Purpose We prospectively evaluated the diagnostic performance of prostate specific membrane antigen targeted 18F-DCFPyL positron emission tomography/computerized tomography in the preoperative staging of men at high risk for harboring metastatic prostate cancer despite a negative conventional staging evaluation. Materials and Methods Men with clinically localized high or very high risk prostate cancer were imaged with 18F-DCFPyL positron emission tomography/computerized tomography before undergoing radical prostatectomy with standardized pelvic lymph node dissection. The scans were interpreted by 2 blinded nuclear medicine readers and assessed for interreader variability as well as diagnostic accuracy for pelvic lymph node staging. Surgical pathology served as the reference standard to which 18F-DCFPyL scan findings were compared. Results A total of 25 men contributed analyzable data to this study. Seven of these patients (28%) were found to have 1 or more positive lymph nodes on surgical pathology. Sites of radiotracer uptake were identified in the prostate of all imaged patients. The 2 readers identified the same number of prostatic lesions in 22 patients (88%), of whom all had at least 1 intraprostatic lesion in common between the 2 reads. Additionally, the readers assigned the same N stage to 46 of 50 individual lymph node packets (92%). Following reconciliation of the relatively few discordant imaging reads, 7 patients (28%) were found to have 1 or more sites of radiotracer uptake in the pelvis consistent with N1 disease, resulting in 71.4% sensitivity (95% CI 29.0–96.3) and 88.9% specificity (95% CI 65.3–98.6). Analysis at the level of individual nodal packets resulted in 66.7% sensitivity (95% CI 29.9–92.5) and 92.7% specificity (95% CI 80.1–98.5). Three men (12%) had evidence of M1a disease. Conclusions 18F-DCFPyL positron emission tomography/computerized tomography allowed for accurate detection of prostate cancer sites in men believed to have clinically localized disease based on conventional imaging. Our results support the need for a larger study to more precisely define the diagnostic accuracy of this novel molecular imaging test.

Background: M2 tumor-associated macrophages (M2-TAMs) can suppress inflammation in the tumor microenvironment and have been reported to modulate cancer progression. We and others have previously reported M2-TAM infiltration in metastatic castration-resistant prostate cancer (mCRPC).

GPNMB (glycoprotein nonmetastatic B) and other TFE3/TFEB transcriptional targets have been proposed as markers for microphthalmia (MiT) translocation renal cell carcinomas (tRCCs). We recently demonstrated that constitutive mTORC1 activation via TSC1/2 loss leads to increased activity of TFE3/TFEB, suggesting that the pathogenesis and molecular markers for tRCCs and TSC1/2-associated tumors may be overlapping. We examined GPNMB expression in human kidney and angiomyolipoma (AML) cell lines with TSC2 and/or TFE3/TFEB loss produced using CRISPR-Cas9 genome editing as well as in a mouse model of Tsc2 inactivation-driven renal tumorigenesis. Using an automated immunohistochemistry (IHC) assay for GPNMB, digital image analysis was employed to quantitatively score expression in clear cell RCC (ccRCC, n = 87), papillary RCC (papRCC, n = 53), chromophobe RCC (chRCC, n = 34), oncocytoma (n = 4), TFE3-or TFEB-driven tRCC (n = 56), eosinophilic solid and cystic RCC (ESC, n = 6), eosinophilic vacuolated tumor (EVT, n = 4), and low-grade oncocytic tumor (LOT, n = 3), as well as AML (n = 29) and perivascular epithelioid cell tumors (PEComas, n = 8). In cell lines, GPNMB was upregulated following TSC2 loss in a MiT/TFE-and mTORC1-dependent fashion. Renal tumors in Tsc2 +/À A/J mice showed upregulation of GPNMB compared with normal kidney. Mean GPNMB expression was significantly higher in tRCC than in ccRCC (p < 0.0001), papRCC (p < 0.0001), and chRCC (p < 0.0001). GPNMB expression in TSC1/2/MTOR alteration-associated renal tumors (including ESC, LOT, AML, and PEComa) was comparable to that in tRCC. The immunophenotype of tRCC and TSC1/2/MTOR alteration-associated renal tumors is highly overlapping, likely due to the increased activity of TFE3/TFEB in both, revealing an important caveat regarding the use of TFE3/TFEB-transcriptional targets as diagnostic markers.