Post-Transurethral Resection of Bladder Tumor Bladder Perforation Resulting in Mitomycin C Extravasation, Pudendal Neuralgia, and Ureterohydronephrosis

Abstract

Background: Mitomycin C (MMC) extravasation after transurethral resection of bladder tumor (TURBT) is a rare and highly morbid complication. Management of these cases may require a multidisciplinary approach with strategies ranging from conservative management to surgical intervention.

Case Presentation: We present a 48-year-old woman who received a TURBT for a 5 mm bladder tumor. Procedure was uneventful and no bladder perforation was noticed. A single dose of instillation of MMC was performed after surgery resulting in extravasation, consequent ipsilateral pudendal neuralgia, and ureterohydronephrosis. Treatment included a second TURBT, Double-J stent placement, and multiple pain management schemes. After 8 months the patient had complete resolution of pain and ureterohydronephrosis.

Conclusion: Perioperative chemotherapy is the standard of care in low-risk bladder cancer. Extravasation of MMC, although rare, can produce severe complications, sometimes irreversible. Other treatment options, such as gemcitabine, are less frequently used despite being less irritant and having similar efficacy. Further studies are needed to compare single-dose instillation regimens.

Introduction and Background

Approximately 70% of bladder cancer (BC) patients present with nonmuscle invasive disease. The European Association of Urology (EAU) and American Urological Association (AUA) guidelines recommend stratification of patients into risk groups according to probabilities of recurrence and progression. Low-risk tumors are defined by the following characteristics: solitary, low-grade Ta, primary, <3 cm in diameter, and no carcinoma in situ (low-risk nonmuscle invasive bladder cancer or LR-NMIBC). The initial approach of LR-NMIBC is transurethral resection of bladder tumor (TURBT) followed by a single dose of adjuvant intravesical chemotherapy. It has been shown that perioperative single instillation significantly reduces disease recurrence rates compared with TURBT alone (Level of evidence: 1a).¹

The use of adjuvant agents in the bladder after TURBT has long been established. Immediate single instillation has been shown to destroy circulating tumor cells after TURBT, and by an ablative effect on residual tumor cells at the resection site and on small overlooked tumors. Evidence shows that the 5-year recurrence rate for nonmuscle invasive bladder cancer (NMIBC) after TURBT alone is 50% to 70% but decreases to 39% when TURBT is followed by adjuvant chemotherapy.¹ The most commonly used agent is mitomycin C (MMC), an alkylating agent that inhibits DNA synthesis and causes single-strand breakage of DNA and chromosomal damage. The most frequent side effects in randomized trials include mild transient irritative bladder symptoms (10%) and allergic skin reactions (3%), but severe complications have been reported, including bladder perforation and drug extravasation with perivesical fat necrosis. We present a case of single instillation of MMC extravasation after TURBT with severe pelvic pain, pudendal neuralgia, and ureterohydronephrosis caused by chemotherapy extravasation.

Presentation of Case

A 48-year-old woman with a history of non-Hodgkin's lymphoma and a papillary thyroid tumor was found to have a 0.5 cm papillary lesion on the left bladder wall by ultrasonography. En bloc resection of a left suprameatal tumor was performed followed by an immediate single instillation of 40 mg of MMC. The surgery was uneventful and there was no evidence of perforation with cystoscopy view. The pathology report informed a low-grade urothelial carcinoma stage pTa.

After surgery, in the recovery room the patient developed an acute urinary retention that was managed with a transient catheter placement. After complete recovery she was discharged. One week later she consulted for left pelvic pain and irritative urinary symptoms; the urine sample and culture did not demonstrate infection and was discharged with analgesics. Despite this initial approach, the pain increased and extended to her left leg. A contrast MRI was performed showing left bladder wall thickening, periureteral edema, perivesical fat, and left pudendal nerve inflammation (Fig. 1). The patient received methadone, gabapentin, and corticosteroids to manage the pain and decrease edema, with mild improvement. For persistent pelvic pain the patient underwent a cystoscopy. A fistula with surrounding congested mucosa was observed on the left bladder wall. A transurethral resection of the fistula was performed (Fig. 2A, B). The histopathology analysis informed inflammatory reactions of mucosa and corion without malignant cells. Two months later she was readmitted because of fever, left lumbar pain, and dysuria. Blood examination showed leukocytosis and the urine culture informed urinary tract infection by Staphylococcus aureus. Ultrasound informed a moderate left hydronephrosis and a contrast computed tomography scan revealed delayed contrast excretion in the left ureter secondary to distal periureteritis (Fig. 3).

FIG. 1.

MRI scan of the pelvis shows bladder wall thickening and abnormal fat enhancement (yellow arrow), periureteral edema (red arrow), and the presence of a fistula with a lateral collection (green arrow).

FIG. 2.

Cystoscopy view of the bladder fistula on the scar of the prior TURBT. A second TURB was performed on the fistulous tract to promote epithelialization. (A) Fistula before second TURB. (B) Appearance after second TURB. TURBT, transurethral resection of bladder tumor.

FIG. 3.

CT of the abdomen shows left hydronephrosis caused by distal ureteral edema (red arrows).

Double-J stent was placed with improvement of the general condition. She completed 14 days of antibiotics and was discharged without urinary symptoms. One month later the Double-J stent was removed because of intolerance without further complications. The cystoscopy showed full epithelialization of the scar. Follow-up at 6 months with subsequent ultrasound demonstrated complete resolution of the hydronephrosis. Currently the patient remains asymptomatic and in control.

Discussion

The use of perioperative intravesical chemotherapy in low-risk NMIBC is recommended by the AUA and EAU supported by several clinical trials and meta-analysis (Level of evidence: 1a). It has been shown that single instillation reduces the 5-year recurrence rate by 14% from 59% to 45% (Ref.¹). Nevertheless, in general practice, administration of perioperative chemotherapy is uncommon, with <33% of urologists using MMC post-TURB in LR-NMIBC patients.

The first published randomized trial assessing the efficacy of perioperative intravesical MMC described dysuria or frequency in <1% of patients. Sylvester et al. in their meta-analysis describing the efficacy of intravesical perioperative chemotherapy reported dysuria, urinary frequency, or gross hematuria in ∼10% of patients and described systemic toxicity as rare.¹ Descriptions of major complications associated with MMC are infrequent, but include eosinophilic cystitis, bladder perforation, perirectal abscesses, chronic cystitis, and ureteral stenosis.

The most important way of minimizing complications associated with the use of MMC is identifying bladder perforation after TURBT. Small but asymptomatic perforations of the bladder should occur more commonly than expected. In a prospective study by Balbay et al.,² the authors reported a bladder perforation rate of 58.3% in 36 patients after TURBT. All the cases were detected by postoperative cystography. Tumor size was the only statistically significant factor associated with this outcome.²

It is generally accepted that the safety of MMC instillation depends on the integrity of the bladder wall after the resection. In this way, it has been suggested that MMC should be given before the resection. Also, to improve the efficacy of single instillation chemotherapy, electromotive drug administration (EMDA) is associated. MMC/EMDA association showed a reduction in recurrence rates and enhancement in the disease-free interval when compared with TURBT alone.

Other drugs such as epirubicin, docetaxel, and gemcitabine have also been tested with beneficial effects. In a prospective randomized clinical trial (RCT), Messing et al. demonstrated that postresection intravesical instillation of gemcitabine significantly reduced the risk of recurrence when compared with instillation of saline, with low rate of adverse events.³ Unfortunately, no RCT has ever been conducted comparing different agents face to face.

In the absence of evidence to define one of these drugs as superior, and given the comparable results among chemotherapeutic agents our choice should be based on their toxicity and safety profile. Drugs may be classified as vesicant, irritant, or nonvesicant depending on the potential to cause local tissue injury. Vesicant drugs are capable of producing ulcers and severe tissue damage after extravasation during intravenous infusion. This may explain why some antineoplastic drugs, such as MMC, produce unwanted and severe irritative symptoms when administered in the bladder, especially when perforation occurs. In contrast, nonvesicant drugs such as gemcitabine may be safer in case of perforation since they have less tissue-damaging capability.

Finally, as an alternative, continuous saline bladder irrigation may be offered. A trial by Onishi et al. showed that there was no significant difference in recurrence-free survival between patients who received 18 hours of saline irrigation vs a single instillation of MMC after TURBT for low-risk BC.⁴

Conclusion

Perioperative chemotherapy is the standard of care in low-risk BC. Extravasation of MMC, although rare, can produce severe complications, sometimes irreversible. An exhaustive control of the bladder should be performed before instillation of intravesical drugs to avoid extravasation. Acceptable alternatives to this treatment are using nonvesicant drugs such as gemcitabine or continuous saline bladder irrigation. These strategies may achieve similar results in recurrence-free survival. Further studies, including randomized controlled trials, should address which is the best approach after TURBT for low-risk BC.

Abbreviations Used

AUA

American Urological Association

BC

bladder cancer

CT

computed tomography

EAU

European Association of Urology

EMDA

electromotive drug administration

LR-NMIBC

low-risk nonmuscle invasive bladder cancer

MMC

mitomycin C

MRI

magnetic resonance image

NMIBC

nonmuscle invasive bladder cancer

RCT

randomized clinical trial

TURBT

transurethral resection of bladder tumor

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Cite this article as: Chemi J, Jaunarena JH, Camean J, Azuri W, Villaronga A, Villoldo GM (2020) Post-transurethral resection of bladder tumor bladder perforation resulting in mitomycin C extravasation, pudendal neuralgia, and ureterohydronephrosis, Journal of Endourology Case Reports 6:4, 315–318, DOI: 10.1089/cren.2020.0117.