Special issue “The advance of solid tumor research in China”: 68Ga‐PSMA‐11 PET/CT for evaluating primary and metastatic lesions in different histological subtypes of renal cell carcinoma

Abstract

Conventional imaging examinations are not sensitive enough for the early detection of recurrent or metastatic lesions in renal cell carcinoma (RCC) patients. We aimed to explore the role of ⁶⁸Ga‐prostate specific membrane antigen (PSMA)‐11 positron emission tomography (PET)/computed tomography (CT) in the detection of primary and metastatic lesions in such patients. We retrospectively analyzed 50 RCC patients who underwent ⁶⁸Ga‐PSMA‐11 PET/CT from November 2017 to December 2020. We observed a higher median accuracy and tumor‐to‐background maximum standard uptake value (SUV_max) ratio (TBR) of ⁶⁸Ga‐PSMA‐11 PET/CT in clear cell RCC (ccRCC; 96.57% and 6.00, respectively) than in non‐clear cell RCC (ncRCC; 82.05% and 2.99, respectively). The accuracies in detecting lesions in the renal region, bone, lymph nodes and lungs in ccRCC were 100.00%, 95.00%, 98.08% and 75.00%, respectively, and those in the renal region, bone and lymph nodes in ncRCC were 100.00%, 86.67% and 36.36%, respectively. The median TBRs of the lesions from the above locations were 0.38, 10.96, 6.69 and 13.71, respectively, in ccRCC and 0.13, 4.02 and 0.73, respectively, in ncRCC. The PSMA score evaluated with immunohistochemistry was correlated with the SUV_max (P = .046) in RCC. Higher PSMA scores were observed in ccRCC than in ncRCC (P = .031). ⁶⁸Ga‐PSMA‐11 PET/CT resulted in changes in clinical management in 12.9% (4/31) of cases because of the discovery of new metastases not detected with conventional imaging. These results indicate that ⁶⁸Ga‐PSMA‐11 PET/CT is a promising method for the detection of metastatic lesions in ccRCC, especially for those in the bone and lymph nodes.

What's new?

Accurate staging and assessment of metastases are important in guiding clinical treatment of patients with renal cell carcinoma (RCC). Early detection of metastatic lesions in RCC, however, presents unique challenges, owing to small lesion size, which escapes conventional imaging. Here, the authors investigated 68Ga‐PSMA‐11, a positron emission tomography (PET) ligand targeted toward prostate‐specific membrane antigen (PMSA) in the tumor neovasculature, for the detection of RCC lesions. Compared with conventional imaging, 68Ga‐PSMA‐11 PET/CT exhibited superior sensitivity and accuracy in metastatic lesion detection in clear cell RCC. Accuracy in the detection of lesions in the lymph nodes and bone was notably high.

1. INTRODUCTION

In 2020, renal cell carcinoma (RCC) was the ninth most frequently diagnosed cancer in men and the 14th most frequently diagnosed cancer in women worldwide. ¹ Accurate staging and assessment of metastases are important for the guidance of clinical treatment. Traditionally, ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI) and bone scanning (BS) have been used to detect and characterize renal masses and metastases. ² , ³ , ⁴ , ⁵ However, in the early phases of metastatic disease, none of these are sensitive enough for the comprehensive detection of small metastatic lesions. ⁶ There is, therefore, an urgent need for more sensitive and specific imaging technologies for the early detection of metastases for accurate staging and timely treatment of RCC.

Prostate‐specific membrane antigen (PSMA) is a type II integral membrane glycoprotein of approximately 100 kDa that was originally considered prostate‐specific, but was subsequently shown to be present on many other normal and pathological tissues, such as the neovasculature of many tumor types, including RCC. ⁷ , ⁸ , ⁹ Thus, the different endothelial expression of PSMA by tumor neovasculature is a potential target in RCC. Positron emission tomography (PET) with ligands of PSMA (eg, ⁶⁸Ga‐PSMA‐11) is a relatively new nuclear imaging modality with great potential, and has been applied in prostate cancer management. ¹⁰ , ¹¹ , ¹² , ¹³ More recently, the clinical use of ⁶⁸Ga‐PSMA‐11 PET/CT for the improved detection of RCC lesions has gained interest, as is clear from the publication of several case reports and retrospective studies with small samples. ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹

However, the difference in detection rates of primary and metastatic lesions by ⁶⁸Ga‐PSMA‐11 PET/CT in RCC remains unclear, and its clinical indications for RCC are yet to be identified. Thus, we aimed to explore the role of ⁶⁸Ga‐PSMA‐11 PET/CT in the detection of primary and metastatic lesions in different histological subtypes of RCC.

2. MATERIALS AND METHODS

2.1. Patients

This was a retrospective case series at a single tertiary institution between November 2017 and December 2020. The inclusion criteria were as follows: (1) pathological diagnosis of RCC, (2) at least one ⁶⁸Ga‐PSMA‐11 PET/CT scan and (3) at least three radiographical follow‐ups every 3 months after ⁶⁸Ga‐PSMA‐11 PET/CT. Considering that increasing attention has been paid in recent years to the local treatment of patients with 5 to 10 metastases, ²² , ²³ we selected patients with ≤10 lesions for statistical analysis by lesions. The exclusion criteria were as follows: (1) previous or sequential second primary cancers, (2) incomplete medical records, including follow‐up, or (3) with more than 10 lesions, without contemporaneous CT or MRI (within 1 month), and without tissue samples sufficient by surgery or biopsy (within 1 month). All reported investigations were conducted in accordance with the Declaration of Helsinki and national regulations.

2.2. ⁶⁸Ga‐PSMA‐11 PET/CT examination

Whole‐body scans were performed by using a combined PET/CT system (Siemens Biograph mCT.X, Siemens AG, Munich, Germany). Patients did not need to fast before the examination but had to drink 500 ml of water within 2 h to ensure sufficient hydration. To reduce urinary radioactivity, the bladder was emptied before imaging. Whole‐body images were collected 60 to 90 min after injection of 0.05 mCi/kg ⁶⁸GA‐PSMA‐11. The scanning range was from the base of the skull to the middle of the femur, and local collection was performed if necessary. Low‐dose CT‐scanning was mainly used for attenuation correction and lesion localization in PET images. Automatic milliampere‐control technology was used for diagnostic CT scanning. PET was conducted in 3D mode for 3 min per bed position. If the lesion was not clear in the initial images, delayed imaging was performed 3 to 4 h later. A syngo TrueD (Siemens AG) workstation was used for the registration and fusion of the acquired images from the PET and CT scans. Corrections were applied for random effects, geometry, attenuation and scatter.

2.3. Conventional imaging examination

CT: All patients received enhanced chest, abdomen and pelvis CT. Patients received were administered a peripheral intravenous injection of nonionic iodinated contrast material (300 mg/ml) via a high‐pressure injector at a flow rate of 2.5 to 3.0 ml/s and a total dose of 80 to 100 ml (1.0 ml/kg) after non‐enhanced CT. The corticomedullary, nephrographic and excretory phases were started 30, 60 and 180 s, respectively, after intravenous injection of the contrast agent.

MRI: MRI was performed for lesions requiring additional attention, such as bone metastases and brain metastases. The MRI protocol comprised coronal turbo inversion recovery, axial T1‐weighted (T1‐w), axial T2‐w and diffusion‐weighted sequences, with b‐values of 0 and 800 s/mm² in the axial plane. After gadolinium injection, T1‐w fat‐saturated sequences were obtained in the axial and coronal planes.

2.4. Imaging analysis

The original images obtained via PET/CT, CT and MRI were individually analyzed by two nuclear medicine physicians (Rongliang Zheng and Wen Long) and two radiologists (Li Tian and Huali Ma) who were blinded to the clinical history of the patients. Any images resulting in different opinions were reevaluated by all four experts until a consensus was reached. Oligometastasis was defined as no more than five metastatic lesions. The intensity of ⁶⁸Ga‐PSMA uptake was assessed based on the standard uptake value (SUV). The maximum SUV (SUV_max) was recorded as a statistical criterion to minimize partial volume effects and improve reproducibility of the measurements. A positive PET/CT scan was defined as containing a moderate or intense PSMA‐avid lesion with an SUV_max ≥2 as reported. ¹⁹ The lesion was considered true positive if histopathology showed RCC or at least two of the following criteria were met: (1) the lesion showed typical appearance on two or more imaging examinations; (2) the lesion increased in size from one imaging exam to the next; (3) the lesion decreased in size from one imaging exam to the next, following appropriate treatment and (4) the lesion was associated with clinical symptoms suggesting malignancy. ²⁴ The lesion was considered true negative if it was pathologically confirmed or had no significant changes after at least 6 months of follow‐up. The lesion was considered true negative if it was pathologically confirmed, or it did not have typical appearance by imaging examinations and significant changes after at least 9 months of follow‐up. ²⁵ , ²⁶ Tumor‐to‐background ratios (TBRs), calculated by dividing the SUV_max of the tumor by the SUV_max of the background tissue, were determined to quantify the image contrast. TBRs were calculated for the primary tumor (relative to morphologically unaltered renal parenchyma) and metastases in the lymph nodes (relative to soft tissue), bone (relative to bone spongiosa), the lungs (relative to lung parenchyma), the liver (relative to liver parenchyma) and soft‐tissue nodules (relative to nearby soft tissue). ¹⁷ , ²⁷

2.5. Histopathological analysis

Renal tumor specimens were sectioned, fixed and subjected to paraffin embedding and hematoxylin and eosin (HE) staining. All sections were reviewed, and consensus was obtained by two urological pathologists according to the 2016 World Health Organization (WHO) classification of tumors of the urinary system and male genital organs. ²⁸ HE staining was used to determine the pathological PSMA expression. Briefly, 5 μm tissue sections were deparaffinized in xylene, rehydrated through a graded alcohol series, immersed in 3% hydrogen peroxide for 10 min to block endogenous peroxidase activity, and subjected to antigen retrieval by pressure cooking for 3 min in citrate buffer (pH 6.0). The slides were subsequently incubated with 10% normal goat serum at room temperature for 30 min to reduce nonspecific reactivity. Thereafter, they were incubated sequentially with primary anti‐PSMA antibody (#12815; Cell Signaling Technology, Danvers, MA; 1:100 dilution) overnight at 4°C, incubated with a secondary antibody (Envision; Dako, Glostrup, Denmark) for 1 h at room temperature, washed twice with phosphate buffered saline for 5 min, and developed by using 3,3‐diaminobenzidine. Finally, the sections were counterstained with Mayer's hematoxylin, dehydrated and mounted. Negative controls were prepared by replacing the primary antibody with normal murine immunoglobulin G.

PSMA is mainly expressed in the endothelial cells of tumor‐associated neovasculature in RCC. ²⁹ The average density (number of PSMA‐positive neovasculatures/high‐power field) was quantitatively scored by two pathologists (Yijun Zhang and Ping Yang). Five fields of view (magnification ×400) were randomly selected in tumor‐tissue areas, the absolute number of PSMA‐positive neovasculatures was counted in each, and the average was calculated. The immunohistochemistry (IHC) score was obtained by multiplying the score for the average density of positively stained neovasculatures (“1” < median number of positive neovasculatures and “2” ≥ median number of positive neovasculatures) according to the staining‐intensity score (“0” negative staining, “1” [weak staining], “2” moderate staining and “3” strong staining) to obtain the final score for each section. ³⁰

2.6. Analysis

IBM SPSS Statistics for Windows version 22.0 (IBM Corp., Armonk, NY) was used for the statistical analysis. The sensitivity, specificity, accuracy and TBR of ⁶⁸Ga‐PSMA‐11 PET/CT in detecting different RCC lesions were also calculated. Accuracy = (true negatives+ true positives)/total number. Values of radiological parameters were compared within different subgroups using Student's t test. Statistical significance was set at P < .05.

3. RESULTS

3.1. Patient characteristics

There were 36 patients whose ⁶⁸Ga‐PSMA‐11 PET/CT scan showed no more than 10 lesions. We retrospectively collected these ⁶⁸Ga‐PSMA‐11 PET/CT scans to analyze the accuracy of different pathological types and sites. We also retrospectively collected 31 ⁶⁸Ga‐PSMA‐11 PET/CT scans from 31 patients who underwent contemporaneous CT or MRI (within 1 month of ⁶⁸Ga‐PSMA‐11 PET/CT scan) to analyze the changes in management due to ⁶⁸Ga‐PSMA‐11 PET/CT. A total of 50 RCC patients were included in the analysis, since there were 17 patients with no more than 10 lesions and contemporaneous images. Of these 50 patients, only nine patients were able to obtain sufficient contemporaneous surgery or biopsy pathological samples for IHC (within 1 month of ⁶⁸Ga‐PSMA‐11 PET/CT scan). We retrospectively collected these nine ⁶⁸Ga‐PSMA‐11 PET/CT scans and unstained pathological sections to analyze the relationship between PSMA score and SUV_max.

The median age of these 50 patients was 55 years. Forty (80%) cases were diagnosed as clear cell RCC (ccRCC), three papillary renal cell carcinoma, two MIT family translocation RCC, one chromophobe RCC, one mucinous tubular and spindle cell carcinoma, one poorly differentiated RCC, and two others. Forty‐one cases were metastatic RCC, 20 of which were oligometastatic. The other nine patients underwent ⁶⁸Ga‐PSMA‐11 PET/CT scans after nephrectomy, of which six were negative and three exhibited recurrences. Lesions were detected in the following locations: the renal region (n = 16), lymph nodes (n = 17), bone (n = 25), lungs (n = 13) and other (n = 17) (Table 1).

TABLE 1.

Baseline characteristics for the whole cohort

	Patients (n = 50)	Patients with no more than 10 lesions (n = 36)	Patients with contemporaneous CT/MRI scans (n = 31)
Sex
Male	39	27	24
Female	11	9	7
Age
Median (IQR)	55 (47‐64)	58 (48‐65)	54 (47‐64)
Negative	6	6	2
Positive
Local	3	3	2
Oligometastases	20	20	10
Multiple metastases	21	7	17
Location
Renal region	16	8	13
Lymph node	17	9	12
Bone	25	13	18
Lungs	13	8	8
Other a	17	10	12
Pathological type
Clear cell	40	29	23
Nonclear cell	10	7	8

Abbreviations: CT, computed tomography; IQR, interquartile range; MRI, magnetic resonance imaging.

^a Eight patients with soft‐tissue nodules in the abdominal cavity, five with adrenal metastases, three with soft‐tissue nodules in the pelvic cavity, three with liver metastases, one with a soft‐tissue nodule in the thoracic cavity and one with brain metastasis.

3.2. Imaging characteristics for patients with no more than 10 lesions

Thirty‐six of the 50 patients had no more than 10 lesions, and the total number of lesions was 94. Among them, 60 lesions were diagnosed as ccRCC (Table 2).

TABLE 2.

Diagnostic values of ⁶⁸Ga‐PSMA‐11 PET/CT

	Lesions n = 94	D max median (IQR) (cm)	SUVmax median	TBR median	Accuracy (%)	Sensitivity (%)	Specificity (%)
Pathological type
Clear cell	60	2.1 (1.3‐3.0)	9.0	6.00	96.57	93.65%	97.87%
Nonclear cell	34	1.8 (1.1‐2.5)	3.7	2.99	82.05	70.59	90.91
Location
Renal region	10	3.9 (3.0‐9.6)	16.8	0.33	100.00	100.00	100.00
Lymph node	21	1.8 (1.5‐2.1)	3.7	2.13	92.17	61.90	98.94
Bone	37	2.0 (0.9‐2.5)	5.4	4.81	90.59	94.59	87.50
Lungs	7	1.6 (1.3‐2.0)	9.6	13.71	75.00	71.43	100.00
Other a	19	1.9 (0.9‐2.8)	6.8	6.00	93.48	85.00	100.00

Abbreviations: CT, computed tomography; D _max, maximum diameter; ⁶⁸Ga, gallium‐68; PET, positron emission tomography; PSMA, prostate‐specific membrane antigen; SUV_max, maximum standard uptake value; TBR, tumor‐to‐background maximum standard uptake value ratio.

^a Seven adrenal metastases, seven soft‐tissue nodules in the abdominal cavity, two soft‐tissue nodules in the pelvic cavity, two brain metastases and one liver metastasis.

The median SUV_max and TBR were higher for lesions in ccRCC (9.0 and 6.00, respectively) than in nonclear cell RCC (ncRCC) (3.7 and 2.99, respectively). The accuracy, sensitivity and specificity were higher in ccRCC (96.57%, 93.65% and 97.87%, respectively) than in ncRCC (82.05%, 70.59% and 90.91%, respectively).

The median SUV_max was higher in primary tumors (16.8) than in metastatic lesions (3.7‐9.6), while the median TBRs were higher in metastatic lesions (2.13‐13.71) than in primary tumors (0.33). The accuracies, sensitivities and specificities of ⁶⁸Ga‐PSMA‐11 PET/CT in detecting different metastatic lesions were 75.00%‐93.48%, 61.90%‐94.59% and 87.50%‐100.00%, respectively.

3.3. Imaging characteristics for different pathological types

We explored the differences in the detection of lesions in ccRCC and ncRCC with ⁶⁸Ga‐PSMA‐11 PET/CT by analyzing SUV_max and TBR values (Table 3). In each location, both the median SUV_max and TBR were higher in ccRCC than those in ncRCC. The median TBRs were higher in metastatic lesions than in primary tumors in both ccRCC (6.03‐13.71 vs 0.38) and ncRCC (0.73‐4.02 vs 0.13).

TABLE 3.

Diagnostic values of ⁶⁸Ga‐PSMA‐11 PET/CT in different pathological types

	Lesions	D max median (IQR) (cm)	SUVmax median	TBR median	Accuracy (%)	Sensitivity (%)	Specificity (%)
Clear cell	60
Renal region	9	3.9 (2.7‐7.9)	18.0	0.38	100.00	100.00	100.00
Lymph node	14	1.9 (1.5‐2.2)	9.6	6.69	98.08	92.86	98.89
Bone	19	1.9 (0.8‐2.2)	7.5	10.96	95.00	100.00	90.48
Lungs	7	1.6 (1.3–2.0)	9.6	13.71	75.00	71.43	100.00
Other a	11	2.4 (1.3‐2.8)	7.4	6.03	93.33	83.33	100.00
Nonclear cell	34
Renal region	1	10.2 (10.2‐10.2)	4.9	0.13	100.00	100.00	100.00
Lymph node	7	1.8 (1.5‐1.9)	0.7	0.73	36.36	0.00	100.00
Bone	18	2.4 (1.5‐2.5)	4.2	4.02	86.67	88.89	85.19
Other b	8	1.2 (0.8–2.2)	4.9	3.92	93.75	87.50	100.00

Abbreviations: CT, computed tomography; D _max, maximum diameter; ⁶⁸Ga, gallium‐68; PET, positron emission tomography; PSMA, prostate‐specific membrane; SUV_max, maximum standard uptake value; TBR, tumor‐to‐background maximum standard uptake value ratio.

^a Six adrenal metastases, three soft‐tissue nodules in the abdominal cavity and two brain metastases.

^b Four soft‐tissue nodules in the abdominal cavity, two soft‐tissue nodules in the pelvic cavity, one adrenal metastasis and one liver metastasis.

In ccRCC, the accuracies of ⁶⁸Ga‐PSMA‐11 PET/CT in detecting lesions in different locations were above 90%, except for in the lungs (75.00%). Their sensitivities were above 80%, except for detecting lesions in the lungs (71.43%), while all the specificities were all above 90%. In ncRCC, the accuracies of ⁶⁸Ga‐PSMA‐11 PET/CT in detecting lesions in lymph nodes and bone were 36.36% and 86.67%, respectively. The sensitivities in detecting metastatic lesions were all below 90%.

3.4. Association of imaging characteristics and pathological characteristics

Hematoxylin and eosin (HE) staining and IHC were implemented in the nine patients who underwent surgery or biopsy at the same time that they underwent ⁶⁸Ga‐PSMA‐11 PET/CT (Table S1). PSMA expression was observed in tumor‐associated neovasculature, and eight of the nine cases exhibited different PSMA‐expression intensity and different density in neovasculature. Only one sample exhibited negative PSMA staining.

In the nine samples, seven were pathologically diagnosed as ccRCC, while five were from metastatic lesions. The SUV_max values are related to the pathologic types and PSMA scores (Figure 1). The mean PSMA score and mean SUV_max were 3.9 ± 1.9 and 12.5 ± 10.0, respectively, in ccRCC, while those in ncRCC were 1.5 ± 0.5 and 3.6 ± 2.5, respectively. Student's t‐test revealed that the PSMA score of ccRCC was significantly higher than that of ncRCC (P = .008), and the PSMA score was significantly correlated with SUV_max in RCC samples (P = .035).

FIGURE 1.

Representative images of radio‐pathological matching cases. (A) Primary lesion of a patient with ncRCC; (B) metastatic lesion (supraclavicular lymph node) of a patient with ncRCC; (C) primary lesion of a patient with ccRCC; (D) metastatic lesion (adrenal gland) of a patient with ccRCC. ccRCC, clear cell renal cell carcinoma; ncRCC, nonclear cell renal cell carcinoma

3.5. Heterogeneity in different imaging examinations

Overall, 31 of the 50 patients underwent contemporaneous CT/MRI within 1 month before or after ⁶⁸Ga‐PSMA‐11 PET/CT. Among them, 23 patients were diagnosed with ccRCC (Table 1). The numbers of patients diagnosed with localized, oligometastatic and multiple metastatic disease were 4, 10 and 15, respectively, by using conventional imaging, compared with 2, 9 and 18, respectively, by using ⁶⁸Ga‐PSMA‐11 PET/CT. The management of four patients (12.9%) was changed after detection of new metastases with ⁶⁸Ga‐PSMA‐11 PET/CT. One patient who was expected to have local recurrence was found with oligometastases. Therefore, the management changed from surgery to radiotherapy. One patient who was expected to have local recurrence was found with multiple metastases. Therefore, the management changed from surgery to medical treatment. Two patients who were expected to have oligometastases were found to have multiple metastases. Therefore, the management changed from radiotherapy to systemic therapy (Figure 2).

FIGURE 2.

Per‐patient analysis of stage using conventional CT/MRI and ⁶⁸Ga‐PSMA‐11 PET/CT. CT, computed tomography; ⁶⁸Ga, gallium‐68; multiple M, multiple metastases; MRI, magnetic resonance imaging; Oligo M, oligometastases; PSMA, prostate‐specific membrane antigen; PET, positron emission tomography

4. DISCUSSION

To the best of our knowledge, only few case reports and series in which the role of 68Ga‐PSMA‐11 PET/CT in RCC staging have been published. ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ Our aim was to explore the potential use of ⁶⁸Ga‐PSMA‐11 PET/CT in the detection of primary and metastatic lesions in different histological subtypes of RCC for the guidance of diagnostic and management decisions compared with conventional imaging. Although this is a small, retrospective study, it contains the largest dataset to date, to our knowledge and the quality of evidence is promising.

The discovery of PSMA expression in RCC dates back to 2007, when Baccala et al ³⁰ observed widespread PSMA expression in the endothelial cells of the neovasculature. Positive PSMA staining was detected in 75% to 100% of ccRCC cases, 30% to 73% of chromophobe RCC cases and 0% of papillary RCC cases. ¹⁸ , ³⁰ , ³¹ In our study, the PSMA score of ccRCC was statistically higher than that of ncRCC, and the PSMA score was statistically significantly correlated with the SUV_max of the RCC lesions. Thus, we speculate that ⁶⁸Ga‐PSMA‐11 PET/CT may be more valuable in ccRCC than in ncRCC. A few case reports and series have been published that indicated that ⁶⁸Ga‐PSMA‐11 PET/CT may have advantages in the detection of metastatic lesions of ccRCC. ¹⁶ , ¹⁸ , ¹⁹ To our knowledge, this was the first time that the utilities of ⁶⁸Ga‐PSMA‐11 PET/CT in ccRCC and ncRCC were compared; we discovered that ⁶⁸Ga‐PSMA‐11 PET/CT had a better accuracy and sensitivity in the detection of lesions in ccRCC.

Another interesting aspect of our study is the differences that were observed in the TBRs and accuracies of ⁶⁸Ga‐PSMA‐11 PET/CT in the detection of lesions from different locations in RCC patients. Some studies have focused on detecting primary RCC. ¹⁷ , ²¹ , ³² In 2021, evaluating 36 ⁶⁸Ga‐PSMA‐11 PET/CT scans in primary RCC staging, Gao et al ²¹ concluded that the SUV_max was high, and the technique could be used to identify aggressive pathological features of primary ccRCC. However, we noticed that the physiological uptake of the surrounding renal parenchyma may be even higher. The addition, TBR, a common indicator of image contrast in PET/CT, may be a better parameter than SUV_max alone for the detection. In 2016, Sawicki et al ¹⁷ observed that, because of the high uptake in the surrounding renal parenchyma, the mean TBR of the five primary RCCs was only 0.2 ± 0.3, while that of the metastases was 11.7 ± 0.2. Similarly, in our study, the median TBR of the lesions in the renal region was 0.33, while those of the metastatic lesions in were 2.13 to 13.71. Considering the relatively high detection rate of CT/MRI for primary lesions ² , ³ , ⁵ and the difficulty in detecting minor metastases with conventional imaging, we believe that the value of ⁶⁸Ga‐PSMA‐11 PET/CT lies in the early detection of metastases, as it may promote accurate staging and guide clinical practice.

In the detection of different metastatic lesions in ccRCC, we discovered that ⁶⁸Ga‐PSMA‐11 PET/CT was more suited to the early detection of lymph node and bone metastases than to that of lung metastases. Evaluation of lymph nodes and bone metastases with CT or MRI solely depends on morphological information, complicating the determination of marginal lymph nodes and small bone metastases. ¹² , ³³ In prostate cancer, a recent meta‐analysis demonstrated higher sensitivity (80%) and specificity (97%) for ⁶⁸Ga‐PSMA‐11 PET/CT in the assessment of lymph node metastases compared with histopathology after salvage lymph node dissection. ³⁴ A prospective study of 113 patients revealed that ⁶⁸Ga‐PSMA‐11 PET/CT had a statistically significantly higher sensitivity and accuracy for the detection of skeletal lesions than did BS (96.2% vs 73.1% and 99.1% vs 84.1%). ³⁵ In ccRCC, we discovered that ⁶⁸Ga‐PSMA‐11 PET/CT is more accurate in the determination of early lymph node metastasis and bone metastasis than conventional imaging (Figure 3A,B). The accuracies of ⁶⁸Ga‐PSMA‐11 PET/CT in detecting lymph node and bone metastatic lesions in ccRCC were as high as 98.08% and 95.00%, respectively. Moreover, we discovered that ⁶⁸Ga‐PSMA‐11 PET/CT had advantages in determining whether there were residual tumors after surgery in the form of uptake of contrast agents despite the influence of metal artifacts (Figure 3C). However, the accuracy of ⁶⁸Ga‐PSMA‐11 PET/CT in the detection of pulmonary metastases was low. Most of the lung metastatic lesions were small, and PET has well‐known difficulties in detecting small lung lesions owing to breathing motion and partial volume effects.

FIGURE 3.

Representative images of three patients with baseline conventional imaging and follow‐up. (A) ⁶⁸Ga‐PSMA‐11 PET/CT revealed a supraclavicular lymph node with increased uptake, which was difficult to diagnose because of its marginal size on conventional MRI. Six‐month follow‐up MRI following systemic treatment revealed regression of the lymph node. (B) ⁶⁸Ga‐PSMA‐11 PET/CT revealed a thoracic vertebral metastasis with increased uptake, which did not appear upon conventional MRI. Twelve‐month follow‐up MRI after systemic treatment revealed obvious erosive osteoclasia of the thoracic vertebra. (C) ⁶⁸Ga‐PSMA‐11 PET/CT revealed a residual thoracic vertebral metastasis after palliative surgery, with increased uptake, which could not be observed upon conventional CT because of metal artifact reduction. Six‐month follow‐up ⁶⁸Ga‐PSMA‐11 PET/CT imaging following radiotherapy revealed a decreased uptake. CT, computed tomography; ⁶⁸Ga, gallium‐68; MRI, magnetic resonance imaging; PET, positron emission tomography; PSMA, prostate‐specific membrane antigen

The value of accurate imaging is in the guidance it can provide for clinical management of RCC patients. In 2019, Raveenthiran et al ¹⁹ noted widespread changes in management after ⁶⁸Ga‐PSMA‐11 PET/CT in a retrospective case series of 38 patients. Of the 16 patients who underwent ⁶⁸Ga‐PSMA‐11 PET/CT for primary staging, management was changed in seven (43.8%). Similarly, in our study, ⁶⁸Ga‐PSMA‐11 PET/CT resulted in a change in management of 12.9% (4/31) of cases because of the discovery of new metastases that were not detected with conventional imaging. The relatively low rate of change of patient management in our study may be because most of our patients already had multiple metastases when they presented with RCC. This suggests that patients with recurrence or oligometastases may benefit more from ⁶⁸Ga‐PSMA‐11 PET/CT than those with multiple metastases.

Our study had several limitations. First, a substantial portion of the patients in our study did not undergo contemporaneous conventional imaging and lacked pathological data, as this was a retrospective study. Second, except for lymph nodes, bone and the lungs, the numbers of other metastatic lesions were too small to be analyzed separately. Third, ncRCC is a group consisting of complex pathological subtypes, but we did not include enough patients for further subgroup analysis. Prospective studies are required to confirm our results.

Considering the paucity of prospective studies and the fact that this retrospective study, despite including only 50 patients, is the largest dataset reported to date, we believe that our study lays the foundation for further exploration of the role of ⁶⁸Ga‐PSMA‐11 PET/CT in RCC staging. Our data suggest that ⁶⁸Ga‐PSMA‐11 PET/CT is a promising method for the detection of metastatic lesions in ccRCC patients, especially for metastases in the bone and lymph nodes.

Abbreviations

⁶⁸Ga

Gallium‐68

BS

bone scan

ccRCC

clear cell renal cell carcinoma

CT

computed tomography

HE

hematoxylin and eosin

IHC

immunohistochemistry

MRI

magnetic resonance imaging

ncRCC

non‐clear cell renal cell carcinoma

PET

positron emission tomography

PSMA

prostate‐specific membrane antigen

RCC

renal cell carcinoma

SUV

standard uptake value

SUV_max

maximum standard uptake value

T1‐w

T1‐weighted

T2‐w

T2‐weighted

TBR

tumor‐to‐background maximum standard uptake value ratio

US

ultrasound

WHO

World Health Organization

AUTHOR CONTRIBUTIONS

Conceptualization: Pei Dong, Liru He; Formal Analysis: Yilin Li, Rongliang Zheng, Ruiqi Liu; Funding acquisition: Liru He; Methodology: Yilin Li, Rongliang Zheng, Yijun Zhang, Chaoyun Huang, Li Tian, Ruiqi Liu, Yang Liu, Zhiling Zhang, Hui Han, Fangjian Zhou; Resources: Rongliang Zheng, Yijun Zhang, Chaoyun Huang, Li Tian, Ruiqi Liu, Yang Liu, Zhiling Zhang, Hui Han, Fangjian Zhou, Liru He, Pei Dong; Writing—original draft: Yilin Li, Rongliang Zheng, Yijun Zhang; Writing—review & editing Yilin Li, Rongliang Zheng, Yijun Zhang, Liru He, Pei Dong. The work reported in the paper has been performed by the authors, unless clearly specified in the text.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ETHICS STATEMENT

Informed consent was obtained from all individual participants included in the study. Ethics approval was obtained from the Sun Yat‐sen University Cancer Center Human Research Ethics Committee (ref.: B2021‐233‐01). All procedures involving human participants were carried out in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments.

Supporting information

TABLE S1 PSMA score and SUV_max of nine patients with contemporaneous pathology

Li Y, Zheng R, Zhang Y, et al. Special issue “The advance of solid tumor research in China”: 68Ga‐PSMA‐11 PET/CT for evaluating primary and metastatic lesions in different histological subtypes of renal cell carcinoma. Int J Cancer. 2023;152(1):42‐50. doi: 10.1002/ijc.34189

DATA AVAILABILITY STATEMENT

The raw imaging data are available at https://figshare.com/articles/figure/PSMA_PET-CT/17696933. Further details and other data that support the findings of this study are available from the corresponding author upon request.