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A Spectrum of Malignant Epithelial Tumors of the Prostate Gland
THE
Vol. 115, June Printed in U.S.A.
JOURNAL OF UROLOGY
Copyright © 1976 by The Williams & Wilkins Co.
A SPECTRUM OF MALIGNANT EPITHELIAL TUMORS OF THE PROSTATE GLAND MEYER M. MELICOW
AND
AURELIO C. USON
From the Departments of Pathology and Urology, the Squier Urological Clinic and the Columbia University, College of Physicians and Surgeons, New York, New York
ABSTRACT
Conceptually, the prostatic territory encompasses neoplasms whose origins are intraprostatic, paraprostatic or extraprostatic. Our objectives in this review are to 1) present a classification of the spectrum of malignant epithelial growths encountered in the prostatic territory, 2) show examples of these neoplasms and remark upon their histogenesis, enzyme production and endocrine sensitivity, and 3) suggest re-evaluation of some of our current routine therapeutic procedures. A review of the histology of any large series of malignant epithelial prostatic neoplasms will reveal a wide range of pathological patterns, whose significance can be appreciated when correlated with the clinical picture and outcome. This statement is based on a study of available clinical material and tissue slides of some 1,600 patients with prostatic cancer treated since 1960. During this survey and after a concomitant
origin was traced to contiguous structures. Lesions metastatic to the prostate in which the primary source was cryptic were often misdiagnosed and mismanaged. Thus, we concluded that a presentation of a spectrum of malignant epithelial tumors arising in or involving the prostate gland would be helpful in diagnosis and treatment. Therefore we classified our cases as indicated in the table.
Patterns of epithelial tumors of prostate gland
I. Intraprostatic A. Glandular (adenocarcinoma) 1. Microacinar: origin usually in posterior lamella a. Early, latent or in situ b. Well differentiated c. Cribriform, sponge d. Anaplastic 2. Macroacinar: original from central sets of alveoli a. Patterns similar to lb, c and so forth but on larger scale b. May be associated with microacinar carcinoma c. May be associated with ductal carcinoma (junctional carcinoma) 3. Rare patterns: signet-ring, mucin-forming, xanthocarcinoma B. Cancer of prostatic ducts 1. Columnar-cell-lined a. Usually endophytic; rarely exophytic ("endometrioid") b. Junctional (with macroacinar cancer) 2. Periurethral urothelium-lined ducts: in situ, urothelial or squamous II. Paraprostatic, cancer of A. Urethral mucosa attached to prostatic bed: in situ, urothelial, squamous, pagetoid, adenocarcinoma, inverted papilloma B. Utricle: endometrial C. Ejaculatory duct ill. Extraprostatic, cancer A. By extension from neighboring organ: bladder, Cowper's gland, seminal vesicles, rectum and so forth B. By metastases from cancer of distant organs: lung, pancreas, stomach, lymphoma, malignant melanoma and so forth
review of pertinent literature we became aware that the prostate gland is not an isolated organ but is intimately bound to neighboring structures and tissues. There were variations in the morphopathology of some apparently primary prostatic tumors that were baffling. Occasionally, there was a discrepancy between the histological findings and expected enzyme activity. Some histologic patterns were confusing until their Accepted for publication September 19, 1975. Read at annual meeting of American Urological Association, Miami Beach, Florida, May 11-15, 1975. Aided by a grant from the Irene Heinz Given and John LaPorte Given Foundation.
INTRAPROSTATIC TUMORS
Glandular adenocarcinoma. This group, by far the most numerous, comprised intrinsic epithelial tumors of the gland, which displayed 2 main patterns that were often intermixed: microacinar and macroacinar. The former was more common and, in most instances, apparently arose from the cells lining the acini of the peripheral secretory units of the posterior or posterolateral lamella or lobe, while the latter developed mainly from the cephalic central glands and their junctional or secondary ducts. The patterns of microacinar adenocarcinoma are early
696
MALIGNANT EPITHELIAL TUMORS OF PROSTATE GLAND
697
FIG. 1. Some variations in patterns of intraprostatic tumors. a, from microacinar: cribriform pattern showing intra-acinar invasion. b, sponge pattern after invasion of loose tissue, viscus or retroperitoneum. c, from macroacini of central or cephalic region: cribriform pattern composed of large cells. Reduced from x200.
(latent or in situ), well differentiated, cribriform (fig. 1, a), sponge (fig. 1, b) and anaplastic. In all these types except some of the anaplastic, intracellular production of acid phosphatase could be demonstrated by the Gomori stain. 1 In the latter, foci of dedifferentiated cells did not take the stain. Serum acid phosphatase was elevated in all when tissue, or lymphatic or SHORT DUCT perineural spaces were invaded. Bone marrow acid phosphatase activity was elevated at times, even when the serum level was not. Microscopic foci of metastases were demonstrated in biopsies of bone, even in some cases with negative radiographic or scan studies. All these types, except some of the completely anaplastic variety, were androgen-dependent. In the latter, dedifferentiation was exemplified by a steady reduction in cell size and their spread in solid sheets or irregular clumps. Some MIDDLE LOBE 2. Region of subcervlcal lobule (Albarran) resembled lymphoma, granuloma or anaplastic secondary 3. " " subtrigonol " (Home) LATERAL LOBES 4. sho(I ductules 5. long ductules tumors. Mitoses were rare. In some cells nuclei were absent, POSTERIOR LAMELLA 6. while in others they were large and deep staining. Rarely, a A. UTRICLE. Orifices of: B. Ejaculatory Ducts, C. Prostatic duciules, O. Cowper's Glands. small round cells with clear cytoplasm were seen-perhaps a ----variant estrogen effect. There was often a drop in the level of enzyme production concomitant with the degree of anaplasia. In some instances osseous metastases were lytic as well as blastic. The patterns of macroacinar adenocarcinoma are shown in figure 1, c. These cancers arose from the columnar cells lining the central cephalic alveolar secretory units and their junctional ducts. Generally, the patterns were similar to the microacinar variety in all respects but size. Epithelial buds I. ANTERIOR LOBE and papillary infoldings were present frequently and also 2. 8, 3. MIDDLE LOBE occasionally a cribriform design. An association with a microacinar component was frequent. Serum acid phosphatase elevation was not always demonstrable, perhaps because of the initial central localization of the tumor and absence of tissue space violation. The macroacinar cancers often were associated B. EJACULATORY DUCT C. ORIFICES of PROSTATIC DUCTS with a similar process in the large columnar cell-lined ducts D. COWPER'S GLAND (junctional tumors). Rare patterns, such as signet-ring, mucin-forming adenocarb M,M.M.,uc<>w,u.o.
Fm. 2. Schematic representation of a, transverse horizontal and b, sagittal vertical sections of prostate gland. Note close relationship of subcervical and subtrigonal glandules to urethra and bladder (2 and 3). Note long and short ductules: some possess columnar epithelium at junction with alveoli, while periurethrally they are lined by urothelium like that of posterior urethra. 4 and 5 refer to lateral lobes; 6 to posterior lobe or lamella. All are intraprostatic and their cancers,
except those that arise from urothelium-lined periurethral ductules, are androgen-dependent. Utricle (A), ejaculatory ducts and orifices (B) and mucosa of posterior urethra attached to prostate comprise paraprostatic zone. Natural history, clinical course and endocrine dependence of tumors arising from these structures differ from those of intraprostatic origin.
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MELICOW AND USON
Fm. 3. a, section shows dilated portion of prostatic duct lined by single layer of low columnar cells (arrow) and narrow portion with heaped up cuboidal cells resembling urothelium. Reduced from x76. b, carcinoma of prostatic duct composed of columnar cells in papillary array. This type of tumor, when exophytic into posterior urethra, has in some cases been labeled endometrioid. Reduced from x 175.
Fm. 4. Paraprostatic tumors. a, urothelial carcinoma of prostatic urethra has invaded gland proper which, coincidentally, is seat of microacinar adenocarcinoma-collision tumor (arrows). Reduced from x160. b, squamous cell carcinoma arising from metaplastic urethral epithelium invading prostate. Reduced from x63. Cancers of posterior urethra invading prostate are similar histologically to those arising from urothelium of periurethral prostatic ductules. None is hormonally dependent.
cinomas (adenoid cystic carcinoma)'· 3 and xanthocarcinomas, • presented problems in diagnosis. In the 2 former types it was essential to rule out a primary focus in the alimentary tract or bladder, while in the latter type the lesion required differentiation from a xanthogranuloma. Xanthogranulomas and xanthocarcinomas appeared orange-colored on section of the gross specimen. Serum acid phosphatase was usually elevated. Ductal tumors. Tumors arising from the prostatic ducts were uncommon, their patterns varied and they were often misdiagnosed. 5 • 9 There is a complexity here that requires clarification. The ducts and ductules draining the secretory alveoli often have a dual lining: 1) the segments continuous with the alveoli are lined by a columnar epithelium, which is possibly secretory, and 2) the segments that continue toward the meatus in the posterior urethra (periurethral ductules) possess a heaped up urothelium contiguous with that lining the meatus and posterior urethra (figs. 2 and 3). Because of this
variation in pavement of the prostatic duct system 2 types of neoplasms were encountered. Carcinomas of the columnar cell-lined ducts, the first type, were usually confined to the gland but at times they were also exophytic into the lumen of the posterior urethra (fig. 3, b). They also occasionally were continuous with a macroacinar cancer (junctional tumors). Some were not accompanied by an elevated serum acid phosphatase, perhaps because of their central location. The exophytic component resembled endometrial tumors and has been labeled endometrioid. In the majority of cases metastases to bone were blastic. 7 • 9 - 11 Neoplasms of the periurethral primary prostatic ductules, the second type, were either urothelial or squamoid-indistinguishable from tumors arising in the posterior urethra. 6 • 6 • 12 They tended to invade the prostatic stroma and to displace acini. It was in this group that transurethral resections and/or perinea! prostatic biopsies presented a variety of perplexing patterns, sometimes leading to errors in management. The
]J_:lALKGNA.N'f EPITHELIAL 'fU?"'iOR.S
tumor cells wex-e now,""'· to tha Gomori were not associated with a rise serum acid phosphatase and were not androgen-dependent. Osseous metastases, when present, were sometimes lytic and patients who had bilateral orchiectorny and estrogen administration did poorly. 6
PARAPROSTATIC TUMORS
The prostatic territory facing the posterior urethra harbors 3 structures: 1) the dorsal mucosa of the posterior urethra, which is intimately attached to the gland, 2) the verumontanum with its utricle and 3) the ejaculatory ducts, which are intruders tunneling their way through the prostate to the urethral lumen. Tumors of the prostatic urethra. The prostatic urethra is a conglomerate lined by cuboidal and squamous epithelium and is pierced by the meatus of the prostatic ductules, ejaculatory ducts and openings of the glands of Littre, crypts and lacunae (fig. 2). Into its lumen juts the promontory of the verumontanum. The area is the twilight zone in the spectrum of neoplasms of the prostatic territory because the patterns produced by these paraprostatic structures varied considerably and their origin could not always be pinpointed. 13 - 15 Urothelial or squamous cell neoplasms often started as carcinomas in situ and later invaded the prostate, compressing, destroying and replacing acini (fig. 4). 13 • 16 Biopsies obtained during transurethral procedures revealed intense inflammation plus hyperplasia and metaplasia of Brunn's nests, and urethritis cystica or glandularis. Masses of cells in disarray, either urothelial or squamous, with an occasional epithelial pearl were observed in biopsies. Rarely, mucin-producing adenocarcinomas occurred. The serum acid phosphatase was either normal or only slightly elevated. These growths were not hormone-dependent and patients treated with estrogens and/or orchiectomy did poorly. After prolonged hormone administration some of the patients suffered urethral obstruction, which required repeated transurethral resection. The tissue revealed squamous cell metaplasia, intense keratinization and a sarcomatoid change. Rarely a pagetoid lesion was observed in the urethra accompanied by a carcinoma of the prostatic ducts and/or acini. 17 Tumors of the utricle. These interesting but rare tumors were usually exophytic, sometimes endophytic, or a combination of both (fig. 5). The patients came to the hospital because of urethral bleeding or hematuria. A surprise finding at cystoscopy was the wormy mass emanating from the utricle or its margin at the apex of the verumontanum. The site of origin was important but usually missed, even during transurethral resection. Sections showed a high columnar epithelium that was convoluted, papillary or in pseudoglandular formation. Cells were devoid of pigment; cilia were sometimes present. There was a remarkable resemblance of these neoplasms to the uterine endometrial growths in the female (fig. 5, a) 11• rn- 21 resembled also the ductal carcinomas. There are some who doubt the existence of an endometrial tumor of this uterine remnant. This is equivalent to denying the possibility of a cancer of the male breast, also a female remnant, or a carcinoma of Skene's glands, which are homologues of the prostate in the female subject. In the endometrial tumors that we saw the serum acid phosphatase was not elevated and the patients did well without estrogen intake or sacrifice of the testes. In some cases (those with metastases) progesterone was administered with beneficial effect. In cases with an associated rnicroacinar cancer (androgen-dependent) the presence of the latter influenced treatment. 11 It is recommended that stains for acid and alkaline phosphatase be performed on all specimens obtained from papillary tumors of this region. Electron microscopy studies should also be performed. Tumors of the ejaculatory ducts (fig. 5, b). Buried in the prostate a neoplasm developing from either duct, when endophytic, resembled a prostatic ductal growth and was usually missed. However, when exophytic the tumors caused hema-
PROS'TATE GLAND
699
turia or and. we:re discovered investigative cystoscopy of urethroscopy. Usualiy a wormy polypoid mass was seen emanating slightly distal and lateral to the edge of the utricle. The component cells were clear, columnar, single or multilayered, and in ribbon-like branchings. The serum acid phosphatase was not elevated. This polypoid neoplasm of the ejaculatory duct or utricle should not be confused with true polyps, which occur in younger patients (4 to 40 years old) and arise from the urethra proximal to the verumontanmn. 22, 2s
FIG. 5. Paraprostatic tumors. a, endometrial carcinoma in situ of utricle. Note columnar cells. Tumor was exophytic and endophytic. Serum acid phosphatase was normal. Reduced from x300. Reproduced with permission. 18 b, papilloma of ejaculatory duct .. Patient was urethroscoped because of urethrorrhagia and papillary, brownish mass extending from left ejaculatory duct orifice was found. Section shows papillary infoldings lined by columnar cells. Yellowish lipochrome pigment was present in cytoplasm of some cells. Reduced from x 76. c, cancer of extraprostatic origin metastasizing to prostate. Perinea! cup biopsy was diagnosed as anaplastic carcinoma of gland. Patient was 39 years old and had had orchiectomy 7 years earlier for embryonal carcinoma of testis. Note hyperchromatic cells, applique forms. Note also benign prostatic acini. Reduced from x 192.
700
MELICOW AND USON EXTRAPROSTATIC TUMORS
REFERENCES
Invasion of the prostate by cancers of adjoining organs. Invasion by a solid urothelial or squamous cell carcinoma of the bladder neck or trigone sometimes produced an area of induration in the prostate discovered during rectal digital examination. This finding usually led to removal of tissue for histological examination by the closed (or open) perineal route. The distorted pathological picture obscured the true condition and a diagnosis of anaplastic carcinoma of the prostate was made. Routine orchiectomy was then performed and estrogens were administered without benefit to the patient. Serum acid phosphatase was not abnormal and metastases to bone, when present, were lytic. Cancer of Cowper's gland was not encountered in our series. Attention to the clinical story was helpful: pain in the perineum, discovery of a firm nodule on either side of the prostatic apex close to the external sphincter and urethroscopic finding of swelling in the region of the membranous urethra. The serum acid phosphatase was not elevated and patients did not benefit from orchiectomy or estrogen administration. Cancer of the seminal vesicle was confused with tumors of Blumer's or rectal shelf. It was symptomless during incipiency but steady growth induced pain in the perineum, hematuria, hemospermia or a brownish discharge. In most cases serum acid phosphatase levels were either not determined, or were normal when carried out or only moderately elevated. In some the lining cells were large, vacuolated and contained a brownish pigment (lipofuscin). In most cases the stain for mucin was also positive. When cancer of the rectum invaded the prostate the clinical history and findings were usual,ly helpful in recognizing the lesion. Biopsy revealed a high columnar epithelium forming glands producing mucin. There was a resemblance to an endometrial tumor or to a primary mucin-forming cancer of the prostate. The serum acid phosphatase was either normal or only slightly elevated. There was no hormone dependence. Metastases to prostate from cancer of distant organs. The prostate gland is not immune to metastasis and this was not a diagnostic problem in patients with disseminated cancer in whom the primary was known. However, there were patients with a cryptic malignancy in whom a hard nodule was palpated during a rectal digital examination and in whom histologic review of tissue obtained by a closed perinea! prostatic nodule or cup procedure revealed masses of anaplastic cells, leading to a diagnosis of an undifferentiatied prostatic cancer. The serum acid phosphatase was usually not elevated but this was attributed to the anaplasia. Bilateral orchiectomy and administration of estrogen affected these patients adversely. They soon died and at autopsy a primary cancer of the lung or pancreas, a lymphoma or malignant melanoma, and so forth with generalized metastases was found. Discovery of an anaplastic carcinoma in the biopsy of the prostate, particularly in patients less than 40 years old, should spur a thorough search to eliminate a possible extraprostatic source.
1. Kirchheim, D., Niles, N. R., Frankus, E. and Hodges, C. V.:
2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
12. 13'. 14. 15. 16.
17. 18. 19. 20. 21. 22. 23.
Correlative histochemical and histological studies of thirty radical prostatectomy specimens. Cancer, 19: 1683, 1966. Edgar, W. M.: Mucin-secreting carcinoma of the prostate. Brit. J. Urol., 30: 213, 1958. Sika, J. W. and Buckley, J. J.: Mucus-forming adenocarcinoma of prostate. Cancer, 17: 949, 1964. Melicow, M. M.: Xanthic lesions; report of 4 cases, including 2 of "xanthomatosis" of the kidney, and a case of xanthocarcinoma of the prostate. J.A.M.A., 105: 768, 1935. Bates, H. R., Jr. and Thornton, J. L.: Adenocarcinomas of primary prostatic ducts and utricle (letter to editor). Arch. Path., 96: 207, 1973. Drake, W. M., Jr. and Burrows, S.: Papillary carcinoma of prostatic ducts. Urology, 3: 621, 1974. Dube, V. E., Farrow, G. M. and Greene, L. F.: Prostatic adenocarcinoma of ductal origin. Cancer, 32: 402, 1973. Ende, N., Woods, L. P. and Shelley, H. S.: Carcinoma originating in ducts surrounding the prostatic urethra. Amer. J. Clin. Path., 40: 183, 1963. Rhamy, R. K., Buchanan, R. D. and Spalding, M. J.: Intraductal carcinoma of the prostate gland. J. Urol., 109: 457, 1973. Bates, H. R., Jr. and Thornton, J. L.: Carcinoma of the prostatic ducts. Amer. J. Clin. Path., 45: 96, 1966. Rotterdam, H. and Melicow, M. M.: Double primary prostatic adenocarcinoma: a report of two cases. Urology, 6: 245, 1975. Belter, L. F. and Dodson, A. I., Jr.: Papillomatosis and papillary adenocarcinoma of prostatic ducts: a case report. J. Urol., 104: 880, 1970. Greene, L. F., Mulcahy, J. J., Warren, M. M. and Dockerty, M. B.: Primary transitional cell carcinoma of the prostate. J. Urol., 110: 235, 1973. Johnson, D. E., Hogan, J.M. and Ayala, A. G.: Transitional cell carcinoma of the prostate. A clinical morphological study. Cancer, 29: 287, 1972. Rubenstein, A. B. and Rubnitz, M. E.: Transitional cell carcinoma of the prostate. Cancer, 24: 543, 1969. Franks, L. M. and Chesterman, F. C.: Intra-epithelial carcinoma of the prostatic urethra, periurethral glands and prostatic ducts (Bowen's disease of urinary epithelium). Brit. J. Cancer, 10: 223, 1956. Salazar, G. and Frable, W. J.: Extramammary Paget's disease: a case involving the prostatic urethra. Amer. J. Clin. Path., 52: 607, 1969. Melicow, M. M. and Pachter, M. R.: Endometrial carcinoma of prostatic utricle (uterus masculinus). Cancer, 20: 1715, 1967. Melicow, M. M. and Tannenbaum, M.: Endometrial carcinoma of uterus masculinus (prostatic utricle). Report of 6 cases. J. Urol., 106: 892, 1971. Satter, E. J. and Blumenfeld, C. M.: Endometrial carcinoma of the prostatic utricle. J. Urol., 112: 505, 197 4. Young, B. W. and Lagios, M. D.: Endometrial (papillary) carcinoma of the prostatic utricle-response to orchiectomy. A case report. Cancer, 32: 1293, 1973. Downs, R. A.: Congenital polyps of the prostatic urethra. A review of the literature and report of two cases. Brit. J. Urol., 42: 76, 1970. Nesbit, R. M.: The genesis of benign polyps in the prostatic urethra. J. Urol., 87: 416, 1962.
Vol. 115, June Printed in U.S.A.
JOURNAL OF UROLOGY
Copyright © 1976 by The Williams & Wilkins Co.
A SPECTRUM OF MALIGNANT EPITHELIAL TUMORS OF THE PROSTATE GLAND MEYER M. MELICOW
AND
AURELIO C. USON
From the Departments of Pathology and Urology, the Squier Urological Clinic and the Columbia University, College of Physicians and Surgeons, New York, New York
ABSTRACT
Conceptually, the prostatic territory encompasses neoplasms whose origins are intraprostatic, paraprostatic or extraprostatic. Our objectives in this review are to 1) present a classification of the spectrum of malignant epithelial growths encountered in the prostatic territory, 2) show examples of these neoplasms and remark upon their histogenesis, enzyme production and endocrine sensitivity, and 3) suggest re-evaluation of some of our current routine therapeutic procedures. A review of the histology of any large series of malignant epithelial prostatic neoplasms will reveal a wide range of pathological patterns, whose significance can be appreciated when correlated with the clinical picture and outcome. This statement is based on a study of available clinical material and tissue slides of some 1,600 patients with prostatic cancer treated since 1960. During this survey and after a concomitant
origin was traced to contiguous structures. Lesions metastatic to the prostate in which the primary source was cryptic were often misdiagnosed and mismanaged. Thus, we concluded that a presentation of a spectrum of malignant epithelial tumors arising in or involving the prostate gland would be helpful in diagnosis and treatment. Therefore we classified our cases as indicated in the table.
Patterns of epithelial tumors of prostate gland
I. Intraprostatic A. Glandular (adenocarcinoma) 1. Microacinar: origin usually in posterior lamella a. Early, latent or in situ b. Well differentiated c. Cribriform, sponge d. Anaplastic 2. Macroacinar: original from central sets of alveoli a. Patterns similar to lb, c and so forth but on larger scale b. May be associated with microacinar carcinoma c. May be associated with ductal carcinoma (junctional carcinoma) 3. Rare patterns: signet-ring, mucin-forming, xanthocarcinoma B. Cancer of prostatic ducts 1. Columnar-cell-lined a. Usually endophytic; rarely exophytic ("endometrioid") b. Junctional (with macroacinar cancer) 2. Periurethral urothelium-lined ducts: in situ, urothelial or squamous II. Paraprostatic, cancer of A. Urethral mucosa attached to prostatic bed: in situ, urothelial, squamous, pagetoid, adenocarcinoma, inverted papilloma B. Utricle: endometrial C. Ejaculatory duct ill. Extraprostatic, cancer A. By extension from neighboring organ: bladder, Cowper's gland, seminal vesicles, rectum and so forth B. By metastases from cancer of distant organs: lung, pancreas, stomach, lymphoma, malignant melanoma and so forth
review of pertinent literature we became aware that the prostate gland is not an isolated organ but is intimately bound to neighboring structures and tissues. There were variations in the morphopathology of some apparently primary prostatic tumors that were baffling. Occasionally, there was a discrepancy between the histological findings and expected enzyme activity. Some histologic patterns were confusing until their Accepted for publication September 19, 1975. Read at annual meeting of American Urological Association, Miami Beach, Florida, May 11-15, 1975. Aided by a grant from the Irene Heinz Given and John LaPorte Given Foundation.
INTRAPROSTATIC TUMORS
Glandular adenocarcinoma. This group, by far the most numerous, comprised intrinsic epithelial tumors of the gland, which displayed 2 main patterns that were often intermixed: microacinar and macroacinar. The former was more common and, in most instances, apparently arose from the cells lining the acini of the peripheral secretory units of the posterior or posterolateral lamella or lobe, while the latter developed mainly from the cephalic central glands and their junctional or secondary ducts. The patterns of microacinar adenocarcinoma are early
696
MALIGNANT EPITHELIAL TUMORS OF PROSTATE GLAND
697
FIG. 1. Some variations in patterns of intraprostatic tumors. a, from microacinar: cribriform pattern showing intra-acinar invasion. b, sponge pattern after invasion of loose tissue, viscus or retroperitoneum. c, from macroacini of central or cephalic region: cribriform pattern composed of large cells. Reduced from x200.
(latent or in situ), well differentiated, cribriform (fig. 1, a), sponge (fig. 1, b) and anaplastic. In all these types except some of the anaplastic, intracellular production of acid phosphatase could be demonstrated by the Gomori stain. 1 In the latter, foci of dedifferentiated cells did not take the stain. Serum acid phosphatase was elevated in all when tissue, or lymphatic or SHORT DUCT perineural spaces were invaded. Bone marrow acid phosphatase activity was elevated at times, even when the serum level was not. Microscopic foci of metastases were demonstrated in biopsies of bone, even in some cases with negative radiographic or scan studies. All these types, except some of the completely anaplastic variety, were androgen-dependent. In the latter, dedifferentiation was exemplified by a steady reduction in cell size and their spread in solid sheets or irregular clumps. Some MIDDLE LOBE 2. Region of subcervlcal lobule (Albarran) resembled lymphoma, granuloma or anaplastic secondary 3. " " subtrigonol " (Home) LATERAL LOBES 4. sho(I ductules 5. long ductules tumors. Mitoses were rare. In some cells nuclei were absent, POSTERIOR LAMELLA 6. while in others they were large and deep staining. Rarely, a A. UTRICLE. Orifices of: B. Ejaculatory Ducts, C. Prostatic duciules, O. Cowper's Glands. small round cells with clear cytoplasm were seen-perhaps a ----variant estrogen effect. There was often a drop in the level of enzyme production concomitant with the degree of anaplasia. In some instances osseous metastases were lytic as well as blastic. The patterns of macroacinar adenocarcinoma are shown in figure 1, c. These cancers arose from the columnar cells lining the central cephalic alveolar secretory units and their junctional ducts. Generally, the patterns were similar to the microacinar variety in all respects but size. Epithelial buds I. ANTERIOR LOBE and papillary infoldings were present frequently and also 2. 8, 3. MIDDLE LOBE occasionally a cribriform design. An association with a microacinar component was frequent. Serum acid phosphatase elevation was not always demonstrable, perhaps because of the initial central localization of the tumor and absence of tissue space violation. The macroacinar cancers often were associated B. EJACULATORY DUCT C. ORIFICES of PROSTATIC DUCTS with a similar process in the large columnar cell-lined ducts D. COWPER'S GLAND (junctional tumors). Rare patterns, such as signet-ring, mucin-forming adenocarb M,M.M.,uc<>w,u.o.
Fm. 2. Schematic representation of a, transverse horizontal and b, sagittal vertical sections of prostate gland. Note close relationship of subcervical and subtrigonal glandules to urethra and bladder (2 and 3). Note long and short ductules: some possess columnar epithelium at junction with alveoli, while periurethrally they are lined by urothelium like that of posterior urethra. 4 and 5 refer to lateral lobes; 6 to posterior lobe or lamella. All are intraprostatic and their cancers,
except those that arise from urothelium-lined periurethral ductules, are androgen-dependent. Utricle (A), ejaculatory ducts and orifices (B) and mucosa of posterior urethra attached to prostate comprise paraprostatic zone. Natural history, clinical course and endocrine dependence of tumors arising from these structures differ from those of intraprostatic origin.
698
MELICOW AND USON
Fm. 3. a, section shows dilated portion of prostatic duct lined by single layer of low columnar cells (arrow) and narrow portion with heaped up cuboidal cells resembling urothelium. Reduced from x76. b, carcinoma of prostatic duct composed of columnar cells in papillary array. This type of tumor, when exophytic into posterior urethra, has in some cases been labeled endometrioid. Reduced from x 175.
Fm. 4. Paraprostatic tumors. a, urothelial carcinoma of prostatic urethra has invaded gland proper which, coincidentally, is seat of microacinar adenocarcinoma-collision tumor (arrows). Reduced from x160. b, squamous cell carcinoma arising from metaplastic urethral epithelium invading prostate. Reduced from x63. Cancers of posterior urethra invading prostate are similar histologically to those arising from urothelium of periurethral prostatic ductules. None is hormonally dependent.
cinomas (adenoid cystic carcinoma)'· 3 and xanthocarcinomas, • presented problems in diagnosis. In the 2 former types it was essential to rule out a primary focus in the alimentary tract or bladder, while in the latter type the lesion required differentiation from a xanthogranuloma. Xanthogranulomas and xanthocarcinomas appeared orange-colored on section of the gross specimen. Serum acid phosphatase was usually elevated. Ductal tumors. Tumors arising from the prostatic ducts were uncommon, their patterns varied and they were often misdiagnosed. 5 • 9 There is a complexity here that requires clarification. The ducts and ductules draining the secretory alveoli often have a dual lining: 1) the segments continuous with the alveoli are lined by a columnar epithelium, which is possibly secretory, and 2) the segments that continue toward the meatus in the posterior urethra (periurethral ductules) possess a heaped up urothelium contiguous with that lining the meatus and posterior urethra (figs. 2 and 3). Because of this
variation in pavement of the prostatic duct system 2 types of neoplasms were encountered. Carcinomas of the columnar cell-lined ducts, the first type, were usually confined to the gland but at times they were also exophytic into the lumen of the posterior urethra (fig. 3, b). They also occasionally were continuous with a macroacinar cancer (junctional tumors). Some were not accompanied by an elevated serum acid phosphatase, perhaps because of their central location. The exophytic component resembled endometrial tumors and has been labeled endometrioid. In the majority of cases metastases to bone were blastic. 7 • 9 - 11 Neoplasms of the periurethral primary prostatic ductules, the second type, were either urothelial or squamoid-indistinguishable from tumors arising in the posterior urethra. 6 • 6 • 12 They tended to invade the prostatic stroma and to displace acini. It was in this group that transurethral resections and/or perinea! prostatic biopsies presented a variety of perplexing patterns, sometimes leading to errors in management. The
]J_:lALKGNA.N'f EPITHELIAL 'fU?"'iOR.S
tumor cells wex-e now,""'· to tha Gomori were not associated with a rise serum acid phosphatase and were not androgen-dependent. Osseous metastases, when present, were sometimes lytic and patients who had bilateral orchiectorny and estrogen administration did poorly. 6
PARAPROSTATIC TUMORS
The prostatic territory facing the posterior urethra harbors 3 structures: 1) the dorsal mucosa of the posterior urethra, which is intimately attached to the gland, 2) the verumontanum with its utricle and 3) the ejaculatory ducts, which are intruders tunneling their way through the prostate to the urethral lumen. Tumors of the prostatic urethra. The prostatic urethra is a conglomerate lined by cuboidal and squamous epithelium and is pierced by the meatus of the prostatic ductules, ejaculatory ducts and openings of the glands of Littre, crypts and lacunae (fig. 2). Into its lumen juts the promontory of the verumontanum. The area is the twilight zone in the spectrum of neoplasms of the prostatic territory because the patterns produced by these paraprostatic structures varied considerably and their origin could not always be pinpointed. 13 - 15 Urothelial or squamous cell neoplasms often started as carcinomas in situ and later invaded the prostate, compressing, destroying and replacing acini (fig. 4). 13 • 16 Biopsies obtained during transurethral procedures revealed intense inflammation plus hyperplasia and metaplasia of Brunn's nests, and urethritis cystica or glandularis. Masses of cells in disarray, either urothelial or squamous, with an occasional epithelial pearl were observed in biopsies. Rarely, mucin-producing adenocarcinomas occurred. The serum acid phosphatase was either normal or only slightly elevated. These growths were not hormone-dependent and patients treated with estrogens and/or orchiectomy did poorly. After prolonged hormone administration some of the patients suffered urethral obstruction, which required repeated transurethral resection. The tissue revealed squamous cell metaplasia, intense keratinization and a sarcomatoid change. Rarely a pagetoid lesion was observed in the urethra accompanied by a carcinoma of the prostatic ducts and/or acini. 17 Tumors of the utricle. These interesting but rare tumors were usually exophytic, sometimes endophytic, or a combination of both (fig. 5). The patients came to the hospital because of urethral bleeding or hematuria. A surprise finding at cystoscopy was the wormy mass emanating from the utricle or its margin at the apex of the verumontanum. The site of origin was important but usually missed, even during transurethral resection. Sections showed a high columnar epithelium that was convoluted, papillary or in pseudoglandular formation. Cells were devoid of pigment; cilia were sometimes present. There was a remarkable resemblance of these neoplasms to the uterine endometrial growths in the female (fig. 5, a) 11• rn- 21 resembled also the ductal carcinomas. There are some who doubt the existence of an endometrial tumor of this uterine remnant. This is equivalent to denying the possibility of a cancer of the male breast, also a female remnant, or a carcinoma of Skene's glands, which are homologues of the prostate in the female subject. In the endometrial tumors that we saw the serum acid phosphatase was not elevated and the patients did well without estrogen intake or sacrifice of the testes. In some cases (those with metastases) progesterone was administered with beneficial effect. In cases with an associated rnicroacinar cancer (androgen-dependent) the presence of the latter influenced treatment. 11 It is recommended that stains for acid and alkaline phosphatase be performed on all specimens obtained from papillary tumors of this region. Electron microscopy studies should also be performed. Tumors of the ejaculatory ducts (fig. 5, b). Buried in the prostate a neoplasm developing from either duct, when endophytic, resembled a prostatic ductal growth and was usually missed. However, when exophytic the tumors caused hema-
PROS'TATE GLAND
699
turia or and. we:re discovered investigative cystoscopy of urethroscopy. Usualiy a wormy polypoid mass was seen emanating slightly distal and lateral to the edge of the utricle. The component cells were clear, columnar, single or multilayered, and in ribbon-like branchings. The serum acid phosphatase was not elevated. This polypoid neoplasm of the ejaculatory duct or utricle should not be confused with true polyps, which occur in younger patients (4 to 40 years old) and arise from the urethra proximal to the verumontanmn. 22, 2s
FIG. 5. Paraprostatic tumors. a, endometrial carcinoma in situ of utricle. Note columnar cells. Tumor was exophytic and endophytic. Serum acid phosphatase was normal. Reduced from x300. Reproduced with permission. 18 b, papilloma of ejaculatory duct .. Patient was urethroscoped because of urethrorrhagia and papillary, brownish mass extending from left ejaculatory duct orifice was found. Section shows papillary infoldings lined by columnar cells. Yellowish lipochrome pigment was present in cytoplasm of some cells. Reduced from x 76. c, cancer of extraprostatic origin metastasizing to prostate. Perinea! cup biopsy was diagnosed as anaplastic carcinoma of gland. Patient was 39 years old and had had orchiectomy 7 years earlier for embryonal carcinoma of testis. Note hyperchromatic cells, applique forms. Note also benign prostatic acini. Reduced from x 192.
700
MELICOW AND USON EXTRAPROSTATIC TUMORS
REFERENCES
Invasion of the prostate by cancers of adjoining organs. Invasion by a solid urothelial or squamous cell carcinoma of the bladder neck or trigone sometimes produced an area of induration in the prostate discovered during rectal digital examination. This finding usually led to removal of tissue for histological examination by the closed (or open) perineal route. The distorted pathological picture obscured the true condition and a diagnosis of anaplastic carcinoma of the prostate was made. Routine orchiectomy was then performed and estrogens were administered without benefit to the patient. Serum acid phosphatase was not abnormal and metastases to bone, when present, were lytic. Cancer of Cowper's gland was not encountered in our series. Attention to the clinical story was helpful: pain in the perineum, discovery of a firm nodule on either side of the prostatic apex close to the external sphincter and urethroscopic finding of swelling in the region of the membranous urethra. The serum acid phosphatase was not elevated and patients did not benefit from orchiectomy or estrogen administration. Cancer of the seminal vesicle was confused with tumors of Blumer's or rectal shelf. It was symptomless during incipiency but steady growth induced pain in the perineum, hematuria, hemospermia or a brownish discharge. In most cases serum acid phosphatase levels were either not determined, or were normal when carried out or only moderately elevated. In some the lining cells were large, vacuolated and contained a brownish pigment (lipofuscin). In most cases the stain for mucin was also positive. When cancer of the rectum invaded the prostate the clinical history and findings were usual,ly helpful in recognizing the lesion. Biopsy revealed a high columnar epithelium forming glands producing mucin. There was a resemblance to an endometrial tumor or to a primary mucin-forming cancer of the prostate. The serum acid phosphatase was either normal or only slightly elevated. There was no hormone dependence. Metastases to prostate from cancer of distant organs. The prostate gland is not immune to metastasis and this was not a diagnostic problem in patients with disseminated cancer in whom the primary was known. However, there were patients with a cryptic malignancy in whom a hard nodule was palpated during a rectal digital examination and in whom histologic review of tissue obtained by a closed perinea! prostatic nodule or cup procedure revealed masses of anaplastic cells, leading to a diagnosis of an undifferentiatied prostatic cancer. The serum acid phosphatase was usually not elevated but this was attributed to the anaplasia. Bilateral orchiectomy and administration of estrogen affected these patients adversely. They soon died and at autopsy a primary cancer of the lung or pancreas, a lymphoma or malignant melanoma, and so forth with generalized metastases was found. Discovery of an anaplastic carcinoma in the biopsy of the prostate, particularly in patients less than 40 years old, should spur a thorough search to eliminate a possible extraprostatic source.
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