Biologic correlates of intratumoral heterogeneity in 18F-FDG distribution with regional expression of glucose transporters and hexokinase-II in experimental tumor.

The biologic mechanisms involved in the intratumoral heterogeneous distribution of 18F-FDG have not been fully investigated. To clarify factors inducing heterogeneous 18F-FDG distribution, we determined the intratumoral distribution of 18F-FDG by autoradiography (ARG) and compared it with the regional expression levels of glucose transporters Glut-1 and Glut-3 and hexokinase-II (HK-II) in a rat model of malignant tumor. METHODS: Rats were inoculated with allogenic hepatoma cells (KDH-8) into the left calf muscle (n = 7). Tumor tissues were excised 1 h after the intravenous injection of 18F-FDG and sectioned to obtain 2 adjacent slices for ARG and histochemical studies. The regions of interest (ROIs) were placed on ARG images to cover mainly the central (CT) and peripheral (PT) regions of viable tumor tissues and necrotic/apoptotic (NA) regions. The radioactivity in each ROI was analyzed quantitatively using a computerized imaging analysis system. The expression levels of Glut-1, Glut-3, and HK-II were determined by immunostaining and semiquantitative evaluation. The hypoxia-inducible factor 1 (HIF-1) was also immunostained. RESULTS: ARG images showed that intratumoral 18F-FDG distribution was heterogeneous. The accumulation of 18F-FDG in the CT region was the highest, which was 1.6 and 2.3 times higher than those in the PT and NA regions, respectively (P < 0.001). The expression levels of Glut-1, Glut-3, and HK-II were markedly higher in the CT region (P < 0.001) compared with those in the PT region. The intratumoral distribution of 18F-FDG significantly correlated with the expression levels of Glut-1, Glut-3, and HK-II (r = 0.923, P < 0.001 for Glut-1; r = 0.829, P < 0.001 for Glut-3; and r = 0.764, P < 0.01 for HK-II). The positive staining of HIF-1 was observed in the CT region. CONCLUSION: These results demonstrate that intratumoral 18F-FDG distribution corresponds well to the expression levels of Glut-1, Glut-3, and HK-II. The elevated expression levels of Glut-1, Glut-3, and HK-II, induced by hypoxia (HIF-1), may be contributing factors to the higher 18F-FDG accumulation in the CT region.     

False positive 18F-FDG PET in an ischial chondroblastoma; an analysis of glucose transporter 1 and hexokinase II expression

We report a rare case of chondroblastoma arising from the ischium which showed an increased ¹⁸F-FDG uptake. Chondroblastoma is an uncommon lesion and usually involves the epiphysis of long bones. However, in this case, the tumor appeared as a well-defined osteolytic lesion in the ischium on radiographs. MR imaging demonstrated two components in the tumor: a solid one and a multilobular cystic component. ¹⁸F-FDG PET imaging revealed an increased uptake in the ischium. The ¹⁸F-FDG uptake resembled the results observed in malignant bone tumors. A histological diagnosis of chondroblastoma was obtained from tissue of an open biopsy. An immunohistochemical analysis demonstrated weak expression of both Glut-1 and HK-II. These findings suggest that Glut-1 and HK-II expression are not strongly related to FDG uptake in chondroblastoma.     

Relations Between Pathological Markers and Radioiodine Scan and 18F-FDG PET/CT Findings in Papillary Thyroid Cancer Patients With Recurrent Cervical Nodal Metastases

Purpose

The aim of this study was to investigate relationships between the immunohistochemical results and radioiodine scan and ¹⁸F-FDG PET findings in papillary thyroid cancer (PTC) patients with recurrent cervical nodal metastases.

Methods

A total of 46 PTC patients who had undergone a radioiodine scan and/or ¹⁸F-FDG PET/CT and a subsequent operation on recurrent cervical lymph nodes were enrolled. Twenty-seven patients underwent ¹⁸F-FDG PET/CT, 8 underwent radioiodine scans, and 11 underwent both scans. In all surgical specimens, the immunoexpressions of thyroglobulin (Tg), sodium-iodide symporter (NIS), glucose transporter 1 (Glut-1), and somatostatin receptor 1 and 2A (SSTR1 and SSTR2A) were assessed, and associations between these expressions and radioiodine scan and ¹⁸F-FDG PET findings were evaluated.

Results

Of the 38 patients who underwent ¹⁸F-FDG PET/CT, all patients with weak Tg expression had positive ¹⁸F-FDG uptake, while only 45 % of the patients with moderate or strong Tg expression showed positive uptake (p = 0.01). The proportion of patients with positive ¹⁸F-FDG uptake increased as the degree of Glut-1 expression with luminal accentuation increased. Of the 19 patients who underwent a radioiodine scan, the proportion with positive radioiodine uptake was greater among patients with strong NIS and SSTR2A expression than among patients expressing these markers at weak levels (p = 0.04 for all). All three patients with weak Tg expression were negative for radioiodine uptake.

Conclusion

The ¹⁸F-FDG uptakes of recurrent cervical nodes are related to strong Glut-1 expression with luminal accentuation and weak Tg expression, whereas radioiodine uptake is related to the strong expressions of NIS and SSTR2A.     

18F-FDG-PET of musculoskeletal tumors: a correlation with the expression of glucose transporter 1 and hexokinase II

Objective  It remains controversial whether positron emission tomography (PET) with 2-deoxy-2-[F-18]fluoro-d-glucose (F-18-FDG) can differentiate between benign and malignant musculoskeletal tumors. To uncover the mechanism of F-18-FDG accumulations, we analyzed the correlation between the F-18-FDG accumulation and the expression of glucose transporter 1 (Glut-1) and hexokinase II (HK-II) in benign and malignant musculoskeletal tumors. Methods  The maximum standardized uptake values (SUV_max) of F-18-FDG in 24 benign and 26 malignant musculoskeletal tumors were compared with the histologic malignancies, and the expression of Glut-1 and HK-II was analyzed by immunohistochemistry. Results  The SUV_max for malignant tumors (6.33 ± 4.79) was significantly higher than those with benign tumors (3.47 ± 3.12, P < 0.01). The expression of Glut-1 was high in 12 patients (all malignant) and low in 38 patients (24 benign and 14 malignant), and the expression of HK-II was high in 36 patients (11 benign and 25 malignant) and low in 14 patients (13 benign and 1 malignant). Cases with high expression of Glut-1 and HK-II at immunohistochemistry showed a higher SUV_max than those with low expression (Glut-1 8.03 ± 5.10 and 3.98 ± 3.53, P < 0.01; HK-II 5.73 ± 4.49 and 2.99 ± 3.02, P < 0.01). No significant dividing threshold of the SUV_max of F-18 FDG was found for the differential diagnosis between benign and malignant tumors or for the expression of Glut-1 and HK-II. Conclusions  The limited capability of F-18 FDG-PET in the differential diagnosis of musculoskeletal tumors is owing partly to the various levels of Glut-1 and HK-II expression in individual tumors.     

18F-FDG uptake on PET in primary mediastinal non-thymic neoplasm: a clinicopathological study

Background

The usefulness of 2-[¹⁸F]-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) positron emission tomography (PET) has been investigated in thymic epithelial tumors. However, little is known about PET imaging of ¹⁸F-FDG in primary non-thymic mediastinal neoplasms. The aim of this study is to explore the clinicopathological significance of ¹⁸F-FDG PET in primary mediastinal (non-thymic) neoplasms.

Methods

Twenty-one patients with mediastinal neoplasms who underwent ¹⁸F-FDG PET before treatment were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (Glut1); glucose transporter 3 (Glut3); hypoxia-inducible factor-1 alpha (HIF-1α); hexokinase I; vascular endothelial growth factor (VEGF); microvessels (CD34); epidermal growth factor receptor (EGFR); Akt/mTOR signaling pathway (p-Akt and p-mTOR); cell cycle control (p53).

Results

Seventeen of 21 patients were imaged on PET system using ¹⁸F-FDG, but 4 patients with a histology of cyst showed nothing abnormal in PET scans. The histology of the resected tumors was as follows: 6 schwannoma, 3 teratoma, 4 cyst, 3 sarcoma, 1 undifferentiated carcinoma, 1 seminoma, 1 mediastinal goiter, 1 ganglioneuroma, and 1 Hodgkin lymphoma. ¹⁸F-FDG uptake was significantly correlated with Glut1, HIF-1α, EGFR, p-Akt and p-S6K. These biomarkers were highly expressed in schwannoma, teratoma and high grade malignancies, whereas all patients with cyst and ganglioneuroma had no positive expression of these biomarkers. High uptake of ¹⁸F-FDG was significant associated with Glut1, VEGF, EGFR, p-Akt, p-S6K and tumor maximal size.

Conclusion

The amount of ¹⁸F-FDG uptake in primary mediastinal non-thymic neoplasms is determined by the presence of glucose metabolism (Glut1), hypoxia (HIF-1α) and upstream components of HIF-1α (EGFR, p-Akt and p-S6K).     

18F-FLT和18F-FDG评价食管癌细胞照射后超早期生物学反应

目的 比较18F-氟代脱氧胸腺嘧啶(18F-FLT)和18F-氟代脱氧葡萄糖(18F-FDG)在反映食管癌细胞受照后超早期生物学反应的差异.方法 将人食管癌Eca-109细胞分别接受5、10、15 Gy剂量X射线照射,照射后2、4、8h检测细胞对18F-FDG和18F-FLT摄取率的变化,以及细胞相对存活率和ATP表达情况的变化.结果 5 Gy照射后2、4h,细胞对18F-FDG摄取率与对照组相比分别减少了9.45％和16.4％,差异无统计学意义;但15 Gy照后2h,对18F-FDG摄取率却增加了26.5％(=3.04,P＜0.05),其余照射组对18F-FDG摄取率均有明显减少(F=25.75,P＜0.05).5 Gy照后2h,18F-FLT摄取率(3.65±0.41)％与对照组(4.00±0.42)％相比,差异无统计学意义,其余照射组对18F-FLT摄取率与对照组比较均有明显减少(F=33.93,P＜0.05).在5、10、15 Gy照后2、4、8h,各组细胞相对存活率差异无统计学意义.经不同剂量照射后,细胞对18F-FLT摄取率与ATP浓度之间的相关性(r=0.887,P＜0.05)优于18F-FDG与ATP浓度之间的相关性(r=0.622,P＞0.05).结论 18F-FDG和18 F-FLT两者均可反映食管癌细胞照射后超早期生物学反应,18F-FLT比18F-FDG能较好地反映食管癌细胞照射后超早期生物学反应.     

Analysis of gene expression profiles of hepatocellular carcinomas with regard to 18F-fluorodeoxyglucose uptake pattern on positron emission tomography

Purpose ¹⁸F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) scan has been found to reflect tumour aggressiveness and prognosis in various types of cancer. In this study, the gene expression profiles of hepatocellular carcinomas (HCCs) were evaluated to determine whether HCCs with high ¹⁸F-FDG uptake have more aggressive biological potential than those with low uptake.Methods Surgical specimens were obtained from ten patients with HCC (six males and four females, age range 38–68 years). The tumour samples were divided into two groups based on the ¹⁸F-FDG PET scan findings: high ¹⁸F-FDG uptake (n=4) and low ¹⁸F-FDG uptake (n=6).Results The pathological tumour grade was closely correlated with the ¹⁸F-FDG uptake pattern: HCCs with high ¹⁸F-FDG uptake were pathologically Edmondson-Steiner grade III, while those with low uptake were either grade II or grade II with a focal area of grade III. The total RNA was extracted from the frozen tissues of all HCCs (n=10) and adjacent non-cancerous tissue (n=7). The gene expression profiles were evaluated using an oligoDNA microarray. The HCCs with high ¹⁸F-FDG uptake showed increased expression of 11 genes—including vascular cell adhesion molecule-1, vinexin beta and core 1 UDP-galactose:N-acetylgalactosamine-alpha-R-beta 1,3-galactosyltransferase and the natural killer cell inhibitory receptor—compared to those with low uptake (p<0.005). Nine genes, including regulator of mitotic spindle assembly 1, grb2-related adaptor protein and beta-1,3-n-acetylglucosaminyltransferase, were repressed.Conclusion Gene expression is closely related to cell survival, cell-to-cell adhesion or cell spreading; therefore, HCCs with high ¹⁸F-FDG uptake appear to have more aggressive biological properties than those with low uptake.     

Expressions of glucose transporter Types 1 and 3 and hexokinase-II in diffuse large B-cell lymphoma and other B-cell non-Hodgkin's lymphomas

IntroductionDiffuse large B-cell lymphoma (DLBCL) has been reported to show higher uptake of 2-deoxy-2-F18-fluoro-d-glucose (FDG) by positron emission tomography than other B-cell non-Hodgkin's lymphomas (non-DLBCL). The authors addressed the mechanism of FDG uptake in DLBCL by immunostaining for glucose transporter Types 1 (Glut-1) and 3 (Glut-3) and hexokinase-II (HK-II) in excised lymphoma tissues.MethodsSixteen B-cell non-Hodgkin's lymphoma patients (11 DLBCL and 5 non-DLBCL patients) were included in the study because the lymphoma tissues obtained by excision were eligible for immunostaining. The expressions of Glut-1, Glut-3 and HK-II were assessed regarding the percentages of positively stained lymphoma cells (%expression), the staining intensities (none=0, weak=1, moderate=2 and strong=3) and the staining patterns (membranous or cytoplasmic) and compared between DLBCL and non-DLBCL.ResultsGlut-1 was not expressed at all in DLBCL or non-DLBCL, and their Glut-3 expressions were not significantly different (P>.05) with respect to %expression (mean±S.E.M., 73.6±7.3% vs. 72.0±3.7%), staining intensity (2.5±0.2 vs. 2.6±0.2) and staining pattern (membranous pattern dominant; 54.5% vs. 60.0%). However, DLBCL expressed more HK-II than non-DLBCL, i.e., %expression (45.2±11.5% vs. 17.0±15.8%, P=.0275) and staining intensity (2.3±0.2 vs. 0.6±0.4, P=.0032). HK-II showed a cytoplasmic location in DLBCL and non-DLBCL.ConclusionsHK-II and Glut-3 contribute significantly to FDG uptake in DLBCL. DLBCL may have higher FDG uptake because it expresses more HK-II, whereas Glut-1 appears to play no role in FDG uptake in B-cell non-Hodgkin's lymphoma.     

FDG PET for grading malignancy in thymic epithelial tumors: Significant differences in FDG uptake and expression of glucose transporter-1 and hexokinase II between low and high-risk tumors: Preliminary study

Purpose

To evaluate ¹⁸F-fluorodeoxyglucose (FDG) uptake to predict the malignant nature and analyze the correlation between FDG uptake and expression of glucose transporter 1 (Glut-1) and hexokinase II (HK-II) in thymic epithelial tumors.

Materials and methods

Eleven patients with a thymic epithelial tumor who underwent FDG PET/CT before therapy were reviewed. The thymic tumors were classified by the WHO histological classification and Masaoka clinical staging. Comparison of maximum standardized uptake value (SUV_max) of the lesion was made between the low-risk (Type A, AB and B1) and high-risk {Type B2, B3 and C (thymic cancer)} groups and among clinical stages. Expression of Glut-1 and HK-II was analyzed immunohistochemically.

Results

All 11 tumors showed FDG uptake visually. SUV_max was significantly higher in the high-risk group (n = 5, 5.24 ± 2.44) than the low-risk group (n = 6, 3.05 ± 0.55) (P = 0.008). Staining scores of both Glut-1 and HK-II were significantly higher in the high-risk group than in the low-risk group (Glut1: P = 0.034 and HK-II: P = 0.036). There were no significant differences in SUV_max (P = 0.11), Glut-1 (P = 0.35) and HK-II scores (P = 0.29) among clinical stages. SUV_max was significantly correlated to each of the staining scores of Glut-1 (ρ = 0.68, P = 0.031) and HK-II (ρ = 0.72, P = 0.024).

Conclusion

These preliminary results support the previously published view that SUV_max may be useful to predict the malignant nature of thymic epitherial tumors and suggest that the degree of FDG uptake in the thymic epitherial tumors is closely related to the amount of Glut-1 and HK-II in the tumor.     

18F-FDG uptake in squamous cell carcinoma of the cervix is correlated with glucose transporter 1 expression.

This prospective study investigates the relationship between glucose transporter-1 (Glut-1) expression and PET images using (18)F-FDG and its uptake and compares them with the tumor status (primary vs. recurrent or persistent), initial grade of histologic differentiation, and International Federation of Gynecologic Obstetrics (FIGO) staging for cervical cancer patients. METHODS: A dual-phase (18)F-FDG PET scan was performed on 51 participants within the 2 wk before surgery or biopsy. (18)F-FDG uptake was quantified by calculating standardized uptake values (SUVs). After (18)F-FDG PET scanning, 51 histologically proven squamous cell carcinoma specimens were examined to determine their degree of differentiation, using hematoxylin and eosin staining, and the expression of Glut-1 by an immunohistochemical stain. Twenty normal cervical and 20 cervical intraepithelial neoplasia (CIN) sets of tissue were also used to compare the results of Glut-1 expression in these tissues. The expression of Glut-1 was the product of (the intensity [with grades 0-3, defined qualitatively]) with (percentages of the lesion area that were positive). The results of Glut-1 expression were analyzed in combination with the SUVs (SUV1 was that at 40 min and SUV2 was that at 3 h), tumor status, initial cell differentiation, and FIGO staging. RESULTS: Significant overexpression of Glut-1 was noted in 48 of the 51 (94.1%) cancer specimens. None or only minimal expression of Glut-1 was observed in basal layers of normal and CIN tissues. Significant positive correlation was observed between Glut-1 expression and the SUVs in cervical cancer specimens (r = 0.74, P < 0.000 for SUV1 and r = 0.65, P < 0.000 for SUV2). In recurrent or persistent tumor, tumor size was significantly associated with both Glut-1 expression (r = 0.508, P = 0.011) and SUV1 (r = 0. 456, P = 0.025). For recurrent or persistent tumor, only SUV1 reached statistical significance when compared with lymph node metastasis (P = 0.0226). CONCLUSION: Glut-1 expression was related to (18)F-FDG uptake in cervical cancer patients. Recurrent or persistent cervical cancer tumor had significantly higher Glut-1 expression than metastatic lymph nodes. The values of SUV and the expression of Glut-1 did not correlate with the initial grade of histologic differentiation and FIGO staging.     

Relationship between retention index in dual-phase (18)F-FDG PET, and hexokinase-II and glucose transporter-1 expression in pancreatic cancer.

Recently, some studies have shown that delayed scanning with (18)F-FDG PET may help to differentiate malignant from benign pancreatic lesions. However, no study has evaluated the relationship between temporal changes in (18)F-FDG uptake and expression of hexokinase or glucose transporter. METHODS: Twenty-one consecutive patients with pancreatic cancer were studied preoperatively by dual-phase (18)F-FDG PET, performed 1 and 2 h after injection of (18)F-FDG. The standardized uptake value (SUV) of the pancreatic cancer was determined, and the retention index (RI) (%) was calculated by subtracting the SUV at 1 h (SUV1) from the SUV at 2 h (SUV2) and dividing by SUV1. The percentages of cells strongly expressing hexokinase type-II (HK-II) and glucose transporter-1 (GLUT-1) were scored on a 5-point scale (1 = 0%-20%, 2 = 20%-40%, 3 = 40%-60%, 4 = 60%-80%, 5 = 80%-100%) by visual analysis of immunohistochemical staining of paraffin sections from the tumor specimens using anti-HK-II and anti-GLUT-1 antibody (HK-index and G-index, respectively). RESULTS: SUV2 (mean +/- SD, 5.7 +/- 2.6) was higher than SUV1 (5.1 +/- 2.1), with an RI of 8.5 +/- 11.0. Four cases of cancer, in which SUV2 showed a decline from SUV1, showed a low HK-index (1.8 +/- 1.1), whereas 4 cases with an RI of > or =20 and 13 cases with an intermediate RI (0-20) showed significantly higher HK-indices (4.3 +/- 0.7 and 3.1 +/- 1.5, respectively; P < 0.05). RI showed a positive correlation with HK-index, with an R(2) of 0.27 (P < 0.05), but no significant correlation with the G-index. SUV1 showed no relationship with the HK-index but showed a weak positive correlation with the G-index, with an R(2) of 0.05 (P = 0.055). CONCLUSION: These preliminary findings suggest that the RI obtained from dual-phase (18)F-FDG PET can predict HK-II expression and that the SUV (at 1 h) has a positive correlation with GLUT-1 expression but not with HK-II expression.     

Clinical values for abnormal F-FDG uptake in the head and neck region of patients with head and neck squamous cell carcinoma

Purpose

Fluorine 18-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT) is used to identify index or second primary cancer (SP) of the head and neck (HN) through changes in ¹⁸F-FDG uptake. However, both physiologic and abnormal lesions increase ¹⁸F-FDG uptake. Therefore, we evaluated ¹⁸F-FDG uptake in the HN region to determine clinical values of abnormal tracer uptake.

Methods

A prospective study approved by the institutional review board was conducted in 314 patients with newly diagnosed HN squamous cell carcinoma (HNSCC) and informed consent was obtained from all enrolled patients. The patients received initial staging workups including ¹⁸F-FDG PET/CT and biopsies. All lesions with abnormal HN ¹⁸F-FDG uptake were recorded and most of those were confirmed by biopsies. Diagnostic values for abnormal ¹⁸F-FDG uptake were calculated.

Results

Abnormal ¹⁸F-FDG uptake was identified in primary tumors from 285 (91.9%) patients. False-negative results were obtained for 22.3% (23/103) T1 tumors and 2.2% (2/93) T2 tumors (P < 0.001). Thirty-eight regions of abnormal ¹⁸F-FDG uptake were identified in 36 (11.5%) patients: the thyroid (n = 13), maxillary sinus (n = 7), palatine tonsil (n = 6), nasopharynx (n = 5), parotid gland (n = 2) and others (n = 5). Synchronous SP of the HN was identified in eight (2.5%) patients: the thyroid (n = 5), palatine tonsil (n = 2), and epiglottis (n = 1). The sensitivity and specificity of ¹⁸F-FDG PET/CT for identification of SPs were 75.0% and 98.7%, respectively.

Conclusions

¹⁸F-FDG PET/CT is a reliable method for tumor staging and identify SP in HN region, promoting appropriate therapeutic planning. Additional examinations may be required to identify superficial or small-volume tumors.     

Different glucose uptake and glycolytic mechanisms between hepatocellular carcinoma and intrahepatic mass-forming cholangiocarcinoma with increased (18)F-FDG uptake.

(18)F-FDG uptake in malignant tumors largely depends on the presence of facilitated glucose transporters, especially type 1 (Glut 1) and a rate-limiting glycolytic enzyme, hexokinase (HK) type II. Low expression of Glut 1 was reported in hepatocellular carcinoma (HCC), whereas high expression was found in cholangiocarcinoma. Immunohistochemistry and proteome analysis were performed to obtain a detailed evaluation of the mechanisms involved in glucose uptake and use in these tumors. METHODS: Tumor tissues obtained from both HCC (n = 7) and mass-forming cholangiocarcinoma patients (n = 7) who showed increased (18)F-FDG uptake on PET were used. Immunohistochemistry for Glut 1 and HK I-III was performed in all tumor tissues. To identify proteins that regulate carbohydrate metabolism, a proteome analysis with matrix-assisted laser desorption ionization-time of flight and enzymatic digestion in-gel were performed using 8 available tumor samples and 3 normal liver tissues. Of the 8 tumor samples, 4 were HCCs; one was an intermediate phenotype HCC, and 3 were cholangiocarcinomas. The spot intensity of the proteins was calculated using proteome data; the tissues then were divided into 2 groups on the basis of the protein expression pattern, because the protein expression pattern of the intermediate-phenotype HCC was close to that of the cholangiocarcinomas. Group A included the HCCs and group B included the intermediate-phenotype HCC as well as the cholangiocarcinomas. RESULTS: Immunoreactivity for Glut 1 was positive in all cholangiocarcinomas, but was negative in all HCCs except the one intermediate phenotype. However, HK II was positive in HCCs but was negative in 6 of the 7 cholangiocarcinomas. A total of 331 protein spots with a P value of <0.05 were identified by proteome analysis. Thirteen of these proteins that regulate carbohydrate metabolism were selected. The pentose phosphate pathway was increased in both groups, but more significantly in group B. Gluconeogenesis enzymes were decreased in both groups, but the tricarboxylic acid cycle-regulating enzyme expression was variable. CONCLUSION: HCCs have different glucose-regulating mechanisms from those of cholangiocarcinomas, even though both tumors showed increased (18)F-FDG uptake on PET scans. Further studies are required with regard to energy metabolism and (18)F-FDG uptake patterns in association with various oncogenic alterations regulating multiple steps of the glycolytic pathways.     

Influence of thyroid-stimulating hormone on 18F-fluorodeoxyglucose and 99mTc-methoxyisobutylisonitrile uptake in human poorly differentiated thyroid cancer cells in vitro

Objective  In poorly differentiated thyroid cancer originating from thyroid follicular cells, the ability to concentrate iodine is lost. This makes recurrence undetectable by ¹³¹I whole-body scan. In this situation, other radiopharmaceuticals, such as ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) and technetium-99m-methoxyisobutylisonitrile (^99mTc-MIBI), are used to evaluate recurrence or metastasis. Some reports suggest that ¹⁸F-FDG uptake is increased by thyroid-stimulating hormone (TSH) stimulation. This study aimed to determine the influence of TSH on ¹⁸F-FDG and ^99mTc-MIBI uptake in human poorly differentiated thyroid cancer cells in vitro. Materials and methods  The cells were stimulated with 1000 μU/ml of recombinant human thyroid-stimulating hormone (rhTSH) for 1 day, 3 days, and 5 days. Each cell was incubated with 0.5 MBq/ml-1 MBq/ml of ¹⁸F-FDG or 0.5 MBq/ml-1 MBq/ml of ^99mTc-MIBI for 1 h at 37°C. The uptake of each radiopharmaceutical in the cells was quantified as a percent of whole radioactivity per total viable cell number. The quantification of glucose transporter 1, 2, 3 and 4 mRNA expression was measured using RT-PCR. Results  TSH stimulation increased ¹⁸F-FDG uptake in a time-dependent manner. Following 5 days of rhTSH stimulation, ¹⁸F-FDG uptake was approximately 2.2 times that of the control. The increase in ¹⁸F-FDG uptake following rhTSH stimulation was correlated to the increase in GLUT4 mRNA level. The GLUT1 mRNA level was unchanged. An increased uptake of ^99mTc-MIBI was observed with a pattern similar to that of ¹⁸F-FDG. The ^99mTc-MIBI uptake was approximately 1.5 times that of the control 5 days later. Conclusions  These results suggest that TSH stimulates ¹⁸F-FDG and ^99mTc-MIBI uptake in poorly differentiated papillary thyroid cancer, and therefore ¹⁸F-FDG-PET or ^99mTc-MIBI scans under TSH stimulation may be more accurate than under suppression.     

Expression of Glut-1 and Glut-3 in untreated oral squamous cell carcinoma compared with FDG accumulation in a PET study

Increased expression of glucose transporter-1 (Glut-1) and glucose transporter-3 (Glut-3) has been reported in many human cancers. The mechanism of glucose entry into oral squamous cell carcinoma (OSCC) remains unclear. In this study we investigated, in untreated human OSCC, the relationship between tumour fluorine-18 fluoro-2-deoxy-d-glucose (FDG) accumulation and the expression of Glut-1 and Glut-3, as well as the association between the expression of Glut-1 and of Glut-3. All patients underwent FDG positron emission tomography (PET) pre-operatively. Standardised uptake values (SUVs) were used for evaluation of tumour FDG uptake. Final diagnoses were established by histology. Immunohistochemical staining results were evaluated according to the percentage (%) of positive area, intensity and staining score. Tumour sections were stained by immunohistochemistry for Glut-1 and Glut-3. Glut-1 immunostaining revealed that 18 (94.7%) of the 19 tumours stained positively, while Glut-3 immunostaining yielded positive findings for 16 (84.2%) tumours. Overall, a relatively low level of agreement (36.8%) in the staining score was observed between Glut-1 and Glut-3 expression. No relationship was found between the staining pattern and tumour differentiation or T grade classification in either Glut-1 or Glut-3 immunostaining. Furthermore, no relationship was found between increased FDG SUV and tumour differentiation, but the former did correlate with T grade. In conclusion, high FDG uptake values were seen in OSCC with overexpression of Glut-1 and Glut-3. However, no significant correlation was found between FDG SUV and Glut-1 or Glut-3 expression.     

Association Between <Superscript>18</Superscript>F-FDG Avidity and the BRAF Mutation in Papillary Thyroid Carcinoma

Purpose

The BRAF mutation, a potential prognostic factor in papillary thyroid carcinoma (PTC), is associated with a high expression of the glucose transporter gene. We investigated which clinicopathologic factors, including BRAF mutation status, influence ¹⁸F-fluoro-2-deoxyglucose (¹⁸F-FDG) avidity.

Methods

We retrospectively reviewed 55 patients who underwent BRAF analysis from biopsy-confirmed PTC and ¹⁸F-FDG positron emission tomography/computed tomography within 6 months before undergoing thyroid surgery from September 2008 to August 2014. Tumors were considered to be ¹⁸F-FDG avid if the uptake was greater than that of the liver. ¹⁸F-FDG uptake of PTCs was also analyzed semiquantitatively using SUV_max. The association between ¹⁸F-FDG avidity and clinicopathologic variables (age, tumor size, perithyroidal extension, cervical lymph node status, and BRAF mutation status) was investigated.

Results

Twenty-nine (52.7 %) of 55 patients had ¹⁸F-FDG-avid PTCs. PTCs with the BRAF mutation showed higher ¹⁸F-FDG avidity (24/38, 63.2 %) than those without (5/17, 29.4 %). The BRAF mutation (p = 0.025) and tumor size (p = 0.003) were significantly associated with ¹⁸F-FDG avidity in univariate analysis, and the BRAF mutation status remained significant after adjusting for tumor size in multivariate analysis (p = 0.015). In the subgroup of tumor size ≥ 1 cm, the BRAF mutation was the only factor significantly associated with ¹⁸F-FDG avidity (p = 0.021). The mean SUV_max of PTCs with the BRAF mutation was significantly higher than that of those without (4.89 ± 6.12 vs. 1.96 ± 1.10, p = 0.039).

Conclusions

The BRAF mutation must be one of the most important factors influencing ¹⁸F-FDG avidity in PTCs, especially in those with a tumor size ≥ 1 cm.     

Advantages and pitfalls of 18F-fluoro-2-deoxy-D-glucose positron emission tomography in detecting locally residual or recurrent nasopharyngeal carcinoma: comparison with magnetic resonance imaging

Introduction This prospective study was designed to elucidate the advantages and pitfalls of ¹⁸F-FDG PET in detecting locally residual/recurrent nasopharyngeal carcinoma (NPC) in comparison with MRI. Methods We recruited NPC patients from two ongoing prospective trials. One is being performed to evaluate suspected local recurrence (group A) and the other to assess local treatment response 3 months after therapy (group B). Both groups received ¹⁸F-FDG PET and head and neck MRI. The gold standard was histopathology or clinical/imaging follow-up. An optimal cut-off standardised uptake value (SUV) was retrospectively determined. Results From January 2002 to August 2004, 146 patients were eligible. Thirty-four were from group A and 112 from group B. In all, 26 had locally recurrent/residual tumours. Differences in detection rate between ¹⁸F-FDG PET and MRI were not statistically significant in either group. However, ¹⁸F-FDG PET showed significantly higher specificity than MRI in detecting residual tumours among patients with initial T4 disease (p=0.04). In contrast, the specificity of ¹⁸F-FDG PET for patients with an initial T1–2 tumour treated with intracavitary brachytherapy (ICBT) was significantly lower than that for patients not treated by ICBT (72.2% vs 98.1%, p=0.003). At an SUV cut-off of 4.2, PET showed an equal and a higher accuracy compared with MRI in groups A and B, respectively. Conclusion ¹⁸F-FDG PET is superior to MRI in identifying locally residual NPC among patients with initial T4 disease but demonstrates limitations in assessing treatment response in patients with initial T1–2 disease after ICBT. A cut-off SUV is a useful index for aiding in the visual detection of locally residual/recurrent NPC.     

Are dual-phase 18F-FDG PET scans necessary in nasopharyngeal carcinoma to assess the primary tumour and loco-regional nodes?

Purpose This prospective study aimed to investigate the efficacy of dual-phase positron emission tomography (PET) in evaluating the loco-regional status of nasopharyngeal carcinoma (NPC).Methods Eighty-four patients with newly diagnosed NPC and a fasting serum glucose level of <200 mg/dl were enrolled. [¹⁸F]fluoro-2-deoxy-D-glucose (¹⁸F-FDG) PET studies (at 40 min and 3 h after injection of 370 MBq ¹⁸F-FDG) and head and neck magnetic resonance imaging (MRI) were performed within 1 week. Diagnostic criteria for NPC comprised the histopathological findings, the joint judgments of the research team and the post-treatment outcome. Each lesions maximum standardised uptake value (SUV) and retention index were obtained. SUV data were evaluated using a paired t test. Receiver operating characteristic curves and calculation of the area under the curve (AUC) determined the discriminative power.Results ¹⁸F-FDG PET was significantly superior to MRI in identifying lower neck NPC nodal metastasis (AUC: 1 vs 0. 972, P=0.046) and overall loco-regional metastases (AUC: 0.985 vs 0.958, P=0.036). However, ¹⁸F-FDG PET was similar to MRI in detecting primary tumour, as well as retropharyngeal, upper neck and supraclavicular nodal metastases. There was no significant difference between early phase (40 min) and delayed phase (3 h) ¹⁸F-FDG PET in the detection of primary tumours (accuracy: 100% vs 100%) or loco-regional nodal metastasis (AUC: 0.984 vs 0.985, P=0.834).Conclusion ¹⁸F-FDG PET is superior to MRI in identifying lower neck nodal metastasis of NPC. Additional 3-h ¹⁸F-FDG PET contributes no further information in the detection of primary tumours or loco-regional metastatic nodes in untreated NPC patients.     

Hexokinase-II expression in untreated oral squamous cell carcinoma: Comparison with FDG PET imaging

Hexokinase is thought to be one of the key factors of glucose catabolism in the cell. The aim of this study was to investigate the relationship between HK-II expression and 18F-fluoro-2-deoxy-D-glucose (FDG) uptake in human untreated oral squamous cell carcinoma (OSCC). Pre-operatively FDG positron emission tomography (PET) was performed 60 min after FDG injection in all the patients. Maximum standardized uptake value (SUV) was used for evaluation of tumor FDG uptake. Tumor sections were stained immunohistochemically for HK-II. All the tumor sections stained positive for HK-II. Eighteen (95%) tumors in HK-II showed immunostained positive area >50%. HK-II findings revealed eleven (58%) tumors with strong intensity, six (32%) with moderate intensity and two with weak intensity (10%). There was no statistically significant correlation between SUV and the expression of HK-II (p = 0.46). In conclusion, OSCC showed increased FDG accumulation and overexpression of HK-II. However, we did not find any significant relationship between high FDG uptake and overexpression of HK-II in this patient population, and thus other properties need to be evaluated in order to elucidate key factors responsible for FDG activity in OSCC.     

Opportunities for 2-[18F] Fluoro-2-Deoxy-D-Glucose PET/CT in Cervical-Vaginal Neuroendocrine Carcinoma: Case Series and Literature Review

Objective

Neuroendocrine cervical carcinoma is a rare subtype of cervical cancer. These tumors exhibit an aggressive behavior with early regional lymph node and distant metastases. The purpose of our study was to describe five cases of neuroendocrine cervical-vaginal carcinoma and to discuss the potential of the 2-[¹⁸F] fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) scan for the detection of this rare malignancy.

Materials and Methods

Five cases of cervical-vaginal neuroendocrine tumor were retrospectively collected, during a two year (from September 2009 to August 2011) period in our hospital. The clinical staging distributions were International Federation of Gynecology and Obstetrics (FIGO) stage IB2 (1 of 5), stage IIA (3 of 5) and stage IVA (1 of 5).

Results

Two cases (cases 1 and 4) were restaged after ¹⁸F-FDG PET/CT scan in the initial staging process. Post-treatment ¹⁸F-FDG PET/CT scans, in three patients, revealed positive findings for tumor recurrence or lymph node metastases. Two patients (cases 2 and 3) died of tumor within two years.

Conclusion

¹⁸F-FDG PET/CT scan is a useful tool in cervical-vaginal neuroendocrine tumor. In its initial staging, the ¹⁸F-FDG PET/CT scan may help assess the possible nodal involvement or early hematogeneous spreading. We can also use the ¹⁸F-FDG PET/CT to detect local recurrence and to evaluate the treatment response after clinical manipulation.