharmDx by Immunohistochemistry with Interpretation, pembrolizumab (KEYTRUDA) 2013284
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

Tissues fixed in alcohol-based or non-formalin fixatives have not been tested using this method

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

Related Tests

Guidelines

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

Arenberg D, American College of Chest Physicians. Bronchioloalveolar lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007; 132(3 Suppl): 306S-13S. PubMed

Colt HG, Murgu SD, Korst RJ, Slatore CG, Unger M, Quadrelli S. Follow-up and surveillance of the patient with lung cancer after curative-intent therapy: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013; 143(5 Suppl): e437S-54S. PubMed

Gould MK, Fletcher J, Iannettoni MD, Lynch WR, Midthun DE, Naidich DP, Ost DE, American College of Chest Physicians. 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. PubMed

Jaklitsch MT, Jacobson FL, Austin JH M, Field JK, Jett JR, Keshavjee S, MacMahon H, Mulshine JL, Munden RF, Salgia R, Strauss GM, Swanson SJ, Travis WD, Sugarbaker DJ. 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 NB, Rekhtman N, Biermann WA, Huang J, Mino-Kenudson M, Ramalingam SS, West H, Whitlock S, Somerfield MR. 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

Lindeman NI, Cagle PT, Beasley MBeth, Chitale DArun, Dacic S, Giaccone G, Jenkins RBrian, Kwiatkowski DJ, Saldivar J, Squire J, Thunnissen E, Ladanyi M. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Patho Arch Pathol Lab Med. 2013; 137(6): 828-60. PubMed

Moyer VA, U.S. Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014; 160(5): 330-8. PubMed

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

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]

Protocol for the Examination of Specimens from Patients with Primary Non-Small Cell Carcinoma, Small Cell Carcinoma, or Carcinoid Tumor of the Lung. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: June 2012. College of American Pathologists (CAP). Northfield, IL [Accessed: Jun 2015]

Wender R, Fontham ET H, Barrera E, Colditz GA, Church TR, Ettinger DS, Etzioni R, Flowers CR, Gazelle S, Kelsey DK, LaMonte SJ, Michaelson JS, Oeffinger KC, Shih YTina, Sullivan DC, Travis W, Walter L, Wolf AM D, Brawley OW, Smith RA. American Cancer Society lung cancer screening guidelines. CA Cancer J Clin. 2013; 63(2): 107-17. PubMed

General References

Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, Byers T, Colditz GA, Gould MK, Jett JR, Sabichi AL, Smith-Bindman R, Wood DE, Qaseem A, Detterbeck FC. Benefits and harms of CT screening for lung cancer: a systematic review. JAMA. 2012; 307(22): 2418-29. PubMed

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

Black WC, Gareen IF, Soneji SS, Sicks JD, Keeler EB, Aberle DR, Naeim A, Church TR, Silvestri GA, Gorelick J, Gatsonis C, National Lung Screening Trial Research Team. Cost-effectiveness of CT screening in the National Lung Screening Trial. N Engl J Med. 2014; 371(19): 1793-802. PubMed

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

Charakidis M, Boyer M. Targeting MET and EGFR in NSCLC-what can we learn from the recently reported phase III trial of onartuzumab in combination with erlotinib in advanced non-small cell lung cancer? Transl Lung Cancer Res. 2014; 3(6): 395-6. PubMed

Cho WChi-Shing. Potentially useful biomarkers for the diagnosis, treatment and prognosis of lung cancer. Biomed Pharmacother. 2007; 61(9): 515-9. PubMed

Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011; 135(5): 622-9. PubMed

Francis G, Stein S. Circulating Cell-Free Tumour DNA in the Management of Cancer Int J Mol Sci. 2015; 16(6): 14122-42. PubMed

Jänne PA, Meyerson M. ROS1 rearrangements in lung cancer: a new genomic subset of lung adenocarcinoma. J Clin Oncol. 2012; 30(8): 878-9. PubMed

Kikano GE, Fabien A, Schilz R. Evaluation of the Solitary Pulmonary Nodule. Am Fam Physician. 2015; 92(12): 1084-91. PubMed

Korpanty GJ, Graham DM, Vincent MD, Leighl NB. Biomarkers That Currently Affect Clinical Practice in Lung Cancer: EGFR, ALK, MET, ROS-1, and KRAS. Front Oncol. 2014; 4: 204. PubMed

Mani H, Zander DS. Immunohistochemistry: applications to the evaluation of lung and pleural neoplasms: part 1. Chest. 2012; 142(5): 1316-23. PubMed

Mani H, Zander DS. Immunohistochemistry: applications to the evaluation of lung and pleural neoplasms: part 2. Chest. 2012; 142(5): 1324-33. PubMed

Mazzone P. Lung cancer screening: examining the issues. Cleve Clin J Med. 2012; 79 Electronic Suppl 1: eS1-6. PubMed

Meghal T, Becker K. Pulmonary Perspectives: Targeted therapy for advanced lung adenocarcinoma. CHEST Physician. Parsippany, NJ [Initial posting May 2015; Accessed: Nov 2015]

Menis J, Levra MGiaj, Novello S. MET inhibition in lung cancer. Transl Lung Cancer Res. 2013; 2(1): 23-39. PubMed

Naidoo J, Drilon A. Molecular Diagnostic Testing in Non-Small Cell Lung Cancer. The American Journal of Hematology/Oncology. Plainsboro, NJ [Accessed: Mar 2016]

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12(4): 252-64. PubMed

Saad RS, Silverman JF. Respiratory cytology: differential diagnosis and pitfalls. Diagn Cytopathol. 2010; 38(4): 297-307. PubMed

Wiener RSoylemez, Gould MK, Arenberg DA, Au DH, Fennig K, Lamb CR, Mazzone PJ, Midthun DE, Napoli M, Ost DE, Powell CA, Rivera P, Slatore CG, Tanner NT, Vachani A, Wisnivesky JP, Yoon SH, ATS/ACCP Committee on Low-Dose CT Lung Cancer Screening in Clinical Practice. An official American Thoracic Society/American College of Chest Physicians policy statement: implementation of low-dose computed tomography lung cancer screening programs in clinical practice. Am J Respir Crit Care Med. 2015; 192(7): 881-91. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Medical Reviewers

Last Update: April 2016