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Original Research |
1 Department of Radiology and Center for Imaging Science, Samsung Medical
Center, Sungkyunkwan University School of Medicine, 50, Ilwon-dong,
Kangnam-gu, Seoul, South Korea, 135-710.
2 Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul, South Korea.
Received April 7, 2006;
accepted after revision August 18, 2006.
Address correspondence to K. S. Lee
(kyungs.lee{at}samsung.com).
Abstract
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MATERIALS AND METHODS. Between May 2003 and February 2005, 37 consecutively enrolled patients (33 men and four women; mean age, 60 years) with histopathologically proven pulmonary neuroendocrine tumors underwent 18F-FDG PET/CT after enhanced standalone CT. CT was used to analyze the morphologic features of the tumors and PET to measure maximum standardized uptake value (SUV). Maximum SUVs of carcinoid tumors, large-cell neuroendocrine carcinomas (LCNECs), and small-cell lung carcinomas (SCLCs) were compared, and maximum SUV and tumor stage and prognosis were correlated.
RESULTS. Four (two typical and two atypical) of the seven carcinoid tumors had no FDG uptake or less than mediastinal uptake. The maximum SUVs of primary tumors, in increasing order, were significantly different for carcinoids (mean, 4.0; median, 3.4), LCNECs (mean, 12.0; median, 10.7), and SCLCs (mean, 11.6; median, 11.7) (p = 0.006, Kruskal-Wallis test). There was no significant correlation between maximum SUV of the primary tumor and the tumor stages of carcinoids, LCNECs, or SCLCs (p = 0.08, Jonckheere-Terpstra test; p = 0.768, Mann-Whitney test). Results of receiver operating characteristics analysis showed a maximum SUV greater than 13.7 suggested a poor survival period in cases of LCNEC and SCLC.
CONCLUSION. The maximum SUVs of neuroendocrine tumors are significantly different for carcinoid tumors, LCNECs, and SCLCs, and a high maximum SUV suggests short survival of patients with LCNEC or SCLC.
Keywords: chest • CT • lung • oncologic imaging • PET/CT
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The imaging findings of neuroendocrine tumors are well recognized. Typical and atypical carcinoid tumors appear on CT as spherical or ovoid nodules or masses with well-defined and slightly lobulated borders. Nonspherical tumors are elongated with the long axis parallel to adjacent bronchi. Calcification or ossification is present in as many as 30% of tumors [4]. The CT findings for LCNEC of the lung are nonspecific and similar to those of other non-small cell carcinoma of the lung [4-6]. Most SCLCs are located centrally and appear with mediastinal (92% of cases) or hilar (84%) lymphadenopathy accompanying lobar atelectasis (30%) or a noncontiguous parenchymal mass [7]. In 5-10% of cases, SCLC manifests as a peripheral nodule without associated lymphadenopathy [8, 9].
It has been anecdotally reported [10] that carcinoid tumors do not exhibit increased activity during PET and usually have less 18F-FDG uptake than is expected for malignant tumors. It also has been reported [10, 11], however, that carcinoids may have increased FDG uptake and thus high metabolic activity and malignant potential. Because it is used to evaluate non-small cell carcinoma of the lung, FDG PET has been studied for evaluation of SCLC. In those studies, FDG PET was found to be highly sensitive in the detection of SCLC and useful for predicting prognosis and tumor stage [12-17]. To our knowledge, however, no study has been conducted on PET of LCNEC. The purpose of our study was to describe integrated PET/CT findings on neuroendocrine tumors of the lung in a relatively large number of patients and to correlate the findings with prognosis.
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Patient Population
Between May 2003 and February 2005, a total of 1,276 patients consecutively
underwent integrated PET/CT examinations after contrast-enhanced standalone CT
for the evaluation of lung neoplasms. At our institution, integrated PET/CT
was usually recommended for cancer staging before surgery on patients with
confirmed lung neoplasms and for tissue characterization in patients with
clinically indeterminate solitary pulmonary nodules. Among the 1,276 patients,
37 patients (33 men and four women; age range, 23-78 years; mean age, 60
years) proved to have a neuroendocrine tumor of the lung. Ten (27%) of the 37
patients (one with atypical carcinoid, seven with LCNEC, and two with SCLC)
had a medical history of pulmonary tuberculosis as determined with clinical or
imaging studies.
Enhanced Standalone CT Acquisition and Image Analysis
CT scans were acquired with helical technique (16-MDCT, HiLight or
LightSpeed Ultra, GE Healthcare). Images were obtained with the following
parameters: 120 kVp, 170 mA, 5-mm collimation, and total active detector
length pitch of 1.3-1.5. The scans covered the level of thoracic inlet to the
middle portion of both kidneys. Image data were reconstructed in the
transverse (5.0-mm thickness) plane only. In all cases, a power injector (MCT
Plus, Medrad) was used for IV injection of 100 mL of contrast medium
([iopamidol], Iopamiron 300, Bracco) at a rate of 2 mL/s.
A thoracic radiologist with 6 years of experience interpreted all CT scans. This reviewer was unaware of integrated PET/CT, surgical, and pathologic findings and of clinical information except that the patient had a lung tumor. CT scans were analyzed for location, size, and shape of the tumor; pattern and degree of enhancement compared with chest wall muscle; marginal characteristics; and the presence of calcification, necrotic low-attenuation area, and associated postobstructive atelectasis or pneumonia. Tumors were regarded as central when located within or proximal to the segmental bronchial lumen. Otherwise, tumors were considered to be peripherally located. Tumor size was defined as longest diameter; tumor shape was classified as round, ovoid, or rectangular; and tumor contour was classified as smooth, lobulated, spiculated, or lobulated and spiculated. Calcifications were classified as stippled, round nodular, popcornlike, diffuse, or laminated.
Tumor staging was performed with the newly revised International System for Staging Lung Cancer as adopted by the American Joint Committee on Cancer and the International Union Against Cancer for the classification of lung cancer [18]. Tumor staging was performed in consideration of size, involvement of surrounding organ and chest wall, and distance of the primary tumor from the carina. Lymph node assessment was based on size. Nodes with a short-axis diameter greater than 10 mm were defined as abnormal, and the presence of necrosis within a lymph node was considered a sign of malignancy, regardless of node size. Hilar lymph nodes were considered positive for malignancy when their greatest diameter exceeded 10 mm.
Integrated PET/CT Acquisition and Image Analysis
All patients fasted for at least 6 hours before PET/CT, although oral
hydration with glucose-free water was allowed. After verification of a normal
blood glucose level in the peripheral blood, patients received an IV injection
of 370 MBq (10 mCi) of FDG and then rested for approximately 45 minutes before
undergoing imaging. Image acquisition was performed with an integrated PET/CT
device (Discovery LS, GE Healthcare) consisting of a PET scanner (Advance NXi)
and an 8-MDCT scanner (Light Speed Plus). The axes of both systems were
mechanically aligned such that the patient could be moved from the CT scanner
to the PET scanner with movement of the examination table 68 cm.
CT was performed from the head to the pelvic floor according to the following standardized protocol: 140 kV, 80 mA, tube rotation time of 0.5 second per rotation, pitch of 6, and a section thickness of 5.0 mm, which matched the PET image section thickness. Patients were allowed normal shallow respiration during acquisition of CT scans. No contrast material was administered. Immediately after CT, PET was performed with an identical axial field of view. The acquisition time for PET was 5 minutes per table position. CT data were resized from a 512 x 512 matrix to a 128 x 128 matrix to match the PET data to allow image fusion, and CT transmission maps were generated. PET image data sets were reconstructed iteratively with the ordered-subsets expectation maximization algorithm with segmented measured attenuation correction (two iterations, 28 subsets) with the CT data. Coregistered images were displayed with eNTEGRA software (GE Healthcare), which allowed image fusion and analysis.
The images were interpreted by one chest radiologist, who was not involved in standalone CT analysis, and one nuclear medicine physician. The chest radiologist had 16 years of CT interpretation experience and 2 years of integrated PET/CT interpretation experience. The nuclear medicine physician had 11 years of PET interpretation experience and 2 years of integrated PET/CT interpretation experience. The reviewers were blinded to clinical, standalone CT, and pathologic results and together prospectively evaluated integrated PET/CT data sets. Decisions on findings were reached by consensus.
After analysis of CT images for tumor location, size, shape, attenuation value, and margin characteristics and for the presence of calcification, necrotic low-attenuation areas, and associated post-obstructive atelectasis or pneumonia, as in the analysis of enhanced standalone CT images, PET maximum standardized uptake values (SUVs) of primary lung tumors were measured. The presence of hilar nodal, mediastinal nodal, and extrathoracic FDG uptake was recorded for carcinoid tumors and LCNEC. For SCLC, maximum SUV was chosen from the node of highest uptake when the disease appeared as extensive hilar or mediastinal lymph node enlargement without pulmonary nodules. When the disease manifested as a pulmonary nodule plus hilar or mediastinal lymph node enlargement, the maximum SUV was chosen from the area of greatest uptake, whether or not greatest uptake was identified as being associated with a pulmonary nodule or lymph node. Hilar or mediastinal nodal uptake was considered positive when it was greater than mediastinal uptake. Extrathoracic uptake was considered positive when it was greater than the normal uptake of the surrounding organ (e.g., positive when adrenal uptake was greater than liver uptake). Even if glucose uptake was high (greater than background activity), calcified lymph nodes and lymph nodes with greater attenuation than the surrounding great vessels on CT images at integrated PET/CT were considered benign [19].
Surgical and Histopathologic Analysis
Surgical staging was performed by one of two experienced thoracic surgeons
who had 17 years and 12 years of experience. Tumor stages were determined with
the TNM and American Joint Committee on Cancer staging systems
[16] for carcinoid tumors and
LCNECs. Surgical staging of carcinoids (n =7) and LCNECs (n
= 15) included mediastinoscopy alone (n = 1), mediastinoscopy and
thoracotomy (n = 10), and thoracotomy alone (n = 10). In one
patient with LCNEC, who underwent only bronchoscopic biopsy, clinical staging
was based on imaging findings alone. For carcinoids (n =7) and LCNECs
(n = 15), patients in whom the primary tumor was limited to a lobe
(n = 13) underwent lobectomy. Patients with hilar node metastasis of
extracapsular invasion or tumor located in the bronchus intermedius underwent
bilobectomy (n = 3) or pneumonectomy (n =4). Two patients
with LCNEC in pathologic stages T1N3 and T2N2 underwent chemoradiation therapy
without surgical removal. Histologic diagnoses of SCLC (n = 15) were
obtained by bronchoscopic biopsy in eight cases and by transthoracic
percutaneous fine needle aspiration biopsy in seven cases.
If thoracotomy was performed, a lung pathologist with 10 years of experience evaluated tumors for histopathologic class, size, surrounding organ involvement, necrosis, and distance from the resection margin and evaluated lymph nodes for location and number. The surgeons labeled dissected lymph nodes using a numbering system based on the lymph node map definition of lung cancer staging proposed by Mountain and Dresler [18]. A pathologist evaluated the nodes as numbered in the surgical field. Specimens were stained with H and E and examined with light microscopy.
Extrathoracic Cancer Staging
In addition to whole-body PET/CT, thoracic and abdominal CT, whole-body
bone scanning, and dedicated brain MRI were used for additional conventional
cancer staging. The use of these staging techniques was considered in the
context of the clinical situation. Tumor staging of SCLC was performed with
the Veterans Administration Lung Study Group definition of SCLC
[20]. Limited-stage SCLC was
defined as carcinoma confined to a tolerable radiation port and included
regional mediastinal and supraclavicular lymph nodes and pleural effusion.
Integration of whole-body integrated PET/CT and brain MRI results and clinical
findings, including follow-up study results if any, served as the reference
standard for tumor staging.
Data Analysis and Statistics
Statistical analysis was performed with SAS 8.2 (SAS Institute).
Differences in maximum SUVs and patient ages among carcinoid tumors, LCNECs,
and SCLCs were analyzed with the Kruskal-Wallis test. Sex difference and
presence of extrathoracic involvement among the three groups were tested with
the chi-square test. Survival rates among the three groups were compared by
use of Kaplan-Meier methods. Correlation between the maximum SUV of primary
tumors and tumor stage in patients with carcinoids and those with LCNECs was
performed with the Jonckheere-Terpstra test. Differences between the maximum
SUVs of limited and extensive stages of SCLC were analyzed with the
Mann-Whitney test. Correlation between maximum SUV and survival length was
evaluated with receiver operating characteristics (ROC) analysis. When any
cutoff value was acquired with ROC analysis, the appropriateness of the value
was tested by use of the Cox proportional hazards model to adjust age and
other variables. For carcinoids, LCNECs, and SCLCs, tumor staging accuracy
with PET/CT was compared with that with standalone CT and the conventional
staging method.
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All seven patients with carcinoids survived a mean follow-up period of 18 months (range, 12-26 months; median, 19 months). Eight (53%) of 15 patients with LCNEC survived a mean follow-up period of 17 months (range, 1-25 months; median, 19 months). Seven (47%) of 15 patients with SCLC survived a follow-up period of 15 months (range, 5-27 months; median, 15 months). There was no significant difference in survival rates among the three groups (p = 0.183, Kaplan-Meier method).
Morphology of Tumors on CT
Of seven carcinoids, three were centrally located and four peripherally
located (Figs. 1A,
1B,
1C and
2A,
2B,
2C). Four tumors were ovoid;
two, round; and one, polygonal. Six tumors had a smooth margin, and one was
lobulated. Punctate calcification was found in one (14%) of seven carcinoids
(Fig. 1A,
1B,
1C). One atypical carcinoid had
a small area (< 10% of tumor volume) of necrosis. Two typical carcinoids
exhibited greater enhancement than chest wall muscle. Two atypical carcinoids
exhibited greater enhancement than chest wall muscle, and three exhibited
isoattenuation. Obstructive pneumonia or atelectasis was found in three
central tumors (Table 1). In
one atypical carcinoid, the tumor appeared as a small (12 mm in longest
diameter) parenchymal nodule with extensive ipsilateral hilar lymph node
enlargement (Fig. 2A,
2B,
2C).
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Comparison of Staging Accuracy Between Conventional Methods and PET/CT
Histologic examination revealed hilar nodal metastatic lesions in two
patients with atypical carcinoid and seven patients with LCNEC. Mediastinal
nodal metastasis was present in three patients with LCNEC (N2 in two patients
and N3 in one patient). For hilar nodal metastasis, false-negative
interpretation was rendered at integrated PET/CT of one patient with LCNEC
(patient 12, Table 1), and
false-positive interpretation was rendered at standalone CT of another patient
(patient 16, Table 1). The two
techniques were correct for prediction of mediastinal nodal metastasis.
However, in a patient with N3 disease in whom right supraclavicular lymph node
metastasis was present (patient 14, Table
1), only PET/CT depicted the nodal metastatic lesion.
Extrathoracic tumor involvement was present in one of 15 patients with LCNEC (bone involvement) and three of 15 patients with SCLC (involvement of colon, brain, and paraaortic nodes in the abdominal cavity). There was no difference in extrathoracic involvement ratios among the three groups (p = 0.499, chi-square test). Bone metastasis in a patient with LCNEC (Fig. 5A, 5B, 5C, 5D) was detected only at integrated PET/CT.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been reported [21] that an atypical carcinoid can appear as a small pulmonary nodule with extensive hilar or mediastinal lymph node enlargement. In our study, one case of atypical carcinoid appeared as a small peripheral nodule and extensive hilar lymph node enlargement (patient 7, Table 1). In this case, the parenchymal nodule had a maximum SUV of 1.7, whereas hilar nodes had a maximum SUV of 11.2. Carcinoids tend to be vascular and can exhibit considerable enhancement. This characteristic is particularly helpful for differentiating tumor from obstructive atelectasis and adjacent mucous plugs [4]. In our study, four of seven carcinoids had high and homogeneous enhancement.
LCNEC manifests as peripheral pulmonary nodules more often (73-84% of cases) than it does as central lesions accompanying obstructive pneumonia or atelectasis [5, 6]. In our study, 10 (67%) of 15 LCNECs appeared as peripheral lung nodules. The frequencies of the presence of tumor necrosis (75%, 12 of 15 tumors) and a lobulated tumor margin (87%, 13 of 15 tumors) in our cases concurred with the findings in previous reports [5, 6]. With regard to maximum SUV, all LCNECs had homogeneously high FDG uptake. The maximum SUV of LCNECs ranged from 3.9 to 25.6 (mean, 12.0; median, 10.7). This finding is somewhat contradictory to the maximum SUV of adenocarcinoma. Adenocarcinoma has low FDG uptake proportional to the extent of the bronchioloalveolar carcinoma component in the tumor and thus simulates benign nodules with a large bronchioloalveolar carcinoma component [22, 23].
In LCNEC, both integrated PET/CT and standalone CT showed similar and high accuracy in prediction of the presence of hilar and mediastinal nodal metastasis. However, PET/CT helped identify supraclavicular nodal metastasis in one patient and bone metastasis in another. Thus in overall staging, integrated PET/CT was better than standalone CT and conventional staging. Moreover, the maximum SUV greater than 13.7 suggested a short survival period. Therefore, integrated PET/CT was useful not only in staging but also in predicting prognosis of LCNEC.
Accurate staging is as important in SCLC as it is in non-small cell carcinoma of the lung. Patients with limited-stage SCLC are treated with chemoradiation therapy, whereas those with extensive-stage disease usually receive chemotherapy alone. PET has been regarded as valuable for initial tumor staging (limited vs extensive) and for the planning of treatment of patients with presumed limited-stage disease [12-17].
According to a report by Pandit et al. [12], PET of patients with SCLC is useful for predicting prognosis, especially among treated patients. After-treatment survival in PET-positive cases is significantly worse than in PET-negative cases. We found a significant negative correlation between maximum SUV and survival. In addition, in the cases of eight untreated patients, PET staging results concurred with the final clinical stage determined by conventional methods. Also in our study, the maximum SUV of SCLC before treatment showed a negative correlation with survival time.
In our study, the maximum SUVs of primary tumors were significantly different for carcinoid tumors, LCNECs, and SCLCs, increasing in that order. However, there was no significant positive correlation between maximum SUV of primary tumors and tumor stage of carcinoids, LCNECs, and SCLCs. The absence of positive correlation between the maximum SUV of the primary tumor and tumor stage has been reported [24]. Therefore, the maximum SUV of primary pulmonary neuroendocrine tumors appears not to be a crucial factor in the initial differentiation of early from advanced stages of disease.
Our study suffered from selection bias. The number of SCLC patients enrolled was small compared with the clinical population. According to tumor registry data [25-27], carcinoid tumors account for 1-2% of pulmonary neoplasms; LCNECs, 3%; and SCLCs, 20%. Therefore, a disproportionate number of carcinoid and LCNEC cases may have been included in our study. In addition, we did not routinely perform immunohistochemical staining, such as Ki 67 marker studies, for quantification of tumor proliferation. A study comparing immunohistochemical marker findings and tumor SUV may help clarify tumor differentiation and proliferation and thus overall prognosis.
In conclusion, approximately one half of carcinoid tumors simulate benign tumors by exhibiting little FDG uptake. The maximum SUVs of neuroendocrine tumors are significantly different for carcinoids, LCNECs, and SCLCs, maximum SUV increasing in the order listed. In addition, maximum SUV greater than 13.7 for LCNEC and SCLC suggests a short survival period. Integrated PET/CT is more accurate than standalone CT or conventional staging methods in the detection of extrapulmonary metastatic lesions.
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