Primary sarcomas of the urinary bladder are uncommon [1
] and most originate from muscle as rhabdomyosarcoma which is dominant in children, whereas leiomyosarcoma is dominant in adults. There are only 30 published cases of primary osteosarcoma of the urinary bladder in the literature [3
] and they show a male to female ratio of 4:1. The age of the patients ranges from 41 to 86 years (mean 64 years) and the most common presentation is hematuria. The tumors are large, polypoid and deeply infiltrative and the most common single location is the trigone where histology shows a high-grade sarcoma with osteoid production. The differential diagnosis includes many possibilities, including: 1) sarcomatoid variant of urothelial carcinoma; 2) urothelial carcinoma with osseous metaplasia and; 3) carcinoma with pseudosarcomatous stromal reaction. Primary sarcomas of the urinary bladder including leiomyosarcoma, chondrosarcoma, rhabdomyosarcoma, angiosarcoma and malignant fibrous histiocytoma as well as osteosarcoma are much more rare than sarcomatoid urothelial carcinoma. The diagnosis of a sarcoma should only be made after excluding all these possibilities. A prior history of urothelial carcinoma may provide sufficient evidence for a mesenchymal-looking malignancy as being in fact a sarcomatous carcinoma even though there may not be an epithelial component at the time. The immunohistochemical profile of a sarcomatoid carcinoma notably includes positivity for epithelial markers, cytokeratins or epithelial membrane antigen at least focally. However, a positive reaction does not necessarily exclude mesenchymal origin as it is well known that some sarcomas such as malignant fibrous histiocytoma and leiomyosarcoma can co-express epithelial antigens. Furthermore, occasional sarcomatoid carcinoma can be completely negative for any epithelial marker applied. Features that are helpful in making a decision towards carcinoma include identification of nested or clustered epitheloid tumor cells, of either conventional or other types of carcinoma, lying adjacent to sarcomatoid cells. The presence of in-situ carcinoma is also another supporting feature for epithelial origins. In our case, the histology of the bladder tumor was identical to osteosarcoma of the bone with characteristic formation of lace-like osteoid in between malignant cells, as well as an abundant chondroid matrix. No past or accompanying urinary epithelial malignancy was identified; immunohistochemistry did not demonstrate epithelial differentiation and all these findings supported a diagnosis of primary vesical osteosarcoma.
Our current presentation is the first case report of osteosarcoma in a patient with SLE. It has been stated that malignant neoplasms occur more commonly in patients with SLE than in the general population [2
]. Cohort studies have yielded varying estimates of the relative cancer risk in SLE, most with fairly wide confidence intervals (CIs). The standardized incidence ratios in these studies ranged from 1.1 (95% CI 0.7–1.6) to 2.6 (95% CI 1.5–4.4) and the risk of non-Hodgkin lymphoma in SLE has been found to be increased 3–4-fold compared with the risk in individuals without SLE [6
]. Several types of sarcomas have been observed in SLE, including leiomyosarcoma, Kaposi sarcoma, angiosarcoma and liposarcoma [6
]. Numerous pathogenic mechanisms have been proposed although hypotheses regarding the specific reasons still remain largely speculative since this issue has not yet been well studied. Patients with SLE have defects in both their cellular and humoral immune systems and prolonged stimulation of B lymphocytes, together with defective immune surveillance, could result in the formation of autonomous B-cell clones and result in lymphoma development. Another possible pathogenic link between SLE and cancer include immunosuppressive treatments.
Our patient had a long history of SLE with her disease being constantly active for 13 years and she was continuously on high dose steroids and cyclophosphamide to achieve immunosuppression. Several groups have described primary leiomyosarcoma in the urinary bladder where patients had been exposed to cyclophosphamide for either neoplastic or non-neoplastic conditions [10
]. Three of those cases were SLE patients, one of which was Epstein-Barr virus associated.
Cyclophosphamide is a commonly used chemotherapeutic and immunosuppressive medication. It is a direct alkylating agent, activated after intake in the liver by cytochrome P-450, and the associated metabolites are excreted in the urine. The bladder cancer risk is increased 6.8-fold in cyclophosphamide-exposed patients, ranging from 6.4 in the absence of cystitis to 11.3 when hemorrhagic cystitis is present [11
]. The carcinogenic action is thought to be secondary to urinary excretion of acrolein, one of the metabolites of cyclophosphamide [10
]. It has been noted that the relative proportion of mesenchymal neoplasms over urothelial malignancies in the urinary bladder is increased with exposure to this drug. Leiomyosarcomas represent 9.2% of bladder tumors in patients exposed to cyclophosphamide compared with 0.1% of sporadic tumors [10
An additional contributing factor for the increased risk of bladder neoplasia in our case could be the frequent urinary tract infections. The patient suffered from recurrent urinary infections due to Gram negative bacteria. Production of carcinogenic nitrites from urinary nitrates by Gram negative bacteria is highly suspected in the etiology of tumor formation.
The prognosis for vesical osteosarcoma is usually dismal with 22 out of 25 patients dying within 6 months, most as a result of local spread with urinary tract obstruction and secondary infections. Distant metastases are uncommon.