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Cystitis Cystica: Bacteriological Studies in a Series of 28 Cases
CYSTITIS CYSTICA: BACTERIOLOGICAL STUDIES IN A SERIES OF 28 CASES WILLIAM D. WARRICK From the Urological Service of Presbyterian Hospital, Chicago, and the Thomson Urological Fund, Rush Medical College, Chicago
Cystitis cystica is a well recognized clinical entity. The fact that the cysts per se rarely produce clinically recognizable symptoms is the reason why they have been overlooked in the past. Urologists have for many years recognized their presence in the bladder. The cysts occur not only in the urinary bladder but also in the urethra, ureter, and renal pelvis. One of the earliest articles in this country to deal with this subject was published by Kretschmer (1908). Since this publication the subject has not received very extensive study until more or less recently. Morse (1928) reviewed the subject and reported all the cases reported in the literature up to that time. Since then comprehensive studies have been published by Patch and Rhea (1935) and Patch in 1939. Stirling (1939) discussed the subject in relation to cystitis follicularis. The histology of this subject has been accurately described in a previous publication by Kretschmer, which article is illustrated and to which those interested may refer. We believe there is much unanimity of opinion among all authors concerning many phases of this subject. Morgagni is accredited with having first mentioned the subject in 1761. However, it was more than 100 years later that Litten made the first microscopical studies in 1876. From his studies he expressed the opinion that the cysts were derived from preformed glands or the proliferation of normal mucous membrane. Osler suggested a parasitic origin. Our modern theories are evolved from the work of Von Limbeck in 1887 and Von Brunn in 1893. These men recognized the presence of groups of epithelial cells beneath the mucous membrane. Some of these groups maintain a connection with the surface epithelium and are called epithelial buds. Other groups are completely isolated from the mucous membrane and are actually epithelial cell nests. Von Brunn expressed the opinion that these epithelial buds and nests were formed by a downward proliferation of the lining mucous membrane in the form of buds which may later separate to become epithelial or Brunn's nests. 835
836
WILLIAM D. WARRICK
He believed that inflammation was the inciting cause of this cell proliferation. In proof of his theory he called attention to the fact that all the cells forming the buds and nests were histologically similar to the cells of the surface epithelium. He carefully distinguished them from glands and added that he saw no glands. He was of the opinion that the cells exhibited none of the usual characteristics of glandular or secretory epithelium. Furthermore no ducts connecting the cell nests with the surface could be demonstrated. The formation of cysts from the cell nests was believed to come about through the degeneration of the central cells of the nests. Lubarsch later confirmed the degeneration of the central cells by the microscopic appearance and staining reactions of the cell contents. He stated that his cases of cystitis cystica had arisen in three separate ways: (1) from Von Brunn's cell nests; (2) from the inflammatory closure of the crypts of the mucous membrane, and (3) apparently from abnormally placed glands of the upper urethra. Aschoff was unable to demonstrate glandular elements in the bladder. He believed that Brunn's nests were formed in 2 ways: (1) by downward proliferation of the deepest layers of urinary epithelium, and (2) by proliferation of fibrous connective tissue which grew upward and cut off islands or nests of the epithelium. These collections of cells in the submucosa have been termed epithelial nests, Limbeck-Brunn's nests, and most commonly Brunn's nests. It appears that the Brunn's nests may produce either of 2 terminal states. Most commonly cysts are formed whereas occasionally glands are produced, the resulting condition being cystitis glandularis. Most authors have expressed the opinion that the inciting cause for the evolution of the cell nests has been infection. However, Giani (1907) produced the lesions experimentally by submitting the bladders of rabbits to curettage through a suprapubic wound. Morse examined 125 necropsy specimens, none of which had macroscopic cysts, and was able microscopically to demonstrate epithelial buds, nests and cysts in 108 of these cases. Inflammatory reaction as judged by lymphocytic infiltration, proliferation of fibrous connective tissue and formation of new capillaries was found in 63 of his 108 cases with epithelial buds, nests and cysts as well as in 4 cases which had none. It occurred to us that no attempt has been made to correlate a series of cases of cystitis cystica from the point of view of bacteriological studies, duration of urinary symptoms, and kind of urinary complica-
CYSTITIS CYSTICA
837
tions, if any. Morse mentioned that cystitis cystica was found in 17.4 per cent of 190 cases of bilateral pyelonephritis. Hinman reported the bacteriological studies on 3 cases, Patch on 2 cases, and Stirling on 1 case. This paper is based on the records of 28 cases of cystitis cystica (table 1). It was undertaken with the hope that it might stimulate the correlation of bacteriological as well as clinical findings in these cases. The diagnosis is most commonly made cystoscopically. Characteristically the cysts appear as small beads immediately beneath the surface and covered only with a very thin layer of mucous membrane. Fine blood vessels may be seen in this covering membrane. The fluid is usually clear and translucent but may have a slight yellowish cast. The common lesions vary from 2 to 5 mm. in diameter. Most often they are observed on the trigon, but frequently are seen all around the bladder neck. Somewhat infrequently they are seen on the lateral walls and in the dome of bladder. The cysts are usually discrete and there is often a tendency for the lesions to be arranged symmetrically. Several diseases may give a somewhat similar cystoscopic picture. Included in these are such lesions as bullous edema, urethral polyps at the bladder neck, granular cystitis, cystitis follicularis and cystitis emphysematosa. A few useful criteria for making this differential diagnosis might be mentioned. Bullous edema usually appears as a circumscribed mass of clear vesicles surrounded by an area of increased vascularity. The vesicles appear to be almost confluent and may be seen in isolated groups in almost any location of the bladder. Urethral polyps may be confusing especially in the female. They are rather frequently seen hanging from the anterior aspect of the bladder neck. Careful inspection will disclose their elongated structure as well as their origin from the walls of the urethra. Granular cystitis is a common condition most often associated with a chronic inflammation and widespread increased vascularity. The mucosa is covered more or less extensively with granulations some of which may appear not unlike confluent vesicles except that they are not translucent. Cystitis follicularis is characterized by nodules having a solid appearance in contrast to the translucent nature of the cysts of cystitis cystica. These nodules are often accompanied by a generalized capillary injection of the mucous membrane such as is seen in chronic cystitis.
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TABLE
BACTERIOLOGY
< -- -- --1 50 8 690 No growth
132
1330
No growth
3 37 4 50
84 12
4 960
No growth Proteus
5 45 6 72
192 18
980 30
B. coli B. coli
7 60
18
14
8 68
6
1
9 32
30
30
10
40
12
4200
11 12 13
61 48 57
24 1 12
362 17 0
14 52
24
1760
15
42
12
2530
16 66 17 55
6 12
2400 7
18 67
12
7
19 60
12
20
20 43
4
20
36
12
900
22 44
72
1800
23
71
36
1100
24 62 25 31
1 8
12 20
26 71 27 36
2 36
190 10
28
36
3600
67
LOCATION OF CYSTS
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21
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1 -Tabulation of cases
Trigon Trigon, bladder neck Trigon Lateral walls
Bladder neck Trigon lateral walls No growth Right wall bladder neck Trigon lateral B. coli walls No growth Trigon bladder neck Trigon bladder B. coli neck No growth All over Trigon B. coli Trigon bladder B. coli neck Trigon lateral B. coli walls Trigon bladder B. coli neck Pyocyaneus Right side No growth Trigon lateral walls Hemolytic All over B. coli Hemolytic Bladder neck B. coli No growth Trigon Hemolytic B. coli Hemolytic B. coli Diplostreptococcus B. coli B. coli
Trigon Trigon lateral walls Trigon
Chronic bilateral pyelonephritis Many Chronic pyelonephritis, chronic prostatitis Few Papilloma of bladder Few Renal calculus, renal tuberculosis Median bar, chronic cystitis Few Many Few
Few
Benign prostatic hypertrophy
Many Chronic pyelonephritis Few
Stricture of urethra
Few
Acute pyelonephritis
Many Carcinoma of bladder Acute pyelonephritis Few Many Hydronephrosis Many Hydronephrosis Few
Chronic prostatitis
Benign prostatic hypertrophy Few Many Chronic pyelonephritis Many Chronic cystitis Few
Chronic pyelonephritis
Many Renal calculus, pyelitis and ureteritis cystica Right hydronephrosis, left Few renal calculus Renal calculus Few Few
Trigon Trigon
Few Few
B. coli Proteus
Trigon Trigon
Few Few
B. coli
Trigon
Few
838
ASSOCIATED UROLOGICAL PATHOLOGY
Acute pyelonephritis, tocoele
cys-
Elusive ulcer, polyposis of bladder neck Median bar, chronic prostatis Right double kidney and ureter Carcinoma of prostate
CYSTITIS CYSTICA
839
Cystitis glandularis is uncommon. Here also the lesions appear as solid nodules. It is rarely recognized except in microscopical preparations. Cystitis emphysematosa is for the most part of theoretical interest since it has rarely been recognized except at autopsy. However, we shall mention some of its characteristics because interest in this condition is increasing. The bladders are generally badly infected. The lesions are described as clear, gas-containing vesicles which vary in size from a pin head to a large pea. Many authors believe that the lesions of cystitis cystica are of inflammatory origin, and although this subject has received some consideration in the literature, not much attention has been given to the presence of infection, and as far as we know, no large series of cases are recorded in which the results of bacteriological studies of the urine are reported. The articles in literature deal in the main with case reports. Furthermore but few articles deal in detail with the co-existing pathological conditions. It therefore occured to us that it might be of interest to study a group of unselected cases and to record the results of this study that it may stimulate .others to report the results of their observations. The average age of the 28 cases studied was 52 years, the youngest being 31 years and the oldest 72 years. Nineteen (68 per cent) were females and nine (32 per cent) were males. The time elapsed since the onset of urinary symptoms varied from 1 month to 192 months with an average of 30 months. Fourteen (50 per cent) had 100 or more pus cells per cubic millimeter of bladder urine. In 21 cases the separated ureteral specimens were studied but no additional information. was obtained. There was 1 case, No. 17 reported as "no growth," in which Staphylococcus albus was grown in the right ureteral specimen, but this may have been a contamination. The most common organism was B. coli found in 12 (43 per cent) cases. Eight (29 per cent) showed "no growth." Hemolytic B. coli were found in 4 (14 per cent), Proteus in 2 (7 per cent), B. pyocyaneus and diplostreptococcus in 1 (3.6 per cent) each. Other organisms previously reported include Staphylococcus aureus, Staphylococcus albus, and short chained cocci. Review of the histories of the 8 cases with sterile bladder urine reveals that all of these patients had clinical symptoms of bladder infection at some previous time. The significance of these bacteriological studies is interesting. Ap-
840
WILLIAM D. WARRICK
parently we are in a position to refute the age-old saying that all cases of cystitis cystica are associated with B. coli infections since only 43 per cent of our cases had this organism. However, the duration of time elapsed since the onset of clinical symptoms is sufficiently long in some cases to have allowed a change in the bacterial flora. It is noted that there were 5 types of organisms found in our series as well as 3 additional strains reported elsewhere. These data would support a theory that no specific bacteria are necessary to induce this condition. The 8 cases with sterile urine present evidence for consideration. The average time elapsed since the onset of urinary symptoms in this group was 39 months, or 9 months longer than the average for the entire series. This finding might be expected since we believe that all of these cases were previously infected but had become sterile in the interim before our examination. In 4 of these cases with sterile urine, "many cysts" were seen. This is a larger percentage than that of the entire series which was 32 per cent. Since we believe that these cysts or their anlage, Brunn's nests, formed in an infected bladder it must follow that retrogression, if any, is slow. It might also follow that the evolution of cysts from preformed Brunn's nests may be attenuated and that production has been continuous hut at a slow rate. In this connection we might add that it would be interesting and informative to check a series of both infected and sterile cases at various time intervals. From such a study conclusions might be reached concerning the rate of growth, disappearance of the cysts if any, and the type of bladder conditions necessary for these changes. We must assume that there is no evidence that any specific bacteria are necessary for the production of Brunn's nests or cystitis cystica. Furthermore we have no evidence to indicate that the cysts disappear when the infection ceases. Rather our data would tend to imply that the cysts remain or may even increase after the urine has become sterile. All histories were checked for 4 common urological symptoms. It was found that 93 per cent had burning on urination, 83 per cent had frequency of urination, 79 per cent had nocturia, and 29 per cent had hematuria. We are not meaning to imply that we believe the clinical symptoms were caused primarily by the cystitis cystica. In 10 (36 per cent) cases the cysts were noted only on the trigon. In 21 (68 per cent) cases the cysts were described as seen on the trigon or around the bladder neck. In 9 (32 per cent) cysts were seen on the
CYSTITIS CYSTICA
841
walls of the bladder. In only 2 (7 per cent) of the cases were cysts seen on all the wall of the bladder. The frequency of the involvement of the trigon might lead to speculation as to why this occurs. Possible explanations for this may be found in the fact that since this part of the bladder is more nearly fixed, its epithelium is not subject to as much stretching as in the regions where the bladder is more distensible. Pus, stones and mucous lie on the floor of the bladder and are in better contact with this region. The role of the trigon and bladder neck in micturition may make them more susceptible to these changes. There is further, the possible role of the difference of embryological development, the trigon being mesodermal, whereas the bladder walls are entodermal in origin. In 19 (68 per cent) cases the cysts were called "few" while in 9 (32 per cent) there were "many". There is no apparent correlation between either the duration of clinical symptoms and the number of cysts or the amount of pus in the urine and the number of cysts. One patient who had many cysts had had clinical symptoms for only 6 months. Somewhat unexpected is the fact that the average duration of clinical symptoms in the cases with many cysts is 27 months which is 3 months less than the average for the entire series. Four of these cases with many cysts had sterile urine. It is noteworthy that these cases were examined for diseases other than cystitis cystica. In no case was this condition considered to be the primary pathological process. There is a great multiplicity of associated urological lesions (table 2). These include chronic pyelonephritis, 5 cases; renal calculi, 4 cases; benign prostatic hypertrophy, 4 cases; chronic prostatitis, 3 cases; acute pyelonephritis, 3 cases; hydronephrosis, 3 cases; chronic cystitis, 2 cases; and 1 case each of stricture of the urethra, papilloma of the bladder, renal tuberculosis, carcinoma of the bladder, elusive ulcer, polyposis of the bladder neck, double kidney and ureter, carcinoma of the prostate, pyelitis and ureteritis cystica. Note was made of the fact that this last mentioned case, No. 20, with cystic involvement of the entire upper tract, had had symptoms for only 4 months, had a sterile bladder urine containing 20 pus cells per cubic centimeter and bilateral renal calculi. These 34 diagnoses of associated lesions are divided almost equally between upper and lower tract diseases; i.e., 18 upper and 16 lower. Certainly we can not say that if cystitis cystica is a secondary lesion that the primary pathological process must necessarily arise in some
842
WILLIAM D. WARRICK
certain anatomical position. ·The initial disease in these cases includes renal, ureteral, bladder, and urethral lesions. There were 2 cases in which the only diagnosis we could make was cystitis cystica. Bladder urines of these patients contained practically no pus, but B. coli were cultured in both instances. Cultures of all kidney urines were sterile. Here again clinical histories of previous infection were obtained. Interesting is the fact that 1 patient dated the onset of her symptoms only 1 month previously. There seems to be no definite correlation to be drawn between cystitis cystica and its associated urological disease. TABLE
2.-Associated urological lesions
LESION
Chronic pyelonephritis ..... .. . .. ... . . .......... .. .. ... . . . . . . .. . . . Renal calculi ....... .. ... ... ... . .... . ...... . ........... . . ... .... . Benign prostatic hypertrophy . ..... . . . . . . .. . .... . . .. ....... .. ... . . Chronic prostatitis .... . . . . .. . . . . . .. . . . ... .. . . .. . . . . .... . . . .. . . .. . Acute pyelonephritis ........... . ... ..... .. ... .... . .. ... . ...... . . . Hydronephrosis .. . . . ... ......... .. . ..... . ........... . .... . . .... . Chronic cystitis .... .. . . . .. ..... . .. ...... . . . . . ..... . ............ . Urethral stricture .. . ... . . . . .. .. . . .... . . . . . . ... .. .. . . . .. ... . .. ... . Papilloma of bladder .. . . .. . . .. .. .... ....... .. .... . . ............. . Renal tuberculosis . ........... ...... . ... . ... . .. . . . ... . ... .. . .... . Carcinoma of bladder . . . . .... .. .......... .. .... . ...... . . ... ..... . Elusive ulcer . . .. . . ..... .. . .... ... .. ... .. . . ...... . . . . .. . . . . . . ... . Polyposis of bladder neck ....... . ..... .. . . ... .. . .. . ... .. . . ....... . Double kidney and ureter .. ..... . . . .. .. ... . . ..... . . ... . .... . ... .. . Carcinoma of prostate ..... . ... . . ....... ... ..... ... .. . ... . ..... .. . Pyelitis and ureteritis cystica .. .... ..... . ... ..... .. . . . ... . ... . .. . . .
CASES
5 4 4 3 3 3 2
1 1 1 1 1 1 1 1 1
We believe that the diagnosis of cystitis cystica would be made more often if microscopical studies were made more frequently as an adjunct to cystoscopy. Where an obvious lesion is seen it is not unlikely that the presence of these cysts will be overlooked. In our cases, Nos. 11 and 28, in which carcinoma of the bladder and carcinoma of the prostate respectively were present, the cysts were recognized cystoscopically and microscopically. In our cases the diagnosis was made by means of the cystoscopic examination. In 4 cases the diagnosis was checked with microscopic preparations. CONCLUSIONS
Twenty-eight cases of cystitis cystica are reported. Data were obtained on the duration of symptoms, amount of pus in
843
CYSTITIS CYSTICA
the urine, bacteriology, anatomical location of the cysts, relative number of cysts present, and associated urological conditions. This is the first time that such a correlation has appeared in the literature. We believe that continued studies along this line will lead to a better understanding of the reactions of urinary epithelium. 306 Medical Arts Bldg., Birmingham, Ala.
REFERENCES J.:
J.
CARSON, W. Pyelitis, ureteritis, and cystitis cystica. Am. Surg., 8: 1256-1258, 1930. HINMAN, F.: Pyelitis and ureteritis cystica. J. Urol., 35: 174-189, 1936. JOELSON, Pyelitis, ureteritis and cystitis cystica. Arch. Surg., 18: 1570-1583, 1929. KRETSCHMER, H. L.: Pathology and cystoscopy of cystitis cystica. Surg., Gynec., and
J. J.:
Obst. 7: 274, 1908. - - - : Pyelitis follicularis. Tr. Am. Urol. A., 7: 94-104, 1913. LIVERMORE, G. R.: Cyst of the bladder. Tr. Am. Ass. G. U. Surg., 28: 209-215, 1935. MORSE, H. D.: Etiology and pathology of pyelitis cystica, ureteritis cystica, cystitis cystica. Am. J. Path. 4: 33-50, 1928. PATCH, F. S.: Pyelitis, ureteritis, and cystitis cystica. New Eng. J. Med., 220: 979-985, 1939. - - - , AND RHEA, L. J.: The genesis and development of Brunn's nests and their relation to cystitis cystica, cystitis glandularis, and primary adeno-carcinoma of the bladder. Canad. M. A. J., 33: 597-606, 1935. STIRLING, W. C.: Cystitis follicularis. J. A. M.A., 112: 1326-1331, 1939.
Cystitis cystica is a well recognized clinical entity. The fact that the cysts per se rarely produce clinically recognizable symptoms is the reason why they have been overlooked in the past. Urologists have for many years recognized their presence in the bladder. The cysts occur not only in the urinary bladder but also in the urethra, ureter, and renal pelvis. One of the earliest articles in this country to deal with this subject was published by Kretschmer (1908). Since this publication the subject has not received very extensive study until more or less recently. Morse (1928) reviewed the subject and reported all the cases reported in the literature up to that time. Since then comprehensive studies have been published by Patch and Rhea (1935) and Patch in 1939. Stirling (1939) discussed the subject in relation to cystitis follicularis. The histology of this subject has been accurately described in a previous publication by Kretschmer, which article is illustrated and to which those interested may refer. We believe there is much unanimity of opinion among all authors concerning many phases of this subject. Morgagni is accredited with having first mentioned the subject in 1761. However, it was more than 100 years later that Litten made the first microscopical studies in 1876. From his studies he expressed the opinion that the cysts were derived from preformed glands or the proliferation of normal mucous membrane. Osler suggested a parasitic origin. Our modern theories are evolved from the work of Von Limbeck in 1887 and Von Brunn in 1893. These men recognized the presence of groups of epithelial cells beneath the mucous membrane. Some of these groups maintain a connection with the surface epithelium and are called epithelial buds. Other groups are completely isolated from the mucous membrane and are actually epithelial cell nests. Von Brunn expressed the opinion that these epithelial buds and nests were formed by a downward proliferation of the lining mucous membrane in the form of buds which may later separate to become epithelial or Brunn's nests. 835
836
WILLIAM D. WARRICK
He believed that inflammation was the inciting cause of this cell proliferation. In proof of his theory he called attention to the fact that all the cells forming the buds and nests were histologically similar to the cells of the surface epithelium. He carefully distinguished them from glands and added that he saw no glands. He was of the opinion that the cells exhibited none of the usual characteristics of glandular or secretory epithelium. Furthermore no ducts connecting the cell nests with the surface could be demonstrated. The formation of cysts from the cell nests was believed to come about through the degeneration of the central cells of the nests. Lubarsch later confirmed the degeneration of the central cells by the microscopic appearance and staining reactions of the cell contents. He stated that his cases of cystitis cystica had arisen in three separate ways: (1) from Von Brunn's cell nests; (2) from the inflammatory closure of the crypts of the mucous membrane, and (3) apparently from abnormally placed glands of the upper urethra. Aschoff was unable to demonstrate glandular elements in the bladder. He believed that Brunn's nests were formed in 2 ways: (1) by downward proliferation of the deepest layers of urinary epithelium, and (2) by proliferation of fibrous connective tissue which grew upward and cut off islands or nests of the epithelium. These collections of cells in the submucosa have been termed epithelial nests, Limbeck-Brunn's nests, and most commonly Brunn's nests. It appears that the Brunn's nests may produce either of 2 terminal states. Most commonly cysts are formed whereas occasionally glands are produced, the resulting condition being cystitis glandularis. Most authors have expressed the opinion that the inciting cause for the evolution of the cell nests has been infection. However, Giani (1907) produced the lesions experimentally by submitting the bladders of rabbits to curettage through a suprapubic wound. Morse examined 125 necropsy specimens, none of which had macroscopic cysts, and was able microscopically to demonstrate epithelial buds, nests and cysts in 108 of these cases. Inflammatory reaction as judged by lymphocytic infiltration, proliferation of fibrous connective tissue and formation of new capillaries was found in 63 of his 108 cases with epithelial buds, nests and cysts as well as in 4 cases which had none. It occurred to us that no attempt has been made to correlate a series of cases of cystitis cystica from the point of view of bacteriological studies, duration of urinary symptoms, and kind of urinary complica-
CYSTITIS CYSTICA
837
tions, if any. Morse mentioned that cystitis cystica was found in 17.4 per cent of 190 cases of bilateral pyelonephritis. Hinman reported the bacteriological studies on 3 cases, Patch on 2 cases, and Stirling on 1 case. This paper is based on the records of 28 cases of cystitis cystica (table 1). It was undertaken with the hope that it might stimulate the correlation of bacteriological as well as clinical findings in these cases. The diagnosis is most commonly made cystoscopically. Characteristically the cysts appear as small beads immediately beneath the surface and covered only with a very thin layer of mucous membrane. Fine blood vessels may be seen in this covering membrane. The fluid is usually clear and translucent but may have a slight yellowish cast. The common lesions vary from 2 to 5 mm. in diameter. Most often they are observed on the trigon, but frequently are seen all around the bladder neck. Somewhat infrequently they are seen on the lateral walls and in the dome of bladder. The cysts are usually discrete and there is often a tendency for the lesions to be arranged symmetrically. Several diseases may give a somewhat similar cystoscopic picture. Included in these are such lesions as bullous edema, urethral polyps at the bladder neck, granular cystitis, cystitis follicularis and cystitis emphysematosa. A few useful criteria for making this differential diagnosis might be mentioned. Bullous edema usually appears as a circumscribed mass of clear vesicles surrounded by an area of increased vascularity. The vesicles appear to be almost confluent and may be seen in isolated groups in almost any location of the bladder. Urethral polyps may be confusing especially in the female. They are rather frequently seen hanging from the anterior aspect of the bladder neck. Careful inspection will disclose their elongated structure as well as their origin from the walls of the urethra. Granular cystitis is a common condition most often associated with a chronic inflammation and widespread increased vascularity. The mucosa is covered more or less extensively with granulations some of which may appear not unlike confluent vesicles except that they are not translucent. Cystitis follicularis is characterized by nodules having a solid appearance in contrast to the translucent nature of the cysts of cystitis cystica. These nodules are often accompanied by a generalized capillary injection of the mucous membrane such as is seen in chronic cystitis.
.., ;p -z
. ~~ g:l., .., ....:5
[3
t5
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u~
TABLE
BACTERIOLOGY
< -- -- --1 50 8 690 No growth
132
1330
No growth
3 37 4 50
84 12
4 960
No growth Proteus
5 45 6 72
192 18
980 30
B. coli B. coli
7 60
18
14
8 68
6
1
9 32
30
30
10
40
12
4200
11 12 13
61 48 57
24 1 12
362 17 0
14 52
24
1760
15
42
12
2530
16 66 17 55
6 12
2400 7
18 67
12
7
19 60
12
20
20 43
4
20
36
12
900
22 44
72
1800
23
71
36
1100
24 62 25 31
1 8
12 20
26 71 27 36
2 36
190 10
28
36
3600
67
LOCATION OF CYSTS
<..>
2 35
21
. ., . ~~~ !;! ~"' ~z~ . 0
~o~
::;
.
1 -Tabulation of cases
Trigon Trigon, bladder neck Trigon Lateral walls
Bladder neck Trigon lateral walls No growth Right wall bladder neck Trigon lateral B. coli walls No growth Trigon bladder neck Trigon bladder B. coli neck No growth All over Trigon B. coli Trigon bladder B. coli neck Trigon lateral B. coli walls Trigon bladder B. coli neck Pyocyaneus Right side No growth Trigon lateral walls Hemolytic All over B. coli Hemolytic Bladder neck B. coli No growth Trigon Hemolytic B. coli Hemolytic B. coli Diplostreptococcus B. coli B. coli
Trigon Trigon lateral walls Trigon
Chronic bilateral pyelonephritis Many Chronic pyelonephritis, chronic prostatitis Few Papilloma of bladder Few Renal calculus, renal tuberculosis Median bar, chronic cystitis Few Many Few
Few
Benign prostatic hypertrophy
Many Chronic pyelonephritis Few
Stricture of urethra
Few
Acute pyelonephritis
Many Carcinoma of bladder Acute pyelonephritis Few Many Hydronephrosis Many Hydronephrosis Few
Chronic prostatitis
Benign prostatic hypertrophy Few Many Chronic pyelonephritis Many Chronic cystitis Few
Chronic pyelonephritis
Many Renal calculus, pyelitis and ureteritis cystica Right hydronephrosis, left Few renal calculus Renal calculus Few Few
Trigon Trigon
Few Few
B. coli Proteus
Trigon Trigon
Few Few
B. coli
Trigon
Few
838
ASSOCIATED UROLOGICAL PATHOLOGY
Acute pyelonephritis, tocoele
cys-
Elusive ulcer, polyposis of bladder neck Median bar, chronic prostatis Right double kidney and ureter Carcinoma of prostate
CYSTITIS CYSTICA
839
Cystitis glandularis is uncommon. Here also the lesions appear as solid nodules. It is rarely recognized except in microscopical preparations. Cystitis emphysematosa is for the most part of theoretical interest since it has rarely been recognized except at autopsy. However, we shall mention some of its characteristics because interest in this condition is increasing. The bladders are generally badly infected. The lesions are described as clear, gas-containing vesicles which vary in size from a pin head to a large pea. Many authors believe that the lesions of cystitis cystica are of inflammatory origin, and although this subject has received some consideration in the literature, not much attention has been given to the presence of infection, and as far as we know, no large series of cases are recorded in which the results of bacteriological studies of the urine are reported. The articles in literature deal in the main with case reports. Furthermore but few articles deal in detail with the co-existing pathological conditions. It therefore occured to us that it might be of interest to study a group of unselected cases and to record the results of this study that it may stimulate .others to report the results of their observations. The average age of the 28 cases studied was 52 years, the youngest being 31 years and the oldest 72 years. Nineteen (68 per cent) were females and nine (32 per cent) were males. The time elapsed since the onset of urinary symptoms varied from 1 month to 192 months with an average of 30 months. Fourteen (50 per cent) had 100 or more pus cells per cubic millimeter of bladder urine. In 21 cases the separated ureteral specimens were studied but no additional information. was obtained. There was 1 case, No. 17 reported as "no growth," in which Staphylococcus albus was grown in the right ureteral specimen, but this may have been a contamination. The most common organism was B. coli found in 12 (43 per cent) cases. Eight (29 per cent) showed "no growth." Hemolytic B. coli were found in 4 (14 per cent), Proteus in 2 (7 per cent), B. pyocyaneus and diplostreptococcus in 1 (3.6 per cent) each. Other organisms previously reported include Staphylococcus aureus, Staphylococcus albus, and short chained cocci. Review of the histories of the 8 cases with sterile bladder urine reveals that all of these patients had clinical symptoms of bladder infection at some previous time. The significance of these bacteriological studies is interesting. Ap-
840
WILLIAM D. WARRICK
parently we are in a position to refute the age-old saying that all cases of cystitis cystica are associated with B. coli infections since only 43 per cent of our cases had this organism. However, the duration of time elapsed since the onset of clinical symptoms is sufficiently long in some cases to have allowed a change in the bacterial flora. It is noted that there were 5 types of organisms found in our series as well as 3 additional strains reported elsewhere. These data would support a theory that no specific bacteria are necessary to induce this condition. The 8 cases with sterile urine present evidence for consideration. The average time elapsed since the onset of urinary symptoms in this group was 39 months, or 9 months longer than the average for the entire series. This finding might be expected since we believe that all of these cases were previously infected but had become sterile in the interim before our examination. In 4 of these cases with sterile urine, "many cysts" were seen. This is a larger percentage than that of the entire series which was 32 per cent. Since we believe that these cysts or their anlage, Brunn's nests, formed in an infected bladder it must follow that retrogression, if any, is slow. It might also follow that the evolution of cysts from preformed Brunn's nests may be attenuated and that production has been continuous hut at a slow rate. In this connection we might add that it would be interesting and informative to check a series of both infected and sterile cases at various time intervals. From such a study conclusions might be reached concerning the rate of growth, disappearance of the cysts if any, and the type of bladder conditions necessary for these changes. We must assume that there is no evidence that any specific bacteria are necessary for the production of Brunn's nests or cystitis cystica. Furthermore we have no evidence to indicate that the cysts disappear when the infection ceases. Rather our data would tend to imply that the cysts remain or may even increase after the urine has become sterile. All histories were checked for 4 common urological symptoms. It was found that 93 per cent had burning on urination, 83 per cent had frequency of urination, 79 per cent had nocturia, and 29 per cent had hematuria. We are not meaning to imply that we believe the clinical symptoms were caused primarily by the cystitis cystica. In 10 (36 per cent) cases the cysts were noted only on the trigon. In 21 (68 per cent) cases the cysts were described as seen on the trigon or around the bladder neck. In 9 (32 per cent) cysts were seen on the
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walls of the bladder. In only 2 (7 per cent) of the cases were cysts seen on all the wall of the bladder. The frequency of the involvement of the trigon might lead to speculation as to why this occurs. Possible explanations for this may be found in the fact that since this part of the bladder is more nearly fixed, its epithelium is not subject to as much stretching as in the regions where the bladder is more distensible. Pus, stones and mucous lie on the floor of the bladder and are in better contact with this region. The role of the trigon and bladder neck in micturition may make them more susceptible to these changes. There is further, the possible role of the difference of embryological development, the trigon being mesodermal, whereas the bladder walls are entodermal in origin. In 19 (68 per cent) cases the cysts were called "few" while in 9 (32 per cent) there were "many". There is no apparent correlation between either the duration of clinical symptoms and the number of cysts or the amount of pus in the urine and the number of cysts. One patient who had many cysts had had clinical symptoms for only 6 months. Somewhat unexpected is the fact that the average duration of clinical symptoms in the cases with many cysts is 27 months which is 3 months less than the average for the entire series. Four of these cases with many cysts had sterile urine. It is noteworthy that these cases were examined for diseases other than cystitis cystica. In no case was this condition considered to be the primary pathological process. There is a great multiplicity of associated urological lesions (table 2). These include chronic pyelonephritis, 5 cases; renal calculi, 4 cases; benign prostatic hypertrophy, 4 cases; chronic prostatitis, 3 cases; acute pyelonephritis, 3 cases; hydronephrosis, 3 cases; chronic cystitis, 2 cases; and 1 case each of stricture of the urethra, papilloma of the bladder, renal tuberculosis, carcinoma of the bladder, elusive ulcer, polyposis of the bladder neck, double kidney and ureter, carcinoma of the prostate, pyelitis and ureteritis cystica. Note was made of the fact that this last mentioned case, No. 20, with cystic involvement of the entire upper tract, had had symptoms for only 4 months, had a sterile bladder urine containing 20 pus cells per cubic centimeter and bilateral renal calculi. These 34 diagnoses of associated lesions are divided almost equally between upper and lower tract diseases; i.e., 18 upper and 16 lower. Certainly we can not say that if cystitis cystica is a secondary lesion that the primary pathological process must necessarily arise in some
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certain anatomical position. ·The initial disease in these cases includes renal, ureteral, bladder, and urethral lesions. There were 2 cases in which the only diagnosis we could make was cystitis cystica. Bladder urines of these patients contained practically no pus, but B. coli were cultured in both instances. Cultures of all kidney urines were sterile. Here again clinical histories of previous infection were obtained. Interesting is the fact that 1 patient dated the onset of her symptoms only 1 month previously. There seems to be no definite correlation to be drawn between cystitis cystica and its associated urological disease. TABLE
2.-Associated urological lesions
LESION
Chronic pyelonephritis ..... .. . .. ... . . .......... .. .. ... . . . . . . .. . . . Renal calculi ....... .. ... ... ... . .... . ...... . ........... . . ... .... . Benign prostatic hypertrophy . ..... . . . . . . .. . .... . . .. ....... .. ... . . Chronic prostatitis .... . . . . .. . . . . . .. . . . ... .. . . .. . . . . .... . . . .. . . .. . Acute pyelonephritis ........... . ... ..... .. ... .... . .. ... . ...... . . . Hydronephrosis .. . . . ... ......... .. . ..... . ........... . .... . . .... . Chronic cystitis .... .. . . . .. ..... . .. ...... . . . . . ..... . ............ . Urethral stricture .. . ... . . . . .. .. . . .... . . . . . . ... .. .. . . . .. ... . .. ... . Papilloma of bladder .. . . .. . . .. .. .... ....... .. .... . . ............. . Renal tuberculosis . ........... ...... . ... . ... . .. . . . ... . ... .. . .... . Carcinoma of bladder . . . . .... .. .......... .. .... . ...... . . ... ..... . Elusive ulcer . . .. . . ..... .. . .... ... .. ... .. . . ...... . . . . .. . . . . . . ... . Polyposis of bladder neck ....... . ..... .. . . ... .. . .. . ... .. . . ....... . Double kidney and ureter .. ..... . . . .. .. ... . . ..... . . ... . .... . ... .. . Carcinoma of prostate ..... . ... . . ....... ... ..... ... .. . ... . ..... .. . Pyelitis and ureteritis cystica .. .... ..... . ... ..... .. . . . ... . ... . .. . . .
CASES
5 4 4 3 3 3 2
1 1 1 1 1 1 1 1 1
We believe that the diagnosis of cystitis cystica would be made more often if microscopical studies were made more frequently as an adjunct to cystoscopy. Where an obvious lesion is seen it is not unlikely that the presence of these cysts will be overlooked. In our cases, Nos. 11 and 28, in which carcinoma of the bladder and carcinoma of the prostate respectively were present, the cysts were recognized cystoscopically and microscopically. In our cases the diagnosis was made by means of the cystoscopic examination. In 4 cases the diagnosis was checked with microscopic preparations. CONCLUSIONS
Twenty-eight cases of cystitis cystica are reported. Data were obtained on the duration of symptoms, amount of pus in
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the urine, bacteriology, anatomical location of the cysts, relative number of cysts present, and associated urological conditions. This is the first time that such a correlation has appeared in the literature. We believe that continued studies along this line will lead to a better understanding of the reactions of urinary epithelium. 306 Medical Arts Bldg., Birmingham, Ala.
REFERENCES J.:
J.
CARSON, W. Pyelitis, ureteritis, and cystitis cystica. Am. Surg., 8: 1256-1258, 1930. HINMAN, F.: Pyelitis and ureteritis cystica. J. Urol., 35: 174-189, 1936. JOELSON, Pyelitis, ureteritis and cystitis cystica. Arch. Surg., 18: 1570-1583, 1929. KRETSCHMER, H. L.: Pathology and cystoscopy of cystitis cystica. Surg., Gynec., and
J. J.:
Obst. 7: 274, 1908. - - - : Pyelitis follicularis. Tr. Am. Urol. A., 7: 94-104, 1913. LIVERMORE, G. R.: Cyst of the bladder. Tr. Am. Ass. G. U. Surg., 28: 209-215, 1935. MORSE, H. D.: Etiology and pathology of pyelitis cystica, ureteritis cystica, cystitis cystica. Am. J. Path. 4: 33-50, 1928. PATCH, F. S.: Pyelitis, ureteritis, and cystitis cystica. New Eng. J. Med., 220: 979-985, 1939. - - - , AND RHEA, L. J.: The genesis and development of Brunn's nests and their relation to cystitis cystica, cystitis glandularis, and primary adeno-carcinoma of the bladder. Canad. M. A. J., 33: 597-606, 1935. STIRLING, W. C.: Cystitis follicularis. J. A. M.A., 112: 1326-1331, 1939.