- Email: [email protected]
Histopathologic changes of transitional cell carcinoma of bladder after M-VAC chemotherapy
HISTOPATHOLOGIC CHANGES OF TRANSITIONAL, CELL CARCINOMA OF BLADDER AFTER M-VAC CHEMOTHERAPY NASSER JAVADPOUR, M.D. P E T E R DALONI, M.D. From the Division of Urology, University of Maryland, School of Medicine, Baltimore, Maryland
ABSTRACT--Over the past several years, we have utilized methotrexate, vinblastine, doxorubicin, and cisTglatin (M-VA C ) as definitive, neoadjuvant, and adjuvant therapy for various stage,s of transitional cell carcinoma with reduced toxicities. Currently, there is little information concerning the histopathologic changes after M-VAC therapy. We report on the histopathologic changes of bladder transitional cell carcinoma following M-VAC chemotherapy in our protocol for treatment of bladder cancer. The main histopathologic findings after M-VAC therapy are squamous rnetaplasia, necrosis, fibrosis, and persistent transitional cell carcinoma. In 2 cases, there were persistent adenocarcinoma and squamous cell carcinoma. The importance of these observations in terms of diagnostic and therapeutic implications is reviewed.
In 1985, Sternberg and co-workers ~ published the results of a clinical trial involving the use of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) therapy for metastatic bladder carcinoma. Since this initial study, multiple reports have been published utilizing this protocol. 20 Over the past several years, we have utilized tMs regimen as neoadjuvant and adjuvant therapy of bladder cancer. This report focuses on the morphologic changes that occur following M-VAC therapy. The histopathologic changes before and after M-VAC chemotherapy are reported in 7 consecutive patients. TABLE I. Pt.
KEY:
Gr. Gr. Gr. Gr. Gr. Gr. Gr. Adenoca
I.:R()IX~(;Y
Patients are from a prospective protocol of M-VAC therapy for bladder cancer. The patients were males with age ranging :from forty to seventy-three years (mean, 57). Initial histopathologic findings on 7 patient,; were reviewed a n d c o m p a r e d w i t h those h i s t o p a t h o l o g i e changes after treatment. The specimens were obtained by transurethral resection, partial and/or radical eysteetomy. Pathologic grades and clinical stages were determined in all patients prior to and after M-VAC chemotherapy.
Clinicaland pathologic features in 7 patients before and after M-VAC treatment
Histopath. Pre-M-VAC
AJ BA BF SC PF VJ RG
Material and Methods
III TCC III TCC III TCC with adenoea III TCC III TCC III TCC III, TCC
Tumor Stage
M-VAC Courses
Histopath. Post-M-VAC
D D B2 C2 D B2 D
2 4 4 4 4 2 4
Fibrosis, TCC No tumor Residual adenoca Fibrosis, sq. metaplasia No tumor Fibrosis, sq. ca. Necrosis + tumor fibrosis
= a d e n o c a r e i n o m a : sq. = s q u a m o u s ; sq. ca = s q u a m o u s c a r c i n o m a .
DECEMBEFi
1989
V O I . U M E XXXIV, N U M B E R 6
357
FictraE 1. Histopathologic sections prior to chemotherapy. (A) Grade III transitional cell carcinoma with lymphatic penetration (arrows), and (B) note fibrosis (arrows) and residual islands of tumor.
FIGURE 2. Grade III transitional cell carcinoma (A) prior to, and (B) after M-VAC chemotherapy; note complete necrosis (arrows).
Each patient received 2-4 courses of M-VAC therapy. The doses used in each course were as follows: methotrexate 30 m g / m ~ on day 1. Twenty-four hours later, vinblastine (3 mg/m2), doxorubicin (70 m g / m ~, and cisplatin 70 mg/ m 2 were administered. Repeat treatment with vinblastine and methotrexate were given on days 15 and 22 of the cycle. Specimens were processed with hematoxylin and eosin staining. These specimens were examined without the observer knowing whether they were obtained before or after treatment with M-VAC.
two to four courses of M-VAC treatment for each patient. After treatment, more tissue was obtained for analysis. Several p r e d o m i n a n t patterns were noted in reviewing the specimens (Figs. 1-3). The major findings were persistent T C C in 5 of 7 (71%) patients. Fibrosis with associated tumor necrosis was present in 3 of 7 (43 %). The third pattern observed was a change from T C C to one consistent with squamous metaplasia or squamous carcinoma in 2 of 7 (28 %) patients. The final pattern was the presence of adenocarcinoma in 1 of 7 (14 %) patients.
Results
Comment
The results of the 7 cases are shown in Table I. All of these patients had grade III transitional cell carcinoma (TCC) of the bladder prior to treatment with M-VAC. Clinical stages were determined prior to chemotherapy and ranged from B2 to D. The chemotherapy consisted of
Some success with M-VAC regimen as a treatm e n t for metastatic or unresectable bladder cancer was initially presented in 1985. ~ The focus of that and subsequent reports has been on clinical outcome. 2 9 While these reports are encouraging, further long-term follow-up and
358
UROLOGY
/
D E C E M B E R 1989
/
V O L U M E XXXIV, N U M B E R 6
FmURF. 3. (A) Grade III transitional cell carcinoma before chemotherapy, and (B) after chemotherapy; note fibrosis with residual squamous cell carcinoma (arrows). l
RANSITIONAL EPITHELIUM
I
NON NEOPLASTIC PROLIFERATION
METAPLASIA
NEOPLASM
f (IUBOIDAL
I OL;O,o \ CYSTITIS CYSTICA
/
/~OPLAI~IA
TRANSITIONAL CELL CA
COLUMNAR
SOUAMOUS CELL CA BRUNN's NESTS
(~t
I
CYSTITIS ANDULARIS
liferation, metaplasia, or neoplastic change (Fig. 4). It is likely that chemotherapeutic agents may facilitate the differentiation of neoplastic into the non-neoplastic components of squamous metaplasia. The other possibility is that only TCC disappears with therapy. However, squamous cell carcinoma or adenocarcinoma component that are resistant to M-VAC chemotherapy remains as the residual tumor. When completely resected, residual tumor may predict the prognosis and spare the bladder. This requires a prospective long-term follow-up study of a large number of patients, which is feasible by cooperative studies.
GLANDULAR STRUCTURES
Baltimore. Maryland 21201 (DR. JAVADPOUR)
ADENOCARCINOMA
FicuR~ 4. lium.
Schema oJ totipotentiality of urothe-
controlled clinical trials are necessary for evaluation of tumor-free survival. There has been little comparative analysis available concerning the histopathologic tumor changes seen after MVAC therapy. The purpose of this report is to provide our comparative analysis of the histopathologic changes occurring after M-VAC therapy. The initial histopathologie pattern in these 7 eases was TCC. The histopathologic changes after M-VAC c h e m o t h e r a p y in these eases are divided into several categories: (1) minimal response to treatment with persistent TCC fibrosis, and (2) squamous metaplasia or differentiation into e i t h e r s q u a m o u s c a r c i n o m a or adenocarcinoma. We have suggested that transitional cell has totipotential ability.l° It may be capable of conversion into non-neoplastic pro-
UROLOGY
,
DECEMBER 1989
/
References 1. Sternberg CN, et al: Preliminary results of M-VAC (methotrexate, vinblastine, doxorubiein and cisplatin) for transitional cell carcinoma of the urothelium, J Urol 133:403 (1985). 2. Schwartz S, et al: Phase II trial of sequentially administered cisplatin, eyclophosphamide and doxorubiein for urothelial tract tumors, J Urol 130:681 (1983). 3. Yagoda A: Chemotherapy for advanced urothelial cancer, Sere Urol 1:60 (1983). 4. Sternberg CN, and Seher HI: Advances in the treatment of urothelial tract tumors, Urol Clin North Am 14:373 (1987). 5. Scher HI, et al: Neoadjuvant M-VAC transitional cell carcinoma of the urothelium, Proe Am Soc Clin North Am 5:108 (1986). 6. Sternberg CN, et al: M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for advanced transitional cell carcinoma of the urothelium, J Urol 139:461 (1988). 7. Yagoda A: Progress in the treatment of advanced urothelial tract tumors, J Clin Oncol 3:1448 (1985). 8. Scher HI, e t al: Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) effect on the primary bladder lesion, J Urol 139:470 (1988). 9. Scher HI, et al: Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for extravesieal urinary tract tumors, J Urol 139:475 (1988). 10. Javadpour N, Hakim AA, and Bush IM: Leukoplakia of the bladder in females, Obstet Gyneeol 35:600 (1970).
VOLUME XXXIV, NUMBER 6
359
ABSTRACT--Over the past several years, we have utilized methotrexate, vinblastine, doxorubicin, and cisTglatin (M-VA C ) as definitive, neoadjuvant, and adjuvant therapy for various stage,s of transitional cell carcinoma with reduced toxicities. Currently, there is little information concerning the histopathologic changes after M-VAC therapy. We report on the histopathologic changes of bladder transitional cell carcinoma following M-VAC chemotherapy in our protocol for treatment of bladder cancer. The main histopathologic findings after M-VAC therapy are squamous rnetaplasia, necrosis, fibrosis, and persistent transitional cell carcinoma. In 2 cases, there were persistent adenocarcinoma and squamous cell carcinoma. The importance of these observations in terms of diagnostic and therapeutic implications is reviewed.
In 1985, Sternberg and co-workers ~ published the results of a clinical trial involving the use of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) therapy for metastatic bladder carcinoma. Since this initial study, multiple reports have been published utilizing this protocol. 20 Over the past several years, we have utilized tMs regimen as neoadjuvant and adjuvant therapy of bladder cancer. This report focuses on the morphologic changes that occur following M-VAC therapy. The histopathologic changes before and after M-VAC chemotherapy are reported in 7 consecutive patients. TABLE I. Pt.
KEY:
Gr. Gr. Gr. Gr. Gr. Gr. Gr. Adenoca
I.:R()IX~(;Y
Patients are from a prospective protocol of M-VAC therapy for bladder cancer. The patients were males with age ranging :from forty to seventy-three years (mean, 57). Initial histopathologic findings on 7 patient,; were reviewed a n d c o m p a r e d w i t h those h i s t o p a t h o l o g i e changes after treatment. The specimens were obtained by transurethral resection, partial and/or radical eysteetomy. Pathologic grades and clinical stages were determined in all patients prior to and after M-VAC chemotherapy.
Clinicaland pathologic features in 7 patients before and after M-VAC treatment
Histopath. Pre-M-VAC
AJ BA BF SC PF VJ RG
Material and Methods
III TCC III TCC III TCC with adenoea III TCC III TCC III TCC III, TCC
Tumor Stage
M-VAC Courses
Histopath. Post-M-VAC
D D B2 C2 D B2 D
2 4 4 4 4 2 4
Fibrosis, TCC No tumor Residual adenoca Fibrosis, sq. metaplasia No tumor Fibrosis, sq. ca. Necrosis + tumor fibrosis
= a d e n o c a r e i n o m a : sq. = s q u a m o u s ; sq. ca = s q u a m o u s c a r c i n o m a .
DECEMBEFi
1989
V O I . U M E XXXIV, N U M B E R 6
357
FictraE 1. Histopathologic sections prior to chemotherapy. (A) Grade III transitional cell carcinoma with lymphatic penetration (arrows), and (B) note fibrosis (arrows) and residual islands of tumor.
FIGURE 2. Grade III transitional cell carcinoma (A) prior to, and (B) after M-VAC chemotherapy; note complete necrosis (arrows).
Each patient received 2-4 courses of M-VAC therapy. The doses used in each course were as follows: methotrexate 30 m g / m ~ on day 1. Twenty-four hours later, vinblastine (3 mg/m2), doxorubicin (70 m g / m ~, and cisplatin 70 mg/ m 2 were administered. Repeat treatment with vinblastine and methotrexate were given on days 15 and 22 of the cycle. Specimens were processed with hematoxylin and eosin staining. These specimens were examined without the observer knowing whether they were obtained before or after treatment with M-VAC.
two to four courses of M-VAC treatment for each patient. After treatment, more tissue was obtained for analysis. Several p r e d o m i n a n t patterns were noted in reviewing the specimens (Figs. 1-3). The major findings were persistent T C C in 5 of 7 (71%) patients. Fibrosis with associated tumor necrosis was present in 3 of 7 (43 %). The third pattern observed was a change from T C C to one consistent with squamous metaplasia or squamous carcinoma in 2 of 7 (28 %) patients. The final pattern was the presence of adenocarcinoma in 1 of 7 (14 %) patients.
Results
Comment
The results of the 7 cases are shown in Table I. All of these patients had grade III transitional cell carcinoma (TCC) of the bladder prior to treatment with M-VAC. Clinical stages were determined prior to chemotherapy and ranged from B2 to D. The chemotherapy consisted of
Some success with M-VAC regimen as a treatm e n t for metastatic or unresectable bladder cancer was initially presented in 1985. ~ The focus of that and subsequent reports has been on clinical outcome. 2 9 While these reports are encouraging, further long-term follow-up and
358
UROLOGY
/
D E C E M B E R 1989
/
V O L U M E XXXIV, N U M B E R 6
FmURF. 3. (A) Grade III transitional cell carcinoma before chemotherapy, and (B) after chemotherapy; note fibrosis with residual squamous cell carcinoma (arrows). l
RANSITIONAL EPITHELIUM
I
NON NEOPLASTIC PROLIFERATION
METAPLASIA
NEOPLASM
f (IUBOIDAL
I OL;O,o \ CYSTITIS CYSTICA
/
/~OPLAI~IA
TRANSITIONAL CELL CA
COLUMNAR
SOUAMOUS CELL CA BRUNN's NESTS
(~t
I
CYSTITIS ANDULARIS
liferation, metaplasia, or neoplastic change (Fig. 4). It is likely that chemotherapeutic agents may facilitate the differentiation of neoplastic into the non-neoplastic components of squamous metaplasia. The other possibility is that only TCC disappears with therapy. However, squamous cell carcinoma or adenocarcinoma component that are resistant to M-VAC chemotherapy remains as the residual tumor. When completely resected, residual tumor may predict the prognosis and spare the bladder. This requires a prospective long-term follow-up study of a large number of patients, which is feasible by cooperative studies.
GLANDULAR STRUCTURES
Baltimore. Maryland 21201 (DR. JAVADPOUR)
ADENOCARCINOMA
FicuR~ 4. lium.
Schema oJ totipotentiality of urothe-
controlled clinical trials are necessary for evaluation of tumor-free survival. There has been little comparative analysis available concerning the histopathologic tumor changes seen after MVAC therapy. The purpose of this report is to provide our comparative analysis of the histopathologic changes occurring after M-VAC therapy. The initial histopathologie pattern in these 7 eases was TCC. The histopathologic changes after M-VAC c h e m o t h e r a p y in these eases are divided into several categories: (1) minimal response to treatment with persistent TCC fibrosis, and (2) squamous metaplasia or differentiation into e i t h e r s q u a m o u s c a r c i n o m a or adenocarcinoma. We have suggested that transitional cell has totipotential ability.l° It may be capable of conversion into non-neoplastic pro-
UROLOGY
,
DECEMBER 1989
/
References 1. Sternberg CN, et al: Preliminary results of M-VAC (methotrexate, vinblastine, doxorubiein and cisplatin) for transitional cell carcinoma of the urothelium, J Urol 133:403 (1985). 2. Schwartz S, et al: Phase II trial of sequentially administered cisplatin, eyclophosphamide and doxorubiein for urothelial tract tumors, J Urol 130:681 (1983). 3. Yagoda A: Chemotherapy for advanced urothelial cancer, Sere Urol 1:60 (1983). 4. Sternberg CN, and Seher HI: Advances in the treatment of urothelial tract tumors, Urol Clin North Am 14:373 (1987). 5. Scher HI, et al: Neoadjuvant M-VAC transitional cell carcinoma of the urothelium, Proe Am Soc Clin North Am 5:108 (1986). 6. Sternberg CN, et al: M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for advanced transitional cell carcinoma of the urothelium, J Urol 139:461 (1988). 7. Yagoda A: Progress in the treatment of advanced urothelial tract tumors, J Clin Oncol 3:1448 (1985). 8. Scher HI, e t al: Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) effect on the primary bladder lesion, J Urol 139:470 (1988). 9. Scher HI, et al: Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for extravesieal urinary tract tumors, J Urol 139:475 (1988). 10. Javadpour N, Hakim AA, and Bush IM: Leukoplakia of the bladder in females, Obstet Gyneeol 35:600 (1970).
VOLUME XXXIV, NUMBER 6
359