Rare Penile Metastasis From Prostate Cancer Slips Past PSA Screening

Prostate cancer has a well-earned reputation for being one of the more trackable malignancies in medicine. Since the mid-1980s, a single blood test measuring prostate-specific antigen, or PSA, has served as the field’s most sensitive barometer of disease activity, rising and falling in near lockstep with tumor burden and treatment response. When PSA drops to low or undetectable levels after surgery, most clinicians consider the disease vanquished and often skip additional imaging or rectal examinations altogether. But a newly published case report in the open-access journal Heliyon delivers a sobering counterexample: a 76-year-old man whose prostate cancer spread to his penis, lungs, liver, and bones even while his serum PSA remained remarkably low, ultimately claiming his life. The report, authored by Zhu Wang and colleagues, documents fewer than 500 similar cases ever recorded in the medical literature and exposes a dangerous blind spot in how advanced prostate cancer can evade its most trusted surveillance tool.

The patient’s clinical journey began in January 2021, when he presented to an outpatient clinic with urinary frequency and progressive difficulty urinating. His initial serum total PSA measured 5.22 micrograms per liter, only modestly above the conventional 4 microgram-per-liter threshold that typically triggers concern. Magnetic resonance imaging revealed abnormal lesions in the peripheral zone of both sides of the prostate, and transrectal biopsy confirmed the suspicion: prostate adenocarcinoma with a Gleason score of 9 (4+5), one of the most aggressive grades assigned to this disease. The clinical stage was classified as T3aN0M0, indicating locally advanced disease that had not yet spread to lymph nodes or distant organs. Because of COVID-19 pandemic disruptions, radical surgery was postponed, and the patient instead began combined androgen blockade using bicalutamide and goserelin, a hormonal regimen designed to starve the cancer of the testosterone it craves.

Two years later, in February 2023, the patient was admitted with worsening urinary symptoms. Repeat MRI showed an enlarged prostate with lesions essentially unchanged from prior imaging, and a bone density scan detected no abnormalities. After a multidisciplinary team evaluation, he underwent laparoscopic radical prostatectomy in March 2023 without complications. Postoperative pathology reconfirmed the high-grade adenocarcinoma, and endocrine therapy with bicalutamide and goserelin continued. By June 2023, follow-up labs showed the total PSA had fallen to 0.86 micrograms per liter, while serum testosterone was undetectable. On paper, everything suggested the treatment was working: the primary tumor had been removed, hormonal therapy had chemically castrated the patient, and the biomarker that defines prostate cancer activity had collapsed to near-baseline levels.

Then, in August 2023, the picture shattered. The patient noticed a soybean-sized mass on his penis, accompanied by urinary frequency, urgency, painful urination, and five to six nighttime bathroom trips. Physical examination revealed a firm mass roughly three centimeters long within the penile corpus cavernosum, the spongy erectile tissue. Doppler ultrasonography identified a solid lesion measuring 26 by 16 by 11 millimeters in the left corpus cavernosum, suspicious for malignancy. MRI confirmed a solid mass with a high probability of metastatic tumor. Critically, his serum PSA at that moment was just 2.58 micrograms per liter, well within a range many clinicians would consider reassuring. He underwent resection of the penile lesion on August 24, 2023, and histopathology revealed poorly differentiated adenocarcinoma with intravascular tumor thrombus, evidence that cancer cells had already invaded blood vessels.

Immunohistochemical staining settled the question of origin. The tumor cells showed diffuse positive expression of androgen receptor, PSA, and P504s, also known as alpha-methylacyl-CoA racemase, a molecular fingerprint characteristic of prostate adenocarcinoma. The diagnosis was confirmed: penile metastasis from prostate cancer, an event with an estimated incidence of only 0.3 to 0.5 percent among prostate cancer patients. By October 2023, the disease had exploded. MRI detected multiple masses in both corpora cavernosa, the right ischium, and the left pubic ramus. Contrast-enhanced CT revealed scattered solid nodules in both lungs, a lesion in the right lobe of the thyroid, and multiple growing liver metastases, the largest measuring about 20 millimeters. His PSA had climbed to 13.39 micrograms per liter, and the team concluded he had relapsed with castration-resistant disease.

The authors place this case within a broader biological framework that may explain the paradox of metastasis without high PSA. In metastatic castration-resistant prostate cancer, low PSA levels often signal neuroendocrine differentiation, a process in which tumor cells undergo what researchers call lineage plasticity. Under the selective pressure of continuous hormonal therapy, adenocarcinoma cells accumulate genomic alterations such as RB1 and TP53 mutations and epigenomic changes including DNA methylation and EZH2 overexpression. The splicing regulator SRRM4 induces alternative splicing that produces a non-functional variant of the neuronal repressor REST, while upregulation of N-MYC, PEG10, and transcription factors like BRN2, SOX2, and SOX11 grants the cells stem-like and neuron-like properties. The cells shift toward a mesenchymal state, marked by elevated vimentin and SNAIL, suppressed androgen receptor signaling and its downstream genes including PSA, and increased neuroendocrine markers such as synaptophysin, chromogranin A, and neuron-specific enolase. The result is a tumor that proliferates aggressively but no longer manufactures the very protein clinicians use to track it.

The authors acknowledge an important limitation: their penile tumor specimen was not stained for neuroendocrine markers, so the evidence for this mechanism in the present case remains indirect. Still, the anatomical route of spread is clearer. Roughly 75 percent of metastatic penile cancer originates from adjacent genitourinary and pelvic organs, chiefly the bladder at 28.6 percent and the prostate at 27.9 percent. About 90 percent of secondary penile tumors disseminate through veins and lymphatics, with the remainder arriving via direct extension or iatrogenic implantation. In this patient, retrograde venous or lymphatic dissemination is the most likely mechanism, supported by the locally advanced initial stage, the intravascular tumor thrombus seen on histopathology, the corpus cavernosum involvement, and the rapid systemic dissemination that followed.

The clinical trajectory after the penile diagnosis was relentless. In November 2023, PSA reached 32.5 micrograms per liter and PET-CT identified extensive systemic metastases. By January 2024, the patient required a suprapubic cystostomy to manage urinary obstruction, and PSA had risen to 39.60 micrograms per liter. Treatment escalated through abiraterone and then enzalutamide, but by April 2024 PSA had surged to 253.01 micrograms per liter, and by late June it hit 577.47. Testosterone remained below detection, confirming that the cancer no longer depended on androgens. Laboratory values painted a picture of systemic decline: low potassium, low albumin, anemia with hemoglobin of 91 grams per liter, and elevated inflammatory markers including C-reactive protein at 71.38 milligrams per liter. Androgen deprivation therapy offered no benefit, so the team transitioned to metronomic therapy with opioid pain control. The patient died in August 2024, 43 months after his initial diagnosis and just 12 months after the penile metastasis was detected.

Survival statistics for this rare complication are grim across the literature. A 2006 review by Cherian and colleagues collected 372 cases of secondary penile tumors, 125 of them from prostate cancer, and found most patients died within a year of presentation. A 2023 update by Landen and colleagues added 72 new cases documented between 2006 and 2021, reporting a median cancer-specific survival of 14.3 months for prostate primaries. Approximately 41 percent of patients with prostate-derived penile metastasis die within six months of diagnosis, and those who develop malignant priapism fare even worse. Metastasis-directed therapies such as surgical excision, radiotherapy, and stereotactic body radiation can achieve favorable local PSA responses and relieve symptoms, but no study has demonstrated a meaningful overall survival benefit. For patients whose low PSA reflects neuroendocrine differentiation, current guidance suggests prioritizing chemotherapy with agents like docetaxel or cabazitaxel, platinum-based regimens, or emerging targeted therapies rather than continuing androgen deprivation alone.

The takeaway from this case is a call for diagnostic humility. The authors recommend that any patient presenting with penile complaints and a history of prostate malignancy should be suspected of harboring penile metastasis, even when bone disease appears controlled and PSA sits in the low range under hormonal therapy. Patients with high-grade, locally advanced prostate cancer and atypical features deserve heightened vigilance. Beyond conventional PSA testing, the report advocates complete physical examination, imaging with MRI or, preferably, gallium-68 PSMA PET/CT, the most sensitive modality for detecting prostate cancer metastasis, and additional serum biomarkers. Notably, this patient never received PSMA PET/CT because it was not part of routine workup at the treating institution, and the authors concede its absence may have allowed additional metastatic lesions to escape detection. As prostate cancer treatment extends survival for millions worldwide, this case stands as a vivid reminder that the disease can rewrite its own molecular identity, slipping beneath the biomarker radar precisely when clinicians feel most confident it has been defeated.

Subject of Research: Penile metastasis of prostate cancer occurring with low serum PSA levels

Article Title: Prostate cancer metastasis to the penis with low serum prostate specific antigen level: A case report

Article References: Wang, Z., Lai, Y., Wu, H., Zhang, J., Liang, H., & Wang, X. (2026). Prostate cancer metastasis to the penis with low serum prostate specific antigen level: A case report. Heliyon, 12(15), Article e45456. https://doi.org/10.1016/j.heliyon.2026.e45456

Image Credits: AI Generated

DOI: 10.1016/j.heliyon.2026.e45456

Keywords: prostate cancer, penile metastasis, PSA, castration-resistant prostate cancer, neuroendocrine differentiation, androgen deprivation therapy, PSMA PET/CT, case report, lineage plasticity, immunohistochemistry, Gleason score, Heliyon