68Ga–Prostate-Specific Membrane Antigen PET/CT in Ovarian Tumors: Potential to Differentiate Benign and Malignant Tumors Before Surgery: A Preliminary Report : Clinical Nuclear Medicine

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68Ga–Prostate-Specific Membrane Antigen PET/CT in Ovarian Tumors

Potential to Differentiate Benign and Malignant Tumors Before Surgery: A Preliminary Report

Kunikowska, Jolanta; Bizoń, Magdalena; Pełka, Kacper∗,‡; Derlatka, Paweł§; Olszewski, Maciej; Królicki, Leszek

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Clinical Nuclear Medicine 48(2):p e60-e66, February 2023. | DOI: 10.1097/RLU.0000000000004486
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Abstract

Ovarian cancer is usually detected in an advanced stage. That complicates further treatment and can shorten the time of recurrence. Nowadays, new markers for early detection of ovarian cancer are still being sought. However, there is no progress in that area.

Suspicion of ovarian cancer is based on the presence of an ovarian or pelvic tumor with or without clinical symptoms. According to the classification created by the International Ovarian Tumor Analysis (IOTA) group, assessment of malignancy of the tumor is possible. Special algorithms such as the simple rules of the IOTA or ADNEX model can be used.1 The sensitivity and specificity of transvaginal ultrasound are 86% to 94% and 94% to 96%, respectively.2,3 Ultrasound is not a sufficient method to differentiate between the types of ovarian tumors.

The CA-125 level used to assess the risk of ovarian cancer diagnosis is not specific.3 The reference range of CA-125 was associated with 50% of early-stage cases of ovarian cancer.4 Especially, it is elevated in approximately 80% of cases of epithelial ovarian cancer in advanced stages.5

Zhang and Zhang6 stated that sensitivity of the use of a combination of serum markers and transvaginal ultrasound with color Doppler in suspicion of ovarian cancer was calculated as 90.6%, and specificity 97.1%. The positive predictive value was assessed as 93.9%, negative as 98.6%.6 Even transvaginal ultrasound could identify primary tumors, but without providing information about suspicion of metastases.

The outcome of a surgical procedure is clinically the most important question. In ovarian cancer, it is usually classified according to the amount of postoperative residual tumor. A resection is regarded as complete if no macroscopically visible tumor is left. If any visible lesion remains after surgery, it is classified according to its largest diameter. Operations that ended with residuals of up to 10 mm in the largest diameter were formerly classified as optimal debulking, whereas those resulting in any larger residual tumor were defined as suboptimal debulking.7,8

According to the European Society of Gynecological Oncology consensus, a midline laparotomy is required for treatment of stage III to IV ovarian cancer (expert consensus). The aim of the surgical procedure is to completely excise all visible disease. Voluntary use of incomplete surgery (in advance or at an interval) is discouraged.9,10 In patients disqualified from primary cytoreduction, exploratory laparoscopy is recommenced to establish the diagnosis, followed by neoadjuvant chemotherapy.10

For presurgery staging, the European Society of Gynecological Oncology recommends obligatory CT scan of the chest and abdominal cavity.9,10 Prior knowledge of the stage and grade of disease allows for better assignment to surgical treatment or neoadjuvant chemotherapy. CT in some cases is not able to indicate very small and diffuse peritoneal implants or bowel wall or mesentery infiltrations. In pretreatment diagnosis of ovarian cancer, MRI or 18F-FDG PET/CT can yield more information than CT.10,11

Nam et al12 and Kitajima et al13 compared CT scan with 18F-FDG PET/CT of ovarian tumors suspected of cancer in preoperative assessment and revealed higher sensitivity of 18F-FDG PET/CT than CT scan (69.4% vs 37.6%). It is due to the increased metabolism of glucose in carcinomatosis cells in comparison with healthy ones. That aspect of 18F-FDG PET/CT was used in the case of recurrent ovarian cancer.14 Unfortunately, there is no reimbursement for 18F-FDG PET/CT scan in diagnosis of primary ovarian cancer in Poland.

Prostate-specific membrane antigen (PSMA) is a highly restricted prostate epithelial cell membrane glycoprotein of approximately 100 kDa. It showed strong immunohistochemical reactivity to prostate epithelia of prostate cancer.15 A frequently used molecule is PSMA-11 labeled with gallium-68, that is, 68Ga-PSMA-11, which allows PET/CT scanning to be performed. 68Ga-PSMA-11 has found application in research in the field of nuclear medicine. It is used mainly for prostate cancer, but PSMA is also overexpressed on other solid tumors, such as ovarian cancer, glioblastoma, primary hepatocellular carcinoma, clear cell renal cancer, and pancreatic cancer.16

For example, it was used to differentiate benign and malignant pancreatic tumors, with the sensitivity and specificity of 68Ga-PSMA-11 higher than 18F-FDG PET/CT (94.7% and 90.5% vs 89.5% and 57.1%, respectively).17 Tolkach et al18 compared expression in histopathology specimens of PSMA in endothelia in several types of breast cancer. The highest rate of PSMA was observed in triple-negative breast cancer.18 Morgenroth et al19 demonstrated PSMA as a target in therapy using a radioligand in triple-negative breast cancer. Expression of PSMA in breast cancer was confirmed by Kasoha et al.20 Uptake of PSMA appeared in tumor cells and tumor-associated neovascularization. Higher expression was detected in distant metastases compared with primary tumors. Moreover, changes with positive PSMA uptake located in the brain are more highly expressed by PSMA than in bones. Based on these observations, PSMA has potential as a therapeutic vascular target.20

There are limited data on PSMA expression in ovarian cancer. However, Wernicke et al21 described PSMA expression in the endothelium of tumor vessels in every case of ovarian cancer with no PSMA staining in ovarian epithelium.

Presence of positive PSMA expression in endothelium of tumor vascularization can be useful in diagnosis of ovarian cancer. According to our knowledge, to date there are no published data about the possibility to use 68Ga-PSMA-11 PET/CT in ovarian cancer, including presurgical differentiation of benign and malignant tumors.

The aim of the study was to perform a preliminary evaluation of the feasibility to use 68Ga-PSMA-11 PET/CT in pelvic tumor suspected of ovarian cancer.

MATERIALS AND METHODS

This prospective study was conducted from July 2020 to February 2021. Eight women with mean age of 56 ± 16.2 years were included in the study. Mean BMI was 25.8 ± 7.84 kg/m2. The median BMI was 22.9 kg/m2 (range, 19.9–43.7). The inclusion criteria were age older than 18 years; tumor with diameter more than 4.5 cm located in the pelvis, which was suspected to be an ovarian cancer; and presence of clinical symptoms coexisting with pelvic tumor suggesting ovarian cancer (ascites, edemas, weakness, losing weight, lower abdominal pain). Exclusion criteria were previous history of cancer, previous use of chemotherapy, hormone therapy or radiotherapy, renal dysfunction, contraindications, or allergy to PSMA marker.

Diagnostic Methods

As a first diagnostic tool, each patient underwent a transvaginal ultrasound examination with IOTA algorithms (GE Voluson S8 RIC5-9D). All patients underwent a 64-slice contrast-enhanced CT (ceCT) scan of the abdomen and CT of the chest as qualification for surgery. The examinations were performed before inclusion in the study. Within a 1-week interval, 68Ga-PSMA-11 PET/CT was performed.

Laboratory Tests

Antigen CA-125 (reference range, 0–35 U/mL) and HE4 (reference range, 0–70 pmol/L for premenopausal age; 0–140 pmol/L for postmenopausal age) were measured in every case. Tumor markers including CEA (reference range, 0–5.0 ng/mL) and CA19-9 (reference range, 0–37.0 U/mL) were assessed.

68Ga-PSMA-11 PET/CT Protocol and Image Interpretation

Radiopharmaceutical preparation of 68Ga-PSMA-11 and the imaging protocol was performed as previously described.22 Briefly, PET/CT was performed from the skull to the thighs (3 minutes per bed position, 3 iterations, 21 subsets) on a Biograph 64 TruePoint (Siemens Medical Solutions Inc, USA) for 60 minutes after injection of 68Ga-PSMA-11 (dose of 2 MBq/kg body weight). Image analyses were performed using the Siemens Workstation (Syngovia, MMWS, Siemens Medical Solutions Inc, USA).

In the visual evaluation of lesions, uptake of 68Ga-PSMA-11 higher than that of the background was considered a positive result.

For quantitative analysis, the SUVmax and SUVmean of a positive lesion were measured on 68Ga-PSMA-11 PET/CT images with spherical volumes of interest.

Histological Examination

All patients underwent laparoscopy with intraoperative histopathological examination of the ovarian tumor. Confirmed diagnosis of ovarian cancer allowed for radical debulking surgery, except for disseminated disease, which does not allow for optimal resection. In those cases, neoadjuvant chemotherapy is recommended. The tissue collected during the surgery was subjected to a standard histopathological procedure. Formalin-fixed paraffin-embedded pieces of tissue were sectioned and stained with hematoxylin-eosin staining and with an additional immunohistochemistry marker panel for CK7, CK20, CA-125, CDX2, and Ki-67.

Statistical Methods

Means and standard deviations were used for characterization of patients. Calculation was done in Microsoft Excel (version 16.60). Statistical analysis was performed in PQStat (version 1.8.4).

RESULTS

68Ga-PSMA-11 PET/CT Imaging and ceCT

No adverse events related to the use of the diagnostic radiopharmaceutical were recorded.

Five patients were negative in 68Ga-PSMA-11 PET/CT (62.5%), and histopathology confirmed the benign nature of the pelvic tumor. However, 4 of them (4/5) apart from the ovarian mass had suspected lesions in ceCT: 2/4 liver metastases, 2/4 iliac lymph nodes, 1/4 infiltration to local fatty tissue, and 1/4 peritoneal metastases near the liver. The latter presented ascites and pleural fluid. The detailed data are presented in Table 1.

TABLE 1 - Detailed Clinical and Imaging Patient Data
No. Age, y BMI, kg/m2 CA-125 Reference Range 0–35, U/mL HE4 Reference Range 0–70 for Premenopausal Age; 0–140 for Postmenopausal Age, pmol/L CEA Reference Range 0–5.0, ng/mL CA19–9 Reference Range 0–37.0, U/mL Ascites Pleural Fluid CT Suspected Lesions FIGO 68Ga-PSMA-11 PSMA Expression Histopathological Result
1 53 22.5 118* 63.9 4.6 241* + Liver metastases, iliac lymph node Serous ovarian cyst
2 43 22.8 360* 112.6* 3.2 10 + + Endometrioid ovarian cyst
3 49 23 21 57.9 2.5 26.2 + + Peritoneal metastases near the liver Serous ovarian cyst
4 72 19.9 1213* 142.3* 1.2 15.1 + Peritoneal metastases, lung metastases IVA + High-grade serous ovarian cancer
5 79 43.7 20 133.2 1.9 18.9 Iliac lymph nodes Pedunculated uterine fibroid
6 73 29.4 811* 2162* 2.3 10.3 + + Peritoneal metastases IIIC + High-grade serous ovarian cancer
7 40 25.2 13 56.8 2.5 8.7 IA + Borderline ovarian tumor
8 39 20 24 105* 7.6* 15.8 Liver metastases, fat tissue infiltration Hemorrhagic ovarian cyst
*Elevated tumor marker level.

Three cases (37.5%) were positive in 68Ga-PSMA-11 PET/CT, whereas histological examination after the surgical procedure revealed 2 cases of serous ovarian cancer of high-grade and 1 of borderline serous ovarian tumor.

The lesions with increased uptake of 68Ga-PSMA-11 were assessed semiquantitatively using SUVmax. The SUVmax in the primary tumor in patients with a diagnosis of serous ovarian cancer was 8.7 and 4.1. In all patients with serous ovarian cancer, 68Ga-PSMA-11 PET/CT revealed metastatic lesions in the peritoneal cavity and distant metastases localized in lungs and/or distant lymph nodes. These foci corresponded to those described in ceCT lesions. The targeted metastases are presented in Table 2.

TABLE 2 - Targeted Metastases With Increased Uptake of 68Ga-PSMA-11
Primary Tumor Peritoneal Metastases Distant Metastases
No. CT size SUVmax SUVmean SUVpeak Location PET Size SUVmax SUVmean SUVpeak Location CT Size SUVmax SUVmean SUVpeak
4 63 × 56 mm 8.7 4.7 7.1 Left adnexa area 22 × 22 mm 7.8 4.3 6.1 Lung nodule 21 × 15 mm 4.6 2.6 2.9
6 148 × 105 mm 4.1 2.4 3.2 Right hypochondriac region 10 × 10 mm 7.9 4.4 5.3 Chest wall metastasis 13 × 8 mm 1.8 1.2 1.3
Left iliac region 17 × 13 mm 8.5 5.0 5.7 Subcranial lymph node 9 × 6 mm 3.6 2.2 2.7
Epigastric region 9 mm 7.6 4.2 4.9
7 45 × 35 mm 13.8 8.2 10.1

The SUVmax of the primary tumor of the borderline ovarian tumor was SUVmax 13.8, and it corresponded to the lesion visible in ceCT. No other lesions were detected in 68Ga-PSMA-11 PET/CT or ceCT in the case of the borderline ovarian tumor.

There was a statistically significant correlation of histological result and presence of PSMA expression (P = 0.038). Patient-based sensitivity of 68Ga-PSMA-11 for ovarian malignancy was 100% (95% confidence interval [CI], 31%–100%) and specificity was 100% (95% CI, 46.3%–100%).

Examples of 68Ga-PSMA-11 PET/CT imaging are shown in Figures 1 to 3.

F1
FIGURE 1:
PET/CT scan with 68Ga-PSMA-11 a 40-year-old woman (patient 7). A, MIP, arrow indicates the lesion with abnormal tracer accumulation. B, CT, arrow indicates the lesion in the right ovary. C, Fusion PET/CT, arrow indicates the high tracer accumulation in the right ovary lesion visible on CT with SUVmax 13.8. Final histopathology revealed borderline ovarian tumor.
F2
FIGURE 2:
PET/CT scan with 68Ga-PSMA-11 in a 72-year-old woman (patient 4). A, MIP, arrows indicate the lesions with abnormal tracer accumulation—corresponding images, lower arrows, in pelvis; upper arrows, in thorax. B, CT left arrow indicates the lesion in the left adnexa area, with the corresponding metastases in the right area of the pelvis (right arrow). C, Fusion PET/CT, arrows indicate the high tracer accumulation in the lesions visible on CT—left adnexa area (SUVmax, 8.7) and metastases in the right area of the pelvis (SUVmax, 7.8). D, Arrows indicate the distant metastases in the thorax. E, Fusion PET/CT, arrows indicate the high tracer accumulation in the distant metastases with SUVmax of 3.9 and SUVmax of 4.6. Final histopathology revealed high-grade serous ovarian cancer.
F3
FIGURE 3:
PET/CT scan with 68Ga-PSMA-11 in a 79-year-old woman (patient 5). A, MIP, only physiological traces accumulation is visible. B, CT, arrow indicates the lesion in the left ovary. C, Fusion PET/CT, arrow indicates the lesion visible in the CT scan, which has no tracer accumulation in the PET scan. Final histopathology revealed pedunculated uterine fibroid.

Compliance With Tumor Markers, CT, and Clinical Symptoms

Antigen CA-125 was increased in 50% (4/8) of patients of the analyzed database with a median value of 585.5 U/mL (range, 118–1213). Increased CA-125 (1213 U/mL and 811 U/mL) was observed in patients with positive uptake of 68Ga-PSMA-11 and final histopathology of high-grade serous ovarian cancer. In the case of a borderline ovarian tumor, the value of CA-125 was at a normal level (13 U/mL).

In 2 cases with an elevated CA-125 value of 118 U/mL and 360 U/mL, 68Ga-PSMA-11 PET/CT was negative, and histopathology confirmed the benign nature of the tumors. ceCT in those cases revealed a suspected lesion in the liver or ascites and pleural fluid.

HE4 concentration was increased in 4/8 patients with a median value of 127.5 pmol/L (range, 105–2162). Higher values of glycoprotein HE4 assessed before surgical treatment were observed in the group with positive expression of PSMA. Patients with serous ovarian cancer were observed with the level of HE4 142.3 pmol/L and 2162 pmol/L. In the case of the borderline ovarian tumor, the concentration of HE4 was at a normal level (56.8 pmol/L). The value of glycoprotein HE4 in the benign ovarian tumors was raised in 2 patients, whereas ceCT revealed suspicion of liver metastases, fat tissue infiltration, or ascites and pleural fluid.

CA19-9 was increased only in 1 patient, with a suspected lesion in ceCT such as liver metastases or iliac lymph node involvement, whereas it was not taken up on 68Ga-PSMA-11 PET/CT. Final histopathology confirmed a benign tumor.

There was no significant correlation between range of CA-125 and positive PSMA detection.

Clinical Impact of 68Ga-PSMA-11 PET CT

All patients qualified for exploratory laparoscopy.

However, after ceCT and 68Ga-PSMA-11 PET/CT due to high probability of distant metastases, 2 of 8 patients (patients 4 and 6) underwent only diagnostic laparoscopy with biopsy of the suspicious area. Intraoperative histological examination confirmed presence of an ovarian cancer, and the surgical procedure was discontinued. These patients underwent neoadjuvant chemotherapy (3 courses of chemotherapy based on carboplatin and paclitaxel), and then were operated on. One patient is still alive with overall survival of 18 months, whereas 1 patient died with overall survival of 14 months.

Patient 7 with only focal uptake of 68Ga-PSMA-11 PET/CT underwent laparotomy with intraoperative histological examination. During the operation, no suspicious area was observed. The intraoperative histological result was not conclusive for ovarian cancer, but a borderline ovarian tumor was suspected, and the patient was operated on conservatively according to the protocol for borderline ovarian tumors. The final histopathology confirmed borderline ovarian tumor.

In the remaining patients without expression of 68Ga-PSMA-11 PET/CT, intraoperative examination did not confirm ovarian cancer. The patients underwent tumor removal without further surgical treatment.

DISCUSSION

68Ga-PSMA-11 was recently introduced for the PET/CT imaging of patients with prostate cancer, but incidental uptake has been described in other cancers, including ovarian cancer.21,23

This pilot study showed encouraging preliminary results confirming the clinical utility of 68Ga-PSMA-11 PET/CT in patients with presurgical differentiation of benign and malignant ovarian tumors. All histopathologically proven cases of ovarian cancer showed increased tracer uptake, corresponding with ceCT. 68Ga-PSMA-11 expression was also detected in the borderline tumor. In the benign tumors, expression of 68Ga-PSMA-11 PET/CT was negative.

There are only a few studies investigating PSMA expression in immunohistochemical staining in ovarian cancer. The first study was conducted in 1998. Zhang et al24 assessed relative protein expression in immunohistochemistry of protein antigens in different cancers. PSMA was only detected in cancers of prostate origin. No expression of PSMA in the ovary was observed in this study.24

Santoro et al25 detected PSMA expression on endothelial cells of vessel-like structures isolated from ovarian cancer. Endothelial cells are activated by positive PSMA regions for neovascularization and create metastases.25 Salas Fragomeni et al26 observed PSMA expression in endothelium of tumor-associated neovasculature for primary and metastatic ovarian carcinoma.

Wernicke et al21 described PSMA expression in gynecological malignancies. They revealed positive PSMA expression in endothelium of tumor vessels in all cases of primary ovarian cancer. Diffuse expression of over 50% of tumor capillaries was detected in 62% of patients. Interestingly, PSMA staining was associated with histological type. High-grade serous ovarian cancer showed up to 100% staining of capillaries, low-grade serous type was positive in 26%–50% and 76%–100%, and the same percentages were observed in clear cell carcinoma. They also reported 10 cases of high-grade ovarian cancer with positive PSMA expression in tumor cells.21 On the other hand, Kinoshita et al23 detected expression of PSMA in ovary stromal cells, but did not detect it in tissue of ovarian cancer. However, the study was conducted only on 5 normal ovaries and 1 ovarian cancer.

Aide et al27 analyzed the largest cohort regarding PSMA expression, with 57 histological samples. Thirty-two samples were taken before chemotherapy and 25 after neoadjuvant platinum/taxane-based chemotherapy. No significant difference in tumor PSMA expression was found between the groups. Aide et al27 observed no correlation between PSMA expression and chemotherapy response. The results of their study showed that PSMA expression is not useful as a prognostic marker in monitoring treatment of ovarian cancer.27 Even though our cohort is small, we observed the same tendency with in vivo PSMA expression: 2 patients with disseminated disease in 68Ga-PSMA-11 PET/CT showed different survival parameters after neoadjuvant chemotherapy.

As we mentioned, to our knowledge, there are no published data about the possibility to use 68Ga-PSMA-11 PET/CT in ovarian cancer. However, there are several ongoing clinical trials, which assess the role of 68Ga-PSMA-11 PET/CT in diagnosing ovarian cancer patients: “68Ga-PSMA-11 PET in diagnosing metastasis in patients with ovarian cancer” (NCT03857087), “18F-FDCFPyL PET/CT in high-grade epithelial ovarian cancer (PET HOC)” (NCT03811899), and “PSMA PET and MRI in gynecological cancers” (NCT03302156), as well as 68Ga-PSMA-11 and 68Ga-FAPi-46: “Experimental PET imaging scans before cancer surgery to study the amount of PET tracer accumulated in normal and cancer tissues” (NCT04147494).

In our study, we additionally analyzed the correlation between 68Ga-PSMA-11 and tumor markers. There was no influence of CA-125 level on expression of PSMA. However, in all cases with serous ovarian cancer with 68Ga-PSMA-11, elevated CA-125 and HE4 were observed.

It is described in the literature that CA19-9 can be used for differentiation of ovarian tumors because of specificity in recognition of ovarian mucinous tumors.28 It is also used in follow-up of mucinous borderline ovarian tumors.29 In or study, no one with malignant tumors was positive for the CA19-9 marker.

The current pilot study has some major limitations. First of all, as mentioned earlier, the number of patients is limited. The relatively small number of cases limits the power of the analysis.

Overall, we observed increased uptake of 68Ga-PSMA-11 in all patients with histopathologically proven ovarian carcinoma, and no uptake in cases of benign ovarian tumors, even tumor markers and/or ceCT suspected malignancy. So it seems that 68Ga-PSMA-11 could be used preoperatively to assess the character of tumors. However, these promising results need further evaluation to confirm the observed dependency.

It is also important to compare 68Ga-PSMA-11 PET/CT with MRI including diffusion-weighted imaging and dynamic contrast-enhanced imaging, which now seems to very promising in differentiation of benign and malignant ovarian tumors.10,30 Another important future task is to calculate sensitivity, specificity, and other validating measures of 68Ga-PSMA-11 PET/CT in ovarian cancer.

The knowledge about the possibility to use 68Ga-PSMA-11 in ovarian cancer will open the way not only for differentiation of primary tumors, but also for its use in suspicion of disease recurrence. As the therapeutic agent 177Lu-PSMA has just been registered for metastatic castrate-resistant metastatic prostate cancer patients, it raises the question of its future use in metastatic ovarian cancer.

CONCLUSIONS

The initial experience supports the potential to use 68Ga-PSMA-11 in ovarian cancer, to differentiate malignant and benign tumors before surgery.

Expression of 68Ga-PSMA-11 seems to be a better indicator of malignant tumors than laboratory tests used in routine practice such as CA-125 and HE4.

ACKNOWLEDGMENTS

We thank the patients who participated in the study, the Radiochemistry Group in the Department of Nuclear Medicine, the nursing staff, and the nuclear medicine technologists of the Medical University of Warsaw for their support.

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Keywords:

PSMA; ovarian cancer; pelvic tumor; 68Ga-PSMA PET/CT

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