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Ectopic ureterocele, hydroureter, and renal dysplasia An embryogenic triad
ECTOPIC
URETEROCELE,
HYDROURETER,
AND
RENAL DYSPLASIA An Embryogenic MICHAEL ELLIOT
Triad
E. GRIBETZ, LEITER,
M.D.
M.D.
From the Division of Pediatric Urology, Department Mount Sinai Hospital, New York, New York
of Urology
ABSTRACT - A review of the literature of the embryogenesis of ectopic ureterocele is presented. A theory linking the triad of ectopic ureterocele, hydroureter, and renal dysplasia to a primary intrinsic developmental abnormality of size and position of the ureteral bud is postulated.
segment, delayed absorption into the urogenital sinus, and delayed ascent into the bladder base. If expansion of the caudal end of the ureter-al bud were to precede its complete absorption into the urogenital sinus, this cystic dilatation might not fully participate in forming the newly evolving hemitrigone and might serve as the anlage of the ectopic ureterocele.
There has been a gradual evolution over the past two decades of our understanding of the ectopic ureterocele. First described as a distinct entity by Ericsson in 1954,’ the ectopic ureterocele is defined as a cystic dilatation of the intravesical distal ureter with an orifice at or distal to the bladder neck.2 Arguing by analogy from experience based on the simple ureterocele, Ericsson and others proposed obstruction at the level of the ureteral orifice as the cause of ectopic ureterocele. As clinical experience with the ectopic ureterocele increased, certain key and fundamental observations were noted that required modification of this concept: (1) The orifice of the ectopic ureterocele was usually present and often very large and gaping. (2) Reflux occurred into 15 per cent of the renal units drained by the ectopic ureterocele.3 (3) Although physiologic obstruction at the level of the bladder neck or urinary sphincter could still be postulated as the obstructive factor, simulating a stenotic orifice, large numbers of ectopic ureters distal to the bladder neck have been noted without ureterocele formation.4 In the 197Os, Stephens4 and Tanagho5 stressed the site of origin of the ureteral bud on the wolffian duct as the key to the explanation of ureteral ectopia as well as ureterocele formation. According to these authors, in a duplicated system, the ureteral bud placed higher on the wolffian duct has a longer trigone precursor
UROLOGY
/ FEBRUARY
1978 / VOLUME
XI, NUMBER
Case Report A seventeen-year-old black female was originally evaluated at age sixteen for weight loss and anemia. The patient denied all urologic complications, specifically dysuria, frequency, incontinence, suprapubic discomfort, fever, chills, or flank pain. Physical examination revealed a thin, pale, black female. No abdominal masses were present; no costovertebral angle tenderness was elicitable. Pelvic examination revealed fullness of the left anterior vaginal wall. Microscopic examination of the urine revealed many white blood cells and gram-negative rods. Urine culture and sensitivity grew Escherichia coli sensitive to all antibiotics. Hemoglobin was 8.0; white blood cell count was 12,000 with a normal differential. Despite successive courses of nitrofurantoin (Macrodantoin), ampicillin, and cephalexin (Keflex), subsequent cultures each grew out E.
2
131
FIGURE 1. (A) Zntravenous pyelogram demonstrating left nonfunctioning upper pole with spheroid filling defect at base of bladder. (B) Cystogram demonstrating catheter coiled in ectopic ureterocele with retrograde filling of hydronephrotic left upper pole collecting system.
coli with unchanged sensitivities. In May, 1976, the patient was admitted to the hospital for a ten-day course of intravenous cephalothin (Keflin), and after obtaining an intravenous urogram reportedly revealing a shrunken, postpyelonephritic left kidney, urologic consultation was obtained. History and physical examination were as described. Review of the intravenous urogram revealed a normal right kidney and ureter. A duplicated left kidney was noted with a nonfunctioning upper pole. A large spherical filling defect was noted at the bladder base on the cystogram phase (Fig. 1A). Cystogram and voiding cystourethrogram revealed prompt grade III-IV reflux with a dilated, dysplastic appearing left upper pole collecting system (Fig. 1B). The urethral catheter was noted to be coiled in a ureterocele in continuity with the left upper pole and corresponding to the collecting system, previously noted filling defect. After control of the E. coli infection of the urinary tract, which responded to intravenous cephalothin, cystourethroscopy revealed a large ectopic ureterocele emanating from the left hemitrigone with a gaping orifice in the proximal urethra just distal to the bladder neck. A left upper pole heminephrectomy and partial ureterectomy, as well as unroofing of the ureterocele were performed. The duplicated ureter of the left upper pole was dissected to approximately 1.5 cm. from the bladder where it joined the normal ureter in a common sheath and was ligated at that level. A postoperative cystogram revealed no reflux to the ipsilateral lower pole represegment and a small 1 cm. diverticulum senting the distal ectopic ureter. Postoperatively the patient has done well. Final pathology report described ureterocele,
132
hydroureter with dysplastic kidney.
chronic
inflammation,
and
Comment Despite her age, this patient characterizes many patients with ectopic ureteroceles. Originally evaluated for chronic urinary infection, an intravenous urogram revealed a ureterocele as well as a nonfunctioning upper pole.6 Cystogram revealed reflux to the upper pole segment, although this may have been secondary to the fortuitous placement of the urethral catheter within the ureterocele.’ Cystourethroscopy confirmed the ureterocele and identified a gaping orifice distal to the bladder neck. Surgical exploration and pathologic evaluation of the specimen revealed a hydroureter and a dysplastic renal upper pole.’ As early as 1954, with Ericsson’s original article, the association of ectopic ureterocele with a hydroureter and an abnormal proximal renal element was noted. The explanation at the time was believed to be obstruction. With obstruction at the distal end of a submucosal ectopic ureter, proximal dilatation could readily be explained. The dilatation was manifest intravesitally as a ureterocele and extravetically as a hydroureter. The secondary effects of this obstructed system on the developing kidney resulted in dysgenesis, hypogenesis, and chronic pyelonephritis. In 1971 Stephens4 reported 3 cases of cecoureterocele and 3 cases of nonobstructive ureterocele, all 6 cases with wide open orifices within the lumen of the bladder. The nonobstructive ureteroceles represented lesser degrees of ectopia than the classic ectopic ureterocele, with the orifice on the trigone but distal to its normal position. Despite the
UROLOGY
/ FEBRUARY
1978
/ VOLUME
XI, NUMBER
2
nonobstructed orifice, the presented cases manifested the triad of hydroureter, ureterocele formation, and renal dysplasia. If ureteroceles with patent orifices distal to the bladder neck are also included in this group (Stephens’ classification: sphincteric orifice), a majority of ectopic ureteroceles might not have obstruction as the primary etiologic factor in their formation. Certainly obstruction is not the sole cause of all ureterocele formation. In 1972 Tanaghog refuted obstruction as the cause of renal dysplasia with his experiment on ureteral obstruction in the fetal lamb at seventy to seventy-five days of gestation. Tanagho and Stephens both theorize that ectopia as well as ureterocele formation occurred as a result of an aberrant takeoff of the ureteral bud from the wolffian duct. A high takeoff of the ureteral bud induces its delayed incorporation into the newly forming bladder with delayed ascent of the orifice from the bladder neck. According to Tanagho, if this ureteral anlage were to undergo its normal caudal expansion prior to its full incorporation into the bladder, it might not fully participate in trigone formation, but rather in the formation of a ureterocele. Stephens stresses that the cystic dilatation of the ureterocele is a pathologic process in which the expansion stimulus which induces globular enlargement of the bladder is misdirected coincidentally at the not yet incorporated ectopic distal ureter, thus causing nonobstructed ureterocele formation. Furthermore, Mackie and StephenslO note that if this abnormally placed ureteral bud met the nephrogenic blastema off-center, renal dysplasia would result. Although Stephens notes ureteral dilatation almost universally present with the ectopic ureterocele, the associated hydroureter represents a puzzle that he believes can best be explained on the basis of obstruction with secondary hypertrophy and hyperplasia. He is quick to point out and appreciate, however, that obstruction is far from a universal finding. The foregoing inconsistencies stimulated a search for an alternate hypothesis that might better fit the observed phenomenon. The ureteral bud in marked ectopia is not only defective in its site of takeoff from the wolffian duct but is also inherently and intrinsically an abnormal ureteral bud. Its primary growth pattern is that of a megaureter, and it interacts both with the developing bladder (urogenital sinus) and kidney (nephrogenic blastema) in an abnormal fashion. This primary megaureter, with possibly a high insertion on the wolffian duct might man-
UROLOGY
/
FEBRUARY
1978
/
VOLUME XI, NUMBER 2
ifest delayed absorption into the urogenital sinus, and as postulated by Stephens, because of its intramural position might be abnormally affected by the globular expansion influence on the bladder, leading to ureterocele formation. A primary abnormality of the ureteral bud wherever its placement on the wolffian duct, will stimulate maldevelopment of the ureterovesical junction. It is similarly reasonable that a primarily abnormal ureteral bud would influence the nephrogenic blastema in an abnormal fashion, causing maldevelopment, dysplasia, and hypoplasia. If, as has been accepted universally, the development of the kidney is triggered and influenced by the growing ureteral bud, a primary congenital abnormality of the ureteral bud could hardly be expected to initiate normal development of the nephrogenic blastema, even with a normally placed nephrogenic blastemaureteral junction. The triad of ectopic ureterocele, hydroureter, and renal dysplasia appears most likely to result from an intrinsic inborn error of development of the ureteral bud with secondary effects on the nephrogenic blastema and urogenital sinus. A primary megaureter thus forms from this ureteral “megabud,” stimulating secondary abnormal development of both the kidney as well as the ureterovesical junction. The hydroureter thus appears to be a primary defect, and the renal dysplasia and the ureterocele with its associated ectopia are secondary phenomena. New York, New York 10029 (DR. LEITER) References 1. Ericsson NO: Ectopic ureterocele in infants and children: a clinical study, Acta Chir. Stand. 197 (Suppl.): 1 (1954). 2. Royle MG, and Goodwin WE: The management of ureteroceles, J. Urol. 196: 42 (1971). 3. Kelalis PP, King LR, and Belman AB: Clinical Pediatric Urology, Philadelphia, W. B. Saunders, 1976, pp. 522-535. 4. Stephens D: Caecoureterocele and concepts in the etiology of ureteroceles, Aust. N.Z. J. Surg. 40: 239 (1971). 5. Tanagho EA: Embryogenic basis for lower ureteral anomalies: a hypothesis, Urology 7: 451 (1976). 6. Williams DI: Ectooic ureterocele, Proc. Ft. Sot. Med. 51: 783 (1958). 7. Williams DI, and Woodard JR: Problems in the management of ectooic ureteroceles, 1. Urol. 92: 635 (1964). 8. Newman LB, McAlister WH, and Kissane J: Segmental renal dysplasia associated with ectopic ureteroceles in childhood, Urology 3: 23 (1974). 9. Tanagho EA: Surgically induced partial urinary obstruction in the fetal lamb. III. Ureteral obstruction, Invest. Urol. 10: 35 (1972). 10. Mackie GG, and Stephens FD: Duplex kidneys: a correlation of renal dysplasia with position of the ureteral orifice, J. Urol. 114: 274 (1975).
133
URETEROCELE,
HYDROURETER,
AND
RENAL DYSPLASIA An Embryogenic MICHAEL ELLIOT
Triad
E. GRIBETZ, LEITER,
M.D.
M.D.
From the Division of Pediatric Urology, Department Mount Sinai Hospital, New York, New York
of Urology
ABSTRACT - A review of the literature of the embryogenesis of ectopic ureterocele is presented. A theory linking the triad of ectopic ureterocele, hydroureter, and renal dysplasia to a primary intrinsic developmental abnormality of size and position of the ureteral bud is postulated.
segment, delayed absorption into the urogenital sinus, and delayed ascent into the bladder base. If expansion of the caudal end of the ureter-al bud were to precede its complete absorption into the urogenital sinus, this cystic dilatation might not fully participate in forming the newly evolving hemitrigone and might serve as the anlage of the ectopic ureterocele.
There has been a gradual evolution over the past two decades of our understanding of the ectopic ureterocele. First described as a distinct entity by Ericsson in 1954,’ the ectopic ureterocele is defined as a cystic dilatation of the intravesical distal ureter with an orifice at or distal to the bladder neck.2 Arguing by analogy from experience based on the simple ureterocele, Ericsson and others proposed obstruction at the level of the ureteral orifice as the cause of ectopic ureterocele. As clinical experience with the ectopic ureterocele increased, certain key and fundamental observations were noted that required modification of this concept: (1) The orifice of the ectopic ureterocele was usually present and often very large and gaping. (2) Reflux occurred into 15 per cent of the renal units drained by the ectopic ureterocele.3 (3) Although physiologic obstruction at the level of the bladder neck or urinary sphincter could still be postulated as the obstructive factor, simulating a stenotic orifice, large numbers of ectopic ureters distal to the bladder neck have been noted without ureterocele formation.4 In the 197Os, Stephens4 and Tanagho5 stressed the site of origin of the ureteral bud on the wolffian duct as the key to the explanation of ureteral ectopia as well as ureterocele formation. According to these authors, in a duplicated system, the ureteral bud placed higher on the wolffian duct has a longer trigone precursor
UROLOGY
/ FEBRUARY
1978 / VOLUME
XI, NUMBER
Case Report A seventeen-year-old black female was originally evaluated at age sixteen for weight loss and anemia. The patient denied all urologic complications, specifically dysuria, frequency, incontinence, suprapubic discomfort, fever, chills, or flank pain. Physical examination revealed a thin, pale, black female. No abdominal masses were present; no costovertebral angle tenderness was elicitable. Pelvic examination revealed fullness of the left anterior vaginal wall. Microscopic examination of the urine revealed many white blood cells and gram-negative rods. Urine culture and sensitivity grew Escherichia coli sensitive to all antibiotics. Hemoglobin was 8.0; white blood cell count was 12,000 with a normal differential. Despite successive courses of nitrofurantoin (Macrodantoin), ampicillin, and cephalexin (Keflex), subsequent cultures each grew out E.
2
131
FIGURE 1. (A) Zntravenous pyelogram demonstrating left nonfunctioning upper pole with spheroid filling defect at base of bladder. (B) Cystogram demonstrating catheter coiled in ectopic ureterocele with retrograde filling of hydronephrotic left upper pole collecting system.
coli with unchanged sensitivities. In May, 1976, the patient was admitted to the hospital for a ten-day course of intravenous cephalothin (Keflin), and after obtaining an intravenous urogram reportedly revealing a shrunken, postpyelonephritic left kidney, urologic consultation was obtained. History and physical examination were as described. Review of the intravenous urogram revealed a normal right kidney and ureter. A duplicated left kidney was noted with a nonfunctioning upper pole. A large spherical filling defect was noted at the bladder base on the cystogram phase (Fig. 1A). Cystogram and voiding cystourethrogram revealed prompt grade III-IV reflux with a dilated, dysplastic appearing left upper pole collecting system (Fig. 1B). The urethral catheter was noted to be coiled in a ureterocele in continuity with the left upper pole and corresponding to the collecting system, previously noted filling defect. After control of the E. coli infection of the urinary tract, which responded to intravenous cephalothin, cystourethroscopy revealed a large ectopic ureterocele emanating from the left hemitrigone with a gaping orifice in the proximal urethra just distal to the bladder neck. A left upper pole heminephrectomy and partial ureterectomy, as well as unroofing of the ureterocele were performed. The duplicated ureter of the left upper pole was dissected to approximately 1.5 cm. from the bladder where it joined the normal ureter in a common sheath and was ligated at that level. A postoperative cystogram revealed no reflux to the ipsilateral lower pole represegment and a small 1 cm. diverticulum senting the distal ectopic ureter. Postoperatively the patient has done well. Final pathology report described ureterocele,
132
hydroureter with dysplastic kidney.
chronic
inflammation,
and
Comment Despite her age, this patient characterizes many patients with ectopic ureteroceles. Originally evaluated for chronic urinary infection, an intravenous urogram revealed a ureterocele as well as a nonfunctioning upper pole.6 Cystogram revealed reflux to the upper pole segment, although this may have been secondary to the fortuitous placement of the urethral catheter within the ureterocele.’ Cystourethroscopy confirmed the ureterocele and identified a gaping orifice distal to the bladder neck. Surgical exploration and pathologic evaluation of the specimen revealed a hydroureter and a dysplastic renal upper pole.’ As early as 1954, with Ericsson’s original article, the association of ectopic ureterocele with a hydroureter and an abnormal proximal renal element was noted. The explanation at the time was believed to be obstruction. With obstruction at the distal end of a submucosal ectopic ureter, proximal dilatation could readily be explained. The dilatation was manifest intravesitally as a ureterocele and extravetically as a hydroureter. The secondary effects of this obstructed system on the developing kidney resulted in dysgenesis, hypogenesis, and chronic pyelonephritis. In 1971 Stephens4 reported 3 cases of cecoureterocele and 3 cases of nonobstructive ureterocele, all 6 cases with wide open orifices within the lumen of the bladder. The nonobstructive ureteroceles represented lesser degrees of ectopia than the classic ectopic ureterocele, with the orifice on the trigone but distal to its normal position. Despite the
UROLOGY
/ FEBRUARY
1978
/ VOLUME
XI, NUMBER
2
nonobstructed orifice, the presented cases manifested the triad of hydroureter, ureterocele formation, and renal dysplasia. If ureteroceles with patent orifices distal to the bladder neck are also included in this group (Stephens’ classification: sphincteric orifice), a majority of ectopic ureteroceles might not have obstruction as the primary etiologic factor in their formation. Certainly obstruction is not the sole cause of all ureterocele formation. In 1972 Tanaghog refuted obstruction as the cause of renal dysplasia with his experiment on ureteral obstruction in the fetal lamb at seventy to seventy-five days of gestation. Tanagho and Stephens both theorize that ectopia as well as ureterocele formation occurred as a result of an aberrant takeoff of the ureteral bud from the wolffian duct. A high takeoff of the ureteral bud induces its delayed incorporation into the newly forming bladder with delayed ascent of the orifice from the bladder neck. According to Tanagho, if this ureteral anlage were to undergo its normal caudal expansion prior to its full incorporation into the bladder, it might not fully participate in trigone formation, but rather in the formation of a ureterocele. Stephens stresses that the cystic dilatation of the ureterocele is a pathologic process in which the expansion stimulus which induces globular enlargement of the bladder is misdirected coincidentally at the not yet incorporated ectopic distal ureter, thus causing nonobstructed ureterocele formation. Furthermore, Mackie and StephenslO note that if this abnormally placed ureteral bud met the nephrogenic blastema off-center, renal dysplasia would result. Although Stephens notes ureteral dilatation almost universally present with the ectopic ureterocele, the associated hydroureter represents a puzzle that he believes can best be explained on the basis of obstruction with secondary hypertrophy and hyperplasia. He is quick to point out and appreciate, however, that obstruction is far from a universal finding. The foregoing inconsistencies stimulated a search for an alternate hypothesis that might better fit the observed phenomenon. The ureteral bud in marked ectopia is not only defective in its site of takeoff from the wolffian duct but is also inherently and intrinsically an abnormal ureteral bud. Its primary growth pattern is that of a megaureter, and it interacts both with the developing bladder (urogenital sinus) and kidney (nephrogenic blastema) in an abnormal fashion. This primary megaureter, with possibly a high insertion on the wolffian duct might man-
UROLOGY
/
FEBRUARY
1978
/
VOLUME XI, NUMBER 2
ifest delayed absorption into the urogenital sinus, and as postulated by Stephens, because of its intramural position might be abnormally affected by the globular expansion influence on the bladder, leading to ureterocele formation. A primary abnormality of the ureteral bud wherever its placement on the wolffian duct, will stimulate maldevelopment of the ureterovesical junction. It is similarly reasonable that a primarily abnormal ureteral bud would influence the nephrogenic blastema in an abnormal fashion, causing maldevelopment, dysplasia, and hypoplasia. If, as has been accepted universally, the development of the kidney is triggered and influenced by the growing ureteral bud, a primary congenital abnormality of the ureteral bud could hardly be expected to initiate normal development of the nephrogenic blastema, even with a normally placed nephrogenic blastemaureteral junction. The triad of ectopic ureterocele, hydroureter, and renal dysplasia appears most likely to result from an intrinsic inborn error of development of the ureteral bud with secondary effects on the nephrogenic blastema and urogenital sinus. A primary megaureter thus forms from this ureteral “megabud,” stimulating secondary abnormal development of both the kidney as well as the ureterovesical junction. The hydroureter thus appears to be a primary defect, and the renal dysplasia and the ureterocele with its associated ectopia are secondary phenomena. New York, New York 10029 (DR. LEITER) References 1. Ericsson NO: Ectopic ureterocele in infants and children: a clinical study, Acta Chir. Stand. 197 (Suppl.): 1 (1954). 2. Royle MG, and Goodwin WE: The management of ureteroceles, J. Urol. 196: 42 (1971). 3. Kelalis PP, King LR, and Belman AB: Clinical Pediatric Urology, Philadelphia, W. B. Saunders, 1976, pp. 522-535. 4. Stephens D: Caecoureterocele and concepts in the etiology of ureteroceles, Aust. N.Z. J. Surg. 40: 239 (1971). 5. Tanagho EA: Embryogenic basis for lower ureteral anomalies: a hypothesis, Urology 7: 451 (1976). 6. Williams DI: Ectooic ureterocele, Proc. Ft. Sot. Med. 51: 783 (1958). 7. Williams DI, and Woodard JR: Problems in the management of ectooic ureteroceles, 1. Urol. 92: 635 (1964). 8. Newman LB, McAlister WH, and Kissane J: Segmental renal dysplasia associated with ectopic ureteroceles in childhood, Urology 3: 23 (1974). 9. Tanagho EA: Surgically induced partial urinary obstruction in the fetal lamb. III. Ureteral obstruction, Invest. Urol. 10: 35 (1972). 10. Mackie GG, and Stephens FD: Duplex kidneys: a correlation of renal dysplasia with position of the ureteral orifice, J. Urol. 114: 274 (1975).
133