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1 School of Medicine, Duke University, Durham, NC 27710.
2 Department of Radiology, Duke University Medical Center, Box 3803, Durham, NC
27710.
Received September 12, 2003;
accepted after revision October 30, 2003.
Address correspondence to E. F. Patz, Jr.
(patz0002{at}mc.duke.edu).
Abstract
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MATERIALS AND METHODS. A total of 3,912 patients between November 1994 and August 2002 underwent thoracic or whole-body PET performed at our institution for evaluation of a pulmonary abnormality suspicious for lung cancer. We identified 20 patients with a biopsy-proven primary lung tumor and a negative PET study at the time of presentation. Surgical, pathologic, radiographic imaging, and clinical follow-up information were reviewed to confirm the histology, stage, and outcome.
RESULTS. Tumor histology included adenocarcinoma (n = 7, 35%), bronchioalveolar cell carcinoma (n = 6, 30%), carcinoid (n = 3, 15%), squamous cell carcinoma (n = 2, 10%), otherwise unspecified non–small cell lung cancer (n = 1, 5%), and sarcomatoid neoplasm (n = 1, 5%). One patient with bronchioalveolar cell carcinoma had multifocal stage IV disease, and all other patients were stage IA (n = 14, 70%) or stage IB (n = 5, 25%). Eighteen (90%) of the 20 patients underwent curative surgical resection. No patient is known to have tumor recurrence after resection, and three (17%) of the 18 patients are known to be living and free of disease 5 years after surgery.
CONCLUSION. With the exception of bronchioalveolar cell carcinoma and carcinoid, newly diagnosed lung cancers with negative PET findings are usually early-stage diseases and are associated with a favorable prognosis, suggesting that indeterminate pulmonary nodules, which are PET-negative, can be managed conservatively with serial radiographic studies to monitor for signs of growth. These findings warrant further study and should be confirmed with sufficient follow-up in a large cohort of patients with PET-negative lung lesions.
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The negative predictive value of an FDG PET scan also appears to be clinically useful [1–4], although several studies have described false-negative PET results in patients with primary lung cancer, most notably bronchioalveolar cell carcinoma and carcinoid tumors [5–10].
To our knowledge, few data have been published, however, on the clinical significance of a false-negative PET lesion that later proves to be malignant [11]. Thus, in an effort to determine the natural history of patients with PET-negative lung cancer, this study retrospectively reviewed the stage and prognosis of indeterminate pulmonary nodules that were interpreted as negative on PET and subsequently proven to be a primary lung malignancy.
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Conventional Imaging
CT of the chest was available for review in 13 patients (65%), and reports
of CT scans obtained at outside institutions were available in the others.
Because of the retrospective nature of the study, the CT scans were obtained
on several scanners using a variety of scanning techniques (collimation,
5–10 mm). The size of the primary tumor and the presence of
lymphadenopathy, pleural disease, and all other abnormalities were recorded.
These studies were used to localize the abnormalities of interest on the FDG
PET studies but were interpreted separately from the FDG PET scans.
PET
PET was begun approximately 30 min after IV injection of FDG. PET was
performed on an Advance system (General Electric Medical Systems) in 2D
acquisition mode. Before January 2000, nonattenuation-corrected scans were
initially obtained for 4 min per bed position from the level of the base of
the brain through the middle of the thighs. A two-bed position
attenuation-corrected regional chest scan was then performed using 8 min for
the emission scan and 10 min for the transmission scan at each bed position.
The images were reconstructed using a Hann filter with a cutoff of 0.71
cm.
PET studies performed after January 2000 used emission images obtained for 4 min per bed position from the level of the base of the brain through the middle of the thighs. Transmission images using a Germanium-68 rod source were then obtained for 2 min 30 sec per bed position. The images were reconstructed using ordered-subset expectation maximization (two iterations) and segmented attenuation correction. Reconstructed images had a matrix of 128 x 128 x 35 with 4.30 x 4.30 x 4.25 mm voxels. The axial, coronal, sagittal, and maximum intensity projection were reviewed on the vendor-supplied workstation.
All PET studies were interpreted by visual inspection and considered
positive if tumor activity was greater than background mediastinal activity
and negative if tumor activity was the same as or less than background
mediastinal activity [12].
Although not usual practice at our institution, in eight PET studies a
three-pixel diameter circular region of interest was placed on the axial PET
image in the tumor on the slice with the maximum pixel value. After correction
for radioactive decay, the region of interest was calculated according to the
following formula:
 |
Tumor Size, Histology, Stage Distribution, and Survival
Medical records from all 20 patients were reviewed to confirm the size,
histology, and stage of disease at the time of presentation. A final
pathologic stage was assigned to each case based on the TNM classification of
the International System for Staging Lung Cancer, using the standard practice
[13]. Patient records were
reviewed to determine survival status.
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PET
All patients had minimal or no significant FDG uptake in their primary lung
lesion. No patient had increased FDG uptake in regional hilar or mediastinal
lymph nodes or any other areas of abnormal FDG activity extrinsic to the lung.
Standardized uptake values were reported for eight patients (40%). The mean
standardized uptake value was 1.6 (SD, 0.4; range, 1.2–2.4).
Indication for Biopsy
Three patients (15%) had biopsy and confirmation of lung cancer before PET
with a delay of less than 6 weeks. The other 17 patients (85%) had a
definitive diagnosis of lung cancer 1–238 days after PET (mean, 78
days). In 15 (88%) of the 17 cases, the pathologic diagnosis of lung cancer
was established as part of a surgical resection procedure. Tissue diagnosis
was obtained in all patients for a variety of reasons: persistent pulmonary
nodule in asymptomatic patient (n = 11, 55%), suspected primary lung
cancer (n = 3, 15%), unresolving pneumonia (n = 2, 10%),
presurgical staging of presumed metastatic lung nodule (n = 2, 10%),
and diagnosis of indeterminate pulmonary lung nodule before inclusion on organ
transplant list (n = 2, 10%).
Histology
All patients had tissue diagnosis of primary lung cancer. Tumor histology
included adenocarcinoma (n = 7, 35%), bronchioalveolar cell carcinoma
(n = 6, 30%), carcinoid (n = 3, 15%), squamous cell
carcinoma (n = 2, 10%), otherwise unspecified non–small cell
lung cancer (n = 1, 5%), and sarcomatoid neoplasm (n = 1,
5%).
Tumor Staging
Eighteen (90%) of the 20 patients were staged at the time of surgical
resection. All of these patients had pathologic T1 N0 M0 stage IA (n
= 14, 70%) or pathologic T2 N0 M0 stage IB (n = 4, 20%) disease (Fig.
1A,
1B). Two patients did not have
surgical intervention. One patient was diagnosed with stage IV multifocal
bronchioalveolar cell carcinoma with contralateral lung metastases seen on CT.
This patient had slowly progressive pulmonary lesions over a 3-year period,
but no evidence for extrathoracic disease (Fig.
2A,
2B). The other nonsurgical
patient died from cardiac arrest within 1 week of diagnosis and had a clinical
T2 N0 M0 stage IB lung cancer that was 0.3 cm in largest dimension on CT.
Seventeen (94%) of the 18 patients who underwent surgical resection had
concomitant resection of at least one regional lymph node. All patients were
N0. Metastasis in the lung was found in one patient (5%) with the multifocal
bronchioalveolar cell carcinoma. No other patients had metastatic disease.
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Prognosis and Survival
Surgical resection was deemed curative in all 18 cases, and no patient
received adjuvant chemotherapy or radiation therapy. Fifteen patients (83%)
had postsurgical follow-up at our institution. None of these patients is known
to have tumor recurrence at a mean follow-up of 24 months (range, 2–61
months). Three patients (17%) have been free of disease for 5 years after
resection, and five other patients (28%) have been free of disease for at
least 2 years after resection. Three of the 20 patients (15%), including the
one patient with multifocal bronchioalveolar cell carcinoma, were lost to
follow-up within 1 week of resection (n = 2) or PET (n = 1).
One patient was discharged from follow-up 5 years after resection.
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Conversely, the high negative predictive value suggests that most patients with pulmonary lesions and no significant FDG uptake have a benign abnormality. These patients are typically followed up with sequential imaging studies rather than having an immediate interventional procedure to establish a diagnosis. Two well-known exceptions are bronchioalveolar cell carcinoma and carcinoid tumors, and reports of PET-negative lung cancers predict these disease subtypes will be more biologically indolent than malignancies found to be positive on PET [7–11].
This study specifically addressed the issue of stage and outcome in lung cancer patients who had negative findings on PET scans, to provide support for current management recommendations. The results showed that nearly all PET-negative lung malignancies were stage I, with most of those being stage IA. These patients had a high rate of curative surgical resection and excellent long-term clinical outcome. Therefore, the results of this study confirm that careful follow-up of patients with lung lesions and negative PET findings is a reasonable diagnostic strategy. If the pulmonary abnormality grows, then a biopsy should be performed because an indolent lung cancer is possible. The delay in diagnosis while following up lesions does not appear to compromise patient outcome. The one patient with advanced multifocal bronchioalveolar cell carcinoma already had diffuse disease at the time of the negative PET finding, and a delay in diagnosis did not affect prognosis.
This study is subject to certain limitations because of its retrospective nature. Many patients receiving PET scans at our institution were referred for PET only. Therefore, information about clinical course and long-term follow-up were not available in all patients. The number of patients with an indeterminate nodule and negative PET findings who actually had a malignancy is unknown because most of these patients are followed up outside of our institution. Unless a tissue diagnosis is established in all cases, this source of bias may artificially inflate the sensitivity and negative predictive value of PET.
Several investigators have commented on potential limitations of PET in the evaluation of small nodules less than 1 cm. Subcentimeter lesions may be predisposed to false-negative results on PET, either because of technical limitations of PET or low overall tumor cell volume [14]. Although this study had a small number of patients, the occurrence of falsely negative subcentimeter nodules appears to depend more on their inherent biologic indolence than on their size [11]. Three primary tumors (15%) in this series were less than 1 cm on pathology, and one tumor (5%) was less than 1 cm on CT. All four tumors were either stage IA or IB, suggesting PET-negative subcentimeter primary lung tumors behave no differently from larger tumors that have no significant FDG activity.
In conclusion, our data suggest a possible strategy of clinical management of indeterminate pulmonary nodules in patients with false-negative findings on PET. Any indeterminate pulmonary nodules in patients with clinical or radiographic findings suspicious for bronchioalveolar cell carcinoma or carcinoid should be followed up closely or should undergo biopsy. In this subpopulation, physicians involved in FDG PET interpretation are advised to correlate imaging data with the CT pattern. In all other cases, PET-negative nodules can be managed conservatively. These nodules may be safely followed up with serial chest radiographs or CT scans to determine changes in size. In those patients with a negative PET finding who later prove to have a primary lung cancer, the disease is usually slow-growing and amenable to curative resection.
The aforementioned strategy holds promise for minimizing morbidity and mortality from invasive procedures while maintaining a low risk of mortality from lung cancer. These recommendations warrant further investigation and confirmation in a larger study with appropriate follow-up in the entire population of patients with PET-negative lung lesions.
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