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Irradiation Cystitis: Diagnosis and Treatment
Irradiation Cystitis: Diagnosis and Treatment THOMAS L. POOL
F ACTITIAL cystitis is defined as an artificial or simulated form of inflammation of the bladder. Irradiation cystitis is one form of such cystitis. Such an entity is not common, yet the frequency of occurrence is increasing. The early diagnosis of malignant lesions of the cervix or the uterus is certainly an improvement over the past. The routine smear from the vagina has changed the picture completely. Also, more and more patients are coming to the medical profession for yearly or routine checks of their health and well-being. Such checkups are being urged by the laity as well as the physicians. Early lesions of the cervix or uterus are frequently treated by radium, x-ray therapy, or a combination of such measures. The true incidence of irradiation cystitis will never be known. Some patients become lost, and follow-up examinations become impossible. In some patients, the symptoms of irradiation cystitis are so mild or are so transient that they are never brought to the attention of a physician. In the years 1950 through 1954, 50 female patients who were given a diagnosis of irradiation cystitis were seen in the Section of Urology of the Clinic. To find these patients, the records of 2360 patients with a diagnosis of cystitis were reviewed. Some of the patients with irradiation cystitis had received irradiation therapy at the Clinic, and some had been treated elsewhere. All had had carcinoma of the uterus, cervix or ovary. The agent causing the factitial cystitis is, of course, the irradiation used in such cases. It is not uncommon for the patients to complain of irritation of the rectum as well as of symptoms of the urinary tract. This is to be expected. Every physician using irradiation therapy tries to protect the body as much as possible. Yet, to reach the malignant tissue, the treatment must involve healthy organs also, and they cannot help but react in an untoward manner. It is impossible to say whether one form of treatment or any combination of treatment is more likely than another to initiate a reaction. Certainly, the sensitivity of patients to irradiation must vary greatly. Also, there seems to be no correlation be947
Thomas L. Pool
948
tween the dose administered and the intensity of the reaction. However, after seeing patients treated with irradiation for many years, in my opinion small dosages given over a longer time are less likely to cause a reaction than a larger dosage given over a short period of time. Many authorities on the subject, however, would debate this point. The ages of the patients may vary greatly also. No patient of any age seems immune to such a reaction, and no single age group has a preponderance of reactions. This is a fact to be expected. Of more interest is the lapse of time from the irradiation to the development of reaction in the bladder. In some patients an acute reaction develops almost immediately after treatment. Most of those who have reactions do so within a year. However, a few may be very late in manifesting reaction. One patient seen here at the Clinic had a typical lesion 14 years after treatment. This again emphasizes the individual sensitivity or resistance to the therapy used. PATHOLOGY
The pathologic process has been described by many authors. There appears to be no doubt that the circulation of the bladder is impaired. Yet, an inflammatory process usually is present as well. This may be superficial or may involve the deeper layers of the vesical wall. The inflammation may be transient and later subside, or an endarteritis may develop which later progresses to ischemia. Even later, necrosis or ulceration may develop, followed either by the formation of a fistula or scar. Any part of the bladder may be involved in the pathologic process. When radium has been used, particularly in the cervix or the body of the uterus, the most common site is on the posterior wall in the midline and just back of the interureteric ridge. When a vesicovaginal fistula is present, this ridge is the usual site of the opening in the bladder. In this particular series of 50 patients, 34 had the lesion at the site just mentioned. However, eight had multiple lesions ulcerative in character (Scattered over the mobile portion of the bladder. Another eight had telangiectatic lesions over various portions of the bladder wall. Of interest to us was the fact that of the 50 patients with the diagnosis of irradiation cystitis the lesions of 31 were typical enough so that biopsy was not warranted. Of the 19 from whom a specimen was removed, only one showed evidence of malignant tissue and it was reported to be transitional cell epithelioma, grade 2. All the rest of the specimens removed were reported by the pathologist to contain only inflammatory tissue. Only one biopsy being positive for malignancy is a surprisingly low number. This lesion was electrocoagulated, and a vesicovaginal fistula developed later. The patient subsequently was found to have bilateral hydronephrosis and died 20 years after the irradiation therapy. It is not unusual for a lesion of irradiation cystitis to be ulcerated and
Irradiation Cystitis: Diagnosis and Treatment the center a mass of necrotic tissue. Incrustations by the urinary salts may develop at any time. SYMPTOMS
The symptoms of irradiation cystitis may be mild and persist for only a short time. However, other patients may complain strenuously of severe symptoms such as frequency of urination, dysuria, urgency of urination and pain in the area of the bladder. Thirty of our patients had gross hematuria as the predominant urinary symptoms. Some noted gross hematuria on only one or two occasions. Others suffered gross hematuria over a long period of time. DIAGNOSIS
The diagnosis of irradiation cystitis may be easy or can be most difficult. The history may be helpful. Any patient who has urinary symptoms and a history of irradiation therapy to the uterus or cervix of the uterus should be suspected of having irradiation cystitis. Simple inflammatory cystitis may confuse the cystoscopic picture. Also, interstitial cystitis may make the diagnosis uncertain. Tuberculous cystitis may obscure the correct diagnosis and should always be considered when pyuria exists. Certainly, any type of grossly inflamed vesical mucosa may leave the correct diagnosis uncertain for a time. Moreover, extension of a lesion from an extra-urinary source or a primary lesion of the bladder may have to be excluded. Whenever the diagnosis is the least doubtful, cystoscopy under general anesthesia should be performed and specimens should be removed. In the majority of cases, the diagnosis is so obvious that such a procedure is unnecessary. CYSTOSCOPIC FINDINGS
The earliest cystoscopic finding seen after irradiation therapy is marked edema of the mucosa of the bladder. The mucosa is glistening and white and with a suggestion of free fluid under the vesical mucosa. This process may disappear and leave the mucosa entirely normal, or it may change to hyperemia, with the blood vessels distended over most of the wall of the bladder. Later, this picture may change until only petechial areas are seen, with small blood vessels extending from small reddened centers which mayor may not be ulcerated. Such areas remain unchanged for years. They also may fade gradually, to be succeeded by scarring in the central area of inflammation. The severe and really late cystoscopic finding is an ulcerated lesion with a raised, granulomatous edge and a central area of sloughing. This lesion also may be covered with a variable amount of mucus. Such a lesion may develop any place in the bladder. As a rule, it is found in the midline, just back of the interureteric ridge. However, the base of the bladder or the lateral walls also may contain such a lesion. This is the
Thomas L. Pool
950
pathologic process which must be distinguished from a primary neoplasm or from an extension of an extra-urinary tumor. The mucus and sloughing tissues may be removed with the blunt specimen-forceps, or the heel of a direct-vision cystoscope may be used to scrape the material away, down to the granulation tissue. A sharp specimen taker then may be used to remove material for microscopic examination. This procedure is not without danger, since perforation of the bladder has been known to occur when tissue is taken. Frequently, blood may ooze rather severely from the region from which the specimen is removed for biopsy. This area should not be fulgurated, since loss of the blood supply to this portion of the bladder already has been sustained. Continuous irrigation of the bladder with saline solution or a dilute solution of silver nitrate will be sufficient to manage any such hemorrhage likely to occur. Sometimes this chronic lesion may be covered with incrusted urinary salts. These incrustations must be removed before a satisfactory specimen can be taken for biopsy. Often the patient with such a lesion of the bladder will be benefited, and the hemorrhage will be controlled if, after the specimen has been removed, the area is touched with a 20 per cent solution of silver nitrate. TREATMENT AND RESULTS
Patients who have mild symptoms need no treatment, and most of them fall into this category. Many patients have only transient symptoms and never again complain of the urinary tract. Those patients with superimposed inflammatory processes benefit greatly from the use of modern chemotherapeutic agents and antibiotics plus local therapy, such as lavage of the bladder and the instillation of a 5 per cent solution of a mild silver-protein preparation (Argyrol). The removal of incrustations or sloughing material at the time of cystoscopy also may prove of great benefit as far as alleviation of symptoms is concerned. However, it is our impression that no form of medication or treatment can assure cure of a severe lesion. The primary objective is to keep the bladder as clean as possible and to keep the patient comfortable. Only time will determine whether the blood supply will return sufficiently to allow healing to take place. The necrosis may become worse or a. fistula may develop. If a fistula becomes apparent, attempt at closure is of little benefit and should be withheld as long as possible. A vesicovaginal fistula developing in a patient with irradiation cystitis has been known to heal spontaneously. The end result for such a patient is much better than it would be if some procedure for urinary diversion had been performed. Thirty-one of our 50 patients left the Clinic without receiving treatment to}he urinary tract. Eighteen of these patients have had no further difficulty with the urinary tract to the time of this writing. We have been unable to follow the condition of seven patients. Three patients have had recurring bouts of gross hematuria. A vesicovaginal fistula developed in
Irradiation Cystitis: Diagnosis and Treatment
951
one patient and a rectovaginal fistula developed in another. Another patient has had repeated bouts of infection of the urinary tract. Nineteen patients were treated at the Clinic during one or more visits. Lavage of the bladder and instillation of a 5 per cent solution of a silverprotein preparation constituted the most common form of therapy. Three patients underwent removal of sloughing tissues and incrustations. Several patients received repeated courses of chemotherapy. It is of interest that 12 patients remained symptom free. Three patients have had recurrent bouts of gross hematuria. Vesicovaginal fistulas have developed in two. One patient has had recurring bouts of urinary infection. One patient underwent cutaneous ureterostomy because of obstruction to the ureters. Thirty of 50 patients who had had irradiation cystitis were without symptoms of disease of the urinary tract at the time of this writing. Eighteen were not treated; 12 were treated. COMMENT
The objective in the care of patients with irradiation cystitis is alleviation of the symptoms and maintenance of the bladder in as clean a condition as possible in the hope that the lesions will heal naturally. In view of the serious nature of the original lesions and the treatment necessary to combat these lesions, it is somewhat surprising that more patients do not suffer from irradiation cystitis. Severe complications do occur and are to be expected. The appearance of irradiation cystitis is not the fearful complication once supposed. Gross hematuria for a patient who has had irradiation therapy does not mean the prognosis has become poor. Many such patients survive and have no further urinary symptoms.
F ACTITIAL cystitis is defined as an artificial or simulated form of inflammation of the bladder. Irradiation cystitis is one form of such cystitis. Such an entity is not common, yet the frequency of occurrence is increasing. The early diagnosis of malignant lesions of the cervix or the uterus is certainly an improvement over the past. The routine smear from the vagina has changed the picture completely. Also, more and more patients are coming to the medical profession for yearly or routine checks of their health and well-being. Such checkups are being urged by the laity as well as the physicians. Early lesions of the cervix or uterus are frequently treated by radium, x-ray therapy, or a combination of such measures. The true incidence of irradiation cystitis will never be known. Some patients become lost, and follow-up examinations become impossible. In some patients, the symptoms of irradiation cystitis are so mild or are so transient that they are never brought to the attention of a physician. In the years 1950 through 1954, 50 female patients who were given a diagnosis of irradiation cystitis were seen in the Section of Urology of the Clinic. To find these patients, the records of 2360 patients with a diagnosis of cystitis were reviewed. Some of the patients with irradiation cystitis had received irradiation therapy at the Clinic, and some had been treated elsewhere. All had had carcinoma of the uterus, cervix or ovary. The agent causing the factitial cystitis is, of course, the irradiation used in such cases. It is not uncommon for the patients to complain of irritation of the rectum as well as of symptoms of the urinary tract. This is to be expected. Every physician using irradiation therapy tries to protect the body as much as possible. Yet, to reach the malignant tissue, the treatment must involve healthy organs also, and they cannot help but react in an untoward manner. It is impossible to say whether one form of treatment or any combination of treatment is more likely than another to initiate a reaction. Certainly, the sensitivity of patients to irradiation must vary greatly. Also, there seems to be no correlation be947
Thomas L. Pool
948
tween the dose administered and the intensity of the reaction. However, after seeing patients treated with irradiation for many years, in my opinion small dosages given over a longer time are less likely to cause a reaction than a larger dosage given over a short period of time. Many authorities on the subject, however, would debate this point. The ages of the patients may vary greatly also. No patient of any age seems immune to such a reaction, and no single age group has a preponderance of reactions. This is a fact to be expected. Of more interest is the lapse of time from the irradiation to the development of reaction in the bladder. In some patients an acute reaction develops almost immediately after treatment. Most of those who have reactions do so within a year. However, a few may be very late in manifesting reaction. One patient seen here at the Clinic had a typical lesion 14 years after treatment. This again emphasizes the individual sensitivity or resistance to the therapy used. PATHOLOGY
The pathologic process has been described by many authors. There appears to be no doubt that the circulation of the bladder is impaired. Yet, an inflammatory process usually is present as well. This may be superficial or may involve the deeper layers of the vesical wall. The inflammation may be transient and later subside, or an endarteritis may develop which later progresses to ischemia. Even later, necrosis or ulceration may develop, followed either by the formation of a fistula or scar. Any part of the bladder may be involved in the pathologic process. When radium has been used, particularly in the cervix or the body of the uterus, the most common site is on the posterior wall in the midline and just back of the interureteric ridge. When a vesicovaginal fistula is present, this ridge is the usual site of the opening in the bladder. In this particular series of 50 patients, 34 had the lesion at the site just mentioned. However, eight had multiple lesions ulcerative in character (Scattered over the mobile portion of the bladder. Another eight had telangiectatic lesions over various portions of the bladder wall. Of interest to us was the fact that of the 50 patients with the diagnosis of irradiation cystitis the lesions of 31 were typical enough so that biopsy was not warranted. Of the 19 from whom a specimen was removed, only one showed evidence of malignant tissue and it was reported to be transitional cell epithelioma, grade 2. All the rest of the specimens removed were reported by the pathologist to contain only inflammatory tissue. Only one biopsy being positive for malignancy is a surprisingly low number. This lesion was electrocoagulated, and a vesicovaginal fistula developed later. The patient subsequently was found to have bilateral hydronephrosis and died 20 years after the irradiation therapy. It is not unusual for a lesion of irradiation cystitis to be ulcerated and
Irradiation Cystitis: Diagnosis and Treatment the center a mass of necrotic tissue. Incrustations by the urinary salts may develop at any time. SYMPTOMS
The symptoms of irradiation cystitis may be mild and persist for only a short time. However, other patients may complain strenuously of severe symptoms such as frequency of urination, dysuria, urgency of urination and pain in the area of the bladder. Thirty of our patients had gross hematuria as the predominant urinary symptoms. Some noted gross hematuria on only one or two occasions. Others suffered gross hematuria over a long period of time. DIAGNOSIS
The diagnosis of irradiation cystitis may be easy or can be most difficult. The history may be helpful. Any patient who has urinary symptoms and a history of irradiation therapy to the uterus or cervix of the uterus should be suspected of having irradiation cystitis. Simple inflammatory cystitis may confuse the cystoscopic picture. Also, interstitial cystitis may make the diagnosis uncertain. Tuberculous cystitis may obscure the correct diagnosis and should always be considered when pyuria exists. Certainly, any type of grossly inflamed vesical mucosa may leave the correct diagnosis uncertain for a time. Moreover, extension of a lesion from an extra-urinary source or a primary lesion of the bladder may have to be excluded. Whenever the diagnosis is the least doubtful, cystoscopy under general anesthesia should be performed and specimens should be removed. In the majority of cases, the diagnosis is so obvious that such a procedure is unnecessary. CYSTOSCOPIC FINDINGS
The earliest cystoscopic finding seen after irradiation therapy is marked edema of the mucosa of the bladder. The mucosa is glistening and white and with a suggestion of free fluid under the vesical mucosa. This process may disappear and leave the mucosa entirely normal, or it may change to hyperemia, with the blood vessels distended over most of the wall of the bladder. Later, this picture may change until only petechial areas are seen, with small blood vessels extending from small reddened centers which mayor may not be ulcerated. Such areas remain unchanged for years. They also may fade gradually, to be succeeded by scarring in the central area of inflammation. The severe and really late cystoscopic finding is an ulcerated lesion with a raised, granulomatous edge and a central area of sloughing. This lesion also may be covered with a variable amount of mucus. Such a lesion may develop any place in the bladder. As a rule, it is found in the midline, just back of the interureteric ridge. However, the base of the bladder or the lateral walls also may contain such a lesion. This is the
Thomas L. Pool
950
pathologic process which must be distinguished from a primary neoplasm or from an extension of an extra-urinary tumor. The mucus and sloughing tissues may be removed with the blunt specimen-forceps, or the heel of a direct-vision cystoscope may be used to scrape the material away, down to the granulation tissue. A sharp specimen taker then may be used to remove material for microscopic examination. This procedure is not without danger, since perforation of the bladder has been known to occur when tissue is taken. Frequently, blood may ooze rather severely from the region from which the specimen is removed for biopsy. This area should not be fulgurated, since loss of the blood supply to this portion of the bladder already has been sustained. Continuous irrigation of the bladder with saline solution or a dilute solution of silver nitrate will be sufficient to manage any such hemorrhage likely to occur. Sometimes this chronic lesion may be covered with incrusted urinary salts. These incrustations must be removed before a satisfactory specimen can be taken for biopsy. Often the patient with such a lesion of the bladder will be benefited, and the hemorrhage will be controlled if, after the specimen has been removed, the area is touched with a 20 per cent solution of silver nitrate. TREATMENT AND RESULTS
Patients who have mild symptoms need no treatment, and most of them fall into this category. Many patients have only transient symptoms and never again complain of the urinary tract. Those patients with superimposed inflammatory processes benefit greatly from the use of modern chemotherapeutic agents and antibiotics plus local therapy, such as lavage of the bladder and the instillation of a 5 per cent solution of a mild silver-protein preparation (Argyrol). The removal of incrustations or sloughing material at the time of cystoscopy also may prove of great benefit as far as alleviation of symptoms is concerned. However, it is our impression that no form of medication or treatment can assure cure of a severe lesion. The primary objective is to keep the bladder as clean as possible and to keep the patient comfortable. Only time will determine whether the blood supply will return sufficiently to allow healing to take place. The necrosis may become worse or a. fistula may develop. If a fistula becomes apparent, attempt at closure is of little benefit and should be withheld as long as possible. A vesicovaginal fistula developing in a patient with irradiation cystitis has been known to heal spontaneously. The end result for such a patient is much better than it would be if some procedure for urinary diversion had been performed. Thirty-one of our 50 patients left the Clinic without receiving treatment to}he urinary tract. Eighteen of these patients have had no further difficulty with the urinary tract to the time of this writing. We have been unable to follow the condition of seven patients. Three patients have had recurring bouts of gross hematuria. A vesicovaginal fistula developed in
Irradiation Cystitis: Diagnosis and Treatment
951
one patient and a rectovaginal fistula developed in another. Another patient has had repeated bouts of infection of the urinary tract. Nineteen patients were treated at the Clinic during one or more visits. Lavage of the bladder and instillation of a 5 per cent solution of a silverprotein preparation constituted the most common form of therapy. Three patients underwent removal of sloughing tissues and incrustations. Several patients received repeated courses of chemotherapy. It is of interest that 12 patients remained symptom free. Three patients have had recurrent bouts of gross hematuria. Vesicovaginal fistulas have developed in two. One patient has had recurring bouts of urinary infection. One patient underwent cutaneous ureterostomy because of obstruction to the ureters. Thirty of 50 patients who had had irradiation cystitis were without symptoms of disease of the urinary tract at the time of this writing. Eighteen were not treated; 12 were treated. COMMENT
The objective in the care of patients with irradiation cystitis is alleviation of the symptoms and maintenance of the bladder in as clean a condition as possible in the hope that the lesions will heal naturally. In view of the serious nature of the original lesions and the treatment necessary to combat these lesions, it is somewhat surprising that more patients do not suffer from irradiation cystitis. Severe complications do occur and are to be expected. The appearance of irradiation cystitis is not the fearful complication once supposed. Gross hematuria for a patient who has had irradiation therapy does not mean the prognosis has become poor. Many such patients survive and have no further urinary symptoms.