Inverted Papilloma: A Rare and Benign Cause for Upper Urinary Tract Neoplasia

Abstract: Inverted papilloma (IP) of the ureter is a very rare benign neoplasm with around 50 cases reported in the literature 1.  Radiologically and endoscopically these lesions are indistinguishable from urothelial cancers. It is therefore essential to obtain a tissue diagnosis prior to treatment.

We present a case of a large ureteric lesion, with radiological and endoscopic appearances of transitional cell carcinoma (TCC). This lesion may have been treated with major radical surgery if there was no tissue diagnosis available owing to the large size on computerised tomography (CT). The patient was initially managed with endoscopic and conservative measures, and as a result, we were able to obtain a histological sample that confirmed the benign disease.

The patient was successfully treated without radical intervention and we were, therefore, able to preserve her renal function and prevent unnecessary co-morbidity associated with major open or laparoscopic surgery. This case highlights the importance of positive histology and multi-disciplinary team (MDT) decision-making to ensure appropriate intervention for patients is planned.

Introduction: Inverted papilloma is a rare, benign neoplastic lesion. It can present anywhere along the urinary tract containing transitional epithelium. IP accounts for around 2% of neoplastic lesions of the urinary tract. It was first described in 1927 by Paschkis 2 and was later named by Potts and Hirst 1963 3, and it was initially thought to be a benign condition. IP is found most commonly in the urinary bladder, but there have also been cases in the renal pelvis 5, ureter and prostatic urethra 4.  There are very few cases of IP in the ureter, with Sung et al reporting 4 of 75 in their case series 4 and Meritz et al commenting that there are around 50 cases that have been reported in the literature 1.  


Case Presentation: A 90-year-old female presented to the emergency department (ED) with a one-day history of right-sided flank pain, lower abdominal pain, and fever. She reported reduced urine output over the previous 24-hours; she denied any other lower urinary tract symptoms. She had a past medical history for cholecystectomy, partial gastrectomy for peptic ulcer and controlled hypertension. Her drug history included perindopril 4mg and had no known drug allergies. She was a non-smoker, did not drink alcohol and lived alone.

On admission, her vital signs recorded a temperature of 37.0oC, 97% oxygen saturation (Fi02=0.21), blood pressure 102/57mmHg, heart rate 88 and respiratory rate 22. Cardiovascular, respiratory and urological examinations were all normal and her abbreviated mental test score was 10/10.  Abdominal examination revealed tenderness in the right flank and suprapubic region but did not show signs of peritonism or any palpable masses.

Investigations were arranged in the ED and included urinalysis that demonstrated blood, leucocytes, and nitrites. Subsequent MSU showed raised white cells but no bacterial growth. She had blood samples sent that showed normal full blood count, coagulation screen and renal function, with a creatinine of 66 and eGFR of 73. However, the blood samples confirmed a raised c-reactive protein at 87 and mildly deranged liver function tests (LFTs) with AST=87, ALT=41, ALP=164, and GGC=145. The bilirubin was normal as was her ECG, chest and abdominal plain films.

The patient was admitted under the elderly care physicians and was treated for suspected urinary tract infection, pyelonephritis or biliary sepsis is given her deranged LFTs. She received intravenous antibiotics (amoxicillin 1g) for 48 hours with a single-dose gentamicin on admission and intravenous fluids. CT abdomen and pelvis was arranged to evaluate her symptoms and deranged LFTs. The CT demonstrated a large-volume, poorly emptying bladder, right hydronephrosis and the possibility of a filling defect in the right distal ureter (figures 1 & 2). It is important to note that a previous CT investigating her gastric ulcer 4 years ago also showed a large bladder and early right hydronephrosis but no filling defect in the distal ureter.

UroToday CT image demonstrating right sided hydroureter
Figure 1: CT image demonstrating right-sided hydroureter (above) and urinary retention and large capacity bladder (below).

UroToday CT images demonstrating right hydronephrosis
Figure 2: CT images demonstrating right hydronephrosis (above) and right distal ureteric lesion (below).

The patient was then referred for assessment by the urology team. Initial management consisted of urethral catheter insertion that yielded a residual urine volume of 1.2 Litres. The patient was discharged with a catheter and 5 days of oral amoxicillin. The LFTs normalised through the course of admission. A follow-up CT Urogram (CTU) was arranged for 6-weeks time, that showed a collapsed bladder and resolution of the right hydronephrosis but there was a persistent filling defect in the right ureter. Her persistent distal ureteric lesion was thought to be TCC until proven otherwise.

UroToday Figure 3 Resolution of right hydroureteroneprhosis following urethral catheter insertion
Figure 3: Resolution of right hydroureteroneprhosis following urethral catheter insertion.

UroToday Right retrograde studies confirming filling defect in right distal ureter
Figure 4: Right retrograde studies confirming filling defect in right distal ureter.

The patient was reviewed in the clinic with the results of the follow-up CTU. The patient and relatives were counselled and it was agreed to continue with diagnostic cystoscopy, right retrograde pyelography +/- right rigid ureteroscopy +/- biopsy +/- insertion of a ureteric stent. She attended preoperative assessment and was deemed ASA 2 and so she went on to have the procedure.

Intra-operatively, cystoscopy showed a normal urethra without stricture excluding obstruction resulting in a poor emptying bladder. There were also features of cystitis and large capacity but no suspicion of malignancy. A right retrograde study showed a large filling defect in the lower ureter. Semi-rigid ureteroscopy revealed a large mass with the visual appearance of TCC. Multiple basket biopsies were taken and a size 6-French multi-length ureteric stent was placed.

The histopathology report detailed that microscopically there was ureteric mucosa covered by flat and bland urothelium and within the stroma, there were nests of urothelium which are sometimes cystic. Anastomosing strands of urothelium were also present.  The urothelium was bland with the nuclei showing only mild variation in nuclear size and shape. Mitotic activity was not seen.  The stroma is vascular and mildly oedematous. The report concluded these were features of an inverted urothelial papilloma that showed low-risk for malignancy.

The case was discussed at MDT and it was decided that the patient would be treated conservatively despite being considered fit for nephroureterectomy. This was because the lesion was too large for local control with laser and that her right hydronephrosis had settled. The patient remains asymptomatic with a catheter and is happy with the outcome.

Discussion: IP of the upper urinary tract is a rare finding, with the majority (around 90%) of lesions developing in the urinary bladder 1. It is commonly found in patients in the 6th or 7th decades of life 2, with Luo et al. 2 reporting a mean age of 67 years in a case series of 10 patients. There are reports of the male predisposition of up to 9:1 6, but other papers report a male to female ratio of 3:1 to 7:1 7.

Upper tract IP can present in a similar fashion to other upper urinary tract neoplasias, with haematuria and flank pain the most common symptoms 2. Despite this, patients can remain without symptoms and the findings can be incidental as in this case. The differential diagnosis for upper tract IP includes urothelial carcinoma (TCC) and less commonly nephrogenic adenoma, the paraganglioma and carcinoid tumours 1.

Lesions are commonly solitary but there have been reports of both multicentric and bilateral lesions 8. Histologically, IP lesions have endophytic trabeculations of the urothelial layer with downward development up to the stoma lining without exophytic papillary component 9.

The aetiology of IP remains unclear and various theories have been proposed in the literature since its discovery. One theory considered by both Cummings 10 and Matz et al. 11 was that the lesion was more a hyperplastic reaction rather than a neoplasm. However, current thinking is that IP remains a true neoplasm but there is continued uncertainty regarding the precise causative agents or processes involved 5.

UroToday Image of lesion taken during semi rigid ureteroscopy prior to biopsies
Figure 5: Image of the lesion taken during semi-rigid ureteroscopy prior to biopsies.

Treatment remains a subject of debate and controversy. There have been a wide variety of surgical procedures (open or laparoscopic) used that include nephroureterectomy, segmental resection of the ureter and endoscopic intervention 2. As endoscopic surgery has developed, there is a greater expert opinion in the value of treating with endoscopic local excision of IP within the ureter 2. The current literature reports that there must be positive histological diagnosis prior to the utilization of this technique though 2.

Conclusion: We present a rare case of ureteral IP successfully treated conservatively with endoscopic urological intervention. The learning points from this case report include the importance of obtaining histological samples when able to assist in the planning of surgical intervention, particularly in the elderly patient. There are many treatment options for patients with upper tract IP, and the authors would recommend early MDT discussion for these cases and referral to appropriate centres dependant on patient suitability to treatments available.


Written by:  Adam Jones MBChB MRCS, Urology Registrar, W. Taylor, Wasim Mahmalji, MBBs, BSc, MSc, FRCS, Consultant Urologist, Hereford County Hospital

References:
  1. Mertziotis N, Kozyrakis D, Petrolekas A et al. Inverted papilloma of the ureter: study of a rare case with emphasis on clinicopathological implications. Can Urol Assoc K 2012; 6(6): 274-6.
  2. Luo JD, Wang P, Chen J et al. Upper urinary tract inverted papillomas: Report of 10 cases. Oncology letters 4: 71-72; 2012.
  3. Potts IF, Hirst E. Inverted papilloma of the bladder. The journal of urology 1963 Aug, 1: 90; 175-9.
  4. Sung MT, Maclennan GT, Lopez-Beltran A et al. Natural history of inverted papilloma. Cancer. 2006 Dec 1;107 (11): 2622-7.
  5. Koizumi K, Shiga J, Yokota H et al. A case of inverted papilloma of the renal pelvis associated with metachronous urothelial carcinoma of the urinary bladder. Hinyokika kiyo. Acta urologica Japonica. 2013 Feb; 59(2): 121-4.
  6. Paschkis R. Uber Adenoma der Harnblase. Z Urol Chir 21; 315-325; 1927 (In German).
  7. Witjes JA, van Balken MR, van de Kaa Ca. The prognostic value of a primary inverted papilloma of the urinary tract. Journal of Urology 1997;158:1500-5.
  8. Rozanski TA: Inverted papilloma: an unusual recurrent, multiple and multifocal lesion. J Urol 155: 1391, 1996.
  9. Kilciler M, Bedir S, Erdemir F et al. Evaluation of Urinary Inverted Papillomas: A Report of Cases and Literature Review. Kaohsiung Journal of Medical Science. 2008;24: 25-30.
  10. Cummings R. Inverted urothelial papilloma: report of two cases. Urology 1969; 101:216-9.
  11. Matz LR, Wishrard VA, Goodman MA. Inverted urothlial papilloma. Pathology 1974; 6:37-44.
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