Diffuse cystitis glandularis Associated with adenocarcinomatous change

DIFFUSE CYSTITIS GLANDULARIS Associated with Adenocarcinomatous Change JAIN I. LIN, M .D . C . H. TSENG, M .D . CHUN CHOY, M.D.

H. S . YONG, M .D . P. S . MARSIDI, M .D . BENJAMIN PILLOFF, M .D .

From the Departments of Pathology and Urology, Veterans Administration Medical Center, and Wright State University School of Medicine, Dayton, Ohio

ABSTRACT - Although cystitis glandularis has been considered a premalignant lesion, the instance of cystitis glandularis progression to adenocarcinoma or cystitis glandularis associated with adenocarcinomatous change is rare . This article includes 4 cases of neurogenic bladder with urinary diversion for different periods of time . In the first case with ureterocutaneostomy for twenty-five years diffuse cystitis glandularis with multifocal adenocarcinomatous change developed . The second case with supra pubic cystostomy for twenty-two years had diffuse cystitis glandularis of gastrointestinal type without evidence of malignancy . The other 2 cases with suprapubic cystostomy for merely ten years showed only mild to moderate cystitis glandularis and chronic cystitis with squamous metaplasia, respectively . The extent of cystitis glandularis appeared to correlate with the duration of urinary stasis . Ureterocutaneostomy rendered constant infection of the urinary bladder of the first case because of inadequate drainage . Thus, we assume that the intensity of the infection with a toxic product and virulence of organism may be responsible for the development of adenocarcinoma in this patient . Cystitis glandularis, especially diffuse type, can undergo malignant degeneration under constant irritation, but it is a long-term process .

The malignant potential of cystitis glandularis has long been emphasized based mainly on the high incidence of coexistence of cystitis glandularis and adenocarcinoma of the bladder ." However, to our knowledge, a conversion of cystitis glandularis to adenocarcinoma has been documented only in 3 cases, and a histologic demonstration of adenocarcinoma arising in cystitis glandularis in only 1 case . 5'8 Because of the rarity of incidence, Davies and Castro 9 were doubtful of the premalignancy of cystitis glandularis after completing their review of 12 cases . Recently we encountered an unusual case of diffuse cystitis glandularis associated with multifoci of adenocarcinomatous change occurring in a quadriplegic patient who had had ureterocutaneostomy for twenty-five years . This finding prompted us to review the history of 3 UROLOGY

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other quadriplegic patients who had had suprapubic cystostomy for varying periods of time to determine if similar pathologic changes occurred in the urinary bladder . Material and Methods Gross, light microscopic, and fine structural features of the urinary bladder from a patient with ureterocutaneostomy were studied in detail. Multiple biopsies from 3 other quadriplegic patients with suprapubic cystostomy were examined for comparison . Sections of the lesions for light microscopy were stained routinely with hematoxylin and eosin and mucicarmine stains . Sections for electron microscopic study were performed according to the standard procedure . A summary of cases is presented in Table I . 411

TABLE I .

Summary of clinical and pathologic findings in 4 patients with neurogenic bladder

Duration of Sex and Neurogenic Bladder Type of Age (Yrs.) (Yrs .) Urinary Diversion M, 50 27 Ureterocutaneostomy

Organism Isolated

M, 48

22

Suprapubic cystostomy

M, 35

12

Suprapubic cystostomy

M, 40

11

Suprapubic cystostomy

Pathologic Findings

Escherichia coli Diffuse cystitis glandularis Proteus rettgeri with adenocarcinomatous change Klebsiella Diffuse cystitis glandularis of gastrointestinal type Proteus vulgaris Mild to moderate cystitis glandularis Proteus vulgaris Chronic cystitis with squamous metaplasia

Case Reports Case I A fifty-year-old white man was admitted to the Veterans Administration Medical Center because of frequent episodes of fever and chills in the past two years . His past history disclosed he had had a spinal cord injury at the level of C-5 in 1950 . He underwent ureterocutaneostomy in 1952 . Since then the patient had repeated attacks of pyelonephritis . In the past two years, he passed approximately 200 cc . of purulent mucus from the bladder each time he had a bowel movement . Physical examination disclosed normal vital signs, and the heart and lungs were unremarkable . The ureterocutaneostomy sites remained patent . Both upper and lower extremities were paralytic and atrophic . Laboratory findings included hemoglobin 12 .5 Gm ./100 ml ., white cell count of 15,500 with normal differential count. Serum chemistries were within normal limits . The urinalysis disclosed a few white cells and epithelial cells . The bladder mucus contained many white cells and bacilli . The culture of the mucus yielded a large amount of Escherichia coli and Proteus rettgeri . Intravenous pyelography showed bilateral mild hydronephrosis . The cystoscopy disclosed multiple small papillary lesions in the trigone and base . A biopsy was taken and interpreted as cystitis glandularis with atypical change . In view of the malignant potential of cystitis glandularis and eradication of the infectious focus, a total cystectomy was performed. Upon opening, the mucosal surface of the urinary bladder showed characteristic "cobble stone" appearance in which variable sizes of nodularities with velvety and mucoid surfaces were seen (Fig . 1) . The light microscopic examinations disclosed thickening of the mucosa with 412

FIGURE 1 . Vesical mucosa shows characteristic "cobble stone" appearance in which variable size of nodules with velvety and mucoid surfaces are seen .

chronic inflammatory cell infiltration in which extensive glandular metaplasia of superficial epithelium and proliferation of glandular elements throughout the submucosa were present . The mucicarmine stains were positive in most of the glandular tissues . Cystitis cystica was rarely seen. At first glance the lesions looked like cystitis glandularis with unusual extent . However, after serial sections many atypical exophytic and invaginated papillary growths were present (Fig. 2A) . The papillary tumor consisted of many closely packed atypical glands with hyperchromatic nuclei and occasional mitosis consistent with low-grade adenocarcinoma (Fig . 2B) . Further sections showed evidence of superficial muscular invasion (Fig . 2C) . The ultrastructural study of the tumor disclosed submucosal invasion of the neoplastic cell which has a relatively large, often indented nuclei with clumping of chromatin and prominent nucleoli . There UROLOGY

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FIGURE 2 . Case 1 . (A) Extensive glandular metaplasia of vesical mucosa with multifoci of atypical exophytic and invaginated papillary growth. (B) Exophytic papillary tumor consisting of closely packed and atypical glands arise in mucosa which are completely replaced by benign glandular structure . (C) Glandular infiltration in superficial muscular layer . (D) Electromicrography of tumor shows invasion of submucosa. Neoplastic cells have relatively large, often indented nuclei with clumping of chromatin and prominent nucleoli . There are abundant rough endoplasmie reticulum, free ribosomes, and mitochondria . Arrow indicates prominent lateral folding (BL : basal lamina ; CF: collagen fiber) . (Hematoxylin and eosin, original magnifications x 80, x 160, x 160, and x 7,700, respectively .)

were tight cell junction, abundant rough endoplasmic reticulum, free ribosomes, and mitochondria (Fig . 2D) . After reviewing with consultants, we all agreed that this was a case of cystitis glandularis associated with well-differentiated adenocarcinoma. The postoperative course was uneventful . The patient was discharged on the fifteenth hospital day . Case 2 A forty-eight-year-old man was admitted because of fever, chills, and back pain . Past history disclosed he had had a spinal cord injury at the level of C-5 in 1956 . Subsequently he underwent suprapubic cystostomy . Physical examination on admission showed no significant findings except mildly elevated temperature and paralysis of the extremities . Laboratory findings included hemoglobin 13 .5 Gm ./100 ml. and white cell count of 16,000 with normal differential count . The urinalysis disclosed 10 to 15 UROLOGY

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white cells per high-power field and bacteria clumps . The urine culture yielded a large amount of Klebsiella. Intravenous pyelography showed normal functioning kidney . Cystoscopy disclosed papillary lesion near the stoma site . The biopsy was taken, and histologic examination disclosed extensive glandular metaplasia of the superficial epithelium simulating gastrointestinal mucosa (Fig . 3A) . There was no evidence of malignancy . His general condition improved after he was treated with antibiotics, and he was discharged after ten days . Case 3 A thirty-five-year-old man was admitted for an annual checkup . His past history disclosed he had had a spinal cord injury at the level of T-6 in 1966 . Subsequently the patient underwent suprapubic cystostomy . Physical examination was unremarkable . The urine culture yielded a small amount of Proteus organisms . Cystoscopy revealed moderate trabeculation and nodular

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Case 2. Diffuse glandular metaplasia of gastrointestinal type . (B) Case 3 . Vesical mucosa showing Brunn nests and metaplastic glands with chronic inflammatory cell infiltration . (Hematoxylin and eosin, original magnifications x 160.) FIGURE 3 . (A)

lesion near the stoma site . The histologic examination of the biopsy revealed Brunn nests and varying degree of glandular metaplasia in the submucosa in which there were many chronic inflammatory cell infiltrations (Fig . 3B) . Case 4 A forty-year-old white man was admitted for an annual checkup. The patient had suprapubic cystostomy because of spinal cord injury at the level of C-5 in 1967 . Physical examination and intravenous pyelography were unremarkable . Cystoscopy disclosed white plaques near the stoma site . The urine culture yielded growth of Proteus organisms . The histologic diagnosis of the biopsy showed chronic cystitis with squamous metaplasia. Comment Cystitis glandularis and adenocarcinoma of the bladder are relatively uncommon . The total incidence of cystitis glandularis has been estimated to be between 0 .1 and 0 .9 per cent and . adenocarcinoma between 0 .5 and 2 per cent .' ... The frequent association of cystitis glandularis with bladder adenocarcinoma has led to the belief that cystitis glandularis may be a precursor of adenocarcinoma . 1.10 • 7 2 This assumption has been elaborated by metaplastic theory which claims that the vesicle mucosa can undergo a series of consecutive changes under stress or irritation.'3'14 The mechanism of this change is believed to start from the epithelial hyperplasia to the formation of Brunn nests which subsequently develop a lumen proceeding to cys-

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titis cystica and cystitis glandularis and finally to adenocarcinoma . However, there has been no substantial evidence to support this supposition until Shaw, Gislason, and Imbriglia in 1958' first described a case of cystitis glandularis with gradual transition to adenocarcinoma within a five-year period . This patient had a long-standing history of chronic urinary tract infection . After a constant follow-up, cystitis glandularis eventually progressed to adenocarcinoma . Later, 2 cases of conversion of cystitis glandularis to adenocarcinoma within a period of seven and fifteen years were reported.s •8 These findings added more support that cystitis glandularis should be considered as a premalignant lesion ." On the other hand, the instance of pathologic demonstration of cystitis glandularis associated with adenocarcinomatous change is extremely rare . The reason is that histologic differentiation between cystitis glandularis and early adenocarcinoma is sometimes difficult and controversial ." A case of diffuse cystitis glandularis reported by Bell and Wendel 10 was diagnosed as adenocarcinoma by a well-known pathologist but was changed to cystitis glandularis with unusual extent by another famous pathologist because of lack of muscular invasion . There were 3 other cases of diffuse cystitis glandularis resembling neoplasm reported in the literature .'2 The microscopic findings of these lesions were described as benign looking despite their extensiveness . In 1967 Salm16 described a case of early malignancy associated with multicentric follicular,

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cystica and glandular cystitis . However, he failed to mention if this malignancy arose in cystitis cystica or cystitis glandularis - transitional cell or glandular type . The only case which we found similar to the present case was reported by Parker in 1970 .' In his extensive study of cystitis cystica and cystitis glandularis, he demonstrated a case of diffuse cystitis glandularis associated with multifoci of low-grade adenocarcinoma in a fifty-five-year-old man with chronic urinary tract infection . After one year, a cystectomy disclosed a full blown papillary adenocarcinoma without muscular invasion . The first case we presented in our series has suffered a chronic urinary tract infection and stasis for twenty-seven years. The gross appearance of the urinary bladder showed characteristic change of "cobble stone ." However, the light microscopic examination revealed diffuse cystitis glandularis with multifocal papillary tumor . The tumor consisted of many atypical glands with hyperchromatic nuclei compatible with well-differentiated adenocarcinoma . In addition, the ultrastructural features of the tumor" and evidence of superficial muscular invasion further confirmed the diagnosis of adenocarcinoma . We believe this was an unequivocal example of demonstrating adenocarcinoma arising in diffuse cystitis glandularis . After a long period of urinary tract infection or stasis, based on our small series, we observed diffuse cystitis glandularis in our first 2 patients who have had neurogenic bladder for more than twenty years . Whereas the other 2 patients with similar conditions for a mere ten years suffered only mild to moderate cystitis glandularis and chronic cystitis with squamous metaplasia . It appeared that the extent of cystitis glandularis correlated with the duration of urinary stasis . Among those 2 patients with diffuse cystitis glandularis, malignant degeneration developed in the one with ureterocutaneostomy, while the other with suprapubic cystostomy showed no evidence of malignancy . A question was raised if this different urinary diversion contributed to the malignant degeneration in the first case . The urinary bladder has been isolated for more than twenty-five years without adequate drainage . Chronic infection developed as a result of urinary stasis . The infection gradually became more severe as evidenced by production of purulent mucus in the bladder . The culture of the mucus yielded a large amount of E . coli and Proteus organisms . Therefore, we assume that the intensity of the

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infection with toxic product and virulence of the organism might have played an important role in the change of pathogenesis of adenocarcinoma in the first case . In conclusion, we believe cystitis glandularis, especially diffuse type, can undergo malignant degeneration if persistently exposed to an extremely unfavorable condition ; and cystitis glandularis progressing to adenocarcinoma is a long-term process as demonstrated by previous as well as present cases . West Third Street Dayton, Ohio 45428 (DR . LIN)

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ACKNOWLEDGMENT . To Charles L Davis, M .D ., Genitourinary Pathology, Armed Forces Institute of Pathology, Washington, DC, for reviewing the slides, and Chung H . Chang, M .D ., for electronmicroscopic assistance . References 1 . hnmergut S, and Cottler 7,R : Mucin-producing adenocarcinoma of the bladder associated with cystitis, follicularis and glandularis, Unit . Cutan . Rev . 54 : 531 (1950) . 2 . Kittredge WE, Collett AJ, and Morgan C, Jr : Adenocarcinoma of the bladder associated with cystitis glandularis : a case report, J . Urnl . 91 : 145 (1964) . 3 . Mostofi FK, Thomson RV, and Dean AL, Jr : Mucous adenocarcinoma of the urinary bladder, Cancer 8 : 741 (1955) . 4 . Wheeler JD . and Hill WT : Adenocarinoma involving the urinary bladder, ibid. 7 : 119 (1954) . 5 . Edwards PD, Hum RA, and Jaeschke WH : Conversion of cystitis glandularis to adenocarcinoma, J . Urol . 108: 568 (,1972) . 6 . Parker C : Cystitis cystica and glandularis : a study of 40 cases, Proc . R. Soc . Med . 63 : 239 (1970) . 7 . Shaw JL. Gislason GJ, and Imbriglia JE : Transition of cystitis glandularis to primary adenocarcinoma of the bladder, J . Urol . 79 : 81 .5 (19.58) . 8 . Susmano D . Ruhenstein AB, Dakin AR, and Lloyd FA : Cystitis glandularis and adenocarcinoma of the bladder, ibid . 105: 671 (1971) . 9 . Davies C, and Castro JE : Cystitis glandularis, Urology 10 : 128 (1977) . 10 . Bell TE. and Wendel RC : Cystitis glandularis : benign or malignant, J . Urol . 100 : 462 (1968) . 11 . Thomas DC, Ward AM, Path MRC, and Williams JL : A study of 52 cases of adenocarcinoma of the bladder, Br . J . Urol . 43 : 4 (1971). 12. Lowry ED, Hamm FC, and Beard DE : Extensive glandular proliferation of the urinary bladder resembling malignant neoplasm, J . Urol. 52 :133 (1944) . 13. Mostofi FK : Potentialities of bladder epithelium . ibid . 71 : 705 (19.54). 14 . Patch FS, and Rhea LJ : Genesis and development of Brunns nests and their relation to cystitis cystica, cystitis glandularis and primary adenocarcinoma of bladder, Canad . Med . Assoc . J . 33 : 597 (1935) . 15 . Emmett JL, and McDonald JR : Proliferation of glands of urinary bladder simulating malignant neoplasm, J . Urol . 48 : 2557 (1942). 16 . Salm R : Neoplasia of the bladder and cystitis cystica, Br . J . Unit. 39 : 67 (1967) . 17, Gyorkcy F . Kriskol MKD, and Cyorkey P : The usefulness of election microscopy in the diagnosis of human tumors . Hum . Pathol. 6 : 421 (1975) .

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