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Bilateral Wilms’s Tumor in a Male Pseudohermaphrodite
THE JOURNAL OF UROLOGY
Vol. 72, No. 6, December 1954 Printed in U.S.A.
BILATERAL WILMS'S TUMOR IN A MALE PSEUDO HERMAPHRODITE THOMAS A. STUMP
AND
ROBERT A. GARRETT
From the Departments of Pathology and Urology of the Indiana University School of Medicine, Indianapolis, Ind.
Wilms's tumor associated with pseudohermaphroditism has not previously been reported in the literature. The case to be presented is even more unusual in that the Wilms's tumor was bilateral. Pseudohermaphroditism is not uncommon, occurring in one out of every one thousand births;1 but bilateral Wilms's tumor is exceedingly rare. Campbell,2 in 1948, when reviewing the literature, found 14 cases of bilateral vVilms's tumors. He reported two additional cases of his own. Of the 14 cases appearing in the literature previous to 1948, ten were reported by Walker3 in a review of the medical literature prior to 1897. Many of these cases were diagnosed by physical examination only and could have easily been polycystic kidneys, hydronephrosis, or some other intra-abdominal tumor. Of the remaining 4 cases reviewed by Campbell, the one reported by Kretschmer and Hibbs4 in 1931 was probably a metastasis. Riches, Griffiths and Thackray 6 in a review of 189 cases of Wilms's tumor found one that was bilateral and two in which there were metastases to the opposite kidney. Barr and Schulte 6 reported a bilateral Wilms's tumor in 1951. CASE REPORT
The patient was born October 24, 1950. Its birth weight was 7 pounds, 9 ounces. The child was normal in all respects except for the genitalia. It had a bifid scrotum, undescended testicles and hypospadias with a urethral opening in the perineum at the base of the penis. The father was 32 years old; the mother was 30 years old and in good health. The pregnancy and delivery were uneventful. The patient had 2 sisters, one 5 years old and the other 8 years old. The mother's first pregnancy ended with the delivery of a stillborn infant at 8 months. There was no family history of any previous congenital abnormalities. The infant developed normally. It was first admitted to James vVhitcomb Riley Hospital on May 12, 1951. A vaginal cystogram made on May 15, 1951 revealed a persistent urogenital sinus into which the urethra and a short vagina Accepted for publication March 17, 1954. 1 Stollmeyer, J.E. C. and Latum, J.P. A.: Pseudohermaphroditism. Canad. M.A. J., 63: 494-495, 1950. 2 Campbell, M. F.: Bilateral embryonal adenomyosarcoma of the kidney. J. Urol., 59: 567-511, 1948. 3 Walker, J. B. :· Sarcoma of the kidney in children. Ann. Surg., 26: 529-602, 1897. 4 Kretschmer, H. L. and Hibbs, W. G.: Mixed tumors of the kidney in infancy and childhood. Surg., Gynec. & Obst., 52: 1-24, 1931. 5 Riches, E. W., Griffiths, I. H. and Thackray, A. C.: New growths of the kidney and ureter. Brit. J. Urol., 23: 297-338, 1951. 6 Barr, J. R. and Schulte, J. W.: Bilateral Wilms' tumor; a case report. West. J. Surg., Obst. & Gynec., 58: 567-570, 1950. 1146
WILMS'S TUMOR IN PSEUDOHERMAPHRODITE
1147
emptied. In one film there was suggestion of dye in a fallopian tube. The patient was discharged May 19, 1951. The infant was re-admitted on October 20, 1951. It weighed 20 pounds at this time and was normal in all respects except for the genitalia. A laparotomy was performed on October 22, 1951, for the purpose of ascertaining the true sex of the infant. A small uterus was found, 1 cm. long and½ cm. in its greatest diameter. Two fallopian tubes arose from the uterus. Near the end of the right fallopian tube was a gonad that looked like a testicle and received its blood
Fm. 1. A, clinical picture taken May 16, 1951, at approximately seven months of age. Note penis, cleft scrotum, and urogenital sinus at base of p~nis. B ,. rihotomicrograph of biopsy taken from right gonad on October 22, 1951. Infantile semm1ferous tubules are easily discernible. Ley dig cells are not apparent.
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T. A. STUMP AND R. A. GARRETT
supply from the region of the right kidney. The end of the left tube was adherent to the colon and had to be dissected free. A matted structure that was thought to be a gonad was found at the end of this tube. Biopsies were taken from the gonadal structures. That taken from the right gonad was infantile testicular tissue. Biopsy of the matted structure on the left proved to be primitive oviduct. The infant did well postoperatively and was discharged on October 31, 1951. It was planned to have the patient return at a later date for an attempt to find the left gonad. The patient was not returned to the out-patient clinic as scheduled and was not seen again until referred to the hospital by the family doctor on September 25, 1952. The child had progressed well until 3 months before this time when the parents noticed that it had a loss of energy and that it was developing a swelling in its abdomen. Physical examination revealed a mass occupying the entire left upper quadrant. Attempted retrograde pyelograms were unsuccessful due to the anomalous urethra and urogenital sinus. An excretory urogram revealed a large, diffuse mass in the left lower quadrant. Only two or three slightly dilated minor calyces were visible on the left. The right kidney showed a moderate dilatation of the lower calyces plus a double renal pelvis. A total of 1660 gamma roentgen units were given the tumor mass over a nineteen-day period without any reduction in its size. A transabdominal nephrectomy was done on September 17, 1952. The tumor mass, together with the kidney, measured 17 by 10 by 8 cm. and weighed 900 gm. The entire mass including the kidney was well encapsulated. The capsule was intact. Grossly and microscopically, the tumor had the appearance of a typical Wilms's tumor with nearly all types of tissue described in a Wilms's tumor present, including small tubules surrounded by spindleshaped primitive connective tissue cells, myxomatous tissue and smooth muscle. On the posterior surface, near the mid-zone of the tumor, there was a small amount of kidney tissue measuring 7 by 5 by 3 cm. and well demarcated from the neoplasm. The patient withstood the operation well and was started on roentgen therapy again on September 24, 1952. He received 900 units in 11 days. Therapy was discontinued on October 8, 1952 because of the accompanying nausea and vomiting. He improved rapidly following the cessation of the x-ray therapy and was discharged on October 14, 1952, in good condition. He got along well until November 1, 1952, when he had an acute attack of asthma. The next day, according to the mother, he was unable to void. For the next few days, he passed only a small amount of bloody urine. He was admitted to the hospital again on November 6, 1952. Physical examination revealed a mass in the right upper quadrant and in the right flank. Hirsutism was noted on this admission. The nonprotein nitrogen on admission was 133 mg. per 100 ml., and the serum potassium was 7.7 mEq. Attempts to do a retrograde pyelogram were again unsuccessful. On November 7, 1952, an exploratory operation was done through a right flank incision. A tumor on the right kidney was found which extended from the liver to the
'\VILMS'S TUMOR IN PSEUDOHERlVIAPHRODITE
1149
pelvic rim. The ureter was tortuous and distended almost to the size of the large intestine. The ureter was incised and gray necrotic tissue protruded from the incision. Urine began to flow from the ureter as the necrotic tissue was removed. Following surgery, urine drained from the wound. The blood pressure increased to 220/160 mm. of Hg, but dropped to 170/125 in the next 24 hours. The patient's temperature remained normal and he began taking some food. By November 15, 1952, urme continued to pass around the Penrose drain
FIG. 2. A, photomicrograph of Wilms's tumor on left, removed at surgery. Tubular structures surrounded by spindle shaped connective tissue cells are demonstrated in this area. B, area in right Wilms' tumor, removed at autopsy, showing similarity to first tumor shown in A. In addition to tubular structures and spindle shaped connective tissue cystic space lined by columnar epithelium is also present. ' ·
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T. A. STUMP AND R. A. GARRETT
and a small fistulous opening in the wound. The blood pressure had decreased to 150/110. A chest x-ray taken on November 7, 1952 demonstrated throughout both lung fields numerous miliary densities which were thought to represent azotemic pneumonia. He was released at the parents' request on November 15, 1952. The Penrose drain came out and the child ceased to urinate the day he went home. He was re-admitted the next day. His blood pressure on November 16, 1952 was 150/100. Physical examination again revealed the mass in the right flank. Hirsutism was still quite prominent. His urine on this admission was grossly bloody and loaded with pus. The TNPN was 225 mg. per 100 ml. of blood on November 21, 1952. He passed very little urineafter hewasre-admitted. He took a little food but soon became unresponsive and was sustained on intravenous and subcutaneous fluid. He died on November 29, 1952 at the age of 25 months. Autopsy findings: A large retroperitoneal mass on the right side extended from the diaphragm to the pelvic rim. This mass consisted of the enlarged right kidney with the central spherical vVilms's tumor. The tumor tissue was 4½ cm. in diameter. The renal calyces showed moderate hydronephrotic changes, although there was no dilatation of the ureter. Scattered throughout the right kidney there were many small abscesses 1 to 3 mm. in diameter. The left kidney had been removed. There was no evidence of any metastases from either the Wilms's tumor on the right or from the Wilms's tumor which had been removed surgically on the left. The left ureter was found 3 cm. above the left pelvic rim and was normal. The urinary bladder was normal. There was a small uterus in normal relationship with a vagina. The urethra and vagina met to form a short urogenital sinus. Normal left and right fallopian tubes were present. The testicle was present on the right side in the position that the ovary normally occupies. No gonad was found on the left. COMMENT
Due to the rarity of bilateral Wilms's tumors and the inability to perform retrograde pyelograms on this patient, the diagnosis was not made when the first kidney was removed. The tumor mass in the left kidney was well encapsulated and gave no evidence of having broken through the capsule at any point. The hydro-ureter and the pelvic changes in the right kidney seen in the intravenous pyelogram were, in retrospect, changes produced by the Wilms's tumor in that kidney. In this case it is impossible to prove that one of these tumors was not a metastasis from the other; however, Wilms's tumor metastasizing to the kidney is in itself a rarity. 5 • 7 The fact that there was no neoplastic tissue anywhere except in the kidneys also implies a bilateral origin. Wilms's tumors usually metastasize first to the lungs, and then to the liver. Hermaphroditism has interested medical science from ancient times. Many 7 Mixter, C. G.: Malignant tumors of the kidney in infancy and childhood. Ann. Surg., 96: 1017-1027, 1932.
WILMS'S TUMOR IN PSEUDOHERMAPHRODITE
1151
races have depicted pseudohermaphrodites in their ancient works of art. 8 The causes of true and pseudohermaphroditism have not been completely solved. It is assumed that sex determination in the human follows the typical mammalian pattern, in which the female sex is determined by the presence of two x chromosomes in the zygote, and the male sex is determined by the presence of a single x chromosome (the y chromosome from the male parent probably being functionless) in the fertilized ovum. It is impossible to determine the sex of the embryo until the sixth week when the embryological seminiferous tubules develop. The ovary does not form structures which positively identify it until the ninth week. The medulla of the gonad differentiates to form the testicle while the cortex first differentiates in forming the primitive ovary. It is believed that the hormone supplied by the medulla, if it is dominant, aids further in establishing male characteristics. 9 True hermaphroditism is probably a genetic factor. Pseudohermaphroditism is probably produced by an excessive stimulation from hormones of the opposite sex from the fetal gonads. 10 Thus, if there are excessive androgens in the case of the female embryo or excessive estrogens in the case of the male embryo, a pseudohermaphrodite will result. This had been demonstrated by Greene, Burrill, and Ivy11 in rats and by Hamilton and 1Volfe 12 in mice. If androgens are given a pregnant rat early in pregnancy, a retention of the upper wolffian derivaties and an inhibition of part of the miillerian derivatives results. Female offspring of mothers treated with androgens during pregnancy are born with a retention of remnants of the epididymal tract, inhibition of part of the uterine tract, enlarged clitoris, large labia and occasionally with an agenesis of the vagina and sometimes with retention of remnants of the prostate. If estrogens are given a pregnant rat early in pregnancy, the male embryo shows retention of the upper miillerian derivatives and an inhibition of wolffian derivatives. Estrogens given late in pregnancy cause a retention of lower miillerian derivatives in the male offspring, and an inhibition of parts of the wolffian derivatives occurs. These rats at birth have an inhibition of parts of the epididymal tract, the retention of parts of the uterine tract, undescended testicles, small penis with hypospadias, cleft scrotum and occasionally a vagina. Sometimes no prostate develops. Strangely enough, in female rats whose mothers are given an increased amount of estrogen during pregnancy, the wolflian ducts persist and the urogenital sinus is inhibited. This effect is not seen in the mouse. 13 In the case of the human pseudohermaphrodite, excessive hormones are 8 Young, H. H.: Genital Abnormalities, Hermaphroditism and Related Adrenal Disease. Baltimore: Williams and Wilkins Co., 1937. 9 Arey, L.B.: Developmental Anatomy. Philadelphia and London: W. B. Saunders Co., 1934. 10 Sisk, I. R. and Cornwell, P. M.: Pseudohermaphroditism. J. Urol., 47: 721-737, 1942. 11 Greene, R.R., Burrill, M. W. and Ivy, A. C. Experimental intersexuality: the effect of estrogens on the antenatal sexual development of the rat. Am. J. Anat., 67: 305-345, 1940. 12 Hamilton, J. B. and Wolfe, J.M. The effect of male hormone substances from birth and prenatal development in the rat. Anat. Rec., 70: 433-440, 1938. 13 Melicow, M. M. and Cahill, G. F.: Role of adrenal cortex in somatosexual disturbances in infants and children: Clinicopathologic analysis. J. Clin. Endocrinol., 10: 24-53, 1950.
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T. A. STUMP AND R. A. GARRETT
available from several sources. In the case of the female pseudohermaphrndite, there is often an associated hyperplasia or neoplasm of the adrenal cort~x. In these infants, the adrenal cortex tumors of adults will often produce androgens which can be easily demonstrated. Vines (as quoted by Sisk and Cornwell10 ) believed that in some female ptjleudohermaphrodites there is a persistence of the fuchsinophil cells in the adrenal cortex in embryonic life over a longer period than usual. The adrenal cortical cells containing fuchsinophil granules were believed to have been the cells which produced androgens. These fuchsinophil cells are present in the female embryo from the twelfth to the fifteenth week; and in the male, from the ninth to the twentieth week. Others believe that the fuchsinophil granules arei of no significance. Sudds14 has shown that they occur in the adult about equ1;tlly in the two sexes. They first appear when an adult is about 25 years old and tend to increase during life. In adults, they are related to age and have nothing to do with sex. There are some who believe that the adrenal cortex of the embryo can produce estrogen in large enough quantities to cause male pseudohermaphroditism. This has never been clearly demonstrated. Only thirteen feminizing tumors of the adrenal cortex have ever been reported; two in children and eleven in adults. 15 The estrogenic hormones could conceivably come from the cortex of the fetal gonad before it has fully differentiated. Another plausible theory is that the estrogens are supplied in excessive amounts by the mother. It is interesting that pseudohermaphroditism is associated here with the bilateral Wilms's tumor. Testicular tumors not infrequently develop in male pseudohermaphrodites; 16 • 17 however, in spite of the fact that both Wilms's tumor and pseudohermaphroditism are related to a disturbance in the tissues developing from the urogenital ridge, the two conditions occurring simultaneously have never been previously reported. SUMMARY
A case of bilateral Wilms's tumor in a male pseudohermaphrodite is reported. We wish to express our gratitude to Frank Vellios, M.D., and John J. Mahoney, Ph.D., for helpful comments and criticism. Photographs were taken by the Department of Medical Illustration of Indiana University School of Medicine. 14 Sudds, V. N.: The cell contents of the cortex of the suprarenal gland. Endocrinology, 26: 895-899, 1940. 15 Wilkins, L.: A feminizing adrenal tumor causing gynecomastia in a boy five years contrasted with a virilizing tumor in a five year old girl. J. Clin. Endocrinol., 8: 111-129, 1948. 16 Carmichael, R. and Oldfield, C.: Complete male pseudohermaphroditism with intrauterine teratoma testis. J. Path. and Bact., 39: 617-622, 1934. 17 Gilbert, J.B.: Malignant testis tumors in pseudohermaphrodites: review of 60 cases and a case report. J. Urol., 48: 665-672, 1942.
Vol. 72, No. 6, December 1954 Printed in U.S.A.
BILATERAL WILMS'S TUMOR IN A MALE PSEUDO HERMAPHRODITE THOMAS A. STUMP
AND
ROBERT A. GARRETT
From the Departments of Pathology and Urology of the Indiana University School of Medicine, Indianapolis, Ind.
Wilms's tumor associated with pseudohermaphroditism has not previously been reported in the literature. The case to be presented is even more unusual in that the Wilms's tumor was bilateral. Pseudohermaphroditism is not uncommon, occurring in one out of every one thousand births;1 but bilateral Wilms's tumor is exceedingly rare. Campbell,2 in 1948, when reviewing the literature, found 14 cases of bilateral vVilms's tumors. He reported two additional cases of his own. Of the 14 cases appearing in the literature previous to 1948, ten were reported by Walker3 in a review of the medical literature prior to 1897. Many of these cases were diagnosed by physical examination only and could have easily been polycystic kidneys, hydronephrosis, or some other intra-abdominal tumor. Of the remaining 4 cases reviewed by Campbell, the one reported by Kretschmer and Hibbs4 in 1931 was probably a metastasis. Riches, Griffiths and Thackray 6 in a review of 189 cases of Wilms's tumor found one that was bilateral and two in which there were metastases to the opposite kidney. Barr and Schulte 6 reported a bilateral Wilms's tumor in 1951. CASE REPORT
The patient was born October 24, 1950. Its birth weight was 7 pounds, 9 ounces. The child was normal in all respects except for the genitalia. It had a bifid scrotum, undescended testicles and hypospadias with a urethral opening in the perineum at the base of the penis. The father was 32 years old; the mother was 30 years old and in good health. The pregnancy and delivery were uneventful. The patient had 2 sisters, one 5 years old and the other 8 years old. The mother's first pregnancy ended with the delivery of a stillborn infant at 8 months. There was no family history of any previous congenital abnormalities. The infant developed normally. It was first admitted to James vVhitcomb Riley Hospital on May 12, 1951. A vaginal cystogram made on May 15, 1951 revealed a persistent urogenital sinus into which the urethra and a short vagina Accepted for publication March 17, 1954. 1 Stollmeyer, J.E. C. and Latum, J.P. A.: Pseudohermaphroditism. Canad. M.A. J., 63: 494-495, 1950. 2 Campbell, M. F.: Bilateral embryonal adenomyosarcoma of the kidney. J. Urol., 59: 567-511, 1948. 3 Walker, J. B. :· Sarcoma of the kidney in children. Ann. Surg., 26: 529-602, 1897. 4 Kretschmer, H. L. and Hibbs, W. G.: Mixed tumors of the kidney in infancy and childhood. Surg., Gynec. & Obst., 52: 1-24, 1931. 5 Riches, E. W., Griffiths, I. H. and Thackray, A. C.: New growths of the kidney and ureter. Brit. J. Urol., 23: 297-338, 1951. 6 Barr, J. R. and Schulte, J. W.: Bilateral Wilms' tumor; a case report. West. J. Surg., Obst. & Gynec., 58: 567-570, 1950. 1146
WILMS'S TUMOR IN PSEUDOHERMAPHRODITE
1147
emptied. In one film there was suggestion of dye in a fallopian tube. The patient was discharged May 19, 1951. The infant was re-admitted on October 20, 1951. It weighed 20 pounds at this time and was normal in all respects except for the genitalia. A laparotomy was performed on October 22, 1951, for the purpose of ascertaining the true sex of the infant. A small uterus was found, 1 cm. long and½ cm. in its greatest diameter. Two fallopian tubes arose from the uterus. Near the end of the right fallopian tube was a gonad that looked like a testicle and received its blood
Fm. 1. A, clinical picture taken May 16, 1951, at approximately seven months of age. Note penis, cleft scrotum, and urogenital sinus at base of p~nis. B ,. rihotomicrograph of biopsy taken from right gonad on October 22, 1951. Infantile semm1ferous tubules are easily discernible. Ley dig cells are not apparent.
1148
T. A. STUMP AND R. A. GARRETT
supply from the region of the right kidney. The end of the left tube was adherent to the colon and had to be dissected free. A matted structure that was thought to be a gonad was found at the end of this tube. Biopsies were taken from the gonadal structures. That taken from the right gonad was infantile testicular tissue. Biopsy of the matted structure on the left proved to be primitive oviduct. The infant did well postoperatively and was discharged on October 31, 1951. It was planned to have the patient return at a later date for an attempt to find the left gonad. The patient was not returned to the out-patient clinic as scheduled and was not seen again until referred to the hospital by the family doctor on September 25, 1952. The child had progressed well until 3 months before this time when the parents noticed that it had a loss of energy and that it was developing a swelling in its abdomen. Physical examination revealed a mass occupying the entire left upper quadrant. Attempted retrograde pyelograms were unsuccessful due to the anomalous urethra and urogenital sinus. An excretory urogram revealed a large, diffuse mass in the left lower quadrant. Only two or three slightly dilated minor calyces were visible on the left. The right kidney showed a moderate dilatation of the lower calyces plus a double renal pelvis. A total of 1660 gamma roentgen units were given the tumor mass over a nineteen-day period without any reduction in its size. A transabdominal nephrectomy was done on September 17, 1952. The tumor mass, together with the kidney, measured 17 by 10 by 8 cm. and weighed 900 gm. The entire mass including the kidney was well encapsulated. The capsule was intact. Grossly and microscopically, the tumor had the appearance of a typical Wilms's tumor with nearly all types of tissue described in a Wilms's tumor present, including small tubules surrounded by spindleshaped primitive connective tissue cells, myxomatous tissue and smooth muscle. On the posterior surface, near the mid-zone of the tumor, there was a small amount of kidney tissue measuring 7 by 5 by 3 cm. and well demarcated from the neoplasm. The patient withstood the operation well and was started on roentgen therapy again on September 24, 1952. He received 900 units in 11 days. Therapy was discontinued on October 8, 1952 because of the accompanying nausea and vomiting. He improved rapidly following the cessation of the x-ray therapy and was discharged on October 14, 1952, in good condition. He got along well until November 1, 1952, when he had an acute attack of asthma. The next day, according to the mother, he was unable to void. For the next few days, he passed only a small amount of bloody urine. He was admitted to the hospital again on November 6, 1952. Physical examination revealed a mass in the right upper quadrant and in the right flank. Hirsutism was noted on this admission. The nonprotein nitrogen on admission was 133 mg. per 100 ml., and the serum potassium was 7.7 mEq. Attempts to do a retrograde pyelogram were again unsuccessful. On November 7, 1952, an exploratory operation was done through a right flank incision. A tumor on the right kidney was found which extended from the liver to the
'\VILMS'S TUMOR IN PSEUDOHERlVIAPHRODITE
1149
pelvic rim. The ureter was tortuous and distended almost to the size of the large intestine. The ureter was incised and gray necrotic tissue protruded from the incision. Urine began to flow from the ureter as the necrotic tissue was removed. Following surgery, urine drained from the wound. The blood pressure increased to 220/160 mm. of Hg, but dropped to 170/125 in the next 24 hours. The patient's temperature remained normal and he began taking some food. By November 15, 1952, urme continued to pass around the Penrose drain
FIG. 2. A, photomicrograph of Wilms's tumor on left, removed at surgery. Tubular structures surrounded by spindle shaped connective tissue cells are demonstrated in this area. B, area in right Wilms' tumor, removed at autopsy, showing similarity to first tumor shown in A. In addition to tubular structures and spindle shaped connective tissue cystic space lined by columnar epithelium is also present. ' ·
1150
T. A. STUMP AND R. A. GARRETT
and a small fistulous opening in the wound. The blood pressure had decreased to 150/110. A chest x-ray taken on November 7, 1952 demonstrated throughout both lung fields numerous miliary densities which were thought to represent azotemic pneumonia. He was released at the parents' request on November 15, 1952. The Penrose drain came out and the child ceased to urinate the day he went home. He was re-admitted the next day. His blood pressure on November 16, 1952 was 150/100. Physical examination again revealed the mass in the right flank. Hirsutism was still quite prominent. His urine on this admission was grossly bloody and loaded with pus. The TNPN was 225 mg. per 100 ml. of blood on November 21, 1952. He passed very little urineafter hewasre-admitted. He took a little food but soon became unresponsive and was sustained on intravenous and subcutaneous fluid. He died on November 29, 1952 at the age of 25 months. Autopsy findings: A large retroperitoneal mass on the right side extended from the diaphragm to the pelvic rim. This mass consisted of the enlarged right kidney with the central spherical vVilms's tumor. The tumor tissue was 4½ cm. in diameter. The renal calyces showed moderate hydronephrotic changes, although there was no dilatation of the ureter. Scattered throughout the right kidney there were many small abscesses 1 to 3 mm. in diameter. The left kidney had been removed. There was no evidence of any metastases from either the Wilms's tumor on the right or from the Wilms's tumor which had been removed surgically on the left. The left ureter was found 3 cm. above the left pelvic rim and was normal. The urinary bladder was normal. There was a small uterus in normal relationship with a vagina. The urethra and vagina met to form a short urogenital sinus. Normal left and right fallopian tubes were present. The testicle was present on the right side in the position that the ovary normally occupies. No gonad was found on the left. COMMENT
Due to the rarity of bilateral Wilms's tumors and the inability to perform retrograde pyelograms on this patient, the diagnosis was not made when the first kidney was removed. The tumor mass in the left kidney was well encapsulated and gave no evidence of having broken through the capsule at any point. The hydro-ureter and the pelvic changes in the right kidney seen in the intravenous pyelogram were, in retrospect, changes produced by the Wilms's tumor in that kidney. In this case it is impossible to prove that one of these tumors was not a metastasis from the other; however, Wilms's tumor metastasizing to the kidney is in itself a rarity. 5 • 7 The fact that there was no neoplastic tissue anywhere except in the kidneys also implies a bilateral origin. Wilms's tumors usually metastasize first to the lungs, and then to the liver. Hermaphroditism has interested medical science from ancient times. Many 7 Mixter, C. G.: Malignant tumors of the kidney in infancy and childhood. Ann. Surg., 96: 1017-1027, 1932.
WILMS'S TUMOR IN PSEUDOHERMAPHRODITE
1151
races have depicted pseudohermaphrodites in their ancient works of art. 8 The causes of true and pseudohermaphroditism have not been completely solved. It is assumed that sex determination in the human follows the typical mammalian pattern, in which the female sex is determined by the presence of two x chromosomes in the zygote, and the male sex is determined by the presence of a single x chromosome (the y chromosome from the male parent probably being functionless) in the fertilized ovum. It is impossible to determine the sex of the embryo until the sixth week when the embryological seminiferous tubules develop. The ovary does not form structures which positively identify it until the ninth week. The medulla of the gonad differentiates to form the testicle while the cortex first differentiates in forming the primitive ovary. It is believed that the hormone supplied by the medulla, if it is dominant, aids further in establishing male characteristics. 9 True hermaphroditism is probably a genetic factor. Pseudohermaphroditism is probably produced by an excessive stimulation from hormones of the opposite sex from the fetal gonads. 10 Thus, if there are excessive androgens in the case of the female embryo or excessive estrogens in the case of the male embryo, a pseudohermaphrodite will result. This had been demonstrated by Greene, Burrill, and Ivy11 in rats and by Hamilton and 1Volfe 12 in mice. If androgens are given a pregnant rat early in pregnancy, a retention of the upper wolffian derivaties and an inhibition of part of the miillerian derivatives results. Female offspring of mothers treated with androgens during pregnancy are born with a retention of remnants of the epididymal tract, inhibition of part of the uterine tract, enlarged clitoris, large labia and occasionally with an agenesis of the vagina and sometimes with retention of remnants of the prostate. If estrogens are given a pregnant rat early in pregnancy, the male embryo shows retention of the upper miillerian derivatives and an inhibition of wolffian derivatives. Estrogens given late in pregnancy cause a retention of lower miillerian derivatives in the male offspring, and an inhibition of parts of the wolffian derivatives occurs. These rats at birth have an inhibition of parts of the epididymal tract, the retention of parts of the uterine tract, undescended testicles, small penis with hypospadias, cleft scrotum and occasionally a vagina. Sometimes no prostate develops. Strangely enough, in female rats whose mothers are given an increased amount of estrogen during pregnancy, the wolflian ducts persist and the urogenital sinus is inhibited. This effect is not seen in the mouse. 13 In the case of the human pseudohermaphrodite, excessive hormones are 8 Young, H. H.: Genital Abnormalities, Hermaphroditism and Related Adrenal Disease. Baltimore: Williams and Wilkins Co., 1937. 9 Arey, L.B.: Developmental Anatomy. Philadelphia and London: W. B. Saunders Co., 1934. 10 Sisk, I. R. and Cornwell, P. M.: Pseudohermaphroditism. J. Urol., 47: 721-737, 1942. 11 Greene, R.R., Burrill, M. W. and Ivy, A. C. Experimental intersexuality: the effect of estrogens on the antenatal sexual development of the rat. Am. J. Anat., 67: 305-345, 1940. 12 Hamilton, J. B. and Wolfe, J.M. The effect of male hormone substances from birth and prenatal development in the rat. Anat. Rec., 70: 433-440, 1938. 13 Melicow, M. M. and Cahill, G. F.: Role of adrenal cortex in somatosexual disturbances in infants and children: Clinicopathologic analysis. J. Clin. Endocrinol., 10: 24-53, 1950.
1152
T. A. STUMP AND R. A. GARRETT
available from several sources. In the case of the female pseudohermaphrndite, there is often an associated hyperplasia or neoplasm of the adrenal cort~x. In these infants, the adrenal cortex tumors of adults will often produce androgens which can be easily demonstrated. Vines (as quoted by Sisk and Cornwell10 ) believed that in some female ptjleudohermaphrodites there is a persistence of the fuchsinophil cells in the adrenal cortex in embryonic life over a longer period than usual. The adrenal cortical cells containing fuchsinophil granules were believed to have been the cells which produced androgens. These fuchsinophil cells are present in the female embryo from the twelfth to the fifteenth week; and in the male, from the ninth to the twentieth week. Others believe that the fuchsinophil granules arei of no significance. Sudds14 has shown that they occur in the adult about equ1;tlly in the two sexes. They first appear when an adult is about 25 years old and tend to increase during life. In adults, they are related to age and have nothing to do with sex. There are some who believe that the adrenal cortex of the embryo can produce estrogen in large enough quantities to cause male pseudohermaphroditism. This has never been clearly demonstrated. Only thirteen feminizing tumors of the adrenal cortex have ever been reported; two in children and eleven in adults. 15 The estrogenic hormones could conceivably come from the cortex of the fetal gonad before it has fully differentiated. Another plausible theory is that the estrogens are supplied in excessive amounts by the mother. It is interesting that pseudohermaphroditism is associated here with the bilateral Wilms's tumor. Testicular tumors not infrequently develop in male pseudohermaphrodites; 16 • 17 however, in spite of the fact that both Wilms's tumor and pseudohermaphroditism are related to a disturbance in the tissues developing from the urogenital ridge, the two conditions occurring simultaneously have never been previously reported. SUMMARY
A case of bilateral Wilms's tumor in a male pseudohermaphrodite is reported. We wish to express our gratitude to Frank Vellios, M.D., and John J. Mahoney, Ph.D., for helpful comments and criticism. Photographs were taken by the Department of Medical Illustration of Indiana University School of Medicine. 14 Sudds, V. N.: The cell contents of the cortex of the suprarenal gland. Endocrinology, 26: 895-899, 1940. 15 Wilkins, L.: A feminizing adrenal tumor causing gynecomastia in a boy five years contrasted with a virilizing tumor in a five year old girl. J. Clin. Endocrinol., 8: 111-129, 1948. 16 Carmichael, R. and Oldfield, C.: Complete male pseudohermaphroditism with intrauterine teratoma testis. J. Path. and Bact., 39: 617-622, 1934. 17 Gilbert, J.B.: Malignant testis tumors in pseudohermaphrodites: review of 60 cases and a case report. J. Urol., 48: 665-672, 1942.