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The difference in relationship between 18F-FDG uptake and clinicopathological factors on thyroid, esophageal, and lung cancers

Kaida, Hayatoa; Kawahara, Akihikob; Hayakawa, Masanobuc; Hattori, Satoshic; Kurata, Seijia; Fujimoto, Kiminoria; Azuma, Koichid; Hirose, Yasumitsua; Takamori, Shinzoe; Hiromatsu, Yujif; Nakashima, Tadashig; Fujita, Hiromasae; Kage, Masayoshib; Hayabuchi, Naofumia; Ishibashi, Masatoshia

Nuclear Medicine Communications: January 2014 - Volume 35 - Issue 1 - p 36–43
doi: 10.1097/MNM.0000000000000019
ORIGINAL ARTICLES

Objectives The aim of this study was to reveal the differences in clinicopathological factors affecting maximum standardized uptake value (SUVmax) between esophageal squamous cell carcinoma (ESCC), non-small-cell lung cancer (NSCLC), and papillary thyroid cancer (PTC).

Methods This study consisted of 119 patients with ESCC (n=43), PTC (n=40), or NSCLC (n=36). We investigated the correlations between SUVmax and clinicopathological factors by using Spearman’s correlation coefficient and the Kruskal–Wallis test. Multiple regression analysis was used to investigate which clinicopathological factors significantly affected SUVmax in each cancer type.

Results The SUVmax correlated with glucose transporter-1 (GLUT-1) expression in NSCLC (r=0.536, P=0.007) and ESCC (r=0.597, P<0.001) but not in PTC. The SUVmax correlated with Ki-67 expression in NSCLC (r=0.381, P=0.022) and PTC (r=0.374, P=0.017) but not in ESCC. A high SUVmax was correlated with a higher pathological T stage (p-T stage) in NSCLC (r=0.536) and ESCC (r=0.597, both P<0.001) but not in PTC. An elevated SUVmax was significantly associated with pathological lymph node status (p-N) in NSCLC, but not in ESCC and PTC. In multiple regression analysis, p-T stage and GLUT-1 expression were statistically significant factors in ESCC, and p-T stage was a statistically significant factor in NSCLC. In PTC, Ki-67 showed a statistically significant association with SUVmax.

Conclusion SUVmax in NSCLC depended on the tumor invasion area; SUVmax in ESCC depended on tumor depth and GLUT-1 expression; and SUVmax in PTC might be associated with cell proliferation. The biological factors affecting SUVmax differ according to tumor type.

aDivision of Nuclear Medicine, PET Center, and Department of Radiology, Kurume University School of Medicine

bDepartment of Diagnostic Pathology, Kurume University Hospital

cBiostatistics Center

dDivision of Respirology, Neurology, and Rheumatology, Department of Internal Medicine

eDepartment of Surgery

fDivision of Endocrinology, Department of Internal Medicine

gDepartment of Otolaryngology and Facial Maxillary Surgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan

Correspondence to Hayato Kaida, MD, Division of Nuclear Medicine, PET Center, and Department of Radiology, Kurume University School of Medicine, 67 Asahi-Machi, Kurume, Fukuoka 830-0011, Japan Tel: +81 942 31 7649; fax: +81 942 32 7925; e-mail: hayato@med.kurume-u.ac.jp

Received September 4, 2013

Accepted September 25, 2013

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Introduction

The glucose transporter (GLUT) family plays a crucial role in 18F-fluorodeoxyglucose (18F-FDG) uptake in malignant tumors 1,2. In non-small-cell lung cancer (NSCLC), GLUT-1 expression has shown an association with the maximum standardized uptake value (SUVmax) 3. In contrast, in oral cancer, GLUT-1 expression has no relationship with SUVmax 4.

The Ki-67 antigen is detectable within the cell nucleus during all active phases of the cell cycle (G1, S, G2, and M); however, it is not detectable in G0 resting cells 5. This antigen provides information about the proportion of active cells in the cell cycle and is an excellent marker for deciding the growth fraction of cell populations 6. Elevated Ki-67 expression has been shown to be associated with increased tumor aggressiveness and invasiveness 7. The Ki-67 labeling index has been reported to correlate with 18F-FDG uptake in NSCLC and bone soft-tissue sarcoma 8,9. However, in pancreas, head and neck, and colorectal cancers, the Ki-67 labeling index has no correlation with 18F-FDG uptake 10–12. To the best of our knowledge, no study has yet reported which clinicopathological factors have the most influence on SUVmax, and the differences in clinicopathological factors affecting SUVmax in biologically distinct tumor malignancies have not been investigated.

The aim of this study was to investigate the relation between 18F-FDG uptake and clinicopathological factors and reveal the differences in clinicopathological factors that affect the SUVmax in esophageal, lung, and thyroid cancers using adjusted multiple regression analysis.

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Methods

Patient selection

This was a retrospective study involving all patients with histopathologically confirmed cancer between January 2004 and January 2009. All patients in our study suffered from one of three main types of cancer [esophageal squamous cell carcinoma (ESCC), NSCLC, or papillary thyroid cancer (PTC)] and underwent surgery after 18F-FDG-PET at our institution. The patient group was further limited to those in whom surgical resection was complete and to those who had not received neoadjuvant chemotherapy or radiation therapy before undergoing 18F-FDG-PET and surgery. None of the patients had a history of other malignant tumors or synchronous tumors. A total of 135 patients were initially selected, from whom 16 were excluded because of a lack of 18F-FDG uptake in the primary tumor, incomplete clinical or pathological findings, indeterminate histopathological results by immunohistochemical (IHC) staining, and tumor size (largest diameter) less than 10 mm based on the full-width at half-maximum of PET. Thus, our final study population consisted of 119 patients (74 men and 45 women; median age, 66 years; age range, 21–87 years). The clinical and histopathological staging was based on the International Union Against Cancer (UICC, 2002) TNM classification 13. Of the 119 patients, 43 had ESCC, 36 had NSCLC, and 40 had PTC. The histopathological findings of NSCLC were as follows: adenocarcinoma (n=26), squamous cell carcinoma (n=8), pleomorphic carcinoma (n=1), and large cell neuroendocrine tumor (n=1). Patients with small cell lung cancer, follicular thyroid carcinoma, anaplastic thyroid cancer, and esophageal adenocarcinoma were excluded from this study because of the small number of patients who had undergone PET examinations and surgery. Informed consent for participation in the study was obtained from patients or from their guardians as a part of the protocol approved by the Institutional Clinical Subpanel on Human Studies.

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18F-FDG-PET imaging acquisition

A dedicated full-ring PET scanner (Allegro; Philips Medical Systems Inc., Cleveland, Ohio, USA) with a germanium oxyorthosilicate crystal was used for data acquisition. Before 18F-FDG injection, all patients had to fast for 4 h, although intake of sugar-free liquids was permitted. Before the examination, the patients drank 500 ml of water to accelerate renal 18F-FDG elimination. Their median blood glucose level was 97 mg/dl (range, 65–206 mg/dl). Patients were administered a median 18F-FDG amount of 6.89 mCi [252 MBq (0.12 mCi/kg) (range, 4.18–9.74)] through the antecubital vein. Whole-body PET imaging was performed at ∼60 min after 18F-FDG injection. Transmission and emission images of the areas from the level of the auditory meatus to the mid-thigh were acquired (transmission images, 23 s, 10 bed positions; emission image, 2 min 30 s, 10 bed positions) with patients in the supine position. Transmission scans were carried out on all patients to provide attenuation correction with a 137Cs point source. Thereafter, both transmission and emission images were reconstructed using 3D-RAMLA (3D-Row Action Maximum Likelihood Algorithm; Philips, Eindhoven, the Netherlands). The average examination time for whole-body PET images was ∼30 min.

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18F-FDG-PET image analysis

Circulatory regions of interest (ROIs) were manually placed over the entire area of abnormal uptake on the primary lesion to include a large amount of radioactivity on a workstation (Sun Microsystems Inc., Santa Clara, California, USA). From the ROIs, the SUVmax was calculated using the following formula: maximum pixel value within the ROI activity (MBq/kg)/[injected dose (MBq)/body weight (kg)].

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IHC staining

Paraffin-embedded tissue samples of 4 μm thickness were examined on coated slide glasses and labeled with GLUT-1 (1 : 100; Neo Markers, Fremont, California, USA) and Ki-67 (1 : 100; DakoCytomation, Glostrup, Denmark) antibodies using BenchMark XT (Ventana Automated Systems Inc., Tucson, Arizona, USA). Each slide was heat-treated for 30 min using Ventana’s CC1 retrieval solution and incubated with the antibody for 30 min. This automated system used the streptavidin–biotin complex method with 3,3′-diaminobenzidine as the chromogen (Ventana iVIEW DAB detection kit; Ventana Medical Systems Inc., Tucson, Arizona, USA).

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Evaluation of IHC

We investigated GLUT-1 and Ki-67 expressions using a scoring analysis. IHC staining results for GLUT-1 and Ki-67 were evaluated as positive or negative on the basis of cytoplasm/membrane reactivity. The intensity of the cytoplasm/membrane staining was scored as follows: 0, absence of staining; 1+, weak staining in less than 10% cancer cells; 2+, moderate staining in at least 10–50% cancer cells; and 3+, strong staining in at least 50% cancer cells. Scores of 1+, 2+, and 3+ were considered to indicate positivity for GLUT-1, and a score of 0 was considered negative for GLUT-1. For the Ki-67 labeling index, at least five different representative high-power (×400) fields containing at least 100 cancer cells each were examined. All IHC staining results were evaluated by two experienced observers who were blinded to the condition of the patients.

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Statistical analysis

Each association between 18F-FDG uptake and GLUT-1, between 18F-FDG uptake and Ki-67, or between 18F-FDG uptake and pathological T stage (p-T stage) or pathological tumor size (p-tumor size) was examined using Spearman’s rank correlation coefficient. The association between 18F-FDG uptake and pathological lymph node status (p-N) was examined by means of the Kruskal–Wallis test. Multiple regression analysis was also performed including the same sets of explanatory variables to contrast the differences in the associations between SUVmax and each factor in the cancer types. Statistical analyses were performed using SAS, version 9.1 (SAS Institute Inc., Cary, North Carolina, USA) and R version 2.9.0. P-values less than 0.05 were considered statistically significant.

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Results

Association between SUVmax and clinicopathological factors

Detailed data on SUVmax and biological parameters in the three cancers are given in Table 1. GLUT-1 positivity was seen in 67% of NSCLCs, 38% of PTCs, and 88% of ESCCs. The median Ki-67 expressions were 0.5% [the 25th and 75th percentiles of the interquartile range (IQR), 0–2%] for PTC, 3% (IQR, 1.0–7.5%) for NSCLC, and 30% (IQR, 20–50%) for ESCC. Spearman’s rank correlation coefficients between SUVmax and other factors including GLUT-1, Ki-67, p-tumor size, and p-T stage are summarized in Table 2 with associated p-values. SUVmax correlated positively with GLUT-1 expression regardless of cancer type, although the P-value for PTC did not reach the 5% significance level. In contrast, the SUVmax correlated positively with Ki-67 expression in NSCLC (Spearman’s r=0.381, P=0.022) and PTC (r=0.374, P=0.017) but not in ESCC (r=−0.002, P=0.992). The SUVmax correlated with p-tumor size in all three cancers (for ESCC, r=0.498, P<0.001; for NSCLC, r=0.661, P<0.001; and for PTC, r=0.437, P=0.005). SUVmax correlated with p-T stage in NSCLC and ESCC but not in PTC (for NSCLC, r=0.536, P<0.001; for ESCC, r=0.597, P<0.001; and for PTC, r=0.321, P=0.673). A high SUVmax was significantly associated with p-N positivity in NSCLC (P=0.019; Kruskal–Wallis test). In ESCC and PTC, the same tendency was present but it was not statistically significant (ESCC, P=0.072; and PTC, P=0.122; Kruskal–Wallis test).

Table 1

Table 1

Table 2

Table 2

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Multivariable analysis with respect to the SUVmax and clinicopathological factors

The resultant data from the multivariable analysis are given in Table 3. Both in NSCLC and ESCC, the p-T stage and GLUT-1 expression were statistically significantly related to SUVmax (estimate=2.098, P=0.016, for p-T stage in NSCLC; estimate=2.105, P=0.016, for GLUT-1; and estimate=3.057, P=0.005, for p-T stage in ESCC) or almost statistically significantly related (estimate=0.661, P=0.071 for GLUT-1 in NSCLC). In contrast, in PTC, Ki-67 was statistically significantly related (estimate=162.8, P=0.016), whereas both p-T stage and GLUT-1 expression were far from being statistically significant. Representative 18F-FDG-PET and IHC staining results for GLUT-1 and Ki-67 expressions in all three cancers are shown in Figs 1–3.

Table 3

Table 3

Fig. 1

Fig. 1

Fig. 2

Fig. 2

Fig. 3

Fig. 3

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Discussion

On univariate analysis, SUVmax in NSCLC showed a significantly positive correlation with the expressions of GLUT-1 and Ki-67 and p-tumor size. The SUVmax of the p-N-positive group was significantly higher than that of the p-N-negative group. Van Baardwijk et al. 14 and Ngyuyen et al. 15 reported a significant correlation between SUVmax and GLUT-1 expression in NSCLC. Doom et al. 8 and Buck et al. 10 suggested a significant correlation between SUVmax and Ki-67 expression in NSCLC. Vessel and colleagues reported that SUVmax in NSCLC correlated with p-T stage and p-tumor size, and Al-Sarraf and colleagues reported that SUVmax in NSCLC was significantly related to p-T stage and p-N stage 16,17. The univariate analysis in the present study agreed with the results of these earlier reports. In NSCLC the adjusted multiple regression analysis showed that p-T stage was statistically significant and GLUT-1 expression was close to statistical significance, but p-tumor size was not significant. In contrast, Suzawa et al. 18 suggested that SUVmax in NSCLC depended on tumor size rather than on GLUT-1 or GLUT-3 expression, and Brown et al. 19 showed that 18F-FDG uptake in NSCLC depended on tumor size. Our data disagreed with these reports. Pathological T stage indicates the pathological tumor invasion area in addition to the p-tumor size. 18F-FDG uptake in NSCLC may depend on the tumor invasion area and on the tumor size.

In ESCC patients, on univariate analysis, SUVmax correlated with GLUT-1 expression, p-T stage, and p-tumor size. On adjusted multiple regression analysis, GLUT-1 expression and p-T stage were statistically significant for SUVmax in ESCC. Hiyoshi et al. 20 suggested that the sensitivity of 18F-FDG PET for ESCC was associated with tumor size and GLUT-1 expression. Westeterp et al. 21 have revealed that tumor size and GLUT-1 expression had an influence on SUVmax in ESCC. In contrast, Nakajo et al. 22 have suggested that 18F-FDG uptake in ESCC is associated with p-tumor size, GLUT-1 expression, and tumor depth. However, the p-tumor size is estimated on the basis of the largest diameter and does not always reflect accurate tumor cell density. The p-T stage reflects tumor depth. 18F-FDG uptake in ESCC may mainly depend on tumor depth and GLUT-1 expression.

In the present study, SUVmax did not correlate with the Ki-67 labeling index. Other reports have suggested that 18F-FDG uptake in ESCC had no correlation with the Ki-67 labeling index 23,24. These data reveal that 18F-FDG uptake in ESCC is not related to cell proliferation. On univariate analysis, a tendency of association was found between lymph node metastasis and SUVmax; this association did not reach statistical significance. Kato et al. 25 reported that a higher SUVmax tended to associate with p-N positivity. The difference between our data and those of Kato and colleagues may lie in patient numbers.

With regard to PTC, on univariate analysis, SUVmax correlated with p-tumor size and Ki-67 expression. On adjusted multiple regression analysis, Ki-67 was statistically significant for SUVmax. Strong GLUT-1 expression appeared on poorly differentiated adenocarcinoma and anaplastic carcinoma, and papillary carcinoma and follicular carcinoma showed an absence of or low GLUT-1 expression 26. Differentiated thyroid carcinoma such as papillary carcinoma or follicular carcinoma retains the ability to trap iodine; however, undifferentiated thyroid carcinoma showed a lower avidity for radioiodine and demonstrated strong GLUT-1 expression 26. In the present study, all PTC cases were differentiated thyroid carcinoma. GLUT-1 negativity was seen in 65% of PTCs, and three of 40 cases (∼8%) had scores greater than 2. This study revealed that SUVmax did not correlate with GLUT-1 expression. Kim and colleagues suggested that SUVmax of PTC was not associated with GLUT-1, and Grabellus and colleagues and Park and colleagues reported that strong GLUT-1 expression did not appear in PTC 26–28. Our data are in agreement with these reports. GLUT-1 does not contribute to 18F-FDG uptake in PTC.

Univariate analysis showed that SUVmax correlated with p-tumor size. Jeong et al. 29 have suggested that only p-tumor size correlated with SUVmax. However, in this study, multivariate analysis showed that the Ki-67 labeling index is statistically significant for SUVmax. To the best of our knowledge, the correlation between SUVmax and the Ki-67 labeling index in PTC patients has not been previously reported. The Ki-67 labeling index of PTC is low; Ito et al. 30 reported that the disease-free survival of patients was significantly worse when the Ki-67 labeling index was greater than 1% than when it was less than 1% (P<0.001). Papillary microcarcinoma of N1b lymph-node status had a significantly higher Ki-67 labeling index compared with those of N0 or N1a status 31. In a retrospective analysis of 93 patients with differentiated thyroid carcinoma, Mussig et al. 32 showed that the Ki-67 labeling index was significantly associated with tumor staging and clinical outcome 5 years after definitive treatment, whereas other histopathological markers such as GLUT-1, C-KIT, somatostatin receptor, and estrogen receptor were not associated with sex, age, tumor entity, or clinical outcome. Bynn et al. 33 have recently demonstrated that the detection rate of 18F-FDG PET for micropapillary carcinoma was 55% and the median value of SUVmax was 3.0 (IQR, 1.8–12.0); they suggested that 18F-FDG uptake in micropapillary carcinoma was associated with central lymph node metastasis. The Ki-67 labeling index could be one of the most useful markers in the evaluation of the cell-proliferating activity and prognosis of PTC. 18F-FDG uptake in PTC may depend on cell proliferation. There was no statistically significant correlation between SUVmax and p-T stage and there was no statistically significant difference in SUVmax between the p-N-positive group and p-N-negative group, although a higher SUVmax tended to be associated with p-N positivity. Jeong et al. 29 reported that 18F-FDG uptake correlated with tumor size and that 18F-FDG uptake did not predict the extrathyroidal invasion of thyroid cancer. Not only tumor size but also extrathyroidal invasion is one of the most important factors that decide the p-T stage 13. The lack of statistical correlation between p-T stage and SUVmax may be due to the presence of extrathyroidal invasion. A study by Yun et al. 34 suggested that there was a significant difference in p-N between 18F-FDG-positive and 18F-FDG-negative PTC. The difference between our data and theirs may be due to the difference in the numbers of patients.

We investigated the difference in clinicopathological factors affecting SUVmax among the three cancers of different origins. In previous studies, the relationship between SUVmax and GLUT-1 expression or between SUVmax and Ki-67 expression has been investigated for each cancer separately; however, the differences in clinicopathological factors affecting SUVmax among biologically distinct cancers have not been investigated in a single-center study. As the patient backgrounds, IHC staining estimations, IHC staining methods, PET instruments, and statistical analyses differ among reports, it is difficult to compare the differences in clinicopathological factors influencing SUVmax simply by reviewing the literature. In this study, the IHC estimation, IHC staining methods, and PET instruments were the same, although there were inevitably some differences in patient characteristics among the three cancers. If the clinicopathological factors affecting SUVmax differ according to cancer type, the molecular 18F-FDG uptake mechanism may differ. In fact, we did reveal a difference in clinicopathological factors affecting SUVmax in three biologically distinct cancers in this study.

This study has some limitations. First, biological factors such as GLUT-3, vascular endothelial growth factor, and hypoxia-inducible factor were not investigated. Recently, these biological factors were reported to be associated with 18F-FDG uptake in some malignant tumors 35. Vascular endothelial growth factor and hypoxia-inducible factor are upper reaches of the transduction pathway involving GLUT-1 in malignant tumors 36. As GLUT-1 has been used extensively to investigate the relationship between GLUT and 18F-FDG uptake in cancers, and Ki-67 has been frequently used to investigate the 18F-FDG uptake and cell proliferation, our study investigated relations of SUVmax with GLUT-1 and Ki-67. Second, breast cancers and gastrointestinal cancers such as colon cancer and gastric cancer were not included in this study. We could not include patients with these types of cancer because of the small number of patients who had undergone PET examinations and/or because of problems with pathological specimens. One reason for selecting NSCLC, PTC, and ESCC patients was that relatively larger numbers of patients in these categories had undergone both PET examinations and surgery at our institution. Differences in clinicopathological factors affecting SUVmax in a wider range of cancers should be investigated in the future.

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Conclusion

SUVmax in NSCLC depended on the tumor invasion area; SUVmax in ESCC depended on the tumor depth and GLUT-1 expression; and SUVmax in PTC was associated with cell proliferation. The clinicopathological factors affecting SUVmax of the primary tumor differ among tumor types.

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Acknowledgements

Conflicts of interests

There are no conflicts of interest.

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Keywords:

18F-FDG-PET; GLUT-1; Ki-67; maximum standardized uptake value; pathological T stage

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