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Prostatic Maldevelopment in the Prune Belly Syndrome: A Defect in Prostatic Stromal-epithelial Interaction
0022-534 7/78/1203-0341$02. 00/0 Vol. 120, September
THE JOURNAL OF UROLOGY
Printed in U.SA.
Copyright © 1978 by The Williams & ~ilkins Co.
PROSTATIC MALDEVELOPMENT IN THE PRUNE BELLY SYNDROME: A DEFECT IN PROSTATIC STROMAL-EPITHELIAL INTERACTION D. P. DEKLERK*
AND
W. W. SCOTT
From the James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Maryland
ABSTRACT
The prune belly syndrome consists of a triad of abdominal wall musculature deficiency, cryptorchidism and urinary tract anomalies. A rarely described but fairly constant component of the syndrome is the lack of development of the epithelial elements of the prostate. We wish to suggest that this is a further expression of a postulated arrest in mesenchymal development responsible for other features of the syndrome. The prune belly syndrome consists of a triad of abdominal wall musculature deficiency, cryptorchidism and urinary tract anomalies. 1• 2 The urinary tract anomalies include renal dysplasia, ureteral dilatation, a dilated, non-trabeculated bladder and urethral stenosis. Associated defects include gastrointestinal anomalies such as malrotation of the gut, imperforate anus and lower extremity anomalies such as talipes equinus varus and congenital dislocation of the hip. A recognized but poorly described feature of the syndrome is the lack of development of the epithelial elements of the prostate. Herein we wish to indicate the consistency of this anomaly and postulate that it may be owing to lack of normal epithelial-stromal interaction in prostatic organogenesis. MATERIALS
Reports and pathological slides from 17 autopsies performed at this hospital were reviewed. There were 8 patients with well documented prune belly syndrome, 3 with posterior urethral valves, 4 with isolated bilateral undescended testes after full-term pregnancy and 2 with so-called pseudo-prune belly syndrome. Adequate pathological slides of the prostate were available in 6 of the patients with prune belly syndrome. In all other patients adequate material for microscopic study was available. To study the prostate sections were generally taken at the level of the verumontanum but in some cases additional longitudinal sections of the prostate were available. RESULTS
Of the 8 cases of prune belly syndrome the absence of prostatic epithelial elements was documented in 5 (fig. 1), while in 1 case sparse glands were present with no sign of proliferation secretion. In 2 patients only gross descriptions were available. One of these apparently was normal, whereas in the other no prostatic tissue could be demonstrated at the time of autopsy. Occasionally, in those prostates with otherwise absent epithelial elements glands could be identified immediately beneath the urethral epithelium in the region of the prostatic utricle (fig. 2). In 3 of 5 cases when the prostatic utricle was clearly identifiable it was dilated markedly and showed squamous metaplasia. In 2 cases the mesenchymal elements could be divided clearly into 3 segments. The first segment was an inner collagenous periurethral area devoid of muscular elements or ducts, with the exception of the posterior submucosal area where occasional small epithelial elements were seen adjacent to the prostatic utricle in association with differentiated muscle fibers. A mid section with sparse muscular elements Accepted for publication November 23, 1977. * AUA scholar and funded in part by NIAMDD-AM19300.
and prominent intermuscular collagen was the second segment. No epithelial elements were noted in this area. In 1 patient this area had the appearance of a primitive mesenchyme with no differentiation to muscle or elaboration of collagen. The third segment was an outer section of relatively well developed muscle and fibroblasts (figs. 1 and 3). In 2 patients the membranous urethra was obstructed completely and no communications could be demonstrated with the anterior urethra. Three patients had membranous urethral stenosis, while in 1 instance mid penile urethral stenosis and in another prostatic urethral stenosis were found. In 3 cases no urethral stenosis could be demonstrated at autopsy. One patient had associated megalourethra. Pseudo-prune belly syndrome. Two patients were seen with features of pseudo-prune belly syndrome. The first case had normal abdominal musculature as well as bilateral cryptorchidism, hydronephrotic and dysplastic kidneys, dilated tortuous ureters and a dilated bladder with thickening of the bladder wall. The prostate was more mature than the previously described cases of prune belly syndrome, especially the stromal elements, but the epithelial elements were hypoplastic when compared to the normal patients of similar age. No anatomical urethral obstruction could be documented at autopsy. In the second case the abdominal wall, testicular, genitourinary and prostatic findings were similar to those of the first case, except for membranous urethral stenosis and a prominent posterior urethral squamous cyst, probably originating from the prostatic utricle. Posterior urethral valves and cryptorchidism. The prostates from patients with posterior urethral valves were studied to eliminate the possibility that the lack of prostatic epithelial development was owing to prostatic compression and dilatation. In all 3 cases of posterior urethral valves the glandular elements were compressed and dilated but otherwise they were developed normally (fig. 4). In 4 patients with bilateral undescended testes, but no abdominal wall deficiency and no other genitourinary defects, the prostates were developed normally and comparable to patients of similar age and development, suggesting, therefore, that in the prune belly syndrome the cryptorchidism was not responsible for the prostatic epithelial maldevelopment (fig. 5). DISCUSSION
The etiology of prune belly syndrome remains obscure. Since male subjects are involved almost exclusively X-linked recessive inheritance has been suggested2 but this seems unlikely because none of the male patients is fertile, male siblings are never involved and a few well documented female subjects with the syndrome have been reported. 3 Chromosomal abnormalities have been suggested4 but as indicated by 341
342
DEKLERK AND SCOTT
Fm. 1. Prostate from child with prune belly syndrome shows lack of glandular development and 3 layers described in text.
Rogers and Ostrow'i 7 reported cases of monozygotic twins with discordant involvement suggest a non-genetic developmental defect. Although a primary anomaly of the abdominal wall or primary obstruction of the urinary tract with subsequent maldevelopment of the abdominal wall was postulated in early discussions of the syndrome, a primary mesenchymal developmental arrest, presumably of the lateral and possibly of the intermediate mesoderm, between 5 and 10 weeks of gestation, now seems likely. 1 This is an attractive postulate, since the resulting mesenchymal non-differentiation would, theoretically, be incapable of inducing abdominal striated and urinary tract smooth musculature. In addition, if the gubernaculum has a role in testicular descent a gubernacular insensitivity to the physiological stimulus responsible for the testicular descent would result in bilateral cryptorchidism. Unfortunately, the gubernaculum was not available for microscopic analysis in this study. A further consequence of poor mesenchymal development may be the lack of induction of the prostatic epithelium by the urogenital sinus mesenchyme. During the third month of gestation (56 to 65 mm. fetus) the fetal prostate develops through the ingrowth of endodermal urogenital sinus buds into the surrounding mesenchyme." The elegant recombinant studies of Cunha have suggested that this induction of prostatic epithelial development is dependent on a competent urogenital stroma but that the role of the mesenchyme is not in the transmission of the androgenic stimulus. i; Prostatic stroma receives contributions from the urogenital sinus, the wolffian duct (the ejaculatory ducts) and the miillerian system (the prostatic utricle), 7 • 8 and it is interesting that the urogenital sinus and wolffian duct mesenchyme can induce prostatic epithelial differentiation in recombinant studies, whereas
Fm. 2. Prostatic utricle with surrounding well developed glands
non-genital mesenchyme is inert. 6 It is well established that dihydrotestosterone is required for prostatic development, while testosterone per se is capable of inducing wolffian derivatives, such as the seminal vesicle, vas deferens and the epididymis. 9 • 10 It is by no means clear whether the urogenital mesenchyme is dependent on a hormonal stimulus, although it has been suggested that estrogens are required for the development of the prostatic fibromuscular stroma. Normally, during the last 2 months of fetal development, prostatic epithelial proliferation occurs under the influence of maternal gonadotropins, 11 so that at birth the male fetus has a well developed prostatic epithelium. In the child with prune belly syndrome, however, these epithelial elements are poorly developed or absent. Prostatic epithelial hypoplasia in the prune belly syndrome is not a new observation since Nunn and Stephens state that in 6 of 7 of their cases the epithelial elements of the prostate were absent or hypoplastic. 1 Williams and Burkholder concur with this observation although no details are given. 2 Our studies suggest that a testicular defect is not responsible for this lack of development since the prostatic epithelial elements were normal in cases of isolated bilateral cryptorchidism. Zondek and Zondek have described previously the prostate in bilateral cryptorchidism and have found that the development was normal in the absence of an associated hormonal defect. 11 In addition, we have found no evidence to support the suggestion that the prostatic maldevelopment may be owing to compression from the massive posterior urethral distension for in infants with posterior urethral valves the prostatic epithelium seemed normal al-
PROSTATIC MALDEVELOPMENT IN PRUNE BELLY SYNDROME
FIG. 3. Case of prune belly syndrome with central layer resembling primitive mesenchyme.
343
FIG. 5. Prostate of child with undescended testes
FIG. 4. Cross section of prostate in child with posterior urethral valves
though compressed. The hypoplastic epithelium of the pseudoprune belly syndrome seems to confirm the postulate that this represents an incomplete variant of the syndrome. We conclude that the lack ofprostatic epithelial differentiation may merely be a further expression of a more generalized mesenchymal defect with the resulting inability of the urogenital mesenchyme to induce epithelial differentiation. Whether the mesenchymal induction defect has a hormonal component is conjectural.
REFERENCES
1. Nunn, I. N. and Stephens; F. D.: The triad syndrome: a compos-
ite anomaly of the abdominal wall, urinary system and testes. J. Urol., 86: 782, 1961. 2. Williams, D. I. and Burkholder, G. V.: The prune belly syndrome. J. Urol., 98: 244, 1967. 3. Rogers, L. W. and Ostrow, P. T.: The prune belly syndrome: report of 20 cases and description of a lethal variant. J. Pediat., 83: 786, 1973.
344
DEKLERK AND SCOTT
4. Harley, L. M., Chen, Y. and Rattner, W. H.: Prune belly syndrome. J. Urol., 108: 174, 1972. 5. Lowsley, 0. S.: The development of the human prostate gland with reference to the development of other structures at the neck of the urinary bladder. Amer. J. Anat., 13: 299, 1912. 6. Cunha, G. R.: The role of androgens in the epithelio-mesenchymal interactions involved in prostatic morphogenesis in embryonic mice. Anat. Rec., 175: 87, 1973. 7. McNeal, J.E.: Developmental and comparative anatomy of the prostate. In: Benign Prostatic Hyperplasia. Edited by J. T. Grayhack, J. D. Wilson and M. J. Scherbenske. NIAMDD Workshop Proceedings, February 20-21, 1975, p. 1, 1976. 8. Narbaitz, R.: Embryology, anatomy, and histology of the male
sex accessory glands. In: Male Accessory Sex Organs. Structure and Function in Mammals. Edited by D. Brandes. New York: Academic Press, Inc., p. 3, 1974. 9. Siiteri, P. K. and Wilson, J. D.: Testosterone formation and metabolism during male sexual differentiation in the human embryo. J. Clin. Endocr. Metab., 38: 113, 1974. 10. Wilson, J. D. and Lasnitzki, I.: Dihydrotestosterone formation in fetal tissues of the rabbit and rat. Endocrinology, 89: 659, 1971. 11. Zondek, T. and Zondek, L.: The fetal and neonatal prostate. In: Normal and Abnormal Growth of the Prostate. Edited by M. Goland. Springfield, Illinois: Charles C Thomas, Publisher, p. 5, 1975.
THE JOURNAL OF UROLOGY
Printed in U.SA.
Copyright © 1978 by The Williams & ~ilkins Co.
PROSTATIC MALDEVELOPMENT IN THE PRUNE BELLY SYNDROME: A DEFECT IN PROSTATIC STROMAL-EPITHELIAL INTERACTION D. P. DEKLERK*
AND
W. W. SCOTT
From the James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Maryland
ABSTRACT
The prune belly syndrome consists of a triad of abdominal wall musculature deficiency, cryptorchidism and urinary tract anomalies. A rarely described but fairly constant component of the syndrome is the lack of development of the epithelial elements of the prostate. We wish to suggest that this is a further expression of a postulated arrest in mesenchymal development responsible for other features of the syndrome. The prune belly syndrome consists of a triad of abdominal wall musculature deficiency, cryptorchidism and urinary tract anomalies. 1• 2 The urinary tract anomalies include renal dysplasia, ureteral dilatation, a dilated, non-trabeculated bladder and urethral stenosis. Associated defects include gastrointestinal anomalies such as malrotation of the gut, imperforate anus and lower extremity anomalies such as talipes equinus varus and congenital dislocation of the hip. A recognized but poorly described feature of the syndrome is the lack of development of the epithelial elements of the prostate. Herein we wish to indicate the consistency of this anomaly and postulate that it may be owing to lack of normal epithelial-stromal interaction in prostatic organogenesis. MATERIALS
Reports and pathological slides from 17 autopsies performed at this hospital were reviewed. There were 8 patients with well documented prune belly syndrome, 3 with posterior urethral valves, 4 with isolated bilateral undescended testes after full-term pregnancy and 2 with so-called pseudo-prune belly syndrome. Adequate pathological slides of the prostate were available in 6 of the patients with prune belly syndrome. In all other patients adequate material for microscopic study was available. To study the prostate sections were generally taken at the level of the verumontanum but in some cases additional longitudinal sections of the prostate were available. RESULTS
Of the 8 cases of prune belly syndrome the absence of prostatic epithelial elements was documented in 5 (fig. 1), while in 1 case sparse glands were present with no sign of proliferation secretion. In 2 patients only gross descriptions were available. One of these apparently was normal, whereas in the other no prostatic tissue could be demonstrated at the time of autopsy. Occasionally, in those prostates with otherwise absent epithelial elements glands could be identified immediately beneath the urethral epithelium in the region of the prostatic utricle (fig. 2). In 3 of 5 cases when the prostatic utricle was clearly identifiable it was dilated markedly and showed squamous metaplasia. In 2 cases the mesenchymal elements could be divided clearly into 3 segments. The first segment was an inner collagenous periurethral area devoid of muscular elements or ducts, with the exception of the posterior submucosal area where occasional small epithelial elements were seen adjacent to the prostatic utricle in association with differentiated muscle fibers. A mid section with sparse muscular elements Accepted for publication November 23, 1977. * AUA scholar and funded in part by NIAMDD-AM19300.
and prominent intermuscular collagen was the second segment. No epithelial elements were noted in this area. In 1 patient this area had the appearance of a primitive mesenchyme with no differentiation to muscle or elaboration of collagen. The third segment was an outer section of relatively well developed muscle and fibroblasts (figs. 1 and 3). In 2 patients the membranous urethra was obstructed completely and no communications could be demonstrated with the anterior urethra. Three patients had membranous urethral stenosis, while in 1 instance mid penile urethral stenosis and in another prostatic urethral stenosis were found. In 3 cases no urethral stenosis could be demonstrated at autopsy. One patient had associated megalourethra. Pseudo-prune belly syndrome. Two patients were seen with features of pseudo-prune belly syndrome. The first case had normal abdominal musculature as well as bilateral cryptorchidism, hydronephrotic and dysplastic kidneys, dilated tortuous ureters and a dilated bladder with thickening of the bladder wall. The prostate was more mature than the previously described cases of prune belly syndrome, especially the stromal elements, but the epithelial elements were hypoplastic when compared to the normal patients of similar age. No anatomical urethral obstruction could be documented at autopsy. In the second case the abdominal wall, testicular, genitourinary and prostatic findings were similar to those of the first case, except for membranous urethral stenosis and a prominent posterior urethral squamous cyst, probably originating from the prostatic utricle. Posterior urethral valves and cryptorchidism. The prostates from patients with posterior urethral valves were studied to eliminate the possibility that the lack of prostatic epithelial development was owing to prostatic compression and dilatation. In all 3 cases of posterior urethral valves the glandular elements were compressed and dilated but otherwise they were developed normally (fig. 4). In 4 patients with bilateral undescended testes, but no abdominal wall deficiency and no other genitourinary defects, the prostates were developed normally and comparable to patients of similar age and development, suggesting, therefore, that in the prune belly syndrome the cryptorchidism was not responsible for the prostatic epithelial maldevelopment (fig. 5). DISCUSSION
The etiology of prune belly syndrome remains obscure. Since male subjects are involved almost exclusively X-linked recessive inheritance has been suggested2 but this seems unlikely because none of the male patients is fertile, male siblings are never involved and a few well documented female subjects with the syndrome have been reported. 3 Chromosomal abnormalities have been suggested4 but as indicated by 341
342
DEKLERK AND SCOTT
Fm. 1. Prostate from child with prune belly syndrome shows lack of glandular development and 3 layers described in text.
Rogers and Ostrow'i 7 reported cases of monozygotic twins with discordant involvement suggest a non-genetic developmental defect. Although a primary anomaly of the abdominal wall or primary obstruction of the urinary tract with subsequent maldevelopment of the abdominal wall was postulated in early discussions of the syndrome, a primary mesenchymal developmental arrest, presumably of the lateral and possibly of the intermediate mesoderm, between 5 and 10 weeks of gestation, now seems likely. 1 This is an attractive postulate, since the resulting mesenchymal non-differentiation would, theoretically, be incapable of inducing abdominal striated and urinary tract smooth musculature. In addition, if the gubernaculum has a role in testicular descent a gubernacular insensitivity to the physiological stimulus responsible for the testicular descent would result in bilateral cryptorchidism. Unfortunately, the gubernaculum was not available for microscopic analysis in this study. A further consequence of poor mesenchymal development may be the lack of induction of the prostatic epithelium by the urogenital sinus mesenchyme. During the third month of gestation (56 to 65 mm. fetus) the fetal prostate develops through the ingrowth of endodermal urogenital sinus buds into the surrounding mesenchyme." The elegant recombinant studies of Cunha have suggested that this induction of prostatic epithelial development is dependent on a competent urogenital stroma but that the role of the mesenchyme is not in the transmission of the androgenic stimulus. i; Prostatic stroma receives contributions from the urogenital sinus, the wolffian duct (the ejaculatory ducts) and the miillerian system (the prostatic utricle), 7 • 8 and it is interesting that the urogenital sinus and wolffian duct mesenchyme can induce prostatic epithelial differentiation in recombinant studies, whereas
Fm. 2. Prostatic utricle with surrounding well developed glands
non-genital mesenchyme is inert. 6 It is well established that dihydrotestosterone is required for prostatic development, while testosterone per se is capable of inducing wolffian derivatives, such as the seminal vesicle, vas deferens and the epididymis. 9 • 10 It is by no means clear whether the urogenital mesenchyme is dependent on a hormonal stimulus, although it has been suggested that estrogens are required for the development of the prostatic fibromuscular stroma. Normally, during the last 2 months of fetal development, prostatic epithelial proliferation occurs under the influence of maternal gonadotropins, 11 so that at birth the male fetus has a well developed prostatic epithelium. In the child with prune belly syndrome, however, these epithelial elements are poorly developed or absent. Prostatic epithelial hypoplasia in the prune belly syndrome is not a new observation since Nunn and Stephens state that in 6 of 7 of their cases the epithelial elements of the prostate were absent or hypoplastic. 1 Williams and Burkholder concur with this observation although no details are given. 2 Our studies suggest that a testicular defect is not responsible for this lack of development since the prostatic epithelial elements were normal in cases of isolated bilateral cryptorchidism. Zondek and Zondek have described previously the prostate in bilateral cryptorchidism and have found that the development was normal in the absence of an associated hormonal defect. 11 In addition, we have found no evidence to support the suggestion that the prostatic maldevelopment may be owing to compression from the massive posterior urethral distension for in infants with posterior urethral valves the prostatic epithelium seemed normal al-
PROSTATIC MALDEVELOPMENT IN PRUNE BELLY SYNDROME
FIG. 3. Case of prune belly syndrome with central layer resembling primitive mesenchyme.
343
FIG. 5. Prostate of child with undescended testes
FIG. 4. Cross section of prostate in child with posterior urethral valves
though compressed. The hypoplastic epithelium of the pseudoprune belly syndrome seems to confirm the postulate that this represents an incomplete variant of the syndrome. We conclude that the lack ofprostatic epithelial differentiation may merely be a further expression of a more generalized mesenchymal defect with the resulting inability of the urogenital mesenchyme to induce epithelial differentiation. Whether the mesenchymal induction defect has a hormonal component is conjectural.
REFERENCES
1. Nunn, I. N. and Stephens; F. D.: The triad syndrome: a compos-
ite anomaly of the abdominal wall, urinary system and testes. J. Urol., 86: 782, 1961. 2. Williams, D. I. and Burkholder, G. V.: The prune belly syndrome. J. Urol., 98: 244, 1967. 3. Rogers, L. W. and Ostrow, P. T.: The prune belly syndrome: report of 20 cases and description of a lethal variant. J. Pediat., 83: 786, 1973.
344
DEKLERK AND SCOTT
4. Harley, L. M., Chen, Y. and Rattner, W. H.: Prune belly syndrome. J. Urol., 108: 174, 1972. 5. Lowsley, 0. S.: The development of the human prostate gland with reference to the development of other structures at the neck of the urinary bladder. Amer. J. Anat., 13: 299, 1912. 6. Cunha, G. R.: The role of androgens in the epithelio-mesenchymal interactions involved in prostatic morphogenesis in embryonic mice. Anat. Rec., 175: 87, 1973. 7. McNeal, J.E.: Developmental and comparative anatomy of the prostate. In: Benign Prostatic Hyperplasia. Edited by J. T. Grayhack, J. D. Wilson and M. J. Scherbenske. NIAMDD Workshop Proceedings, February 20-21, 1975, p. 1, 1976. 8. Narbaitz, R.: Embryology, anatomy, and histology of the male
sex accessory glands. In: Male Accessory Sex Organs. Structure and Function in Mammals. Edited by D. Brandes. New York: Academic Press, Inc., p. 3, 1974. 9. Siiteri, P. K. and Wilson, J. D.: Testosterone formation and metabolism during male sexual differentiation in the human embryo. J. Clin. Endocr. Metab., 38: 113, 1974. 10. Wilson, J. D. and Lasnitzki, I.: Dihydrotestosterone formation in fetal tissues of the rabbit and rat. Endocrinology, 89: 659, 1971. 11. Zondek, T. and Zondek, L.: The fetal and neonatal prostate. In: Normal and Abnormal Growth of the Prostate. Edited by M. Goland. Springfield, Illinois: Charles C Thomas, Publisher, p. 5, 1975.