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Ann Thorac Surg 1998;65:1821-1829
© 1998 The Society of Thoracic Surgeons

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Current Review

Positron Emission Tomography in Lung Cancer

^a Department of Nuclear Medicine, St. Louis University Health Sciences Center, St. Louis, Missouri, USA
^b Department of Surgery, St. Louis University Health Sciences Center, St. Louis, Missouri, USA

Address reprint requests to Dr Lowe, PET Imaging Facility, St. Louis University Health Sciences Center, 3635 Vista Ave at Grand Blvd, St. Louis, MO 63110-0250
e-mail: (lowe{at}nucmed.slu.edu)

	Abstract

Top Abstract Introduction Characterization of focal lung... Lung cancer staging Evaluation of therapy and... Summary References

 
Reports on positron emission tomography have become more common in the oncology literature. After a short introduction to positron emission tomography, this review will look at the data relating to the use of this technology in the diagnosis, the staging, and the posttreatment evaluation of patients with lung cancer and will discuss its potential role in these evaluations.

	Introduction

Top Abstract Introduction Characterization of focal lung... Lung cancer staging Evaluation of therapy and... Summary References

 
Although surprising to some, positron emission tomography (PET) has been in existence and continually developing over the past 20 to 30 years. The positron was postulated as a counterpart to the electron in the late 1920s by Dirac. It was discovered experimentally in 1932 by Anderson. Positrons are emitted from an unstable nucleus and travel some distance before combining their mass with that of an electron, resulting in the production of two light pulses. These light pulses are detected by light-sensitive crystals in a PET camera. The locations of the decays within the human body can be estimated, and a picture of their distribution can be constructed.

Early attempts at scanning positron-emitting isotopes with specialized light-sensitive crystals were made in the 1950s and 1960s. It was not until the development of computed tomography (CT) in the 1970s that early PET scanners were built. The first PET scanner was developed in 1974 at Washington University, but many changes were necessary to transfer those early ideas into the production of today’s PET machine. Since the 1970s, steady advances in PET camera hardware, development of small self-contained medical cyclotrons for PET radionuclide production, and progress in the speed of computer systems have all led to the performance of whole-body imaging with this modality. Today’s high-resolution (4 to 6 mm) PET machines contain thousands of small 2 to 4 mm crystals. These crystals are arranged in rings around the tomographic gantry. Tomographs with slightly larger crystals are available with a corresponding reduction in cost and image resolution (6 to 8 mm). In recent years, scanners that will image positron-emitting isotopes and that have a few large block detectors similar to those used in other radionuclide scanners have been produced. These scanners have reduced image quality but are also less expensive than the higher-resolution PET machines.

Positron emission tomographic imaging depends on the detection of specific radioactive isotopes that decay by positron emission. Most of the common molecules in organic processes can be labeled with positron-emitting isotopes. Atoms of low atomic number such as carbon, oxygen, nitrogen, and fluorine have positron-emitting isotopes. Molecules of specific functional import can be labeled with positron-emitting isotopes. Although many tracers can be discussed in a review of PET imaging, we will focus on the use of one tracer, [¹⁸F]fluorodeoxyglucose (FDG), the most widely used PET tracer for the detection of malignancy.

Malignant cells have increased metabolism and usually undergo rapid cell proliferation. In the 1930s, malignant cells were shown to have increased glucose metabolism [1–3]. Comparable enhancements of glucose and FDG uptake in malignant cells have permitted the identification of malignancy using PET imaging [4]. A unique feature of FDG as a marker of glucose metabolism is the fact that after FDG phosphorylation, FDG-6-PO₄ does not proceed further in the metabolic pathway but remains trapped within tumor cells, thus becoming a marker of metabolism (Fig 1). This persistence of the tracer in the tumor is essential for successful imaging to be performed [5]. The relative uptake of FDG can be used as a marker of tumor aggressiveness and correlates with tumor growth rates [6].

View larger version (30K): [in this window] [in a new window]   Fig 1. Glucose and [18F]fluorodeoxyglucose (18FDG) are transported into the cell in a similar fashion. After FDG phosphorylation, FDG-6-PO4 does not proceed down cellular metabolic pathways, and only minimal amounts leave the cell.

Positron emission tomography technology allows for attenuation correction of the images if this is desired. Attenuation correction entails measuring the radiation attenuation properties of the patient’s body and then mathematically correcting the radiation detected for this effect. This can produce a more accurate final image that may detect smaller lesions, especially when they are deep within the body. The disadvantages of this technique are that it requires more time and that there is the potential to add noise to the image if the attenuation measurements become at all misaligned by patient motion.

Although images of localized areas can be obtained in 15 to 30 minutes, the same injection will allow whole-body images to be made. A whole-body image may require an hour or more. An example of an imaging protocol in a patient with lung cancer may include a whole-body scan without attentuation correction to look for distant metastatic disease and a localized scan of the chest with attenuation correction to assess local nodal disease. In the near future, whole-body images including attenuation correction may well be performed in about 30 to 40 minutes largely as a result of new imaging software and faster computers. Development of new kinds of light-detection crystals for use in the next generation of PET scanners is also underway, and this may allow improved image resolution over today’s systems.

Medical insurance payment for PET has been limited to date. A full PET scan costs between $2,000 and $3,000, depending on the imaging time required, so few patients can pay on their own. Thanks to the educational efforts of physicians, insurance company medical directors have seen the utility of PET imaging in many instances. Therefore, insurance reimbursement has been a reality for many PET centers, whereas others have struggled and a few have been forced to close. This reimbursement inconsistency has been due partly to the fact that Medicare has not paid for PET. This should be resolved to some extent as Medicare begins to fund PET imaging of cancer in 1998.

	Characterization of focal lung abnormalities

Top Abstract Introduction Characterization of focal lung... Lung cancer staging Evaluation of therapy and... Summary References

 
Lung cancer commonly presents as a focal lung abnormality such as a nodule or a nonspecific opacity. Imaging with chest radiography, CT, or magnetic resonance imaging often will not differentiate definitively between benign and malignant focal lung abnormalities, as the classic radiographic finding of centralized calcification is seen only infrequently [10, 11]. This difficulty in differentiating benign from malignant lesions exists both for newly identified lung lesions and for residual abnormalities persisting after surgical resection or radiation therapy.

Several invasive modalities are available to assist in the diagnosis of these radiographic lesions. However, negative results from either transbronchial or transthoracic biopsies cannot be accepted as reliable negatives. There are also risks to these more aggressive and invasive diagnostic maneuvers. An accurate, noninvasive test for evaluating indeterminate pulmonary lesions would avoid considerable patient morbidity and potentially reduce cost compared with invasive procedures.

Recently published data have demonstrated the ability of PET to characterize lung abnormalities and have been particularly encouraging. After the identification of a pulmonary abnormality by an anatomic study such as a chest radiograph, FDG-PET imaging can be performed to evaluate the metabolic activity of the lesion in an attempt to distinguish a benign process from a malignant process.

Positron emission tomographic imaging provides numerical data (related to the number of positron emissions occurring) for each pixel of an image that accurately reflects the amount of FDG accumulating in a selected region. The standardized uptake ratio (SUR) is an uptake measurement normalized for patient body weight and imaging dose that provides a means of comparison of FDG uptake between patients. It is calculated in the following way: Standardized uptake ratio values of 2.5 or greater have been considered indicative of malignancy by some authors, whereas slightly different values are used by others. Some groups depend on visual interpretation of abnormality, ie, FDG uptake greater than mediastinal uptake as seen on the images.

Studies with PET
Investigators have used FDG-PET in the assessment of focal pulmonary nodules and other pulmonary opacities. In an early report [12], one center investigated FDG-PET imaging of solitary pulmonary nodules in 30 patients and found that PET had a sensitivity and a specificity of 95% and 80%, respectively. In another study [13], 51 patients with focal opacities that could not be characterized as benign or malignant by chest radiograph or CT scan were investigated, and the sensitivity and the specificity of FDG-PET for malignancy were found to be 100% and 89%, respectively. Figure 2 illustrates such findings. When FDG uptake within the focal opacities was analyzed, a highly significant difference was found between the standardized uptake ratios of malignant (6.8 ± 3.7) and benign (1.5 ± 0.9) lesions (p = 0.0001).

View larger version (58K): [in this window] [in a new window]   Fig 2. (A) Pulmonary nodule (broken arrow) in left anterior lung on computed tomography is hypermetabolic on (B) [18F]fluorodeoxyglucose positron emission tomography (solid arrow). A biopsy sample from the nodule was positive for adenocarcinoma.

False-negative PET studies can also occur and are seen in three specific settings. The first is tumors with relatively low metabolic activity. In a recent report [21], four of seven bronchioloalveolar tumors did not demonstrate increased FDG accumulation. Carcinoid tumors, too, had low levels of FDG accumulation in the series in Table 1 [15, 18]. All other types of primary lung cancer have increased FDG accumulation. Occasionally, well-differentiated adenocarcinomas will have relatively less marked elevation of FDG accumulation, but the standardized uptake ratio is still abnormal [21].

Size is another potential limitation of accurately identifying cancer with PET. False-negative findings can occur because of the relatively limited resolution (4 to 8 mm) of current PET tomographs. This could play a role when the tumors are physically small or when the histologic complement of malignant cells is small relative to the rest of the nodule’s tissue (ie, high fibrous tissue content). The PIOPLIN study demonstrated a lower sensitivity for malignancy (80% versus 96%) when the tumors were less than 1.5 cm in size, although the difference was not significant. Another study [19] found no difference in the accuracy of PET when evaluating nodules 2 cm or less compared with those larger than 2 cm. This is an area where future improvements in PET systems may improve overall accuracy. No studies have been performed to look specifically at the accuracy of PET in very small nodules, although each of the studies mentioned had a few nodules in the 5 to 8 mm range, and about half of them were characterized correctly.

The final possible, albeit uncommon, cause of a false-negative PET study is hyperglycemia. Competitive inhibition from high serum glucose levels appears to hinder FDG uptake in some instances. Research has shown that the inhibitory effect is most important with acute hyperglycemia, whereas a chronically elevated glucose level only minimally inhibits (about 10% reduction) tumor uptake of FDG [8]. Therefore, control of diabetes should be optimized and serum glucose values checked before PET imaging. If marked hyperglycemia (>300 mg/dL) is identified, a return appointment at a time when control of diabetes is improved is the suggested course of action. In the series of Torizuka and colleagues [8], false-negative results because of hyperglycemia were described only twice. Most investigators did monitor glucose values in their series.

Potential clinical utility of PET in focal lung abnormalities
The optimal algorithm incorporating PET for the evaluation of pulmonary abnormalities has not yet been identified. Evaluation of solitary pulmonary nodules by FDG-PET could identify nonmetabolically active benign lesions and allow patients to be followed up by sequential imaging studies rather than undergo invasive sampling procedures. One study [22] has compared the use of transthoracic needle aspiration and PET in the investigation of indeterminate nodules. The sensitivity and specificities were 100% and 78%, respectively, for PET and 81% and 100% for transthoracic needle aspiration. These data suggest that more malignancies may in fact be missed using a traditional transthoracic needle aspiration approach when selecting patients for thoracotomy. Conversely, on the basis of the data from this series, a PET approach may lead to more unnecessary thoracotomies. Also, 27% (9/33) of the patients in the series required chest tube placement for pneumothoraces secondary to the transthoracic needle aspiration.

The costs and benefits of different approaches are being evaluated. One report [23] has suggested that a noninvasive approach using FDG-PET can be more cost-effective without compromising patient survival. The investigators looked at immediate operation as well as various combinations of noninvasive testing of solitary pulmonary nodules using decision tree analysis. They suggested that given a low prevalence of malignant solitary pulmonary nodules (<50%), using either PET with radiologic follow-up for 2 years or PET and CT with follow-up resulted in a net cost reduction of $1,600 per patient versus CT alone with follow-up. The majority of the savings would result from reducing the number of invasive procedures.

	Lung cancer staging

Top Abstract Introduction Characterization of focal lung... Lung cancer staging Evaluation of therapy and... Summary References

 
Clinical staging of bronchogenic carcinoma is performed using the TNM system, which requires accurate characterization of the primary tumor (T), regional lymph nodes (N), and distant metastasis (M). The role of FDG-PET scanning is quite different for these three components of staging.

Primary tumor
Positron emission tomography has relatively limited usefulness in determining the T status of the primary lesion. Although tumor size can be estimated on PET, thus allowing classification into T1 (<3.0 cm) and T2 (>3 cm) lesions, this is accurately accomplished on CT scanning. Similarly, PET scanning has poor accuracy in determining invasion into adjacent structures such as chest wall, diaphragm, or large vessels—characteristics that define T3 status. The identification of malignant pleural implants (which constitute T4 disease) is perhaps the most useful, if highly infrequent, discovery that can be made accurately by PET when dealing with the determination of the T status.

Nodal disease
Positron emission tomography has more potential utility in nodal staging of bronchogenic carcinoma. Table 2 is a summary of data from studies examining the accuracy of PET in staging lung cancer [24–31]. Staging of the mediastinum can be performed by mediastinoscopy, which has a sensitivity of 87% to 91% for disease [32–35]. Staging by anatomic studies such as CT has been attempted, but it is considered by some to be only complementary to mediastinoscopy because of its poor accuracy. Adenopathy as defined by CT imaging (> 1-cm short-axis diameter) is both insensitive and nonspecific for malignancy. Staging of bronchogenic carcinoma by CT and magnetic resonance imaging has been reported to have a sensitivity of about 50% to 60% [32, 35]. Interestingly, nodes greater than 2 cm have a 30% to 37% chance of being benign [36, 37].

Metastatic disease
When a PET scan is done, a whole-body image can be obtained to assess distant metastatic disease status. Imaging from the head to the toes can be performed in the same visit without additional radiation exposure. Table 3 shows the results in three studies [30, 38, 39] that looked at the data provided by PET in assessing distant metastatic disease. In each of the reports, at least 10% of the patients were found to have distant metastasis not otherwise detected by routine chest CT scans or, in some cases, additional imaging studies such as bone scans. The results imply that information regarding the advisability of tumor resection will be affected by the addition of PET. Not only was unsuspected disease identified on PET, thus resulting in "up-staging," but many false-positive findings on CT (including findings outside the chest such as adrenal nodules) were correctly interpreted as negative by PET. This was illustrated in a study of 99 patients by Valk and associates [30]. In their patient cohort, PET correctly characterized as benign 14 of the 19 false-positive findings on CT scans. Thus, PET could aid in identifying patients with cancer as surgical candidates who might otherwise be considered to have unresectable disease. In considering both contributions, the change in management brought about by PET information can reach very high proportions of study populations, as illustrated by the study of Lewis and coworkers [38], where management changes occurred in 41% of patients. Figure 3 is an example of PET scan findings that can have an impact on resectability in this manner.

View larger version (91K): [in this window] [in a new window]   Fig 3. (A) A 53-year-old man had a large left lung mass (large cell undifferentiated tumor) with associated left hilar adenopathy (arrow) on computed tomography. (B) It also demonstrated a 1.8-cm nonspecific left adrenal mass (arrow). (C) Coronal positron emission tomography showed hypermetabolism indicative of tumor in the left lung mass and left hilar nodes as well as right tracheobronchial nodal (broken arrow), left pleural, and left adrenal (solid arrow) disease. Right-sided adrenal disease is also likely present as seen on position emission tomography, although the right adrenal gland was not enlarged on computed tomography.

	Evaluation of therapy and recurrence

Top Abstract Introduction Characterization of focal lung... Lung cancer staging Evaluation of therapy and... Summary References

 
Most patients with bronchogenic carcinoma are seen in an advanced state of the disease, a fact that helps explain the poor prognosis and the 5-year survival rate of 13% [41]. An accurate assessment of the efficacy of chemotherapy and radiation therapy might prove of enormous benefit in directing therapy for patients with advanced stages of lung cancer. Historically, clinicians have used tumor shrinkage to assess efficacy, but this may not be the best indicator of response to therapy. Positron emission tomography using FDG can identify changes in glucose uptake after treatment and may prove to be a better indicator of a favorable response to therapy. However, it may be important to differentiate between a decrease in FDG uptake and the complete absence of FDG uptake. Some investigators [42] have concluded that a simple decrease in FDG uptake does not necessarily indicate a good prognosis. Rather, it has been suggested that a decrease in FDG uptake may indicate only a partial response resulting from destruction of cells sensitive to the therapy while other resistant cells continue to be metabolically active.

Normalization of FDG uptake after treatment, on the other hand, appears to be a good prognostic sign. A study by Hebert and coworkers [43] has demonstrated that negative PET findings after radiation therapy, even in the presence of nonspecific radiographic changes, are an indicator of a good response. This group noted that all of their patients with negative PET findings were alive 2 years after treatment, whereas 50% of patients with residual hypermetabolism, albeit reduced, had died within that same 2-year period. Other investigators have used this logic to justify further treatment of asymptomatic patients whose PET scans demonstrate residual hypermetabolism after an initial course of therapy. Frank and colleagues [44] treated 5 such asymptomatic patients in their study solely on the basis of residual hypermetabolism, and all were alive at 3 years.

Early diagnosis of recurrent lung cancer is another potential use of FDG-PET. Radiologic changes occurring after therapy such as scarring and necrosis may obscure the identification of recurrent tumor unless there are substantial volume changes over time. The recognition of recurrence is often not made until the disease progresses to the point of marked enlargement of previously questionable abnormalities. A tissue biopsy specimen that is negative for tumor in such situations is suspect because of the inherent difficulty of identifying and accurately sampling the areas of viable tumor in the midst of scar. A PET evaluation of tumor recurrence can potentially assist in this determination. Patients who have chest radiographic findings suggestive of tumor recurrence can be accurately characterized by FDG-PET imaging (Fig 4).

View larger version (77K): [in this window] [in a new window]   Fig 4. A 52-year-old man had a history of right upper lobe lung cancer. (A) The chest radiograph showed an ill-defined right hilar opacity and right paratracheal fullness. (B) Coronal positron emission tomography demonstrated right hilar (arrow) and right paratracheal hypermetabolism indicative of recurrent tumor.

View larger version (77K): [in this window] [in a new window]   Fig 5. Transaxial 18F-fluorodeoxyglucose positron emission tomography (PET) image from patient with a history of left lung cancer seen with a new left pleural effusion demonstrating multiple focal areas of hypermetabolism involving the left pleural surface (arrow). The PET metabolic image (bright white) is superimposed on a PET soft-tissue density image or attenuation scan (seen as light gray), also routinely obtained for PET imaging, that shows increased density (pleural fluid) in left lung region. The biopsy specimen documented recurrent tumor in this pleural region.

	Summary

Top Abstract Introduction Characterization of focal lung... Lung cancer staging Evaluation of therapy and... Summary References

 
Continuing advances in imaging technology have resulted in an improved ability to evaluate thoracic malignancies with PET. Published reports demonstrate that PET provides accurate, noninvasive detection of malignancy that is useful in the characterization of nonspecific radiographic lung lesions, staging of known lung cancer, and identification of recurrent disease after treatment. Preliminary studies suggest that PET may also be able to accurately assess therapeutic response. The studies investigating PET have been relatively small but have shown significant advantages over conventional noninvasive techniques in accuracy and cost/benefit performance. Positron emission tomographic imaging will likely become an increasingly important part of the evaluation of patients with lung cancer.

	References

Top Abstract Introduction Characterization of focal lung... Lung cancer staging Evaluation of therapy and... Summary References

 

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