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Masculinization of a female fetus by krukenberg tumor during pregnancy
Masculinization of a Female Fetus by Krukenberg Tumor During Pregnancy By E. Vicens, J. Martinez-Mora, N. Potau, M. Sans, and J. Boix-Ochoa Barcelona, Spain 9 A case of fetal masculinization resulting from a Krukenberg t u m o r in a pregnant w o m a n is reported in a newborn infant with a sexual ambiguity of t h e external genitals, of t h e feminine pseudohermaphrodite type. She also had an incarceration of both ovaries and tubes in a right inguinoscrotal hernia that was surgically corrected. INDEX W O R D S : masculinization.
Krukenberg
tumor; fetal f e m a l e
N O N E C A S E it w a s a b e n i g n s u p r a r e n a l a d e n o m a ~ w h i l e in all t h e o t h e r cases, it w a s an ovarian tumor. The anatomic pathologic diagnosis of these ovarian tumors was Krukenb e r g t y p e in 4 c a s e s , 2-5 a r r h e n o b l a s t o m a in 3, 6.8 l u t e o m a in 2, 9.m a l i p o m a in 1 case, t~ a n d a s t r o m a cell t u m o r in a n o t h e r J 2
I
CASE REPORT A newborn infant, of 23 wk gestation, weighing 1700 g, was born on August 20, 1974, and admitted to the Infants Hospital for "ambiguous external genitalia." It was an otherwise normal infant with a large phallus and partial labioscrotal fusion with hypospadias or an urogenital sinus in the intermedian raphe; a nodule was palpated in the right inguinal region (Figs. 1 and 2). Laboratory tests showed Barr chromatin positive caryotype 46XX, 17-KS urinary excretion 0.1-0.4 rag/24 hr, urinary pregnanestriol 0.2 mg/24 hr, 17-hydroxiprogesterone 1.7, and, half an hour after ACTH injection, 1.8 #g/100 ml, respectively. Congenital suprarenal hyperplasia was discarded as a diagnosis and other causes of masculinization were investigated. Retrograde urethrography was carried out showing the urinary bladder and vagina with a common urogenital sinus (Fig. 3). The mother had had epigastric pains that were diagnosed as a gastric ulcer. During pregnancy she suffered from acute abdominal pains and was admitted to a hospital. During the eighth month of pregnancy, spontaneous birth occurred and 1 wk later a laparotomy was carried out. Tumors were found in both ovaries that were removed. The suprarenals and all other abdominal organs were normal. On
From the Autonomous University. Children's Hospital of the Seguridad Social, School of Medicine, Barcelona, Spain. Address reprint requests to J. Martinez-Mora, Children's Hospital of the Seguridad Social, Department of Surgery, Paseo Valle Hebron s/n, Barcelona-16, Spain. 9 1980 by Grune & Stratton, Inc. 0022-3468/80/150 2~)012501.00/0 188
the tenth day of the postsurgical period, the urinary 17-KS were 1.25 mg/24 hr and testosterone in the plasma 28.5 #g/100 ml. Her general condition became worse and she died 3 wk after the operation. Autopsy was not permitted. Microscopy showed (Fig. 4) massive invasion by atypical epithelial cells, mostly cuboidal in shape, with the nucleus displaced towards the periphery and the cytoplasm occupied by a vacuole of a mucoid substance that was PAS-positive (seal ring cells). No ovarian structures were identified. The appendix was normal and it did not show any neoplasic invasion. Diagnosis: Krukenberg tumor. Correlating all these facts, a secreting Krukenberg tumor was considered the cause for the masculinization, but in view of the nodule found in the infant's inguinal region and the few pathologic findings on urethrography as far as the internal genitals were concerned, an exploratory operation was carried out. At [aparotomy the uterus was found pushed towards the right. The herniated fallopian tubes and ovaries were in the right inguinal canal and in the scrotum. The ovary was infarcted and the right tube incarcerated. The adherent parts were freed and placed into the abdomen with the uterus and related parts put in their normal positions. Right herniorrhaphy was performed. A gynetography was carried out and the vagina, uterus and tube as well as the urinary bladder and the urethra joining in front in a common duct leading to the exterior through the urogenital sinus were shown (Fig. 5). DISCUSSION I n a c c o r d a n c e w i t h e x p e r i e n c e o f J o s t 13 a n d G r u m b a c h , j4 t h e l a b i o s c r o t a l f u s i o n a n d t h e f o r m a t i o n o f t h e u r o g e n i t a l s i n u s t a k e s p l a c e in a female fetus between the 8th and 13th week of g e s t a t i o n ; a f t e r t h i s p e r i o d o n l y e n l a r g e m e n t of t h e c l i t o r i s is o b s e r v e d . T h e a b i l i t y of a K r u k e n b e r g t u m o r to p r o d u c e a n d r o g e n s c a n b e s e e n in s o m e c a s e s a n d a l w a y s coincides with an ovarian metastasis. In the c a s e s o b s e r v e d b y F r i e d m a n , 15 O b e r , ~6 a n d S p a doni, 4 resection of the ovarian tumor produced disappearance of the masculinization that did not reappear when multiple metastasis occurred in o t h e r o r g a n s . Another characteristic of these ovarian t u m o r s is t h e i r g o n a d o t r o p h i n - d e p e n d e n c y , a f a c t a l r e a d y m e n t i o n e d b y C o n n o r e t al. 5 I n his o b s e r v a t i o n , t h e o v a r i a n t u m o r d e c r e a s e d in size after the baby was born and at the same time the 1 7 - K S v a l u e in t h e u r i n e r e t u r n e d to n o r m a l . A d m i n i s t r a t i o n o f A C G b e f o r e o p e r a t i o n proJournal of Pediatric Surgery, VoI. 15, No. 2 (April), 1980
FETAL MASCULINIZATION BY MOTHER'S TUMOR
Figs. 1 and 2.
189
Photographs of ambiguous external genitals: large phallus and scrotal urogenital sinus.
Fig. 3. Genitograph retrograde urethrography: (1) urinary bladder. (2) vagina. (3) urethro-vaginal junction. (4) common urogenital duct.
Fig. 4. Microscopic study of ovaries. Massive invasion by atypical epithelial cells which are mostly cuboid with the nucleus displaced towards the periphery and the cytoplasm occupied by a vacuole of mucoid substance pas-positive (seal ring cells). No maintained ovary structures are identified. (400 x).
190
VICENS ET AL.
Fig. 5. Gynetography: the vagina, uterus and tube filling out; the urinary bladder and the urethra joining in the front in a common duct leading to the exterior through the urogenital sinus.
duced an increase in the tumor mass and the 17-KS level. A similar p h e n o m e n o n has been observed in the luteomas of pregnancy. In M a l i n a k ' s 9 observation, in which the secreting luteoma caused a high value of the u r i n a r y 17-KS, these n o r m a l ized after birth in spite of the fact that more than half of the t u m o r mass remained in situ. A high level of luteinization is frequently present in the n o n t u m o r areas of these ovaries. This confirms their gonadotrophin dependence
a n d suggests that it is the stroma that secretes the androgens and not the t u m o r i t s e l f : In the case we are reporting, the K r u k e n b e r g t u m o r secretion was shown because of the progressive masculinization of the mother during pregnancy as well as the high degree of masculinization of the infant, and also by the fact that after resection of the ovarian t u m o r normal values of u r i n a r y 17-KS and plasmatic testosterone were found indicating that the excessive production of androgens had been eliminated by surgery. Histologic e x a m i n a t i o n of several samples of the tumor showed the K r u k e n b e r g t u m o r characteristics, but no normal ovarian tissue was examined and the degree of luteinization was not observed. If the diagnosis of a m a t e r n a l masculinization t u m o r is established, and confirmed by normal morphology of the internal genitalia by means of a urethrography and subsequent genitography, or in a negative case by means of laparoscopy, exploration is not necessary. In our case, the first gynetography provided insufficient information and the fact that a gonad was palpated in the right inguinal canal obliged us to carry out a n exploratory laparotomy in order to eliminate the possibility of any other cause of masculinization.
REFERENCES
1. Murset G, Zachmann M, Prader A, et al: Male external genitalia of a girl caused by virilizing adrenal tumor in the mother. Acta Endocrinol 65:627, 1970 2. Ameline A, Lepage F, Huguier J, et al: Sur la valeur s6m6iologique des m6tastases ombilicales des epitheliomas digestifs. Apropos d'une tumeur do Krukenberg. Arch Mal Appareil Digest 41:559, 1952 3. Fox LP, Stamm WJ: Krukenberg tumor complicating pregnancy. Am J Obstet Gynecol 92:702, 1965 4. Spadoni LR, Lindberg MC, Mottet NK, et al: Virilization coexisting with Krukenberg tumor during pregnancy. Am J Obstet Gynecol 92:981, 1965 5. Connor TB, Ganis FM, Levin HS, et al: Gonadotrophin-dependent Krukenberg tumor causing virilization during pregnancy. J Clin Endocrinol Metab 28:198, 1968 6. Felicissimo P: Sobre un caso de arrhenoblastoma do ovario e gradides topica simultanea. Virilisacfioda gestante e do feto femenio. Rev Gynecol Obstet 32:356, 1938 7. Brentnall CP: A case of arrhenoblastoma complicating pregnancy. J Obstet Gynecol Br Emp 52:325, 1945 8. Coignet J, Rampal M, Bernard PJ, et al: Pseudohermaphrodisme congenital par tumeur virilisante maternelle Mars. Medicine 103:638, 1966
9. Malinak LR, Miller GV: Bilateral multicentric ovarian luteomas of pregnancy associated with masculinization of a female infant. Am J Obstet Gynecol 91:251, 1965 10. Jenkins ME, Surana RB, Russell-Cuts CM: Ambiguous genitals in a female infant associated with luteoma of pregnancy. Am J Obstet Gynecol 101:923, 1968 11. Sandberg AA, Slaunwhite WR Jr, Jackson JE, et al: Androgen biosyntesis by ovarian lipoid cell tumor. J Clin Endocrinol Metab 22:929, 1962 12. Haymond MW, Weldon VV: Female pseudohermaphroditism secondary to a maternal virilizing tumor. J Pediatr 82:682, 1973 13. Jost A: The secretory activities of fetal endocrine glands and their effect upon target organs. Jasiah Macy, Jr. Foundation Conferenceon Gestation. 3:129, 1956 14. Grumbach MM, Ducharme JR: The effect of androgens on fetal sexual development.Fertil Ster 11:157, 1960 15. Friedman IS, Mackles A, Daichman I: Development of virilization during pregnancy. J Clin Endocrinol 15:1281, 1955 16. Ober WB, Pollak A, Gerstmann KE, et al: Krukenberg tumor with androgenic and progestational activity. Am J Obstet Gynecol 15:739, 1962
Krukenberg
tumor; fetal f e m a l e
N O N E C A S E it w a s a b e n i g n s u p r a r e n a l a d e n o m a ~ w h i l e in all t h e o t h e r cases, it w a s an ovarian tumor. The anatomic pathologic diagnosis of these ovarian tumors was Krukenb e r g t y p e in 4 c a s e s , 2-5 a r r h e n o b l a s t o m a in 3, 6.8 l u t e o m a in 2, 9.m a l i p o m a in 1 case, t~ a n d a s t r o m a cell t u m o r in a n o t h e r J 2
I
CASE REPORT A newborn infant, of 23 wk gestation, weighing 1700 g, was born on August 20, 1974, and admitted to the Infants Hospital for "ambiguous external genitalia." It was an otherwise normal infant with a large phallus and partial labioscrotal fusion with hypospadias or an urogenital sinus in the intermedian raphe; a nodule was palpated in the right inguinal region (Figs. 1 and 2). Laboratory tests showed Barr chromatin positive caryotype 46XX, 17-KS urinary excretion 0.1-0.4 rag/24 hr, urinary pregnanestriol 0.2 mg/24 hr, 17-hydroxiprogesterone 1.7, and, half an hour after ACTH injection, 1.8 #g/100 ml, respectively. Congenital suprarenal hyperplasia was discarded as a diagnosis and other causes of masculinization were investigated. Retrograde urethrography was carried out showing the urinary bladder and vagina with a common urogenital sinus (Fig. 3). The mother had had epigastric pains that were diagnosed as a gastric ulcer. During pregnancy she suffered from acute abdominal pains and was admitted to a hospital. During the eighth month of pregnancy, spontaneous birth occurred and 1 wk later a laparotomy was carried out. Tumors were found in both ovaries that were removed. The suprarenals and all other abdominal organs were normal. On
From the Autonomous University. Children's Hospital of the Seguridad Social, School of Medicine, Barcelona, Spain. Address reprint requests to J. Martinez-Mora, Children's Hospital of the Seguridad Social, Department of Surgery, Paseo Valle Hebron s/n, Barcelona-16, Spain. 9 1980 by Grune & Stratton, Inc. 0022-3468/80/150 2~)012501.00/0 188
the tenth day of the postsurgical period, the urinary 17-KS were 1.25 mg/24 hr and testosterone in the plasma 28.5 #g/100 ml. Her general condition became worse and she died 3 wk after the operation. Autopsy was not permitted. Microscopy showed (Fig. 4) massive invasion by atypical epithelial cells, mostly cuboidal in shape, with the nucleus displaced towards the periphery and the cytoplasm occupied by a vacuole of a mucoid substance that was PAS-positive (seal ring cells). No ovarian structures were identified. The appendix was normal and it did not show any neoplasic invasion. Diagnosis: Krukenberg tumor. Correlating all these facts, a secreting Krukenberg tumor was considered the cause for the masculinization, but in view of the nodule found in the infant's inguinal region and the few pathologic findings on urethrography as far as the internal genitals were concerned, an exploratory operation was carried out. At [aparotomy the uterus was found pushed towards the right. The herniated fallopian tubes and ovaries were in the right inguinal canal and in the scrotum. The ovary was infarcted and the right tube incarcerated. The adherent parts were freed and placed into the abdomen with the uterus and related parts put in their normal positions. Right herniorrhaphy was performed. A gynetography was carried out and the vagina, uterus and tube as well as the urinary bladder and the urethra joining in front in a common duct leading to the exterior through the urogenital sinus were shown (Fig. 5). DISCUSSION I n a c c o r d a n c e w i t h e x p e r i e n c e o f J o s t 13 a n d G r u m b a c h , j4 t h e l a b i o s c r o t a l f u s i o n a n d t h e f o r m a t i o n o f t h e u r o g e n i t a l s i n u s t a k e s p l a c e in a female fetus between the 8th and 13th week of g e s t a t i o n ; a f t e r t h i s p e r i o d o n l y e n l a r g e m e n t of t h e c l i t o r i s is o b s e r v e d . T h e a b i l i t y of a K r u k e n b e r g t u m o r to p r o d u c e a n d r o g e n s c a n b e s e e n in s o m e c a s e s a n d a l w a y s coincides with an ovarian metastasis. In the c a s e s o b s e r v e d b y F r i e d m a n , 15 O b e r , ~6 a n d S p a doni, 4 resection of the ovarian tumor produced disappearance of the masculinization that did not reappear when multiple metastasis occurred in o t h e r o r g a n s . Another characteristic of these ovarian t u m o r s is t h e i r g o n a d o t r o p h i n - d e p e n d e n c y , a f a c t a l r e a d y m e n t i o n e d b y C o n n o r e t al. 5 I n his o b s e r v a t i o n , t h e o v a r i a n t u m o r d e c r e a s e d in size after the baby was born and at the same time the 1 7 - K S v a l u e in t h e u r i n e r e t u r n e d to n o r m a l . A d m i n i s t r a t i o n o f A C G b e f o r e o p e r a t i o n proJournal of Pediatric Surgery, VoI. 15, No. 2 (April), 1980
FETAL MASCULINIZATION BY MOTHER'S TUMOR
Figs. 1 and 2.
189
Photographs of ambiguous external genitals: large phallus and scrotal urogenital sinus.
Fig. 3. Genitograph retrograde urethrography: (1) urinary bladder. (2) vagina. (3) urethro-vaginal junction. (4) common urogenital duct.
Fig. 4. Microscopic study of ovaries. Massive invasion by atypical epithelial cells which are mostly cuboid with the nucleus displaced towards the periphery and the cytoplasm occupied by a vacuole of mucoid substance pas-positive (seal ring cells). No maintained ovary structures are identified. (400 x).
190
VICENS ET AL.
Fig. 5. Gynetography: the vagina, uterus and tube filling out; the urinary bladder and the urethra joining in the front in a common duct leading to the exterior through the urogenital sinus.
duced an increase in the tumor mass and the 17-KS level. A similar p h e n o m e n o n has been observed in the luteomas of pregnancy. In M a l i n a k ' s 9 observation, in which the secreting luteoma caused a high value of the u r i n a r y 17-KS, these n o r m a l ized after birth in spite of the fact that more than half of the t u m o r mass remained in situ. A high level of luteinization is frequently present in the n o n t u m o r areas of these ovaries. This confirms their gonadotrophin dependence
a n d suggests that it is the stroma that secretes the androgens and not the t u m o r i t s e l f : In the case we are reporting, the K r u k e n b e r g t u m o r secretion was shown because of the progressive masculinization of the mother during pregnancy as well as the high degree of masculinization of the infant, and also by the fact that after resection of the ovarian t u m o r normal values of u r i n a r y 17-KS and plasmatic testosterone were found indicating that the excessive production of androgens had been eliminated by surgery. Histologic e x a m i n a t i o n of several samples of the tumor showed the K r u k e n b e r g t u m o r characteristics, but no normal ovarian tissue was examined and the degree of luteinization was not observed. If the diagnosis of a m a t e r n a l masculinization t u m o r is established, and confirmed by normal morphology of the internal genitalia by means of a urethrography and subsequent genitography, or in a negative case by means of laparoscopy, exploration is not necessary. In our case, the first gynetography provided insufficient information and the fact that a gonad was palpated in the right inguinal canal obliged us to carry out a n exploratory laparotomy in order to eliminate the possibility of any other cause of masculinization.
REFERENCES
1. Murset G, Zachmann M, Prader A, et al: Male external genitalia of a girl caused by virilizing adrenal tumor in the mother. Acta Endocrinol 65:627, 1970 2. Ameline A, Lepage F, Huguier J, et al: Sur la valeur s6m6iologique des m6tastases ombilicales des epitheliomas digestifs. Apropos d'une tumeur do Krukenberg. Arch Mal Appareil Digest 41:559, 1952 3. Fox LP, Stamm WJ: Krukenberg tumor complicating pregnancy. Am J Obstet Gynecol 92:702, 1965 4. Spadoni LR, Lindberg MC, Mottet NK, et al: Virilization coexisting with Krukenberg tumor during pregnancy. Am J Obstet Gynecol 92:981, 1965 5. Connor TB, Ganis FM, Levin HS, et al: Gonadotrophin-dependent Krukenberg tumor causing virilization during pregnancy. J Clin Endocrinol Metab 28:198, 1968 6. Felicissimo P: Sobre un caso de arrhenoblastoma do ovario e gradides topica simultanea. Virilisacfioda gestante e do feto femenio. Rev Gynecol Obstet 32:356, 1938 7. Brentnall CP: A case of arrhenoblastoma complicating pregnancy. J Obstet Gynecol Br Emp 52:325, 1945 8. Coignet J, Rampal M, Bernard PJ, et al: Pseudohermaphrodisme congenital par tumeur virilisante maternelle Mars. Medicine 103:638, 1966
9. Malinak LR, Miller GV: Bilateral multicentric ovarian luteomas of pregnancy associated with masculinization of a female infant. Am J Obstet Gynecol 91:251, 1965 10. Jenkins ME, Surana RB, Russell-Cuts CM: Ambiguous genitals in a female infant associated with luteoma of pregnancy. Am J Obstet Gynecol 101:923, 1968 11. Sandberg AA, Slaunwhite WR Jr, Jackson JE, et al: Androgen biosyntesis by ovarian lipoid cell tumor. J Clin Endocrinol Metab 22:929, 1962 12. Haymond MW, Weldon VV: Female pseudohermaphroditism secondary to a maternal virilizing tumor. J Pediatr 82:682, 1973 13. Jost A: The secretory activities of fetal endocrine glands and their effect upon target organs. Jasiah Macy, Jr. Foundation Conferenceon Gestation. 3:129, 1956 14. Grumbach MM, Ducharme JR: The effect of androgens on fetal sexual development.Fertil Ster 11:157, 1960 15. Friedman IS, Mackles A, Daichman I: Development of virilization during pregnancy. J Clin Endocrinol 15:1281, 1955 16. Ober WB, Pollak A, Gerstmann KE, et al: Krukenberg tumor with androgenic and progestational activity. Am J Obstet Gynecol 15:739, 1962