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

In non-small cell lung cancer (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.

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.

The proceduresprocess used to determine staging include the following:

• History.
• Physical examination.
• Routine laboratory evaluations.
• Chest x-ray.
• 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 if patients with stage III disease 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.

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.[3] In the 35 studies published from 1991 through June, 2006, 5,111 evaluable patients were identified. The median prevalence of mediastinal metastasis was 28% (range, 18%–56%). 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. The pooled sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis were 51% (95% confidence interval [CI], 47%–54%) and 86% (95% CI, 84%–88%), respectively. The corresponding positive and negative likelihood ratios were 3.4 and 0.6, respectively. These results 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.[4] An earlier meta-analysis reported average sensitivity and specificity of 64% and 74%, respectively.[5]

Another 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 18-FDG-PET in the diagnosis and staging of lung cancer.[6] Through a systematic search of the literature, 12 evidence summary reports and 15 prospective studies of the diagnostic accuracy of positron emission tomography (PET) were identified. PET appears to have high sensitivity and reasonable specificity for differentiating benign from malignant lesions as small as 1 cm. PET also appears superior to CT imaging for mediastinal staging in NSCLC. Randomized trials evaluating the utility of PET 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, PET 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.

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.[7] 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 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.[3] 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 PET scanning were 4.9 and 0.3, respectively. These findings demonstrate that PET scanning is more accurate than CT scanning for staging of the mediastinum in patients with lung cancer.

In a meta-analysis evaluating the conditional test performance of FDG-PET and CT scanning, the median sensitivity and specificity of PET scans were reported as 100% and 78%, respectively, in patients with enlarged lymph nodes.[4] PET scanning is considered very accurate in identifying malignant nodal involvement when nodes are enlarged. However, 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.[8,9]

The median sensitivity and specificity of PET scanning in patients with normal-sized mediastinal lymph nodes were 82% and 93%, respectively.[4] These data indicate that nearly 20% of patients with normal-sized nodes but with malignant involvement had falsely negative PET scan findings. For patients with clinically operable NSCLC, the recommendation is for a biopsy of mediastinal lymph nodes that were found on chest CT scan to be larger than 1 cm in shortest transverse axis or were found to be positive on FDG-PET scanning. 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.[10]

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.[11-13] 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.[11-13] A randomized study found that the addition of FDG-PET to conventional staging was associated with significantly fewer thoracotomies.[14] A second 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.[15].

Accurate staging of the mediastinal lymph nodes provides important prognostic information. 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.[16] A total of 16,800 patients were included in the study. The overall survival analysis for patients without radiation therapy demonstrated that in comparison to the reference group (1–4 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% CI, 0.84–0.97). For patients with nine to 12 lymph nodes and 13 to 16 lymph nodes examined, HRs were 0.86 (95% CI, 0.79–0.95) and 0.78 (95% CI, 0.68–0.90), respectively. There appeared to be no incremental improvement after evaluating more than 16 lymph nodes. The corresponding results for lung cancer-specific 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.[16] 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 between 11 to 16 lymph nodes.

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.[10] 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.

Pathological staging requires:

• 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.

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.[17,18] 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.[18]

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. (For more information on pleural effusions, refer to the Cardiopulmonary Syndromes ¹ summary.)]

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:

Notation Key for Tumor Sites

Enlarge ²

BRA = brain	EYE = eye	HEP = hepatic
LYM = lymph nodes	MAR = bone marrow	OSS = osseous
OTH = other	OVR = ovary	PER = peritoneal
PLE = pleura	PUL = pulmonary	SKI = skin

AJCC Stage Groupings

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

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