1 Background

Primary urethral cancers are rare and account for less than 1% of all malignancies [1]. They are uncommon in males and are mostly urothelial carcinomas (75%) and squamous cell carcinoma (12%). Only 6% are adenocarcinoma [2]. A review of 142 cases of male urethral cancer revealed no primary male urethral adenocarcinoma [3]. Clear cell adenocarcinoma (CCA) involving the male urethra is even more rare [4]. Ten definite cases in males have been reported in the literature, with none emanating from Africa. We report a CCA of the urethra in an adult African male presenting with features suggestive of a urethral stricture.

2 Case presentation

A 66-year-old Nigerian male of Yoruba heritage presented with mixed lower urinary tract symptoms of eight-month duration and intermittent bleeding per urethra. His symptoms culminated in an episode of acute urinary retention. Attempt at urethral catheterisation failed, necessitating suprapubic catheterisation, raising the suspicion of a urethral stricture. He had no prior history of urologic surgery, purulent urethritis or trauma to the pelvis, perineum or external genitalia. At presentation, he was pale. He had no significant peripheral lymphadenopathy. There was no palpable abdominal or groin mass, nor urethral induration. A digital rectal examination revealed an enlarged prostate with benign features.

A retrograde urethrogram revealed an incomplete narrowing of the proximal bulbar urethra with elevated bladder neck and multiple filling defects (Fig. 1). His clotting profile was within normal limits. Serum PSA was 4.7 ng/ml. An abdominopelvic ultrasound scan showed a normal liver and kidneys, with a thickened bladder wall and 60 cc prostate with a prominent middle lobe. Urethroscopy showed multiple polypoid masses in the anterior urethra with areas of necrosis and blood clots (Fig. 2). The 24Fr urethroscope could not be advanced beyond the bulbar urethra. Biopsies of the visualised masses were taken. A pelvic magnetic resonance image showed an anterior urethral hyperintensity which did not extend to the corpus spongiosum (Fig. 3a and b). There were no concerning features for prostate malignancy.

Fig. 1
figure 1

Retrograde urethrogram showing multiple irregular filling defects in the anterior urethra with contrast intravasation, most

Full size image
Fig. 2
figure 2

a Multifocal masses within the urethral lumen b Mass occluding the urethral lumen at the bulb

Full size image
Fig. 3
figure 3

MRI showing a predominantly hyperdense lesion within the penile urethra in a coronal view b Axial view

Full size image

The gross specimen comprised were multiple fragments of greyish white tissue. Cut surfaces of these fragments were greyish white in appearance with areas of haemorrhage and necrosis. The histology showed fragments of fibrocollagenous tissue infiltrated by malignant glands, solid nest of pleomorphic cells and papillary structures. The component cells had large hyperchromatic to vesicular nuclei with prominent nucleoli and abundant clear to pale eosinophilic cytoplasm on haematoxylin and eosin staining. These clear cells stained positively with periodic acid–Schiff (PAS) as shown in Fig. 4. Some hobnail cells were seen lining the lumen of cystically dilated acini containing mucinous material. Mitosis was brisk with abnormal mitotic figures. There were extensive areas of coagulative and haemorrhagic necrosis with mild infiltration by inflammatory cells mainly lymphocytes and neutrophil polymorphs. Immunohistochemical markers to affirm the urethral origin of the tumour such as PAX8 and PSA to rule out an invasive prostate carcinoma were unavailable in our immediate environment.

Fig. 4
figure 4

a Haematoxylin & Eosin, (H&E) × 40: Section shows diffuse sheet of malignant cells with abundant clear to pale eosinophilic cytoplasm b H&E × 400: Section shows clear cells with pleomorphic vesicular nuclei and prominent nucleoli c Periodic-acid Schiff (PAS) (× 400): Section shows the cytoplasm of the clear cells contain magenta-coloured PAS-positive glycogen

Full size image

The patient declined the options of a urethrectomy, cystoprostatourethrectomy and/or penectomy. He defaulted from definitive management but presented intermittently with symptomatic anaemia for which he received multiple blood transfusions. Two years after diagnosis, a home visit revealed significant weight loss with poor performance status. The tumour had infiltrated the suprapubic stoma and the scrotal skin was indurated (Fig. 5). Multiple groin lymph nodes were palpable. He died within two weeks of the last review.

Fig. 5
figure 5

Progression of disease two years following initial diagnosis

Full size image

3 Discussion

Primary urethral CCA is a rare and aggressive tumour found predominantly in women and may be associated with a urethral diverticulum [5]. The term CCA was proposed by Young and Scully in 1985 due to its histopathological spectrum similar to CCA of female genital tract. It may arise from either Müllerian rests or metaplastic urothelium. [4,5,6]

The main prognostic factors are location and depth of invasion. Anterior lesions tend to be superficial and have a good prognosis. Posterior lesions are deeply invasive and have higher rates of distant metastasis [7]. Compared with other urinary tract malignancies, the prognosis is poor. Patients often present with metastatic or locally advanced disease [5, 8]. Our patient presented with features of locally advanced disease, viz. obstructive symptoms, haematuria and bloody urethral discharge. Periurethral abscess and fistulae have also been documented to occur. [8]

Although our patient had a urethroscopy which shed more light on the diagnosis and ruled out benign urethral stricture as a differential diagnosis, a report from another centre in Southwestern Nigeria showed that only 7 percent of patients with suspected urethral strictures were able to have urethroscopies due to financial and resource-limited challenges [9]. Another report from Ethiopia highlighted the difficulties many Sub-Saharan or low-income nations face with access to endoscopy for routine diagnosis and/or therapeutics [10]. Endoscopic diagnosis is further recommended due to the presentation with visible haematuria [11]. The retrograde urethrogram, which is a cheaper and more readily accessible test in low-income nations, showed multiple filling defects which could have been neoplasms or inadvertent air bubbles, and the urethroscopy served as a complementary investigation to improve accuracy. [12]

Histologically, CCAs typically display tubulocystic, papillary, mucinous, villous and diffuse patterns [2, 13, 14]. Sun et al. [13] reported the papillary variant as the most common, followed by tubulocystic patterns. Typical cytological characteristics of clear cell adenocarcinoma include hobnail cells, flattened cells and cells with abundant clear cytoplasm. These cytologic features should aid in the distinction of CCA from benign nephrogenic adenoma, another rare but benign tumour. [13,14,15,16] CCA of the urethra exhibits positive immunohistochemical staining with PAS, paired box protein (PAX) 2, PAX8, cytokeratin (CK) 7, p16, p53, cancer antigen (CA) 125, cell adhesion molecule (CAM) 5.2, AE1/AE3 and stains negatively with prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), thrombomodulin, oestrogen, progesterone, CK20, p63, cluster of differentiation (CD) 10, polyclonal carcinoembryonic antigen (CEAp), Wilm’s tumour (WT) 1, alpha foetoprotein (AFP), S-100. [15, 17,18,19]

Due to the rarity of CCA of the urethra, the optimal treatment of the advanced disease is unknown [20]. Our patient declined any form of intervention, thus limiting the contribution of this report to intervention armamentarium. However, the scenario provided a natural history for the untreated case of primary urethral CCA. Cantrell et al. [21]treated their male patient with total pelvic radiation after staging pelvic lymphadenectomy. The patient died 26 months later. Seseke et al. [18] performed total urethrectomy with suprapubic urinary diversion. The patient died 30 months following his surgery. A case series of 15 CCA of various male genitourinary organs included two definite urethral and seven possible prostatic or prostatic urethral origins. This latter set was not included in the sum total of urethral cases reported in this write-up due to the uncertain origin. Therapies used included transurethral resections, targeted therapy with gefitinib, hormonal therapy and nivolumab immunotherapy. Poor prognosis occurred in those with ambiguous origin from the prostatic urethra or the prostate itself [22]. Other noted therapies for male urethral CCA include radical cystoprostatectomy, urethrectomy, bilateral inguinal and pelvic lymph node dissection and ileal conduit urinary diversion with adjuvant chemotherapy [20], partial penectomy with cystoprostatectomy and partial urethrectomy. [23]

There is a dearth of knowledge on the effectiveness of chemotherapy in the treatment of primary urethral CCA. Liu et al. [24] reported a case of metastatic urethral CCA in a male treated with maximal cystoscopic resection of the tumour and palliative systemic therapy (cisplatin and gemcitabine) intermittently for nearly 2 years. Second-line therapy with nab-paclitaxel was ineffective. Two other documented cases had no long-term follow-up. [4, 15]

4 Conclusion

CCA of the urethra is rare in men. It may be a cause of acute urinary retention in an adult male with lower urinary tract symptoms and bloody urethral discharge. Endoscopic investigations are recommended to aid diagnosis and as an adjunct to urethrography. A consensus for the optimal treatment of advanced disease has remained elusive due to paucity of cases.