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. Author manuscript; available in PMC: 2022 Aug 19.
Published in final edited form as: Abdom Radiol (NY). 2021 Mar 10;46(7):3301–3308. doi: 10.1007/s00261-021-02999-9

18Fluorodeoxyglucose-positron emission tomography/computed tomography for differentiation of renal tumors in hereditary kidney cancer syndromes

Moozhan Nikpanah 1, Anna K Paschall 2, Mark A Ahlman 1, Ali Cahid Civelek 3, Faraz Farhadi 1,4, S Mojdeh Mirmomen 5, Xiaobai Li 6, Babak Saboury 1, Mark W Ball 7, Maria J Merino 8, Ramaprasad Srinivasan 7, Elizabeth C Jones 1, W Marston Linehan 7, Ashkan A Malayeri 1
PMCID: PMC9389933  NIHMSID: NIHMS1829151  PMID: 33688985

Abstract

Purpose

To assess differences in FDG-PET/CT uptake among four subtypes of renal tumors: clear cell RCC (ccRCC), papillary type I and II RCC (pRCC), and oncocytoma.

Methods

This retrospective study investigated 33 patients with 98 hereditary renal tumors. Lesions greater than 1 cm and patients with a timeframe of less than 18 months between preoperative imaging and surgery were considered. FDG-PET/CT images were independently reviewed by two nuclear medicine physicians, blinded to clinical information. Volumetric lesion SUVmean was measured and used to calculate a target-to-background ratio respective to liver (TBR). The Shrout-Fleiss intra-class correlation coefficient was used to assess reliability between readers. A linear mixed effects model, accounting for within-patient correlations, was used to compare TBR values of primary renal lesions with and without distant metastasis.

Results

The time interval between imaging and surgery for all tumors had a median of 77 (Mean: 139; Range: 1–512) days. Intra-class reliability of mean TBR resulted in a mean κ score of 0.93, indicating strong agreement between the readers. The mixed model showed a significant difference in mean TBR among the subtypes (p < 0.0001). Pairwise comparison showed significant differences between pRCC type II and ccRCC (p < 0.0001), pRCC type II and pRCC type I (p = 0.0001), and pRCC type II and oncocytoma (p = 0.0016). Furthermore, a significant difference in FDG uptake was present between primary pRCC type II renal lesions with and without distant metastasis (p = 0.023).

Conclusion

pRCC type II lesions demonstrated significantly higher FDG activity than ccRCC, pRCC type I, or oncocytoma. These findings indicate that FDG may prove useful in studying the metabolic activity of renal neoplasms, identifying lesions of highest clinical concern, and ultimately optimizing active surveillance, and personalizing management plans.

Keywords: 18FDG-PET/CT, Renal tumors, Subtype differentiation, Hereditary Kidney Cancer Syndromes

Introduction

Renal cell carcinoma (RCC) is the most common primary kidney tumor, accounting for more than 90% of all malignant renal neoplasms. Being responsible for approximately 2–3% of all adult cancers, RCC is among the ten most common cancers worldwide [1–3]. RCC is an umbrella term for multiple genetically distinct subtypes of renal cancer (clear cell, papillary type I and type II, chromophobe, etc.), each differing in aggression and treatment strategy [4–6]. Due to increased utilization of computed tomography (CT) and magnetic resonance imaging (MRI) in routine clinical practice over the past few decades, detection of RCC has greatly increased, with 50% of renal lesions discovered incidentally [7]. Primary RCC tumors without distant metastasis are commonly resected through nephron-sparing or radical nephrectomy surgery or treated through ablation [8, 9]. However, approximately 22% of lesions removed are either indolent or benign in nature [1, 7, 10–12]. As such, non-invasive phenotyping is of great interest [11–13].

Many of the mutated genes responsible for RCC subtypes heavily influence cellular metabolism [14]. 18Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) provides a semi-quantitative measurement of glucose utilization and is widely used to stage cancer and monitor treatment response [15–23]. As such, FDG-PET is based on the premise that malignant cells will demonstrate increased FDG uptake and trapping compared to surrounding tissues, resulting in greater conspicuity with imaging [19, 21]. While the use of FDG-PET to evaluate renal neoplasms is hindered due to excretion of FDG through the urinary tract, several recent studies showed differences in lesion uptake among RCC subtypes [15–17, 24–27]. However, most of these studies have limited samples of papillary RCC (pRCC) type I and did not separate between types of pRCC for analysis, despite differences in their genetics and aggressiveness [15, 25, 26]. With a unique cohort that includes a high number of rare RCC subtypes, the primary objective of this study was to examine FDG-PET uptake among histologically confirmed ccRCC, pRCC types I and II, and oncocytoma. A secondary objective was to assess differences in FDG uptake among primary renal lesion subtypes with and without distant metastasis.

Materials and methods

Patient selection

This Health Insurance Portability and Accountability Act (HIPAA) compliant, retrospective study was performed at the National Institutes of Health in Bethesda, MD. All patients signed informed consent, and all data were acquired under Institutional Review Board approved protocols between December 2010 and June 2017.

A database of patients with hereditary renal tumors from the urologic oncology branch of the National Cancer Institute (NCI) was reviewed. Patients with a histopathological diagnosis of ccRCC, pRCC type I and II, and oncocytoma with a preoperative FDG-PET/CT were selected. The initial cohort consisted of 50 patients with 137 lesions. For inclusion, lesions had to be greater than 1 cm in diameter, and patients had to have a preoperative FDG-PET/CT within 18 months of surgery. To avoid measurement influence by tracer excretion, lesions close to the collecting system were excluded (Fig. 1).

Fig. 1.

Fig. 1

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Study workflow summarizing the patient selection. The broken lines indicate the excluded number of lesions and patients

Imaging parameters

FDG-PET/CT imaging studies were obtained with a Siemens Biograph mCT (Siemens Medical Solutions, Erlangen, Germany) following a 60-min uptake phase. Patient preparation included fasting for more than 4 h, and a blood glucose of less than 200 mg/dL measured immediately prior to injection of 259 MBq (7 mCi) for subjects < 100 kg and 370 MBq (10 mCi) for subjects ≥ 100 kg. Iterative image reconstruction used time-of-flight, point spread function correction, and CT attenuation correction (without IV contrast) for a slice thickness of 1.5 mm and final voxel dimension of 3 × 3 × 1.5 mm without post-reconstruction filtering.

Image analysis

An imaging fellow (M.N with 2 years of experience) reviewed the full set of contrast-enhanced CT images to identify tumors and evaluate metastatic disease. Two nuclear medicine physicians (A.C.C with more than 35 years and M.A.A with 11 years of experience), blinded to clinical information, independently evaluated the FDG-PET/CT and morphologic imaging studies of the renal tumors, which were selected by the imaging fellow. With care to avoid urinary FDG activity, volumetric lesion mean standardized uptake value (SUV) relative to body weight was measured on the axial plane of the FDG PET/CT images with Carestream Vue PACS version 12.1.6 (Carestream Health, Rochester, NY, USA) and a target-to-background ratio (TBR) respective to mean liver activity was calculated.

Statistical analysis

For continuous variables, summary measures including mean, median, standard deviation, and inter-quartile range were calculated. The intra-class correlation coefficient (ICC) was used to assess agreement of measurement values between readers [28]. A linear mixed effects model was fitted to the data to compare TBR values among the four neoplasm subtypes. The model included lesion subtype as the fixed effect and the patient as the random effect to account for within-patient correlation. A linear mixed model was fitted to the data to assess the differences among renal lesion subtypes with and without distant metastasis. However, oncocytoma was excluded from this analysis because the lesions are rarely metastatic [26, 27]. To satisfy the normality assumption of the model, log-transformation was performed. Pearson correlation coefficient was used to investigate the correlation between size and TBR of renal tumors in different subtypes. One-way analysis of variance was used to investigate size difference among categories. A p-value less than 0.05 was considered statistically significant. Statistical analysis was performed with SAS (SAS, Version 14.3; Cary, NC).

Results

Patient demographics are listed in Table 1. Thirty-three patients with 98 pathology-proven renal neoplasms were included in this study. This cohort comprised 22 males with an average age of 52.4 ± 10.5 years (range 27–76) and 11 females with an average age of 58.5 ± 9.5 years (range 43–76); the overall average age was 56 ± 11.2 years (range 27–76). Tumors included 54 ccRCC (52 Fuhrman grade 2, 1 Fuhrman grade 3/4, 1 Fuhrman grade 4) from sixteen patients with Von Hippel-Lindau (VHL) syndrome, 27 pRCC type I from eight patients with Hereditary Papillary Renal Carcinoma (HPRC) syndrome, 7 pRCC type II from seven patients with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome, and 10 oncocytoma lesions from two patients with Birt-Hogg-Dubé (BHD) syndrome. Additionally, distant metastases were present in 1 of 16 (6%) patients with ccRCC, 2 of 8 (25%) patients with papillary type I, and 3 of 8 (38%) patients with papillary type II lesions. Patients with oncocytoma did not have metastases, consistent with the expected behavior of the disease.

Table 1.

Demographic and tumor characteristics data of the present cohort

Clear cell RCC Papillary type I RCC Papillary type II RCC Oncocytoma
# Patients (lesions) 16 (54) 8 (27) 7 (7) 2 (10)
Male 9 (29) 7 (24) 5 (5) 1 (9)
Female 7 (25) 1 (3) 2 (2) 1 (1)
Mean TBR 0.93 1.43 4.66 1.03
IQR 0.20 0.46 4.96 0.30
SD 0.19 0.91 2.54 0.21
Distant Metastasis Without With Without With Without With N/A
# Patients (Lesions) 15 (44) 1 (10) 6 (18) 2 (9) 4 (4) 3 (3) 2 (10)
Mean Size (cm) 2.37 1.95 3.19 2.03 2.33 7.4 2.47
IQR 1.00 0.60 1.73 0.70 1.93 2.5 1.50
SD 0.62 0.43 1.50 0.55 0.86 1.08 1.13
Mean TBR 0.95 0.84 1.46 1.38 3.35 6.41 1.03
IQR 0.24 0.27 0.48 0.38 3.62 5.51 0.30
SD 0.15 0.13 1.10 0.20 1.66 2.5 0.21
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TBR target-to-background ratio, IQR inter-quartile range, SD standard deviation, N/A not applicable

The mean primary tumor sizes of the renal tumor subtypes were 2.46 (SD: ± 0.94) cm for ccRCC, 2.80 (SD: ± 1.36) for pRCC type I, 4.50 (SD: ± 2.68) for pRCC type II, and 2.47 (SD: ± 1.13) for oncocytoma. There was no significant difference (p = 0.17) in lesion size among subtypes.

The time interval between imaging and surgery for all tumors had a median of 77 (Mean: 139; Range: 1–512) days. Intra-class reliability of SUVmean measurement resulted in a mean κ score of 0.93, indicating strong agreement between raters. Mean TBR of renal lesions was 0.93 (SD: ± 0.19) for ccRCC, 1.43 (SD: ± 0.91) for pRCC type I, 4.66 (± 2.54) for pRCC type II, and 1.03 (± 0.21) for oncocytoma. The mixed model showed a statistically significant difference in mean TBR among the four RCC subtypes (p < 0.0001). Pairwise comparison showed a significant difference in the TBR between ccRCC and pRCC type II (p < 0.0001), pRCC type I and pRCC type II (p = 0.0001), and oncocytoma and pRCC type II (p = 0.0016) (Fig. 2).

Fig. 2.

Fig. 2

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Box plot showing the average TBR of renal tumors with and without distant metastases, including ccRCC, pRCC type I and II, and oncocytoma

There was no statistically significant difference in TBR of renal tumors with and without distant metastasis in ccRCC (p = 0.67) and pRCC type I (p = 0.99). However, there was a statistically significant higher TBR of papillary type II renal lesions that also had distant metastasis (p = 0.023) (Fig. 2).

There was no statistically significant correlation between size and TBR in pRCC type I (p = 0.32), pRCC type II (p = 0.10), and oncocytoma (p = 0.63) lesions. However, there was a weak (r = 0.2) statistically significant (p = 0.04) correlation between size and TBR in ccRCC subtype lesions.

RCC subtype summary statistics of size and TBR for renal lesions with or without distant metastasis are provided in Table 1. Figure 3 shows samples of CT and corresponding PET images of the renal tumor subtypes included in our study.

Fig. 3.

Fig. 3

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a Coronal contrast-enhanced CT and b corresponding coronal 18F-FDG-PET in a 48-year-old male patient, showing a 2.9 cm clear cell RCC lesion (SUVmax = 3.0) in the left kidney. c Coronal contrast-enhanced CT and d corresponding coronal 18F-FDG-PET presenting a 2.4 cm papillary type I RCC lesion (SUVmax = 4.1) in the left kidney in a 64-year-old male. e Coronal contrast-enhanced CT shows a 6.0 cm infiltrative mass in the left kidney of a 42-year-old female with metastatic pRCC type II, which demonstrates hyperactivity (SUVmax = 23.2) on 18F-FDG-PET (f). g Axial abdominal CT without contrast demonstrating a 5.2 cm benign oncocytoma lesion with mild FDG uptake (SUVmax = 5.0) on axial 18F-FDG-PET (h) in the right kidney of a 75-year-old male patient

Discussion

FDG-PET/CT is widely used to stage and monitor neoplastic disease [15, 25, 29, 30]. The rate of FDG uptake by tumor cells is primarily affected by abundance of membrane glucose transporters (GLUTs), hexose kinase activity, and glucose-6 phosphatase activity [31, 32]. While the main use of FDG-PET in neoplastic disease is to detect metastases and monitor treatment response, it can also provide insight into tumor biology, and thus may provide quantitative information to aid in identification of RCC lesions of the highest concern (i.e., high-grade ccRCC, pRCC type II) [17, 26].

FDG PET is currently not preferred over conventional anatomical imaging modalities such as MRI and CT for pre-operative evaluation of intra-renal RCC lesions. The reported sensitivity (46.6–94%) for detection and characterization of renal tumors is likely affected by the confounding influence of urinary excretion within close proximity [15, 17, 25, 31, 33]. Despite these limitations, FDG-PET aids in pre-operative therapeutic decision making, as disease stage (particularly for detecting metastatic disease) and FDG avidity are predictive of patient survival and disease recurrence [18, 26].

Studies have shown that lesion subtype and grade significantly influence patient outcome, with ccRCC and pRCC type II demonstrating higher rates of disease recurrence and metastasis, and ultimately reduced survival [2, 25, 34, 35]. Knowledge of differences in FDG avidity among RCC subtypes could provide insight into the clinical utility of FDG-PET for evaluation of various renal lesions and guide toward optimization of active surveillance and individualization of clinical management plans.

Prior studies have demonstrated significantly higher FDG avidity in high-grade ccRCC and pRCC lesions compared to low-grade ccRCC, chromophobe RCC (chRCC), and benign entities such as oncocytoma and angiomyolipoma [15, 16, 25, 26]. In the study by Takahashi et al., the majority (4/5) of papillary lesions considered were type II subtype, leading them to conclude that the higher FDG avidity of pRCC tumors could be related to the pRCC type II lesions [15]. Consistent with the mentioned study, we showed significantly higher FDG avidity in pRCC type II lesions compared to pRCC type I, ccRCC, and oncocytoma. Our findings did not show a difference in TBR between ccRCC, pRCC type I, and oncocytoma. We demonstrated that differences in renal lesion FDG activity was primarily driven by tumor subtype rather than size.

In addition to subtype specific differences in FDG avidity, the correlation between primary renal tumor size and SUV was investigated by Lee et al., who reported a moderate positive correlation between size and SUVmax [36]. The majority of tumors in their study were of ccRCC subtype [20–23]. These findings are concurrent with our observation of a positive correlation between ccRCC tumor size and TBR.

Lee et al. also showed that primary ccRCCs with higher SUVmax carry an increased likelihood of existence of distant metastases [36]. Herein, we found significantly higher TBR in pRCC type II subtype renal tumors with distant metastasis compared to cases without metastatic disease. However, we did not observe similar relationship in ccRCC or pRCC type I. This discrepancy in findings is possibly attributable to the lack of diversity in grade of the ccRCC lesions examined in the present study. Although our study has almost twice the sample size, the majority of our ccRCC cohort (52/54) consisted of low-grade pathology (Fuhrman grade < 3). In the work by Lee et al., Fuhrman grading of ccRCC tumors was not reported.

While renal mass biopsy or surgical intervention is necessary for definitive pathologic diagnosis, RCC subtyping using noninvasive preoperative imaging such as FDG-PET may prove useful in cases where tissue diagnosis is not clinically beneficial, such as for patients with comorbidities or extensive metastatic disease. In these patients, surgical procedures carry a higher risk-to-benefit ratio, and active surveillance is a critical option [15]. Therefore, while the use of FDG-PET may prove clinically useful for identification of high-risk lesions, our study confirmed the prior reports that it cannot accurately discriminate between low-grade ccRCC and oncocytoma, a limitation often shared with other modalities such as CT or MRI [3, 9, 37]. Our study was not able to show that FDG avidity sufficiently distinguishes aggressive pRCC type I and low-grade ccRCC lesions from benign entities. Because these malignant subtypes carry metastatic potential, histopathological diagnosis remains necessary.

Limitations of this study included its retrospective nature and limited nuclear-grade diversity within the clear cell subtype. Moreover, even though our study has a large cohort compared to previous studies, small sample size within subtypes could influence the power of statistical tests. Lastly, the real-world clinical application of FDG-PET for the detection, measurement, and monitoring of intra-renal lesions with FDG-PET remains challenging due to FDG elimination through the renal collecting system [15, 17, 24]. This was mitigated in our study by excluding the lesions that were close to the urinary collecting system and therefore compromised by urinary FDG activity. These criteria likely resulted in our high agreement between operators. Caution must be used when applying discrete cutoff values for SUV and TBR in this study because these values are specific to the technique, instrumentation, and image reconstruction used at a single institution.

Conclusion

Papillary type II RCC lesions have significantly higher FDG avidity compared to low-grade clear cell RCC, papillary type I RCC, and oncocytoma lesions. Papillary type II RCC lesions with distant metastases demonstrate significantly higher FDG uptake, independent of size. Thus, higher FDG activity in pRCC type II may indicate a more aggressive nature. These findings may demonstrate that FDG may prove useful in identification of renal tumors of highest clinical concern, which allows for customization of active surveillance and individualization of patient care.

Funding

This work was supported by the Intramural Research Programs of the Center for Cancer Research-National Cancer Institute and the National Institutes of Health Clinical Center, Bethesda, Maryland, USA.

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