Vol. 116, December Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1976 by The Williams & Wilkins Co.
PRIMARY TRANSITIONAL CELL CARCINOMA OF THE PROSTATE LAURENCE F. GREENE,* MICHAEL J. O'DEA
AND
MALCOLM B. DOCKERTY
From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota
ABSTRACT
The symptoms and physical findings in patients with transitional cell carcinoma of the prostate were similar to those in patients with prostatic adenocarcinoma. Usually the neoplasm was poorly differentiated and advanced when the diagnosis was first established. Osseous metastases were commonly osteolytic. Frequently, elevations of serum alkaline or acid phosphatase levels were associated with metastasis. Tartrate-inhibited fractions of the serum acid phosphatase were not elevated. The best form of treatment is radical ablation of the prostate and radiation therapy is next best. Because these neoplasms are not hormonally dependent, hormonal manipulation is not indicated. Prognosis for patients with this malignancy is guarded. Carcinomas of the prostate arise from the columnar epithelial cells lining the prostatic acini or from the epithelial cells lining the primary and secondary ducts of the prostate. Those originating in the peripheral tubuloalveolar acini account for approximately 98 per cent of prostatic carcinomas, and their clinical manifestations, management and response to therapy have been discussed widely. Carcinomas arising from prostatic ducts are uncommon and may appear as adenocarcinomas of ductal origin or as primary transitional cell carcinomas. Dube and associates have presented a report of 55 cases of prostatic adenocarcinoma of ductal origin. 1 Reportedly, primary transitional cell carcinomas of the prostate arise in the transitional epithelium in the distal portion of the prostatic duct and account for 1 per cent of prostatic carcinomas. 2 Published reports of this disease have been concerned chiefly with the pathology. Recently, Rhamy and associates noted that 55 cases of transitional cell carcinoma had been reported and added 20 cases of their own.• Nevertheless, when confronted by this disease the urologist is uncertain of its clinical course, its optimal treatment (surgical extirpation, hormonal manipulation, chemotherapy or radiation therapy) and its prognosis. Consequently, a report of our experience in treating 39 patients with this disease seemed advisable. The findings in 26 of these patients have been described previously. 4 We hope that analysis of this larger series of cases will help determine the effectiveness of the various forms of treatment. Patients with a history of a vesical neoplasm or with a coexisting vesical neoplasm were excluded from this study. CLINICAL FINDINGS
The patients ranged in age from 45 to 91 years, with a mean of 67. Urinary obstructive symptoms predominated in 24 patients and 10 complained chiefly of hematuria. Seven patients had irritative symptoms, such as frequency, dysuria and urgency, and 7 patients complained of pain, which was caused by metastasis in 5. Hematospermia was not observed. Values for serum creatinine or urea were normal in 31 patients and slightly elevated in the remaining 8. The serum alkaline phosphatase level was elevated in 8 of the 36 patients in whom it was determined. Of these 8 patients 3 had x-ray evidence of osteolytic metastasis, 1 of osteoblastic metastasis and 1 of nodular pulmonary metastasis. The serum acid Accepted for publication May 21, 1976. Read at annual meeting of Western Section, American Urological Association, Coronado, California, February 22-26, 1976. * Requests for reprints: Mayo Clinic, Rochester, Minnesota 55901.
phosphatase level was elevated in 4 of the 32 patients in whom it was determined, 1 of whom had osteolytic metastasis in the femur and pulmonary metastasis, 1 had osteolytic metastasis in the bony pelvis and 1 had osteoblastic metastasis in the pelvis and shoulder. Three of these 4 patients with elevated acid phosphatase levels had prostatic adenocarcinoma as well as transitional cell carcinoma. The tartrate-inhibited fraction of the serum acid phosphatase was normal in the 28 patients in whom it was measured. The upper part of the urinary tract was studied by excretory urography in 33 cases. The study was normal in 27 cases, hydronephrosis was noted in 4 and the study was indeterminate in 2. Cystoscopically, transitional cell carcinoma of the prostate did not appear distinctive. Rigidity and fixation, commonly associated with adenocarcinoma of the prostate, were noted, while ulceration and superficial necrosis were seen less frequently. Often the lesion was described as shaggy. The lesion was stage A in 6 cases, Bin 6, C in 19 and Din 7, • and staging was not available in 1 case. PATHOLOGIC FINDINGS
The pathologic findings have been well described. 4 Except for an observed lack of the yellowish fragments that characterize adenocarcinomas of the prostate, no reliable gross features were specific for primary prostatic transitional cell carcinoma. Highlighting the microscopic picture of transitional cell carcinoma of the prostate were prominent plugs composed of large hyperchromatic epithelial cells, with no evidence of glandular differentiation (part A of figure). Cellular anaplasia was so striking that the central portions of the plugs were often necrotic as a consequence of the tumor outstripping its blood supply and these necrotic zones frequently exhibited dystrophic calcification. Cell spindling was often a prominent feature (part B of figure). In some sections the tumor appeared to be confined to distended prostatic ducts but further search almost always disclosed invasion of the surrounding stroma, including lymphatics and even blood vascular spaces. However, perineural involvement was not observed. Unlike its bladder counterpart, transitional cell carcinoma of the prostate failed to exhibit a papillary type of architecture. Neoplasms were grade 3 (Broders' method) in 27 patients, grade 4 in 7 and grade 2 in 4. In 12 patients an independent prostatic adenocarcinoma and the primary transitional cell carcinoma coexisted, with the adeno component always dominating the picture. Significant degrees of subacute and chronic prostatitis were found in more than half of the patients, possibly reflecting the degree of obstruction of pros tatic ducts.
761
762
GREENE, o'DEA AND DOCKERTY
survival of 9 patients treated by radiation alone was 26 months (table 3). These data may be compared to an average survival of 11 months after hormonal manipulation (table 4) and 4 months for patients who received no treatment (table 5). DISCUSSION
The characteristics of primary transitional cell carcinoma of the prostate in this larger study group were consistent with those described in our previous report. 4 The symptoms and findings of this disease are indistinguishable from those of adenocarcinoma of the prostate. On digital rectal examination the prostate was usually hard and fixed, although in 6 patients it was considered to be benign or equivocal. Elevation of the serum alkaline phosphatase level, noted in 8 patients, was usually indicative of metastatic lesions to the ribs, femur, pelvis or lungs. In all but 1 patient bony metastases were osteolytic. The serum acid phosphatase level was elevated in 4 patients, each of whom also had adenocarcinoma of the prostate, and 3 of these patients had distant metastasis. The 2. Radical prostatic ablation-4 patients
TABLE
Stage
Grade
A
:l 3 3 3
A
A C
* Average A, transitional cell carcinoma, grade 3. H & E, reduced from x75. B, hyperchromatism of nuclei, with many cells of spindle type. H & E, reduced from x 225. Reprinted with permission. 4 TABLE 1.
Treatment
Prostatocystectomy, estrogen
40 months.
3. Radiation therapy-9 patients Survival* (mos.)
Present Status
A
2 3
13 11 22 38 60 26 6
Dead Dead Dead Dead Dead Dead Dead Poor Dead
B B B
4 4
C
2
Well Dead Well Dead
Grade
2 3
C C
9 5 3 3
2 2
42 48 60 8
Stage
;,lo. Pts.
Estrogen Estrogen, radiation 5-Fluorouracil Radical prostatectomy Orchiectomy, estrogen, radiation Orchiectomy Radiation, 5-fluorouracil Radiation. 5-fluorouracil, estrogen Estrogen, orchiectomy Estrogen, prostatocystectomy Prostatocystectomy Estrogen, orchiectomy, radiation, 5-fluorouracil Progesterone, radiation None
Present Status
Prostatocystectorny Radical prostatectomy Radical prostatectomy
TABLE
Treatment used in primary transitional cell carcinoma of the prostate
Radiation
Survival* (mos.)
C
3 3t
38
:J
16
* Average 26 months.
t Adenocarcinorna
in addition.
2 1 TABLE 4.
Grade
Treatment
A
2
B C C
3t
Estrogen Estrogen Estrogen Estrogen Orchiectomy Estrogen Orchiectomy Estrogen, orchiectorny
Stage 5
TREATMENT
The therapeutic regimens used are summarized in table 1. The radiation dosage ranged from 6,000 to 7,700 rads. Daily doses of 1 or 5 mg. diethylstilbestrol were prescribed. The dosage of 5-fluorouracil was approximately 12 mg. per kg. body weight daily for 5 days.
3
3t
C
3
D D D
3t 3t
:it
Survival* (mos.)
Present Status
18 12
Dead Dead Well Dead Poor Dead Dead Dead
7 2 18 4
24
* Average 11 months. t Adenocarcinoma in addition.
RESULTS
The prognosis of patients with primary transitional cell carcinoma is poor. When this study was completed 34 patients had died, the majority of prostatic carcinoma. Survival after diagnosis ranged from 1 month to 5 years, with an average of 17 months. Five patients are alive 7 months to 5 years after diagnosis (average 33 months) and 3 of these patients are well but the condition of the other 2 is deteriorating. Four patients who had radical ablation of the prostate survived an average of 40 months (table 2). The average
Hormonal manipulation-8 patients
TABLE
5. No treatment-5 patients
Stage
Grade
A C
3
C C D
:l 3
3t 3t
* Average 4 months.
t Adenocarcinoma in addition.
Survival* (mos.)
Present Status
6 2
Dead Dead Dead Dead Dead
4 5 4
',,;;r,
_[_]t ,_,
763
TRANSITIONAL CELL CARCINOMA TABLE
6. Patients who survived longer than 3 years after diagnosis-7 patients
Stage
Grade
Treatment
Survival* (mos.)
Present Status
A A A B C C C
3 3 3 4 2 3 3
Prostatocystectomy Radical prostatectomy Radical prostatectomy Radiation Radiation Radiation Radiation, estrogen
42 48 60 38 60 38 60
Well Dead Well Dead Dead Poor Dead
* Average 49 months.
tartrate-inhibited fraction of the serum acid phosphatase was not elevated in the 28 patients in whom it was determined. Microscopically, the majority of carcinomas were anaplastic and poorly differentiated. Adenocarcinoma, usually anaplastic, was noted in addition to transitional cell carcinoma in 12 of the 39 patients studied. Because of the few cases, the wide variety of therapeutic modalities and the inability to compare adequate numbers of similar cases, evaluation of the effectiveness of the various forms of treatment is difficult. Acknowledging the limitations, we attempted such an evaluation. The best results were obtained by radical surgical ablation of the prostate. With 1 exception the disease was least advanced in this group. (The value of early diagnosis is apparent.) The group with the next
best survival rates was treated by radiation. The disease was more advanced in this group than in the preceding one. We examined the composition of the group of patients who had survived longer than 3 years after diagnosis (table 6). Three patients with stage A lesions had had radical prostatic ablation. The remaining 4 patients, who had stage B and C lesions, were treated by radiation. Therefore, the data suggest that radical ablation of the prostate, if feasible, is the best form of treatment for primary transitional cell carcinoma of the prostate and that radiation therapy is next best. Furthermore, the data refute the theory that hormonal manipulation has a salutary effect on these neoplasms. REFERENCES
1. Dube, V. E., Farrow, G. M. and Greene, L. F.: Prostatic adenocar-
cinoma of ductal origin. Cancer, 32: 402, 1973. 2. Ende, N., Woods, L. P. and Shelley, H. S.: Carcinoma originating in ducts surrounding the prostatic urethra. Amer. J. Clin. Path., 40: 183, 1963. 3. Rhamy, R. K., Buchanan, R. D. and Spalding, M. J.: Intraductal carcinoma of the prostate gland. J. Urol., 109: 457, 1973. 4. Greene, L. F., Mulcahy, J. J., Warren, M. M. and Dockerty, M. B.: Primary transitional cell carcinoma of the prostate. J. Ural., 110: 235, 1973. 5. Del Regato, J. A.: Radiotherapy for carcinoma of the prostate. Committee for the Cooperative Study of Radiotherapy for Carcinoma of the Prostate, Colorado Springs, Colorado, Penrose Cancer Hospital, p. 10, 1968.
THE JOURNAL OF UROLOGY
Copyright © 1976 by The Williams & Wilkins Co.
PRIMARY TRANSITIONAL CELL CARCINOMA OF THE PROSTATE LAURENCE F. GREENE,* MICHAEL J. O'DEA
AND
MALCOLM B. DOCKERTY
From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota
ABSTRACT
The symptoms and physical findings in patients with transitional cell carcinoma of the prostate were similar to those in patients with prostatic adenocarcinoma. Usually the neoplasm was poorly differentiated and advanced when the diagnosis was first established. Osseous metastases were commonly osteolytic. Frequently, elevations of serum alkaline or acid phosphatase levels were associated with metastasis. Tartrate-inhibited fractions of the serum acid phosphatase were not elevated. The best form of treatment is radical ablation of the prostate and radiation therapy is next best. Because these neoplasms are not hormonally dependent, hormonal manipulation is not indicated. Prognosis for patients with this malignancy is guarded. Carcinomas of the prostate arise from the columnar epithelial cells lining the prostatic acini or from the epithelial cells lining the primary and secondary ducts of the prostate. Those originating in the peripheral tubuloalveolar acini account for approximately 98 per cent of prostatic carcinomas, and their clinical manifestations, management and response to therapy have been discussed widely. Carcinomas arising from prostatic ducts are uncommon and may appear as adenocarcinomas of ductal origin or as primary transitional cell carcinomas. Dube and associates have presented a report of 55 cases of prostatic adenocarcinoma of ductal origin. 1 Reportedly, primary transitional cell carcinomas of the prostate arise in the transitional epithelium in the distal portion of the prostatic duct and account for 1 per cent of prostatic carcinomas. 2 Published reports of this disease have been concerned chiefly with the pathology. Recently, Rhamy and associates noted that 55 cases of transitional cell carcinoma had been reported and added 20 cases of their own.• Nevertheless, when confronted by this disease the urologist is uncertain of its clinical course, its optimal treatment (surgical extirpation, hormonal manipulation, chemotherapy or radiation therapy) and its prognosis. Consequently, a report of our experience in treating 39 patients with this disease seemed advisable. The findings in 26 of these patients have been described previously. 4 We hope that analysis of this larger series of cases will help determine the effectiveness of the various forms of treatment. Patients with a history of a vesical neoplasm or with a coexisting vesical neoplasm were excluded from this study. CLINICAL FINDINGS
The patients ranged in age from 45 to 91 years, with a mean of 67. Urinary obstructive symptoms predominated in 24 patients and 10 complained chiefly of hematuria. Seven patients had irritative symptoms, such as frequency, dysuria and urgency, and 7 patients complained of pain, which was caused by metastasis in 5. Hematospermia was not observed. Values for serum creatinine or urea were normal in 31 patients and slightly elevated in the remaining 8. The serum alkaline phosphatase level was elevated in 8 of the 36 patients in whom it was determined. Of these 8 patients 3 had x-ray evidence of osteolytic metastasis, 1 of osteoblastic metastasis and 1 of nodular pulmonary metastasis. The serum acid Accepted for publication May 21, 1976. Read at annual meeting of Western Section, American Urological Association, Coronado, California, February 22-26, 1976. * Requests for reprints: Mayo Clinic, Rochester, Minnesota 55901.
phosphatase level was elevated in 4 of the 32 patients in whom it was determined, 1 of whom had osteolytic metastasis in the femur and pulmonary metastasis, 1 had osteolytic metastasis in the bony pelvis and 1 had osteoblastic metastasis in the pelvis and shoulder. Three of these 4 patients with elevated acid phosphatase levels had prostatic adenocarcinoma as well as transitional cell carcinoma. The tartrate-inhibited fraction of the serum acid phosphatase was normal in the 28 patients in whom it was measured. The upper part of the urinary tract was studied by excretory urography in 33 cases. The study was normal in 27 cases, hydronephrosis was noted in 4 and the study was indeterminate in 2. Cystoscopically, transitional cell carcinoma of the prostate did not appear distinctive. Rigidity and fixation, commonly associated with adenocarcinoma of the prostate, were noted, while ulceration and superficial necrosis were seen less frequently. Often the lesion was described as shaggy. The lesion was stage A in 6 cases, Bin 6, C in 19 and Din 7, • and staging was not available in 1 case. PATHOLOGIC FINDINGS
The pathologic findings have been well described. 4 Except for an observed lack of the yellowish fragments that characterize adenocarcinomas of the prostate, no reliable gross features were specific for primary prostatic transitional cell carcinoma. Highlighting the microscopic picture of transitional cell carcinoma of the prostate were prominent plugs composed of large hyperchromatic epithelial cells, with no evidence of glandular differentiation (part A of figure). Cellular anaplasia was so striking that the central portions of the plugs were often necrotic as a consequence of the tumor outstripping its blood supply and these necrotic zones frequently exhibited dystrophic calcification. Cell spindling was often a prominent feature (part B of figure). In some sections the tumor appeared to be confined to distended prostatic ducts but further search almost always disclosed invasion of the surrounding stroma, including lymphatics and even blood vascular spaces. However, perineural involvement was not observed. Unlike its bladder counterpart, transitional cell carcinoma of the prostate failed to exhibit a papillary type of architecture. Neoplasms were grade 3 (Broders' method) in 27 patients, grade 4 in 7 and grade 2 in 4. In 12 patients an independent prostatic adenocarcinoma and the primary transitional cell carcinoma coexisted, with the adeno component always dominating the picture. Significant degrees of subacute and chronic prostatitis were found in more than half of the patients, possibly reflecting the degree of obstruction of pros tatic ducts.
761
762
GREENE, o'DEA AND DOCKERTY
survival of 9 patients treated by radiation alone was 26 months (table 3). These data may be compared to an average survival of 11 months after hormonal manipulation (table 4) and 4 months for patients who received no treatment (table 5). DISCUSSION
The characteristics of primary transitional cell carcinoma of the prostate in this larger study group were consistent with those described in our previous report. 4 The symptoms and findings of this disease are indistinguishable from those of adenocarcinoma of the prostate. On digital rectal examination the prostate was usually hard and fixed, although in 6 patients it was considered to be benign or equivocal. Elevation of the serum alkaline phosphatase level, noted in 8 patients, was usually indicative of metastatic lesions to the ribs, femur, pelvis or lungs. In all but 1 patient bony metastases were osteolytic. The serum acid phosphatase level was elevated in 4 patients, each of whom also had adenocarcinoma of the prostate, and 3 of these patients had distant metastasis. The 2. Radical prostatic ablation-4 patients
TABLE
Stage
Grade
A
:l 3 3 3
A
A C
* Average A, transitional cell carcinoma, grade 3. H & E, reduced from x75. B, hyperchromatism of nuclei, with many cells of spindle type. H & E, reduced from x 225. Reprinted with permission. 4 TABLE 1.
Treatment
Prostatocystectomy, estrogen
40 months.
3. Radiation therapy-9 patients Survival* (mos.)
Present Status
A
2 3
13 11 22 38 60 26 6
Dead Dead Dead Dead Dead Dead Dead Poor Dead
B B B
4 4
C
2
Well Dead Well Dead
Grade
2 3
C C
9 5 3 3
2 2
42 48 60 8
Stage
;,lo. Pts.
Estrogen Estrogen, radiation 5-Fluorouracil Radical prostatectomy Orchiectomy, estrogen, radiation Orchiectomy Radiation, 5-fluorouracil Radiation. 5-fluorouracil, estrogen Estrogen, orchiectomy Estrogen, prostatocystectomy Prostatocystectomy Estrogen, orchiectomy, radiation, 5-fluorouracil Progesterone, radiation None
Present Status
Prostatocystectorny Radical prostatectomy Radical prostatectomy
TABLE
Treatment used in primary transitional cell carcinoma of the prostate
Radiation
Survival* (mos.)
C
3 3t
38
:J
16
* Average 26 months.
t Adenocarcinorna
in addition.
2 1 TABLE 4.
Grade
Treatment
A
2
B C C
3t
Estrogen Estrogen Estrogen Estrogen Orchiectomy Estrogen Orchiectomy Estrogen, orchiectorny
Stage 5
TREATMENT
The therapeutic regimens used are summarized in table 1. The radiation dosage ranged from 6,000 to 7,700 rads. Daily doses of 1 or 5 mg. diethylstilbestrol were prescribed. The dosage of 5-fluorouracil was approximately 12 mg. per kg. body weight daily for 5 days.
3
3t
C
3
D D D
3t 3t
:it
Survival* (mos.)
Present Status
18 12
Dead Dead Well Dead Poor Dead Dead Dead
7 2 18 4
24
* Average 11 months. t Adenocarcinoma in addition.
RESULTS
The prognosis of patients with primary transitional cell carcinoma is poor. When this study was completed 34 patients had died, the majority of prostatic carcinoma. Survival after diagnosis ranged from 1 month to 5 years, with an average of 17 months. Five patients are alive 7 months to 5 years after diagnosis (average 33 months) and 3 of these patients are well but the condition of the other 2 is deteriorating. Four patients who had radical ablation of the prostate survived an average of 40 months (table 2). The average
Hormonal manipulation-8 patients
TABLE
5. No treatment-5 patients
Stage
Grade
A C
3
C C D
:l 3
3t 3t
* Average 4 months.
t Adenocarcinoma in addition.
Survival* (mos.)
Present Status
6 2
Dead Dead Dead Dead Dead
4 5 4
',,;;r,
_[_]t ,_,
763
TRANSITIONAL CELL CARCINOMA TABLE
6. Patients who survived longer than 3 years after diagnosis-7 patients
Stage
Grade
Treatment
Survival* (mos.)
Present Status
A A A B C C C
3 3 3 4 2 3 3
Prostatocystectomy Radical prostatectomy Radical prostatectomy Radiation Radiation Radiation Radiation, estrogen
42 48 60 38 60 38 60
Well Dead Well Dead Dead Poor Dead
* Average 49 months.
tartrate-inhibited fraction of the serum acid phosphatase was not elevated in the 28 patients in whom it was determined. Microscopically, the majority of carcinomas were anaplastic and poorly differentiated. Adenocarcinoma, usually anaplastic, was noted in addition to transitional cell carcinoma in 12 of the 39 patients studied. Because of the few cases, the wide variety of therapeutic modalities and the inability to compare adequate numbers of similar cases, evaluation of the effectiveness of the various forms of treatment is difficult. Acknowledging the limitations, we attempted such an evaluation. The best results were obtained by radical surgical ablation of the prostate. With 1 exception the disease was least advanced in this group. (The value of early diagnosis is apparent.) The group with the next
best survival rates was treated by radiation. The disease was more advanced in this group than in the preceding one. We examined the composition of the group of patients who had survived longer than 3 years after diagnosis (table 6). Three patients with stage A lesions had had radical prostatic ablation. The remaining 4 patients, who had stage B and C lesions, were treated by radiation. Therefore, the data suggest that radical ablation of the prostate, if feasible, is the best form of treatment for primary transitional cell carcinoma of the prostate and that radiation therapy is next best. Furthermore, the data refute the theory that hormonal manipulation has a salutary effect on these neoplasms. REFERENCES
1. Dube, V. E., Farrow, G. M. and Greene, L. F.: Prostatic adenocar-
cinoma of ductal origin. Cancer, 32: 402, 1973. 2. Ende, N., Woods, L. P. and Shelley, H. S.: Carcinoma originating in ducts surrounding the prostatic urethra. Amer. J. Clin. Path., 40: 183, 1963. 3. Rhamy, R. K., Buchanan, R. D. and Spalding, M. J.: Intraductal carcinoma of the prostate gland. J. Urol., 109: 457, 1973. 4. Greene, L. F., Mulcahy, J. J., Warren, M. M. and Dockerty, M. B.: Primary transitional cell carcinoma of the prostate. J. Ural., 110: 235, 1973. 5. Del Regato, J. A.: Radiotherapy for carcinoma of the prostate. Committee for the Cooperative Study of Radiotherapy for Carcinoma of the Prostate, Colorado Springs, Colorado, Penrose Cancer Hospital, p. 10, 1968.
