Malignant glandular lesions and glandular differentiation in invasive/noninvasive urothelial carcinoma of the urinary bladder

Although the lumen of the urinary bladder is covered with only urothelial epithelium, malign glandular lesions (eg, nonurachal adenocarcinoma) and benign lesions (eg, cystitis cystica and cystitis glandularis) can also rarely occur in this site due to its characteristic embryologic development. Glandular differentiation is uncommon in urothelial carcinomas and is even less common in noninvasive urothelial cancers. In addition, in situ urothelial carcinomas are more likely to progress in the presence of glandular differentiation toward high-grade urothelial carcinomas and/or aggressive urothelial carcinomas. Pure nonurachal adenocarcinomas and mixed carcinomas (urothelial carcinoma and adenocarcinoma) are very rare, and their pathogenesis is not clear. Most of the nonurachal adenocarcinomas are thought to arise on the grounds of cystitis glandularus with intestinal metaplasia. Here, I present 2 cases with noninvasive urothelial carcinoma with substantial glandular differentiation showing progression to signet ring cell carcinoma and invasive urothelial carcinoma, one case with mixed carcinoma (urothelial carcinoma and adenocarcinoma) and another case with pure adenocarcinoma developing from cystitis glandularis with intestinal metaplasia, and discuss malign glandular lesions in the bladder and invasive/noninvasive urothelial carcinomas with glandular differentiation.     

Präneoplastische Läsionen und Vorstufen des Urothelkarzinoms

As even a mere thickening of the urothelium can harbor genetic changes identical to that of low grade papillary urothelial tumors, it is not always possible to clearly recognize a precursor lesion of urothelial carcinoma by routine histological diagnostics. Complementary immunohistochemical and molecular diagnostic methods assist the recognition of these entities. These methods especially help to identify clinically important genetically unstable cells as the hallmark of carcinoma in situ (CIS). Little is known about the clinical significance of the morphological subtypes of CIS, which range from large cell to micropapillary variants. For a better understanding of special types of bladder cancer (e.g. adenocarcinoma and squamous cell carcinoma), it seems to be important to define the phenotype and the molecular pattern of non-urothelial lesions, such as intestinal metaplasia and squamous metaplasia, better and more precisely.     

Atypical squamous cells in the urine revealing endometrioid adenocarcinoma of the endometrium with squamous cell differentiation: A case report

Urine cytology is mainly used to detect urothelial carcinoma (UC), especially for high‐grade lesions including urothelial carcinoma in situ. Benign squamous cells are often seen in the urine specimens of women, they are either exfoliated from the trigone area of the bladder, the urethra, or the cervicovaginal region. However, abnormal squamous cells in the urine raise concerns of abnormalities of the urinary tract and cervicovaginal area which range from squamous metaplasia of the urothelium, a cervicovaginal squamous intraepithelial lesion, condyloma acuminatum of the bladder, UC with squamous differentiation, and squamous cell carcinoma. We present here a unique case of atypical squamous cells (ASCs) in the urine subsequently leading to the diagnosis of endometrioid adenocarcinoma of the endometrium with squamous differentiation. The presence of ASCs in voided urine is a rare finding that may indicate an underlying malignancy. Careful evaluation of squamous cells in the urine is an important part of our daily cytopathology practice. Diagn. Cytopathol. 2015;43:49–52. © 2014 Wiley Periodicals, Inc.     

Intestinal metaplasia in glandular and cystic formations and human urothelial adenocarcinoma]

Thirteen cases of inflammatory changes in the urothelium with formation of glandular and cystous structures, 3 cases of glandular metaplasia in transitional cell carcinoma and 8 adenocarcinomas were examined. In inflammation, initial glandular and cystic structures have signs of somehow incompleted metaplasia of the intestinal type. In advanced glandular structures metaplasia is completed and urothelium acquires similarity in the structure and properties of the produced mucus with the large intestine epithelium (numerous goblet, cylindrical limbic and non-differentiated cells, prevalence of argentaffinic cells over argirophilic, lack of Panet cells, secretion of sulfomucines). In loci of glandular metaplasia of transitional cell carcinoma there are also signs of somehow incompleted intestinal differentiation. Most typical variants of urothelial adenocarcinoma are quite similar to glandular carcinoma by the structure and properties of the produced mucus.     

Immunohistochemical analysis of sex hormone receptors in squamous changes of the urothelium

Objective: Squamous cell transformation of the urinary bladder urothelium has various causes, symptoms, and few treatment options. The aim of this study was to analyze and compare the expression of sex hormone receptors in non-keratinized and keratinized squamous metaplasia (NKSM, KSM), squamous cell carcinoma (SCC), and healthy urothelium with regard to possible therapeutic approaches. Methods: Biopsies from 26 patients with urothelial NKSM, KSM, and SCC were analyzed retrospectively. Tissue microarrays (TMA) of formalin-fixed paraffin-embedded (FFPE) bladder biopsies were stained with hematoxylin and eosin followed by immunohistochemical analysis with specific antibodies against estrogen, progesterone, and androgen receptors (ER, PR, AR) and assessment using the immunoreactive score. Statistical evaluations included the Wilcoxon signed-rank test and the Wilcoxon rank-sum test in the form of permutation tests. Results: Of the 15 women and 11 men included in this explorative study, 17 had metaplasia: 15 (six men, nine women) had NKSM and two KSM (both men). A total of nine patients (three men, six women) had keratinized SCC or urothelial carcinoma with squamous differentiation. The comparison between normal urothelial cells and metaplasia showed a significantly stronger expression in the metaplastic tissue (P=0.0374). The invasive carcinoma showed significantly less PR than the extracellular matrix of the healthy urothelium (P=0.0026). Expression of AR was nearly absent in healthy and metaplastic urothelium. Conclusion: There appears to be an association between squamous metaplasia of the bladder mucosa and sex steroid hormone receptor expression, especially estrogen receptors. Topical hormone therapy should be considered.     

Colonic adenocarcinoma metastatic to the urinary tract versus primary tumors of the urinary tract with glandular differentiation: a report of 7 cases and investigation using a limited immunohistochemical panel

OBJECTIVE: To determine whether a limited immunohistochemical panel can help differentiate metastatic colonic adenocarcinoma from primary enteric-type adenocarcinoma of the urinary tract and urothelial (transitional cell) carcinoma with glandular differentiation, which appear morphologically similar but most often necessitate different treatment protocols. DESIGN: We examined lower urinary tract tumors (5 urinary bladder, 2 urethral) from 7 patients with a history of colonic adenocarcinoma. The differential diagnoses in these cases included metastatic colonic adenocarcinoma, primary enteric-type adenocarcinoma of the urinary tract, and urothelial carcinoma with glandular differentiation. An immunohistochemical panel consisting of cytokeratin 7 (CK-7), cytokeratin 20 (CK-20), and villin was evaluated in all cases. Four primary enteric-type adenocarcinomas of the urinary tract and 5 conventional urothelial carcinomas were also studied to compare morphologic features and immunohistochemical staining patterns. RESULTS: Of the 7 cases, 6 were determined to be metastatic colonic adenocarcinoma and 1 was diagnosed as a primary urothelial carcinoma with glandular differentiation. All 6 metastatic colonic adenocarcinomas, 6 of the 7 primary colonic adenocarcinomas, and all 4 primary enteric-type adenocarcinomas of the urinary tract were CK-20 positive (1 was CK-20 negative), villin positive, and CK-7 negative. The single urothelial carcinoma with glandular differentiation and all 5 control cases of urothelial carcinoma were CK-7 and CK-20 positive, and villin negative. CONCLUSIONS: We conclude that (1) villin is expressed in primary enteric-type adenocarcinoma of the urinary tract; (2) in difficult cases, urothelial carcinoma with glandular differentiation can be distinguished from colonic adenocarcinoma because the former is CK-7 positive, CK-20 positive, and villin negative, whereas the latter is CK-20 positive, villin positive, and CK-7 negative; (3) clinical information is essential when evaluating lower urinary tract tumors that are clinically and morphologically similar to enteric-type adenocarcinoma of the urinary tract; and (4) the similar immunohistochemical profiles of metastatic colonic adenocarcinoma and primary enteric-type adenocarcinoma of the urinary tract may be in keeping with the hypothesis that the latter arise from intestinal metaplasia.     

Inappropriate mucin production in gall bladder metaplasia and neoplasia–an immunohistological study

This study demonstrates the presence of three antigens in glandular metaplasia occurring in patients with cholecystitis and cholelithiasis: specifically carcinoembryonic antigen (CEA), large intestinal mucin antigen (LIMA) and small intestinal mucin antigen (SIMA). These antigens could not be detected in normal gall bladder mucosa or in squamous metaplasia of the gall bladder. The occurrence of the three intestine-associated antigens in three carcinomas was irregular. In one mucinous carcinoma, only SIMA could be demonstrated. In one adenocarcinoma, SIMA was present in small areas of mucinous change, whilst CEA was present in the nonmucinous malignant tissue. In a mixed mucinous and non-mucinous adenocarcinoma with widespread dissemination, the three antigens were present both in the primary tumour and the metastases. These observations suggest that all forms of glandular metaplasia of the gall bladder are intestinal in nature and at least a proportion of gall bladder carcinomas are of an intestinal type. Finally they provide further immunological evidence that glandular metaplasia of the gall bladder should be considered a pre-malignant condition.     

Detection of squamous cell differentiation in experimental tumors of urothelium by using epidermal G2 chalone

The presence of epidermal G2 chalone was investigated by different immunochemical methods in normal urothelium and in tumors of the urinary bladder induced in rats with N-butyl-N-butanol-(4)-nitrosamine. This chalone was not revealed in normal urothelium but found in 37 out of 56 tumors examined. In all these 37 tumors, squamous urothelial metaplasia was detected by electron or even light microscopy. The extent of morphological manifestations of squamous metaplasia showed a definite correlation with the concentration of chalone in tissue extracts. The method used may be applied as a subsidiary test for the determination of focal squamous metaplasia in biopsy material of human urothelial tumors which is of importance for prognosis of the disease.     

Urothelial metaplasia of the seminal vesicles: a report of 2 cases

Although urothelial metaplasia has been reported in the fallopian tube, urothelium in the seminal vesicle has been rarely reported. We report 2 cases of urothelial epithelium in seminal vesicles from radical prostatectomy specimens. One case involved a 63-year-old patient with pT2c prostatic adenocarcinoma (Gleason pattern 3+4; total score, 7). The other case involved a 60-year-old patient with pT2c prostatic adenocarcinoma (Gleason pattern 4+3; total score, 7; with focal Gleason pattern 5). Representative sections of the left seminal vesicles from both patients demonstrated a portion of urothelial epithelium consisting of 3 to 8 cell layers, which included superficial (umbrella), intermediate, and basal cells. An abrupt transition from the normal single layer of cuboidal cells of seminal vesicle to multilayered urothelium was identified in 1 case, and circumferential urothelium was identified in the other case. No urothelial metaplasia was seen in the prostatic tissue. The histogenesis of urothelial metaplasia in the seminal vesicle is unclear, but it possibly is a reaction to mechanical irritation, inflammation, or infection, as has been proposed for urothelial metaplasia in the fallopian tube and squamous metaplasia of the pelvic peritoneum. Nevertheless, a rare congenital malformation cannot be ruled out as an etiology. Clinical follow-up of patients with urothelial cell metaplasia of the fimbriae suggests that it bears no biologic significance, yielding no instances of carcinoma. However, whether there will be an impact on fertility awaits further study.     

Pathology of flat bladder lesions with emphasis on putative precursors

Flat bladder lesions comprise a spectrum of morphologic changes ranging from reactive atypia to carcinoma in situ (CIS). Differentiating these lesions is important because of differences in patient management and clinical outcome. The precise nature of precursor lesions of bladder cancer remains incompletely understood. Urothelial CIS is the most definitely characterized precursor lesion of high grade bladder cancer. Atypia of unknown significance (AUS) is somewhat controversial. For practical purposes, AUS and reactive urothelial changes should be considered a single entity, since neither lesion has established preneoplastic potential. Simple hyperplasia and papillary hyperplasia are recently identified putative preneoplastic lesions. More recent molecular data also support the precursor nature of intestinal metaplasia and keratinizing squamous metaplasia. In this review, we also discuss the utility of molecular ancillary studies in establishing premalignant lesions, diagnosis, and differential diagnosis of flat bladder lesions.     

Villous adenoma of the urinary tract: a lesion frequently associated with malignancy

Villous adenomas arising in the urinary tract are rare. We identified 18 cases of villous adenomas of the bladder, urachus, and prostatic urethra. Patients ranged in age from 53 to 93 years with an average age of 69.6 years and a male preponderance of 67%. In six cases (33%), the lesion was pure villous adenoma. In three cases (17%), there was villous adenoma with in situ adenocarcinoma. In six cases (33%) there was villous adenoma with in situ and infiltrating adenocarcinoma. One case (6%) had villous adenomas with in situ (noninvasive) papillary urothelial carcinoma. One case (6%) had villous adenomas with in situ adenocarcinoma and in situ papillary (noninvasive) and infiltrating urothelial carcinoma. The remaining case (6%) had villous adenoma with in situ and infiltrating adenocarcinoma and in situ (noninvasive) papillary and infiltrating urothelial carcinoma. Clinical outcome was available in eight of the cases, with a mean follow-up of 4.6 years. No evidence of recurrence was found in two patients with pure villous adenoma or in two patients with villous adenoma and only in situ adenocarcinoma, all of whom were treated by nonradical excision. However, two of three cases with infiltrating cancer developed distant metastases despite radical surgery; the remaining patient was disease-free 11 years after transurethral resection. The case with villous adenoma and in situ urothelial carcinoma progressed to sarcomatoid urothelial carcinoma following partial cystectomy. Eight of 10 villous adenomas cases studied expressed the epitope for mAbDas1, found on colonic epithelium and primary adenocarcinomas of the bladder and urachus but not on normal or neoplastic urothelium. This study expands the spectrum of histologic features accompanying villous adenomas of the urinary tract. Coexisting infiltrating adenocarcinoma is often present, necessitating thorough sampling of any lesion diagnosed by biopsy as villous adenoma. Pure villous adenoma and those well-sampled lesions also containing in situ adenocarcinoma portend a favorable prognosis, even without radical treatment. Coexisting in situ or infiltrating carcinoma suggests a more aggressive course. Histologically, immunohistochemically, and prognostically, these lesions appear analogous to their counterparts in the intestine.     

Stereotypes of Structural Modification of the Urothelium in Various Diseases of the Urinary Bladder and Prostate

Structural modification of the urothelium was studied in various diseases of the urinary bladder and prostate, including urinary bladder cancer, vibration cystopathy, chronic prostatitis, benign prostate hyperplasia, and chronic cystitis. The general phenomena of changes in urinary bladder epithelium were atrophy, squamous metaplasia, and instability of the urothelium (focal atrophy, dysplasia, hyperplasia, and metaplasia). This phenomenon can be interpreted as a morphological marker for cancer risk. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 146, No. 10, pp. 395–399, October, 2008     

Squamous cell carcinoma of the prostate

Eleven case of squamous cell carcinoma of the prostate have been divided into four groups according to their histological features and natural history: a pure squamous cell carcinoma of the prostate (one case); b common prostatic adenocarcinoma with malignant squamous component after oestrogen treatment (two); c urothelial carcinoma of the prostate with malignant squamous cell metaplasia (four); and d urothelial carcinoma of the urinary bladder with squamous cell metaplasia growing into the prostate (four). The squamous portions may spread to invade the fibromuscular stroma and grow in prostatic ducts. Necrosis of comedo type and inflammatory infiltrates appeared in a number of cases. The survival times of nine patients ranged from 1 to 17 months. Squamous components were shown by immunohistochemistry to contain various keratin types, carcino-embryonic antigen and peanut agglutinin binding sites. Whenever a squamous cell carcinoma in the prostate is diagnosed histologically various possibilities as to its origin should be considered.     

Divergent differentiation in urothelial carcinoma and other bladder cancer subtypes with selected mimics

Conventional urothelial carcinoma accounts for most carcinomas of the urinary tract lining. However, neoplastic urothelium has the capacity to demonstrate enormous plasticity. A variety of unusual architectural patterns of urothelial carcinoma, such as the nested, microcystic and inverted variants, can be mistaken for reactive processes or benign tumours. Others such as the micropapillary, plasmacytoid and discohesive variants, can mimic metastatic tumour from other sites. The micropapillary variant in particular is more aggressive. In addition, urothelial carcinoma has a propensity to demonstrate divergent differentiation with glandular, squamous, small cell neuroendocrine, lymphoepithelioma-like, sarcomatoid or other elements. Pure squamous carcinoma or adenocarcinoma (the latter in particular) can be difficult to distinguish from contiguous or metastatic spread. Some variants have prognostic and potential therapeutic implications. Molecular genetic evidence has emerged recently supporting a close relationship between urothelial carcinoma and various divergent elements. Sarcomatoid carcinoma and its differential diagnosis with other spindle cell lesions of urinary tract will be covered in a separate review.     

Non‐urothelial carcinomas of the bladder

Non‐urothelial carcinomas involving the bladder are uncommon and often diagnostically challenging. These carcinomas may show squamous, adenocarcinomatous or neuroendocrine features, with immunohistochemical stains aiding the diagnosis in only a subset of cases. The clinical history in non‐urothelial bladder carcinomas is important, given that the differential diagnosis often includes secondary involvement of the bladder by direct extension or metastasis from carcinomas at other sites. This paper will review non‐urothelial carcinomas in each of these three morphological categories, emphasising recent changes in diagnostic grouping and challenges in the histopathological diagnosis. Review of bladder cancers with squamous morphology will include discussion of conventional squamous cell carcinoma and verrucous carcinoma and their distinction from urothelial carcinoma with extensive squamous differentiation. Bladder carcinomas with adenocarcinomatous change will include primary bladder adenocarcinoma, urachal adenocarcinoma and tumours of Müllerian type. Finally, neuroendocrine neoplasms of the bladder, including well‐differentiated neuroendocrine tumour and neuroendocrine carcinomas, will be discussed. Associated surface findings, risk factors and prognostic features will be described.     

Concurrent tubulovillous adenoma and transitional cell carcinoma associated with diffuse gastric and intestinal metaplasia of the defunctioned ureter

Villous adenoma is a common lesion of the gastrointestinal tract, but it is rare in the ureter. Thus, as far as we know, only one case limited to this location has been described. Intestinal metaplasia of the urothelium is not rare. However, only one case of gastric metaplasia with pseudopyloric glands has been described in the literature. We here report in detail on a tubulovillous adenoma of the ureter associated with diffuse gastric and intestinal metaplasia and a concurrent primary, solid, high grade transitional cell carcinoma, with extensive clear cell change, in a 56-year-old male patient. He had undergone a left nephrectomy for renal tuberculosis twenty years earlier, and the lesions developed in the ureteric stump. To the best of our knowledge, such a combination of lesions has not been reported previously either in the ureter or in the rest of the urinary tract. The coexistence of diverse lesions in our case might represent the pluripotentiality of the urothelium in association with chronic inflammation and neoplastic induction. The present report also emphasizes the metaplastic and malignant potential of a defunctioned urothelial structure. This case is of particular interest, because these coexistent lesions arose simultaneously with an anatomically separate adenocarcinoma of the rectum (Dukes' B). The patient died 76 days after admission. The dismal prognosis of our case was determined by the advanced anatomical stage and the histological high grade of the transitional cell carcinoma of the ureter.     

Invasive urothelial carcinoma with squamous differentiation and associated high-risk human papilloma virus infection: Clinical,cytologic, and histologic features of a rare entity

We correlate the fine needle aspiration (FNA) cytologic findings with the histologic features of an invasive high-grade urothelial carcinoma showing squamous differentiation in the setting of high-risk Human Papilloma Virus (hrHPV) infection. To our knowledge, only extensive urinary bladder catheterization has been associated with hrHPV-positive urothelial carcinoma with squamous differentiation, and rarely at that. Herein, we present a case arising in a patient with only sparse and intermittent catheterization. A 69-year-old woman presented with voiding difficulties, and after continued symptoms, a Foley catheter was placed, and a cystoscopy procedure revealed two 1–2 cm inflammatory masses. Excisional biopsies were interpreted as papillary urothelial carcinoma. One month follow-up pelvic imaging demonstrated a new mass involving the urinary bladder neck, with irregular wall thickening and perivesical fat stranding, as well as probable vaginal involvement. CT-guided FNA (CT-FNA) to collect smears and core biopsies revealed an invasive urothelial carcinoma with squamous differentiation. HPV-cytopathic changes amid squamous metaplasia and dysplasia were noted on FNA smears with HPV E6/E7 RNA in situ hybridization (ISH) showing on the FNA core biopsy specimen. Immunostains showed that the tumor cells were positive for P16 (strong, diffuse), CK7, p63, ER, and GATA3 (patchy). Subsequent radical cystectomy revealed the extent of the patient's carcinoma, with direct extension to the vaginal wall, and involvement of the radial soft tissue resection margins. Describing the cytomorphologic features of a hrHPV positive urothelial carcinoma with squamous differentiation, without an extensive history of urinary catheterization or prior known history of HPV infection, emphasizes the role of cytopathology as a powerful diagnostic tool for recognizing a unique and unexpected lesion.     

The L1 antigen and squamous metaplasia in the bladder

The L1 antigen was investigated as a marker of squamous differentiation in urothelium using a monoclonal antibody Mac387, and the results were compared with the expression of high molecular weight cytokeratins. L1 antigen was consistently demonstrated in all instances of partial and complete squamous metaplasia and in squamous carcinomas. In contrast, pure transitional cell carcinomas (except one with minor focal staining), adenocarcinomas and normal and hyperplastic urothelium did not label. In a few squamous carcinomas in situ, the pattern of labelling obtained with Mac387 was different from that seen in invasive squamous carcinomas and metaplasias. Compared with high molecular weight cytokeratins, the expression of L1 was more intense in areas of squamous differentiation. L1 expression, as identified by antibody Mac387, may therefore serve as a useful marker of squamous differentiation in urothelial lesions.     

Sarcomatoid carcinoma with small cell carcinoma component of the urinary bladder: a case report with review of the literature

Sarcomatoid carcinoma of the urinary bladder is an uncommon neoplasm characterized histopathologically by the presence of malignant spindle cell and epithelial components. Albeit extremely rare, sarcomatoid carcinoma with small cell carcinoma has been reported. Herein, we describe an additional case of sarcomatoid carcinoma with small cell carcinoma and squamous cell carcinoma of the urinary bladder and review the clinicopathological features of this type of tumor. An 82-year-old Japanese male presented with hematuria. Computed tomography demonstrated a large tumor in the urinary bladder. Histopathological study of the resected urinary bladder tumor showed that approximately 80% of the tumor was comprised of small cell carcinoma, and the remaining components were spindle cell proliferation (approximately 15%) and squamous cell carcinoma (5%). Both the spindle cell and squamous cell carcinoma components were intermingled with nests of the small cell carcinoma. This is the fifth documented case of sarcomatoid carcinoma with small cell carcinoma of the urinary bladder. Our review of the clinicopathological features of this type of tumor revealed that: i) elderly males are mainly affected, ii) the most common chief complaint is hematuria, iii) the epithelial component may include urothelial carcinoma, adenocarcinoma, and/or squamous cell carcinoma, and iv) the sarcomatous component is composed of spindle cell proliferation. The histogenesis of this type of tumor remains a matter of controversy. However, recent molecular analyses demonstrated a monoclonal origin of both components. This theory can account for the various types of carcinomatous components in this tumor as seen in the present case.     

Squamous lesions of the bladder

Squamous lesions of the bladder encompass a broad range of benign and malignant lesions. Many of the squamous lesions restricted to the urothelial surface are generally indolent, such as squamous metaplasia, squamous papilloma and condyloma acuminatum. However, some superficial lesions such as verrucous squamous hyperplasia and squamous cell carcinoma in situ may precede the development of invasive squamous cell carcinoma. Squamous lesions present within the wall of the bladder are often malignant and include classic squamous cell carcinoma and the verrucous squamous cell carcinoma and basaloid squamous cell carcinoma variants. One exception, however, is pseudoepitheliomatous (pseudocarcinomatous) hyperplasia, which is a benign mimicker of invasive squamous cell carcinoma. Our review summarizes the available data on clinical presentation, histopathologic features, differential diagnosis and ancillary tests of the squamous lesions of the bladder.