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Squamous metaplasia and invasive epidermoid carcinoma of bladder
SQUAMOUS
METAPLASIA
EPIDERMOID
AND INVASIVE
CARCINOMA
OF BLADDER
ANN E. WALTS, M.D. STEPHEN A. SACKS, M.D. From the Division of Anatomic Pathology of Urology, Cedars-Sinai Medical Center, Los Angeles, California
and Department
ABSTRACT - Znuasiue epidermoid carcinoma of the urinary bladder is described in a young woman with a long history of bladder infections and extensive squamous metaplasia without atypia. The literature on squamous metaplasia and leukoplakia progressing to epidermoid carcinoma of the bladder is reuiewed, and the confusion between the two terms is explored. Young women with chronic dysuria, bladder infections, and long histories of squamous metaplasia of the bladder should be followed up very closely. Zf epidermoid carcinoma of the bladder develops, they should undergo radical surgery.
Squamous metaplasia is a fairly common lesion associated with inflammatory conditions of the urinary bladder. In menstruating women it is frequently limited to the trigone. The lesion may appear as a white plaque when observed cystoscopically, and the confusing term “leukoplakia” has been used to describe this lesion. Unlike leukoplakia which is considered premalignant, squamous metaplasia is not generally considered premalignant in the absence of squamous cell atypia. This report describes an invasive epidermoid carcinoma of the urinary bladder which occurred in a twenty-nine-year-old woman who had a twenty-year history of bladder infections and extensive squamous metaplasia. We believe this is the youngest patient reported with epidermoid carcinoma in a normally formed bladder. Case Report A twenty-nine-year-old woman was admitted for evaluation of recurrent irritative dysuria, left flank pain, and recurrent urinary tract infections. The patient stated that these infections had occurred since the age of three and that she was told of bladder “leukoplakia” at the age of nine. Bladder biopsies performed within the last
UROLOGY
/
MARCH
1977
/
VOLUME
IX,
NUMBER
3
six years revealed extensive squamous metaplasia without atypia, the most recent biopsy being performed nineteen months prior to her current evaluation (Fig. 1). The past medical history was significant in that a vaginal hysterectomy was performed at the age of twenty-one for epidermoid carcinoma in situ of the uterine cervix. Microinvasion had not been found in the cervical cone, and there was no tumor in the uterus. Rheumatoid arthritis was diagnosed at the age of twenty-two, and a synovectomy of the right wrist and triple arthrodesis of the left ankle were performed. Current medications include indomethacin (Indocin) and prednisone. Gold injections have recently been instituted. The patient has smoked one package of cigarettes per day for the last twelve years but has no history of exposure to known bladder carcinogens. Physical examination revealed a chronically ill young woman in no acute distress. Vital signs were normal. She weighed 45 Kg. and was 157 cm. tall. Examination of the abdomen revealed a large suprapubic mass located slightly to the left of the midline and a second fusiform mass extending to the left lateral pelvic wall. Laboratory evaluation showed a normal complete blood count. Urinalysis showed many
317
The patient underwent an extensive pelvic lymphadenectomy, anterior exenteration, and cutaneous ureteroileal urinary diversion. At operation, tumor was found extending directly into the left obturator fossa. No tumor was visible in the lymph nodes above the level of the aortic bifurcation. All visible tumor was removed. Twenty days after operation she was discharged under the care of an oncologist. Pathologic
*L--
Bladder biopsy nineteen months prior to current evaluation showing squamous metaplasia without atypia; hematoxylin and eosin stain, original magnijication X 300.
FIGURE 1.
white blood cells, epithelial cells, and one plus proteinuria. Urine cultures demonstrated more than 100,000 colonies of Escherichia coli and enterococcus. The serum electrolytes, urea nitrogen, and creatinine were normal. Cystoscopic examination demonstrated a large necrotic tumor that occupied most of the anterosuperior bladder wall. There were no apparent satellite lesions. Retrograde urograms showed encasement of the left distal ureter to the level of the left common iliac artery and lateral deviation of the right ureter. An excretory urogram showed markedly delayed function and severe hydronephrosis of the left kidney. Bimanual examination revealed a 6 by 8-cm. fusiform mass which extended extravesically to the left side of the bony pelvis. Complete metastatic evaluation was negative.
report
The anterior exenteration specimen was received en bloc including the urinary bladder, ovaries, fallopian tubes, cuff of vagina, and urethra. A gray-white granular solid tumor measuring 7 by 5 cm. was present within the dome of the bladder (Fig. 2). The tumor almost filled the bladder lumen and was apparent beneath the The remainder of the peritoneal reflection. bladder mucosa was wrinkled and gray-white and showed no gross lesions. The ureteral orifices were not identifiable. The pelvic organs were displaced by tumor and tumorous adhesions. The left ovary contained metastatic tumor. Tumor was present in most of the lymph nodes removed and in the perivesical soft tissue. The right ovary, fallopian tubes, vaginal cuff, and appendix were free of tumor. The large exophytic keratinizing epidermoid carcinoma deeply infiltrated the bladder wall (Fig. 3A). The tumor showed no transitional cell features. There was extensive squamous metaplasia of the bladder epithelium immediately adjacent to the tumor (Fig. 3B). The entire bladder was lined by squamous epithelium that showed no cellular atypia although it was focally keratinized (Fig. 3C). Transitional epithelium was not identified. Comment
FIGURE 2. GOSS surgical specimen showing large bladder tumor.
318
There is considerable confusion arising from the use of the terms leukoplakia and squamous metaplasia. Koss’ omitted the term “leukoplakia” in his recent review of tumors of the urinary bladder. Although both lesions may appear as white plaques when observed through a cystoscope, a microscopic distinction should be made. Squamous metaplasia describes welldifferentiated, mature stratified squamous epithelium with little or no keratinization. The rete pegs may be prominent and the epithelium may be quite thick. The microscopic appearance may resemble vaginal mucosa, hence the process has been called “vaginal metaplasia.“2
UROLOGY
/
MARCH
1977
/
VOLUME
IX,
NUMBER
3
FIGURE3. (A) Full thickness section of bladder wall showing ulcerated tumor that extends through entire thickness of bladder wall; hematoxylin and eosin stain, original magni;fication X 8. (B) Transistion between tumor and squamous metaplasia of bladder; hematoxylin and eosin stain, original magnijcation X 20. (C) Bladder mucosa removed from tumor showing squamous metaplasia without atypia resembling vaginal mucosa; hematoxylin and eorin stain, original magnijication X 600.
Reasons have been sought to explain the higher incidence of vesical (especially trigonal) squamous metaplasia in menstruating women. The influence of estrogens on squamous metaplasia of the trigone is not clear. Findings which support an estrogenic effect on this cellular alteration include the following: the lesion has not been described in stillbirths, newborns, or children studied at autopsy;3 the lesion has not been seen before menarche;3,4 the lesion is less frequent in postmenopausal women;3 estrogens cause thickening in squamous metaplasia of the epithelium derived from the urogenital sinus;5 and estrogens may produce a squamous metaplasia in the prostatic ducts and trigone of men
UROLOGY
/
MARCH
1977
/
VOLUME
IX,
NUMBER
3
when administered for the treatment of carcinoma of the prostate.1*3 Alternatively, the findings of Johnson6 suggest that squamous metaplasia of the trigone is not changed in menopause and is not affected by exogenous estrogens. The relationship between squamous metaplasia and epidermoid carcinoma of the bladder is a subject of controversy. Widran, Sanchez, and Gruhn4 studied 450 patients with squamous metaplasia of the urinary bladder, 88 per cent of whom were women. The most frequent concurrent lesions were cystitis or urethritis. In that series, every man with squamous metaplasia of the bladder had prostatic disease.4 Vesical car-
319
cinema did not develop in any patient in the study during the period of observation (time not given), although 3 women and 8 men were reported to have coexistent epidermoid carcinoma of the bladder. These authors concluded that squamous metaplasia may coexist with epidermoid carcinoma in the bladder. Surprisingly, they also concluded that squamous metaplasia is not a premalignant lesion in women. Richie et al7 in their review of 33 patients who underwent radical cystectomy for epidermoid carcinoma of the bladder found eight bladders showing squamous metaplasia in areas distant from the tumor and only one bladder showing leukoplakia. In contrast, the malignant potential of atypical squamous metaplasia (leukoplakia) has long been recognized. 8*g The first instance in which leukoplakia was followed until it developed into vesical epidermoid carcinoma was published in 1961.‘O Since then 6 men with similar histories have been reported. ‘l-l3 They were between twenty-three and fifty-three years old at initial diagnosis of leukoplakia. The time interval between the diagnosis of leukoplakia and of carcinoma ranged from five to twenty-one years. Vesical leukoplakia is extremely rare in children. Only two instances of prepuberal males with documented leukoplakia were found in the literature.” One child was well without recurrence eleven years after transurethral resection of a single plaque. Follow-up was not available for the other child. The incidence of carcinoma of the bladder is increasing in the western world. There is an increased incidence of bladder neoplasm in cigarette smokers, in individuals with chronic urinary infections,14 and in Caucasian women with carcinoma of the cervix. l5 The vast majority of bladder carcinomas are transitional cell tumors. In contrast to transitional cell carcinoma of the bladder, epidermoid carcinoma is found more frequently in females (3 : 2).’ A plea for the aggressive surgical management of epidermoid carcinoma of the bladder has recently been made by Richie et al’ who report an over-all five-year survival of 48 per cent after radical surgery. The present patient illustrates the need for very close follow-up of young women with
320
dysuria and chronic urinary infections, especially those with a long history of squamous metaplasia and/or leukoplakia. Squamous metaplasia of the bladder should be regarded as a suspicious lesion in these patients, and follow-up should include periodic bladder cytologic and cystoscopic examinations. Cedars-Sinai Medical Center 8700 Beverly Boulevard Los Angeles, California 90048 (DR. WALTS) References 1. Koss, L.: Tumors of the Urinary Bladder, Washington, D.C., Armed Forces Institute of Pathology, part 11, 2nd series, 1974. 2. HENRY, L., and FOX, M.: Histological findings in pseudomembranous trigonitis, J. Clin. Path. 24: 605 (1971). 3 TYLER, D. E.: Stratified squamous epithelium in the vesical trigone and urethra: findings correlated with the menstrual cycle and age, Am. J. Anat. 111: 319 (1962). 4. WIDFUN, J., SANCHEZ,R., and GRUHN, J.: Squamous metaplasia of the bladder: a study of 450 patients, J. Urol. 112: 479 (1974). 5. STREITZ, J. M.: Squamous epithelium in the female trigone, ibid. 90: 62 (1963). 6. JOHNSON,F. R.: Some proliferative and metaplastic changes in transitional epithelium, Br. J. Urol. 29: 112 (1957). 7. RICHIE, J. P., WAISMAN, J., SKINNER, D. G., and DRETLER, S. P.: Squamous carcinoma of the urinary bladder: treatment by radical cystectomy, J. Ural., in press. 8. F~ABSON,S. M.: Leukoplakia and carcinoma of the urinary bladder: report of a case with a review of the literature, ibid. 35: 321 (1936). 9. CONNERY,D. B.: Leukoplakia of the urinary bladder and its association with carcinoma, ibid. 69: 21 (1953). 10. HOLLEY, P. S., and MELLINGER, G. T.: Leukoplakia of the bladder and carcinoma, ibid. 86: 235 (1961). 11. KELALIS, P. P., EMMETT, J. L., and DEWEERD, J. H.: Leukoplakia of the urinary bladder: report of a case with unusual features, Proc. Mayo Clin. 38: 514 (1963). 12. O'FLYNN, J. D., and MULLANEY, J.: Leukoplakia of the bladder, Br. J. Urol. 39: 461 (1967). 13. IDEM: Vesical leukoplakia progressing to carcinoma, ibid. 46: 31 (1974). 14. SILVERBERG,E., and HOLLEB, A. I.: Cancer Statistics 1974 - worldwide epidemiology, Cancer J. Clin. 24: 11 (1974). 15. NEWELL, G. R., KFUZMENTZ,E. T., and ROBERTS,J. D.: Excess occurrence of cancer of the oral cavity, lung, and bladder following cancer of cervix, Cancer 36: 2155 (1975).
UROLOGY
/
MARCH
1977
/
VOLUME
IX,
NUMBER
3
METAPLASIA
EPIDERMOID
AND INVASIVE
CARCINOMA
OF BLADDER
ANN E. WALTS, M.D. STEPHEN A. SACKS, M.D. From the Division of Anatomic Pathology of Urology, Cedars-Sinai Medical Center, Los Angeles, California
and Department
ABSTRACT - Znuasiue epidermoid carcinoma of the urinary bladder is described in a young woman with a long history of bladder infections and extensive squamous metaplasia without atypia. The literature on squamous metaplasia and leukoplakia progressing to epidermoid carcinoma of the bladder is reuiewed, and the confusion between the two terms is explored. Young women with chronic dysuria, bladder infections, and long histories of squamous metaplasia of the bladder should be followed up very closely. Zf epidermoid carcinoma of the bladder develops, they should undergo radical surgery.
Squamous metaplasia is a fairly common lesion associated with inflammatory conditions of the urinary bladder. In menstruating women it is frequently limited to the trigone. The lesion may appear as a white plaque when observed cystoscopically, and the confusing term “leukoplakia” has been used to describe this lesion. Unlike leukoplakia which is considered premalignant, squamous metaplasia is not generally considered premalignant in the absence of squamous cell atypia. This report describes an invasive epidermoid carcinoma of the urinary bladder which occurred in a twenty-nine-year-old woman who had a twenty-year history of bladder infections and extensive squamous metaplasia. We believe this is the youngest patient reported with epidermoid carcinoma in a normally formed bladder. Case Report A twenty-nine-year-old woman was admitted for evaluation of recurrent irritative dysuria, left flank pain, and recurrent urinary tract infections. The patient stated that these infections had occurred since the age of three and that she was told of bladder “leukoplakia” at the age of nine. Bladder biopsies performed within the last
UROLOGY
/
MARCH
1977
/
VOLUME
IX,
NUMBER
3
six years revealed extensive squamous metaplasia without atypia, the most recent biopsy being performed nineteen months prior to her current evaluation (Fig. 1). The past medical history was significant in that a vaginal hysterectomy was performed at the age of twenty-one for epidermoid carcinoma in situ of the uterine cervix. Microinvasion had not been found in the cervical cone, and there was no tumor in the uterus. Rheumatoid arthritis was diagnosed at the age of twenty-two, and a synovectomy of the right wrist and triple arthrodesis of the left ankle were performed. Current medications include indomethacin (Indocin) and prednisone. Gold injections have recently been instituted. The patient has smoked one package of cigarettes per day for the last twelve years but has no history of exposure to known bladder carcinogens. Physical examination revealed a chronically ill young woman in no acute distress. Vital signs were normal. She weighed 45 Kg. and was 157 cm. tall. Examination of the abdomen revealed a large suprapubic mass located slightly to the left of the midline and a second fusiform mass extending to the left lateral pelvic wall. Laboratory evaluation showed a normal complete blood count. Urinalysis showed many
317
The patient underwent an extensive pelvic lymphadenectomy, anterior exenteration, and cutaneous ureteroileal urinary diversion. At operation, tumor was found extending directly into the left obturator fossa. No tumor was visible in the lymph nodes above the level of the aortic bifurcation. All visible tumor was removed. Twenty days after operation she was discharged under the care of an oncologist. Pathologic
*L--
Bladder biopsy nineteen months prior to current evaluation showing squamous metaplasia without atypia; hematoxylin and eosin stain, original magnijication X 300.
FIGURE 1.
white blood cells, epithelial cells, and one plus proteinuria. Urine cultures demonstrated more than 100,000 colonies of Escherichia coli and enterococcus. The serum electrolytes, urea nitrogen, and creatinine were normal. Cystoscopic examination demonstrated a large necrotic tumor that occupied most of the anterosuperior bladder wall. There were no apparent satellite lesions. Retrograde urograms showed encasement of the left distal ureter to the level of the left common iliac artery and lateral deviation of the right ureter. An excretory urogram showed markedly delayed function and severe hydronephrosis of the left kidney. Bimanual examination revealed a 6 by 8-cm. fusiform mass which extended extravesically to the left side of the bony pelvis. Complete metastatic evaluation was negative.
report
The anterior exenteration specimen was received en bloc including the urinary bladder, ovaries, fallopian tubes, cuff of vagina, and urethra. A gray-white granular solid tumor measuring 7 by 5 cm. was present within the dome of the bladder (Fig. 2). The tumor almost filled the bladder lumen and was apparent beneath the The remainder of the peritoneal reflection. bladder mucosa was wrinkled and gray-white and showed no gross lesions. The ureteral orifices were not identifiable. The pelvic organs were displaced by tumor and tumorous adhesions. The left ovary contained metastatic tumor. Tumor was present in most of the lymph nodes removed and in the perivesical soft tissue. The right ovary, fallopian tubes, vaginal cuff, and appendix were free of tumor. The large exophytic keratinizing epidermoid carcinoma deeply infiltrated the bladder wall (Fig. 3A). The tumor showed no transitional cell features. There was extensive squamous metaplasia of the bladder epithelium immediately adjacent to the tumor (Fig. 3B). The entire bladder was lined by squamous epithelium that showed no cellular atypia although it was focally keratinized (Fig. 3C). Transitional epithelium was not identified. Comment
FIGURE 2. GOSS surgical specimen showing large bladder tumor.
318
There is considerable confusion arising from the use of the terms leukoplakia and squamous metaplasia. Koss’ omitted the term “leukoplakia” in his recent review of tumors of the urinary bladder. Although both lesions may appear as white plaques when observed through a cystoscope, a microscopic distinction should be made. Squamous metaplasia describes welldifferentiated, mature stratified squamous epithelium with little or no keratinization. The rete pegs may be prominent and the epithelium may be quite thick. The microscopic appearance may resemble vaginal mucosa, hence the process has been called “vaginal metaplasia.“2
UROLOGY
/
MARCH
1977
/
VOLUME
IX,
NUMBER
3
FIGURE3. (A) Full thickness section of bladder wall showing ulcerated tumor that extends through entire thickness of bladder wall; hematoxylin and eosin stain, original magni;fication X 8. (B) Transistion between tumor and squamous metaplasia of bladder; hematoxylin and eosin stain, original magnijcation X 20. (C) Bladder mucosa removed from tumor showing squamous metaplasia without atypia resembling vaginal mucosa; hematoxylin and eorin stain, original magnijication X 600.
Reasons have been sought to explain the higher incidence of vesical (especially trigonal) squamous metaplasia in menstruating women. The influence of estrogens on squamous metaplasia of the trigone is not clear. Findings which support an estrogenic effect on this cellular alteration include the following: the lesion has not been described in stillbirths, newborns, or children studied at autopsy;3 the lesion has not been seen before menarche;3,4 the lesion is less frequent in postmenopausal women;3 estrogens cause thickening in squamous metaplasia of the epithelium derived from the urogenital sinus;5 and estrogens may produce a squamous metaplasia in the prostatic ducts and trigone of men
UROLOGY
/
MARCH
1977
/
VOLUME
IX,
NUMBER
3
when administered for the treatment of carcinoma of the prostate.1*3 Alternatively, the findings of Johnson6 suggest that squamous metaplasia of the trigone is not changed in menopause and is not affected by exogenous estrogens. The relationship between squamous metaplasia and epidermoid carcinoma of the bladder is a subject of controversy. Widran, Sanchez, and Gruhn4 studied 450 patients with squamous metaplasia of the urinary bladder, 88 per cent of whom were women. The most frequent concurrent lesions were cystitis or urethritis. In that series, every man with squamous metaplasia of the bladder had prostatic disease.4 Vesical car-
319
cinema did not develop in any patient in the study during the period of observation (time not given), although 3 women and 8 men were reported to have coexistent epidermoid carcinoma of the bladder. These authors concluded that squamous metaplasia may coexist with epidermoid carcinoma in the bladder. Surprisingly, they also concluded that squamous metaplasia is not a premalignant lesion in women. Richie et al7 in their review of 33 patients who underwent radical cystectomy for epidermoid carcinoma of the bladder found eight bladders showing squamous metaplasia in areas distant from the tumor and only one bladder showing leukoplakia. In contrast, the malignant potential of atypical squamous metaplasia (leukoplakia) has long been recognized. 8*g The first instance in which leukoplakia was followed until it developed into vesical epidermoid carcinoma was published in 1961.‘O Since then 6 men with similar histories have been reported. ‘l-l3 They were between twenty-three and fifty-three years old at initial diagnosis of leukoplakia. The time interval between the diagnosis of leukoplakia and of carcinoma ranged from five to twenty-one years. Vesical leukoplakia is extremely rare in children. Only two instances of prepuberal males with documented leukoplakia were found in the literature.” One child was well without recurrence eleven years after transurethral resection of a single plaque. Follow-up was not available for the other child. The incidence of carcinoma of the bladder is increasing in the western world. There is an increased incidence of bladder neoplasm in cigarette smokers, in individuals with chronic urinary infections,14 and in Caucasian women with carcinoma of the cervix. l5 The vast majority of bladder carcinomas are transitional cell tumors. In contrast to transitional cell carcinoma of the bladder, epidermoid carcinoma is found more frequently in females (3 : 2).’ A plea for the aggressive surgical management of epidermoid carcinoma of the bladder has recently been made by Richie et al’ who report an over-all five-year survival of 48 per cent after radical surgery. The present patient illustrates the need for very close follow-up of young women with
320
dysuria and chronic urinary infections, especially those with a long history of squamous metaplasia and/or leukoplakia. Squamous metaplasia of the bladder should be regarded as a suspicious lesion in these patients, and follow-up should include periodic bladder cytologic and cystoscopic examinations. Cedars-Sinai Medical Center 8700 Beverly Boulevard Los Angeles, California 90048 (DR. WALTS) References 1. Koss, L.: Tumors of the Urinary Bladder, Washington, D.C., Armed Forces Institute of Pathology, part 11, 2nd series, 1974. 2. HENRY, L., and FOX, M.: Histological findings in pseudomembranous trigonitis, J. Clin. Path. 24: 605 (1971). 3 TYLER, D. E.: Stratified squamous epithelium in the vesical trigone and urethra: findings correlated with the menstrual cycle and age, Am. J. Anat. 111: 319 (1962). 4. WIDFUN, J., SANCHEZ,R., and GRUHN, J.: Squamous metaplasia of the bladder: a study of 450 patients, J. Urol. 112: 479 (1974). 5. STREITZ, J. M.: Squamous epithelium in the female trigone, ibid. 90: 62 (1963). 6. JOHNSON,F. R.: Some proliferative and metaplastic changes in transitional epithelium, Br. J. Urol. 29: 112 (1957). 7. RICHIE, J. P., WAISMAN, J., SKINNER, D. G., and DRETLER, S. P.: Squamous carcinoma of the urinary bladder: treatment by radical cystectomy, J. Ural., in press. 8. F~ABSON,S. M.: Leukoplakia and carcinoma of the urinary bladder: report of a case with a review of the literature, ibid. 35: 321 (1936). 9. CONNERY,D. B.: Leukoplakia of the urinary bladder and its association with carcinoma, ibid. 69: 21 (1953). 10. HOLLEY, P. S., and MELLINGER, G. T.: Leukoplakia of the bladder and carcinoma, ibid. 86: 235 (1961). 11. KELALIS, P. P., EMMETT, J. L., and DEWEERD, J. H.: Leukoplakia of the urinary bladder: report of a case with unusual features, Proc. Mayo Clin. 38: 514 (1963). 12. O'FLYNN, J. D., and MULLANEY, J.: Leukoplakia of the bladder, Br. J. Urol. 39: 461 (1967). 13. IDEM: Vesical leukoplakia progressing to carcinoma, ibid. 46: 31 (1974). 14. SILVERBERG,E., and HOLLEB, A. I.: Cancer Statistics 1974 - worldwide epidemiology, Cancer J. Clin. 24: 11 (1974). 15. NEWELL, G. R., KFUZMENTZ,E. T., and ROBERTS,J. D.: Excess occurrence of cancer of the oral cavity, lung, and bladder following cancer of cervix, Cancer 36: 2155 (1975).
UROLOGY
/
MARCH
1977
/
VOLUME
IX,
NUMBER
3