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Radiographic and metabolic evolution of prostate cancer lung metastasis detected by prostate‐specific membrane antigen and fluoro‐2‐deoxy‐D‐glucose positron emission tomography/computed tomography

We describe the case of a 75-year-old patient who progressed over a 12-year period from localized to symptomatic metastatic prostate cancer (PrCa) with lung as the sole organ of involvement. In this case, the specific sequence of positron emission tomography (PET)-based next-generation imaging with 18F-sodium fluoride-, 18F-fluoro-2-deoxy-D-glucose-, and 18F-DCFPyL PET/computed tomography and biopsies allowed illustration of the pathway of disease progression from nonglycolytic hormone-sensitive PrCa to glycolytic castrate-resistant PrCa without neuroendocrine features. The observations provide a unique insight into the timelines of anatomical and metabolic progression of metastatic PrCa. They highlight the value of close radiographic surveillance of metastatic PrCa with modern imaging to guide early treatment interventions.


INTRODUCTION
Modern nuclear medicine imaging opens new avenues for observation of prostate cancer (PrCa) behavior and shows earlier points for intervention. [1] Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) helps illustrate the complexity of the patterns of PrCa metastatic behavior .. [2] On the other hand, incidental identification of PrCa metastasis by 18 F-fluoro-2-deoxy-D-glucose PET (FDG-PET), when other malignancies are suspected, provides new information on the patterns of metabolic progression of PrCa. Castrate-resistant prostate cancer (CRPC) progresses frequently from a non-glycolytic to glycolytic phenotype, a phenomenon that is associated with expression of glucose and monocarboxylate transporters [3,4] and has been frequently attributed to neuroendocrine differentiation. [2] Despite such observations, the potential timelines of biochemical and radiographic progression of metastatic hormone-sensitive prostate cancer (HSPC) and its transformation to CRPC, without or with glycolytic features, Radiographic and metabolic evolution of prostate cancer lung metastasis detected by prostate-specific membrane antigen and fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography Submitted: 18-Feb-2020, Revised: 19-Mar-2020, Accepted: 31-Mar-2020, Published: 14-Sep-2020 This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

CASE REPORT
At 63 years of age (2007), our patient was diagnosed with high-intermediate risk PrCa (Gleason score 7 (4 + 3), prostate-specific antigen [PSA]: 5.1 ng/ml). Baseline staging with computed tomography (CT) of the abdomen and pelvis showed a heterogeneous prostate gland and no evidence of extraprostatic extension or pelvic lymph node enlargement [ Figure 1a], and he underwent laparoscopic prostatectomy with standard nodal dissection. Operative pathology indicated pT2c, N0, prostatic adenocarcinoma without lymphovascular or perineural invasion and led to undetectable PSA levels for 4 years (till 2011).
In 2012, PSA became detectable (0.11 ng/ml). Conventional imaging with CT of the abdomen and pelvis and 18 F-sodium fluoride (NaF)-PET/CT did not detect metastatic foci, and the patient was treated with standard salvage pelvic (4500 cGy) and prostatic bed boost (1980 cGy) radiotherapy with no biochemical response.
PSA continued to rise reaching 5ng/ml in early 2016 when imaging with CT and 18 F-NaF-PET/CT showed a solitary (2.0 cm × 1.8 cm) left lower lobe nodule [ Figure 1b]. Due to the patient's previous smoking history, thoracic cancer was suspected and he was referred to a lung cancer diagnostic program. 18F FDG-PET showed a minimally FDG-avid tumor [ Figure 1c]. CT-guided biopsy proved PSA-expressing metastatic PrCa. He was started on androgen deprivation therapy (ADT), which produced PSAs of <1 ng/ml in the period 2017-2018. However, he progressed to CRPC in 2019 [ Figure 2].
In January 2019, PSA rose to 13.26 ng/ml and he began developing shortness of breath. Repeat CT of the chest showed a new mass of 5.9 cm × 3.9 cm × 2.4 cm encasing remain poorly understood. Detection of such metastatic progression within a single organ, years after definitive local therapy, in the absence of local disease recurrence, presents a unique setting to understand better the natural history of metastatic PrCa and opens opportunities to study its unique biology.
We describe the case of a 75-year-old patient who developed a secondary rapidly progressing ipsilateral glycolytic CRPC metastasis 3 years after detection of a sole metastatic site of non-glycolytic HSPC in the left lung and 12 years after radical prostatectomy. Once again, the radiographic features could not exclude lung malignancy. 18 F-FDG-PET/CT showed that the primary left lower lobe nodule remained radiographically stable and was mildly FDG-avid [ Figure 3]. However, the new left hilar mass was intensely FDG-avid raising the suspicion for de novo bronchogenic carcinoma [ Figure 3].
Two months later, PSA increased to 24.22 ng/ml while on ADT. CT-guided biopsy of the left hilar mass showed histomorphology consistent with prostatic adenocarcinoma with mild-to-moderate anisonucleosis and gland formation. The disease was negative for neuroendocrine features (nuclear molding and scant cytoplasm). These findings were consistent with those found in the 2016 biopsy. Both tumors were positive for PSA and prostatic acid phosphatase and negative for thyroid transcription factor-1, CK7, napsin A, and CD56 [ Figure 4]. 18 F-DCFPyL PET/CT showed that both the primary metastasis in the left lower lobe (detected in 2016) and the secondary hilar tumor (FDG avid, detected in 2019) were PSMAavid [ Figure 5]. There was no evidence of local prostatic bed recurrence, involvement of other organs, or skeletal metastasis throughout the course of his disease.
The pathologic and radiographic features of this case depicted oligometastatic CRPC, a setting where radiotherapy is being investigated. Our patient participated in a randomized trial investigating high-precision radiotherapy in this setting (NCT02685397). Before treatment initiation, PSA reached 30 ng/ml. He was randomized to the radiotherapy arm and received hypofractionated radiotherapy to primary and secondary metastases in combination with enzalutamide and luteinizing hormone-releasing hormone agonist therapy. In early 2020, his PSA remained well-controlled [ Figure 2].

DISCUSSION
PrCa metastasis to multiple organs, including the lungs, is well-described, [5,6] but isolated lung metastasis from PrCa without concurrent bone or lymph node disease is fairly rare. Gago et al. [7] described three patients with isolated pulmonary lesions after radical prostatectomy. One patient underwent chemotherapy but died from his disease. The other two were treated with ADT therapy with either complete or partial response. Ciriaco et al. (2019) described 9 cases that underwent resection of lung metastases without preoperative ADT. [8] There are no reports describing the time-course of progression of isolated lung metastases from HSPC to CRPC in PrCa that remained confined to the lungs for over a decade.
The case presented here illustrates important features of metastatic PrCa behavior that points to a unique biology. It shows that PrCa can: (1) remain quiescent at metastatic sites for long periods of time before progressing biochemically, (2) show a slow progression and serial metastases within a single-organ site without evidence of skeletal involvement, (3) exhibit clonal transformation to glycolytic CRPC, without neuroendocrine differentiation, and (4) the latter can take place without modification of the metabolic characteristics and hormone responsiveness of the primary metastatic focus.

CONCLUSION
Modern imaging will continue to improve our understanding of PrCa progression. It is expected that in the next few years studies will identify the specific genomic signatures that guide metastatic behavior in prostate cancer. [9] Early detection with improved imaging techniques opens avenues for local management of such lesions with surgery or radiotherapy. [8] Accrual of such patients to clinical trials and biospecimen collection is crucial in achieving a better understanding and improved management of this disease. The reported case illustrates the validity of utilization of ADT and modern anti-androgen therapy as well as the on-going investigation of stereotactic body radiotherapy in oligometastatic PrCa.