|Year : 2019 | Volume
| Issue : 3 | Page : 429-438
Survival of primary adenocarcinoma of the urinary bladder after radical treatment: National Cancer Institute, 5-years’ experience
Ahmed Abbas1, Ibrahim Abdelrahman1, Ghada Abdelsalam2
1 Department of Surgical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
2 Department of Pathology, National Cancer Institute, Cairo University, Cairo, Egypt
|Date of Submission||27-Jan-2019|
|Date of Acceptance||05-Mar-2019|
|Date of Web Publication||14-Aug-2019|
Surgical Oncology Department, National Cancer Institute, Cairo University
Source of Support: None, Conflict of Interest: None
Introduction Primary adenocarcinoma of the urinary bladder (UB) is rare but often aggressive urologic cancer. It represents 0.5–2% of all bladder cancers and affects patients mostly in their sixth decade of life. The incidence is greater in areas where bilharziasis is endemic and is more common in men than women.
Aim of the work The aim of the study was to review this rare UB malignancy with special emphasis on patients’ survival including; disease-free survival (DFS) and overall survival (OS) in relation to different clinical and pathological factors.
Patients and methods We conducted this retrospective review of 40 patients with primary UB adenocarcinoma who were treated and followed up in the National Cancer Institute, Cairo University between January 2013 and December 2017.
Results The study included 40 patients with a male to female ratio of 82.5 : 17.5%. The mean age at diagnosis was 61 years. Hematuria was the most common presenting symptom followed by dysuria and frequency. Pathologically, stage III disease, tumor grade II, and adenocarcinoma, not otherwise specified, were the most common findings. Radical cystectomy was done in 82.5% of cases, while anterior pelvic exenteration was done in 17.55% of cases followed in both by different methods of urinary diversions. The median follow-up was 31 months, and the 2-year DFS of all patients was 60.7%. Two-year DFS was significantly affected by tumor grade, disease stage, and lymph node (LN) status (P=0.019, 0.021, 0.001, respectively). Furthermore, 3-year OS of all groups was 57% with a median follow-up of 39.9 month. Tumor grade, disease stage, and LN involvement had an impact on OS. However, the only statistically significant effect is due to LN involvement (P=0.037).
Conclusion Patients with UB adenocarcinoma commonly present in an advanced disease. DFS and OS are affected by disease stage, tumor grade, and LN involvement. We recommend radical rather than any form of conservative surgery as a primary treatment modality.
Keywords: adenocarcinoma, survival, urinary bladder
|How to cite this article:|
Abbas A, Abdelrahman I, Abdelsalam G. Survival of primary adenocarcinoma of the urinary bladder after radical treatment: National Cancer Institute, 5-years’ experience. Egypt J Surg 2019;38:429-38
|How to cite this URL:|
Abbas A, Abdelrahman I, Abdelsalam G. Survival of primary adenocarcinoma of the urinary bladder after radical treatment: National Cancer Institute, 5-years’ experience. Egypt J Surg [serial online] 2019 [cited 2019 Nov 19];38:429-38. Available from: http://www.ejs.eg.net/text.asp?2019/38/3/429/264329
| Introduction|| |
Adenocarcinoma of the urinary bladder (UB) is the third most common histologic type of bladder carcinoma. It accounts for 0.5–2.0% of all bladder tumors  with urachal carcinoma representing 0.34–0.7% . In addition, adenocarcinoma of the bladder may also occur in association with schistosomiasis, endometriosis, bladder augmentation, and other irritative conditions of the UB 
Adenocarcinoma of the UB is classified according to its origin into three categories: primary, urachal, and metastatic . The pathogenesis of primary nonurachal adenocarcinoma is based on the ability of the urothelium to undergo metaplastic changes. Mostofi and colleagues proposed that the metaplastic potential of the urothelium has two distinct patterns. Progressive invagination of hyperplastic epithelial buds into the lamina propria (von Brunn’s nests) leading to the formation of cystitis cystica. Subsequently, metaplasia of the urothelial lining of these cysts to columnar mucin-producing cells results in the production of cystitis glandularis, which is a premalignant lesion . Chronic vesical irritation and infection are the predisposing factors for these changes. This explains the higher incidence of these tumors among patients with bilharzial cystitis .
The WHO 2016 classification of bladder adenocarcinoma is as follows: enteric, mucinous, mixed, and adenocarcinoma, not otherwise specified (NOS) .
In most of the patients, primary adenocarcinoma of the bladder presents with hematuria, which may be associated with irritative voiding symptoms and, occasionally, passage of mucus in the urine. In addition, it shows a male predominance, with a male to female ratio of 2.7 : 1 . The prognostic factors for bladder adenocarcinoma outcomes have been reported to include tumor stage, grade, and lymph node (LN) involvement . Recently, it has been identified that tumor locations in the urachus and dome of the bladder were associated with favorable survival and better oncological outcomes, whereas basal location confers poorer outcomes .
| Patients and methods|| |
Patients and methods :This is a retrospective study of 40 patients with primary adenocarcinoma of the UB who presented and treated at the National Cancer Institute, Cairo University from January 2013 to December 2017 after obtaining IRB approval. All patients signed informed consent. All patients were subjected to radical surgery in the form of radical cystectomy or anterior pelvic exenteration plus pelvic lymphadenectomy. Only patients with final pathology of primary UB adenocarcinoma were included. The pathologic specimens were reviewed by the same pathologist and were subclassified according to the Grignon et al.  classification. Any specimens with extension to the prostate had to be proven primary UB adenocarcinoma by negative immunohistochemical stain for prostatic specific antigen to be included in the study. Pathologically, primary UB adenocarcinoma was divided into four histological subtypes: (a) enteric (papillary), when the architectural and cytologic features resembled those of the typical colonic adenocarcinoma; (b) mucinous, when the tumor was characterized by single cells or nests of cells floating in lakes of extracellular mucin; (c) signet ring, when the tumor was composed of single signet-ring cells diffusely permeating the tissues; and (d) adenocarcinoma NOS, when the pattern did not fit into any of these previously mentioned categories. Patients and tumor characteristics were reviewed in detail. Different treatment modalities including the type of radical surgery, type of urinary diversion, and adjuvant therapy were thoroughly documented.
All patients were kept under close follow-up that ranged between 21.9 and 40.2 months, with a median of 31.3 months. During follow-up, the patients were examined clinically and evaluated radiologically for any suspicious symptoms or signs of treatment failure. Any local, regional, or distant failure was documented.
Comparison between different percentages and frequencies were performed using the standard Student’s t test, F test, and χ2 test. The 5-year disease-free survival (DFS) rates, local control rates, and distant metastasis-free rates were measured using the Kaplan–Meier product limit method. The log-rank test was used for comparison between survival curves. The Cox multivariate analysis was performed to determine the independent prognostic variables that affected the DFS, local control, and distant metastasis-free rates.
| Results|| |
The study included 40 patients diagnosed with primary adenocarcinoma of UB treated and followed up at the National Cancer Institute, Cairo University during the period from January 2013 to December 2017. The mean age at diagnosis was 61 years ranging from 35 to 85 years. Male to female ratio was 82.5 : 17.5%. Four (10%) patients were diabetic, seven (17.5%) patients were hypertensive, and 26 (65%) patients were smokers. History of schistosomiasis infestation was noticed in 21 (52.5%) patients, ignored in 12 (30%) patients, and not known in seven (17.5%) patients ([Table 1]).
The most frequent symptoms were hematuria, dysuria, and others like frequency and urgency [31 (77.5%) patients, 17 (47.5%) patients, and five (12.5%) patients, respectively] ([Figure 1]).
All patients underwent radical surgery and urinary diversion as follows: radical cystectomy and pelvic lymphadenectomy was done in 33 (82.5%) male patients while anterior pelvic exenteration and pelvic lymphadenectomy was done in seven (17.5%) female patients. Different types of urinary diversion were done including ileal loop conduit in 22 (55%) patients, orthotopic neobladder in 10 (25%) patients (ileocecal pouch in six patients and ileal Y-Pouch in four patients). Uretero-cutaneous diversion was done in six (15%) patients, while two (5%) patients underwent Indiana pouch diversion ([Figure 2]).
Detailed postoperative histopathology showed a predominance of adenocarcinoma NOS followed by adenocarcinoma with signet-ring cell differentiation and then mucinous adenocarcinoma and finally enteric-type adenocarcinoma [21 (52.5%) patients, nine (22.5%) patients, six (15%) patients, four (10%) patients, respectively]. Tumor grade II was found in 21 (52.5%) patients, grade III in 17 (42.5%) patients, and grade I in only two (5%) patients. Pelvic lymphadenectomy showed positive metastatic LNs in 13 (32.5%) patients and negative LNs for metastases in 27 (68.5%) patients. TNM staging system showed 16 (40%) patients stage III, 13 (32.5%) patients stage IV, nine (22.5%) patients stage II, and two (5%) patients of stage I ([Table 2]).
Tumor locations within the UB is shown in [Table 3] and [Figure 3] where the most common tumor locations were the posterior bladder wall and the dome of the bladder (45.5 and 25%, respectively).
During the follow-up period, treatment failure was detected in 12 (30%) patients and was fractionated as follows: loco-regional recurrence in seven (17.5%) patients including six (15%) patients with iliac and para-aortic nodal recurrence and one (2.5%) patient with intestinal recurrence after ileocecal orthotopic diversion, distant metastasis in three (7.5%) patients in addition to loco-regional recurrence plus distant metastases in two (5%) patients.
The median follow-up period was 31 months, and the 2-year DFS of all patients was 60.7% ([Table 4], [Figure 4]). Two-year DFS for tumor grades (I–II) was 85.7%, while it dropped to 28.6% for grade III (P=0.019) ([Figure 5]). Two-year DFS for patients with early stages of the disease (I, II) was 100% compared with 48% in late stages (III, IV) with a P value of 0.021. There was also significant difference between both groups (early vs. advanced disease) in 3-year DFS (75 vs. 24%, respectively) ([Figure 6]). In regard to the effect of LN metastases on DFS, patients with negative LN involvement showed a 2-year DFS of 78.8% while in patients with positive LN involvement, 2-year DFS was 28.8% (P=0.001) ([Figure 7]). It was found that adenocarcinoma subtype had an impact on DFS, as 2-year DFS for adenocarcinoma NOS was 80%, for mucinous adenocarcinoma was 50%, and for signet-ring adenocarcinoma it was 41.7%. However, these differences were of borderline significance statistically (P=0.09) ([Figure 8]). Furthermore, 3-year overall survival (OS) of all groups was 57% with a median follow-up of 39.9 month ([Table 5], [Figure 9]). Tumor grade, disease stage, and LN involvement had an impact on OS. However, the only statistically significant value was due to LN involvement (P=0.037) ([Figure 10],[Figure 11],[Figure 12],[Figure 13]). The other factors was of borderline significance mainly due to the small number of cases and the short period of follow-up.
|Figure 5 DFS in relation to the tumor grade. DFS, disease-free survival.|
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|Figure 6 DFS in relation to different disease stages. DFS, disease-free survival.|
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|Figure 7 DFS in relation to LN metastases. DFS, disease-free survival; LN, lymph node.|
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|Figure 8 DFS in relation to the subtype of adenocarcinoma. DFS, disease-free survival.|
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|Figure 11 OS in relation to different disease stages. OS, overall survival.|
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|Figure 12 OS in relation to LN metastases. OS, overall survival; LN, lymph node.|
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|Figure 13 OS in relation to the subtype of adenocarcinoma. OS, overall survival.|
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| Discussion|| |
Adenocarcinoma is a rare malignancy of the UB which may arise primarily in the bladder as well as secondarily from a number of other organs. Primary UB adenocarcinoma exhibits several different growth patterns, including enteric, mucinous, signet-ring cell, adenocarcinoma NOS, and mixed patterns. Urachal adenocarcinoma demonstrates similar histologic features but it can be distinguished from bladder adenocarcinoma on careful pathological examination. Noninvasive neoplastic glandular lesions, adenocarcinoma in situ, and villous adenoma are frequently associated with bladder adenocarcinoma. Primary UB adenocarcinoma has a poor prognosis largely because it is usually diagnosed at an advanced stage. Urachal adenocarcinoma shares similar histologic features with bladder adenocarcinoma, but it has a more favorable prognosis than bladder adenocarcinoma, partly due to the relatively young age of patients with urachal adenocarcinoma. Worldwide, UB adenocarcinoma is the third most common histologic type (0.5–2% of all bladder cancers). However, the incidence is reported to be higher up to 10% in regions where schistosomiasis is endemic. Patients are usually in the their sixth and seventh decades of life at the time of diagnosis with male predominance ,,. The reported incidence of primary UB adenocarcinoma in the National Cancer Institute, Cairo is 3.8% of all UB cancers. Zheng and colleagues reported that adenocarcinoma, like squamous cell carcinoma, appears to occur at a younger age than urothelial carcinoma (UC). Indeed the mean ages for men and women were, respectively, 54.3 and 54.2 years, significantly younger than the mean ages we reported for UC that were 61.3 and 60.2 year, respectively . Similarly, Lughezzani et al.  reported a younger age at diagnosis in a sureillance epidemiology and end results (SEER)-based series of 306 adenocarcinoma cases compared with nearly 12 000 UC, but did not report sex-specific age differences. In one of the largest studies of 192 patients with primary adenocarcinoma of UB, Zaghloul et al.  reported a mean age of 51 years with less male predominance (male to female ratio of 2.25 : 1) in addition to approximately one-third of the patients who had LN metastases at the time of presentation. These reports did not concur with our results where the mean age of our patients was 61 years with male predominance (male to female ratio is 4.7 : 1). However, they were similar in terms of regional LNs metastases where in our series; 13 (32.5%) the patients were found to have pelvic LN metastases while in 27 (67.5%) patients, the LNs were free of metastases. In their work, Rogers et al.  found that most of the patients were at an advanced stage at the time of diagnosis due to late presentation. Even in our study, early disease stages (I and II) were found only in 11 (27.5%) patients while advanced stages (III and IV) were found in 29 (72.5%) patients.
Although the pathogenesis of UB adenocarcinoma is not yet entirely understood, several risk factors have been described. Most notably, almost 90% of bladder tumors in patients with exstrophy of the bladder are adenocarcinoma . Other possible risk factors include chronic irritation, obstruction, cystocele, and endometriosis . Cystitis glandularis and intestinal metaplasia, on the other hand, are often found adjacent to bladder adenocarcinoma, but recent studies have shown that cystitis glandularis and intestinal metaplasia are not associated with an increased risk of adenocarcinoma . Between 2006 and 2014, in a large multicenter case–control study in Egypt to address the risk factors associated with UB cancer, Amr et al.  found that smoking, schistosomiasis, and urinary tract infection were significantly associated with adenocarcinoma of the UB in both men and women. Similarly in our study, smoking was highly prevalent among men (79% of male patients) but not present in female patients. History of schistosomiasis was also documented in more than 50% of patients where bilharzial eggs were found in 20% of pathology specimens. This explains why male sex, smoking, and schistosomiasis were the highest risk factors for primary UB adenocarcinoma in our study. The symptoms of adenocarcinoma do not differ from other kinds of bladder tumors. In our series, hematuria was the most frequent presenting symptom (77.5%). Irritative symptoms including irritability, frequency, urgency, and dysuria were less common. In a population-based study from Wright et al.  including 151 patients with urachal adenocarcinomas and 1374 patients with primary bladder adenocarcinomas, the mucinous/colloid pattern was detected in 48% of urachal adenocarcinomas. But in our analysis, the mucinous type represented the third most common special type of adenocarcinomas (15%). In Wright and colleagues’ work, the second most common pattern was the adenocarcinoma NOS type (39%), which in our analysis accounted for the most dominant type (52.5%). However, in their analysis, the enteric type was not explicitly mentioned, which comprised 5% in our study. Additionally, they described the signet-ring cell type and the mixed type in 7% each contrary to our results in which adenocarcinoma with signet ring differentiation and mucinous adenocarcinoma comprised 22.5 and 15% of cases, respectively. The difference in the distribution of adenocarcinoma subtypes in our study and the other studies may be due to the differentiation between urachal and nonurachal adenocarcinoma in the other’s studies but not in our study. The prognostic value of these histopathologic features, however, remains to be established while a more favorable clinical course for urachal adenocarcinomas as compared with primary bladder adenocarcinomas was found . Additionally, the presence of high tumor grade and adenocarcinoma of signet-ring cell morphology were identified to be of unfavorable prognostic value in some ,,,, but not all series . In our study, detailed pathologic data showed the tumor grade II to be the most common (52.5%) and grade I is the rarest (5%), adenocarcinoma. NOS was reported in more than 50% of cases followed by adenocarcinoma with signet-ring differentiation and mucinous adenocarcinoma (22.5 and 15%, respectively). To the best of our knowledge, the identification of urachal from nonurachal adenocarcinoma is a clinicopathologic problem and there is still no agreed diagnostic criteria. An important question here: Is it necessary to separate adenocarcinoma into urachal and nonurachal types? Most authors agree that both of these tumors probably have, in most instances, the same pathogenesis. It remains unclear whether the survival of patients with urachal adenocarcinoma differs from that of patients with nonurachal adenocarcinoma. Dandekar et al.  found the difference between the two was not significant. Wright et al.  found that urachal cancer had a significantly better prognosis than nonurachal cancer, while Mostofi et al.  found that urachal adenocarcinomas were associated with a significantly worse prognosis. In the current study, although the tumor location was determined accurately within the UB, we did not differentiate between urachal and non-urachal UB adenocarcinoma in terms of prognosis or survival. The majority of patients with primary bladder adenocarcinoma have a muscle-invasive disease, and these patients are usually treated with radical cystectomy and pelvic LN dissection ,,. Primary radiation therapy may be considered for some patients who are not appropriate cystectomy candidates. The efficacy of which in comparison to surgery is unclear due to the limited experience with this rare disease. The traditional cisplatin-based chemotherapy regimens [i.e. MVAC (Methotrxate–Vinbalstine, Doxorubicin , Cisplatin)] that are used effectively for UC appear to have little impact on adenocarcinoma. In our institute, there is no role for any chemotherapy in the treatment of patients with UB adenocarcinoma even in recurrent or metastatic cases. In regard to radiotherapy, it was given as an adjuvant treatment after surgery in certain cases as indicated but not as a primary therapy. Many surgical treatment strategies for treatment of UB adenocarcinoma are available including transurethral resection, partial cystectomy, and radical cystectomy. We believe that transurethral resection is not sufficient for muscle invasive bladder cancer. However, it is agreed that partial cystectomy with removal of the urachal tract and umbilectomy is the treatment of choice for tumors localized to the dome . We are in favor of radical surgery. Nevertheless, the treatment selected reflected the local extent as well as the disease stage, so in our study, all patients underwent radical cystectomy and pelvic LN dissection followed by different types of urinary diversions (22 patients with ileal loop conduit, 10 patients with orthotopic neobladder, six patients with uretero-cutaneous, and one patient with Indian pouch diversion). Khaled and colleagues established bladder prognostic index for bilharzial-related invasive bladder cancer [squamous cell carcinoma (SCC) and adenocarcinoma] and they found that disease stage, tumor grade, and nodal involvement were the only significant factors with impact on survival (P=0.008, 0.051, 0.004, respectively). These three prognostic indexes were used to design a model to predict an individual patient’s risk factor for recurrence . Adenocarcinoma of the bladder is believed to be associated with a poor prognosis in most studies; however, recent observations indicate that bladder adenocarcinoma might have the same natural history as transitional cell carcinoma. Survival analysis in the Netherlands Cancer Registry showed that the survival of patients with muscle-invasive bladder adenocarcinoma is similar to the survival of patients with muscle-invasive UC . Ghoneim et al.  also found no statistically significant differences between bladder adenocarcinoma and UC in terms of mortality. In our study, the median follow-up period was 31 months. DFS for all patients is shown in [Table 4] and [Figure 4]. Among the different clinicopathologic factors, the most effective with a significant P value were the LN status (P=0.001), tumor grade (P=0.019), and the pathologic stage (P=0.021). We also found that adenocarcinoma tumor subtype had an impact on DFS as the 2-year DFS for adenocarcinoma NOS, mucinous adenocarcinoma, and signet adenocarcinoma was 80, 50, and 41.7%, respectively. However, these differences were of borderline significance statistically (P=0.09). ([Figure 5],[Figure 6],[Figure 7],[Figure 8]). In the current study, a 3-year OS of all groups was 57% with a median follow-up of 39.9 months ([Table 5] and [Figure 9]). Adenocarcinoma subtype, tumor grade, disease stage, and LN involvement had an impact on OS but the only factor that had a statistically significant value was the LN involvement (P=0.037) ([Figure 10],[Figure 11],[Figure 12],[Figure 13]). The other factors was of borderline significance mainly due to the small number of cases and short period of follow-up. In our survival analysis, due to the small number of cases and short follow-up period, the impact of these different histological subtypes on DFS or OS was of borderline significance (P=0.097 and 0.080, respectively).
| Conclusion|| |
Primary adenocarcinoma of the UB is rare but often aggressive urologic cancer. It represents 0.5–2% of all bladder cancers and affects patients mostly in their sixth decade of life. The incidence is greater in areas where bilharziasis is endemic and is more common in men than women. Patients with UB adenocarcinoma commonly present in an advanced disease which in fact lead to poor prognosis. DFS and OS are affected by disease stage, tumor grade, and LN involvement. Radical surgery is the primary treatment of choice and the standard of care is followed by adjuvant radiation therapy if indicated.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]