Clear cell adenocarcinoma of the urinary bladder: a short review.
Abstract: * In this short review, we discuss clear cell adenocarcinoma of the urinary bladder, a rare tumor that primarily affects women. The histogenesis of this neoplasm is uncertain; in some tumors the clinicopathologic and histologic features are suggestive of a mullerian origin. Clear cell adenocarcinoma consists of cells with abundant clear cytoplasm, arranged in solid, glandular, or tubulocystic patterns. These tumors are positive for pancytokeratin, cytokeratin 7, and CA 125 immunohistochemical stains. Patients typically present with gross hematuria, dysuria, and discharge. The natural history is poorly understood and patient outcomes remain unclear. Currently, surgery is the treatment of choice. Nephrogenic adenoma is the most important differential diagnostic consideration, followed by metastatic clear cell carcinoma.
Article Type: Disease/Disorder overview
Subject: Bladder cancer (Diagnosis)
Immunohistochemistry (Usage)
Immunohistochemistry (Analysis)
Adenocarcinoma (Diagnosis)
Authors: Adeniran, Adebowale J.
Tamboli, Pheroze
Pub Date: 06/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: June, 2009 Source Volume: 133 Source Issue: 6
Accession Number: 230152031
Full Text: Clear cell adenocarcinoma (CCA) usually arises from the female genital tract. However, CCA is sometimes found in the lower urinary tract in women, most commonly involving the urethra, (1) where it may arise in paraurethral ducts or diverticula. (2,3)

Clear cell adenocarcinoma of the urinary bladder is rare and primarily affects women. (4) Its cytologic and ultrastructural features are similar to those of CCA arising in the female genital tract. (5) The findings of most previous studies of CCA of the urinary tract suggest mullerian differentiation. (5) Morphologic changes suggestive of endometriosis, or mesonephric or nephrogenic differentiation, may also be observed; however, some authors do not believe that CCA of the urinary bladder originates from these cell types. (6,7) In this article, we present a short review of CCA with emphasis on clinicopathologic characteristics. We also discuss the differential diagnosis of the entities that are likely to be confused with CCA.


The histogenesis of CCA of the urinary tract is uncertain. The prevailing theories on its histogenesis include the following: (1) these tumors arise from mullerian elements in the urinary bladder and are histogenetically identical to CCA arising in the female genital tract (5); (2) CCA of the urinary bladder is a variant of vesical adenocarcinoma of mesonephric derivation; and (3) CCA is a morphologic expression of urothelial (transitional cell) carcinoma with glandular differentiation. (4) In a few cases, CCA has been associated with vesical endometriosis or has arisen in a mullerian duct cyst or remnant in the urinary bladder. (8) Furthermore, the condition is more common in women than in men. These findings are suggestive of a mullerian origin. In addition, more cases of CCA of the urinary bladder may beofmullerian origin than have been documented, as overgrowth and obliteration of benign mullerian elements may occur in some cases.

The theory of histogenesis from a mesonephric origin is supported by the fact that CCA commonly arises in the trigone and urethra and also because most reported cases have not been associated with endometriosis. (1,3,9,10) However, tumors arising from the posterior and lateral walls of the bladder (which do not embryologically arise from mesonephric remnants) have also been reported, (11,12) and this may be the basis for the second theory, which assumes that CCA of the urinary bladder is a variant of vesical adenocarcinoma that may originate from aberrant mullerian remnants, much like clear cell carcinomas of the uterus, vagina, and fallopian tube. (1,10,11,13) The focal presence of conventional urothelial carcinoma in some cases, the occasional occurrence of this tumor in male patients, and the overlap of CCA's immunohistochemical profile with that of urothelial carcinoma, supports the third theory--that of glandular differentiation in urothelial carcinoma. (4,9)


The reported mean age of patients with CCA of the urinary bladder is 57 years (range, 22-83 years). (4) Gross hematuria, dysuria, suprapubic pain, and discharge are the usual presenting symptoms. Rarely, patients present with complications of local tumor effects (eg, obstruction of the ureterovesical junction or bilateral hydronephrosis) or pain from local spread of the tumor. (11)

A cystoscopic examination of the urinary bladder reveals a visible mass in nearly all cases; this mass usually appears as an elevated lesion covered with edematous mucosa. A rare case of CCA within a bladder diverticulum has also been reported. (14) T1- and T2-weighted magnetic resonance imaging reveal irregularly shaped, broad-based masses of relatively low intensity. (11,14)




Clear cell adenocarcinoma tumors ranging from 1 to 7 cm in greatest dimension have been reported. Most were polypoid or papillary masses involving either the trigone, posterior wall, or left wall of the urinary bladder. (4) Glycogen-rich clear cells are cells are characteristic of CCA. The morphologic features of CCA are distinctive: The tumors are composed predominantly of sheets of uniform ovoid cells with clear cytoplasm. Flat, cuboidal, and columnar cells may also be present. Although most cells have clear cytoplasm, cell cytoplasm ranges from clear to pale eosinophilic. Solid (Figure 1), papillary, and tubulocystic (Figure 2) areas are common, and all of these areas may be partially lined by "hobnail" cells. A single layer of neoplastic cells usually lines the papillae or tubules. Small amounts of luminal mucin and psammoma bodies have also been reported. Cytologic atypia is usually moderate to severe. The nuclei of the clear cells tend to have irregular borders, finely granular and evenly distributed chromatin, and prominent nucleoli. Mitoses are readily apparent, ranging from 2 to 17 mitotic figures per 10 high-power fields. (4,9) Other findings include cystitis glandularis close to the tumor, prominent inflammatory infiltrate composed mostly of plasma cells, occasional calcifications, and focal myxomatous stroma. (4)

Cytologic and ultrastructural studies complement the histologic findings of CCA. (5,15,16) In cytology specimens, CCA typically forms numerous scattered aggregates of tumor cells or single tumor cells in a background of inflammatory cells. The cells are large and have abundant clear, wispy cytoplasm with discrete vacuolation. Hobnail and signet ring cells may also be apparent. The nuclei have granular to vesicular chromatin with prominent, often multiple, nucleoli. (15) Ultrastructurally the cells have apical caps, short microvilli, and complex cell bases and contain abundant glycogen. (16)

The immunohistochemical findings in CCA of the urinary bladder vary. (9) Most tumors are reported to be positive for pancytokeratin, cytokeratin 7 (Figure 3, A), and CA 125. Some tumors are reported to be positive for cytokeratin 20, epithelial membrane antigen (Figure 3, B), S100, carcinoembryonic antigen (CEA), CA 19.9, and LeuM1. In one study, a high tumor cell proliferation rate was observed with the MIB-1 stain (Figure 3, C), and most tumors were positive for p53. Stains for prostatic antigens are almost uniformly negative (9) (Table 1).


The recommended treatment for CCA of the urinary bladder is surgical resection, and cystectomy is the most common surgical procedure. (11) Adjuvant radiation therapy to a total dose of 50 to 60 Gy has been used, as has combination chemotherapy, including cisplatin plus etoposide, doxorubicin, and cyclophosphamide. However, the impact of these therapies on long-term survival is uncertain, as follow-up information after combination therapy has been reported on only 3 patients who died 18 months, 18 months, and 22 months, respectively, after surgery. (6,12,17)

The natural history of CCA remains poorly understood, as CCA of the urinary bladder is rare, and the follow-up periods of previously reported cases have been relatively short (<5 years). Although the prognosis of patients with this malignancy remains unclear, the survival period of the few reported cases suggests that CCA may have a worse prognosis than conventional urothelial carcinoma.


The differential diagnosis of CCA includes nephrogenic adenoma and other benign reactive processes, as well as primary malignant tumors of the urinary bladder and metastases to the urinary bladder. Differentiating CCA from nephrogenic adenoma may be difficult. (13) The clinical and histologic features of nephrogenic adenomas indicate that they are most likely metaplastic, not neoplastic. Nephrogenic adenomas appear to arise either from adjacent urothelium or from stromal cells of mesonephric duct origin and are predominantly found in young males. (9,13) Most of these lesions are small and occasionally multiple lesions may be found. Nephrogenic adenomas usually form papillary, polypoid, or sessile structures. Microscopically, nephrogenic adenomas are composed of small tubules and cysts that resemble renal tubules (Figure 4). They are lined by a single layer of flattened, cuboidal, low columnar, or hobnail cells and generally have scant eosinophilic or amphophilic cytoplasm and bland nuclei. They are sometimes associated with adjacent areas of squamous or mucinous metaplasia. Mitotic figures are usually not seen. (9) In contrast, CCA consists of cells with abundant clear cytoplasm in solid, glandular, or tubulocystic patterns. A high mitotic rate and prominent cytologic atypia are usually present. Nephrogenic adenomas are positive for epithelial membrane antigen and low-molecularweight cytokeratin (CAM 5.2) and negative for CEA. Clear cell adenocarcinoma is positive for CAM 5.2, epithelial membrane antigen, and CEA. Variable staining is observed with antibodies to S100 protein. (9,13) [alpha]-Methylacyl coenzyme A racemase expression has also been reported in nephrogenic adenomas.18 The mean number of MIB-1-positive cells in nephrogenic adenomas is 5.5 per 200 cells, whereas the mean number reported in CCA is 41 per 200 cells. (9) Strong staining for p53 is typical in CCA but not in nephrogenic adenoma (9) (Table 1). Most cases of nephrogenic adenoma are associated with a history of genitourinary trauma, surgery, calculous disease, or renal transplant; these clinical features have not been reported in cases of CCA.




The cells of urothelial carcinoma of the urinary bladder may have abundant glycogen-rich clear cytoplasm19;however, they lack the typical patterns of CCA.

Metastases, especially from renal and ovarian carcinoma, may be difficult to distinguish from CCA on histologic grounds alone. Correlation with clinical and radiographic findings may be required in selected cases. Immunohistochemical analysis may be valuable in differentiating between CCA and metastases. Metastatic CCA from the ovary is typically found in women with a mean age of 57 years, particularly nulliparous women. It is commonly associated with endometriosis. Most ovarian CCA tumors are cystic with solid areas, but some have papillary, tubulocystic, solid, or mixed patterns. The papillae, tubules, and cysts may be lined by polyhedral glycogenrich clear cells with round or angular nuclei (Figure 5), and they may be arranged in nests. Nuclear atypia with abnormal mitoses are frequently found. The cells are typically strongly and diffusely immunoreactive for cytokeratin, epithelial membrane antigen, Leu-M1, and B72.3; they show variable immunoreactivity for CEA and CA 12520 (Table 2).

Renal cell carcinoma (RCC) is the most common clear cell carcinoma (Figure 6), but RCC metastases to the lower urinary tract are rare. The mechanism of RCC metastasis to the bladder is not well understood, but it could involve direct extension and seed implantation of cancer cells, venous embolization of cancer cells from the venous drainage of the kidney, or lymphatic spread. (21) Renal cell carcinoma metastases consist of confluent nests or tubules composed of epithelium with uniformly clear cytoplasm containing atypical, enlarged nuclei with prominent nucleoli. Hobnail cells are usually not present. The clear cells of RCC are immunoreactive for CAM 5.2, vimentin, LeuM1, CD10, carbonic anhydrase isoenzyme IX, and epithelial membrane antigen and negative for cytokeratin 20, cytokeratin 7, 34[beta]E12, CEA, S100 protein, HMB-45, and chromogranin (22) (Table 2). Clear cell myelomelanocytic tumors, which are perivascular epithelioid tumors, are rarely found in the urinary bladder. (23) Clear cell myelomelanocytic tumors consist of nests of clear to eosinophilic epithelioid cells with delicate vascular stroma. Immunohistochemically, the tumor cells are typically positive for HMB-45 and smooth muscle actin and are negative for S100, Melan-A, desmin, and pancytokeratin. (23)

Other rare tumors that could potentially involve the urinary bladder include tubulocystic CCA of the prostate (24) and renal-type clear cell carcinoma of the prostate. (25) A single case of tubulocystic CCA arising within the prostate has been reported. This tumor was composed of tubulocystic and papillary glands lined by glycogen-rich, cuboidal, or hobnail cells with clear to eosinophilic cytoplasm. (24) In this single case report, the tumor cells were strongly positive for pan-cytokeratin, CAM 5.2, and epithelial membrane antigen; focally positive for high-molecular-weight keratin; and negative for prostate-specific antigen and prostatic acid phosphatase. (24) Renal-type clear cell carcinoma of the prostate presents as tubules and solid nests or sheets in a richly vascularized stroma with interstitial inflammatory infiltrate. (25) Hobnail cells are absent. The clear cells in this single case report expressed vimentin, epithelial membrane antigen, and CAM 5.2 but were not immunoreactive for prostate-specific antigen, prostatic acid phosphatase, or cytokeratin AE1/AE3. (25) Although these 2 entities are rare, they may pose a diagnostic dilemma in the rare event of metastasis to the bladder, as they might be mistaken for CCA of the bladder.


Clear cell carcinoma is a distinct type of carcinoma that may involve the urinary bladder. This tumor mostly affects women and morphologically resembles its mullerian counterpart in the female genital tract, and in a subset of patients this lesion is likely of mullerian origin. Clear cell carcinoma occasionally occurs in men, and in a number of cases there is a lack of mullerian elements, or there is focal presence of conventional urothelial neoplasia. These findings suggest that some of these tumors originate from a specific form of glandular differentiation in the urothelium. However, as the cytokeratin immunoprofiles of CCA of mullerian and nonmullerian origin overlap, differentiating between the two can be difficult. Morphologically, CCA of the urinary bladder shows 1 or more of 3 typical morphologic patterns: solid, tubulocystic, and papillary. The cells range from flat to cuboidal to columnar and have clear or eosinophilic cytoplasm, or a combination of both, with moderate to severe cytologic atypia and frequent brisk mitotic activity. The most important differential diagnosis is nephrogenic adenoma. Histopathologic features that can help distinguish CCA from nephrogenic adenoma include a predominance of clear cells, severe cytologic atypia, and mitosis. In addition strong MIB-1 positivity and strong staining for p53 support a diagnosis of CCA rather than nephrogenic adenoma. Metastases from clear cell RCC and ovarian CCA are also important differential diagnostic considerations. Although these 2 lesions may be morphologically similar to CCA of the urinary bladder, immunohistochemical stains are helpful in distinguishing them from CCA. The clear cells of RCC are typically immunoreactive for CAM 5.2, vimentin, Leu-M1, CD10, and carbonic anhydrase isoenzyme IX, whereas those of ovarian CCA are typically positive for Leu-M1 and B72.3 and show variable immunoreactivity for CEA and CA 125.


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Adebowale J. Adeniran, MD; Pheroze Tamboli, MD

Accepted for publication September 12, 2008.

From the Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

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

Reprints: Pheroze Tamboli, MD, Department of Pathology, Unit 085, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail:
Table 1. Immunohistochemical Comparison of Clear
Cell Adenocarcinoma of the Urinary Bladder and
Nephrogenic Adenoma

                            Clear Cell
Immunohistochemical     Adenocarcinoma of     Nephrogenic
       Stain           the Urinary Bladder      Adenoma

Cytokeratin AE1/AE3             +                  +
CAM 5.2                         +                  +
Cytokeratin 7                   +                  +
Cytokeratin 20               [+ or -]           [+ or -]
EMA PSAP                        +                  +
PSA                             -                  -
CA 125                          +               [+ or -]
CEA (polyclonal)                +                  -
Leu-M1                          +                  +
CA 19.9                         +                  +
AMACR                           -                  +
p53                             +                  -
MIB-1                          High               Low

Abbreviations: AMACR, [alpha]-methylacyl coenzyme A racemase; CEA,
carcinoembryonic antigen; EMA, epithelial membrane antigen; PSA,
prostate-specific antigen; PSAP, prostate-specific acid phosphatase;
+, positive; -, negative; [+ or -], equivocal.

Table 2. Immunohistochemical Comparison of
Clear Cell Adenocarcinoma of the Urinary Bladder,
Clear Cell Carcinoma of the Ovary, and Clear Renal
Cell Carcinoma

                        Clear Cell
                      Adenocarcinoma    Clear Cell    Clear Renal
Immunohistochemical   of the Urinary    Carcinoma        Cell
Stain                    Bladder       of the Ovary    Carcinoma

Cytokeratin AE1/AE3         +               +              +
CAM 5.2                     +               +              +
Cytokeratin 7               +               +              -
Cytokeratin 20           [+ or -]           -              -
EMA                         +               +              +
CEA (polyclonal)            +            [+ or -]          -
Leu-M1                      +               +              +
CA 125                      +            [+ or -]          -
B72.3                       -               +              -
Vimentin                    -               -              +
RCC                         -               -              +
CD10                        -               -              +
CA-IX                       -               -              +

Abbreviations: CA-IX, carbonic anhydrase isoenzyme IX; CEA,
carcinoembryonic antigen; EMA, epithelial membrane antigen;
RCC, renal cell carcinoma; +, positive; -, negative;
[+ or -], equivocal.
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