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Adenocarcinoma of the Bladder
THE JOURNAL OF UROLOGY
Vol. 93, No. 1 January 1965 Copyright © 1965 by The Williams & Wilkins Co. Printed in U.S.A.
ADENOCARCINOMA OF THE BLADDER TERRY D. ALLEN
AND
B. W. HENDERSON
From the Departments of Urology and Pathology, Parkland Memorial Hospital and Southwestern Medical School, Dallas, Texas
Primary adenocarcinoma of the bladder is a relatively uncommon lesion which represents a cell type somewhat incongruous with its location; a fact which provokes some speculation as to the embryologic and histologic derivation of the tumor. Recent experience with several such cases has heightened our interest in vesical adenocarcinoma and prompted a perusal of the literature sufficient to convince us that there is need for clarification of some of the etiologic and pathologic features of these lesions. By reviewing the records at Parkland Memorial Hospital over a 10-year period from 1953 to 1963, we have been able to compile 6 cases of primary adenocarcinoma of the bladder to serve as a basis for our study.
bladder neck. 3 • 4 These tumors tend to invade locally with late metastases, but the prognosis, like that of deeply infiltrating bladder tumors of other cell types, is extremely poor. Adenocarcinoma metastastic from other sites, especially the colon, must be excluded before the diagnosis can be considered firmly established, but Mostofi2 has noted that it is unusual for adenocarcinoma arising elsewhere to present first with symptoms referable to the urinary tract. Pathology. Adenocarcinomas of the bladder are nodular tumors, composed of pinkish-gray, friable and granular tissue. Some are polypoid and form a nodular fungating mass that protrudes into the vesical lumen with only superficial ulceration. Others are sessile and infiltrative, producing an ulcerated lesion with elevated nodular margins. Local spread within the wall of the bladder is usually limited and frequently, the bulk of the neoplasm is beyond the adventitia of the organ. Microscopically, the lesions have similar histologic patterns, but vary in the degree of cytologic differentiation. The poorly circumscribed nodules of columnar cells form irregular duct-like or gland-like spaces supported by scant fibrous stroma .. Sub-classification into mucin and non-mucin-producing tumors is arbitrary, since mucus production is evident in most of the lesions. 3 These tumors are frequently pure mucus carcinomas, comprised of signet ring cells and mucus cysts. 5 The formation of gland-like or ductlike structures is an essential microscopic feature for diagnosis. The presence of mucus alone cannot be utilized since mucus production has been observed in transitional cell carcinomas. 6• 7 4 Winter, C. C. and Goodwin, W. E.: Mucous secreting adenocarcinoma of the urinary bladder simulating carcinoma of the gastrointestinal tract. Amer. Surg., 25: 875-882, 1959. 5 Saphir, 0.: Signet-ring cell carcinoma of the urinary bladder. Amer. J. Path., 31: 228, 1955. • Foster, E. A. and Levine, A. J.: Mucin production in metastatic carcinomas. Cancer, 16:
BACKGROUND
Clinical. Primary adenocarcinoma of the bladder constitutes about 1 per cent of bladder tumors1 and, like transitional cell carcinoma, occurs more commonly in the male patient. 2 Symptoms are usually non-specific and include hematuria, pyuria and lower tract symptoms, although occasionally the passage of urinary mucus3 may suggest the possibility of a glandular tumor. The cystoscopic appearance of these tumors is seldom diagnostic in itself but as a group they tend to produce infiltrative lesions requiring open excision rather than endoscopic removal. Though usually single, multiple tumors may be seen and even mixed lesions containing both glandular and transitional cell carcinomas have been reported. 3 While the tumors may arise from any point in the bladder, they are most commonly located around the dome, trigone, and
Accepted for publication June 11, 1964. 1 Williams, J. I., Godwin, M. C. and Cross, R. R., Jr.: Adenocarcinoma of the urinary bladder. J. Int. Coll. Surg., 26: 461-470, 1956. 2 Mostofi, F. K., Thomson, R. V. and Dean, A. L., Jr.: Mucous adenocarcinoma of the urinary bladder. Cancer, 8: 741-758, 1955. 3 Wheeler, J. D. and Hill, W. T.: Adenocarcinoma involving the urinary bladder. Cancer, 7:
506--509, 1963. 7 Hamper!, H. and Hellweg, G.: On mucoepidermoid tumors of different sites. Cancer, 10: 1187-
1192, 1957.
119-135, 1954. 50
ADE1':l"0CARCIN0MA OF BLADDER
Pathogenesis. According to Coppridge, 8 the development of adenocarcinoma within the bladder might be explained by any of three prevailing theories. The anatomical theory is based upon the assumption that glandular epithelium normally exists in the trigone and bladder neck and that adenocarcinoma merely represents malignant transformation of this tissue. Albarran described short, tubular gland-like structures in the trigone which bear his name, but many subsequent investigators have failed to confirm the existence of such epithelium in the normal bladder. At any rate, this theory fails to explain vesical adenocarcinoma arising from sites other than the trigone. Because of the common derivation of bladder and rectum, displaced "cell rests" of glandular epithelium have been suggested as a source for adenocarcinoma. In support of this theory, Friedman and Ash 9 point out that nephrogenic adenomas, endometriomas and hamartomas, occasionally found in the bladder, are evidences of the existence of this phenomenon. However, glandular "cell rests" have never been identified in the newborn 10 and the age range of patients with adenocarcinoma of the bladder is more suggestive of an acquired lesion, rather than one of embryologic origin. The most widely accepted theory is based upon the demonstrated ability of epithelium to undergo metaplastic change to other cell types in the face of chronic infection and irritation. The metaplastic ability of urothelium has been shown by Patchn and by Mostofi. 2 It is suggested that chronic irritation leads to epithelial hyperplasia, Brunn's nests, cystitis cystica and cystitis glandularis in a stepwise manner and that adenocarcinoma is merely a malignant counterpart of this glandular transformation. This concept presupposes that cystitis cystica and glandularis are 8 Coppridge, W. M., Roberts, L. C. and Culp, D. A.: Glandular tumors of the bladder. J. Urol., 65: 540-549, 1951. 9 Friedman, N. B. and Ash, J.E.: Tumors of the urinary bladder. In: Atlas of Tumor Pathology. Washington: Armed Forces Institute of Pathology, sec. 8, fasc. 31a, 1959. 10 Elliott, G. B. and Freigang, B.: Observations on the nature of mucin secreting urachal cystadenoma. Ann. Surg., 175: 613-616, 1964. 11 Patch, F. S. and Rhea, L. V.: The genesis and development of Brunn's nests and their relation to cystitis, cystitis glandularis and primary adenocarcinoma of the bladder. Canad. M. A. J., 33: 597-606, 1935.
51
precancerous lesions, convincing proof of which is lacking although Shaw and associates12 reported 1 case supposedly demonstrating such a phenomenon. Kittredge13 originally questioned the role of chronic inflammation in the production of cystitis glandularis, noting that four of seven such patients had normal urine and that 1 patient was totally asymptomatic, but in a subsequent communication,14 he appeared more impressed by this relationship and expressed the belief that cystitis glandularis may be a pre-malignant lesion. Regardless of whether cystitis cystica and glandularis are necessary precursors, the high incidence of concomitant infection, obstruction and associated vesical disease overwhelmingly supports the viewpoint that adenocarcinoma arises in the bladder as a result of metaplastic change. Mucus production by transitional epithelium under the stimulus of chronic inflammation has been demonstrated by Hamperl and Hellweg,7 illustrating that glandular tranRformation of this tissue is not an unreasonable concept. Such a mechanism would tend to explain also the rare reports of adenocarcinoma of the renal pelvis and ureter. The urachus and the exstrophied bladder. The association of glandular carcinoma with the urachus and the exstrophied bladder merits special consideration. Wheeler and Hill3 cited 5 criteria to be satisfied in order to make a diagnosis of adenocarcinoma of urachal origin: 1) The tumor must arise from the dome of the bladder. 2) There must be no cystitis cystica or glandularis which might have served as the origin for the lesion. 3) The adenocarcinoma must involve the muscularis and deeper tissues and an intact or ulcerated epithelium should overlie it. 4) A urachal remnant connected with the neoplasm should be demonstrated. 5) A suprapubic neoplastic mass should be present. Strict application of these criteria reduces considerably the incidence of reported adenocarcinoma of the urachus. Many of these lesions were 12 Shaw, J. L., Gislason, G. J. and Imbriglia, J. E.: Transition of cystitis glandularis to primary adenocarcinoma of the bladder. J. Urol., 79: 815822, 1958. 13 Kittredge, W. E. and Brannan, W.: Cystitis glandularis. J. Urol., 81: 419-430, 1959. 14 Kittredge, W. E., Collett, A. J. and Morgan, C., Jr.: Adenocarcinoma of the bladder associated with cystitis glandularis: A case report. J. Urol., 145-150, 1964.
52
ALLEN AND HENDERSON
assumed to be urachal in origin purely on the basis of their location in the dome of the bladder. The true urachal cancer is a very rare lesion with an extremely poor outlook because of its extension directly into the adjacent tissues of the abdominal wall and because of its tendency to remain "silent" until quite late in its development. While it is tempting to think of urachal tumors as evidence of dysontogenesis, Begg15 has shown that the urachus is not merely an embryologic remnant, but a normal adult structure lined predominantly by stratified epithelium of a transitional type. There is no reason to believe that glandular tumors arising from the epithelium of the urachus should represent "cell rest" tumors any more than those arising from transitional epithelium elsewhere. It should also be remembered that the urachus may be the site of origin of transitional and squamous cell carcinomas as well.2 Carcinoma has been reported in about 4 per cent of exstrophied bladders12 with adenocarcinoma predominating heavily. Scott and Sorbie16 noted that 94 per cent of such tumors were of a glandular epithelial type. While such facts may imply a dysontogenetic mechanism, no glandular epithelium has ever been identified in the exstrophied bladder at birth. 2 Furthermore, the neoplasms do not appear prior to the third decade of life,3 suggesting that they are acquired as the result of continued exposure and chronic irritation of the vesical mucosa. While metaplasia offers a convenient explanation for the appearance of carcinoma in the urachus and exstrophied bladder, it must be admitted that this alone does explain the preferential development of a glandular type of cancer in these two specific instances. Elliott and Freigang10 theorized that urothelium removed from contact with the urinary stream might have a greater propensity for developing adenocarcinoma. Earlier, Pund17 suggested that epithelium derived from specific embryological tissues tends to develop specific tumor types in response to the same stimulus. He felt that adenocarcinoma 15 Begg, R. C.: The urachus: Its anatomy, histology and development. J. Anat., 64: 170-183 1930. ' 16 Scott, L. S. and Sorbie, C.: The development of carcinoma in an ectopic bladder. Brit. J. Urol. 28: 264-267, 1956. ' 17 Pund, E. R., Yount, H. A. and Blumberg, J.M.: Variations in morphology of urinary bladder epithelium. Special reference to cystitis glandularis and carcinomas. J. Urol., 68: 242-251, 1952.
arising from the trigone should simulate prostatic cancer while that arising from the dome should have the histologic characteristics of adenocarcinoma of enteric origin. Neither explanation withstands critical analysis. CASE REPORTS
Case 1. PMH 096433, a 62-year-old Negress was seen first in 1952 following an episode of hematuria and was found to have a staghorn calculus in the right kidney. A right nephrectomy was done, but 2 months later she was readmitted with pyuria at which time severe cystitis was seen on cystoscopy. She was treated conservatively and did well until about 14 months later when she was readmitted because of hematuria. Cystoscopy revealed a necrotic mass of tissue on the left between the bladder neck and the left ureteral orifice. A biopsy was reported papillary adenocarcinoma. Proctoscopy and barium enema were negative. The patient underwent cystectomy, hysterectomy and ureterosigmoid implantation. A 4~i by 3 cm. tumor involved the entire thickness of the bladder. Her immediate convalescence was uneventful, but within a year xray evidence of pulmonary metastasis was present. She died elsewhere in 1955, two years after cystectomy. No details of the terminal events are available. Case 2. PMH 190281, a 47-year-old white woman had urinary retention following cholecystectomy and was referred to the urology clinic. A history of hesitancy and lower tract symptoms was elicited and cystoscopy revealed cystitis cystica and a cylindrical polypoid structure about 0.5 cm. in length occupying the central portion of the trigone. Excisional biopsy was carried out and the base was fulgurated. Histologically the polypoid structure proved to be adenocarcinoma (fig. 1,A). The patient has been followed for 3 years with no evidence of recurrence. Comment: A definite relationship between cystitis cystica and adenocarcinoma was strongly suggested by the unusual and early lesion (fig. 1, B), but this remained the only case in our series where such an association could be demonstrated. Case 3. PMH 246400, a 63-year-old white man was discovered to have cirrhosis and prostatic obstruction during hospitalization for a perforated peptic ulcer and a subsequent subtotal gastrectomy. Five days after discharge he had urinary
ADE:\'OCAHCI:',;O:\JA OF BLA TJDEH
FrG. 1. Case 2. A well-differentiated adenocarcinoma. B, cystitis cystiea c,o-existing with 11dcno-e,i.rcinoma in deeper
retention and was admitted 1-o the urology ,service. Frograms ,ver-e umemarkablc. Ile \Ya,, ,scheduled for a transurcthral prostatie resection, but at c.ystoscopy a ;3 cm. papillary and sessile tumor was seen in the dome of' the bladder, slightly to the right of midline. Au attempt to rcsr:c:t the lesion transurcthrally led to a ,small perforation of' the bladder necessitat.ing; open surgery which inclmled wide excision of the bladder tumor
and closure of the bladder arnuncl a tube. The, adjacent bowel shmn,d no e1·id.enc·c of neopla,sia. Histologically, the bladder tumor pron'd to be an aclenocan:inoma. Lion from a urothelial lining to a epithC'lium ,Yas dernonstrakd i11 some sect.ions (fig. 2,, ! ) . In adclition, a para-aminosalieyli,, stain on sections from other areas of tlrn hlaclcle:r wall (fig 2, B) exhibited positinc reactions ,u_gg;est-
54
ALLEN AND HENDERSON
Fm. 2. Case 3. A, abrupt transition of urothelium on right to glandular epithelium on left. B, PASpositive material revealed as dark density just beneath surface in middle of field. This material, characteristic of glandular epithelium, is demonstrated in this section of inflamed transitional epithelium taken from bladder of patient with vesical adenocarcinoma.
ing beginning mucus production by an inflamed transitional epithelium. Two weeks later he underwent a transurethral resection of the prostate, but his general condition steadily declined after this final procedure and he died several weeks later of what was thought to be hepatic failure. Autopsy disclosed metastases to the
brain, spinal cord, left iliac, periaortic and right hilar nodes. Comment: In spite of its location in the dome, this cancer evidently arose from the urothelium of the bladder rather than from the urachus. Widespread metastases from a relatively small primary lesion are not typical of this tumor.
ADE~OCARCI'
Jira. :3. Case 5. J\lucus-secreting adcnocnrcinoma distrmdcd with large pools of rnm,uB
Case 4 PMH 234086, a ]\egro was examined for complications of a previou," herniorand was found incidentall:-· to have a blood urea nitrogen value of ,50 rng. per cent and symptoms. No function wa,o obstructive seen on excretory urography but on cystogrnphy a vesical diverticulum was seen on the left. The patient was treated with catheter drainage, but persistent azotemia and cloudy urine led to the decision to perform a suprnpubic Howen'r, at surgery a fungating mass was found occupying the entire t.rigone including both ureternl orifiees, but not innlhing the vesical diverticulum. and hilgurntion were rarried out. ":'dicroscopic examination disclm,ed mucm,-seereting aclenocarc:inorna. Po.stop, proc:t.oscopy and barium enema were The patient wa,, treated with palliative radiotherapy using rotational cobalt bL1t his course was progn·ssiYdy downhill with extension of the cancer to the pelvis and cord. He died at home, 10 months was obtained. Case ii. PMH 230082, a was and frequency assoeiated with an episode of hematuria. At eystosropy a bladder neoplasrn measuring about 3 cm. in diameter was noted involving the trigone and left ureteral orifice. Th
the right urcteral orifice and a flat sessi Jc and papillary lesion present on the dome, clown the left lateral wall. A m(wable mass was palpable, but it was not clear whether this represented bladder or uteru~. re-,-ealecl adenocarc:inoma. disclosed hydronephrmis of system and non-visualization of the left PrucLo scopic examination and barium cnen1a were negative. The patient left the orders and did not return for 10 months al wbid1 tixne she had terminal renal failure .\ pelvic mas,'3 was present. She died a few and autopsy re\·ealed a diffusely mueinous carcinoma completely bladder (fig :3). Bilateral uretnal hydronephrosis, nccrntizinp; lonephritis were riresent, but there were nn metastases to lymph nodc,s, bone or visrera. Comment: Exte1rnive bladder involvetJ1ent without widespread metastases is not an uneommon finding in vcsical adenouar(·inoma Case 6. PMH 164454, a 92-ycar-old white man was admitted with a :3-rlay history of hematuria,. Cystoscopy disdosed a 2 cm. lesion uf the pos· terior wall of foe bladder behind the ,md just to the right of midline. Tlw was contiguous with a baseball sized mass in tlrn pelYis. Froctoscopy and barium cncrna rm·ealed
56
ALLEN AND HEXDERSON
normal bowel mucosa overlying the mass with no evidence of any intrinsic lesion of the bowel. Excretory urograms were normal. During this hospitalization a spontaneous colovesical fistula developed, necessitating a diverting colostomy. A week later at exploratory laparotomy a large tumor was found arising from the bladder and invading the sigmoid. Since resection was technically impossible, a biopsy was obtained and suprapubic cystostomy carried out. Histologically the tumor was a poorly differentiated adenocarcinoma. The patient slowly deteriorated and died 46 days following surgery. Permission for autopsy was denied.
only one survivor in the series, a patient with an unusually early lesion discovered fortuitously. Concomitant or pre-existing infection or obstruction was an almost invariable rule in this series, but in only one instance was cystitis cystica seen in conjunction with tumor and cystitis glandularis was not seen at all. It would appear from our observations that metaplasia best explains the origin of vesical adenocarcinoma, but we have uncovered no evidence that cystitis cystica or glandularis is a necessary precursor. Of 2 autopsies, one revealed a small primary lesion with widespread metastases and the other an extensive lesion locally contained without evidence of spread.
ANALYSIS OF PRESENT SERIES SUMMARY AND CONCLUSIONS
These cases were analyzed in the light of knowledge gained previously from other reports, a review of which has been given earlier in this paper. The age range of 47 to 92 years is similar to that seen in transitional cell carcinoma and is compatible with an acquired lesion. The neoplasms arose from any area of the bladder, but most often from the region of the trigone. No relationship was noted between location and histologic appearance. None ap]Jeared to be of urachal origin. There was considerable variation in the nrncus-secreting capacity of the tumors, though in general, the larger tumors appeared more likely to be associated with this phenomenon. All of these lesions tended to be infiltrating. The poor prognosis associated with adenocarcinoma is evidenced by the fact that there was
Six cases of priniary vesical adenocarcinoma have been studied particularly from the standpoint of etiology and pathology. It was confirmed that adenocarcinoma of the bladder is an infiltrative lesion with a poor prognosis. Only 1 patient in the series survived. There was nothing characteristic about the location or histologic features of the tumors which would lend support to a "cell rest" theory of origin. Instead, the high incidence of associated vesical disease favored a metaplastic mechanism though cystitis cystica or glandularis did not appear to be necesrnry precursors. The study, however, has failed to offer a satisfactory explanation for the overwhelming preponderance of glandular tumors in instances of carcinoma arising in the urachus and exstrophied bladder.
Vol. 93, No. 1 January 1965 Copyright © 1965 by The Williams & Wilkins Co. Printed in U.S.A.
ADENOCARCINOMA OF THE BLADDER TERRY D. ALLEN
AND
B. W. HENDERSON
From the Departments of Urology and Pathology, Parkland Memorial Hospital and Southwestern Medical School, Dallas, Texas
Primary adenocarcinoma of the bladder is a relatively uncommon lesion which represents a cell type somewhat incongruous with its location; a fact which provokes some speculation as to the embryologic and histologic derivation of the tumor. Recent experience with several such cases has heightened our interest in vesical adenocarcinoma and prompted a perusal of the literature sufficient to convince us that there is need for clarification of some of the etiologic and pathologic features of these lesions. By reviewing the records at Parkland Memorial Hospital over a 10-year period from 1953 to 1963, we have been able to compile 6 cases of primary adenocarcinoma of the bladder to serve as a basis for our study.
bladder neck. 3 • 4 These tumors tend to invade locally with late metastases, but the prognosis, like that of deeply infiltrating bladder tumors of other cell types, is extremely poor. Adenocarcinoma metastastic from other sites, especially the colon, must be excluded before the diagnosis can be considered firmly established, but Mostofi2 has noted that it is unusual for adenocarcinoma arising elsewhere to present first with symptoms referable to the urinary tract. Pathology. Adenocarcinomas of the bladder are nodular tumors, composed of pinkish-gray, friable and granular tissue. Some are polypoid and form a nodular fungating mass that protrudes into the vesical lumen with only superficial ulceration. Others are sessile and infiltrative, producing an ulcerated lesion with elevated nodular margins. Local spread within the wall of the bladder is usually limited and frequently, the bulk of the neoplasm is beyond the adventitia of the organ. Microscopically, the lesions have similar histologic patterns, but vary in the degree of cytologic differentiation. The poorly circumscribed nodules of columnar cells form irregular duct-like or gland-like spaces supported by scant fibrous stroma .. Sub-classification into mucin and non-mucin-producing tumors is arbitrary, since mucus production is evident in most of the lesions. 3 These tumors are frequently pure mucus carcinomas, comprised of signet ring cells and mucus cysts. 5 The formation of gland-like or ductlike structures is an essential microscopic feature for diagnosis. The presence of mucus alone cannot be utilized since mucus production has been observed in transitional cell carcinomas. 6• 7 4 Winter, C. C. and Goodwin, W. E.: Mucous secreting adenocarcinoma of the urinary bladder simulating carcinoma of the gastrointestinal tract. Amer. Surg., 25: 875-882, 1959. 5 Saphir, 0.: Signet-ring cell carcinoma of the urinary bladder. Amer. J. Path., 31: 228, 1955. • Foster, E. A. and Levine, A. J.: Mucin production in metastatic carcinomas. Cancer, 16:
BACKGROUND
Clinical. Primary adenocarcinoma of the bladder constitutes about 1 per cent of bladder tumors1 and, like transitional cell carcinoma, occurs more commonly in the male patient. 2 Symptoms are usually non-specific and include hematuria, pyuria and lower tract symptoms, although occasionally the passage of urinary mucus3 may suggest the possibility of a glandular tumor. The cystoscopic appearance of these tumors is seldom diagnostic in itself but as a group they tend to produce infiltrative lesions requiring open excision rather than endoscopic removal. Though usually single, multiple tumors may be seen and even mixed lesions containing both glandular and transitional cell carcinomas have been reported. 3 While the tumors may arise from any point in the bladder, they are most commonly located around the dome, trigone, and
Accepted for publication June 11, 1964. 1 Williams, J. I., Godwin, M. C. and Cross, R. R., Jr.: Adenocarcinoma of the urinary bladder. J. Int. Coll. Surg., 26: 461-470, 1956. 2 Mostofi, F. K., Thomson, R. V. and Dean, A. L., Jr.: Mucous adenocarcinoma of the urinary bladder. Cancer, 8: 741-758, 1955. 3 Wheeler, J. D. and Hill, W. T.: Adenocarcinoma involving the urinary bladder. Cancer, 7:
506--509, 1963. 7 Hamper!, H. and Hellweg, G.: On mucoepidermoid tumors of different sites. Cancer, 10: 1187-
1192, 1957.
119-135, 1954. 50
ADE1':l"0CARCIN0MA OF BLADDER
Pathogenesis. According to Coppridge, 8 the development of adenocarcinoma within the bladder might be explained by any of three prevailing theories. The anatomical theory is based upon the assumption that glandular epithelium normally exists in the trigone and bladder neck and that adenocarcinoma merely represents malignant transformation of this tissue. Albarran described short, tubular gland-like structures in the trigone which bear his name, but many subsequent investigators have failed to confirm the existence of such epithelium in the normal bladder. At any rate, this theory fails to explain vesical adenocarcinoma arising from sites other than the trigone. Because of the common derivation of bladder and rectum, displaced "cell rests" of glandular epithelium have been suggested as a source for adenocarcinoma. In support of this theory, Friedman and Ash 9 point out that nephrogenic adenomas, endometriomas and hamartomas, occasionally found in the bladder, are evidences of the existence of this phenomenon. However, glandular "cell rests" have never been identified in the newborn 10 and the age range of patients with adenocarcinoma of the bladder is more suggestive of an acquired lesion, rather than one of embryologic origin. The most widely accepted theory is based upon the demonstrated ability of epithelium to undergo metaplastic change to other cell types in the face of chronic infection and irritation. The metaplastic ability of urothelium has been shown by Patchn and by Mostofi. 2 It is suggested that chronic irritation leads to epithelial hyperplasia, Brunn's nests, cystitis cystica and cystitis glandularis in a stepwise manner and that adenocarcinoma is merely a malignant counterpart of this glandular transformation. This concept presupposes that cystitis cystica and glandularis are 8 Coppridge, W. M., Roberts, L. C. and Culp, D. A.: Glandular tumors of the bladder. J. Urol., 65: 540-549, 1951. 9 Friedman, N. B. and Ash, J.E.: Tumors of the urinary bladder. In: Atlas of Tumor Pathology. Washington: Armed Forces Institute of Pathology, sec. 8, fasc. 31a, 1959. 10 Elliott, G. B. and Freigang, B.: Observations on the nature of mucin secreting urachal cystadenoma. Ann. Surg., 175: 613-616, 1964. 11 Patch, F. S. and Rhea, L. V.: The genesis and development of Brunn's nests and their relation to cystitis, cystitis glandularis and primary adenocarcinoma of the bladder. Canad. M. A. J., 33: 597-606, 1935.
51
precancerous lesions, convincing proof of which is lacking although Shaw and associates12 reported 1 case supposedly demonstrating such a phenomenon. Kittredge13 originally questioned the role of chronic inflammation in the production of cystitis glandularis, noting that four of seven such patients had normal urine and that 1 patient was totally asymptomatic, but in a subsequent communication,14 he appeared more impressed by this relationship and expressed the belief that cystitis glandularis may be a pre-malignant lesion. Regardless of whether cystitis cystica and glandularis are necessary precursors, the high incidence of concomitant infection, obstruction and associated vesical disease overwhelmingly supports the viewpoint that adenocarcinoma arises in the bladder as a result of metaplastic change. Mucus production by transitional epithelium under the stimulus of chronic inflammation has been demonstrated by Hamperl and Hellweg,7 illustrating that glandular tranRformation of this tissue is not an unreasonable concept. Such a mechanism would tend to explain also the rare reports of adenocarcinoma of the renal pelvis and ureter. The urachus and the exstrophied bladder. The association of glandular carcinoma with the urachus and the exstrophied bladder merits special consideration. Wheeler and Hill3 cited 5 criteria to be satisfied in order to make a diagnosis of adenocarcinoma of urachal origin: 1) The tumor must arise from the dome of the bladder. 2) There must be no cystitis cystica or glandularis which might have served as the origin for the lesion. 3) The adenocarcinoma must involve the muscularis and deeper tissues and an intact or ulcerated epithelium should overlie it. 4) A urachal remnant connected with the neoplasm should be demonstrated. 5) A suprapubic neoplastic mass should be present. Strict application of these criteria reduces considerably the incidence of reported adenocarcinoma of the urachus. Many of these lesions were 12 Shaw, J. L., Gislason, G. J. and Imbriglia, J. E.: Transition of cystitis glandularis to primary adenocarcinoma of the bladder. J. Urol., 79: 815822, 1958. 13 Kittredge, W. E. and Brannan, W.: Cystitis glandularis. J. Urol., 81: 419-430, 1959. 14 Kittredge, W. E., Collett, A. J. and Morgan, C., Jr.: Adenocarcinoma of the bladder associated with cystitis glandularis: A case report. J. Urol., 145-150, 1964.
52
ALLEN AND HENDERSON
assumed to be urachal in origin purely on the basis of their location in the dome of the bladder. The true urachal cancer is a very rare lesion with an extremely poor outlook because of its extension directly into the adjacent tissues of the abdominal wall and because of its tendency to remain "silent" until quite late in its development. While it is tempting to think of urachal tumors as evidence of dysontogenesis, Begg15 has shown that the urachus is not merely an embryologic remnant, but a normal adult structure lined predominantly by stratified epithelium of a transitional type. There is no reason to believe that glandular tumors arising from the epithelium of the urachus should represent "cell rest" tumors any more than those arising from transitional epithelium elsewhere. It should also be remembered that the urachus may be the site of origin of transitional and squamous cell carcinomas as well.2 Carcinoma has been reported in about 4 per cent of exstrophied bladders12 with adenocarcinoma predominating heavily. Scott and Sorbie16 noted that 94 per cent of such tumors were of a glandular epithelial type. While such facts may imply a dysontogenetic mechanism, no glandular epithelium has ever been identified in the exstrophied bladder at birth. 2 Furthermore, the neoplasms do not appear prior to the third decade of life,3 suggesting that they are acquired as the result of continued exposure and chronic irritation of the vesical mucosa. While metaplasia offers a convenient explanation for the appearance of carcinoma in the urachus and exstrophied bladder, it must be admitted that this alone does explain the preferential development of a glandular type of cancer in these two specific instances. Elliott and Freigang10 theorized that urothelium removed from contact with the urinary stream might have a greater propensity for developing adenocarcinoma. Earlier, Pund17 suggested that epithelium derived from specific embryological tissues tends to develop specific tumor types in response to the same stimulus. He felt that adenocarcinoma 15 Begg, R. C.: The urachus: Its anatomy, histology and development. J. Anat., 64: 170-183 1930. ' 16 Scott, L. S. and Sorbie, C.: The development of carcinoma in an ectopic bladder. Brit. J. Urol. 28: 264-267, 1956. ' 17 Pund, E. R., Yount, H. A. and Blumberg, J.M.: Variations in morphology of urinary bladder epithelium. Special reference to cystitis glandularis and carcinomas. J. Urol., 68: 242-251, 1952.
arising from the trigone should simulate prostatic cancer while that arising from the dome should have the histologic characteristics of adenocarcinoma of enteric origin. Neither explanation withstands critical analysis. CASE REPORTS
Case 1. PMH 096433, a 62-year-old Negress was seen first in 1952 following an episode of hematuria and was found to have a staghorn calculus in the right kidney. A right nephrectomy was done, but 2 months later she was readmitted with pyuria at which time severe cystitis was seen on cystoscopy. She was treated conservatively and did well until about 14 months later when she was readmitted because of hematuria. Cystoscopy revealed a necrotic mass of tissue on the left between the bladder neck and the left ureteral orifice. A biopsy was reported papillary adenocarcinoma. Proctoscopy and barium enema were negative. The patient underwent cystectomy, hysterectomy and ureterosigmoid implantation. A 4~i by 3 cm. tumor involved the entire thickness of the bladder. Her immediate convalescence was uneventful, but within a year xray evidence of pulmonary metastasis was present. She died elsewhere in 1955, two years after cystectomy. No details of the terminal events are available. Case 2. PMH 190281, a 47-year-old white woman had urinary retention following cholecystectomy and was referred to the urology clinic. A history of hesitancy and lower tract symptoms was elicited and cystoscopy revealed cystitis cystica and a cylindrical polypoid structure about 0.5 cm. in length occupying the central portion of the trigone. Excisional biopsy was carried out and the base was fulgurated. Histologically the polypoid structure proved to be adenocarcinoma (fig. 1,A). The patient has been followed for 3 years with no evidence of recurrence. Comment: A definite relationship between cystitis cystica and adenocarcinoma was strongly suggested by the unusual and early lesion (fig. 1, B), but this remained the only case in our series where such an association could be demonstrated. Case 3. PMH 246400, a 63-year-old white man was discovered to have cirrhosis and prostatic obstruction during hospitalization for a perforated peptic ulcer and a subsequent subtotal gastrectomy. Five days after discharge he had urinary
ADE:\'OCAHCI:',;O:\JA OF BLA TJDEH
FrG. 1. Case 2. A well-differentiated adenocarcinoma. B, cystitis cystiea c,o-existing with 11dcno-e,i.rcinoma in deeper
retention and was admitted 1-o the urology ,service. Frograms ,ver-e umemarkablc. Ile \Ya,, ,scheduled for a transurcthral prostatie resection, but at c.ystoscopy a ;3 cm. papillary and sessile tumor was seen in the dome of' the bladder, slightly to the right of midline. Au attempt to rcsr:c:t the lesion transurcthrally led to a ,small perforation of' the bladder necessitat.ing; open surgery which inclmled wide excision of the bladder tumor
and closure of the bladder arnuncl a tube. The, adjacent bowel shmn,d no e1·id.enc·c of neopla,sia. Histologically, the bladder tumor pron'd to be an aclenocan:inoma. Lion from a urothelial lining to a epithC'lium ,Yas dernonstrakd i11 some sect.ions (fig. 2,, ! ) . In adclition, a para-aminosalieyli,, stain on sections from other areas of tlrn hlaclcle:r wall (fig 2, B) exhibited positinc reactions ,u_gg;est-
54
ALLEN AND HENDERSON
Fm. 2. Case 3. A, abrupt transition of urothelium on right to glandular epithelium on left. B, PASpositive material revealed as dark density just beneath surface in middle of field. This material, characteristic of glandular epithelium, is demonstrated in this section of inflamed transitional epithelium taken from bladder of patient with vesical adenocarcinoma.
ing beginning mucus production by an inflamed transitional epithelium. Two weeks later he underwent a transurethral resection of the prostate, but his general condition steadily declined after this final procedure and he died several weeks later of what was thought to be hepatic failure. Autopsy disclosed metastases to the
brain, spinal cord, left iliac, periaortic and right hilar nodes. Comment: In spite of its location in the dome, this cancer evidently arose from the urothelium of the bladder rather than from the urachus. Widespread metastases from a relatively small primary lesion are not typical of this tumor.
ADE~OCARCI'
Jira. :3. Case 5. J\lucus-secreting adcnocnrcinoma distrmdcd with large pools of rnm,uB
Case 4 PMH 234086, a ]\egro was examined for complications of a previou," herniorand was found incidentall:-· to have a blood urea nitrogen value of ,50 rng. per cent and symptoms. No function wa,o obstructive seen on excretory urography but on cystogrnphy a vesical diverticulum was seen on the left. The patient was treated with catheter drainage, but persistent azotemia and cloudy urine led to the decision to perform a suprnpubic Howen'r, at surgery a fungating mass was found occupying the entire t.rigone including both ureternl orifiees, but not innlhing the vesical diverticulum. and hilgurntion were rarried out. ":'dicroscopic examination disclm,ed mucm,-seereting aclenocarc:inorna. Po.stop, proc:t.oscopy and barium enema were The patient wa,, treated with palliative radiotherapy using rotational cobalt bL1t his course was progn·ssiYdy downhill with extension of the cancer to the pelvis and cord. He died at home, 10 months was obtained. Case ii. PMH 230082, a was and frequency assoeiated with an episode of hematuria. At eystosropy a bladder neoplasrn measuring about 3 cm. in diameter was noted involving the trigone and left ureteral orifice. Th
the right urcteral orifice and a flat sessi Jc and papillary lesion present on the dome, clown the left lateral wall. A m(wable mass was palpable, but it was not clear whether this represented bladder or uteru~. re-,-ealecl adenocarc:inoma. disclosed hydronephrmis of system and non-visualization of the left PrucLo scopic examination and barium cnen1a were negative. The patient left the orders and did not return for 10 months al wbid1 tixne she had terminal renal failure .\ pelvic mas,'3 was present. She died a few and autopsy re\·ealed a diffusely mueinous carcinoma completely bladder (fig :3). Bilateral uretnal hydronephrosis, nccrntizinp; lonephritis were riresent, but there were nn metastases to lymph nodc,s, bone or visrera. Comment: Exte1rnive bladder involvetJ1ent without widespread metastases is not an uneommon finding in vcsical adenouar(·inoma Case 6. PMH 164454, a 92-ycar-old white man was admitted with a :3-rlay history of hematuria,. Cystoscopy disdosed a 2 cm. lesion uf the pos· terior wall of foe bladder behind the ,md just to the right of midline. Tlw was contiguous with a baseball sized mass in tlrn pelYis. Froctoscopy and barium cncrna rm·ealed
56
ALLEN AND HEXDERSON
normal bowel mucosa overlying the mass with no evidence of any intrinsic lesion of the bowel. Excretory urograms were normal. During this hospitalization a spontaneous colovesical fistula developed, necessitating a diverting colostomy. A week later at exploratory laparotomy a large tumor was found arising from the bladder and invading the sigmoid. Since resection was technically impossible, a biopsy was obtained and suprapubic cystostomy carried out. Histologically the tumor was a poorly differentiated adenocarcinoma. The patient slowly deteriorated and died 46 days following surgery. Permission for autopsy was denied.
only one survivor in the series, a patient with an unusually early lesion discovered fortuitously. Concomitant or pre-existing infection or obstruction was an almost invariable rule in this series, but in only one instance was cystitis cystica seen in conjunction with tumor and cystitis glandularis was not seen at all. It would appear from our observations that metaplasia best explains the origin of vesical adenocarcinoma, but we have uncovered no evidence that cystitis cystica or glandularis is a necessary precursor. Of 2 autopsies, one revealed a small primary lesion with widespread metastases and the other an extensive lesion locally contained without evidence of spread.
ANALYSIS OF PRESENT SERIES SUMMARY AND CONCLUSIONS
These cases were analyzed in the light of knowledge gained previously from other reports, a review of which has been given earlier in this paper. The age range of 47 to 92 years is similar to that seen in transitional cell carcinoma and is compatible with an acquired lesion. The neoplasms arose from any area of the bladder, but most often from the region of the trigone. No relationship was noted between location and histologic appearance. None ap]Jeared to be of urachal origin. There was considerable variation in the nrncus-secreting capacity of the tumors, though in general, the larger tumors appeared more likely to be associated with this phenomenon. All of these lesions tended to be infiltrating. The poor prognosis associated with adenocarcinoma is evidenced by the fact that there was
Six cases of priniary vesical adenocarcinoma have been studied particularly from the standpoint of etiology and pathology. It was confirmed that adenocarcinoma of the bladder is an infiltrative lesion with a poor prognosis. Only 1 patient in the series survived. There was nothing characteristic about the location or histologic features of the tumors which would lend support to a "cell rest" theory of origin. Instead, the high incidence of associated vesical disease favored a metaplastic mechanism though cystitis cystica or glandularis did not appear to be necesrnry precursors. The study, however, has failed to offer a satisfactory explanation for the overwhelming preponderance of glandular tumors in instances of carcinoma arising in the urachus and exstrophied bladder.