Abstract
Background/Aim: Urothelial carcinoma, common in older adults, is rare in younger populations and even less common in the prostatic urethra. Advanced disease is typically managed with platinum-based chemotherapy, immune checkpoint inhibitors, and targeted therapies. However, rare presentations in young patients with aggressive disease highlight the need for innovative and personalized treatment strategies. Case Report: This case report presents a rare instance of metastatic urothelial carcinoma originating in the prostatic urethra of a 37-year-old male. Initial symptoms led to diagnosis through imaging, biopsy, and genetic profiling, revealing mutations in TP53 and RB1. The patient underwent multiple treatments, including dose-dense chemotherapy, pembrolizumab immunotherapy, and targeted antibody-drug conjugates (Enfortumab Vedotin and Sacituzumab Govitecan). Despite aggressive therapies, disease management remained challenging, leading to experimental treatments, including a personalized vaccine. Conclusion: This case underscores the importance of precision medicine and the need for innovative treatment options for rare and aggressive cancers.
Urothelial carcinoma represents the 9th most common cancer worldwide and the 2nd most prevalent malignancy after prostate cancer in middle-aged and older adult males. It is extremely rare in children and young adults (1). Until recently, the first-line standard of care treatment for metastatic cisplatin-eligible urothelial carcinoma (UC) patients has been either dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin (DD-MVAC) with growth factor support or gemcitabine and cisplatin, followed by maintenance with Avelumab (2). Based on NCCN guidelines, for patients with advanced urothelial carcinoma that has progressed after platinum-based chemotherapy and has a poor prognosis with limited treatment options, an immuno-therapeutic agent is recommended as the preferred second-line therapy. Pembrolizumab has been associated with significantly longer overall survival (OS) and with a lower rate of treatment-related adverse events than chemotherapy (3). We are reporting an extremely unusual case of a young patient with metastatic urothelial cancer arising from the prostatic urethra.
Case Report
A 37-year-old male presented to the emergency department (ED) in 2020 with fever, weight loss, decreased urinary stream, and a prostate-specific antigen (PSA) of 0.5 ng/ml. He was treated with urethral dilation. In March 2021, he visited the Weill Cornell Medicine (WCM) Genitourinary clinic with pelvic discomfort. A digital rectal examination (DRE) revealed a grossly abnormal finding, suggestive of an enlarged prostate, and his PSA was 0.05 ng/ml. Magnetic resonance imaging (MRI) of the pelvis revealed a bilobed 7.7 cm mass in the prostate region and bilateral external iliac lymph nodes, with the largest node on the left measuring 2.8 cm. A fluoro-deoxyglucose (FDG)-positron emission tomography (FDG PET) was performed and showed a heterogeneously intense FDG-avid enlarged prostate with an irregular, nodular left border, raising suspicion for primary malignancy. FDG-avid bilateral pelvic lymph nodes, suspicious for metastasis, were also identified (Figure 1A and B).
Fluorodeoxyglucose positron emission tomography (FDG PET) of the abdomen and pelvis. A) Abdominopelvic nodes with heterogeneously intensely FDG-avid prostatomegaly with an irregular nodular left border. B) FDG-avid bilateral pelvic nodes, left greater than right, are shown; additional subcentimeter abdominal retroperitoneal nodes below resolution of PET can be seen. C) We can observe a decrease in the size of the prostate gland. D) Arrows: orange, lymph node; green/blue, bladder; purple, prostate.
The patient had a prostate biopsy. The findings were consistent with poorly differentiated carcinoma compatible with high-grade urothelial malignancy, with positive markers for p63, GATA3, CK7, and PDL-1. Immunohistochemistry was negative for HER-2/neu and no abnormalities were detected in DNA repair mechanisms (MLH1, MSH2, MSH6, and PMS2). DNA and RNA were extracted from the tissue and then amplified using the Oncomine Comprehensive Panel (OCP) and subjected to next-generation sequencing (NGS). The Oncomine analysis on the biopsy revealed variants with potential diagnostic or prognostic implications (Tier 2), specifically RB1 splice site alteration and a TP53 nonsense mutation. Whole exome sequencing (WES) was performed, and no clinically significant mutations associated with the patient’s tumor were detected.
The patient provided consent to participate in Precision Medicine research and the sample was sent to BostonGene for comprehensive genomic profiling. The BostonGene platform uses whole exome sequencing and whole transcriptome sequencing to detect genomic alterations.
BostonGene Tumor Portrait™ was assembled as a DNA-only report, therefore it does not include gene expression, fusions, molecular functional portrait, tumor microenvironment, tumor transcriptomics and microenvironment composition.
According to the test, the patient has a low tumor mutational burden (TMB) of 1.42 mut/mb and stable micro-satellite status. The tumor was found to be monoclonal, with the presence of two mutations: a TP53 R196* nonsense mutation (VAF 14%) and an RB1 c.861+1G>A splice site mutation (VAF 19%), both likely oncogenic loss-of-function mutations. These mutations were also detected in another sample from the same patient, which was a biopsy specimen of a brain metastasis.
In April 2021, the patient began cycle 1 of Dose Dense - Methotrexate, Vinblastine, Doxorubicin, and Cisplatin (DD-MVAC). After completing four cycles of treatment by June, follow up scans showed a decrease in the size of the prostate gland, and prior FDG-avid pelvic lymphadenopathy had resolved (Figure 1C and D).
In July 2021, he underwent a cystoprostatectomy. The specimen was analyzed and showed a minute focus of residual (1.2 mm) poorly differentiated carcinoma in the right posterior midgland. The bladder was negative for carcinoma (Figure 2). In November 2021, follow up scans revealed no evidence of progression.
Bladder biopsy. Hematoxylin and eosin staining: The tumor is composed of large nests of atypical and pleomorphic epithelial cells with brisk mitotic activity, necrosis, and associated acute and chronic inflammation (200 μm).
In March 2022, the patient presented with slurred speech. A computed tomography (CT) scan was performed that evidenced a nodular hyperdensity of 11 mm in the frontal lobe (Figure 3). An MRI of the brain showed an enhancing mass in the left frontal lobe, consistent with an intracranial metastatic lesion (Figure 4). In March 2022, a left frontal craniotomy was performed. Findings in the pathology report showed a poorly differentiated carcinoma consistent with metastatic high-grade urothelial carcinoma, positive for CK7, GATA-3, p63, and PDL-1 (Figure 5). Oncomine was performed, revealing a Tier 2 RB1 splice alteration and TP53 missense mutation, as well as a Tier 3 TSC2 missense mutation.
Computed tomography (CT) scan of the head. CT scan of the head: 11 mm nodular hyperdensity within the left frontal lobe with surrounding hypoattenuation, suspicious for hemorrhagic mass with surrounding vasogenic edema. Contrast-enhanced MRI of the brain was recommended for additional characterization. There is no midline shift, herniation, or hydrocephalus. Chronic left cerebellar infarct is also noted.
Magnetic resonance imaging of the brain with and without intravenous Contras. Enhancing left frontal lobe mass with internal hemorrhage and surrounding adjacent vasogenic edema, most consistent with intracranial metastatic lesion in the setting of history of prior cancer. No midline shift or herniation. Additional enhancing focus in the right parietal lobe, suspicious for metastasis.
Biopsy of brain metastasis. A) Sections show a poorly differentiated metastatic carcinoma with (markedly bizarre cytomorphology and) frequent mitotic figures. Hematoxylin and eosin staining. B) Programmed death-ligand 1 (PD-L1) positive immune cells, which often show a cytoplasmic staining.
In April 2022, the patient had radiotherapy for the brain metastasis and in May 2022, he initiated cycle 1 of pembrolizumab. In July 2022, after cycle 3 of pembrolizumab he underwent new scans without evidence of progression. In August 2022, during cycle 4 of pembrolizumab, the patient presented to the emergency department with a focal seizure. An MRI was performed and a new 2.2 cm enhancement in the anterior aspect of the left frontal lobe was found (Figure 6). Surgery was again performed. In September, the patient received radiotherapy for his brain metastasis and continued with cycle 5 of pembrolizumab.
Magnetic resonance imaging of the brain revealing a new mass-like enhancement along the anterior aspect of the left frontal resection cavity, measuring up to 2.2 cm, with corresponding plasma volume elevation and surrounding increased vasogenic edema, raising concern for recurrent disease. Post-treatment changes are considered significantly less likely. The mass closely abuts the middle 3rd of the superior sagittal sinus. There is no midline shift or herniation.
In October 2022, the patient had a new MRI showing new dural metastases that were treated with proton beam radiotherapy and temozolomide, a radiosensitizer.
In November 2022, the patient received experimental combination therapy with C1 Sacituzumab Govitecan at 8 mg/kg on days 1 and 8, every 21 days, in combination with Enfortumab Vedotin at 1.25 mg/kg on days 1 and 8. He continued this treatment until March 2023.
In May 2023, an MRI showed no evidence of a new disease. He traveled for a personalized vaccine in Stuttgart, Germany. The personalized vaccine was applied along with an adjuvant typically Sargramostim/GM-CSF (LeukineR) and/or Imiquimod (AldaraR) to increase stimulation of the immune system. The plan includes a priming phase (four vaccinations within four days) and subsequent injections every 4-6 weeks planned for about 10-12 months.
In April 2024, the patient started cycle 1 of Bevacizumab. Later that month, he presented to the emergency department with right-sided weakness and speech changes. A computed tomography angiography (CTA) of the head was performed, revealing a left thalamic infarct. After this episode, he underwent a transthoracic echocardiography (TTE), which demonstrated a large patent foramen ovale (PFO), that could possibly explain the stroke mechanism. The PFO was closed. In June 2024, the patient underwent new scans, which showed no evidence of disease progression.
Urethral cancer is an uncommon malignancy, with the highest incidence rates observed among males, the elderly, African Americans, and those with urothelial histological subtypes (1). Men diagnosed with urethral cancer frequently have a medical history that includes sexually transmitted infections, urethritis, or urethral strictures (3). Strictures are primarily observed in the bulbomembranous portion of the urethra, which is also the segment most frequently affected by cancer, constituting 60% of all urethral cancer cases. This is succeeded by the penile portion in 30% of cases, and the prostatic section in 10% of cases (4).
The most frequent sites of metastasis in urethral cancer are the lymph nodes, liver, lungs, peritoneum, and bones. Metastases in the brain are rare and often indicate a poor prognosis (2).
Systemic treatment for metastatic urothelial carcinoma originating in the renal pelvis or ureter is guided by existing data on urothelial carcinoma of the bladder. Available systemic therapies include chemotherapy, immune checkpoint inhibitors, and targeted treatment options based on genomic testing results.
This patient was treated with DD-MVAC, which is a modification of the traditional M-VAC chemotherapy protocol used for the treatment of urothelial carcinoma, particularly in locally advanced and metastatic settings. The dose-dense approach involves administering the same drugs at higher frequencies, usually with shorter intervals between cycles, to improve the therapeutic index and potentially enhance treatment outcomes (5).
Subsequent pembrolizumab, a highly selective, humanized monoclonal antibody against programmed death 1 (PD-1) was administrated. Long-term data corroborate earlier findings, confirming the sustained clinical advantages of pembrolizumab over traditional chemotherapy in terms of both efficacy and safety for treating locally advanced or metastatic, platinum-refractory urothelial carcinoma (6).
Despite these first- and second-line therapies, the patient experienced disease progression, requiring alternative therapeutic strategies. Enfortumab Vedotin (EV) and Sacituzumab Govitecan (SG), both innovative antibody-drug conjugates, have received approval for use in patients with advanced bladder cancer who have previously undergone platinum-based and immune checkpoint inhibitor therapies. Specifically, EV, which targets Nectin-4, has been shown to enhance overall survival, especially in combination with pembrolizumab as compared with standard first-line chemotherapy (gemcitabine with either cisplatin or carboplatin) (4, 7). On the other hand, SG, which targets Trop-2, has demonstrated a response rate of 27%, and a phase III trial is in course. As these novel treatments emerge, it becomes imperative to comprehensively evaluate their safety and efficacy, to maximize patient outcomes (4, 5).
This patient has already received EV and pembrolizumab. New data are emerging that this combination is superior to platinum-based chemotherapy. Novel therapeutics are still needed for patients such as this young patient, whose case likely originates from the prostatic urethra and presents in an unusual manner.
Conclusion
This case highlights the complexity of treating metastatic urothelial carcinoma in a young patient, particularly with its unusual origin in the prostatic urethra. Despite conventional and advanced therapies, including chemotherapy, immuno-therapy, and targeted antibody-drug conjugates, disease management remained challenging. Ongoing advancements in targeted and immune-based therapies offer hope for improved outcomes in such rare and aggressive presentations.
Footnotes
Authors’ Contributions
Nara Shin: Project coordination, manuscript review. Alexandra Boiko: report coordination, manuscript review. Ivan Valiev: Bioinformatics. Alisa Zaichikova: molecular analysis. Victoria Fomchenkova: molecular analyst QC. Leysan Yunusova: clinical analysis. Sofia Smirnova: clinical analyst QC. Daniela Guevara (manuscript writing and review), Cora N. Sternberg, Juan Miguel Mosquera, Majd Al Assaad, Ahmed G. Elsaeed, David Nanus, Olivier Elemento: manuscript review. Jyothi Manohar, Michael Sigouros: Data curation.
Conflicts of Interest
Nara Shin, Alexandra Boiko, Ivan Valiev, Alisa Zaichikova, Victoria Fomchenkova, Leysan Yunusova, Sofia Smirnova are employees of BostonGene. The remaining Authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding
The Author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Englander Institute for Precision Medicine at Weill Cornell Medicine and New York-Presbyterian.
- Received November 5, 2024.
- Revision received November 19, 2024.
- Accepted November 21, 2024.
- Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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