Clinical value of combined ¹⁸F-FDG and ¹⁸F-P3BZA imaging in the diagnosis of melanoma

Abstract

Objective:

This study aims to explore the clinical value of the combination of ¹⁸F fluorodeoxyglucose (¹⁸F-FDG) and N-[2-(dimethylamino) ethyl]-¹⁸F-5-fluoropicolinamide (¹⁸F-P3BZA) positron emission tomography/computed tomography (PET/CT) in melanoma patients.

Methods:

A retrospective study was conducted on 19 melanoma patients who underwent ¹⁸F-FDG and ¹⁸F-P3BZA PET/CT scans at the Nuclear Medicine Department/PET Imaging Center of the Second Xiangya Hospital, Central South University, from March 2022 to March 2024. The diagnostic efficacy of ¹⁸F-FDG, ¹⁸F-P3BZA, and the combination of both for melanoma was compared, and the value of combined imaging for TNM staging and clinical treatment decision-making in melanoma patients was discussed.

Results:

The sensitivity of ¹⁸F-P3BZA in diagnosing primary lesions of melanoma, all metastases, sentinel lymph node metastases (SLNM), distant lymph node metastases (DLNM), and bone metastases (BM) was 100% (12/12), 71.4% (40/56), 72.4% (21/29), 66.7% (14/21), and 83.3% (5/6), respectively. The corresponding values for ¹⁸F-FDG were 91.7% (11/12), 91.1% (51/56), 86.2% (25/29), 95.2% (20/21), and 100% (6/6), respectively. Combined imaging showed a higher sensitivity in diagnosing SLNM, DLNM, and all metastases than ¹⁸F-P3BZA (χ² = 7.105, p = 0.004; χ² = 3.860，p = 0.045; χ² = 15.604; p < 0.001). In addition, the specificity of ¹⁸F-FDG in diagnosing all metastases, SLNM, DLNM, and BM, was 50.0, 69.2, 56.3, and 100%, respectively, and the corresponding values for ¹⁸F-P3BZA were 81.8, 100, 75.0, and 100%, respectively. Combined imaging improved N and M staging in 31.6% (6/19) of melanoma patients and changed clinical treatment decisions in 26.3% (5/19) of melanoma patients.

Conclusion:

The specificity of ¹⁸F-FDG alone in diagnosing melanoma is low, but it can be combined effectively with ¹⁸F-P3BZA. The combination of ¹⁸F-FDG and ¹⁸F-P3BZA PET/CT can further improve the detection efficiency of lesions, TNM staging, and clinical treatment decisions.

Introduction

Melanoma is one of the most aggressive types of cancer, and its incidence continues to rise globally (1). It usually occurs on the skin of the extremities, with its incidence peaking at the age of 65 years; however, it can affect individuals of any age (2). The American Joint Committee on Cancer (AJCC) points out that the 5-year survival rate for early-stage patients after surgery is higher than 95% and that the incidence of distant metastasis is less than 10% (3, 4).

The diagnosis of skin melanoma is performed through physical examination and local biopsy by clinical physicians, whereas for its clinical staging and treatment evaluation, imaging methods are required. However, on the one hand, conventional imaging generally provides morphological information but has low specificity; on the other hand, due to its single-site imaging, its staging value is relatively low (5, 6).

Positron emission tomography/computed tomography (PET/CT) has been widely used for staging, post-treatment restaging, and evaluating the efficacy of various solid malignant tumors in humans (7–10). ¹⁸F fluorodeoxyglucose (¹⁸F-FDG) PET/CT has changed the diagnostic approach of melanoma and has become the most clinically valuable method for clinical staging and follow-up treatment of melanoma (1, 11, 12). However, ¹⁸F-FDG has some limitations, primarily due to its low specificity. In addition, the high uptake of brain tissue during ¹⁸F-FDG PET/CT imaging may affect the detection of brain metastases (13, 14).

In recent years, various novel molecular probes for melanoma have been developed, including benzamide (BZA) and its derivatives, antibodies, receptors, very late antigen-4 (VLA-4), and metabolic glutamate receptor-1 (mGluR1) (1, 15–19). Among these, BZA derivatives have been the most extensively investigated. Due to the presence of melanin in more than 90% of melanoma cells, targeting melanoma lesions by targeting melanin is theoretically possible. BZA derivatives are polycyclic aromatic compounds and can specifically bind to melanin in cells (20, 21). Therefore, melanoma lesions can be targeted by labeling BZA derivatives with radioactive isotopes.

In 2013, Liu et al. (22) designed and synthesized several ¹⁸F-labeled BZA analogs as positron probes for targeting melanoma lesions in B16F10 tumor-bearing mice. They found that N-[2-(dimethylamino) ethyl]-¹⁸F-5-fluoropicolinamide (¹⁸F-P3BZA) had a highly specific melanin-binding ability and the highest target-to-background uptake ratio. In 2019, Ma et al. (23) utilized ¹⁸F-P3BZA PET/CT for the diagnosis of melanoma and found that its imaging effect was superior to that of ¹⁸F-FDG PET/CT. This finding confirms that ¹⁸F-P3BZA has the potential for clinical application. However, this study included only five cases of melanoma and did not analyze the detection rate of the lesions, let alone clarify their exact clinical application value.

The present study included 19 patients with melanoma and compared the clinical application value of ¹⁸F-P3BZA PET/CT, ¹⁸F-FDG PET/CT, and the combination of both. This study adhered to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Xiangya Second Hospital, Central South University (ethics approval number: 2021–165). All participants provided their signed informed consent.

Patients and methods

Patients

We conducted a retrospective analysis of melanoma patients who underwent ¹⁸F-FDG and ¹⁸F-P3BZA PET/CT scans at the Nuclear Medicine Department/PET Imaging Center of the Second Xiangya Hospital, Central South University, from March 2022 to March 2024. Clinical data and PET/CT scan data of the patients were collected, and it was ensured that the interval between two PET/CT scans did not exceed 7 days.

Inclusion criteria were as follows: (1) those diagnosed with melanoma by pathological findings; (2) those with access to clinical and pathological data; (3) those who accepted to undergo ¹⁸F-FDG and ¹⁸F-P3BZA PET/CT scans with good image quality; and (4) those with complete follow-up information.

Exclusion criteria were as follows: (1) those who had incomplete clinical data or were lost to follow-up; (2) having other malignant tumors or serious systemic diseases; and (3) those with contraindications for radionuclide scanning.

Based on these criteria, 19 patients were included in this study.

Synthesis and quality control of ¹⁸F-P3BZA and ¹⁸F-FDG

¹⁸F-P3BZA: ¹⁸F-P3BZA was generated using a cyclotron at the Nuclear Medicine Department/PET Imaging Center of the Second Xiangya Hospital, Central South University (Siemens, Germany). ¹⁸F-P3BZA was synthesized using the AllInOne™ synthesizer (TRASIS, Belgium) based on previous research methods (23). Both the radiochemical purity and labeling rate of ¹⁸F-P3BZA were higher than 95%.

¹⁸F-FDG: ¹⁸F-FDG was synthesized using the Explora FDG4 and Explora GN chemical synthesis modules, and its radiochemical purity and labeling rate were both higher than 95%.

For PET/CT, uMI780 PET/CT (Shanghai United Imaging Healthcare Co., Ltd.) was used.

¹⁸F-FDG PET/CT image acquisition

The ¹⁸F-FDG injection was administered at a dosage of 3.5 MBq/kg. Before administering the injection, patients were asked to fast for at least 6 h, and it was ensured that their blood sugar level did not exceed 11.1 mmol/L. Patients were subjected to scanning 60 min after injection, with the scan area being from the top of the skull to the sole of the plantar. First, CT and PET scans of the body (neck to the plantar) were performed with the following parameters: voltage: 120 kV; radiation dose: 120 mAs; matrix: 600 × 600; and layer thickness: 3.75 mm. PET acquisition was performed in 3D, with a speed of 2 min per bed for a total of 5–9 beds. Then, separate head CT and PET acquisitions were performed, with a head PET acquisition speed of 2 min per bed for one bed. The collected data were reconstructed using iterative methods and transferred to an MMWP image post-processing workstation.

¹⁸F-P3BZA PET/CT image acquisition

The ¹⁸F-P3BZA injection was administered at a dosage of 2.5 MBq/kg (lower than Ma et al.’s study dose for radiation safety issues), and scanning was performed 60 min after the injection (our team’s previous research confirmed the highest target background uptake ratio at 60 min). Patients were instructed to drink approximately 200–500 mL of water 10 min before scanning to dilute and excrete the radioactive accumulation of ¹⁸F-P3BZA in the stomach. The scanning range was from the top of the skull to the plantar, and the patients were asked to remain stationary on the examination bed throughout the entire process. First, a low-dose CT scan was performed with the following parameters: voltage: 120 kV; radiation dose: 120 mAs; matrix: 600 × 600; and layer thickness: 3.75 mm. Then, another PET scan was performed, with 3D PET acquisition at a speed of 2 min per bed for a total of 6–10 beds. The collected data were iteratively reconstructed to obtain whole-body CT images, PET images, and PET/CT fusion images. Then, the reconstructed data were transferred to the MMWP image post-processing workstation.

Image analysis

Two senior nuclear medicine physicians who were involved in PET/CT diagnosis jointly reviewed the PET/CT images. In case of disagreement, the final decision was made through mutual consultation and agreement between the two physicians. The images were primarily analyzed using visual and quantitative methods.

¹⁸F-FDG pet/CT

Visual analysis: Except for lesions in the brain and kidneys, any lesions characterized by localized skin thickening, nodules, or masses, along with an increased radioactive uptake or significantly higher radioactive uptake compared with the surrounding normal tissues, were considered primary lesions. For a lymph node (LN) in the drainage pathway of the melanoma, if its volume or radioactive uptake was found to increase, it was considered a metastasis. If there was a bone change on the whole-body scan with increased local radioactive uptake, it was considered a bone metastasis (BM).

Quantitative analysis: For a primary lesion, in addition to monitoring its morphological changes, if its maximum standardized uptake value (SUVmax) was higher than 2.5, it was considered a primary melanoma lesion (24, 25). For an LN in the drainage pathway of the melanoma, if the short diameter was higher than 10 mm or its SUVmax was higher than 2.5, it was considered a metastasis. If there was a change in bone density or the SUVmax was higher than 2.5 in the whole-body scan, it was considered a BM.

¹⁸F-P3BZA pet/CT

Visual analysis: In ¹⁸F-P3BZA PET/CT images, except for lesions in the kidneys, liver, gallbladder, spleen, and stomach, any lesions characterized by local skin thickening, nodules, or masses, along with an increased radioactive uptake or significantly higher radioactive uptake than the surrounding normal tissues, were considered primary lesions. If the volume or radioactive uptake of an LN in the drainage pathway of the melanoma was found to increase, it was considered a metastasis. If a bone change was observed on the whole-body scan along with increased local radioactive uptake, it was considered a BM.

Quantitative analysis: If the SUVmax of a primary lesion was higher than 2.5, in addition to showing morphological changes, it was considered a primary melanoma lesion. If the short diameter of an LN in the drainage pathway of the melanoma was higher than 10 mm or its SUVmax was higher than 2.5, it was considered a metastasis. If a change in bone density was observed on the whole-body scan and the SUVmax was higher than 2.5, it was considered a BM.

Clinical TNM staging of melanoma patients was recommended according to the latest AJCC guidelines (26).

Follow-up

For each patient, follow-up began at the end of their scan and continued for at least 1 month. Among the 19 melanoma patients, 12 were newly diagnosed, while 7 received postoperative care after their surgery. All primary lesions were validated using pathological results. Metastases were validated through histopathological, clinical, and imaging follow-up (including ultrasound, CT, MRI, and PET/CT) results. If a lesion was found to be significantly enlarged or had a significantly increased metabolism during follow-up, or if a lesion was found to be significantly shrunken or had a significantly decreased metabolism after drug treatment, it was considered a metastasis.

Statistical analysis

The diagnostic consistency between two nuclear medicine physicians was evaluated using the Kappa test. IBS SPSS 26.0 and Origin 2023 were used for statistical analysis and image plotting. Count data were expressed as mean ± standard deviation (x ± s), frequency, and percentage (%). In addition, the t-test was performed to compare the differences in semi-quantitative parameters between ¹⁸F-FDG and ¹⁸F-P3BZA, and the Chi-squared test was utilized to compare the differences in diagnostic efficacy between ¹⁸F-FDG, ¹⁸F-P3BZA, and combined imaging. A p-value of less than 0.05 was considered statistically significant.

Results

Study population

Of the 19 melanoma patients, 12 were initially diagnosed, and 7 underwent postoperative follow-up. Partial clinical data and PET/CT scan results of the 19 patients are presented in Table 1.

Distribution of ¹⁸F-P3BZA in melanoma patients

The distribution of ¹⁸F-P3BZA in important organs and tissues of 19 patients with melanoma is presented in Table 2.

¹⁸F-P3BZA PET/CT scan results

¹⁸F-P3BZA PET/CT detected primary lesions in all newly diagnosed patients (100%, 12/12). The SUVmax of 12 primary tumors was 9.5 ± 9.1, with 10 cases of cutaneous melanoma having an SUVmax of 5.6 ± 3.3 (Figures 1A–D) and 2 cases of ocular melanoma having an SUVmax of 33.4 and 16.8 (Figures 1E–H). No abnormalities were observed at the surgical site in seven postoperative follow-up patients.

Figure 1

As shown in Table 3, ¹⁸F-P3BZA PET/CT detected 40 metastases. The SUVmax and SUVmean of all metastases were 12.3 ± 10.0 and 6.8 ± 4.1, respectively. The SUVmax of LNM was 11.7 ± 9.4, and that of BM was 8.4 ± 3.0.

¹⁸F-FDG PET/CT scan results

Of the 12 newly diagnosed patients, ¹⁸F-FDG PET/CT detected primary lesions in 11 patients (91.7%, 11/12). No statistically significant difference in sensitivity was observed between ¹⁸F-FDG and ¹⁸F-P3BZA (100% vs. 91.7%, χ² = 1.043, p = 1). The SUVmax of 12 primary tumors was 8.1 ± 5.3, with no statistically significant difference between ¹⁸F-FDG and ¹⁸F-P3BZA (t = 0.501, p = 0.630). In addition, the SUVmax of 10 cases of skin melanoma was 5.6 ± 3.3, and the SUVmax of two cases of ocular melanoma were 3.8 and 8.3. A patient with melanoma of the plantar after surgery presented with false-positive results (mild uptake of ¹⁸F-FDG).

As shown in Table 4, ¹⁸F-FDG PET/CT detected 51 metastases. The detection rate of ¹⁸F-FDG in the diagnosis of DLNM was higher than that of ¹⁸F-P3BZA (p = 0.045). The SUVmax of all metastases was 14.2 ± 7.2. In addition, the SUVmax values for LNM and BM were 15.5 ± 6.4 and 9.3 ± 3.3, respectively. No statistically significant difference in SUVmax was observed between ¹⁸F-FDG and ¹⁸F-P3BZA (t = 0.877, p = 0.410).

Combined imaging scan results

Combined imaging detected primary lesions in all newly diagnosed patients (100%, 12/12) (Figures 2, 3 A). No statistically significant difference in the detection rate was observed between combined imaging, ¹⁸F-FDG, and ¹⁸F-P3BZA (χ² = 2.057, p = 0.358).

Figure 2

Figure 3

As shown in Table 5, combined imaging detected 55 metastases. The sensitivity of combined imaging in the diagnosis of SLNM, DLNM, and all metastases was higher than that of ¹⁸F-P3BZA (χ² = 7.105, p = 0.004; χ² = 3.860, p = 0.045; χ² = 15.604, p < 0.001).

For all three imaging methods, the diagnostic consistency between two nuclear medicine physicians was good (¹⁸F-P3BZA: Kappa = 0.762, p < 0.001; ¹⁸F-FDG: Kappa = 0.877, p < 0.001; combined imaging: Kappa = 0.825, p < 0.001).

Combined imaging improved N and M staging in 31.6% (6/19) of melanoma patients. In addition, it changed the clinical treatment decisions in 26.3% (5/19) of patients (Figure 4; Table 6).

Figure 4

Discussion

The ¹⁸F-P3BZA used in this study is a derivative of BZA. One hour after injection, ¹⁸F-P3BZA was mainly distributed in the melanoma lesions of the patients, showing a strong melanin-targeting ability. In addition, the probe showed varying degrees of physiological distribution in the stomach, liver, gallbladder, spleen, and eyes of the patients.

Both the primary lesions and metastases showed a high tumor-to-muscle uptake ratio 60 min after ¹⁸F-P3BZA injection. The SUVmax of the primary lesion in the eye reached 36.5 ± 19.7. Ma et al. (23) performed ¹⁸F-P3BZA PET/CT scans on five melanoma patients, and the results showed that the SUVmax values of their primary lesions and metastases were 19.7 ± 5.3 and 18.2 ± 3.7, respectively. Consistent with the results of this study, our findings indicate that ¹⁸F-P3BZA can specifically bind to melanin in vivo, thereby clearly displaying melanoma lesions.

Although ¹⁸F-P3BZA PET/CT detected all primary lesions (12/12, 100%), its performance in detecting metastases was unsatisfactory, particularly in detecting LNM (70.0%, 35/50), especially DLNM (66.7%, 14/21). This may not be related to the size of the metastases (this study shows that many small LNM also significantly uptake ¹⁸F-P3BZA) but may be related to the level of melanin in the metastases. In a study on Bomirski hamster melanoma cells, Saud et al. (20) showed that tumor cells exhibit a significantly reduced ability to produce melanin after each generation. Therefore, the insufficient uptake of ¹⁸F-P3BZA by metastases (especially by DLNM) in the present study may be attributed to a significant decrease in their ability to produce melanin. In addition, we speculate that the synthesis and transport process of melanin requires the participation of multiple enzymes, and the synthesis of these enzymes requires a certain amount of time (27). This leads to a slower increase in melanin levels in metastases (insufficient uptake of ¹⁸F-P3BZA).

This study showed that the sensitivity, specificity, PPV, and NPV of ¹⁸F-P3BZA combined with ¹⁸F-FDG PET/CT in detecting primary lesions were all 100%. Moreover, only one metastasis was missed with the combined imaging, with a sensitivity of 98.2%. It showed significantly lower false-positive and false-negative rates than ¹⁸F-FDG and ¹⁸F-P3BZA, respectively. In addition, accurate diagnosis of N and M staging is crucial for the clinical management of patients (28). In the present study, combined imaging improved N and M staging in 31.6% (6/19) of patients, and as a result, treatment plans were changed in 26.3% (5/19) of patients. This change is quite helpful for clinical practice as unnecessary or incorrect treatment can be prevented to some extent. Although there was no statistically significant difference in diagnostic efficacy between combined imaging and ¹⁸F-FDG alone, the former showed improved final diagnostic results and clinical treatment decisions. However, combined imaging is not suitable for all melanoma patients.

In addition, our PET/CT system is different from the long axial field of view (LAFOV) PET/CT system, which allows for the injection of two tracers on the same day or even simultaneously (29). Although LAFOV PET/CT is currently applied only in a few centers worldwide, this innovative imaging system will soon become available in numerous institutions. Compared to traditional PET/CT systems, LAFOV PET/CT has many advantages in detecting both tumor and non-tumor diseases (30, 31). For instance, using LAFOV, PET/CT PET/CT examinations can be completed on the same day, which can reduce the burden on patients; its higher image quality and optimized lesion quantification can increase lesion detectability; it has low radiation exposure and short collection time; it does not require CT attenuation correction (significantly reducing radiation exposure); and whole-body dynamic imaging can provide more information.

Due to the limitations of using ¹⁸F-FDG PET/CT for the diagnosis of melanoma in clinical practice, the addition of ¹⁸F-P3BZA PET/CT as a melanin-specific positron tracer can provide more information for diagnosis. Therefore, this study proposes the following indications for using a combination of ¹⁸F-FDG and ¹⁸F-P3BZA PET/CT scanning: (1) the primary lesion or metastasis is located in the brain; (2) conventional ¹⁸F-FDG PET/CT cannot determine the presence of LNM; (3) there is interference from inflammation in the surgical area; and (4) conventional ¹⁸F-FDG PET/CT scan is negative although clinical suspicion of melanoma is high.

The findings of this study show that the combination of ¹⁸F-FDG and ¹⁸F-P3BZA PET/CT imaging can be effective in diagnosing melanoma, guiding TNM staging, and informing clinical treatment decisions. This can enhance physicians’ confidence in managing melanoma and may indirectly improve patients’ prognosis.

This study has some limitations: (1) the number of patients included in this study is relatively small, and further validation of the findings with a large sample size is needed in the future. In addition, melanoma in the skin and other areas was not been analyzed separately; (2) some patients underwent surgery and medication before the PET/CT scanning, which may have affected the semiquantitative parameters of PET; and (3) this study did not quantitatively analyze melanin in melanoma lesions and investigate its correlation with PET metabolic parameters.

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