PMC8503647_01
Clinical timeline, systemic therapy, imaging data, and pathologic diagnosis. (A) systemic therapy: continuous adjusted treatment protocols in disease progression and changes in the levels of PSA and NSE during the treatment course. (B) pathologic diagnosis: (left picture) HE staining revealing prostate adenocarcinomas in the prostate puncture tissue; (middle picture) HE staining revealing metastatic prostate adenocarcinoma with neuroendocrine differentiation in the thoracic vertebral tissue; (right picture) HE staining revealing small-cell cancer in the tissue after TURP surgery. Magnification: x200. (C) Imaging data: whole-body magnetic imaging resonance showing changes in the prostate lesion before treatment in July 2018. PSMA-PET/CT showing multiple bone lesions in May 2019, after termination of docetaxel chemotherapy, and elevation of the levels of the patient's PSA to 0.132 ng/mL. PSMA-PET/CT in June 2020 showing metastases in the left seminal vesicle, liver, and multiple bones. FDG-PET/CT in June 2020 showing metastases in the left seminal vesicle, liver, and multiple bones. PSMA-PET/MRI in November 2020 showing a metastasis in the posterior wall of the bladder, diffuse bone metastases, bilateral pleural effusion liquid, and a chronic subdural hematoma in bilateral brain. FDG-PET/CT in November 2020 showing multiple metastases in the bones and liver, and bilateral pleural effusion liquid, but no abnormalities in brain.
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Figure 1A ). From June 2018 to December 2020, the patient presented with three stages of prostate cancer, according to treatment, mHSPC, mCRPC, and small cell. Whole-body magnetic resonance imaging (WB-MRI) indicated metastases involving the prostate capsule, bilateral seminal vesicles, pelvic lymph nodes, and extensive osteosclerotic lesions ( Figure 1C ). Both WB-MRI and a bone scan showed no obvious active lesions in the prostate, pelvic lymph nodes, and bones ( Supplementary Figure 1 ). May 2019. Meanwhile, PSMA positron emission tomography (PET)/computed tomography (CT) revealed the presence of metabolically active lesions in multiple bones, but not in the prostate ( Figure 1C ). The posttreatment thoracic vertebral biopsy specimen revealed metastatic prostate adenocarcinoma with neuroendocrine differentiation ( Figure 1B ). Neuron-specific enolase (NSE) levels were elevated at 36.23 ng/mL ( Figure 1A ). However, PSMA-PET/CT revealed metabolically active lesions on the left seminal vesicle, liver, and multiple bones, indicating cancer progression ( Figure 1C ).
(A) Liver metastases detected using magnetic resonance imaging (MRI) in November 2019. (B) Response of liver metastases detected using MRI in January 2020 after treatment with etoposide combined with cisplatin and continued ADT plus pembrolizumab. Metastases are indicated by red arrows. (C) Clivus and adjacent right sphenoid bone metastases detected by MRI in April 2020. (D) Meningeal clivus and adjacent right sphenoid metastases in November 2020. Metastases are indicated by red arrows.
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Magnetic resonance imaging (MRI) revealed new lesions in the liver ( Figure 2A ). ADT therapy plus pembrolizumab specific for NEPC. After two cycles, an MRI showed that the liver lesions had almost disappeared ( Figure 2B ). A new MRI revealed metastases involving the clivus and adjacent right sphenoid bone ( Figure 2C ). We obtained four pre- and posttreatment biopsy specimens, which revealed the histological progression of tumors ( Table 1 ) ( Supplementary Figure 2 ).
The altered landscape and phylogenetic reconstruction of the two samples. (A) The second panel shows the cancer cell fraction estimated by using PyClone and calculated using the read depth of mutations, copy numbers, and purity of tumors. Other panels are showing the frequency of mutations in three types of prostate cancer using public data from the cBioPortal (1400 primary tumors, 54 NEPC samples, and 880 mCRPC samples). Important functional cancer genes are marked in red. (B) Overview of copy number alterations and cancer genes encompassed in segments are shown in red. (C, D) Fishplot indicating the dynamic clonal progression of the tumor, and clonal evolution tree showing the phylogenetic relationship between the two samples.
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We observed that both samples shared the most recent common ancestor (MRCA) encompassing 23 mutations and an exon1-exon13 truncation of the neurofibromin 2 (NF2) gene, indicating their common origin ( Figure 3 ). We integrated the mutation frequency of all mutated genes in different types of prostate cancer in this patient, according to the existing data using "cBioPortal" () as previously described ( Figure 3A ). Consequently, the two samples obtained individual subclones after MRCA in the clonal evolutionary tree ( Figures 3C, D ).