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NCI/PDQ^® Health professionals: Non-Small Cell Lung Cancer Treatment (PDQ®)

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National Cancer Institute
Last Modified: November 5, 2012

TABLE OF CONTENTS

• General Information About Non-Small Cell Lung Cancer (NSCLC)
  • Incidence and Mortality
  • Anatomy
  • Pathogenesis
  • Pathology
  • Risk Factors
  • Prevention
  • Screening
  • Clinical Features
  • Diagnosis
  • Molecular Features
  • Prognostic Factors
  • Related Summaries

• Cellular Classification of NSCLC
  • WHO/IASLC Histologic Classification of NSCLC
    • Squamous cell carcinoma
    • Adenocarcinoma
    • Large cell carcinoma
    • Neuroendocrine tumors
    • Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements
    • Molecular Features

• Stage Information for NSCLC
  • Background
  • Staging Evaluation
    • Evaluation of mediastinal lymph node metastasis
      • Surgical evaluation
      • CT imaging
      • FDG-PET scanning
      • Cost effectiveness of FDG-PET scanning
      • Combination of CT imaging and FDG-PET scanning
    • Evaluation of brain metastasis
    • Evaluation of distant metastasis other than the brain
  • The Revised International System for Staging Lung Cancer
  • AJCC Stage Groupings and TNM Definitions

• Treatment Option Overview for NSCLC
  • Follow-Up
  • Current Clinical Trials

• Occult NSCLC Treatment
  • Standard Treatment Options for Occult NSCLC
  • Current Clinical Trials

• Stage 0 NSCLC Treatment
  • Standard Treatment Options for Stage 0 NSCLC
    • Surgery
    • Endobronchial therapies
  • Current Clinical Trials

• Stages IA and IB NSCLC Treatment
  • Standard Treatment Options for Stages IA and IB NSCLC
    • Surgery
    • Adjuvant therapy
      • Adjuvant radiation therapy
      • Adjuvant chemotherapy
    • Radiation therapy
  • Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

• Stages IIA and IIB NSCLC Treatment
  • Standard Treatment Options for Stages IIA and IIB NSCLC
    • Surgery
      • Neoadjuvant chemotherapy
        • Adjuvant radiation therapy
        • Adjuvant chemotherapy
    • Radiation therapy
  • Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

• Stage IIIA NSCLC Treatment
  • Standard Treatment Options for Resected/Resectable Stage IIIA N2 NSCLC
    • Surgery
    • Neoadjuvant therapy
      • Neoadjuvant chemotherapy
    • Adjuvant therapy
      • Adjuvant chemotherapy
      • Adjuvant chemoradiation therapy
      • Adjuvant radiation therapy
  • Standard Treatment Options for Unresectable Stage IIIA N2 NSCLC
    • Radiation therapy
      • For treatment of locally advanced unresectable tumor
      • For palliative treatment
    • Chemoradiation therapy
      • Concurrent versus sequential chemoradiation therapy
  • Standard Treatment Options for Superior Sulcus Tumors (T3, N0 or N1, M0)
    • Radiation therapy alone
    • Surgery
    • Chemoradiation therapy
  • Standard Treatment Options for Tumors That Invade the Chest Wall (T3, N0 or N1, M0)
  • Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

• Stage IIIB NSCLC Treatment
  • Standard Treatment Options for Stage IIIB NSCLC
    • Sequential or concurrent chemotherapy and radiation therapy
    • Radiation therapy alone
      • For treatment of locally advanced unresectable tumor
      • For palliative treatment
  • Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

• Stage IV NSCLC Treatment
  • Standard Treatment Options for Stage IV NSCLC
    • Cytotoxic combination chemotherapy (first line)
      • Factors influencing treatment
        • Histology
        • Age versus comorbidity
        • Performance status (PS)
    • Combination chemotherapy with bevacizumab or cetuximab
    • EGFR tyrosine kinase inhibitors (first line)
    • Maintenance therapy following first-line chemotherapy
    • Radiation therapy
  • Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

• Recurrent NSCLC Treatment
  • Standard Treatment Options for Recurrent NSCLC
    • Treatment of second primary tumor
    • Treatment of brain metastases
  • Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

• Changes to This Summary (11/05/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
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General Information About Non-Small Cell Lung Cancer (NSCLC)

NSCLC is any type of epithelial lung cancer other than small cell lung cancer (SCLC). The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, but there are several other types that occur less frequently, and all types can occur in unusual histologic variants. Although NSCLCs are associated with cigarette smoke, adenocarcinomas may be found in patients who have never smoked. As a class, NSCLCs are relatively insensitive to chemotherapy and radiation therapy compared with SCLC. Patients with resectable disease may be cured by surgery or surgery followed by chemotherapy. Local control can be achieved with radiation therapy in a large number of patients with unresectable disease, but cure is seen only in a small number of patients. Patients with locally advanced unresectable disease may achieve long-term survival with radiation therapy combined with chemotherapy. Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy, targeted agents, and other supportive measures.

Incidence and Mortality

Estimated new cases and deaths from lung cancer (non-small cell and small cell combined) in the United States in 2012: 1

• New cases: 226,160.
• Deaths: 160,340.

Lung cancer is the leading cause of cancer-related mortality in the United States. 1 The 5-year relative survival rate from 1995 to 2001 for patients with lung cancer was 15.7%. The 5-year relative survival rate varies markedly depending on the stage at diagnosis, from 49% to 16% to 2% for patients with local, regional, and distant stage disease, respectively. 2

Anatomy

NSCLC arises from the epithelial cells of the lung of the central bronchi to terminal alveoli. The histological type of NSCLC correlates with site of origin, reflecting the variation in respiratory tract epithelium of the bronchi to alveoli. Squamous cell carcinoma usually starts near a central bronchus. Adenocarcinoma and bronchioloalveolar carcinoma usually originate in peripheral lung tissue.

Pathogenesis

Smoking-related lung carcinogenesis is a multistep process. Squamous cell carcinoma and adenocarcinoma have defined premalignant precursor lesions. Before becoming invasive, lung epithelium may undergo morphological changes that include the following:

• Hyperplasia.
• Metaplasia.
• Dysplasia.
• Carcinoma in situ.

Dysplasia and carcinoma in situ are considered the principal premalignant lesions because they are more likely to progress to invasive cancer and less likely to spontaneously regress.

In addition, after resection of a lung cancer, there is a 1% to 2% risk per patient per year that a second lung cancer will occur. 3

Pathology

NSCLC is a heterogeneous aggregate of histologies. The most common histologies include the following:

• Epidermoid or squamous cell carcinoma.
• Adenocarcinoma.
• Large cell carcinoma.

These histologies are often classified together because approaches to diagnosis, staging, prognosis, and treatment are similar.

Risk Factors

Several risk factors contribute to the development of lung cancer. These risk factors may include the following:

• Cigarette, pipe, or cigar smoking.
• Exposure to second-hand smoke, radon, arsenic, asbestos, chromates, chloromethyl ethers, nickel, polycyclic aromatic hydrocarbons, radon progeny, other agents, and air pollution. 4
• Radiation therapy to the breast or chest.

The single most important risk factor for the development of lung cancer is smoking. For smokers, the risk for lung cancer is on average tenfold higher than in lifetime nonsmokers (defined as a person who has smoked <100 cigarettes in his or her lifetime). The risk increases with the quantity of cigarettes, duration of smoking, and starting age.

Smoking cessation results in a decrease in precancerous lesions and a reduction in the risk of developing lung cancer. Former smokers continue to have an elevated risk for lung cancer for years after quitting. Asbestos exposure may exert a synergistic effect of cigarette smoking on the lung cancer risk. 4

Prevention

A significant number of patients cured of their smoking-related lung cancer may develop a second malignancy. In the Lung Cancer Study Group trial of 907 patients with stage T1, N0 resected tumors, the rate was 1.8% per year for nonpulmonary second cancers and 1.6% per year for new lung cancers. 5 Other studies have reported even higher risks of second tumors in long-term survivors, including rates of 10% for second lung cancers and 20% for all second cancers. 6

Because of the persistent risk of developing second lung cancers in former smokers, various chemoprevention strategies have been evaluated in randomized control trials. None of the phase III trials with the agents beta carotene, retinol, 13-cis-retinoic acid, [alpha]-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results. 7 8 9 10 11[Level of evidence: 1iiA] Chemoprevention of second primary cancers of the upper aerodigestive tract is undergoing clinical evaluation in patients with early-stage lung cancer.

Refer to the PDQ® summaries on Lung Cancer Prevention and Smoking in Cancer Care for more information.

Screening

In patients considered at high risk for developing lung cancer, the only screening modality for early detection that has been shown to alter mortality is low-dose helical CT scanning. 12 Studies of lung cancer screening with chest radiography and sputum cytology have failed to demonstrate that screening lowers lung cancer mortality rates.

(Refer to the Screening by low-dose helical computed tomography subsection in the PDQ® summary on Lung Cancer Screening for more information.)

Clinical Features

Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough or chest pain. Other presenting symptoms include the following:

• Hemoptysis.
• Malaise.
• Weight loss.
• Dyspnea.
• Hoarseness.

Symptoms may result from local invasion or compression of adjacent thoracic structures such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases. Infrequently, patients may present with symptoms and signs of paraneoplastic diseases such as hypertrophic osteoarthropathy with digital clubbing or hypercalcemia from parathyroid hormone-related protein. Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease or pulmonary fibrosis.

Diagnosis

Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient. Investigations of patients with suspected NSCLC focus on confirming the diagnosis and determining the extent of the disease.

The procedures used to determine the presence of cancer include the following:

• History.
• Physical examination.
• Routine laboratory evaluations.
• Chest x-ray.
• Chest CT scan with infusion of contrast material.
• Biopsy.

Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC. 13 Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

(Refer to the Staging Evaluation section of this summary for more information on tests and procedures used for staging.)

Molecular Features

The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease. 14 In particular, subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of the epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K) signaling pathways. These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors.

Other genetic abnormalities of potential relevance to treatment decisions include translocations involving the anaplastic lymphoma kinase (ALK)-tyrosine kinase receptor, which are sensitive to ALK inhibitors, and amplification of MET (mesenchymal epithelial transition factor), which encodes the hepatocyte growth factor receptor. MET amplification has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

Prognostic Factors

Multiple studies have attempted to identify the prognostic importance of a variety of clinicopathologic factors. 6 15 16 17 18 Factors that have correlated with adverse prognosis include the following:

• Presence of pulmonary symptoms.
• Large tumor size (>3 cm).
• Nonsquamous histology.
• Metastases to multiple lymph nodes within a TNM-defined nodal station. 19 20 21 22 23 24 25 26 27 28 29 (Refer to the Evaluation of Mediastinal Lymph Node Metastasis section of this summary for more information.)
• Vascular invasion. 16 30 31 32

For patients with inoperable disease, prognosis is adversely affected by poor performance status and weight loss of more than 10%. These patients have been excluded from clinical trials evaluating aggressive multimodality interventions.

In multiple retrospective analyses of clinical trial data, advanced age alone has not been shown to influence response or survival with therapy. 33

Refer to the separate treatment sections for each stage of NSCLC in this summary for more information about prognosis.

Because treatment is not satisfactory for almost all patients with NSCLC, eligible patients should be considered for clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Related Summaries

Other PDQ® summaries containing information related to lung cancer include the following:

• Lung Cancer Prevention
• Lung Cancer Screening
• Small Cell Lung Cancer Treatment
• Smoking in Cancer Care

References:

1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
2. Ries L, Eisner M, Kosary C, et al., eds.: Cancer Statistics Review, 1975-2002. Bethesda, Md: National Cancer Institute, 2005. Available online. [PUBMED Abstract]
3. Johnson BE: Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 90 (18): 1335-45, 1998. [PUBMED Abstract]
4. Wingo PA, Ries LA, Giovino GA, et al.: Annual report to the nation on the status of cancer, 1973-1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst 91 (8): 675-90, 1999. [PUBMED Abstract]
5. Thomas P, Rubinstein L: Cancer recurrence after resection: T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 49 (2): 242-6; discussion 246-7, 1990. [PUBMED Abstract]
6. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995. [PUBMED Abstract]
7. van Boxem AJ, Westerga J, Venmans BJ, et al.: Photodynamic therapy, Nd-YAG laser and electrocautery for treating early-stage intraluminal cancer: which to choose? Lung Cancer 31 (1): 31-6, 2001. [PUBMED Abstract]
8. Blumberg J, Block G: The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study in Finland. Nutr Rev 52 (7): 242-5, 1994. [PUBMED Abstract]
9. Omenn GS, Goodman GE, Thornquist MD, et al.: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334 (18): 1150-5, 1996. [PUBMED Abstract]
10. Lippman SM, Lee JJ, Karp DD, et al.: Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J Natl Cancer Inst 93 (8): 605-18, 2001. [PUBMED Abstract]
11. van Zandwijk N, Dalesio O, Pastorino U, et al.: EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 92 (12): 977-86, 2000. [PUBMED Abstract]
12. Aberle DR, Adams AM, Berg CD, et al.: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365 (5): 395-409, 2011. [PUBMED Abstract]
13. Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999. [PUBMED Abstract]
14. Pao W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol 12 (2): 175-80, 2011. [PUBMED Abstract]
15. Albain KS, Crowley JJ, LeBlanc M, et al.: Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 9 (9): 1618-26, 1991. [PUBMED Abstract]
16. Macchiarini P, Fontanini G, Hardin MJ, et al.: Blood vessel invasion by tumor cells predicts recurrence in completely resected T1 N0 M0 non-small-cell lung cancer. J Thorac Cardiovasc Surg 106 (1): 80-9, 1993. [PUBMED Abstract]
17. Ichinose Y, Yano T, Asoh H, et al.: Prognostic factors obtained by a pathologic examination in completely resected non-small-cell lung cancer. An analysis in each pathologic stage. J Thorac Cardiovasc Surg 110 (3): 601-5, 1995. [PUBMED Abstract]
18. Fontanini G, Bigini D, Vignati S, et al.: Microvessel count predicts metastatic disease and survival in non-small cell lung cancer. J Pathol 177 (1): 57-63, 1995. [PUBMED Abstract]
19. Sayar A, Turna A, Kiliígí¼n A, et al.: Prognostic significance of surgical-pathologic multiple-station N1 disease in non-small cell carcinoma of the lung. Eur J Cardiothorac Surg 25 (3): 434-8, 2004. [PUBMED Abstract]
20. Osaki T, Nagashima A, Yoshimatsu T, et al.: Survival and characteristics of lymph node involvement in patients with N1 non-small cell lung cancer. Lung Cancer 43 (2): 151-7, 2004. [PUBMED Abstract]
21. Ichinose Y, Kato H, Koike T, et al.: Overall survival and local recurrence of 406 completely resected stage IIIa-N2 non-small cell lung cancer patients: questionnaire survey of the Japan Clinical Oncology Group to plan for clinical trials. Lung Cancer 34 (1): 29-36, 2001. [PUBMED Abstract]
22. Tanaka F, Yanagihara K, Otake Y, et al.: Prognostic factors in patients with resected pathologic (p-) T1-2N1M0 non-small cell lung cancer (NSCLC). Eur J Cardiothorac Surg 19 (5): 555-61, 2001. [PUBMED Abstract]
23. Asamura H, Suzuki K, Kondo H, et al.: Where is the boundary between N1 and N2 stations in lung cancer? Ann Thorac Surg 70 (6): 1839-45; discussion 1845-6, 2000. [PUBMED Abstract]
24. Riquet M, Manac'h D, Le Pimpec-Barthes F, et al.: Prognostic significance of surgical-pathologic N1 disease in non-small cell carcinoma of the lung. Ann Thorac Surg 67 (6): 1572-6, 1999. [PUBMED Abstract]
25. van Velzen E, Snijder RJ, Brutel de la Riviíre A, et al.: Lymph node type as a prognostic factor for survival in T2 N1 M0 non-small cell lung carcinoma. Ann Thorac Surg 63 (5): 1436-40, 1997. [PUBMED Abstract]
26. Vansteenkiste JF, De Leyn PR, Deneffe GJ, et al.: Survival and prognostic factors in resected N2 non-small cell lung cancer: a study of 140 cases. Leuven Lung Cancer Group. Ann Thorac Surg 63 (5): 1441-50, 1997. [PUBMED Abstract]
27. Izbicki JR, Passlick B, Karg O, et al.: Impact of radical systematic mediastinal lymphadenectomy on tumor staging in lung cancer. Ann Thorac Surg 59 (1): 209-14, 1995. [PUBMED Abstract]
28. Martini N, Burt ME, Bains MS, et al.: Survival after resection of stage II non-small cell lung cancer. Ann Thorac Surg 54 (3): 460-5; discussion 466, 1992. [PUBMED Abstract]
29. Naruke T, Goya T, Tsuchiya R, et al.: Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 96 (3): 440-7, 1988. [PUBMED Abstract]
30. Thomas P, Doddoli C, Thirion X, et al.: Stage I non-small cell lung cancer: a pragmatic approach to prognosis after complete resection. Ann Thorac Surg 73 (4): 1065-70, 2002. [PUBMED Abstract]
31. Macchiarini P, Fontanini G, Hardin MJ, et al.: Relation of neovascularisation to metastasis of non-small-cell lung cancer. Lancet 340 (8812): 145-6, 1992. [PUBMED Abstract]
32. Khan OA, Fitzgerald JJ, Field ML, et al.: Histological determinants of survival in completely resected T1-2N1M0 nonsmall cell cancer of the lung. Ann Thorac Surg 77 (4): 1173-8, 2004. [PUBMED Abstract]
33. Earle CC, Tsai JS, Gelber RD, et al.: Effectiveness of chemotherapy for advanced lung cancer in the elderly: instrumental variable and propensity analysis. J Clin Oncol 19 (4): 1064-70, 2001. [PUBMED Abstract]

Cellular Classification of NSCLC

Malignant non-small cell epithelial tumors of the lung are classified by the World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC). There are three main subtypes of non-small cell lung cancer (NSCLC), including the following:

• Squamous cell carcinoma (25% of lung cancers).
• Adenocarcinoma (40% of lung cancers).
• Large cell carcinoma (10% of lung cancers).

There are numerous additional subtypes of decreasing frequency. 1

WHO/IASLC Histologic Classification of NSCLC

1. Squamous cell carcinoma.
   1. Papillary.
   2. Clear cell.
   3. Small cell.
   4. Basaloid.

2. Adenocarcinoma.
   1. Acinar.
   2. Papillary.
   3. Bronchioloalveolar carcinoma.
      1. Nonmucinous.
      2. Mucinous.
      3. Mixed mucinous and nonmucinous or indeterminate cell type.

   4. Solid adenocarcinoma with mucin.
   5. Adenocarcinoma with mixed subtypes.
   6. Variants.
      1. Well-differentiated fetal adenocarcinoma.
      2. Mucinous (colloid) adenocarcinoma.
      3. Mucinous cystadenocarcinoma.
      4. Signet ring adenocarcinoma.
      5. Clear cell adenocarcinoma.

3. Large cell carcinoma.
   1. Variants.
      1. Large cell neuroendocrine carcinoma (LCNEC).
      2. Combined LCNEC.
      3. Basaloid carcinoma.
      4. Lymphoepithelioma-like carcinoma.
      5. Clear cell carcinoma.
      6. Large cell carcinoma with rhabdoid phenotype.

4. Adenosquamous carcinoma.
5. Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.
   1. Carcinomas with spindle and/or giant cells.
   2. Spindle cell carcinoma.
   3. Giant cell carcinoma.
   4. Carcinosarcoma.
   5. Pulmonary blastoma.

6. Carcinoid tumor.
   1. Typical carcinoid.
   2. Atypical carcinoid.

7. Carcinomas of salivary gland type.
   1. Mucoepidermoid carcinoma.
   2. Adenoid cystic carcinoma.
   3. Others.

8. Unclassified carcinoma.

Squamous cell carcinoma

Most squamous cell carcinomas of the lung are located centrally, in the larger bronchi of the lung. Squamous cell carcinomas are linked more strongly with smoking than other forms of NSCLC. The incidence of squamous cell carcinoma of the lung has been decreasing in recent years.

Adenocarcinoma

Adenocarcinoma is now the most common histologic subtype in many countries, and subclassification of adenocarcinoma is important. One of the biggest problems with lung adenocarcinomas is the frequent histologic heterogeneity. In fact, mixtures of adenocarcinoma histologic subtypes are more common than tumors consisting purely of a single pattern of acinar, papillary, bronchioloalveolar, and solid adenocarcinoma with mucin formation.

Criteria for the diagnosis of bronchioloalveolar carcinoma have varied widely in the past. The current WHO/IASLC definition is much more restrictive than that previously used by many pathologists because it is limited to only noninvasive tumors.

If stromal, vascular, or pleural invasion are identified in an adenocarcinoma that has an extensive bronchioloalveolar carcinoma component, the classification would be an adenocarcinoma of mixed subtype with predominant bronchioloalveolar pattern and a focal acinar, solid, or papillary pattern, depending on which pattern is seen in the invasive component. However, the future of bronchioloalveolar carcinoma as a distinct clinical entity is unclear; a multidisciplinary expert panel representing the IASLC, the American Thoracic Society, and the European Respiratory Society proposed a major revision of the classification of adenocarcinomas in 2011 that entails a reclassification of what was called bronchioloalveolar carcinoma into newly defined histologic subgroups.

The following variants of adenocarcinoma are recognized in the WHO/IASLC classification:

• Well-differentiated fetal adenocarcinoma.
• Mucinous (colloid) adenocarcinoma.
• Mucinous cystadenocarcinoma.
• Signet ring adenocarcinoma.
• Clear cell adenocarcinoma.

Large cell carcinoma

In addition to the general category of large cell carcinoma, several uncommon variants are recognized in the WHO/IASLC classification, including the following:

• LCNEC.
• Basaloid carcinoma.
• Lymphoepithelioma-like carcinoma.
• Clear cell carcinoma.
• Large cell carcinoma with rhabdoid phenotype.

Basaloid carcinoma is also recognized as a variant of squamous cell carcinoma, and rarely, adenocarcinomas may have a basaloid pattern; however, in tumors without either of these features, they are regarded as a variant of large cell carcinoma.

Neuroendocrine tumors

LCNEC is recognized as a histologically high-grade non-small cell carcinoma. It has a very poor prognosis similar to that of small cell lung cancer (SCLC). Atypical carcinoid is recognized as an intermediate-grade neuroendocrine tumor with a prognosis that falls between typical carcinoid and high-grade SCLC and LCNEC.

Neuroendocrine differentiation can be demonstrated by immunohistochemistry or electron microscopy in 10% to 20% of common NSCLCs that do not have any neuroendocrine morphology. These tumors are not formally recognized within the WHO/IASLC classification scheme because the clinical and therapeutic significance of neuroendocrine differentiation in NSCLC is not firmly established. These tumors are referred to collectively as NSCLC with neuroendocrine differentiation.

Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements

This is a group of rare tumors. Spindle cell carcinomas and giant cell carcinomas comprise only 0.4% of all lung malignancies, and carcinosarcomas comprise only 0.1% of all lung malignancies. In addition, this group of tumors reflects a continuum in histologic heterogeneity as well as epithelial and mesenchymal differentiation. On the basis of clinical and molecular data, biphasic pulmonary blastoma is regarded as part of the spectrum of carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.

Molecular Features

The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease. 2 In particular, subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of the epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K) signaling pathways. These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors. Other mutations of potential relevance to treatment decisions include:

• Kirsten rat sarcoma viral oncogene (KRAS).
• Anaplastic lymphoma kinase receptor (ALK).
• Human epidermal growth factor receptor 2 (HER2).
• V-raf murine sarcoma viral oncogene homolog B1 (BRAF).
• PIK3 catalytic protein alpha (PI3KCA).
• AKT1.
• MAPK kinase 1 (MAP2K1 or MEK1).
• MET, which encodes the hepatocyte growth factor receptor (HGFR).

These mutations are mutually exclusive, except for those in PIK3CA and EGFR mutations and ALK translocations. 3

EGFR and ALK mutations predominate in adenocarcinomas that develop in nonsmokers, and KRAS and BRAF mutations are more common in smokers or former smokers. EGFR mutations strongly predict the improved response rate and progression-free survival of EGFR inhibitors. In a set of 2,142 lung adenocarcinoma specimens from patients treated at Memorial Sloan Kettering Cancer Center, EGFR exon 19 deletions and L858R were found in 15% of tumors from former smokers (181 of 1,218; 95% CI, 1317), 6% from current smokers (20 of 344; 95% CI, 49), and 52% from never-smokers (302 of 580; 95% CI, 4856; P < .001 for ever- vs. never-smokers). 4

Fusions of ALK with EML4 genes form translocation products that occur in ranges from 3% to 7% in unselected NSCLC and are responsive to pharmacological inhibition of ALK by agents such as crizotinib. Other mutations that occur in less than 5% of NSCLC tumors include:

• HER2, present in 2% of tumors.
• PI3KCA, present in 2% of tumors.
• AKT1, present in 1% of tumors.
• BRAF mutations, present in 1% to 3% of tumors.

BRAF mutations are mutually exclusive of EGFR and KRAS mutations. Somatic mutations in MAP2K1 (also known as MEK) have been identified in 1% of NSCLC. MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

References:

1. Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999. [PUBMED Abstract]
2. Pao W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol 12 (2): 175-80, 2011. [PUBMED Abstract]
3. Tiseo M, Gelsomino F, Boggiani D, et al.: EGFR and EML4-ALK gene mutations in NSCLC: a case report of erlotinib-resistant patient with both concomitant mutations. Lung Cancer 71 (2): 241-3, 2011. [PUBMED Abstract]
4. D'Angelo SP, Pietanza MC, Johnson ML, et al.: Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol 29 (15): 2066-70, 2011. [PUBMED Abstract]

Stage Information for NSCLC

Background

In NSCLC, the determination of stage is important in terms of therapeutic and prognostic implications. Careful initial diagnostic evaluation to define the location and to determine the extent of primary and metastatic tumor involvement is critical for the appropriate care of patients.

In general, symptoms, physical signs, laboratory findings, or perceived risk of distant metastasis lead to an evaluation for distant metastatic disease. Additional tests such as bone scans and computed tomography (CT)/magnetic resonance imaging (MRI) of the brain may be performed if initial assessments suggest metastases or if patients with stage III disease are under consideration for aggressive local and combined modality treatments.

Stage has a critical role in the selection of therapy. The stage of disease is based on a combination of clinical factors and pathological factors. 1 The distinction between clinical stage and pathological stage should be considered when evaluating reports of survival outcome.

Procedures used to determine staging include the following:

• History.
• Physical examination.
• Routine laboratory evaluations.
• Chest x-ray.
• Chest CT scan with infusion of contrast material.
• Fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning.

Procedures used to obtain tissue samples include bronchoscopy, mediastinoscopy, or anterior mediastinotomy. Pathological staging of NSCLC requires the following:

• Examination of the tumor.
• Resection margins.
• Lymph nodes.

Prognostic and treatment decisions are based on some of the following factors:

• Knowledge of histologic type.
• Tumor size and location.
• Involvement of pleura.
• Surgical margins.
• Status and location of lymph nodes by station.
• Tumor grade.
• Lymphovascular invasion.

At diagnosis, patients with NSCLC can be divided into the following three groups that reflect both the extent of the disease and the treatment approach:

1. Surgically resectable disease (generally stage I, stage II, and selected stage III tumors).
   • Has the best prognosis, which depends on a variety of tumor and host factors.
   • Patients with resectable disease who have medical contraindications to surgery are candidates for curative radiation therapy.
   • Postoperative cisplatin-based combination chemotherapy may provide a survival advantage to patients with resected stage II or stage IIIA NSCLC.

2. Locally (T3T4) and/or regionally (N2N3) advanced disease.
   • Has a diverse natural history.
   • Selected patients with locally advanced tumors may benefit from combined modality treatments.
   • Patients with unresectable or N2-N3 disease are treated with radiation therapy in combination with chemotherapy.
   • Selected patients with T3 or N2 disease can be treated effectively with surgical resection and either preoperative or postoperative chemotherapy or chemoradiation therapy.

3. Distant metastatic disease (includes distant metastases [M1] that were found at the time of diagnosis).
   • May be treated with radiation therapy or chemotherapy for palliation of symptoms from the primary tumor.
   • Patients with good performance status, women, and patients with distant metastases confined to a single site live longer than others. 2
   • Platinum-based chemotherapy has been associated with short-term palliation of symptoms and with a survival advantage.
   • Currently, no single chemotherapy regimen can be recommended for routine use.
   • Patients previously treated with platinum combination chemotherapy may derive symptom control and survival benefit from docetaxel, pemetrexed, or epidermal growth factor receptor inhibitors.

Staging Evaluation

Evaluation of mediastinal lymph node metastasis

Surgical evaluation

Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy.

Accurate staging of the mediastinal lymph nodes provides important prognostic information.

Evidence (nodal status):

1. The association between survival and the number of examined lymph nodes during surgery for patients with stage I NSCLC treated with definitive surgical resection was assessed from the population-based Surveillance, Epidemiology and End Results database for the period from 1990 to 2000. 3 A total of 16,800 patients were included in the study.
   • The overall survival (OS) analysis for patients without radiation therapy demonstrated that in comparison to the reference group (one to four lymph nodes), patients with five to eight lymph nodes examined during surgery had a modest but statistically significant increase in survival, with a proportionate hazard ratio (HR) of 0.90 (95% confidence interval [CI], 0.840.97). For patients with 9 to 12 lymph nodes and 13 to 16 lymph nodes examined, HRs were 0.86 (95% CI, 0.790.95) and 0.78 (95% CI, 0.680.90), respectively. There appeared to be no incremental improvement after evaluating more than 16 lymph nodes. The corresponding results for lung cancerspecific mortality and for patients receiving radiation therapy were not substantially different.
   • These results indicate that patient survival following resection for NSCLC is associated with the number of lymph nodes evaluated during surgery. Because this is most likely the result of a reduction-of-staging error, namely, a decreased likelihood of missing positive lymph nodes with an increasing number of lymph nodes sampled, it suggests that an evaluation of nodal status should include 11 to 16 lymph nodes.

CT imaging

CT scanning is primarily used for determining the size of the tumor. The CT scan should extend inferiorly to include the liver and adrenal glands. MRI scans of the thorax and upper abdomen do not appear to yield advantages over CT scans. 4

Evidence (CT scan):

1. A systematic review of the medical literature relating to the accuracy of CT scanning for noninvasive staging of the mediastinum in patients with lung cancer has been conducted. In the 35 studies published between 1991 and June 2006, 5,111 evaluable patients were identified. Almost all studies specified that CT scanning was performed following the administration of IV contrast material and that a positive test result was defined as the presence of one or more lymph nodes that measured larger than 1 cm on the short-axis diameter. 5
   • The median prevalence of mediastinal metastasis was 28% (range, 18%56%).
   • The pooled sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis were 51% (95% CI, 47%54%) and 86% (95% CI, 84%88%), respectively. The corresponding positive and negative likelihood ratios were 3.4 and 0.6, respectively.

2. The results from the systematic review are similar to those of a large meta-analysis that reported the median sensitivity and specificity of CT scanning for identifying malignant mediastinal nodes as 61% and 79%, respectively. 6
3. An earlier meta-analysis reported average sensitivity and specificity of 64% and 74%, respectively. 7

FDG-PET scanning

The wider availability and use of FDG-PET scanning for staging has modified the approach to staging mediastinal lymph nodes and distant metastases.

Randomized trials evaluating the utility of FDG-PET scanning in potentially resectable NSCLC report conflicting results in terms of the relative reduction in the number of noncurative thoracotomies.

Although the current evidence is conflicting, FDG-PET scanning may improve results of early-stage lung cancer by identifying patients who have evidence of metastatic disease that is beyond the scope of surgical resection and that is not evident by standard preoperative staging procedures.

Evidence (FDG-PET scan):

1. A systematic review, an expansion of a health technology assessment conducted in 2001 by the Institute for Clinical and Evaluative Sciences, evaluated the accuracy and utility of FDG-PET scanning in the diagnosis and staging of lung cancer. 8 Through a systematic search of the literature, 12 evidence summary reports and 15 prospective studies of the diagnostic accuracy of FDG-PET scanning were identified. FDG-PET scanning appears to be superior to CT imaging for mediastinal staging in NSCLC. FDG-PET scanning also appears to have high sensitivity and reasonable specificity for differentiating benign from malignant lesions as small as 1 cm.
2. A systematic review of the medical literature relating to the accuracy of FDG-PET scanning for noninvasive staging of the mediastinum in patients with lung cancer identified 44 studies published between 1994 and 2006 with 2,865 evaluable patients. 5 The median prevalence of mediastinal metastases was 29% (range, 5%64%). Pooled estimates of sensitivity and specificity for identifying mediastinal metastasis were 74% (95% CI, 69%79%) and 85% (95% CI, 82%88%), respectively. Corresponding positive and negative likelihood ratios for mediastinal staging with FDG-PET scanning were 4.9 and 0.3, respectively. These findings demonstrate that FDG-PET scanning is more accurate than CT scanning for staging of the mediastinum in patients with lung cancer.

Cost effectiveness of FDG-PET scanning

Decision analyses demonstrate that FDG-PET scanning may reduce the overall costs of medical care by identifying patients with falsely negative CT scans in the mediastinum or otherwise undetected sites of metastases. 9 10 11 Studies concluded that the money saved by forgoing mediastinoscopy in FDG-PET-positive mediastinal lesions was not justified because of the unacceptably high number of false-positive results. 9 10 11 A randomized study found that the addition of FDG-PET scanning to conventional staging was associated with significantly fewer thoracotomies. 12 A second randomized trial evaluating the impact of FDG-PET scanning on clinical management found that FDG-PET scanning provided additional information regarding appropriate stage but did not lead to significantly fewer thoracotomies. 13

Combination of CT imaging and FDG-PET scanning

The combination of CT imaging and FDG-PET scanning has greater sensitivity and specificity than CT imaging alone. 14

Evidence (CT/FDG-PET scan):

1. If there is no evidence of distant metastatic disease on CT scan, FDG-PET scanning complements CT scan staging of the mediastinum. Numerous nonrandomized studies of FDG-PET scanning have evaluated mediastinal lymph nodes using surgery (i.e., mediastinoscopy and/or thoracotomy with mediastinal lymph node dissection) as the gold standard of comparison.
2. In a meta-analysis evaluating the conditional test performance of FDG-PET scanning and CT scanning, the median sensitivity and specificity of FDG-PET scans were reported as 100% and 78%, respectively, in patients with enlarged lymph nodes. 6 FDG-PET scanning is considered very accurate in identifying malignant nodal involvement when nodes are enlarged. However, FDG-PET scanning will falsely identify a malignancy in approximately one-fourth of patients with nodes that are enlarged for other reasons, usually as a result of inflammation or infection. 15 16
3. The median sensitivity and specificity of FDG-PET scanning in patients with normal-sized mediastinal lymph nodes were 82% and 93%, respectively. 6 These data indicate that nearly 20% of patients with normal-sized nodes but with malignant involvement had falsely negative FDG-PET scan findings.

For patients with clinically operable NSCLC, the recommendation is for a biopsy of mediastinal lymph nodes that were found to be larger than 1 cm in shortest transverse axis on chest CT scan or were found to be positive on FDG-PET scan. Negative FDG-PET scanning does not preclude biopsy of radiographically enlarged mediastinal lymph nodes. Mediastinoscopy is necessary for the detection of cancer in mediastinal lymph nodes when the results of the CT scan and FDG-PET scan do not corroborate each other.

Evaluation of brain metastasis

Patients at risk for brain metastases may be staged with CT or MRI scans. One study randomly assigned 332 patients with potentially operable NSCLC and no neurological symptoms to brain CT or MRI imaging to detect occult brain metastasis before lung surgery. MRI showed a trend towards a higher preoperative detection rate than CT scan (P = .069), with an overall detection rate of approximately 7% from pretreatment to 12 months after surgery. 17 Patients with stage I or stage II disease had a detection rate of 4% (i.e., eight detections out of 200 patients); however, individuals with stage III disease had a detection rate of 11.4% (i.e., 15 detections out of 132 patients). The mean maximal diameter of the brain metastases was significantly smaller in the MRI group. Whether the improved detection rate of MRI translates into improved outcome remains unknown. Not all patients are able to tolerate MRI, and for these patients contrast-enhanced CT scan is a reasonable substitute.

Evaluation of distant metastasis other than the brain

Numerous nonrandomized, prospective, and retrospective studies have demonstrated that FDG-PET scanning seems to offer diagnostic advantages over conventional imaging in staging distant metastatic disease; however, standard FDG-PET scans have limitations. FDG-PET scans may not extend below the pelvis and may not detect bone metastases in the long bones of the lower extremities. Because the metabolic tracer used in FDG-PET scanning accumulates in the brain and urinary tract, FDG-PET scanning is not reliable for detection of metastases in these sites. 17

The Revised International System for Staging Lung Cancer

The Revised International System for Staging Lung Cancer, based on information from a clinical database of more than 5,000 patients, was adopted in 2010 by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer. 18 19 These revisions provide greater prognostic specificity for patient groups; however, the correlation between stage and prognosis predates the widespread availability of PET imaging.

Summary of Changes

This staging system is now recommended for the classification of both NSCLC and small cell lung carcinomas and for carcinoid tumors of the lung. 19

The T (primary tumor) classifications have been redefined as follows: 19

• T1 has been subclassified into T1a (2 cm in size) and T1b (>23 cm in size).
• T2 has been subclassified into T2a (>35 cm in size) and T2b (>57 cm in size).
• T2 (>7 cm in size) has been reclassified as T3.
• Multiple tumor nodules in the same lobe have been reclassified from T4 to T3.
• Multiple tumor nodules in the same lung but a different lobe have been reclassified from M1 to T4.

No changes have been made to the N (regional lymph nodes) classification. However, a new international lymph node map defining the anatomical boundaries for lymph node stations has been developed.

The M (distant metastasis) classifications have been redefined as follows:

• M1 has been subdivided into M1a and M1b.
• Malignant pleural and pericardial effusions have been reclassified from T4 to M1a.
• Separate tumor nodules in the contralateral lung are considered M1a.
• M1b designates distant metastasis.