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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-0779
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 1 328-334
Copyright © 2005 by The Endocrine Society

[18F]Fluorodeoxyglucose Uptake in Recurrent Thyroid Cancer Is Related to Hexokinase I Expression in the Primary Tumor

L. Hooft, A. A. M. van der Veldt, P. J. van Diest, O. S. Hoekstra, J. Berkhof, G. J. J. Teule and C. F. M. Molthoff

Departments of Nuclear Medicine and PET Research (L.H., A.A.M.v.d.V., O.S.H., G.J.J.T., C.F.M.M.), Clinical Epidemiology and Biostatistics (L.H., O.S.H., J.B.), and Pathology (P.J.v.D.), Vrije Universiteit Medical Center, Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. C. F. M. Molthoff, Department of Nuclear Medicine and PET Research, Room 5A86, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: cfm.molthoff{at}vumc.nl.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Patients suspected of recurrent differentiated thyroid cancer (DTC) may require "blind" 131I therapy, with the disadvantage of unpredictable efficacy and toxicity. Alternatively, positron emission tomography (PET) with [18F]fluorodeoxyglucose (18FDG) can document the recurrence, thereby rationalizing therapeutic options. This study compared 18FDG uptake in vivo with biomarkers expected to be involved in the underlying biological mechanisms. Additionally, we investigated whether such features were present in the primary tumors. Preoperatively, 19 patients with recurrent DTC underwent PET. 18FDG uptake was compared with histological and immunohistochemical features in surgical specimens of recurrent and primary tumor. Thirteen of 19 recurrences were positive at PET, and 18FDG uptake was associated with the expression of hexokinase type I (HK I; P = 0.011). All lesions with HK I overexpression were positive on 18FDG PET. HK I expression in the original primary tumor and the metastases was similar in 82% ({rho} = 0.648; P = 0.005). In suspected recurrent thyroid cancer, stratification for 18FDG PET may benefit from pretest immunohistochemical analysis of HK I of the primary tumor, as HK I negativity indicates a low likelihood of PET positivity.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THYROID CANCER IS the most common malignant endocrine tumor. In areas not associated with nuclear fallout, the annual incidence ranges between 2.0–3.8 cases/100,000 in women and 1.2–2.6/100,000 in men (1). Because most patients present at an early stage of disease, a 10-yr survival in about 80% can be achieved after thyroidectomy and 131I ablative therapy (2, 3). This implies that the prevalence of patients under surveillance for recurrent cancer is high with an estimated European population of patients and survivors of 200,000 (4). The vast majority of thyroid cancers concerns differentiated (papillary and follicular) variants (DTC) with a relatively favorable prognosis. Suspicion of recurrence usually arises when the level of serum thyroglobulin (Tg; sensitivity, 91%; specificity, 99%) is rising (5, 6). In 10–15% of these patients, a diagnostic 131I whole body scintigraphy (WBS) is negative (5). Not uncommonly, blind 131I therapies are given with variable efficacy and concomitant toxicities (radiation and hypothyroidism) (7). Moreover, increased TSH levels required for 131I therapy may stimulate tumor growth (8, 9). Alternatively, positron emission tomography (PET) with [18F]fluorodeoxyglucose (18FDG) can document the recurrence, thereby rationalizing therapeutic options. Apart from the diagnostic relief that can be offered by PET, 18FDG uptake appears to be inversely related to prognosis (10), as has been shown for other cancers (11, 12, 13, 14, 15). This adds another dimension to the use of 18FDG PET in well differentiated thyroid cancer, because patients who would benefit from a more aggressive therapy could be identified. However, literature on the yield and accuracy of 18FDG PET cannot be automatically extrapolated to this upfront situation (i.e. before high dose 131I scanning), because current data typically apply to patients with elevated serum Tg levels and negative 131I WBS (16, 17).

A substantial proportion of DTC does not accumulate 18FDG (18). For (cost-)effective application of 18FDG PET, as it requires expensive equipment, the challenge is to predict which patients would benefit from this modality by early detection of recurrence. We therefore used oncological and PET pharmacokinetic principles to explore which (immuno)histologically reflected factors were associated with the presence or absence of 18FDG uptake in thyroid cancer metastases. At the lowest level, 18FDG uptake is a function of substrate supply and extraction (19), and visualization by PET depends on the relative contrast of this uptake vs. background and lesion size. Glucose delivery is a function of perfusion, which itself is associated with angiogenesis [a frequently used vascular marker is CD31, and vascular endothelial growth factor 165 (VEGF165) is the major angiogenic factor in cancer]. On a cellular level, glucose uptake is mediated by transmembrane transport [the most common glucose transporter expressed in all tissues is glucose transporter-1 (Glut-1)] (20, 21) and phosphorylation of glucose [hexokinases (HKs) are key glucose phosphorylators] (22). At the same time, glucose demand is enhanced by hypoxia (23), which can be visualized by hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) and necrosis, and proliferative activity (determined by the proliferation markers Ki-67 and cyclin A). Moreover, the dissociation between 18FDG and 131I uptake (18) suggests that 18FDG uptake is positively associated with increasing dedifferentiation [low Tg (24, 25, 26, 27) and/or high p53 protein levels (28, 29)]. Immunohistochemistry allows for visualization of each of these steps, including the contribution of nonspecific uptake to the PET signal (with CD68 as a marker for macrophages).

In breast cancer, a similar situation prevails, with variable 18FDG avidity of tumors as a result of a multifactor process, as apparent from in vitro features obtained with histology and immunohistochemistry (30). The aim of the present study was to investigate which of the properties of the above-described biological model might be associated with 18FDG PET positivity in recurrent DTC and whether these features were also present in the original primary tumors.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Surgical specimens of all consecutive recurrent DTC patients who had undergone surgery to remove a metastatic lesion within 12 months after 18FDG PET were investigated. PET scanning was performed between June 1997 and November 2002. Under Dutch law in force at the time the tissue samples were taken, consent was assumed for scientific use of remaining tissue. Current guidelines specify that the scientific use of such tissue is permissible without obtaining informed consent if adequate safeguards to protect patient privacy are maintained (31).

131I scanning

131I uptake in metastases was evaluated with post-131I WBS, performed with single- or dual-headed {gamma}-cameras (ADAC, Geneseys, CA) equipped with high energy, parallel hole collimators. Scintigraphy was performed 1 wk after 5.5 GBq. Thyroid hormone therapy was stopped for 3 wk before 131I (so that TSH levels were >30 mU/liter), and patients were kept on a low iodine diet.

PET imaging

Whole body 18FDG PET scans were performed in fasting patients using the ECAT Exact HR+ (Siemens/CTI, Knoxville, TN). Sixteen scans were performed during TSH suppression, and three scans were performed during TSH stimulation (patients 5, 10, and 15). Serum glucose levels were within the normal range in all patients. Emission scans (midskull to midfemur) of 5 min/bed position were performed 60 min after iv injection of 370 MBq 18FDG. All scans were corrected for decay, scatter, and randoms and reconstructed using ordered subset expectation maximization with two iterations and 16 subsets, followed by postsmoothing of the reconstructed image using a 5-mm full width half maximum Gaussian filter. No attenuation correction was performed.

PET analysis

PET images were analyzed by three independent observers (certified nuclear medicine professionals with expertise in interpreting PET scans), blinded to clinical history and outcome. The observers were not aware of which lesion was surgically removed; they were instructed to describe all metabolically active lesions. The level of 18FDG accumulation was visually assessed as negative (grade 0), weak (grade 1), moderate (grade 2), or intense (grade 3). The summed score of the observers was used for statistical analysis. Patients were regarded as having high 18FDG accumulation (positive 18FDG PET scan) when the total intensity score was at least 6; all other patients were classified as having low 18FDG accumulation (negative 18FDG PET scan).

Finally, an experienced nuclear medicine physician correlated 131I WBS, 18FDG PET, and clinical data to ensure that the scan readings anatomically matched the surgical and histological data (the surgical records contained the exact localization of resected specimens, e.g. lymph nodes).

Immunohistochemistry

All tissue specimens were fixed in neutral 4% buffered formaldehyde for at least 12 h. Table 1Go lists all antibodies, dilutions, incubation times, and antigen retrieval methods used. Immunohistochemistry was performed on 4-µm thick paraffin tissue sections. After deparaffination and rehydration, endogenous peroxidase activity was blocked for 30 min in a methanol/0.3% hydrogen peroxide solution. After antigen retrieval, a cooling-off period of at least 30 min preceded the incubation of primary antibodies. Biotinylated rabbit antimurine or swine antirabbit antibodies (DakoCytomation, Glostrup, Denmark) were used as second antibodies. The standard avidin-biotin complex method (DakoCytomation) was used for detection, with the exception of CD31 (detected with the LabVision kit, Lab Vision Corp., Fremont, CA) and HIF-1{alpha} (detected with the catalyzed signal amplification kit). Stainings were developed with diaminobenzidine, and counterstaining was performed with hematoxylin and eosin. Negative (obtained by omission of the primary antibody) and positive controls were used throughout.


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  		TABLE 1. Antibodies, dilution, incubation, and detection methods

 
Assessment of immunohistochemically stained slides was performed on a multiheaded microscope by one pathologist very experienced in reading such slides (P.J.v.D.) in the presence of two junior (L.H. and A.A.M.v.d.V.) and one senior (C.F.M.M.) researcher with experience in histochemistry. The leading pathologist was blinded to all other data, and agreement on scoring was obtained in all cases. Representative sections of tumors were visually analyzed for the percentage of tumor cells and necrosis. The numbers of CD68-positive macrophages, CD31-positive microvessels, and Tg-producing cells were graded as none (–), occasionally (+), moderately frequent (2+), or frequent (3+). The results of immunohistochemistry of p53, Ki-67, and cyclin A (32) were expressed as the percentage of tumor cells with positive nuclear staining. The intensity of tumor cell cytoplasmic staining for VEGF165 and HK isoforms I, II and III was categorized as negative (–), weak (+), positive (2+), and strongly positive (3+), ignoring nonspecific nuclear staining, which was frequently noted for all HKs. The presence of Glut-1 membrane or cytoplasmic staining was interpreted as overexpression. For estimation of the percentage of nuclei with expression of HIF-1{alpha}, only homogeneously and darkly stained nuclei were regarded (30). A pattern of positive staining (homogeneous or heterogeneous) was noted for all tumors.

Statistical analysis

For statistical evaluation (SPSS for Windows 11.0.1, SPSS, Inc., Chicago, IL), Fisher’s exact test for testing associations between 18FDG accumulation (defined as low vs. high) and biological markers (defined as negative/weak expression vs. positive expression) was performed. Median values were used as a cut-off level for the nominal variables, except for HIF-1{alpha} (cut-off, 5%), for which a previously established value was chosen (33). The categorical variables were dichotomized in negative/weak expression when scores – and + were obtained, and as positive expression for 2+ or 3+. In addition, associations between 18FDG PET intensity and categorical variables were tested using the Kruskal-Wallis test. The strength of association with ordinal variables was represented by Spearman’s rank correlation. The significant level was set at 0.05. Stepwise logistic regression analysis was performed to investigate which combination of parameters best explained 18FDG uptake in thyroid metastases. Finally, Spearman’s {rho} values were computed between biological variables of metastasis and primary tumor


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Patients

Nineteen patients were identified with histologically proven recurrent thyroid cancer (mean age, 60 ± 12 yr; range, 30–78 yr). Thirteen patients had presented with papillary and six with follicular tumors. At initial presentation, tumor stages were Tx (n = 1), T1 (n = 1), T2 (n = 6), T3 (n = 3), T4 (n = 8), N1 (n = 12), and M1 (n = 2). Patient characteristics are summarized in Table 2Go. The time interval between primary presentation of DTC and 18FDG PET scanning varied from 7–108 months (median, 20 months). Indications for 18FDG PET scanning were 1) to identify anatomical substrates for elevated Tg levels (n = 7) or TgAb (n = 1), after negative high dose 131I WBS, and 2) to stage patients with known neoplastic foci in whom surgery was considered (n = 11). Serum Tg was elevated in 17 of 19 patients, and two had Tg antibodies. The mean interval between PET scanning and surgery (for metastasis) was 5 months (±3 SD). The 19 resected and histologically evaluable tumors comprised local recurrences (n = 6) and lymph node (n = 9), bone (n = 3), or lung metastases (n = 1). Tumor diameter measured 1.0 cm or greater in all patients.


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  		TABLE 2. Characteristics and diagnostic results (n = 19)

 
131I WBS, 18FDG PET, and histological results

As shown in Table 2Go, patients were evaluated with 18FDG (n = 19) and posttherapy 131I WBS (5.5 GBq; n = 18) within 12 months. Uptake of 131I and 18FDG in the resected lesion was discordant in 12 patients (131I positive, n = 5; 18FDG positive, n = 7), five metastases demonstrated similar uptake of either tracer, and one tumor was negative with 131I as well as 18FDG. Thirteen of the surgically removed tumor sites were 18FDG positive (typically with intense uptake). Interobserver agreement of the PET classification system was high [intraclass coefficient, 0.97; 95% confidence interval (CI), 0.94–0.99]. 18FDG uptake patterns in recurrent tumors were not related to gender, age, location of recurrent disease, histological tumor type, or tumor cell density.

Table 3Go summarizes the immunohistochemical results of the 19 histologically evaluable recurrences together with the PET score, tumor cell density, and necrosis. Notable findings were lack of necrosis, low levels of Glut-1 membrane expression (three of 19) and HIF-1{alpha} staining (three of 19), and high VEGF165 (17 of 19) and Tg (14 of 19) protein expression. The statistical comparison between 18FDG uptake and the biomarkers (Table 4Go) revealed a strong positive association between 18FDG uptake and the presence of HK I; all metastases positive for HK I cytoplasmic staining (n = 9) showed 18FDG uptake [positive predictive value (PPV), 100%; 95% CI, 70–100], leaving four 18FDG PET-positive patients without HK I staining (negative predictive value, 60%; 95% CI, 31–83). Also, a positive association was found for cytoplasmic Glut-1 staining (PPV, 90%; 95% CI, 60–98). HK I and Glut-1 cytoplasmic expression were significantly correlated (Spearman’s {rho} = 0.478; P = 0.039). All other tested biomarkers demonstrated no univariate significant correlation with 18FDG uptake. The tumor cell density (P = 0.088) and the presence of macrophages (P = 0.222) were not significantly correlated with 18FDG uptake. Sensitivity analysis with different cut-off levels for 18FDG PET intensity (scoring 6–9) revealed one other significant variable at cut-off levels 8 (P = 0.011) and 9 (P = 0.022): Tg protein expression was inversely related to 18FDG uptake. Correlation of HK I and Glut-1 cytoplasmic expression with 18FDG uptake was even stronger at all other cut-off points (levels 7, 8, and 9). In logistic regression, no significant combination of variables was found that predicted 18FDG PET positivity better than HK I.


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  		TABLE 3. Immunohistochemical results in 19 metastases of thyroid cancer

 

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  		TABLE 4. Correlation between 18FDG PET intensity and different biological variables using Fisher’s exact and Spearman’s {rho}

 
Additional analysis (data not shown) suggested trends (however, not significantly) toward inverse relations between HK I expression and 131I uptake ({rho} = –0.174), Tg protein expression ({rho} = –0.391), p53 ({rho} = –0.258), and CD31 ({rho} = –0.367) and toward positive association with HIF-1{alpha} ({rho} = 0.167) and the proliferation markers cyclin A ({rho} = 0.169) and Ki-67 ({rho} = 0.069).

From 17 of 19 patients with histologically proven recurrent thyroid cancer, specimens of both primary tumor and metastases were available for additional immunohistochemical analysis (missing patients 16 and 17). Comparison (using Spearman’s test) of all biological variables showed that immunohistochemistry results in primary tumors and recurrences were associated for HK I and Glut-1 cytoplasmic ({rho} = 0.648, P = 0.005; {rho} = 0.509, P = 0.037), with expression concordant in 14 and 13 patients, respectively (Table 5Go).


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  		TABLE 5. Expression of HK I and Glut-1 in primary tumor compared with metastasis

 
Projecting these data on the predicted yield of 18FDG PET applied to patients suspected of recurrent disease positioned before 131I WBS (Table 6Go) gives a positive predictive value (proportion of patients with 18FDG-positive recurrent disease) for HK I cytoplasmic expression in primary tumors of 80% (95% CI, 49–94). When limited to patients with negative 131I WBS, the PPV of HK I overexpression was 100% (95% CI, 57–100).


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  		TABLE 6. Prediction of 18FDG uptake by HK I-expression in the primary thyroid tumor

 
Scenario for use of 18FDG PET in DTC

If HK I positivity of the primary tumor would have been used to set the indication for 18FDG PET at suspected recurrence, PET scanning would have been performed in 10 of 17 patients in an upfront setting, with true positive results in eight. The remaining seven HK I-negative patients would have been directed toward 131I WBS, revealing recurrent disease in five.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study the roles of various biomarkers possibly involved in 18FDG uptake in human thyroid cancer tissue have been evaluated to predict in which patients 18FDG PET will show recurrences. Accumulation of 18FDG in metastases correlates with HK I; all patients with HK I overexpression in the cytoplasm had positive 18FDG PET results. Also, a positive association was found for cytoplasmic Glut-1 staining. The expression of Tg protein was negatively associated with strongly positive 18FDG-PET results, affirming that 18FDG uptake is more frequent in poorly differentiated thyroid cancer (18), because a low level of Tg protein expression correlates with a poorly differentiated histotype (25, 34, 35). It was also investigated whether the presence of macrophages or necrosis could explain 18FDG uptake, because they may have an impact on 18FDG uptake (36). In this study no correlation was found. Furthermore, HK I and Glut-1 expressions in the original primary tumor and metastases were similar in most patients. Based on these results, the yield of 18FDG PET positivity seems to be predicted by HK I expression at presentation.

High dose 131I therapy appears to have little or no effect on the viability of metastatic 18FDG-positive thyroid cancer lesions (37). If HK I staining of the primary tumor would have been used to set the indication, 18FDG PET scanning would have been performed in 10 of 17 patients in an upfront setting with true positive results in eight, thereby avoiding undesirable side-effects inherent to T4 withdrawal and (blind) 131I WBS (i.e. salivary gland impairment: dryness of mouth, altered taste, pain in the parotid region, and difficulty in swallowing). Patient management would especially be improved when merely surgery or focused radiotherapy could be used to eradicate the tumor.

In various types of cancer, correlations have been reported between 18FDG uptake and Glut-1 and HK II expression (30, 38, 39, 40, 41). HK II was expressed in virtually all tumors without a significant relation with 18FDG uptake. However, a role for HK I in 18FDG uptake was in agreement with previous reports in breast cancer (30). Because, to the best of our knowledge, nothing is known about the function of the different isozymes of HKs in thyroid cancer, additional research to confirm our results and to explore the role of HKs in thyroid cancer is therefore warranted.

Well differentiated thyroid cancer expressed immunohistochemically detectable Glut-1 predominantly in the cytoplasm, rather than on the cell membrane. These results correspond with the data presented by Haber et al. (42) and Schönberger et al. (43), who also found Glut-1 expression more often located in the cytoplasm than on the membrane in DTC. Several studies reported (30, 42, 43, 44) the striking finding that Glut-1 expression on the membrane is most prominent found around necrotic areas. Tumors that grow too rapidly or have a deficient vascular system are characterized by the formation of necrosis. Neither is common in DTC, which may result in a lack of Glut-1 expression on the cell membrane. TSH treatment of rat thyroid cells in vitro resulted in an increased cell surface expression of Glut-1 (45, 46, 47). Previous studies have reported more accurate 18FDG PET when patients were treated with recombinant human TSH (48, 49); in this study, however, 16 of 19 PET scans were performed during TSH suppression.

In search of a biological explanation for the variable expression of HK I in metastases of thyroid cancer, several biological plausible trends were determined. These trends indicate that HK I expression is inversely related to features corresponding to differentiation grade and supply and is positively correlated to demand (the proliferation markers). However, because of the small sample size, the effects observed were indicative rather than statistically significant.

A potential limitation of the study was the use of visual, rather than quantitative, assessment of 18FDG uptake. To date, a semiquantitative approach (standardized uptake value) is often used to approximate glucose consumption. Quantifying 18FDG uptake requires dynamic scanning and nonlinear regression of tissue time-activity curves using a measured (arterial) input function. This implies that only a single predefined bed position of 15 cm can be scanned. The present studies served a diagnostic purpose (i.e. detection of possible metastases and lymph nodes), implying the use of WBS.

Visual inspection of uptake intensity correlates with quantitative tumor/nontumor ratios (30). In retrospect, the interpatient contrasts of 18FDG uptake were so large that it is unlikely that quantification would have led to significantly different results, and we believe that the present correlations are valid. Finally, because most tumors were larger than twice the spatial resolution of the HR+ PET scanner, we estimated that the effect of partial volume on the observed correlations will be negligible.

In conclusion, in suspected recurrent thyroid cancer, stratification for 18FDG PET may benefit from pretest immunohistochemical analysis (HK I) of the primary tumor. If confirmed in larger studies, and this is feasible because many institutions have similar databases, our results may have important clinical implications by providing a more rational and biological basis, and therefore more cost-effective, for the role of 18FDG PET scanning in DTC management.


   Acknowledgments
 
We thank the Departments of Pathology of Verbeeten Institute (Tilburg, The Netherlands), Lucas Andreas Hospital (Amsterdam, The Netherlands), Hospital Hilversum (Hilversum, The Netherlands), and Hospital de Heel (Zaandam, The Netherlands), who provided primary tumor material from some of the patients. We thank Petra van der Groep for performing the HIF-1{alpha} staining for all tumors, and Dr. Emile Comans and Arjan van Dijk for scoring the 18FDG PET scans.


   Footnotes
 
First Published Online October 27, 2004

Abbreviations: CI, Confidence interval; DTC, differentiated thyroid cancer; 18FDG, [18F]fluorodeoxyglucose; Glut-1, glucose transporter-1; HIF-1{alpha}, hypoxia-inducible factor-1{alpha}; HK, hexokinase; PET, positron emission tomography; PPV, positive predictive value; Tg, thyroglobulin; VEGF, vascular endothelial growth factor; WBS, whole body scintigraphy.

Received April 27, 2004.

Accepted October 20, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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