Efficacy of pembrolizumab in a rare type of bladder cancer arising 25 years after augmentation cystoplasty

Abstract

We report using the checkpoint inhibitor, pembrolizumab, as part of a multimodal treatment plan in a 36-year-old man with a rare bladder cancer arising 25 years after augmentation cystoplasty (sigmoid colonic cystectomy for neuropathic bladder was performed at 9 years old). On a regular clinic visit for clean intermittent catheterisation, the patient presented with gross haematuria and was diagnosed with urothelial carcinoma with sarcomatoid change. Gemcitabine and cisplatin-based neoadjuvant chemotherapy was unsuccessful, and pembrolizumab infusions (200 mg every 3 weeks) were initiated. A partial response was confirmed after six courses of pembrolizumab, with significant tumour shrinkage. A radical cystoprostatectomy and ileal conduit construction was performed, and pathology revealed no evidence of malignancy (ypT0, N0). The patient was successfully treated with the anti-programmed death-1 inhibitor, pembrolizumab, which was curative after total cystectomy. Further research is required to elucidate the potential role of checkpoint inhibitors in bladder cancers arising after augmentation cystoplasty.

Background

While augmentation cystoplasty represents the gold standard in the management of refractory detrusor instability, there is an increasing concern of malignant transformation following surgery. Currently, limited data exist for the risk of malignant transformation, due to the long latency period between surgery and tumour occurrence. In the published long-term data that are available (follow-up ≥10 years), bladder tumours appear to develop in a higher percentage of patients with bladder augmentation (4%, 8/203 patients), compared with age-matched control patients with a similar primary congenital bladder abnormality, managed by anticholinergics and intermittent catheterisation (2.5%, 5/203).¹ At the time of diagnosis, 75% of patients in this study presented with locally advanced disease or nodal metastases. These tumours were highly aggressive, with a cancer-specific mortality of 75% at 15 months following diagnosis.¹ These aggressive tumours often respond poorly to chemotherapy and radical surgery is often performed.^2–4 We report a unique case of a rare bladder cancer in a patient who had undergone augmentation cystoplasty; this was successfully treated with the checkpoint inhibitor, pembrolizumab, as part of a multimodal treatment plan.

Case presentation

A 36-year-old man presented at our institution with macroscopic haematuria and fatigue. His medical history includes a sigmoid colonic cystectomy for neuropathic bladder after meningocele surgery at the age of 9 years old. He has been followed regularly every 1 or 2 months for the management of clean intermittent catheterisation. Despite the highly inflammatory findings observed at presentation, and treatment of the suspected urinary tract infection, the gross haematuria did not subside; transurethral surgery was planned to achieve haemostasis.

Investigations

Cystoscopy revealed a lobulated tumour in the bladder and no abnormalities in the mucosal part of the intestine used in the dilatation. Transurethral resection of the tumour was attempted; however, due to large tumour size, complete resection was difficult, so a tumour biopsy was collected and haemostasis achieved. The pathological diagnosis was urothelial carcinoma with sarcomatoid change, with a negative microsatellite status from the formalin-fixed paraffin-embedded tissue sample (figure 1). A plain CT scan showed dilated bladder and left hydronephrosis. An MRI T2-weighted image revealed a tumour protruding from the trigone of the bladder to the prostatic region, with suggestion of extramural infiltration. The left obturator lymph node was enlarged, but no distant metastases were observed (urothelial carcinoma with sarcomatoid change of the bladder; cT3bN1M0) (figure 2).

Figure 1.

Tumour cross-section: urothelial carcinoma with sarcomatoid change (H&E staining, magnification ×200).

Figure 2.

(A) CT image of the urothelial carcinoma showing enlargement of the left obturator lymph node. (B) MRI T2-weighted image revealing the urothelial carcinoma protruding from the trigone of the bladder to the prostatic region.

Treatment

Cystoscopy findings showed no abnormalities in the mucosal part of the intestine used in the augmentation, and no adenocarcinoma component derived from the sigmoid colon was found. We considered that sarcomatoid changes developed from the urothelial cancer. The patient was initiated on gemcitabine and cisplatin (GC)-based neoadjuvant chemotherapy (NAC; gemcitabine 1000 mg/m² on days 1, 8 and 15, and cisplatin 70 mg/m² on day 2). After 1 NAC cycle, the appearance of left hydronephrosis was evident on CT imagining, but there was no change in lymph node enlargement and no distant metastases. However, after two additional NAC cycles, progression of the local bladder cancer as well as bilateral enlargement of the pelvic lymph nodes was visible on CT and MRI scans. The patient was then started on immunotherapy with the monoclonal antibody pembrolizumab, an anti-programmed death (PD)-1 inhibitor. Pembrolizumab infusions (200 mg) were carried out every 3 weeks. A partial response was confirmed by MRI and positron emission tomography (PET)-CT imaging after six courses of pembrolizumab therapy (figure 3). Accumulation of bilateral enlargement of pelvic lymph nodes seen on PET-CT disappeared after 12 courses of pembrolizumab therapy (figure 3). The patient then underwent a radical cystoprostatectomy and ileal conduit construction. Subsequent pathological examination of the removed tissue revealed no evidence of malignant lesions (no viable tumour cells, no lymph node metastasis, fibrous tissue was evident from the bladder wall; ypT0, N0). It was considered that this unusual bladder cancer was successfully treated with pembrolizumab.

Figure 3.

MRI and positron emission tomography CT (PET-CT) imaging results before and after treatment with pembrolizumab (200 mg infusions every 3 weeks). (A) T2-weighted MRI and PET-CT before pembrolizumab therapy, showing local tumour and lymph nodes metastases. (B) T2-weighted MRI and PET-CT after six courses of pembrolizumab therapy, showing significant shrinkage of tumour and lymph node metastases compared with the pre-treatment scan (A). (C) T2-weighted MRI and PET-CT after 12 courses of pembrolizumab, and before radical cystoprostatectomy and ileal conduit construction, showing significant shrinkage of tumour and disappeared lymph nodes metastases compared with the pre-treatment scan (A).

Follow-up

Six months after surgery, the patient was hospitalised for a urinary tract infection; this was treated with antibiotics without the need for a surgical procedure. More than 1 year after surgery, he still alive and no tumour recurrence or metastases are evident.

Discussion

There are many published cases for augmentation cystoplasty performed for neurogenic bladder diagnosed in childhood.⁵ However, there are limited reports of bladder cancer occurring after this procedure. This lack of data on the risk of bladder cancer after augmentation cystoplasty can be explained by its unusual incidence, and the long latency period between surgery and the occurrence of a malignant tumour. In a systematic review by Biardeau et al the follow-up time probability to develop a malignant tumour after augmentation cystoplasty, using different types of bowel segments, ranged from 0% to 5.5%.⁴ The median latency period until a reported malignant tumour following augmentation cystoplasty was 19 years (range 0.25–42 years), with the incidence of urothelial cell carcinoma 35% after augmentation cystoplasty. About 35% of patients had a locally advanced tumour on histopathological diagnosis.⁴

The exact mechanism of carcinogenesis after augmentation cystoplasty remains unknown; however, it has been suggested that the development of bladder extension tumours is associated with the coexistence of carcinogenic stimuli. Sung et al reported on four cases in which malignant tumours associated with augmentation cystoplasty were extremely aggressive, and exhibited distinct morphological, immunohistochemical and genetic characteristics compared with conventional urothelial carcinoma.⁶ Radical surgery with radical cystectomy or pelvic exenteration is the procedure most often performed.⁴

In this particular case of urothelial carcinoma, the sarcomatoid variant was identified; this unusual malignancy comprises both carcinomatous and sarcomatous components. With the rareness of the sarcomatoid variant in urothelial carcinoma, and the absence of randomised controlled trials in this area, no standardised treatment protocol is available. The sarcomatoid variant has been associated with aggressive disease and poor response to chemotherapy, suggesting that immediate radical cystectomy would be appropriate as first-line therapy for patients with localised disease.^{2 3} The combination of GC is an effective and well-tolerated chemotherapy regimen for the treatment of advanced urothelial carcinoma. However, few data are available regarding its use in the sarcomatoid variant.⁷ Several retrospective case reports and series have shown that GC is a well-tolerated and effective regimen, given its ability to induce complete remission in selected patients.² Genitsch et al have reported morphologic and genomic characterisation of urothelial to sarcomatoid transition in muscle-invasive bladder cancer, with an overexpression of PD-L1 in the sarcomatoid morphology.⁸ These findings are in line with increased PD-L1 expression in sarcomatoid differentiated kidney and lung carcinomas, suggesting a role for checkpoint inhibition as a promising strategy for successful treatment.^{9 10} There are arguments on the clinical utility of PD-L1 expression; the expression of PD-L1 as a predictive biomarker is limited, pembrolizumab demonstrated a survival benefit irrespective of PD-L1 status.^{11 12} Thus, the clinical utility of PD-L1 in urothelial carcinoma could be limited.

This current case of bladder cancer with sarcomatoid variant after bladder augmentation by colocystoplasty was resistant to chemotherapy, leaving the patient with a poor prognosis. The authors consider that the patient was successfully treated with six courses of the anti-PD-1 inhibitor, pembrolizumab, and this was curative after radical cystoprostatectomy and ileal conduit surgery.

Learning points.

• In this case of a rare bladder cancer arising after augmentation cystoplasty, pembrolizumab has shown promise as a potential curative therapy combined with radical cystoprostatectomy and ileal conduit surgery.

• Further research is required to elucidate the potential role of checkpoint inhibitors in bladder cancers arising after augmentation cystoplasty.

• Collection of long-term follow-up data (>40 years) in patients who have undergone surgery for neuropathic bladder is needed to add to the current sparse evidence base of malignant transformation following surgery.

• Further research is required to understand the uniqueness of aggressive malignant bladder cancers following augmentation cystoplasty, compared with conventional urothelial carcinomas.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).