Modern methods in managing urachal adenocarcinoma

Abstract

Objectives

We sought to evaluate modern diagnostic and treatment options for urachal adenocarcinoma (UAC) and to provide clarity regarding the available options and their outcomes for this poorly understood yet damaging disease.

Material and methods

We conducted a systematic literature search in PubMed and Medline focusing on updated management of UAC.

Results

Surgical intervention continues to be the mainstay of treatment for localized UAC. However, with the increased availability of molecular and genetic profiling, chemotherapy has consistently demonstrated promising response rates and survival outcomes, especially for a disease that commonly presents in a metastatic stage. The role of checkpoint inhibitors remains under investigation. Cross-sectional imaging is vital during postoperative surveillance. However, there may also be a role for the adoption of cystoscopy to detect bladder recurrence.

Conclusions

Although the importance of surgical resection remains unchanged, improved survival outcomes with chemotherapy have been found in small retrospective studies. Randomized trial data are required to further assess the influence of systemic treatment as a primary or adjuvant therapy. Moreover, a stringent follow-up regimen incorporating evaluation for distant and local recurrence of UAC must be evaluated and adopted.

1. Introduction

Urachal adenocarcinoma (UAC) remains a rare urological entity, constituting less than 1% of all bladder cancer and between 10% and 35% of bladder adenocarcinoma (AC) cases. Recent analysis has found the median age of diagnosis to be during the sixth decade of life, ranging from 33 to 77 years, with a male to female predominance of 1.4–1.6:1.^[1,2] Embryologically, the urachus is a structure connecting the allantois to the fetal bladder to facilitate waste exchange during development. During months 5–6 of gestation, the urachus undergoes stretching and luminal obliteration as the fetal bladder descends, giving rise to the median umbilical ligament. Failure of this mechanism results in the formation of a tubular structure with the potential for anomalies including sinuses, cysts, or abscesses. In adulthood, UAC is a rare sequela.^[3] Urachal adenocarcinomas often occur in a midline position involving the dome of the bladder and retropubic space (cave of Retzius). The majority of patients present with hematuria. Less commonly, dysuria, mucosuria, recurrent urinary tract infections, and systemic symptoms such as fever, abdominal pain, and gastrointestinal disturbances have been described.^[4] Surgical intervention is the standard treatment for UAC; however, chemotherapy and immunotherapy have been increasingly used recently. Our objective is to review current diagnostic and treatment strategies, evaluate their clinical outcomes, and provide an overview of this rare yet potentially aggressive disease.

2. Materials and methods

A literature search was conducted in February 2021 in PubMed and Medline databases. Inclusion criteria were a combination of the keywords “urachal,” “urachus,” “adenocarcinoma,” “carcinoma,” “malignancy,” “neoplasm,” and “cancer” (see Supplemental Digital Content 1, http://links.lww.com/CURRUROL/A41). Exclusion criteria consisted of articles published in languages other than English and nonhuman animal studies. Of a total of 428 articles identified, 125 articles describing nonhuman animal studies were excluded, as well as 1 duplicate citation. Abstracts were subsequently analyzed, which resulted in a further 150 citations being excluded, which did not focus on UAC. Only original research articles over the last 10 years were included, as shown in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram (Fig. 1). In the end, 7 studies were incorporated into this review (Table 1).

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram.

Table 1.

Included studies with observations.

Author, yr	Study type	Country	Patients, n	Subgroup focus	Treatment	Recurrence	Survival
Mertens et al.[5] (2019)	Retrospective case series	Netherlands	55	PM vs. local treatment vs. metastatic palliation	CRS + HIPEC in PM	50% Median 8 mo (4–22 mo)	DSS 5-yr 55.6% (CI, 24%–84%) vs. 57.5% (CI, 40%–74%) vs. 20% (CI, 4%–56%) (p < 0.001)
Kim et al.[6] (2018)	Retrospective case series	South Korea	15	UAC vs. bladder AC	Chemotherapy	‐	PFS 10.4 vs. 20.6 mo (p = 0.024)
Hayashi et al.[7] (2016)	Retrospective case series	Japan	28	Localized disease	Surgery	41% 42.6 mo observation	RFS 5-yr 44.3%
				Metastatic disease	Chemotherapy	‐	OS 23.5 mo (CI, 11.8–33.3)
Jung et al.[8] (2014)	Retrospective case series	South Korea	24	Metastatic disease	5-FU vs. other chemotherapy	‐	RR 50.0% vs. 16.7% overall
Chen et al.[9] (2014)	Retrospective case series	China	17	Localized vs. metastatic disease	Surgery	‐	OS 6.2 yr vs. 1.8 yr (p < 0.001)
Cho et al.[10] (2013)	Retrospective case series	South Korea	31	UAC vs. bladder AC	Surgery	DFS 52.9 vs. 50.0 mo (p = 0.507)	‐
Bruins et al.[11] (2012)	Retrospective case series	Netherlands	152	Localized vs. metastatic disease	Surgery ± chemotherapy	‐	RS 5-yr 61% vs. 15%

CRS = cytoreductive surgery; DFS = disease-free survival; DSS = disease-specific survival; HIPEC = hyperthermic intraperitoneal chemotherapy; PM = peritoneal metastasis; RFS = recurrence-free survival; RR = response rate; RS = relative survival. UAC = urachal adenocarcinoma; AC = adenocarcinoma; 5-FU = 5-flurouracil; CI = confidence interval; PFS = progression-free survival; OS = overall survival.

3. Discussion

3.1. Diagnosis

The staging system for UAC was proposed by Sheldon et al.,^[2] highlighting it as a distinct clinical entity different from other bladder cancers, which led to the modern-day approach for surgical intervention for these tumors. With this came histological subtyping, before UAC being recognized in the World Health Organization's 2004 “blue book” of genitourinary pathology. Nowadays, the Tumour, Nodes Metastasis Staging Classification developed by Hamilou et al.^[12] is widely used to stage UAC (Fig. 2).

Figure 2.

Tumour, Nodes Metastasis Staging Classification for urachal cancer.

It is postulated that most UAC develops adjacent to the bladder and subsequently develops cranially. Despite urachal remnants typically being lined by urothelium, metaplasia due to chronic irritation and/or inflammation gives rise to columnar epithelium.^[13] Given that the presenting symptoms of UAC patients are often urological, almost all UACs are found after cystoscopy or incidentally on cross-sectional imaging, such as computed tomography (CT).

Magnetic resonance imaging has often been used to further evaluate disease burden and nodal status, demonstrating heterogeneity and high-signal intensity on T2-weighted imaging ^[14] with enhancement upon contrast administration. These findings are postulated to be a consequence of the presence of mucin within the tumor site, as well as calcifications throughout the lesion.^[4] There is no clear advantage in the literature favoring one imaging modality over another.

Das et al.^[15] sought to evaluate the role of ¹⁸F-fluorodeoxyglucose positron emission tomography (PET) CT scan in 21 treatment-naive patients within 6 weeks of initial cross-sectional imaging. Notably, 38% patients (n = 8) were found to have previously unidentified metastatic disease, including bone, nodal, pancreatic, and hepatic lesions. Nineteen percent (n = 4) of patients then required additional systemic treatment in addition to the originally planned surgical intervention. It is worth noting that direct imaging of the tumor by each modality did not alter the diagnosis, although all tumors assessed demonstrated ¹⁸F-fluorodeoxyglucose uptake. Xu et al.^[16] also found that 1 of 6 UAC patients required systemic treatment for previously unknown metastatic disease after PET-CT evaluation, without a change in primary tumor diagnosis between imaging modalities. The upstaging to advanced disease found in a select group of patients signifies a potential role for PET-CT imaging in the evaluation of metastatic UAC. However, given the rarity of this disease and small sample sizes, direct conclusions are limited.

Interestingly, a retrospective case series of 31 patients with localized UAC versus nonurachal AC by Cho et al.^[10] found similar rates of recurrence (47.1% vs. 50.0%; p = 0.507). Upon critical analysis, however, the follow-up time for UAC (70.1 months; range, 6.6–188.3 months) clearly exceeded nonurachal AC follow-up time (34.9 months; range, 6.7–93.8 months), potentially affecting the validity of this finding. Furthermore, a primary tumor greater than 4 cm was associated with a statistically significant reduction in disease-free survival (p = 0.043). This finding provides a valuable reference for determining prognostic outcomes, suggesting that diagnostic imaging modalities might assist surgeons in delineating which patients may have more aggressive disease that warrants earlier intervention. Unfortunately, given the small sample size, it is difficult to reach a reliable conclusion about the impact of tumor size on survival outcomes. It is worth noting that only patients with localized disease were selected; therefore, more aggressive variants causing early metastatic disease have been excluded from analysis because of selection bias.

Urachal adenocarcinoma is considered an extramucosal entity, and as such, urine cytology in adjunct to cystoscopy and imaging plays a limited role in diagnosis. On the other hand, serum tumor markers such as carcinoembryonic antigen, cancer antigen 19-9, and cancer antigen 125 have been used as adjunct tests during diagnosis because of histopathological similarities with other cancers, as demonstrated in a study by Szarvas et al.^[17] that found 40%–60% of UAC patients had elevated markers. Moreover, Siefker-Radtke^[18] described a response in these markers after intervention, which seemed to correlate with radiological findings, demonstrating a potential role for these markers during postoperative follow-up.

3.2. Treatment

Localized UAC treatment is centered around surgical resection. Partial cystectomy with removal of the urachal ligament is often performed. Numerous studies, as reviewed by Hamilou et al.,^[12] have demonstrated the superiority of this technique over cystectomy without umbilectomy while preserving better quality of life. This approach is now the mainstay of surgical intervention.

A retrospective case series of 17 UAC patients by Chen et al.^[9] demonstrated a statistically significant improvement in overall survival (OS) in the surgical treatment of localized disease versus metastatic disease (6.2 years vs. 1.8 years; p < 0.001), with a median OS among all patients of 4.8 years. This result highlights a potentially poor outcome despite surgical intervention in the setting of metastatic disease and the need for systemic treatment to be adopted in such cases. Clearly, a difference in survival is to be expected with an increased burden of disease, and OS will be skewed in favor of localized versus metastatic disease, but the importance of systemic therapy to prevent disease progression should be considered nonetheless. Furthermore, selection bias may exist, given that aggressive variants will likely metastasize sooner, leaving comparatively less assessed in the localized disease cohort.

Controversy exists regarding the utility of pelvic lymph node dissection (PLND), as highlighted by findings reported by Szarvas et al.^[17] whereby PLND was performed in only 38% of 248 cases, with a 17% positivity rate. Previously, there has been no recommendation to perform PLND.^[19] A retrospective case series of 152 patients by Bruins et al.^[11] highlighted that lymph node metastasis was an independent prognostic factor associated with reduced OS, alongside distant metastasis and residual tumor. Despite this correlation, there was no significant difference in OS between patients who underwent PLND and those who did not. This finding was substantiated by Chen et al.,^[9] who described 5 of 17 patients who underwent PLND without any survival benefit. Small sample sizes clearly limit the ability to arrive at reliable conclusions, especially in a node-free setting, as only 2 of 5 patients who had lymphadenopathy on cross-sectional imaging had pathologically confirmed nodal involvement.

The study by Bruins et al.^[11] demonstrated a lack of significant survival benefit in 36.4% of patients who underwent PLND (Fig. 3). Lymphadenopathy was associated with impaired survival and with an increased hazard ratio (1.7; confidence interval [CI], 1.2–2.6; p = 0.006) but not to the extent of distant metastasis (5.3; CI, 2.8–9.9, p < 0.001). Study limitations included a lack of randomization to undergo PLND or not, and information regarding adjuvant systemic treatment was not provided. Moreover, justification of the rationale for patients with radiologically negative lymph nodes undergoing PLND (n = 5) would increase the robustness of any conclusions drawn. It is therefore impossible to categorically state that PLND, especially in clinically positive cases, would not improve survival figures. In patients with localized disease, improvement in long-term survival outcomes has been associated with negative lymph node sampling and negative surgical margins. This experience highlights the potential prognostic effect of early detection of positive lymph nodes in staging and altering treatment regimes in patients with UAC, and the potential benefit if PLND were to be performed alongside en bloc resection. Given the limitations of studies to date, prospective randomized trials are required to evaluate the efficacy of PLND in UAC patients.

Figure 3.

Overall survival by lymphadenectomy (taken from Ref. 11).

After surgical intervention, recurrence rates (RRs) of about 40% have been reported, ranging from local recurrence to lung and/or liver disease, often seen at 2 years postoperatively.^[18] Currently, no recommendation exists with regard to neoadjuvant or adjuvant systemic therapy in this scenario. However, chemotherapy has been advised when patients have lymph node disease or distant metastasis or positive surgical margins. The use of radiotherapy as a treatment option currently has no evidence base, with less than 1% of patients in the literature offered this as monotherapy, often in the setting of invasive disease as a palliative approach.^[20]

Given the high risk of relapse in patients with UAC, adjuvant chemotherapy in the form of 5-flurouracil (5-FU) and cisplatin is an available treatment option that has shown promise. Kim et al.^[6] highlighted the poor progression-free survival of UAC as compared with bladder AC (10.4 vs. 20.6 months; p = 0.024). When chemotherapy regimens were analyzed, no patients who underwent 5-FU-combination therapy demonstrated disease progression, and 5 patients showed partial responses. However, study limitations included the ad hoc nature of chemotherapy regimens used, a retrospective study design, and small samples size, making generalizability difficult and reducing the reliability of any conclusions. Jung et al.^[8] demonstrated promising RR figures with 5-FU compared with all other chemotherapy regimens tested (50.0% vs. 16.7%). However, not all patients had metastatic disease at diagnosis, and chemotherapy regimens were given to 3 patients as salvage therapy, potentially skewing the data given that patients selected for salvage therapy may have represented more aggressive variants of disease, which relapsed after initial treatment. Randomized trials with direct comparison of chemotherapeutic agents in a validated setting are required to enhance the reliability of conclusions, both for adjuvant and salvage therapy.

Metastatic disease is commonly found at the time of diagnosis of UAC, in as many as 1 in 5 patients.^[17] Recently identified associations between UAC and KRAS genetic mutations have prompted new research into systemic treatment options, given similar findings noted with colorectal carcinoma. Szarvas et al.^[17] described the successful use of combination 5-FU and cisplatin (n = 74) in patients with metastatic disease, with a progression rate of 14% compared with 31% with cisplatin only, as well as a 43% overall RR. Siefker-Radtke^[18] also proposed the use of 5-FU for patients with locally advanced and metastatic disease and in patients with localized disease who wish to pursue more aggressive therapy, recommending 2 cycles beyond maximal response in patients with nodal involvement, and a regimen of 4–6 cycles for use as adjuvant therapy. Hayashi et al.^[7] retrospectively analyzed 17 patients undergoing chemotherapy for metastatic disease, with favorable median OS (23.5 months; CI, 11.8–33.3) when compared with a recurrence-free survival of 44.3% at 5 years in patients with localized disease. Four patients also showed “significant” RR, including one complete response with 5-FU combination. However, major limitations of this study include the small sample size and retrospective study design as well as the fact that no objective definition of “significant” benefit exists in the setting of metastatic disease.

Mertens et al.^[5] recently demonstrated satisfactory oncological outcomes with hyperthermic intraperitoneal chemotherapy in the setting of peritoneal metastasis due to UAC, with over half of patients reported to be disease-free at 5 years of follow-up when compared with local treatment and metastatic palliation respectively (55.6% [CI, 24%–84%] vs. 57.5% [CI, 40%–74%] vs. 20% [CI, 4%–56%]) (p < 0.001). However, limitations such as small sample size impeded generalizability, leaving the authors being unable to objectively grade the cytoreductive outcome of surgical intervention. There is currently no clear guideline for the use of neoadjuvant or adjuvant chemotherapy in this setting in lieu of randomized clinical trial data. Therefore, as mentioned previously, the rare nature of this disease process will require multicenter collaborative research to develop guidelines backed by high-level evidence.

Antiepidermal growth factor receptor has shown promise in treating metastatic colorectal AC and, as such, has been hypothesized as a potential systemic therapy for UAC. Collazo-Lorduy et al.^[21] found a partial response to epidermal growth factor receptor inhibitors for up to 8 months. Programmed death-ligand 1 inhibitors are used to treat advanced urothelial carcinoma, and as such, a case report demonstrated regression of lung metastases at follow-up with the use of atezolizumab.^[22] Considering these findings, larger-scale studies into the genetics behind UAC and the use of checkpoint inhibitors are underway, especially given their postulated manageable toxicity profile when compared with chemotherapeutic agents, albeit recruitment has been slow given the rarity of this disease. No original research articles have yet been published regarding immunotherapy regimens, but given the increasing awareness of this treatment modality and success in other aggressive malignant tumors, we expect promising results to arise from the current studies evaluating their use in UAC.

3.3. Prognosis

Urachal anomalies are generally found incidentally in a pediatric population, and although, theoretically, their excision would prevent subsequent development of UAC. Gleason et al.^[23] estimated the number needed to prevent 1 case of UAC at 5721. For context, the incidence of urachal anomaly in this study was around 600. This low incidence supports guidance that excision of urachus in childhood is not warranted prophylactically.

Controversy exists with regard to the postoperative follow-up of UAC patients. Cho et al.^[10] evaluated the follow-up of 17 patients with localized UAC who underwent surgical intervention, including 2 patients who received adjuvant chemotherapy, 3 who received adjuvant radiotherapy, and the remaining 12 receiving no further treatment. During a mean follow-up of 54 months (range, 9–49 months), 47.1% of patients developed local or distant recurrence, ranging from local lymphadenopathy to lung and bone involvement. They concluded that cross-sectional imaging in the form of CT alone would be suitable for surveillance, in a similar format to muscle-invasive bladder transitional cell carcinoma.

Siefker-Radtke^[18] and Pinthus et al.^[24] evaluated patients up until 2001 and reported 5-year survival rates of 40% and 50.7%, respectively. They found a statistically significant survival advantage with well-differentiated tumors as compared with poorly differentiated tumors, in lieu of a formal grading system for UAC, with well-differentiated tumors reaching a disease-specific survival of 90%. Herr et al.^[25] highlighted that invasive UAC was directly related to OS, with 93% of patients with tumors confined to the urachus or bladder surviving 5 years, as compared with 69% with extravesical or periurachal spread. They described tumor “seeding” into the lower urinary tract, which was seen in 8.3% of patients despite partial cystectomy for noninvasive UAC. This finding suggests a role for cystoscopy follow-up to identify early “seeded” recurrence. Although no definitive follow-up regimen yet exists, given the high risk of recurrence and metastatic relapse seen in UAC, an intensive cross-sectional imaging protocol should be adhered to, and serious consideration be given to cystoscopic surveillance given the nearly 1 in 10 risk of “seeding,” especially if any symptoms develop.

4. Conclusions

Urachal adenocarcinoma remains a rare clinical entity in the urological world. With further development of systemic therapies to supplement surgical intervention, the potential for progress exists to improve historically poor survival outcomes. Prospective, multicenter trials to evaluate and establish protocols for treatment and follow-up are needed. With advances in understanding of this disease, combination modality therapy is becoming available. At the same time, clinicians must ensure adequate and intensive follow-up of UAC patients, with the aim to extend recurrence-free periods.

Acknowledgments

None.

Statement of ethics

Not applicable.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Funding source

This work received no specific grant nor funding from any agency.

Author contributions

ST: Conception and design, literature search and study selection, data collection, analysis and interpretation, writing the article;

OE: Literature search and study selection, analysis and interpretation;

All authors: Critical revision of the article, final approval of the article.