The prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II, N-acetyl-L-aspartyl-L-glutamate peptidase I, and folate hydrolase 1, is a type II transmembrane protein highly expressed in prostatic cancer. 68Ga-PSMA PET/CT has been used for imaging of prostate cancer and its metastatic spread.1 Other benign and malignant nonprostatic neoplasms also demonstrate PSMA expression particularly by its increased transcription and expression in the tumor neovascular endothelial cells.1,2
Juvenile nasal angiofibroma (JNA) is an extremely vascular, benign but locally aggressive tumor that characteristically develops in the posterior nasal cavity of adolescent males.3 Diagnosis is usually based on clinicoradiological features wherein contrast-enhanced computed tomography (CECT), contrast-enhanced MRI (CEMRI), and angiography demonstrate the characteristic and diagnostic tumor vascularity and its location and extensions.4 Juvenile nasal angiofibroma, being highly vascular with an abundance of neovascularization and endothelial cells, can be anticipated to demonstrate increased PSMA expression. Sakthivel et al5 have recently published the first case of 68Ga-PSMA-HBED-CC PET/CT undertaken for primary JNA and demonstrated uptake in the primary tumor and its intracranial extension. The present study seeks to build on this initial finding by reporting on 68Ga-PSMA-HBED-CC PET scans in a consecutive series of 25 primary cases of JNA to explore its theranostic potential.
PATIENTS AND METHODS
The investigational clinical test (68Ga-PSMA-HBED-CC PET/CT scan) was evaluated for the detection of tumor uptake (intensity and pattern) and tumor extensions. The study protocol was approved by the institutional ethics committee and registered in the Clinical Trials Registry of India (CTRI/2018/08/015479). All clinicoradiologically diagnosed cases (n = 25) of primary JNA during the period from January 2018 to June 2019 were included in the study after obtaining informed written consent. All patients underwent a standard clinical examination and radiological imaging (CECT and CEMRI) of the nose and paranasal sinuses along with infratemporal fossa, orbit, and brain.
PET/CT scan was performed after 45 to 60 minutes of intravenous injection of 2 to 3 mCi (74–111 MBq) of 68Ga-PSMA-HBED-CC on a dedicated PET/CT scanner (Biograph mCT 64; Siemens Inc, Erlangen, Germany). To limit the radiation exposure, a low-dose CT scan was acquired from vertex to sternoclavicular joint (100 mA, 20 kVp, 3-mm slice thickness, 0.8 pitch) as the disease is benign. Head and neck spot PET scan was acquired at 2 minutes per bed position. Images were reconstructed with iterative reconstruction technique (4 iterations, 24 subsets). Reconstructed images were used for the analysis of PSMA expression.
The PSMA expression was assessed in the tumor and the other known physiological uptake sites in the head and neck region (salivary and lacrimal glands) and in the left paraspinal muscles at C1–C2, C3–C6, and C7 level. The left C1–C2 paraspinal muscle value was considered as standard background activity for comparison. All patients underwent subsequent surgical excision and had histological confirmation of the diagnosis on the excision specimen.
Differences in 68Ga-PSMA-HBED-CC SUVmax ratio values between different subgroups were assessed using Student t test and Mann-Whitney U test. Correlation analysis was performed using the Spearman rank correlation analysis. P = 0.05 was considered statistically significant.
Twenty-five patients of primary JNA were included in the study. The median age was 15 years (range, 7–24 years). The tumors were classified according to modified Radkowski staging.6 The clinical characteristics of the study population are given in Table 1. Nine of the 25 patients (36%) had had a 6-week course of antiandrogen flutamide in an attempt to bring about tumor shrinkage before surgery.
All cases (25/25 [100%]) demonstrated positive PSMA expression in the tumor (Fig. 1; Table 2). The uptake was intense in certain areas of the tumor, concordant with the expected distribution of neovascularization. Uptake was also noted in the salivary glands, lacrimal glands, and the Eustachian tube (Table 2). The Eustachian tube SUVmax values were calculated by observing the uptake on the contralateral side of the tumor with minimal interference by tumor activity. No tumor had an SUVmax value greater than the uptake by the salivary and lacrimal glands (Table 2).
The median value of PSMA SUVmax in the tumor was 3.6 (range, 1.6–7.5). The tumor had significantly increased uptake compared with the background (P < 0.001), and the median ratio of tumor to background PSMA SUVmax was 4.6 (range, 2.1–7.3) (Table 2).
All major tumor extensions (nose, nasopharynx, infratemporal fossa, orbit, middle cranial fossa), as identified on the MRI, were also consistently identified on the PSMA PET/CT scans. The intracranial extension in 14 of 25 patients was readily visualized as there was a complete absence of background uptake in the brain (Fig. 1).
Advanced stage tumors (stage III) demonstrated significantly increased uptake in comparison to early-stage tumors (stage I/II) (P = 0.014) (Fig. 2). No difference was noted in stage III tumors that had presurgical treatment with flutamide versus those that did not (P = 0.67).
A correlation between age and PSMA uptake was explored, and a trend was noted for decreasing PSMA uptake with increasing age, but this was not statistically significant (Spearman correlation coefficient r = −0.19, P = 0.36). The trend persisted even in advanced-stage tumors (Spearman correlation coefficient r = −0.08, P = 0.77) (Fig. 3).
To date, PSMA-PET CT is routinely performed in specialized centers as part of staging and restaging for prostatic cancers. The current study demonstrates its role in JNA with universal uptake demonstrated in all 25 tumors evaluated. Prostate-specific membrane antigen expression has previously been demonstrated in the endothelium of tumor-associated neovasculature,7–9 and it can be accordingly surmised that the uptake in JNA represents the vascular component and vascularity in JNA.
Prostate-specific membrane antigen PET/CT radioactivity intensity of the tumor was measured by SUVmax intensity and also by the ratio of SUVmax tumor to SUVmax background activity. The SUVmax intensity was noted to be in the range of 1.6 to 7.5 (median, 3.6). Measurement of SUVmax activity, however, may be influenced by interscanner variability, and the ratio of tumor to background activity is therefore proposed as a more valid measure.10 The SUVmax tumor-to-background ratio was noted to be from 2.1 to 7.3 (median, 4.6).
The salivary glands consistently demonstrated greater uptake than the tumor. This is in harmony with previous literature, which has demonstrated intense PSMA tracer uptake in the kidneys and salivary glands and moderate uptake in the lacrimal glands, Waldeyer ring, thyroid gland, liver, spleen, small bowel, large bowel, rectum, and the synovium of the knee joint.1,11,12 In this present study being for a benign pathology, full-body scanning was deemed unnecessary, and the PSMA PET scan was restricted to the head and neck region. In addition to the uptake in the salivary and lacrimal glands, physiological uptake was also noted in all cases in the Eustachian tube, which was relatively a new finding (Table 2). The physiological uptake by the Eustachian tube and the parotid needs to be kept in mind to avoid false-positive interpretations.
Intracranial extensions were clearly demarcated with 100% sensitivity, as they show brightly in contrast to the brain tissue, which demonstrated absolutely no PSMA uptake. Other extensions to the major anatomical sites, that is, the nose, nasopharynx, infratemporal fossa, and orbit, were also consistently identified (Fig. 1).
Further analysis of the impact of various factors on PSMA uptake is limited by the relatively small number for statistical subanalysis. Nevertheless, greater activity was noted in stage III tumors than in stage I/II tumors, and similarly a trend was noted for greater activity in younger age and decreasing activity in the older age group. Prostate-specific membrane antigen scans are predicated on tumor neovascularization and endothelial cells, and therefore, these trends may indicate greater vascularity in larger tumors and in younger patients. Similar themes have been reported in the literature based on surgical impression, radiology and angiographic investigations, and histological evaluation.3,4,13
Presurgical treatment with flutamide has been demonstrated to lead to tumor shrinkage in postpubertal males14,15 and is frequently used in our practice, particularly for stage III tumors. Prostate-specific membrane antigen uptake was not noted to be different in patients receiving flutamide compared with patients not receiving such treatment. Flutamide is an androgen receptor–blocking drug and would therefore be expected to impact mainly on the stromal cells, which harbor the androgen and sex hormone receptors, but may have a lesser impact on the less hormone-sensitive neovascular capillaries and endothelial cells, which are the component for the PSMA scan activity.16
As it is already known that the tumor-associated neovasculature expresses PSMA,1,7,8 a histopathologic correlation with PSMA immunohistochemistry and its expression in endothelial cells was not done in our study to further prove it. Further, the diagnostic performance of PSMA PET/CT was not compared with that of CECT and/or CEMRI, as the primary intent of our study was to identify only the intensity and pattern of PSMA uptake in already clinicoradiologically diagnosed primary JNA patients.
The consistent and predictable PSMA activity by JNA as noted in this study opens up the possibility for further physiological and clinical applications. On the premise of the PSMA scan being an indicator of neovascularization and endothelial cell density, it may be used for such physiological evaluations. In this context, it is plausible that PSMA PET/CT imaging may play a role in selection of those JNA patients who may benefit from non–PSMA-targeted antiangiogenic treatment strategies such as anti–vascular endothelial growth factor therapies, for example, bevacizumab treatment response monitoring.17
Although not useful for initial diagnosis, the added value of PSMA PET/CT in the clinical management of these patients lies in the detection of residual/recurrent disease,18 as conventional CEMRI and CECT are often unable to clearly demarcate residual/recurrent disease from postsurgical healing tissue, while the PSMA scan targeting tumor endothelial tissue may aid this differentiation. All the patients in our cohort are being followed up, and in the future, we aim to compare the diagnostic efficacy of CEMRI and PSMA for detection of residual/recurrent disease.
Theoretically, PSMA expression in tumor neovasculature and absence in normal vascular endothelium makes PSMA an interesting potential target for antiangiogenic therapy. More specifically, PSMA-targeting therapeutic agents may selectively destroy the vessels perfusing tumor tissue and achieve high regional doses of drugs while sparing normal tissue. The possibility of peptide receptor radiotherapy to the tumor by tagging PSMA to a more intense radioactive molecule is, however, limited by its physiological uptake by other organs, which would therefore be an unacceptable risk for any such therapy at present.
The 68Ga-PSMA PET/CT is demonstrated to universally and consistently show activity in JNA. This is the first radionuclide imaging scan that has found application in JNA and opens up possibilities to physiological imaging with a promise of greater specificity and sensitivity than can be expected with conventional anatomic imaging.
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