Pulmonary Medicine

Staging of Non-Small-Cell Lung Cancer

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What every physician needs to know:

Accurate staging is crucial in patients with known or suspected non-small-cell lung cancer (NSCLC). Staging is performed using the tumor (T), node (N), mestastasis (M) system. The TNM staging system for lung cancer was recently revised by a working group of the International Association for the Study of Lung Cancer (IASLC) after collecting data from more than 65,000 patients in nineteen countries between 1990 and 2000 (Goldstraw et al., 2007). Rigorous methods were used to develop and validate a classification system that accurately distinguishes patients by prognosis. The new system consists of seven descriptors of T status, four descriptors of N status, and three descriptors of M status, all combined into seven stage groupings.

Stage groupings

Stage IA: T1a-1b N0 M0

Stage 1B: T2a N0 M0

Stage IIA: T1a-2a N1 M0, or T2b N0 M0

Stage IIB: T2b N1 M0, or T3 N0 M0

Stage IIIA: T1-3 N2 M0, or T3 N1 M0, or T4 N0-1 M0

Stage IIIB: Any T N3 M0, or T4 N2 M0

Stage IV: Any T, any N M1a or 1b

T descriptors

T1a: smaller than or equal to 2 cm, surrounded completely by lung, no extension proximal to lobar bronchus, and no satellites

T1b: larger than 2 cm and smaller than or equal to 3 cm, surrounded completely by lung, no extension proximal to lobar bronchus, and no satellites

T2a: larger than 3 cm and smaller than or equal to 5 cm, or smaller tumor with extension proximal to lobar bronchus but larger than or equal to 2 cm distal to main carina, or atelectasis/pneumonia extending to the hilum but not involving entire lung, or visceral pleural involvement; and no satellites

T2b: larger than 5 cm and smaller than or equal to 7 cm, with or without extension proximal to lobar bronchus but larger than or equal to 2 cm distal to main carina, or atelectasis/pneumonia extending to the hilum but not involving the entire lung, or visceral pleural involvement; and no satellites

T3: larger than 7 cm; or involvement of the main bronchus less than 2 cm from the main carina; or atelectasis/pneumonia involving the entire lung; or involvement of chest wall, diaphragm, phrenic nerve, mediastinal pleura or parietal pericardium; or separate tumor nodule(s) within the same lobe

T4: any size tumor with involvement of the main carina; or involvement of the mediastinum, heart, great vessels, recurrent laryngeal nerve, esophagus or vertebral body; or separate tumor nodule(s) in a different but ipsilateral lobe

N descriptors

N0: no hilar or mediastinal lymphadenopathy

N1: isolated ipsilateral hilar lymphadenopathy

N2: ipsilateral mediastinal (including subcarinal) lymphadenopathy, with or without ipsilateral hilar adenopathy

N3: contralateral hilar or mediastinal lymphadenopathy, or any scalene or supraclavicular adenopathy, with or without ipsilateral hilar and/or mediastinal adenopathy

The new staging system also harmonizes the map that is used to describe sites of suspected or confirmed lymph node involvement (Table 1).

Table 1

Lymph node stations
Station # Description
1 Cervical, supraclavicular, sternal notch
2R, 2L Upper paratracheal
3a Prevascular
3p Retrotracheal
4R, 4L Lower paratracheal
5 Subaortic (A-P window)
6 Para-aortic
7 Subcarinal
8 Paraesophageal
9 Pulmonary ligament
10 Hilar
11-14 Intrapulmonary

M descriptors

M0: no distant metastasis

M1a: separate tumor nodule(s) in contralateral lung, or pleural nodules, or malignant pleural or pericardial effusion

M1b: distant (extrathoracic) metastasis

Staging evaluation

The staging evaluation should be tailored to the presentation of the individual patient. Computed tomography (CT) of the chest should be performed in every patient, with the possible exception of those with clearly advanced disease and/or poor performance status. Chest CT cuts should include the upper abdomen so the liver and adrenal glands can be visualized. While neither sensitive nor specific for identifying malignancy, abnormalities on chest CT can be used to establish a preliminary clinical stage (CT stage) that will then guide the remainder of the staging evaluation. (See "Classification.") The most effective and efficient evaluations can subsequently be planned by considering the following guiding principles (Gould and Wiener, 2009):

  • Use symptoms, signs, and the results of chest CT to guide subsequent test selection.

  • Obtain tissue confirmation of metastasis when results of imaging tests are positive.

  • Perform as few procedures as necessary; try to establish diagnosis and stage with a single procedure.

  • Select an accessible site for biopsy that will establish the highest-stage disease.

  • Minimize risk by selecting the least invasive alternative for biopsy.

  • Seek specialist or multidisciplinary input when there are two or more potential targets for biopsy.

  • Maximize yield by using direct visualization.

Staging procedures

Staging tests include non-invasive imaging tests (Table 2) and invasive biopsy procedures (Table 3). "Clinical stage" refers to the results of any staging evaluation performed prior to definitive surgical treatment. "Pathological stage" refers to staging performed during surgical resection. Clinical stage includes histopathological information obtained by mediastinoscopy, bronchoscopy, or other closed (non-surgical) biopsy.

Table 2

Non-invasive staging tests
Staging Test Sensitivity Specificity Advantages Limitations
Computed tomography (CT) 51% 86% Provides a roadmap for subsequent staging evaluation Relatively poor sensitivity and specificity for identifying mediastinal or distant metastasis; abnormal findings require histopathological confirmation
Positron emission tomography (PET), usually integrated PET-CT 74% 85% Can identify occult metastasis and reduce the frequency of unnecessary or "futile" thoracotomy More accurate than CT or dedicated PET alone, but positive findings still require histopathological confirmation unless there is overwhelming evidence of metastasis
Brain imaging (CT, MRI) 76% (CT) 82% (CT) Identification of disease that may be amenable to palliation or cure; MRI is more sensitive than CT Detection and treatment of asymptomatic metastasis may or may not be more effective than treatment of symptomatic disease.
Bone imaging (x-rays, CT, PET) >90% (PET) >90% (PET) Identification of disease that may be amenable to palliation or cure Detection and treatment of asymptomatic metastasis may or may not be more effective than treatment of symptomatic disease.

Table 3

Invasive staging tests
Test Accessible mediastinal stations Reported Sensitivity Limitations
Transbronchial needle aspiration biopsy (TBNA) 2, 4, 7 36-78% Limited sensitivity for "low prevalence" disease, such as single-station or discrete adenopathy
Endobronchial ultrasound (EBUS)-guided TBNA 1, 2, 4, 7, 10, 11 69% Requires special training
Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) 2, 4, 5, 7, 8, 9 69% Requires special training in upper endoscopy
Combined EBUS-TBNA and EUS-FNA 1, 2, 4, 5, 7, 8, 9, 10, 11 93% Requires two procures, although both can be done in one setting
Cervical mediastinoscopy 1, 2, 3, 4, anterior 7 78-90% Surgical procedure; general anesthesia; no access to posterior subcarinal, paraesophageal, and pulmonary ligament nodes
Anterior mediastinotomy 5, 6 63-86% Surgical procedure; general anesthesia; no access to right-sided, subcarinal, paraesophageal, or pulmonary ligament lymph nodes
Video-assisted thoracoscopic surgical (VATS) biopsy ipsilateral 2, 4, 5, 6, 7, 8, 9 75% Not able to sample contralateral lymph nodes; surgical procedure; general anesthesia; requires single-lung ventilation

TNM stage, treatment and prognosis

TNM stage is a strong but imperfect predictor of prognosis, but it provides a framework to guide treatment decisions. In general, stages IA and IB disease are treated with surgery alone if the patient is fit to tolerate resection, stages IIA and IIB disease are treated with surgery followed by adjuvant chemotherapy, stages IIIa and IIIB disease are treated with combined (preferably concurrent) chemoradiation, and stage IV disease is treated with chemotherapy alone. In the IASLC staging project, five-year survival percentages for patients with clinical stages IA, IB, IIA, IIB, IIIA, IIIB and IV NSCLC were 50 percent, 43 percent, 36 percent, 25 percent, 19 percent, 7 percent and 2 percent, respectively (Goldstraw et al., 2007). Five-year survival percentages for patients with corresponding pathological stages were somewhat higher because of upstaging at the time of surgery.

Classification:

A preliminary clinical stage should be assigned based on the results of chest CT to guide the subsequent evaluation.

Suspected stage IV

In patients with suspected M1 disease on chest CT (preliminary clinical stage IV), a biopsy of one of the involved sites should be performed in an attempt to establish both the diagnosis and the presence of stage IV disease in a single procedure. When present, a moderate or large pleural effusion is an easily accessible target that can be sampled by simple thoracentesis. If the fluid is exudative and cytology is negative, diagnostic thoracentesis should be repeated once. If cytopathological examination of the second sample is also negative and the extent of disease is otherwise resectable, video-assisted thoracoscopic surgical (VATS) pleural biopsy should be performed to exclude metastasis (Rivera and Mehta, 2007).

Other common sites of suspected M1 involvement that may be accessible via needle biopsy include the liver, the adrenal glands, and (sometimes) the bones. Biopsy of brain lesions is rarely necessary, as these patients commonly have other sites of metastatic involvement. However, patients with a suspected isolated, solitary brain metastasis should be evaluated for resection.

Suspected stage IV, not amenable to biopsy

In some patients with suspected M1 disease on chest CT that is not accessible or too risky to biopsy, it is sufficient to establish the diagnosis by obtaining a biopsy from another site of disease involvement. In such patients, histopathological confirmation of stage IIIA or IIIB disease is preferred, but this is not always practical. In some cases, biopsy of the primary tumor exposes the patient to the least risk, and the presence of M1 disease can be assumed if there is overwhelming evidence of metastatic disease on imaging. While such metastatic involvement is usually grossly apparent on chest CT, sometimes positron emission tomography (PET) can help to clarify the extent of disease.

Suspected stage IV, based on symptoms, signs or laboratory abnormalities

Patients without obvious M1 disease on chest CT but with one or more of the following findings should undergo a clinically-directed evaluation for distant metastasis:

  • Patients with altered mental status, headache, visual change, and/or focal motor weakness or sensory loss should undergo head CT or (preferably) MRI.

  • Patients with back pain and/or incontinence should undergo CT or MRI of the spine.

  • Patients with other bony pain, elevated serum alkaline phosphatase, and/or hypercalcemia should be evaluated with a bone scan, whole body PET scan, and/or x-rays of involved bones.

  • While most patients with substantial unintended weight loss have obvious evidence of M1 disease on chest CT, it is reasonable to perform a PET scan if CT findings are subtle or absent.

Because of the relatively high prevalence of brain metastasis in patients without neurologic symptoms if they have suspected stage III or IV disease, many experts believe that brain imaging is indicated in these patients, but there is little evidence to support this approach (Silvestri et al., 2007).

Suspected stage III

Clinical stage III NSCLC is a heterogeneous group.

In the absence of suspicion for N2, N3, or M1 lymph node involvement, many patients with T3 tumors have resectable disease and should be referred for thoracic surgical evaluation.

Mediastinal lymph node (N2 or N3) involvement has several different presentations, including: occult N2 disease identified at the time of surgery, limited N2 disease identified preoperatively, and bulky N2 and/or N3 lymph node involvement. Each of these presentations is managed differently, as described in .

Occult N2 disease identified at the time of surgery

By definition, these patients have ipsilateral mediastinal metastasis that was not identified during the preoperative staging evaluation, so they were upstaged at surgery from clinical stage I or II (N0 or N1) disease to pathological stage IIIA (N2) disease. Accordingly, they should be referred post-operatively for consideration for adjuvant combined chemoradiation.

Limited or N2 disease identified preoperatively

Patients with discrete, single-station lymphadenopathy and those with non-bulky, mildly enlarged nodes at two or more stations have limited N2 disease according to CT criteria. In such patients, histopathological confirmation of mediastinal metastasis is mandatory (Silvestri et al, 2007). Ideally, biopsy should be performed by the least invasive means possible. When the subcarinal lymph nodes are involved (station 7), they can often be accessed bronchoscopically with blind TBNA. Skilled bronchoscopists can often sample lower right paratracheal lymph nodes (station 4R) with blind TBNA as well, but better diagnostic yields for lymph node involvement at these and other mediastinal stations can be obtained with either EBUS-guided TBNA or EUS-guided FNA.

Lymph nodes at stations 2 (upper paratracheal), 4 (lower paratracheal), and 7 (subcarinal) can be sampled with either technique. EBUS-guided TBNA has the advantage of being able to sample hilar (station 10) and even intrapulmonary (station 11) lymph nodes, while EUS-guided FNA enables sampling of lymph nodes at stations 8 (paraesophageal) and 9 (pulmonary ligament). One study demonstrated that combined EBUS-guided TBNA and EUS-guided FNA had a sensitivity of 93 percent for identifying malignant mediastinal metastasis, which is comparable (and maybe even superior) to the sensitivity of cervical mediastinoscopy (Wallace et al., 2008).

Bulky N2 or N3 disease

In patients with evidence of bulky mediastinal adenopathy or extensive mediastinal infiltration on chest CT, it is desirable but not mandatory to obtain histopathological confirmation of metastasis, especially when the pattern of involvement is consistent with lung cancer. For example, stage III disease can be safely assumed in an older patient with a smoking history and a large, right hilar mass that is accompanied by bulky involvement of right paratracheal and subcarinal lymph nodes.

In such a patient, the diagnosis (and stage) can be established by endobronchial biopsy of the primary tumor, in which case the stage is inferred based on imaging, or by biopsy of involved lymph nodes, in which case the stage is histopathologically confirmed. The choice of staging procedure is similar to that for patients with limited or discrete adenopathy, although many patients with bulky adenopathy will have involvement of the subcarinal space that can often be sampled successfully with blind TBNA.

Use of PET in suspected stage III

There is evidence to support routine use of PET scanning in patients with clinical stage III NSCLC. Several randomized, controlled trials have demonstrated that PET reduces the frequency of futile thoracotomy, defined as identification of unresectable or benign disease at the time of surgery, or recurrence or death within one year of surgery (van Tinteren et al., 2002; Maziak et al., 2009; Fischer et al., 2009). In some cases, PET can help to identify the most suitable target for invasive staging. In others, PET identifies occult extrathoracic metastasis that would have gone undetected. However, improvements in survival have not been demonstrated.

Suspected stages IB, IIA and IIB

Patients with T2 tumors (including those with pulmonary masses measuring greater than 3 cm in diameter) and those with enlarged ipsilateral hilar lymph nodes on chest CT (N1) have clinical stage IB, IIA, or IIB disease. It is important that these patients first be evaluated for comorbidities that would preclude definitive surgical resection, but in the absence of severe comorbidities, thoracic surgical consultation should be arranged. Patients who are not surgical candidates should be referred for radiation oncology consultation if they have good performance status.

In surgical candidates with IB-IIB NSCLC, staging practices vary widely. Some surgeons perform routine preoperative cervical mediastinoscopy to exclude N2 or N3 disease, while others stage the mediastinum via thoracotomy or VATS at the time of resection. Preoperative use of PET is also controversial in this group. As described above, several randomized, controlled trials have shown that preoperative PET reduces the incidence of "futile thoracotomy," but improvements in survival have not been demonstrated or excluded (van Tinteren et al., 2002; Maziak et al., 2009; Fischer et al,. 2009).

If PET is performed and if it reveals one or more sites of possible metastasis, it is imperative to obtain histopathological confirmation of metastasis by invasive staging before excluding the patient from potentially curative surgery. As is true for patients with clinical stage III disease, options for invasive staging include bronchoscopy with blind TBNA or EBUS-guided TBNA, EUS-guided FNA, cervical mediastinoscopy, and anterior mediastinotomy.

Ipsilateral hilar (N1 enlargement)

While ipsilateral hilar (N1) lymph node involvement can sometimes be confirmed preoperatively via EBUS-guided TBNA, such confirmation will not necessarily change management because such patients are still eligible for surgical resection. More often, the presence of N1 disease is established by pathological review of resection specimens. In either case, demonstration of N1 lymph node involvement has important implications for treatment because randomized, controlled trials have confirmed that post-operative adjuvant chemotherapy improves survival in stages IIA and IIB NSCLC, whereas adjuvant chemotherapy leads to worse outcomes in patients with stage IA disease and neither benefits nor harms patients with stage IB disease (Pignon et al., 2008).

Suspected stage IA

Patients with suspected stage IA NSCLC have solitary pulmonary nodules. Most nodules are detected incidentally on chest imaging that is performed for some other reason. In the near future, it is likely that more nodules will be detected if and when lung cancer screening with low-dose CT is implemented. In patients with lung nodules that are detected incidentally, the first step is to determine whether the patient is a candidate for surgery or radiotherapy with intent to cure. If not, the patient can be followed for development of symptoms and subsequent palliation. Presumably, eligibility for curative treatment will have already been determined in patients with a screening-detected nodule.

By definition, patients with clinical (CT) stage IA lung cancer have no evidence of mediastinal or distant metastasis. The risk of occult metastasis is relatively low (5-10%). Practices for staging are highly variable. Some surgeons perform routine mediastinoscopy in these patients, but many do not. Similarly, some authorities recommend performing PET preoperatively to identify occult distant metastasis, but this approach is controversial and not mandatory.

Management of lung nodules

In patients who are candidates for curative treatment, the next step is to estimate the clinical probability that the nodule is malignant (Gould et al., 2007), and a number of quantitative models have been developed and validated to facilitate this task. Risk factors for cancer include older age, smoking, history of prior malignancy, larger nodule diameter, irregular or spiculated margins, and (possibly) upper lobe location (Swensen et al., 1997). Subsequent management depends on whether the probability of cancer is low, intermediate, or high. In all cases, patient preferences for management should be elicited, as the choice among surgery, non-surgical biopsy, and active surveillance is considered a "close call," with similar expected outcomes among the three options (Gould et al., 2003).

Management of lung nodules: high clinical probability

If the clinical probability of cancer is high (>60), the patient should be referred for thoracic surgical consultation. One should consider ordering PET to identify occult extrathoracic metastasis, but this approach is controversial because the prevalence of M1 disease is very low in these patients.

Management of lung nodules: low clinical probability

If the clinical probability of cancer is low (<10%), it is probably safe to adopt a strategy of active surveillance, usually by performing serial chest CT scans. Expert consensus-based guidelines for the frequency and duration of surveillance have been published for small, sub-centimeter nodules and ground-glass nodules.

Management of lung nodules: intermediate clinical probability

If the clinical probability of cancer is intermediate, further characterization with PET imaging and/or non-surgical biopsy is reasonable. Patients with non-hypermetabolic nodules can be followed by active surveillance, while patients with hypermetabolic nodules should be referred for surgical evaluation if there is no evidence of mediastinal or distant metastasis on the PET scan. However, if there is such evidence, histopathological confirmation of metastasis should be obtained by biopsy.

Non-surgical biopsy is preferred when PET is not available or when geographic location, symptoms, or imaging characteristics suggest a high likelihood of active infection or inflammation. For peripheral lesions, CT-guided transthoracic biopsy is usually preferred, but newer, advanced bronchoscopic techniques, such as electromagnetic navigation-guided biopsy and radial probe endobronchial ultrasound, can also be applied in centers with experience. More centrally located nodules are sometimes accessible by conventional bronchoscopy, especially if there is an airway leading to the lesion (Gould et al., 2007).

Are you sure your patient has non-small-cell lung cancer? What should you expect to find?

Please see the chapter, "Lung Cancer: General Considerations."

Beware: there are other diseases that can mimic non-small-cell lung cancer:

Please see the chapter, "Lung Cancer: General Considerations."

How and/or why did the patient develop non-small-cell lung cancer?

Please see the chapter, "Lung Cancer: General Considerations."

Which individuals are of greatest risk of developing non-small-cell lung cancer?

Please see the chapter, "Lung Cancer: General Considerations."

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

All patients with suspected or confirmed NSCLC should have a complete blood count and complete metabolic panel. The presence of anemia, liver function abnormalities, or hypercalcemia raises the suspicion for metastatic disease. Abnormal liver function tests are usually accompanied by the presence of gross hepatic involvement on CT. Hypercalcemia is usually due to paraneoplastic production of a parathyroid hormone-like substance by squamous cell carcinomas, but this finding can also be explained by bone metastasis, so it should be evaluated by bone imaging and confirmatory biopsy. When there is overwhelming evidence of metastasis on hepatic or bone imaging, histopathological confirmation is not mandatory, but patients with isolated or oligometastasis should undergo confirmatory biopsy.

What imaging studies will be helpful in making or excluding the diagnosis of non-small-cell lung cancer?

Non-invasive imaging studies that are commonly used for lung cancer staging include CT, PET, brain imaging with CT or MRI, and bone imaging with plain x-rays, CT or PET.

Chest CT

Chest CT is used to assign a preliminary stage in most patients with known or suspected NSCLC, and subsequent staging evaluation is guided by the CT results. For mediastinal staging, CT uses lymph node size as a proxy for metastatic involvement; a cut-point of 1 cm in short-axis diameter is usually applied to define abnormal lymph node enlargement. CT has limited sensitivity and specificity for identifying mediastinal metastasis because enlarged lymph nodes can be reactive and non-enlarged lymph nodes can harbor foci of metastasis. In a systematic review of forty-three studies of diagnostic accuracy, the sensitivity and specificity of CT for identifying mediastinal metastasis were 51percent (95% CI 47-54%) and 86 percent (95% CI 84-88%), respectively (Silvestri et al., 2007).

CT is also imperfect for identifying extrathoracic metastatic disease, although some findings are highly specific, such as multiple areas of low attenuation in the liver and multiple lytic bone lesions.

PET and PET/CT

PET is a functional imaging test that uses hypermetabolism as a proxy for tumor involvement. PET imaging makes use of a radio-labled glucose analog (fluorodeoxyglucose or FDG), which is selectively taken up by and subsequently trapped in metabolically active cells. False negative findings can be seen in small tumors and in those that are metabolically indolent, such as some bronchalveolar carcinomas and carcinoid tumors. False positive findings can be seen in virtually any infectious or inflammatory condition, some of which may co-exist with bronchogenic carcinoma. In a systematic review of forty-four studies of diagnostic accuracy, the sensitivity and specificity of PET for identifying mediastinal metastasis were 74 percent (95% CI 69-79%) and 85 percent (95% CI 82-88%), respectively (Silvestri et al., 2007).

In many clinical settings in the U.S., integrated PET/CT has largely replaced dedicated PET imaging. ET/CT is probably more accurate than dedicated PET in identifying metastasis, and it enables more precise localization of even minor hypermetabolic foci (Lardinois et al., 2003).

Whole-body PET identifies occult metastasis in up to 8 percent of patients with clinical (CT) stage 1 NSCLC and up to 20 percent of patients with stage II disease. In one study of 102 patients with potentially resectable NSCLC, the sensitivity and specificity of PET for identifying distant metastasis were 82 percent (95% CI 64-100%) and 93 percent (95% CI, 88-98%) (Pieterman et al., 2000).

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of non-small-cell lung cancer?

The peri-operative evaluation of patients with potentially resectable NSCLC should include pulmonary function testing. Most patients in whom the percent predicted post-operative FEV-1 and diffusing capacity (DLCO) are greater than 40 will be eligible for resection. In borderline cases, quantitative perfusion lung scanning and/or cardiopulmonary exercise testing may be indicated. Patients with limited pulmonary reserve who are unable to tolerate lobectomy may be candidates for sub-lobar resection.

Pre-operative non-invasive cardiac evaluation should be reserved for patients with major cardiovascular risk factors, including those with unstable angina, decompensated heart failure, uncontrolled dysrhythmias or conduction disturbances, or severe valve disease.

What diagnostic procedures will be helpful in making or excluding the diagnosis of non-small-cell lung cancer?

Invasive staging is crucial in order to exclude mediastinal metastasis in patients with potentially resectable NSCLC. Invasive staging can be performed by using surgical or minimally invasive methods. Surgical methods include cervical mediastinoscopy, anterior mediastinoscopy, and video-assisted thoracoscopic surgery (VATS), while minimally-invasive staging methods include bronchoscopic "blind" TBNA, EBUS-guided TBNA, and EUS-guided FNA.

Cervical mediastinoscopy and anterior mediastinotomy

As summarized in Table 3, cervical mediastinoscopy provides access to mediastinal stations 1, 2, 4, and 7, although posterior subcarinal (station 7) nodes may be difficult or impossible to approach. The sensitivity of video-assisted mediastinoscopy for identifying lymph node metastasis may be as high as 90 percent (Detterbeck et al., 2007).

Anterior mediastinoscopy is useful in approaching the lymph nodes at stations 5 and 6 that are commonly involved in patients with left upper lobe tumors and that are difficult or impossible to access via other methods. When performed, anterior mediastinoscopy is commonly accompanied by cervical mediastinoscopy, and the reported sensitivity of the combined procedure for identifying metastasis is 87 percent (Detterbeck et al., 2007). Surgical staging can also be performed by VATS, which enables sampling of ipsilateral, but not contralateral, lymph nodes.

Minimally-invasive staging methods: TBNA

A meta-analysis of thirteen studies of diagnostic accuracy reported that the sensitivity of blind TBNA was directly correlated with the prevalence (and perhaps the extent) of mediastinal metastasis. Pooled sensitivity was 40 percent in low-prevalence studies, compared with 84 percent in studies that reported a high prevalence of metastasis (Holty et al., 2005). Subcarinal lymph nodes are easiest to approach by blind TBNA, but skilled operators can also sample high and low paratracheal lymph nodes.

Minimally invasive staging methods: EBUS-TBNA

Endobronchial ultrasound (EBUS)-guided TBNA, which is more sensitive than blind TBNA, facilitates sampling of mediastinal, hilar, and intrapulmonary lymph nodes that are adjacent to the tracheobronchial tree (stations 1, 2, 4, 7, 10, and 11) (Table 1). EBUS-guided TBNA uses a 7.5 MHz linear (or convex) ultrasound probe to perform biopsy under real-time guidance. In a review of twelve studies of diagnostic accuracy, the pooled sensitivity was 93 percent (Gomez and Silvestri, 2009).

In most studies, the prevalence of metastasis was high, suggesting that many of these patients probably had bulky adenopathy. Nevertheless, two studies from a group with extensive experience in the technique reported high sensitivity even in lower-prevalence populations with non-enlarged or PET-negative lymph nodes (Herth et al., 2006; Herth et al., 2008).

Minimally invasive staging methods: EUS-FNA

Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is useful in sampling lymph nodes that are adjacent to the esophagus, including those at stations 2, 4, 5, 7, 8, and 9 ( Table 1). While lymph nodes at stations 8 and 9 are less commonly involved than are nodes at other stations, they are accessible only by EUS-FNA or VATS.

Minimally invasive staging methods: combined EBUS-TBNA and EUS-FNA

In a study of 138 consecutive patients with known or suspected lung cancer and no proven extrathoracic metastasis, all patients underwent, in sequence, blind TBNA, EBUS-TBNA, and EUS-FNA under conscious sedation (Wallace et al., 2008). Reported sensitivities for identifying metastasis were 36 percent (95% CI 22-52%) for blind TBNA, 69 percent (95% CI 53-82%) for EBUS-TBNA, 69 percent (95% CI 53-82%) for EUS-FNA, and 93 percent (95% CI 81-99%) for the combination of EBUS-TBNA and EUS-FNA. Therefore, the combination of EBUS-TBNA and EUS-FNA appears to be highly sensitive for invasive staging, and it can probably replace cervical mediastinoscopy if it is performed by experienced practitioners.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of non-small-cell lung cancer?

Molecular markers that predict survival and treatment response have been identified. Mutations in the epidermal growth factor receptor (EGFR) are particularly common in non-smokers, Asians, and women with adenocarcinoma. Overall, these mutations are associated with a more favorable prognosis. More importantly, among patients with advanced-stage adenocarcinoma, several studies have reported an association between the presence of an EGFR mutation and a more favorable response to first-line treatment with tyrosine kinase inhibitors.

Another relatively common marker, KRAS, is more common in non-Asians and smokers than in others and is associated with resistance to therapy with tyrosine kinase inhibitors. As we learn more about the molecular diversity of lung cancer, molecular staging and diagnosis will play an increasingly large role in the management of patients with NSCLC. Recently, an international expert panel recommended molecular testing for EGFR mutations in all patients with advanced adenocarcinoma (Travis et al., 2011).

If you decide the patient has non-small-cell lung cancer, how should the patient be managed?

Please see the chapter, "Lung Cancer: General Considerations."

What is the prognosis for patients managed in the recommended ways?

Please see the chapter, "Lung Cancer: General Considerations."

What other considerations exist for patients with non-small-cell lung cancer?

Please see the chapter, "Lung Cancer: General Considerations."

What’s the evidence?

Detterbeck, FC, Jantz, MA, Wallace, M, Vansteenkiste, J, Silvestri, GA. "Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition).". Chest. vol. 132. 2007. pp. 202S-220S.

Guidelines for lung cancer staging from the American College of Chest Physicians.

Fischer, B, Lassen, U, Mortensen, J, Larsen, S, Loft, A, Bertelsen, A. "Preoperative staging of lung cancer with combined PET-CT.". N Engl J Med. vol. 364. 2011. pp. 982-9.

Randomized trial showed that, compared with conventional staging, the use of PET-CT reduced the frequency of futile thoracotomy among patients referred for preoperative staging.

Goldstraw, P, Crowley, J, Chansky, K, Giroux, DJ, Groome, PA, Rami-Porta, R. "International Association for the Study of Lung Cancer International Staging Committee, participating institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours.". J Thorac Oncol. vol. 2. 2007. pp. 985-14.

Describes a new, rigorously developed and validated system for lung cancer staging.

Gomez, M, Silvestri, GA. "Endobronchial ultrasound for the diagnosis and staging of lung cancer". Proc Am Thorac Soc. vol. 6. 2009. pp. 180-6.

Review article that summarizes results of studies of endobronchial ultrasound-guided biopsy for lymph node staging.

Gould, MK, Sanders, GD, Barnett, PG, Rydzak, CE, Maclean, CC, McClellan, MB. "Cost-effectiveness of alternative management strategies for patients with solitary pulmonary nodules.". Ann Intern Med . vol. 138. 2003. pp. 724-736.

Cost-effectiveness analysis that compares strategies for pulmonary nodule evaluation and management.

Gould, MK, Fletcher, J, Iannettoni, M, Lynch, W, Naidich, D, Midthun, D. "Evaluation of patients with pulmonary nodules: when is it lung cancer? ACCP evidence-based clinical practice guideline (2nd edition).". Chest. vol. 132. 2007. pp. 108S-130S.

Guidelines for pulmonary nodule management from the American College of Chest Physicians.

Gould, MK, Wiener, RS. "Shared decision making in patients with pulmonary nodules. PCCSU: Pulmonary, Critical Care, Sleep Update". Available at: http://www.chestnet.org/accp/pccsu. vol. 23. 2009.

Review article summarizes options for managing patients with lung nodules.

Herth, FJ, Ernst, A, Eberhardt, R, Vilmann, P, Dienemann, H, Krasnik, M. "Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically normal mediastinum.". Eur Respir J. 2006. pp. 910-14.

Herth, FJ, Eberhardt, R, Krasnik, M, Ernst, A. "Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically and positron emission tomography-normal mediastinum in patients with lung cancer". Chest. vol. 13. 2008. pp. 887-91.

Two studies demonstrating that, in expert hands, EBUS-TBNA is highly sensitive for identifying mediastinal metastasis even when lymph nodes are not enlarged or hypermetabolic.

Holty, JC, Kuschner, WK, Gould, MK. "Accuracy of transbronchial needle aspiration in the staging of non-small cell lung cancer: a meta-analysis". Thorax. vol. 60. 2005. pp. 949-955.

Systematic review of studies of bronchoscopic (blind) TBNA that highlights limited sensitivity in populations with a low prevalence of nodal metastasis.

Lardinois, D, Weder, W, Hany, TF, Kamel, EM, Korom, S, Seifert, B. "Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography.". N Engl J Med . vol. 348. 2003. pp. 2500-7.

Small, prospective study of diagnostic accuracy showed that staging with PET-CT was more accurate than CT alone, PET alone, or visual correlation of PET and CT.

Maziak, DE, Darling, GE, Inculet, RI, Gulenchyn, KY, Driedger, AA, Ung, YC. "Positron emission tomography in staging early lung cancer: a randomized trial.". Ann Intern Med. vol. 151. 2009. pp. 221-8,W-48..

Randomized trial showed that, compared with CT and bone scintography, staging with PET-CT reduced the frequency of futile thoracotomy among patients with stage I-IIIA NSCLC.

Pieterman, RM, van Putten, JW, Meuzelaar, JJ, Mooyaart, EL, Vaalburg, W, Koeter, GH. "Preoperative staging of non-small-cell lung cancer with positron-emission tomography.". N Engl J Med . vol. 343. 2000. pp. 254-61.

Prospective study of the accuracy of PET for mediastinal and distant staging in patients with NSCLC.

Pignon, JP, Tribodet, H, Scagliotti, GV, Douillard, JY, Shepherd, FA, Stephens, RJ. "LACE Collaborative Group. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group.". J Clin Oncol. vol. 26. 2008. pp. 3552-9.

Meta-analysis using individual patient data demonstrated benefits of adjuvant chemotherapy following resection in patients with stage II-III NSCLC.

Rivera, MP, Mehta, AC. "Initial diagnosis of lung cancer: ACCP evidence-based clinical practice guideline (2nd edition).". Chest. vol. 132. 2007. pp. 131S-148S.

Guidelines for lung cancer diagnosis from the American College of Chest Physicians.

Rusch, VW, Crowley, J, Giroux, DJ, Goldstraw, P, Im, JG, Tsuboi, M. "International Staging Committee, Cancer Research and Biostatistics, Observers to the Committee, participating institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer.". J Thorac Oncol. vol. 2. 2007. pp. 603-12.

Paper describes the most recent iteration of a harmonized system for mapping thoracic lymph node stations.

Silvestri, GA, Gould, MK, Margolis, ML, Tanoue, LT, McCrory, D, Detterbeck, F. "The non-invasive staging of non-small cell lung cancer: ACCP evidence-based clinical practice guideline (2nd edition).". Chest. vol. 132. 2007. pp. 178S-201S.

Guidelines for use of non-invasive tests in the staging of NSCLC from the American College of Chest Physicians.

Swensen, SJ, Silverstein, MD, Ilstrup, DM, Schleck, CD, Edell, ES. "The probability of malignancy in solitary pulmonary nodules: application to small radiologically indeterminate nodules". Arch Intern Med. vol. 157. 1997. pp. 849-55.

Rigorously developed and validated model that estimates the clinical probability of malignancy in radiographically detected lung nodules measuring 4 to 30 mm in diameter. Independent predictors of malignancy included older age, smoking, prior history of extrathoracic cancer, larger nodule diameter, spiculated margins and upper lobe location.

Travis, WD, Brambilla, E, Noguchi, M, Nicholson, AG, Geisinger, K, Yatabe, Y. "International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma.". Journal J Thorac Oncol . vol. 6. 2011. pp. 244-285.

Official statement that describes clinical, radiolological, histopathological and molecular features of pulmonary adenocarcinoma.

van Tinteren, H, Hoekstra, OS, Smit, EF, van den Bergh, JH, Schreurs, AJM, Stallaert, RALM. "Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial.". Lancet . vol. 359. 2002. pp. 1388-93.

Randomized trial showed that compared with conventional staging, the addition of PET reduced the frequency of futile thoracotomy among patients with potentially resectable NSCLC.

Wallace, MB, Pascual, JM, Raimondo, M, Woodward, TA, McComb, BL, Crook, JE. "Minimally invasive endoscopic staging of suspected lung cancer.". JAMA . vol. 299. 2008. pp. 540-6.

Prospective comparison of transbronchial needle aspiration (TBNA), endobronchial ultrasound (EBUS)-guided TBNA and endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) for lymph node staging demonstrated that combined EBUS-TBNA and EUS-FNA had excellent sensitivity in identifying mediastinal metastasis.
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