Revised 6 July 2012
Diagnostic Evaluation of Patients with Non-small Cell Lung Cancer
A variety of tools assist in the diagnostic evaluation of patients with lung cancer. These tools, when used in conjunction with the history, physical examination and chemistry panel, help determine the patient's cancer stage, prognosis and treatment options according to stage. Aside from a general history and physical it is useful to question regarding overall respiratory function and exercise tolerance, symptoms related to local tumour spread (dysphagia, hoarseness, shortness of breath, facial swelling) and systemic symptoms or symptoms suggestive of paraneoplastic syndromes.
Diagnostic Imaging
Chest x-rays alone are inadequate for staging although they provide initial information on the presence of lung mass and temporal changes in size.
Computed tomography (CT) of the mediastinum with infusion of contrast material is recommended to stage locoregional disease. The CT scan should extend inferiorly to include the liver and the adrenal glands. CT scans are used to characterize the primary tumour. CT scans detect enlarged nodes but have inadequate sensitivity and specificity and thus should be supplemented by mediastinoscopy. A major role of CT is to aid in decisions regarding respectability and to detect synchronous/metastatic cancers that are not visible on the chest radiograph.
Magnetic Resonance Imaging (MRI) is not superior to CT scans for staging of mediastinal nodes but may be of value in selected cases (Pancoast tumours) for assessment of the operability of the primary tumour.
Positron emission tomography (PET) scanning is a newer technology that is not widely available throughout B.C. PET does not aid in accurate staging for T stage. PET is more sensitive and specific then CT in radiologic detection of malignant lymph nodes yet there is still a high false positive rate and there are multiple benign reasons that lymph nodes may be PET positive. As a result PET may not be considered definitive proof of a positive lymph node and definitive biopsy would be recommended. The role of PET in the routine staging of lung cancer has not been established but preliminary reports indicate that it may be useful in selected cases. In B.C. current indications for PET include:
- Staging of patients with clinical stage I and IIA lesions being treated with curative intent.
- Staging of potentially resectable stage IIB and III disease.
- To aid in planning of radical radiotherapy.
- Staging prior to resection of solitary lung metastases.
NOTE: No definite indications exist for bronchial carcinoid or small cell lung cancer.
Mediastinoscopy
For patients with clinically operable NSCLC, biopsy is recommended of mediastinal lymph nodes found on chest CT scan to be greater than 1.0 cm in shortest transverse axis.
Mediastinoscopic evidence of metastases to N3 lymph nodes indicates inoperability (Stage IIIB). Mediastinoscopic evidence of metastases to N2 position nodes also represents inoperability in the majority of circumstances. However it is among this group of patients that the surgeon may identify selected ipsilateral nodal metastases that may be suitable for combined modality therapy possibly including resection (see section 6).
Clinical Considerations
Ipsilateral vocal cord paralysis generally indicates dysfunction of the recurrent laryngeal nerve by pressure or involvement by tumour involving mediastinal nodes; this is a criterion of in-operability.
Similarly, Horner's Syndrome, phrenic nerve palsy and neurologic deficits associated with Pancoast's superior sulcus tumours usually indicate inoperable disease
Splaying of the tracheal carina may indicate subcarinal involvement and contralateral subcarinal node metastases are evidence of in-operability and should be confirmed by needle biopsy or mediastinoscopy.
Assessment of Pleural Effusions
If a pleural effusion is present, all efforts must be made to determine whether it is malignant or benign. Useful investigations include pleural fluid cytology, pleural biopsy, and thoracoscopy. A benign effusion has no independent significance in staging, whereas a malignant effusion indicates T4 status and in-operability (see footnotes to staging classification criteria).
The most common extrathoracic metastatic sites for lung cancer are supraclavicular lymph nodes, brain, bone, adrenals and liver. History and physical examination should focus on these sites. A search for metastatic disease in an asymptomatic patient with advanced NSCLC should be based on the evidence outlined below, with the understanding that the likelihood of finding metastasis increases with increasing T and N status, particularly in patients with non-squamous pathological subtypes.
Serum Chemistry
Initial serum chemistry should routinely include serum calcium and serum albumin. Anorexia, nausea and vomiting and other gastrointestinal symptoms suggest hypercalcemia. Alkaline phosphatase, LDH and SGOT help to assess liver function and possible presence of liver metastases and bone metastases. CEA, if elevated, is a useful tumour marker for assessment of treatment for patients with index lesions that are difficult to evaluate (e.g. bone metastases).
Brain Metastases
There is a very high incidence of detectable metastases in patients with specific neurologic complaints (focal seizures, focal weakness) and CT confirmation is advised in such patients. There is a twenty-five to thirty percent incidence of detectable metastases in patients with non-specific neurologic complaints (headache, personality change, dementia). Asymptomatic patients with bulky primary or extensive nodal involvement with non-squamous carcinomas have a 0% to 10% probability of brain metastases.
CT brain screening is not recommended for asymptomatic patients receiving treatment with palliative intent but such assessment should be considered in locally advanced cases where radical curative intent therapy is planned.
CT scanning with infusion of contrast material is the routine assessment in suspect cases. MRI is more sensitive than CT scanning, and should be considered in cases where suspicion persists after a normal or equivocal CT scan. MRI may also be useful to delineate if there is a solitary lesion or multiple lesions which may affect surgical and radiation planning.
Bone Metastases
Bone scans are not recommended unless the patient has bone pain, chest pain or elevation of serum calcium and/or alkaline phosphatase. Clinical correlation with trauma and arthritis is necessary.
Adrenal Metastases
The adrenal glands are abnormal by CT scan in ten percent of patients with lung cancer. It is technically easy and cost effective to include the adrenal glands routinely in the chest CT scan and this procedure is recommended. The finding of an isolated adrenal mass on ultrasonographic or CT examination requires biopsy to rule out metastatic disease if the patient is otherwise considered to be potentially resectable. PET scanning may be useful in select circumstances.
Liver
It is not common for the liver to harbour detectable metastases in the absence of liver enzyme abnormalities. Nevertheless, as is the case for the adrenal glands, the extended chest CT scan and ultrasound can accurately assess the liver. Malignancy should be confirmed in an isolated hepatic mass if the patient is otherwise considered to be potentially resectable.
Pulmonary Function Evaluation
The general fitness of the patient is important since a relatively fit young patient may have a good post-treatment exercise tolerance despite poor lung function. Patients with chronic obstructive lung disease and consequent reduced pulmonary function tests will have more postoperative complications with greater need for pulmonary ventilation. Pulmonary function can improve after poorly ventilated or perfused lung is removed.
The measurement of preoperative lung function is intended to predict the patient's post-treatment pulmonary status. Spirometric examination and arterial blood gases while the patient breathes room air are minimum investigations for proper planning.
Key References:
1. Silvestri, GA, Gould, MK, Margolis, ML, et al. Noninvasive Staging of Non-small Cell Lung Cancer: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition). Chest 2007: 132:178S.
2. Vansteenkiste JF, Stroobants SS. PET scan in lung cancer: current recommendations and innovation. J Thorac Oncol. 2006;1(1):71.
3. Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. Adopted on May 16, 1997 by the American Society of Clinical Oncology. JCO. 1997 Aug;15(8):2996-3018.
Because the intent (curative versus palliative) and structure of treatment for SCLC is determined by the extent of disease, accurate and expedient staging is crucial.
Clinical Assessment
Small cell lung cancer is metastatic outside the chest in 60% of cases. Common sites of extrathoracic spread include the supraclavicular and cervical lymph nodes, liver, adrenals, bones, brain and subcutaneous sites. Careful history and physical examination are the most important staging procedures.
Assessment of Intrathoracic Disease
Chest radiograph and computed tomography (CT) of the mediastinum with infusion of contrast material is recommended to stage locoregional disease. The CT scan should extend inferiorly to include the liver and the adrenal glands.
Pleural effusions in SCLC are presumed to be malignant if they are readily visible on the routine chest radiograph. Pleural effusions seen on the CT scan but not evident on the chest radiograph are of uncertain significance and for treatment purposes, the patient should be considered to have limited stage disease. Although a definite effusion is technically evidence of extensive stage disease, if pleural effusion or pericardial effusion is the only site of metastatic spread, patients should be considered for early integrated chemoradiation if the pleural effusion readily responds to systemic chemotherapy.
Blood Tests
Initial blood work should include CBC, electrolytes, calcium, alkaline phosphatase, SGOT, LDH, serum albumin, BUN, and creatinine. Serum LDH is an independent prognostic factor in both limited and extensive stage SCLC. Approximately 5% of SCLC patients will present with hyponatremia secondary to inappropriate secretion of antidiuretic hormone. Hypercalcemia is uncommon with pure SCLC and should prompt careful review of pathology to exclude a non-small cell component. Ectopic secretion of ACTH is present in only 1-2% of cases and is usually associated with hypertension, hypernatremia and hypokalemia. CEA is elevated in about half of extensive stage SCLC patients and it may be useful to assess chemotherapy response in cases that do not have easily measurable lesions.
CNS Metastases
CT assessment of the brain should be routine for all patients with suspicious neurological
symptoms. CT screening of the brain is recommended for asymptomatic patients that are intended to receive integrated chemoradiation with curative intent. Brain scanning is not mandatory for asymptomatic patients that already have documented extensive stage disease that precludes treatment with curative intent.
Bone Metastases
Radionuclide bone scans are recommended for symptomatic patients and asymptomatic patients intended for combined modality therapy with curative intent. Clinical correlation with trauma and arthritis is necessary. An equivocal bone scan should not preclude combined modality therapy in a patient that otherwise has limited stage SCLC.
Bone marrow biopsy is no longer routinely performed as a staging procedure for small cell lung cancer. Bone marrow aspiration and biopsy is positive for tumour involvement in <5% of patients who have limited disease on all imaging procedures. Bone marrow biopsy may be considered for patients that have negative clinical assessment and staging procedures but extensive stage disease continues to be highly suspect because of poor performance status, weight loss, abnormal LDH or abnormalities of the CBC (anemia or leukoerythroblastic changes on the peripheral smear).
Liver and Adrenal
The CT scan used for assessment of thoracic disease should include the liver and adrenal glands. The finding of an isolated mass on ultrasonographic or CT examination requires biopsy to rule out metastatic disease if the patient is otherwise considered a candidate for combined modality therapy with curative intent. Ultrasound of the abdomen is accepted as an alternative to CT scanning for staging of the upper abdomen.
Pulmonary Function Evaluation
Patients receiving integrated chemotherapy and thoracic irradiation for limited stage small cell lung cancer must have adequate pulmonary reserve. As a rough generalisation, pulmonary function loss associated with thoracic irradiation for SCLC is similar to the loss from surgical lobectomy.
The measurement of lung function is intended to predict the patient's post-treatment pulmonary status. Spirometric examination and arterial blood gases should be obtained in all patients where adequate pulmonary reserve is uncertain. A FEV 1 of 0.8 to 1.0 litre is the minimum acceptable function for most patients after thoracic irradiation.
Key References:
Argiris A, Murren JR. Staging and clinical prognostic factors for small-cell lung cancer. Cancer J. 2001;7(5):437.
van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet. 2011 Nov 12;378(9804):1741-55. Epub 2011 May 10.
Richardson G, Venzon D, Phelps R, et al. Application of an algorithm for staging small cell lung cancer can save one third of the initial evaluation costs. Arch Intern Med 1993;153:329.
Shepherd FA. Screening, diagnosis and staging of lung cancer. Curr Opin Oncol 1993;5:310.
