Case Report

Male Urethral Clear Cell Adenocarcinoma: Case Presentation and Literature Review of a Rare Cancer


  • Basil Razi
  • Jonathan Kam
  • Fiona Maclean
  • Howard Gurney
  • Mohan Arianayagam

Received Date: 07.03.2022 Accepted Date: 30.05.2022 J Urol Surg 2023;10(1):77-81

Primary urethral carcinomas account for less than one percent of all genitourinary cancers. Primary clear cell adenocarcinoma of the urethra (CCAU) is an extremely rare and aggressive tumor which predominantly presents in adult women but has rarely been documented in males. Diagnosis of CCAU is difficult as its clinical presentation shows significant overlap with various other conditions and carcinomas. Controversies remain regarding the histogenesis of CCAU. The histological diagnosis can be challenging and there are no definitive treatment guidelines. English literature to date only describes 17 previous cases of CCAU in males. Here we present an 18th case in a 29-year-old man.

Keywords: Clear cell adenocarcinoma, urethral cancer, nephrogenic metaplasia


Urethral malignancies are rare, compromising less than one percent of all genitourinary cancers (1). Clear cell adenocarcinoma of the urethra (CCAU) is the least common subtype, which is an aggressive tumor with a poor five-year survival rate and a strong female predominance (2). Diagnosis of CCAU is difficult as it often clinically presents similar to various other conditions and carcinomas (2). One previous case series of CCAU raised the possibility of association with diverticula, documenting their presence in 12 of 18 cases (3). The histopathological origin of CCAU is poorly understood and many possible theories have been postulated, including origins from mesonephric (4), Müllerian duct (5) or pre-existing areas of nephrogenic metaplasia (6). As the pathophysiology of CCAU is not fully understood there has been no definitive treatment guideline. The literature to date only describes 17 previous cases of CCAU in males. Here we present an 18th case in a 29-year-old man.

Case Report

A 29-year-old male presented with several weeks of macroscopic hematuria and perineal pain. Urine microscopy showed sterile pyuria and the cytology was atypical flexible cystoscopy revealed multiple papillary lesions in his urethra and a normal bladder. Subsequently, rigid cystoscopy, biopsy and diathermy of the urethral tumors were performed. Histopathological assessment demonstrated a clear cell adenocarcinoma, with superficial invasion of the lamina propria. The tumor had a tubulopapillary architecture and comprised large pleomorphic cells with hobnail cytology, eosinophilic cytoplasm, and areas of cytoplasmic clearing (Figure 1). A panel of immunohistochemical (IHC) stains was performed, with the tumour cells showing diffuse strong positive staining for PAX8, CK7, and p53, with MIB1 (Ki-67) staining 75% of tumour nuclei. There was no significant staining within the tumour cells for CK20 or GATA3. The morphology and IHC staining pattern were in keeping with a diagnosis of CCAU.

Magnetic resonance imaging (MRI) showed no significant invasive lesions in the urethra and staging computed tomography (CT) demonstrated no metastatic disease. The patient declined a cystoprostourethectomy and after a multi-disciplinary discussion, underwent a urethrectomy, apical prostatectomy and suprapubic catheter insertion. Despite the MRI findings, histopathology of the excision specimen did show the CCAU invaded the lamina propria of the urethra. No muscularis propria invasion was identified.

The patient was subsequently placed on a surveillance program, which comprised six-monthly cystoscopy and CT scans. Two and half years later, he was diagnosed with dyspnea. A CT at that time demonstrated mediastinal lymphadenopathy, pericardial and pleural effusions, and abnormal interstitial markings suggestive of diffuse lymphangitic disease within the lungs. Cytology and IHC of the pericardial fluid demonstrated metastatic clear cell adenocarcinoma.

He received four cycles of gemcitabine and cisplatin chemotherapy with complete radiological remission. Twenty months after chemotherapy, he developed metastatic disease to his left adrenal gland and pembrolizumab was started. There was no response and disease progression was shown on positron emission tomography-CT in the adrenal with new metastases in the para-aortic lymph nodes and liver. He was enrolled in a clinical trial and completed 6 cycles of enfortumab vedotin with further progression. Further gemcitabine and cisplatin treatment was associated with a significant radiological response, but isolated relapse occurred in the paraaortic nodes eight months later, treated with radiotherapy. Fifteen months further recurrence occurred in the kidney and liver that again responded platinum-based chemotherapy. Next-generation sequencing of the primary urethral tumour DNA revealed a mutation in SMARCB1 (p.T9Dfs*61NM_001007468.1 c.23dup, reflected by lack of staining for INI-1/SMARCB1 IHC). After further progression, he was started on tazemetostat, an inhibitor of enhancer of zeste-homolog-2 (EZH2), without response. He is currently relatively well and active, and on platinum-based chemotherapy awaiting a suitable phase 1 trial. Written and informed consent was obtained from the patient for the publication.


CCAU is a rare and aggressive carcinoma that predominantly affects females in 60-70 s (2). As with our case, CCAU typically present like a urothelial carcinoma with non-specific irritative or obstructive urinary symptoms including hematuria, frequency and dysuria. Histopathological features characteristic of CCAU include hobnail cells, clear cytoplasm and pleomorphic nuclei and mitotic figures (2,3,7). CCAU tumour cells exhibit a classic triad of tubulocystic, papillary and diffuse growth patterns, in variable proportions (2). The mainstay treatment for CCAU is surgical resection and in cases with pelvic lymph node involvement, radiotherapy may be of benefit, however there is a paucity of the literature surrounding the effectiveness of chemotherapy.

The histogenesis of CCAU is unclear, it was first described in 1973 by Konnak (4), who used the term “mesonephric carcinoma” postulating a mesonephric origin. However, most authors have suggested that CCAU most likely arises from a Müllerian (paramesonephric) origin (5,8,9) or areas of nephrogenic metaplasia, due to the morphologic and IHC overlap with the latter (6,10). Nephrogenic metaplasia/adenoma is a benign condition which is believed to arise in areas of chronic irritation or infection, and is most commonly seen in adult males (2,3,11). Interestingly, in renal transplant patients, nephrogenic adenomas have been shown to originate from the tubular epithelium of the donor kidney (12). In contrast, Kawano et al. (13), hypothesized that CCAU in females is an entirely separate entity, arising from the para-urethral ducts. Additionally, there appears to be an association between CCAU and urethral diverticulum, with possibly up to 56% of cases in females presenting in such a manner (3).

The relationship between nephrogenic metaplasia and clear cell adenocarcinoma remains controversial. Generally, nephrogenic metaplasia is usually thought of as benign though some evidence exists for its malignant potential (11). For example, Hartmann et al. (10), presented molecular evidence of the progression of nephrogenic metaplasia to clear cell adenocarcinoma in the urinary bladder. To date, in English literature, there have only been 17 reported cases of urethral clear cell adenocarcinoma in males (Table 1) with no clear demonstrable relationship to nephrogenic metaplasia. Here we present an interesting case of a male patient with evidence of both CCAU and nephrogenic metaplasia, which unfortunately progressed to distant metastasis. Furthermore, our case is the only one in the literature in which demonstrates a mutation in SMARCB1 and loss of INI1. Mehra et al. (14), demonstrated a dysregulation in different genetic/molecular pathways (ATM, ARID2). Whether nephrogenic metaplasia exists concurrently with CCAU or serves as a precursor to CCAU requires further study.

Despite the limited number of reported cases of CCAU in males, the prognosis is poor. Of the 17 previously reported cases, only three reported long-term survival past three years. Most of these cases presented with either irritative or obstructive symptoms and were treated with surgery and radiotherapy or chemotherapy. Seven patients progressed to distant metastases despite therapy. Only four patients received cisplatin-based chemotherapy; however three patients succumbed to progressive disease (15-18). In this study, the patient’s tumor seemed extremely sensitive to platinum-based chemotherapy but resistant to anti-PD-1 immunotherapy and a novel EZH2 inhibitor. This case report demonstrates to our knowledge the 18th case of CCAU in a male patient who appears  responsive to cisplatin-gemcitabine chemotherapy, partially responsive to immunotherapy, and is also the longest surviving CCAU patient in the literature.


Our case contributes to the current limited literature that shows that CCAU is an aggressive cancer and often presents with lower urinary tract symptoms. These patients should be closely monitored with regular surveillance for the development of local and distant metastases and managed with a multi-disciplinary input. Further studies are required to identify its relationship to nephrogenic metaplasia, which may reveal more robust treatment options.


Informed Consent: Written and informed consent was obtained from the patient for the publication.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices:  J.K., F.M., H.G., M.A., Concept: B.R., J.K., F.M., H.G., M.A., Design: B.R., J.K., F.M., H.G., M.A., Data Collection or Processing: B.R., J.K., F.M., H.G., M.A., Analysis or Interpretation: B.R., J.K., F.M., H.G., M.A., Literature Search: B.R., J.K., F.M., Writing: B.R., J.K., F.M., H.G., M.A.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.


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