The Ureteral and Renal Complications of Carcinoma of the Cervix

THE URETERAL AND RENAL COMPLICATIONS OF CARCINOMA OF THE CERVIX A

STUDY OF

257

CASES 1

ROGER C. GRAVES, C. J.E. KICKHAM

AND

IRA T. NATHANSON2

From the Urological and Gynecological Clinics of the Pondville Hospital (Massachusetts Department of Public Health)

Our observations during the past several years in a hospital devoted entirely to the care of cancer patients, have convinced us that far too little attention has been given to the pathological changes that commonly occur in the upper urinary tract, in cases of carcinoma of the cervix, as a direct result of the disease, or as a complication of its treatment. Ewing states that "The natural termination of most cases of uterine cancer is through uremia from occlusion of the ureters." Warren has said that impairment of renal function due to ureteral obstruction is the most common cause of death in this disease. There have been many references to the subject since the middle of the last century but there have been surprisingly few comprehensive discussions in recent gynecological and urological literature. In 1868 Wagner wrote that onethird of his cases showed marked ureteral involvement at post-mortem examination. Williams in 1895 in a serie·s of 78 autopsy studies, reported an incidence of hydro-ureter or hydronephrosis of 85.9 per cent. An excellent recent contribution by Faerber states that in a series of 150 post-mortem examinations the ureters had been affected in 56 per cent of the cases; obstructive renal changes were encountered in 72 per cent. Behney in a post-mortem study of 166 cases reported that ureteral dilatation was found in 65 per cent and that occlusion sufficient to cause death was present in 21 per cent of the cases. Herger and Schreiner in a clinical study of SO cases of carcinoma of the cervix, demonstrated dilatation of the ureters and hydronephrosis in 48 per cent of the group. Drexler and Howes in a clinical-pathological investigation of patients with broad ligament extension, reported that hydronephrosis was found on cystoscopic examination in 68 per cent of their cases. Thirty-seven cases of uterine cancer were discussed by Colby in 1933. He wrote that intravenous urograms revealed ureteral 1 Read before the annual meeting of the American Urological Association, Boston, Mass., May 19, 1936. 2 Lucius N. Littauer Fellow in Cancer, Harvard University Medical School. 618

COMPLICATIONS OF CARCINOMA OF CERVIX

619

obstruction, partial or complete, in 35.1 per cent of this group. Schmitz, Everett, Hufnagel, and others, have made similar contributions to this subject and excellent work, both clinical and experimental, has been presented by Martin and Rogers. In assembling our material for this discussion we have reviewed through the courtesy of Dr. J. V. Meigs, Chief of the Gynecological Service, six hundred cases of carcinoma of the cervix that have been admitted to the Pondville Hospital, from June 1, 1927, to June 1, 1935. In the earlier days of the hospital, before our attention was directed to the phenomena under consideration, many patients were received who were in the late stages of the disease and many of the records were incomplete. There were also patients who returned home after treatment or who later entered other institutions, and while they were darefully followed in every instance, and the end-results are known, complete data are not available. We have selected, therefore, 257 cases which have been sufficiently well studied to form a satisfactory basis for this investigation. In this group there were 87 post-mortem examinations; 92 of the more recent cases were subjected to the urological study which is now routine at Pondville in malignant disease of the cervix; the remainder had records complete enough to warrant their inclusion in this series. Of the 257 patients, 7 were between 20 and 29 years of age; 43 between 30 and 39; 88 between 40 and 49; 59 between 50 and 59; 43 between 60 and 69; and 17 between 70 and 80. Thus it will be seen that the greatest number were in the middle-age group. All but 13 had cervix cancer, proved by biopsy examination; these 13 cases had been treated elsewhere before coming to the Pondville Hospital, and all had undoubted clinical diagnoses of carcinoma in our clinic. (In each instance a pathological examination had been made but the exact report could not be obtained.) Two hundred and thirty had epidermoid carcinoma, and grading them as to the degree of malignancy from I to III, the greater number were Grades II and III. There were 14 cases of adeno-carcinoma. In classifying the cases with reference to the extent of malignant disease, we have employed, for purposes of simplification, the method of the American College of Surgeons, without the more detailed subdivisions which have no important significance in this discussion. There were 5 cases in Group A, that is, in which the carcinoma was confined to the cervix. There were 11 in Group B, in which there is involvement also of the uterine cavity or vaginal wall. Group C includes those patients who have disease extending into the broad ligaments; there were 81 of THE JOURNAL OF UROLOGY, VOL.

36,

NO,

6

620

R. C. GRAVES, C.

J.

E. KICKHAM AND I. T. NATHANSON

these. One hundred sixty cases were in Group D, with wide pelvic fixation and in some instances, remote metastases. Attention should be called to the fact that the grouping of cervix cancer cases on the basis of extent of disease, while clinically useful, is subject to error as itis often impossible to differentiate accurately between the purely neoplastic changes in the pelvis and the inflammatory processes which may be associated with the tumor. It is also true as we have emphasized in a previous paper, that cases which have been, classified as B on pelvic examination, have been found in some instances to belong in the D group, because of bladder extension disclosed only by cystoscopy. A review of the entire series of 257 cases from a purely clinical point of view, gives basis for certain observations which we hope to substantiate with the more accurate information obtained from the smaller groups which were subjected to urological study or post-mortem examination. As has been stated, many of the records were made before attention had been directed to the high incidence of ureteral occlusion. An analysis of symptomatology, therefore, is often difficult and unsatisfactory. It is probable that in history taking specific questions bearing upon this subject were not asked in many instances. We find that 22 patients complained definitely of renal or ureteral pain ; only 10 were reported as presenting uremic symptoms at the time of admission. Uremia is a toxemia; it may be mild or severe, and it may vary in its manifestations as may any toxemia. It is especially difficult to interpret case histories with reference to purely subjective symptoms which may or may not have been regarded as significant at the time, but which may have been indicative of some degree of renal insufficiency. Such disturbances as headache, nausea, vomiting, drowsiness, and visual changes were noted in 106 cases. One hundred and seventy-nine patients reported none of these before treatment; 22 presented such symptoms prior to cervix therapy, and all of these with one exception, showed progressive disturbances of this type after treatment. Sixty-two of those who had no such symptoms before treatment developed them at some time after the completion of their therapeutic program. There is no dependable record of symptomatology in 49 cases. There was renal tenderness reported in 22 cases. Palpable enlargement of a kidney was noted in 19 cases. Oliguria which is a highly important sign when present, or anuria, occurred in 12 cases. One hundred thirty-nine patients had blood-chemistry estimations of total non-protein nitrogen retention with the following results: Fifty-eight

COMPLICATIONS OF CARCINOMA OF CERVIX

621

gave readings below 40 mgm. per 100 cc. In 81 the figures were above this level. Of the latter group, 24 had normal readings at the time of admission to the hospital, thus evidencing a progression of deteriorative renal changes during the course of their disease. In 1 case, for example, the level of blood N.P.N. rose from 33 to 250 mgm. per 100 cc. in the period of hospitalization, which was 23 days. The routine 2-hour test of renal function with phenolsulphonphthalein was carried out in 68 cases. The excretion was below 20 per cent in 12 cases, and actually O in 4; between 20 and 40 per cent in 32 cases, and above 40 per cent in 24 cases; 6 patients with initial excretion of 40 per cent or more dropped to below 20 per cent while under observation. While it is recognized that this test is subject to wide variations, even under normal conditions, it is of the greatest significance when properly carried out, as will be emphasized in our later discussion of this subject. Ninety-two patients, most of them more recent cases, were subjected to some form of definite urological investigation. There were 67 cystoscopic examinations, in practically all of which ureteral catheterization was accomplished or attempted; retrograde pyelograms were made in 32 cases; intravenous pyelography was employed in 40 cases, in some instances in conjunction with cystoscopic study. The intravenous method was especially useful in those cases in which ureter catheterization proved impossible. Ureteral narrowing evidenced by obstruction, varying from slight to complete, to the passage of a ureter catheter size 5 French, was encountered in 25 cases, or 37.3 per cent of the 67 patients studied by cystoscopy. In this group of 25 cases, the obstruction was unilateral in 16, and bilateral in 9. When ureter catheterization proved entirely impossible, there was usually distortion or upward elevation of the trigone and posterior bladder wall, trigonitis, trigonal edema, or actual tumor invasion in this region. Obstruction within the ureter was met usually at a point 4 to 6 cm. above the orifice, and in the cases where it was pos-sible to pass the catheter even for this distance, pathological changes around the ureteral openings were usually lacking. In these cystoscopic examinations, and in many other bladder inspections which are not included, vesical lesions resulting from the local spread of disease or from cervix irradiation were observed, and occasional vesico-vaginal fi.stulae, but these are purposely excluded from this discussion. Intravenous indigocarmin was used in difficult cases as an aid in finding the ureteral orifices, and as an index of renal function in those cases in which obstruction in the ureter was encountered. Where catheterization proved

_

........

-

622

-

: ..:. . L . ~

R. C. GRAVES, C.

J. E. KICKHAM AND

I. T. NATHANSON

possible, intravenous phenolsulphonphthalein was employed more often for the study of kidney function . Retrograde pyelography in 32 cases found 26 patients, or 81.3 per cent, with ureteral or renal pelvis dilatation, varying from slight enlargement

FrG. 1. Photograph of pyelograms in case of woman, aged 49, with anterior vaginal wall involvement and extension into the broad ligament areas from carcinoma of the cervix. Note early ureteral dilatation on one side and well marked hydroureter and hydronephrosis on the other.

to advanced hydronephrosis and hydroureter. Seventeen showed unilateral dilatation, and 9 bilateral. It is important to note that in many instances in which there was no obstruction to the passage of the ureter catheter, definite dilatation was revealed by pyelography. This

623

COMPLICATIONS OF CARCINOMA OF CERVIX

was found to be true in 11 of the 42 apparently normal catheterizations, and the incidence of dilatation may have been higher, as pyelograms were were not made in all cases. It is obvious, therefore, that the ready passage of the ureteral catheter does not prove the absence of ureteral obstruction (fig. 1) . TABLE

1.-Illustrating the necessity of doing complete urological studies on these patients OBSTRUCTION

TOTAL

NUMBER

Unilateral

Cystoscopy .. ............ . .... . . .. . . . . . Intravenous pyelogram ...... . .. . . . . ... . . Retrograde pyelogram .... .. . ..... . ..... . Autopsy findings .. . . .. ....... . . . . .. . .. . TABLE

67 40 32 87

PER CENT OBSTRUCTION

NORMAL

Bilateral

---

---

9 9 9 46

37.3 77 .5 81.3 79.3

16 22 17 23

42 9 6 18

2.-Showing findings of first examination in relation to time examined and necessity of studies before treatment is instituted NORMAL

EXAMINATIONS

Before treatment

Cystoscopy . .................. Retrograde pyelogram ... . ..... Intravenous pyelogram .. . . . . .. TABLE

26 12 12

After treatment

--

Before treatment --

40 20 28

18 3 3

INVOLVEMENT

After treatrnent

Before treatment

23 3 6

8 9 9

-- --

PER CENT INVOLVEMENT

After treatment

Before treatment

17 17 22

30.8 75.0 75.0

-- --

After treatment

-42.5 85.0 78.5

3.-Relation of urological findings to activity of disease

STAGE OF DISEASE

UROGRAPHS

CYSTOSCOPY

Active ... . ...... ... ... .... .... . .. . Quiescent ..... .... . . . . ... .. .. . . ... . Cured ....... . . . .............. .. .. .

34 15 1

18 7 0

1

Active .. .. ... . . . . . . . .. . ..... . .. . Quiescent. ...... . ...... .. . . ... . . . . . Cured ..... . . ..... . . .... . ... ...... .

11

28

3

11

1

3

)

Total procedures . . .... . . . . .. .. .

65

67

j

Positive findings

Negative findings

Intravenous urograms in 40 cases, showed dilatation or complete absence of excretion in 31, or 77.5 per cent. The changes were bilateral in 9, and unilateral in 22 . Failure of the dye to appear on one side or the other may be accepted as evidence of practically complete cessation of kidney function, as we have found by comparison with other clinical tests

624

R. C. GRAVES, C.

J.

E. KICKHAM AND I. T. NATHANSON

of renal activity in such cases, by observation of surgical material and by post-mortem study. (See table 1.) The incidence of ureteral occlusion in patients seen prior to cervix treatment, and the incidence found in those who were first examined after such treatment, is shown in the table devoted to this subject. (See table 2.) We attempted also to correlate the occurrence of ureteralobstruction and the degree of activity of the malignant process in the cervix and adnexa. Sixty-five patients were studied by retrograde or intravenous pyelography, or both. Fifty of these showed positive signs of dilatation of the ureter, and of this group, 34 were described as having active carcinoma; 15 were called quiescent, and 1 was reported as cured. The remaining 15 who had negative pyelographic findings, had active cervix disease in 11 cases; 3 were quiescent, and 1 cured. (See table 3.) There were 67 cystoscopies, and in these the evidence of ureteral obstruction found by catheterization alone was positive in 25 cases. Eighteen of these had active disease in the cervix; 7 were quiescent. In 42 cases the ureters admitted catheters readily; 28 had active disease; 11 were quiescent, and 3 were cured. There were 87 post-mortem examinations. Hydronephrosis due to ureteral occlusion by malignant disease was found in 69 cases, or 79.3 per cent. The obstruction was unilateral in 23 cases, and bilateral in 46 cases. Thirty-four of these 69 patients had pyelonephritis in addition to their purely obstructive changes, unilateral in 11 cases, and bilateral in 23. Ten of the autopsied cases had had no cervix treatment. Five of the post-mortem series had had urological investigation before death, and in every instance the conditions found were in exact accord with the clinical findings. There were 174 cases studied by urological investigation, or by postmortem examination, or both. One hundred twenty-three, or 70.7 per cent, showed positive signs of ureteral obstruction. Forty-six of these were classified as carcinoma of the cervix, Class C; 77 were D cases. It is obvious, therefore, as one would expect, that the more extensive the disease in the pelvis, the higher the incidence of interference with ureteral drainage. (The occurrence of unilateral and bilateral ureter involvement is shown in table 4.) Of the 51 negative cases, 27 were in Class C, and 24 in Class D. Of the entire group, 193 have died. In 69 of 87 post-mortem examinations, there was kidney damage sufficiently marked to have produced

625

COMPLICATIONS OF CARCINOMA OF CERVIX

definite renal insufficiency. There were 85 patients who died at Pondville and who were not subjected to autopsy study. Of these, 32 had had clinical and laboratory evidence of uremia, and 24 others had had suggestive uremic symptoms without, for one reason or another, complete laboratory proof of this condition. It is an interesting comment on the general lack of realization of the renal changes that so commonly accompany advanced carcinoma of the cervix, that death certificates in the 20 cases in which death occurred outside the hospital, failed in any instance to record uremia as a contributing factor in the final result, though their hospital records had shown definite signs of urinary tract involvement. Discussion. It is obvious from a review of the foregoing material that ureteral occlusion occurs commonly in carcinoma of the cervix, especially in those cases in which the disease has extended beyond the TABLE

4.-Relation of extent of obstruction to clinical classification of disease, showing as to be expected, more involvement in the Class D cases CYSTOSCOPY

RETROGRADE PYELOGRAPHY

INTRA VENOUS PYELOGRAPRY

AUTOPSY

OPERATION

UniUniBiUniBiUniBiBiUniBilateral lateral lateral lateral lateral lateral lateral lateral lateral lateral

ClassC ................... ClassD ...................

13 3

-- -- -2 2 10 7 12 7

-- -- -- -- -- -12 5

7 3

5

9

18

37

0 0

0 1

limits of the cervix itself. It becomes of the utmost importance, then, to consider the early recognition of this complication and its clinical management when such obstructive changes have occurred. We believe that all cases of malignant disease of the cervix should be subjected to complete urological investigation when first seen, and before treatment is instituted. Thus, obstruction of the ureter with its attendant deteriorative changes in the upper urinary tract, will be detected as promptly as possible, while in those early, Group A, cases of cervix disease in which the first urological study may be negative, a base-line of information will be afforded for later comparisons as the case progresses. Surely the neglect of this investigation may result, as we have shown, in needless suffering for the patient in many instances, and in uremia which will spell defeat for the surgeon, quite apart from the effectiveness of his treatment of the malignant lesion. Complete study first includes of course, a decision as to the exact

626

R. C. GRAVES, C.

J.

E. KICKHAM AND I. T. NATHANSON

nature and extent of the process in the cervix. The latter program of therapy as regards the urinary organs will be influenced primarily by this information. One must have sound reasons for surgery in the patient hopelessly afflicted with advanced carcinoma! Urological investigation begins with complete physical examination and a careful questioning of the patient to detect those symptoms which may signal the development of ureteral occlusion with resulting renal impairment. As we have learned from our own early records, a specific questionnaire in historytaking must be insisted upon. It is important not to be led astray by the absence of renal pain and tenderness, for, as has been emphasized by Graves and Militzer of this clinic, advanced kidney damage may occur without such local signs and symptoms. The silent death of a kidney is by no means uncommon. It has also been our observation, that renal insufficiency is earliest and best detected by . the function test with phthalein, and not by estimations of blood-chemistry. The level of TABLE

S.- Necropsy findings.

Showing frequency of bladder and ureteral involvement

Negative. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bladder alone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ureters alone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ureters and bladder .... .... . .. . . .... . . . . . ... ... . . .... .. ... . . . .. . . . . ...... . . .. ..

12 13 16 52

Total ...... . .... . . .... .. ..... . ...... . ... .. . ...... . ..... . . ... . ...... . ....... . 93

blood nitrogen may remain within normal limits until late stages of destruction have been reached, as we have stated in the earlier communication above noted; Colby, also, has called attention to this phenomenon. Blood-nitrogen determinations should always be considered in conjunction with the percentage excretion of 'phthalein and it is ominous indeed when the latter is low or absent, and the former elevated. The next and most informing step in urological study begins with cystoscopy. The routine inspection of the bladder (and urethra) will detect local invasion by new growth, fistulae, and late radium reactions, with which we are not concerned in this discussion. While distortion of the normal bladder contour, especially in the region of the trigone and posterior wall, from extra-vesical pressure or actual extension of disease, is encountered almost uniformly in the more advanced cases, a negative bladder picture does not exclude the possibility of ureteral obstruction at a higher level. The orifices of the ureters may or may not present an abnormal appearance; they are often normal even in the presence of

COMPLICATIONS OF CARCINOMA OF CERVIX

627

occlusion above. (See table 5.) When abnormal, the most common change is edema on the obstructed side. Ureteral catheterization, therefore, becomes imperative as a routine in these cases. Resistance to the catheter when encountered is found usually at a point 4 to 6 cm. above the bladder. The obstruction may vary in degree from complete occlusion to lesser grades of narrowing which will still permit the passage of small catheters. It must be emphasized, however, that easy catheterization with a catheter of ordinary size does not preclude, as we have often observed, the possibility of sufficient stenosis to produce definite obstructive changes in the ureter and renal pelvis. The picture is never complete without visualization by the x-ray studies which should follow. When ureteral catheterization has been accomplished, the separate urine specimens should be examined microscopically and by culture, for the fate of the obstructed kidney is affected materially by the presence of infection. The divided test of renal function should follow. Phenolsulphonphthalein given intravenously is usually employed for this purpose; indigocarmin is used in those cases in which the ureters are difficult to find or in which catheters cannot be passed. The retrograde pyelogram completes the cystoscopic study of which it is the vital part, for it depicts better than in any other way, the varying degrees of hydronephrosis and hydrometer which result from lower ureteral occlusion. Intravenous urograms are of the greatest value in those cases in which the condition of the patient will not permit complete cystoscopic investigation, and in those cases in which catheterization of the ureters cannot be accomplished, but the information obtained in this manner is less accurate as regards obstructive changes than that afforded by retrograde pyelography. We have seen repeatedly patients with relatively normal intravenous pyelograms, who were found to show definite obstructive uropathy by the retrograde method. When it is necessary to depend upon the intravenous technique, the evidence which it gives concerning renal function is well understood and should not be overlooked. It might be stated at this time that the reason for the average level of ureteral occlusion at a point 4 to 6 cm. above the orifice in the bladder, lies in the anatomical position of the ureter at this level beneath the broad ligament and close to the cervix. Attention may be called to the fact, which is pertinent to this whole discussion, that the vesico-uterine pouch of peritoneum reaches to the level of the internal os, and that

628

R. C. GRAVES, C.

J.

E. KICKHAM AND I. T. NATHANSON

FIG. 2. Photomicrograph showing tumor in ureteral ,val!. of plicae, and invasion of ureter by infiltrating carcinoma.

FIG. 3. Photomicrograph. carcinoma.

Note narrowing of lumen, loss

Complete obliteration of lumen of ureter by ingrowth of

COMPLICATIONS OF CARCINOMA OF CERVIX

629

FrG. 4. Photomicrograph showing compression of lumen of ureter by surrounding tumor.

In this section there is shown fibrosis of ureteral wall, but no actual invasion by carcinoma.

630

R. C. GRAVES, C.

J.

E. KICKHAM AND I. T. NATHANSON

"below this level the bladder is attached by connective tissue to the front of the cervix and the upper part of the anterior wall of the vagina." Further, according to Piersol, "On the pelvic floor the ureter enters the base of the broad ligament, within which duplicature it is crossed by the uterine artery, passes between the veins of the vesicovaginal plexus, and continues downward and forward in the vicinity of the uterine cervix to the vagina; its terminal segment lies embedded within the connective tissue between the cervix and bladder close to the anterior vaginal wall for a distance of from 1 to 1.5 cm., where, bending somewhat inward, it reaches the posterior vesical wall." It is perhaps obvious, but nevertheless worthy of comment, that the proximity of the distal end of the ureter to the anterior wall of the vagina makes possible ureteral involvement at even this lower level when vaginal extension of disease has occurred. We believe that the cause of ureteral obstruction is found in most instances in the encroaching tumor itself. There may be first a constricting effect from edema or inflammation adjacent to the growth, but as malignant disease advances in the paracervical or parametrial region, there follows actual compression of the ureter or direct invasion of its wall, or lumen, (figs. 2, 3, 4). While there is no basis of proof for the assertion, it is our impression based upon definite clinical experiences, that edema following irradiation also may be a factor in some cases by precipitating complete obstruction where marked partial occlusion already has taken place. We have seen anuria develop so soon after treatment that there seemed no other reasonable explanation for its occurrence. Further, it is probable that in patients who are quiescent or cured as regards malignancy, ureteral stenosis may be the result of fibrosis alone, from infection or as replacement fibrosis following the regression of tumor in that region. The fact that the ready passage of a catheter does not always exclude obstruction and dilatation of the ureter, as we have stated, is not difficult to explain. An instrument may pass easily through an area of edema or soft compression by tumor, though the persistent presence of these changes will produce sufficient stenosis and interference with normal peristalsis to result inevitably in hydrometer and hydronephrosis. As regards the treatment of ureteral occlusion in carcinoma of the cervix, it may be said that the urologist is blessed with both good fortune and added responsibility in that there may be more than one solution available for the problem at hand. The procedure adopted must be

COMPLICATIONS OF CARCINOMA OF CERVIX

631

selected always with a view to the needs of the individual case, for no two are quite alike, although the underlying disease and the ureteral obstruction may be essentially the same. One may use for the relief of these patients, simple dilatation with a ureteral catheter at cystoscopy, nephrostomy, ureterostomy, and nephrectomy. Uretero-intestinal anastomosis for permanent diversion of the urinary stream is not suitable in most instances for these cases. It involves more hazardous surgery than the patient should be subjected to; the obstructed kidney has suffered too great damage, usually, to withstand well the added infection that may occur with intestinal transplantation, and extensive changes in the pelvis, whether neoplastic or fibrotic, do not provide a favorable field for this procedure. Ureteral dilatation is the simplest method to be employed and it should be used first always when the passage of a catheter is possible, and when the condition of the patient warrants this conservative program. The catheter is sometimes withdrawn promptly and sometimes left in situ for drainage for a brief period. In cases of early obstruction, and where radiation edema alone, perhaps transient, may produce the occlusion, this method may suffice for the relief of symptoms and thus avoid the interruption of active cervix treatment. The greatest and most long-standing benefits with simple dilatation will be obtained as a rule in the lesser degrees of obstruction and especially those due to fibrosis. We do not believe that ureteral dilatation is of lasting benefit when the narrowing of the ureter is produced by the pressure or invasion of actual tumor. Indeed, in such circumstances, there may be definite danger in catheterization in that complete obstruction may be precipitated or, as in one of our own cases, hemorrhage may follow . Finally, with reference to simple dilatation, there are certain fundamental considerations to be borne in mind in evaluating this method. A ureter which has lost its tone and contractility through stenosis of long duration and often also through infection, cannot be expected to resume normal urinary drainage after the mere passage of an instrument through its obstructed portion, especially when the obstruction is produced by a progressive disease. In these cases also, we may be confronted with the occlusion of a definite segment of the ureter, of considerable extent, and as compared with the simple inflammatory stricture encountered in ordinary practice, the disturbance of normal physiology and the degree of interference with ureteral peristalsis will be vastly different and more lasting.

632

R. C. GRAVES, C.

J.

E . KICKHAM AND I. T. NATHANSON

Nephrostomy is a palliative procedure which may be performed to meet an emergency, or which may be an operation of election. Its indications are: the pain of ureteral and renal pelvis distention, unrelieved by simpler measures; sepsis within the obstructed kidney ; the signs of advancing uremia with oliguria or anuria from extreme ureteral occlusion. Its performance is justified often, even in the presence of extensive malignant disease, to relieve the patient of pain and the distressing symptoms which accompany the advanced uremic state. Nephrostomy, either unilateral or bilateral, is the emergency operation of choice to meet the urgent conditions arising from marked or complete ureteral obstruction. It may be performed with safety and without measurable shock even in those patients who are profoundly sick, and its results in palliation are often dramatic. Regional and local anesthesia suffice and are used routinely in our clinic in all these cases in which the conditions present preclude the possibility of extensive surgery and the other forms of anesthesia. Pain has just been mentioned as one of the indications for nephrostomy; it perhaps merits further discussion. In character and location it may be typically renal or ureteral, but in some instances pain is so low, encircling the hip on the affected side, that there is doubt as to its origin and one questions whether it arises in the urinary tract or in the diseaseinvaded structures of the pelvis. Martin and Rogers in discussing broad ligament extension in carcinoma of the cervix, have stated that : "The most distressing symptom encountered is a constant aching pain located deep in the groin and radiating down to the thigh, laterally to the hip, posteriorly to the sacro-iliac and upwards to the costovertebral angle. It may occur on one or both sides and is, we believe, in almost every instance due to partial or complete stricture of one or both ureters resulting from lateral malignant extension into the broad ligament areas." Obviously the proof of the ureteral origin of pain in a given case requires careful urological investigation before measures of relief are undertaken, and if such cause is excluded the aid of the neuro-surgeon should be enlisted. Attention should be called perhaps to the fact that the ultimate recovery of a kidney and its resumption of function following nephrostomy depend in large measure on the duration of its obstruction. Infection, also, is probably a factor of importance in this regard, together with the degree of stenosis in the ureter. In two of our patients who had emergency bilateral nephrostomies because of complete obstruction and marked uremia, there was no return of function on one side, and nephrec-

COMPLICATIONS OF CARCINOMA OF CERVIX

633

tomies were performed at later dates to remove these chronic sources of infection and fever. As yet we have no data as to the length of time that a kidney may remain obstructed under these conditions and still resume activity when urinary drainage has been afforded. Ureterostomy to the flank or iliac region offers complete and permanent diversion of the urinary stream, while with nephrostomy there is at least a chance that normal channels may be reestablished at some later time. It may be resorted to in those cases in which the condition of the patient will permit this operation and its necessary anesthesia, and in which there is sufficient expectancy of life to warrant it; and when there is no thought of the eventual restoration of normal ureteral drainage. It is our feeling that ureterostomy will be employed much less frequently than nephrostomy in carcinoma of the cervix. In fact, in many instances, the upward spread of malignant disease from the pelvis will seriously interfere with its comfortable and satisfactory performance. Nephrectomy is not indicated often in these cases. In our series it has been performed in two cases only. Fundamentally the removal of a kidney is advised when it is the source of symptoms which have not been relieved by the other simpler measures we have described. Persistent pain or chills and fever emanating from an active pyelonephritis finally may justify nephrectomy. As has been emphasized, however, nephrostomy should be resorted to first in most instances because it is simpler, less hazardous, and holds some hope at least, of eventual restoration of function if normal ureteral drainage can be reestablished at some later date. Moreover, if the organ has eventually to be sacrificed, the value of a preliminary operation for drainage in preparation for nephrectomy is well understood. It is obvious in all these considerations, that one is influenced by the general condition of the patient, the extent and activity of the cervix disease, the probable expectancy of life, and the facts and prognosis with reference to the other kidney. In a cured case for example, with one normal kidney to depend upon, a primary nephrectomy might well be the procedure of choice. Finally, and in closing, a few illustrative case reports are briefly presented. They have been selected because each exemplifies some particular phase of the problem under discussion. Case 1. Pondville Hospital No. 4687. An American house-wife, aged 34, entered the hospital on June 8, 1932, complaining of irregular vaginal bleeding of one-year's duration. The diagnosis was epidermoid carcinoma of the cer~ vix, Grade II, Class 1 C (A.C.S.). During a stay of one month in the hospital,

634

R. C. GRAVES, C.

J.

E. KICKHAM AND I. T. NATHANSON

treatment was given as follows: 1500 R. units of deep x-ray therapy anteriorly over the pelvis and the same posteriorly, through 20 x 20 cm. portals, by divided dosage technique. This was followed by two applications of intracervical gamma radiation of 1500 millicurie hours each, with a 4-day interval. Observation was continued in the Out-Patient Department until January 1933, at which time she again entered the hospital. Treatment: 1200 R. units each to the left and right pelvis anteriorly, and to the left and right side posteriorly through 6 x 8 cm. portals. Out-Patient observation was then resumed. In April 1935, pelvic examination found evidence of extensive fibrosis but no sign of active malignant disease. However, because of the broad ligament fixation the patient was referred to the Urological Clinic for ureteral investigation. There were no symptoms referable to the urinary tract, and she felt well. There had been a gain of 15 pounds in weight in six months. Two years and nine months before, intravenous urograms were normal. Cystoscopy found the right side of the trigone reddened and the ureteral orifice was found with some difficulty; the left orifice was normal in appearance. No. 6 catheters were passed readily on each side without evidence of obstruction! X-rays: Right uretero-pyelogram, using 18 cc. and giving no pain. There was uniform and marked dilatation of the entire ureter above the catheter tip, which lay at the level of the lower border of the :;;aero-iliac synchondrosis, together with a moderately advanced hydronephrosis. The left ureteropyelogram showed the same changes, but less advanced. This patient was ambulatory and symptom-free, and a program of ureteral dilatation was advised. Case 2. Pondville Hospital No. 7906. An American house-wife, aged 49, entered the hospital on May 21, 1934, because of bloody vaginal discharge of eleven month's duration. The diagnosis was epidermoid carcinoma of the cervix, Grade III, Class I C. Routine urological study before treatment found: Abdomen negative except that the right kidney could be felt. Cystoscopy: The trigone was elevated. The ureteral orifices were normal in appearance, but below the right one was an area of circumscribed redness and edema. No. 5 catheters were passed 28 cm. into both ureters without encountering obstruction. There was a normal rhythmic drip of clear urine from each side, and phthalein appeared in good concentration in three minutes from each kidney. Bilateral uretero-pyelograms were normal (May 26, 1934). A course of deep x-ray therapy was completed June 14, 1934. This consisted of 1800 R. units each to the left and right anterior pelvis, and the same posteriorly, through 6 x 8 cm. portals; total, 7200 R. units. Two intra-cervical applications of gamma radiation followed, four days apart, of 1500 millicurie hours each. After an interval of Out-Patient visits, the patient reentered the hospital January 8, 1935, complaining of abdominal pain and increasing constipation.

COMPLICATIONS OF CARCINOMA OF CERVIX

635

A barium enema found evidence of pressure in the recto-sigmoid region. Cystoscopy, January 19 : a No. S catheter was passed for 26 cm. along each ureter. There was no resistance on the left side. On the right slight obstruction, easily overcome, was encountered 6 cm. above the orifice in the bladder. There was a clear intermittent drip from the left catheter and a rapid, constant, clear drip from the right. The dye appeared in good concentration from the left kidney in 3½ minutes after intravenous injection. There was no appearance of color in twenty minutes from the right kidney. The left ureteropyelogram was normal; on the right the film revealed pronounced dilatation of the ureter and renal pelvis, with some blunting of the calyces. Disease of the cervix was still active, and showed marked progression. Additional deep therapy was given, 600 R . units anteriorly and posteriorly through 20 x 20 cm. portals. The patient was next seen in the Urological Clinic in March 1935, at which time she complained of increased frequency of urination and urgency. There was still no right renal pain. There had been some recent nausea and vomiting. Abdominal examination found the right kidney definitely enlarged but not tender. Cystoscopy: There were signs of extension of malignant disease through the posterior wall of the bladder. A No. 8 catheter was passed for dilatation into the right ureter, the orifice of which was still normal. Obstruction was met at S cm. but the catheter was finally passed to a point 7 cm. above the bladder. Thick, purulent material under pressure then escaped from the catheter; 30 cc. was obtained. Ureteral irrigations with boric solution were given. It was felt that the condition of the patient did not warrant surgical intervention at this time. In April 1935, she again returned to the Clinic. She had no abdominal pain and complained only of some bladder discomfort. Examination found definite advance of the disease invading the vesical wall. Obstruction in the right ureter was now complete. M ay 8, 1935 : There was no appreciable change in general health, and no abdominal pain. The right kidney was markedly enlarged, but not tender. On cystoscopy the right ureteral orifice could no longer be identified. This patient will remain under observation, and if necessary for the relief of symptoms, nephrostomy or ureterostomy on the right side will be performed. The ultimate prognosis in this case of course, is hopeless because of the rapidly advancing malignant process in the pelvis. The patient was readmitted to the hospital on November 6, 1935, presenting the signs and symptoms of impending uremia. The right kidney which was previously enlarged and tender, had apparently undergone silent atrophy. The left kidney was found to be distended and tender. Since it was felt that her life expectancy was sufficient to warrant it, a left nephrostomy was performed, following which there was a general improvement in her condition.

636

R. C. GRAVES, C.

J.

E. KICKHAM AND I. T . NATHANSON

The nephrostomy drainage average 60 ounces daily, and the renal values returned to normal. She expired on January 1, 1936, following the development of signs and symptoms consistent with a general peritonitis, which was confirmed at postmortem examination. This terminal infection was apparently uterine in origin. Case 3. Pondville Hospital No. 6967. An American housewife, aged 49, was admitted October 10, 1933, complaining of constant vaginal discharge and bleeding of three month's duration, pain in the back and in both sides of the abdomen. Diagnosis: Epidermoid carcinoma of the cervix, Grade III, Class 1 C. A few days after admission she complained of pain in the left lower abdomen and in the left lumbar area. Urological examination: Abdomen: Moderate tenderness in the left lower quadrant and in the left costovertebral region. Cystoscopy: The trigone and posterior wall of the bladder were elevated. The ureteral orifices were normal. Indigocarmin, 10 cc. intravenously, appeared in.'excellent concentration from the right kidney in 3½ minutes. No dye appeared from the left kidney in 20 minutes. The right ureter was easily catheterized. In the left, obstruction was encountered 1½ cm. above the bladder; this point was finally passed with a small No. 4 catheter. The right retrograde pyelogram was normal; none was obtained on the left because the catheter was blocked. Intravenous pyefography revealed normal conditions on the right side; there was no excretion of dye on the left. The N.P.N. on admission was 30.7 mgm. and the 2-hour excretion of phthalein was 55%. Deep x-ray therapy was begun but was discontinued after one treatment because of a sharp rise in temperature with recurrent pain in the left lumbar region. The fever subsided but the pain persisted and on November 25, 1933, a left ureterostomy was performed. The convalescence was uneventful and there was a copious drainage of urine from the left kidney. The pain disappeared, and it became possible to resume routine radiation therapy. Treatment: 1200 R. units each to the anterior and posterior pelvis; 20 x 20 cm. portals. Intra-cervical radium for 1500 millicurie hours, in each of two applications, four days apart. When this program was completed, the patient returned home. She did not return to the Clinic, but it was learned through the attending physician and the Social Service Department, that she remained quite comfortable for about eighteen months, then shortly before her death on June 3, 1935, she began to fail and she died in coma. Case 4, Pondville Hospital No. 7743. An Irish housewife, aged 39, entered the hospital on April 17, 1934, because of nine months of irregular vaginal bleeding. Five to seven months prior to admission, she was given elsewhere, radium treatment of the cervix totalling 6000 mgm. hours. The diagnosis was epidermoid carcinoma, Grade III. Four months before admission she began to suffer increasing left lumbar pain radiating to the left knee. In addition

COMPLICATIONS OF CARCINOMA OF CERVIX

637

there was loss of appetite, nausea and vomiting. One month before entry, there developed progressive bladder distress marked by terminal dysuria, urgency, and increased diurnal and nocturnal frequency. Admission diagnosis: Epidermoid carcinoma of the cervix, Grade III, Class 5 D. N.P.N. 35.9 mgm.; two-hour excretion of phthalein 40%. The temperature was elevated and the patient complained of pain in the left flank. Abdomen: The left kidney was palpable but not tender. There was tenderness in the left lower quadrant. Cystoscopy: The trigone and posterior wall of the bladder were elevated but the mucosa was normal, as were the ureteral orifices. Intravenous indigocarmin appeared in good concentration on the right in 4½. minutes. No dye appeared on the left after fifteen minutes. The right ureter was readily catheterized without evident obstruction. No. 6, and 5, and 4 catheters met impassable obstruction on the left, 5 cm. above the bladder. No pyelographic solution could be injected above this point. Intravenous urograms found normal conditions on the right; there was no excretion of dye by the left kidney. April 30, 1934, a course of deep x-ray therapy was completed. This consisted of 1200 R. units each, to the anterior and posterior pelvis. The temperature remained irregularly elevated, ranging from 98 to 102 degrees. The left flank pain persisted but was less severe. The urine contained only a few leucocytes. With a diagnosis of pyelonephritis, probably accountable for the persistent fever, exploration of the left kidney was carried out on May 19, 1934. A left nephrectomy was performed because a marked hydronephrosis was found, with evidence of cortical infection. The convalescence was uneventful and the fever subsided. The patient was discharged home on June 24, 1934. She returned October 10, 1934, complaining of pain in the lumbo-sacral region. There was extensive pelvic involvement by malignant disease. Intravenous pyelogram: Moderately advanced hydronephrosis and hydroureter on the right side. N.P.N. 43 mgm.; two-hour excretion of phthalein 5%. Ureteral dilatation was advised. On October 27, a No. 5 catheter was passed without difficulty along the right ureter. The urine was clear. Ten days later a No. 5 catheter met obstruction 6 cm. above the orifice in the bladder; a No. 4 catheter could be passed. Forty cubic centimeters of clear amber urine was withdrawn from the right renal pelvis. In addition to renal insufficiency, there was marked hypo-chromic anemia and rapidly advancing malignant disease in this case, and the patient began a progressive down-hill course. On January 7, 1935, the N.P.N. was 80 mgm. Three weeks later coma developed and death occurred within 36 hours. The N.P.N. at the onset of coma was 105 mgm. Permission for postmortem examination was not granted.

Case 5. Pondville Hospital No. 4478. An American housewife, aged 34, entered April 15, 1932, because of irregular vaginal bleeding of six month's

638

R. C. GRAVES, C.

J.

E. KICKHAM AND I. T. NATHANSON

duration. She had had pain in the region of the right hip. Hysterectomy had been done in another hospital 3½ months before. Examination found a vaginal scar involved in new growth, particularly on the right where a small crater was present. Rectally there was definite infiltration extending from the lesion into the right broad ligament. There was thickening also in the left broad ligament. Biopsy report: Epidermoid carcinoma, Grade II. Classification: 2 D. April 21, 1932, a lead bomb was placed against the tumor in the vagina, and 2260 millicurie hours was given. On April 30, a course of deep x-ray therapy was completed; 1200 R. units to the pelvis anteriorly and the same posteriorly, through 20 x 20 portals. The patient was then discharged. She was readmitted in September 1932 because of repeated hemorrhages. A second course of deep therapy was given, identical in dosage with the first. Marked improvement followed and she was seen thereafter in the Out-Patient Clinic at intervals of 3 months. January 21, 1935, having failed to appear at the Clinic for six months, the patient returned complaining of nausea and vomiting of two months' duration. There was dragging pain in the sides and she reported also that she had dizziness and severe headaches. Examination found marked anemia; edema of eyes, ankles, and sacral region; dry tongue; and the blood-pressure was 190/100. The kidneys were markedly enlarged and tender. On pelvic examination there was no evidence of active disease, but thickening could be felt in the broad ligaments, especially on the right side. N.P.N. 89 mgm. per 100 cc. The two-hour excretion of phthalein was 0. There was pronounced oliguria. About thirty-six hours after this readmission to the hospital, a bilateral nephrostomy was performed under novocain. The right kidney was markedly enlarged, pale, and distended. The cortex was extremely thin. When the nephrostomy tube was introduced, cloudy urine escaped under great pressure. Similar conditions, but less marked, were encountered on the left side. Following the operation, there was excellent urinary drainage from the left kidney; there was practically no return of renal activity on the right side. The N.P.N. dropped from 89 to 30 mgm. in three weeks, and the phthalein output rose from z'ero to 35%. There was a corresponding improvement in the general condition of the patient, but her temperature remained elevated. Two blood transfusions were given. In view of persistent purulent drainage from the functionless right kidney, and the continued fever, a right nephrectomy was finally performed on March 13, 1935. The recovery from this operation was highly satisfactory, and the temperature promptly subsided to a normal level. The patient returned to her home in excellent condition, on April 18, 1935. At this time the N.P.N. was 26 mg. and the left nephrostomy was draining well. The Gynecological Department reported no evidence of active malignant disease. Since discharge from the hospital, she has been seen at regular intervals, the

COMPLICATIONS OF CARCINOMA OF CERVIX

639

last time on April 11, 1936. She presents the appearance of vigorous general health and has gained 18 pounds in weight. There are no complaints. She is employed as a clerk in a store and has worked during the past winter without interruption. The nephrostomy functions well. At the most recent visit to the Gynecological Clinic on February 4, 1936, the report was : No active disease present. It is probable in this case that ureteral occlusion was caused by :fibrosis rather than by compression or invasion by tumor. On several occasions attempt has been made to reestablish normal ureteral function on the left side by catheter dilatation; but the stricture in the distal segment is complete and catheters cannot be passed. Granted a continuance of satisfactory renal function the outlook for this patient seems good, inasmuch as four and one-half years have elapsed since the onset of her pelvic symptoms. CONCLUSIONS

In a large series of cases studied clinically and at post-mortem examination, with reference to the upper urinary tract changes in carcinoma of the cervix, obstruction of the ureters was encountered in more than 70 per cent of the group. Because of this high incidence of ureteral occlusion, confirmed by other writers on this subject, it is urged that complete urological investigation be included in the management of this disease. As we have shown, both diagnosis and prognosis will thus be rendered more accurate, and measures of relief may be made available for the pain and distressing symptoms of uremia which so often confront these patients. It is our opinion that the urologist may find in this difficult problem a new and highly important field of usefulness. REFERENCES BEHNEY, C. A. : Advanced carcinoma of cervix with report of 166 necropsies. Amer. Jour. Obst. and Gynec., 9: 832, 1933 COLBY, F . H.: Urinary tract complications from uterine cancer. New Eng. Jour. Med., 209: 231, 1933. DREXLER, L., AND HOWES, W. E.: Ureteral obstruction in carcinoma of the cervix. Amer. Jour. Obst. and Gynec., 28 : 197, 1934. EVERETT, H . S.: Urological complications following pelvic irradiation. Amer. Jour. Obst. and Gynec., 28: 1, 1934. EWING, JAMES : Neoplastic diseases. W. B. Saunders Co., Philadelphia, 1922. P. 541. FAERBER, H .: Woran Sterben die nicht operierten bzu. rezidiv gewordenen uteruskarzinomkranken. Ztschr. f. Geburtsch u. gynak, 99: 213, 1931. GRAVES, R. C.: The anatomy and physiology of the bladder. Practice of Surgery, Dean Lewis. W. F . Prior Co., Inc., Hagerstown, Md., Vol. 8, Chap. 12. GRAVES, R . C., AND MILITZER, R. E. : Carcinoma of the prostate with metastases. Jour. Urol., 33: 235, 1935. GRAVES, R. C., C. J.E. KrcKHAM, IRA T . NATHANSON : Bladder complications of carcinoma of the cervix. Surg. Gynec. and Obstet., Dec. 1936. HERGER, C. C., AND SCHREINER, B. F.: Strictured ureters, hydronephrosis and pyonephrosis occurring in carcinoma of the cervix. Surg. Gynec. and Obstet. , 43: 740, 1926. Hi.iFNAGL, K.: Ureterstenose bei Collumcarcinom. Ztschr. f. Urol. Chir., 39 : 7-19, 1934. MARTIN, C. L., AND ROGERS, F . T .: Broad ligament extension in carcinoma of the cervix. Amer. Jour. Roent. and Radium Therapy, 16: 336-344, 1926.

640

DISCUSSION

MARTIN, C. L., AND ROGERS, F. T.: The effect of irradiation on the ureter. Amer. Jour. Roent. and Radium Therapy, 16: 215, 1926. MARTIN, C. L., AND ROGERS, F. T.: Treatment of pain in carcinoma of the cervix uteri with special reference to stricture of the ureter. Amer. Jour. Roent. and Radium Therapy, 20: 30, 1928. PIERSOL, G. A.: Human Anatomy. J. B. Lippincott Co., Phila. and London. Ed. 3, 2: 1896. ScmrrTz, H.: Complications in the urinary tract due to carcinoma of the uterine cervix or radiation treatment. Amer. Jour. Roent., 24: 47, 1930. WAGNER: Der Gebormutterkrebs, eine pathologischanatomisch. Monographie. 2 Tafeln Leipzig, 6: 169, 1868. WARREN, S.: Grading of carcinoma of the cervix as checked at autopsy. Arch. Path., 12: 783, 1931. WARREN, S.: Personal co=unication. WILLIAMS, R.: On morphology of uterine cancer. Brit. Gynec. Jour., 11: 529, 1895.

DISCUSSION DR. Roy B. HENLINE (New York City): Because of the close proximity of the cervix to the lower ureters, it is not surprising that the tumor mass of carcinoma of the cervix should often interfere with urinary drainage to some extent. It was my impression that this usually becomes apparent clinically only in the terminal stages of the disease. Direct extension of the tumor around the ureter is not infrequent, resulting in distortion of the ureter. However, this extension rarely if ever invades the ureteral lumen, although localized inflammatory reaction does cause stricture. The usual treatment of carcinoma of the cervix is with radium. Partial or complete ureteral occlusion often is the result of radiation. We must assume this risk of ureteral injury from radium since this is the accepted method of treatment of cervical malignancy. Dr. Healy of Memorial Hospital, New York, states that he has only seen 2 oases of complete ureteral occlusion in over 3,000 cases of carcinoma of the cervix. These probably resulted from excessive irradiation. Such strictures are fibrous when they do occur and do not usually respond readily to dilatation. In complete occlusion, drainage by nephrostomy is frequently indicated. It is timely to call attention to gynecologists of the possibility of such ureteral injuries so that the method and extent of radiation may be carefully carried out. Careful urological checkup should routinely be done. I am happy to have heard Dr. Graves' paper because it was not my impression that these strictures, narrowing of the lumen of the ureter, occurred nearly as frequently as he has found. DR. FLETCHER H. COLBY (Boston, Massachusetts): Gentlemen, I have read Dr. Graves' entire paper, of which he has given but a brief