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Original Studies |
Nuclear Medicine and Endocrinology Services, Departments of Radiology (W.W., S.M.L., H.Y., H.M.), Medicine (R.R.), Medical Physics (K.K., G.S.), Epidemiology and Biostatistics (M.F.), and Pathology (S.T., J.R.), The Laurent and Alberta Gerschel PET Center, Memorial Sloan Kettering Cancer Center, New York, New York 10021
Address all correspondence and requests for reprints to: Richard J. Robbins, M.D., Endocrinology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The ability of metastatic thyroid lesions to concentrate radioactive [131I]iodine (RAI) is generally held to indicate a more differentiated phenotype. Metastatic lesions that do not concentrate RAI are associated with more aggressive clinical progression (10, 11, 12, 13). Recent studies using [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning have discovered that lesions that do not concentrate RAI often have elevated glucose uptake rates (14, 15). Enhanced glucose metabolism by malignant tumor tissues was first shown by Warburg in 1923 (16). With the development of FDG and large field of view PET scanners, the in vivo visualization of lesional glucose metabolism is now possible. Benign or well differentiated thyroid tumors retain FDG poorly, whereas the more malignant ones appear to have a higher uptake of FDG (14, 17). In a retrospective analysis of 125 patients followed at our medical center, we analyzed the ability of FDG-PET to identify thyroid cancer patients who may have a poor prognosis. We hypothesized that patients with metastatic lesions that did not concentrate RAI but did have high glucose uptake would have reduced survival. We discovered that survival was significantly reduced when the FDG volume was over 125 mL or the standard uptake of FDG was greater than 10 g/mL.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A total of 125 patients with differentiated thyroid cancer underwent both FDG-PET and diagnostic [131I]iodine whole body scans (DxWBS) over a 41-month period (November 1995 to March 1999). Indications for FDG-PET imaging included negative DxWBS with elevated serum thyroglobulin (Tg), high risk patients on initial presentation, and known distant metastases by other imaging modalities (plain films, magnetic resonance imaging, computed tomography, or ultrasound). High risk was defined as age over 45 yr, less than well differentiated histology, extrathyroidal extension of tumor into adjacent neck structures, or tumor size greater than 4 cm. Not all consecutive patients fulfilling those entrance criteria had a FDG-PET study due to scheduling limitations, patient consent, and recommendation of the primary physician. Of 125 patients, 81 were female and 44 were male. The average age at diagnosis was 48.2 yr (minimum, 7 yr; maximum, 81 yr). The average age at the time of FDG-PET study was 53.3 yr (minimum, 16 yr; maximum, 84 yr). The average interval between diagnosis and FDG-PET was 63.1 months (minimum, 1.5 months; maximum, 448.5 months).
Pathological analyses
Histological diagnoses were made on surgical specimens by attending pathologists at Memorial Sloan-Kettering Cancer Center (18). As a part of this study, all available primary tumors (n = 84) were reexamined for grading purposes by two of the authors (S.T. and J.R.). The grade of the lesion was judged high or low based on architectural and cytological morphology. Architectural grade was judged low if the predominant pattern was papillary and/or follicular and high if the pattern was solid, nesting (insular), or trabecular. The cytological grade was judged to be high if the nuclei were hyperchromatic and mitotically active, and/or tumor necrosis was present. Tall cell variants of papillary thyroid cancer were categorized as low grade both architecturally and cytologically.
Clinical stage
The clinical and pathological staging was performed as a modification of the American Joint Committee on Cancer (AJCC) system (19). The patient’s initial AJCC stage was modified only to document the presence of distant metastases at the time of entry into this study. This changed the status from M0 to M1 in 14 patients. This modification was made to provide a real-time assessment of the current clinical status. The patients had the following tumor types: 93 papillary, 18 follicular, 12 Hurthle cell (including 1 case with mixed clear cell), and 2 anaplastic carcinomas. Tumor stage was T1 in 6 cases, T2 in 20 cases, T3 in 12 cases, T4 in 69 cases, and Tx in 18 cases. The lymph node status was as follow: 26 patients were node negative (N0), 77 patients were node positive (N1 = 40; N1a = 16; N1b = 21), and 22 patients had no information concerning lymph nodes metastasis (Nx). Among the 125 patients, 58 patients had distant metastases (M1). The modified AJCC stages were as follows: 30 stage I, 21 stage II, 27 stage III, and 47 stage IV.
Treatments before FDG-PET evaluation
The initial surgical procedure was total thyroidectomy in 92 patients, subtotal thyroidectomy in 13 patients, and hemithyroidectomy in 17 patients. Three patients had no surgery for the primary tumors. Before FDG-PET was performed, 101 of 125 cases had received at least 1 RAI treatment (with up to 5 treatments). The average cumulative dose of RAI before FDG-PET was 12.48 gigabecquerels (337.4 mCi), with a minimum of zero (not including the diagnostic dose) and a maximum of 64.46 gigabecquerels (1895.9 mCi).
Diagnostic RAI whole body scans
DxWBS were performed as part of the thyroid dosimetry protocol of Benua and Leeper (20, 21). Five patients had dosimetry with the aid of recombinant human TSH (Genzyme Transgenics Corp., Cambridge, MA). The procedure was similar, except that the patient continued T4 treatment and received im injections of recombinant human TSH on the 2 days before the dosimetry study (22).
FDG-PET imaging
The technical details of FDG-PET scanning and determination of the standard uptake value (SUV) in thyroid cancer patients were described in a previous report (17). The study was performed in 65 patients in a high TSH state (including 5 patients with rhTSH) and in 60 patients when TSH was low. We have previously reported that serum TSH levels do not alter FDG-PET outcomes in a clinically significant manner (17). In patients with multiple lesions, the SUV is that of the single highest lesion.
FDG volume calculation
Volume estimates were obtained using a three-dimensional dosimetry software package (3D-ID) (23, 24). Contours were manually drawn to define regions of likely tumor involvement and to exclude regions of physiological FDG uptake. Within these regions, a thresholding technique (25) was used to obtain the total area of pixels whose uptake value was greater than a user-defined foreground to background contrast ratio. The sum of the area defined in each slice and the thickness of each slice gave the total tumor volume.
Statistical methods
Univariate significance of all factors with respect to survival from the time of the PET scan was performed using the log-rank test for overall survival differences (26). All resulting P values are two sided. Survival curves were generated using Kaplan-Meier estimates (27). Multivariate methods were used to assess which subset of variables contributed the most information. To evaluate the level of information achieved, the score statistic obtained from the Cox proportional hazards model (28) was evaluated for each potential subset using the all subsets procedure in SAS (SAS Institute, Cary, NC).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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).
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Seventy-six (61%) of the patients were 45 yr or older at the time
of diagnosis. By univariate analysis, those over 45 yr had a
statistically significant reduced survival (P = 0.004;
Fig. 1A). The gender of the patient (64%
were female) did not influence survival over the 3-yr follow-up period
(P = 0.16).
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Fifty-eight patients had lung, bone, and other distant metastases.
Locoregional cervical metastases were not included as distant
metastases in accordance with the AJCC staging system. All deaths due
to thyroid cancer occurred in patients with distant metastases. In
univariate analysis, the presence of distant metastases had a
statistically significant (P = 0.0001) negative effect
on survival (Fig. 1B
). The single death in the group without distant
metastases and in the PET-negative group was due to one patient with
acute leukemia.
Histological type and grade of primary tumors
Papillary thyroid cancer and its variant were diagnosed in 74% of
the patients, follicular thyroid cancer in 18%, Hurthle cell carcinoma
in 9%, and anaplastic carcinoma in 1% of the patients. There was a
weak relationship between survival and histological type that was not
significant at the 0.05 level. Furthermore, there was no significant
relationship between survival and grade of the initial tumor
(P = 0.60; Fig. 1C).
Radioactive [131I]iodine uptake
There was no difference in survival between those with or without
(including thyroid bed uptake only) RAI uptake in metastatic lesions
(P = 0.34) during this short follow-up. Survival was lower in
those who had both RAI and FDG uptake in distant metastases compared
with those who had RAI uptake and negative FDG-PET scans
(P = 0.0008; Figs. 1D and 2).
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One death (due to acute myelocytic leukemia) occurred in the
subgroup of patients with negative FDG-PET scans. All 13 patients who
died of thyroid cancer had FDG-avid metastatic lesions. Univariate
analysis showed that FDG uptake predicted a significantly shorter
survival (P = 0.001; Fig. 3A).
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Among the 59 patients with positive FDG-PET scans, 27 had SUVs
greater than 10 g/mL. Patients with SUV greater than 10 g/mL had a
significantly shorter survival (P = 0.0002) than those
with SUV of 10 g/mL or less (Fig. 3B). Removing Hurthle cell carcinoma
patients from the analysis (due to their uniquely high SUV patterns)
did not change the significance level (P = 0.0002).
Volume of FDG lesions
Due to the small number of events in each volume subcategory
(Table 1), patients with volumes of 125 mL or less were compared to
those with volumes greater than 125 mL. The median survival, after PET
scanning, with FDG volumes greater than 125 mL was 19.2 months [95%
confidence interval (CI), 8.0, 34.0]. For volumes of 125 mL or less,
the median was not reached. By univariate analysis, patients with FDG
lesions greater than 125 mL had a significantly reduced survival
(P = 0.0001). The 3-yr survival probability of patients
with FDG volumes of 125 mL or less was 0.96 (95% CI, 0.91, 1.0)
compared with 0.18 (95% CI, 0.04, 0.85) in patients with FDG volume
greater than 125 mL (Fig. 3C). In analysis of only those with distant
metastases (M1), patients with FDG-avid lesions more than 125 mL had a
significantly shortened survival compared to those with volumes less
than 125 mL or no FDG uptake (Fig. 3D).
Multivariate analyses
Based on the univariate analyses, age, distant metastases, a
positive PET scan, maximum SUV, and volume of FDG lesions were all
significantly correlated with survival. To define which of these
variables carried the greatest prognostic value, we performed a
multivariate analysis. The score test was chosen to rank the relative
strengths of all possible subsets of the five variables. The score test
produced a 
2 value of 58, corresponding to
Fluorodeoxyglucose Avid-Disease volume alone, whereas all
other individual variables produced 2 values
below 17. When any other variable(s) was considered with
Fluorodeoxyglucose Avid-Disease volume, there was no significant
rise in the value of the 2 test. This suggests
that PET scanning in thyroid cancer patients may provide more useful
information about prognosis than the presence of distant metastases.
However, due to the small number of events, this multivariate analysis
is considered exploratory, and the resulting model imprecise.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Preliminary basic and clinical studies suggest that the most rapidly growing thyroid neoplasms have high metabolic rates. This retrospective study monitored the health and survival of a group of 125 patients with thyroid cancer over a 41-month interval. The initial intention was to assess metabolic rate via FDG-PET scans along with other standard monitoring assays over a 10-yr period. However, the high number of deaths in certain subsets of this cohort prompted us to issue this report. We found that the total volume of FDG-avid disease correlated with prognosis and was the strongest single risk fact predicting survival in this cohort. The fact that 80% of the patients with high volume disease died during a short interval begs the question of the need for long term follow-up of this subset.
Unlike larger long term studies, in which male patients have lower survival rates (5, 32), gender did not have a strong enough influence to be detected in this study (P = 0.16). The effect of age on the prognosis, however, was significant, even over this short follow-up period. All 14 deaths (including 1 not due to thyroid cancer) occurred in patients who were over 45 yr old when thyroid cancer was first diagnosed (P = 0.004).
The correlation between histological type and survival is well established for thyroid carcinomas. Long term survival rates for papillary carcinoma are generally higher than those for follicular carcinoma, and both are significantly higher than those for anaplastic carcinoma (4, 33). As in most reports of differentiated thyroid carcinoma, the majority of our patients had papillary thyroid cancer. This histological subtype alone did not significantly influence survival in this short term follow-up study.
The presence of distant metastases strongly influences survival and weighs heavily in the TNM and AMES staging systems. It is not surprising that all of the thyroid cancer deaths in our cohort occurred in those with distant metastases. However, if we stratify the 58 patients with distant metastases according to the PET findings, the clinical outcomes are different; there were no deaths in the 10 negative FDG-PET patients, whereas 13 of 48 (27%) PET-positive patients died of thyroid cancer. This was highly statistically significant (P = 0.0001).
The uptake of RAI implies that some of the malignant cells retain a differentiated phenotype and can, in theory, respond to treatment with RAI. Feine et al. (14) were the first to formally propose a pattern in which an inverse relationship between RAI uptake and FDG uptake ("flip-flop") existed in metastatic thyroid cancer lesions. However, the clinical significance of this flip-flop phenomenon has not been fully defined. Nakada et al. (13) also found that it was not the RAI uptake, but, rather, the uptake of thallium 201 that predicted the rate of growth of thyroid cancer lesions. In the present study, 88 patients had clinical evidence of local or distant metastases. Twenty-one patients had RAI uptake only (23.8%), 26 patients had FDG uptake only (29.5%), 33 patients had mixed RAI/FDG uptake (37.5%), and 8 patients had negative RAI and FDG-PET scans (9%). All of the deaths occurred in either the FDG only or the mixed RAI/FDG groups. Therefore, survival appears to be less related to the residual disease that concentrates RAI and strongly correlated with the disease that concentrates FDG.
PET has established itself as an important new tool in clinical oncology. Compared to other noniodine radionuclide imaging agents, FDG-PET appears to provide the highest resolution for detecting aggressive metastatic thyroid cancer lesions (34, 35, 36). Although the utility of FDG-PET for detecting thyroid cancer lesions in patients who have negative DxWBS and elevated serum Tg has been established (17), its potential as a prognostic marker has yet to be determined. A recent study demonstrated that primary tumor SUV was the single best predictor for survival in nonsmall cell lung carcinoma (37). In addition to showing reduced survival in those with FDG-avid disease, we also found a significant correlation with the maximum SUV, suggesting that tumors with the highest metabolic activity might be those with the most rapid growth potential.
Finally, we explored a new approach by measuring the three-dimensional FDG volume (23, 25). We discovered that survival was directly related to the total volume of FDG disease; the higher the volume, the shorter the survival. Multivariate analyses revealed that high volume (>125 mL) of the FDG-avid diseases provided stronger prognostic information than did age, gender, initial histological type or grade, presence of RAI uptake, or modified AJCC stage. In fact, the strongest single predictor of short term survival was the volume of FDG-avid tumor. Eighty percent of those with FDG-PET volumes over 125 mL had expired by 41 months. We do not have sufficient data to estimate the rate of progression of FDG volume; however, strong consideration should be given to periodic FDG-PET scanning in patients with metastatic thyroid carcinoma who have FDG-positive lesions. Unfortunately, there is no established treatment that will improve survival in patients with metastatic FDG-PET-positive disease. Our preliminary data suggest that high dose RAI is not able to eradicate FDG-avid metastases (38). This is in agreement with a recent report on the inability of radioiodine to eradicate thyroid cancer lesions that take up high levels of thallium 201 (13).
In summary, we identified a group of patients with metastatic thyroid cancer at very high risk for dying within a 41-month interval. These patients had distant metastases that concentrated FDG regardless of whether they also concentrated RAI. The presence of FDG uptake was not as strong a predictor of survival as was the FDG-PET volume of disease. Therapeutic research protocols for such high risk patients need to be designed, possibly using FDG-PET assessments as quantitative outcome measures.
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Acknowledgments |
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Footnotes |
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Received July 23, 1999.
Revised November 12, 1999.
Accepted November 30, 1999.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
, high/low; 
, low/low;
P = 0.6), and those with distant metastases who
were RAI-/PET- (
