The associations among the glucose metabolic rate, tumor progression, and histopathological grade in metabolically active renal cell carcinoma: A comparison using whole-body 4D parametric FDG-PET/CT imaging

The associations among the glucose metabolic rate, tumor progression, and histopathological grade in metabolically active renal cell carcinoma: A comparison using whole-body 4D parametric FDG-PET/CT imaging | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The associations among the glucose metabolic rate, tumor progression, and histopathological grade in metabolically active renal cell carcinoma: A comparison using whole-body 4D parametric FDG-PET/CT imaging Koichiro Kaneko, Yui Maekawa, Kazuhiko Yoshida, Satoru Morita, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6900672/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective: To investigate the associations among the tissue metabolic rate of 18 F-fluorodeoxyglucose (FDG), i.e., the MR FDG value (mg/min/10 mL), tumor progression, and the histopathological grade in metabolically active renal cell carcinoma (RCC), using four-dimensional parametric FDG-positron emission tomography (PET)/computed tomography (CT) imaging. Methods: Dynamic whole-body FDG-PET/CT scans were performed for 28 patients newly diagnosed with RCC. We compared the obtained MR FDG values with the patients' tumor size, T stage, presence/absence of metastasis and venous tumor thrombus (VTT), and histopathological grade based on the Fuhrman and World Health Organization/International Society of Urological Pathology classifications. Results: A total of 30 RCC lesions were analyzed. A strong positive correlation was observed between the MR FDG values and tumor size (R=0.68, p<0.0001). The tumors at ≥T2 stage showed significantly higher MR FDG values compared to the T1-stage tumors (8.30 ± 7.33 vs. 2.20 ± 1.44, p=0.003). The tumors with VTT had significantly higher MR FDG values versus those without VTT (6.70 ± 5.39 vs. 3.38 ± 6.07, p=0.002), but the tumors showed similar MR FDG values regardless of the presence/absence of metastasis (5.83 ± 4.57 vs. 4.65 ± 1.50, p=0.07). The Fuhrman G4 tumors showed significantly higher MR FDG values versus the G1–3 tumors (11.05 ± 9.97 vs. 2.50 ± 2.67, p=0.03), although no significant differences were observed between the G1/2 and G3/4 tumors by either classification. Conclusions: High values of the MR FDG in RCC reflected a high degree of local development and a high Fuhrman grade, but they did not reflect a propensity for metastasis. Renal cell carcinoma Glucose metabolic rate Local tumor progression Histopathological grade Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Renal cell carcinoma (RCC) represents the most common cancer in the kidney, and the most common histological subtype of RCC is clear cell RCC (ccRCC, ~ 70–80% of RCC cases), followed by papillary RCC (pRCC, ~ 10–15%) and chromophobe RCC (chRCC, ~ 5%) [ 1 ]. Metastatic disease occurs approximately 10% of patients with newly diagnosed RCC patients, and 10% of patients with localized RCC will develop metastatic disease at a later time [ 2 ]. CcRCC is characterized by a high proliferation rate compared to the other subtypes, and is potentially more metastatic than the other two variants [ 3 , 4 ]. Another hallmark of RCC is its biological predisposition for vascular invasion; approx. 4–10% of patients with RCC have venous tumor thrombus (VTT) [ 5 ]. RCC is not a typical Warburg tumor, and due to the excretion of 18 F-fluorodeoxyglucose (FDG) through the genitourinary tract, the use of FDG-positron emission tomography (PET)/computed tomography (CT) in primary RCC is challenging. Many PET studies have demonstrated a correlation between FDG uptake and the histopathological grade or prognosis by using static PET parameters such as the standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) [ 6 – 11 ]. Multi-pass, multi-bed PET acquisition has been used to perform dynamic whole-body (D-WB) FDG-PET/CT imaging [ 12 , 13 ], which can provide two parametric images: metabolic rate (MR FDG ; mg/min/10 mL) images and distribution volume (DV FDG ; %) images. Our research group recently demonstrated a strong correlation between static and dynamic PET parameters, a difference in FDG dynamics, and the high diagnostic value of MR FDG images in malignant liver tumors [ 14 ]. We also demonstrated that MR FDG values were not correlated with tumor size [ 14 ]. Another of our studies revealed that the MR FDG value was significantly lower in sarcoid lesions compared to malignant lesions, and in patients with sarcoidosis or a malignant tumor, MR FDG values improved the identification of sarcoid lesions over the SUV alone [ 15 ]. However, D-WB PET imaging findings in RCC, including their association with tumor progression and the histopathological grade, have remained unknown. We conducted the present study to investigate the associations among MR FDG values, tumor progression, and the histopathological grade in RCC. Patients and Methods Patient population This was a retrospective analysis of the cases of 28 consecutive patients with 30 RCC lesions (16 males and 12 females, mean age 66 years) who underwent D-WB FDG-PET/CT scans at Tokyo Women’s Medical University during the period from February 2022 through January 2025. Their clinical characteristics are summarized in Table 1 . Table 1 Characteristics of the RCC patients (n = 28) Males/females 16/12 Age, yrs; mean ± SD 65.9 ± 10.9 Lesions, n 30 Size, mm; median/range 65.4/2.5–141.6 T stage, T1a/1b/2a/2b/2c/3a/3b/3c/4 7/5/2/0/6/6/2/2 Histopathology: Clear cell RCC 18 Papillary RCC 2 TFE3-rearranged RCC 2 Unclassified RCC 2 Chromophobe RCC 1 Mit family translocation RCC 1 Sarcomatoid and rhabdoid RCC 1 Xp11.2 translation RCC 1 Unknown 2 Metastasis, LN/distant/both 1/5/4 Fuhrman grade, 1/2/3/4 1/6/7/6 WHO/ISUP grade, 1/2/3/4 1/6/7/4 SUVmax, median/range 6.0/2.2–34.6 ISUP: International Society of Urological Pathology, LN: lymph node, RCC: renal cell carcinoma, SUV: standardized uptake value, WHO: World Health Organization. Histopathological confirmation was obtained in 23 RCC lesions by surgical resection and in five lesions by biopsy. These lesions consisted of 18 ccRCCs, two papillary RCCs, two TFE3-rearranged RCCs, two unclassified RCCs, one chromophobe RCC, one Mit family translocation RCC, one sarcomatoid and rhabdoid RCC, and one Xp11.2 translation RCC. Histopathological confirmation was lacking in two of the 28 patients because of a serious condition due to extensive tumor progression or hospital transfer. Twenty surgically resected RCCs were graded according to the Fuhrman and WHO/ISUP classifications [ 16 , 17 ]. The study complied with the Declaration of Helsinki, and the protocol was approved by the ethics committee of Tokyo Women’s Medical University (no. 2021 − 0153). Written informed consent was obtained from all patients. Data acquisition and image reconstruction All FDG-PET/CT scans were performed on a Biograph Vision 600 PET/CT scanner (Siemens Healthineers, Erlangen, Germany), which integrates 64-slice multidetector computed tomography (MDCT) images using a fully automated multiparametric PET acquisition protocol (Flow Motion Multiparametric PET). All patients fasted for ≥ 5 hr prior to imaging and received a single intravenous injection of FDG (3.7 MBq/kg). First, a low-dose non-contrast-enhanced CT scan was performed for attenuation correction, covering the top of the patient's skull to the proximal thigh. A shortened multiparametric PET acquisition consisting of 4×5 min (total 20 min, starting 30 min post-injection) continuous bed motion passes was then performed as described [ 18 , 19 ]. After the D-WB scan, static PET data acquisition was performed in three-dimensional (3D) mode for 90 sec per position (step and shoot) from 60 min post-injection. The multiparametric scan protocol generates parametric images based on the Patlak model [ 20 ]. Parametric images of MR FDG (the rate of irreversible uptake) were generated using list-mode data from the four last passes and the population-based input function (PBIF) derived from Naganawa et al.'s study [ 21 ], with which our PET/CT system is equipped. In the dynamic and static scans, emission data were reconstructed with a time of flight (TOF) point-spread-function (PSF) algorithm with four iterations and five subsets. A Gaussian filter was applied, and the in-plane spatial resolution (full width at half maximum) was 4 mm. Image analysis The MR FDG images were analyzed by an experienced nuclear physician (KK, 28 years of experience) using syngo.via software ver. VB60S_HF01 (Siemens Healthineers). The maximum values of MR FDG were measured using a voxel of interest (VOI) drawn on each target lesion. The tumor size was measured on CT and MRI images that had been obtained prior to the FDG-PET/CT scans, and T stages were evaluated according to the Eighth Edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual [ 22 ]. The presence of lymph node (LN)/distant metastasis and that of VTT were determined based on static PET/CT, CT, and MRI findings or post-surgery histopathological findings. Statistical analysis The statistical analysis of the extracted data was performed using JMP Pro ver. 17.0 (SAS, Cary, NC, USA). Pearson product–moment correlation coefficients were used to assess the relationships between the MR FDG values and the tumor sizes. The Wilcoxon signed-rank test was used to compare the MR FDG values between ( i ) the tumors at T1 stage and the tumors at ≥ T2 stage, ( ii ) the tumors with and without LN/distant metastasis, and ( iii ) the tumors with and without VTT. The MR FDG values were also compared according to histological grade, and comparisons of the G4 vs. G1–G3 tumors and the G3/4 vs. G1/2 tumors according to the Fuhrman or WHO/ISUP classification were performed. Probability (p)-values < 0.05 were considered significant. Results A total of 30 RCC lesions were analyzed. As illustrated in Fig. 1 , the MR FDG values and the tumor sizes were highly positively correlated (R = 0.68, p < 0.0001). The ≥ T2-stage tumors showed significantly higher MR FDG values compared to the T1-stage tumors (8.30 ± 7.33 vs. 2.20 ± 1.44, p = 0.003). The tumors with VTT showed significantly higher MR FDG values than those without VTT (6.70 ± 5.39 vs. 3.38 ± 6.07, p = 0.002), but the tumors with or without LN/distant metastasis showed similar MR FDG values (5.83 ± 4.57 vs. 4.65 ± 1.50, p = 0.07), as depicted in Fig. 2 . The Fuhrman G4 tumors had significantly higher MR FDG values compared to the G1–G3 tumors (11.05 ± 9.97 vs. 2.50 ± 2.67, p = 0.03), whereas no significant differences were observed between the Fuhrman G3/4 tumors and G1/2 tumors (6.48 ± 8.29 vs. 2.89 ± 3.23, p = 0.26). The WHO/ISUP G3/4 and G1/2 tumors also showed similar MR FDG values (4.80 ± 6.19 vs. 3.21 ± 3.34, p = 0.65), and the G4 tumors tended to show higher MR FDG values than the G1–G3 tumors (9.58 ± 8.75 vs. 2.64 ± 2.51, p = 0.12) (Fig. 3 ), Figs. 4 – 6 provide parametric and static images from three representative RCC cases. Discussion We investigated the MR FDG values of RCC in this study, focusing on their association with tumor progression and histopathological grade. The results of our analyses demonstrated that ( i ) the MR FDG values of the 30 RCC lesions were strongly correlated with the tumor size; ( ii ) the MR FDG values were associated with the T stage including presence of VTT, but not with metastasis; and ( iii ) high MR FDG values revealed high histopathological grades, especially in the G4 tumors. The prognosis of RCC is associated with the tumor size, spread to lymph nodes, metastases, and histopathological grade [ 23 ]. Several FDG-PET/CT studies demonstrated that high SUVmax, MTV, and TLG values of the primary tumor and a high pathological (p) TNM stage were significant prognostic factors for patients with RCC [ 9 , 10 , 24 ]. Our group's earlier D-WB FDG-PET/CT study of patients with malignant liver tumors demonstrated that the MR FDG of hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and metastatic liver tumor from various primary sites were strongly correlated with the SUVmax values, but none were correlated with the tumor size (R = 0.14–0.52) [ 14 ]. In our present investigation, the MR FDG values of RCC showed a strong correlation with tumor size in addition to the SUVmax values (R = 0.91, p < 0.0001; data not shown), unlike the primary/metastatic malignant liver tumors examined in our previous study. The close relationship between MR FDG values and tumor size may be a unique finding of RCC, and our present findings suggest that as the RCC tumor size became larger, the lesions' glucose metabolism became more highly activated. Local tumor progression, i.e., the T stage and VTT, were also correlated with the MR FDG values in this study, but it was not correlated with metastasis. A VTT, which is a form of locally advanced disease, commonly arises from the intrarenal veins, through the main renal vein, and up the inferior vena cava. Approximately 4–10% of RCC patients have VTT, which is one of the significant adverse prognostic factors [ 5 ]. An FDG-PET/CT study demonstrated that elevated SUVmax values of VTT and distant metastasis were significant independent predictors of disease-free survival [ 11 ]. A multi-institution study of patients with pT3N0M0 ccRCC revealed that the histopathological grade a discrepancy (upgrading or downgrading) between the primary tumor grade and the VTT grade is common in nonmetastatic ccRCC cases, and upgrading for a VTT was a predictor of worse prognosis [ 25 ]. Our present results showed that RCC lesions with VTT had higher glucose metabolism activity compared to those without VTT, which is consistent with the results of these studies [ 11 , 25 ]. Clear cell RCC is characterized by a high proliferation rate and the worst prognosis compared to the other subtypes, and ~ 20–30% of ccRCC patients have metastasis at the time of diagnosis [ 26 ]. Despite having characteristics that make it easy for RCC to metastasize, our present analyses indicate that the MR FDG values were not correlated with metastasis in the RCC lesions. Our results suggest that RCC can metastasize without high glucose metabolism; this may explain the propensity of RCC to develop metastasis. The histopathological grade is a measure of histopathological aggressiveness, and the Fuhrman grade, growth pattern, and tumor necrosis in cancer tissues have been proposed as predictive factors for the prognosis of RCC [ 27 – 29 ]. The WHO/ISUP grading system correlates more reliably with the prognosis in ccRCC and pRCC compared to the Fuhrman grading system [ 17 ]. Glucose metabolism was reported to be correlated with the histopathological tumor grade in RCC [ 6 , 8 ]. Takahashi et al. reported that Fuhrman G3/4 (high-grade) ccRCC showed higher glucose metabolism than G1/2 (low-grade) ccRCC, and they noted that a high pathological nuclear grade was the most significant predictive factor among SUV values [ 6 ]. Our group's earlier FDG-PET/CT study confirmed that FDG accumulation reflects tumor aggressiveness and correlated with the Fuhrman grade, and we observed that the use of FDG-PET/CT enables the differentiation of high- and low-grade ccRCC and pRCCs [ 8 ]. In our present study, the Fuhrman G4 tumors showed significantly higher MR FDG values than the lower-grade tumors, and high MR FDG values was related to more aggressive features of G4 tumors. The G3 tumors in this study showed significantly lower MR FDG values compared to the G4 tumors, unlike the results of static FDG-PET/CT studies [ 6 , 8 ]. There may be several explanations for this discrepancy in findings, such as differences in the patient populations and the dynamic/static parameters used. We speculate that the significantly larger size of the G4 tumors compared to that of the G3 tumurs in the present study (94.4 ± 29.4mm vs. 53.5 ± 29.3mm, p = 0.04) may be the main reason for the discrepancy, because the MR FDG values were closely related to the tumor size. Our results suggest that G4 tumors could have higher glucose metabolism activity and a larger tumor size at diagnosis, reflecting their aggressive features. However, the numbers of patients at each tumor grade were limited in this study. Further investigations should be performed based on the Fuhrman and WHO/ISUP classifications. This study has several limitations to address. The retrospective nature of the study could be a major limitation. The numbers of patients were relatively small, especially for those with tumors with a confirmation of the histopathological grade. In addition, the Patlak analysis model requires that k4 be negligible, and this factor may have caused an underestimation of the MR FDG values in the RCC lesions. Conclusion High values of the MR FDG in RCC reflected a high degree of local development and a high Fuhrman grade, but they did not reflect a propensity for metastasis. Declarations Acknowledgement We thank all the patients that participated in this study, and the nuclear medicine staff and nursing staff at the Tokyo Women’s Medical University Hospital for their commitment to providing excellent care for their patients. Disclosures The authors report no relationships that could be construed as a conflict of interest. Funding and grant support None References Jonasch E, Gao J. Rathmell WK Renal cell carcinoma. BMJ. 2014;349:g4797. 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Multiinstitutional validation of a new renal cancer-specific survival nomogram. J Clin Oncol. 2007;25:1316–22. Dall'Oglio MF, Ribeiro-Filho LA, Antunes AA, Crippa A, Nesrallah L, Gonçalves PD, et al. Microvascular tumor invasion, tumor size and Fuhrman grade: A pathological triad for prognostic evaluation of renal cell carcinoma. J Urol. 2007;178:425–8. Sun M, Shariat SF, Cheng C, Ficarra V, Murai M, Oudard S, et al. Prognostic factors and predictive models in renal cell carcinoma: A contemporary review. Eur Urol. 2011;60:644–61. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6900672","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":472231960,"identity":"645baf39-4140-4b37-bfc6-bc0fff5dc2a2","order_by":0,"name":"Koichiro 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Univeristy","correspondingAuthor":false,"prefix":"","firstName":"Atsuhi","middleName":"","lastName":"Yamamoto","suffix":""},{"id":472231965,"identity":"66987de9-4f26-4ed8-ad37-280e48c0e33e","order_by":5,"name":"Yukihisa Takayama","email":"","orcid":"","institution":"Fukuoka University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yukihisa","middleName":"","lastName":"Takayama","suffix":""},{"id":472231966,"identity":"318c40d1-6cf6-4e10-a2d4-4e077c35e155","order_by":6,"name":"Michinobu Nagao","email":"","orcid":"","institution":"Tokyo Women's Medical Univeristy","correspondingAuthor":false,"prefix":"","firstName":"Michinobu","middleName":"","lastName":"Nagao","suffix":""},{"id":472231967,"identity":"740f98e9-ac6f-47fe-a93b-96dba866005f","order_by":7,"name":"Kengo Yoshimitsu","email":"","orcid":"","institution":"Fukuoka University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kengo","middleName":"","lastName":"Yoshimitsu","suffix":""},{"id":472231968,"identity":"7257b91c-b4e5-497d-be0d-d9a13db35215","order_by":8,"name":"Shuji Sakai","email":"","orcid":"","institution":"Tokyo Women's Medical Univeristy","correspondingAuthor":false,"prefix":"","firstName":"Shuji","middleName":"","lastName":"Sakai","suffix":""}],"badges":[],"createdAt":"2025-06-16 01:43:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6900672/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6900672/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85178427,"identity":"aa5cb01d-d90e-42e5-abc1-8974d013072e","added_by":"auto","created_at":"2025-06-23 06:54:49","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":57038,"visible":true,"origin":"","legend":"\u003cp\u003eThe MR\u003csub\u003eFDG\u003c/sub\u003e values were highly positively correlated with the tumor size.\u003c/p\u003e","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6900672/v1/a0888bd8d540b67b7f41e193.jpg"},{"id":85178430,"identity":"1a2e31fd-968d-44e4-a602-d115b6df94ae","added_by":"auto","created_at":"2025-06-23 06:54:49","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":66474,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(a)\u003c/strong\u003e The ≥T2-stage tumors showed significantly higher MR\u003csub\u003eFDG\u003c/sub\u003e values compared to the T1-stage tumors (8.30 ± 7.33 vs. 2.20 ± 1.44, p=0.003). \u003cstrong\u003e(b)\u003c/strong\u003e The tumors with venous tumor thrombus (VTT) showed significantly higher MR\u003csub\u003eFDG\u003c/sub\u003e values vs. those without VTT (6.70 ± 5.39 vs. 3.38 ± 6.07, p=0.002). \u003cstrong\u003e(c)\u003c/strong\u003e The RCCs showed similar MR\u003csub\u003eFDG\u003c/sub\u003e values regardless of the presence/absence of metastasis (5.83 ± 4.57 vs. 4.65 ± 1.50, p=0.07).\u003c/p\u003e","description":"","filename":"Fig.2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6900672/v1/353fffa14067b2b8c442f378.jpg"},{"id":85178408,"identity":"bf6bcef2-7afb-4381-960d-26aa55bb5301","added_by":"auto","created_at":"2025-06-23 06:54:48","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":85613,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(a)\u003c/strong\u003e The MR\u003csub\u003eFDG\u003c/sub\u003e value of the Fuhrman G3/4 and 1/2 tumors showed no significant differences (6.48 ± 8.29 vs. 2.89 ± 3.23, p=0.26). \u003cstrong\u003e(b)\u003c/strong\u003e The Fuhrman G4 tumors showed significantly higher MR\u003csub\u003eFDG\u003c/sub\u003e values than the G1–G3 tumors (11.05 ± 9.97 vs. 2.50 ± 2.67, p=0.03). \u003cstrong\u003e(c)\u003c/strong\u003e The WHO/ISUP G3/4 and 1/2 tumors showed similar MR\u003csub\u003eFDG\u003c/sub\u003e value (4.80 ± 6.19 vs. 3.21 ± 3.34, p=0.65). \u003cstrong\u003e(d)\u003c/strong\u003e The WHO/ISUP G4 tumors tended to show higher MR\u003csub\u003eFDG\u003c/sub\u003e than the G1-3 tumors (9.58 ± 8.75 vs. 2.64 ± 2.51, p=0.12).\u003c/p\u003e","description":"","filename":"Fig.3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6900672/v1/148a7126936f18836b0d1ce5.jpg"},{"id":85178434,"identity":"30aeeb69-0369-4483-993f-a0f78f84b78b","added_by":"auto","created_at":"2025-06-23 06:54:51","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":153269,"visible":true,"origin":"","legend":"\u003cp\u003eStatic and dynamic FDG-PET/CT images of an 86-year-old man with bilateral clear cell (cc)RCC (G4/G2, right/left) and VTT. \u003cstrong\u003e(a)\u003c/strong\u003e A maximum intensity projection (MIP) standardized uptake value (SUV) image shows intense FDG uptake in the right ccRCC (\u003cem\u003earrow\u003c/em\u003e) with VTT (\u003cem\u003edotted arrow\u003c/em\u003e). The left ccRCC showed weak FDG uptake (\u003cem\u003ecurved arrow\u003c/em\u003e). The SUVmax values are also shown. \u003cstrong\u003e(b)\u003c/strong\u003e A MIP MR\u003csub\u003eFDG\u003c/sub\u003e image showed high MR\u003csub\u003eFDG\u003c/sub\u003e in the right ccRCC (\u003cem\u003earrow\u003c/em\u003e) and VTT (\u003cem\u003edotted arrow\u003c/em\u003e) and low MR\u003csub\u003eFDG\u003c/sub\u003e in the left ccRCC (\u003cem\u003ecurved arrow\u003c/em\u003e). \u003cstrong\u003e(c–e)\u003c/strong\u003e The axial PET/CT fused MR\u003csub\u003eFDG\u003c/sub\u003e images (\u003cem\u003elower column\u003c/em\u003e) showed high (right ccRCC and VTT) or low (left ccRCC) MR\u003csub\u003eFDG\u003c/sub\u003e values in the tumors obtained by contrast-enhanced-CT images (\u003cem\u003ewhite arrows in upper column\u003c/em\u003e).\u003c/p\u003e","description":"","filename":"Fig.4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6900672/v1/53ea107e85b60dae34238346.jpg"},{"id":85178428,"identity":"a7337f26-4c53-46e4-b0e9-fb3cbf289433","added_by":"auto","created_at":"2025-06-23 06:54:49","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":139286,"visible":true,"origin":"","legend":"\u003cp\u003eStatic and dynamic FDG-PET/CT images of an 80-year-old woman with G1 ccRCC and multiple lung metastases. \u003cstrong\u003e(a)\u003c/strong\u003e A MIP SUV image showing moderate FDG uptake in the right RCC (\u003cem\u003earrow\u003c/em\u003e) and left lung metastasis (\u003cem\u003edotted arrow\u003c/em\u003e). \u003cstrong\u003e(b)\u003c/strong\u003e A MIP MR\u003csub\u003eFDG\u003c/sub\u003e image showed low MR\u003csub\u003eFDG\u003c/sub\u003e in the right ccRCC (\u003cem\u003earrow\u003c/em\u003e) and VTT (\u003cem\u003edotted arrow\u003c/em\u003e). \u003cstrong\u003e(c)\u003c/strong\u003e The PET (\u003cem\u003emiddle column\u003c/em\u003e) and PET/CT fused MR\u003csub\u003eFDG\u003c/sub\u003e (\u003cem\u003ebottom column\u003c/em\u003e) images showed low MR\u003csub\u003eFDG\u003c/sub\u003e values in the tumors obtained by T2-weighted MRI and CT (\u003cem\u003ewhite arrows in top column\u003c/em\u003e).\u003c/p\u003e","description":"","filename":"Fig.5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6900672/v1/34829148d9de9ab16c669c0d.jpg"},{"id":85178429,"identity":"6d0ba302-1018-4288-9dca-2e3db4e1e79a","added_by":"auto","created_at":"2025-06-23 06:54:49","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":118789,"visible":true,"origin":"","legend":"\u003cp\u003eStatic and dynamic FDG-PET/CT images of a 58-year-old woman with G4 chromophobe (ch)RCC. \u003cstrong\u003e(a)\u003c/strong\u003e A MIP SUV image showing extremely high FDG uptake in the right chRCC (\u003cem\u003earrow\u003c/em\u003e). \u003cstrong\u003e(b)\u003c/strong\u003e A MIP MR\u003csub\u003eFDG\u003c/sub\u003e image (\u003cem\u003etop column\u003c/em\u003e) showed an extremely high MR\u003csub\u003eFDG\u003c/sub\u003e value in the right chRCC. Axial PET (\u003cem\u003emiddle column\u003c/em\u003e) and PET/CT fused axial MR\u003csub\u003eFDG\u003c/sub\u003e (\u003cem\u003ebottom column\u003c/em\u003e) images also showed extremely high MR\u003csub\u003eFDG\u003c/sub\u003e values. Note the low FDG uptake inside the tumor, indicating intra-tumoral necrosis. The SUVmax and MR\u003csub\u003eFDG\u003c/sub\u003e values are shown (\u003cem\u003earrows\u003c/em\u003e in panels a and b). \u003cstrong\u003e(c)\u003c/strong\u003e Axial (\u003cem\u003eupper column\u003c/em\u003e) and coronal (\u003cem\u003elower column\u003c/em\u003e) CE-CT (arterial phase) showed a huge right renal tumor with inhomogenous enhancement.\u003c/p\u003e","description":"","filename":"Fig.6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6900672/v1/5adc51313f9a33592202b3e2.jpg"},{"id":85717007,"identity":"7ddd1c93-4d3c-4cd8-bb4f-ef0aa2ad3e23","added_by":"auto","created_at":"2025-07-01 04:23:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1250925,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6900672/v1/ce2d509e-c32f-4c86-b64b-128a94a30961.pdf"}],"financialInterests":"","formattedTitle":"The associations among the glucose metabolic rate, tumor progression, and histopathological grade in metabolically active renal cell carcinoma: A comparison using whole-body 4D parametric FDG-PET/CT imaging","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRenal cell carcinoma (RCC) represents the most common cancer in the kidney, and the most common histological subtype of RCC is clear cell RCC (ccRCC, ~\u0026thinsp;70\u0026ndash;80% of RCC cases), followed by papillary RCC (pRCC, ~\u0026thinsp;10\u0026ndash;15%) and chromophobe RCC (chRCC, ~\u0026thinsp;5%) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Metastatic disease occurs approximately 10% of patients with newly diagnosed RCC patients, and 10% of patients with localized RCC will develop metastatic disease at a later time [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. CcRCC is characterized by a high proliferation rate compared to the other subtypes, and is potentially more metastatic than the other two variants [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Another hallmark of RCC is its biological predisposition for vascular invasion; approx. 4\u0026ndash;10% of patients with RCC have venous tumor thrombus (VTT) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. RCC is not a typical Warburg tumor, and due to the excretion of \u003csup\u003e18\u003c/sup\u003eF-fluorodeoxyglucose (FDG) through the genitourinary tract, the use of FDG-positron emission tomography (PET)/computed tomography (CT) in primary RCC is challenging. Many PET studies have demonstrated a correlation between FDG uptake and the histopathological grade or prognosis by using static PET parameters such as the standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) [\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Multi-pass, multi-bed PET acquisition has been used to perform dynamic whole-body (D-WB) FDG-PET/CT imaging [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], which can provide two parametric images: metabolic rate (MR\u003csub\u003eFDG\u003c/sub\u003e; mg/min/10 mL) images and distribution volume (DV\u003csub\u003eFDG\u003c/sub\u003e; %) images. Our research group recently demonstrated a strong correlation between static and dynamic PET parameters, a difference in FDG dynamics, and the high diagnostic value of MR\u003csub\u003eFDG\u003c/sub\u003e images in malignant liver tumors [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. We also demonstrated that MR\u003csub\u003eFDG\u003c/sub\u003e values were not correlated with tumor size [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Another of our studies revealed that the MR\u003csub\u003eFDG\u003c/sub\u003e value was significantly lower in sarcoid lesions compared to malignant lesions, and in patients with sarcoidosis or a malignant tumor, MR\u003csub\u003eFDG\u003c/sub\u003e values improved the identification of sarcoid lesions over the SUV alone [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, D-WB PET imaging findings in RCC, including their association with tumor progression and the histopathological grade, have remained unknown. We conducted the present study to investigate the associations among MR\u003csub\u003eFDG\u003c/sub\u003e values, tumor progression, and the histopathological grade in RCC.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient population\u003c/h2\u003e \u003cp\u003eThis was a retrospective analysis of the cases of 28 consecutive patients with 30 RCC lesions (16 males and 12 females, mean age 66 years) who underwent D-WB FDG-PET/CT scans at Tokyo Women\u0026rsquo;s Medical University during the period from February 2022 through January 2025. Their clinical characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the RCC patients (n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMales/females\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16/12\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, yrs; mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65.9\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLesions, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSize, mm; median/range\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65.4/2.5\u0026ndash;141.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT stage, T1a/1b/2a/2b/2c/3a/3b/3c/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7/5/2/0/6/6/2/2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistopathology:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClear cell RCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePapillary RCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTFE3-rearranged RCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnclassified RCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChromophobe RCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMit family translocation RCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSarcomatoid and rhabdoid RCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eXp11.2 translation RCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastasis, LN/distant/both\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/5/4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFuhrman grade, 1/2/3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/6/7/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWHO/ISUP grade, 1/2/3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/6/7/4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSUVmax, median/range\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.0/2.2\u0026ndash;34.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eISUP: International Society of Urological Pathology, LN: lymph node, RCC: renal cell carcinoma, SUV: standardized uptake value, WHO: World Health Organization.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHistopathological confirmation was obtained in 23 RCC lesions by surgical resection and in five lesions by biopsy. These lesions consisted of 18 ccRCCs, two papillary RCCs, two TFE3-rearranged RCCs, two unclassified RCCs, one chromophobe RCC, one Mit family translocation RCC, one sarcomatoid and rhabdoid RCC, and one Xp11.2 translation RCC. Histopathological confirmation was lacking in two of the 28 patients because of a serious condition due to extensive tumor progression or hospital transfer. Twenty surgically resected RCCs were graded according to the Fuhrman and WHO/ISUP classifications [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The study complied with the Declaration of Helsinki, and the protocol was approved by the ethics committee of Tokyo Women\u0026rsquo;s Medical University (no. 2021\u0026thinsp;\u0026minus;\u0026thinsp;0153). Written informed consent was obtained from all patients.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData acquisition and image reconstruction\u003c/h3\u003e\n\u003cp\u003eAll FDG-PET/CT scans were performed on a Biograph Vision 600 PET/CT scanner (Siemens Healthineers, Erlangen, Germany), which integrates 64-slice multidetector computed tomography (MDCT) images using a fully automated multiparametric PET acquisition protocol (Flow Motion Multiparametric PET). All patients fasted for \u0026ge;\u0026thinsp;5 hr prior to imaging and received a single intravenous injection of FDG (3.7 MBq/kg). First, a low-dose non-contrast-enhanced CT scan was performed for attenuation correction, covering the top of the patient's skull to the proximal thigh. A shortened multiparametric PET acquisition consisting of 4\u0026times;5 min (total 20 min, starting 30 min post-injection) continuous bed motion passes was then performed as described [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAfter the D-WB scan, static PET data acquisition was performed in three-dimensional (3D) mode for 90 sec per position (step and shoot) from 60 min post-injection. The multiparametric scan protocol generates parametric images based on the Patlak model [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Parametric images of MR\u003csub\u003eFDG\u003c/sub\u003e (the rate of irreversible uptake) were generated using list-mode data from the four last passes and the population-based input function (PBIF) derived from Naganawa et al.'s study [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], with which our PET/CT system is equipped. In the dynamic and static scans, emission data were reconstructed with a time of flight (TOF) point-spread-function (PSF) algorithm with four iterations and five subsets. A Gaussian filter was applied, and the in-plane spatial resolution (full width at half maximum) was 4 mm.\u003c/p\u003e\n\u003ch3\u003eImage analysis\u003c/h3\u003e\n\u003cp\u003eThe MR\u003csub\u003eFDG\u003c/sub\u003e images were analyzed by an experienced nuclear physician (KK, 28 years of experience) using syngo.via software ver. VB60S_HF01 (Siemens Healthineers). The maximum values of MR\u003csub\u003eFDG\u003c/sub\u003e were measured using a voxel of interest (VOI) drawn on each target lesion. The tumor size was measured on CT and MRI images that had been obtained prior to the FDG-PET/CT scans, and T stages were evaluated according to the Eighth Edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The presence of lymph node (LN)/distant metastasis and that of VTT were determined based on static PET/CT, CT, and MRI findings or post-surgery histopathological findings.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe statistical analysis of the extracted data was performed using JMP Pro ver. 17.0 (SAS, Cary, NC, USA). Pearson product\u0026ndash;moment correlation coefficients were used to assess the relationships between the MR\u003csub\u003eFDG\u003c/sub\u003e values and the tumor sizes. The Wilcoxon signed-rank test was used to compare the MR\u003csub\u003eFDG\u003c/sub\u003e values between (\u003cem\u003ei\u003c/em\u003e) the tumors at T1 stage and the tumors at \u0026ge;\u0026thinsp;T2 stage, (\u003cem\u003eii\u003c/em\u003e) the tumors with and without LN/distant metastasis, and (\u003cem\u003eiii\u003c/em\u003e) the tumors with and without VTT. The MR\u003csub\u003eFDG\u003c/sub\u003e values were also compared according to histological grade, and comparisons of the G4 vs. G1\u0026ndash;G3 tumors and the G3/4 vs. G1/2 tumors according to the Fuhrman or WHO/ISUP classification were performed. Probability (p)-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 30 RCC lesions were analyzed. As illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the MR\u003csub\u003eFDG\u003c/sub\u003e values and the tumor sizes were highly positively correlated (R\u0026thinsp;=\u0026thinsp;0.68, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). The \u0026ge;\u0026thinsp;T2-stage tumors showed significantly higher MR\u003csub\u003eFDG\u003c/sub\u003e values compared to the T1-stage tumors (8.30\u0026thinsp;\u0026plusmn;\u0026thinsp;7.33 vs. 2.20\u0026thinsp;\u0026plusmn;\u0026thinsp;1.44, p\u0026thinsp;=\u0026thinsp;0.003). The tumors with VTT showed significantly higher MR\u003csub\u003eFDG\u003c/sub\u003e values than those without VTT (6.70\u0026thinsp;\u0026plusmn;\u0026thinsp;5.39 vs. 3.38\u0026thinsp;\u0026plusmn;\u0026thinsp;6.07, p\u0026thinsp;=\u0026thinsp;0.002), but the tumors with or without LN/distant metastasis showed similar MR\u003csub\u003eFDG\u003c/sub\u003e values (5.83\u0026thinsp;\u0026plusmn;\u0026thinsp;4.57 vs. 4.65\u0026thinsp;\u0026plusmn;\u0026thinsp;1.50, p\u0026thinsp;=\u0026thinsp;0.07), as depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe Fuhrman G4 tumors had significantly higher MR\u003csub\u003eFDG\u003c/sub\u003e values compared to the G1\u0026ndash;G3 tumors (11.05\u0026thinsp;\u0026plusmn;\u0026thinsp;9.97 vs. 2.50\u0026thinsp;\u0026plusmn;\u0026thinsp;2.67, p\u0026thinsp;=\u0026thinsp;0.03), whereas no significant differences were observed between the Fuhrman G3/4 tumors and G1/2 tumors (6.48\u0026thinsp;\u0026plusmn;\u0026thinsp;8.29 vs. 2.89\u0026thinsp;\u0026plusmn;\u0026thinsp;3.23, p\u0026thinsp;=\u0026thinsp;0.26). The WHO/ISUP G3/4 and G1/2 tumors also showed similar MR\u003csub\u003eFDG\u003c/sub\u003e values (4.80\u0026thinsp;\u0026plusmn;\u0026thinsp;6.19 vs. 3.21\u0026thinsp;\u0026plusmn;\u0026thinsp;3.34, p\u0026thinsp;=\u0026thinsp;0.65), and the G4 tumors tended to show higher MR\u003csub\u003eFDG\u003c/sub\u003e values than the G1\u0026ndash;G3 tumors (9.58\u0026thinsp;\u0026plusmn;\u0026thinsp;8.75 vs. 2.64\u0026thinsp;\u0026plusmn;\u0026thinsp;2.51, p\u0026thinsp;=\u0026thinsp;0.12) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e provide parametric and static images from three representative RCC cases.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe investigated the MR\u003csub\u003eFDG\u003c/sub\u003e values of RCC in this study, focusing on their association with tumor progression and histopathological grade. The results of our analyses demonstrated that (\u003cem\u003ei\u003c/em\u003e) the MR\u003csub\u003eFDG\u003c/sub\u003e values of the 30 RCC lesions were strongly correlated with the tumor size; (\u003cem\u003eii\u003c/em\u003e) the MR\u003csub\u003eFDG\u003c/sub\u003e values were associated with the T stage including presence of VTT, but not with metastasis; and (\u003cem\u003eiii\u003c/em\u003e) high MR\u003csub\u003eFDG\u003c/sub\u003e values revealed high histopathological grades, especially in the G4 tumors.\u003c/p\u003e \u003cp\u003eThe prognosis of RCC is associated with the tumor size, spread to lymph nodes, metastases, and histopathological grade [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Several FDG-PET/CT studies demonstrated that high SUVmax, MTV, and TLG values of the primary tumor and a high pathological (p) TNM stage were significant prognostic factors for patients with RCC [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Our group's earlier D-WB FDG-PET/CT study of patients with malignant liver tumors demonstrated that the MR\u003csub\u003eFDG\u003c/sub\u003e of hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and metastatic liver tumor from various primary sites were strongly correlated with the SUVmax values, but none were correlated with the tumor size (R\u0026thinsp;=\u0026thinsp;0.14\u0026ndash;0.52) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In our present investigation, the MR\u003csub\u003eFDG\u003c/sub\u003e values of RCC showed a strong correlation with tumor size in addition to the SUVmax values (R\u0026thinsp;=\u0026thinsp;0.91, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; data not shown), unlike the primary/metastatic malignant liver tumors examined in our previous study. The close relationship between MR\u003csub\u003eFDG\u003c/sub\u003e values and tumor size may be a unique finding of RCC, and our present findings suggest that as the RCC tumor size became larger, the lesions' glucose metabolism became more highly activated.\u003c/p\u003e \u003cp\u003eLocal tumor progression, i.e., the T stage and VTT, were also correlated with the MR\u003csub\u003eFDG\u003c/sub\u003e values in this study, but it was not correlated with metastasis. A VTT, which is a form of locally advanced disease, commonly arises from the intrarenal veins, through the main renal vein, and up the inferior vena cava. Approximately 4\u0026ndash;10% of RCC patients have VTT, which is one of the significant adverse prognostic factors [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. An FDG-PET/CT study demonstrated that elevated SUVmax values of VTT and distant metastasis were significant independent predictors of disease-free survival [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. A multi-institution study of patients with pT3N0M0 ccRCC revealed that the histopathological grade a discrepancy (upgrading or downgrading) between the primary tumor grade and the VTT grade is common in nonmetastatic ccRCC cases, and upgrading for a VTT was a predictor of worse prognosis [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Our present results showed that RCC lesions with VTT had higher glucose metabolism activity compared to those without VTT, which is consistent with the results of these studies [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClear cell RCC is characterized by a high proliferation rate and the worst prognosis compared to the other subtypes, and ~\u0026thinsp;20\u0026ndash;30% of ccRCC patients have metastasis at the time of diagnosis [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Despite having characteristics that make it easy for RCC to metastasize, our present analyses indicate that the MR\u003csub\u003eFDG\u003c/sub\u003e values were not correlated with metastasis in the RCC lesions. Our results suggest that RCC can metastasize without high glucose metabolism; this may explain the propensity of RCC to develop metastasis.\u003c/p\u003e \u003cp\u003eThe histopathological grade is a measure of histopathological aggressiveness, and the Fuhrman grade, growth pattern, and tumor necrosis in cancer tissues have been proposed as predictive factors for the prognosis of RCC [\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The WHO/ISUP grading system correlates more reliably with the prognosis in ccRCC and pRCC compared to the Fuhrman grading system [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Glucose metabolism was reported to be correlated with the histopathological tumor grade in RCC [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Takahashi et al. reported that Fuhrman G3/4 (high-grade) ccRCC showed higher glucose metabolism than G1/2 (low-grade) ccRCC, and they noted that a high pathological nuclear grade was the most significant predictive factor among SUV values [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Our group's earlier FDG-PET/CT study confirmed that FDG accumulation reflects tumor aggressiveness and correlated with the Fuhrman grade, and we observed that the use of FDG-PET/CT enables the differentiation of high- and low-grade ccRCC and pRCCs [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In our present study, the Fuhrman G4 tumors showed significantly higher MR\u003csub\u003eFDG\u003c/sub\u003e values than the lower-grade tumors, and high MR\u003csub\u003eFDG\u003c/sub\u003e values was related to more aggressive features of G4 tumors. The G3 tumors in this study showed significantly lower MR\u003csub\u003eFDG\u003c/sub\u003e values compared to the G4 tumors, unlike the results of static FDG-PET/CT studies [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere may be several explanations for this discrepancy in findings, such as differences in the patient populations and the dynamic/static parameters used. We speculate that the significantly larger size of the G4 tumors compared to that of the G3 tumurs in the present study (94.4\u0026thinsp;\u0026plusmn;\u0026thinsp;29.4mm vs. 53.5\u0026thinsp;\u0026plusmn;\u0026thinsp;29.3mm, p\u0026thinsp;=\u0026thinsp;0.04) may be the main reason for the discrepancy, because the MR\u003csub\u003eFDG\u003c/sub\u003e values were closely related to the tumor size. Our results suggest that G4 tumors could have higher glucose metabolism activity and a larger tumor size at diagnosis, reflecting their aggressive features. However, the numbers of patients at each tumor grade were limited in this study. Further investigations should be performed based on the Fuhrman and WHO/ISUP classifications.\u003c/p\u003e \u003cp\u003eThis study has several limitations to address. The retrospective nature of the study could be a major limitation. The numbers of patients were relatively small, especially for those with tumors with a confirmation of the histopathological grade. In addition, the Patlak analysis model requires that k4 be negligible, and this factor may have caused an underestimation of the MR\u003csub\u003eFDG\u003c/sub\u003e values in the RCC lesions.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eHigh values of the MR\u003csub\u003eFDG\u003c/sub\u003e in RCC reflected a high degree of local development and a high Fuhrman grade, but they did not reflect a propensity for metastasis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the patients that participated in this study, and the nuclear medicine staff and nursing staff at the Tokyo Women’s Medical University Hospital for their commitment to providing excellent care for their patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors report no relationships that could be construed as a conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding and grant support\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJonasch E, Gao J. 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Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982;6:655\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDagher J, Delahunt B, Rioux-Leclercq N, Egevad L, Srigley JR, Coughlin G, et al. Clear cell renal cell carcinoma: Validation of World Health Organization/International Society of Urological pathology grading. Histopathology. 2017;71:918\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Sluis J, van Snick JH, Brouwers AH, Noordzij W, Dierckx RAJO, Borra RJH, et al. Shortened duration whole body. EJNMMI Phys. 2022;9:74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDias AH, Smith AM, Shah V, Pigg D, Gormsen LC. Munk OL Clinical validation of a population-based input function for 20-min dynamic whole-body \u003csup\u003e18\u003c/sup\u003eF-FDG multiparametric PET imaging. EJNMMI Phys. 2022;9:60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatlak CS, Blasberg RG. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations J Cereb Blood Flow Metab. 1985;5:584\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNaganawa M, Gallezot JD, Shah V, Mulnix T, Young C, Dias M, et al. Assessment of population-based input functions for Patlak imaging of whole body dynamic. EJNMMI Phys. 2020;7:67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmin MB, Edge SB, Greene FL, Byrd DR, Brookland RK et al. Mary Kay Washington,. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalumbo C, Pecoraro A, Knipper S, Rosiello G, Luzzago S, Deuker M, et al. Contemporary age-adjusted incidence and mortality rates of renal cell carcinoma: Analysis according to gender, race, stage, grade, and histology. 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Urol Oncol. 2018;36:31\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarakiewicz PI, Briganti A, Chun FK, Trinh QD, Perrotte P, Ficarra V, et al. Multiinstitutional validation of a new renal cancer-specific survival nomogram. J Clin Oncol. 2007;25:1316\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDall'Oglio MF, Ribeiro-Filho LA, Antunes AA, Crippa A, Nesrallah L, Gon\u0026ccedil;alves PD, et al. Microvascular tumor invasion, tumor size and Fuhrman grade: A pathological triad for prognostic evaluation of renal cell carcinoma. J Urol. 2007;178:425\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun M, Shariat SF, Cheng C, Ficarra V, Murai M, Oudard S, et al. Prognostic factors and predictive models in renal cell carcinoma: A contemporary review. Eur Urol. 2011;60:644\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Renal cell carcinoma, Glucose metabolic rate, Local tumor progression, Histopathological grade","lastPublishedDoi":"10.21203/rs.3.rs-6900672/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6900672/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e To investigate the associations among the tissue metabolic rate of \u003csup\u003e18\u003c/sup\u003eF-fluorodeoxyglucose (FDG), i.e., the MR\u003csub\u003eFDG\u003c/sub\u003e value (mg/min/10 mL), tumor progression, and the histopathological grade in metabolically active renal cell carcinoma (RCC), using four-dimensional parametric FDG-positron emission tomography (PET)/computed tomography (CT) imaging.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Dynamic whole-body FDG-PET/CT scans were performed for 28 patients newly diagnosed with RCC. \u003cstrong\u003eWe compared the obtained \u003c/strong\u003eMR\u003csub\u003eFDG\u003c/sub\u003e values with the patients' tumor size, T stage, presence/absence of metastasis and venous tumor thrombus (VTT), and histopathological grade based on the Fuhrman and World Health Organization/International Society of Urological Pathology classifications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e A total of 30 RCC lesions were analyzed. A strong positive correlation was observed between the MR\u003csub\u003eFDG\u003c/sub\u003e values and tumor size (R=0.68, p\u0026lt;0.0001). The tumors at ≥T2 stage showed significantly higher MR\u003csub\u003eFDG\u003c/sub\u003e values compared to the T1-stage tumors (8.30 ± 7.33 vs. 2.20 ± 1.44, p=0.003). The tumors with VTT had significantly higher MR\u003csub\u003eFDG\u003c/sub\u003e values versus those without VTT (6.70 ± 5.39 vs. 3.38 ± 6.07, p=0.002), but the tumors showed similar MR\u003csub\u003eFDG\u003c/sub\u003e values regardless of the presence/absence of metastasis (5.83 ± 4.57 vs. 4.65 ± 1.50, p=0.07). The Fuhrman G4 tumors showed significantly higher MR\u003csub\u003eFDG\u003c/sub\u003e values versus the G1–3 tumors (11.05 ± 9.97 vs. 2.50 ± 2.67, p=0.03), although no significant differences were observed between the G1/2 and G3/4 tumors by either classification.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eHigh values of the MR\u003csub\u003eFDG\u003c/sub\u003e in RCC reflected a high degree of local development and a high Fuhrman grade, but they did not reflect a propensity for metastasis.\u003c/p\u003e","manuscriptTitle":"The associations among the glucose metabolic rate, tumor progression, and histopathological grade in metabolically active renal cell carcinoma: A comparison using whole-body 4D parametric FDG-PET/CT imaging","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-23 06:54:43","doi":"10.21203/rs.3.rs-6900672/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fd7e0e48-42f8-40d0-99e3-97dc1bc4759c","owner":[],"postedDate":"June 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-01T04:15:07+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-23 06:54:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6900672","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6900672","identity":"rs-6900672","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}