Tissue Differentiation and Diagnostic Accuracy of 99m Tc-PSMA and 99m Tc-MDP Bone Scans in Prostate Cancer Patients

doi:10.21203/rs.3.rs-3246740/v1

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Tissue Differentiation and Diagnostic Accuracy of 99m Tc-PSMA and 99m Tc-MDP Bone Scans in Prostate Cancer Patients

https://doi.org/10.21203/rs.3.rs-3246740/v1

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Purpose: Prostate cancer is currently the second most common cancer among men worldwide. Given the prevalence of this disease and the costs incurred by society in its diagnosis and treatment, awareness of diagnostic and therapeutic modalities and factors influencing their outcomes is of particular importance.

Methods: This prospective study aimed to investigate the diagnostic accuracy of ^99mTc- PSMA scan and ^99mTc-MDP Bone scan in 40 patients with prostate cancer and bone metastases. The study was conducted between 2020 and 2023, and the results were compared based on the tissue differentiation of cancerous tissues.

Results: The data analysis revealed that the diagnostic accuracy of ^99mTc- PSMA scan and ^99mTc-MDP Bone scan for grade groups 1-5 ranged from 95.4% to 100% and 95.4% to 100%, respectively. However, none of the results were statistically significant. Specifically, the ^99mTc- PSMA scan demonstrated diagnostic accuracy percentages of 100%, 98.7%, 96.1%, 96.6%, and 95.4%, respectively, for grade groups 1 to 5. Similarly, the diagnostic accuracy of ^99mTc-MDP Bone scan for grade groups 1 to 5 was 100%, 96.3%, 98.7%, 96.6%, and 95.4%, respectively.

Conclusion: The statistical analysis of the data suggests that tissue differentiation of prostate cancer does not impact the diagnostic accuracy of ^99mTc- PSMA scan and ^99mTc-MDP Bone scan. Moreover, the Gleason score of tissue samples did not affect the differentiation of cancerous tissues by the scans. Therefore, the findings suggest that ^99mTc- PSMA scan and ^99mTc-MDP Bone scan can provide accurate diagnostic results for prostate cancer patients with bone metastases, regardless of the tissue differentiation or Gleason score.

Prostate cancer

99mTc- PSMA scan

99mTc-MDP Bone scan

Tissue differentiation

Prostate cancer is currently the second most common cancer among men worldwide [1]. Although the rate of spread of this cancer varies in different regions of the world, studies show that about 30% of these patients, especially in developing countries, present with bone metastases[2]. Due to the progressive nature of the disease and the lack of financial resources in developing countries, extensive research has been carried out to find early and inexpensive methods for diagnosing this disease worldwide. These include using specific antigen combinations such as Prostate-Specific Antigen (PSA) and Digital Rectal Examination (DRE), or whole body scanning using radiopharmaceuticals such as gallium and technetium to detect metastases in symptomatic patients[3]. However, none of these methods are effective in detecting the spread of the disease alone, and they have not been able to surpass other methods as a single method.

Due to the cellular and biological nature of prostate cancer and the receptors that exist on the surface of prostate cancer cells, different types of scans are used to detect these cancers. Although many imaging modalities used in other scans are not applicable to prostate cancer, for example, fluorine-labeled deoxyglucose (18F-FDG PET) scan, which is used in the diagnosis of many cancers due to lack of absorption in the prostate bed, it can only be effective in detecting metastases, particularly bone metastases, which is not common in the clinic[4, 5]. Nowadays, some studies have shown that performing a full-body MRI in patients with prostate cancer and breast cancer to check for the presence of metastases can provide information equivalent to FDG PET CT scan. In situations where these scans are not available, it can be used as a substitute[6]. In some studies, it has been seen that MRI provides better anatomical information than nuclear scans[7], but lower value in comparison with PSMA PET/CT scan.

The most recent epidemiological studies conducted on this disease show that prostate cancer is more prevalent in African and American races. Additionally, this disease is more aggressive in these regions[8, 9]. This highlights the importance of using the best diagnostic methods with maximum efficiency, particularly in developing countries, where the prevalence of invasive cancers is high due to the lack of financial resources and diagnostic facilities [10-13]

Considering these shortcomings, in this study, we aimed to investigate and compare two scans - ^99mTc-PSMA scan and ^99mTc-MDP Bone scan. We also aimed to evaluate the effect of differentiation of cancer tissue samples in these patients on the diagnostic accuracy of these scans.

In this prospective study conducted between 2020 and 2023, we examined and studied 51 patients with prostate cancer whose disease was diagnosed using tests and paraclinical methods. Patients with at least one of the following indications were included in the study after providing full explanations and ensuring the availability of scans:

High alkaline phosphatase levels (more than 180 ng/ml in this study)
Presence of bone pain
Stage T2c and above
PSA>20 + Stage T1
Stage T2+ PSA > 10
Gleason score of 8 to 10.

Patients who did not consent to the scans, had received radiopharmaceuticals within 10 days before the study, or had a history of sensitivity to radiopharmaceuticals were excluded from the study. Eleven patients willing to participate in the study did not meet the inclusion criteria and were excluded, leaving a total of 40 patients who were included in the study.

At first, questionnaires containing demographic information, PSA level, Gleason score of the pathological sample obtained from the prostate biopsy, and results of routine tests were completed. Then, The Alborz Engineering Research Center of Molecular Imaging Probes supplied a lyophilized kit for PSMA. Before each use, a bottle of lyophilized reagent was chosen and dissolved by adding 4 mL 0.9% NaCl solution, followed by approximately 5 mL 3.7–4.44 GBq 99mTcO-4 solution. The mixture was heated in a 100 °C water bath for 10 min and analyzed for radiochemical purity (RCP) using high-performance liquid chromatography (HPLC) on an Agilent 1200 system. The ^99mTc-PSMA was rejected if the RCP was less than 95%. The ^99mTc-MDP was obtained from Guangdong CI Pharmaceutical Co., LTD. Fuzhou Branch and underwent quality control (QC) by the manufacturer.

For the ^99mTc-PSMA scan, all patients received an intravenous injection of 0.74 GBq (20 mCi) ^99mTc-PSMA. Whole-body planar imaging SPECT/CT was performed 2 h after injection on a Discovery NM/CT 670Pro (GE, USA) with low energy high-resolution collimators. The imaging protocol included planar imaging with a peak energy of 140 keV (99mTc) and scan velocity of 15 cm/min in a 1025 × 256 matrix, and regional SPECT/CT with a camera matrix size of 128 × 128, zoom 1.0, rotation 360°, and 30s/frame for a total of 60 frames. Low-dose CT (130 keV; 60 mAs) was used for CT.

For the 99mTc-MDP scan, a dose of 0.74 GBq (20 mCi) ^99mTc-MDP was injected intravenously, and imaging was performed 3 to 5 h later. The imaging instrument and acquisition protocol were the same as those used for the ^99mTc-PSMA scan.

Image processing was performed on workstations (Xeleris, General Electric, Waukesha, WI). All images were anonymized and interpreted by 3 senior nuclear medicine physicians and 3 senior radiologists. On SPECT/CT, areas with higher imaging agent uptake than normal tissue after excluding physiological uptake and traumatic fracture were considered “imaging positive bone lesions”. Areas with abnormal SPECT/CT findings but no imaging agent uptake on the corresponding site of SPECT were considered negative lesions.

.To facilitate statistical analysis, the whole body was divided into 11 zones:

Zone 1: Skull
Zone 2: Clavicle
Zone 3: Sternum
Zone 4: Thorax including the ribs
Zone 5: Scapula
Zone 6: Forearm, wrist, and fingers of the upper limb
Zone 7: Humerus
Zone 8: Vertebral column, sacrum, and pelvis
Zone 9: Femur
Zone 10: Knee
Zone 11: Tibia, fibula, and ankle of the lower limb

A total of 440 regions (40 patients × 11 regions = 440 regions) were investigated and analyzed statistically.

Statistical analysis was performed using SPSS version 25.0. The sensitivity, specificity, and accuracy of both imaging modalities were calculated and compared using the McNemar test. The diagnostic performance of each imaging modality was assessed using receiver operating characteristic (ROC) curves. A p-value less than 0.05 was considered statistically significant.

In the analysis of the results of this study, a total of 3 patients had Gleason score 3 + 3 = 6 (GG = 1), 15 patients had Gleason score 3 + 4 = 7 (GG = 2), 7 patients had Gleason score 4 + 3 = 7 (GG = 3), 11 patients had Gleason score 4 + 4 = 8 (GG = 4), 2 patients had Gleason score 4 + 5 = 9, and 2 patients had Gleason score 5 + 5 = 10 (GG = 5).

In the GG = 1 group, the diagnostic accuracy was 100% for both scans, and no false positives or false negatives were observed.

In the GG = 2 group, the diagnostic accuracy of ^99mTc-PSMA scan was 98.7%, and the diagnostic accuracy of ^99mTc-MDP Bone scan was 96.3%. This difference was not statistically significant (P = 0.12).

In the GG = 3 group, the diagnostic accuracy of ^99mTc-PSMA scan was 96.1%, and the diagnostic accuracy of ^99mTc-MDP Bone scan was 98.7%. This difference was not statistically significant (P = 0.19).

In the GG = 4 group, the diagnostic accuracy of ^99mTc-PSMA scan was 96.6%, and the diagnostic accuracy of ^99mTc-MDP Bone scan was also 96.6%. The two groups were completely equal.

In the GG = 5 group, the diagnostic accuracy of ^99mTc-PSMA scan and ^99mTc-MDP Bone scan was 95.4%, and the two groups were completely equal.

Table 1 summarizes the findings.

Table 1

Scans Findings in details
GG = 1	Scan type	The results of the scans	The results of the scans separately
	^99mTc-PSMA SCAN The number of 3 patients and a total of 33 areas	0 positive areas	0 true positive areas [0%]
			0 false positive areas [0%]
		33 negative areas	33 true negative areas [100%]
			0 false negative areas [0%]
	^99mTc-MDP SCAN The number of 3 patients and a total of 33 areas	0 positive areas	0 true positive areas [0%]
			0 false negative areas [0%]
		33 negative areas	33 true negative areas [100%]
			0 false positive areas [0%]
GG = 2
	^99mTc-PSMA SCAN The number of 15 patients and a total of 165 areas	18 positive areas	18 true positive areas [10.9%]
			0 false positive areas [0%]
		147 negative areas	145 true negative areas [87.9%]
			2 false negative areas [1.2%]
	^99mTc-MDP SCAN The number of 15 patients and a total of 165 areas	22 positive areas	18 true positive areas [10.9%]
			4 false positive areas [2.4%]
		143 negative areas	141 true negative areas [85.5%]
			2 false negative areas [1.2%]
GG = 3
	^99mTc-PSMA SCAN The number of 7 patients and a total of 77 areas	12 positive areas	10 true positive areas [12.9%]
			2 false positive areas [2.6%]
		65 negative areas	64 true negative areas [83.2%]
			1 false negative areas [1.3%]
	^99mTc-MDP SCAN The number of 7 patients and a total of 77 areas	9 positive areas	9 true positive areas [11.7%]
			0 false positive areas [0%]
		68 negative areas	67 true negative areas [87%]
			1 false negative areas [1.3%]
GG = 4
	^99mTc-PSMA SCAN The number of 11 patients and a total of 121 areas	21 positive areas	17 true positive areas [14%]
			4 false positive areas [3.3%]
		100 negative areas	100 true negative areas [82.7%]
			0 false negative areas [0%]
	^99mTc-MDP SCAN The number of 11 patients and a total of 121 areas	19 positive areas	16 true positive areas [13.2%]
			3 false positive areas [2.4%]
		102 negative areas	101 true negative areas [83.4%]
			1 false negative areas [1.2%]
GG = 5
	^99mTc-PSMA SCAN The number of 4 patients and a total of 44 areas	13 positive areas	11 true positive areas [25%]
			2 false positive areas [4.4%]
		31 negative areas	31 true negative areas [70.6%]
			0 false negative areas [0%]
	^99mTc-MDP SCAN The number of 4 patients and a total of 44 areas	11 positive areas	10 true positive areas [22.8%]
			1 false positive areas [2.2%]
		33 negative areas	32 true negative areas [72.8%]

Given the increasing prevalence of prostate cancer and the exorbitant costs associated with its diagnosis and treatment, it is crucial to use the fastest, most accurate, and cost-effective methods of diagnosis and treatment. In Minamimoto's study, the researchers investigated and compared the power of detecting metastases with various scintigraphy methods. They concluded that some radiological imaging can be as accurate as scans in detecting non-metastases from prostate and breast cancer[6]. Similarly, Gutzeit and colleagues found that MRI has the same accuracy as nuclear scans but provides more detailed anatomical information [7].

In a study conducted by Wang and colleagues to investigate the detection power of ^99mTc-PSMA, they showed that combining the scan result with the PSA level and Gleason score of the pathology sample increases the sensitivity of this scan to 92%[14]. In Nepal's study, which investigated the accuracy of diagnostic modalities and prostate volume, it was found that biopsy accuracy is lower in larger prostate volumes than in lower volumes [15].

Abdollah and colleagues investigated the relationship between MRI results, biopsy results, and tissue differentiation levels. They found that imaging results can greatly influence the selection of patients for biopsy and the reliability of clinical decisions [16].

In cancers with a higher Gleason score, the tissue differentiation rate is lower, and cancer cells grow and multiply at a faster rate. Furthermore, the higher expression of the PSMA gene in cancer cells with higher Gleason scores indicates that these cells are more metabolically active and absorb more radiotracer. This naturally increases the diagnostic accuracy of the scan. However, due to the lack of a similar study, we investigated the validity of this hypothesis.

Our study was designed to investigate this question. We found that the diagnostic accuracy of both the ^99mTc-PSMA scan and ^99mTc-MDP Bone scan in low-grade groups is around 100%, while in high-grade groups, it is around 96%. This difference was not statistically significant, partially rejecting the hypothesis. Therefore, from the analysis of statistical data, it can be concluded that the reduction of tissue differentiation in prostate cancer does not significantly affect the results of scans.

Considering the costs of using PSMA PET CT scan and MRI and the complications of gadolinium injection, such as systemic nephrogenic fibrosis, and the fact that MRI examinations are limited to certain areas of the body, the use of scans such as ^99mTc-PSMA and ^99mTc-MDP Bone scan is more economical. If only one diagnostic modality is considered, the use of PSMA is a more preferable and cost-effective method, considering its role in therapeutic procedures such as lutein therapy.

The limitations of prostate cancer detection in developing countries are multifactorial and complex. Therefore, efforts should be made to increase access to screening and diagnostic tools, improve healthcare infrastructure and public education, and increase awareness about prostate cancer among the general population. Addressing these challenges will be critical in reducing the burden of prostate cancer in developing countries.

Due to the limitation of this study including the small sample size, Further studies with more samples and using PSMA PET CT scan may be necessary to investigate the hypothesis of the effect of tissue differentiation on the accuracy of scans.

In conclusion, given the progressive progress in diagnostic methods for cancers, especially prostate cancer, and the heavy costs of these diagnostic modalities on society, it is vital for physicians to understand the factors that affect the results of these modalities. This knowledge can help avoid unnecessary paraclinical measures for patients.

Statements & Declarations:

Funding:

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript

Competing Interests:

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions:

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Farshad Banouei. The first draft of the manuscript was written by Farshad Banouei.

Data Availability:

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval:

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Hamedan University of Medical Sciences in Iran (Date: 2021/05/08/No: IR.UMSHA.REC.1400.284)

Consent to participate:

Written informed consent was obtained from the parents

Consent to publish:

The authors affirm that human research participants provided informed consent for publication of all data.

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No competing interests reported.

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Tissue Differentiation and Diagnostic Accuracy of 99m Tc-PSMA and 99m Tc-MDP Bone Scans in Prostate Cancer Patients

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