TUMOR-NODE-METASTASIS AND STAGE GROUPINGS

The original tumor-node-metastasis (TNM) descriptors for lung cancer are listed in Table 1-1 . The original staging system for lung cancer was developed by Dr. Clifton Mountain using the M.D. Anderson Cancer Center database and by Dr. Naruke from Japan, with a combined institutional experience of nearly 5000 patients. This staging system divided lung cancer into clinical and pathologic stages. Five stages of lung cancer were defined, with four T descriptors and four N descriptors, resulting in 16 subgroupings, as follows: stage I (T1N0 and T2N0), stage II (T1N1 and T2N1), stage IIIA (any T3 or any N2: T3N0, T3N1, T3N2, T1N2, and T2N2), stage IIIB (any T4 and any N3: T4N0, T4N1, T4N2, T4N3, T1N3, T2N3, T3N3), and stage IV (any T plus any N, with M1 disease). As required for all staging systems, a reassessment was performed 10 years after the original implementation. The resulting minor refinements and modifications, published in 1997, included the following:

• 1.
  

  Stage I and stage II were divided into two subcategories, IA and IB and IIA and IIB, in recognition of the effect of the size of the tumor (T1 or T2) on survival.

  
  
• 2.
  

  T3N0 was moved into a IIB category, based on the favorable survival statistics of these patients compared with other patients in the IIIA category.

  
  
• 3.
  

  A satellite lesion in the same lobe, which previously moved up the T descriptor by one grouping, was now considered to represent T4 disease.

Now at the second-decade mark, the International Association for the Study of Lung Cancer (IASLC) has revised the system for a second time, based on long-term data for more than 100,000 patients. This revision further refines and permits better prognostication for patients with lung cancer and allows a more accurate comparison between patients in clinical trial outcomes and enrollments. A summary of the changes proposed in the IASLC system, to be adopted in 2009, follows:

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  T1 (3 cm or less in greatest dimension) tumors will be further subclassified into T1a (2 cm or less) and T1b (larger than 2 cm up to 3 cm).

  
  
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  T2 tumors will be subclassified into T2a (larger than 3 to 5 cm in greatest dimension) and T2b (larger than 5 to 7 cm).

  
  
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  T2 tumors greater than 7 cm will be reclassified as T3.

  
  
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  Satellite T4 nodules in the same lobe will be reclassified as T3.

  
  
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  Nodules in an ipsilateral lung will be down-classified from M1 disease to T4 disease.

  
  
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  Pleural effusions, which have always been classified as T4, will be up-classified to M1a.

  
  
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  M disease will be subclassified into M1a and M1b, with M1a denoting nodules in the contralateral lung, pleural nodules, or malignant pleural or pericardial effusions.

  
  
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  M1b will designate distant metastases.

No changes in the nodal descriptors have been implemented between the three versions of the classification system. However, a new anatomic nodule map is prepared to clarify differences between the current Asian and Western nomenclatures with groupings of nodes into zones.

The staging of small cell carcinoma of the lung previously used a dichotomous staging system of limited versus extensive disease, with limited defined as that confined to the chest and extensive as presence of extrathoracic disease. The stage groupings for non-small cell lung cancer seem to work reasonably well for small cell carcinoma and will be adopted as a more universal staging system.

SURGICAL GUIDELINES

As a general rule, surgery is always indicated for stage I and stage II disease, provided that the patient has sufficient cardiopulmonary reserve to tolerate the resection. Patients with T3N0 and T4N0 lesions are still evaluated for potential curative intent (i.e., for feasibility of R0 resection); however, extended resection of more than just the lung tissue is required for these T3 and T4 tumors. Such tumors can involve chest wall, diaphragm, pericardium, mediastinal vascular structures, carina, vertebral body, and even the heart itself. The surgical morbidity and perioperative mortality will be increased, but the risks and benefits must be weighed and individualized for each patient on the basis of the tumor’s anatomic characteristics and the patient’s comorbidities.

Nodal disease must be evaluated separately and is a major factor in the final surgical equation. Surgeons work backwards to try to rule out N3 and then N2 disease, to identify patients as candidates for surgery after involvement of mediastinal nodes has been ruled out. Patients with N1 and N0 disease, regardless of their T status, are considered to be potential surgical candidates.

Patients with proven N3 disease (supraclavicular or contralateral mediastinal nodal disease) are not surgical candidates. Patients with N2 disease (involvement of ipsilateral mediastinal nodes) have very poor results with surgery alone. This category represents the most complex gray area in decision making regarding treatment for lung cancer. N2 disease is quite heterogeneous and can range in extent from microscopic disease encapsulated in a single node at a solitary nodal station to advanced bulky N2 multistation disease with extracapsular spread. Neoadjuvant chemotherapy followed by surgery may be of benefit in very limited disease, as in the former instance, but has no role to play in the latter instance. The patient with bulky disease or extracapsular spread is treated with definitive chemotherapy combined with radiation therapy given either sequentially or concurrently as indicated by the patient’s medical condition and age. The patient with N2 disease that is not recognized preoperatively and is discovered on the final pathology review requires adjuvant treatment in the postoperative setting.

N1 disease is less frequently diagnosed radiographically preoperatively. Recent advances in endoscopic bronchial ultrasound imaging permit sampling of nodes contained within the hilum. N0 disease is diagnosed by exclusion. Patients with N1 and N0 disease are considered to be potential candidates for R0 resections.

STAGING PHASE I: CLINICAL ASSESSMENT AND DIAGNOSTIC TESTING

Despite significant advances in radiographic imaging, including the use of PET scanning, the clinical evaluation by the surgeon remains crucial in the ultimate selection of patients who will benefit from surgery. The initial history and review of systems must focus on symptoms of potentially locally advanced or systemic disease. Asymptomatic patients in whom the tumor is discovered on routine imaging usually for unrelated problems often have the best chance of having localized disease. The vast majority of patients, however, present with signs and symptoms usually related to more locally advanced or metastatic disease. Paraneoplastic presentations, including Eaton-Lambert syndrome and hypertrophic pulmonary osteoarthropathy, may mimic systemic disease but can be reversed with resection of the primary localized tumor.

Presence of cough, often dry and nonproductive, can signify an endobronchial lesion—possible in a lobar airway (T2) or the main bronchial airway within 2 cm of the carina (T3), or involving the carina or trachea proper (T4). In addition, stimulation of the cough receptors that surround the trachea or the bronchial tree by either the primary tumor or involved lymph nodes can induce coughing. Fever with a cough implies a proximal airway obstruction and distal pneumonitis. The obstruction can result from intrinsic airway involvement or extrinsic compression.

Tumors that extend to the pain sensitive parietal pleura (T3) can manifest with pleuritic chest pain, a pleural rub, or constant discomfort. Extension of tumors into the chest wall proper (also T3 disease) usually are associated with greater discomfort that typically is constant and not easily relieved by any movement or shift in body position, including sitting and standing. The location of pain often is classic in superior sulcus tumors—interscapular pain with radiation down the medial aspect of the arm with the involvement of the intercostal brachial nerve. Extension into the spine (T4 disease) can result in pain that may be aggravated by axial loading with weight bearing as the integrity and support of the spine are progressively destroyed by the tumor. Destruction of the vertebral body can result in its collapse with retropulsion of the bone into the spinal canal, with worsening neurologic symptoms (gait disturbance, bowel and bladder dysfunction) from direct compression of the spinal cord within the dural sac. Extension into the neural foramen can have a similar effect with spinal cord compression.

The mediastinal extension of tumors can cause a variety of signs and symptoms. Voice hoarseness is an extremely important symptom and often signifies unresectable disease. This can occur either from direct involvement of the tumor or with nodal disease. With left-sided lesions, the recurrent nerve typically is involved in the aortopulmonary window from station #5 lymph nodes or tumor extension beneath the aortic arch. Demonstration of left vocal cord paralysis by means of simple indirect laryngoscopy is all that is required to confirm advanced disease, unlikely to be helped by surgery. On the right, the recurrent nerve comes off on a more oblique angle as the vagus nerve passes over the right subclavian artery and “recurs” where the innominate artery divides into the right carotid and right subclavian arteries. Such involvement can occur with high, medially positioned right upper lobe lung tumors or high paratracheal nodal disease.

Involvement of mediastinal structures is defined as T4 disease in describing the primary tumor with its direct involvement. Structures that can be involved include the superior vena cava, often manifesting with signs and symptoms of superior vena cava syndrome. This presentation can be subtle in the beginning, with some blurring of vision, early-morning facial edema, headaches, and prominence of some veins on the neck or chest.

The pericardium (T3) can be resected en bloc with a tumor, but direct involvement of the heart (T4) is a more advanced presentation. In such cases, the patient can present with a dysrhythmia or signs of a pericardial effusion and tamponade. The aorta can be invaded, in which case usually severe localized pain from nerve fibers in the aortic adventitia will help to make the diagnosis. Although imaging studies often cannot clearly delineate aortic wall involvement, the presence of severe pain (either anterior or posterior in the interscapular region) is a very strong indicator of locally advanced disease beyond the confines of the lung. Other mediastinal structures include the trachea and the esophagus. A cough immediately after swallowing liquids usually indicates a tracheoesophageal fistula—an example of an advanced lesion usually treated with palliative intent only.

Evidence of metastatic disease must be detected by a detailed and focused review of signs and symptoms. Recent onset of a headache, a new hip or back pain, unexplained weight loss, and anorexia are all important clinical features that warrant further investigation. Paraneoplastic presentations are often seen and must be separated from mechanical symptoms from metastatic disease.

The physical examination can be quite helpful. Palpation of the supraclavicular fossa for nodal disease is the single most important aspect of the physical examination for staging. Small firm nodes—which often are too small to be picked up by PET imaging and would be too small to exceed the 1-cm threshold for the radiologist to comment on a computed tomography (CT) scan—are best discovered on physical examination by an experienced clinician. Auscultatory findings of a localized wheeze or stridor often indicate advanced disease. Diminished breath sounds can mean proximal obstruction or a pleural effusion. Shift of the trachea can mean either lobar or total volume loss on the affected side. An irregular cardiac rhythm or distended neck veins can indicate pericardial involvement with tamponade. Distended collateral veins on the chest or engorgement of neck veins may indicate a superior vena cava obstruction. Pain on percussion of the thoracic or lumbar spine or pain with movement of the hip may signify localized metastatic disease involving bones. The neurologic findings of a Horner’s syndrome may signify involvement of the thoracic sympathetic plexus with secondary lid droop and meiosis.

Brain metastases can manifest in myriad ways, depending on the location of the metastatic lesion or lesions. In a patient without neurologic signs or symptoms, however, MRI has less than a 5% chance of finding an occult metastatic lesion.

Physiologic testing of the patient often can be done in the clinic. In general, a patient who can climb a flight of stairs can tolerate a lobectomy. The ability to climb two flights is required for a pneumonectomy. Although these are relatively crude measures of exercise performance, they have stood up well over the past 50 years or so to even more sophisticated exercise testing, including exercise oxygen consumption testing. Pulmonary function tests include spirometry and diffusion capacity testing; nuclear xenon split perfusion and ventilation function tests are used when spirometry demonstrates a forced expiratory volume in 1 second (FEV ₁ ) below 70%. Such testing permits calculation of a predicted postoperative FEV ₁ . A minimum of 33% of predicted based on the patient’s age and height has served well as the lower limit of postoperative function, to avoid rendering the patient a respiratory cripple from the resection. Exercise oxygen consumption testing is performed when the predicted FEV ₁ is less than 40%. Remarkably, some patients with good cardiac function and good peripheral muscle utilization of oxygen can tolerate a resection with marginal pulmonary function.

Cardiac workup often is performed in patients with a history of cardiac disease, stent placement, or cardiac valvular or coronary bypass operations. The physiologic demands from a pulmonary resection on the patient are greater than those from a routine open heart procedure. As a result, the perioperative mortality after lung surgery is greater than after cardiac surgery. After cardiac surgery, the mechanical cardiac defects are usually corrected, so the patient should be in better functional status postoperatively than preoperatively. When a cancer operation is performed, however, the tumor and otherwise normal-functioning lung must be removed. As a result, the patient will have less physiologic reserve postoperatively than preoperatively. Again, this observation emphasizes the importance of accurate preoperative staging, to limit surgery to those who will be benefited.

Patients should abstain from cigarette smoking for a minimum of 2 to 3 weeks before an operation is performed, to improve their mucociliary clearance in the postoperative setting, thereby avoiding the cascading complications of sputum retention, airway occlusion, atelectasis, and pneumonia. Several weeks are required, because an immediate reactive bronchorrhea results from the immediate cessation of smoking.

The appropriate radiologic tests for a patient with lung cancer include a standard chest radiograph, a CT scan of the chest including the upper abdomen (to look for adrenal metastases), and a brain MRI study if the patient has relevant symptoms or the primary tumor is large or central or is associated with nodal disease. Positron emission tomography (PET) scans or integrated CT-PET scans, when available, have become routine in the evaluation of all patients with lung cancer. A focused radiographic examination is done to evaluate any suspicious area identified by PET scanning. Similarly, any new bone-related symptom in a patient necessitates spot films of the region to help differentiate between degenerative bone lesions and metastatic disease.