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Nephroblastoma (Wilms Tumor) and Congenital Aniridia
Vol. 101, Feb. Printed in U.S.A.
THE JouRNAL OF UROLOGY
Copyright © 1969 by The Williams & Wilkins Co.
NEPHROBLASTOMA (WILMS TUMOR) AND CONGEKITAL ANIRIDIA JOHN R. WOODARD*
AND
MICHAEL K. LEVINE
From lhe Department of Surgery/Urology, Emory University School of Jl![edicine ancl the Henrietta Egleston Hospital for Children, A_tlanta, Georgia
Aniridia refers to the congenital absence of the iris. Ocular nystagmus and deficient macular vision accompany this condition which is frequently complicated by cataracts and glaucoma. In the lower peninsula of Michigan in 1959, there was one individual with aniridia for every 64,448 living persons. The incidence of congenital aniridia in Denmark in 1944 was reported as 1 in 96,100. 1 • 2 Nephroblastoma, though one of the most frequently encountered malignant tumors in infants and children, is also rare. An association between nephroblastoma and congenital aniridia was first reported by Miller and associates in 1964.3 That report was based on a review of the records of 440 patients with nephroblastoma at six different institutions and included 6 patients who also had aniridia, an incidence of 1 in 73. 3 Subsequently, 5 cases of nephroblastoma with aniridia have appeared in the literature. 4 • 5 \Ve herein report case 12 and point out some important aspects of this association. CASE REPORT
L. K. O'D., a 7-month-old Caucasian girl, wa8 admitted to the hospital for an eye examination. She had been the 5-pound, 14-ounce product of an uneventful pregnancy and had a congenital left ear deformity and aniridia. Six siblings were in Accepted for publication March 26, 19Ci8. * Current address: University of Alabama Medical Center, Birmingham, Alabama. 1 1Vl\;51lenbach, C. J.: Congenital defects in internal membranes of the eye: clinical and genetic aspects. In: Copenhagen University Institute for Human Genetics. Copenhagen: Munksgaard, vol. 15, p. 152, 1947. 2 Shaw, M. W., Falls, H. ]!'. and Neel, J. V.:
Congenital aniridia. Amer. J. Hum. Genet., 12: 389-415, 19Ci0. ":\liller, R. W., Fraumeni, J. F., Jr. and Manning, JVl. D.: Association of Wilms' tumor with
aniridia, hemihypertrophy and other congenital malformations. New Engl. J. Med., 270: 922-927,
1964.
4 DiGeorge, A. M. and Harley, R. D.: The association of aniridia, Wilms' tumor, and genital abnormalities. Arch. Ophthal., 75: 79Ci-798, 19Ci6. 5 Fontana, V. J., Ferrara, A. and Perciaccante, R.: Wilm's tumor and associated abnormalities. Amer. J. Dis. Child., 109: 459-461, 1965.
140
good health and a seventh had died of neuroblastoma. Doth parents were healthy and there was no family history of aniridia or other ::;ignificant disorders. An admission examination revealed a temperature of 98.6F; pulse, 130 per minute; blood pressure, 140/60 (arm) and 140 systolic (leg). The child was chubby and alert with marked horizontal nystagmus. There was bilateral absence of the iris and a small white opacity was evident in the media of the left eye. The pinna of the left ear was recurved. The right kidney could be palpated but was not considered enlarged. Laboratory data included a hemoglobin of 11 gm., white blood count (WI3C) of 15,600, a normal urinalysis, normal serum electrolytes, a blood urea nitrogen of 18.2 mg. per cent, a serum creatinine of 0.54 mg. per cent, urine vanillyl mandelic acid excretion of 0.4 mg. per 12 hours and 17 ketosteroid excretion of less than 1 mg. per 24 hours. An ophthalmic examination under general anesthesia revealed a corneal diameter of 11 mm. on the right and 10.5 mm. on the left with eye pressures of 20.6 mm. Hg on the right and 17 .3 mm. Hg on the left. Gonioscopy revealed an anterior polar cataract on the left and no cataract on the right. Excretory urography and retrograde pyelography were negative (fig.1). During anesthesia for cystoscopy, the systolic blood pressure averaged 160 mm. Hg. Careful abdominal palpation under anesthesia revealed the right kidney to be palpable but of normal size and shape. Though aortography was considered, it was not carried out and the infant was discharged from the hospital with arrangements for repeat eye examination and excretory urography after 6 months. "\Vhen re-admitted 6 months later, the child's condition was found to be unchanged. An additional 6 months later, at the age of 18 months, the child was taken to her pediatrician's office because of bloody urine, 5 days in duration. A large abdominal mass was evident on the right side, and the child was re-admitted to the hospital. On this admission, the pulse was 110 per minute and temperature lOOF. Since the child was restless and irritable, a reliable blood pressure de-
SEPHHOBLASTOMA AND CONGJ
termination was unobtainable. The remaining physical findings were unchanged from previous aclrni.,sions except for a largP, firm, smooth, apparently nontender mas,, filling the right ~icle of
F1G.
her abdomen a11cl extending 1,o the rnidJine Laboratory cla.ta. iucluclecl a hemoglobin of i gm., a \VBC of 10,500, a normal urina.lysi~ a11rl. a. normal chest x-ra.y. An excretory urogrnm
1. A, excretory 1u·ogram shows bifid right renal pelvis, lrnt 110 other 11bnormality. B. 1111tero-· right retrograde pyelogrnm and C, right posterior oblique retrogrndc pyelogram shinv over--
but no deformity of pelviocalyceal system.
FIG.
2. A, excretory nrog;ram shows evidence of large mass in lo_wer pole of right kid1_1cy with dih-
tation of c11lyces and displacement of calyccal system upward. B, nght k,dm,c· at time ot shows large tumor in lower portion of kidney.
142
WOODARD AND LEVINE
FIG. 3. Photomicrograph of tissue section from tumor shows typical histologic characteristics of nephroblastoma.
vealed a large mass in the lower portion of the right kidney with distortion and displacement of the calyces upward and medially along with some calyceal dilatation (fig. 2, A). A diagnosis of nephroblastoma of the right kidney was made and actinomycin-D was given (a total intravenous dose of 0.075 mg. per kg. divided into 5 daily doses). The next morning a transabdominal right nephrectomy was clone; the tumor was confined to the kidney and well encapsulated (fig. 2, B). The operation was technically satisfactory. Histologically, the tumor was a nephroblastoma (fig. 3). On the day following nephrectomy, external irradiation to the kidney area was started using cobalt 60 and delivering a total tumor dose of 3,038 rads. Convalescence was uneventful. Two months later the blood pressure was 110/40 and a chest film was negative. DISCUSSION
In a detailed review of congenital aniridia, Shaw noted that 76 of 118 living aniridics in Michigan had a parent with the same congenital defect. That is, approximately % of the cases of aniridia had a definite hereditary basis. The anomaly is apparently caused by an autosomal dominant gene with high penetrance and constant expression. The remaining }13 of the cases of aniridia occur as isolated instances with no familial history. When Shaw attempted to analyze the data on these latter patients, he found
the months of conception to be evenly distributed, the birth rank to be irrelevant and the pregnancy histories to be negative. 2 The nephroblastomas that have been reported in association with aniridia, including our own case, have been associated with non-familial or isolated type of aniridia. That 12 cases of nephroblastoma have occurred in association with this rare congenital abnormality seems most significant. Of the 7 cases described by Fontana, 5 also had associated cataracts, 3 microcephaly, 3 mental retardation, 4 curved pinna and 2 retarded bone age. 5
It follows that a nephroblastoma should be suspected in any infant with non-familial aniridia. If the excretory urogram is negative one wonders whether further studies such as arteriography should be undertaken. Williams has stated that he knew of no patient with nephroblastoma who had had a previously normal excretory urogram. 6 Reports, however, of bilateral nephroblastoma do include pyelograms originally interpreted as normal though there is the question of a metastatic lesion rather than a new primary in these instances. 7 • 8 6
Williams, D. I.: Personal communication,
1968. 7 Bishop, H. C. and Hope, J. W.: Bilateral Wilms' tumors. J. Pediat. Surg., 1: 476-487, 1966. 8 l\Iartin, L. \V. and Kloecker, R. J.: Bilateral nephroblastoma (Wilms' tumor). Pediatrics,
28: 101-106, 1961.
NEPHROBLASTOMA AND CONGENITAL ANIRIDIA
It is evident that patients whose nephroblastoma is diagnosed at an early age, prior to 2 years, l1ave a better prognosis than patients having their diagnosis made after 2 years of age. 9 Though the apparent cure rate has improved remarkably in recent years, the age at diagnosis remains very important. The high incidence of nephroblastoma, arnong patients with non-familial aniridia should produce a much earlier diagnosis in these particular patients. Of those reported in the literature, the average age at the time of diagnosis has been less than 3 years, as compared with an average age at diagnosis of 3.2 years rcr;ordecl for nephroblastoma generally .10 ,vith the increasing awareness of this association, the diagnosis of these cases should be made even earlier. 9 Gross, R, E. and Neuhauser, E. B. S.: Treatment of mixed tumors of kidney in childhood. Pediatrics, 6: 843-852, 1943. 10 Abeshonse, B. S.: The management of Wilms' tumor as determined by national survey and review of the literature. J. UroL, 77: 792-813,
1957.
Two things are evident from our patient: patients with nephroblastoma may in at some stage, have an excretory urogram tlmt would be interpreted as normal and 2) even 6-month intervab are not frequent enough for obtaining followup excretory urograms in infants with nonfarnilial aniridia. It was lfoappointing; that our patient. finally presented with the classical picture of nephroblastoma in of being evaluated at 6-rnonth intervals. SUMMARY AND COKCLUSIONS
Since 1964 there have been 12 cases of nephroblastoma reported in patients with non-famifail aniridia. In view of the low incidence of both die· eases, this is a. most significant association. Tn spite of this awareness, a truly early diagnosis of nephroblastorna may be difficult, making careful and frequent re-evaluation necessary.
THE JouRNAL OF UROLOGY
Copyright © 1969 by The Williams & Wilkins Co.
NEPHROBLASTOMA (WILMS TUMOR) AND CONGEKITAL ANIRIDIA JOHN R. WOODARD*
AND
MICHAEL K. LEVINE
From lhe Department of Surgery/Urology, Emory University School of Jl![edicine ancl the Henrietta Egleston Hospital for Children, A_tlanta, Georgia
Aniridia refers to the congenital absence of the iris. Ocular nystagmus and deficient macular vision accompany this condition which is frequently complicated by cataracts and glaucoma. In the lower peninsula of Michigan in 1959, there was one individual with aniridia for every 64,448 living persons. The incidence of congenital aniridia in Denmark in 1944 was reported as 1 in 96,100. 1 • 2 Nephroblastoma, though one of the most frequently encountered malignant tumors in infants and children, is also rare. An association between nephroblastoma and congenital aniridia was first reported by Miller and associates in 1964.3 That report was based on a review of the records of 440 patients with nephroblastoma at six different institutions and included 6 patients who also had aniridia, an incidence of 1 in 73. 3 Subsequently, 5 cases of nephroblastoma with aniridia have appeared in the literature. 4 • 5 \Ve herein report case 12 and point out some important aspects of this association. CASE REPORT
L. K. O'D., a 7-month-old Caucasian girl, wa8 admitted to the hospital for an eye examination. She had been the 5-pound, 14-ounce product of an uneventful pregnancy and had a congenital left ear deformity and aniridia. Six siblings were in Accepted for publication March 26, 19Ci8. * Current address: University of Alabama Medical Center, Birmingham, Alabama. 1 1Vl\;51lenbach, C. J.: Congenital defects in internal membranes of the eye: clinical and genetic aspects. In: Copenhagen University Institute for Human Genetics. Copenhagen: Munksgaard, vol. 15, p. 152, 1947. 2 Shaw, M. W., Falls, H. ]!'. and Neel, J. V.:
Congenital aniridia. Amer. J. Hum. Genet., 12: 389-415, 19Ci0. ":\liller, R. W., Fraumeni, J. F., Jr. and Manning, JVl. D.: Association of Wilms' tumor with
aniridia, hemihypertrophy and other congenital malformations. New Engl. J. Med., 270: 922-927,
1964.
4 DiGeorge, A. M. and Harley, R. D.: The association of aniridia, Wilms' tumor, and genital abnormalities. Arch. Ophthal., 75: 79Ci-798, 19Ci6. 5 Fontana, V. J., Ferrara, A. and Perciaccante, R.: Wilm's tumor and associated abnormalities. Amer. J. Dis. Child., 109: 459-461, 1965.
140
good health and a seventh had died of neuroblastoma. Doth parents were healthy and there was no family history of aniridia or other ::;ignificant disorders. An admission examination revealed a temperature of 98.6F; pulse, 130 per minute; blood pressure, 140/60 (arm) and 140 systolic (leg). The child was chubby and alert with marked horizontal nystagmus. There was bilateral absence of the iris and a small white opacity was evident in the media of the left eye. The pinna of the left ear was recurved. The right kidney could be palpated but was not considered enlarged. Laboratory data included a hemoglobin of 11 gm., white blood count (WI3C) of 15,600, a normal urinalysis, normal serum electrolytes, a blood urea nitrogen of 18.2 mg. per cent, a serum creatinine of 0.54 mg. per cent, urine vanillyl mandelic acid excretion of 0.4 mg. per 12 hours and 17 ketosteroid excretion of less than 1 mg. per 24 hours. An ophthalmic examination under general anesthesia revealed a corneal diameter of 11 mm. on the right and 10.5 mm. on the left with eye pressures of 20.6 mm. Hg on the right and 17 .3 mm. Hg on the left. Gonioscopy revealed an anterior polar cataract on the left and no cataract on the right. Excretory urography and retrograde pyelography were negative (fig.1). During anesthesia for cystoscopy, the systolic blood pressure averaged 160 mm. Hg. Careful abdominal palpation under anesthesia revealed the right kidney to be palpable but of normal size and shape. Though aortography was considered, it was not carried out and the infant was discharged from the hospital with arrangements for repeat eye examination and excretory urography after 6 months. "\Vhen re-admitted 6 months later, the child's condition was found to be unchanged. An additional 6 months later, at the age of 18 months, the child was taken to her pediatrician's office because of bloody urine, 5 days in duration. A large abdominal mass was evident on the right side, and the child was re-admitted to the hospital. On this admission, the pulse was 110 per minute and temperature lOOF. Since the child was restless and irritable, a reliable blood pressure de-
SEPHHOBLASTOMA AND CONGJ
termination was unobtainable. The remaining physical findings were unchanged from previous aclrni.,sions except for a largP, firm, smooth, apparently nontender mas,, filling the right ~icle of
F1G.
her abdomen a11cl extending 1,o the rnidJine Laboratory cla.ta. iucluclecl a hemoglobin of i gm., a \VBC of 10,500, a normal urina.lysi~ a11rl. a. normal chest x-ra.y. An excretory urogrnm
1. A, excretory 1u·ogram shows bifid right renal pelvis, lrnt 110 other 11bnormality. B. 1111tero-· right retrograde pyelogrnm and C, right posterior oblique retrogrndc pyelogram shinv over--
but no deformity of pelviocalyceal system.
FIG.
2. A, excretory nrog;ram shows evidence of large mass in lo_wer pole of right kid1_1cy with dih-
tation of c11lyces and displacement of calyccal system upward. B, nght k,dm,c· at time ot shows large tumor in lower portion of kidney.
142
WOODARD AND LEVINE
FIG. 3. Photomicrograph of tissue section from tumor shows typical histologic characteristics of nephroblastoma.
vealed a large mass in the lower portion of the right kidney with distortion and displacement of the calyces upward and medially along with some calyceal dilatation (fig. 2, A). A diagnosis of nephroblastoma of the right kidney was made and actinomycin-D was given (a total intravenous dose of 0.075 mg. per kg. divided into 5 daily doses). The next morning a transabdominal right nephrectomy was clone; the tumor was confined to the kidney and well encapsulated (fig. 2, B). The operation was technically satisfactory. Histologically, the tumor was a nephroblastoma (fig. 3). On the day following nephrectomy, external irradiation to the kidney area was started using cobalt 60 and delivering a total tumor dose of 3,038 rads. Convalescence was uneventful. Two months later the blood pressure was 110/40 and a chest film was negative. DISCUSSION
In a detailed review of congenital aniridia, Shaw noted that 76 of 118 living aniridics in Michigan had a parent with the same congenital defect. That is, approximately % of the cases of aniridia had a definite hereditary basis. The anomaly is apparently caused by an autosomal dominant gene with high penetrance and constant expression. The remaining }13 of the cases of aniridia occur as isolated instances with no familial history. When Shaw attempted to analyze the data on these latter patients, he found
the months of conception to be evenly distributed, the birth rank to be irrelevant and the pregnancy histories to be negative. 2 The nephroblastomas that have been reported in association with aniridia, including our own case, have been associated with non-familial or isolated type of aniridia. That 12 cases of nephroblastoma have occurred in association with this rare congenital abnormality seems most significant. Of the 7 cases described by Fontana, 5 also had associated cataracts, 3 microcephaly, 3 mental retardation, 4 curved pinna and 2 retarded bone age. 5
It follows that a nephroblastoma should be suspected in any infant with non-familial aniridia. If the excretory urogram is negative one wonders whether further studies such as arteriography should be undertaken. Williams has stated that he knew of no patient with nephroblastoma who had had a previously normal excretory urogram. 6 Reports, however, of bilateral nephroblastoma do include pyelograms originally interpreted as normal though there is the question of a metastatic lesion rather than a new primary in these instances. 7 • 8 6
Williams, D. I.: Personal communication,
1968. 7 Bishop, H. C. and Hope, J. W.: Bilateral Wilms' tumors. J. Pediat. Surg., 1: 476-487, 1966. 8 l\Iartin, L. \V. and Kloecker, R. J.: Bilateral nephroblastoma (Wilms' tumor). Pediatrics,
28: 101-106, 1961.
NEPHROBLASTOMA AND CONGENITAL ANIRIDIA
It is evident that patients whose nephroblastoma is diagnosed at an early age, prior to 2 years, l1ave a better prognosis than patients having their diagnosis made after 2 years of age. 9 Though the apparent cure rate has improved remarkably in recent years, the age at diagnosis remains very important. The high incidence of nephroblastoma, arnong patients with non-familial aniridia should produce a much earlier diagnosis in these particular patients. Of those reported in the literature, the average age at the time of diagnosis has been less than 3 years, as compared with an average age at diagnosis of 3.2 years rcr;ordecl for nephroblastoma generally .10 ,vith the increasing awareness of this association, the diagnosis of these cases should be made even earlier. 9 Gross, R, E. and Neuhauser, E. B. S.: Treatment of mixed tumors of kidney in childhood. Pediatrics, 6: 843-852, 1943. 10 Abeshonse, B. S.: The management of Wilms' tumor as determined by national survey and review of the literature. J. UroL, 77: 792-813,
1957.
Two things are evident from our patient: patients with nephroblastoma may in at some stage, have an excretory urogram tlmt would be interpreted as normal and 2) even 6-month intervab are not frequent enough for obtaining followup excretory urograms in infants with nonfarnilial aniridia. It was lfoappointing; that our patient. finally presented with the classical picture of nephroblastoma in of being evaluated at 6-rnonth intervals. SUMMARY AND COKCLUSIONS
Since 1964 there have been 12 cases of nephroblastoma reported in patients with non-famifail aniridia. In view of the low incidence of both die· eases, this is a. most significant association. Tn spite of this awareness, a truly early diagnosis of nephroblastorna may be difficult, making careful and frequent re-evaluation necessary.