- Email: [email protected]
Primary Epithelioma of the Ureter: A Follow-Up Study of Eighteen Cases with the Addition of Nine New Cases
PRIMARY EPITHELIOMA OF THE URETER: A FOLLOW-UP STUDY OF EIGHTEEN CASES WITH THE ADDITION OF NINE NEW CASES VIRGIL S. COUNSELLER Division of Surgery, Mayo Clinic
EDWARD N. COOK Section on Urology, Mayo Clinic AND
PHILIP H. SEEFELD Fellow in Surgery, Mayo Foundation Rochester, Minnesota
It is now generally agreed that primary carcinoma of the ureter is not as rarely encountered as was thought 10 or 15 years ago when reports of cases were sporadic and relatively few. During the past decade much attention has been given to reviews of the literature, presentation of new cases, pathologic and clinical considerations and methods of management. From Rayer's report of the first case in 1842 until 1930, when Rousselot and Lamon reviewed the literature and reported a case of their own, there were only 50 cases in the literature, including the case of these writers. Then, in 1939 the literature was again studied by Foord and Ferrier with a total of 139 cases and the addition of 6 new cases of their own. Soon after, two of us (Cook and Counseller) added 18 cases from the records of the Mayo Clinic. A recent contribution to the ever increasing data on this disease has been made by Scott, who brought the information up to date with a restudy of the literature, totaling 180 cases, and the addition of 2 cases of his own. With the recent remarkable increase of the frequency of recorded cases of carcinoma of the ureter, it is to be expected that interest in the clinical and pathologic aspects of the disease should increase. This surmise has been true and many excellent articles dealing with these features have appeared. Carcinoma of the ureter usually appears in the sixth and seventh decades of life. The lesion occurs more frequently among men than among women and is usually located in the lower segment of the ureter, more frequently in the right than in the left ureter. The predominant symptoms, though not specific, have been found to be hematuria of variable characteristics, pain which varies from a dull aching in the renal or lower abdominal region to typical ureteral colic, and the least frequently encountered symptom of the three, tumor or mass, usually the concomitant hydronephrotic kidney. Improvement of diagnostic procedures and their use earlier in the course of the disease have made the recognition of the disorder less difficult than formerly. Urinalysis, with occasional finding of tumor cells, cystoscopy with ureteral instrumentation, and also urography, both excretory to determine functional capacity and retrograde to show the actual deformity and its situation, have all improved the accuracy of diagnosis. 606
PRIMARY EPITHELIOMA OF THE URETER
607
These fundamental advances coupled with increased dissemination of the knowledge of the disease, resulting in the realization by the physician that primary carcinoma of the ureter is not an exceptionally rare disorder, have all contributed to the more general interest and its favorable effect upon early diagnosis and adequate treatment. One still unsettled feature of primary carcinoma of the ureter is its pathologic classification. "\Vhile these tumors resemble those of the bladder, a great deal of variation exists in the descriptions of types. Scott mentioned 22 different terms by which these tumors have been designated in the literature, although he preferred to divide them into papillary and nonpapillary types. We have adopted the classification presented by Broders, and the type of tumor with which we are concerned is the primary squamous cell epithelioma, most examples of which tend to be of a papillary type. Two of us (Cook and Counseller) emphasized the danger involved in referring to "benign papillomas" of the ureter and "benign papillomas" of the bladder, as they are not benign either pathologically or clinically and must be considered as malignant lesions. That primary malignant lesions of the ureter spread early and may do so extensively is recognized. Metastasis from these lesions tends to occur earlier than from tumors within the bladder, and both recurrence and metastasis increase in direct proportion to the grade of malignancy. Metastatic lesions have been found in retroperitoneal lymph nodes, liver, lumbar vertebrae, sacral vertebrae, lungs and kidneys, and more rarely in the adrenals, spleen, brain, pancreas and skin. Sauer reported a case of carcinoma in the middle third of the ureter with metastatic lesions in the upper third of the right humerus. Nesler reported direct invasion of the iliopsoas muscle by a carcinoma of the middle two-thirds of the ureter. Although, as we have pointed out, knowledge of primary carcinoma of the ureter is increasing and the outlook for early diagnosis is improving, there is still one phase of the disease on which more data need to be studied, namely, adequate treatment. One difficulty in the study of this aspect is the scant information that can be obtained concerning the results of therapeutic procedures which have been undertaken. Scott, in his review, found more than 30 different types of operative procedures used in the treatment of 149 patients and attributed the great variety of procedures used to the failure to make a correct preoperative diagnosis in about 50 per cent of cases, as well as the fact that many of the operations were performed as palliative measures. The operative mortality rate as stated by Scott was 24 per cent. Foord and Ferrier reported a mortality rate of 10 per cent. These authors expressed the belief that while the one-stage removal of the kidney, ureter and cuff of bladder is the ideal procedure, the operation may be done more safely in many cases in two stages ,-vith removal of the tumor as the first stage, preferably by the extraperitoneal route. Kelly, in 1896, was perhaps the first to advocate nephro-ureterectomy in the treatment of primary carcinoma of the ureter and preferred using one long incision. Of the 149 surgical cases reported by Scott, nephro-ureterectomy or
608
V. S. COUNSELLER, E. N. C.OOK AND P.
II.
SEEFELD
nephrectomy and partial ureterectomy were the most frequently performed procedures. Fortunately, less radical procedures such as local excision, cautery, TABLE
1. Data on cases of primary epithelioma of the ureter previously reported TREATMENT
TUMOR
SubseCASE
Grade
--- --years
1 2 3 4 5 6 7 8 9
63 54 64 38 56 64 47
10 11
64 40 54 65 46 57
12 13
14 15 16 17 18
tomy, partial ureterec-
quent complet~ ureterectomy,
tomy
cystec-
Nephrec-
AGE
---
37 71
71
62 57
Diameter average
----
Cau~~ry, exc1s10n of tumor
----
partial tomy
RESULTS
Complete nephroureterectomy, partial cystec-
Recurrent Survival, tumors of months after bladder operation
Deaths, months
after
operation
tomy
- - - ---- - - -
---
----
----
cm.
1 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 4
4 2 3 2 2.5 5 3.5 4.5 1 4 1.5 1 1
+
+ + + + + + + + + +
4
* 2
+ + + +
+ + + + +
+
+ + + + + +
51 165 14 92 87 82 36 62 52 50
+
30 6 P.O.
+
+
7
+
153 27 9 17
* Huge inoperable mass. TABLE
2. Data on cases of primary epithelioma of the ureter newly reported TREATMENT
TUMOR
SubseCASE
Nephrec-
AGE
Grade
Diameter average
Cau_t1:;ry,
tomy,
exc1s10n
partial
of tumor
ureterec-
tomy
71
Complete nephroureterec-
tomy partial cystec-
Death, Recurrent Survival, months tumors of months after after bladder operation operation
tomy
---
---- ----
cm.
years
61 67 57 66 58 58 64 58
partial cystec-
tomy
--- --- --- ----
1 2 3 4 5 6 7 8 9
quent complete ureterectomy,
RESULTS
1 1 1
2 2 2 2 4 4
5 7.5 6 4 2 2 2 1.4
+* +
* Active pulmonary tuberculosis.
+ + +
+ + + +
+
1
+ + +
17 20 4 4 40 5 20 5
PRIMARY EPITHELIOMA OF THE URETER
609
ureteral resection and transplantation, have been used less frequently than measures which are now thought to be of greater value. It is our purpose at this time to present a follow-up of fairly long duration on the 18 cases of primary epithelioma of the ureter on which data were given by two of us (Cook and Counseller) in 1941, and to add 9 new cases in which the patients have been seen at the Mayo Clinic since the previous report, thus increasing the total reported cases to 191. As -will be observed in tables 1 and 2, the majority of the lesions are of a low grade of malignancy according to Broders' classification. This feature, coupled with early diagnosis of the lesion, should increase the probability of obtaining good results in the surgical treatment of the disease. FOLLOW-UP DATA ON
18
CASES PREVIOUSLY REPORTED
Regardless of the type of operation employed, 7 of the 10 patients in table 1 who had lesions graded 1 or 2 are alive more than 4 years after operation and 1 of these has lived more than 13 years. Of the 8 patients who had lesions graded 3 or 4, 6 died within 2½ years, excluding 1 postoperative death. The remaining patient in the group whose lesions were high grade has lived more than 12 years but at the time of writing shows indications of probable recurrence in the bladdeL In the light of these findings, it must be stressed that in cases of low grade ureteral cancer-and the majority of these cancers are of low grade-early diagnosis is of the utmost importance, because there should be chance for moderately long survival if adequate treatment is undertaken at once. The tendency for these tumors to recur in the bladder has been pointed out and this feature is emphasized as the follow-up studies become of longer duration. It will be noted that tumors of the bladder may follow the occurrence of a ureteral neoplasm ,vith no apparent relation to the method of treating the tumor in the ureter. The hypothesis of multicentric origin of vesical, ureteral and renal pelvic tumors and the hypothesis of implantation of fragments of these tumors are not within the scope of this study, but again the need is emphasized for frequent periodic cystoscopic examination of the patient for a moderately long time after operation. Two of us (Cook and Counseller) pointed out the possibility of growth of these tumors by lymphatic extension or by direct extension down the ureter and through its -walls to contiguous structures, and it was brought out that complete extirpation of the kidney, ureter, all periureteral adipose tissue and the ureterovesical segment of the bladder would be the procedure of choice. These observations and the need for complete nephro-ureterectomy and segmental cystectomy are made apparent by the findings at necropsy in the single case of the 18 in which the lesions was grade 4. The patient (case 18, table 1) underwent nephrectomy and partial ureterectomy, leaving a small stump of ureter remaining at the ureterovesical juncture. The patient died 17 months after operation in a greatly debilitated state. At necropsy it was found that the lymph nodes of the pelvis, particularly on the right side, the side of the involved ureter, were tremendously enlarged and the
610
V. S. COUNSELLER, E. N. COOK AND P. H. SEEFELD
lymphoid tissue was completely replaced by neoplastic tissue. In addition, the entire areolar tissue of the pelvis was infiltrated with a neoplastic mass which also extended beneath the peritoneum to the opposite side of the pelvis and had invaded the wall of the bladder. From within, the bladder presented nodules of tumor over the dome, 1 to 2 cm. in diameter, invading the wall from the outside. Both ureteral orifices appeared normal. The tumor extended up along the aorta to the celiac axis, along the mesenteric arteries and also along the splenic artery to the spleen. The tumor extended out along the parietal pleura to the anterior axillary line at the base of the lung, where it also extended to the left visceral pleura. It extended up the aorta to the arch and above the clavicle into the left side of the neck. The eleventh dorsal vertebra was destroyed by tumor. A further observation in relation to the foregoing is furnished by case 2 (table 1). The patient had a grade 2 lesion which was cauterized and excised through the ureter. After 3 years, there was a recurrent lesion within the ureter protruding from the ureteral meatus. This was cauterized. A few months later, left nephrectomy and partial ureterectomy without removal of a cuff of bladder, ~vere done for stricture and pyonephrosis. Three years later a segmental resection of the bladder was performed for a recurrence within the bladder. Then this patient, who had had 2 recurrences within a period of 38 months following his first operative procedure, continued for 10½ years without any evidence of trouble until the date of writing (1943) when a large abdominal mass has appeared which gives every indication of being a recurrence of the old neoplasm. The subsequent developments in these 2 cases should serve to emphasize the need for complete extirpation of all tissue possible at the first operation, to obviate the danger of local recurrence, which is almost bound to take place if any part of the ureter is allowed to remain. DATA ON
9
NEW CASES
There have been 9 new cases of proved primary epithelioma of the ureter at the Mayo Clinic since the report of two of us (Cook and Counseller). We wish to present data (table 2) on these new cases at this time. All of these patients were positively proved to have primary ureteral neoplasms after examination of the pelvis of the removed kidney. In 1 case the kidney was not removed because of extensive bilateral pulmonary tuberculosis which made the patient an extremely poor surgical risk. In this case the tumor was seen to be located at the right uretero-vesical juncture in the intramural portion of the ureter, and transurethral electro-coagulation was considered to be the only feasible therapeutic procedure to be followed under the circumstances. However, retrograde pyelography subsequently revealed the renal pelvis to be of normal outline. In these 9 new cases, 6 patients were men and 3 were vrnmen. The average age of this group was 62.2 years, all of the patients falling in the age group from 57 to 71 years, inclusive. All the tumors were graded according to the classification of Broders for vesical tumors: three were grade 1, four were grade 2 and two were grade 4. Of the 9, six tumors were of the papillary type, and three were infiltrating, one being grade
PRIMARY EPITHELIOMA OF THE URETER
611
2, and the other two being grade 4. The smallest lesion measured 1.4 cm. in diameter. The largest lesion occupied the lower 15 cm. of the ureter. The grade of malignancy does not appear to be related to the size of the tumor. Five of the tumors occurred in the right ureter and 4 occurred in the left. One lesion was located in the upper third of the ureter, one in the middle third while the rest were all found to occupy the lower third, as has been found in more than two-thirds of the cases reported in the literature. In 5 cases there was found to be peri-ureteritis of mild to marked degree. Mentioned by two of us (Cook and Counseller) in their report, a significant accompanying lesion found secondary to the tumor is dilatation of the ureter and hydronephrosis. This was a prominent feature present in all of the 9 cases under consideration. Destruction of renal substance was found to be as high as 90 per cent in 1 case and 80 per cent in another. In 2 cases a palpable mass was present at the first examination. In 4 cases secondary infection accompanied by pyonephritis was present. Calculi were not observed as an accompanying feature in any case. As has been emphasized in all reports, hematuria and pain are the primary symptoms, with a mass in the loin also frequent. Hematuria was present in 8 of the 9 cases being reported, occurring as the first symptom in 4 cases and the only symptom in 2 cases. Hematuria was gross in 4 cases and microscopic in 4. Pain was present in 6 cases, occurring as the first symptom in 5 cases and varying from a dull aching in the loin or lower quadrant, to typical renal and ureteral colic with chills and fever. Other symptoms included dysuria, frequency, urgency and backache in a small percentage of cases. In the 2 cases in which there was a palpable mass, it was thought to be the accompanying hydronephrotic kidney, as the tumors were small. In summary, it may be stated that hematuria and pain were found to be the most prominent and most important symptoms. Microscopic analysis of the urine was of little aid in diagnosis beyond revealing the presence of erythrocytes. In no case were tumor cells found. Cystoscopic examination was found to be of real value in the diagnosis of these ureteral neoplasms. In 3 of the 9 cases, the tumor was seen to protrude from the ureteral orifice and biopsy was facilitated. In 1 case, there was a large tumor surrounding the ureteral orifice, which appeared at first to be attached to the left anterior wall of the bladder and left vesicoprostatic juncture, but when the tumor was removed from the region of the ureteral meatus, it became apparent that the tumor protruded from the ureter. In another case, cystoscopy revealed an apparently normal bladder except for an edematous, bulging, red left ureteral meatus which suggested the possible presence of a stone in its intramural portion. In 5 cases, no evidence of tumor was found on cystoscopic examination. In all cases, however, passage of a ureteral catheter met with obstruction at the site of the tumor, and in the majority of instances catheterization of the involved ureter was accompanied by bleeding which tended to be moderately profuse" Blood spurting from the ureteral orifice was seen even before instrumentation was attempted in one case. Excretory urography was of no aid in actually demonstrating the presence
612
V. S. COUNSELLER, E. N. COOK AND P. H. SEEFELD
or position of the lesion in any of these nine cases but was helpful in revealing the degree of renal function present. In the majority of cases, function was diminished to such a degree that the amount of dilatation of the urinary tract above the lesion was not shown. The presence and position of the lesion itself were best seen in retrograde pyelo-ureterography. Ureterectasis, incomplete filling, complete obstruction to the media and filling defect ·were all observed in these cases, permitting a more
Frn. 1. Grade ,1 squamous cell epithelioma involving distal 4 cm. of ureter and penetrating ureteral wall to a depth of 2 mm. Ureter above neoplasm dilated grade 2. Kidney reveals hydronephrosis grade 1, with destruction of about 5 per cent of renal substance. Note small cuff of bladder.
accurate and exact evaluation of the underlying obstructive process than if pyelo-ureterography had not been done. vVith the aid of these diagnostic methods, it ,vas possible to reach a correct preoperative diagnosis in all the cases under discussion. In regard to the new cases being added to the older series of 18 insufficient time has elapsed to include them in the same follow-up. However, 2 patients (cases 8 and 9, table 2) have died and necropsy was performed on one of them at the clinic. The patient lived 20 months, during which time there were 2 vesical recurrences. Nineteen months after nephrectomy and complete ureterectomy with
FIG. 3 FIG. 2 Fm. 2. Papillary grade 2 squamous cell epithelioma involving 6 cm. of ureter in region of lower and middle thirds. Ureter and kidney proximal to neoplasm show hydro-ureter and hydronephrosis. FIG. 3. Chronic pyelonephritis with hydronephrosis and hydro-ureter of the upper third of ureter. An infiltrating grade 4 squamous cell epithelioma (1.4 by 1 by 3 cm.) is located 7 cm. below ureteropelvic juncture.
Fm. 4a and b. Sarne lesion as in figure 3. Excretory urograms, taken at 20 and 30 minutes respectively, demonstrating dilatation of the calyces and renal pelvis with a definite suggestion of obstruction at the ureteropelvic juncture; c, retrograde pyelograrn demonstrating pyelectasis and caliectasis as well as dilatation of the ureter grade 3 below the ureteropelvic juncture. There is tortuosity and irregularity immediately below the dilated portion of the ureter with an apparent filling defect. (Barium in bowel remains from previous roentgenographic studies.) 613
614
V. S. COUNSELLER, E. N. COOK AND P. H. SEEFELD
removal of a segment of the bladder, this patient returned to the clinic complaining of occipital headache, nausea and emesis, tendency to fall to the right
FIG. 5. Tumor located in lower 15 cm. of right ureter. a, Excretory urogram failing to show evidence of function in right kidney; b, attempted right retrograde pyelogram with lead catheter in right ureter, demonstrating irregular filling of entire ureter with numerous filling defects.
FIG. 6. Tumor situated at right ureterovesical juncture. a, Excretory urogram demonstrating normal function with dilatation grade 1 of middle third of the right ureter; b, right pyelo-ureterogram showing irregular dilatation of middle third of right ureter, with an irregular filling defect at juncture of ureter with bladder.
and hemoptysis in addition to asthenia and loss of weight. Neurologic studies were suggestive of metastatic tumor of the brain. A roentgenogram of the
PRIMARY EPITHELIOMA OF THE URETER
615
thorax revealed a mass in the lower lobe of the right lung which was diagnosed as a metastatic malignant lesion. The patient later became comatose and remained so until death. Necropsy revealed a grade 4 metastatic lesion in the lower lobe of the right lung. Permission to examine the brain was not obtained. There was no evidence of local recurrence of malignant tissue in the renal bed nor along the course of the removed ureter. The ureteral orifice was obliterated by scar tissue and there was no evidence of recurrence within the bladder. This patient's distant metastatic lesions became manifest after removal of the primary tumor but were probably in an early stage before operation was undertaken. Thus, it is seen that early diagnosis is of the utmost importance. The absence of local recurrence indicates that complete removal of kidney, ureter and segment of bladder together with thorough removal of all peri-ureteral adipose tissue will prevent this sequela. Figures 1 to 6 illustrate various important points about these tumors. CONCLUSIONS
Again attention is called to the importance of keeping in mind a very interesting condition which although not common occurs often enough to keep one on the lookout for it. Unexplained hydronephrosis among patients of more than 50 years or hematuria should warrant investigation of the ureters if no other pathologic change is found. Hematuria is the usual and most common symptom, Experience has revealed that surgical intervention is the treatment of choice and should be instituted early. Complete nephro-ureterectomy with the removal of a cuff of bladder should be done. The grade of the tumor is undoubtedly the main factor influencing the prognosis in this condition. Patients who had the lower grades have done well with radical surgical treatment. Tumors of the higher grades are not so common as those of lul'rnr grades but when encountered do not respond well to any form of therapy. REFERENCES CooK, E. N., AND CouNSELLER, V. S.: Primary epithelioma of the ureter. J. A. M. A. 116:122-126, 1941. FooRD, A. G., AND FERRIER, P.A.: Primary carcinoma of the ureter; with report of seven cases. J. A. M. A., 112: 596-601, 1939. KELLY H. A.: Nephro-ureterectomy. Bull. Johns Hopkins Hosp., 7: 31-37, 1896. NESLE~, A. B.: Primary carcinoma of the ureter. J. Iowa M. Soc., 30: 539-542, 1940. RAYER, P.: Quoted by RoussELOT, L. M., AND LAMON, J. D. RoussELOT, L. M., AND LAMON, J. D.: Primary carcinoma of the ureter; report of a case and a review of the literature. Surg., Gynec. & Obst., 50: 17-28, 1930. SAUER, H. R.: Case of large bone metastasis from carcinoma of the ureter complicated by congenital giant hydronephrosis. J. Urol., 48: 467-473, 1942. ScoTT, W. W.: A review of primary carcinoma of the ureter; presenting two cases. J, Urol., 50: 45-64, 1943.
EDWARD N. COOK Section on Urology, Mayo Clinic AND
PHILIP H. SEEFELD Fellow in Surgery, Mayo Foundation Rochester, Minnesota
It is now generally agreed that primary carcinoma of the ureter is not as rarely encountered as was thought 10 or 15 years ago when reports of cases were sporadic and relatively few. During the past decade much attention has been given to reviews of the literature, presentation of new cases, pathologic and clinical considerations and methods of management. From Rayer's report of the first case in 1842 until 1930, when Rousselot and Lamon reviewed the literature and reported a case of their own, there were only 50 cases in the literature, including the case of these writers. Then, in 1939 the literature was again studied by Foord and Ferrier with a total of 139 cases and the addition of 6 new cases of their own. Soon after, two of us (Cook and Counseller) added 18 cases from the records of the Mayo Clinic. A recent contribution to the ever increasing data on this disease has been made by Scott, who brought the information up to date with a restudy of the literature, totaling 180 cases, and the addition of 2 cases of his own. With the recent remarkable increase of the frequency of recorded cases of carcinoma of the ureter, it is to be expected that interest in the clinical and pathologic aspects of the disease should increase. This surmise has been true and many excellent articles dealing with these features have appeared. Carcinoma of the ureter usually appears in the sixth and seventh decades of life. The lesion occurs more frequently among men than among women and is usually located in the lower segment of the ureter, more frequently in the right than in the left ureter. The predominant symptoms, though not specific, have been found to be hematuria of variable characteristics, pain which varies from a dull aching in the renal or lower abdominal region to typical ureteral colic, and the least frequently encountered symptom of the three, tumor or mass, usually the concomitant hydronephrotic kidney. Improvement of diagnostic procedures and their use earlier in the course of the disease have made the recognition of the disorder less difficult than formerly. Urinalysis, with occasional finding of tumor cells, cystoscopy with ureteral instrumentation, and also urography, both excretory to determine functional capacity and retrograde to show the actual deformity and its situation, have all improved the accuracy of diagnosis. 606
PRIMARY EPITHELIOMA OF THE URETER
607
These fundamental advances coupled with increased dissemination of the knowledge of the disease, resulting in the realization by the physician that primary carcinoma of the ureter is not an exceptionally rare disorder, have all contributed to the more general interest and its favorable effect upon early diagnosis and adequate treatment. One still unsettled feature of primary carcinoma of the ureter is its pathologic classification. "\Vhile these tumors resemble those of the bladder, a great deal of variation exists in the descriptions of types. Scott mentioned 22 different terms by which these tumors have been designated in the literature, although he preferred to divide them into papillary and nonpapillary types. We have adopted the classification presented by Broders, and the type of tumor with which we are concerned is the primary squamous cell epithelioma, most examples of which tend to be of a papillary type. Two of us (Cook and Counseller) emphasized the danger involved in referring to "benign papillomas" of the ureter and "benign papillomas" of the bladder, as they are not benign either pathologically or clinically and must be considered as malignant lesions. That primary malignant lesions of the ureter spread early and may do so extensively is recognized. Metastasis from these lesions tends to occur earlier than from tumors within the bladder, and both recurrence and metastasis increase in direct proportion to the grade of malignancy. Metastatic lesions have been found in retroperitoneal lymph nodes, liver, lumbar vertebrae, sacral vertebrae, lungs and kidneys, and more rarely in the adrenals, spleen, brain, pancreas and skin. Sauer reported a case of carcinoma in the middle third of the ureter with metastatic lesions in the upper third of the right humerus. Nesler reported direct invasion of the iliopsoas muscle by a carcinoma of the middle two-thirds of the ureter. Although, as we have pointed out, knowledge of primary carcinoma of the ureter is increasing and the outlook for early diagnosis is improving, there is still one phase of the disease on which more data need to be studied, namely, adequate treatment. One difficulty in the study of this aspect is the scant information that can be obtained concerning the results of therapeutic procedures which have been undertaken. Scott, in his review, found more than 30 different types of operative procedures used in the treatment of 149 patients and attributed the great variety of procedures used to the failure to make a correct preoperative diagnosis in about 50 per cent of cases, as well as the fact that many of the operations were performed as palliative measures. The operative mortality rate as stated by Scott was 24 per cent. Foord and Ferrier reported a mortality rate of 10 per cent. These authors expressed the belief that while the one-stage removal of the kidney, ureter and cuff of bladder is the ideal procedure, the operation may be done more safely in many cases in two stages ,-vith removal of the tumor as the first stage, preferably by the extraperitoneal route. Kelly, in 1896, was perhaps the first to advocate nephro-ureterectomy in the treatment of primary carcinoma of the ureter and preferred using one long incision. Of the 149 surgical cases reported by Scott, nephro-ureterectomy or
608
V. S. COUNSELLER, E. N. C.OOK AND P.
II.
SEEFELD
nephrectomy and partial ureterectomy were the most frequently performed procedures. Fortunately, less radical procedures such as local excision, cautery, TABLE
1. Data on cases of primary epithelioma of the ureter previously reported TREATMENT
TUMOR
SubseCASE
Grade
--- --years
1 2 3 4 5 6 7 8 9
63 54 64 38 56 64 47
10 11
64 40 54 65 46 57
12 13
14 15 16 17 18
tomy, partial ureterec-
quent complet~ ureterectomy,
tomy
cystec-
Nephrec-
AGE
---
37 71
71
62 57
Diameter average
----
Cau~~ry, exc1s10n of tumor
----
partial tomy
RESULTS
Complete nephroureterectomy, partial cystec-
Recurrent Survival, tumors of months after bladder operation
Deaths, months
after
operation
tomy
- - - ---- - - -
---
----
----
cm.
1 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 4
4 2 3 2 2.5 5 3.5 4.5 1 4 1.5 1 1
+
+ + + + + + + + + +
4
* 2
+ + + +
+ + + + +
+
+ + + + + +
51 165 14 92 87 82 36 62 52 50
+
30 6 P.O.
+
+
7
+
153 27 9 17
* Huge inoperable mass. TABLE
2. Data on cases of primary epithelioma of the ureter newly reported TREATMENT
TUMOR
SubseCASE
Nephrec-
AGE
Grade
Diameter average
Cau_t1:;ry,
tomy,
exc1s10n
partial
of tumor
ureterec-
tomy
71
Complete nephroureterec-
tomy partial cystec-
Death, Recurrent Survival, months tumors of months after after bladder operation operation
tomy
---
---- ----
cm.
years
61 67 57 66 58 58 64 58
partial cystec-
tomy
--- --- --- ----
1 2 3 4 5 6 7 8 9
quent complete ureterectomy,
RESULTS
1 1 1
2 2 2 2 4 4
5 7.5 6 4 2 2 2 1.4
+* +
* Active pulmonary tuberculosis.
+ + +
+ + + +
+
1
+ + +
17 20 4 4 40 5 20 5
PRIMARY EPITHELIOMA OF THE URETER
609
ureteral resection and transplantation, have been used less frequently than measures which are now thought to be of greater value. It is our purpose at this time to present a follow-up of fairly long duration on the 18 cases of primary epithelioma of the ureter on which data were given by two of us (Cook and Counseller) in 1941, and to add 9 new cases in which the patients have been seen at the Mayo Clinic since the previous report, thus increasing the total reported cases to 191. As -will be observed in tables 1 and 2, the majority of the lesions are of a low grade of malignancy according to Broders' classification. This feature, coupled with early diagnosis of the lesion, should increase the probability of obtaining good results in the surgical treatment of the disease. FOLLOW-UP DATA ON
18
CASES PREVIOUSLY REPORTED
Regardless of the type of operation employed, 7 of the 10 patients in table 1 who had lesions graded 1 or 2 are alive more than 4 years after operation and 1 of these has lived more than 13 years. Of the 8 patients who had lesions graded 3 or 4, 6 died within 2½ years, excluding 1 postoperative death. The remaining patient in the group whose lesions were high grade has lived more than 12 years but at the time of writing shows indications of probable recurrence in the bladdeL In the light of these findings, it must be stressed that in cases of low grade ureteral cancer-and the majority of these cancers are of low grade-early diagnosis is of the utmost importance, because there should be chance for moderately long survival if adequate treatment is undertaken at once. The tendency for these tumors to recur in the bladder has been pointed out and this feature is emphasized as the follow-up studies become of longer duration. It will be noted that tumors of the bladder may follow the occurrence of a ureteral neoplasm ,vith no apparent relation to the method of treating the tumor in the ureter. The hypothesis of multicentric origin of vesical, ureteral and renal pelvic tumors and the hypothesis of implantation of fragments of these tumors are not within the scope of this study, but again the need is emphasized for frequent periodic cystoscopic examination of the patient for a moderately long time after operation. Two of us (Cook and Counseller) pointed out the possibility of growth of these tumors by lymphatic extension or by direct extension down the ureter and through its -walls to contiguous structures, and it was brought out that complete extirpation of the kidney, ureter, all periureteral adipose tissue and the ureterovesical segment of the bladder would be the procedure of choice. These observations and the need for complete nephro-ureterectomy and segmental cystectomy are made apparent by the findings at necropsy in the single case of the 18 in which the lesions was grade 4. The patient (case 18, table 1) underwent nephrectomy and partial ureterectomy, leaving a small stump of ureter remaining at the ureterovesical juncture. The patient died 17 months after operation in a greatly debilitated state. At necropsy it was found that the lymph nodes of the pelvis, particularly on the right side, the side of the involved ureter, were tremendously enlarged and the
610
V. S. COUNSELLER, E. N. COOK AND P. H. SEEFELD
lymphoid tissue was completely replaced by neoplastic tissue. In addition, the entire areolar tissue of the pelvis was infiltrated with a neoplastic mass which also extended beneath the peritoneum to the opposite side of the pelvis and had invaded the wall of the bladder. From within, the bladder presented nodules of tumor over the dome, 1 to 2 cm. in diameter, invading the wall from the outside. Both ureteral orifices appeared normal. The tumor extended up along the aorta to the celiac axis, along the mesenteric arteries and also along the splenic artery to the spleen. The tumor extended out along the parietal pleura to the anterior axillary line at the base of the lung, where it also extended to the left visceral pleura. It extended up the aorta to the arch and above the clavicle into the left side of the neck. The eleventh dorsal vertebra was destroyed by tumor. A further observation in relation to the foregoing is furnished by case 2 (table 1). The patient had a grade 2 lesion which was cauterized and excised through the ureter. After 3 years, there was a recurrent lesion within the ureter protruding from the ureteral meatus. This was cauterized. A few months later, left nephrectomy and partial ureterectomy without removal of a cuff of bladder, ~vere done for stricture and pyonephrosis. Three years later a segmental resection of the bladder was performed for a recurrence within the bladder. Then this patient, who had had 2 recurrences within a period of 38 months following his first operative procedure, continued for 10½ years without any evidence of trouble until the date of writing (1943) when a large abdominal mass has appeared which gives every indication of being a recurrence of the old neoplasm. The subsequent developments in these 2 cases should serve to emphasize the need for complete extirpation of all tissue possible at the first operation, to obviate the danger of local recurrence, which is almost bound to take place if any part of the ureter is allowed to remain. DATA ON
9
NEW CASES
There have been 9 new cases of proved primary epithelioma of the ureter at the Mayo Clinic since the report of two of us (Cook and Counseller). We wish to present data (table 2) on these new cases at this time. All of these patients were positively proved to have primary ureteral neoplasms after examination of the pelvis of the removed kidney. In 1 case the kidney was not removed because of extensive bilateral pulmonary tuberculosis which made the patient an extremely poor surgical risk. In this case the tumor was seen to be located at the right uretero-vesical juncture in the intramural portion of the ureter, and transurethral electro-coagulation was considered to be the only feasible therapeutic procedure to be followed under the circumstances. However, retrograde pyelography subsequently revealed the renal pelvis to be of normal outline. In these 9 new cases, 6 patients were men and 3 were vrnmen. The average age of this group was 62.2 years, all of the patients falling in the age group from 57 to 71 years, inclusive. All the tumors were graded according to the classification of Broders for vesical tumors: three were grade 1, four were grade 2 and two were grade 4. Of the 9, six tumors were of the papillary type, and three were infiltrating, one being grade
PRIMARY EPITHELIOMA OF THE URETER
611
2, and the other two being grade 4. The smallest lesion measured 1.4 cm. in diameter. The largest lesion occupied the lower 15 cm. of the ureter. The grade of malignancy does not appear to be related to the size of the tumor. Five of the tumors occurred in the right ureter and 4 occurred in the left. One lesion was located in the upper third of the ureter, one in the middle third while the rest were all found to occupy the lower third, as has been found in more than two-thirds of the cases reported in the literature. In 5 cases there was found to be peri-ureteritis of mild to marked degree. Mentioned by two of us (Cook and Counseller) in their report, a significant accompanying lesion found secondary to the tumor is dilatation of the ureter and hydronephrosis. This was a prominent feature present in all of the 9 cases under consideration. Destruction of renal substance was found to be as high as 90 per cent in 1 case and 80 per cent in another. In 2 cases a palpable mass was present at the first examination. In 4 cases secondary infection accompanied by pyonephritis was present. Calculi were not observed as an accompanying feature in any case. As has been emphasized in all reports, hematuria and pain are the primary symptoms, with a mass in the loin also frequent. Hematuria was present in 8 of the 9 cases being reported, occurring as the first symptom in 4 cases and the only symptom in 2 cases. Hematuria was gross in 4 cases and microscopic in 4. Pain was present in 6 cases, occurring as the first symptom in 5 cases and varying from a dull aching in the loin or lower quadrant, to typical renal and ureteral colic with chills and fever. Other symptoms included dysuria, frequency, urgency and backache in a small percentage of cases. In the 2 cases in which there was a palpable mass, it was thought to be the accompanying hydronephrotic kidney, as the tumors were small. In summary, it may be stated that hematuria and pain were found to be the most prominent and most important symptoms. Microscopic analysis of the urine was of little aid in diagnosis beyond revealing the presence of erythrocytes. In no case were tumor cells found. Cystoscopic examination was found to be of real value in the diagnosis of these ureteral neoplasms. In 3 of the 9 cases, the tumor was seen to protrude from the ureteral orifice and biopsy was facilitated. In 1 case, there was a large tumor surrounding the ureteral orifice, which appeared at first to be attached to the left anterior wall of the bladder and left vesicoprostatic juncture, but when the tumor was removed from the region of the ureteral meatus, it became apparent that the tumor protruded from the ureter. In another case, cystoscopy revealed an apparently normal bladder except for an edematous, bulging, red left ureteral meatus which suggested the possible presence of a stone in its intramural portion. In 5 cases, no evidence of tumor was found on cystoscopic examination. In all cases, however, passage of a ureteral catheter met with obstruction at the site of the tumor, and in the majority of instances catheterization of the involved ureter was accompanied by bleeding which tended to be moderately profuse" Blood spurting from the ureteral orifice was seen even before instrumentation was attempted in one case. Excretory urography was of no aid in actually demonstrating the presence
612
V. S. COUNSELLER, E. N. COOK AND P. H. SEEFELD
or position of the lesion in any of these nine cases but was helpful in revealing the degree of renal function present. In the majority of cases, function was diminished to such a degree that the amount of dilatation of the urinary tract above the lesion was not shown. The presence and position of the lesion itself were best seen in retrograde pyelo-ureterography. Ureterectasis, incomplete filling, complete obstruction to the media and filling defect ·were all observed in these cases, permitting a more
Frn. 1. Grade ,1 squamous cell epithelioma involving distal 4 cm. of ureter and penetrating ureteral wall to a depth of 2 mm. Ureter above neoplasm dilated grade 2. Kidney reveals hydronephrosis grade 1, with destruction of about 5 per cent of renal substance. Note small cuff of bladder.
accurate and exact evaluation of the underlying obstructive process than if pyelo-ureterography had not been done. vVith the aid of these diagnostic methods, it ,vas possible to reach a correct preoperative diagnosis in all the cases under discussion. In regard to the new cases being added to the older series of 18 insufficient time has elapsed to include them in the same follow-up. However, 2 patients (cases 8 and 9, table 2) have died and necropsy was performed on one of them at the clinic. The patient lived 20 months, during which time there were 2 vesical recurrences. Nineteen months after nephrectomy and complete ureterectomy with
FIG. 3 FIG. 2 Fm. 2. Papillary grade 2 squamous cell epithelioma involving 6 cm. of ureter in region of lower and middle thirds. Ureter and kidney proximal to neoplasm show hydro-ureter and hydronephrosis. FIG. 3. Chronic pyelonephritis with hydronephrosis and hydro-ureter of the upper third of ureter. An infiltrating grade 4 squamous cell epithelioma (1.4 by 1 by 3 cm.) is located 7 cm. below ureteropelvic juncture.
Fm. 4a and b. Sarne lesion as in figure 3. Excretory urograms, taken at 20 and 30 minutes respectively, demonstrating dilatation of the calyces and renal pelvis with a definite suggestion of obstruction at the ureteropelvic juncture; c, retrograde pyelograrn demonstrating pyelectasis and caliectasis as well as dilatation of the ureter grade 3 below the ureteropelvic juncture. There is tortuosity and irregularity immediately below the dilated portion of the ureter with an apparent filling defect. (Barium in bowel remains from previous roentgenographic studies.) 613
614
V. S. COUNSELLER, E. N. COOK AND P. H. SEEFELD
removal of a segment of the bladder, this patient returned to the clinic complaining of occipital headache, nausea and emesis, tendency to fall to the right
FIG. 5. Tumor located in lower 15 cm. of right ureter. a, Excretory urogram failing to show evidence of function in right kidney; b, attempted right retrograde pyelogram with lead catheter in right ureter, demonstrating irregular filling of entire ureter with numerous filling defects.
FIG. 6. Tumor situated at right ureterovesical juncture. a, Excretory urogram demonstrating normal function with dilatation grade 1 of middle third of the right ureter; b, right pyelo-ureterogram showing irregular dilatation of middle third of right ureter, with an irregular filling defect at juncture of ureter with bladder.
and hemoptysis in addition to asthenia and loss of weight. Neurologic studies were suggestive of metastatic tumor of the brain. A roentgenogram of the
PRIMARY EPITHELIOMA OF THE URETER
615
thorax revealed a mass in the lower lobe of the right lung which was diagnosed as a metastatic malignant lesion. The patient later became comatose and remained so until death. Necropsy revealed a grade 4 metastatic lesion in the lower lobe of the right lung. Permission to examine the brain was not obtained. There was no evidence of local recurrence of malignant tissue in the renal bed nor along the course of the removed ureter. The ureteral orifice was obliterated by scar tissue and there was no evidence of recurrence within the bladder. This patient's distant metastatic lesions became manifest after removal of the primary tumor but were probably in an early stage before operation was undertaken. Thus, it is seen that early diagnosis is of the utmost importance. The absence of local recurrence indicates that complete removal of kidney, ureter and segment of bladder together with thorough removal of all peri-ureteral adipose tissue will prevent this sequela. Figures 1 to 6 illustrate various important points about these tumors. CONCLUSIONS
Again attention is called to the importance of keeping in mind a very interesting condition which although not common occurs often enough to keep one on the lookout for it. Unexplained hydronephrosis among patients of more than 50 years or hematuria should warrant investigation of the ureters if no other pathologic change is found. Hematuria is the usual and most common symptom, Experience has revealed that surgical intervention is the treatment of choice and should be instituted early. Complete nephro-ureterectomy with the removal of a cuff of bladder should be done. The grade of the tumor is undoubtedly the main factor influencing the prognosis in this condition. Patients who had the lower grades have done well with radical surgical treatment. Tumors of the higher grades are not so common as those of lul'rnr grades but when encountered do not respond well to any form of therapy. REFERENCES CooK, E. N., AND CouNSELLER, V. S.: Primary epithelioma of the ureter. J. A. M. A. 116:122-126, 1941. FooRD, A. G., AND FERRIER, P.A.: Primary carcinoma of the ureter; with report of seven cases. J. A. M. A., 112: 596-601, 1939. KELLY H. A.: Nephro-ureterectomy. Bull. Johns Hopkins Hosp., 7: 31-37, 1896. NESLE~, A. B.: Primary carcinoma of the ureter. J. Iowa M. Soc., 30: 539-542, 1940. RAYER, P.: Quoted by RoussELOT, L. M., AND LAMON, J. D. RoussELOT, L. M., AND LAMON, J. D.: Primary carcinoma of the ureter; report of a case and a review of the literature. Surg., Gynec. & Obst., 50: 17-28, 1930. SAUER, H. R.: Case of large bone metastasis from carcinoma of the ureter complicated by congenital giant hydronephrosis. J. Urol., 48: 467-473, 1942. ScoTT, W. W.: A review of primary carcinoma of the ureter; presenting two cases. J, Urol., 50: 45-64, 1943.