Upcoming Role of Prostate Specific Membrane Antigen Positron Emission Tomography-Computed Tomography in Detecting Occult Metastases in Prostate Cancer

Introduction

Prostate cancer (PCa) is the second most common cancer and the sixth leading cause of cancer death in men worldwide.[1] Abdominopelvic lymph nodal and skeletal metastases are the most common sites of disease involvement other than the prostate gland. Early detection of metastases is highly relevant in terms of prognosis and therapy management as even a single extrapelvic nodal metastasis turns PCa from a local to a systemic disease.

Conventional imaging focuses on morphologic information. Several studies promise accurate staging of primary PCa and restaging after biochemical recurrence with Ga-68 prostate-specific membrane antigen (PSMA) positron emission tomography–computed tomography (PET-CT). Ga-68 PSMA PET-CT is being increasingly used in the diagnosis and evaluation of PCa. Ga-68 PSMA PET-CT has the incremental value in identifying the disease outside the expected sites of involvement (pelvis), such as systemic lymph nodes (in the cervical region, mediastinum, etc.,) and bone and visceral metastases.

In our center, we routinely do Ga-68 PSMA PET-CT for PCa staging, recurrence, and response evaluation.

Case Report

A 69-year-old male with PCa underwent prostatectomy in May 2015. Histopathological examination revealed acinar adenocarcinoma with Gleason score 4 + 4 and Stage pT3a N1. Surgery was uneventful with low follow-up serum prostate-specific antigen (PSA) levels (<0.1 ng/ml). His PSA started rising slowly and had become 2.48 ng/ml in July 2017 with doubling time <6 months. Therefore, he was referred to us for Ga-68 PSMA PET-CT which revealed intensely PSMA-avid subcentimeter right internal mammary lymph node (1.1 cm × 0.6 cm and standardized uptake value – 11.5) with the mildly PSMA-expressing multiple bilateral subcentimeter lung ground-glass infiltrates and left internal iliac lymph node (<5 mm), as shown in Figures 1, 2 and 3. In view of rising PSA, positive Ga-68 PSMA PET-CT, and the fact that the sites of lesions were not amenable to cytology, it was discussed in multimodality meeting and hormonal treatment (degarelix) was started. Follow-up Ga-68 PSMA PET-CT after 3 months did not show any abnormal sites of PSMA uptake with insignificant serum PSA levels (0.062 ng/ml), proving the right internal mammary and left internal iliac lymph node as well as bilateral lung infiltrates to be a part of the primary disease process.

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Figure 1 (a) Axial sections of fusion positron emission tomography–computed tomography images revealing mildly fluorodeoxyglucose-avid left internal iliac lymph node in the scan in June 2017. (b) Axial sections of fusion positron emission tomography–computed tomography images revealing complete remission of the mildly fluorodeoxyglucose-avid left internal iliac lymph node in follow-up scan in November 2017

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Figure 2 (a) Axial sections of fusion positron emission tomography–computed tomography images revealing mildly fluorodeoxyglucose-avid left internal mammary lymph node in the scan in June 2017. (b) Axial sections of fusion positron emission tomography–computed tomography images revealing complete remission of the mildly fluorodeoxyglucose-avid left mammary lymph node in follow-up scan in November 2017

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Figure 3 (a) Axial sections of fusion positron emission tomography–computed tomography images revealing fluorodeoxyglucose-avid bilateral lung nodular infiltrates in the scan in June 2017. (b) Axial sections of fusion positron emission tomography–computed tomography images revealing complete remission of the fluorodeoxyglucose-avid bilateral lung nodular infiltrates in follow-up scan in November 2017

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Discussion

The current published literature indicates that CT and magnetic resonance imaging perform similarly in the detection of pelvic lymph node metastasis (LNM) as, in either case, the lymph nodal involvement criteria is solely based on the size and shape. A threshold of 1 cm in the short axis for the oval lymph node and 0.8 cm for the round lymph node has been a recommended criterion for abnormal lymph node in morphological imaging despite the fact that a significant number of metastatic lymph nodes can be subcentimeter in size.[2] To overcome these limitations, functional imaging techniques using radiopharmaceuticals and targets have been recently identified.

At least 30%–50% of patients with intermediate-to-high risk but clinically localized PCa, treated initially with a curative intent, will manifest biochemical failure, suggesting a combination of persistent local, periprostatic, regional (pelvic lymph nodes), or distant (i.e., systemic) disease.[23456] Despite higher doses of radiation and good surgical techniques, there is an increasing number of failures due to nonlocal treatment failure. If LNMs are present in a patient, curative treatment using radical prostatectomy or radical radiotherapy, directed only at the prostate, will inevitably be doomed to failure.

Molecular imaging of PCa with Ga-68 PSMA PET-CT has recently received significant attention and frequently used with a signature to PCa-specific remark. PSMA is a Type II membrane glycoprotein consisting of 750 amino acids. PSMA exhibits folate hydrolase/glutamate carboxypeptidase II enzymatic activity; however, its precise role in vivo has not yet fully elucidated. In vitro its folate hydrolase activity has been associated with prostate carcinogenesis.[5] In a large study in primary intermediate-to-high-risk PC, 68Ga-PSMA ligand imaging has been reported to clearly improve the detection of LNMs compared to morphological imaging, thus potentially allowing for a more tailored therapeutic concept.[7] 68Ga-PSMA ligand PET imaging has been shown to increase the detection of metastatic sites even at low PSA values in comparison to conventional imaging or PET examination with other tracers.[8]

One of the major challenges in the management of PCa is the identification of early physical (as opposed to biochemical) evidence of metastatic disease. In this particular case of interest, the sites of abnormally increased PSMA uptake such as right internal mammary lymph node and bilateral lung infiltrates were unusual sites of presentation and not amenable to histopathological correlation. The mildly PSMA-expressing left internal mammary lymph node was subcentimetric and hence not clearly metastatic following the structural imaging. Following three cycles of Firmagon (degarelix), a follow-up PSMA PET-CT did not show any abnormal sites of PSMA uptake with no significant serum PSA levels (0.062 ng/ml), proving the right internal mammary and left internal iliac lymph node as well as bilateral lung infiltrates to be a part of primary disease process.

Improvements in the predictive accuracy of imaging are of great interest in PCa. Conventional imaging has not been reliable in identifying LNM. Advances in imaging technology, such as the development of hybrid imaging systems such as PSMA PET-CT, which provide both structural and metabolic information, thus, have a promising future in identifying the disease recurrence, hence guarding the therapeutic planning.