Specificity of ⁶⁸Ga-PSMA PET/CT for Prostate Cancer - Myths and Reality

The introduction of ⁶⁸Ga-PSMA-11 for imaging prostate cancer is one of the most remarkable developments in nuclear medicine in the recent years. It is not surprising that the use of this new radiopharmaceutical for PET-CT imaging of prostate cancer worldwide has happened in a very short span of time. This is probably due to the high prevalence of prostate cancer and the absence of a suitable PET tracer for this indication. Prostate specific membrane antigen (PSMA) is a metalloenzyme, a type II membrane glycoprotein with 19-aminoacid intracellular, 24 amino acid transmembrane and 707 amino acid extracellular domain and having two major enzymatic actions that is folate hydrolase and NAALDase, and in both cases the enzymatic role is to release the terminal glutamate residue, which acts as a neurotransmitter.[1] Initially, it was detected to be expressed in prostate and thus was named as PSMA However, eventual histopathological studies confirmed its physiological expression at non-prostatic sites including duodenal epithelial (brush border) cells, salivary glands, lacrimal glands, proximal tubule cells in the kidney etc.[2] While the most documented over expression of PSMA is in prostate adenocarcinoma, the enzyme is also over-expressed in renal cell carcinoma, glioma, hepatocellular carcinoma and in the neovasculature of several other solid tumors.[3] The radiopharmaceutical, ⁶⁸Ga-PSMA-11, is a small molecular weight (~1000 Da) radiolabelled enzyme inhibitor that targets the extracellular portion of the enzyme and hence is suitable for imaging any tissues that over express PSMA.

Although histopathological evidence of PSMA over expression in non-prostatic malignancies is documented in literature, ⁶⁸Ga-PSMA-11 PET/CT imaging started to be used in a major way for imaging prostate cancer. Sufficient evidence has been accumulated in literature regarding the usefulness of ⁶⁸Ga-PSMA-11 PET/CT in prostate cancer.[4] Potential applications of this tracer in prostate cancer management include identification of suspected primary site, helping in PET based targeted biopsy, staging, recurrence evaluation as well as for radiotherapy planning.

In parallel, the localization of ⁶⁸Ga-PSMA-11 PET/CT imaging in non-prostatic malignancies is also being reported in literature. These include clear cell renal carcinoma, breast cancer, gliomas, primary hepatocellular carcinoma, differentiated thyroid cancer, and more indications are getting added.[56] These reports have cast a shadow on the specificity of ⁶⁸Ga-PSMA-11 for prostate cancer. When it comes to medical imaging, specificity is not the only important factor; in which case ¹⁸F-FDG would not have become the ‘molecule of the century’ in nuclear medicine and not so widely successful in oncology.

⁶⁸Ga-PSMA-11 PET/CT is the best available imaging tool in the management of prostate cancer. The expected sites of involvement like prostate gland, seminal vesicles, pelvic nodes and skeleton may not pose difficulties during interpretation of ⁶⁸Ga-PSMA-11 PET/CT. Unusual sites of involvement have to be attended carefully while interpreting ⁶⁸Ga-PSMA-11 PET/CT scan. This issue of the journal presents an article entitled ’Rare sites of metastases in Prostate cancer detected on ⁶⁸Ga-PSMA PET/CT scan - A Case Series’ describing three unusual sites of metastases (brain, penis and liver) from prostate cancer. While, histopathology to confirm metastasis from prostate cancer was done for liver and penile sites, the brain metastasis is assumed to be from prostate cancer. Like with any other nuclear medicine imaging, a careful and meticulous clinical history and correlative investigations will help in ascertaining the true nature of unusual sites of tracer avid lesions seen in ⁶⁸Ga-PSMA-11 PET/CT. Histopathological evidence may be required from these unusual sites in those cases where an alternate diagnosis would change the management strategy in the index case. The pit falls of ⁶⁸Ga-PSMA-11 uptake in non malignant conditions are also getting documented for e.g. the tracer is taken up in Paget's disease[7] further questioning its specificity and warranting caution in the interpretation of tracer avid bone lesions.

To conclude, though ⁶⁸Ga-PSMA-11 PET/CT is not unique to prostate cancer it is the best and most specific tracer available for imaging of prostate cancer as of now. An understanding of the possible conditions of uptake in ⁶⁸Ga-PSMA-11 PET/CT will help the nuclear medicine physician to minimize reporting fallacies. Whenever an unusual site of involvement is noted in the ⁶⁸Ga-PSMA-11 PET/CT, a careful history and correlative imaging will help resolve the reporting dilemma in most cases. In still unsettled cases and where a change in management is expected based on the unusual site of involvement, histopathological confirmation is warranted. ⁶⁸Ga-PSMA-11 PET/CT is in its early stages and is eventually expected to make a definitive mark in diagnostic nuclear medicine.