Review

Nuclear Medicine Applications in Diagnosis of Urological Tumors

10.4274/uob.galenos.2018.1132

  • Mine Araz
  • Yüksel Ürün

Received Date: 06.11.2018 Accepted Date: 08.11.2018 Bull Urooncol 2019;18(2):80-88

Except for prostate carcinoma, there is limited data in the literature on the role of nuclear imaging methods in the management of urological cancers. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is generally the most widely used method in oncological imaging. However, the diagnostic power of this radiopharmaceutical in urological tumors is weakened partially due to its physiological urinary excretion. For this reason, some other 18F-labeled molecules, especially Ga-68 prostate-specific membrane antigen for prostate cancer and 18F-sodium fluoride for bone metastases, have recently gained importance. In addition, characterization of renal masses with Tc-99m methoxy isobutyl isonitrile (MIBI), a nonspecific tumor agent, and detection of bone metastases with whole-body Tc-99m methylene diphosphonate (MDP) bone scintigraphy are still used. In this review, scintigraphic methods and PET/CT imaging used in diagnosis and follow-up of urological tumors will be discussed.

Keywords: Urological neoplasms, radionuclide imaging, radiology

Introduction

Computerized tomography (CT) is the most commonly used imaging method for diagnosis, staging, treatment planning and follow-up of kidney tumors and bladder tumors. Magnetic resonance imaging (MRI) can provide more detailed information about local advanced disease. In particular, the use of multiparametric MRI in prostate cancer is increasing (1).

Nuclear imaging methods can provide information on the function, behavior and receptor status of tumoral tissue, unlike anatomical imaging. 18F-fluorodeoxyglucose (18F-FDG) is the most commonly used metabolic agent in oncologic PET/CT studies and provides whole-body evaluation in one step. Although urinary excretion of 18F-FDG in urological tumors is intense and thus its role in local disease evaluation is limited, it provides a significant advantage by demonstrating extent of disease. Imaging studies with new radiopharmaceuticals undergoing lower urinary excretion continue.


Kidney Tumors


18F-FDG PET/CT

Sensitivity of 18F-FDG PET/CT has been reported between 50% and 60% in the primary diagnosis and determination of kidney tumors. For this purpose, it has not been shown to have a significant contribution to conventional imaging methods such as CT and MRI. In the literature, although imaging after forced diuresis or dual-phase delayed imaging method have been tried in order to reduce the effect of physiological urine activity, no superiority was achieved with these methods over routine imaging protocol. In addition, it was found that there was no correlation between the amount of GLUT 1 expression and 18F-FDG uptake after surgical excision of the primary tumor (2,3,4).

Routine use of 18F-FDG PET/CT in the staging of kidney tumors is not recommended in standard protocols and guidelines. The most important reason for this is that 18F-FDG has a high rate of false negativity for the primary tumor due to the intense physiological urine activity. However, it has been reported that it may be useful in demonstrating extrarenal metastatic disease in risky patients (5,6).

Early detection and treatment of recurrence after nephrectomy shows a certain survival benefit for some patients. As a whole-body imaging method, 18F-FDG PET/CT can make a significant contribution to patient management during the restaging phase. Metabolic characterization can provide more accurate diagnosis in patients with recurrent or metastatic suspicious findings in postoperative follow-up radiological imaging results. In addition, it is more successful in detecting bone metastases than whole-body bone scintigraphy. The studies published in the literature are small sample studies and mostly retrospective. Recently, a meta-analysis of the results of 1158 patients in 15 studies was published and the sensitivity and the specificity of 18F-FDG PET/CT were 86% and 88%, respectively (7,8,9,10). The sensitivity and specificity of 18F-FDG PET/CT in restaging in 104 patients with renal cell carcinoma (RCC) at postoperative 2nd year were 74% and 80%, respectively. In this series, follow-up treatment strategies were changed in 43% of patients with 18F-FDG PET/CT. In this study, patients with and without pathologic uptake in 18F-FDG PET/CT were compared in terms of survival, and three-year progression-free survival and five-year overall survival rates were significantly lower in patients with positive PET/CT compared to patients with normal PET/CT (20% vs 67% for progression-free survival, 19% vs 69% for overall survival). Thus, 18F-FDG PET/CT can also be used as a prognostic marker in the follow-up of patients with kidney tumors, besides its ability to detect recurrence or metastasis (11). However, routine use is not recommended with existing data and the results of prospective studies to be performed in large patient groups are needed in order to better determine its role in the staging (Table 1).

In RCC, partial/radical nephrectomy or local ablative treatments are performed as definitive treatment in the presence of local disease. In advanced stage disease, anti-angiogenic agents or immune checkpoint inhibitors targeting the vascular endothelial growth factor pathway are used alone or in combination. Since these treatments are very expensive and require close follow-up in terms of the side effects profile, it is important to determine the patients who will benefit from the treatment in the early period in order to prevent both complications and unnecessary treatment costs. As the response evaluation criteria in solid tumors (RECIST) criteria predict, only size-based assessment may not reflect the actual clinical response in this patient group, especially in patients with bone metastasis. A clinical response can be achieved and survival may be prolonged, even if the lesion size is very small or the lesion is growing. Therefore, other methods were searched for the evaluation of the actual treatment response and 18F-FDG, which is the most frequently used agent for evaluating the metabolic response, was tried. When the data of a few studies were examined, it was demonstrated that its role might be important in the evaluation of response in patients using tyrosine kinase inhibitors, that the change between baseline maximum standardized uptake value (SUVmax) values and post-treatment SUVmax values could be prognostically significant and that the prognosis was worse in patients with higher activity in baseline 18F-FDG PET/CT study (12,13,14,15,16,17,18,19,20,21).


18F Florotymidine (18F-FLT) PET/CT

Another PET agent, which is tried for restaging in the follow-up of RCC, is 18F-FLT. 18F-FLT is a proliferation agent that remains in the cell by phosphorylation with thymidine kinase in proliferating tumors. Since thymidine is not a substrate of phosphorylase, it undergoes glucuronidation and is kept intensely in the liver and bone marrow in the body (22). In a multicenter study comparing the role of 18F-FDG PET/CT with 18F-FLT PET/CT in evaluating the treatment response of patients treated with sunitinib for diagnosis of metastatic RCC, it has been reported that baseline 18F-FDT PET/CT has a prognostic value, and that 18F- FLT PET/CT does not have such a benefit but it can be used much earlier in the evaluation of response to treatment than in 18F-FDG (1-2 weeks) (23).


Ga-68 Prostate-specific membrane antigen PET/CT

Renal cell cancers are highly vascular tumors. A high (75-97%) expression of PSMA was shown in the neovascularization bed (24). Therefore, Ga-68 PSMA was also tested in the diagnosis and follow-up of RCC. Although it is not effective in demonstrating primary tumor due to renal excretion, it is an agent that can be useful in the characterization of lesions that are considered as suspicious by conventional methods (25). Higher uptake is observed in clear cell carcinoma than in papillary type (26,27). In the literature, the data on this subject consisted of case reports and case series, and the sensitivity and positive predictive value of Ga-68 Prostate-specific membrane antigen (PSMA) PET/CT were better compared to CT (92% vs 69% and 97% vs 80%) (28).


Tc-99m Myocardial Perfusion Imaging Test SPECT/CT

Benign and malignant differentiation cannot be performed by conventional methods in 14% of operated T1 kidney masses (<4 cm), and pathological results of 20-30% of operated cases are reported as benign. Thus, although no PET agent can be shown for preoperative characterization of primary renal masses, there is a SPECT agent that may be useful. Tc-99m MIBI is a nonspecific tumor agent used for imaging by conventional gamma cameras. In benign and malignant tumors with increased metabolic rate, it is retained in mitochondria within the cell (29). Because oncocytomas contain more mitochondria than other types of RCC, they show higher Tc-99m MIBI uptake (30). When the results of the few studies on this subject were evaluated, Tc-99m MIBI was positive in almost all of the patients who were diagnosed as oncocytoma pathologically and who were evaluated with Tc-99m MIBI SPECT/CT in the preoperative period, and Tc-99m MIBI uptake was not observed in patients diagnosed as having other RCC subtypes. Sensitivity for oncocytomas was reported as 83-100% (31). In a recent study, Tc-99m MIBI SPECT/CT was performed in 48 patients who had T1 tumors before the nephrectomy, and Tc-99m MIBI SPECT/CT was positive in nine patients with pre-operative benign diagnosis. Out of these nine patients, pathology report was compatible with oncocytoma in seven patients and chromophobe RCC in two patients. Five patients with negative Tc-99m MIBI SPECT/CT were confirmed to have RCC in the postoperative period (32).


Bladder Tumors


18F-FDG PET/CT

Its role in the detection of primary bladder tumor is limited due to urinary excretion of radiopharmaceuticals, as in all urologic tumors. No superiority to CT or MRI was demonstrated (33). In lymph node staging, the sensitivity was reported as 46-82%, the specificity was 89-97%, and the accuracy rate was reported as 84-92%. It was reported that it contributed to the conventional imaging methods in 20-40% of the patients and caused a change in treatment management in 68% (34,35,36,37). In order to determine its role in restaging after primary treatment, large series are needed. In a study conducted in 35 patients, it was reported that 17% of the patients had a change in the planned treatment strategy after 18F-FDG PET/CT (38,39). There are publications showing that it can be useful than conventional methods in the differentiation of residual tumor and necrosis for evaluation of neoadjuvant chemotherapy response (40,41). It was reported that occult metastases which cannot be demonstrated by radiological imaging methods in patients with muscle invasive bladder tumor could be demonstrated by 18F-FDG PET/CT and that preoperative 18F-FDG PET/CT positive patients have worse survival compared to negative patients (median overall survival 14 vs 50 months, progression-free survival 16 vs 50 months, p<0.001). In addition, the presence of extravesical lesion was shown to be an independent prognostic marker by multiple variance analysis (42,43) (Table 2).


C-11 Choline PET/CT

C-11 choline is phosphorylated by choline kinase after being taken into the cell and incorporated into the structure of cell membrane phospholipids. C11-choline uptake was also increased in tumors with increased proliferation rates (44).

In the functional imaging of bladder tumors, agents with less urinary excretion than 18F-FDG were tested. Since C-11 choline is a radiopharmaceutical with short half-life, it is thought that the need for faster imaging after injection would minimize handicaps due to physiological urinary excretion. However, in a few studies, the sensitivity in demonstrating lymph node metastases before radical cystectomy was found to be low. For this purpose, its superiority to CT has not been proved. It may be more useful in patients with recurrence after cystectomy (Table 2) (45,46,47,48).


C-11 Acetate PET/CT

In the literature, the accuracy rates of CT and MRI and C-11 acetate PET/CT have been shown to be similar and it is stated that it is not superior to C-11 choline (49,50). In a recent study by Salminen et al. (51), C-11 acetate PET/MR has been reported to have high sensitivity and accuracy rates in detecting muscle invasive bladder cancer and response to neoadjuvant chemotherapy in these patients and to have limited success in lymph node staging (Table 2).


Prostate Cancer


Ga-68 PSMA PET/CT

Prostate-specific membrane antigen (PSMA) is an integral protein found in the neovascularized endothelial cell membrane, not in the tumor itself. In prostate cancer, it is 10 times more expressed than non-cancerous prostate. In the literature, there are studies conducted with more than one PSMA ligand labeled with Ga-68 and the most widely used is PSMA 11 (52,53,54).

Ga-68 PSMA uptake is known to increase in dedifferentiated, metastatic, hormone refractory disease. PSMA expression level is closely related to Gleason score, serum PSA level and prognosis (55,56,57). In demonstration of primary tumor in moderate-high-risk disease, the sensitivity and specificity of were 58% and 82%, respectively, and were 64% and 94%, respectively, for Ga-68 PSMA PET/CT. These values are even higher (76% and 97%) when Ga-68 PET imaging is combined with MRI, which is known to be superior to CT in soft-tissue imaging. This difference was found to be statistically significant between the successes of all three studies (p=0.03) (58). In the literature, there are new publications demonstrating the superiority of Ga-68 PSMA PET/MR combination only to MR (59,60). PET/MR studies, which can be performed in a single session of multiparametric MR, which is the anatomical imaging method with the highest accuracy and sensitivity in prostate cancer, with functional data provided by Ga-68 PSMA PET, are predicted to be used as a routine for imaging in prostate cancer patients in centers with PET/MRI facilities (61).

The most commonly used indication of Ga-68 PSMA PET/CT in prostate cancer is re-staging in patients with biochemical recurrence after primary treatment. The effectiveness of Ga-68 PSMA PET/CT at this stage has been demonstrated in numerous studies. In general, while the lesion detection rate is around 80%, there is a direct relationship between the serum PSA levels and the success of the examination. In a study, the detection rate was calculated as 58% in patients with serum PSA level of 0.2-1.0 ng/mL, 76% in patients with serum PSA level of 1-2 ng/mL and 95% in patients with serum PSA level of > 2 ng/mL. In a recent study, Ga-68 PSMA PET/CT was performed in 117 patients for biomechanical recurrence, and it was reported that Ga-68 PSMA PET/CT changed treatment strategy in 62-76% of patients and that 86% of these patients were given treatment for metastases detected by Ga-68 PET/CT (58). In these patients, Ga-68 PSMA PET/CT can show lymph node metastases in unexpected regions such as mesorectal, posterior pelvic region and supraclavicular region, and can detect occult metastases in lymph nodes below 1 cm that are not suspected radiologically (Figure 1). The sensitivity and specificity in lymph node assessment were 80% and 97%, respectively. It was found to be more successful than bone scintigraphy in demonstrating bone lesions (62,63,64,65,66) (Table 3).

In a recently published meta-analysis, the effect of Ga-68 PSMA PET/CT on the treatment plan of the patients was investigated, and it was reported that Ga-68 PSMA PET/CT caused a change in the treatment plan in 54% of the patients, that the number of patients with systemic treatment decreased significantly and that the number of patients undergoing radiotherapy, focal therapy and surgery increased (67).

It has been reported that performing pre-treatment Ga-68 PSMA PET/CT for patients planned to receive primary or salvage RT may cause changes in the RT plan in 20-60% of patients. A better clinical response was found in patients with negative Ga-68 PSMA PET/CT before RT compared to positive results. A better response to RT is expected in patients with micrometastasis that is too small to be detected even with CT. It has been shown in a small number of small-scale studies that it was also successful in the evaluation of RT response in patients who developed biochemical recurrence after RT (68,69,70,71). It is also used to evaluate the response to treatment in patients under hormone therapy (Figure 2).

Although it has been introduced as a specific agent for prostate cancer, in recent years, incidental Ga-68 PSMA uptake has been reported in numerous benign and malign pathologies, except for prostate cancer. In patients diagnosed with prostate cancer, a secondary malignancy or benign events should be kept in mind in clinical interpretation when Ga-68 PSMA uptake is detected in atypical or unexpected localizations (72).

Although Ga-68 PSMA PET/CT is successful in showing occult lymph node metastases, <5 mm lymph nodes can be omitted with the partial volume effect under the PET resolution limit. Neuroendocrine differentiation was reported in prostate cancer as another cause of false negativity for Ga-68 PSMA PET/CT. In this group of patients, imaging with Ga-68 labeled DOTA peptides may be more appropriate (73,74,75,76,77).


C-11 Choline PET/CT

C-11 Choline is a PET agent that has been used for many years in prostate cancer, but there are many new studies reporting the superiority of Ga-68 PSMA PET/CT to C-11 Choline PET/CT in recurrent disease. While C-11 Choline seems to be advantageous because urinary excretion is less than that of Ga-68 PSMA, some lesions can be omitted because of its short half-life and need for imaging with short-term and rapid procedures. In addition, because it is a nonspecific agent compared to PSMA, numerous pathologies are known to cause false positivity (76,77).


F-18 Fluciclovin PET/CT

Anti-1-amino-3-F-18-fluorocyclobutane-1-carboxylic acid (Fluciclovin) is a synthetic amino acid analogue and is retained in prostate cancer through increased amino acid transport. It has been shown to be effective as a radiopharmaceutical in a large number of patients in prostate cancer and was approved by Food and Drug Administration (FDA) in 2016 for the re-staging of patients with PSA recurrence after primary treatment (78).

In a prospective clinical study comparing the role of Fluciclovin PET/CT, PET/MR and multiparametric MRI in the diagnosis of primary prostate cancer, it was shown that quantitative values obtained from Fluciclovin PET images were correlated with Gleason score but were not superior to multiparametric MR in detecting lesion. In this case, it was concluded that hybrid PET/MR images may be useful in prostate biopsies (79).

In a prospective study of 24 patients in whom biochemical response could not be obtained despite a primary treatment other than prostatectomy, the diagnostic power of Fluciclovin PET/CT was found to be significantly higher than multiparametric MRI (94.7% vs 31.6-36.8%). It was reported that this difference was particularly evident in the demonstration of extraprostatic disease, however, the sensitivity of Fluciclovin PET/CT for primary prostate tumor after treatment and the specificity of multiparametric MRI were higher (80).

In a prospective, multicentric study of the data of 213 patients, the efficacy of Fluciclovin PET/CT was investigated in the examination of biochemical recurrence after curative treatment, and in 57% of the patients, recurrence was shown in one or more foci with Flucyclovin PET/CT, and treatment approach was changed in 59% (81).

The most important advantage of Fluciclovin compared to other mentioned PET radiopharmaceuticals is that urinary excretion is significantly less. Thus, small foci present in the prostate bed and pelvic lymph nodes can be shown more easily. However, it has been reported that metastases in these areas may be omitted due to the relatively intense bone marrow and liver activity (78).

In a retrospective study demonstrating the efficacy of Fluciclovin PET/CT in 596 prostate cancer patients, it was reported as 41.4% even in patients with serum PSA levels <0.79 ng/mL. In a study comparing F-18 Fluciclovin PET/CT with Ga-68PSMA PET/CT in a small group of patients, Ga-68 PSMA PET/CT was positive in 7/10 patients, whereas Fluciclovin PET/CT was negative in 8/10 patients. While widespread disease could be demonstrated with Ga-68 PSMA PET/CT in 4/10 patients, it was reported that Fluciclovin PET/CT was negative in these patients (82).


Whole-Body Tc-99m MDP Bone Scintigraphy and 18F-NaF PET/CT

Tc-99m MDP and 18F-NaF are retained in bone lesions by binding to hydroxyapatite crystals. Although the mechanisms of retention are similar, Tc-99m MDP is a SPECT imaging agent used in conventional whole-body bone scintigraphy, and 18F-NaF is used as a positron spreading agent in PET/CT imaging. Generally, 18F-NaF is a more sensitive agent than Tc-99m MDP because of resolution superiority of PET imaging and its success in demonstrating both lytic and blastic lesions. However, because its relatively high cost, harder to obtain due to being a cyclotron product, and adequate and established success of Tc-99m MDP in demonstrating bone metastases in prostate cancer in the present protocols, 18F-NaF PET/CT is indicated only in suspected cases in this patient group. 18F-NaF PET/CT is most commonly used for imaging before Ra-223 treatment and for evaluating post-treatment response (83,84,85,86).


Testicular Tumors


18F-FDG PET/CT

In the diagnosis of primary testicular tumors, the disease can be diagnosed correctly primarily by ultrasound and then MRI in almost all patients (87,88). It has been shown that metabolic imaging provides more accurate results in studies comparing 18F-FDG PET to conventional CT for staging in patients with primary testicular tumors. The success of detecting radiologically normal sized metastatic lymph nodes was reported as 70%, and this could significantly change the treatment approach in this patient group (89). The sensitivity in seminomatous germ cell tumors (SGCT) is slightly better in comparison with nonseminomatous germ cell tumors (NSGCT) (90-92% vs 77-96%) (90).

In the presence of metastatic disease, residual masses may continue in 55-80% of patients after chemotherapy. In particular, 11-37% of the masses >3 cm can still have live tumor tissue in seminoma cases. Surgical interventions after chemotherapy may be challenging and morbid due to fibrosis. For this reason, it is important to distinguish between live tumor tissue and fibrosis before surgery. 18F-FDG PET/CT has been used for many years for this indication and there are studies in the literature about its role in postoperative follow-up of testicular tumors (91,92,93). In a meta-analysis, for this purpose, sensitivity was reported as 78%, specificity as 86%, and overall accuracy rate as 84% in SGCT. 18F-FDG PET/CT has been shown to be more successful in lesions greater than three centimeters (94). The success in predicting live tumor tissue decreases to 56% in NSGCT (95). Since residual masses may contain up to 40% mature teratoma in this patient group, necrosis-live tissue distinction may not be clearly performed with 18F-FDG PET/CT (96). Prospective, large-scale studies are needed to clarify the role of 18F-FDG PET/CT in NSGCT (Table 4).


18F-FLT PET/CT

The fact that 18F-FDG uptake is observed in false positive lesions in inflammatory lesions has led to the hypothesis that more accurate results can be obtained with other tumor-specific agents in the differentiation of live tumor-necrosis or fibrosis. In a small-scale study of 18F-FLT, a cell proliferation marker, its success in evaluating early response to treatment was investigated. Although false positivity rates could be reduced by 18F-FLT in this study, the presence of live tumor tissue in residual masses could not be ruled out with 18F-FLT, as negative predictive value was not high enough (97).


Conclusion

* 18F-FDG PET/CT in RCC is successful in staging in high-risk disease and demonstrating response to treatment in patients with metastatic disease. However, there is a need for further studies on routine use. Tc-99m MIBI SPECT/CT has high sensitivity and specificity in the malignant-benign differentiation of indeterminate renal masses.

* 18F-FDG PET/CT has a role in staging and re-staging of muscle-invasive bladder cancer, and can provide an idea about prognosis.

* Although not involved in the metabolic characterization of primary scrotal masses, 18F-FDG PET/CT is useful in the staging, restaging and follow-up of testicular tumors, especially in the evaluation of seminoma patients with a >3 cm residual retroperitoneal lesion after treatment. The role of imaging with F-18 and C-11 labeled other radiopharmaceuticals in order to reduce the rate of false negativity associated with physiological renal clearance of 18F-FDG has not yet been elucidated.

* Ga-68 PSMA PET/CT in prostate cancer has high sensitivity in every stage, especially in patients with biochemical recurrence and its use is becoming more common. In addition, conventional bone scintigraphy with Tc-99m MDP is still sufficient for imaging bone metastases. 18F-NaF PET/CT can be used as a more expensive but more sensitive alternative in selective cases, such as patients who are scheduled for treatment with Ra-223.


Ethics

Peer-review: Externally peer-reviewed.

Authorship Contributions

Concept: M.A., Y.Ü., Design: M.A., Y.Ü., Data Collection or Processing: M.A., Y.Ü., Analysis or Interpretation: M.A., Y.Ü., Literature Search: M.A., Y.Ü., Writing: M.A., Y.Ü.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

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