Positron emission tomography (PET) is an important noninvasive diagnostic modality that has had a significant impact on the evaluation and management of patients with thoracic cancer. The author discusses the use of PET in three important areas. Evaluation of solitary pulmonary nodule, the staging and management of non-small-cell-lung cancer, and the workup of patients with esophageal cancer.
is a Professor of Radiology,
is a Fellow in Nuclear Radiology, and
is a Research Associate, in the Division of Nuclear Medicine,
Department of Radiology, University of Maryland Medical Center,
Baltimore, MD. Dr. Line is also a member of the Editorial Board
of this journal.
Positron emission tomography (PET) imaging is strongly indicated
for the diagnosis of solitary pulmonary nodules and for the
diagnosis, staging, and restaging of both nonsmall-cell lung
cancer and esophageal cancer. PET is also used in guiding treatment
plans, monitoring therapeutic response, and detecting tumor
recurrence. PET imaging can also be used to guide invasive
diagnostic procedures by determining the most readily accessible
and metabolically active lesions. In surgically high-risk patients,
PET can be an alternative to biopsy or surgical evaluation. PET is
as sensitive as transthoracic needle aspiration (TTNA) biopsy with
less risk in identifying malignant pulmonary lesions.
Other uses of PET include planning radiotherapy fields, measuring
tumor aggressiveness, and assessing prognosis.
These applications stem from the metabolically key glucose
analogue, fluorine-18-labeled fluoro-2-deoxy-D-glucose (FDG). This
molecule is similar enough to glucose to be transported through the
cell membrane and to be phosphorylated by hexose-6-phosphate. The
cellular enzymatic machinery that processes glucose cannot further
metabolize FDG, and the molecule becomes trapped inside tumor
Image region localization that appears greater than blood pool
activity is often associated with malignancy, especially for foci
smaller than 1.5 cm in size. The amount of FDG localized in a tumor
is characterized by comparing its uptake to the total body
administered dose. The standardized uptake value (SUV) or
standardized uptake ratio is defined as the FDG concentration in
the region of interest to the average FDG concentration in the body
(injected dose divided by [lean] body mass). The factors that can
affect the SUV include the body surface area (distribution of FDG
is higher in muscle than in fat), the time after the FDG injection,
the partial volume effects, and the blood glucose level at the time
of injection. An SUV >2.5 is sensitive and specific for
The following discussion focuses on the use of PET in three
important areas in thoracic oncology: Evaluation of solitary
pulmonary nodule (SPN), the staging and management of
nonsmall-cell lung cancer (NSCLC), and the workup of patients with
Solitary pulmonary nodule
Patients with an SPN rarely have symptoms attributable to the
nodule, and so the detection of the SPN is usually serendipitous.
The plain chest radiograph usually defines the presence and
appearance of the SPN, unless it was discovered on CT or other
radiographic imaging performed for another purpose. The lesion must
be singular, surrounded by normal lung tissue, and not be involved
with obstructive atelectasis or hilar enlargement. There are many
benign and malignant processes that may present as a solitary
pulmonary nodule (SPN) on a chest radiograph (Table 1). The most
common benign causes of SPNs are granulomas from histoplasmosis,
coccidioidomycosis, and mycobacteria. Hamartomas are the most
common benign neoplasms and constitute approximately 10% of benign
Bronchogenic carcinoma is, by far, the most common malignant
lesion in surgical series of SPNs. Adenocarcinoma and large-cell
carcinoma account for more peripheral nodules than squamous and
small-cell carcinomas, although all histologic types of lung cancer
may present as an SPN. Metastatic lesions from non-lung primary
tumors constitute about 10% to 30% of resected malignant nodules.
The most frequent sources of metastasis are squamous carcinomas of
the head and neck and adenocarcinomas of the breast, kidney, and
Most stage I lung cancers (T1-2,N0,M0) are within the definition
of SPN (Figure 1). The 5-year survival for resection of stage I
bronchogenic carcinoma is 75% and is more than 80% for lesions
<3 cm. Ideally, all malignant SPNs would be resected shortly
after detection, and all benign lesions would be identified without
surgical intervention. The overall goal in the evaluation of the
SPN is to resect potentially curable cancers expeditiously and to
avoid surgical resection of benign nodules. As many nodules are
indeterminate in appearance, the presence of an SPN presents a
Increasing incidence of SPN malignancy has been demonstrated
with advancing age. The probability that a nodule is malignant also
increases with increasing size of the nodule. Approximately 93% to
99% of nodules >3 cm in CT diameter are malignant. The rate of
enlargement is also important. Malignant pulmonary nodules have
doubling times between 21 and 400 days. Shorter times are usually
related to infections and longer times are nearly always benign
growths. How a nodule looks (ie, its size, shape, pattern of
calcification, and whether there are any surrounding or "satellite"
lesions) provides important clues about whether or not it is
cancerous. Radiographically, malignant SPNs tend to have lobulated
or shaggy borders, and there is usually some distortion of the
adjacent blood vessels. A calcification pattern that appears
irregular or spotty is a good indication of malignancy. Other
characteristic features that may appear on the radiograph include a
tail on the lesion and a
(a soft halo around the lesion). The presence of calcification
within a nodule on plain film, tomography, or a CT scan is a
reliable indicator that the nodule is benign. Granulomas
classically may show a laminated or a concentrically ringed
calcification pattern. Other benign calcification patterns include
central, diffuse, and "popcorn ball," which may be seen with
hamartomas. Unfortunately, about 10% of malignant lesions show
evidence of calcification on plain chest film.
With the possible exception of the heavy central calcification
characteristic of an old granuloma, lesion morphology is not a
reliable indicator of whether a nodule is benign or malignant.
Absolute CT density is also unreliable and irreproducible. CT
contrast enhancement may provide important help. In a study of 163
reported a sensitivity of 100%, a specificity of 76.9%, and an
overall accuracy of 93% in identifying malignant neoplasms by the
amount of CT contrast enhancement. Malignant neoplasms enhanced
significantly more (>20 Hounsfield units) than granulomas and
benign neoplasms, although hamartomas and active granulomas also
showed high enhancement. The degree of enhancement was related to
the amount of central vascular staining in histologic evaluation of
Given a radiographically indeterminate nodule <3 cm in
diameter, patients can be managed by observation, biopsy, or
thoracotomy. Observation involves careful follow-up with serial
chest radiographs every 3 months for the first year, every 6 months
for the second year, and yearly thereafter, if necessary, to
exclude the possibility of a slow-growing malignancy. Whether life
expectancy changes if malignant SPNs are observed for growth is
unknown. Some studies suggest that the prognosis (outcome) is the
same whether immediate action involves no action at all, surgery,
or biopsy. On the other hand, survival appears to be longer among
patients following resection of small malignant nodules compared
with larger ones. Further, it is difficult for most patients to
live with the uncertainty of whether a malignancy is being left
untreated. Unfortunately, immediate resection of indeterminate
nodules requires expensive and invasive thoracotomies for a large
number of benign lesions that might have been identified by
observation or biopsy techniques.
Biopsy by means of TTNA has a diagnostic yield of 43% to 97%
in peripheral pulmonary lesions. For malignant lesions <2 cm in
size, the yield of a positive tissue diagnosis is about 60%.
Pneumothorax, the most frequent complication of TTNA, is in the
range of 15% to 30%, with approximately half requiring tube
thoracostomy. Although bronchoscopy with transbronchial biopsy is a
low-risk procedure, the likelihood of obtaining a diagnostic
specimen is approximately 10% for nodules <2 cm in diameter and
40% to 50% for nodules 2 to 4 cm in diameter.
An SPN can be removed via video-assisted thoracoscopic surgery
(VATS) if it is smaller than 2 to 3 cm in diameter and is located
<2 cm from the pleural surface. However, nearly half of the
lesions removed using VATS are benign. Considering the expense and
potential morbidity of thoracoscopy, PET appears to offer a less
expensive, less invasive, and a more specific diagnostic
FDG PET imaging can be used to determine, based on its metabolic
utilization of glucose, whether an SPN is benign or malignant.
Dewan et al
showed that PET scanning was able to identify malignant lesions
with a sensitivity of 95% to 100% and a specificity of 80% to 89%,
respectively. Using an SUV >= 2.5 as an indicator of malignancy,
FDG PET has a sensitivity and specificity ranging from 83% to 100%
and 63% to 90%, respectively (Figure 2). Tumors with high FDG
uptake (SUV >10) and diameter >3 cm have the worst prognosis,
with a survival time of less than 6 months. Studies suggest a
strong association between PET and cell differentiation, which in
turn correlates with prognosis.
PET may be used to guide invasive diagnostic procedures by
determining the most readily accessible and metabolically active
lesions. In surgically high-risk patients, PET can be an
alternative to biopsy or surgical evaluation. PET is as sensitive
as TTNA biopsy in identifying malignant pulmonary lesions with less
False-positive results can be seen with granulomas
(tuberculosis, histoplasmosis, aspergillosis, cryptococcosis, and
inflammatory pseudotumor), or inflammatory processes (sarcoid,
Wegener's), and rheumatoid nodules. In these conditions, increased
FDG uptake may be related to enhanced glycolytic activity in
False-negative examinations can occur in small lesions (under
0.7 to 0.8 cm in size) or in neoplasms having low metabolic
activity (ie, bronchoalveolar cell carcinoma and carcinoid tumors).
Competitive inhibition from high-serum glucose levels (>250 to
300 mg/dL) interferes with tumor cell FDG uptake. This is more
pronounced in acute hyperglycemia while a chronic increase in
glucose level results in less inhibition. PET imaging should be
postponed until the serum glucose is <200 mg/dL.
PET in NSCLC
Nonsmall-cell lung cancer includes different histopathological
cell types (adenocarcinoma, squamous-cell carcinoma, large cell,
and mixed cell histologies) and comprises 75% to 80% of all new
cases of lung cancer.
Squamous-cell carcinoma associated with major bronchi is the most
common type, followed by adenocarcinoma, the most common type of
lung cancer in people who have never smoked. This usually arises in
the peripheral regions of the lung under the bronchial mucosa.
Large-cell carcinoma also presents in the lung periphery.
In NSCLC, tumor stage is the most important prognostic factor
that guides treatment planning. Patients with metastasis to the
mediastinal lymph nodes have an average 5-year survival rate of
approximately 10% compared with a survival rate of 50% in the
absence of mediastinal metastases.
Unfortunately, surgery with curative intent is an option in only
30% of patients. Patients with nonresectable but loco-regionally
confined disease may have prolonged survival and even cure with
radical radiotherapy. The combination of radiation to 60 to 66 Gy
and platinum-based chemotherapy is a common approach in inoperable
Unfortunately, conventional staging commonly underestimates the
true extent of nonsmall-cell lung cancer. PET has proven to be
more sensitive and specific compared with conventional imaging of
NSCLC in several important areas, principally in staging of the
mediastinum and in the detection of distant metastases (Figure 3).
A recent analysis of 40 studies showed that PET is a highly
accurate noninvasive imaging test for the diagnosis of pulmonary
nodules and larger mass lesions. The mean sensitivity and
specificity were 96.8% and 77.8%, respectively.
FDG PET imaging can have a significant impact on patient
management by heightening suspicion for pulmonary malignancy,
identifying unsuspected sites of disease, and by guiding selection
of a biopsy site. Similarly, a negative PET can indicate a low
likelihood of malignancy and supports the use of conservative
management and follow-up. PET scans influence treatment in 65% of
patients with NSCLC and offer new information in 85% of patients.
FDG PET has been found to be superior to CT, MRI, and
mediastinoscopy in the nodal staging of bronchogenic carcinoma. In
suspected or proven lung cancer, PET is equally accurate and
reliable for detecting disease in small (<1 cm) and large (>3
cm) lymph node lesions, with better accuracy than CT. In a study by
the diagnostic accuracy for PET was 92% versus 75% for CT. The
positive predictive value for PET was 90% versus 50% for CT and the
negative predictive value was 93% for PET versus 85% for CT. A
meta-analysis of 14 PET studies and 29 CT studies showed PET to be
superior to CT in mediastinal imaging with a mean sensitivity and
specificity of 79% and 91%, respectively, for PET in contrast to
60% and 77%, respectively, for CT.
Vansteenkiste et al
also found a high negative predictive value (86%) of FDG PET for
disease in the mediastinal lymph nodes. It has been suggested that
negative PET results can be used as a basis for proceeding to
potentially curative thoracotomy even though a small fraction of
patients have lymph node involvement undetected by FDG PET.
One of the benefits of FDG PET is that the whole body can be
imaged without additional radiation exposure. At least 10% of
patients are found to have metastatic disease on PET scanning when
routine CT scan fails to show evidence of metastasis (Figure
Between 30% and 50% of patients with resected nonsmall-cell
lung cancer will develop recurrent tumor. FDG uptake in NSCLC has
been correlated with tumor growth rate, aggressiveness, and
proliferation capacity. The higher the SUV, the higher the
aggressiveness of the tumor and the worse the prognosis.
Determination of the extent of the primary tumor and of nodal
involvement is crucial for successful surgery and radical
radiotherapy. Most patients treated with radical chemotherapy
relapse with disease progression in the thorax or with distant
metastasis, suggesting that, in many cases, the initial staging
assessment underestimated the true extent of disease. Accurate
staging helps to avoid futile surgery or radical radiotherapy in
patients with incurable extensive disease. Bradley
reported that gross tumor volume was the sole independent predictor
of survival in NSCLC treated with conformal radiotherapy indicating
the importance of accuracy in tumor delineation. High-dose
radiotherapy is of little value if existent tumor is not included
in the target volume.
PET imaging has been very useful in assessing the response to
chemotherapy or radiation therapy in patients with advanced NSCLC
(Figure 5). Decrease in FDG uptake after treatment may prove to be
a better indicator of a favorable response rather than change in
tumor size. In a recent study, all patients with negative
post-therapy PET findings were alive 2 years after completion of
treatment, whereas in the group with residual hypermetabolism, 50%
of patients died.
PET imaging is very sensitive and highly accurate in
distinguishing recurrent malignancy from scarring or fibrosis and
from radiation-induced benign pleural thickening (Figure 6). It has
been shown to have a sensitivity of 98% to 100% for the
differentiation of posttreatment scar from tumor recurrence. There
are potential pitfalls when PET is used for the purpose of
differentiating hypermetabolic inflammatory changes induced by
radiation therapy (Figure 7) from recurrent tumor. Radiation
produces a diffuse mildly elevated FDG accumulation within the
tissues, which is due to the inflammatory changes caused by the
radiation. This activity decreases over time (3 to 6 months).
PET in esophageal cancer
Approximately 13,200 Americans are diagnosed with esophageal
cancer and 12,500 die from this malignancy annually.
There are two histologic types of esophageal carcinoma that account
for the majority of malignant cases: Squamous-cell carcinoma
(>75% to 90%) and adenocarcinoma. Esophageal cancer tends to be
aggressive in its behavior. It invades locally, spreads to local
lymph nodes, and then metastasizes throughout the body.
Approximately 15% of esophageal cancers occur in the upper third of
the esophagus, 45% in the middle third of the esophagus, and 40% in
the distal third of the esophagus.
Patients with esophageal carcinoma have a poor prognosis.
Although it is a disease that can be treated, it can rarely be
cured. By the time the patient becomes symptomatic, their disease
is usually at an advanced stage. The overall 5-year survival rate
in patients who undergo surgery ranges from 5% to 20%, while the
5-year survival rate in patients with lymph node metastases
(nonsurgical patients) ranges from 0% to 7%.
Once the diagnosis of esophageal cancer has been made, staging is
the next critical step in determining the most appropriate
treatment plan for the patient.
One of the major difficulties in planning treatment for patients
with esophageal cancer is the lack of precise preoperative staging.
Noninvasive imaging modalities include CT, endoscopic ultrasound
(EUS), and FDG PET. The overall staging accuracy of EUS in
esophageal cancer is 85% to 90%, as compared with 50% to 80% for
The reported sensitivities for FDG PET imaging is between 91% and
100%. False-positive uptake can occur due to inflammation, and
there can be normal mild FDG activity from muscular contractions.
The accuracy of regional nodal staging is 70% to 80% for EUS, while
CT has an accuracy of 40% to 73% for the detection of pathologic
mediastinal nodes (using a 1-cm size criteria).
The reported accuracy of FDG PET in the staging of regional lymph
node metastases ranges from 24% to 90%.
The major limitation of FDG PET with regard to the detection of
nodal metastases adjacent to the primary tumor is its relatively
poor spatial resolution (approximately 6 mm for a dedicated PET
scanner), which reduces sensitivity.
The major advantage of FDG PET over conventional imaging is its
ability to detect distant metastases to facilitate treatment
planning (Figures 8 and 9). Distant metastatic disease has a
significant impact on patient management because these patients are
no longer eligible for surgical resection. FDG PET has a reported
sensitivity of 69% to 100%, a specificity of 84% to 90%, and an
accuracy of 84% to 91% for the evaluation of distant metastases,
while the sensitivity of CT for distant metastases has been
reported to be lower.
FDG PET scans have also excluded metastatic disease at sites
considered abnormal on conventional imaging.
Primary treatment modalities include surgery, or chemotherapy
with radiation therapy. Combined modality therapy, which includes
chemotherapy plus surgery, or chemotherapy and radiation therapy
plus surgery, is another form of treatment. Palliative therapy
includes various combinations of surgery, chemotherapy, radiation
therapy, photodynamic therapy, endoscopic therapy, and stent
Two-thirds of patients with esophageal carcinoma have recurrence
within 1 year after primary operation and the majority of
recurrences are distant metastases (Figure 10).
For the diagnosis of regional and distant recurrences, FDG PET has
a sensitivity of 94%, a specificity of 82%, and an accuracy of 87%
(compared with 81%, 82%, and 81% for conventional imaging).
Positron emission tomography has had a significant impact on the
evaluation and management of patients with lung and esophageal
cancer. It provides an important noninvasive diagnostic modality
for localizing nodal involvement, primary tumor extent, and distant
metastases. The metabolic foundation of FDG PET imaging provides
the sensitivity to better define the fields for radiation therapy
and allow assessment of the effectiveness of either chemotherapy or
radiation therapy. With the use of combined functional and anatomic
imaging devices (PET/CT), this modality will become even more
valuable. The future will bring continued expansion of clinical
applications and new positron radiopharmaceuticals that should
greatly enhance the care delivered to patients with thoracic