The Revised International Staging System for Lung Cancer
TNM Definitions
AJCC Stage Groupings

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.

Stage has a critical role in the selection of therapy. The stage of disease is based on a combination of clinical factors (i.e., physical examination, radiology, and laboratory studies) and pathological factors (i.e., biopsy of lymph nodes, bronchoscopy, mediastinoscopy, or anterior mediastinotomy).[1] The distinction between clinical stage and pathologic stage should be considered when evaluating reports of survival outcome.

Staging procedures include history, physical examination, routine laboratory evaluations, chest x-ray, and chest computed tomography (CT) scan with infusion of contrast material. The CT scan should extend inferiorly to include the liver and adrenal glands. Magnetic resonance imaging (MRI) scans of the thorax and upper abdomen do not appear to yield advantages over CT scans.[2] 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 CT/MRI of the brain may be performed if initial assessments suggest metastases, or for patients with stage III disease who are under consideration for aggressive local and combined modality treatments. Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy. The wider availability and use of fluorodeoxyglucose positron emission tomography (FDG-PET) for staging has modified this approach to staging mediastinal lymph nodes and distant metastases.

If there is no evidence of distant metastatic disease on CT scan, FDG-PET scanning complements CT scan staging of the mediastinum. The combination of CT scanning and PET scanning has greater sensitivity and specificity than CT scanning alone.[3] Numerous nonrandomized studies of FDG-PET have evaluated mediastinal lymph nodes using surgery (i.e., mediastinoscopy and/or thoracotomy with mediastinal lymph node dissection) as the gold standard of comparison. A prospective trial studied the impact of FDG-PET on the staging of 102 patients with NSCLC and found that the sensitivity, specificity, negative predictive value and positive predictive value of FDG-PET alone for detection of mediastinal metastases were 91%, 86%, 95%, and 74%, respectively, as compared with CT scan alone, which had a sensitivity of 75% and a specificity of 66%.[4] False-negative results from FDG-PET were seen in small tumors and when FDG-PET was unable to distinguish the primary lesion from contiguous lymphadenopathy. False-positive results were often caused by the presence of benign inflammatory disease. These results have been corroborated by other studies.[5,6] For patients with clinically operable NSCLC, biopsy of mediastinal lymph nodes, found on chest CT scan to be larger than 1 cm in shortest transverse axis or positive on FDG-PET scanning, is recommended. 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 do not corroborate each other.

Numerous nonrandomized, prospective and retrospective studies have demonstrated that FDG-PET 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 is not reliable for detection of metastases in these sites.[7]

Decision analyses demonstrate that FDG-PET 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.[8-10] 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.[8-10] A randomized trial evaluating the impact of PET on clinical management found that PET provided additional information regarding appropriate stage but did not lead to significantly fewer thoracotomies.[11]

Patients at risk for brain metastases may be staged with CT or MRI scans. One study randomly assigned 332 patients with potentially operable NSCLC but without neurological symptoms to brain CT or MRI imaging to detect occult brain metastasis before lung surgery. MRI showed a trend toward a higher preoperative detection rate than CT (P = .069), with an overall detection rate of approximately 7% from pretreatment to 12 months after surgery.[7] Patients with stage I or stage II disease had a detection rate of 4% (i.e., 8 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.

The Revised International System for Staging Lung Cancer, based on information from a clinical database of more than 5,000 patients, was adopted in 1997 by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer.[12,13] These revisions provide greater prognostic specificity for patient groups; however, the correlation between stage and prognosis predates the widespread availability of PET imaging. Stage I is divided into two categories by the size of the tumor: IA (T1, N0, M0) and IB (T2, N0, M0). Stage II is divided into two categories by the size of the tumor and by the nodal status: IIA (T1, N1, M0) and IIB (T2, N1, M0). T3, N0 has been moved from stage IIIA in the 1986 version of the staging system to stage IIB in the latest version. This change reflects the slightly superior prognosis of these patients and shows that many patients with invasion of the parietal pleura or chest wall caused by pleural-based or superior sulcus tumors (T3) but with negative lymph nodes (N0) are often treated with surgery, sometimes combined with radiation therapy or chemoradiation therapy, and the results are similar to those of patients with resected stage II disease. Another change clarifies the classification of multiple tumor nodules. Satellite tumor nodules located in the same lobe as the primary lesion, which are not lymph nodes, should be classified as T4 lesions. Intrapulmonary ipsilateral metastasis in a lobe other than the lobe containing the primary lesions should be classified as an M1 lesion (stage IV).

The AJCC has designated staging by TNM classification.[13]

Primary tumor (T)

• TX: Primary tumor cannot be assessed, or tumor is proven by the presence of malignant cells in sputum or bronchial washings but is not visualized by imaging or bronchoscopy



• T0: No evidence of primary tumor



• Tis: Carcinoma in situ



• T1: A tumor that is 3 cm or smaller in greatest dimension, is surrounded by lung or visceral pleura, and is without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).  [Note: The uncommon superficial tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified as T1.]



• T2: A tumor with any of the following features of size or extent:
  • Larger than 3 cm in greatest dimension
  • Involves the main bronchus and is 2 cm or larger distal to the carina
  • Invades the visceral pleura
  • Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung



• T3: A tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or, tumor in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; or, associated atelectasis or obstructive pneumonitis of the entire lung



• T4: A tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; or, separate tumor nodules in the same lobe; or, tumor with a malignant pleural effusion.  [Note: Most pleural effusions associated with lung cancer are due to tumor; however, in a few patients multiple cytopathologic examinations of pleural fluid are negative for tumor. In these cases, fluid is nonbloody and is not an exudate. Such patients may be further evaluated by videothoracoscopy and direct pleural biopsies. When these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element, and the patient should be staged as T1, T2, or T3.]

Regional lymph nodes (N)

• NX: Regional lymph nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes including involvement by direct extension of the primary tumor
• N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)
• N3: Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

Distant metastasis (M)

• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis present.  [Note: M1 includes separate tumor nodule(s) in a different lobe (ipsilateral or contralateral).]

Specify sites according to the following notations:

Occult carcinoma

• TX, N0, M0

Stage 0

• Tis, N0, M0

Stage IA

• T1, N0, M0

Stage IB

• T2, N0, M0

Stage IIA

• T1, N1, M0

Stage IIB

• T2, N1, M0
• T3, N0, M0

Stage IIIA

• T1, N2, M0
• T2, N2, M0
• T3, N1, M0
• T3, N2, M0

Stage IIIB

• Any T, N3, M0
• T4, any N, M0

Stage IV

• Any T, any N, M1

References

1. Pfister DG, Johnson DH, Azzoli CG, et al.: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 22 (2): 330-53, 2004.  [PUBMED Abstract]
   
   
2. Webb WR, Gatsonis C, Zerhouni EA, et al.: CT and MR imaging in staging non-small cell bronchogenic carcinoma: report of the Radiologic Diagnostic Oncology Group. Radiology 178 (3): 705-13, 1991.  [PUBMED Abstract]
   
   
3. Vansteenkiste JF, Stroobants SG, De Leyn PR, et al.: Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients. J Clin Oncol 16 (6): 2142-9, 1998.  [PUBMED Abstract]
   
   
4. Pieterman RM, van Putten JW, Meuzelaar JJ, et al.: Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med 343 (4): 254-61, 2000.  [PUBMED Abstract]
   
   
5. Roberts PF, Follette DM, von Haag D, et al.: Factors associated with false-positive staging of lung cancer by positron emission tomography. Ann Thorac Surg 70 (4): 1154-9; discussion 1159-60, 2000.  [PUBMED Abstract]
   
   
6. Liewald F, Grosse S, Storck M, et al.: How useful is positron emission tomography for lymphnode staging in non-small-cell lung cancer? Thorac Cardiovasc Surg 48 (2): 93-6, 2000.  [PUBMED Abstract]
   
   
7. Yokoi K, Kamiya N, Matsuguma H, et al.: Detection of brain metastasis in potentially operable non-small cell lung cancer: a comparison of CT and MRI. Chest 115 (3): 714-9, 1999.  [PUBMED Abstract]
   
   
8. Dietlein M, Weber K, Gandjour A, et al.: Cost-effectiveness of FDG-PET for the management of potentially operable non-small cell lung cancer: priority for a PET-based strategy after nodal-negative CT results. Eur J Nucl Med 27 (11): 1598-609, 2000.  [PUBMED Abstract]
   
   
9. Scott WJ, Shepherd J, Gambhir SS: Cost-effectiveness of FDG-PET for staging non-small cell lung cancer: a decision analysis. Ann Thorac Surg 66 (6): 1876-83; discussion 1883-5, 1998.  [PUBMED Abstract]
   
   
10. Gambhir SS, Hoh CK, Phelps ME, et al.: Decision tree sensitivity analysis for cost-effectiveness of FDG-PET in the staging and management of non-small-cell lung carcinoma. J Nucl Med 37 (9): 1428-36, 1996.  [PUBMED Abstract]
    
    
11. Viney RC, Boyer MJ, King MT, et al.: Randomized controlled trial of the role of positron emission tomography in the management of stage I and II non-small-cell lung cancer. J Clin Oncol 22 (12): 2357-62, 2004.  [PUBMED Abstract]
    
    
12. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111 (6): 1710-7, 1997.  [PUBMED Abstract]
    
    
13. Lung. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 167-181. 
    
    

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