Introduction

Periurethral bulking agents have become increasingly utilized over the past several decades for treatment of female stress urinary incontinence (SUI) [1]. Injectable agents, primarily collagen-based, are an attractive treatment options as they are minimally invasive and may often be placed without the need for a general anesthetic. Current compounds enjoy both efficacy and an acceptable safety profile. Despite improved outcomes with definitive surgical interventions, patient satisfaction, and improvement in quality of life following injection therapy compares favorably to traditional surgical treatment in randomized trials [2]. Overall, complications were significantly less frequent and less severe in the injection group. Several studies employing collagen reported cure and improved rates ranging on average from 40–60% with up to 1 year of follow-up [1]. However, there is sparse literature regarding potential long-term sequela of periurethral bulking agents. Reports of durability vary by type of injectable, and comparisons are difficult due to vastly differing study methodologies. In one randomized trial comparing the efficacy and durability of Contigen to Durasphere, treatment was initially effective in 63% of both groups, but decreased by 36 months 21% in the Durasphere group, and 9% in the Contigen group [3]. In addition to issues with overall durability, multiple injections may be required to achieve and maintain effect. As such, a certain proportion of patients will ultimately decide to undergo surgery after initial injection therapy in an effort to obtain a more sustained outcome.

Potential long-term issues involving collagen injections include migration of the particles and loss of efficacy. Preliminary studies have determined placement of bulking agents is not deleterious with regard to future sling placement [4]. However, more obscure complications and presentations are sparsely reported in the current literature. Herein, we present two cases of misdiagnosis of urethral diverticulum in patients who had undergone prior periurethral bulking agent implant.

Case #1

Mrs. BC, a 69-year-old female, was referred from an outside urologist for evaluation and management of a urethral diverticulum. She presented with primary symptoms of a vaginal bulge and associated vaginal pressure. She additionally reported occasional dribbling incontinence, but otherwise did not have lower urinary tract symptoms and did not regularly utilize incontinence pads.

Her past medical history was significant for cervical cancer and stress urinary incontinence. She had previously undergone hysterectomy with brachytherapy implants and several anti-incontinence procedures including two bladder suspensions or unknown type as well as periurethral collagen injections.

On physical exam in the clinic, she demonstrated a large cystic suburethral mass which was ballotable and extended from the mid-urethra to the bladder neck. She, otherwise, demonstrated no pelvic organ prolapse or other abnormalities.

Outside hospital imaging included a pelvic magnetic resonance imaging (MRI) exam revealing a 4-cm cystic mass which appeared to wrap around the urethra, bulging into the floor of the urinary bladder, and causing some compression of the bladder (Fig. 1a). She additionally underwent a voiding cystourethrogram that demonstrated a smooth filling defect on the floor of the urethra due to an extrinsic mass effect (Fig. 1b).

Fig. 1
figure 1

a A pelvic MRI revealing a 4-cm cystic mass which appeared to wrap around the urethra and bulge into the floor of the urinary bladder. b Voiding cystourethrogram demonstrated a smooth filling defect on the floor of the urethra due to an extrinsic mass effect

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She underwent operative cystoscopy with bilateral retrograde pyelograms. No ostia were identified within the urethra, but cystoscopic exam did demonstrate an extrinsic compressing defect at the level of the left bladder neck. She subsequently underwent operative exploration with resection of the complex urethral mass and placement of an autologous fascia pubovaginal sling. Following dissection of the vaginal mucosa and periurethral fascia, a large periurethral lesion was encountered (Fig. 2a). Upon sharp opening of the mass, large amounts of a white foreign body substance exuded (Fig. 2b). The cyst was completely dissected without evidence of communication with the urethral lumen (Fig. 2c). The periurethral cyst wall was sent to pathology and identified as a benign fibrous cyst.

Fig. 2
figure 2

a Dissection of the vaginal mucosa and periurethral fascia reveals a large periurethral lesion. b Upon sharp opening of the mass, large amounts of a white foreign body substance exuded. c The cyst was completely dissected without evidence of communication with the urethral lumen

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Postoperatively, the patient convalesced without incident. At last follow-up, approximately 24 months following her operative intervention, she was without SUI and reported normal voiding with the exception of rare episodes of urge incontinence for which she declined any further treatment.

Case #2

A 74-year-old female was referred for evaluation of recurrent urinary tract infections and possible urethral diverticulum identified on CT imaging (Fig. 3a). The patient had undergone operative cystoscopy and bilateral retrograde pyelograms at an outside hospital prior to presentation which failed to reveal any urethral abnormalities or a diverticular ostium. The patient described a 20-year history of chronic UTI with voiding symptoms that included dysuria, urgency, frequency, urge urinary incontinence, and systemic chills. She reports these symptoms would transiently resolve with antibiotic therapy.

Fig. 3
figure 3

a CT imaging of a possible urethral diverticulum in a 74-year-old female referred for evaluation of recurrent urinary tract infections. b At presentation pelvic MRI additionally elucidated periurethral calcifications but failed to definitively reveal presence of a urethral diverticulum

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Her past medical history was significant only for a history of stress urinary incontinence for which she had undergone placement of a mid-urethral sling approximately 5 years prior to presentation. The patient indicated that preceding her sling surgery she underwent several periurethral collagen injections. She noted the interventions for her SUI did not change the recurrence of her symptoms of urinary infection.

Physical exam did not reveal evidence for a periurethral mass, urethral discharge, or anatomic abnormality. She additionally did not demonstrate pelvic organ prolapse.

At presentation she underwent pelvic MRI which additionally elucidated periurethral calcifications but failed to definitively reveal presence of a urethral diverticulum (Fig. 3b). She was treated with transvaginal estrogen cream and anticholinergic medication with resolution of her symptoms.

Discussion

Urethral diverticula are presumed to arise from periurethral glands, most likely due to recurrent infection and obstruction with suburethral abscess formation and rupture of the glands into the urethral lumen [5]. There is often a discrete connection between the diverticulum and the urethral lumen, but anatomical variations do exist. These include partial extension around the urethra, dorsal to the urethra, or circumferentially around the urethra [6]. Size can also vary depending on the level of inflammation, intermittent obstruction of the ostium, and drainage into the urethral lumen. The classic presentation of urethral diverticula includes dyspareunia, dysuria, and post-void dribbling. Fifty percent of women with a urethral diverticulum demonstrate stress urinary incontinence as well. As demonstrated in these cases, long-term sequela of periurethral bulking agents may present similarly to classic diverticuli.

The FDA approved the use of collagen injections for treatment of stress urinary incontinence in 1993 as an effective and low-risk alternative to surgery. Recent meta-analysis determined urethral injection therapy, a viable modality of treatment for most patients with uncomplicated stress urinary incontinence, and may be offered as a first-line option for patients who have failed pelvic floor exercises or pharmacological therapy [7]. With greater use of urethral bulking agents for treatment of stress urinary incontinence, local complications were inevitable although poorly described in the literature. Early studies on collagen injections did not adequately report outcomes and complications over 24 months following therapy. Overall, collagen injection therapy has proven to be relatively safe in the short run for patients, with few local or systemic complications documented. However, many patients need reinjections to maintain the desired outcome.

Prior literature reports one other documented case of urethral diverticulum following transurethral collagen injection therapy [8]. In this case, the patient had normal physical exam findings 4 months after the last injection for stress urinary incontinence, but developed urinary retention postoperatively from a dental procedure. Similar to the presentation in case #1, this patient also had symptoms related to the mass effect from the urethral diverticulum. Upon surgical exploration, a non-communicating urethral diverticulum was found. It was hypothesized that the previous collagen injections caused obstruction of periurethral glands due to accumulation of glandular secretions, especially since there was no history of urinary tract infections and no connection between the urethra and diverticulum where the collagen was injected.

Other documented complications after collagen injection therapy include urinary tract infections, transient periods of complete urinary retention, and de novo frequency and urgency [9–15]. Rare occurrences of suburethral swellings have been reported with use of collagen, polytetrafluoroethylene, carbon-coated zirconium beads, and non-animal stabilized hyaluronic acid/dextranomer gel. It has been proposed that the suburethral swellings are related to a tissue reaction to the injectable agent, and resolve with needle drainage [7, 16–23]. Hypersensitivity reactions have also been reported in 3% of patients with use of collagen and previous collagen exposure [23]. Recent studies have revealed periurethral use of substances other than collagen, such as dextranomer hyaluronic acid, for stress urinary incontinence has not been shown to be safe or efficacious [24]. In this report, dextranomer hyaluronic acid was associated with increased incidence of pseudoabscesses, de novo urge incontinence, and poor efficacy.

Sterile and non-sterile abscess formation [25, 26] and periurethral pseudocyst formation after transurethral collagen injections [27] are documented complications. Patients often present with irritative voiding symptoms and suburethral swelling and tenderness and require open for treatment. Sterile abscess formation has been reported to occur from use of a periurethral injection of Zuidex (dextranomer/hyaluronic copolymer) [26]. Reports of abscess formation from collagen injections are limited [16]. Pseudocyst formation has been previously document to occur through distal migration of the collagen along the urethra to create a non-tender collagen-filled periurethral mass at the meatus. Distal particle migration has also been described in non-biodegradable agents such as silicone and carbon-coated zirconium beads [7]. Accumulation of these substances could be harmful, especially with risks of granuloma formation and carcinogenesis.

Another documented complication of periurethral collagen injections was urethral prolapse causing recurrent episodes of cystitis [28]. This possibly manifested due to collagen intervening between mucosa and the underlying muscle wall. However, distal migration of the collagen along the urethra could not be ruled out in this circumstance.

Conclusion

Based on these patient’s presentation, imaging, and pathology, it was reasonable to conclude that their lower urinary tract symptoms were most likely iatrogenic from the use of collagen urethral bulking agents. With the increasing use of such bulking agents, awareness of these potential complications is paramount to allow appropriate counseling and avoid the morbidity of possible unnecessary operative interventions.