UROPATHOLOGY
TRANSITIONAL CELL CARCINOMA OF PROSTATE* MYRON TANNENBAUM,
M.D.,
PH.D.
From the Uropathology Laboratories, Departments of Urology and Pathology, Columbia-Presbyterian Medical Center, New York, New York
Carcinoma of the prostate should be categorized into different histologic types. This is clinically important if there is a different biologic course for a particular histologic type. The periurethral type or transitional cell carcinoma of the prostate is seldom recognized or categorized as a distinct morphologic or clinical variety of prostatic carcinoma.l The facts enumerated will justify the separation of prostatic carcinoma into different histologic patterns. Melicow and HoBowell’ referred to transitional cell prostatic carcinoma when they described 30 cases of Bowen’s disease of the urinary tract of which 3 cases involved the prostatic urethra. They did not, however, state whether or not two of these patients were devoid of urothelial neoplasia in other parts of the urinary tract. A third patient, who had undergone total cystectomy, including prostatectomy for infiltrating carcinoma of the bladder, on sectioning, revealed an intraurothelial carcinoma of the posterior urethra. This had a distinctly different histologic appearance from that of the bladder tumor. There was no notation that the periurethral ducts were involved by this process. Ortega, Whitmore, and Murphy3 described a lesion of similar histologic appearance to Melicow and Hollowell’s third case; however, they also noted Pagetoid cells both in the prostatic urethra and urinary bladder. They did describe the process as spreading up the periurethral prostatic ducts into the various lobes of the prostate. Some of their photomicrographs could also be interpreted as demonstrating that the lesions were in situ as well as invasive into the prostatic fibromuscular stroma. *Supported by The James H. M. Ewart Memorial Fund.
Franks and Chesterman also described in situ undifferentiated carcinoma of a transitional cell type that involved the periurethral prostatic ducts. Their patient also had an undifferentiated infiltrating tumor of the urinary bladder. They also suggested that the prostatic lesions were caused by the same carcinogenic stimulus that affected the urothelium of the bladder. Ende, Woods, and Shelley5 reviewed 200 consecutive cases of prostatic carcinoma and reported 7 cases that arose within the periurethral prostatic ducts. Three of these cases were of a pure transitional cell type, and 4 were a mixture of glands and transitional cells that were neoplastic. They postulated that this type of neoplasm began in the periurethral and prostatic ducts in the junctional area of the columnar and the transitional epithelia. Their tumors had a propensity for causing ureteral obstruction, but these tumors did not seem to be especially aggressive since widespread metastases were not commonly seen. The tumors were not associated with elevated blood acid phosphatase. Even though their data were scant, these lesions did not appear to have an innocuous clinical course but extended readily into the retroperitoneal lymph nodes with subsequent obstructive uropathy and ensuing uremia. These patients did not have any associated urothelial neoplasia elsewhere in the urinary tract. Additional pathologic evidence supporting the concept of pathogenesis of this lesion was given by Ullmann and ROSS.~They provided 9 cases in which the epithelium of the periurethral prostatic ducts ranged from an unremarkable hyperplasia through marked atypicality to a definitive carcinoma in situ. They inferred that the rare invasive transitional cell carcinoma of
the prostate gland originates in the periurethral prostatic ducts and secondarily invades the prostatic stroma by breaking through the glandular basement membrane. Four of their 9 cases demonstrated a urothelium in which the transitional cells were well differentiated and the nuclei were generally of uniform size. Mitotic figures were rarely observed. However, with the advent of atypical hyperplasia and carcinoma in situ, the number of mitoses was greatly increased. Most forms of prostatic carcinoma, with the exception of the cribiform pattern, do not have great numbers of mitoses per single highpower field.
type. On gross examination, they found no difference between adenocarcinoma and transitional cell carcinoma of the prostate. Both types produced an enlarged, hard, fixed, and irregular gland. The most important distinction between the two types is found on histologic examination. Adenocarcinoma of the prostate has a distinct pattern of infiltration, that is, small, hyperchromatic cells that often produce well-formed and/or abortive glands. Occasionally, there is only an insidious infiltration of the fibromuscular stroma by cords or islands of small dark-staining cells with no light histologically demonstrable glandular lumens.
Karpas and Moumgis’ took routine serial sections from the prostate of 400 consecutive autopsies. Four cases revealed pronounced epithelial hyperplasia of the periurethral prostatic ducts. One case demonstrated a grade I papillary transitional cell carcinoma lying wholely within the confines of the prostatic ducts. They believed that the hyperplastic transitional cells arose from the indifferent or reserve cells lying between the luminal epithelium and the basement membrane in the periurethral prostatic ducts. They were unable to demonstrate direct continuity of these proliferating cells with transitional cells lining the prostatic urethra per se. They inferred that these cells were the same as those described in an electron microscopic study of prostatic ducts by Mao and Angrist.
The cytologic criteria of malignancy, such as anaplasia and mitoses, are usually absent. Mitoses are usually present in the cribiform pattern of prostatic carcinoma. Transitional cell carcinoma is, however, characterized by clusters of large anaplastic tumor cells arising in and filling the periurethral prostatic ducts as well as spreading into the prostatic alveoli. Cellular variation and mitotic figures are frequently seen. A propensity for the perineural spaces is not commonly seen in transitional cell carcinoma as it is in adenocarcinoma of the prostate. In their 10 cases of transitional cell carcinoma of the prostate, hormonal manipulation was of no benefit, and the clinical course, in all instances, was steadily downhill with no patient surviving more than twenty-three months after the diagnosis was made.
The conclusions of Karpas and Moumgis also will require an ultrastructural study for confirmation of the reserve cell being the cell of origin of the transitional cell hyperplasia and carcinoma. An ultrastructural study may possibly explain the pathogenesis or reason for the prostatic urethral and periurethral involvement in approximately 20 per cent of the patients with transitional cell carcinoma of the bladder. It is not unreasonable to accept a multifocal alteration of the urothelium by a urinary carcinogen to explain the multiple or asynchronous development of these urothelial neoplasms that occur within the prostatic periurethral glands. However, for a long period of time, the majority of these neoplasms have been attributed to direct extension from the malignant primary tumor in the urinary bladder.
Additional evidence of the great malignant potential and rapid death of patients with this type of prostatic cancer was also provided by Johnson, Hogan, and Ayala.‘O Transitional cell carcinoma of the prostate developed in 6 patients without an antecedent history of vesical malignant lesion or coexisting bladder tumor. The diagnosis was usually established late in the course of the disease, and treatment with radiotherapy did not appear to improve survival, The 6 patients died twelve to thirty-six months after the tissue diagnosis was established. In 14 other patients, there was noted prostatic lesions at the time of treatment for a noncontiguous bladder lesion (10 patients) or asynchronously in patients with previous bladder malignancies (4).
Finally, Rubenstein and Rubnitzg provided data for a pathobiologic evaluation of transitional cell prostatic cancer. They examined 670 cases of prostatic carcinoma and found about 2 per cent of their cases to be of the transitional cell
UROLOGY
/ MAY 1975 / VOLUME
V, NUMBER
5
Conservative treatment was advocated if the transitional cell carcinoma was confined to the periurethral prostatic ducts. Radical treatment using either radiotherapy, surgical extirpation, or a combination of both was indicated when the fibromuscular stroma was invaded. They concluded from careful histologic observations of the
675
FIGXJRE 1. Transitional cell tumors of prostate: (A) Transitional cell hyperplasia and ! (B) higher magnijication of luminal and basal cells (X 135): (C) lnjiltrating cart :inoma ( X 67), and (D) higher magnijkation (X 206).
676
UROLOGY
of periurethral ducts (X 5% undifferentiated transiti onal
/ MAY 1975 / VOLUME
V, NUMBER 5
Transitional cell in situ carcinoma of prostate: (A) Upper part demonstrates duct in situ carci noma and (B) higher magnijkation ( X 135). (C) B asal and luminal carcinoma cells (X 206). (0) Co medo ‘tern in in situ tumor (X 206). XJRE 2.
34),
UROLOGY
I
MAY 1975 / VOLUME
V, NUMBER 5
677
tissue from these 20 patients that in both groups the lesions began as carcinoma in situ in the periurethral prostatic ducts without subsequent breakthrough into the prostatic fibromuscular stroma. Interestingly, this second group of patients presented chiefly with symptoms of hematuria and vesical irritability rather than prostatic obstruction. When the prostatic fibromuscular stroma is invaded by direct extension of a vesical malignant lesion, then the assignment, according to the classification of Jewett and Strong,ll of clinical stage Di is certainly warranted. However, the indiscriminant assignment of all patients with transitional cell carcinoma of the prostate into such a category most certainly fails to take into account those patients in whom the malignant process arises primarily in the periurethral prostatic ducts. The prostatic and vesical lesions must be staged independently. It is very important for urologists and pathologists to be aware of these types of lesions because they are biologically different from most forms of prostatic cancer. They should not be considered rare and can vary from 2 to 3 per cent of the prostatic carcinomas reported in the literature to 4 per cent at our institution. The various histologic patterns of proliferating transitional cell lesions of the periurethral ducts are shown in Figures 1 and 2. In Figure 1A and B, there is transitional cell hyperplasia almost occluding the prostatic ducts. Figure 1B shows at a higher magnification that there are surface cells of a columnar type surrounding a lumen, and beneath this are numerous cells that are similar to the basal cells that are against the basement membrane. The exact nature of these cells awaits ultrastructural confirmation as to their type. In Figure 1C and D, there is an invasive undifferentiated form of transitional cell carcinoma arising only in the periurethral prostatic ducts. These cells exhibit numerous mitoses. In Figure 2A, upper part, there is discernible in situ transitional cell carcinoma of the periurethral prostatic ducts. The tumor occupies most of the lumen of the ducts and does not invade the fibromuscular stroma. The lower part of
678
Figure 2B contains some prostatic acini involved by tumor cells. Figure 2C contains basal or reserve cells surrounding these neoplastic transitional cells. Figure 2D demonstrates a comedo pattern that is also seen with this type of carcinoma of the prostate. It is important to recognize the neoplastic patterns because this type of prostatic carcinoma is hormonally unresponsive, and other forms of therapy must be instituted immediately. 630 West 168th Street New York, New York 10032 References 1. MOSTOFI, F. K., and PRICE, E. B., JR.: Malignant tumors of the prostate, in Tumors of the Male Genital System, Atlas of Tumor Pathology, series 2, part 8, Washington, D.C., Armed Forces Institute of Pathology, 1973, pp. 269-73. 2. MELICOW, M. M., and HOLLOWELL, J. W.: Intraurothelial cancer: carcinoma in situ, Bowen’s disease of the urinary systems. Discussion of thirty cases, J. Urol. 68: 763 (1952). 3. ORTEGA, L. G., WHITMORE, W. F., JR., and MURPHY, A. J.: In situ carcinoma of the prostate with intraepithelial extension into the urethra and bladder, Cancer 6: 892 (1953). Intra4. FRANKS, L. M., and CHESTERMAN, F. C.: epithelial carcinoma of prostatic urethra, peri-urethral glands and prostatic ducts (Bowen’s disease of urinary epithelium), Br. J. Cancer 10: 223 (1956). 5. ENDE, N., WOODS, L. P., and SHELLEY, H. S.: Carcinoma originating in ducts surrounding the prostatic urethra, Am. J. Clin. Pathol. 40: 183 (1963). 6. ULLMANN, A. S., and ROSS, 0. A.: Hyperplasia, atypism, and carcinoma in situ in prostatic periurethral glands, ibid. 47: 497 (1967). 7. KARPAS, C. M., and MOUMGIS, B.: Primary transitional cell carcinoma of prostate gland: possible pathogenesis and relationship to reserve cell hyperplasia of prostatic periurethral ducts, J. Urol. 101: 201 (1969). 8. MAO, P., and ANGRIST, A.: The fine structure of the basal cell of human prostate, Lab. Invest. 15: 1768 (1966). 9. RUBENSTEIN, A. B., and RUBNITZ, M. E.: Transitional cell carcinoma of the prostate, Cancer 24: 543 (1969). 10. JOHNSON, D. E., HOGAN, J. M., and AYALA, A. G.: Transitional cell carcinoma of the prostate. A clinical morphological study, ibid. 29: 287 (1972). 11. JEWEL, H. J., and STRONG, G. H. : Infiltrating carcinoma of the urinary bladder: diagnosis and clinical evaluation of curability, South. Med. J. 39: 203 (1946).
UROLOGY
/
MAY 1975 / VOLUME V, NUMBER 5
TRANSITIONAL CELL CARCINOMA OF PROSTATE* MYRON TANNENBAUM,
M.D.,
PH.D.
From the Uropathology Laboratories, Departments of Urology and Pathology, Columbia-Presbyterian Medical Center, New York, New York
Carcinoma of the prostate should be categorized into different histologic types. This is clinically important if there is a different biologic course for a particular histologic type. The periurethral type or transitional cell carcinoma of the prostate is seldom recognized or categorized as a distinct morphologic or clinical variety of prostatic carcinoma.l The facts enumerated will justify the separation of prostatic carcinoma into different histologic patterns. Melicow and HoBowell’ referred to transitional cell prostatic carcinoma when they described 30 cases of Bowen’s disease of the urinary tract of which 3 cases involved the prostatic urethra. They did not, however, state whether or not two of these patients were devoid of urothelial neoplasia in other parts of the urinary tract. A third patient, who had undergone total cystectomy, including prostatectomy for infiltrating carcinoma of the bladder, on sectioning, revealed an intraurothelial carcinoma of the posterior urethra. This had a distinctly different histologic appearance from that of the bladder tumor. There was no notation that the periurethral ducts were involved by this process. Ortega, Whitmore, and Murphy3 described a lesion of similar histologic appearance to Melicow and Hollowell’s third case; however, they also noted Pagetoid cells both in the prostatic urethra and urinary bladder. They did describe the process as spreading up the periurethral prostatic ducts into the various lobes of the prostate. Some of their photomicrographs could also be interpreted as demonstrating that the lesions were in situ as well as invasive into the prostatic fibromuscular stroma. *Supported by The James H. M. Ewart Memorial Fund.
Franks and Chesterman also described in situ undifferentiated carcinoma of a transitional cell type that involved the periurethral prostatic ducts. Their patient also had an undifferentiated infiltrating tumor of the urinary bladder. They also suggested that the prostatic lesions were caused by the same carcinogenic stimulus that affected the urothelium of the bladder. Ende, Woods, and Shelley5 reviewed 200 consecutive cases of prostatic carcinoma and reported 7 cases that arose within the periurethral prostatic ducts. Three of these cases were of a pure transitional cell type, and 4 were a mixture of glands and transitional cells that were neoplastic. They postulated that this type of neoplasm began in the periurethral and prostatic ducts in the junctional area of the columnar and the transitional epithelia. Their tumors had a propensity for causing ureteral obstruction, but these tumors did not seem to be especially aggressive since widespread metastases were not commonly seen. The tumors were not associated with elevated blood acid phosphatase. Even though their data were scant, these lesions did not appear to have an innocuous clinical course but extended readily into the retroperitoneal lymph nodes with subsequent obstructive uropathy and ensuing uremia. These patients did not have any associated urothelial neoplasia elsewhere in the urinary tract. Additional pathologic evidence supporting the concept of pathogenesis of this lesion was given by Ullmann and ROSS.~They provided 9 cases in which the epithelium of the periurethral prostatic ducts ranged from an unremarkable hyperplasia through marked atypicality to a definitive carcinoma in situ. They inferred that the rare invasive transitional cell carcinoma of
the prostate gland originates in the periurethral prostatic ducts and secondarily invades the prostatic stroma by breaking through the glandular basement membrane. Four of their 9 cases demonstrated a urothelium in which the transitional cells were well differentiated and the nuclei were generally of uniform size. Mitotic figures were rarely observed. However, with the advent of atypical hyperplasia and carcinoma in situ, the number of mitoses was greatly increased. Most forms of prostatic carcinoma, with the exception of the cribiform pattern, do not have great numbers of mitoses per single highpower field.
type. On gross examination, they found no difference between adenocarcinoma and transitional cell carcinoma of the prostate. Both types produced an enlarged, hard, fixed, and irregular gland. The most important distinction between the two types is found on histologic examination. Adenocarcinoma of the prostate has a distinct pattern of infiltration, that is, small, hyperchromatic cells that often produce well-formed and/or abortive glands. Occasionally, there is only an insidious infiltration of the fibromuscular stroma by cords or islands of small dark-staining cells with no light histologically demonstrable glandular lumens.
Karpas and Moumgis’ took routine serial sections from the prostate of 400 consecutive autopsies. Four cases revealed pronounced epithelial hyperplasia of the periurethral prostatic ducts. One case demonstrated a grade I papillary transitional cell carcinoma lying wholely within the confines of the prostatic ducts. They believed that the hyperplastic transitional cells arose from the indifferent or reserve cells lying between the luminal epithelium and the basement membrane in the periurethral prostatic ducts. They were unable to demonstrate direct continuity of these proliferating cells with transitional cells lining the prostatic urethra per se. They inferred that these cells were the same as those described in an electron microscopic study of prostatic ducts by Mao and Angrist.
The cytologic criteria of malignancy, such as anaplasia and mitoses, are usually absent. Mitoses are usually present in the cribiform pattern of prostatic carcinoma. Transitional cell carcinoma is, however, characterized by clusters of large anaplastic tumor cells arising in and filling the periurethral prostatic ducts as well as spreading into the prostatic alveoli. Cellular variation and mitotic figures are frequently seen. A propensity for the perineural spaces is not commonly seen in transitional cell carcinoma as it is in adenocarcinoma of the prostate. In their 10 cases of transitional cell carcinoma of the prostate, hormonal manipulation was of no benefit, and the clinical course, in all instances, was steadily downhill with no patient surviving more than twenty-three months after the diagnosis was made.
The conclusions of Karpas and Moumgis also will require an ultrastructural study for confirmation of the reserve cell being the cell of origin of the transitional cell hyperplasia and carcinoma. An ultrastructural study may possibly explain the pathogenesis or reason for the prostatic urethral and periurethral involvement in approximately 20 per cent of the patients with transitional cell carcinoma of the bladder. It is not unreasonable to accept a multifocal alteration of the urothelium by a urinary carcinogen to explain the multiple or asynchronous development of these urothelial neoplasms that occur within the prostatic periurethral glands. However, for a long period of time, the majority of these neoplasms have been attributed to direct extension from the malignant primary tumor in the urinary bladder.
Additional evidence of the great malignant potential and rapid death of patients with this type of prostatic cancer was also provided by Johnson, Hogan, and Ayala.‘O Transitional cell carcinoma of the prostate developed in 6 patients without an antecedent history of vesical malignant lesion or coexisting bladder tumor. The diagnosis was usually established late in the course of the disease, and treatment with radiotherapy did not appear to improve survival, The 6 patients died twelve to thirty-six months after the tissue diagnosis was established. In 14 other patients, there was noted prostatic lesions at the time of treatment for a noncontiguous bladder lesion (10 patients) or asynchronously in patients with previous bladder malignancies (4).
Finally, Rubenstein and Rubnitzg provided data for a pathobiologic evaluation of transitional cell prostatic cancer. They examined 670 cases of prostatic carcinoma and found about 2 per cent of their cases to be of the transitional cell
UROLOGY
/ MAY 1975 / VOLUME
V, NUMBER
5
Conservative treatment was advocated if the transitional cell carcinoma was confined to the periurethral prostatic ducts. Radical treatment using either radiotherapy, surgical extirpation, or a combination of both was indicated when the fibromuscular stroma was invaded. They concluded from careful histologic observations of the
675
FIGXJRE 1. Transitional cell tumors of prostate: (A) Transitional cell hyperplasia and ! (B) higher magnijication of luminal and basal cells (X 135): (C) lnjiltrating cart :inoma ( X 67), and (D) higher magnijkation (X 206).
676
UROLOGY
of periurethral ducts (X 5% undifferentiated transiti onal
/ MAY 1975 / VOLUME
V, NUMBER 5
Transitional cell in situ carcinoma of prostate: (A) Upper part demonstrates duct in situ carci noma and (B) higher magnijkation ( X 135). (C) B asal and luminal carcinoma cells (X 206). (0) Co medo ‘tern in in situ tumor (X 206). XJRE 2.
34),
UROLOGY
I
MAY 1975 / VOLUME
V, NUMBER 5
677
tissue from these 20 patients that in both groups the lesions began as carcinoma in situ in the periurethral prostatic ducts without subsequent breakthrough into the prostatic fibromuscular stroma. Interestingly, this second group of patients presented chiefly with symptoms of hematuria and vesical irritability rather than prostatic obstruction. When the prostatic fibromuscular stroma is invaded by direct extension of a vesical malignant lesion, then the assignment, according to the classification of Jewett and Strong,ll of clinical stage Di is certainly warranted. However, the indiscriminant assignment of all patients with transitional cell carcinoma of the prostate into such a category most certainly fails to take into account those patients in whom the malignant process arises primarily in the periurethral prostatic ducts. The prostatic and vesical lesions must be staged independently. It is very important for urologists and pathologists to be aware of these types of lesions because they are biologically different from most forms of prostatic cancer. They should not be considered rare and can vary from 2 to 3 per cent of the prostatic carcinomas reported in the literature to 4 per cent at our institution. The various histologic patterns of proliferating transitional cell lesions of the periurethral ducts are shown in Figures 1 and 2. In Figure 1A and B, there is transitional cell hyperplasia almost occluding the prostatic ducts. Figure 1B shows at a higher magnification that there are surface cells of a columnar type surrounding a lumen, and beneath this are numerous cells that are similar to the basal cells that are against the basement membrane. The exact nature of these cells awaits ultrastructural confirmation as to their type. In Figure 1C and D, there is an invasive undifferentiated form of transitional cell carcinoma arising only in the periurethral prostatic ducts. These cells exhibit numerous mitoses. In Figure 2A, upper part, there is discernible in situ transitional cell carcinoma of the periurethral prostatic ducts. The tumor occupies most of the lumen of the ducts and does not invade the fibromuscular stroma. The lower part of
678
Figure 2B contains some prostatic acini involved by tumor cells. Figure 2C contains basal or reserve cells surrounding these neoplastic transitional cells. Figure 2D demonstrates a comedo pattern that is also seen with this type of carcinoma of the prostate. It is important to recognize the neoplastic patterns because this type of prostatic carcinoma is hormonally unresponsive, and other forms of therapy must be instituted immediately. 630 West 168th Street New York, New York 10032 References 1. MOSTOFI, F. K., and PRICE, E. B., JR.: Malignant tumors of the prostate, in Tumors of the Male Genital System, Atlas of Tumor Pathology, series 2, part 8, Washington, D.C., Armed Forces Institute of Pathology, 1973, pp. 269-73. 2. MELICOW, M. M., and HOLLOWELL, J. W.: Intraurothelial cancer: carcinoma in situ, Bowen’s disease of the urinary systems. Discussion of thirty cases, J. Urol. 68: 763 (1952). 3. ORTEGA, L. G., WHITMORE, W. F., JR., and MURPHY, A. J.: In situ carcinoma of the prostate with intraepithelial extension into the urethra and bladder, Cancer 6: 892 (1953). Intra4. FRANKS, L. M., and CHESTERMAN, F. C.: epithelial carcinoma of prostatic urethra, peri-urethral glands and prostatic ducts (Bowen’s disease of urinary epithelium), Br. J. Cancer 10: 223 (1956). 5. ENDE, N., WOODS, L. P., and SHELLEY, H. S.: Carcinoma originating in ducts surrounding the prostatic urethra, Am. J. Clin. Pathol. 40: 183 (1963). 6. ULLMANN, A. S., and ROSS, 0. A.: Hyperplasia, atypism, and carcinoma in situ in prostatic periurethral glands, ibid. 47: 497 (1967). 7. KARPAS, C. M., and MOUMGIS, B.: Primary transitional cell carcinoma of prostate gland: possible pathogenesis and relationship to reserve cell hyperplasia of prostatic periurethral ducts, J. Urol. 101: 201 (1969). 8. MAO, P., and ANGRIST, A.: The fine structure of the basal cell of human prostate, Lab. Invest. 15: 1768 (1966). 9. RUBENSTEIN, A. B., and RUBNITZ, M. E.: Transitional cell carcinoma of the prostate, Cancer 24: 543 (1969). 10. JOHNSON, D. E., HOGAN, J. M., and AYALA, A. G.: Transitional cell carcinoma of the prostate. A clinical morphological study, ibid. 29: 287 (1972). 11. JEWEL, H. J., and STRONG, G. H. : Infiltrating carcinoma of the urinary bladder: diagnosis and clinical evaluation of curability, South. Med. J. 39: 203 (1946).
UROLOGY
/
MAY 1975 / VOLUME V, NUMBER 5
