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The Histology of the Exstrophied Bladder
TI-IE JouR::-rAL OF UROLOGY
Vol. 91, No. 5 May 1964 Copyright © 1964 by The Williams & Wilkins Co. Printed in U.S.A.
THE HISTOLOGY OF THE EXSTROPHIED BLADDER DAVID A. CULP From the Department of Urology, State University of Iowa, Iowa City, Iowa
Many different operative procedures have been devised in an effort to improve the status of patients with exstrophy of the bladder. In general, these procedures may be divided into 2 groups: 1) those that discard the bladder and divert the urinary stream and 2) those that salvage the bladder by reconstructive surgery. Since neither approach to the problem has been sufficiently sucessful to gain a clear-cut advantage over the other, much discussion has revolved around the advantages and disadvantages of each method. However, one basic aspect seems to have been ignored ahnost completely, that is, the histology of the anomalous bladder. Is the exstrophied bladder a normal structure except for the absence of the anterior half? Have the various coats of the bladder wall undergone normal development? The success of reconstructive procedures is directly dependent upon the condition of the exstrophied bladder but nothing has appeared in recent literature concerning this aspect of the problem. Enderlen, 1 in 1904, studied the exstrophied bladder of 2 newborn infants and found normal transitional cell epithelium. Formiggini 2 described cystic cavities but no glandular structures in the exstrophied bladder of an infant 9 days old. On the other hand, glandular structures were demonstrated in a compilation of 18 cases observed by Shattock, 3 Enderlen, 1 and Scholl. 4 These patients ranged in age from a few months to 77 years. Accepted for publication November 22, 1963. Read at annual meeting of North Central Section, American Urological Association, Inc., Chicago, Illinois, September 11-14, 1963. Study supported by grants from National Science Foundation (GB-454) and the Krannert Foundation. 1 Enderlen, E.: Zur Histologie der Schleimhaut der ektopierten Blase Verhandl d. deutsch. path., Gesellsch., 7: 167, 1904. 2 Formiggini, B.: Contributo allo studio istologico della mucosa vesicale extrofica. Riforma med., 36: 252, 1920. 3 Shattock, S. G.: Specimens of epispadias and exstroversio vesicae showing an attachment of the muscular wall of the bladder to the back of the pubic bones. Trans. Path. Soc., London, 45: 117124, 1894. 4 Scholl, A. J.: The potential malignancy in exstrophy of the bladder. Ann. Surg., 75: 365, 1922.
In an attempt to improve our own knowledge, a histological study of the bladders removed from 23 patients with exstrophy, varying in age from 1 months to 52 years, was undertaken. As a basis for comparison a parallel series of normal bladders obtained from postmortem material was included in the study (fig. 1). In brief, all of the normal bladders were lined by stratified transitional cell epithelium which was separated from a well-developed, orderly-arranged, muscular layer by loose areolar tissue. No glandular structures or epithelial inclusions were noted. Not one of the exstrophied bladders was entirely normal. The most frequent pathological process encountered was acute and chronic follicular inflammation with edema of the submucosal layer (fig. 2, A). Areas of acute ulceration and chronic granulation were common. In fact, only one patient failed to demonstrate an inflammatory response and this was the 1-month-old child. This high incidence of inflammation in the exstrophied bladder is not surprising because of the availability of the exposed bladder surface to contamination. Organisms originating from the individual's environment, the skin, or gastrointestinal tract have ready access to this fertile area which is kept moist by the urine and constantly irritated by diapers or clothing. The second most frequent abnormal finding was a change in the type of epithelial covering. Patchy areas of squamous metaplasia (fig. 2, B) were found in 19 of the 23 cases studied. In eight of these 19 cases, a well-developed keratin layer was observed. The 2 patients under 1 year and six of the 8 patients under 2 years of age demonstrated this metaplastic change. Squamous cell metaplasia is a self-protective mechanism initiated by constant surface irritation to the transitional cell epithelium. It appeared very early and became more extensive with age. In some instances the metaplastic change had been so complete that questions arose whether the sections included adjacent skin. Neoplastic changes of a squamous cell type were not encountered. Glandular formations were noted in the submucosal and muscular layers in the majority of
538
HISTOLOGY OF EXSTROPHIED BLADDER
539
Fm. 1. Histological structure of normal bladder the sections. In 18 of the 23 patients, glands lined with mucus-secreting columnar cells were observed (fig. 3, A). Their resemblance to rectal glands was striking. Glands lined with columnar or cuboidal epithelium but devoid of goblet cells (fig. 3, B) were noted with almost equal frequency (17 out of 23 patients). No glandular structures were found in the bladders of 3 patients; they were 1, 16 and 70 months of age. However, the remainder of the bladders examined showed either mucoid or non-mucoid glands, and in most instances, a combination of these structures. The development of non-mucoid glands in the bladder probably stems from an invagination of the transitional epithelium which eventually loses its connection with the surface. In 2 patients in whom no glandular structures were demonstrated (patients 1 and 30 months of age), a downgrowth of the epithelium with budding and pocketing was noted. Initially these glands are lined by a multiple layer of cells; but as growth occurs, the stratification gives way to a single layer of columnar epithelium. The lumen of these glands contained eosinophilic material. In many instances the microscopic picture of these glands resembled
the prostatic acinus as previously described by Pund, Yount and Blumberg. 5 The origin of the mucoid cells cannot be explained in such a direct manner. However, because of the embryological origin of the bladder, it can be postulated that these elements arise through the process of cataplasia in which the cells revert to a more primitive stage in their development. Since the bladder and rectum have originated from a common structure (the cloaca) it is understandable that reversion to the undifferentiated state may lead to the formation of tall columnar mucus-secreting epithelium. Loss of normal environment and function may be responsible for such a reaction. On the other hand, it is conceivable that maldevelopment of the organ has been responsible also for misplacement of epithelial remnants. Righetti 6 histologically studied the rectum of a patient with exstrophy of the bladder and found that the mucosa of the rectum contained areas of 6
Pund, E. R., Yount, H. A. and Blumberg,
J. M.: Variations in morphology of urinary blad-
epithelium, special reference to cystitis glandularis and carcinomas. J. Urol., 68: 242, 1952. 6 Righetti: Quoted by Formiggini, B. 2
540
CULP
Fm. 2. A, follicular inflammation of bladder wall. B, squamous cell metaplasia
epithelium of the vesical type and in other areas thermore, some exstrophied bladders have been undifferentiated epithelium which in some in- . observed to contain a plate of intestinal mucosa stances seemed to be evolving toward the urinary which has no connection with the intestinal tract. type and others toward the intestinal type. Fur- Such a situation was seen in the 50-year-old
HISTOLOGY OF EXSTROPHIED BLADDER
FIG. 3. Cystitis glandularis. A, mucoid variety. B, non-mucoid variety
541
542
CULP
FIG. 4. A, exstrophy of bladder with patch of intestinal mucosa. B, microscopic appearance of patch of intestinal mucosa removed from surface of exstrophied bladder.
.1
HISTOLOGY OF EXSTROPHIED BLADDER
543 !
'I
j1
FIGo 50 Cystitis cystica woman in our serieso A red, velvety patch of mucosa was located on the right side of the exstrophied bladder (figo 4, A) and regular peristaltic waves traversed this segment just as they "'ould through the intact boweL This area was completely surrounded by vesical wall which was primarily lined with transitional cell epithelium in which mucoid glandular elements were foundo Histological studies of this area revealed a pattern that could not be differentiated from the rectum (figo 4, B) Therefore, it is possible for an intestinal type of epithelial cell to be included in the exstrophied bladder either through misplaced remnants (ectopia) or a process of cataplasiao Large cystic cavities (cystitis cystica) lined with a flat pavement-type epithelium were found in 15 of the 23 cases (figo 5) These cavities varied greatly in size and number but were generally confined to the submucosal layer, although an occasional cystic structure was encountered in the musculariso Usually the lumen was filled with an eosinophilic materiaL Similar cystic cavities have been desc1ibed in the intact bladder resulting from chronic inflammationo Von Brunn7 and 7 Von Brunn, Ao: Ueber drlisenahnliche Bildun0
0
Aschoff 8 described the histogenesis of these structures as an epithelial sprout extending from the mucosao The stalk of the downward growth became pinched off by proliferating connective tissue, isolating nests of epithelial bodies within the wall of the bladder. Proliferation, central degeneration and liquefaction convert these epithelial cell nests into cystic ca vitieso The attention of previous histological studies of the exstrophied bladder has been focused primarily on the spectacular epithelial findings with little or no mention of the condition of the musculariso Since this study was performed primarily on surgical specimens, the entire thickness of the bladder wall was rarely attainableo Usually a portion of the detrusor muscle was preserved to aid in the support of the defect in the abdominal walL Nevertheless, sufficient muscularis was available for study in 20 patientso gen in der Schleimhaut des Nierenbeckens, der Ureters und der Harnblase beim Menscheno Archo L mikro Anato, 41: 294, 18930 8 Aschoff, Lo: Ein Beitrag zur normalen und pathologischen Anatomie der Schleimhaut der Harnwege und ihrer drusiger Anhaugeo Archo L patho Anato, 138: 119 and 195, 18940
544
CULP
FIG. 6. Disorganization of muscle fiber and fibrosis of muscularis layer
However, one of these was heavily infiltrated with neoplasm and evaluation of the muscle was not possible. In the 19 specimens suitable for evaluation, marked fibrosis of the muscle layer was noted in seven. In addition, one of the seven with fibrosis exhibited disorganization in arrangement of the muscle bundles (fig. 6). The remaining 12 sections showed no definite histological abnormality of the muscle layer. Fibrosis was encountered more commonly in the older patients and seemed to be directly dependent upon the degree of inflammation. Only 1 patient under 2 years of age demonstrated this change and this bladder was also besieged with severe acute and chronic inflammation. Disorganization which is a much more serious abnormal finding, particularly in situations where bladder reconstruction is contemplated, is not acquired, but a reflection of the developmental error. A neoplastic change was encountered in only one of the 23 patients. It was an adenocarcinoma and appeared in the oldest patient in the series, a 52-year-old man. 9 Microscopically the neoplasm 9
Bunge, R. G.: Podophyllin in treatment of
was poorly differentiated with many of the cells filled with a mucoid material (fig. 7). Widespread lymphatic and hematogenous dissemination had occurred and the patient died shortly after radical surgical excision. Adenocarcinoma is the most frequent type of malignant change noted in the exstrophied bladder. Goyanna, Emmett and NI.cDonald, 10 in 1951, found only 29 cases of carcinoma in an exstrophied bladder reported in the literature and of these, 24 were adenocarcinomas, two were squamous cell carcinomas and three were unidentified. Potentially, however, four different epithelial neoplastic changes are possible in the exstrophied bladder (fig. 8). The epithelium may produce papillary or non-papillary transitional cell carcinomas. However, should a process of metaplasia precede malignant degeneration, squamous cell carcinoma may result, while glandular elements formed by epithelial inclusions, cataplasia or ectopia lead to the development of mucoid or non-mucoid adenocarcinomas. human adenocarcinoma of bladder. J. Urol., 68: 475, 1952. 10 Goyanna, IL, Emmett, J. L., andl\/IcDonald, J. R.: Exstrophy of the bladder complicated by adenocarcinoma. J. Urol., 65: 391, 1951.
HISTOLOGY OF EXSTROPHIED BLADDER
545
,,i
Fm. 7. Adenocarcinoma of exstrophied bladder
";r;.. 'r"·\""\
I 7. ,. ·"\ 'ft~\ Stratified squamous
Inclusion epithelium
Glandular
epithelium
Cystitis cyslico
epithelium
Cystitis glandu/oris
Stratified
squamous cell carcinoma
Adenocorcinomo Adenocorcinomo (prostalk: cell type) (colonic type)
Fm. 8. Potentialities of transitional cell epithelium
The results of this histological study of the exstrophied bladder are tabulated in table 1. All of the 23 bladders were abnormal in one respect or another. Extensive squamous metaplasia with keratin formation and inflammation was observed in the bladder of the l-n10nth-old child. Cystitis
I I
Normal Bladder Mucos"
Papil/oryptronsiliono/ neoplasms
;I
cystica, cystitis glandularis and fibrosis within the detrusor muscle were found as early as 11 months. However, one of the essential questions remains unanswered. Is the exstrophied bladder normal at birth? The study of the newborn exstrophied bladder has been inadequate. Only a
546
CULP
TABLE
Age
Patient
R. C.
1 mo.
T.B.
11 mos.
D. K.
16 mos.
E. K.
20 mos.
M.K.
22 mos.
G. S.
22 mos.
T.H. R.W.
23 mos. 24 mos.
E.L. L. C.
28 mos. 30 mos.
D.L.
3 yrs.
F. E.
M.D.
3 2 3 3 3 6 5
J.B.
1. Histological study of exstrophy of the bladder
GianCystitis dularis cuboiCystitis columnar dal or Metaplasia Cystica (mutransicoid) tional Squamous
--- --- --+(keratin) +(keratin) +(keratin) +(keratin)
-
Fibrosis
-
-
-
-
-
-
-
-
+
Acute edematous
-
-
-
+
-
+
-
+
+
+
+
+ +
+ +
Acute and chronic ulcerative and granulating Acute and chronic ulcerative Chronic edematous Acute and chronic ulcerative Chronic ulcerative Fibrosis Acute congestive
-
-
-
-
-
-
Fibrosis
-
-
+ +
+
+
+
+
+
+
+
+
-
+
+
+
+
-
+
+
+
+
+
+
5 yrs.
+
-
+
+
W.G.
10 yrs.
-
+
T.A.
13 yrs.
+
B. T.
25 yrs.
W.H.
25 yrs.
+(keratin) +(keratin) +(keratin) +(keratin)
D.H. M. S.
28 yrs. 50 yrs. 52 yrs.
s.
-
Severe acute and chronic Chronic ulcerative
+
I.
--
+
-
H. L.
Neoplasma
+
-
R.H.
Muscularis
+
+(keratin) + +(keratin) +
yrs. mos. yrs. mos. yrs. mos. yrs.
Inflammation
+ + +
-
-
-
Fibrosis
-
Disorganization and fibrosis Fibrosis
-
+
Acute and chronic congestive Acute and chronic ulcerative Acute and chronic ulcerative Acute and chronic ulcerative Acute and chronic ulcerative and granulating Acute and chronic edematous Chronic ulcerative
-
+
-
Chronic edematous
-
-
+
+
+
Chronic ulcerative
Fibrosis
-
+
+
+
-
-
+ + +
+ + +
+ + +
Acute and chronic ulcerative and granulating Chronic ulcerative Chronic ulcerative Chronic ulcerative
-
-
Infiltrated with neoplastic cells
+
mUCOl d adenocarcinoma
HISTOLOGY OF EXSTROPHIED BLADDER
547
Fm. 9. Exstrophy of bladder, 2 weeks old. A, acute ulcerative inflammation and squamous cell metaplasia. B, cystitis glandularis, 11011-mucoid.
548
CULP
Fm. 10. Exstrophy of bladder, 2 weeks old. Fibrosis of muscularis few isolated cases have been reported in the literature and since the inception of this study the opportunity to examine the exstrophied bladder at birth has not presented itself. A study of this nature must be done and I would invite urologists to join in such an investigation. Even if one assumes that the bladder is histologically normal at birth, then it is evident that it acquires the abnormalities observed in this study within the first few weeks of life. Therefore, if a functional closure of the bladder is performed after the first few months of life, it is obvious that the bladder will not be a normal histological structure. What happens to these changes when the bladder is returned to a normal habitat cannot be answered at this time, and, in fact, presents another problem for investigation. ADDENDUM
Since the completion of this article, a 2-weekold boy with exstrophy of the bladder has been observed. Biopsies were obtained from each of the 4 quadrants of the exposed bladder surface, and microscopic studies demonstrated extensive histologic changes. Normal transitional cell epithelial
lining was difficult to find. Acute ulcerative inflammation involved most of the bladder surface and well-developed, mature squamous cell metaplasia was found, particularly in the sections of the more cephalad quadrants (fig. 9, A). In some areas the metaplasia was covered by a layer of keratin. Epithelial inclusion within the submucosal layer was characterized by sprouts of epithelial downgrowth, small epithelial-lined cysts and nests of glandular cells with large vacuoles in the cytoplasm (fig. 9, B). Goblet cells were not observed. Marked proliferation of fibrous tissue was interspersed between the muscle bundles separating them quite widely in some areas (fig. 10). The individual muscle bundles appeared normal. Observations have been made on 24 exstrophied bladders varying in age from 2 weeks to 52 years, and not one of these structures was normal histologically. Acknowledgement for assistance in histological study of slides is given to Dr. Herbert Miller, Department of Pathology, State University of Iowa, Iowa City, Iowa.
Vol. 91, No. 5 May 1964 Copyright © 1964 by The Williams & Wilkins Co. Printed in U.S.A.
THE HISTOLOGY OF THE EXSTROPHIED BLADDER DAVID A. CULP From the Department of Urology, State University of Iowa, Iowa City, Iowa
Many different operative procedures have been devised in an effort to improve the status of patients with exstrophy of the bladder. In general, these procedures may be divided into 2 groups: 1) those that discard the bladder and divert the urinary stream and 2) those that salvage the bladder by reconstructive surgery. Since neither approach to the problem has been sufficiently sucessful to gain a clear-cut advantage over the other, much discussion has revolved around the advantages and disadvantages of each method. However, one basic aspect seems to have been ignored ahnost completely, that is, the histology of the anomalous bladder. Is the exstrophied bladder a normal structure except for the absence of the anterior half? Have the various coats of the bladder wall undergone normal development? The success of reconstructive procedures is directly dependent upon the condition of the exstrophied bladder but nothing has appeared in recent literature concerning this aspect of the problem. Enderlen, 1 in 1904, studied the exstrophied bladder of 2 newborn infants and found normal transitional cell epithelium. Formiggini 2 described cystic cavities but no glandular structures in the exstrophied bladder of an infant 9 days old. On the other hand, glandular structures were demonstrated in a compilation of 18 cases observed by Shattock, 3 Enderlen, 1 and Scholl. 4 These patients ranged in age from a few months to 77 years. Accepted for publication November 22, 1963. Read at annual meeting of North Central Section, American Urological Association, Inc., Chicago, Illinois, September 11-14, 1963. Study supported by grants from National Science Foundation (GB-454) and the Krannert Foundation. 1 Enderlen, E.: Zur Histologie der Schleimhaut der ektopierten Blase Verhandl d. deutsch. path., Gesellsch., 7: 167, 1904. 2 Formiggini, B.: Contributo allo studio istologico della mucosa vesicale extrofica. Riforma med., 36: 252, 1920. 3 Shattock, S. G.: Specimens of epispadias and exstroversio vesicae showing an attachment of the muscular wall of the bladder to the back of the pubic bones. Trans. Path. Soc., London, 45: 117124, 1894. 4 Scholl, A. J.: The potential malignancy in exstrophy of the bladder. Ann. Surg., 75: 365, 1922.
In an attempt to improve our own knowledge, a histological study of the bladders removed from 23 patients with exstrophy, varying in age from 1 months to 52 years, was undertaken. As a basis for comparison a parallel series of normal bladders obtained from postmortem material was included in the study (fig. 1). In brief, all of the normal bladders were lined by stratified transitional cell epithelium which was separated from a well-developed, orderly-arranged, muscular layer by loose areolar tissue. No glandular structures or epithelial inclusions were noted. Not one of the exstrophied bladders was entirely normal. The most frequent pathological process encountered was acute and chronic follicular inflammation with edema of the submucosal layer (fig. 2, A). Areas of acute ulceration and chronic granulation were common. In fact, only one patient failed to demonstrate an inflammatory response and this was the 1-month-old child. This high incidence of inflammation in the exstrophied bladder is not surprising because of the availability of the exposed bladder surface to contamination. Organisms originating from the individual's environment, the skin, or gastrointestinal tract have ready access to this fertile area which is kept moist by the urine and constantly irritated by diapers or clothing. The second most frequent abnormal finding was a change in the type of epithelial covering. Patchy areas of squamous metaplasia (fig. 2, B) were found in 19 of the 23 cases studied. In eight of these 19 cases, a well-developed keratin layer was observed. The 2 patients under 1 year and six of the 8 patients under 2 years of age demonstrated this metaplastic change. Squamous cell metaplasia is a self-protective mechanism initiated by constant surface irritation to the transitional cell epithelium. It appeared very early and became more extensive with age. In some instances the metaplastic change had been so complete that questions arose whether the sections included adjacent skin. Neoplastic changes of a squamous cell type were not encountered. Glandular formations were noted in the submucosal and muscular layers in the majority of
538
HISTOLOGY OF EXSTROPHIED BLADDER
539
Fm. 1. Histological structure of normal bladder the sections. In 18 of the 23 patients, glands lined with mucus-secreting columnar cells were observed (fig. 3, A). Their resemblance to rectal glands was striking. Glands lined with columnar or cuboidal epithelium but devoid of goblet cells (fig. 3, B) were noted with almost equal frequency (17 out of 23 patients). No glandular structures were found in the bladders of 3 patients; they were 1, 16 and 70 months of age. However, the remainder of the bladders examined showed either mucoid or non-mucoid glands, and in most instances, a combination of these structures. The development of non-mucoid glands in the bladder probably stems from an invagination of the transitional epithelium which eventually loses its connection with the surface. In 2 patients in whom no glandular structures were demonstrated (patients 1 and 30 months of age), a downgrowth of the epithelium with budding and pocketing was noted. Initially these glands are lined by a multiple layer of cells; but as growth occurs, the stratification gives way to a single layer of columnar epithelium. The lumen of these glands contained eosinophilic material. In many instances the microscopic picture of these glands resembled
the prostatic acinus as previously described by Pund, Yount and Blumberg. 5 The origin of the mucoid cells cannot be explained in such a direct manner. However, because of the embryological origin of the bladder, it can be postulated that these elements arise through the process of cataplasia in which the cells revert to a more primitive stage in their development. Since the bladder and rectum have originated from a common structure (the cloaca) it is understandable that reversion to the undifferentiated state may lead to the formation of tall columnar mucus-secreting epithelium. Loss of normal environment and function may be responsible for such a reaction. On the other hand, it is conceivable that maldevelopment of the organ has been responsible also for misplacement of epithelial remnants. Righetti 6 histologically studied the rectum of a patient with exstrophy of the bladder and found that the mucosa of the rectum contained areas of 6
Pund, E. R., Yount, H. A. and Blumberg,
J. M.: Variations in morphology of urinary blad-
epithelium, special reference to cystitis glandularis and carcinomas. J. Urol., 68: 242, 1952. 6 Righetti: Quoted by Formiggini, B. 2
540
CULP
Fm. 2. A, follicular inflammation of bladder wall. B, squamous cell metaplasia
epithelium of the vesical type and in other areas thermore, some exstrophied bladders have been undifferentiated epithelium which in some in- . observed to contain a plate of intestinal mucosa stances seemed to be evolving toward the urinary which has no connection with the intestinal tract. type and others toward the intestinal type. Fur- Such a situation was seen in the 50-year-old
HISTOLOGY OF EXSTROPHIED BLADDER
FIG. 3. Cystitis glandularis. A, mucoid variety. B, non-mucoid variety
541
542
CULP
FIG. 4. A, exstrophy of bladder with patch of intestinal mucosa. B, microscopic appearance of patch of intestinal mucosa removed from surface of exstrophied bladder.
.1
HISTOLOGY OF EXSTROPHIED BLADDER
543 !
'I
j1
FIGo 50 Cystitis cystica woman in our serieso A red, velvety patch of mucosa was located on the right side of the exstrophied bladder (figo 4, A) and regular peristaltic waves traversed this segment just as they "'ould through the intact boweL This area was completely surrounded by vesical wall which was primarily lined with transitional cell epithelium in which mucoid glandular elements were foundo Histological studies of this area revealed a pattern that could not be differentiated from the rectum (figo 4, B) Therefore, it is possible for an intestinal type of epithelial cell to be included in the exstrophied bladder either through misplaced remnants (ectopia) or a process of cataplasiao Large cystic cavities (cystitis cystica) lined with a flat pavement-type epithelium were found in 15 of the 23 cases (figo 5) These cavities varied greatly in size and number but were generally confined to the submucosal layer, although an occasional cystic structure was encountered in the musculariso Usually the lumen was filled with an eosinophilic materiaL Similar cystic cavities have been desc1ibed in the intact bladder resulting from chronic inflammationo Von Brunn7 and 7 Von Brunn, Ao: Ueber drlisenahnliche Bildun0
0
Aschoff 8 described the histogenesis of these structures as an epithelial sprout extending from the mucosao The stalk of the downward growth became pinched off by proliferating connective tissue, isolating nests of epithelial bodies within the wall of the bladder. Proliferation, central degeneration and liquefaction convert these epithelial cell nests into cystic ca vitieso The attention of previous histological studies of the exstrophied bladder has been focused primarily on the spectacular epithelial findings with little or no mention of the condition of the musculariso Since this study was performed primarily on surgical specimens, the entire thickness of the bladder wall was rarely attainableo Usually a portion of the detrusor muscle was preserved to aid in the support of the defect in the abdominal walL Nevertheless, sufficient muscularis was available for study in 20 patientso gen in der Schleimhaut des Nierenbeckens, der Ureters und der Harnblase beim Menscheno Archo L mikro Anato, 41: 294, 18930 8 Aschoff, Lo: Ein Beitrag zur normalen und pathologischen Anatomie der Schleimhaut der Harnwege und ihrer drusiger Anhaugeo Archo L patho Anato, 138: 119 and 195, 18940
544
CULP
FIG. 6. Disorganization of muscle fiber and fibrosis of muscularis layer
However, one of these was heavily infiltrated with neoplasm and evaluation of the muscle was not possible. In the 19 specimens suitable for evaluation, marked fibrosis of the muscle layer was noted in seven. In addition, one of the seven with fibrosis exhibited disorganization in arrangement of the muscle bundles (fig. 6). The remaining 12 sections showed no definite histological abnormality of the muscle layer. Fibrosis was encountered more commonly in the older patients and seemed to be directly dependent upon the degree of inflammation. Only 1 patient under 2 years of age demonstrated this change and this bladder was also besieged with severe acute and chronic inflammation. Disorganization which is a much more serious abnormal finding, particularly in situations where bladder reconstruction is contemplated, is not acquired, but a reflection of the developmental error. A neoplastic change was encountered in only one of the 23 patients. It was an adenocarcinoma and appeared in the oldest patient in the series, a 52-year-old man. 9 Microscopically the neoplasm 9
Bunge, R. G.: Podophyllin in treatment of
was poorly differentiated with many of the cells filled with a mucoid material (fig. 7). Widespread lymphatic and hematogenous dissemination had occurred and the patient died shortly after radical surgical excision. Adenocarcinoma is the most frequent type of malignant change noted in the exstrophied bladder. Goyanna, Emmett and NI.cDonald, 10 in 1951, found only 29 cases of carcinoma in an exstrophied bladder reported in the literature and of these, 24 were adenocarcinomas, two were squamous cell carcinomas and three were unidentified. Potentially, however, four different epithelial neoplastic changes are possible in the exstrophied bladder (fig. 8). The epithelium may produce papillary or non-papillary transitional cell carcinomas. However, should a process of metaplasia precede malignant degeneration, squamous cell carcinoma may result, while glandular elements formed by epithelial inclusions, cataplasia or ectopia lead to the development of mucoid or non-mucoid adenocarcinomas. human adenocarcinoma of bladder. J. Urol., 68: 475, 1952. 10 Goyanna, IL, Emmett, J. L., andl\/IcDonald, J. R.: Exstrophy of the bladder complicated by adenocarcinoma. J. Urol., 65: 391, 1951.
HISTOLOGY OF EXSTROPHIED BLADDER
545
,,i
Fm. 7. Adenocarcinoma of exstrophied bladder
";r;.. 'r"·\""\
I 7. ,. ·"\ 'ft~\ Stratified squamous
Inclusion epithelium
Glandular
epithelium
Cystitis cyslico
epithelium
Cystitis glandu/oris
Stratified
squamous cell carcinoma
Adenocorcinomo Adenocorcinomo (prostalk: cell type) (colonic type)
Fm. 8. Potentialities of transitional cell epithelium
The results of this histological study of the exstrophied bladder are tabulated in table 1. All of the 23 bladders were abnormal in one respect or another. Extensive squamous metaplasia with keratin formation and inflammation was observed in the bladder of the l-n10nth-old child. Cystitis
I I
Normal Bladder Mucos"
Papil/oryptronsiliono/ neoplasms
;I
cystica, cystitis glandularis and fibrosis within the detrusor muscle were found as early as 11 months. However, one of the essential questions remains unanswered. Is the exstrophied bladder normal at birth? The study of the newborn exstrophied bladder has been inadequate. Only a
546
CULP
TABLE
Age
Patient
R. C.
1 mo.
T.B.
11 mos.
D. K.
16 mos.
E. K.
20 mos.
M.K.
22 mos.
G. S.
22 mos.
T.H. R.W.
23 mos. 24 mos.
E.L. L. C.
28 mos. 30 mos.
D.L.
3 yrs.
F. E.
M.D.
3 2 3 3 3 6 5
J.B.
1. Histological study of exstrophy of the bladder
GianCystitis dularis cuboiCystitis columnar dal or Metaplasia Cystica (mutransicoid) tional Squamous
--- --- --+(keratin) +(keratin) +(keratin) +(keratin)
-
Fibrosis
-
-
-
-
-
-
-
-
+
Acute edematous
-
-
-
+
-
+
-
+
+
+
+
+ +
+ +
Acute and chronic ulcerative and granulating Acute and chronic ulcerative Chronic edematous Acute and chronic ulcerative Chronic ulcerative Fibrosis Acute congestive
-
-
-
-
-
-
Fibrosis
-
-
+ +
+
+
+
+
+
+
+
+
-
+
+
+
+
-
+
+
+
+
+
+
5 yrs.
+
-
+
+
W.G.
10 yrs.
-
+
T.A.
13 yrs.
+
B. T.
25 yrs.
W.H.
25 yrs.
+(keratin) +(keratin) +(keratin) +(keratin)
D.H. M. S.
28 yrs. 50 yrs. 52 yrs.
s.
-
Severe acute and chronic Chronic ulcerative
+
I.
--
+
-
H. L.
Neoplasma
+
-
R.H.
Muscularis
+
+(keratin) + +(keratin) +
yrs. mos. yrs. mos. yrs. mos. yrs.
Inflammation
+ + +
-
-
-
Fibrosis
-
Disorganization and fibrosis Fibrosis
-
+
Acute and chronic congestive Acute and chronic ulcerative Acute and chronic ulcerative Acute and chronic ulcerative Acute and chronic ulcerative and granulating Acute and chronic edematous Chronic ulcerative
-
+
-
Chronic edematous
-
-
+
+
+
Chronic ulcerative
Fibrosis
-
+
+
+
-
-
+ + +
+ + +
+ + +
Acute and chronic ulcerative and granulating Chronic ulcerative Chronic ulcerative Chronic ulcerative
-
-
Infiltrated with neoplastic cells
+
mUCOl d adenocarcinoma
HISTOLOGY OF EXSTROPHIED BLADDER
547
Fm. 9. Exstrophy of bladder, 2 weeks old. A, acute ulcerative inflammation and squamous cell metaplasia. B, cystitis glandularis, 11011-mucoid.
548
CULP
Fm. 10. Exstrophy of bladder, 2 weeks old. Fibrosis of muscularis few isolated cases have been reported in the literature and since the inception of this study the opportunity to examine the exstrophied bladder at birth has not presented itself. A study of this nature must be done and I would invite urologists to join in such an investigation. Even if one assumes that the bladder is histologically normal at birth, then it is evident that it acquires the abnormalities observed in this study within the first few weeks of life. Therefore, if a functional closure of the bladder is performed after the first few months of life, it is obvious that the bladder will not be a normal histological structure. What happens to these changes when the bladder is returned to a normal habitat cannot be answered at this time, and, in fact, presents another problem for investigation. ADDENDUM
Since the completion of this article, a 2-weekold boy with exstrophy of the bladder has been observed. Biopsies were obtained from each of the 4 quadrants of the exposed bladder surface, and microscopic studies demonstrated extensive histologic changes. Normal transitional cell epithelial
lining was difficult to find. Acute ulcerative inflammation involved most of the bladder surface and well-developed, mature squamous cell metaplasia was found, particularly in the sections of the more cephalad quadrants (fig. 9, A). In some areas the metaplasia was covered by a layer of keratin. Epithelial inclusion within the submucosal layer was characterized by sprouts of epithelial downgrowth, small epithelial-lined cysts and nests of glandular cells with large vacuoles in the cytoplasm (fig. 9, B). Goblet cells were not observed. Marked proliferation of fibrous tissue was interspersed between the muscle bundles separating them quite widely in some areas (fig. 10). The individual muscle bundles appeared normal. Observations have been made on 24 exstrophied bladders varying in age from 2 weeks to 52 years, and not one of these structures was normal histologically. Acknowledgement for assistance in histological study of slides is given to Dr. Herbert Miller, Department of Pathology, State University of Iowa, Iowa City, Iowa.