James Harris
Alicia Hulbert
Malcolm V. Brock
Presentation
A 65-year-old man with shortness of breath and tachycardia undergoes a spiral CT scan of the chest to rule out pulmonary emboli. The CT scan is negative for pulmonary emboli, but a noncalcified solitary pulmonary nodule (SPN) measuring 2.3 cm in diameter with spiculated borders is incidentally found in the right upper lobe of the lung. There is no mediastinal adenopathy on the CT scan. The patient has a past medical history significant for anxiety disorder (which he now admits usually presents with shortness of breath) and hypertension but denies a history of pulmonary disease. The patient has a 25 pack-year tobacco history without a family history of lung cancer or any other malignancies. His physical examination is unremarkable.
Differential Diagnosis
An SPN is classified as a single-lung parenchymal lesion that measures <3 cm, is surrounded by pulmonary parenchyma, and is without atelectasis or adenopathy. Lesions measuring >3 cm are classified as masses and are more likely to be malignant. The differential diagnosis of a SPN starts with the question of whether it is benign versus malignant. The range of incidences of cancer found in an SPN is quite wide, between 10% and 70%, largely because of varied patient characteristics. Of those SPNs found to be cancer, up to 75% are non-small cell lung cancer (NSCLC), with 50% being adenocarcinoma and 25% being squamous cell carcinoma. The remaining 25% of malignancies associated with SPN consist of large cell carcinoma, small cell carcinoma, carcinoid, lymphoma, and solitary metastatic lesions from extrapulmonary sources. Any patient with a known history of an extrapulmonary malignancy has a 25% chance of having an SPN pathologically consistent with a metastasis. SPNs that prove to be benign lesions are most often (80% of the time) consistent with infectious granulomas, while hamartomas make up a distant second at 10%. Other benign etiologies comprise the remaining 10% and are due to trauma, arteriovenous malformations, rheumatoid nodules, sarcoidosis, intrapulmonary lymph nodes, and plasma cell granulomas.
Workup
In order to establish an accurate diagnosis for an SPN found incidentally on a CT scan or a chest x-ray, the clinician must first perform a thorough history and physical exam along with a basic set of laboratory analysis to assess those patients at risk for malignancy versus those who may have a benign etiology. Probably the most important first question to an asymptomatic patient with an incidental radiographic finding concerns any previous chest x-rays or CT scans available for review. The existence of previous radiologic evidence of disease may be very helpful not only in assessing if the SPN is a new or preexisting lesion but also in establishing the tumor’s doubling time. The latter can also be used as a rough predictor of the presence of cancer; lesions with a doubling time of <465 days are three to four times more likely to be malignant. One exception is a nodule doubling in <20 days, which usually suggests an acute inflammatory process.
Since cancer is a disease of aging, chronologic age has been shown to have a significant effect on the likelihood of an SPN harboring cancer; patients over the age of 70 years with an SPN are four times more likely to have cancer than those under the age of 70 years old. Any patient over the age of 60 years is considered high risk, those 40 to 59 years old are intermediate risk, and patients under 40 years are low risk. While one study found that only 3% of patients between the ages of 35 and 39 years old had SPNs found to be cancer, it is very important to evaluate each patient as other factors can significantly influence the likelihood of malignancy, regardless of age.
Importantly, tobacco use of 20 pack-years and greater has been associated with a high probability of cancer among patients with an SPN. Patients with less than a 20 pack-year history maintain an intermediate probability of cancer, while nonsmokers have a low probability. Other important factors that can significantly increase the likelihood of an SPN being cancer, even in nonsmokers, are exposure to second-hand smoke, asbestos, radon, a previous history of any malignancy, and a family history of cancer.
The radiographic characteristics of the SPN are very important in predicting the presence of cancer. Nodule size seems important with SPNs >2.2 cm having a high probability of being cancer. Lesions measuring 1.1 to 2.2 cm have an intermediate risk of malignancy, while those <1.1 cm are low risk. The shape of the SPN is also critical with nodules having spiculated borders with the highest risk of being cancer in comparison. One study by Gurney revealed that SPNs identified on CT scan with spiculated borders were five to six times more likely to be cancer in comparison to those without a spiculated border (Table 1).
TABLE 1. Risk of Lung Cancer Based on Characteristics of Patient or Lesion
Calcification patterns are another radiographic feature that can help to determine whether a lesion is benign or malignant. The most important characteristic of a benign nodule is the presence of calcification, such as the large central nidus, concentric calcification typical of a granuloma (Figure 1), or the diffuse speckled, “popcorn” pattern, typical of a hamartoma (Figure 2). Occasionally, however, a malignant nodule can exhibit a small “fleck” of calcification or it engulfs a nearby small granuloma during its growth (Figure 3). Metastatic osteogenic sarcoma may also have calcifications; thus, the presence of calcification alone does not ensure a benign diagnosis (Figure 4).
FIGURE 1 • Calcification in granuloma–benign. (Image provided by Dr. S. Siegelman, Johns Hopkins Hospital, Department of Radiology.)
FIGURE 2 • Pulmonary hamartoma with “popcorn calcifications.” (Image provided by Dr. S. Siegelman, Johns Hopkins Hospital, Department of Radiology.)
FIGURE 3 • Calcification in carcinoma. (Image provided by Dr. S. Siegelman, Johns Hopkins Hospital, Department of Radiology.)
FIGURE 4 • Pathology specimen obtained from lesion seen in Figure 3. (Image provided by Dr. S. Siegelman, Johns Hopkins Hospital, Department of Radiology.).
For any SPN with low clinical and radiographic likelihood of cancer, it is appropriate to monitor the patient with serial CT scans to ensure that there is no change in size or characteristics of the SPN that would warrant further evaluation. Patients with SPNs of intermediate cancer risk that measure 1 cm or more should receive positron emission tomography (PET) imaging, to help distinguish benign from malignant pulmonary nodules by measuring 18-fluorodeoxy-glucose (FDG) and by showing increased FDG uptake and retention in malignant cells. FDG-PET scanning is a valuable, noninvasive tool with a 95% sensitivity for identifying malignancy and a specificity of 85% or greater; however, false-positive results may be obtained in lesions containing an active inflammatory process. FDG-PET scans lack sensitivity in SPNs <1 cm; thus, lesions this size should be followed by serial CT scans. Although for SPNs that are considered clinically and/or radiographically high risk, it is appropriate to take patients with these lesions directly to the operative suite, tumor staging has been reported to be significantly better with integrated PET-CT rather than CT alone.
There are various recommendations in the literature regarding the appropriate timeline for CT scan follow-up; recommendations out of the Fleischner Society state that any SPN >8 mm should be monitored at 3, 9, and 24 months in patients over the age of 35 years, regardless of the risk status and less frequently in lesions <8 mm. For low-risk patients with lesions <4 mm, there is no need for further follow-up, and those with lesions between 4 and 8 mm should undergo increasing frequencies of surveillance CT scans based on the exact size of the lesion and the risk status of the patient.
In our 65-year-old heavy smoker, after appropriate questioning, the patient revealed the availability of an old CT scan from 12 months previously. The same SPN was evident, but with a diameter of 1.0 cm. Since the volume of a sphere is proportional to the square of the radius, this doubling of the CT diameter in a year suggests a very large increase in tumor volume. A PET/CT scan was ordered both to investigate the primary lung nodule and to render more accurate tumor staging. The PET/CT revealed a single focus of high FDG uptake in the right upper lobe. Given the radiologic evidence combined with the patient’s age as well as the patient’s substantial smoking history, the probability of a malignant process underlying this patient’s tumor growth is very high.
Diagnosis and Treatment
All patients with an SPN who have a high clinical and/or radiographic probability of cancer, without evidence of malignancy outside of the area of surgical resection, should undergo surgical excision. Those individuals with an intermediate probability of a malignant SPN and negative PET scan findings should be followed with serial CT scans. Those with an SPN of intermediate probability and a positive PET scan should undergo surgical excision.
Although the definitive approach in most malignancies located outside of the chest cavity is to distinguish benign from malignant lesions with a tissue biopsy, often patients with a documented rapidly enlarging SPN are taken directly to the operating room without biopsy-proven carcinoma. The traditional argument has been that benign lesions account for <10% of rapidly growing tumors in the chest, a figure that has recently been confirmed by prospective data from 31,567 asymptomatic patients screened with helical CT scans. With advances in fiberoptic bronchoscopy and image-guided transthoracic needle biopsy, however, many lesions are now amendable to these minimally invasive alternatives for obtaining tissue for diagnosis. Still, most thoracic surgeons adhere to the principle that SPNs with an intermediate to high suspicion for cancer, which are not accessible to biopsy because of small size or location as well as high-risk SPNs with negative biopsy findings, should undergo excisional biopsy preferably via video-assisted thoracic surgery (VATS) with possibility of conversion to thoracotomy if indicated.
Surgical Approach
In patients with an SPN that is biopsy-proven NSCLC, but there is no evidence of mediastinal adenopathy (all mediastinal lymph nodes ≤1 cm), there is <10% prevalence of occult metastases. Although many thoracic surgeons perform mediastinoscopy routinely for appropriate staging, others prefer mediastinoscopy only for patients with radiologically evident mediastinal adenopathy. The exception is for those patients with small cell lung cancer (SCLC) found preoperatively within an SPN. All of these patients should undergo mediastinoscopy to rule out occult mediastinal metastases.
The current recommendation by the National Comprehensive Cancer Network for patients, such as our 65-year-old man with suspected NSCLC (<4 cm) with node-negative lesions, is lobectomy alone. Five-year survival rates in such patients with SPN and NSCLC who undergo curative resection alone can be as high as 80%. For patients with node negative disease but larger tumors, the addition of adjuvant chemotherapy is encouraged. Multiple retrospective and prospective studies have shown that there is additional survival benefit in patients with stage 1 SCLC when treated with both lobectomy and adjuvant platinum-based chemotherapy.
In the operating room after a time out is performed and after induction of general anesthesia with subsequent placement of a double-lumen endotracheal tube, the patient is positioned with the nonoperative side down in the lateral decubitus position. Care is taken to pad and support all pressure points. It is then appropriate to ask the anesthesia team to begin one-lung ventilation, ventilating the nonoperative side so as to allow the lung with the SPN to collapse away from the chest wall. This will not only decrease risk of injury to the lung upon entry to the pleural space but also make smaller nodules more apparent to detection as the normal air-filled lung parenchyma collapses around the solid SPN.
Typically, three ports are placed between the fifth to the eighth intercostal spaces, depending upon the location of the tumor, in a triangulated position usually with placement of the camera first. Under direct vision, safe entry of the other two sites is attained. If the SPN is not apparent upon visual inspection, the lung can be indirectly palpated with a grasper or palpated directly as an alternate way of identifying a lesion before converting to thoracotomy. If the SPN is identified, it is resected using a grasper and an endoscopic stapler device. If the specimen is small enough, it can be easily removed through the port; otherwise, it must be placed into an endoscopic specimen bag for removal so as to avoid seeding of tumor cells at the patients port site. If an SPN excised with a wedge resection is determined to be malignant on frozen section, and if the patient is thought to be a suitable candidate, a pulmonary lobectomy (either by VATS or open) is almost always warranted. Upon completion, an intercostal block can be performed under direct visualization along with chest tube placement through the thoracoscope port site.
Special Intraoperative Considerations
As indicated, when performing a VATS wedge lung resection on a patient, it is not only appropriate to consent for the possibility of conversion to open thoracotomy, but also to consent for the likely possibility of a more complete oncologic resection of the entire lobe if the specimen is found to be malignant. In preparation for such a scenario, pulmonary function tests should be performed on each patient to ensure that a lobectomy, if necessary, can be performed safely without significant postoperative morbidity or mortality as a result of preexisting pulmonary disease. In terms of technique during a VATS lobectomy for an SPN, perhaps the steepest learning curve is in understanding the 3-D anatomical relationships of the pulmonary vasculature and the bronchi, proper positioning and manipulation of the stapling devices as well as providing adequate exposure and traction for dissection during the procedure. The anatomy presents itself on the video monitor from an unfamiliar perspective if one has only been accustomed to open thoracotomy cases. The stapling devices are rigid instruments that must be manipulated deftly in the closed confines of the chest. Finally, an experienced first assistant is absolutely critical in enabling a risk-free procedure since good traction and exposure allow for meticulous dissection especially when there is dense hilar lymphadenopathy or a fused fissure. Conversion rates to open thoracotomy tend to decrease as the surgeon’s experience with the VATS technique increases (Table 2).
TABLE 2. Key Technical Steps and Potential Pitfalls to VATS Pulmonary Wedge Resection
Postoperative Management
Most patients undergoing a VATS lung wedge resection do fairly well postoperatively with very low morbidity and mortality. Most patients have their chest tubes removed on postoperative day 1 as long as they remain with low output and without an air leak and are sent home that same day. Increasingly, surgeons who are performing VATS lobectomies for malignant SPNs are reporting similar complication rates as the open thoracotomy equivalents.
Case Conclusion
In this clinical scenario, with an isolated SPN and no evidence of extrathoracic malignancy, there is a high probability of this SPN being a cancer; especially given his age >60 years, tobacco history >20 pack-years, and the size/characteristics/doubling time of his SPN. It would be appropriate to take this patient straight to surgical excision by VATS or even thoracotomy if the SPN is not easily accessible for biopsy by transthoracic needle biopsy or bronchoscopy. He should undergo the appropriate preoperative medical clearance in addition to pulmonary function testing to ensure that a lobectomy, if required, can be performed safely.
TAKE HOME POINTS
· Among all SPNs found to be cancer, 75% are NSCLC.
· Among all SPNs found to be benign, 80% are infectious granulomas.
· Six important factors that significantly increase the likelihood of an SPN being cancer: (1) age >60 years, (2) tobacco history >20 pack-years, (3) prior history of cancer, (4) size >2 cm on chest x-ray or CT, (5) the presence of spiculations on chest x-ray or CT, (6) doubling size <465 days.
· Calcification patterns on CXR and/or CT of an SPN can be suggestive of a benign etiology but should not be used to exclude the diagnosis of cancer since some malignancies can also have the presence of calcifications.
· Patients with an SPN >1 cm who have an intermediate probability of cancer should have an FDG-PET scan to assess the need for surgical excision versus surveillance with serial CT scans.
· All patients with an SPN who have a high clinical and/or radiographic probability of cancer should undergo surgical excision.
· For patients with an SPN found to be stage 1a NSCLC, lobectomy alone is recommended.
· For patients with an SPN found to be stage 1 SCLC, lobectomy followed by platinum-based adjuvant chemotherapy is recommended.
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