Tissue and Organ-specific Tumor Heterogeneity on dual tracer PET-CT ([⁶⁸Ga] Ga-PSMA-11 and [¹⁸F] FDG) and Dural-based Brain metastasis in Metastatic Prostate Cancer

Introduction

The clinical experience and research over the recent years have confirmed the safety and efficacy of [¹⁷⁷Lu] Lu-prostate specific membrane antigen (PSMA)-617 in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). A key requirement for maximizing the efficacy of PSMA-targeted radioligand therapy (PRLT) is identifying significant PSMA expression on imaging. The role of [¹⁸F] fluorodeoxyglucose ([¹⁸F] FDG)-positron emission tomography computed tomography (PET/CT) in managing advanced prostate cancer is still being explored. The use of dual tracer PET/CT imaging with [⁶⁸Ga] Ga-PSMA-11 and [¹⁸F] FDG is pivotal for individualized treatment plans and assessing tumor heterogeneity.[1] Patients displaying discordant disease on FDG imaging have several connotations, including limited response to PRLT. This report discusses a patient featuring with extensive skeletal metastases (PSMA avid) and discordant visceral organ metastasis (FDG avid) identified on dual tracer PET/CT imaging.

Case Report

A 65-year-old male presented with a 6-month history of lower urinary tract symptoms. Sonographic assessment revealed a significantly enlarged prostate gland measuring 4.5 cm × 2.9 cm with median lobe involvement extending to the posterior bladder wall. His serum prostate-specific antigen (PSA) levels were more than 100 ng/ml. Histopathology confirmed Grade-IV conventional prostate adenocarcinoma with perineural and lymphovascular invasion (Gleason score 4 + 4 = 8). Following surgical castration, the patient developed a postoperative wound infection, necessitating incision and drainage. Initial [⁶⁸Ga] Ga-PSMA-11 PET/CT scan showed uptake in the prostatic primary lesion, retroperitoneal lymph nodes, and extensive skeletal sites. A decrease in PSA levels (to 55.6 ng/ml) was noted postsurgery, and he was started on abiraterone and prednisolone. After 3 months, his PSA levels increased to 94.3 ng/ml, which coincided with an increase in lower back pain, despite an initial improvement (PSA at 26.4 ng/ml). A follow-up [⁶⁸Ga] Ga-PSMA-11 PET/CT indicated high uptake in skeletal lesions, whereas a left frontal lobe of brain lesion and hepatic lesion lacked uptake. Subsequent [¹⁸F] FDG-PET/CT imaging revealed increased uptake in these discordant sites, suggesting tumor heterogeneity Figure 1. Due to poor performance status Eastern Cooperative Oncology Group (ECOG 3), low hemoglobin 6.5 mg/dl, and widespread disease, further treatment was not pursued, and the patient received palliative care, succumbing within 3 months.

Close

Figure 1 [⁶⁸Ga] Ga-prostate specific membrane antigen (PSMA)-11 positron emission tomography computed tomography (PET/CT) (a, Maximum intensity projection (MIP)) showed high disease burden with extensive [⁶⁸Ga] Ga-PSMA-11 uptake in skeletal lesions. No [⁶⁸Ga] Ga-PSMA-11 uptake noted in left frontal lobe brain lesion (b, fused transaxial image) and hepatic lesion (c, fused transaxial image). [¹⁸F] fluorodeoxyglucose ([¹⁸F] FDG)-PET/CT (d, MIP) showed tumor heterogeneity with discordant increased [¹⁸F] FDG uptake in left frontal lobe brain lesion (e, fused transaxial image) and hepatic lesions (f, fused transaxial image), Different sites of metastasis are demarcated with different colour for easy identification by the readers

Export to PPT

Discussion

Prostate cancer accounts for the fifth-highest incidence rate with 4.8 per 100,000 males in India, with a significant increase in age-standardized incidence rate by 30% from 1990 to 2016. The developing countries have more advanced stages with relatively lower 5-year and 10-year survival rates. PSMA expression can shift during the disease progression, making biopsy-based assessments insufficient for gauging the entire tumor burden. Molecular imaging provides a broader understanding of tumor heterogeneity, and it is essential for treatment decisions.

Heterogeneous PSMA expression in metastatic sites can lead to clonal selection, which may result in PRLT resistance in a subset of mCRPC patients. Dual tracer PET/CT imaging plays a crucial role in distinguishing these cases and identification of responders to PRLT. Discordant results on dual tracer PET/CT imaging may suggest the presence of alternative causes, including neuroendocrine differentiation, metachronous secondary primary malignancies, and so forth. A prospective trial evaluated dual-tracer PET/CT imaging in 37 patients, 33 among 114 (28%) lesions were seen only on [¹⁸F] FDG-PET/CT, on further evaluation had poor prognosis and resistance to castration. A dual tracer PET/CT imaging biomarker analysis from a phase II trial of [¹⁷⁷ Lu] Lu-PSMA-617 and cabazitaxel showed that high metabolic tumor volume was linked to lower response rates, indicating a need for treatment intensification.[2] The use of dual tracer PET/CT imaging in prostate cancer has led to reports of detecting secondary primary cancers (SPCs). Population studies in Germany showed an increased SPC risk, suggesting shared genetic, hormonal, or others.[3] Chalikandy et al.[4] reported cases of SPC linked to discordant imaging findings include a hepatocellular carcinoma and a poorly differentiated squamous cell carcinoma. The authors, with their case illustrations, emphasized the need to evaluate such discordant findings for early diagnosis of SPC. In our case, discordant lesions were found in two different distant metastatic sites, including liver and brain, suggesting a likelihood of metastasis rather than 2 s primaries.

Rare prostate cancer subtypes such as small cell carcinoma and neuroendocrine carcinoma can metastasize to atypical sites. The incidence of prostate adenocarcinoma with intracranial metastasis is 0.7%, whereas it was 15.8% in prostate small cell carcinoma in one study. Intracranial metastases from prostate adenocarcinoma are uncommon, occurring in only 0.7–2.8% of patients and are often dural based. Treatment of brain metastases typically includes radiotherapy and surgical intervention, with median survival ranging from 4.6 to 13 months posttreatment. Hepatic metastasis is more commonly associated with neuroendocrine differentiation (also termed Neuroendocrine differentiation of Prostate Cancer (NEPC) transformation), and it is frequently associated with poor prognosis. Such lesions may show no uptake on [⁶⁸Ga] Ga-PSMA-11 PET/CT imaging but can be detected with [¹⁸F] FDG, which can be further explored on histopathology.

Neuroendocrine transformed cells in prostate cancer lack androgen receptor expression and PSA production while secrete peptides hormones and growth factors that promote tumor progression and contribute to treatment resistance. Reduced [⁶⁸Ga] Ga-PSMA-11 and high FDG uptake on [¹⁸F] FDG-PET/CT constitutes an important characteristic and correlates with GLUT overexpression and hexokinase overactivity.[5]

Conclusion

Dual tracer PET/CT imaging provides an accurate assessment of tumor burden and heterogeneity in prostate cancer patients with advanced disease. The discordant findings on PET/CT need to be evaluated further since they may have treatment implications in evaluating dedifferentiation and neuroendocrine transformation in prostate cancer with aggressive biology or detecting an altogether different SPC.