Conservatively Aggressive Management Bilateral W ilms’ Tumors By John
J. White,
E. Stevers
Golladay,
and J. Alex
Herbert Holler,
Kaizer,
J. Douglas
with Pinney,
Jr.
R
ADICAL PRIMARY EXCISION, up to and including bilateral nephrectomy with renal allotransplantation, has been advocated for bilateral Wilms’ tumors. Since 1953 we have treated nine children with bilateral Wilms’ tumors. Only two of them died of their malignancies: both had primary radical excision and received less than the currently recommended dosages of radiotherapy and chemotherapy. More recently, we have excised the more involved kidney and treated the less involved side with radiotherapy and multiple courses of chemotherapy. We have termed this conservatively aggressive management; it has resulted in no evidence of residual malignancy in any of the six children so treated. Three of these six patients were left with residual benign rhabdomyomas. These results suggest that this less radical approach to bilateral Wilms’ tumors is an effective method of management. CLINICAL
PRESENTATION
The records of The Johns Hopkins Hospital were reviewed for the 22-yr period 195331975. Complete records were obtained for 65 of the 74 children listed in our Pediatric Tumor Registry as having Wilms’ tumors; 9 patients in this group had bilateral Wilms’ tumors (14”/). In 6 patients of the bilateral group the tumors presented synchronously; in the remaining 3 patients the presentation was metachronous, with an average interval of 2.4 yr between the onsets of the two tumors (Table 1). The tumors were diagnosed before the age of 2 yr in 6 of the 9 cases (674,,,) , (Table 1). With unilateral Wilms’ tumors, 290; presented before 2 yr of age (Table 2). Among the 9 patients with bilateral tumors were 7 boys and 7 white children (Table 1). The racial incidence reflects the referral pattern for pediatric oncology to The Johns Hopkins Hospital and is concordant with the unilateral Wilms’ tumor group. The sex distribution of 789” boys differs from the 52’1, incidence in our unilateral group (Table 2). An abdominal mass was the presenting sign in approximately 75% of both unilateral and bilateral cases: abdominal pain was a symptom in approximately 33”{ (Table 3). Hematuria was present in about 207;. Hypertension was noted in only 20”/;, of those with unilateral tumors, but it was present in 7 of the 9 children with bilateral Wilms’ tumors (7896) (p < 0.005). A strong family history From the Division oy Pediatric Surgery. the Department qf Pediatrics. and the Oncology Center, The Johns Hopkins University School of Medicine. Baltimore. Md. Presented before the 7th Annual Meeting of the American Pediatric Surgical Association. Boca Raton. Fla., April29-May I. 1976. Address for reprint requests: John J. White, M.D.. Division 01 Pediatric Surgery. Albanv Medical Center, Albany, N. Y. 12208. :Q 1976 by Grune & Stratton, Inc.
Journal
of Pediotrrc
Surgery,
Vol. 11, No. 5 (October), 1976
a59
860
WHITE
Table 1. Age/Sex/Race:
Bilateral
Al.
Wilms’ Tumors (1953-1975)
Age (Years)
Case No. (year)
ET
Sex
Race
Synchronous 1. (1958)
23
2. (1964)
2 3 a
F
W
F
W
3.
(1971)
4.
(1973)
1;
5.
(1975)
8
M
W
6.
(1975)
1:
M*
W
Average
age
M
W
M
W
2;
Metachronous 7.
(1964,
1967)
4,7
M
W
8.
(1964,
1965)
1.2
M
B
9.
(1972,
1975)
0,3:
M
B
Average
age
‘pseudohermaphrodite
1% 4
with
glomerulonephritis.
Table 2. Age/Sex
Comporison:
Wilms’ Tumor (1953-1975)
Age ot Presentation 2-4
o-2
(years) 4-8
Sex Ratio 8
(M/F)
Unilateral (Stages
I-IV)
16
16
17
(29%)
(29%)
(30%)
7
29127 52%f48%
(12%)
Biloterol (Stage
V)
6
2
(67%)
(24%)
I
712 78%/22%
(12%)
of malignancy was present in 6 of those in the bilateral group (67x), but in only 14% of our patients with unilateral Wilms tumors (p < 0.005). TREATMENT
AND RESULTS
As newer treatment modalities became available and philosophies of therapy were adjusted during the 22 yr covered by this report, a gradual evolution took place toward the current operative, radiotherapeutic, and chemotherapeutic regimen. Details of the therapy administered to these patients are presented in Table 4, along with their current status and length of follow-up. Excision is the mainstay of management. In our early experience, extirpation (as radical as possible) constituted the initial operative approach (Cases 1, 2, Table 3. Clinical Presentation:
Bilateral
Wilms’ Tumors (1953-1975) Unilateral
(Sager
I-IV)
Bilateral (Stage V)
(56 Cases)
(9 Cares)
Abdominal
moss
39 (70%)
7 (78%)
Abdominal
pain
19 (34%)
4 (44%)
7 (12%)
2 (22%)
Vomiting Hemoturio
11 (20%)
3 (33%)
Hypertension
11 (20%)
7 (78%)
Fomily
history
of malignancy
8 (14%)
6
(67%)
Case No.
(1964)
(1971)
(1973)
(1975)
(1975)
3.
4.
5.
6.
(1972,
9.
1975)
1965)
1967)
died
of disease;
D(GN)
In the metochronously
(1964,
(1964,
7.
8.
Metochronous
(1958)
1.
2.
Synchronous
(Year of Presentation)
N
died
group,
Tot N
nephritis
with
-
-
nodes
A,
alive
is in italics.
-
-
LU lobectomy
-
-
Bx mesent
-
Metastoses
with
AMD,
0
tumor
D; VCR,
1500
2500
1500
2100
1200
1080
1500
0
2200
maturation.
actinomycin
1750
1000
1200
3800
1800
2400
2500
2200
left
0
0
0
0
(lungs)
(lungs)
Vincristine;
1200
1200
0
0
0
Other
(rods)
Tumors (1953-1975)
Radiotherapy
Wilmr’
Primary(r) Right
and Results: Bilateral
maturation;
procedure
tumor
the first operative
N
Tof N
Port
Tot N
of progressive
presenting
Bx
3 8x’s
Tot N
BX
-
N
Delayed
3 Bx’s
Tot N
part
U Bx
Tot N
N
N
Others
Therapy
-
Port
Part
Left
Operatwe
Treatment
Tot N
Tot N
Part
Right
Initial
Table 4.
ADR,
adriomycin.
5+
6
0
2
6+
7
7
3
0
no evidence
5+
0
0
0
5+
7
0
0
0
ADR
Courses
NED,
5+
8
8
3
10+
7
7
1
0
VCR
Chemotherapy AM0
(1.5)
(4)
(4)
(11)
(l/2)
(3)
of disease;
NED
A (11)
DOD
D(GN)(1/2)
NED
A (3)
NED
DOD
NED
DOD,
(years)
Status and Follow-up
WHITE
862
ET At.
and 7). We were encouraged by the surprising outcome in one patient with a metachronous presentation (Case 8) who had a nephrectomy for his first tumor and only radiation and combined chemotherapy (AMD + VCR) for his second tumor. For this reason our operative management remains aggressive, but has become more conservative. Following this case, we have preferred to excise only the more involved kidney in the patient with simultaneous bilateral Wilms’ tumor (Cases 3-6). After metal clip demarcation and biopsy of the tumor on the Iess involved side in simultaneous cases, and on the second side in metachronous cases (Cases 8 and 9), we have administered radiotherapy and multiple courses of chemotherapy. Wide excision of lung metastases has been carried out in one patient in whom there was no radiologic evidence of disappearance after whole chest radiotherapy and systemic chemotherapy (Case 5). For the most part, radiotherapy has consisted of a maximally tolerated dose to the nephrectomy bed (more involved side) and a limited dose to the less involved kidney in synchronous cases and to the second involved kidney in metachronous cases (Cases 3-6,8, and 9). Our first case received maximal-dose bilateral irradiation without chemotherapy and was alive without disease 11 yr later, when she moved and was lost to follow-up. The two patients who died of their disease received only unilateral radiotherapy, in one case to the bed of the excised kidney (Case 2) and in the other to the second involved kidney (Case 7). Pulmonary irradiation was used in two cases, one prophylactically (Case 8) and one for metastases (Case 5); a lobectomy was subsequently done in the latter case. Chemotherapy has consisted in most cases of multiple courses of actinomycin D (AMD) and vincristine (VCR) administered for 15 mo essentially as outlined in the National Wilms’ Tumor Study (NWTS).’ One early patient received no chemotherapy and is apparently cured (Case 1). The two patients who died were given only a limited regimen in one instance (Case 2) and no AMD in the other (Case 7). Adriamycin (ADR) has been given in three cases (Cases 4, 5, and 9). Six of the nine patients with bilateral Wilms’ tumors in this series are alive with no evidence of malignancy (67%). Four have no evidence of neoplasm at all (Cases 1, 3, 5, and 9). Two have been left with residual tumor (benign rhabdomyoma). In one, the tumor is still in situ (Case 8); in the other, excision of the tumor in the lower pole of the kidney was performed because of obstructive uropathy (Case 4). With the exception of Case 1, all of these patients have been treated by conservatively aggressive operative therapy, adequate radiotherapy, and multiple courses of chemotherapy. Two patients died of their Wilms’ tumors. Both had initial radical bilateral excisions and inadequate radiotherapy and chemotherapy by current standards (Cases 2 and 7). The child with pseudohermaphroditism died of glomerulonephritis. There was no evidence of malignancy in the less involved kidney; benign rhabdomyoma was present (Case 6). HISTOPATHOLOGY The Wilms’ tumors in this series were all typical nephroblastomas. Benign rhabdomyomas were found in three cases after radiotherapy and multiple courses of chemotherapy. The affected kidney was not biopsied initially in two
BILATERAL
WILMS’
a63
TUMORS
children. The second tumor was presumed to be a nephroblastoma in one metachronously presenting case (Case 8). In a patient with synchronous presentation of grossly identical-appearing tumors, the less involved side was not biopsied for fear of tumor spillage: the excised tumor 2 yr later was composed of benign rhabdomyoma and mature tubular structures. Definite nephroblastoma was present in the less involved left kidney on initial biopsy in the child with pseudohermaphroditism and glomeronephritis (Case 6). Death was due to renal failure secondary to progressive nephritis. At autopsy, only benign rhabdomyoma was present in the left kidney. DISCUSSION
Bilateral disease has been reported in 4% to 1l”i, of all cases in series of Wilms tumors.2m6 The 9 patients in our series from 65 available records (14%) (or 9 of the total 74 cases listed in our registry [ 12”,/,]) may reflect a referral pattern of more involved cases, with relatively uncomplicated unilateral tumors being treated at other institutions. In accord with the suggestion of Jagasia and associates2 that bilateral Wilms tumors represent separate primaries, we have listed the tumors in our series as occurring concurrently (synchronous tumors) or nonconcurrently (metachronous tumors). The majority of the children with bilateral Wilms’ tumors in our series (785:) were boys, which is distinctly different from the nearly even sex ratio for children with unilateral disease. This is not statistically significant. Analysis of a large number of cases of bilateral tumors has shown a 1.13: 1.OO male-to-female ratio.’ However, the earlier age at which the bilateral tumors presented (677” below 2 yr) and the 67% positive family history for malignancy support suggestions that strong hereditary factors are operative.’ The increased incidence of hypertension among children with bilateral Wilms’ tumors in our series suggests that in patients with apparent unilateral disease and hypertension, palpation alone of the opposite kidney for evidence of bilateral tumors may be inadequate at operation. In agreement with the findings of Sukarochana and associates,’ hypertension in our series had no bearing on survival. In three cases, apparent transformation of the malignant Wilms’ tumor to benign rhabdomyoma occurred in the residual kidney. The finding of bilateral rhabdomyomas of the kidneys following radiation therapy has been reported by Constance? Al! three of our cases received radiotherapy and multiple courses of chemotherapy. Prior biopsy was not obtained in two; however, the other had evidence of the typical histology of nephroblastoma before therapy. It is doubtful that the first two represent benign tumors arising independently opposite to a malignant Wilms’ tumor. Whether these cases represent maturation of the rhabdomyomatous elements in Wilms’ tumor with eradication and/or maturation of the other elements remains speculative. The poor outcome associated with immediate bilateral excision with limited radiation and chemotherapy early in our series, and the significant improvement in prognosis in unilateral Wilms’ tumors associated with adequate radiotherapy and multiple courses of combination chemotherapy, have encouraged US in our conservatively aggressive approach to management. Despite occasional reports of apparent cure of bilateral Wilms tumors with radiation and
864
WHITE
ET AL.
chemotherapy a10ne,4~5~‘o~1’ we have elected to utilize excision of the more involved kidney in synchronous cases. Nephrectomy already has been performed in metachronous cases. Such an approach theoretically may debulk tumor sufficiently that radiotherapy and chemotherapy may have more effect. Delayed contralateral partial nephrectomy may be elected on an individual basis if identifiable malignant tumor remains or urinary obstruction is present. The only two patients who died of Wilms’ tumor in our series were those with early radical excision followed by inadequate radiation and chemotherapy by current standards. A third child died of progressive glomerulonephritis after adequate radiotherapy with several courses of chemotherapy; benign rhabdomyoma was present in the residual kidney at autopsy. This triad of pseudohermaphroditism, Wilms’ tumor, and progressive nephritis has been described.i2 The five children treated with aggressively conservative management are alive without evidence of malignant disease; two were left with residual benign tumors. Bilateral nephrectomy with renal transplantation has been recommended for bilateral Wilms’ tumors.‘3-‘5 The cumulative experience with renal allotransplantation for renal failure is a 36% 3-yr survival and 20% graft function among cadaver-donor renal transplants in children under 5 yr of age; there is a 75% 3-yr survival with 47% graft function among parent-donor transplants.16 Surviving patients with renal transplants for renal failure are also at higher risk of developing other malignancies, especially reticulum cell sarcoma and lymphoma. I7 In view of these data and the potential for impaired growth and susceptibility to intercurrent infection while on immunosuppressive therapy, bilateral nephrectomy and renal transplantation appear to have little place in the current management of bilateral Wilms’ tumors. Limited and staged excisional therapy, with adequate radiotherapy and multiple courses of combined chemotherapy, seems to offer more promise. Another approach that has been suggestedIs consists of initial biopsy bilaterally, followed by chemotherapy and/or radiation therapy; subsequent excision of residual tumor masses is then carried out. Its potential advantage is maximal renal preservation. Its potential disadvantage lies in the increased mass of tumor that must be destroyed, thereby increasing the chance of selecting resistant clones of tumor cells. We have had no experience with this approach. SUMMARY
AND CONCLUSIONS
Among a total of 65 children with Wilms’ tumors treated from 1953 to 1975, bilateral Wilms’ tumors presented synchronously in 6 children and metachronously in 3 others. Most of the bilateral tumors occurred before the age of 2 yr in children with hypertension and a strong family history for malignancy. Two children with initial bilateral excisional therapy and less than currently recommended radiation and chemotherapy died of their disease. Another infant with pseudohermaphroditism died of progressive glomerulonephritis; only benign rhabdomyoma was present at autopsy. Six children with bilateral Wilms’ tumors are alive without evidence of mahgnancy (67%). Five were treated by nephrectomy of the more involved side (synchronously presenting group) or of the first involved kidney (metachro-
BILATERAL
WILMS’
a65
TUMORS
nously occurring group). A full course of radiotherapy to the bed of the excised kidney and a limited dose to the residual kidney was accompanied by multiple courses of AMD and VCR, and recently ADR therapy. Delayed excision of residual tumor for obstructive uropathy has been performed in one case. With this therapy, three children have been left with benign renal rhabdomyomas. Our experience suggests that initial radical excision with or without transplantation should not be recommended for children with bilateral Wilms’ tumors. Conservatively aggressive management emphasizing excision of the more involved kidney plus adequate radiation and multiple courses of chemotherapy appears to constitute an effective treatment regimen. REFERENCES 1. D’Angio GJ, Beckwith JB, Bishop HC, et al: The national Wilms’ tumor study: A progress report, in: Seventh National Cancer Conference Proceedings. 1973, p 627. AM Cancer Society 2. Jagasia KH, Thurman WC, Pickett E, et al: Bilateral Wilms’ tumors in children. J Pediatr 65371, 1964 3. Johnston JH, Shah MB: Recovery from bilateral Wilms’ tumors. Clin Pediatr 4:394, 1965 4. Bishop HC, Hope JW: Bilateral tumor. J Pediatr Surg 1:476, 1966
Wilms’
5. Ragab AH, Vietti TJ, Crist W, et al: Bilateral Wilms’ tumor. A review. Cancer 30: 983, 1972 6. Fay R, Brosman S, Williams DJ: Bilateral nephroblastoma. J Urol 1 IO: 119,973 7. Cochran W, Groggatt P: Bilateral nephroblastoma in two sisters. J Urol 97:216, 1967 8. Sukarochana K, Tolentino W, Kieswetter WB: Wilms’ tumor and hypertension, J Pediatr Surg 7:573, 1972 9. Constance TJ: Bilateral rhabdomyoma of the kidney. J Pathol Bacterial 59:492, 1947 10. Gypes MT: Diffuse bilateral Wilms’ tu-
mor simulating
multicystic
ology
1964
182:1029,
Radi-
EE, Herlong JH, Harper JM, Wilms’ tumor: Diagnosis and
I I, Anderson et al: Bilateral management.
renal disease.
Clin Pediatr
7:596, 1968
12. Barakat AY, Papadopoulou dra RS, et al: Pseudohermaphroditism, disorder and Wilms’ tumor: Pediatrics 54:366, 1974
ZL,
A unifying
Channephron concept.
13. deLorimier AE, Belzer FO, Kountz SL, et al: Simultaneous bilateral Wilms’ tumor. Surgery
64:850,
1968
14. David HS, Lavengood RW Jr: Bilateral Wilms’ tumor: Treatment, management, and review of the literature. Urology 3:71, 1974 15. Ehrlich RM, Goldman R, Kaufman JJ: Surgery of bilateral Wilms’ tumors: The role of renal transplantation. J Urol 1 I1:276, 1974 16. Bergan JJ, Braun WE, Fraumeni JF Jr, et al: The 11 th report of the human renal transplant registry. JAMA 226: 1197, 1973 17. Newsletter No. 15, ACS/NIH Organ Transplant Registry. Bethesda. NIH. February, 1976 18. Evans A: Personal
communication.
J. White,
E. Stevers
Golladay,
and J. Alex
Herbert Holler,
Kaizer,
J. Douglas
with Pinney,
Jr.
R
ADICAL PRIMARY EXCISION, up to and including bilateral nephrectomy with renal allotransplantation, has been advocated for bilateral Wilms’ tumors. Since 1953 we have treated nine children with bilateral Wilms’ tumors. Only two of them died of their malignancies: both had primary radical excision and received less than the currently recommended dosages of radiotherapy and chemotherapy. More recently, we have excised the more involved kidney and treated the less involved side with radiotherapy and multiple courses of chemotherapy. We have termed this conservatively aggressive management; it has resulted in no evidence of residual malignancy in any of the six children so treated. Three of these six patients were left with residual benign rhabdomyomas. These results suggest that this less radical approach to bilateral Wilms’ tumors is an effective method of management. CLINICAL
PRESENTATION
The records of The Johns Hopkins Hospital were reviewed for the 22-yr period 195331975. Complete records were obtained for 65 of the 74 children listed in our Pediatric Tumor Registry as having Wilms’ tumors; 9 patients in this group had bilateral Wilms’ tumors (14”/). In 6 patients of the bilateral group the tumors presented synchronously; in the remaining 3 patients the presentation was metachronous, with an average interval of 2.4 yr between the onsets of the two tumors (Table 1). The tumors were diagnosed before the age of 2 yr in 6 of the 9 cases (674,,,) , (Table 1). With unilateral Wilms’ tumors, 290; presented before 2 yr of age (Table 2). Among the 9 patients with bilateral tumors were 7 boys and 7 white children (Table 1). The racial incidence reflects the referral pattern for pediatric oncology to The Johns Hopkins Hospital and is concordant with the unilateral Wilms’ tumor group. The sex distribution of 789” boys differs from the 52’1, incidence in our unilateral group (Table 2). An abdominal mass was the presenting sign in approximately 75% of both unilateral and bilateral cases: abdominal pain was a symptom in approximately 33”{ (Table 3). Hematuria was present in about 207;. Hypertension was noted in only 20”/;, of those with unilateral tumors, but it was present in 7 of the 9 children with bilateral Wilms’ tumors (7896) (p < 0.005). A strong family history From the Division oy Pediatric Surgery. the Department qf Pediatrics. and the Oncology Center, The Johns Hopkins University School of Medicine. Baltimore. Md. Presented before the 7th Annual Meeting of the American Pediatric Surgical Association. Boca Raton. Fla., April29-May I. 1976. Address for reprint requests: John J. White, M.D.. Division 01 Pediatric Surgery. Albanv Medical Center, Albany, N. Y. 12208. :Q 1976 by Grune & Stratton, Inc.
Journal
of Pediotrrc
Surgery,
Vol. 11, No. 5 (October), 1976
a59
860
WHITE
Table 1. Age/Sex/Race:
Bilateral
Al.
Wilms’ Tumors (1953-1975)
Age (Years)
Case No. (year)
ET
Sex
Race
Synchronous 1. (1958)
23
2. (1964)
2 3 a
F
W
F
W
3.
(1971)
4.
(1973)
1;
5.
(1975)
8
M
W
6.
(1975)
1:
M*
W
Average
age
M
W
M
W
2;
Metachronous 7.
(1964,
1967)
4,7
M
W
8.
(1964,
1965)
1.2
M
B
9.
(1972,
1975)
0,3:
M
B
Average
age
‘pseudohermaphrodite
1% 4
with
glomerulonephritis.
Table 2. Age/Sex
Comporison:
Wilms’ Tumor (1953-1975)
Age ot Presentation 2-4
o-2
(years) 4-8
Sex Ratio 8
(M/F)
Unilateral (Stages
I-IV)
16
16
17
(29%)
(29%)
(30%)
7
29127 52%f48%
(12%)
Biloterol (Stage
V)
6
2
(67%)
(24%)
I
712 78%/22%
(12%)
of malignancy was present in 6 of those in the bilateral group (67x), but in only 14% of our patients with unilateral Wilms tumors (p < 0.005). TREATMENT
AND RESULTS
As newer treatment modalities became available and philosophies of therapy were adjusted during the 22 yr covered by this report, a gradual evolution took place toward the current operative, radiotherapeutic, and chemotherapeutic regimen. Details of the therapy administered to these patients are presented in Table 4, along with their current status and length of follow-up. Excision is the mainstay of management. In our early experience, extirpation (as radical as possible) constituted the initial operative approach (Cases 1, 2, Table 3. Clinical Presentation:
Bilateral
Wilms’ Tumors (1953-1975) Unilateral
(Sager
I-IV)
Bilateral (Stage V)
(56 Cases)
(9 Cares)
Abdominal
moss
39 (70%)
7 (78%)
Abdominal
pain
19 (34%)
4 (44%)
7 (12%)
2 (22%)
Vomiting Hemoturio
11 (20%)
3 (33%)
Hypertension
11 (20%)
7 (78%)
Fomily
history
of malignancy
8 (14%)
6
(67%)
Case No.
(1964)
(1971)
(1973)
(1975)
(1975)
3.
4.
5.
6.
(1972,
9.
1975)
1965)
1967)
died
of disease;
D(GN)
In the metochronously
(1964,
(1964,
7.
8.
Metochronous
(1958)
1.
2.
Synchronous
(Year of Presentation)
N
died
group,
Tot N
nephritis
with
-
-
nodes
A,
alive
is in italics.
-
-
LU lobectomy
-
-
Bx mesent
-
Metastoses
with
AMD,
0
tumor
D; VCR,
1500
2500
1500
2100
1200
1080
1500
0
2200
maturation.
actinomycin
1750
1000
1200
3800
1800
2400
2500
2200
left
0
0
0
0
(lungs)
(lungs)
Vincristine;
1200
1200
0
0
0
Other
(rods)
Tumors (1953-1975)
Radiotherapy
Wilmr’
Primary(r) Right
and Results: Bilateral
maturation;
procedure
tumor
the first operative
N
Tof N
Port
Tot N
of progressive
presenting
Bx
3 8x’s
Tot N
BX
-
N
Delayed
3 Bx’s
Tot N
part
U Bx
Tot N
N
N
Others
Therapy
-
Port
Part
Left
Operatwe
Treatment
Tot N
Tot N
Part
Right
Initial
Table 4.
ADR,
adriomycin.
5+
6
0
2
6+
7
7
3
0
no evidence
5+
0
0
0
5+
7
0
0
0
ADR
Courses
NED,
5+
8
8
3
10+
7
7
1
0
VCR
Chemotherapy AM0
(1.5)
(4)
(4)
(11)
(l/2)
(3)
of disease;
NED
A (11)
DOD
D(GN)(1/2)
NED
A (3)
NED
DOD
NED
DOD,
(years)
Status and Follow-up
WHITE
862
ET At.
and 7). We were encouraged by the surprising outcome in one patient with a metachronous presentation (Case 8) who had a nephrectomy for his first tumor and only radiation and combined chemotherapy (AMD + VCR) for his second tumor. For this reason our operative management remains aggressive, but has become more conservative. Following this case, we have preferred to excise only the more involved kidney in the patient with simultaneous bilateral Wilms’ tumor (Cases 3-6). After metal clip demarcation and biopsy of the tumor on the Iess involved side in simultaneous cases, and on the second side in metachronous cases (Cases 8 and 9), we have administered radiotherapy and multiple courses of chemotherapy. Wide excision of lung metastases has been carried out in one patient in whom there was no radiologic evidence of disappearance after whole chest radiotherapy and systemic chemotherapy (Case 5). For the most part, radiotherapy has consisted of a maximally tolerated dose to the nephrectomy bed (more involved side) and a limited dose to the less involved kidney in synchronous cases and to the second involved kidney in metachronous cases (Cases 3-6,8, and 9). Our first case received maximal-dose bilateral irradiation without chemotherapy and was alive without disease 11 yr later, when she moved and was lost to follow-up. The two patients who died of their disease received only unilateral radiotherapy, in one case to the bed of the excised kidney (Case 2) and in the other to the second involved kidney (Case 7). Pulmonary irradiation was used in two cases, one prophylactically (Case 8) and one for metastases (Case 5); a lobectomy was subsequently done in the latter case. Chemotherapy has consisted in most cases of multiple courses of actinomycin D (AMD) and vincristine (VCR) administered for 15 mo essentially as outlined in the National Wilms’ Tumor Study (NWTS).’ One early patient received no chemotherapy and is apparently cured (Case 1). The two patients who died were given only a limited regimen in one instance (Case 2) and no AMD in the other (Case 7). Adriamycin (ADR) has been given in three cases (Cases 4, 5, and 9). Six of the nine patients with bilateral Wilms’ tumors in this series are alive with no evidence of malignancy (67%). Four have no evidence of neoplasm at all (Cases 1, 3, 5, and 9). Two have been left with residual tumor (benign rhabdomyoma). In one, the tumor is still in situ (Case 8); in the other, excision of the tumor in the lower pole of the kidney was performed because of obstructive uropathy (Case 4). With the exception of Case 1, all of these patients have been treated by conservatively aggressive operative therapy, adequate radiotherapy, and multiple courses of chemotherapy. Two patients died of their Wilms’ tumors. Both had initial radical bilateral excisions and inadequate radiotherapy and chemotherapy by current standards (Cases 2 and 7). The child with pseudohermaphroditism died of glomerulonephritis. There was no evidence of malignancy in the less involved kidney; benign rhabdomyoma was present (Case 6). HISTOPATHOLOGY The Wilms’ tumors in this series were all typical nephroblastomas. Benign rhabdomyomas were found in three cases after radiotherapy and multiple courses of chemotherapy. The affected kidney was not biopsied initially in two
BILATERAL
WILMS’
a63
TUMORS
children. The second tumor was presumed to be a nephroblastoma in one metachronously presenting case (Case 8). In a patient with synchronous presentation of grossly identical-appearing tumors, the less involved side was not biopsied for fear of tumor spillage: the excised tumor 2 yr later was composed of benign rhabdomyoma and mature tubular structures. Definite nephroblastoma was present in the less involved left kidney on initial biopsy in the child with pseudohermaphroditism and glomeronephritis (Case 6). Death was due to renal failure secondary to progressive nephritis. At autopsy, only benign rhabdomyoma was present in the left kidney. DISCUSSION
Bilateral disease has been reported in 4% to 1l”i, of all cases in series of Wilms tumors.2m6 The 9 patients in our series from 65 available records (14%) (or 9 of the total 74 cases listed in our registry [ 12”,/,]) may reflect a referral pattern of more involved cases, with relatively uncomplicated unilateral tumors being treated at other institutions. In accord with the suggestion of Jagasia and associates2 that bilateral Wilms tumors represent separate primaries, we have listed the tumors in our series as occurring concurrently (synchronous tumors) or nonconcurrently (metachronous tumors). The majority of the children with bilateral Wilms’ tumors in our series (785:) were boys, which is distinctly different from the nearly even sex ratio for children with unilateral disease. This is not statistically significant. Analysis of a large number of cases of bilateral tumors has shown a 1.13: 1.OO male-to-female ratio.’ However, the earlier age at which the bilateral tumors presented (677” below 2 yr) and the 67% positive family history for malignancy support suggestions that strong hereditary factors are operative.’ The increased incidence of hypertension among children with bilateral Wilms’ tumors in our series suggests that in patients with apparent unilateral disease and hypertension, palpation alone of the opposite kidney for evidence of bilateral tumors may be inadequate at operation. In agreement with the findings of Sukarochana and associates,’ hypertension in our series had no bearing on survival. In three cases, apparent transformation of the malignant Wilms’ tumor to benign rhabdomyoma occurred in the residual kidney. The finding of bilateral rhabdomyomas of the kidneys following radiation therapy has been reported by Constance? Al! three of our cases received radiotherapy and multiple courses of chemotherapy. Prior biopsy was not obtained in two; however, the other had evidence of the typical histology of nephroblastoma before therapy. It is doubtful that the first two represent benign tumors arising independently opposite to a malignant Wilms’ tumor. Whether these cases represent maturation of the rhabdomyomatous elements in Wilms’ tumor with eradication and/or maturation of the other elements remains speculative. The poor outcome associated with immediate bilateral excision with limited radiation and chemotherapy early in our series, and the significant improvement in prognosis in unilateral Wilms’ tumors associated with adequate radiotherapy and multiple courses of combination chemotherapy, have encouraged US in our conservatively aggressive approach to management. Despite occasional reports of apparent cure of bilateral Wilms tumors with radiation and
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ET AL.
chemotherapy a10ne,4~5~‘o~1’ we have elected to utilize excision of the more involved kidney in synchronous cases. Nephrectomy already has been performed in metachronous cases. Such an approach theoretically may debulk tumor sufficiently that radiotherapy and chemotherapy may have more effect. Delayed contralateral partial nephrectomy may be elected on an individual basis if identifiable malignant tumor remains or urinary obstruction is present. The only two patients who died of Wilms’ tumor in our series were those with early radical excision followed by inadequate radiation and chemotherapy by current standards. A third child died of progressive glomerulonephritis after adequate radiotherapy with several courses of chemotherapy; benign rhabdomyoma was present in the residual kidney at autopsy. This triad of pseudohermaphroditism, Wilms’ tumor, and progressive nephritis has been described.i2 The five children treated with aggressively conservative management are alive without evidence of malignant disease; two were left with residual benign tumors. Bilateral nephrectomy with renal transplantation has been recommended for bilateral Wilms’ tumors.‘3-‘5 The cumulative experience with renal allotransplantation for renal failure is a 36% 3-yr survival and 20% graft function among cadaver-donor renal transplants in children under 5 yr of age; there is a 75% 3-yr survival with 47% graft function among parent-donor transplants.16 Surviving patients with renal transplants for renal failure are also at higher risk of developing other malignancies, especially reticulum cell sarcoma and lymphoma. I7 In view of these data and the potential for impaired growth and susceptibility to intercurrent infection while on immunosuppressive therapy, bilateral nephrectomy and renal transplantation appear to have little place in the current management of bilateral Wilms’ tumors. Limited and staged excisional therapy, with adequate radiotherapy and multiple courses of combined chemotherapy, seems to offer more promise. Another approach that has been suggestedIs consists of initial biopsy bilaterally, followed by chemotherapy and/or radiation therapy; subsequent excision of residual tumor masses is then carried out. Its potential advantage is maximal renal preservation. Its potential disadvantage lies in the increased mass of tumor that must be destroyed, thereby increasing the chance of selecting resistant clones of tumor cells. We have had no experience with this approach. SUMMARY
AND CONCLUSIONS
Among a total of 65 children with Wilms’ tumors treated from 1953 to 1975, bilateral Wilms’ tumors presented synchronously in 6 children and metachronously in 3 others. Most of the bilateral tumors occurred before the age of 2 yr in children with hypertension and a strong family history for malignancy. Two children with initial bilateral excisional therapy and less than currently recommended radiation and chemotherapy died of their disease. Another infant with pseudohermaphroditism died of progressive glomerulonephritis; only benign rhabdomyoma was present at autopsy. Six children with bilateral Wilms’ tumors are alive without evidence of mahgnancy (67%). Five were treated by nephrectomy of the more involved side (synchronously presenting group) or of the first involved kidney (metachro-
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WILMS’
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nously occurring group). A full course of radiotherapy to the bed of the excised kidney and a limited dose to the residual kidney was accompanied by multiple courses of AMD and VCR, and recently ADR therapy. Delayed excision of residual tumor for obstructive uropathy has been performed in one case. With this therapy, three children have been left with benign renal rhabdomyomas. Our experience suggests that initial radical excision with or without transplantation should not be recommended for children with bilateral Wilms’ tumors. Conservatively aggressive management emphasizing excision of the more involved kidney plus adequate radiation and multiple courses of chemotherapy appears to constitute an effective treatment regimen. REFERENCES 1. D’Angio GJ, Beckwith JB, Bishop HC, et al: The national Wilms’ tumor study: A progress report, in: Seventh National Cancer Conference Proceedings. 1973, p 627. AM Cancer Society 2. Jagasia KH, Thurman WC, Pickett E, et al: Bilateral Wilms’ tumors in children. J Pediatr 65371, 1964 3. Johnston JH, Shah MB: Recovery from bilateral Wilms’ tumors. Clin Pediatr 4:394, 1965 4. Bishop HC, Hope JW: Bilateral tumor. J Pediatr Surg 1:476, 1966
Wilms’
5. Ragab AH, Vietti TJ, Crist W, et al: Bilateral Wilms’ tumor. A review. Cancer 30: 983, 1972 6. Fay R, Brosman S, Williams DJ: Bilateral nephroblastoma. J Urol 1 IO: 119,973 7. Cochran W, Groggatt P: Bilateral nephroblastoma in two sisters. J Urol 97:216, 1967 8. Sukarochana K, Tolentino W, Kieswetter WB: Wilms’ tumor and hypertension, J Pediatr Surg 7:573, 1972 9. Constance TJ: Bilateral rhabdomyoma of the kidney. J Pathol Bacterial 59:492, 1947 10. Gypes MT: Diffuse bilateral Wilms’ tu-
mor simulating
multicystic
ology
1964
182:1029,
Radi-
EE, Herlong JH, Harper JM, Wilms’ tumor: Diagnosis and
I I, Anderson et al: Bilateral management.
renal disease.
Clin Pediatr
7:596, 1968
12. Barakat AY, Papadopoulou dra RS, et al: Pseudohermaphroditism, disorder and Wilms’ tumor: Pediatrics 54:366, 1974
ZL,
A unifying
Channephron concept.
13. deLorimier AE, Belzer FO, Kountz SL, et al: Simultaneous bilateral Wilms’ tumor. Surgery
64:850,
1968
14. David HS, Lavengood RW Jr: Bilateral Wilms’ tumor: Treatment, management, and review of the literature. Urology 3:71, 1974 15. Ehrlich RM, Goldman R, Kaufman JJ: Surgery of bilateral Wilms’ tumors: The role of renal transplantation. J Urol 1 I1:276, 1974 16. Bergan JJ, Braun WE, Fraumeni JF Jr, et al: The 11 th report of the human renal transplant registry. JAMA 226: 1197, 1973 17. Newsletter No. 15, ACS/NIH Organ Transplant Registry. Bethesda. NIH. February, 1976 18. Evans A: Personal
communication.
