Clear cell adenocarcinoma of the lower urinary tract: Cytopathologic characteristics and differential diagnoses


  • Scott A. Whitworth MD,

    1. Department of Pathology, Division of Cytopathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Andrea P. Subhawong MD,

    1. Department of Pathology, Division of Cytopathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Dorothy L. Rosenthal MD,

    1. Department of Pathology, Division of Cytopathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Syed Z. Ali MD

    Corresponding author
    1. Department of Pathology, Division of Cytopathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
    • Department of Cytopathology, Johns Hopkins Hospital, Pathology Building Room 406, 600 North Wolfe Street, Baltimore, MD 21287
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    • Fax: (410) 955-3438


Clear cell adenocarcinomas (CCAs) of the lower urinary tract are uncommon neoplasms that may present in routinely processed urinary cytology specimens. There is only limited discussion of the features of CCA of the lower urinary tract in the cytology literature. The authors report a series of 3 cases of this unusual tumor, and correlate cytomorphology with histologic specimens. Two of the cases were diagnosed accurately as adenocarcinoma, and 1 case was diagnosed as atypical cells of undetermined significance. Cytomorphologic features included variably cellular samples with 3-dimensional fragments of malignant cells that had enlarged nuclei, prominent nucleoli, and occasional hobnail configurations. Some fragments showed luminal formation with collections of neutrophils. CCA must be included in the differential diagnosis of malignant cells in a urinary specimen, particularly if the features are not typical of urothelial carcinoma. Other diagnostic considerations include metastatic adenocarcinomas, nephrogenic adenomas, and benign glandular lesions involving the bladder and urinary tract such as mullerianosis. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society.

Clear cell adenocarcinoma (CCA) of the lower urinary tract is an uncommon but well-recognized neoplasm with uncertain histogenesis. The majority of reported cases1, 2 have been identified in older female patients presenting with hematuria and a urethral mass. CCA arising in the prostate or periprostatic tissue in male patients has also rarely been reported.3 CCAs of the lower urinary tract behave in a locally aggressive manner and can develop metastases to regional lymph nodes.1 They have a varying histologic appearance, with a combination of papillary, tubulocystic, microglandular, and diffuse architectural growth patterns with nuclear pleomorphism and prominent nucleoli, similar to CCA of the female genital tract. Surgical resection of the mass is the typical treatment modality.

Reports discussing the morphologic features of CCA of the lower urinary tract are limited in the cytology literature.4-6 In this series, we describe cytopathologic characteristics of 3 cases of this unusual tumor in urine cytology, and correlate with histologic specimens.


Clinical histories and laboratory studies were obtained from the Pathology Data Systems at Johns Hopkins Hospital. Papanicolaou-stained SurePath liquid-based specimens from routinely collected catheterized urine specimens from 3 patients were reviewed and compared with histologic sections from surgical biopsy and resection specimens. Tissue submitted for microscopic evaluation was fixed in 10% buffered formalin and embedded in paraffin, and 4-μm cut sections were stained with hematoxylin and eosin.

Case 1

A 62-year-old woman presented with a urethral mass that was discovered incidentally on a computed tomography scan. Initial cystoscopy revealed urethral tissue destruction and frayed urothelial mucosa with an otherwise normal bladder. A diagnosis of CCA was made after examination of a catheterized urine specimen and biopsy of the periurethral mass. A radical cystectomy with ileal conduit was performed, and a 5.0-cm tumor was located in the urethral wall and the periurethral soft tissue, with the presence of vascular invasion. The surgical margins were negative for tumor. Clinically involved pelvic lymph nodes were deemed unresectable. The pelvic lymph nodes were strongly fluorodeoxyglucose-avid by positron emission tomography in the postoperative period, suggesting metastatic disease. The patient was treated with adjuvant chemotherapy, but this course was halted because of recurrent deep venous thrombosis related to venous stasis caused by the pelvic lymphadenopathy. She remained on home hospice 12 months after surgery with residual locoregional disease.

Case 2

A 51-year-old woman presented with difficulty urinating for several months and intermittent hematuria. Initial cystoscopy showed a large urethral mass protruding into the bladder neck and vagina. A diagnosis of CCA was established after examination of the catheterized urine specimen and cystoscopic biopsy of the urethral mass. Magnetic resonance imaging of the pelvis demonstrated a 3.9-cm periurethral mass without evidence of regional or distant metastatic spread. The patient is currently receiving neoadjuvant radiation therapy, before definitive surgical intervention.

Case 3

A 42-year-old man had a prostatic mass identified on digital rectal exam. Initial core biopsies of this mass were interpreted as prostatic adenocarcinoma with signet ring features and a high Gleason score. A diagnosis of CCA was established after a bladder washing specimen and radical prostatectomy, where a 2.5-cm tumor was identified in the soft tissue adjacent to the right anterolateral region of the prostate. The surgical margins were negative for tumor. The patient remained free of disease for 10 months postoperatively and was then lost to follow-up.

Cytologic Features

Cytologic examination of Papanicolaou-stained SurePath preparations of urinary specimens showed similar findings for all 3 patients. The sample cellularity varied from sparse to abundant and contained 3-dimensional hypercellular fragments arranged in sheets and tight glandular formations with central lumina, which were apparent while focusing through the groups (Figs. 1 and 2). Some of the glandular lumina contained prominent collections of neutrophils. Scattered mitotic figures were noted in several of the larger cell sheets. Rare tumor groups had focal hobnail cells with a peripherally placed nucleus and a thin cytoplasmic connection to the larger group (Fig. 3). The malignant cells varied in size, and had enlarged nuclei with thickened and irregular nuclear membranes, and large prominent nucleoli or multiple small nucleoli (Fig. 4). The scant-to-moderate cytoplasm was clear, with multiple small vacuoles and rare signet ring forms. Intracytoplasmic neutrophils were occasionally noted. Case 3 had fewer tumor cells and was interpreted as atypia of undetermined significance at the time of primary cytologic diagnosis (Fig. 5).

Figure 1.

Three-dimensional groups of tumor cells in a papillary configuration are shown (Papanicolaou; original magnification, ×200).

Figure 2.

Tumor cells are arranged as a gland around a central lumen (Papanicolaou; original magnification, ×200).

Figure 3.

Tumor cells form a gland with hobnail configuration (Papanicolaou; original magnification, ×400).

Figure 4.

A cluster of tumor cells with prominent nucleoli and vacuolated cytoplasm (arrows) is shown (Papanicolaou; original magnification, ×400).

Figure 5.

Atypia of undetermined significance is shown, consisting of rare enlarged cells with nuclear pleomorphism, angulation, and a suggestion of vacuolated cytoplasm against a background of other cells with reactive changes (Papanicolaou; original magnification, ×400).

The specimen backgrounds were altered from that typically found in SurePath urinary cytology specimens. A scant amount of degenerating normal-appearing urothelial cells was present, along with rare superficial and intermediate squamous epithelial cells. A heavy infiltrate of acute inflammatory cells was present, and formed the predominant, near-obscuring component in 1 specimen (case 2). Prominent red blood cells and cellular debris were also noted in the specimen backgrounds.

Histologic Features

Architecturally, CCA consisted of various proportions of tubular and cystic growth patterns with focal areas of micropapillary and solid growth. Hobnailing of the luminal cells was prominent in the tubular pattern. Anisonucleosis was marked, with thickened, irregular nuclear membranes and chromatin patterns that varied from hyperchromatic to fine and powdery. Large, eosinophilic nucleoli were present in a majority of cells, with a minority containing multiple small nucleoli (Fig. 6). Scattered intranuclear inclusions were also seen. The mitotic activity was high, with occasional tripolar forms observed. The cytoplasm varied in appearance from eosinophilic to clear and often was multivacuolated. The stroma varied from edematous to dense, with numerous mixed inflammatory cells. Rare psammoma bodies were noted in the tubular areas.

Figure 6.

Histologic sections show hobnail growth of tumor cells lining papillary projections. Note the nuclear pleomorphism, prominent nucleoli, and eosinophilic cytoplasm (Top: original magnification, ×10; Bottom: original magnification, ×40; H & E).


CCA of the lower urinary tract is an uncommon neoplasm that is predominantly identified in the urethra and bladder of women. The histogenesis of the neoplasm is controversial. It was once thought to arise from mesonephric duct remnants and was labeled as mesonephroid adenocarcinoma.7 More recently, it has been thought to arise from remnants of the Mullerian duct, given the similarities in appearance to CCAs of the female genital tract, associations with endometriosis in some cases, and expression of CA125.8, 9 A recent study has used molecular techniques to suggest that CCAs of the urinary tract have an origin in nephrogenic metaplasia of urothelial tissue.10

The reports of the cytologic features of CCA in urinary specimens are limited,4-6 which may be because of the variable shedding of tumor cells into the urine, obscuring inflammation, hematuria, and cellular degeneration. In addition, the yield of malignant cells may be influenced by the method of collection. The specimen collected by bladder washing showed fewer malignant cells than the catheterized specimens in this series.

The differential diagnosis of CCA in urinary specimens should include primary adenocarcinoma of the urinary tract, metastatic adenocarcinomas, nephrogenic adenomas, and benign glandular lesions involving the bladder and urinary tract such as mullerianosis. Adenocarcinoma is suggested by the presence of atypical columnar/cuboidal cells in the urine that may demonstrate glandular features such as prominent vacuoles, large nucleoli, or 3-dimensional arrangements with a central luminal space. In individual cases, it may be impossible to ascribe a primary site of origin based solely upon the urinary cytologic features. In such cases, careful correlation with the clinical history and radiographic, cystoscopic, and other clinical findings along with microscopic evaluation of tissue biopsies may prove necessary to identify the source of the neoplasm.

Nephrogenic adenoma of the lower urinary tract is a benign proliferation that may mimic CCA histologically. It is thought to represent a reactive proliferation in response to injury; most are small, superficial lesions, in contrast to the deeply invasive CCA. The histologic appearance of nephrogenic adenoma can mimic CCA, as it is composed of small tubules and papillae; indeed, it has been recently reported that a subset of CCA can closely resemble the histologic appearance of nephrogenic adenoma throughout the entire tumor, making this distinction more challenging on small biopsy material.11 However, nephrogenic adenomas typically lack the cytologic atypia and diffuse growth that usually characterize CCA.

Mullerianosis involving the bladder is uncommon, but could be a potential source for glandular cells identified in urinary cytology. The lesion is characterized by an admixture of at least 2 types of mullerian tissue in the wall of the bladder. Reports of mullerianosis involving the urine have noted 3-dimensional aggregates of glandular cells with scant cytoplasm and small nucleoli that resemble endometrial cells, or monolayered sheets of epithelial cells with scant cytoplasm and isolated signet ring forms.12, 13 This presents a potential diagnostic pitfall in urinary cytology specimens, but correlation with biopsy material should aid in the interpretation of the classic morphologic features of endometriosis, endosalpingiosis, or endocervicosis.

In summary, this series is among the few cytology studies describing the cytopathologic features of CCA in the urine. Three-dimensional clusters and sheets of vacuolated tumor cells with signet ring features, along with scattered atypical single cells with prominent nucleoli, should raise suspicion for uncommon glandular lesions such as CCA. Although it might be difficult to precisely subclassify urinary tract adenocarcinoma presenting in the urine, the presence of these malignant features should prompt a diagnosis of adenocarcinoma with suggestion for further tissue studies; the clear cell variant can be strongly suggested. The distinctive tubulocystic and papillary appearance of the tumor in histologic sections correlates with the cytomorphology of the tumor cells in the urine.


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The authors made no disclosures.