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Inverted urothelial papilloma of the upper urinary tract: description of two cases with systematic literature review

Diagnostic Pathology volume 15, Article number: 40 (2020) Cite this article

Abstract

Background

Inverted urothelial papilloma (IUP) of the upper urinary tract is an uncommon benign tumour that occasionally presents as a polypoid mass causing urinary obstruction. Histologically, IUP is characterised by a proliferating urothelium arranged in cords and trabeculae, in continuity with overlying intact epithelium, and extending into the lamina propria in a non-invasive, endophytic manner. Cytological atypia is minimal or absent. Top differential diagnoses include urothelial carcinoma with inverted growth pattern and florid ureteritis cystica. Although urothelial carcinomas of the upper urinary tract with prominent inverted growth pattern commonly harbour microsatellite instability, the role of the mutator phenotype pathway in IUP development is still unclear. The aim of this study was to describe two additional cases of IUP of the upper urinary tract, along with an extensive literature review.

Case presentation

We observed two polypoid tumours originating in the renal pelvis and the distal ureter, respectively. Both patients, a 76-year-old woman and a 56-year-old man, underwent surgery because of the increased likelihood of malignancy. Histology was consistent with IUP and patients are alive and asymptomatic after long-term follow-up (6 years for the renal pelvis lesion and 5 years for the ureter lesion). The tumours retained the expression of the mismatch-repair protein MLH1, MSH2, and PMS2 whereas loss of MSH6 was found in both cases.

Conclusions

When completely resected, IUP does not require rigorous surveillance protocols, such as those for urothelial carcinoma and exophytic urothelial papilloma. It is therefore important for the surgical pathologist to be aware of this rare entity in order to ensure correct patient management.

Background

Inverted urothelial papilloma (IUP) is a rare lesion, histologically similar to inverted papilloma of the nasal cavity and paranasal sinuses. First reported in 1927 by Paschkis as “polypoid adenoma of the bladder” [1], it was later described in 1963 by Potts and Hirst as a distinct tumour entity of the urinary bladder [2]. IUP accounts for approximately 2% of all urothelial neoplasms. It usually occurs at the bladder neck, trigone or prostatic urethra, but is rare in the upper urinary tract. To the best of our knowledge, 68 IUP cases of the renal pelvis and ureter have been described in the English literature (Tables 1 and 2) [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52].

Table 1 IUP of the renal pelvis (RP) previously reported in the English Literature (NS = Not Stated; NA = Not Assessed)
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Table 2 IUP of the ureter (U) previously reported in the English Literature (NS = Not Stated; NA = Not Assessed)
Full size table

Histological diagnosis of IUP can be difficult and several pathological conditions may enter differential diagnosis, including other urothelial neoplasms with endophytic growth patterns (i.e. papillary urothelial neoplasm of low malignant potential, low- and high-grade urothelial carcinoma), nested urothelial carcinoma, paraganglioma, carcinoid tumour, florid von Brunn nest proliferation and cystitis cystica et glandularis. Most of the investigated immunohistochemical markers are of little use in routine practice, and microscopic assessment remains the current gold standard. IUPs are benign tumours and can be successfully treated by conservative surgery. While specific molecular alterations are well described for papillary urothelial neoplasms, only few studies have been conducted on inverted lesions, suggesting a correlation between inverted growth and mismatch repair deficiency in urothelial carcinoma of the upper urinary tract [53].

Two additional cases of polypoid IUP of the renal pelvis and the ureter are herein presented with a systematic review of the literature.

Clinical cases

Case 1

A 76-year-old woman was admitted with persistent right flank pain and macroscopic haematuria. A computed tomography (CT) scan revealed a 2-cm polypoid lesion in the right renal pelvis, causing mild proximal hydronephrosis. The patient was otherwise in good health and advised to undergo nephroureterectomy due to the high likelihood of malignancy. Postoperative course was unremarkable, and the patient was discharged eight days after admission. She is alive and free of disease six years after treatment.

Case 2

A 56-year-old man presented with gross haematuria. A CT scan demonstrated a filling defect in the lower third of the right ureter with no evidence of lithiasis. Owing to the distal location of the lesion, segmentary ureterectomy was performed. The patient is asymptomatic five years after complete excision of the tumour.

Pathological findings

Both cases displayed similar gross and histological features. In case 1, a sessile polypoid tumour measured 2 cm in greatest diameter. Case 2 presented as a 1.4-cm polypoid mass with a thin stalk. Microscopically, both lesions consisted of anastomosing trabeculae and cords growing downward into the lamina propria and lacked any true exophytic papillary component. Prominent peripheral palisading was seen in the trabeculae. There was no evidence of significant nuclear atypia and less than 1/10 high-power field mitotic figures were found. Hyalinised collagenous stroma was seen in case 1. Microcyst formation and foci of squamous metaplasia were occasionally observed in case 2. Histology was consistent with IUP (Fig. 1).

Fig. 1
figure 1

Histological features of two cases of IUP of the upper urinary tract. Sessile polypoid tumour of the renal pelvis consisting of anastomosing trabeculae and cords growing downward into the lamina propria, with prominent peripheral palisading in the trabeculae (Case 1: a, b). Pedunculated polypoid IUP of the distal ureter characterized by microcyst formation and foci of squamous metaplasia (Case 2: c, d)

Full size image

Representative sections of the lesions were selected for immunohistochemical analysis. As primary antibodies, we used rabbit monoclonal Ki-67 (clone 30.9, ready to use; Ventana, Tucson, AZ), rabbit monoclonal CK20 (clone SP33, ready to use; Ventana), mouse monoclonal PMS2 (clone A16–4, ready to use; Ventana), mouse monoclonal MLH1 (clone M1, ready to use; Ventana), mouse monoclonal MSH2 (clone G219–1129, ready to use; Ventana) and rabbit monoclonal MSH6 (clone SP93, ready to use; Ventana). Sections were stained on a Ventana BenchMark ULTRA immunostainer (Ventana Medical Systems). The procedure involved pretreatment with Cell Conditioning 1 followed by antibody incubation. The signal was then developed with ultraView Universal DAB Detection Kit for antibodies against Ki-67 and CK20. OptiView DAB IHC Detection Kit was employed for all other antibodies.

Both lesions were negative for CK20 and exhibited uniformly low Ki-67 (< 1%) (Fig. 2). Expression of the mismatch-repair protein was considered positive if at least 10% of neoplastic cells showed nuclear staining [54]. Loss of MSH6 was seen in both cases, alongside with retention of MLH1, MSH2, and PMS2 expression (Fig. 3).

Fig. 2
figure 2

Immunohistochemical results in two cases of IUP pf the upper urinary tract. Both cases were negative for CK20 immunostaining (Case 1: a; Case 2: c) and showed low Ki-67 labelling index (< 1%) (Case 2: b; Case 2: d)

Full size image
Fig. 3
figure 3

Expression of the mismatch-repair proteins in two cases of IUP of the upper urinary tract (Case 1: a-d; Case 2: e-h). Nuclear staining for MLH1 (a, e), MSH2 (b, f), PMS2 (c, g) was observed in both cases, whereas the tumours showed loss of MSH6 expression (d, h)

Full size image

Discussion

IUP of the upper urinary tract is a benign tumour with 68 cases described to date in the English literature. It usually manifests in middle-aged adults within the 6th or 7th decade of life, and males are more commonly affected than females [26].

The most frequent presenting symptoms are haematuria, macroscopic or microscopic, and renal colic. Irritative symptoms, as well as urinary tract obstruction, have also been reported [55]. In a high percentage of cases, however, tumours are asymptomatic and detected during unrelated clinical investigations.

Preoperative diagnosis of IUP is difficult. Imaging studies may reveal non-specific findings such as filling defects of obstructive masses, often associated with hydronephrosis, hydroureter or renal stones [56]. Cytological morphology falls within the range of normal or mild atypia since IUP is covered by a normal and intact mucosal layer. Accurate preoperative diagnosis requires biopsy and visualisation through endoscopic examination. These procedures also provide therapeutic indications, thus avoiding unnecessary nephroureterectomy [26]. Due to the high likelihood of malignancy, preoperative biopsies were not carried out in our cases and patients underwent radical surgery.

Grossly, IUP presents as a solid or polypoid mass with smooth mucosal, non-papillary covering surface. Most tumours measure less than 3 cm in diameter but can reach up to 8 cm or more. They usually occur as solitary lesions, although 3.6–6% are bilateral or multicentric [55].

Histologically, IUP is characterised by endophytic growth of epithelial elements arranged in nests and cords, growing down from the surface urothelium into the lamina propria with expansible borders. Cystic areas and foci of squamous metaplasia are common. Neither fibrovascular cores nor desmoplasia are seen in IUP and stromal inflammation is minimal. Necrosis and mitotic activity are absent. Distinction between inverted papilloma and urothelial carcinoma with an endophytic growth pattern can be challenging. Contrary to IUP, urothelial carcinoma with inverted configuration shows cytological atypia, mitoses, nuclear pleomorphism and often displays an exophytic papillary component. In addition, invasion into the muscularis propria may occur in urothelial carcinoma but not in IUP. When biopsies are of small size or morphological artefacts and tangential sectioning obscure the lesion, differentiating between these biologically different entities becomes increasingly difficult [57].

Recently, Wobker et al. described 13 cases of a unique urothelial tumour occurring exclusively in the renal pelvis and ureter, named polypoid urothelial proliferation with inverted growth pattern (PUTIP). Morphologically, PUTIP exhibits hybrid features between a totally inverted PUNLMP, IUP and florid proliferation of von Brunn nests [58]. PUTIP may show a distinct inverted papilloma–like component with densely hyalinised collagenous stroma, but lacks the thin anastomosing cords typical of IUP.

In the present study, we observed low Ki-67 proliferation index and negativity for CK20 in both cases. A number of immunohistochemical markers have been shown to be frequently expressed in urothelial carcinomas, including the proliferation marker Ki-67 and CK20 [59]. IUP may be aneuploid and demonstrate high proliferative activity, although these features do not necessarily correlate with malignant behaviour [60, 61].

Our cases showed loss of MSH6 by immunohistochemistry, whereas expression of MSH2, MLH1 and PMS2 was retained. The molecular genetic abnormalities of IUP appear to differ from those of urothelial carcinoma, suggesting that these two neoplasms are unrelated [62]. Inverted-type urothelial carcinomas of the renal pelvis can be associated with MSI. Hartmann and co-authors examined 132 urothelial carcinomas of the upper urinary tract exhibiting some degree of inverted growth, and found that 35 (26.5%) were microsatellite unstable by polymerase chain reaction analysis [53]. Similar results were obtained by Harper in 214 patients with upper tract urothelial carcinoma tested for mismatch repair protein loss by immunohistochemistry [63]. In a multicentric study conducted on 62 IUPs of the urinary bladder Eiber and co-authors demonstrated aberrant immunostaining for MSH2 (5.8%), MLH1 (11.8%) and MSH6 (3.8%) [62]. As previously described, cellular loss of one MMR protein is not sufficient to cause detectable microsatellite defects [64]. Therefore, our observation may be spurious and unrelated to microsatellite instability, and should be confirmed in a larger series of IUPs of the upper urinary tract. In addition, our patients did not show any stigmata of Lynch syndrome or HNPCC-associated background.

Regarding treatment options, nephroureterectomy, local resection or partial ureterectomy with preservation of the kidney, and endoscopic surgery may be of use [65]. After excision, some authors recommend a follow-up protocol (endoscopy and radiographical studies) similar to that used in patients with low-grade urothelial carcinoma [26], while others do not advocate this rigorous and long-term follow-up due to the low risk of recurrence and favourable prognosis of IUP [66].

In conclusion, IUP of the upper urinary tract is an extremely rare tumour characterised by an inverted pattern of growth and constituted by normal to minimally atypical proliferating urothelium. The absence of progression of IUP on long-term follow-up argues against the need of patients’ continuous surveillance when strict diagnostic criteria are followed, a complete resection can be ascertained and no history of previous or concurrent urothelial malignancies is recorded.

Availability of data and materials

The authors confirm that the data supporting the findings of this study are available within the article.

Abbreviations

IUP:

Inverted Urothelial Papilloma

CT:

Computed Tomography

PUTIP:

Polypoid Urothelial Proliferation with Inverted Growth Pattern

RP:

Renal Pelvis

NS:

Not Stated

NA:

Not Applicable

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Authors and Affiliations

  1. Pathology Unit, Careggi University Hospital, Florence, Italy

    R. Santi

  2. Pathology Section, Department of Health Sciences, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy

    I. C. Galli & G. Nesi

  3. Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy

    V. Canzonieri

  4. Department of Medical, Surgical and Health Sciences, University of Trieste Medical School, Trieste, Italy

    V. Canzonieri

  5. University of the Basque Country, Barakaldo, Spain

    J. I. Lopez

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Contributions

RS conceived and designed the study, evaluated histological slides and contributed in writing the manuscript. ICG contributed in evaluating histological slides, collecting the data and writing the manuscript. JIL contributed with a case and participated to the design and implementation of the research. GN contributed to the design and implementation of the research, to the analysis of the results and in writing the manuscript. VC contributed in writing the manuscript. The author(s) read and approved the final manuscript.

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Correspondence to G. Nesi.

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Santi, R., Galli, I.C., Canzonieri, V. et al. Inverted urothelial papilloma of the upper urinary tract: description of two cases with systematic literature review. Diagn Pathol 15, 40 (2020). https://doi.org/10.1186/s13000-020-00961-9

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  • DOI: https://doi.org/10.1186/s13000-020-00961-9

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Diagnostic Pathology

ISSN: 1746-1596

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