Case Report
Intravesical Mitomycin Therapy for Stage T1 and Tis High-Grade Squamous Cell Carcinoma of the Bladder Joan C. Delto, Ravi Kacker, Glenn Bubley, William C. DeWolf Clinical Practice Points Primary squamous cell carcinoma (SCC) invasive into
In this case report, the patient was initially treated
the lamina propria (stage T1) and squamous cell carcinoma in situ (SCCIS) (Stage Tis) are considered high risk and are associated with poor prognoses, even when the disease is nonemuscle invasive. Therefore, radical cystectomy is usually considered the first-line standard of care. However, in patients who are poor surgical candidates, intravesical mitomycin may be a reasonable treatment option.
for nonemuscle-invasive urothelial carcinoma with local resection and intravesical bacillus CalmetteGuérin (BCG) and after 20 years of recurrence-free surveillance, he developed nonemuscle-invasive stage T1, Tis bladder SCC. This case report supports long-term surveillance of bladder cancer.
Clinical Genitourinary Cancer, Vol. 12, No. 1, e35-6 ª 2014 Elsevier Inc. All rights reserved. Keywords: Bladder, CIS, Intravesical chemotherapy, Mitomycin, Squamous cell carcinoma
Introduction Squamous cell carcinoma (SCC) is an uncommon variant of bladder cancer, representing 5% to 10% of nonurothelial bladder cancers.1 SCC often presents at an advanced stage and is associated with poor prognosis.1-3 Moreover, SCCIS and T1 SCC are often associated with concurrent or subsequent muscle-invasive disease.4 Thus, radical cystectomy with lymph-node dissection is the gold standard of treatment.1,5,6 However, for patients with nonemuscleinvasive SCC who are not surgical candidates or for those who desire bladder-sparing treatment, intravesical chemotherapy should be considered. Although intravesical BCG therapy is known to decrease the recurrence and progression of urothelial nonemuscleinvasive disease, including CIS, it has not been shown to be a successful treatment regimen for SCC.7-10 To our knowledge, intravesical mitomycin has not been reported to be a successful treatment for nonemuscle-invasive high-risk SCC of the bladder. In this case report, we describe an 84-year-old man with a previous diagnosis of grade 2-3 urothelial cell carcinoma of the bladder. He was treated successfully with multiple transurethral
resections, in which all visible tumors were resected or fulgurated, followed by intravesical thiotepa, and later, BCG therapy. The patient remained under surveillance for 20 years, until he developed urothelial dysplasia with stage T1, Tis SCC diagnosed by
Figure 1 An Invasive Keratinizing Squamous Cell Carcinoma Prior to Intravesical Mitomycin Treatment. Malignant Squamous Cells Invade the Lamina Propria in Irregular Nests and Cords. Original Magnification 3100
Beth Israel Deaconess Medical Center, Boston, MA Submitted: May 20, 2013; Revised: Aug 2, 2013; Accepted: Aug 27, 2013; Epub: Oct 26, 2013 Address for correspondence: Joan C. Delto, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Rabb 4, Boston, MA, 02215 E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.08.005
Clinical Genitourinary Cancer February 2014
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Intravesical Mitomycin for Non-Muscle Invasive Bladder SCC Figure 2 A Bladder Biopsy Post Intravesical Mitomycin Treatment. The Squamous Epithelium was Partially Detached, With Focal Cytological Atypia. No Carcinoma in Situ was Seen. Original Magnification 3400
a Schistosoma infection, a long-term indwelling catheter, a history of bladder stones, nor chronic exposure to environmental agents. The use of mitomycin in this patient was based on 2 premises. First, although other intravesical chemotherapies and immunotherapies exist, mitomycin is a common agent used as a single postoperative intravesical dose to reduce the risk of recurrence of urothelial cancer compared with recurrence after resection alone.13 Although BCG therapy is thought to produce an increased immune response, perhaps the increased efficacy of mitomycin is due to its acting through a different mechanism of action, direct cytotoxicity. Secondly, mitomycin has been used for the treatment of other squamous cell cancers, including anal and ocular diseases.14,15
Conclusion Intravesical mitomycin for the treatment of stage T1, Tis SCC in this case has resulted in a durable, complete remission. Intravesical mitomycin may be a reasonable treatment option for nonemuscleinvasive bladder stage T1, Tis SCC, but it will need to be confirmed in other studies or case reports.
Disclosure random bladder biopsies (Fig. 1). The patient is a former smoker who has multiple comorbidities, so he was not a candidate for cystectomy. Therefore, intravesical mitomycin was tried as the firstline treatment. The patient received induction intravesical mitomycin followed by maintenance therapy. Induction therapy consisted of 6 weekly cycles of mitomycin given at a dose of 40 mg per 40 mL of water. A restaging biopsy after induction mitomycin therapy demonstrated squamous metaplasia with few areas of dysplasia but no CIS (Fig. 2). He received a second induction treatment 3 months later, again consisting of 6 weekly cycles. Cystoscopy, urine cytology, and nuclear matrix protein 22 (NMP-22) test results were negative. The patient was was placed on maintenance therapy after 3 months. Maintenance therapy was delivered at 3 weekly cycles and given every 6 months. The patient tolerated treatments well and complained only of urinary frequency. He had no other urinary complaints, fevers, chills, or skin rashes. The patient, now 30 months after initial treatment, has no evidence of recurrence on surveillance with biannual cystoscopy, urine cytology, NMP-22 testing, and radiologic imaging.
Discussion Interestingly, SCC of the bladder has been reported in patients who had previously been treated successfully with BCG therapy and transurethral resection of bladder tumor.8,11,12 In this case, the patient had no evidence of disease for approximately 20 years before he was diagnosed with stage T1, Tis SCC of the bladder. It is uncertain whether SCC developed as a result of dysplastic changes after urothelial carcinoma or as a consequence of chronic inflammation. However, the patient did not have any of the following:
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Clinical Genitourinary Cancer February 2014
The authors have stated that they have no conflicts of interest.
References 1. Lagwinski N, Thomas A, Stephenson AJ, et al. Squamous cell carcinoma of the bladder: a clinicopathologic analysis of 45 cases. Am J Surg Pathol 2007; 12: 1777-87. 2. Guo CC, Gomez E, Tamboli P, et al. Squamous cell carcinoma of the urinary bladder: a clinicopathologic and immunohistochemical study of 16 cases. Hum Pathol 2009; 10:1448-52. 3. Balci U, Ozer K, Gorgel SN, et al. Do pure squamous cell carcinomas and urothelial carcinomas have similar prognosis after radical cystectomy? World J Urol 2013; 31:1177-82. 4. Guo CC, Fine SW, Epstein JI. Noninvasive squamous lesions in the urinary bladder: a clinicopathologic analysis of 29 cases. Am J Surg Pathol 2006; 7:883-91. 5. Rausch S, Hofmann R, von Knobloch R. Nonbilharzial squamous cell carcinoma and transitional cell carcinoma with squamous differentiation of the lower and upper urinary tract. Urol Ann 2012; 1:14-8. 6. Ehdale B, Maschino A, Shariat SF, et al. Comparative outcomes of pure squamous cell carcinoma and urothelial carcinoma with squamous differentiation in patients treated with radical cystectomy. J Urol 2012; 1:74-9. 7. Bassi P, Milani C, Meneghini A, et al. Clinical value of pathologic changes after intravesical BCG therapy of superficial bladder cancer. Urology 1992; 2:175-9. 8. Brenner DW, Yore LM, Schellhammer PF. Squamous cell carcinoma of bladder after successful intravesical therapy with bacillus Calmette-Guérin. Urology 1989; 2:93-5. 9. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus CalmetteGuérin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000; 4:1124-9. 10. Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus CalmetteGuérin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol 2005; 174:86-91; discussion 91-2. 11. Yurdakul T, Avunduk MC, Piskin MM. Pure squamous cell carcinoma after intravesical BCG treatment. A case report. Urol Int 2005; 3:283-5. 12. Uemura M, Nishimura K, Nakagawa M. Squamous cell carcinoma of the urinary bladder after intravesical bacillus Calmette-Guérin therapy for carcinoma in situ: a case report. Hinyokika Kiyo 2004; 11:809-11. 13. Islam MA, Bhuiyan ZH, Shameem IA. Intravesical adjuvant therapy using mitomycin C. Mymensingh Med J 2006; 1:40-4. 14. Glynne-Jones R, Renehan A. Current treatment of anal squamous cell carcinoma. Hematol Oncol Clin North Am 2012; 6:1315-50. 15. Birkholz ES, Goins KM, Sutphin JE. Treatment of ocular surface squamous cell intraepithelial neoplasia with and without mitomycin C. Cornea 2011; 1:37-41.
Intravesical Mitomycin Therapy for Stage T1 and Tis High-Grade Squamous Cell Carcinoma of the Bladder Joan C. Delto, Ravi Kacker, Glenn Bubley, William C. DeWolf Clinical Practice Points Primary squamous cell carcinoma (SCC) invasive into
In this case report, the patient was initially treated
the lamina propria (stage T1) and squamous cell carcinoma in situ (SCCIS) (Stage Tis) are considered high risk and are associated with poor prognoses, even when the disease is nonemuscle invasive. Therefore, radical cystectomy is usually considered the first-line standard of care. However, in patients who are poor surgical candidates, intravesical mitomycin may be a reasonable treatment option.
for nonemuscle-invasive urothelial carcinoma with local resection and intravesical bacillus CalmetteGuérin (BCG) and after 20 years of recurrence-free surveillance, he developed nonemuscle-invasive stage T1, Tis bladder SCC. This case report supports long-term surveillance of bladder cancer.
Clinical Genitourinary Cancer, Vol. 12, No. 1, e35-6 ª 2014 Elsevier Inc. All rights reserved. Keywords: Bladder, CIS, Intravesical chemotherapy, Mitomycin, Squamous cell carcinoma
Introduction Squamous cell carcinoma (SCC) is an uncommon variant of bladder cancer, representing 5% to 10% of nonurothelial bladder cancers.1 SCC often presents at an advanced stage and is associated with poor prognosis.1-3 Moreover, SCCIS and T1 SCC are often associated with concurrent or subsequent muscle-invasive disease.4 Thus, radical cystectomy with lymph-node dissection is the gold standard of treatment.1,5,6 However, for patients with nonemuscleinvasive SCC who are not surgical candidates or for those who desire bladder-sparing treatment, intravesical chemotherapy should be considered. Although intravesical BCG therapy is known to decrease the recurrence and progression of urothelial nonemuscleinvasive disease, including CIS, it has not been shown to be a successful treatment regimen for SCC.7-10 To our knowledge, intravesical mitomycin has not been reported to be a successful treatment for nonemuscle-invasive high-risk SCC of the bladder. In this case report, we describe an 84-year-old man with a previous diagnosis of grade 2-3 urothelial cell carcinoma of the bladder. He was treated successfully with multiple transurethral
resections, in which all visible tumors were resected or fulgurated, followed by intravesical thiotepa, and later, BCG therapy. The patient remained under surveillance for 20 years, until he developed urothelial dysplasia with stage T1, Tis SCC diagnosed by
Figure 1 An Invasive Keratinizing Squamous Cell Carcinoma Prior to Intravesical Mitomycin Treatment. Malignant Squamous Cells Invade the Lamina Propria in Irregular Nests and Cords. Original Magnification 3100
Beth Israel Deaconess Medical Center, Boston, MA Submitted: May 20, 2013; Revised: Aug 2, 2013; Accepted: Aug 27, 2013; Epub: Oct 26, 2013 Address for correspondence: Joan C. Delto, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Rabb 4, Boston, MA, 02215 E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.08.005
Clinical Genitourinary Cancer February 2014
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Intravesical Mitomycin for Non-Muscle Invasive Bladder SCC Figure 2 A Bladder Biopsy Post Intravesical Mitomycin Treatment. The Squamous Epithelium was Partially Detached, With Focal Cytological Atypia. No Carcinoma in Situ was Seen. Original Magnification 3400
a Schistosoma infection, a long-term indwelling catheter, a history of bladder stones, nor chronic exposure to environmental agents. The use of mitomycin in this patient was based on 2 premises. First, although other intravesical chemotherapies and immunotherapies exist, mitomycin is a common agent used as a single postoperative intravesical dose to reduce the risk of recurrence of urothelial cancer compared with recurrence after resection alone.13 Although BCG therapy is thought to produce an increased immune response, perhaps the increased efficacy of mitomycin is due to its acting through a different mechanism of action, direct cytotoxicity. Secondly, mitomycin has been used for the treatment of other squamous cell cancers, including anal and ocular diseases.14,15
Conclusion Intravesical mitomycin for the treatment of stage T1, Tis SCC in this case has resulted in a durable, complete remission. Intravesical mitomycin may be a reasonable treatment option for nonemuscleinvasive bladder stage T1, Tis SCC, but it will need to be confirmed in other studies or case reports.
Disclosure random bladder biopsies (Fig. 1). The patient is a former smoker who has multiple comorbidities, so he was not a candidate for cystectomy. Therefore, intravesical mitomycin was tried as the firstline treatment. The patient received induction intravesical mitomycin followed by maintenance therapy. Induction therapy consisted of 6 weekly cycles of mitomycin given at a dose of 40 mg per 40 mL of water. A restaging biopsy after induction mitomycin therapy demonstrated squamous metaplasia with few areas of dysplasia but no CIS (Fig. 2). He received a second induction treatment 3 months later, again consisting of 6 weekly cycles. Cystoscopy, urine cytology, and nuclear matrix protein 22 (NMP-22) test results were negative. The patient was was placed on maintenance therapy after 3 months. Maintenance therapy was delivered at 3 weekly cycles and given every 6 months. The patient tolerated treatments well and complained only of urinary frequency. He had no other urinary complaints, fevers, chills, or skin rashes. The patient, now 30 months after initial treatment, has no evidence of recurrence on surveillance with biannual cystoscopy, urine cytology, NMP-22 testing, and radiologic imaging.
Discussion Interestingly, SCC of the bladder has been reported in patients who had previously been treated successfully with BCG therapy and transurethral resection of bladder tumor.8,11,12 In this case, the patient had no evidence of disease for approximately 20 years before he was diagnosed with stage T1, Tis SCC of the bladder. It is uncertain whether SCC developed as a result of dysplastic changes after urothelial carcinoma or as a consequence of chronic inflammation. However, the patient did not have any of the following:
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Clinical Genitourinary Cancer February 2014
The authors have stated that they have no conflicts of interest.
References 1. Lagwinski N, Thomas A, Stephenson AJ, et al. Squamous cell carcinoma of the bladder: a clinicopathologic analysis of 45 cases. Am J Surg Pathol 2007; 12: 1777-87. 2. Guo CC, Gomez E, Tamboli P, et al. Squamous cell carcinoma of the urinary bladder: a clinicopathologic and immunohistochemical study of 16 cases. Hum Pathol 2009; 10:1448-52. 3. Balci U, Ozer K, Gorgel SN, et al. Do pure squamous cell carcinomas and urothelial carcinomas have similar prognosis after radical cystectomy? World J Urol 2013; 31:1177-82. 4. Guo CC, Fine SW, Epstein JI. Noninvasive squamous lesions in the urinary bladder: a clinicopathologic analysis of 29 cases. Am J Surg Pathol 2006; 7:883-91. 5. Rausch S, Hofmann R, von Knobloch R. Nonbilharzial squamous cell carcinoma and transitional cell carcinoma with squamous differentiation of the lower and upper urinary tract. Urol Ann 2012; 1:14-8. 6. Ehdale B, Maschino A, Shariat SF, et al. Comparative outcomes of pure squamous cell carcinoma and urothelial carcinoma with squamous differentiation in patients treated with radical cystectomy. J Urol 2012; 1:74-9. 7. Bassi P, Milani C, Meneghini A, et al. Clinical value of pathologic changes after intravesical BCG therapy of superficial bladder cancer. Urology 1992; 2:175-9. 8. Brenner DW, Yore LM, Schellhammer PF. Squamous cell carcinoma of bladder after successful intravesical therapy with bacillus Calmette-Guérin. Urology 1989; 2:93-5. 9. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus CalmetteGuérin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000; 4:1124-9. 10. Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus CalmetteGuérin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol 2005; 174:86-91; discussion 91-2. 11. Yurdakul T, Avunduk MC, Piskin MM. Pure squamous cell carcinoma after intravesical BCG treatment. A case report. Urol Int 2005; 3:283-5. 12. Uemura M, Nishimura K, Nakagawa M. Squamous cell carcinoma of the urinary bladder after intravesical bacillus Calmette-Guérin therapy for carcinoma in situ: a case report. Hinyokika Kiyo 2004; 11:809-11. 13. Islam MA, Bhuiyan ZH, Shameem IA. Intravesical adjuvant therapy using mitomycin C. Mymensingh Med J 2006; 1:40-4. 14. Glynne-Jones R, Renehan A. Current treatment of anal squamous cell carcinoma. Hematol Oncol Clin North Am 2012; 6:1315-50. 15. Birkholz ES, Goins KM, Sutphin JE. Treatment of ocular surface squamous cell intraepithelial neoplasia with and without mitomycin C. Cornea 2011; 1:37-41.
