- Email: [email protected]
Transition of Cystitis Glandularis to Primary Adenocarcinoma of the Bladder
1.'ug JOURNAL OF UnoLOG'i'" Vol. 79, No. 5, ~lay 1958 vn·nted 1:n [l.8.A.
TRANSITIOX OF CYSTITIS GLANDULARIS TO PRIMARY ADEXOCARCINOMA OF THE BLADDER JOHN L. SHAW,* G. JOHN GISLASO.'\
AND
JOSEPH E. IJ\IBIUGLIA
Pro/// ihe Deparlnwnts uf Urology ancl Pathology, Hahnemann Medical College ancl Hospital, Philadelphia, Pa.
The manifestations of the forms of proliferative cystitis, particularly glandularis and are well known and are recognized as difficult clinical problems to evaluate and treat. J\Iucm: secreting adenoc:arcinoma arising primarily in the bladder is not commonly seen, but it is not a rnre veRical tumor. That these lesions am closely related is generally agreed, and the fact that cystitis cystica and glandulari:c; are pre-malignant lesions has been postulated. The demonstration of a direet transition and progression of a case of ('ystitis glandularic1 to adenoc:arcinorna should lend emphasis to the consideration of the malignant potentialities in the clinical management. of these forn1:" of THIWRrns OF PATHOGEXESlS
glandnlaris and primary mueus adenm:an:inoma of the bladder are closely related lesions. 1 - 15 The similarity of ac:c:epted theories of etiology as well as the high incidenc·e of the co-existenc:e of these lesions is evidence of this relationship. "Embryonic: rests," originating in the nrnchus or as persistent inclusions of intestinal epithelium misplaced in the process of the rfrvision of the rectum from the urogenital sinus, may manifest themselves as areas of Accepted for publication October 24, 1957. * Captain, U.S.A.F. (IVIC). Resident in urology, now at 6208th U.S.A.F. 1 Patch, F. S.: Epithelial metaplasia of the urinary tract. J.A.M.A., 136: Hl48. 2 }\1ostofi, F. K .. Potentialities of bladder epithelium. J. Urol., 71: 705-714, 1954. 3 Emmett, J. L. and McDonald, .J. R.: Proliferation of glands of the urinary bladder simulating neoplasm. J. 1Jrol., 48: 257-265, 1\l42. "Abes house, B. S.: Exstroph~- of the bladder complicated by a.dcnocarcinoma, of the bladder and renal calculi ..L Urol., 49: 259-289, 1943. 5 Wheeler, J. D. and Hill, vV. T.: Adenornrcinoma involving the urinary bladder. Cancer, 7: 119-135, 1954. 6 Melicow, M. !VI.: Tumors of the minary bladder: A clinico-pathological analysis of over 2500 specimens and biopsies. J. Urol., 74: 498-521, 1955. 7 Stirling, C. and Ash, .J.E.: Chronic proliferative lesions of the 11rinary tract ..J. Urol.. , 45: 3±2-360. 19~1. 8 Patch,· F. S. and Rhea, L .. The genesis and development of Brunn 's nests and tbeir relation to cystica, cystitis glandularis, and primary adenocarcinoma of the bladder. Canad. Assc. ,J., 33: 597-606, 1935. 9 Foot, N. C.: (}landular mcta.plasia of the epithelium of the minary tract. South ::\.'Ied ,J., 37: l:'17-142, 1944. to Kretschmer, H. : Cystitis glandularis and follicularis. Am . .J. Smg., 82: 198-2()] 1951, 11 Williams, J. I., Godwin, ;\1, C. ancl Cross, R.R.: Adenocarcinoma of the bladder. J. Internat. Coll. Smg., 25: 461-470, 1956. 12 Kretschmer, H. L.: Primary mucus secreting a.denoca.rcinoma. oft.he bladder. ,J UroL 61: 754-765, 194\l. 13 Dukes, C. E and ,l\fasina, F.: Classification of epithelial tumors of the bladder. Brit. J. U rnl., 21: 273-295, l9ci9. 14 Craig, L. G. Cystitis cystica glandularis. J. Urol., 42: 1197-1203, l9:-l9 . . . •1: Sa.phir, 0.: Signet-ring cell carcinoma of the urinary bladder. Am ..J. Path., 31: 228, 1900.
815
816
JOHN L. SHAW, G. JOHN GISLASON AND JOSEPH E. IMBRIGLIA
glandularis or glandular carcinoma3 • 9 · 16 · 17 The number of cases that have been reported is not many, but it must be accepted that these lesions may arise on this basis. Foot 9 believes that embryonic rests are responsible for all glandular elements found in the fundus of the bladder. Primary adenocarcinoma arising in the vesical end of the urachus is well recognized, and the opinion that all primary adenocarcinoma arising in the fundus of the bladder is of urachal origin is frequently documented. It has been reported by some observers that a few glands may occur under normal circumstances in the base and trigonal area of the bladder, and it is on this fact that the anatomical theory of the origin of these lesions is based. Emmett and McDonald 3 described five of nine cases of cystitis glandularis which they felt originated in subtrigonal glands. They also stated that these glands may give rise to adenocarcinoma. Lowry and associates18 reported three cases demonstrating proliferative cystitis of a glandular type arising from glands of Albarran. The marked ability of transitional epitheliun1 to undergo metaplasia is one of its characteristics, and it is on this basis that the majority of critical opinion believes the etiology of cystitis glandularis, as well as the other forms of proliferative cystitis, and primary adenocarcinoma of the bladder may be best explained. 1 • 2 • 4 • 6 • 10 , 13 • 14 • 18 • 19 vVith the majority of the vesical epithelium being of entodermal origin, it is theorized that the transitional epithelium retains a tendency, under certain indefinite and incompletely defined forms of stimulation, to form glandular epithelium. Beginning with the transitional epithelial unit of metaplasia, the cell nest of von Brunn, the potentialities of change to a glandular type epithelium and thence to a mucus adenocarcinoma have been repeatedly described. COMMENT
The observations of others as well as the pathological studies of the case herein reported lead us to believe that cystitis glandularis is and should be identified as a pre-malignant lesion. As Craig 14 has stated, "proof of the relationship of these lesions to adenocarcinoma depends largely on presumptive evidence." However, this evidence is quite convincing even if based only on the high incidence of their reported coexistence. In discussing the differential diagnosis of a primary from a metastatic adenocarcinoma of the bladder, Wheeler and Hill5 stated that one of the criteria for a diagnosis of primary adenocarcinoma is the coexistence of cystitis glandularis. Mostofi, 2 rejecting all theories of origin of adenocarcinoma of the bladder other than that of a direct and progressive metaplasia from transitional epithelium, 16 Coppridge, W. C., Roberts, L. C. and Culp, D. A.: Glandular tumors of the bladder. J. Urol., 65: 540-549, 1951. 17 Saphir, 0. and Kurland, S. K.: Adenocarcinoma of the urinary bladder. Urol. and Cutan. Rev., 43: 709-719, 1939. 18 Lowry, E. C., Hamm, F. C. and Beard, D. E.: Extensive glandular proliferation of the urinary bladder resembling malignant neoplasm. J. Urol., 52: 133-138, 1944. 19 Howard, A.H. and Bergman, R. T.: :Mucus adenocarcinoma of the urinary bladder. J. Urol., 59: 455-459, 1948.
TK\NSITION OF CYSTITIS GLcl.'\'.lH;LidtIS TO l'ltll\,L!;_RY A DE:'iOC',RCIXOMA
81.
state:c; that to call a tumor a primary vesical carcinoma, Brunn's nests, glalldular and mucus metaplasia, as well as polypoid epithelial projet:tions must be pre;;ent. The evidence of these reports as ,vell as that of the case herein desC'ribed that the obserYations of the coexi::,tence of adenocarcinorna and gl11ndularis are but, further and more important, that cystitis ghmdu Iaris may he only the mid-point of a progressi,·c transition iu the metaplasia of transitional epithelium to adcnocareinoma. stated that ''it would be diflieult to Lw·ogni;r,e Hw conditi011" i.e., glandularic:1 "in the inflammatory stage during life and follow it over of years to the development of 1nalignancy." Patc:h and Rhea,8 in stated that it "must be admitted that the progressive change" in clularis leading to adenocan;inoma have not been den1cmstrnted ." Roberts and Cnlp, 16 in 1 although agreeing that it does oc:cur, stated thal '·adenocarcinoma has Bever been observed to oc:cur from cystitis gbndularis. '\Ve hrwe been miable to find any report in which the transition of dularis to adenocarc:inoma has actually been demonstrated C.I.SE REPORT
The following case clemonstrnted this transition from (:ystitis glandularis to mucus adenoearcinoma. 1\1. A (R.H. a 41-year-old white ,rnman, was admitted to Hahnemann Ho,,pital 011 April 12, 1951 with the chief complaint of an incisional and urine. The urmary symptorns dated bad'" eight years to
Fm. l A inlrnveno1ts urog:rnm shows normal upper urinary tract with filling defect in right wall of bladder.- B, section of bladder mncosa shows t,·pieal mucus glands (ga.strointe,tirrnl l.1·pe) seen in c)·stitis glanclula.ris.
818
JOHN L. SHAW, G. JOHN GISLASON AND JOSEPH E. IMBRIGLIA
Fm. 2. A, intravenous urogram again shows defect in right lateral wall of bladder. Shadow over bladder region is wire mesh used in repairing incisional hernia. B, section of bladder shows typical cystic glands. In addition, however, there are atypical glands nestled between cystic glands, characterized by hyperchromatism, hyperplasia and invasion of muscle wall.
their first appearance following an abdominal operation of an indefinite nature done for a benign gynecological complaint. In 1949 dilatation and curettage had been done; the specimen was negative for malignancy. Dysuria recurred and had been present for two months prior to the present admission. There was no history of hematuria. Physical examination showed a very obese white woman with an incisional hernia in the midline of her lower abdomen, first degree cystocele, two plus pedal and pre-tibial edema. The urine showed many mucus shreds, 30 to 40 red blood cells per high power field, and was loaded with white blood cells. Aerobacter aerogenes and coliform bacilli were cultured. An intravenous urogram revealed good bilateral function with a morphologically normal upper urinary tract. There was a large filling defect in the right side of the bladder (fig. 1, A). Cystoscopy revealed a large, broad base, somewhat elevated tumor mass involving most of the right lateral wall of the bladder. The upper portion of the tumor was irregular, the lower part smooth. Biopsies taken from the lower and middle areas of the tumor revealed "polypoid masses lined by adenomatous glands which were mucus secreting in type. Diagnosis: cystitis glandularis (aberrant gastrointestinal tissue)." Cystoscopy was repeated six days later and it was noted that the tumor appeared infiltrating. Another biopsy was again reported to be cystitis glandularis. Gastrointestinal studies were negative except for multiple small diverticula of the upper sigmoid.
TR\NSITION Qlf CYSTITIS GLANDULARIS '1'0 PTIIJ\IARY .\DENOCAHCTKOMA
8J\l
At opernti011 the bladder -was opened through a suprapubic incision, and the major portion of the tumor was removed hy loop resertion and the base fulgurnted. Pathological examination revealed "nests of adenornatous glands lined by tall columnar aud mucus secreting epithelium_ An occasiollal neHt of trnm,i-tioual epithelium is noted. Again the possibility of gastrointestinal cannot be excluded. Diagnosis: cyHtitis glandularis (fig. 1, " During the six mouths follmYing her discharge from the hol-'pital, the clinical picture wns that of marked frequency, urgency, suprapubi('. pain, hematuria and doudy urine with large amounts of mucus. Resistant B. proteus ,Yas cultured. The ,,·as hospitalized for c:ystoscopy under anesthesia and a generalized ,Yith an elentted area, cystic: in appearance, and in form, 2 to :-; c-111, ahove the right ureteral orifice, was described. An interval a nrnnth to this admission had revealed mucoid and areas of extreme hyperemia limited to the right lateral wall. Biopsy and cysto1oc:opic: treatment 11·rre adYised, but the patient left the hospital. The patient returned to the clinic 22 months later complaining of nocturia and burning on Yoiding. During the interval the incisional hernia had been corrected at another hospital using a wire mesh repair. Her urine contained mucul-3 shred,;. T"'"""'"'m, revealed a red, velvety mucosa with a mucoid exudate. l\ o mention of tumor ,n,ti made. She was not cieen for another eight months at which time she was admitted the hoHpital lwc:au:csc of severe pain in her right hip. Bladder symptoms were not promi11e11t. Boue x-rays were negative. An intravenous urogram reYealed n normal upper tract and again shmYed a :filling defect on the right side of the
Fie;. 3. High power photomicrogmphs of sections taken from specimen removed total cystectomy reveal hyperchromatism of nuclei, loss of nuclear polarity, and mitotic figure and invasion. Strorna is characterized by diffuse mononuclear cell infiltrate.
820
JOHN L. SHAW, G. JOHN GISLASON AXD JOSEPH E. IMBRIGLIA
bladder (fig. 2, A). B. proteus and coliform organisms sensitive to streptomycin were cultured from the urine. Cystoscopy revealed a papillary tumor on the right lateral ,vall with hyperemia of the bladder base. The clinical impression was transitional cell carcinoma. Another biopsy was reported "mucosa entirely replaced by mucinous glandular formations which invaginate up to the submucosa. The interglandular stroma shows loose fibrous connective tissue with diffuse lymphocytic infiltration. Diagnosis: cystitis glandularis" (fig. 2, B). The patient was discharged t,vo day8 later. She returned intermittently during the next seven months during which time her bladder symptoms remained unchanged. A culture during this period revealed paracolon and coliform bacilli. The patient was then not seen until her return to the clinic in ::\fay 1956, five years and one month from the time of the original biopsy and diagnosis of cystitis glandularis. Her complaints were frequency, nocturia and, now, stress incontinence. Cystoscopy revealed an irregular, non-ulcerated, hyperemic tumor involving mo8t of the right lateral wall. The clinical impression was again that of carcinoma and she was admitted to the hospital, her fourth hospital admission. Physical examination revealed a well preserved, extremely obese white woman. Routine blood studies were within normal limits. An intravenous urogram again showed the deformity of the right wall of the bladder. Repeat studies of the lower bowel ,vere unchanged from previous studies. The chest x-ray was negative. Her urine showed many red and white blood cells and culture yielded coliform bacilli. Transurethral biopsy of the right lateral wall lesion was reported by the pathologist that "the tissue is composed of mucus secreting glands in a loose granulation tissue type of stroma. Lymphocytes infiltrate diffusely. Many areas of the glands show loss of polarity and hyperchromatism of nuclei with occasional mitoses. Comparison ,vith previous biopsies shows that this lesion has undergone malignant change and should be thought of as a low-grade adenocarcinoma primary in the bladder. Diagnosis: "Adenocarcinoma of the urinary bladder, low-grade." A subtotal cystectomy was performed. A large papillary tumor ,vhich involved most of the right lateral wall ,vas removed with ,vhat was felt to be an adequate margin of normal bladder wall. There was no evidence of local or distant extension of the lesion. The postoperative course was prolonged by persistent drainage from her suprapubic fistula. She was discharged on the thirty-fourth postoperative day. The pathology report stated that, "The major specimen reveals a glandular tumor composed of well differentiated mucus producing glands. These grow up from the surface in a polypoid tumor, but some glands are invasive and extend down to the muscle. Diagnosis: Adenocarcinoma of the urinary bladder" (fig. 3). On her return to the clinic two weeks after discharge she was voiding four times during the day and twice at night without pain.
TRANSITION OF' CYSTITIS GL.~c''.DULARIS TO PRIMARY ADENOCARCINOl\L\_
8:2:J
DISCUSSIOJ\
In Hl:31 the lesi011 ,vas unequivocably eystitis glandularis (fig. 1, . After three years of chronic infection the patient returned with a lesion in the :-mnrn area of the bladder, ,vhich on biopsy was again diagnosed as cystitis glanclularis; but in revimYing the slides \\"e find beginning carciuomatous change with piling up of nuclei and loss of polarity (fig. 2, B). Then after two additional years of chronic infedion, the was seen with the same lesion -which had progressed to an early infiltrating mucus adenocarcinoma with areas of loss of and hyperchromatism of the nuclei 1Yith mitoses (fig. :-l). In a period of five years unequivocal cystitis glandularis had progressed to unequiv(_wa.l mucus adenocarcinoma "·ith beginning malignant change in the third year. The role of chronie infection in the produetion of these lesiorrn has been Rtre,;sed many authort-,. 1 ' "' r,, 7 - H, 20 There is little doubt that it ,vas a factor in this case. Perhaps the progression to anaplasia \Yot1ld not have occurred without the inflanunatory stimulation. Sauer and Blick21 followed five cases, in which there was no infection initially or it had been for periods of one to s1x years, aud reported no evidence of malignant degenerntioll. Their observations ,rnre made on ''"'"''Q" ev.ldcnce. No mention was rnade of repeat biopsy, We shall follow our case -with interest to see if her bladder epithelium will remain normal follmving eradicati.ou of infeetion. If her infection persists, will cystitis glandularis recur and progress to malignancy, or ,vill she have a recurrence of aclenocarcinorna without glaudular metaplasia? The clinical and pathological diagnosis of an eiirly primary adcnoc:arc:inon1a and it:, differential diaguosis from that of cystitis glanclularis is not always easy infection is usually present. That a biopsy or seYern i A resistant, "'"'''-·'"'m biopsies would be truly reprrnmntativc of the areas showing the greatest degree of anaplasia 1Yill be a doubtful fact, Adequate rotucly and interpretation of the biopsy submitted are cJubsequent problem,, whic:h need further elaboration. Having arriYed at the diagnosis of early primary adenocarcinorna. and ruled out a primary lesions elsewhere, the lesion should be treated acl any other carcinoma of th(i bladder. If the diagnosi::, be cyBtitis glandularis, the lesion should be adequately resected aud its base fulgura.ted, The patient\; infections should be treated and eradicated. Failure to respond to treatrnent should alert the clinician to the necessity of close followup, repeated biopsies, and constant attention to the possibility that he is dealing \Yith a potentially malignant lesion. 20 J\/Ie[icow, l\I. 1\-I : Histological study of vesical urothelium between gross neoplasms in total cystectomy. J. Urol., 68: 261-279, 1952. 21 Sauer, H. R. aud Blick, M. S.: Cystitis glandularis · A consideration of tbe ;symptom,, diagnosis, and clinieal cause of the disease. J. Urol., 60: 446--458, 1948.
822
JOHN L. SHAW, G. JOHN GISLASON AND JOSEPH E. IMBRIGLIA
SUMMARY
There is a close relationship between cystitis glandularis, one of the common forms of proliferative cystitis, and primary mucus secreting adenocarcinoma of the bladder. This relationship has been emphasized in the past but only on presumptive evidence based on the high incidence of the coexistence of these lesions and the similarities of theories of pathogenesis. The embryonic rest theory, the anatomical theory, and the theory of the metaplastic transposition of transitional epithelium to a glandular type epithelium and adenocarcinoma are noted. The latter is the most widely accepted. A patient with cystitis glandularis was followed carefully over a period of five and a half years and a definite transposition to a mucus secreting adenocarcinoma was demonstrated. To the authors' knowledge, this is the first report in which this change was actually observed and demonstrated in a given case. This report adds to the evidence that cystitis glandularis, as -well as the other forms of proliferative cystitis, is a premalignant lesion of the bladder, and it is urged that this fact be kept in mind in the clinical management of these forms of cystitis. The authors wish to thank Dr. F. Mostofi and his staff at the Armed Forces Institute of Pathology for reviewing the slides in this case. 1818 Medical Arts Bldg., Philadelphia 2, Pa. (G. J. G.)
TRANSITIOX OF CYSTITIS GLANDULARIS TO PRIMARY ADEXOCARCINOMA OF THE BLADDER JOHN L. SHAW,* G. JOHN GISLASO.'\
AND
JOSEPH E. IJ\IBIUGLIA
Pro/// ihe Deparlnwnts uf Urology ancl Pathology, Hahnemann Medical College ancl Hospital, Philadelphia, Pa.
The manifestations of the forms of proliferative cystitis, particularly glandularis and are well known and are recognized as difficult clinical problems to evaluate and treat. J\Iucm: secreting adenoc:arcinoma arising primarily in the bladder is not commonly seen, but it is not a rnre veRical tumor. That these lesions am closely related is generally agreed, and the fact that cystitis cystica and glandulari:c; are pre-malignant lesions has been postulated. The demonstration of a direet transition and progression of a case of ('ystitis glandularic1 to adenoc:arcinorna should lend emphasis to the consideration of the malignant potentialities in the clinical management. of these forn1:" of THIWRrns OF PATHOGEXESlS
glandnlaris and primary mueus adenm:an:inoma of the bladder are closely related lesions. 1 - 15 The similarity of ac:c:epted theories of etiology as well as the high incidenc·e of the co-existenc:e of these lesions is evidence of this relationship. "Embryonic: rests," originating in the nrnchus or as persistent inclusions of intestinal epithelium misplaced in the process of the rfrvision of the rectum from the urogenital sinus, may manifest themselves as areas of Accepted for publication October 24, 1957. * Captain, U.S.A.F. (IVIC). Resident in urology, now at 6208th U.S.A.F. 1 Patch, F. S.: Epithelial metaplasia of the urinary tract. J.A.M.A., 136: Hl48. 2 }\1ostofi, F. K .. Potentialities of bladder epithelium. J. Urol., 71: 705-714, 1954. 3 Emmett, J. L. and McDonald, .J. R.: Proliferation of glands of the urinary bladder simulating neoplasm. J. 1Jrol., 48: 257-265, 1\l42. "Abes house, B. S.: Exstroph~- of the bladder complicated by a.dcnocarcinoma, of the bladder and renal calculi ..L Urol., 49: 259-289, 1943. 5 Wheeler, J. D. and Hill, vV. T.: Adenornrcinoma involving the urinary bladder. Cancer, 7: 119-135, 1954. 6 Melicow, M. !VI.: Tumors of the minary bladder: A clinico-pathological analysis of over 2500 specimens and biopsies. J. Urol., 74: 498-521, 1955. 7 Stirling, C. and Ash, .J.E.: Chronic proliferative lesions of the 11rinary tract ..J. Urol.. , 45: 3±2-360. 19~1. 8 Patch,· F. S. and Rhea, L .. The genesis and development of Brunn 's nests and tbeir relation to cystica, cystitis glandularis, and primary adenocarcinoma of the bladder. Canad. Assc. ,J., 33: 597-606, 1935. 9 Foot, N. C.: (}landular mcta.plasia of the epithelium of the minary tract. South ::\.'Ied ,J., 37: l:'17-142, 1944. to Kretschmer, H. : Cystitis glandularis and follicularis. Am . .J. Smg., 82: 198-2()] 1951, 11 Williams, J. I., Godwin, ;\1, C. ancl Cross, R.R.: Adenocarcinoma of the bladder. J. Internat. Coll. Smg., 25: 461-470, 1956. 12 Kretschmer, H. L.: Primary mucus secreting a.denoca.rcinoma. oft.he bladder. ,J UroL 61: 754-765, 194\l. 13 Dukes, C. E and ,l\fasina, F.: Classification of epithelial tumors of the bladder. Brit. J. U rnl., 21: 273-295, l9ci9. 14 Craig, L. G. Cystitis cystica glandularis. J. Urol., 42: 1197-1203, l9:-l9 . . . •1: Sa.phir, 0.: Signet-ring cell carcinoma of the urinary bladder. Am ..J. Path., 31: 228, 1900.
815
816
JOHN L. SHAW, G. JOHN GISLASON AND JOSEPH E. IMBRIGLIA
glandularis or glandular carcinoma3 • 9 · 16 · 17 The number of cases that have been reported is not many, but it must be accepted that these lesions may arise on this basis. Foot 9 believes that embryonic rests are responsible for all glandular elements found in the fundus of the bladder. Primary adenocarcinoma arising in the vesical end of the urachus is well recognized, and the opinion that all primary adenocarcinoma arising in the fundus of the bladder is of urachal origin is frequently documented. It has been reported by some observers that a few glands may occur under normal circumstances in the base and trigonal area of the bladder, and it is on this fact that the anatomical theory of the origin of these lesions is based. Emmett and McDonald 3 described five of nine cases of cystitis glandularis which they felt originated in subtrigonal glands. They also stated that these glands may give rise to adenocarcinoma. Lowry and associates18 reported three cases demonstrating proliferative cystitis of a glandular type arising from glands of Albarran. The marked ability of transitional epitheliun1 to undergo metaplasia is one of its characteristics, and it is on this basis that the majority of critical opinion believes the etiology of cystitis glandularis, as well as the other forms of proliferative cystitis, and primary adenocarcinoma of the bladder may be best explained. 1 • 2 • 4 • 6 • 10 , 13 • 14 • 18 • 19 vVith the majority of the vesical epithelium being of entodermal origin, it is theorized that the transitional epithelium retains a tendency, under certain indefinite and incompletely defined forms of stimulation, to form glandular epithelium. Beginning with the transitional epithelial unit of metaplasia, the cell nest of von Brunn, the potentialities of change to a glandular type epithelium and thence to a mucus adenocarcinoma have been repeatedly described. COMMENT
The observations of others as well as the pathological studies of the case herein reported lead us to believe that cystitis glandularis is and should be identified as a pre-malignant lesion. As Craig 14 has stated, "proof of the relationship of these lesions to adenocarcinoma depends largely on presumptive evidence." However, this evidence is quite convincing even if based only on the high incidence of their reported coexistence. In discussing the differential diagnosis of a primary from a metastatic adenocarcinoma of the bladder, Wheeler and Hill5 stated that one of the criteria for a diagnosis of primary adenocarcinoma is the coexistence of cystitis glandularis. Mostofi, 2 rejecting all theories of origin of adenocarcinoma of the bladder other than that of a direct and progressive metaplasia from transitional epithelium, 16 Coppridge, W. C., Roberts, L. C. and Culp, D. A.: Glandular tumors of the bladder. J. Urol., 65: 540-549, 1951. 17 Saphir, 0. and Kurland, S. K.: Adenocarcinoma of the urinary bladder. Urol. and Cutan. Rev., 43: 709-719, 1939. 18 Lowry, E. C., Hamm, F. C. and Beard, D. E.: Extensive glandular proliferation of the urinary bladder resembling malignant neoplasm. J. Urol., 52: 133-138, 1944. 19 Howard, A.H. and Bergman, R. T.: :Mucus adenocarcinoma of the urinary bladder. J. Urol., 59: 455-459, 1948.
TK\NSITION OF CYSTITIS GLcl.'\'.lH;LidtIS TO l'ltll\,L!;_RY A DE:'iOC',RCIXOMA
81.
state:c; that to call a tumor a primary vesical carcinoma, Brunn's nests, glalldular and mucus metaplasia, as well as polypoid epithelial projet:tions must be pre;;ent. The evidence of these reports as ,vell as that of the case herein desC'ribed that the obserYations of the coexi::,tence of adenocarcinorna and gl11ndularis are but, further and more important, that cystitis ghmdu Iaris may he only the mid-point of a progressi,·c transition iu the metaplasia of transitional epithelium to adcnocareinoma. stated that ''it would be diflieult to Lw·ogni;r,e Hw conditi011" i.e., glandularic:1 "in the inflammatory stage during life and follow it over of years to the development of 1nalignancy." Patc:h and Rhea,8 in stated that it "must be admitted that the progressive change" in clularis leading to adenocan;inoma have not been den1cmstrnted ." Roberts and Cnlp, 16 in 1 although agreeing that it does oc:cur, stated thal '·adenocarcinoma has Bever been observed to oc:cur from cystitis gbndularis. '\Ve hrwe been miable to find any report in which the transition of dularis to adenocarc:inoma has actually been demonstrated C.I.SE REPORT
The following case clemonstrnted this transition from (:ystitis glandularis to mucus adenoearcinoma. 1\1. A (R.H. a 41-year-old white ,rnman, was admitted to Hahnemann Ho,,pital 011 April 12, 1951 with the chief complaint of an incisional and urine. The urmary symptorns dated bad'" eight years to
Fm. l A inlrnveno1ts urog:rnm shows normal upper urinary tract with filling defect in right wall of bladder.- B, section of bladder mncosa shows t,·pieal mucus glands (ga.strointe,tirrnl l.1·pe) seen in c)·stitis glanclula.ris.
818
JOHN L. SHAW, G. JOHN GISLASON AND JOSEPH E. IMBRIGLIA
Fm. 2. A, intravenous urogram again shows defect in right lateral wall of bladder. Shadow over bladder region is wire mesh used in repairing incisional hernia. B, section of bladder shows typical cystic glands. In addition, however, there are atypical glands nestled between cystic glands, characterized by hyperchromatism, hyperplasia and invasion of muscle wall.
their first appearance following an abdominal operation of an indefinite nature done for a benign gynecological complaint. In 1949 dilatation and curettage had been done; the specimen was negative for malignancy. Dysuria recurred and had been present for two months prior to the present admission. There was no history of hematuria. Physical examination showed a very obese white woman with an incisional hernia in the midline of her lower abdomen, first degree cystocele, two plus pedal and pre-tibial edema. The urine showed many mucus shreds, 30 to 40 red blood cells per high power field, and was loaded with white blood cells. Aerobacter aerogenes and coliform bacilli were cultured. An intravenous urogram revealed good bilateral function with a morphologically normal upper urinary tract. There was a large filling defect in the right side of the bladder (fig. 1, A). Cystoscopy revealed a large, broad base, somewhat elevated tumor mass involving most of the right lateral wall of the bladder. The upper portion of the tumor was irregular, the lower part smooth. Biopsies taken from the lower and middle areas of the tumor revealed "polypoid masses lined by adenomatous glands which were mucus secreting in type. Diagnosis: cystitis glandularis (aberrant gastrointestinal tissue)." Cystoscopy was repeated six days later and it was noted that the tumor appeared infiltrating. Another biopsy was again reported to be cystitis glandularis. Gastrointestinal studies were negative except for multiple small diverticula of the upper sigmoid.
TR\NSITION Qlf CYSTITIS GLANDULARIS '1'0 PTIIJ\IARY .\DENOCAHCTKOMA
8J\l
At opernti011 the bladder -was opened through a suprapubic incision, and the major portion of the tumor was removed hy loop resertion and the base fulgurnted. Pathological examination revealed "nests of adenornatous glands lined by tall columnar aud mucus secreting epithelium_ An occasiollal neHt of trnm,i-tioual epithelium is noted. Again the possibility of gastrointestinal cannot be excluded. Diagnosis: cyHtitis glandularis (fig. 1, " During the six mouths follmYing her discharge from the hol-'pital, the clinical picture wns that of marked frequency, urgency, suprapubi('. pain, hematuria and doudy urine with large amounts of mucus. Resistant B. proteus ,Yas cultured. The ,,·as hospitalized for c:ystoscopy under anesthesia and a generalized ,Yith an elentted area, cystic: in appearance, and in form, 2 to :-; c-111, ahove the right ureteral orifice, was described. An interval a nrnnth to this admission had revealed mucoid and areas of extreme hyperemia limited to the right lateral wall. Biopsy and cysto1oc:opic: treatment 11·rre adYised, but the patient left the hospital. The patient returned to the clinic 22 months later complaining of nocturia and burning on Yoiding. During the interval the incisional hernia had been corrected at another hospital using a wire mesh repair. Her urine contained mucul-3 shred,;. T"'"""'"'m, revealed a red, velvety mucosa with a mucoid exudate. l\ o mention of tumor ,n,ti made. She was not cieen for another eight months at which time she was admitted the hoHpital lwc:au:csc of severe pain in her right hip. Bladder symptoms were not promi11e11t. Boue x-rays were negative. An intravenous urogram reYealed n normal upper tract and again shmYed a :filling defect on the right side of the
Fie;. 3. High power photomicrogmphs of sections taken from specimen removed total cystectomy reveal hyperchromatism of nuclei, loss of nuclear polarity, and mitotic figure and invasion. Strorna is characterized by diffuse mononuclear cell infiltrate.
820
JOHN L. SHAW, G. JOHN GISLASON AXD JOSEPH E. IMBRIGLIA
bladder (fig. 2, A). B. proteus and coliform organisms sensitive to streptomycin were cultured from the urine. Cystoscopy revealed a papillary tumor on the right lateral ,vall with hyperemia of the bladder base. The clinical impression was transitional cell carcinoma. Another biopsy was reported "mucosa entirely replaced by mucinous glandular formations which invaginate up to the submucosa. The interglandular stroma shows loose fibrous connective tissue with diffuse lymphocytic infiltration. Diagnosis: cystitis glandularis" (fig. 2, B). The patient was discharged t,vo day8 later. She returned intermittently during the next seven months during which time her bladder symptoms remained unchanged. A culture during this period revealed paracolon and coliform bacilli. The patient was then not seen until her return to the clinic in ::\fay 1956, five years and one month from the time of the original biopsy and diagnosis of cystitis glandularis. Her complaints were frequency, nocturia and, now, stress incontinence. Cystoscopy revealed an irregular, non-ulcerated, hyperemic tumor involving mo8t of the right lateral wall. The clinical impression was again that of carcinoma and she was admitted to the hospital, her fourth hospital admission. Physical examination revealed a well preserved, extremely obese white woman. Routine blood studies were within normal limits. An intravenous urogram again showed the deformity of the right wall of the bladder. Repeat studies of the lower bowel ,vere unchanged from previous studies. The chest x-ray was negative. Her urine showed many red and white blood cells and culture yielded coliform bacilli. Transurethral biopsy of the right lateral wall lesion was reported by the pathologist that "the tissue is composed of mucus secreting glands in a loose granulation tissue type of stroma. Lymphocytes infiltrate diffusely. Many areas of the glands show loss of polarity and hyperchromatism of nuclei with occasional mitoses. Comparison ,vith previous biopsies shows that this lesion has undergone malignant change and should be thought of as a low-grade adenocarcinoma primary in the bladder. Diagnosis: "Adenocarcinoma of the urinary bladder, low-grade." A subtotal cystectomy was performed. A large papillary tumor ,vhich involved most of the right lateral wall ,vas removed with ,vhat was felt to be an adequate margin of normal bladder wall. There was no evidence of local or distant extension of the lesion. The postoperative course was prolonged by persistent drainage from her suprapubic fistula. She was discharged on the thirty-fourth postoperative day. The pathology report stated that, "The major specimen reveals a glandular tumor composed of well differentiated mucus producing glands. These grow up from the surface in a polypoid tumor, but some glands are invasive and extend down to the muscle. Diagnosis: Adenocarcinoma of the urinary bladder" (fig. 3). On her return to the clinic two weeks after discharge she was voiding four times during the day and twice at night without pain.
TRANSITION OF' CYSTITIS GL.~c''.DULARIS TO PRIMARY ADENOCARCINOl\L\_
8:2:J
DISCUSSIOJ\
In Hl:31 the lesi011 ,vas unequivocably eystitis glandularis (fig. 1, . After three years of chronic infection the patient returned with a lesion in the :-mnrn area of the bladder, ,vhich on biopsy was again diagnosed as cystitis glanclularis; but in revimYing the slides \\"e find beginning carciuomatous change with piling up of nuclei and loss of polarity (fig. 2, B). Then after two additional years of chronic infedion, the was seen with the same lesion -which had progressed to an early infiltrating mucus adenocarcinoma with areas of loss of and hyperchromatism of the nuclei 1Yith mitoses (fig. :-l). In a period of five years unequivocal cystitis glandularis had progressed to unequiv(_wa.l mucus adenocarcinoma "·ith beginning malignant change in the third year. The role of chronie infection in the produetion of these lesiorrn has been Rtre,;sed many authort-,. 1 ' "' r,, 7 - H, 20 There is little doubt that it ,vas a factor in this case. Perhaps the progression to anaplasia \Yot1ld not have occurred without the inflanunatory stimulation. Sauer and Blick21 followed five cases, in which there was no infection initially or it had been for periods of one to s1x years, aud reported no evidence of malignant degenerntioll. Their observations ,rnre made on ''"'"''Q" ev.ldcnce. No mention was rnade of repeat biopsy, We shall follow our case -with interest to see if her bladder epithelium will remain normal follmving eradicati.ou of infeetion. If her infection persists, will cystitis glandularis recur and progress to malignancy, or ,vill she have a recurrence of aclenocarcinorna without glaudular metaplasia? The clinical and pathological diagnosis of an eiirly primary adcnoc:arc:inon1a and it:, differential diaguosis from that of cystitis glanclularis is not always easy infection is usually present. That a biopsy or seYern i A resistant, "'"'''-·'"'m biopsies would be truly reprrnmntativc of the areas showing the greatest degree of anaplasia 1Yill be a doubtful fact, Adequate rotucly and interpretation of the biopsy submitted are cJubsequent problem,, whic:h need further elaboration. Having arriYed at the diagnosis of early primary adenocarcinorna. and ruled out a primary lesions elsewhere, the lesion should be treated acl any other carcinoma of th(i bladder. If the diagnosi::, be cyBtitis glandularis, the lesion should be adequately resected aud its base fulgura.ted, The patient\; infections should be treated and eradicated. Failure to respond to treatrnent should alert the clinician to the necessity of close followup, repeated biopsies, and constant attention to the possibility that he is dealing \Yith a potentially malignant lesion. 20 J\/Ie[icow, l\I. 1\-I : Histological study of vesical urothelium between gross neoplasms in total cystectomy. J. Urol., 68: 261-279, 1952. 21 Sauer, H. R. aud Blick, M. S.: Cystitis glandularis · A consideration of tbe ;symptom,, diagnosis, and clinieal cause of the disease. J. Urol., 60: 446--458, 1948.
822
JOHN L. SHAW, G. JOHN GISLASON AND JOSEPH E. IMBRIGLIA
SUMMARY
There is a close relationship between cystitis glandularis, one of the common forms of proliferative cystitis, and primary mucus secreting adenocarcinoma of the bladder. This relationship has been emphasized in the past but only on presumptive evidence based on the high incidence of the coexistence of these lesions and the similarities of theories of pathogenesis. The embryonic rest theory, the anatomical theory, and the theory of the metaplastic transposition of transitional epithelium to a glandular type epithelium and adenocarcinoma are noted. The latter is the most widely accepted. A patient with cystitis glandularis was followed carefully over a period of five and a half years and a definite transposition to a mucus secreting adenocarcinoma was demonstrated. To the authors' knowledge, this is the first report in which this change was actually observed and demonstrated in a given case. This report adds to the evidence that cystitis glandularis, as -well as the other forms of proliferative cystitis, is a premalignant lesion of the bladder, and it is urged that this fact be kept in mind in the clinical management of these forms of cystitis. The authors wish to thank Dr. F. Mostofi and his staff at the Armed Forces Institute of Pathology for reviewing the slides in this case. 1818 Medical Arts Bldg., Philadelphia 2, Pa. (G. J. G.)