Bladder adenocarcinoma (BAC) is rare, accounting for only 0.5–2% of bladder malignancies (1, 2). According to clinical and pathology multidisciplinary diagnostic criteria, BAC can be classified as urachal adenocarcinoma (UrAC), primary BAC, and metastatic adenocarcinoma. UrAC accounts for about 10% of BAC (3, 4). The incidence of BAC is higher in patients with bladder exstrophy (90%) and in regions where schistosomiasis is endemic (9%–10%) (5), owing to the rarity of the disease, the pathogenesis and natural history of BAC have not been well defined (6).

Primary BAC is usually treated with radical cystectomy, while UrAC is usually treated with partial cystectomy; thus, differentiating these two diseases is very important (7). There is good reason to believe that the prognoses of UrAC and primary BAC differ (8). In most studies, UrAC had a better prognosis than primary BAC (8–11). Most of these studies examined the Surveillance, Epidemiology, and End Results (SEER) database, which were limited by race, economy, education level, medical technology development level and incomplete data although the cases were large (8, 9). While these data are of great significance to the American population, China lacks long-term, reliable data for prognostic evaluation of UrAC and primary BAC, as a country with a high incidence of bladder cancer.

Urothelial carcinoma (UC) is the most common histological type of bladder cancer and is characterized by histological variation. The 2016 World Health Organization (WHO) classification of urothelial and reproductive system tumors distinguishes 12 subtypes, the prognoses of which differ significantly from that of typical UC, usually characterized by high grade and stage on discovery, rapid progression, and high recurrence and metastasis rates (12). Glandular differentiation, the second most common subtype, accounts for about 6% of UCs and is diagnosed based on true glandular involvement, excluding pseudoadenoid areas caused by necrosis and cells containing intracellular mucus (8). Many studies have reported prognosis differences between urothelial carcinoma with glandular differentiation (UCGD) and UC, UC and BAC. However, the prognosis difference between BAC and UCGD, two clinically differentiated diseases, is rarely reported.

Therefore, this study compared the prognosis and prognostic factors of three pathological types of bladder tumor: UrAC, primary BAC, and UCGD. Our results may provide guidance for Chinese clinicians.

UrAC, primary BAC and UCGD are rare pathological types of bladder cancer that have been relatively understudied due to the small numbers of cases. There have been five comparative systematic prognostic studies of UrAC and primary BAC, none of which examined a Chinese population (8–11, 16). And the prognostic difference between BAC and UCGD, two clinically confused diseases, is rarely reported. Therefore, this study analyzed cases from 2005 to 2019, seen at a single center in China, to compare the prognosis and prognostic factors of UrAC, primary BAC, and UCGD.

In our series, we found significant differences in clinical and neoplastic features among the UrAC, primary BAC, and UCGD groups. The median age of the UrAC group was about 10 years lower (52 years) compared with the primary BAC and UCGD groups (61 and 64 years, respectively). There was an overwhelming male predominance in all three groups. However, the previously reported significantly higher proportion of men with UrAC versus the other types was not seen, which we believe was related to the small sample size. Interestingly, poorly differentiated tumors were less common among the UrAC patients, although they had more advanced T stages. Combined with previous studies, we believe that high stage and high differentiation are clinicopathological features of UrAC in particular. Partial cystectomy was the most common surgical method for UrAC, while total cystectomy was the most common for UCGD (17, 18). However, almost equal numbers of primary BAC patients underwent transurethral resection, partial cystectomy, and total cystectomy as the first operation. We believe that this is attributable to surgeon preferences. Many factors play a role in management decisions, such as patient preference, tumor location, degree of differentiation, whether the tumor is isolated, and comorbidities. BAC can perform various phenotypes: mucinous/colloid, enteric/colonic, signet-ring cell, clear cell, hepatoid, mixed and adenocarcinoma not otherwise specified (NOS; if without a specific glandular growth pattern) (12). Mucinous adenocarcinoma is considered a less aggressive histological subtype (19) and was more common in UrAC than primary BAC patients in this study, consistent with previous results.

The survival advantage of UrAC is controversial. Grignonet et al. (11) reported a 5-year OS of 61% for UrAC and 31% for primary BAC. Wright et al. (8) found that the 5-year OS of UrAC patients was higher than that of primary BAC patients. Anderstromet et al. (19) published similar results, a survival advantage for UrAC, although this was not statistically significant. By contrast, Wilson et al. reported a 3-year cancer-specific survival rate of 31% for patients with UrAC and 48% for those with primary BAC (20). The reported 5-year survival rates are 27–61% and 11–55% for UrAC and primary BAC, respectively (5, 21–23). In our series, we found that patients with UrAC had a longer median survival time and lower risk of death compared with patients with primary BAC.

Bladder cancer is a heterogeneous entity characterized by a wide range of morphologies and clinical processes. Due to the ability of urothelial cells to differentiate polytropically and heterotrophically, there are many heterotrophic subtypes. In 2016, the WHO distinguished 12 subtypes of UC, including those with squamous differentiation and glandular differentiation (24). The WHO defined UCGD as a mixed tumor with glandular and urothelial differentiation, because its clinical manifestations and pathology are similar to many other bladder lesions, including BAC (which is prone to misdiagnosis and mismanagement) (25). Reports on the prognosis of UC and UCGD indicate that patients with glandular differentiation have more obvious tumor invasion and relatively poor postoperative recovery, although in other reports the difference in prognosis was not significant (26–29).

And several studies have reported the prognoses of BAC and UC. One study showed that patients with muscle-infiltrating BAC had similar survival rates to those with muscle-infiltrating UC (30). A SEER database analysis found that the 5-year cancer specific survival rate was 56.6% for patients with primary BAC and 61% for those with UC (27). To conclude, many studies have reported differences between UCGD and UC, UC and BAC. However, the difference in prognosis between BAC and UCGD has rarely been reported. Our study fills in the data.

Our study had many shortcomings. First, the sample size was relatively small, which is a common problem due to the rarity of the diseases. Second, this was a retrospective study; the rarity of the diseases makes prospective studies almost impossible. In addition, many patients did not undergo lymph node dissection, so the N stage results can only be used as a reference. Despite these shortcomings, this study provides valuable data for patient counseling, treatment planning, and prognostic predictions. Although few cases were included in this study compared to the SEER database, our data are reliable and detailed. As one of the largest urology treatment centers in China, we believe that this analysis of 15 years of follow-up data is highly meaningful. Larger, multicenter studies should nevertheless be performed to validate our results.

Our study found that UrAC, primary BAC, and UCGD differed in pathological and clinical features. Patients with UrAC were the most likely to be stage T3–4 and the primary BAC patients had the highest rate of poorly differentiated tumors. Patients with mucinous adenocarcinoma tended to have better OS and PFS. This analysis of UrAC, primary BAC, and UCGD indicated a worse prognosis for cases with primary BAC. Attempts should be made to diagnose these aggressive tumors early, since patients in whom tumors are detected early appear to survive longer.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by People’s Liberation Army General Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Conception and design: XL and TW. Acquisition of data: ZL and HF. Analysis and interpretation of data: TW and XL. Writing, review, and/or revision of the manuscript: TW, YY, XH, XZ, BC, and ZL. Administrative, technical, or material support: JL and XM. Study supervision: XL. All authors contributed to the article and approved the submitted version.

The present work was financially supported by the National Natural Science Foundation of China (No. 81900718 and No.81970665) and Chinese Postdoctoral Science Foundation (No.BSH47933-JD).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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