Virchows Arch (2002) 441:148–153 DOI 10.1007/s00428-002-0627-8 O R I G I N A L A RT I C L E A. Lopez-Beltran · R.J. Luque · A. Moreno E. Bollito · E. Carmona · R. Montironi The pagetoid variant of bladder urothelial carcinoma in situ A clinicopathological study of 11 cases Received: 19 November 2001 / Accepted: 30 January 2002 / Published online: 4 April 2002 © Springer-Verlag 2002 Abstract Pagetoid urothelial carcinoma in situ (CIS) is a rare variant of bladder cancer that is characterized by an intraepithelial proliferation of large cells arranged singly or in clusters and randomly distributed. These neoplasms deserve recognition and attention, chiefly because they may be overlooked or misdiagnosed as urothelial dysplasia, then causing unsuspected tumor recurrence after surgery. We report on the clinicopathological features and immunohistochemical findings of 11 (14.86%) cases of pagetoid CIS in a retrospective study of 74 cases of conventional carcinoma in situ. Most patients were male (n=10). Their ages ranged from 31 years to 78 years. The lesion can be present with primary (n=2) or secondary (n=9) CIS. Pagetoid CIS is usually a focal lesion occurring in a clinical and histological setting of conventional CIS, and these patients essentially have the same progression and survival rates as patients without pagetoid changes and are treated in the same way. In cases with extensive urothelial denudation, pagetoid CIS may be focally present in otherwise normal-looking urothelium, thus alerting the pathologist to search for additional CIS elsewhere in the bladder. Given that primary extramammary Paget disease of the external genitalia and of the anal canal may extend to the bladder and, conversely, some bladder cases of pagetoid CIS may extend to the urethra, ureter, and beyond to the external genitalia, the differential diagnoses between these two entities represent an important therapeutic consideration. Our data suggest that a panel of immunostains including CK7+/CK20+/TM+ may assist in differentiating urothelial pagetoid CIS from extramammary Paget disease which is known to be CK7+/CK20–. A. Lopez-Beltran (✉) Department of Pathology, Cordoba University Medical School and Reina Sofia University Hospital, Cordoba, Spain e-mail: em1lobea@uco.es Tel.: +34-957-21-8993, Fax: +34-957-21-8229 Introduction E. Carmona Department of Urology, Cordoba University Medical School and Reina Sofia University Hospital, Cordoba, Spain R.J. Luque Princesa de España Hospital, Jaen and Cordoba, Spain A. Moreno Infanta Margarita Hospital, Jaen and Cordoba, Spain E. Bollito Department of Pathology, San Luigi Gonzaga Hospital, Orbassano and Torrette, Italy R. Montironi Department of Pathology, University of Ancona, Orbassano and Torrette, Italy Present address: A. Lopez-Beltran, Unidad de Anatomia Patologica, Facultad de Medicina, 14004 Cordoba, Spain Keywords Pagetoid cell · CIS · Tumor recurrence · Immunohistochemistry · Bladder cancer The pagetoid variant of carcinoma in situ (CIS) of the urinary bladder is distinctive in that its histological pattern resembles that of Paget disease arising in the nipple and the perineum [5]. Little is known of the biological behavior or clinical significance of this form of CIS [20]. Pagetoid CIS occurs either in cases of primary or secondary CIS [20]. In these cases it may be associated with papillary and/or solid invasive carcinomas. Pagetoid changes in urothelial CIS are rare and represent 12–16% of all cases of bladder CIS [16, 20]. Pagetoid growth is characterized by large single cells or small clusters of cells within otherwise normal urothelium, in squamous metaplasia of the urinary bladder, or within prostatic ducts. Individual cells showing pagetoid spread have enlarged nuclei with coarse chromatin, single or multiple nucleoli, and abundant pale to eosinophilic cytoplasm that is negative for mucin [5]. Pagetoid CIS is an unusual variant of urothelial CIS that can be mistaken for urothelial dysplasia because of the paucity of tumor cells spreading through otherwise normal or reactive urotheli- 149 um [8]. Although the final diagnostic report in this case should be urothelial CIS, not otherwise specified, it is important for pathologists to be aware of that this is true CIS and not dysplasia [8, 13, 15, 16]. In addition, misdiagnosis of pagetoid CIS at time of surgery may result in unsuspected recurrence of the tumor at the resection margin [12]. In addition, its recognition in a small biopsy specimen can alert the pathologist to the presence of a conventional urothelial CIS elsewhere in the bladder, even in cases with extensive bladder denudation in which the lesion may be present in normal-looking urothelium [5]. Some cases of pagetoid CIS may extend to the urethra, ureter, and beyond to the external genitalia where they represent an important differential diagnostic problem, given that primary extramammary Paget disease (EMPD) of the external genitalia may also extend to the bladder [1, 3, 4, 5, 7, 9, 11, 21, 23, 24, 26, 27]. An appropriate approach to differential diagnosis in this case, may need immunohistochemical analysis in addition to a complete patient’s work-up. Although the immunophenotype of EMPD is well established and characterized by a CK7+/CK20– profile, the immunophenotype of urothelial pagetoid CIS needs to be documented in detail. Hence, we have tested a panel of immunohistochemical markers whose results together with the clinicopathological features of 11 cases of pagetoid CIS of the urinary bladder are presented in this report. Materials and methods Patients This study included resection specimens and cold-cup biopsies from 11 patients. The cases were retrieved from the surgical pathology files from both Reina Sofia and Infanta Margarita hospitals (Cordoba, Spain) and San Luigi Gonzaga Hospital (Orbassano, Italy). In a retrospective study of 74 cases of urothelial CIS, 11 (14.86%) had pagetoid features. The pagetoid CIS was defined as intraepithelial urothelial proliferation with large cells arranged singly or in clusters and randomly distributed among normal-looking urothelial cells. The cells were large with well-defined borders, wide and acidophilic cytoplasm, large nuclei with granular chromatin and single or multiple prominent nucleoli. Clinical information was obtained from patients’ clinical records. Table 1 Immunhistochemical findings on 11 cases of pagetoid urothelial carcinoma in situ (CIS) of the urinary bladder. All antibodies used were mouse monoclonal. CK cytokeratin a Biosystems Spain) S.A (Barcelona, Histological and immunohistochemical examinations Routine hematoxylin-and-eosin-stained histological sections from 11 cases of pagetoid urothelial CIS were selected from a review series of 74 cases of conventional CIS (11 with primary CIS). All lesions showed intraepithelial pagetoid spread of tumors cells. Histological slides were reviewed by at least three different experienced pathologists. The tissue had been routinely fixed in buffered formalin and paraffin embedded. Selected 4-µm-thick tissue sections from all cases in the study were processed for histochemical staining and immunohistochemistry. Tissue sections were mounted on coated slides. The sections were deparaffinized in xylene for 10 min and rehydrated in graded alcohol (100, 96, and 70%). The presence of mucin in pagetoid tumor cells was assessed in sections stained with alcian blue (pH 2.5; acid mucin) and periodic acid Schiff (PAS) with diastase (neutral mucin). Immunohistochemistry was performed on parallel slides from all 11 study cases. Serial sections were incubated with the monoclonal antibodies to cytokeratins (CKs; AE1, AE3, 7, 20) and high-molecular-weight cytokeratin (HMWCK), epithelial membrane antigen (EMA), luminal epithelial antigen (LEA135), and carcinoembryonic antigen (CEA). Pagetoid cell proliferation was assessed using ki67-MIB1, and p53 accumulation using the p53 (DO7) antibodies. Both p53 and ki67-MIB1 were quantified using a square grid attached to the ocular of the microscope, and the total number of pagetoid cells in each case was recorded. The source, working dilution, and incubation time of each antibody are listed in Table 1. After washing, antigen localization was accomplished using the streptavidin–biotin peroxidase method. Briefly, sections were incubated overnight with primary antibodies at 4°C. Biotinylated secondary antibodies and the streptavidin–biotin peroxidase complex were applied according to the manufacturer’s instructions (LSAB2 kit, Dako, Glostrup, Denmark). Diaminobenzidine was used as chromogen for visualization (Biomeda Corp., Foster City, Calif.). Endogenous peroxidase activity was blocked by incubating the slides in 1% hydrogen peroxide in methanol for 10 min. For heat epitope retrieval, the slides were treated by boiling in 10 mM citrate buffer (pH 6.0) for 10 min. The slides were counterstained with light hematoxylin. Appropriate positive and negative controls were included in every experimental procedure. DNA ploidy analysis DNA ploidy was available in four cases, using the CAS 200 image analysis system on parallel slides from formalin-fixed, paraffinembedded tissue, stained according to the Feulgen technique. In each of the cases, the total number of nuclei of pagetoid cells (approximately 80–100 nuclei per case) was investigated. Before analysis, instrument calibration was achieved using normal rat hepatocytes. Marker Source Dilution Incubation time (min) Immunoreactivity (Pagetoid CIS) CK AE1 CK AE3 CK 7 CK20 High-molecular-weight cytokeratin (34βE12) Epithelial membrane antigen Carcinoembryonic antigen Luminal epithelial antigen 135 ki67-MIB 1 p53 (DO7) Thrombomodulin Signet Signet Dako Dako Dako Prediluted Prediluted 1:50 1:50 1:50 30 30 40 40 40 + + + (>75%) + (>75%) – Signet Signet Dako Conceptaa Signet Dako Prediluted Prediluted 1:30 Prediluted Prediluted 1:100 30 30 40 30 30 40 + (<5%) – + (<5%) + (<10%) + (<10%) + 150 Fig. 1 Pagetoid carcinoma in situ (CIS) of the urinary bladder. a Medium power (hematoxylin and eosin, ×250). b CKAE1. c CKAE3. d CK7. e CK20. f High-molecular-weight cytokeratin (note negative immunostaining in pagetoid cells). g Epithelial membrane antigen. h Carcinoembryonic antigen (note negative immunostaining in pagetoid cells). i Luminal epithelial antigen 135. j ki67-MIB1. k p53. l Thrombomodulin Results Clinical and pathological data The main clinical and pathological data from 11 cases of pagetoid CIS of the urinary bladder included in this study are presented in Table 2. Of 11 patients, 10 were men, and the mean age was 64 years (range 31– 78 years). Two cases were primary CIS (18%). The secondary CIS was always adjacent to invasive urothelial carcinoma of grade 3 (according to WHO 1973), the stage being T1 in five (56%) cases,T3a in two (22%) cases, T3b in one (11%) case, and T4 in one (11%) case. The mean follow-up was 40.5 months (range 14– 67 months). Because of the associated invasive carcinoma, four (44%) patients were treated by radical cystectomy (two of them associated with chemotherapy). The remaining seven (66%) patients received intravesical BCG (Bacillus Calmette-Guérin). Two patients with primary pagetoid CIS who received intravesical BCG were alive (mean 40 months, range 19–61 months). Of the nine patients with secondary pagetoid CIS, one had persistent CIS at 19 months follow-up, one had recurrent grade 3/T1 cancer at 20 months, and two died of disease (mean 16.5 months, range 14–19 months). The remaining seven patients were alive without evidence of disease (mean 42 months, range 24–57 months). Pagetoid cells were focally present in a background of conventional-type urothelial CIS. Pagetoid CIS was the only finding in case 1 and the main finding in case 2. 151 Table 2 Clinicopathological features of 11 patients with pagetoid urothelial carcinoma in situ (CIS) of the urinary bladder. TURB transurethral resection of bladder, NED no evidence of disease, DOD died of disease, Chem chemotherapy Case Sex/age no. (years) Pagetoid CIS Diagnostic specimen Tissue site Treatment Associated bladder carcinoma Follow-up (months) DOD (14) 1 Male 73 Secondary TURB Left lateral wall Cystectomy 2 Male 76 Primary Cold biopsy Left lateral wall BCG G3/pT3a, Micropapillary variant – 3 4 5 Male 66 Female 72 Male 78 Secondary Secondary Secondary Anterior and lateral wall Trigone Trigone+right lateral wall Cystectomy+Chem BCG BCG G3/pT3b, LELCA G3/pT1 G3/T1 6 7 Male 31 Male 70 Primary Secondary Left lateral wall Right lateral wall BCG BCG – G3/pT1 NED (61) NED (67) 8 9 Male 47 Male 67 Secondary Secondary Cystectomy TURB TURB+cold biopsy cold biopsy TURB+cold biopsy Cystectomy TURB Persistent CIS (19) NED (32) NED (42) NED (39) Posterior wall Not specified Cystectomy+Chem BCG G3/pT4 G3/pT1 10 Male 57 Secondary Trigone left lateral wall BCG G3/pT1 11 Male 69 Secondary TURB+cold biopsy Cystectomy DOD (19) Recurrent disease (20) NED (30) multifocal Cystectomy G3/pT3a NED (24) antibodies against CEA and HMWCK (Fig. 1). Proliferation in the pagetoid cells was below 10%, and p53 accumulation was below 10% in pagetoid cells. No mucin could be demonstrated in any of the pagetoid cells using PAS or alcian blue stainings. Image DNA ploidy analysis of nuclei in all four cases of pagetoid CIS of the urinary bladder gave DNA histograms with aneuploid peaks (DNA indices of 1.4, 1.5, 1.3, and 1.4, respectively; Fig. 2). Discussion Fig. 2 Pagetoid carcinoma in situ (CIS) of the urinary bladder. Aneuploid DNA ploidy histogram (DNA index 1.4) Immunohistochemistry and DNA ploidy As seen in Table 1, the immunohistochemical study demonstrated staining of the pagetoid CIS component as well as the reactive adjacent urothelium with antibodies against cytokeratins AE1 and AE3, and thrombomodulin. Both cytokeratins 7 and 20 were positive in most pagetoid cells, but there were a few negative pagetoid cells as well as a reduced number of cells exhibiting weak (1+/3+) staining. There were no cases that were both CK7 and CK20 negative. Immunostaining against EMA and LEA 135 stained rare pagetoid cells (<5%). We failed to demonstrate any pagetoid cell positive with Pagetoid changes in urothelial CIS have been observed since the disease was first described in 1952 [17], and the present study was designed to better characterize the clinicopathological and immunohistochemical features of this unusual form of urothelial CIS. Pagetoid changes have been recently considered as a pattern of growth of CIS, also designed as a “cancerization” of the urothelium [16]. This agrees with most clinicopathological observations including our own, indicating that pagetoid CIS is not a distinct clinicopathological entity but a morphological pattern of growth of a conventional CIS [20]. The lesion is rare among bladder cancer patients and unusual even in those patients with conventional CIS in which pagetoid CIS, as observed in our series, represents 14.86% of 74 cases of conventional CIS, an incidence that falls into the reported average (range 11–16%) [16, 20]. Both in previous reports and in our series of 11 cases, the lesion tends to be focal, randomly distributed, and so far never occurs as the only manifestation of the disease [20]. Although individual biopsy specimens may be composed predominantly of pagetoid CIS, the lesion represents only a minute portion of the total tissue sampled during the course of the disease [20]. In addition, the finding of pagetoid changes in a small bladder 152 biopsy would argue in favor that a wider CIS is present elsewhere in the bladder, and hence the patient should be worked up to search for a wider lesion [5]. Also, in rare instances, pagetoid CIS is the only morphological manifestation of the disease in cases with extensive denudation of the urothelium. Given that the lesion occurred in patients with primary as well as secondary CIS, with or without associated invasive carcinomas, the presence of pagetoid changes did not identify any particular group of bladder cancer patients, nor did it seem to have additional clinical implications [6, 20]. Two of our cases had associated unusual bladder tumors (micropapillary and lymphoepithelioma-like carcinomas), and, so far, no data support any specific association [14]. The age, sex, and race of patients with and without pagetoid changes are variable, but the progression and survival rates of these patients were similar to the reported series [20]. Most authors agreed that pagetoid changes should not be labeled as urothelial dysplasia, and cases misdiagnosed as dysplasia that remain untreated are at higher risk for recurrence and progression [3, 8, 26] Pagetoid changes at extramammary sites (EMPD) are rare alterations most often recorded in the anogenital region [1, 3, 4, 7, 9, 11, 21, 23, 24, 26, 27]. Cells comprising EMPD may not be associated with carcinomas in adjacent sites [24]. They are generally considered to differentiate toward glandular rather than squamous epithelium, although detailed studies documenting this hypothesis have been performed in only a few instances [24]. The immunohistochemical profile of EMPD has been recently addressed in a number of publications [2, 10, 12, 15, 18, 19, 22, 25, 28, 29], and an immunohistochemical profile characterized by CK7+ and CK20– has been considered specific of EMPD [18]; meanwhile, other regional internal malignancies with pagetoid growth, such as pagetoid urothelial CIS, are CK7+ and CK20+ [18]. In addition, rare cases have been illustrated in which EMPD extended to the urethral and bladder urothelium, as well as pagetoid CIS of the bladder extended to the perineum, thus creating confusion on what is the primary origen of the tumor, that is EMPD versus urothelial pagetoid CIS [1]. Also, pagetoid changes have been observed in the penis. Interestingly, almost all these patients have had previous high-grade urothelial carcinoma and CIS of the urinary bladder, suggesting that in fact they represent urothelial pagetoid CIS [1, 3, 4, 7, 9, 11, 21, 23, 26, 27]. These lesions have been usually detected months to years after cystectomy, are not in contiguity to the bladder neoplasm, and tend to localize to the urethral meatus [3, 7, 26]. Focal mucin and CEA positivity have been recorded in one case [2] of pagetoid urothelial CIS, but none of our cases showed such positivity. Our immunohistochemical study confirmed CK7+ and CK20+ as immunohistochemical profile of urothelial pagetoid CIS and expand it using additional markers such as thrombomodulin (TM), LEA 135, cytokeratins AE1, AE3 and HMWCK, EMA and CEA. It seems possible that a pattern of immunostaining characterized by CK7+/CK20+/TM+ favors urothelial pagetoid CIS. Also, negative immunostaining against CEA and HMWCK, as found in our series, might be of value in such a differential diagnosis. The rarity and sporadic occurrence of pagetoid changes in patients with urothelial CIS provide little data for histogenetic considerations and make the process difficult to understand [20]. Case reports over the last four decades suggest that the phenomenon is not related to patient population or any therapeutic regiment [20]. The rare association with subsequent pagetoid CIS in the penis and vulva indicates a relationship, even though the cells at extravesical sites may differ in their degree of glandular differentiation, as evidenced by a tendency toward mucin production [2], and also may differ in its cytokeratin profile as shown in this report. Our cases did not show any mucin stain or immunoreactivity to CEA, and the cytokeratin profile together with the immunoreactivity against thrombomodulin favors urothelial origen. Seeding from a primary tumor may account for these isolated lesions, but it fails to explain the pagetoid differentiation [20]. The absence of pagetoid changes in the primary tumor tissues in the series of Orozco et al. [20] suggests that the process is a secondary phenomenon, perhaps related to a nonspecific local reaction of neoplastic cells to injury [20]. Also, it is possible that pagetoid appearance in the urinary bladder tends to evolve when CIS cells are partially separated from the influences of contiguous neoplastic elements, as might happen at the leading edge of an invasive area [20]. A recent report found that bladder carcinoma cells lacking E-cadherin expression infiltrate into the adjacent urothelium as individual cells, hence showing a pagetoid pattern of growth [22]. This favors that pagetoid changes are a primary event in bladder tumor cells related to the loss of some cellular adhesion molecules. In this particular study, it was considered that this process plays an important role in the high recurrence rate that is observed in some of these patients [22]. 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