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Bladder Squamous Cell Carcinoma¹

¹ From the Department of Radiology, University of Minnesota, Minnesota Veterans Administration Medical Center, Minneapolis, Minn. Received June 24, 2003; revision requested July 23 and received September 5; accepted September 5. Address correspondence to J.T.W., Department of Radiology, University of Minnesota, 420 Delaware St SE, Minneapolis, MN 55455 (e-mail: wongx036@umn.edu).

Index Terms: Bladder, diseases, 83.322 • Bladder neoplasms, 83.322 • Bladder neoplasms, diagnosis, 83.1211, 83.1214, 83.1298

	History

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A 50-year-old male Vietnam War veteran presented with a 26-year history of traumatic paraplegia. The patient had total left hip disarticulation and bilateral amputations below the knee. Lateral bladder augmentation and cystoplasty had been performed in 1989, but lower urinary tract drainage had been achieved with suprapubic catheterization for the past 10 years. However, the patient had recurrent urinary tract infections. Previous transrectal ultrasonography (US)–guided biopsies of the prostate gland had revealed chronic prostatic inflammation. Unenhanced abdominopelvic computed tomography (CT) was performed, followed by CT cystography.

	Imaging Findings

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Unenhanced CT scans revealed hip disarticulation and bilateral destruction of the ischial tuberosities. Extensive low-attenuation areas with thin septa associated with iliac and sacral alar expansion were seen in the upper and lower pelvis and were thought to represent Paget disease or fibrous dysplasia rather than lytic metastases. Prostatic calcifications without abnormal prostatic enlargement were seen, a finding that is consistent with chronic inflammation. No renal, ureteral, or bladder calculi were present.

Contrast material was instilled into the bladder through a suprapubic catheter with the help of gravity. CT cystography was performed once the bladder was adequately distended and revealed a 3.0 x 5.5-cm lobulated soft-tissue filling defect that extended along the right superolateral bladder wall from the level of the suprapubic catheter. Anterior extension of the mass through the bladder wall was suspected on two images (Fig 1). No hepatic or abdominal metastases or lymphadenopathy was demonstrated.

View larger version (137K): [in this window] [in a new window] [Download PPT slide]   Figure 1a.  Contrast material-enhanced CT cystograms demonstrate a lobulated soft-tissue filling defect. Anterior extension into the prevesical fat is suggested in a (arrow). In b, the mass is seen to extend superiorly along the right superior lateral wall from the point of suprapubic catheter insertion.

View larger version (136K): [in this window] [in a new window] [Download PPT slide]   Figure 1b.  Contrast material-enhanced CT cystograms demonstrate a lobulated soft-tissue filling defect. Anterior extension into the prevesical fat is suggested in a (arrow). In b, the mass is seen to extend superiorly along the right superior lateral wall from the point of suprapubic catheter insertion.

	Pathologic Evaluation

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Dissection revealed a 7.0 x 5.0 x 3.0-cm white friable mass that arose from the right posterolateral bladder wall and extended to the ureteral orifice, 3.5 cm above the proximal prostate gland (Fig 2). Macroscopic and histologic analysis showed a moderately differentiated squamous cell carcinoma that invaded the muscularis propria and extended into the prevesical fat at the resection margin (Figs 3, 4). All resected lymph nodes were tumor free. The tumor was given the TNM classification of T3b N0 MX and the Jewett and Strong classification (Marshal modification) of stage C.

View larger version (107K): [in this window] [in a new window] [Download PPT slide]   Figure 2.  Photograph of the bladder (opened anteriorly with the prostate gland placed to the left) demonstrates a white friable mass that corresponds to the filling defect seen at CT cystography. A separate partial segment of urethra over a section of red rubber tubing (arrow) was submitted for pathologic analysis.

View larger version (110K): [in this window] [in a new window] [Download PPT slide]   Figure 3.  Photograph of the cross-sectioned lesion suggests tumor extension through the muscular layers into the prevesical fat (arrow).

View larger version (177K): [in this window] [in a new window] [Download PPT slide]   Figure 4.  Low-power photomicrograph (original magnification, x40; hematoxylin-eosin stain) demonstrates extension of squamous cell carcinoma into the prevesical fat (arrows). Note the keratinized islands (squamous pearls) composed of concentric cell aggregations (arrowheads).

	Discussion

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In this case, the CT cystoscopic findings of a solid soft-tissue-attenuation mass and the patient’s clinical history of chronic recurrent urinary tract infections and a long-term indwelling catheter pointed to a likely diagnosis of an inflammatory mass or a neoplasm. As the most common bladder tumor (90% of cases [1]), transitional cell carcinoma had to be considered, and because of the patient’s history of chronic bladder inflammation, squamous cell carcinoma (the most common non–transitional cell bladder tumor) and nephrogenic adenoma (a rare lesion that is thought to represent a metaplastic urothelial response to local traumatic irritation) also had to be included in the differential diagnosis.

Differential Diagnosis
Numerous entities may mimic a bladder tumor. Bladder filling defects or wall irregularity and thickening may result from air, blood clot, calculi, infection, bezoar ("fungus ball"), or an extrinsic or intrinsic bladder mass.

Cystitis, either infectious or noninfectious, may mimic a bladder tumor. Infectious causes include bacteria (Escherichia coli; Proteus, Klebsiella, or Pseudomonas species), granulomatous disease, viruses (adenovirus type 11 or type 21, influenza A, BK polyoma virus, or, rarely, varicella), fungi (usually Candida species), or parasites (Schistosoma hematobium). Noninfectious causes include bladder extrophy, systemic lupus erythematosus vasculitis, eosinophilic cystitis, and interstitial cystitis (2). Inflammatory changes in cystitis may produce irregularity and thickening of the bladder wall, and focal thickening can mimic a discrete mass.

Bullous edema, manifesting as fluid-filled cystic collections in the lamina propria, is a nonspecific inflammatory reaction that may occur with any cause of bladder irritation. Differentiation from tumor may be difficult at radiology and may be better achieved with cystoscopy. Focal forms of edema, especially polypoid forms (inflammatory pseudotumor), are less common and may be more difficult to differentiate from tumor (2).

Pseudotumoral cystitis refers to a heterogeneous group of bladder inflammatory changes in children that may mimic bladder tumors. Most reported cases are secondary to eosinophilic cystitis, although other causes include chronic granulomatous disease and cystitis cystica (2).

Extrinsic inflammatory diseases in adjacent pelvic organs (eg, vagina, cervix, uterus, prostate gland, colon) can involve the bladder wall and mimic a bladder tumor.

Intrinsic bladder masses include a variety of nonepithelial and mucosal tumors. Nonepithelial tumors include neurofibroma, neurofibrosarcoma, pheochromocytoma, lymphoma, angiosarcoma, hemangioma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, plasmacytoma, granular cell myoblastoma, malignant melanoma, choriocarcinoma, and yolk sac tumors. Bladder pheochromocytomas account for less than 1% of bladder tumors and less than 1% of all pheochromocytomas (1). In the bladder, most pheochromocytomas are hormonally active. Primary bladder lymphoma, the second most common nonepithelial bladder tumor, arises from the submucosal lymphoid follicles and may represent any of the histologic types of lymphoma. Leiomyosarcoma is the most common malignant tumor of the bladder mesenchyma in adults. Rhabdomyosarcomas are more common in children but may arise at any age (1).

Mucosal tumors that may affect the bladder include inverted papillomas, nephrogenic adenoma, vesical leukoplakia, pseudosarcoma (postoperative spindle cell nodule), carcinoma in situ, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, urachal carcinoma, and metastases.

Nephrogenic adenoma is a rare lesion that produces nonspecific radiologic findings of an intravesical or mural mass. It is thought to represent a metaplastic urothelial response to local traumatic irritation due to infection, urologic procedures, calculi, immunotherapy, chemotherapy, or radiation therapy (2). At histologic analysis, nephrogenic adenoma resembles primitive renal collecting tubules and is located predominantly in the tunica propria (2). The malignant counterpart of nephrogenic adenoma is mesonephric adenocarcinoma (1). Nephrogenic adenoma associations with transitional cell carcinoma, squamous cell carcinoma, and adenocarcinoma have been reported (2).

As with inflammatory diseases, extrinsic neoplasms in adjacent pelvic organs can involve the bladder wall and mimic a primary bladder tumor. Prostatic hyperplasia, adenocarcinoma, or transitional cell carcinoma may protrude into or invade the bladder base. Prostatic transitional cell carcinoma with involvement of the bladder wall may be particularly difficult to differentiate from a tumor that arises from the bladder. Uterine masses, either malignant or benign (fibroids), may distort the bladder.

Bladder Squamous Cell Carcinoma
Our patient had bladder squamous cell carcinoma with minimal perivesical extension, and radical prostocystectomy was performed without complication.

The prevalence of squamous cell carcinoma varies considerably depending on geographic location. Squamous cell carcinomas account for only 3%–7% of bladder cancers in the United States and 1% in England, but up to 75% in Egypt (1).

In Egypt, about 80% of squamous cell carcinomas are associated with chronic S hematobium infection. On average, patients are 10–20 years younger at presentation than are patients with transitional cell carcinoma. Bilharzial, in contrast to nonbilharzial, squamous cell cancers are usually well differentiated with a relatively low prevalence of nodal and distant metastases and manifest as exophytic, nodular, fungating lesions. Whether this low prevalence of nodal and distant metastases is due to the lymphatic and capillary fibrosis associated with chronic schistosomal infection or the lower histologic grade of these tumors is not clear (1).

In the United States, nonbilharzial squamous cell cancers predominate and are usually associated with chronic inflammation due to chronic urinary tract infections, urinary calculi, long-term indwelling catheters, or bladder diverticula (1). Up to 80% of paraplegic patients with indwelling catheters or chronic infections have squamous metaplasia, and approximately 5% develop squamous cell carcinoma (1). Bladder squamous cell carcinoma has been reported to have an increased risk associated with cigarette smoking. Unlike transitional cell carcinoma, which has a definite male predilection, squamous cell carcinoma has no definite sex predilection (1).

Most U.S. patients with squamous cell carcinoma are 60–70 years old, and many present with hematuria. The prognosis is generally poor due to advanced disease at presentation. Nonbilharzial squamous cell carcinomas, unlike transitional cell carcinomas or bilharzial squamous cell carcinomas, are often diffusely spread and may be distant from the bladder base. The majority manifest as large, solitary masses, and more than 80% demonstrate muscle wall invasion. Metastases are identified in at least 10% of cases at the time of diagnosis (3). Metastases may involve sites other than regional lymph nodes and spread to bone, lung, and bowel.

At histologic analysis, squamous cell carcinomas characteristically exhibit keratinized islands, called squamous pearls, which are composed of concentric cell aggregations (Fig 4). Squamous cell tumors may show varying degrees of differentiation. Stage for stage, histologic differentiation in squamous cell carcinoma correlates more loosely with prognosis than in other urothelial carcinomas, but grade and node status still help predict subsequent metastases (1). Staging of squamous cell carcinomas follows the same TNM classification (based on depth of invasion, degree of nodal involvement, and presence of distant metastases) as other uroepithelial tumors (Table) (3).

All patients with suspected bladder cancer should undergo cystoscopy and bimanual examination (1). Cystoscopy remains the standard of reference, providing direct visualization of the bladder and an opportunity for cytologic washings, biopsy, or local excision. Retrograde ureterography may also be performed. Cystoscopic biopsies provide invaluable staging information regarding depth of bladder wall invasion.

Imaging Evaluation.— Imaging modalities for bladder cancer include IVU, cystography, US, CT, MR imaging, and scintigraphy.

Previously, IVU and cystography were used extensively for detecting and staging suspected bladder tumors, but they have largely been supplanted by US, CT, and MR imaging. The inability to evaluate the full thickness of the bladder wall limits IVU, but this modality may provide useful information about the upper urinary tract and obstructive disease. Because urothelial tumors are often multifocal, IVU may help identify synchronous lesions. Renal function and detailed morphologic information regarding the renal pelves and ureters may be ascertained. Bladder tumors usually appear at IVU as nonspecific filling defects surrounded by contrast material. Oblique, early-filling-phase, peak distention, prone, and postvoiding views may help delineate smaller tumors. Oblique views may help distinguish confounding bowel gas from true bladder disease and localize tumors within the bladder. However, IVU is not reliable for detecting or staging bladder tumors. Studies have shown a 60% detection rate at best (4).

Cystography may occasionally be used to supplement IVU in patients with tumors seen at cystoscopy or urography, especially in the evaluation of bladder diverticula. Neoplasm within a diverticulum may occur in 2%–10% of cases, and cystoscopic access to the diverticulum may be limited (4). Cystography may provide additional information regarding known bladder diverticula and suspected neoplasm.

US methods of bladder evaluation include transabdominal (suprapubic), transrectal, transvaginal, and intravesical US. In the United States, US is not routinely used to evaluate bladder tumors. US has a mediocre staging accuracy (61%–84%) and the additional limitation of interobserver variability (4). Bladder visualization may be limited by patient body habitus, overlying bowel gas, or poor bladder distention. In addition, accuracy in the detection of lymph node metastases remains very low. If found incidentally, the lesion may appear as a hypoechoic plaquelike or polypoid mass that may project into the bladder. Fibrosis or calcifications may create increased echogenicity. Doppler US evaluation may reveal internal blood flow (5).

Currently, CT is the primary imaging modality in the evaluation of bladder tumors. Local CT staging accuracy ranges from 55% to 92% (4). Rapid scanning in the early vascular phase (40– 90 seconds after contrast material injection) may reveal an enhancing lesion against a background of low-attenuation urine in the bladder. Delayed scans may reveal a filling defect against the high-attenuation contrast material as the bladder fills. Bladder tumors may appear plaquelike, polypoid, or papillary. Tumoral calcifications may be noted on unenhanced images. Circumferential bladder wall thickening may be seen as the tumor enlarges. Other causes of wall thickening (eg, biopsy, inflammation, hypertrophy from chronic outlet obstruction, radiation fibrosis, chemotherapy) may complicate the CT diagnosis.

As with other imaging modalities, discerning the depth of bladder wall invasion is problematic. It may be impossible to differentiate among Ta–T3a tumors, leading some to group them together as "stage Ta–T3a" (4). T3b or T4 tumor invasion through the serosa exhibits soft-tissue-attenuation stranding in the low-attenuation perivesical fat. Axial evaluation of the bladder dome or base may be limited by partial volume averaging. Newer multi–detector row thin-section CT evaluation with multiplanar reformatting may improve the visualization of problematic areas but may not provide adequate information for accurate staging.

The lymph node staging accuracy of CT ranges from 50% to 97% (4). As with other tumors, however, CT allows visualization of lymph node size or enhancement abnormalities only. Pelvic lymphadenopathy is defined as pelvic lymph nodes larger than 15 mm in the short axis (6). Microscopic metastases are easily missed in small or normal-sized nodes. Differentiating between enlarged metastatic nodes and benign reactive nodes remains problematic.

CT virtual cystoscopy is a newer technique that shows promise for detecting bladder tumors greater than 5 mm in diameter in patients who are unable to tolerate conventional cystoscopy. Because this technique is limited to evaluating the epithelial surface of the bladder, it is inappropriate for staging bladder tumors. However, the clinical utility of virtual cystoscopy remains indeterminate, and further studies are necessary (7).

MR imaging is superior to CT in terms of its multiplanar capability and higher soft-tissue contrast but has been shown to have a similar staging accuracy (72%–96%) (5). Staging accuracy improves with gadolinium enhancement; however, a consensus that MR imaging is superior to CT in this context has yet to be reached. Nevertheless, the role of MR imaging continues to evolve as new pulse sequences, surface coils, and MR imaging–guided biopsy techniques are developed.

On T2-weighted images, the tumor has intermediate signal intensity, slightly higher than that of the bladder wall. Fat usually has low T2 signal intensity but may have high signal intensity with fast spin-echo sequences. Urine has high T2 signal intensity. On T1-weighted images, the tumor has intermediate signal intensity compared with the high-signal-intensity fat, a fact that aids in detecting perivesical fat extension. Urine usually has lower T1 signal intensity than the tumor. Squamous cell carcinoma, like transitional cell tumors, enhances with gadolinium administration. Peak tumor enhancement usually occurs prior to bladder wall enhancement, which may aid in detection if dynamic imaging techniques are used (8). Fat-saturated T1-weighted imaging allows differentiation of the enhancing tumor from the adjacent high-signal-intensity fat. Gadolinium-enhanced T1-weighted sequences, with or without fat saturation, can reveal adjacent organ involvement. As with other imaging modalities, however, it is difficult to evaluate the depth of bladder wall invasion with MR imaging.

Multiplanar imaging helps identify perivesical invasion, particularly at the bladder base and dome. MR imaging may also help detect synchronous or metachronous ureteral or urethral lesions. The same causes of bladder wall thickening that confound CT are also problematic for MR imaging. Bone marrow replacement by metastatic lesions may be visualized with MR imaging. Current MR imaging techniques have the same limitations as CT in lymph node evaluation; however, developments with ultrasmall paramagnetic iron oxide noncolloid particles show promise in identifying lymph node metastases, although they have yet to enjoy widespread use (9).

The role of scintigraphy in the evaluation of bladder cancer has been limited to staging for bone metastases. Initial metastases replace normal marrow, resulting in increased bone metabolism and osteolysis. Bone scintigraphy may show foci of either increased or decreased activity and reveal lesions that are undetectable with CT. However, scintigraphy remains limited to the detection of bone destruction. MR imaging remains the most sensitive and specific modality for the detection of bone metastases because the bone marrow and cellular signal intensity abnormalities, rather than bone metabolism, are directly visualized (4).

Tumor Staging, Grading, and Prognosis.— Uroepithelial tumors are classified according to the TNM classification system (Table) (4).

Well-differentiated (grade 1) tumors exhibit only mild anaplasia and pleomorphism and rare mitotic figures at histologic analysis. These tumors have a thin, fibrovascular stalk with a thickened urothelium containing more than seven cell layers. Moderately differentiated (grade 2) tumors have a higher nucleus-cytoplasm ratio, more nuclear pleomorphism, prominent nucleoli, more frequent mitotic figures, and a wider fibrovascular core. Poorly differentiated (grade 3) tumors have a high nucleus-cytoplasm ratio with marked nuclear pleomorphism and frequent mitotic figures (1).

According to Jewett (4), stage T1 or T2 tumors with low-grade malignancy (histologic grade 1 or 2) have a 5-year survival rate of 58%. If the stage T1 or T2 tumor is a high-grade malignancy (grade 3), the 5-year survival rate is 48%. With greater depth of invasion (stage T3b or T4 tumors), the 5-year survival rates for low- and high-grade malignancy are 16% and 15%, respectively (4).

Treatment.— Bladder cancer treatment depends on the depth of tumor invasion. Superficial tumors without muscle invasion are treated with endoscopic resection with or without adjuvant intravesical agents. If the tumor invades the muscle layer or there is minimal perivesical extension, curative radical cystectomy, radiation therapy, or both are attempted. If there is advanced disease with nodal or distant metastases, palliative chemotherapy or radiation therapy is used (4).

	References

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1. Messing EM. Urothelial tumors of the urinary tract. In: Walsh PC, Retik AB, Vaughan ED, et al., eds. Campbell’s urology. 8th ed. Philadelphia, Pa: Elsevier Science, 2002; 2732-2765.
2. Saluja S, Lazzarini KM, Smith RC. Inflammation of the urinary bladder. In: Pollack HM, McClennan BL, Dyer R, Kenney PJ, eds. Clinical urography. 2nd ed. Philadelphia, Pa: Saunders, 2000; 1019-1039.
3. Tekes A, Kamel IR, Chan TY, Schoenberg MP, Bleumke DA. MR imaging features of non-transitional cell carcinoma of the urinary bladder with pathologic correlation. AJR Am J Roentgenol 2003; 180:779-784.[Free Full Text]
4. Barentsz J. Bladder cancer. In: Pollack HM, McClennan BL, Dyer R, Kenney PJ, eds. Clinical urography. 2nd ed. Philadelphia, Pa: Saunders, 2000; 1642-1668.
5. Kundra V, Silverman PM. Imaging in the diagnosis, staging, and follow-up of cancer of the urinary bladder. AJR Am J Roentgenol 2003; 180:1045-1054.[Free Full Text]
6. Einstein DM, Singer AA, Chilcote WA, Desai RK. Abdominal lymphadenopathy: spectrum of CT findings. RadioGraphics 1991; 11:457-472.[Abstract]
7. Song JH, Francis IR, Platt JF, et al. Bladder tumor detection at virtual cystoscopy. Radiology 2001; 218:95-100.[Abstract/Free Full Text]
8. Barentsz JO, Jager GJ, van Vierzen PB, et al. Staging urinary bladder cancer after transurethral biopsy: value of fast dynamic contrast-enhanced MR imaging. Radiology 1996; 201:185-193.[Abstract/Free Full Text]
9. Bellin MF, Roy C, Kinkel K, et al. Lymph node metastases: safety and effectiveness of MR imaging with ultrasmall superparamagnetic iron oxide particles—initial clinical experience. Radiology 1998; 207:799-808.[Abstract/Free Full Text]

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