Ectopic Prostatic Tissue in Urethra: A Clinicopathological Entity and a Significant Cause of Hematuria

THE JOURNAL OF UROLOGY

Vol. 105, Jan. Printed in U.S.A.

Copyright © 1971 by The Williams & Wilkins Co.

ECTOPIC PROSTATIC TISSUE IN URETHRA: A CLI='JICOPATHOLOGICAL ENTITY AND A SIGNIFICANT CAUSE OF HE:\IATURIA JAMES D. BUTTERICK,* BERTRAM SCHNITZER ..\.ND MURRAY R. ABELL From the Department of Pathology, The University of Michigan Medical Center, Ann Arbor, Michigan

In 1962 N esbit1 described the occurrence of ectopic prostatic tissue in the prostatic urethra and discussed its clinical manifestations and pathogenesis. However, the lesion has not received the recognition it deserves particularly as a cause of hematuria in the young male adult. Some skepticism has been expressed about its prostatic nature. Since N esbit's report, we have encountered many additional examples of this condition and herein we will critically assess their clinical, histological and ultrastructural features.

dehydrated through alcohols and propylene oxide and embedded in epoxy resin (epon 812). Sections 1 µ. thick were stained with toluidine blue and used for orientation. Thin sections were cut with glass knives on a Porter-Blum microtome and doubly stained with aqueous 1 per cent uranyl acetate and lead citrate. 4 The grids were examined and photographed with an RCA El\IU 3H electron microscope. 18 16

MATERIALS AND METHODS

Of 73 cases of ectopic prostatic tissue of the urethra seen between July 1960 and July 1969, 5 cases were excluded from detailed consideration because of questionable tissue diagnoses, uncertainty as to site of biopsy and grossly inadequate clinical information. One example of ectopic tissue in the bladder was also excluded. 2 Clinical findings and the cystoscopic and microscopic characteristics of the remaining fully acceptable cases were assessed in detail. Five of these cases were probably included in the report by Nesbit. 1 In addition to routine hematoxylin and eosin stained preparations on all specimens, sections from a number of cases were stained for calcium, iron and acid phosphatase by the Gomori technique, by the periodic acid-Schiff reaction and with alcian green. Ectopic prostatic tissue from the urethra of 3 patients and prostatic tissue from 1 patient with benign glandular hyperplasia were prepared for ultrastructural studies. These tissues were immersed immediately in cold cacodylate-buffered 4 per cent glutaraldehyde, pH 7.4, diced into 1 mm. cubes and fixed for 24 hours. Tissue blocks were post-fixed in Zetterqvist's 3 osmium solution,

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Age Distribution of Coses

FIG. 1 OBSERVATIONS

Clinical features. The age range of the patients

was 13 to 63 years with a mean of 31 years (fig. 1). The majority of patients were in the range of 16 to 35 years of age. Hematuria was a sign in 65 of 68 patients. Intermittent gross hematuria was observed in 46 patients (68 per cent) and was usually total, less frequently initial or terminal. Microscopic

Accepted for publication January 23, 1970. * Work done in part while Clinical Cancer Student Fellow supported by the National Institutes of Health, Grant Tl2 CA 08098-04. 1 Nesbit, R. M.: The genesis of benign polyps in the prostatic urethra. J. Urol., 87: 416, 1962. 2 Gutierrez, J. and Nesbit, R. M.: Ectopic prostatic tissue in bladder. J. Urol., 98: 474, 1967. 3 Zetterqvist, H.: The ultrastructural organiza-

tion of the columnar absorbing cells of the mouse jejunum. Thesis, Department of Anatomy, Karolinska Institute, Stockholm, 1956. 4 Reynolds E. S.: The use of lead citrate at high pH as an el~ctron-opaque stain in electron microscopy. J. Cell Biol., 17: 208, 1963. 97

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Fw. 2. A, polyp from prostatic urethra consisting of nodule of pros ta tic acini covered by thin transitional epithelium. H & E, reduced from 90X. B, luminal surface of ectopic prostate from pros ta tic urethra. Edematous fibrovascnlar folds are covered by columnar epithelium of prostatic type which is continuous with underlying prostatic acini. H & E, reduced from 97X.

hematuria was documented in 23 patients (34 per cent) and 4 of these were patients with gross hematuria. The duration of the hematuria ranged from less than 1 week for 7 cases to more than 2 years for 6 cases. Fifty patients had known hematuria for less than 1 year. Of the 3 patients without demonstrable hema-

turia, 1 had a bloody discharge following intercourse, 1 had symptoms of prostatism and urethral obstruction and 1 gave evidence of chronic urinary tract disease. Other complaints in 28 cases (41 per cent) were dysuria and urinary frequency. Only 5 patients had documented urinary tract infection.

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FIG. 3. A, characteristic prostatic acm1 formed of uniform colnmnar cells with pale cytoplasm and small, spherical, basally placed nuclei. H & E, reduced from 200X. B, ectopic pros ta tic acini formed of characteristic glandular and basal cells. Central acinus contains corpora amylacea and small dark cytoplasmic bodies are discernible in the epithelial cells at right. H & E, reduced from 400X.

All lesions but one were restricted to the prostatic urethra. The exception was located at the outlet of the bladder. In 27 instances (40 per cent) lesions were described as being on the verumontanum, while 12 (18 per cent) were at the base of the verumontanum and 10 (15 per

cent) were distal to it. The other lesions were listed merely as being in the posterior urethra. The most frequently used terms to describe the gross appearance of the lesions in situ were frond-like, filiform, papillomatous and papilliferous; less commonly they were called polyp,

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Fm. 4. A, prominent cytoplasmic bodies in ectopic prostatic epithelium. PAS, reduced from 450X. B, black stippling indicative of acid phosphatase in ectopic prostatic tissue. Gomori method, reduced from 400X. mass or cap. In recent years gross descriptions often have been lacking since the urological staff has become so accustomed to recognizing the lesion that they often report it as ectopic prostatic tissue in their cystoscopic reports. Jl!licroscopic features. All lesions consisted of prostatic acini of varying sizes and shapes, sometimes complete with corpora amylacea

(figs. 2 and 3). urothelium and, to a lesser extent, prostatic epithelium covered the polypoid lesions (fig. 2, A). Immediately beneath their surfaces were characteristic prostatic glands. The papillary lesions consisted of fibrovascular papillae projecting into the urethral lurnens and covered by prostatic epithelium continuous with that of underlying prostatic glands (fig. 2, B). The

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Fw. 5. A, electron micrograph of 3 glandular cells of acinus from ectopic prostatic tissue. Cytoplasm contains numerous secretory vacnoles (SV) many of which contain an electron-dense secretory product. Parallel flattened cisternae of Golgi (G) are prominent. Microvilli (}\!IV) project into lumen (L) of acinus. Mitochondria (ilf) and dense bodies (DB) are present. Lead citrate and uranyl acetate, reduced from 11,000X. B, higher magnification of glandular cells containing dense bodies (DB) and secretory vacuoles (SV), nucleus (N) and ribosomes (arrows). Lead citrate and uranyl acetate, reduced from 29,500X.

supportive fibrovascular stroma about the glands was scant to moderate with a few bands of smooth muscle in some specimens. Inflammation, when present, was a minor component and consisted of scattered lymphocytes. There were

superficial erosions of some of the papillary projections. The prostatic epithelium was columnar or cuboidal with faintly stained reticulated or vacuolated cytoplasm and basally situated small,

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Fm. 6. Higher magnification of luminal portion of 3 glandular cells of figure 5, A. Plasma membranes (PM) show complex interdigitations. Desmosomes (D) are seen at apical part of cells. Secretory vacuole (SV) appears to be discharging its contents into acinar lumen (L). Free cytoplasmic ribosomes (arrow) are present. Lead citrate and uranyl acetate, reduced from 31,000X. round to oval nuclei (fig. 3). Within the epithelial cytoplasm of all specimens were small, somewhat irregular bodies which were deeply basophilic in the routine hematoxylin and eosin stains. These bodies gave negative reactions for iron and calcium but stained intensely with the periodic acidSchiff reaction and with the alcian green stain (fig. 4, A). The corpora amylacea gave the same staining reactions. The acid phosphatase stains revealed positive diffuse intracytoplasmic reactions of the type seen in the epithelium of normal prostatic glands (fig. 4, B). Electron microscopic .findings. Ultrastructural features of the acinar cells of the ectopic prostatic

tissue and the hyperplastic prostate were essentially identical. The epithelium of both consisted of 2 types of cells~large cells which reached the luminal surface of the acini and smaller cells which did not appear to extend to the surface. The cells which border on the surface have been termed the glandular cells and those which do not the basal cells. 5 , 6 5 Brandes, D., Kirchheim, D. and Scott, W.W.: Ultrastructure of the human prostate: normal and neoplastic. Lab. Invest., 13: 1541, 1964. 6 Fisher, E. R. and Jeffrey, W.: Ultrastructure of human normal and neoplastic prostate; with comments relative to prostatic effects of hormonal stimulation in the rabbit. Amer. J. Clin. Path., 44: 119, 1965.

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FIG. 7. Electron micrograph of 2 basal cells. Cytoplasm is more election-dense than glandnlar cells and contains more mitochondria (M) and ribosomes (R). Rongh endoplasmic reticulum (short arrow) may be seen. Complex infoldings of plasma membranes of these adjoining cells are seen (long a.rrow) and nucleus (N). Lead citrate and uranyl acetate, reduced from 14,000X. The glandular cells were more common than the basal cells and were characterized by numerous cytoplasmic vacuoles which were especially prominent in the supranuclear regions (fig. 5, A). These vacuoles were irregular in shape and size and were bound by single membranes. Some appeared to fuse with neighboring vacuoles. Varying amounts of amorphous electron-dense material were noted within some of the vacuoles while other vacuoles appeared devoid of this material. The Golgi apparatuses were conspicuous and were located on the luminal sides of the nuclei. In addition, the glandular cells contained mitochondria which were relatively few in number, dense bodies and free cytoplasmic ribosomes (fig. 5, B). :\Iembranes of endoplasmic reticulum were infrequently seen and were usually studded with ribosomes. The nuclei of the glandular cells were round to oval, fairly uniform in size and basally located. Nucleoli were occasionally observed. The luminal surfaces of the cells formed numerous projecting microvillous structures. Desmosomal connections were seen between the cells in addition to rather complex intercellular interdigitations of the plasma membranes (fig. 6). In contrast to the glandular cells, the basal cells were more electron dense, contained few or no cytoplasmic vacuoles but had more mito-

chondria and more cytoplasmic ribosomes (fig. 7). The endoplasmic reticulum which was not often observed was mainly granular. Complex infoldings of plasma membranes between cells were conspicuous (fig. 7). DISCUSSION

The notion that prostatic tissue in an abnormal location might be of clinicopathologic significance is not new. In 1928 Goodale described a submucosal cystadenoma of the bladder which he believed had developed from aberrant prostatic glands. 7 He cited earlier reports by Jores 8 and Thorel 9 of aberrant prostate in various locations. Randall divided benign polyps of the prostatic urethra into fibrous, villous and glandular types. 10 He postulated that the latter type might have arisen from a "tuft" of aberrant prostatic tissue as a result of early prostatic hypertrophy 7 Goodale, R. H.: Cystadenoma of the bladder from aberrant prostatic gland. Arch. Path., 6: 210, 1928. 8 J ores, L.: Ueber die Hypertrophie des sogen· annten mittleren Lappens der Prostata. Arch. f. path. Anat., 135: 224, 1894. 9 Thorel, C.: Ueber die Aberration von Prostatadriisen und ihre Beziehnng zn den Fibroadenomen der Blase. Beitr. klin. Chir., 36: 630, 1902. 10 R.andall, A.: A study of the benign polyps of the male urethra. Surg., Gynec. & Obst., 1.7: 548,

1913.

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and described an example in a 30-year-old man which histologically consisted of scant connective tissue stroma and numerous acini lined by tall columnar epithelium. Lazarus reported 3 examples of "adenomata" which he believed probably arose from submucosal glands of the prosta tic urethra. There have been other reports of urethral polyps but they have been more akin to Randall's fibrous and villous varieties. The lesions reported in this paper bear a resemblance to the adenomas described by Randall 10 and Lazarus 11 but none to the polyps described in the more recent literature except those reported by N esbit 1 and Gutierrez and N esbit. 2 Since Nesbit's report in 1962, many cases have been diagnosed at this medical center and ectopic prostate is considered to be one, if not the most common, cause of hematuria in the young male adult. Several patients in our series had clinical diag110.~es of chronic renal disease with persistent microhematuria or intermittent gross hematuria until cystoscopic examinations revealed ectopic prostatic tissue to be the cause of the hematuria. Subsequent studies on the majority of cases presented here indicate that simple fulguration has been curative for the hematuria. There has been no evidence of recurrent growth or malignant transformation. Microscopic features, histochemical characteristics of cells and their cytoplasmic bodies and ultrastructural studies support the conclusion that the lesions described are truly of prostatic nature. The ;;taining reactions of the cytoplasmic bodies were the same as those described in the acinar epithelium of the prostatic glancl12 and as those of prostatic corpora amylacea. 13 There were no morphological differences between the acinar cells of the aberrant prostate and those of hyperplastic and normal prostates. The glandular cells contained well-formed Golgi apparatuses and numerous vacuoles typical of a secretory type of cell. Expulsion of secretory products from vacuoles into the acinar lumens was seen and in some areas similar secretory material was present in the lumens. The dense bodies which also have been observed by other investigations have been 11 Lazarus, J. A.: Primary benign tnmors of the urethra; report of three cases. Urol. & Cutan. Rev., 37: 604, 1933. 12 Brandes, D. and Bourne, G. H.: Histochemistry of the hnman prostate: normal and neoplastic. J. Path. Bact ., 71: 33, 1956. 13 Smith, V.: Prostaiic corpora amylacea and their calcification. Surg. Forum, 16: 501, 1965.

shown to contain acid phosphatase12 and therefore represent lysosomes. The basal cells which did not contain secretory vacuoles are probably reserve cells and do not participate in the secretory function of the acini. Our evidence clearly confirms N esbit's contention that these lesions consist of prostatic epithelium but the pathogenesis remains uncertain. Inflammation would not appear to be a significant factor as clinical evidence of such was only occasionally present and microscopically it was absent or minimal. The presence of small nests of prostatic acini beneath the mucosa of the upper urethra and bladder neck has been described. 8 The few polypoid specimens covered entirely by a transitional epithelium could have developed as post-pubertal hyperplasia of these foci. It would not explain the majority of polypoid lesions and the papillary lesions in which the prostatic gland cells fronted on the urethral lumen. A prostatic gland prosopla.~ia of transitional epithelium would account for this finding but the possibility seems unlikely. Nesbit suggested that the lesions might represent persistent evaginations of glandular epithelium which normally invaginate to form the prostate during embryonic development. 1 This hypothesis most readily explains the position and structure of the lesions. No symptomatic examples of ectopic prostate have been encountered prior to puberty suggesting that hormonal stimulation may play a pathogenetic role. Our experience would indicate that ectopic prostatic tissue in the urethra should be seriously considered as the cause of hematuria in the postpubertal male individual in the absence of readily demonstrable renal disease. SUMMARY

Clinical manifestations and structural characteristics of 68 examples of ectopic prostatic tissue from the prostatic urethra have been assessed. They occurred predominately in young men and the presenting symptom was usi~ally hematuria, gross or microscopic. Histological, histochemical and ultrastructural characteristics of the lesions confirmed their prostatic nature. A developmental abnormality most readily explains their position and structure. Professor J. Lapides assisted in obtaining the fresh specimens for the histochemical and ultrastructural studies.