1 INTRODUCTION
A small percentage of individuals with advanced-stage prostate cancer have changes in the differentiation pathway, which can lead to a neuroendocrine/anaplastic transformation[
1,
2]. Normal prostate tissue contains androgen receptor-negative neuroendocrine (NE) cells, which may help to sustain early neoplastic alterations. These cells may become more active as a result of microenvironmental alterations brought on by androgen deprivation therapy (ADT). At the very least, it is certain that a lack of testosterone led to their selection. The substances that the growing number of NE cells excrete, help the carcinoma prostate (CaP) cells proliferate in an androgen-independent way, gradually becoming more independent of androgen regulation[
2].
Because tumors exhibiting this phenotype typically represent an intrinsically endocrine-resistant subtype, and because their clinical and biological characteristics differ from those of a typical prostate adenocarcinoma, these tumors also necessitate distinct treatment approaches. The therapeutic implications of this finding are significant.
Patients with such tumors typically exhibit advanced stages of the disease, and fast-growing disease accompanied by any of the following clinical features should trigger an evaluation for the neuroendocrine subtype: pelvic masses, visceral involvement, osteolytic metastasis with hypercalcemia (linked to elevated serum parathyroid hormone-related protein), and parenchymal brain metastases.
With penile metastases and urinary retention, our case exemplifies an exceptional presentation of neuroendocrine prostate cancer. It highlights the effectiveness of ADT and radiation therapy, but it also highlights the cancer's rapid visceral spread, adding to its complexity.
2 CASE PRESENTATION
A 61-year-old South Asian gentleman presented with a complaint of inability to void, palpable painful bladder and penile swelling that was gradually increasing in size. A suprapubic catheter had to be inserted. The patient was a beedi smoker (one pack containing 20–25 beedis every day, for the past 30–40 years), an occasional alcoholic, a well-controlled diabetic and hypertensive, with no relevant family history. On physical examination, the patient was found to have a hard penile lump measuring 2.5 cm × 2.5 cm × 1 cm, situated on the distal penile shaft. As a part of the urologic examination, a digital rectal examination was done and the patient was found to have a hard prostate, which was further biopsied and proved to be adenocarcinoma prostate (Gleason Score 4 + 4) with neuroendocrine differentiation. The patient did not have any symptoms suggestive of neuroendocrine tumors, nor did he exhibit any cognitive symptoms.
Baseline prostate-specific antigen (PSA) was 6.08 ng/mL, at the time of presentation. Imaging and fine-needle aspiration cytology of the penile lump revealed the presence of metastatic penile involvement with neuroendocrine differentiation. Cytomorphology (Figure 1A,B) showed cohesive acinar clusters of tumor cells and neuroendocrine differentiation indicated by cells with a high nuclear-to-cytoplasmic (N:C) ratio and crushing. Tumor cells with neuroendocrine differentiation showed nuclear molding with stippled chromatin (Figure 1C). Cell block section (Figure 1D) showed similar morphology to that in Figure 1C. There was strong, granular and diffuse positivity for PSA (Figure 1E), confirming metastasis from the prostate. Diffuse cytoplasmic staining with synaptophysin (Figure 1F), confirmed neuroendocrine differentiation.
Magnetic resonance imaging (MRI) of the pelvis (Figure 2) demonstrated the dimensions of the large multilobulated infiltrative prostatic mass to be 7.5 cm × 6 cm × 5 cm, infiltrating along the prostatic urethra and penile shaft, involving the corpora spongiosa, with multifocal discontinuous lesions along the tunica albuginea around the left corpus cavernosum. Prostate-specific membrane antigen positron emission tomography-computed tomography (PSMA-PET-CT) findings also confirmed the same, along with presence of lymph nodal and skeletal metastases to the right femur and iliac bone. The patient was started on a combination of palliative pelvic radiotherapy (30 Gy over 10 fractions, in 2 weeks) and androgen deprivation therapy (leuprolide acetate) followed by five cycles of taxane-based (docetaxel) chemotherapy. PSA decreased to 2.39 ng/mL after 4 months of treatment, and 0.009 ng/mL at 8 months of treatment.
Repeat PSMA-PET-CT (done postradiotherapy and first cycle of chemotherapy, i.e., 6 months after the initial one) confirmed complete resolution of penile and lymph nodal metastatic lesions (no tracer uptake was noted in the pelvis and penis), with the appearance of a new renal exophytic lesion (measuring 4 cm × 3.6 cm × 3.5 cm, which was subsequently confirmed to be metastatic neuroendocrine involvement on biopsy), lung nodules and clavicular metastases (tracer-avid lytic expansile lesion with soft tissue mass measuring 6.5 cm × 4 cm × 4.9 cm in the lateral half of right clavicle).
The patient was able to void via the urethral route, subsequent to resolution of the penile metastases. Subsequently, the patient was receiving second-line cisplatin-based chemotherapy (since neuroendocrine tumors are sensitive to platinum-based treatment)[
3], that is, at 9 months of follow-up. Due to the aggressive nature of the disease and intolerable side effects, the patient's outcome was unfavorable, resulting in mortality at 12 months of follow-up.
3 DISCUSSION
Only three cases of penile metastasis from prostatic neuroendocrine carcinoma are reported in the literature[
4–
6] (a detailed comparison of all four cases is outlined in Table 1). Our case was different from other cases reported in that the patient presented with penile lump and acute urinary retention, which completely resolved with pelvic radiotherapy and ADT. Despite localized treatment successes, our case serves as a poignant reminder that aggressive tumor phenotypes demand ongoing vigilance and comprehensive management strategies.
A limitation of our case study was that after local radiotherapy, a follow-up MRI of the pelvis was not done, which would have exactly gauged and documented the degree of resolution of the prostatic pathology and the penile lesions. We also acknowledge the single-case nature of the report, potential biases, and the need for further research.
Possible reasons for penile metastases in prostate cancer with neuroendocrine differentiation include: aggressive tumor biology coupled with the rich vascularity of the penis, hormone-refractory disease and advanced tumor stage. The prognosis in such cases is uniformly poor.
Patients with neuroendocrine tumors (such as lung small cell carcinoma) typically receive treatment for their neuroendocrine/anaplastic phenotype with combinations of cisplatin and etoposide[
8] or a taxane plus carboplatin[
3].
Table 2 summarizes the current different treatment approaches, their rationale, and advantages.
By improving our knowledge of early post-castration molecular processes, NED (neuroendocrine differentiation) can be targeted for adjunctive treatment, which will reduce the amount of CaP cells that resist hormone regulation. Molecular expression profiling will be made possible by novel markers and associated imaging modalities for NED, enabling personalized treatment plans based on each patient's distinct microcellular environment[
2].
Future case studies on penile metastasis from neuroendocrine prostate cancer should investigate rare metastasis patterns, treatment efficacy, and correlations between tumor biology and outcomes. Research questions may include clinical and pathological characteristics, treatment outcomes, biomarker utility, and patient-related factors. Multicentre, international collaborations and data-sharing platforms can facilitate research.
4 CONCLUSION
This case of penile metastasis from prostatic neuroendocrine carcinoma adds to the limited literature on this rare presentation, highlighting its unique manifestation with penile lump and acute urinary retention, which resolved with pelvic radiotherapy and ADT. While localized treatments proved successful, this case underscores the importance of ongoing vigilance and comprehensive management in aggressive tumor phenotypes.
2025 The Author(s). UroPrecision published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.
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