Carcinosarcoma of the Urinary Bladder--An Aggressive Tumor With Diverse Histogenesis.
Carcinosarcomas are neoplasms characterized by the presence of both malignant epithelial and mesenchymal components. The occurrence of these tumors has been documented in a variety of anatomic sites. Carcinosarcomas in the urinary bladder are rare, with fewer than 80 well-documented cases reported to date.[2-10] The histopathologic appearance of these neoplasms differs from case to case, although diagnosis requires the presence of well-defined malignant epithelial and mesenchymal elements. In the current paper, we present 4 additional cases of urinary bladder carcinosarcomas and discuss the morphogenesis and unusual histologic features of these neoplasms. In addition, all previously reported cases are reviewed and summarized.
PRESENTATION OF CASES
A 77-year-old white man with a 50-pack-year history of smoking presented with gross hematuria. A cystourethroscopy revealed a 10-cm bladder tumor, which extended into the prostate and prostatic urethra. Multiple superficial biopsies were performed with partial transurethral resection of the tumor. The tumor was considered surgically unresectable. Renal ultrasound disclosed moderate-to-severe ureteral obstruction. Bilateral percutaneous nephrostomy tubes were placed as palliative treatment for the bilateral hydronephrosis. The patient became cachectic; developed urosepsis, hypokalemia, hypotension, acute renal failure, and anemia; and died 6 months after initial diagnosis.
A 67-year-old white man with a 40-pack-year history of smoking presented with hematuria. Cystoscopy revealed a 5-cm polypoid tumor. Multiple biopsies showed a high-grade transitional cell carcinoma with invasion of the lamina propria. No muscular invasion was identified. Intravesical immunotherapy with Bacillus Calmette-Guerin (BCG) was carried out for 2 months. A follow-up computed axial tomographic (CT) scan at 3 months revealed mild left hydronephrosis with a thickened bladder wall near the left ureteral orifice. One month later, the patient underwent a radical retropubic cystoprostatectomy with orthotopic urinary diversion, along with bilateral pelvic lymphadenectomy. The patient received no additional treatment. Six months after the radical operation, he is well with no evidence of metastatic disease.
A 72-year-old man with a 40-pack-year history of smoking presented with gross painless hematuria of 5 days' duration, which was followed by urinary retention. An intravenous pyelogram was performed and revealed a large fungating mass on the left lateral bladder wall. A cystoscopy with transurethral resection of the tumor was performed. On pathologic examination of the initial resection specimens, the tumor had invaded the muscular layers of the bladder Radical cystectomy was performed 1 month after the initial operation. The patient received no additional treatment. He died of metastatic disease 2 years after initial diagnosis.
A 54-year-old woman with an 80-pack-year history of smoking presented with gross hematuria. Cystoscopic examination revealed a tumor on the right bladder wall that was removed via transurethral excision. A subsequent CT scan of the abdomen and pelvis suggested possible tumor invasion into the perivesicular fat. One month later, a total cystectomy with urostomy placement was performed. No residual tumor was identified in the surgical resection specimen. The patient is alive and well with no evidence of disease 2 years after initial diagnosis.
MATERIALS AND METHODS
All cases were retrieved from the Anatomic Pathology files of the Ohio State University Medical Center The sections were fixed in 10% buffered formalin, processed in standard fashion, embedded in paraffin, cut at 4 [micro] m, and stained with hematoxylin-eosin. The immunohistochemical stains were performed using the standard avidin-biotin immunoperoxidase technique. The antibodies used included cytokeratin cocktail (AE1/AE3, Boehringer Mannheim, Indianapolis, Ind, 1:1000; CAM 5.2, Becton-Dickinson, San Jose, Calif, 1:100; Mak-6, Zymed, South San Francisco, Calif 1:20); S100 protein (Dako Corporation, Carpinteria, Calif, 1:3000); vimentin (BioGenex, San Ramon, Calif, 1: 80); muscle-specific actin (HHF-35, Enzo, New York, NY, 1: 32000); smooth muscle actin (SMA, Sigma, St Louis, Mo, 1: 3000); chromogranin (Dako, 1:5); synaptophysin (Dako, 1:100); monoclonal carcinoembryonic antigen (mCEA, BioGenex, 1: 100); prostate-specific antigen (PSA, Dako, 1:2000); CD31 (Dako, 1:5); and factor VIII (Dako, 1:200).
The initial biopsies showed high-grade transitional cell carcinoma with no evidence of additional mesenchymal component. At autopsy, the bladder was distended by a large fungating mass measuring 10 x 9 x 8 cm (Figure 1, a). The mass was invading the posterior wall of the bladder and the prostate. Multiple metastatic nodules were seen in the intra-abdominal and thoracic organs. Histologic sections of the bladder tumor and metastatic nodules revealed a highly malignant neoplasm with a biphasic pattern of growth. Parts of the tumor consisted of epithelial cells with hyperchromatic nuclei and scant cytoplasm, typical of the high-grade transitional cell carcinoma (Figure 1, b). Another part of the tumor was characterized by proliferation of spindle cells with elongated and blunted nuclei in fascicles and bundles (Figure 1, c). The epithelial component of the tumor revealed strong immunoreactivity with anticytokeratin antibodies (Figure 1, d), and no immunoreactivity for HHF-35, SMA, and desmin. The spindle cell component showed the reverse pattern of immunoreactivity and stained positive for HHF35, SMA, and desmin, and negatively for cytokeratin (Figure 1, e).
[Figure 1 ILLUSTRATION OMITTED]
The initial cystoscopic biopsies showed transitional cell carcinoma with the invasion of the lamina propria, There was no evidence of a malignant mesenchymal component. The radical cystectomy specimen revealed a gray polypoid mass measuring 5.5 cm in greatest dimension and containing dark brown, ulcerated areas. The tumor grossly extended around the ureters and infiltrated the seminal vesicles bilaterally. Histologically the tumor was characterized by biphasic proliferation of malignant epithelial and sarcomatoid elements. The superficial aspect of the tumor showed high-grade urothelial carcinoma in situ. An extensive malignant mesenchymal proliferation with polyphenotypic differentiation was located beneath the highgrade urothelial carsinoma in situ. Distinct areas of rhabdomyosarcoma, liposarcoma, and spindle cell sarcoma with features of malignant pheripheral nerve sheath tumor were indentified (figure 2, a through d). Foci of adenocarcinoma were also noted. Sections of the bladder wall showed extensive infiltration by micropapillary carcinoma with prominent lymphovascular space invasion (Figure 2, e). The invasive carcinoma extended into the perivesicular fat and the serosal surface. Immunohistochemically, the adenocarcinoma, urothelial carcinoma, and micropapillary carcinoma stained positive for cytokeratin; the adenocarcinoma foci showed mCEA immunoreactivity; the rhabdomysarcomatous areas stained positive for desmin and HHF-35; and the spindle cell areas stained positive for S100 and negative for SMA, desmin and HHF-35. The stain for PSA was negative.
[Figure 2 ILLUSTRATION OMITTED]
Histologically, the tumor was composed of a typical, high-grade papillary transitional cell carcinoma characterized by fibrovascular papillae. The papillae were lined with urothelial cells with nuclear pleomorphism. Reticulated oval-to-spindle-shaped cells with abundant amounts of intervening, acellular myxoid material (Figure 3, a) replaced the supporting stroma. Invasion into the lamina propria was seen on pathologic examination; however, invasion into the muscularis propria could not be determined due to extensive crush artifact. The spindle cells showed moderate nuclear pleomorphism and scattered mitotic figures. Upon immmunohistochemical staining, the spindle cells showed reactivity with the antibody to vimentin. There was no reactivity with the antibodies to cytokeratin, mCEA, HHF-35, SMA, or S100 protein. The transitional cell component showed strong reactivity with the antibody to cytokeratin and focal reactivity with the antibody to mCEA.
[Figure 3 ILLUSTRATION OMITTED]
Histologic sections of the tumor showed a biphasic composition of both neoplastic epithelial and connective tissue components. The epithelial component showed glandular, transitional, and squamous elements. Rare foci contained nests of small-to-intermediate-sized cells with high nuclear-to-cytoplasmic ratios and a stippled chromatin pattern characteristic of small cell carcinoma (Figure 4, a). The stromal component was largely a hypercellular cartilaginous element (Figure 4, b). Immunohistochemical stains showed immunoreactivity of the small cell carcinoma areas with antibodies against chromogranin and synaptophysin, and weak perinuclear reactivity with anticytokeratin antibodies. Stains for the S100 protein highlighted cartilaginous areas. The cystectomy specimen revealed a thick white-gray tumor measuring 3.5 x 1.6 x 0.5 cm, which extended from the left anterior bladder wall through the dome and into the left posterior bladder wall. Histologic findings in the cystectomy specimen were similar to the previous cystoscopic biopsy. No additional histologic elements were identified in the resection specimen.
[Figure 4 ILLUSTRATION OMITTED]
Carcinosarcomas are defined by the World Health Organization as tumors composed of intimately admixed malignant epithelial and mesenchymal elements. Although their existence was recognized as early as the mid-19th century, the exact histogenesis of these neoplasms remained enigmatic for many decades, and even today remains one of the controversial issues in tumor pathology. Carcinosarcomas are rare neoplasms. Most commonly, pathologists identify these tumors in the female genital tract, where they have historically been termed malignant mixed mullerian tumors. The relative prevalence of this location over other anatomic sites outlined the prototype clinicopathologic setting for carcinosarcomas: these tumors commonly occur in older individuals and display aggressive biologic behavior.
The rapid growth of these neoplasms is often reflected by the typical gross appearance: a partially necrotic, polypoid mass protruding into the lumen of a hollow viscus. Although, many investigators have attempted to clarify the association of carcinosarcomas and a number of environmental hazards and noxious stimuli, no decisive epidemiologic data have set them apart from other common malignancies. In addition to the female genital tract, carcinosarcomas have been reported in the skin, gastrointestinal tract, hepatobiliary system, head and neck, respiratory system, and urinary tract.
In the urinary bladder, the majority of the neoplasms are of pure epithelial origin. In contrast, pure mesenchymal tumors and biphasic epithelial-mesenchymal neoplasms, although documented, rarely occur at this site. An extensive literature search identified 78 well-documented cases of urinary bladder carcinosarcomas, most of which were single case reports or short case series. The review of these cases and the findings from our 4 patients are presented in Tables 1 and 2.[2-10] There is a male predominance among patients with carcinosarcomas of the urinary bladder, with a male-to-female ratio of 1.7:1.0. The age range is very broad, 21 years to 91 years, with a mean age of 66.4 years. These epidemiologic data are similar to those of conventional urothelial carcinoma. The presenting features of carcinosarcomas are also similar to those of conventional bladder tumors: hematuria, dysuria, pollakisuria, and urinary tract infection. The majority of patients with carcinosarcomas (79%) underwent surgical treatment as a single therapeutic modality. Other patients underwent surgical treatment followed by radiation, chemotherapy; or some combination of both. In 6% of cases no further treatment was given after the diagnosis was established. Similar to the behavior of this tumor in other anatomic sites, carcinosarcomas of the urinary bladder proved to be very aggressive neoplasms: in 74 cases that provided clinical follow-up, half of the patients died within 1 year of the diagnosis.
Table 1. Summary of the Clinical Features of Carcinosarcoma of the Urinary Bladder Reported in the Literature
Total No. cases 82 Age range (mean), y 21-91 (66.4) Male: female ratio 1.7:1.0 Clinical symptoms Gross or microscopic hematuria, dysuria pollakisuria, back pain, urinary tract infections Treatment modality, Surgical resection only 65 (79) No. of cases (%) Surgical resection + radiation therapy 8 (9) Surgical resection + chemotherapy 2 (3) Surgical resection +radiation therapy +chemotherapy 2 (3) Biopsies only, no further treatment 5 (6) Clinical follow-up Available in 74 cases: 37 patients (50%) died within 1 year of diagnosis Common risk factors, Previous chemotherapy No. of cases (%) administration 5 (6) Previous radiation exposure 7 (8.5) Smoking history (available in 12 cases) 9 (75) Previous intravesical immunotherapy with Bacillus Calmette-Guiren 1 (1.2) (BCG, risk factor status unknown)
Table 2. Summary of Pathologic Features of Carcinosarcoma of the Urinary Bladder Reported in the Literature
Tumor size variation (mean), cm 1.5-12 (5.7) Epithelial component, Urothelial carcinoma 66 (80) No. of cases (%) Squamous cell carcinoma 26 (32) Adenocarcinoma 21 (26) Small cell carcinoma 4 (5) Micropapillary urothelial carcino 1 (1.2) Presence of 2 or more epithelial components 27 (33) Sarcomatoid component, Osteosarcoma 30 (37) No. of cases (%) Chondrosarcoma 24 (30) Rhabdomyosarcoma 16 (20) Undifferentiated spindle cell sarcoma 14 (17) Leiomyosarcoma 6 (7) Liposarcoma 2 (2.4) Malignant peripheral nerve sheath tumor 1 (1.2) Presence of 2 or more sarcomatoid components 14 (17) Summary of pathologic Stage I 9 (14) Stage groupings, Stage II 30 (45) No. of cases (%) Stage III 20 (30) Stage IV 7 (11)
The etiology and risk factors for development of malignant, mixed epithelial-mesenchymal tumors in the urinary bladder are largely unknown. Smoking has been implicated as a significant risk factor for conventional urothelial carcinoma. In this review, smoking history was available in only 12 cases. However, among these 12 patients with carcinosarcoma, 9 (75%) were current or past smokers. All of our 4 patients were smokers. Some investigators an association between previous radiation exposure and development of carcinosarcomas in the urinary bladder. In the current review, we were able to identify 7 patients (8.5%) with previous radiation exposure. In 1 study, an association was reported between long-term chemotherapy with cyclophosphamide and urinary bladder carcinosarcoma. Several other cases with previous history of systemic chemotherapy have been described, giving a total number of 5 carcinosarcoma cases (6%) associated with previous systemic chemotherapy exposure. None of the 4 patients in our series had any history of radiation exposure or systemic chemotherapy. In case 2, the patient was treated with BCG for low-grade transitional cell carcinoma over a period of 2 months, suggesting a possible association between this treatment and development of carcinosarcoma. However, a period of 2 months appears to be very short for a case of induced carcinogenesis. Most likely, the sarcomatoid component was present in the original tumor but was missed in the initial biopsies due to a sampling error.
Pathologically, the majority of tumors in this review had the typical gross features of carcinosarcomas: exophytic polypoid masses with areas of necrosis and ulceration. The size of the primary tumor varied from 1.5 to 12 cm (mean, 5.7 cm) in greatest dimension. Histologically, all carcinosarcomas were true biphasic neoplasms with an admixture of malignant epithelial and mesenchymal components. The most common epithelial component was urothelial carcinoma (80%), followed by squamous cell carcinoma (32%), adenocarcinoma (26%), and small cell carcinoma (5%). One case from the current study was remarkable for the presence of a distinctive variant of urothelial carcinoma-micropapillary carcinoma. The presence of 2 and more epithelial components in the same tumor was noted in one third of cases (33%). The most common mesenchymal component was osteosarcoma (37%), followed by chondrosarcoma (30%), rhabdomyosarcoma (20%), undifferentiated spindle cell sarcoma (17%), and leiomyosarcoma (7%). Areas of pleomorphic liposarcoma were identified in 2 cases, including 1 case in the current study, which also showed the presence of a previously unreported malignant peripheral nerve sheath tumor. The presence of 2 or more mesenchymal components in the same tumor was noted in 17% of cases. Seventy-five percent of patients presented in stage II or III of the disease, whereas 14% and 11% of patients presented in stages I and IV, respectively.
The overall clinical and pathologic features of our 4 cases paralleled findings from previously reported series. The most unusual feature was the presence of pleomorphic liposarcoma, micropapillary carcinoma, and malignant peripheral nerve sheath tumor in case 2 in our study. To our knowledge, the latter 2 components have not been previously reported in carcinosarcomas of the urinary bladder and pleomorphic liposarcoma was formerly identified in only a single case.[7,13] The clinical significance of the presence of these histologic components in carcinosarcoma is not clear. In a review of 41 cases of mixed epithelial-mesenchymal neoplasms (which included cases of both sarcomatoid carcinomas as well as true heterologous carcinosarcomas of the urinary bladder) from the Mayo Clinic, the overall prognosis for these tumors was poor, regardless of histologic findings and treatment employed; the pathologic stage was the best single predictive factor of a patient's survival. In the study by Amin et al of micropapillary carcinoma of the urinary bladder, this morphologic variant was highly infiltrative with foci of lymphovascular space invasion and was associated with poor prognosis. In their study, true areas of lymphovascular space invasion were immunohistochemically identified only in limited microscopic foci of micropapillary carcinomas, whereas the majority of the tumor tissue exhibited "pseudoinvasion" of lymphovascular spaces, characterized by prominent stromal retraction artifact around tumor micropapillary structures. In 1 of our cases, areas morphologically consistent with micropapillary carcinoma were identified. Immunohistochemical staining with factor VIII and CD31 antibodies did not demonstrate definitive lymphovascular spaces around the tumor foci, although the H&E evaluation was highly suggestive of their presence. Whether this can be explained by the limited number of microscopic foci of micropapillary carcinoma in our case is unclear. In reality, the limited number of cases precludes a definitive assessment of whether the presence of rare histologic elements in carcinosarcomas of the urinary bladder can aggravate the already sinister prognosis of these tumors.
As previously mentioned, the histogenesis of carcinosarcomas remains uncertain and there is no agreement on the nomenclature.[1,12,14-17] Some investigators feel that these tumors develop as a result of the capability of the undifferentiated, totipotential neoplastic cell to undergo multiple pathways of terminal differentiation into histologically recognizable mesenchymal and epithelial elements. This theory is supported by the presence of immunoreactivity for epithelial markers (cytokeratin or EMA) in mesenchymal areas as well as the presence of ultrastructural features (desmosomes or tonofilaments) of epithelial differentiation in sarcomatoid elements. Others believe that in cases where different components share no common features on immunohistochemical and electron microscopic examinations, carcinosarcomas might be the result of true "collision" tumors, where both malignant epithelial and mesenchymal components arise independently from each other.[1,16] Unifying terms, such as monophasic sarcomatoid carcinoma and biphasic sarcomatoid carcinoma, have been proposed to differentiate between carcinomas that show areas of sarcomatoid differentiation and true carcinosarcomas with heterologous, nonepithelial mesenchymal components. In the case of the former, the immumoreactivity in the sarcomatoid areas for epithelial markers can almost always be demonstrated. We decided to use the term carcinosarcoma for all 4 of our cases because specimens from all cases contained true malignant heterologous elements that lacked immunoreactivity for epithelial markers. These findings, of course, do not preclude the epithelial derivation of "sarcomatous" elements; however, the term "carcinosarcoma" may be more illustrative of the true morphologic appearance of these neoplasms. Carcinosarcomas of the female genital tract (malignant mixed miullerian tumors) were also studied for monoclonality in both epithelial and stromal components. In the study by Thompson et al, the authors evaluated clonality in both malignant epithelial and mesenchymal elements using the X-chromosome inactivation technique. In all 6 cases studied, the tumor cells from both tumor components showed monoclonality and clonal, identity, thus supporting the monoclonal origin, and not a "collision" origin, of these neoplasms.
In the majority of cases, carsinosarcomas of the urinary bladder do not pose diagnostic difficulties for pathologists. Most of the time, the diagnosis can be established on conventional H&E examination of the tumor sections. The sarcomatous component must be distinguished from primary sarcomas of the urinary bladder. The presence of malignant epithelial elements is usually helpful in these circumstances. Another diagnostic pitfall may be confusion with primary urinary bladder carcinoma showing areas of osseous and cartilaginous metaplasia. The diagnostic clue in these cases may be the presence of overtly atypical cytologic features and mitotic figures in the sarcomatous areas, as opposed to a bland cytologic appearance of the metaplastic areas. Carcinosarcomas of the urinary bladder should also be distinguished from carcinomas with pseudosarcomatous stroma, sarcomas with pseudoepitheliomatous hyperplasia, and teratomas. Pseudosarcomatous stroma, as well as other morphologic forms of pseudosarcomatous proliferations (such as inflammatory pseudotumors and postoperative spindle cell nodules) are usually highly vascularized with numerous small slitlike vessels. The cells show minimal reactive-type atypia and the atypical mitotic figures are absent. Pseudoepitheliomatous hyperplasia associated with sarcomas of the urinary bladder can resemble the architecture of malignant epithelial proliferation on brief low-power examination. However, more detailed examination shows a less intimate association between the 2 components, with a more abrupt interface between true malignant sarcomatous elements and epithelial elements of purely hyperplastic nature. Teratomas can have a somewhat similar morphologic appearance to carcinosarcomas due to the presence of multiple histologic elements. However, by definition, teratomas are tumors derived from all 3 embryologic layers and the presence of abundant histologically benign epidermoid elements with dermal adnexal structures is usually a distinctive feature. This pattern is not typically observed in carcinosarcomas of the urinary bladder
In summary, 4 cases of carcinosarcoma of the urinary bladder have been reported and findings from 78 other cases from the literature have been summarized and reviewed. These unusual tumors present as high-stage malignancies and exhibit aggressive biologic behavior, regardless of the treatment employed. The pathologic stage appears to be the best prognostic factor; however, more cases with longer clinical follow-ups are needed to determine if certain histologic features can predict even more aggressive biologic behavior. Although controversy still exists regarding the exact histogenesis of these neoplasms and their classification remains obscure, practicing pathologists should recognize and diagnose carcinosarcomas of the urinary bladder to assign the correct prognosis and ensure the appropriate treatment for the patient.
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Accepted for publication January 25, 2000.
From the Department of Pathology (Drs Baschinsky, Vadmal, Lucas, and Niemann and Ms Chen) and Division of Urology (Dr Bahnson), The Ohio State University Medical Center and Arthur G. James Cancer Hospital and Research Institute, Columbus, Ohio.
Reprints: Dmitry Y. Baschinsky, MD, Department of Pathology, N-343 Doan Hall, The Ohio State University Medical Center, 410 W 10th Ave, Columbus, OH 43210-1240 (e-mail: baschinsky-1@medctr. osu.edu).