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Approach to the solitary pulmonary nodule
G.A. Lillington, L.T. Vaszar
diagnosis, lung cancer, screening, nodule, lung
A solitary pulmonary nodule (SPN) is currently defined as a single parenchymal lung lesion which is 3 cm or less in diameter, and relatively spherical in contour. Some authorities consider that this definition does not apply if there are major surrounding or associated abnormalities on a standard chest radiograph. SPNs provide some of the more vexing clinical challenges facing a pulmonary practitioner. These lesions are common, as approximately 170,000 SPN are detected each year in the United States1. Approximately 1 in 500 standard chest radiographs in adults will show an SPN2 (GL).

Solitary pulmonary nodules are malignant, usually bronchogenic carcinomas, in 20-40% of cases3. Early resection of a malignant nodule improves the otherwise dismal prognosis of bronchogenic carcinoma2,3. In several reports, the 5-year survival has been as high as 75-80%4,5. Resection of a benign nodule however, rarely confers significant benefit to the patient, and carries its own likelihoods for mortality and morbidity.

MANAGEMENT GOALS

The goals are to resect all malignant SPNs promptly, and, at the same time, to avoid resection of benign nodules where possible. The criterion has always been, and still is, that an indeterminate nodule should be regarded as malignant unless proof of benignity can be obtained. Consequently, the most important practical question is how to differentiate benign from malignant (or probably) SPNs prior to surgery.

TESTING FOR BENIGNITY

Two criteria for benignity of SPNs were proposed in the 1950s: nodular calcification and retrospective stability6 These are useful and still employed, although it is now clear that some modifications of this dictum are required7,8.

Intranodular calcification may present a variety of appearances. Features indicative of benignity include central, diffuse, concentric rings or "popcorn" patterns. Patterns of eccentric calcification or multiple small concentric deposits can be benign or malignant (Figure 1), and in such cases, transthoracic needle biopsy or even diagnostic thoracotomy may still be indicated. Absence of calcification favors malignancy, but does not prove it. Even in a nodule with central calcification, malignancy is occasionally present9. With any apparently benign calcification pattern, it is prudent to monitor with serial x-rays or CT scans for several months or a year to detect growth, which might suggest malignancy.

Figure 1
Figure 1. Patterns of calcification in solitary pulmonary nodules. A, central; B, laminated; C, diffuse; D, popcorn; E, stippled, and F, eccentric. Patterns A through D are virtually always indicative of benignity. Pattenrs E and F may occur in benign or malignant nodules. (From Lillington GA: Systemic diagnostic approach to pulmonary noduls, in AP Fishman [ed]: Pulmonary Disease and Disorders [ed 2]. New York, McGraw-Hill, 1988, p 1947. Used by permission).

Retrospective stability implies little or no growth of the nodule, and is ordinarily assessed by comparison of any available prior chest x-rays with the current images. Stability has traditionally been defined as no detectable increase in nodule size during the previous 24 months or longer. This criterion is not always absolute, mainly because attempting to detect and monitor growth of small nodules using standard x-rays sometimes provides misleading results. In such instances, a small nodule may double or even triple in size before the increase in volume is recognized10. The accuracy of detecting growth is improved if the nodule is 1.0 cm or greater in diameter.

Prior computed tomographic (CT) scans, if available, are much more reliable in assessing retrospective stability than standard chest x-rays, particularly if the nodule is small (less than 10 mm in diameter). Retrograde assessment of nodule growth by comparing CT images with standard chest x-ray images may lead to serious errors10.

If the time interval between the first available and current images is less than 2 years, it is may be appropriate in many instances to continue the evaluation with CT scans at 3-6 month intervals.

BIOPSY TESTS

Transthoracic needle aspiration biopsy. This relatively simple and safe test can be very valuable, and is often decisive. The test has a 80 to 95% sensitivity for malignancy, and a specificity of approximately 50%11. The biopsy needle is positioned under fluoroscopic or CT guidance.

If the biopsy fails to establish that the nodule is malignant, there are two further possibilities. The biopsy material may provide convincing evidence for a specific benign lung disease, in which case the nodule is usually classified as "benign". If the biopsy material is not definitive for either malignant or benign disease, the classification is "indeterminate". In the latter situation, it is often desirable to repeat the biopsy. On-site technology for immediate sampling of the biopsy material facilitates repeat sampling in a single session and reduces the likelihood of "indeterminate" results12,13.

In the case of solitary nodules, an endobronchial biopsy through a bronchoscope has a relatively low sensitivity, unless the lesion is large in size and central in location. It is only employed occasionally in patients with SPNs.

IMAGING TESTS

Computed Tomography (CT). Chest CT is not able to definitively establish malignancy or benignity in most solitary nodules, but it will often provide information that is very helpful in estimating the likelihood of malignancy. CT is invaluable in determining whether the lesion is intrapulmonary, and provides much more accurate measurements of nodular diameters13. It may also demonstrate hitherto unsuspected multiple lesions in the lungs.

CT may prove or strongly suggest that the lesion is benign if the nodule is a hamartoma, a vascular lesion, or has a benign calcification pattern not apparent in the standard chest x-rays.

Features suggestive of malignancy include large size of the nodule, certain features of the nodule-lung interface (Figure 2), the absence of calcification, and demonstrable proof of growth of the nodule with serial x-rays or CT scan studies. CT is superior to standard chest roentgenograms in all of these respects, and also provides valuable information on the possible presence of enlarged mediastinal nodes.

 

Figure 2
Figure 2. Characteristic appearances of nodule edges. Type I is sharp and smooth and the probability of cancer based on this is 20%. Type 2 is sharp but lobulated, and the probability that the nodule is malignant is about 45%. Type 3 shows irregular undulations, and one or two spiculations. The likelihood of malignancy is 2:1 in this case. Type 4. There are multiple spiculations. This has been termed "corona radiata" or "corona maligna". The odds favoring malignancy are 14:1 in such cases. (Redraw from Siegelman SS, Khouri NF, Fishman EK, et al: Solitary pulmonary nodules: CT assessment. Radiology 1986; 160(8): 307-312, Used by permission).

 

Magnetic Resonance Imaging (MRI) is not useful for the detection or identifying malignancy in solitary nodules, but it can be helpful in detecting and assessing hilar/and mediastinal adenopathy.

Positron Emission Tomography (PET). The PET scan modality now plays a major role in the evaluation of solitary nodules14,15. The most accurate and helpful technique is a combined CT/PET scan, which is particularly helpful for achieving precise localization of the abnormality. The overall sensitivity for tumors is 96.8%, but false negative results may occur with bronchoalveolar tumors, and with malignant nodules less than 1 cm in diameter. As false positives may occur in active inflammatory lesions, the specificity is only 77.8%14. A positive result strongly suggests malignancy and surgery should be actively considered. A negative PET scan strongly suggests benignity, but does not absolutely rule out malignancy.

PET scans are also very helpful in detection of hilar, mediastinal and even distant metastases16.

CALCULATION OF THE PROBABILITY OF CANCER (PCA)

An estimate of the probability that the solitary nodule is a cancer is useful in the formulation of management strategies. The value of PCA can be calculated by an assessment of "predictor variables", which include clinical data (age, smoking history, presence or absence of previous malignancies) and radiographic characteristics (position of nodule in the lung, diameter of the nodule, edge characteristics, cavity wall thickness, and presence or absence of calcifications). Bayesian analysis17,18 or logistic regression19 can be employed to provide a quantitative estimation (PCA) that the SPN is malignant.

Calculating the PCA of SPNs is simplified by online algorithms, which can be accessed from the Internet with the following URL: http://www.chestx-ray.com/SPN/SPNProb.html. Experienced observers are capable of estimating PCA with considerable accuracy in many cases by reviewing the predictor variables without formal calculations of probability.

 

 

MANAGEMENT STRATEGIES

In practice, most SPNs initially fall into the category of "indeterminate". This includes cases in which benign patterns of calcification are not present, and retrospective determination of stability is not possible or not decisive.

There are five available strategies in these circumstances. These are not mutually exclusive, and are often employed sequentially. "Effectiveness" is measured by 5-year survival after the initial detection of the SPN. Ignoring the presence of the nodule is not an appropriate strategy!

Thoracotomy. This is commonly chosen as the initial (and definitive) strategy because it is both diagnostic and therapeutic. Decision analysis studies20 suggest that if the PCA is relatively high (>60 %), prompt thoracotomy is the most effective and cost-effective strategy. However, thoracotomy may be considered at virtually any PCA level if the patient and/or the physician so choose. Surgical mortality is 1-4%. Compared with standard (classic) thoracotomy, morbidity is lower with Video Assisted Thoracoscopy (VAT). If other strategies are first employed, thoracotomy is necessarily delayed to some degree, and there is concern that the passage of time might allow a curable lesion to become incurable20.

Transthoracic needle biopsy. This may be employed at any calculated PCA level, and in the past has been considered to be the most effective strategy over intermediate levels of PCA (10-60%). A positive biopsy for tumor indicates that prompt thoracotomy is required. If the biopsy proves a specific benign lesion, thoracotomy is deferred, but it is prudent to follow the subsequent course of the nodule by serial CT scans for at least a year.

 An indeterminate biopsy result is not proof of benignity or malignancy, and further action must be taken. In such cases, the further options may include a repeat needle aspiration biopsy, a PET scan, a "Watch and Wait" approach (see below) or a prompt thoracotomy

"Wait and watch" strategy. This is a prospective determination of stability, determined by serial CT studies after the detection of the SPN. It may be a reasonable choice20 if the PCA is very low <10%, but it is important that the patient understands the possible "hazard of delay"20,21. The initial CT followup should be 3-6 weeks after the detection of the nodule, and then at 3 month intervals for at least two years, or even longer in some cases.

Growth is measured in terms of the "doubling time" - the time taken for the nodule to double its volume. An increase in diameter of 28% indicates a doubling of volume. Malignant nodules tend to have doubling times between 80 and 140 days. Benign nodules usually do not grow in size, although slow growth of the nodule may occur in some instances. Most authorities would probably advise prompt thoracotomy if the calculated doubling time is shown to be less than one year, but some malignant nodules have considerably greater doubling times. If the lesion has shown any detectable increase in size, thoracotomy or VAT is often carried out.

Some students of SPN management consider that Wait and Watch is rarely indicated.

PET Scan strategy. This test has such high sensitivities and specificities that its use is really a strategy, limited only by the restricted availability of the equipment required. Pet scans may be employed in conjunction with or following the initiation of other strategies. A recent study has suggested that PET scan should be the initial strategy in most cases22.

A positive test strongly suggests malignancy and in most cases should mandate thoracotomy. If the results of PET scans and the PCA are discordant, needle aspiration biopsy may be advisable.

MANAGEMENT PATHWAYS

Spherical lung lesions greater than 3 centimeters in diameter are very frequently malignant, and should be biopsied or resected without delay in most instances. The pathways employed in the assessment of solitary nodules are not very appropriate for these larger masses. Factors such as patient preference or the concurrent presence of serious concurrent diseases must be considered. Needle biopsy or PET Scans may help in the decision process under such circumstances.

Previous chest x-rays or chest CT scans should be sought, and compared with the current studies. These may provide a retrograde estimation of stability, regardless of the size of the nodule or mass. Recognizable growth in the prior two years carries a high likelihood that the nodule is malignant, and resection must be seriously considered. Comparison of current with previous studies may be seriously misleading, particularly if the nodule is small or if previous studies were obtained with standard x-rays rather than CTs ( Henschke).

Needle aspiration biopsy should be the initial strategy if the solitary or multiple pulmonary nodules are present in a subject with a prior history of an extrapulmonary neoplasm, or with other clinical features suggesting the possibility that the nodule is metastatic. In some cases a VATS biopsy may be required.

The clinical value of PCA calculation lies in its use in suggesting the most effective management strategy or sequence of strategies. If the calculated PCA is 15-20% or less, the Wait and Watch strategy is reasonable although not imperative. Biopsy should still be considered. If the PCA is 60% or greater, prompt thoracotomy is usually advisable. These suggestions are not absolute, and it is clear that the wishes of the patient must be given major consideration.

In the intermediate range of probabilities (20 to 60%), the use of needle biopsy has generally been favored in most instances. If the biopsy is nondiagnostic, it may be repeated one or more times, and if the result is still indeterminate, the further two choices include immediate thoracotomy, PET scanning, or Watch and Wait in selected circumstances. If the biopsy indicates a specific benign process, including benign tumor or granulomatous disease, it is often prudent to carry out Watch and Wait, with repeat x-rays or CT scans every three months for a year or so.

The use of PET scanning has recently been recommended as the initial strategy in many or most cases, particularly if the PCA is within the wide intermediate change. An initial cost-effective study22 provides support for this, although further studies are clearly desirable.

Ideally, the patient should play an active role in the decision process. This requires a thorough discussion of the pros and cons of the various strategies.

STAGING

Μost malignant SPNs fall into the clinical category of T1 N0 M0, but it is still important to obtain a high resolution CT scan of the chest to explore the status of the hilar and mediastinal nodes. Enlargement of the nodes does not, in itself, invariably prove nodal involvement with tumor. PET scans are particularly helpful in this situation. Mediastinal node biopsy will sometimes be required.

SCREENING FOR LUNG CANCER

The development of the helical single pass chest CT scan has spurred attempts to detect and resect lung cancers as small as 2-3 mm in diameter. The supposition is that early detection and prompt surgical resection will reduce the mortality from lung cancer. The efficacy of CT lung screening however remains to be determined by the several studies now in progress23.

REFERENCES

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