Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications

doi:10.1016/j.humpath.2006.05.009

Human Pathology

Volume 37, Issue 11, November 2006, Pages 1371-1388

https://doi.org/10.1016/j.humpath.2006.05.009 Get rights and content

Summary

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.

Section snippets

Nested variant

The nested variant of urothelial carcinoma is an aggressive neoplasm with fewer than 50 reported cases. There is a marked male predominance, and 70% of the patients died 4 to 40 months after diagnosis, despite aggressive therapy [2]. This rare pattern of urothelial carcinoma was first described as a tumor with a “deceptively benign” appearance that closely resembles Brunn's nests infiltrating the lamina propria (Fig. 1) [3], [4]. Some nests have small tubular lumens, and they may, in some

Inverted papilloma-like (inverted growth) urothelial carcinoma

The potential for misinterpretation of the urothelial carcinoma with endophytic growth as inverted papilloma is high [4], [13], [14]. By definition, this variant of urothelial carcinoma has significant nuclear pleomorphism, mitotic figures, and architectural abnormalities consistent with low- or high-grade urothelial carcinoma (Fig. 2). In most cases, the overlying epithelium has similar abnormalities and contains typical urothelial carcinoma. The inverted papilloma-type carcinoma with minimal

Micropapillary carcinoma

The micropapillary carcinoma (Fig. 3) is a distinct variant of urothelial carcinoma that resembles serous carcinoma of the ovary, and approximately 80 cases have been reported in the literature. There is a male predominance, and the patients' ages range from the fifth to the ninth decade with a mean age of 66 years. The most common presenting symptom is hematuria. The first report of micropapillary carcinoma consisted of 18 patients whose ages ranged from 47 to 81 years (mean, 67 years), with a

Microcystic carcinoma

The microcystic variant of invasive urothelial carcinoma is characterized by the formation of microcysts, macrocysts, or tubular structures ranging in size from microscopic to 2 cm in diameter (Fig. 4) [17]. The cysts and tubules may be empty or contain necrotic debris or mucin that stains with periodic acid–Schiff stain after diastase digestion. This variant has also been reported in association with renal pelvic carcinoma.

Differential diagnosis. This variant of cancer may be confused with

Lymphoepithelioma-like carcinoma

Almost 40 cases of carcinoma histologically resembling lymphoepithelioma of the nasopharynx have been described in the urinary bladder [7], [24], [25], [26], [27], [28]. This variant is more common in men than in women (male-to-female ratio, 3:1) and occurs in late adulthood (range, 52-81 years; mean, 69 years) [25], [28]. Most patients present with hematuria. The tumor is solitary and usually involves the dome, posterior wall, or trigone, often with a sessile growth pattern. Histologically, it

Lymphoma-like or plasmacytoma-like carcinoma

Zukerberg et al [30] described 2 cases of bladder carcinoma that diffusely permeated the bladder wall and were composed of cells with a monotonous appearance mimicking lymphoma. The tumor cells were medium sized, with eosinophilic cytoplasm and eccentric nuclei producing a plasmacytoid appearance (Fig. 6). An additional case was diagnosed initially as a metastasis. The epithelial nature of the malignancy was confirmed by immunohistochemistry in these cases. This tumor is an aggressive neoplasm

Clear cell (glycogen-rich) carcinoma

Up to two thirds of cases of urothelial carcinoma have foci of clear cell change, resulting from abundant glycogen (Fig. 7). The glycogen-rich clear cell “variant” of urothelial carcinoma, recently described, appears to represent the extreme end of the morphological spectrum, consisting predominantly or exclusively of cells with abundant clear cytoplasm that stain for CK7 [7], [32], [33], [34].

Differential diagnosis. Recognition of this pattern avoids confusion with clear cell adenocarcinoma of

Lipoid cell variant

The lipoid cell variant is a rare neoplasm defined by the World Health Organization (1999, 2004) as a type of urothelial carcinoma that exhibits transition to cells resembling signet ring lipoblasts (Fig. 8). It is currently considered an ill-defined tumor variant, and whether it should be classified as carcinosarcoma remains to be established. In 7 reported cases, gross hematuria was the initial symptom [37]. All patients were elderly men (mean age, 74 years; range, 63-94 years). On

Urothelial carcinoma with syncytiotrophoblastic giant cells

Syncytiotrophoblastic giant cells are present in up to 12% of cases of urothelial carcinoma, producing substantial amounts of immunoreactive β-HCG (Fig. 9) [38], [39], [40], [41], [42], [43]. The number of HCG-immunoreactive cells is inversely related to tumor grade [44], [45]. Secretion of HCG into the serum may be associated with a poor response to radiation therapy [46].

Differential diagnosis. The most important differential diagnostic consideration is choriocarcinoma. Most previously

Sarcomatoid carcinoma with/without heterologous elements (carcinosarcoma, metaplastic carcinoma)

The term sarcomatoid variant of urothelial carcinoma should be used for all biphasic malignant neoplasms exhibiting morphological and/or immunohistochemical evidence of epithelial and mesenchymal differentiation, with the presence or absence of heterologous elements acknowledged in the pathology report [50]. There is considerable confusion and disagreement in the literature regarding the nomenclature and histogenesis of these tumors. As with other organs, various terms have been used for these

Small cell carcinoma

The urothelium has the capacity for divergent differentiation [67], and small cell carcinoma of the urinary bladder often coexists with conventional urothelial carcinoma [68]. A recent molecular study indicated that small cell carcinoma and urothelial carcinoma are derived from the same clonal population [69]. Therefore, the authors consider small cell carcinoma of the urinary bladder as a special variant of urothelial carcinoma.

Small cell carcinoma is a malignant neuroendocrine neoplasm

Urothelial carcinoma with mixed differentiation

About one fifth of the urothelial carcinomas contain areas of squamous or glandular differentiation [79]. Squamous differentiation, defined by the presence of intercellular bridges or keratinization, occurs in 21% of urothelial carcinomas of the bladder. Its frequency increases with grade and stage. The proportion of the squamous component may vary considerably, with some cases having urothelial carcinoma in situ as the only urothelial component. Urothelial carcinoma with a squamous or

Large cell undifferentiated carcinoma

This category contains large cell–type tumors that cannot be otherwise classified. They are extremely rare in the urinary tract, aggressive, and of high stage at presentation. One reported case had elevated serum α-fetoprotein levels and α-fetoprotein expression by immunohistochemistry in tumor cells that otherwise did not show any morphological recognizable differentiation [88]. High-grade urothelial carcinoma may contain epithelial tumor giant cells resembling giant cell carcinoma of the lung

Urothelial carcinoma with unusual stromal reaction

The infiltrating urothelial carcinoma may be associated with a variety of stromal reactions, which are occasionally pronounced (Fig. 14). Urothelial carcinoma may have a pseudosarcomatous stroma, which rarely displays sufficient cellularity, cytologic atypia, spindle cell proliferation, or myxoid appearance to raise serious concern about sarcomatoid carcinoma or true sarcoma of the bladder [63], [92]. The stromal cells reveal immunohistochemical evidence of fibroblastic or myofibroblastic

Other uncommon morphological variations in bladder cancer

Baldwin et al [104] described a series of 10 cases of urothelial carcinoma with a striking discohesive growth pattern that shows morphological features that mimicked infiltrating lobular carcinoma of the breast and diffuse carcinoma of the stomach. Eight of the patients were male and 2 were female. The mean age was 67 years at presentation (range, 52-77 years). All the cases showed areas where the tumor was composed of uniform cells with a discohesive, single-cell, diffusely infiltrative growth

Secondary neoplasms of the bladder

Practicing pathologists should be aware of the incidence and histologic appearances of secondary neoplasms of the urinary bladder, with emphasis on the points of distinction from primary tumors and their histologic variants. In a recent retrospective study of 282 tumors, secondary bladder neoplasms represented 2.3% of all malignant bladder tumors in surgical specimens at 1 institution [35]. The most common primary sites were the colon (21% of secondary neoplasms), prostate (19%), rectum (12%),

Histologic grading of urothelial carcinoma variants (Table 1)

The significance of grading variants of urothelial carcinoma remains unsettled, mainly because of a limited experience in management of these uncommon neoplasms. Table 1 shows some cases that might be considered high-grade tumors based on the reported data.

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A 62-year-old male presented with pain and haematuria starting 3 months before. The computed tomography showed focal and mural bladder thickening with ureteropelvic dilatation. The following transurethral bladder resection revealed a high-grade muscle-invasive urothelial carcinoma. In the subsequent cystoprostatectomy we found the same tumour, but adding focal tumour-associated stromal osseous metaplasia.
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Varón de 62 años que consulta por dolor y hematuria desde hace 3 meses. En la tomografía computarizada se observó un engrosamiento focal y mural de la vejiga con dilatación ureteropélvica. La resección vesical transuretral reveló un carcinoma urotelial infiltrante de alto grado músculo-invasivo. En la cistoprostatectomía posterior encontramos el mismo tumor, pero añadiendo focos de metaplasia ósea estromal asociada al tumor.
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Characterizing the Genomic Landscape of the Micropapillary Subtype of Urothelial Carcinoma of the Bladder Harboring Activating Extracellular Mutations of ERBB2
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The micropapillary subtype of urothelial carcinoma (MPUC) of the bladder is a very aggressive histological variant of urothelial bladder cancer (UBC). A high frequency of MPUC contains activating mutations in the extracellular domain (ECD) of ERBB2. We sought to further characterize ERBB2 ECD-mutated MPUC to identify additional genomic alterations that have been associated with tumor progression and therapeutic response. In total, 5,485 cases of archived formalin-fixed, paraffin-embedded UBC underwent comprehensive genomic profiling to identify ERBB2 ECD-mutated MPUC and evaluate the frequencies of genomic co-alterations. We identified 219 cases of UBC with ERBB2 ECD mutations (74% S310F and 26% S310Y), of which 63 (28.8%) were MPUC. Genomic analysis revealed that TERT, TP53, and ARID1A were the most common co-altered genes in ERBB2-mutant MPUC (82.5%, 58.7%, and 39.7%, respectively) and did not differ from ERBB2-mutant non-MPUC (86.5%, 51.9%, and 35.3%). The main differences between ERBB2 ECD-mutated MPUC compared with non-MPUC were KMT2D, RB1, and MTAP alterations. KMT2D and RB1 are tumor-suppressor genes. KMT2D frequency was significantly decreased in ERBB2 ECD-mutated MPUC (6.3%) in contrast to non-MPUC (27.6%; P < .001). RB1 mutations were more frequent in ERBB2 ECD-mutated MPUC (33.3%) than in non-MPUC (17.3%; P = .012). Finally, MTAP loss, an emerging biomarker for new synthetic lethality-based anticancer drugs, was less frequent in ERBB2 ECD-mutated MPUC (11.1%) than in non-MPUC (26.9%; P = .018). Characterizing the genomic landscape of MPUC may not only improve our fundamental knowledge about this aggressive morphological variant of UBC but also has the potential to identify possible prognostic and predictive biomarkers that may drive tumor progression and dictate treatment response to therapeutic approaches.
Effectiveness of Adjuvant Chemotherapy in Variant Histology Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy: Stabilized Inverse Probability Treatment Weighting Analysis of Single Center Experience
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The study aimed to investigate the impact of adjuvant chemotherapy on time to recurrence (TTR) and overall survival (OS) in patients with histologic variants of upper tract urothelial carcinoma (VUTUC) following radical nephroureterectomy (RNU).
A retrospective review of 131 VUTUC patients' medical records, from a pool of 368 non-metastatic localized or locally advanced UTUC cases, treated at a single tertiary referral center between January 2011 and January 2021. The intervention was adjuvant chemotherapy administration post-RNU. TTR and OS were evaluated using Kaplan-Meier and Cox proportional hazard regression, covariates adjusted for age, postoperative GFR, history of neoadjuvant chemotherapy, T and N stage with stabilized inverse probability of treatment weighting (sIPTW).
The application of adjuvant chemotherapy showed a significant extension in TTR (P = .01), but no substantial impact on OS (P = .19) after sIPTW adjustment for covariates. Multivariate analysis revealed adjuvant chemotherapy, tumor size, and lymphovascular invasion as significant prognostic factors for TTR. In contrast, only tumor size and perineural invasion were significant for OS. Adjuvant chemotherapy reduced the progression risk in certain VUTUC subtypes (squamous or glandular/micropapillary), but not in sarcomatoid variants.
Adjuvant chemotherapy appears to improve TTR, albeit without a significant effect on OS, in nonmetastatic localized and locally advanced VUTUC patients post-RNU. While beneficial to some VUTUC subtypes, it did not yield significant advantages for sarcomatoid variants. Despite adjustments for known confounders, the study's findings may be subject to potential selection bias and unmeasured confounding factors.
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A growing body of evidence has shown bladder-preservation with chemo-radiotherapy achieves comparable survival to Radical Cystectomy (5-year OS 50%-70%) and superior quality of life outcomes for patients with muscle-invasive urothelial carcinoma of the bladder (UC). However, up to 55% of patients harbor variant histology and in this review we aim to clarify the role of bladder-preservation for this group. We first draw the distinction between urothelial carcinoma with divergent differentiation (UCDD) and non-urothelial carcinoma (NUC). UCDD is common, increasing in prevalence, and whilst each subtype may have its own characteristics current evidence suggests comparable outcomes with radical cystectomy and bladder-preservation.
Non-urothelial carcinoma is a collection of distinct pathologies each deserving of its own management strategy. However, these tumors are rare, and evidence is generated from retrospective studies with significant inherent bias. Small cell carcinoma of the bladder has good evidence for bladder-preservation; however, other pathologies such as Squamous Cell Carcinoma and Adenocarcinoma are not well supported. We recommend careful multidisciplinary appraisal of the evidence for each subtype and honest patient discussion about the limited evidence before reaching management decisions. As we look to the future molecular-profiling may help better characterize these tumors and aid in treatment selection.
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Citation Excerpt :
Our institutional database was searched to identify patients with PUC who underwent MRI between January 1, 2000 and March 15, 2020. Exclusion criteria were [1] patients in whom MRI was done for post-treatment surveillance or for restaging after neoadjuvant treatment and [2] severe artifacts precluding image analysis. The final study population consisted of 41 patients.
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Perspectives in pathologyHistologic variants of urothelial carcinoma: differential diagnosis and clinical implications

Summary

Section snippets

Nested variant

Inverted papilloma-like (inverted growth) urothelial carcinoma

Micropapillary carcinoma

Microcystic carcinoma

Lymphoepithelioma-like carcinoma

Lymphoma-like or plasmacytoma-like carcinoma

Clear cell (glycogen-rich) carcinoma

Lipoid cell variant

Urothelial carcinoma with syncytiotrophoblastic giant cells

Sarcomatoid carcinoma with/without heterologous elements (carcinosarcoma, metaplastic carcinoma)

Small cell carcinoma

Urothelial carcinoma with mixed differentiation

Large cell undifferentiated carcinoma

Urothelial carcinoma with unusual stromal reaction

Other uncommon morphological variations in bladder cancer

Secondary neoplasms of the bladder

Histologic grading of urothelial carcinoma variants (Table 1)

Hum Pathol

J Urol

J Urol

Mod Pathol

Hum Pathol

Hum Pathol

J Urol

J Urol

Hum Pathol

J Urol

J Urol

Pathol Res Pract

Urology

J Urol

Hum Pathol

Mod Pathol

Am J Pathol

Hum Pathol

Mod Pathol

Pathol Res Pract

Urol Clin North Am

Pathology

J Urol

J Urol

J Urol

J Urol

J Urol

Urology

Carcinoma of the urinary bladder: a review of its diverse morphology

Semin Diagn Pathol

The nested variant of transitional cell carcinoma—a rare neoplasm with poor prognosis

Scand J Urol Nephrol

The nested variant of transitional cell carcinoma: a neoplasm resembling proliferation of Brunn's nests

Mod Pathol

Carcinomas of the urinary bladder with deceptively benign-appearing foci. A report of three cases

Am J Surg Pathol

The nested variant of transitional cell carcinoma: an aggressive neoplasm with innocuous histology

Mod Pathol

The nested variant of transitional cell carcinoma of the urinary bladder

Br J Urol

Transitional cell carcinomas of the urinary bladder that may be underdiagnosed. A report of four invasive cases exemplifying the homology between neoplastic and non-neoplastic transitional cell lesions

Am J Surg Pathol

A nested variant of transitional cell carcinoma of the urinary bladder: a case report

Jpn J Clin Oncol

Atypical nephrogenic metaplasia of the urinary tract: a precursor lesion?

Cancer

Paraganglioma of the urinary bladder: can biologic potential be predicted?

Cancer

Hepatoid adenocarcinoma of the urinary bladder

Virchows Arch

Urothelial transitional cell carcinoma with endophytic growth patterns: a discussion of patterns of invasion and problems associated with assessment of invasion in 18 cases

Am J Surg Pathol

Inverted papilloma of the lower urinary tract

Br J Urol

Clinical pathology of inverted papillomas of the urinary bladder. A complex morphologic and catamnestic study

Pathologe

Micropapillary variant of transitional cell carcinoma of the urinary bladder. Histologic pattern resembling ovarian papillary serous carcinoma

Am J Surg Pathol

Microcystic transitional cell carcinomas of the urinary bladder. A report of four cases

Am J Clin Pathol

Perspectives in pathology
Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications