Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications

An increasing number of histologic variants of urothelial carcinoma have been recognized in recent years. It is important for surgical pathologists to be aware of these morphological variants that, on occasion, may lead to misinterpretation as benign. Some also require a specific therapeutic approach. In this article, we review the most common histologic variants of urothelial carcinoma of the bladder. Emphasis is placed on clinical significance and differential diagnosis.     

Variants and new entities of bladder cancer

Pathological evaluation of bladder cancer typically reveals great tumour heterogeneity, and therefore the common observation of urothelial carcinoma exhibiting a wide variety of histopathological patterns is not surprising. Some of these patterns are so distinctive that they have been recognised as specific variants of urothelial carcinoma. Classifications have recently been revised in the 2016 World Health Organisation (WHO) classification of tumours of the urinary system and male genital organs. The current WHO classifications clarify terminological issues and provide better definition criteria, but also incorporate some new entities. Many of these variants have important prognostic or therapeutic implications worth knowing by the urologist and oncologist, but also represent diagnostic challenges in daily pathology practice. This review will discuss the features of variants of urothelial carcinoma in the context of our current clinical practice. Histological variations and new entities of bladder cancer not included in the current WHO classification of urothelial tumours will be briefly discussed.     

Rhabdoid variant of urothelial carcinoma of the urinary bladder: a case report with emphasis on immunohistochemical analysis regarding the formation of rhabdoid morphology

Various histological variants of urothelial carcinoma (UC) have been described. They are associated with different clinical outcomes and/or therapeutic approaches; in addition, recognition of these histological variants is also important in preventing diagnostic misinterpretations. Histological variants based on cytoplasmic features, such as plasmacytoid, rhabdoid, clear-cell, and lipoid-rich variants, have been described in invasive UC. Herein, we report an exceedingly rare case of a rhabdoid variant of UC arising in the urinary bladder of a 61-year-old man. Including UC, the presence of rhabdoid cells has been described in various types of malignant tumors. These tumors are regarded as more aggressive neoplasms than those without rhabdoid cells. It has been previously found that non-degraded aggregation of intermediate filaments and membrane proteins conjugated with ubiquitin and p62 is a noticeable finding in the formation of rhabdoid morphology. We have validated the existence of this mechanism in a rhabdoid variant of UC by extensive immunohistochemical analysis.     

Transition between urothelial carcinoma in situ and non-invasive micropapillary carcinoma as a pivot connection between diverse morphologies of bladder carcinoma: a case report of urothelial carcinoma with villoglandular differentiation

Urothelial carcinoma has numerous histological variants, and these variants may coexist in a single case. Here, we present a case of a 70-year-old man with urothelial carcinoma of the bladder with a maximal diameter of 5 mm that involved micropapillary and plasmacytoid variants, with villoglandular differentiation. The presence of these variants was confirmed by pathological examination of a transurethral resection specimen, and high-grade urothelial carcinoma was found as a minor component. Although this bladder carcinoma was classified as pT1, cystoprostatectomy, urethrectomy, and lymphadenectomy were performed due to the presence of the micropapillary and plasmacytoid variants, which are known to be aggressive. Examination of a surgically resected specimen revealed no carcinoma. A transition between urothelial carcinoma in situ and non-invasive micropapillary carcinoma was found to be a pivot point connecting the diverse morphologies of this bladder carcinoma, from which there existed two pathways. One pathway was from urothelial carcinoma in situ to the plasmacytoid variant through invasive high-grade urothelial carcinoma, and the other was from non-invasive micropapillary carcinoma to urothelial carcinoma with villoglandular differentiation or to the micropapillary variant. This is the 16th reported case of urothelial carcinoma with villoglandular differentiation in the literature. As urothelial carcinoma with villoglandular differentiation is often associated with aggressive variants, as shown in our case, it should be reported whenever encountered in routine pathological practice.     

Histological variants of prostatic carcinoma and their significance

The vast majority of prostatic cancers are acinar adenocarcinomas. Histological variants of prostatic carcinoma have been variably defined. One approach is to consider two groups of variants. The first group comprises histological variants of acinar adenocarcinoma and the second group non-acinar carcinoma variants or types. Variants of usual acinar adenocarcinoma defined in 2004 by the World Health Organization (WHO) include atrophic, pseudohyperplastic, foamy, colloid, signet ring, oncocytic and lymphoepithelioma-like carcinomas. The second group of non-acinar carcinoma histological variants or types of prostatic carcinoma accounts for about 5-10% of carcinomas that originate in the prostate. These include sarcomatoid carcinoma, ductal adenocarcinoma, urothelial carcinoma, squamous and adenosquamous carcinoma, basal cell carcinoma, and neuroendocrine tumours, specifically small-cell carcinoma. Recently characterized variants not present in the 2004 WHO classification, including microcystic adenocarcinoma, prostatic intraepithelial neoplasia-like adenocarcinoma, large-cell neuroendocrine carcinoma, and pleomorphic giant cell carcinoma, are also described. The aims of this review are to present the essential histomorphological diagnostic attributes of these variants, and to emphasize the clinical signficance of the variants, when different from usual acinar adenocarcinoma, including clinical presentation and outcome.     

Uncommon tumours in the adult bladder: rare entities with recognized diagnostic pitfalls

Non-urothelial neoplasms and masses in the bladder such as myofibroblastic and smooth muscle proliferations, paraganglioma and lymphoma are uncommon. Nonetheless, pathologists must correctly classify these lesions to ensure optimal patient management. It is also recognized that particular entities in each of the aforementioned categories can be misconstrued as urothelial carcinoma or a spindle cell variant of urothelial carcinoma. This review will cover the clinicopathological features of selected lesions in the adult bladder including; myofibroblastic proliferations (occurring with antecedent trauma or spontaneously), smooth muscle neoplasms, sarcomatoid carcinoma, paraganglioma and lymphoma. The morphologic, immunohistochemical and, where appropriate, molecular/cytogenetic features described herein should help pathologists correctly classify these uncommon lesions.     

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.     

Spezifische Typen des Harnblasenkarzinoms

Bladder cancer shows rare variants and special subtypes with diverse prognostic importance and therefore may necessitate different therapeutic approaches. For pathologists it is important to histologically diagnose and specify such variants. Nested variants of urothelial carcinoma with inconspicuous, well-formed tumor cell nests present with an aggressive course. The plasmacytoid variant, which morphologically resembles plasma cells is associated with a shorter survival time and a high frequency of peritoneal metastasis. Micropapillary urothelial carcinoma with small papillary tumor cell islands within artificial tissue retraction spaces and frequent lymphovascular invasion also has a poor prognosis. Other important rare differential variants listed in the World Health Organization (WHO) classification are microcystic, lymphoepithelioma-like, sarcomatoid, giant cell and undifferentiated urothelial carcinomas. Additionally, there are three special types of bladder cancer: squamous cell carcinoma, adenocarcinoma and small cell neuroendocrine carcinoma of the bladder. These tumors are characterized by pure squamous cell or glandular differentiation and are sometimes less responsive to adjuvant (chemo)therapy. Small cell carcinoma of the bladder mimics the neuroendocrine features of its pulmonary counterpart, shows an aggressive course but is sensitive to (neo–)adjuvant chemotherapy. The morphology and histology of the most important variants and special types are discussed in this review.     

Variant chromophobe renal cell carcinoma

Separation of renal cell tumors into different prognostic groups is an imperative function of the diagnostic pathologist. Recently, chromophobe renal carcinoma has been described as a tumor that is morphologically distinct from conventional "clear cell" carcinoma and that has a low metastatic potential. Identification is based on routine light microscopic features and is confirmed by special stains, immunohistochemistry, and electron microscopy. We present a variant of chromophobe renal carcinoma that did not show the typical cytomorphologic features on light microscopy after formaldehyde fixation. After fixation in Solufix (a commercial fixative), these features were recognized and the diagnosis was confirmed. The tumor also showed an unusual form of calcification and psammoma body formation not previously recognized in chromophobe tumors. Molecular biological assessment was inconclusive, but excluded a chromosome 3p deletion usually found in conventional renal carcinoma. The use of a different primary fixative may provide a cost-effective screening tool to detect variant renal tumors and may have important prognostic implications.     

The spectrum of papillary thyroid carcinoma variants

Papillary thyroid carcinoma is the most common type of thyroid malignancy. The diagnostic features of these tumors include characteristic nuclear cytology. However, many variants have been reported with different morphology and molecular profiles. Although the vast majority of papillary thyroid carcinomas have an excellent prognosis, some variants of papillary thyroid carcinoma can have a more aggressive course. With this increased attention to papillary thyroid carcinoma variants has come the need to sort out which variants are clinically important and should be recognized by practicing pathologists. The main objectives of this review article are to (1) summarize the gross and histopathologic features of papillary thyroid carcinoma; (2) provide an overview of the subtypes of papillary thyroid carcinoma and their prognosis; (3) discuss established and emerging data on the immunohistochemical findings that are helpful in differential diagnosis; and (4) summarize molecular findings and pathogenesis of these lesions.     

Invasive urothelial carcinoma with chordoid features may be an ominous sign predicting sarcomatoid change: a case report of a bladder carcinoma

Invasive urothelial carcinoma with chordoid features has not been reported since being first documented in 2009. Here we report a further case of it, involving an 85-year-old man with a papillary tumor of the urinary bladder, measuring 3 cm in diameter. This case is unique in that an epithelial–mesenchymal transition was suspected to have occurred in the transformation of a conventional urothelial carcinoma to a sarcomatoid variant, with invasive urothelial carcinoma with chordoid features acting as an intermediate stage. Based on this finding, we recommend that the presence of invasive urothelial carcinoma with chordoid features should be reported as it may predict the coexistence or future development of an aggressive sarcomatoid variant.     

Unusual forms of carcinoma of the urinary bladder.

Carcinomas of the urinary bladder, which differ histologically from the usual transitional cell carcinoma of the bladder, are reviewed. These tumors, which account for approximately 15% of all bladder carcinomas, have diverse microscopic appearances. They fall into four major categories: variant forms of urothelial (transitional cell) carcinoma, squamous cell carcinoma, adenocarcinoma, and undifferentiated carcinoma. In the first category, the most common are carcinomas with glandular or squamous differentiation. Less common, but more troublesome diagnostically, are variants in which the cells are spindle shaped (sarcomatoid carcinoma), form small cysts (microcystic carcinoma), or differentiate toward trophoblast. In other variants, the stroma has unusual features that may lead to diagnostic difficulty. These are carcinomas with pseudosarcomatous stroma, osseous or cartilaginous metaplasia, or osteoclast-type giant cells. Also reviewed are squamous cell carcinoma and its variant, verrucous carcinoma. Vesical adenocarcinoma has several variants, including signet-ring cell and clear cell types. Finally, the category of undifferentiated carcinoma, including small cell carcinoma, giant cell carcinoma, and lymphoepithelioma-like carcinoma, is discussed.     

The many faces and mimics of papillary thyroid carcinoma

This article provides an overview of the 15 histologic variants of papillary thyroid carcinoma listed by the 2004 World Health Organization (WHO) monograph on endocrine tumors. The histologic features, differential diagnosis, and clinical course of each variant are discussed in some detail. The follicular variants (conventional and macrofollicular) constitute a morphologic challenge because the majority of these tumors are encapsulated and, also, because, in many tumors, not all neoplastic cells show the nuclear features considered to be diagnostic of papillary carcinoma. As a result, most of these tumors are missed even by experienced pathologists. Moreover, hyperplastic thyroid lesions, follicular adenomas, and Hashimoto’s thyroiditis may contain cells with clear nuclei resembling those of papillary carcinoma. Papillary carcinomas composed entirely of hyperchromatic cells have been overlooked. The WHO monograph defines papillary carcinoma with focal spindle and giant cell carcinoma components but its clinical behavior is unknown. Papillary carcinoma with an insular pattern that does not show the artifactual separation of the cell nests has been misinterpreted as the solid variant of papillary carcinoma. Papillary microcarcinomas include not only the conventional type and the follicular variants but also the tall cell and columnar cell variants.     

Papillary carcinoma of the thyroid and its variants: a cytohistological correlation

Fine-needle aspiration cytology (FNAC) is considered highly specific for the diagnosis of papillary carcinoma of the thyroid (PCT). In recent years, several variants of PCT have been described. An attempt was made to gauge the accuracy of classification of variants of PCT on aspirates. Cytology smears from 124 of 150 cases of histologically proven PCT with a prior FNAC were reviewed over a 16-yr period. A diagnosis of papillary carcinoma on FNAC was made in 93 cases. Further subclassification of these cases was done on cytology and tissue sections independently. The variants of PCT classified on FNAC were classical PCT (PCT-CL), 76 cases; Hurthle-cell variant (PCT-HCV), 3 cases; follicular variant (PCT-FV), 6 cases; tall-cell variant (PCT-TCV), 2 cases; high-grade variant (PCT-HG), 2 cases; and 2 cases each which were debatably PCT-CL/PCT-FV and PCT-CL/PCT-HG. Cytology typing was accurate in 65 of the 72 classical variants, while only 7 of the 22 follicular variants were correctly identified on cytology. Two of the 3 high-grade papillary carcinomas (PCT-HG) were identified on FNAC, and the solitary case of tall-cell variant could readily be classified on cytology. In conclusion, identification of the various variants of PCT is possible, though difficulty is encountered in correctly categorizing the follicular variant, which is often mistaken for a follicular neoplasm. Also, identification of the solid variant and the papillary carcinoma with nodular fasciitis-like stroma was a problem on cytology. Another interesting observation in our series is that an admixture of various cell types was seen in the smears and corroborated on histology to be present in focal areas.     

Infectious Coryza: Overview of the Disease and New Diagnostic Options

Infectious coryza is a well-recognized and commonly encountered upper respiratory tract disease of chickens that is caused by the bacterium Haemophilus paragallinarum. The occurrence of recent outbreaks in North America has emphasized that the disease can be significant in meat chickens as well as layer chickens. In developing countries, coryza is commonly complicated by the presence of a range of other infections, resulting in severe disease and significant economic losses. Unusual forms of the disease, involving arthritis and septicemia, again associated with the presence of other pathogens, have been found in South America. Newly recognized bacteria such as Ornithobacterium rhinotracheale and phenotypic variant forms of both H. paragallinarum and close relatives (variant in that they no longer require V-factor for growth in vitro) have increased the difficulty associated with diagnosing the disease. There have been suggestions in both South America and South Africa that new serovars or serovar variants, associated with unusual clinical manifestations and causing vaccine failures, are emerging. Definitive evidence to confirm or deny the role of these "variants" in vaccine failures is currently not available. A new DNA-based diagnostic technique, involving PCR, has been recently described and will greatly assist in the diagnosis of infectious coryza.     

Nested variant of urothelial carcinoma: a clinicopathologic and immunohistochemical study of 12 cases.

Nested variant of urothelial carcinoma is characterized by confluent small nests and abortive tubules of mildly atypical neoplastic cells infiltrating the lamina propria and/or muscularis propria of the bladder. Despite its deceptively bland histomorphologic appearance, the lesion is reported to have an aggressive behavior. The collective immunohistochemical expression of suppressor genes, growth factor, and proliferation activity marker has not been previously studied in this disease. Formalin-fixed, paraffin-embedded archival tissues from 12 cases of nested variant of urothelial carcinoma were stained with monoclonal antibodies to p21, p27, p53, EGF-R, and bcl-2, as well as the proliferation marker MIB-1. The area of predominant immunoreactivity was also evaluated. The pattern of immunostaining was compared with the clinical parameters. p21 was positive in 10 of 12 cases and located at the deepest portion of the tumor in 5 of 10 positive cases. Immunoreactivity for p27 was seen in 11 of 12 cases and limited to the superficial portion of the tumor in 9 of 11 positive cases. Only 3 and 2 of 12 cases were positive for p53 and bcl-2, respectively. MIB-1 immunoreactivity ranged from 2 to 35% of the neoplastic cells, with most tumors showing a proliferation index of >15%. Follow-up ranged from 3 to 30 months (mean, 17.6 mo). All patients except one were alive, although three patients developed metastases. Nested variant of urothelial carcinoma is a deceptively benign-appearing neoplasm with potential of deep invasion and metastases. Immunohistochemically, nested variant of urothelial carcinoma shares some features with high-risk conventional urothelial carcinomas, such as loss of p27 expression and high proliferation index. Nevertheless, p53, bcl-2, or EGF-r immunoreactivity is not frequently seen.     

Cytologic features of insular carcinoma of the thyroid: a case report

Fine-needle aspiration of the thyroid has been accepted as one of the initial diagnostic tools in the evaluation of thyroid nodules. As its use becomes more widespread, the demand for more precise diagnosis has increased. The histopathology of insular carcinoma of the thyroid is now well recognized. However, the cytologic diagnostic criteria are not well established. The reported series have been small (4-6 cases), which is not surprising because of the rarity of this tumor. They consist of retrospective reviews of the aspirates (after the histologic diagnosis had been made from the thyroidectomy specimens). Also, the case reports do not provide uniform cytologic criteria; this could be due to limited sampling of these tumors (which are usually large). A cytologic diagnosis of insular carcinoma can be suggested if multiple samples of a thyroidal mass are markedly cellular, with a cytologic pattern reminiscent of a follicular variant of papillary carcinoma. However, the follicular cells are arranged predominantly in rosettes, their nuclei appear more monotonous, some "intranuclear cytoplasmic pseudoinclusions" are seen, and there is an occasional large cell with a pleomorphic nucleus.     

Nested variant of urothelial carcinoma of the renal pelvis

The nested variant of urothelial carcinoma is an uncommon form of urothelial carcinoma with distinctive histopathologic features. The majority of cases of this unusual type of urothelial carcinoma have been described in the urinary bladder, with examples of this neoplasm involving the upper urinary tract being extremely limited. The present report details the clinical and pathologic features of an unusual case of a nested variant of urothelial carcinoma occurring in the renal pelvis of a 71-year-old woman. The tumor was characterized by a nested pattern of growth and relatively bland cytologic features, and presented with locally advanced disease at the time of nephroureterectomy. Although rare, awareness that the nested variant of urothelial carcinoma may occur at this particular site is important so as not to confuse this unusual form of urothelial carcinoma with other pathologic lesions of the renal pelvis.     

The Paris System: achievement of a standardized diagnostic reporting system for urine cytology

Urinary tract cytology is a common diagnostic test used in the initial work up of bladder cancer. Since its inception as an utilizable diagnostic technique by Dr. Papanicolaou in 1945, urinary cytology has proven to be a cheap, easily obtained, and accurate method in the detection of high-grade urothelial carcinoma. Despite readily agreed upon features of high-grade urothelial carcinoma, a reproducible, universally accepted reporting method has not been attained. The Paris System for Reporting Urinary Cytology was developed to bring about a standardized reporting system with specific diagnostic categories and clear cytomorphologic criteria for the reliable diagnosis of high-grade urothelial carcinoma. This paper sets out to review the utility of urinary cytology, the current understanding of urothelial carcinoma, and the diagnostic categories of The Paris System. We finish with a review of the current literature regarding implementation of The Paris System.