Context.—

A variety of glandular and clear cell lesions may be seen in the urinary bladder and/or urethra, ranging from benign to malignant primary and secondary tumors. Lesions with no malignant potential include reactive processes, such as nephrogenic metaplasia, and may show similar morphologic features as an infiltrative neoplasm, particularly in small biopsies. Similarly, ectopic tissues of Müllerian origin may be seen in the lower urinary tract, and their distinction from a true glandular neoplasm is essential to avoid overtreatment. A wide variety of primary and secondary malignant tumors exist with varying degrees of glandular and clear cell features. Therefore, surgical pathologists must be aware of the full scope of possible lesions to avoid misdiagnosis.

Objective.—

To provide a practical framework for approaching the diagnosis of clear cell and glandular lesions of the urinary bladder/urethra and prostate, highlighting the strengths and limitations of various diagnostic features and ancillary tests.

Data Sources.—

A review of the current literature was performed to obtain data regarding up-to-date diagnostic features and ancillary studies.

Conclusions.—

In summary, distinct morphologic and immunohistochemical features and clinical and radiologic correlation are essential to establish an accurate diagnosis when such cases with glandular and clear features are encountered in the lower urinary tract.

The differential diagnosis of clear cell and glandular lesions of the urinary bladder/urethra is broad and includes both primary lesions/tumors that arise in the urinary bladder and/or urethra and those demonstrating secondary involvement via direct extension from nearby organs or metastasis from distant sites. These entities can demonstrate remarkable morphologic similarities, and therefore surgical pathologists must be aware of the full scope of possible lesions to avoid misdiagnosis. Moreover, there are important prognostic and therapeutic implications to accurate diagnosis because the knowledge base surrounding the natural histories and molecular drivers of these neoplasms continues to grow. In this review, we provide a practical framework for approaching the diagnosis of clear cell and glandular lesions of the urinary bladder/urethra and prostate, highlighting the strengths and limitations of various diagnostic features and ancillary tests.

Urothelial Carcinoma With Clear Cell Features

Reports have described urothelial carcinoma with glycogen-rich, clear cytoplasm.1–3  These carcinomas are typically high grade, have a more sheetlike (solid) growth pattern, and often have more characteristic appearing areas, at least focally, of urothelial carcinoma with conventional morphology. Urothelial carcinomas with clear cell features are positive for cytokeratin 7 (CK7) and CK20, high–molecular weight CK, and for urothelial markers (p63 and GATA-3) and are negative for PAX-8 expression (Figure 1; Table 1).

Figure 1.

Urothelial carcinoma with clear cell features. These tumors are composed of solid sheets and nests of tumor cells (A) with abundant clear cytoplasm (B). They express GATA-3 (C) and are negative for PAX-8 expression (D) (hematoxylin-eosin, original magnifications ×100 [A, C, and D] and ×200 [B]).

Figure 1.

Urothelial carcinoma with clear cell features. These tumors are composed of solid sheets and nests of tumor cells (A) with abundant clear cytoplasm (B). They express GATA-3 (C) and are negative for PAX-8 expression (D) (hematoxylin-eosin, original magnifications ×100 [A, C, and D] and ×200 [B]).

Close modal

Immunohistochemical Markers in Clear Cell and Glandular Lesions of the Lower Urinary Tract

Immunohistochemical Markers in Clear Cell and Glandular Lesions of the Lower Urinary Tract
Immunohistochemical Markers in Clear Cell and Glandular Lesions of the Lower Urinary Tract

Urothelial Carcinomas With Glandular Features

Approximately 10% of urothelial carcinomas contain foci of glandular differentiation. Glandular differentiation is usually in the form of small tubular or glandlike spaces in conventional urothelial carcinoma.4  The presence of a surface/noninvasive or invasive conventional urothelial carcinoma component is required to establish such a diagnosis. These tumors are positive for urothelial markers (p63 and GATA-3) and are negative for PAX-8 expression (Figure 2). The prognostic significance of glandular differentiation is unclear, although some studies have suggested an adverse outcome.5 

Figure 2.

Urothelial carcinoma with glandular features. Hematoxylin-eosin section shows areas of conventional urothelial carcinoma adjacent to glandular and tubular structures (A). High-power hematoxylin-eosin image (B). These tumors express urothelial markers, such as GATA-3 (C), and are negative for PAX-8 expression (D) (original magnifications ×100 [A, C, and D] and ×200 [B]).

Figure 2.

Urothelial carcinoma with glandular features. Hematoxylin-eosin section shows areas of conventional urothelial carcinoma adjacent to glandular and tubular structures (A). High-power hematoxylin-eosin image (B). These tumors express urothelial markers, such as GATA-3 (C), and are negative for PAX-8 expression (D) (original magnifications ×100 [A, C, and D] and ×200 [B]).

Close modal

Primary Adenocarcinoma

In contrast to urothelial carcinoma with glandular features, primary urinary bladder adenocarcinoma is defined as a primary tumor with exclusive glandular differentiation and without concurrent or previous noninvasive or invasive conventional urothelial carcinoma. These are rare tumors, representing up to 2% of all bladder malignancies.6,7  Some cases may be due to progression of extensive intestinal metaplasia (cystitis glandularis) or villous adenoma or exstrophy (diffuse intestinalization). Compared with urothelial carcinoma, patients with bladder adenocarcinoma have a worse prognosis because they commonly present at a more advanced stage. Morphologically, these tumors comprise a spectrum of histologic subtypes, including enteric, mucinous, signet ring, and adenocarcinoma, not otherwise specified. It is critical to exclude the possibility of a secondary adenocarcinoma involving the urinary bladder either by metastasis (gastric, ovarian, etc) or direct extension (colorectal, prostate, endometrium, etc). Importantly, colorectal adenocarcinomas extending into the bladder can colonize the urothelium, mimicking in situ disease. They generally show variable CK7 and diffuse CK20, CDX2, and β-catenin (nuclear) expression (Figure 3). This immunophenotype is nonspecific with regard to other glandular tumors in the differential diagnosis, and thus clinical and radiographic correlation is typically required for diagnosis. These tumors are also negative for urothelial markers (p63, GATA-3, and thrombomodulin) and PAX-8 expression.

Figure 3.

Pure adenocarcinoma consisting of exclusive glandular differentiation demonstrating a spectrum of histologic subtypes, including adenocarcinoma not otherwise specified (A), mucinous (B), and enteric (C), and expressing KRT 20 (D) (hematoxylin-eosin, original magnification ×100).

Figure 3.

Pure adenocarcinoma consisting of exclusive glandular differentiation demonstrating a spectrum of histologic subtypes, including adenocarcinoma not otherwise specified (A), mucinous (B), and enteric (C), and expressing KRT 20 (D) (hematoxylin-eosin, original magnification ×100).

Close modal

Urachal Adenocarcinoma

Urachal remnants are a potential source of malignancy, accounting for less than 1% of bladder carcinomas8  but up to 10% of bladder adenocarcinomas.9  The definition of a primary glandular urachal tumor includes: (1) the location of the tumor in the dome and/or anterior bladder wall, (2) epicenter of the tumor in the bladder wall, (3) absence of widespread cystitis cystica/glandularis beyond the dome and/or anterior bladder wall, and (4) absence of a known primary elsewhere. These tumors are divided into 2 broad categories based on overall architecture: mucinous cystic tumors and noncystic adenocarcinomas. Morphologically, noncystic urachal adenocarcinomas are similar to primary adenocarcinomas of the urinary bladder.10  These tumors typically demonstrate variable CK7 expression and diffuse CK20 and CDX2 expression; these tumors are also usually negative for p63, GATA-3, and PAX-8 expression.

Prostatic Adenocarcinoma

Carcinomas originating from the urinary bladder or prostate may spread frequently into the other organs because of their anatomic proximity. Although in many cases urothelial carcinoma and prostatic acinar or ductal adenocarcinoma demonstrate distinct histologic appearances, in some cases their differentiation may be challenging. This may be particularly challenging if the tumor is poorly differentiated or when a neoplasm of urothelial origin demonstrates extensive glandular features. Immunohistochemical stains are helpful to make such distinction; prostatic adenocarcinomas express prostate-specific antigen (PSA), prostate-specific acid phosphatase (PSAP), and NKX3.1. Urothelial carcinomas are typically negative for these markers.

Furthermore, in the prostate, a very rare variant of prostatic adenocarcinoma, termed renal-type clear cell carcinoma of the prostate, has been described in which the cancer is arranged in nests simulating clear cell renal cell carcinoma.11  Subsequent reports have described this tumor intimately admixed with conventional prostatic adenocarcinoma.12,13  Staining for prostatic markers (PSA and NKX3.1) has been inconsistent in the cases described thus far, but evidence of admixed conventional prostatic adenocarcinoma should help make the diagnosis. These tumors are negative for PAX-8 expression.

Skene Gland Adenocarcinoma and Other Urethral Adenocarcinomas

Skene (periurethral) gland adenocarcinoma is very rare, with only a few cases reported in the literature. The cases reported to date occurred in older women and usually presented as polypoid or flat periurethral tumors. The pathologic findings were frequently consistent with prostatic acinar adenocarcinoma with cribriform architecture and immunohistochemical stains were positive for PSA and PSAP in all cases.14 

Metastatic Carcinomas With Clear Cells or Glandular Features

Clear cell renal cell carcinoma can metastasize to the urinary bladder and may present a diagnostic challenge. Clinical evidence of kidney tumor (mass) is helpful in such cases. Morphologically, clear cell renal cell carcinoma is typically composed of solid sheets and nests of clear cells showing the classic intervening thin-walled blood vessels. In distinguishing clear cell renal cell carcinoma from other primary bladder tumors with clear cells, PAX-8 immunohistochemical stain is not helpful because both metastatic clear cell renal cell carcinoma and primary clear cell adenocarcinoma express PAX-8, but diffuse positivity of CK7 might favor clear cell adenocarcinoma versus clear cell renal cell carcinoma because the latter is usually negative or only focally positive. Additionally, carbonic anhydrase-IX (CA-IX) diffuse membranous staining is a hallmark of clear cell renal cell carcinoma.

Clear Cell Adenocarcinoma (Primary or Secondary)

Clear cell adenocarcinoma of the lower urinary tract is a rare type of carcinoma that arises in the urethra and/or bladder, predominantly in women, and in general is regarded as an aggressive neoplasm with an associated poor prognosis.15–17  It was first reported by Dow and Young18  in 1968 as mesonephric adenocarcinoma. The term clear cell adenocarcinoma was first introduced in 1985 by Young and Scully19  because of its histologic resemblance to clear cell carcinoma of the female genital tract. It was then classified under glandular neoplasms in the 2004 World Health Organization (WHO) classification of tumors of the urinary tract.20  The 2016 and the most recent 2022 WHO classification of tumors of the urothelial tract included clear cell adenocarcinoma under its new chapter of “Tumours of Mullerian type.”21,22  The histogenesis of clear cell adenocarcinoma of the lower urinary tract is controversial. Müllerian origin has been suggested by most authors, partially because of its reported association with endometriosis in some women as well as its expression of CA125.3,23,24  Studies using molecular techniques found evidence to support urothelial origin for most clear cell adenocarcinomas of the urinary tract.25  Recently, Oliva et al3  proposed that clear cell adenocarcinomas represented a distinctive form of glandular differentiation within urothelial carcinoma. Some studies have also questioned whether nephrogenic adenoma is a precursor lesion for these adenocarcinomas. A history of prior nephrogenic adenoma in some patients, as well as some similarities in immunohistochemical staining, has been used to favor this hypothesis.26  Other studies have also suggested that urethral clear cell adenocarcinoma was found mainly in female individuals with a particular association with urethral diverticulum.17,27 

The current diagnosis of primary clear cell adenocarcinoma of the lower urinary tract is largely based on morphologic and immunohistochemical staining features. These tumors exhibit a triad of papillary, tubulocystic, and solid growth patterns and are composed of clear cells, eosinophilic, and hobnail cells. Immunohistochemical stains can aid in establishing a definitive diagnosis of clear cell adenocarcinoma of the lower urinary tract (Figures 4 and 5). These tumors express CK7, PAX-8, napsin-A, CA125, and AMACR, and are typically negative for urothelial markers (GATA-3 and p63), estrogen receptor (ER), progesterone receptor (PR), and PSA.28,29  The lack of urothelial marker expression in clear cell adenocarcinoma suggests a nonurothelial origin of these tumors and argues against the proposed theory that these tumors represent a distinctive form of glandular differentiation within urothelial carcinoma.3 

Figure 4.

Clear cell adenocarcinoma showing several architectural patterns, including papillary (A), tubulocystic (B), and solid (C and D) growth patterns (hematoxylin-eosin, original magnification ×100).

Figure 4.

Clear cell adenocarcinoma showing several architectural patterns, including papillary (A), tubulocystic (B), and solid (C and D) growth patterns (hematoxylin-eosin, original magnification ×100).

Close modal
Figure 5.

On higher magnification of clear cell adenocarcinoma, most of the neoplasm is composed of cells with abundant clear cytoplasm (A). Additionally, cells with abundant eosinophilic cytoplasm (B) and cells with hobnail nuclei (C) were also present. The tumor cells were diffusely positive for PAX-8 expression on immunohistochemistry (D) (hematoxylin-eosin, original magnifications ×100 [A] and ×200 [B and C]; original magnification ×100 [D]).

Figure 5.

On higher magnification of clear cell adenocarcinoma, most of the neoplasm is composed of cells with abundant clear cytoplasm (A). Additionally, cells with abundant eosinophilic cytoplasm (B) and cells with hobnail nuclei (C) were also present. The tumor cells were diffusely positive for PAX-8 expression on immunohistochemistry (D) (hematoxylin-eosin, original magnifications ×100 [A] and ×200 [B and C]; original magnification ×100 [D]).

Close modal

Hepatocyte nuclear factor factor–1β (HNF-1β), a homeodomain protein that has been reported to be frequently overexpressed in ovarian clear cell adenocarcinoma in comparison with rare or no expression in other types of epithelial ovarian tumors, has also been reported in clear cell adenocarcinoma of the lower urinary tract. Brimo et al30  assessed the expression of HNF-1β in 18 clear cell adenocarcinomas of the bladder and urethra compared with that of urothelial carcinoma, primary adenocarcinomas of the bladder/urethra, and nephrogenic adenomas, and found that HNF-1β was expressed in 100% of clear cell adenocarcinomas, 2% of urothelial carcinomas, 5% of primary adenocarcinoma, and 20% of nephrogenic adenomas.30  Therefore, HNF-1β is a useful marker in differentiating clear cell adenocarcinoma of the bladder and urethra from urothelial carcinoma and primary bladder adenocarcinoma and to a lesser extent from nephrogenic adenoma; however, this marker has no diagnostic utility in discriminating primary bladder/urethral clear cell adenocarcinoma from secondary clear cell adenocarcinoma from the female genital tract.

Distinguishing between primary and secondary (direct extension or metastasis from gynecologic tract) clear cell adenocarcinoma depends on careful clinical/radiologic correlation), because these 2 entities are indistinguishable on histologic and immunohistochemical grounds.

The molecular landscape of clear cell adenocarcinomas of the lower urinary tract is lacking. Molecular characterization of a small series of clear cell adenocarcinoma of the urethra and bladder showed recurrent alterations in the PI3K/AKT/mTOR pathway.31  PIK3CA p.E545K and KRAS p. G12D mutations were identified in 75% (3 of 4) of the cases sequenced, both of which have also been noted in ovarian clear cell adenocarcinoma.32  Ongoing biomarker-based clinical trials would provide more insights into the therapeutic, predictive, and prognostic values of PIK3CA and KRAS variants in solid tumors in general and clear cell adenocarcinomas in particular.

Studies showed a poorer prognosis of clear cell adenocarcinomas compared with all other carcinomas of the urinary bladder, attributable to their high stage at presentation.33  Disease recurrence/progression was documented in 37.3% of the cases, and 28.8% died of disease. Multivariate analysis found that increased age and presence of distant disease predicted shorter overall and disease-specific survival, as did surgical intervention (with patients undergoing surgery showing longer survival). Radiation and chemotherapy showed no correlation with survival on multivariate or univariate analysis.34–36 

Benign Lesions and Benign Mimickers With Glandular Features

Nephrogenic Adenoma (Metaplasia)

Nephrogenic adenoma (metaplasia) is a relatively uncommon urothelial lesion and has a broad histologic spectrum. In its most classic form, it is composed of small tubules resembling renal tubules that are confined to the lamina propria. Low-power architecture of nephrogenic adenoma is identical to that of clear cell adenocarcinomas, generally mixed tubulocystic and papillary with hobnail nuclei but rarely solid and diffuse (Figure 6). It lacks significant nuclear pleomorphism, including nuclear enlargement and hyperchromasia, and mitosis is rare.

Figure 6.

Hematoxylin-eosin sections of nephrogenic adenoma demonstrating papillary (A and B) and tubulocystic (C) architecture but rarely solid and diffuse growth pattern, and lacking significant nuclear pleomorphism. They are diffusely positive for PAX-8 expression (D) (original magnifications ×100 [A] and ×200 [B through D]).

Figure 6.

Hematoxylin-eosin sections of nephrogenic adenoma demonstrating papillary (A and B) and tubulocystic (C) architecture but rarely solid and diffuse growth pattern, and lacking significant nuclear pleomorphism. They are diffusely positive for PAX-8 expression (D) (original magnifications ×100 [A] and ×200 [B through D]).

Close modal

The morphologic overlap between clear cell adenocarcinoma and nephrogenic adenoma is a source of diagnostic difficulty. It is also recognized that focally within a clear cell adenocarcinoma, there may be areas mimicking nephrogenic adenomas, composed primarily of tubules and papillae without significant cytologic atypia (Figure 7).36–38  A distinction is usually made by examining other areas of the tumor that show more obvious malignant features of clear cell adenocarcinoma.3  Herawi et al17  compared the histologic and immunohistochemical patterns of 7 nephrogenic adenoma–like clear cell adenocarcinomas with 12 classic clear cell adenocarcinomas and 10 nephrogenic adenomas to establish distinctive diagnostic criteria. Nephrogenic adenoma–like clear cell adenocarcinomas were architecturally almost entirely consistent with nephrogenic adenoma because they predominantly showed tubular, cystic, and papillary patterns throughout the lesion, although the presence of focal solid areas in a minority of nephrogenic adenoma—like clear cell adenocarcinomas and diffuse hobnail morphology—would argue against a diagnosis of nephrogenic adenoma. The key distinguishing feature of nephrogenic adenoma–like clear cell adenocarcinoma was the presence of cytologic atypia, often in the form of diffuse hyperchromatic and enlarged nuclei. By immunohistochemistry, nephrogenic adenomas are positive for PAX-8 and AMACR and are negative for urothelial markers (GATA-3 and p63). Identification of mitotic figures with the corresponding elevated Ki-67 and clonal p53 nuclear expression is adjunct in differentiating nephrogenic adenoma-like clear cell adenocarcinoma and nephrogenic adenoma.26  Necrosis within the tubules and vascular invasion in nephrogenic adenoma–like clear cell adenocarcinoma are not features of nephrogenic adenoma. A feature that is also helpful, but one that is typically better appreciated on resection specimens, is the deeply infiltrative architecture of nephrogenic adenoma–like clear cell adenocarcinoma tumors. In contrast, nephrogenic adenoma typically involves only the lamina propria, with rare cases showing focal superficial muscularis propria infiltration. In terms of prognosis, data indicate that most nephrogenic adenoma–like clear cell adenocarcinomas have a dismal prognosis, similar to classic clear cell adenocarcinomas.17 

Figure 7.

Hematoxylin-eosin sections of clear cell adenocarcinoma with nephrogenic adenoma–like foci on low-power magnification (A). Diffuse nuclear hyperchromasia is seen (B) (original magnification ×100).

Figure 7.

Hematoxylin-eosin sections of clear cell adenocarcinoma with nephrogenic adenoma–like foci on low-power magnification (A). Diffuse nuclear hyperchromasia is seen (B) (original magnification ×100).

Close modal

Endometriosis

The presence of endometrial tissue outside of the endometrial cavity is rare in the urinary tract, with an incidence of less than 3%.39  The glands present in these lesions resemble those of an inactive or proliferative-type endometrium, whereas the stromal component resembles normal endometrial stroma. Involvement of the smooth muscle is very common. Immunohistochemical staining may be helpful in demonstrating the ectopic nature of the tissue. ER, PR, CK7, and CA125 expression in the epithelial component, with CD10 expression in the stromal component, is specific and may be helpful for resolving the differential diagnosis.

Precursor/Premalignant Lesions: Villous Adenoma

Villous adenoma is an uncommon glandular neoplastic process in the urinary bladder.40  Histologically, these lesions, identical to their counterparts in the colon, are composed of villous projections lined by mucin-producing goblet cells in a pseudostratified columnar arrangement with nuclear crowding, occasional prominent nucleoli, and hyperchromasia. Villous adenoma is often associated with malignancy, particularly urachal adenocarcinoma. However, isolated villous adenoma appears to be associated with excellent prognosis.41  These lesions are positive for CK7, CK20, and CDX2 expression, suggesting the limited utility of immunohistochemical staining in differentiating primary villous adenoma from secondary involvement of colonic adenocarcinoma.

In summary, distinct morphologic features, immunohistochemical features, and clinical and radiologic correlation are essential to establish an accurate diagnosis. There exists a subset of clear cell adenocarcinoma of the bladder and urethra with a striking resemblance to nephrogenic adenoma that has similar patient outcomes compared with classic clear cell adenocarcinoma. Biopsy specimens that resemble nephrogenic adenoma morphology, yet either show nuclear enlargement with hyperchromasia, mitotic figures, intraluminal necrosis, or focal solid areas, should raise the differential diagnosis of nephrogenic adenoma–like clear cell adenocarcinoma. Immunohistochemically, elevated Ki-67 and p53 expressions are helpful in differentiating this carcinoma from nephrogenic adenoma. In cases where the diagnosis remains uncertain on limited biopsy material, clinical correlation and repeat biopsy with more extensive sampling may be necessary.

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Author notes

Presented at the New Frontiers in Pathology Conference; October 26–28, 2022; Ann Arbor, Michigan.

Competing Interests

The authors have no relevant financial interest in the products or companies described in this article.