Introduction
Bladder cancer is a very common cancer of the urinary system and the ninth most common type of cancer worldwide. Bladder cancers are categorized as urothelial and non-urothelial histologic types. Urothelial carcinoma (transitional-cell carcinoma) is the predominant variety with an incidence of around 90–95%. Non-urothelial histology is further subdivided as epithelial and nonepithelial. Those of epithelial origin are adenocarcinoma, squamous cell carcinoma, and small cell tumors [1]. Nonepithelial cancers are very rare and include sarcomas, paragangliomas, melanomas, and lymphomas. Squamous cell carcinoma and adenocarcinoma represent only 3 and 2% of the primary bladder cancer cases, respectively. The most common age-group affected by adenocarcinoma is around 50–60 years. Patients with bladder exstrophy or persistent remnant urachus are at a higher risk of developing vesical adenocarcinoma. Chronic inflammation of the bladder mucosa induces metaplasia to the more protective squamous cell or glandular-type epithelium. Bladder adenocarcinoma is resistant to chemotherapy and radiation, so surgery is currently considered the most effective treatment option [3]. Thus, early diagnosis is crucial. Mucinous subtype of primary bladder adenocarcinoma (PBA) is extremely rare. Progressive change from mucinous metaplasia to mucinous adenoma to mucinous adenocarcinoma has been suggested as pathogenesis [2]. Diagnostic investigations are urinary cytology, cystoscopy, and biopsy followed by histopathological evaluation. To differentiate primary bladder adenocarcinoma from secondary type, immunohistochemistry might be helpful. Due to the unique etiopathogenesis and clinical course, management, and prognosis when compared to urothelial cancers and the relative lack of clinical reports, we herein report the case of a patient with primary mucinous adenocarcinoma of the bladder to help elucidate the characteristics of this tumor.
Case Report
The patient was a 63-year-old male, nonsmoker, and nondrinker, who presented with suprapubic pain for 5 months. He had history of hematuria for past 1 month.
The initial cystoscopy biopsy report was that of muscle-invasive urothelial carcinoma. As a part of staging workup, he underwent PET CT scan, which showed focal polypoidal mural thickening involving base of the bladder near the bilateral VUJ and neck of the urinary bladder without distant metastasis (Fig. 1). His renal parameters were within normal limits. As he had locally advanced urothelial cancer, radical cystectomy and urinary diversion were planned; he underwent laparoscopic radical cystoprostatectomy with pelvic lymph node dissection and urinary diversion by ileal conduit using Wallace uretero-ileal anastomosis. Intraoperatively, the prostatic urethral margin was sent for frozen section and was positive for malignancy, and hence urethrectomy was done.
Fig. 1.
PET CT showing tumour involving bladder base
Final histopathology showed ill-defined glands with solid nests of malignant epithelial cells invading the lamina propria and muscularis propria of the bladder. Resection margins were free and pelvic lymph nodes were free of tumor. There was abundant extracellular mucin with clusters of tumor cells floating in mucin lakes (Fig. 2). The individual tumor cells show high nucleocytoplasmic ratio and severe nuclear pleomorphism. Immunohistochemistry showed CK20 positivity, CDX-2 negativity, and GATA3 negativity confirming primary bladder adenocarcinoma (Fig. 3). The patient recovered well after surgery. He has been recommended to undergo clinical evaluation once every 3 months and computed tomography every year as follow-up.
Fig. 2.
Abundant extracellular mucin with clusters of tumor cells floating in mucin lakes
Fig. 3.
a GATA3 negativity, b CDX-2 negativity, and c CK20 positivity confirming primary bladder adenocarcinoma
Discussion
Mucinous primary bladder adenocarcinoma (PBA) is a rare type of cancer, accounting for < 2% of all bladder cancers [4]. It usually appears at the bladder dome, trigone, and lateral wall. PBA occurs more frequently in geographic regions where schistosomiasis is endemic and is the most common cancer arising in the bladder of patients with exstrophy, who have a higher risk than the general population [5]. PBA is categorized as urachal and non-urachal adenocarcinoma because of the different natural history, pathologic diagnosis, and prognosis and treatment. Approximately 70% of PBA cases arise in the bladder cavity, especially in the posterior wall and trigone, and approximately 30% originate from the urachal remnant near the dome and anterior wall of the bladder. Distinguishing mucinous bladder adenocarcinoma from urachal carcinoma is crucial but may be challenging due to similar presentation. The treatment of urachal carcinoma is partial cystectomy with en bloc resection of the urachus, rather than radical cystectomy. In addition, urachal carcinoma has a better prognosis and high survival rate compared with mucinous adenocarcinoma of the bladder [6].
There are two hypotheses regarding the histological origin – the first is a vestigial embryonal gland in the transitional epithelium of the bladder, and the second is the transitional epithelium of the bladder undergoing glandular metaplasia [7]. Chronic irritation, like recurrent UTI, induces metaplasia of the bladder mucosa causing glandular cystitis – precancerous condition for bladder adenocarcinoma. The accumulation of secretions and associated secondary infection may promote the development of adenocarcinoma.
PBA is an epithelial neoplasm characterized by a neoplastic glandular structure lined by mucin-secreting cells similar to intestinal carcinoma. Adenocarcinoma cells grow by infiltration into the deep muscular layer; thus, cystoscopy and B-mode ultrasound may be unable to assess the extent of infiltration. So, majority of bladder mucinous adenocarcinoma patients are stage T2 or T3 at diagnosis. When a tumor is identified at the bladder dome, trigone, or lateral wall or in patients presenting with mucous floccules in the bladder during micturition or cystoscopy, the diagnosis of mucinous PBA should be considered.
The main primary symptom is hematuria, with or without signs of irritation of the bladder. The diagnosis is based on investigations such as cystoscopy, urinary cytology CT, and transurethral biopsy of the bladder tumor.
Morphologically, PBA causes a diagnostic dilemma for pathologists because it is difficult to differentiate from secondary involvement of the bladder by adenocarcinomas arising in adjacent organs, typically the colorectum, prostate, and female genital tract [8]. This distinction is important to define staging and prognosis and to deliver appropriate therapy. In the reported case, extensive workup ruled out both the possibility of other sites of primary tumor and the possibility of metastasis, confirming the diagnosis of a primary bladder lesion. The prognosis of mucinous bladder adenocarcinoma depends mainly on the stage at diagnosis. For bladder-confined tumor, the survival rate is 75% (Table 1).
Table 1.
Other studies on adenocarcinoma of the bladder
| Study | Total cases | Adenocarcinoma | Overall survival rates | 5-yr DPFS rates |
|---|---|---|---|---|
| Rogers et al. 2005 (TCC vs non-TCC) | 955 | 13 (1.3%) | 68% (TCC) vs 13% | 60% (TCC) vs 8% |
| Zaghloul et al. 2006 (subtypes of adenocarcinoma) | 3659 | 192 (5.24) | 46% | |
| #Grignon et al. 1991 (urachal vs non-urachal) | 72 | 72 | 61% (urachal) vs 31% (non-urachal) | |
| *Wright et al. 2006 | 1525 | 48% (urachal) vs 35% (non-urachal) |
# – one of the very first studies of primary bladder adenocarcinoma
*– 28-year analysis of SEER data, largest population-based study
Immunohistochemical staining is helpful to distinguish PBA from secondary neoplasm involving the bladder, most commonly colorectal adenocarcinoma. CK 20 is a marker of adenocarcinoma, CDX-2 and beta-catenin are strong indicators of colorectal malignancy, and GATA 3 is a marker of urothelial malignancy. In our patient, immunohistochemistry showed CK20 positivity, beta-catenin weak positivity, and CDX-2 and GATA3 negativity, confirming primary bladder mucinous adenocarcinoma ruling out secondary spread from colorectal cancer [9].
Current clinical decisions on the treatment of PBA are based on small case series and case reports as there are no prospective randomized trials. The natural history and clinical behavior of urachal carcinoma are distinct from those of non-urachal carcinoma. Radical cystectomy with pelvic lymph nodes dissection is the treatment of choice for patients with non-urachal bladder adenocarcinoma. Local relapse after radical cystectomy is common, and few centers advice adjuvant radiotherapy. A non-randomized retrospective series of the Egyptian National Cancer Institute showed that disease-free survival was 37% in patients who underwent cystectomy alone compared with 61% of patients treated with cystectomy followed by radiotherapy. There is no established evidence for role of chemotherapy for metastatic disease or adjuvant chemotherapy for patients with PBA. In a series of MD Anderson Cancer Center, 20 patients with metastatic urachal adenocarcinoma of the bladder treated with chemotherapy (largely 5-fluorouracil and cisplatin-based regimen) had a median survival of 20 months. Only 4 of 20 patients responded to chemotherapy without a significant survival improvement. In a prospective study of ifosfamide, paclitaxel, and cisplatin in men with advanced non-urothelial bladder cancer (11/20 were adenocarcinomas), Galsky et al. reported a response rate of 38% and median overall survival of 25 months.
The natural history, etiopathogenesis, and clinical course of primary bladder adenocarcinoma are different from that of urothelial malignancies of the bladder. Though these patients present at an advanced stage, they are still treatable with radical surgery as there is no role for chemoradiation in bladder adenocarcinoma. Mucinous bladder adenocarcinoma is mostly secondary and metastatic from colonic primary, and hence an immunohistochemistry evaluation to ascertain that they are primarily from the bladder helps in further management of the patient. When compared to urachal adenocarcinoma which is less aggressive and can be even managed by partial cystectomy, non-urachal primary bladder adenocarcinoma warrants radical surgery as the best treatment option.
There is a proven role of cytoreductive surgery and hyperthermia intraperitoneal chemotherapy for mucinous tumors of other organs with peritoneal metastasis [10]. Similar role of HIPEC for primary bladder mucinous adenocarcinoma with peritoneal recurrence is an exciting treatment option, yet to be evaluated by clinical trials.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Footnotes
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