Lung Cancer

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

Epidemiology

Incidence – 62.5/100,000
- >200,000 new cases annually in the U.S.
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 smoke
- 13-fold increase in risk for primary user
- Secondhand exposure – 20-30% increased risk for those who live/lived with smokers
Radon/uranium exposure
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)
- 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, sarcomas, neuroendocrine tumors

Clinical Presentation

20% of cases incidentally identified while asymptomatic by chest x-ray for other reasons
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

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
Other testing
- MicroRNA (mRNA) expression – may be used to distinguish NSCLC from SCLC
- Neuron specific enolase (NSE), serum – may have diagnostic value for SCLC
- EGFR (epidermal growth factor receptor) – frequently overexpressed in NSCLC (80-85%)
  - Can improve rate of detection of lung cancer when used in conjunction with cytology (either bronchial brushings or washings are suitable specimens)

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
- Fine needle aspiration using endobronchial ultrasound (EBUS)
- EBUS
Immunohistochemistry
- Should be used adjunctly and interpreted in clinical context
- 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
- SCC
  - Usually negative for CK 7, CK 20, TTF-1
  - Does not typically require immunohistochemical staining for diagnosis
- SCLC and neuroendocrine carcinomas
  - Typically negative for CK 7, CK 20
  - Positive for neuroendocrine markers such as chromogranin A, CD56 (NCAM), synaptophysin, NSE
  - Differentiating poorly differentiated SCC from SCLC
    - p63 and CK 5,6 positive and TTF-1 negative supports SCC
- Differentiating NSCLC adenocarcinoma from mesothelioma
  - Positive in NSCLC/negative in mesothelioma – CEA-P, b72.3, Ber-EP4, MOC-31, TTF-1
- Differentiating metastatic adenocarcinomas
  - Pulmonary – CK 7+/CK 20-
  - Colorectal – CK 7-/CK 20+
- Differentiating primary lung tumors from metastatic gastrointestinal tumors – CDX2 specific for gastrointestinal tumors

Solitary Pulmonary Nodule (SPN)

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 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

Prognosis

Useful markers
- EGFR mutation
  - LREA (exon 19del) found in 45% of NSCLC; L858R (exon 21 mutation) found in 40%
  - Not prognostic of survival for patients with NSCLC, independent of therapy
  - Presence of mutation predictive of treatment benefit from EGFR tyrosine kinase inhibitors (EGFR-TKI) therapy
  - Typically found in Asian lung cancer populations and in nonsmokers or moderate tobacco users
    - Majority have adenocarcinoma – should not be used in tumors of pure squamous origin or small cell
- EGFR protein
  - Positive EGFR expression indicates survival benefit in patients treated with EGFR TKI therapy
  - Not currently recommended as a test to exclude patients from treatment with EGFR TKI
- EGFR copy number
  - High copy number associated with worse prognosis; also predictive of benefit from EGFR-TKI therapy
- ERCC1 expression
  - High level prognostic of better survival in NSCLC independent of therapy
  - High level predictive of poor response to platinum-based chemotherapy; low level associated with sensitivity
- KRAS mutation
  - Presence indicates poor prognosis in NSCLC
  - Poor response to both platinum/vinorelbine therapy and to EGFR TKI therapy
- RRM1 expression
  - High level prognostic of better survival in NSCLC independent of therapy
  - High level predictive of poor response to gemcitabine-based chemotherapy
- EML4-ALK
  - Rare mutation in NSCLC (small subset of NSCLC patients harbor translocations involving the 5’ portion of the EML4 gene and the 3’ portion of the ALK gene)
  - Suggests unresponsiveness to EGFR TKI therapy
Promising markers without sufficient evidence to suggest helpfulness in prognosis
- Cytokeratin-19 fragment (CYFRA 21-1)
  - Most sensitive tumor marker for NSCLC (particularly squamous)
    - May also be elevated in urological, gastrointestinal and gynecological tumors
  - Potential role as independent prognostic factor in both early and late stages of NSCLC; may serve same role in SCLC
  - Potential role for predicting response to therapy
- 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 gene
  - Presence prognostic of short survival and potential benefit from adjuvant chemotherapy in patients with NSCLC
- Pro GRP – SCLC
- CA 125 (available as an immunohistochemical stain) – NSCLC
- STK11 – adenocarcinoma
- RAS – adenocarcinoma
- HER-2 – NSCLC
- Tumor M2-PK (TU M2-PK) – all types
- BCL-2 (available as an immunohistochemical stain) – SCLC

Differential Diagnosis

Solitary pulmonary nodule
- Granuloma
  - M. tuberculosis
  - Yeasts – Coccidiomycosis, Histoplasma, Cryptococcus
  - Molds – Aspergillus
- Hamartoma
- Round pneumonia
- Bronchogenic cyst
- Pulmonary infarction
- Focal hemorrhage
- Arteriovenous malformation
- Other malignancy
  - Carcinoid tumor
  - Lung metastases
Mass
- Pneumonia
- Metastatic tumor
- Fibrotic lung disease
- Mesothelioma
- Other lung tumor
  - Lymphoma
  - Carcinoid

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; DANTE European Trial [Infante, 2009]) found no meaningful reduction in deaths from lung cancer
Ongoing trials evaluating screening
- U.S. trials
  - National Lung Screening Trial ( National Cancer Institute) – results expected in 2011
- European trials
  - NELSON Trial – Netherlands and Belgium
  - Danish Lung Screening Trial
  - LUSI Trial – Germany
  - ITALUNG – Italy
  - MILD Trial – Italy

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)
SCLC
- Serial NSE may be useful to monitor tumor recurrence in SCLC
NSCLC
- CK 19 – potential role for monitoring therapy in advanced NSCLC

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

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

General screening for metastases

Recommended for disease followup

Test name: Hepatic Function Panel

ARUP #: 0020416

Methodology: Refer to individual components.

Use:

General screening for metastases

Test name: Cytology, Pulmonary

ARUP #: 8209702

Methodology: Routine Cytopathologic Evaluation

Use:

May be used as initial diagnostic 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:

Negative result 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: EGFR Gene Amplification by FISH

ARUP #: 0049234

Methodology: Fluorescence in situ Hybridization

Use:

Predict prognosis in lung cancer

Limitations:

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

Follow-up:

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

Test name: EGFR Mutation Detection by PCR and Fragment Analysis

ARUP #: 2002440

Methodology: Polymerase Chain Reaction/Fragment Analysis

Use:

Predict prognosis in lung cancer and response to therapy

Test name: EGFR Mutation Detection with Reflex to EML4/ALK Translocation by RT-PCR

ARUP #: 2004857

Methodology: Qualitative Polymerase Chain Reaction/Qualitative Reverse Transcription Polymerase Chain Reaction

Use:

Predict prognosis in lung cancer and response to therapy

Detects exon 19 deletions and exon 21 point mutations; these mutations account for ~90% of all reported EGFR mutations

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

ARUP #: 0081344

Methodology: Quantitative Enzyme-linked Immunosorbent Assay

Use:

Predict prognosis in early and late stages of NSCLC; potential role for monitoring therapy in advanced NSCLC

Limitations:

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

Test name: Neuron Specific Enolase

ARUP #: 0098198

Methodology: Quantitative Enzyme-Linked Immunosorbent Assay

Use: May be useful to monitor tumor recurrence in SCLC; may have prognostic utility

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

Test name: KRAS Mutation Detection

ARUP #: 0040248

Methodology: Polymerase Chain Reaction/Pyrosequencing

Use:

Predict prognosis in lung cancer

Test name: EML4/ALK Translocation by RT-PCR

ARUP #: 2004547

Methodology: Reverse Transcription Polymerase Chain Reaction

Use:

Identify translocations in NSCLC carcinomas, especially adenocarcinomas in patients being considered for anti-tyrosine kinase therapy

Limitations:

Only detects EML4-ALK translocations involving EML4 exons 6 or 13 and ALK exon 20

Test name: Cytokeratin 7 (CK 7) by Immunohistochemistry

ARUP #: 2003854

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of lung cancer