Urothelial Lesions with Inverted Growth Patterns: Histogenesis, Molecular Genetic ﬁndings, Differential Diagnosis and Clinical Management BJUIBJU INTERNATIONAL Kurt B

2010 THE AUTHORS; BJU INTERNATIONAL 2010 BJU INTERNATIONAL Mini Reviews INVERTED UROTHELIAL LESIONS HODGES

ET AL.

Urothelial lesions with inverted growth patterns: histogenesis, molecular genetic ﬁndings, differential diagnosis and clinical management BJUIBJU INTERNATIONAL Kurt B. Hodges*, Antonio Lopez-Beltran†, Gregory T. MacLennan‡, Rodolfo Montironi§ and Liang Cheng*,¶ *Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, ‡Department of Pathology, Case Western Reserve University, Cleveland, OH, ¶Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA, †Department of Pathology, Cordoba University, Cordoba, Spain, and §Institute of Pathological Anatomy and Histopathology, Polytechnic University of the Marche Region (Ancona), United Hospitals, Ancona, Italy Accepted for publication 25 May 2010

A number of well-recognized urothelial What’s known on the subject? and What does the study add? lesions with inverted morphology occur Inverted lesions of the urinary bladder comprise a spectrum of changes ranging from von in the urinary bladder. Some are so Brunn’s nests to inverted urothelial carcinoma. Differentiating these lesions is important common that they are considered normal because their proper clinical management and their expected clinical outcomes are variants of urothelium, whereas others distinctly different. are rare. It is important for the surgical pathologist to recognize these lesions and In this article, we review the spectrum of inverted urothelial lesions of the bladder, their overlapping morphological features, including current morphological criteria, key differential diagnosis, molecular genetic because in some cases establishing an findings and histogenesis. We have refined the diagnostic criteria for various bladder accurate diagnosis is challenging. In this lesions with inverted growth patterns. article, we review the spectrum of inverted urothelial lesions of the bladder. Emphasis is placed on differential diagnosis, molecular KEYWORDS and nested TCC urothelial carcinoma, genetic findings, morphology and tumourigenesis(carcinogenesis), molecular histogenesis. urinary bladder, transitional cell (urothelial) genetics, fibroblast growth factor receptor 3 carcinoma, urothelial papilloma, molecular (FGFR3), histological variant, differential pathology, precursor lesions, inverted diagnosis

INTRODUCTION in patient care. While most of these lesions pedunculated lesion with a smooth surface. can be diagnosed on morphological findings, Most arise in the trigone or bladder neck [2]. Except for von Brunn’s nests, inverted some might require ancillary studies to They are usually small (<3 cm) but can be urothelial lesions of the bladder are establish a definitive diagnosis [1]. as large as 8 cm. Most lesions are single, uncommon. Familiarity with these lesions although the incidence of multiple lesions is important if the surgical pathologist is ranges from 1.3 to 4.4% [2,5,6]. Inverted to avoid misdiagnoses. In the present review INVERTED UROTHELIAL PAPILLOMA papilloma is associated with a low risk of we will discuss the differential diagnosis, recurrence (<5%), in marked contrast to the molecular genetic findings, morphology Inverted papilloma of the urinary bladder high recurrence rates of papillary urothelial and histogenesis of benign and malignant accounts for less than 1% of all urothelial neoplasms [2,6]. lesions of the urinary bladder with endophytic neoplasms [2,3]. The age range of affected (or inverted) growth pattern (Table 1). patients is broad, but most are in their Morphologically, there are two main subtypes Von Brunn’s nests, cystitis cystica/cystitis sixth or seventh decade of life [2,4]. of inverted papillomas: trabecular and glandularis and inverted papilloma represent Inverted papilloma is far more common glandular. The trabecular subtype is the classic a spectrum of proliferative lesions, which in men than in women (7.3:1 ratio). Most lesion composed of irregularly ramifying are histogenetically related. Inverted patients present with haematuria and/or cords and sheets of urothelium arranged at papilloma and urothelial carcinoma irritative voiding symptoms [2]. Rarely, various angles to the surface mucosa and with inverted growth pattern are distinct patients might present with obstructive arising directly from the overlying urothelium clinicopathological entities with overlapping voiding symptoms. (Fig. 1A). The trabeculae are thin and orderly morphological features. These represent with a relatively uniform width. The cords of particularly challenging lesions that if Cystoscopically, inverted papilloma urothelium have characteristic peripheral misinterpreted, could result in serious errors characteristically appears as a sessile or palisading of basaloid cells. The neoplastic

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FIG1. Urothelial lesions with inverted growth pattern. A, Inverted papilloma, trabecular type, with anastomosing trabeculae of urothelium extending in to the lamina propria. B, von Brunn's nests and ﬂorid von Brunn's nest proliferations (note the rounded and smooth contours). C, Cystitis glandularis of the typical type and ﬂorid cystitis glandularis (note the irregularly spaced tubular glands lined by columnar epithelium; intestinal metaplasia is also present resembling colonic glands, indicated by arrow). D, Inverted urothelial carcinoma mimicking inverted papilloma. E, Inverted urothelial carcinoma involving the renal pelvis (gross image). F, Panoramic view of the case (from image E). G, Nested variant of urothelial carcinoma growing as relatively uniform round nests. H, Verrucous squamous cell carcinoma (note the blunt pushing architecture).

down into the loose stroma of the lamina from urothelial carcinoma [9]. Recently, TABLE 1 Main urothelial lesions with inverted propria. It is thought that these urothelial inverted papillomas with focal papillary growth patterns buds are the source of new tumour cords. The features have been described, broadening overlying surface urothelium can be normal, the morphological spectrum of inverted Benign lesions attenuated or hyperplastic, and by definition papillomas [10]. The key diagnostic features of • Inverted urothelial papilloma an exophytic component is either absent or inverted papilloma are listed in Table 2. • von Brunn’s nests and florid von Brunn’s minimal. Some inverted papillomas of the nest proliferations trabecular type are punctuated by cystic Histogenetically, the trabecular subtype is • Cystitis cystica and cystitis glandularis spaces lined by flattened urothelial cells and thought to develop by proliferation of the Malignant lesions containing eosinophilic material, producing basal cells of the overlying urothelium [4]. • Inverted urothelial carcinoma an appearance reminiscent of cystitis Supporting this hypothesis is the presence of • Nested variant of urothelial carcinoma cystica. Foci of non-keratinizing squamous bud-like basal proliferations overlying the • Verrucous squamous cell carcinoma metaplasia are often present, and rare cases tumor and the close resemblance between can show neuroendocrine differentiation [7]. trabecular cells and normal basal cells. Marked cytological atypia and mitotic activity Microcysts, which are frequently present in are absent. An uncommon variant, designated the trabecular type, are pseudoglandular TABLE 2 Key features to recognition of inverted inverted papilloma with atypia, exhibits focal structures that are incapable of mucin papilloma mild cytological atypia, with prominent production. Microcyst formation is most nucleoli, atypical squamous features and probably the result of cell necrosis within the • Relatively smooth surface with minimal to degenerate-appearing multinucleated giant core of the trabeculae. The glandular subtype absent exophytic component cells. These features are not known to have is thought to arise from cystitis cystica and • Lesional circumscription with smooth base any clinical significance [4,8]. cystitis glandularis in a multi-step process [4]. and no obvious infiltration This involves formation of von Brunn’s nests, • Minimal to absent cytological atypia The glandular subtype has morphological which undergo cystic degeneration and overlap with cystitis glandularis. It is pseudoglandular metaplasia, resulting in composed of nests of mature urothelium cystitis cystica and cystitis glandularis, with either pseudoglandular spaces lined respectively, followed eventually by neoplastic cells within the nests and cords of urothelium by urothelium or true glandular spaces transformation. often have a spindled appearance. The containing mucus-secreting goblet cells. The intervening stroma is variable in amount and luminal secretions stain with mucicarmine. While inverted papillomas are generally can be fibrotic. Urothelial buds are frequently Some inverted urothelial papillomas exhibit considered to be benign neoplasms, there are present at various points along the vacuolizated or foamy cytoplasm, which conflicting data in the literature regarding undersurface of the urothelium, protruding might make them difficult to distinguish their biological behavior [5,11,12]. Previous

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studies have reported an increased incidence The key differential diagnostic considerations variant of urothelial carcinoma is generally of urothelial carcinoma in some patients [13]. are limited. Cystitis cystica is characterized by characterized by smaller, crowded, irregularly However, most of those patients had a well-delineated, round nests of normal- spaced nests of tumour cells that appear to history of previous or concurrent urothelial appearing urothelium, whereas inverted infiltrate deeply and haphazardly, and that carcinoma. By contrast, Sung et al. [2] papilloma shows cords with anastomosing usually do not exhibit a marked degree of cyst reported on 75 patients with resected growth patterns. In contrast to inverted formation within the cell clusters. inverted papilloma, none of whom had a papilloma, inverted urothelial carcinoma is, at history of previous or concurrent urothelial least in part, exophytic, the endophytic cords carcinoma. During a mean follow-up of 68 and trabeculae are less uniform, and varying CYSTITIS CYSTICA AND CYSTITIS months, there was only one recurrence in degrees of cytological atypia are evident [18]. GLANDULARIS these patients [4]. Therefore, complete The presence of cytological atypia of a degree transurethral resection of inverted papilloma seen in high-grade urothelial carcinoma is Cystitis cystica and cystitis glandularis appears to be adequate surgical therapy, and unacceptable in inverted papilloma, and represent a continuum of proliferative and surveillance protocols as rigorous as those warrants a diagnosis of inverted urothelial presumed reactive changes that evolve from employed in the management of urothelial carcinoma. von Brunn’s nests. Cystitis cystica represents carcinoma seem unnecessary [5]. von Brunn’s nests in which the central cells are absent, resulting in the formation of Molecular genetic studies, including X- VON BRUNN’S NESTS AND FLORID VON small cystic cavities (Fig. 1C). Cystitis cystica chromosome inactivation, have shown that BRUNN’S NEST PROLIFERATIONS is demonstrable in up to 60% of bladders. inverted papilloma is a clonal, usually diploid, Cystitis cystica manifests as translucent, neoplasm that arises from a single progenitor Von Brunn’s nests are well-circumscribed submucosal cysts containing clear yellow cell [14]. The low incidence of loss of clusters of urothelial cells in the lamina fluid. Microscopically, the cysts contain heterozygosity in inverted papilloma is similar propria. The nests appear to arise by the eosinophilic fluid and are lined by a few layers to normal urothelium [14,15,16]. Recently, process of invagination of the overlying of urothelium or cuboidal epithelium. Lott et al. [17] conducted fibroblast growth urothelium. The nests may or may not be factor receptor 3 (FGFR3) and TP53 mutation demonstrably attached to the overlying Two subtypes of cystitis glandularis exist analysis in a number of inverted papillomas. urothelium [19]. Although some investigators [4]. The typical (non-intestinal) subtype is Point mutations of the FGFR3 gene were hypothesize that von Brunn’s nests arise characterized by glands lined by cuboidal identified in 45% (nine of 20) of cases. It is secondary to inflammatory injury, autopsy to low columnar cells surrounded by notable that papillary urothelial neoplasms of studies have documented their presence in transitional cells. The intestinal subtype has low malignant potential and most low-grade 85–95% of bladders, suggesting that they similar architecture to the typical subtype urothelial carcinomas also are characterized could be part of the spectrum of normal of cystitis glandularis; however, the cells by the FGFR3 mutations seen in inverted bladder histology [20,21]. Cystoscopically, lining the glands of the intestinal subtype papilloma, and yet have substantial rates of they characteristically appear as small are tall and columnar, with abundant recurrence, as well as low but still significant mucosal nodules with smooth surfaces. mucin-secreting goblet cells closely rates of progression to more aggressive forms Microscopically, the nests typically have resembling intestinal epithelium (we prefer of urothelial carcinoma. The underlying smooth, rounded contours but they can be the term cystitis glandularis with intestinal mechanisms that account for the different slightly irregular. They are usually regularly metaplasia when goblet cells are present; biological behaviours of these neoplasms that spaced. They usually occupy the superficial Fig. 1C, indicated by arrow). The two types share a common set of mutations remain to lamina propria and typically are at a uniform of cystitis glandularis can coexist, but one be elucidated. Lott et al. [17] also found no depth, but occasionally are found deeper in form usually predominates. Although the TP53 mutations in the large cohort of inverted the lamina propria. Cell nuclei in von Brunn’s overall incidences of the two types are not papillomas they studied, indicating that nests are bland and lack substantial atypia, well documented, the intestinal type is inverted papillomas do not harbour key although they can show reactive and much less common than the typical type genetic abnormalities predisposing to metaplastic changes. Carcinoma in situ of of cystitis glandularis. Rare cases of florid development of high-grade papillary the surface urothelium can extend into von cystitis glandularis with extensive intestinal urothelial carcinoma. As will be discussed Brunn’s nests, but this should not be mistaken metaplasia and mucin extravasation have in a later section, there are pronounced for invasion into the lamina propria. been reported, and such cases can be difficult differences between inverted papillomas to distinguish from adenocarcinoma [23,24]. and inverted urothelial carcinomas, in their Florid von Brunn’s nests are characterized by However, the degree of cytological and immunohistochemical expression of Ki-67, larger nests with regular spacing (Fig. 1B) architectural atypicality of adenocarcinoma p53 and CD20, and in their frequency of [22]. They frequently have lobular or linear far exceeds that seen in florid cystitis molecular alterations in chromosomes 3, configurations. Components of cystitis cystica glandularis. Adenocarcinomas usually exhibits 7, 17 and 9p21 as detected by UroVysion and cystitis glandularis can be present in such obvious destruction of the lamina propria, fluorescence in situ hybridization (FISH) proliferations. The key differential diagnostic and in the colloid variant, clusters of analysis, supporting the notion that inverted consideration of von Brunn’s nests, florid or malignant cells are seen floating in pools of papillomas arise through entirely different otherwise, is the nested variant of urothelial mucin, a feature that excludes a diagnosis pathogenetic mechanisms from inverted carcinoma (see later discussion). In contrast of extensive intestinal metaplasia with mucin urothelial carcinoma. to florid von Brunn’s nests, the nested extravasation. Although cystitis glandularis

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TABLE 3 Morphological, immunological and molecular genetic features of urothelial carcinoma with inverted pattern and inverted papilloma

Characteristic Urothelial carcinoma with inverted growth Inverted papilloma Surface Usually exophytic papillary lesions present Smooth, dome-shaped, usually intact cytologically normal Growth pattern Endophytic, lesional circumscription variable Endophytic, expansive, sharply delineated, anastomosing cords and trabeculae Cytological features Variable, nuclear pleomorphism and atypia present Orderly polarized cells, some with spindling and palisading at the periphery. No marked atypia, mitoses rare Biological potential Recurrences and progression can occur Benign, rare recurrences* Immunohistochemistry Variable, usually high p53 and Ki-67 proliferation index Low p53 expression and Ki-67 proliferation index Molecular analysis Frequent FGFR3 mutation, chromosome 9 and 17 deletions Rare deletions at chromosome 9 or 17, rare FGFR3 mutations, low rate of LOH

*Rare recurrences related to incomplete excision. LOH, loss of heterozygosity.

9p21, which are commonly seen in bladder TABLE 4 Urothelial carcinoma with inverted pattern criteria for invasion cancer. Inverted papillomas usually did not show immunoreactivity for Ki-67, p53 or Features Non-invasive Invasive CD20, whereas the urothelial carcinomas Contours of neoplastic nests/cords Regular Irregular frequently expressed one or more of Size and shape of nests Similar, rounded edges Variable, irregular these biomarkers. In addition, the inverted and jagged edges papillomas did not show the classic molecular Inflammatory and desmoplastic stroma Absent Present alterations typically seen in urothelial carcinomas using UroVysion FISH analysis. These findings further support the notion that inverted papillomas are benign and arise from with intestinal metaplasia has been proposed consistent with low- or high-grade urothelial a different pathogenetic mechanism from by some investigators as a precursor to carcinoma [3]. These features are not seen in urothelial carcinoma. adenocarcinoma, clear-cut evidence for this inverted papilloma. Frequently, components association is not well documented [25–27]. of otherwise typical exophytic or invasive One of the most challenging aspects when urothelial carcinoma accompany inverted dealing with an inverted urothelial carcinoma urothelial carcinoma. This raises the question is determining the presence or absence of INVERTED UROTHELIAL CARCINOMA of what constitutes the bona fide inverted invasion (Table 4). This is particularly true urothelial carcinoma. We require at least when there is tangential sectioning or Urothelial carcinoma with inverted growth 25% of the tumour to have an inverted when tumour is intermingled with delicate pattern can be difficult to distinguish from component to be considered inverted muscle bundles of the lamina propria. The inverted papilloma [18,28]. Distinction urothelial carcinoma. Urothelial carcinoma smoothness of the epithelial–lamina propria between these two neoplasms requires strict in situ, if present in the surface urothelium, interface is an important feature. Irregularly attention to architectural and cytological provides further support for a diagnosis of shaped nests with disruption or absence of features (Table 3). Amin et al. [18] reported 18 inverted urothelial carcinoma. Inverted the basement membrane are features of cases of urothelial carcinoma with endophytic urothelial carcinoma may also occur in the invasion. In these situations, the lamina growth pattern. The mean (range) age of renal pelvis (Fig. 1E and 1F). propria can elicit a brisk inflammatory patients was 68 (32–94) years with a male response, which could obscure the preponderance (3.5:1 ratio). Some cases Immunohistochemical stains as well as FISH invading edge of the tumor. Desmoplasia had architectural features similar to inverted can further aid in making the distinction and/or a fibrotic stromal response are papilloma (inverted papilloma-like pattern), between inverted papilloma and inverted reliable indicators of invasion. Paradoxical while others had broad-pushing bulbous urothelial carcinoma. Jones et al. [29] differentiation can aid in the diagnosis of invaginations into the lamina propria (broad- compared specimens from 15 patients early invasion. It is important to note that front pattern; Fig. 1D). In some cases, both with classic inverted papillomas and microinvasion usually does not elicit a patterns coexisted. In general, the trabeculae specimens from 29 patients with urothelial stromal reaction, making its identification of inverted urothelial carcinomas are wider carcinomas exhibiting an inverted growth more difficult. In these cases, cytokeratin and more variable than those of inverted pattern. The cases were analysed for immunostaining can be helpful. The reason papillomas. Inverted urothelial carcinoma, immunohistochemical expression of Ki-67, why some urothelial carcinomas develop by definition, has substantial nuclear p53 and CD20. In addition, UroVysion FISH an inverted growth pattern is not known; pleomorphism, readily apparent mitotic analysis was performed to assess the tumours however, it can be related to a propensity to figures and architectural abnormalities for alterations in chromosomes 3, 7, 17 and involve and expand von Brunn’s nests.

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An entity that must also be distinguished TABLE 5 Key morphological features distinguishing nested variant of urothelial carcinoma from ﬂorid from inverted urothelial carcinoma is inverted von Brunn’s nests papilloma with atypia [8]. In contrast to inverted urothelial carcinoma, inverted Cytologic papilloma with atypia has only rare mitotic Organization Lumen formation atypia Muscle invasion ﬁgures and exhibits a very low proliferation Nested variant Crowded, irregular glands Yes, variable Present Yes, frequent rate as estimated by Ki-67 immunostaining. Florid von Brunn’s Large, regularly spaced, Yes, variable Absent No nests rounded nests NESTED VARIANT OF UROTHELIAL CARCINOMA

The nested variant of urothelial carcinoma is a well-differentiated keratinizing squamous that inverted papillomas arise through rare, aggressive neoplasm that, particularly in epithelium with broad-based pushing deep molecular mechanisms distinctly different limited biopsy specimens, can be notoriously margin (Fig. 1H). Its morphological features from those that give rise to high-grade difficult to distinguish from aggregates of von overlap to some degree with those of urothelial carcinomas. Considering the Brunn’s nests. This cancer typically occurs squamous papilloma and condyloma evidence gathered so far, it appears quite in men in the fifth and sixth decades of life acuminatum, although both of the latter unlikely that inverted papilloma is a precursor [28,30]. Most patients die from disease entities are predominantly exophytic of inverted urothelial carcinoma. from 4 to 40 months after diagnosis despite lesions. Condyloma acuminatum is a aggressive treatment [31,32]. Although it squamous epithelial papillary growth that The most challenging aspect of assessing has an innocuous appearance, it invariably often displays koilocytosis characteristic inverted urothelial carcinoma is the contains cells with enlarged nucleoli and of human papillomavirus infection. Cheng determination of the presence or absence of coarse chromatin, indicative of urothelial et al. [36] compared three cases of verrucous stromal invasion. We consider the following carcinoma, particularly in the deeper portions carcinoma to three cases of condyloma morphological findings to be indicators of of the tumour (Fig. 1G). In addition, the nests acuminatum and found that condyloma invasion: variably sized and shaped cords and have an infiltrative pattern and often fuse acuminatum contained HPV DNA. All cases of nests of tumour cells with irregular contours, with one another. verrucous carcinoma were negative for HPV particularly irregular and jagged edges, and a DNA, indicating that HPV infection does not desmoplastic stromal response. Currently, Volmer et al. [22] compared 21 cases of florid play a role in the pathogenesis of verrucous there are insufficient data in the literature to von Brunn’s nests and 11 cases of nested carcinoma. The clinical history is helpful indicate whether, on a stage-for-stage basis, variant of urothelial carcinoma for biomarker because condyloma acuminatum of the patients with urothelial carcinomas with expression. They found that nested urothelial bladder is almost always associated with endophytic growth patterns have a better carcinomas had significantly higher MIB-1 external genitalia lesions. prognosis than those whose tumours are and p53 expression parameters than florid exclusively exophytic. von Brunn’s nests, suggesting that these immunohistochemical stains might be useful CONCLUSIONS in making the distinction between these two CONFLICT OF INTEREST lesions in difficult cases. Features helpful in Inverted lesions of the urinary bladder distinguishing the nested variant of urothelial comprise a spectrum of changes ranging from None declared. carcinoma from florid von Brunn’s nests are von Brunn’s nests to inverted urothelial summarized in Table 5. carcinoma. Differentiating these lesions is important because their proper clinical REFERENCES management and their expected clinical VERRUCOUS SQUAMOUS CELL outcomes are distinctly different. 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