eMedicine Specialties > Oncology > Carcinomas of the Lung and Other Intrathoracic Carcinomas

Lung Cancer, Non-Small Cell: Differential Diagnoses & Workup

Author: Syed Huq, MD, Fellow, Division of Hematology-Oncology, Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Ellis Fischel Cancer Center
Coauthor(s): Irfan Maghfoor, MD, Consulting Oncologist, Department of Oncology, King Faisal Specialist Hospital and Research Center, Saudi Arabia; Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology Emeritus, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri/Ellis Fischel Cancer Center
Contributor Information and Disclosures

Updated: Nov 10, 2009

Differential Diagnoses

Benign Lung Tumors
Carcinoid Lung Tumors
Pleural Effusion

Workup

Laboratory Studies

Apart from a handful of asymptomatic patients in whom lung cancer is diagnosed incidentally, virtually all patients with lung cancer are symptomatic at presentation. In the presence of a long history of smoking or other risk factors for lung cancer, the presence of persistent respiratory symptoms should prompt a chest radiograph. Because benign conditions and metastatic malignancies can mimic lung cancer on radiographs, histologic confirmation is necessary. This can be achieved by sputum cytologic studies, bronchoscopy, or CT-guided transthoracic needle biopsy of the mass, depending on the location of the tumor. The authors' approach to diagnosing lung cancer is illustrated in the image below.

Non–small cell lung cancer. Diagnostic appr...

Non–small cell lung cancer. Diagnostic approach for possible lung cancer.

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Non–small cell lung cancer. Diagnostic appr...

Non–small cell lung cancer. Diagnostic approach for possible lung cancer.

 

  • Sputum cytologic studies
    • Centrally located endobronchial tumors may exfoliate malignant cells into sputum. (This location and tendency to exfoliate are most common in squamous cell carcinomas.) Therefore, sputum cytology can be a quick and inexpensive diagnostic test if results are positive.
    • The false-positive rate for sputum cytology is 1%, but the false-negative rate is as high as 40%.
    • A positive finding for malignancy from a cytologic specimen is accurate in as many as 90% of cases, but any distinction between different histologic subtypes is not accurate. Discordant results are often observed between cytologic and histologic findings of specimens obtained from bronchoscopy or transthoracic biopsy.
    • With the development of advanced x-ray imaging techniques and biopsy procedures, sputum cytology is not commonly employed in the diagnosis of non-small cell lung cancer.
  • Complete blood cell count: This should be obtained in every patient, especially before instituting chemotherapy.
  • Electrolytes and renal function studies: Because of the propensity of lung cancers to cause paraneoplastic syndromes, serum electrolyte levels should be evaluated. For a complete listing of common paraneoplastic syndromes associated with lung cancer, see Image 1. 
  • Staging workup for non-small cell lung cancer
    • Because of the importance of stage on the therapeutic decision-making process, all patients with non-small cell lung cancer must be staged adequately.
    • In the United States, the standard staging workup for NSCLC includes at least the following (also see Image 3):
      • Complete history and physical examination
      • CT scan of the chest and upper abdomen (including liver and adrenals)
      • Complete blood cell counts
      • Liver and kidney function tests
      • Serum electrolytes
    • Information obtained from these tests can then be used to guide further testing (eg, imaging studies).
    • Invasive staging procedures such as mediastinoscopy and mediastinotomy may be required to assess mediastinal lymph nodes in patients who are candidates for potentially curative surgical resection. PET scans may be useful in the detection of involved nodes, the presence of which may influence decisions about operability. See Imaging Studies for further discussion of this modality of imaging.

Imaging Studies

  • A complete staging workup for non-small cell lung cancer should be used to evaluate the extent of disease.
  • A chest radiograph is usually the first test ordered in patients in whom a lung malignancy is suggested.
    • If the tumor is clearly visible and measurable, a chest radiograph can sometimes be used to monitor response to therapy.
    • Popcorn calcification is usually a radiologic characteristic of benign lesions.
  • CT scan
    • Common sites of spread of a non-small cell lung cancer include the liver and adrenals; hence, a CT scan of the chest and upper abdomen, to include the liver and adrenals, is the minimum standard for a staging workup for a person newly diagnosed with non-small cell lung cancer.
    • A CT scan or MRI of the brain may be required if neurological symptoms or signs are present. Most thoracic surgeons perform imaging of the brain before attempting definitive resection of a lung malignancy.
  • Bone scintigraphy: The skeletal system is another common site of metastases for lung cancers. If patients report bone pain or if their serum calcium and/or alkaline phosphatase levels are elevated, a bone scan should be obtained to search for bone metastases.
  • Positron emission tomography
    • Positron emission tomography (PET) scanning is approved by the US Food and Drug Administration (FDA) for the workup of solitary lung nodules.
    • Recent studies suggest that PET scanning is useful for searching for systemic spread if other diagnostic modalities cannot clarify an abnormality that may change the treatment of the patient's condition. However, false-positive and false-negative results occur.
    • Recently, additional data have emerged that underscore the importance of PET scanning in patients with non-small cell lung cancer. PET scans appear to be more sensitive, specific, and accurate than CT scans for staging mediastinal disease. While radiographs and CT scans show images of structures, PET scans reveal the nature of the area under study. PET scans often detect abnormalities not demonstrated on CT scans.
    • Published reports suggest that staging of non-small cell lung cancer may be influenced by PET scan results in up to 60% of the cases and as many as 25% may be up-staged after PET scanning.
    • Caution is required when interpreting the results of PET scans in patients who may be denied potentially curative surgical resection based on PET results.
  • MRI: MRI is most useful when evaluating a patient in whom spinal cord compression is suggested. In addition, brain MRI has a greater sensitivity than CT scan for detection of central nervous system metastasis.

Procedures

  • Bronchoscopy
    • When a lung cancer is suggested, especially if centrally located, bronchoscopy provides a means for direct visualization of the tumor, allows determination of the extent of airway obstruction, and allows collection of pathologic material under direct visualization.
    • Fiberoptic bronchoscopy has the advantage of providing direct visualization of the bronchial tree. Diagnostic material can be obtained with direct biopsy of the visualized tumor, bronchial brushings and washing, and transbronchial biopsies.
  • Mediastinoscopy: This is usually performed to evaluate the status of enlarged mediastinal lymph nodes (seen on CT scan) before attempting definitive surgical resection of lung cancer.
  • Thoracoscopy: This is usually reserved for tumors that remain undiagnosed after bronchoscopy or CT-guided biopsy. Thoracoscopy is also an important tool in the management of malignant pleural effusions.
  • CT-guided biopsy: This procedure is preferred for tumors located in the periphery of the lungs because peripheral tumors may not be accessible through a bronchoscope.
  • Biopsy of other sites: Diagnostic material can also be obtained from other abnormal sites (eg, enlarged palpable lymph nodes, liver, pleural, or pericardial effusions).

Histologic Findings

The updated World Health Organization classification of lung cancer is widely used. Non-small cell lung cancer includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Sometimes, lung cancers can exhibit 2 or more histologic patterns.

Adenocarcinoma appears to be increasing in incidence, especially in women, compared with squamous cell carcinoma, which was previously the most common type of non-small cell lung cancer.

Histologically, adenocarcinomas form glands and produce mucin. Mucin production can be identified with mucicarmine or periodic acid-Schiff staining. The World Health Organization classification of lung cancer divides adenocarcinomas into (1) acinar, (2) papillary, (3) bronchoalveolar, and (4) mucus-secreting. Bronchoalveolar carcinoma is a distinct clinicopathologic entity that appears to arise from type II pneumocytes and may manifest as a solitary peripheral nodule, multifocal disease, or a pneumonic form, which can spread rapidly from one lobe to another. Stages for stage adenocarcinomas are associated with worse prognoses than squamous cell carcinomas, with the exception of T1 N0 M0 tumors.

Squamous cell carcinoma has a distinct dose-response relationship to tobacco smoking and usually develops in proximal airways, progressing through stages of squamous metaplasia to carcinoma in situ. Well-differentiated squamous cell carcinomas contain keratin pearls, while poorly differentiated squamous cell carcinomas may stain positive for keratin. Microscopic examination reveals cells with large, irregular nuclei and coarse nuclear chromatin with large nucleoli. Cells are arranged in sheets, and the presence of intercellular bridging is diagnostic.

Large cell carcinoma is the least common of all non-small cell lung cancers. It is composed of large cells with prominent nucleoli, and no mucin production or intercellular bridging is identified. Many tumors previously diagnosed as large cell carcinomas are identified as poorly differentiated adenocarcinomas or squamous cell carcinomas after advanced immunohistochemical staining, electron microscopy, and monoclonal antibody studies. A variant of large cell carcinoma has been identified; it contains neuroendocrine features and is called large cell neuroendocrine carcinoma. Large cell neuroendocrine carcinomas are associated with a worse prognosis than large cell carcinomas.

WHO classification of epithelial lung tumors
Preinvasive lesions
  • Squamous dysplasia/carcinoma in situ
  • Atypical adenomatous hyperplasia
  • Diffuse idiopathic pulmonary neuroendocrine hyperplasia
Invasive malignant lesions

  • Squamous cell carcinoma
    • Variants
    • Papillary
    • Clear cell
    • Small cell
    • Basaloid
  • Small cell carcinoma
    • Variant
    • Combined small cell carcinoma
  • Adenocarcinoma
    • Acinar
    • Papillary
    • Bronchoalveolar
    • Nonmucinous (Clara cell/type II pneumocyte) type
    • Mixed mucinous and nonmucinous (Clara cell/type II pneumocyte and goblet cell) type or intermediate cell type
    • Solid adenocarcinoma with mucin formation
    • Adenocarcinoma with mixed subtypes
    • Variants
    • Well-differentiated fetal adenocarcinoma
    • Mucinous (colloid) adenocarcinoma
    • Mucinous cystadenocarcinoma
    • Signet-ring adenocarcinoma
    • Clear cell adenocarcinoma
  • Large cell carcinoma
    • Variants
    • Large cell neuroendocrine carcinoma
    • Combined large cell neuroendocrine carcinoma
    • Basaloid carcinoma
    • Lymphoepitheliomalike carcinoma
    • Clear cell carcinoma
    • Large cell carcinoma with rhabdoid phenotype
  • Adenosquamous carcinoma
  • Carcinoma with sarcomatoid, pleomorphic, or sarcomatous elements
    • Carcinoma with spindle or giant cells
    • Pleomorphic carcinoma
    • Spindle cell carcinoma
    • Giant cell carcinoma
    • Carcinosarcoma
    • Pulmonary blastoma
  • Carcinoid tumors
    • Typical carcinoid
    • Atypical carcinoid
  • Carcinoma of salivary gland type
    • Mucoepidermoid carcinoma
    • Adenoid cystic carcinoma
    • Others
  • Unclassified

Staging

The staging of all non-small cell lung cancers follows the TNM (Tumor, Node, Metastasis) system. The current 6th edition of the TNM staging system came into effect in 1997 after revisions for stage groupings for stages I, II, and III. The following images also list stages and stage groupings.6,7


TNM staging system for non–small cell lung ...

TNM staging system for non–small cell lung cancer.

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TNM staging system for non–small cell lung ...

TNM staging system for non–small cell lung cancer.



Stage grouping for TNM system of non–small ...

Stage grouping for TNM system of non–small cell lung cancer.

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Stage grouping for TNM system of non–small ...

Stage grouping for TNM system of non–small cell lung cancer.


The most important prognostic indicator in lung cancer is the extent of disease and lymph node involvement. The American Joint Committee for Cancer Staging and End Results Reporting has developed the TNM staging system, which takes into account the degree of spread of primary tumor, the extent of regional lymph node involvement, and the presence or absence of distant metastases. The TNM system is used for all lung carcinomas except small cell lung carcinomas.

For TNM staging, non-small cell lung cancer is divided into 4 stages, with further subdivision of stages I-III into A and B subtypes. These stages have important therapeutic and prognostic implications, which are discussed later.

  • Tumor (T)
    • TX - Positive malignant cytology results, no lesion seen
    • T1 - Diameter 3 cm or smaller
    • T2 - Diameter larger than 3 cm
    • T3 - Extension to pleura, chest wall, diaphragm, pericardium, within 2 cm of carina, or total atelectasis
    • T4 - Invasion of mediastinal organs (eg, esophagus, trachea, great vessels, heart), malignant pleural effusion, or satellite nodules within the primary lobe
  • Regional lymph node involvement (N)
    • N0 - No lymph nodes involved
    • N1 - Ipsilateral bronchopulmonary or hilar nodes involved
    • N2 - Ipsilateral mediastinal or subcarinal nodes
    • N3 - Contralateral mediastinal, hilar, any supraclavicular nodes involved
  • Metastatic involvement (M)
    • M0 - No metastases
    • M1 - Metastases present
  • Stage groupings
    • IA - T1 N0 M0
    • IB - T2 N0 M0
    • IIA - T1 N1 M0
    • IIB - T2 N1 M0 or T3 N0 M0
    • IIIA - T1-3 N2 M0 or T3 N1 M0
    • IIIB - Any T4 or any N3 M0
    • IV - Any M1

This staging system is scheduled to be modified in late 2009, drawing upon the results of a large International Association for the Study of Lung Cancer (IASLC) analysis of 100,879 patients drawn from 19 countries.8 Prominent anticipated changes include the following:

  • Change in primary tumor size cut offs of 2, 3, 5, and 7 cm
  • Further subdivision of T1 and T2 disease into a and b, based on size
  • Satellite nodules in same lobe to be considered as T3 instead of T4
  • Satellite nodules in different lobes of the same lung will be classified as T4 instead of M1 lesions
  • Malignant pleural effusions, nodules or pericardial effusions to be considered M1 disease instead of T4
  • M1 disease further classified into M1a – implying local metastases to pleura, pericardium or opposite lung or M1b – for distant metastases
This will impact the staging of lung cancer, and is believed to better correlate with lung cancer survival, as well as more consonant with management paradigms. It is expected that the American Joint Committee on Cancer (AJCC) and its international counterpart, the International Union against Cancer (UICC) will accept these proposed changes.

More on Lung Cancer, Non-Small Cell

Overview: Lung Cancer, Non-Small Cell
Differential Diagnoses & Workup: Lung Cancer, Non-Small Cell
Treatment & Medication: Lung Cancer, Non-Small Cell
Follow-up: Lung Cancer, Non-Small Cell
Multimedia: Lung Cancer, Non-Small Cell
References
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Further Reading

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Keywords

bronchogenic carcinoma, NSCLC, non-small cell lung cancer, non-small-cell lung cancer, nonsmall cell lung cancer, adenocarcinoma, squamous cell carcinoma, SCC, lung SCC, large cell carcinoma, bronchoalveolar carcinoma, broncho-alveolar carcinoma, lung carcinoma, lung malignancy, tobacco, smoking, asbestos, radon, secondhand smoke, passive smoking, second-hand smoke, smoking-related cancer, lung cancer

acinar adenocarcinoma, papillary adenocarcinoma, bronchoalveolar adenocarcinoma, mucus-secreting adenocarcinoma, large cell neuroendocrine carcinoma, lobectomy, pneumonectomy, ras oncogene, H-ras, K-ras, N-ras, c-myc, c-raf, ectopic hormone production, atelectasis, postobstructive pneumonia, wheezing, hemoptysis, pleural effusion, superior vena cava obstruction, superior vena cava syndrome, paralysis of recurrent laryngeal nerve, phrenic nerve palsy, paralysis of the diaphragm, Horner syndrome, dysphagia, esophageal compression, pericardial effusion, Pancoast tumor, paraneoplastic syndromes, hypercalcemia, clubbing, hypertrophic pulmonary osteoarthropathy, Trousseau syndrome of hypercoagulability, scar carcinoma, gynecomastia, galactorrhea, spinal cord compression, silicate type of asbestos, HIV infection, diesel exhaust

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Contributor Information and Disclosures

Author

Syed Huq, MD, Fellow, Division of Hematology-Oncology, Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Ellis Fischel Cancer Center
Syed Huq, MD is a member of the following medical societies: American Medical Informatics Association, American Society of Clinical Oncology, and American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Irfan Maghfoor, MD, Consulting Oncologist, Department of Oncology, King Faisal Specialist Hospital and Research Center, Saudi Arabia
Irfan Maghfoor, MD is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology Emeritus, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri/Ellis Fischel Cancer Center
Michael Perry, MD, MS, MACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, International Association for the Study of Lung Cancer, and Missouri State Medical Association
Disclosure: Bionumerik Consulting fee Consulting; Proactya Consulting fee Consulting; GSK Consulting fee Consulting; NovoNordisk Consulting fee Consulting; Amgen Honoraria Speaking and teaching; GSK Consulting fee Speaking and teaching

Medical Editor

Antoni Ribas, MD, Department of Medicine, Division of Hematology-Oncology, Assistant Professor of Medicine, University of California at Los Angeles Medical Center
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Benjamin Movsas, MD, Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center
Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, and American Society for Therapeutic Radiology and Oncology
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

 
 
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