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THE OUTCOME OF PRENATALLY DIAGNOSED RENAL TUMORS
0022-5347/05/1731-0186/0 THE JOURNAL OF UROLOGY® Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 173, 186 –189, January 2005 Printed in U.S.A.
DOI: 10.1097/01.ju.0000147300.53837.8f
THE OUTCOME OF PRENATALLY DIAGNOSED RENAL TUMORS MARC-DAVID LECLAIR,* ALAA EL-GHONEIMI, GEORGES AUDRY, PHILIPPE RAVASSE, JACQUES MOSCOVICI AND YVES HELOURY ON BEHALF OF THE FRENCH PEDIATRIC UROLOGY STUDY GROUP From the Departments of Pediatric Urology, Hoˆpital Me`re-Enfant (M-DL, YH), Nantes, Hoˆpital Robert Debre´ (AE-G) and Hoˆpital d’Enfants Armand Trousseau (GA), Paris, Centre Hospitalier Universitaire de Caen (PR), Caen and Hoˆpital des Enfants (JM), Toulouse, France
ABSTRACT
Purpose: We assessed the incidence of perinatal morbidity and evaluated the outcome in children with prenatally diagnosed renal tumors in a retrospective multicenter study. Materials and Methods: A review of the records of patients from 20 institutions identified 28 children with prenatally diagnosed renal tumors. Prenatal findings, clinical charts, and radiological, surgical and pathological reports were reviewed in this study. Results: There were 26 congenital mesoblastic nephromas and 2 Wilms tumors. One or more complications were identified in 20 of the 28 cases (71%) during the perinatal period. Polyhydramnios was observed in 11 fetuses (39%), 2 presented with hydrops fetalis and 7 presented in acute fetal distress requiring emergency cesarean section, of which 1 died in utero before delivery. Median gestational age of the 27 neonates born alive was 35 weeks (range 29 to 39), including 13 (46%) who were pre-term (less than 34 weeks of gestation). Complications at birth included hemodynamic instability in 3 newborns, of whom 2 underwent emergency surgery, respiratory distress syndrome in 8 (30%) and hypertension in 6 (22%). Surgical complications occurred in 7 patients (26%), including tumor rupture in 1 and intraoperative bleeding with postoperative death in 1. At a median followup of 42 months (range 2 to 105) 26 of the 27 children were in complete remission. Conclusions: Fetal renal tumors have an excellent oncological outcome but a high risk of perinatal complications. Prenatal diagnosis should allow planning the delivery at a pediatric tertiary care center to avoid a potentially life threatening condition in neonates in the first hours of life. KEY WORDS: kidney, kidney neoplasms, prenatal diagnosis, nephroblastoma, survival
Neonatal solid renal tumors are uncommon. They represent less than 10% of all tumors arising in the neonate, far behind teratoma and neuroblastoma.1 Congenital mesoblastic nephroma (CMN) has been the most common renal neoplasm in the neonatal period since it was recognized as a histopathological entity distinct from Wilms tumor (WT).2 With the widespread use of routine prenatal ultrasonography (US) the prenatal detection and complications of renal tumors have been occasionally reported. In this study we assessed the incidence of perinatal complications and present guidelines for the optimal management of prenatally detected renal tumors. PATIENTS AND METHODS
In this retrospective multicenter study a questionnaire was mailed to participating institutions of the French Groupe d’Etude en Urologie Pe´diatrique (see Appendix). All children with a solid renal tumor prenatally diagnosed from 1985 to 2002 were included in this study. Prenatal findings, clinical charts, and radiological, surgical and pathological reports were collected and reviewed. Quantitative data are expressed as the median and range. Comparisons between proportions were performed with the chi-square test corrected for heterogeneity or Fisher’s exact 2-tailed test when appropriate.
RESULTS
In this study 28 children were included after prenatal diagnosis of a solid renal mass, which was confirmed postnatally to be CMN or WT. There were 19 females (68%) and 9 males. Prenatal sonographic findings. The diagnosis of renal tumor was made on routine US during the third trimester of gestation in all except 2 cases, which were diagnosed at 23 and 25 weeks of gestation (WG), respectively. Median fetal age at diagnosis was 30 WG (range 23 to 38). Prenatal US findings regarding renal tumor morphological characteristics were fully available on 24 patients. Tumors were usually heterogenous (16 of 24 cases or 67%), more often arising from the right kidney (18 of 28 or 64%) and without any distinct capsule (14 of 24 or 58%). Other, more unusual features included cystic components (7 of 24 cases or 29%), tumor calcifications (3) and increased vascularity (6). None of these characteristics allowed one to distinguish between CMN and WT. One or more complications were identified in 20 of the 28 cases (71%) during the prenatal period, at birth or during the postoperative course. Prenatal complications. As defined by an increased amniotic fluid index above the 95th percentile for gestation, polyhydramnios was observed in 11 cases (39%). Two of these neonates had hypercalcemia at birth. Polyhydramnios was significantly associated with pre-term labor and prematurity. Patients with polyhydramnios were born at a median term of 33 WG (range 29 to 37) compared to 36 WG (range 32 to 39) for those with a normal amniotic fluid index (p ⬍0.01).
Submitted for publication March 30, 2004. * Correspondence: Service de Chirurgie Infantile-Urologie Pe´diatrique, Hoˆpital Me`re-Enfant, Centre Hospitalier Universitaire de Nantes, 44093 Nantes, Cedex 01, France (telephone: ⫹33 2 40 08 35 85; FAX: ⫹33 2 40 08 35 46; e-mail: [email protected]). 186
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Nonimmune fetal hydrops was observed in 2 cases. The first patient was a female fetus with a renal tumor diagnosed at 30 WG. Two weeks later US revealed polyhydramnios and extensive subcutaneous edema suggestive of hydrops. Further scans showed worsening of polyhydramnios and hydrops, leading to the decision to perform cesarean section at 34 WG. Respiratory distress at birth required intubation and mechanical ventilation. The neonate underwent nephrectomy at 7 days of life, allowing complete resection of a 70 mm Wilms tumor of the right kidney. She was discharged home at 30 days of life and followup was uneventful. The second patient was a female diagnosed at 29 WG with a 100 mm right solid renal tumor that had high intratumoral vascular signal intensity on Doppler examination. US showed polyhydramnios, hydrops fetalis with subcutaneous edema, ascites, pleural effusions and evidence of high output heart failure. After urgent cesarean section and adequate resuscitation in the neonatal intensive care unit the newborn was still unstable and surgery was performed at 1 day of life. A large CMN (cellular variant) was removed with major blood loss. Despite full supportive care the infant died on day 2. Acute fetal distress occurred in 7 fetuses (25%) at a median term of 31 WG (range 29 to 34). Persistent decelerations on cardiotocograph monitoring in these cases led to the decision to perform emergency delivery by cesarean section. One fetus died in utero before delivery at 34 WG, 2 weeks after the diagnosis of a renal tumor associated with oligohydramnios. As defined by birth at or before 34 WG, prematurity was observed in 13 newborns (46%). Of these premature newborns 11 had 1 or more previously detailed prenatal complications. Median age at birth of the 27 neonates born alive was 35 WG (range 29 to 39). Birth. Patients in this study were born by vaginal delivery (15), cesarean section (12) and unknown (1). The indication for cesarean section was a worsening condition in 7 fetuses, obstetric reasons in 3 and a large, noncomplicated abdominal mass in 2. Median birth weight was 3,080 gm (range 1,700 to 3,980). Except for the 2 patients with hydrops fetalis all newborns had a birth weight within the normal range ⫾ 2 SD when matched for gestational age. There were no cases of in utero growth retardation. Postnatal complications. Three newborns with severe fetal distress presented after emergency extraction with hemodynamic instability and required cardiocirculatory resuscitation. Two of them underwent emergency surgical procedure for resection of the abdominal mass. Eight newborns (30%) who presented at birth with severe respiratory distress syndrome required mechanical ventilation. The median term of birth was 32 WG (range 30 to 36). Arterial hypertension, requiring specific anti-hypertensive treatment was noted at birth in 6 neonates (22%), of whom 3 had documented, increased plasma renin activity and aldosterone. Two of the 6 newborns with hypertension had prenatal polyhydramnios and hypercalcemia at birth. In all cases blood pressure and calcemia returned to normal values after nephrectomy. Surgery. All neonates born alive underwent complete surgical resection of the renal tumor at a median age of 7 days (range 0 to 38). The surgical procedure was performed via a transperitoneal transverse approach in all except 1 case. Median operative time was 80 minutes (range 50 to 180). The overall rate of surgical complication was 26% (7 of 27 cases). There were 2 major intraoperative complications, which occurred in the 2 patients who underwent surgery in the first hours of life for hemodynamic instability. In 1 case partial rupture of the tumor capsule occurred, resulting in intraperitoneal tumor spillage of a classic form of CMN. This child had no evidence of recurrent disease at a followup of 2 years. The second complication was intraoperative bleeding in the patient with fetal hydrops who died during the postoperative course. Postoperative complications developed in 5 patients (19%), namely ischemic colonic perforation with
peritonitis at day 2 in 1, an adhesive intestinal obstruction requiring surgery at day 36 in 1, postoperative necrotizing enterocolitis in a full-term 3,040 gm male newborn with long-term neurological sequelae, septicemia from a central venous line in 1 and a sacral bedsore requiring further plastic surgery in 1. On histological examination 26 renal tumors were diagnosed as CMN, of which 5 (19%) were a cellular variant of CMN. The remaining 2 patients had International Society of Paediatric Oncology stage I favorable histology Wilms tumor. None of the children of this series had received adjuvant therapy. As of August 2003, the median followup was 42 months (range 2 to 105). At the current followup 26 of the 27 patients born alive had no evidence of recurrent disease. The 2 children with WT were in complete remission 42 and 64 months after diagnosis, respectively.
DISCUSSION
To our knowledge this multicenter study is the first large series describing the outcome of prenatally diagnosed renal tumors. It confirms the excellent oncological outcome but shows a high incidence of perinatal complications of fetal renal tumors. Mesoblastic nephroma represents approximately 2% to 3% of pediatric renal tumors3 but most cases occur within the neonatal period. CMN is a mesenchymal tumor that is histologically characterized by the proliferation of spindleshaped cells arranged in fascicles that dissect into the normal renal parenchyma.2, 3 The main differential diagnoses of CMN are Wilms tumor and malignant rhabdoid tumor of the kidney, which are rare in neonates. It seems difficult to differentiate reliably between CMN and WT based on prenatal US. Experience with WT in infancy and childhood shows that WT is frequently a well encapsulated, heterogeneous tumor, whereas CMN is often reported to have an homogenous solid aspect on ultrasonography4, 5 and it lacks a welldefined capsule because tumor proliferation blends with the adjacent renal parenchyma. However, several ultrasonographic variants have also been described,6, 7 as confirmed in this series by tumors with microcalcifications or hypoechoic (cystic) components. Other imaging modalities, such as magnetic resonance imaging, may help make a more precise diagnosis, especially in poor sonographic conditions such as obesity of the mother or oligohydramnios. Polyhydramnios is reported to be a frequent clinical feature of CMN.8 In the current study it was observed in almost 40% of the fetuses. The physiopathology of polyhydramnios in renal tumors is still debated and several mechanisms have been suggested, including excessive fetal urine production and impaired gastrointestinal function due to bowel compression.5, 6 Fetal polyuria could be related to renal hyperperfusion, impaired renal concentrating ability and hypercalcemia.9 Nonimmune fetal hydrops had already been observed in CMN10, 11 and Wilms tumor.12 In the context of a renal tumor hydrops fetalis may be attributable to the compression of major infradiaphragmatic vessels by a large abdominal mass12 or the consequence of prenatal high output heart failure due to vascular shunting in a large angiomatous lesion, as in 1 patient in the current series. The poor outcome in patients with fetal hydrops11, 12 justifies close monitoring after prenatal diagnosis of a renal tumor. This report underlines the high risk of prematurity in fetal renal tumors because almost half of the newborns were delivered before week 34 of gestation. Of the 13 premature newborns 11 presented with polyhydramnios and repeat therapeutic amniocenteses may have contributed to the onset of pre-term labor and amniotic membrane rupture. Alterations in fetal condition were also an important factor of
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prematurity since 25% of the fetuses showed evidence of acute fetal distress and were delivered prematurely. The neonatal morbidity of congenital renal tumors may be related to prematurity and/or to the tumor itself. A large renal tumor appears to be a life threatening condition because 3 newborns needed immediate resuscitation at birth and 1 fetus died in utero with acute fetal distress. Eight infants in the current study required ventilatory support at birth for respiratory distress syndrome as a consequence of delayed maturation of the lungs or diaphragmatic compression by the abdominal mass. Hypertension has long been recognized as a presenting feature of CMN since Malone et al reported an association of hypertension, plasmatic hyperreninism and a distinctive pattern of immunoreactive renin staining within the tumor.13 Hypertension was found in 22% of the neonates in the current study with hyperreninism in 3. Blood pressure in neonates with a renal tumor should be monitored and controlled before surgery to avoid perioperative fluctuations. The high rate of surgical complications in this study was related to several factors, such as complications of an emergency procedure performed in infants in poor condition (major bleeding and subsequent death, and tumor rupture), complications of major abdominal and oncological surgery (necrotizing enterocolitis, bowel ischemic perforation and intestinal obstruction) or complications of neonatal nursing (septicemia and a sacral bedsore). Safe resection of abdominal neonatal tumors may be challenging in cases of large and fragile tumors with rich peripheral neovascularization. In their study of 51 infants or children with CMN Howell et al reported 12 (23%) with intraoperative rupture and tumor spillage or incomplete resection for local extension.14 Wilms tumor is extremely rare in neonates with an incidence lower than 0.2% in the experience of the National Wilms’ Tumor Study.15, 16 In neonates Ritchey et al reported an outcome comparable to that in the older population with WT with some risk of relapse when treated without adjuvant therapy, and a high incidence of nephrogenic rests with the subsequent risk of metachronous tumor formation.16 They concluded that neonates could benefit from de-escalation in adjuvant therapy but they require close and prolonged surveillance. In a report from the National Wilms Tumor Study-5 protocol Green et al observed that children younger than 24 months with stage 1 favorable histology WT treated with surgery alone had an 86.5% 2-year disease-free survival rate, which was marginally inferior to that in children treated with adjuvant chemotherapy.17 When considering the potential risks of chemotherapy (central venous line complications and hepatic toxicity), it seems that surgery only is an acceptable strategy in neonates, although it is not the standard of care. In contrast to WT, CMN has benign biological behavior and a more favorable outcome if adequate surgical resection is achieved.14, 18 Metastatic spread of CMN is extremely rare, although recurrence and distant metastases in the brain, heart and lungs have been reported.19 The cellular variant is a potentially more aggressive form of CMN but a positive surgical margin seems to be the only prognostic factor related to tumor recurrence.18 The data in the current study confirm the excellent outcome after treatment of congenital renal tumors with an overall survival rate of 96% and no recurrence in a population with 27 renal tumors, including 2 WTs and 5 cellular variants of CMN. The optimal perinatal management of fetal renal tumors includes a multidisciplinary approach involving obstetricians, pediatricians, pediatric surgeons and oncologists. The good outcome of these tumors may help parental counseling before birth. Data in this study regarding morbidity provide support for careful, continuous observation of the fetus when a renal tumor is diagnosed during routine prenatal US. Maternal referral to a perinatal care center should be considered, and close US followup and maternal-fetal monitoring
should be performed to detect fetal complications. Considering the high incidence of polyhydramnios and the influence of prematurity in perinatal complications, control of polyhydramnios is essential.20 When severe fetal complications are detected, pre-term delivery should be balanced with the morbidity of consented prematurity. With the eventuality of severe cardiocirculatory or respiratory distress at birth maternal transportation for induced elective delivery at a pediatric tertiary care center may be considered in some cases. APPENDIX
Main investigators at the departments of pediatric urology at the following institutions participated in the study on behalf of the Groupe d’Etude en Urologie Pe´diatrique: L. Coupris, Centre Hospitalier Universitaire (CHU) d’Angers, Angers, F. Sauvat and F. Gauthier, CHU de Biceˆtre, Biceˆtre, E. Dobremez and P. Vergnes, CHU de Bourdeaux, Bordeaux, P. Ravasse, CHU de Caen, Caen, E. Sapin, CHU de Dijon, Dijon, J. F. Colombani, CHU de Fort-de-France, Fort-deFrance, C. Piolat and J. F. Dyon, CHU de Grenoble, Grenoble, D. Weil, Centre Hospitalier de Le Mans, Le Mans, L. Fourcade, CHU de Limoges, Limoges, M. D. Leclair and Y. Heloury, CHU de Nantes, Nantes, H. Steyaert, Hoˆpital Lenval, Nice, A. El-Ghoneimi, A. Bonnard and Y. Aigrain, Hoˆpital Robert Debre´, A. Lironi and C. Fekete, Hoˆpital des Enfantes Malades and M. Williamson and G. Audry, Hoˆpital d’Enfants Armand Trousseau, Paris, G. Levard, CHU de Poitiers, Poitiers, F. Lefebre, CHU de Reims, Reims, O. Azzis and B. Fremond, CHU de Rennes, Rennes, D. Eurin and A. Liard, CHU de Rouen, Rouen, F. Varlet, CHU de SaintEtienne, Saint-Etienne, and F. Lemasson and J. Moscovici, CHU de Toulouse, Toulouse, France; J. M. Joseph, CHU de Lausanne, Lausanne, Switzerland; and C. Esposito, Universita` di Napoli Federico II, Naples, Italy. REFERENCES
1. Barson, A. J.: Congenital neoplasia: the Society’s experience. Arch Dis Child, 53: 436, abstract, 1978 2. Bolande, R. P., Brough, A. J. and Izant, R. J., Jr.: Congenital mesoblastic nephroma of infancy. A report of eight cases and the relationship to Wilms’ tumor. Pediatrics, 40: 272, 1967 3. Argani, P. and Ladanyi, M.: Recent advances in pediatric renal neoplasia. Adv Anat Pathol, 10: 243, 2003 4. Chan, K. L., Tang, M. H., Tse, H. Y., Tang, R. Y., Lam, H. S., Lee, C. P. et al: Factors affecting outcomes of prenatally-diagnosed tumours. Prenat Diagn, 22: 437, 2002 5. Fuchs, I. B., Henrich, W., Brauer, M., Stover, B., Guschmann, M., Degenhardt, P. et al: Prenatal diagnosis of congenital mesoblastic nephroma in 2 siblings. J Ultrasound Med, 22: 823, 2003 6. Daskas, N., Argyropoulou, M., Pavlou, M. and Andronikou, S.: Congenital mesoblastic nephroma associated with polyhydramnios and hypercalcemia. Pediatr Nephrol, 17: 187, 2002 7. Murthi, G. V., Carachi, R. and Howatson, A.: Congenital cystic mesoblastic nephroma. Pediatr Surg Int, 19: 109, 2003 8. Chan, H. S., Cheng, M. Y., Mancer, K., Payton, D., Weitzman, S. S., Kotecha, P. et al: Congenital mesoblastic nephroma: a clinicoradiologic study of 17 cases representing the pathologic spectrum of the disease. J Pediatr, 111: 64, 1987 9. Fung, T. Y., Fung, Y. M., Ng, P. C., Yeung, C. K. and Chang, M. Z.: Polyhydramnios and hypercalcemia associated with congenital mesoblastic nephroma: case report and a new appraisal. Obstet Gynecol, 85: 815, 1995 10. Chen, W. Y., Lin, C. N., Chao, C. S., Yan-Sheng Lin, M., Mak, C. W., Chuang, S. S. et al: Prenatal diagnosis of congenital mesoblastic nephroma in mid-second trimester by sonography and magnetic resonance imaging. Prenat Diagn, 23: 927, 2003 11. Liu, Y. C., Mai, Y. L., Chang, C. C., Chen, K. W. and Chow, S. N.: The presence of hydrops fetalis in a fetus with congenital mesoblastic nephroma. Prenat Diagn, 16: 363, 1996 12. Vadeyar, S., Ramsay, M., James, D. and O’Neill, D.: Prenatal diagnosis of congenital Wilms’ tumor (nephroblastoma) presenting as fetal hydrops. Ultrasound Obstet Gynecol, 16: 80, 2000
OUTCOME OF FETAL RENAL TUMORS 13. Malone, P. S., Duffy, P. G., Ransley, P. G., Ridson, R. A., Cook, T. and Taylor, M.: Congenital mesoblastic nephroma, renin production, and hypertension. J Pediatr Surg, 24: 599, 1989 14. Howell, C. G., Othersen, H. B., Kiviat, N. E., Norkool, P., Beckwith, J. B. and D’Angio, G. J.: Therapy and outcome in 51 children with mesoblastic nephroma: a report of the National Wilms’ Tumor Study. J Pediatr Surg, 17: 826, 1982 15. Hrabovsky, E. E., Othersen, H. B., Jr., deLorimier, A., Kelalis, P., Beckwith, J. B. and Takashima, J.: Wilms’ tumor in the neonate: a report from the National Wilms’ Tumor Study. J Pediatr Surg, 21: 385, 1986 16. Ritchey, M. L., Azizkhan, R. G., Beckwith, J. B., Hrabovsky, E. E. and Haase, G. M.: Neonatal Wilms tumor. J Pediatr Surg, 30: 856, 1995
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17. Green, D. M., Breslow, N. E., Beckwith, J. B., Ritchey, M. L., Shamberger, R. G., Haase, G. M. et al: Treatment with nephrectomy only for small stage I/favorable histology Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol, 19: 3719, 2001 18. Gormley, T. S., Skoog, S. J., Jones, R. V. and Maybee, D.: Cellular congenital mesoblastic nephroma: what are the options? J Urol, 142: 479, 1989 19. Loeb, D. M., Hill, D. A. and Dome, J. S.: Complete response of recurrent cellular congenital mesoblastic nephroma to chemotherapy. J Pediatr Hematol Oncol, 24: 478, 2002 20. Matsumura, M., Nishi, T., Sasaki, Y., Yamada, R., Yamamoto, H., Ohhama, Y. et al: Prenatal diagnosis and treatment strategy for congenital mesoblastic nephroma. J Pediatr Surg, 28: 1607, 1993
Vol. 173, 186 –189, January 2005 Printed in U.S.A.
DOI: 10.1097/01.ju.0000147300.53837.8f
THE OUTCOME OF PRENATALLY DIAGNOSED RENAL TUMORS MARC-DAVID LECLAIR,* ALAA EL-GHONEIMI, GEORGES AUDRY, PHILIPPE RAVASSE, JACQUES MOSCOVICI AND YVES HELOURY ON BEHALF OF THE FRENCH PEDIATRIC UROLOGY STUDY GROUP From the Departments of Pediatric Urology, Hoˆpital Me`re-Enfant (M-DL, YH), Nantes, Hoˆpital Robert Debre´ (AE-G) and Hoˆpital d’Enfants Armand Trousseau (GA), Paris, Centre Hospitalier Universitaire de Caen (PR), Caen and Hoˆpital des Enfants (JM), Toulouse, France
ABSTRACT
Purpose: We assessed the incidence of perinatal morbidity and evaluated the outcome in children with prenatally diagnosed renal tumors in a retrospective multicenter study. Materials and Methods: A review of the records of patients from 20 institutions identified 28 children with prenatally diagnosed renal tumors. Prenatal findings, clinical charts, and radiological, surgical and pathological reports were reviewed in this study. Results: There were 26 congenital mesoblastic nephromas and 2 Wilms tumors. One or more complications were identified in 20 of the 28 cases (71%) during the perinatal period. Polyhydramnios was observed in 11 fetuses (39%), 2 presented with hydrops fetalis and 7 presented in acute fetal distress requiring emergency cesarean section, of which 1 died in utero before delivery. Median gestational age of the 27 neonates born alive was 35 weeks (range 29 to 39), including 13 (46%) who were pre-term (less than 34 weeks of gestation). Complications at birth included hemodynamic instability in 3 newborns, of whom 2 underwent emergency surgery, respiratory distress syndrome in 8 (30%) and hypertension in 6 (22%). Surgical complications occurred in 7 patients (26%), including tumor rupture in 1 and intraoperative bleeding with postoperative death in 1. At a median followup of 42 months (range 2 to 105) 26 of the 27 children were in complete remission. Conclusions: Fetal renal tumors have an excellent oncological outcome but a high risk of perinatal complications. Prenatal diagnosis should allow planning the delivery at a pediatric tertiary care center to avoid a potentially life threatening condition in neonates in the first hours of life. KEY WORDS: kidney, kidney neoplasms, prenatal diagnosis, nephroblastoma, survival
Neonatal solid renal tumors are uncommon. They represent less than 10% of all tumors arising in the neonate, far behind teratoma and neuroblastoma.1 Congenital mesoblastic nephroma (CMN) has been the most common renal neoplasm in the neonatal period since it was recognized as a histopathological entity distinct from Wilms tumor (WT).2 With the widespread use of routine prenatal ultrasonography (US) the prenatal detection and complications of renal tumors have been occasionally reported. In this study we assessed the incidence of perinatal complications and present guidelines for the optimal management of prenatally detected renal tumors. PATIENTS AND METHODS
In this retrospective multicenter study a questionnaire was mailed to participating institutions of the French Groupe d’Etude en Urologie Pe´diatrique (see Appendix). All children with a solid renal tumor prenatally diagnosed from 1985 to 2002 were included in this study. Prenatal findings, clinical charts, and radiological, surgical and pathological reports were collected and reviewed. Quantitative data are expressed as the median and range. Comparisons between proportions were performed with the chi-square test corrected for heterogeneity or Fisher’s exact 2-tailed test when appropriate.
RESULTS
In this study 28 children were included after prenatal diagnosis of a solid renal mass, which was confirmed postnatally to be CMN or WT. There were 19 females (68%) and 9 males. Prenatal sonographic findings. The diagnosis of renal tumor was made on routine US during the third trimester of gestation in all except 2 cases, which were diagnosed at 23 and 25 weeks of gestation (WG), respectively. Median fetal age at diagnosis was 30 WG (range 23 to 38). Prenatal US findings regarding renal tumor morphological characteristics were fully available on 24 patients. Tumors were usually heterogenous (16 of 24 cases or 67%), more often arising from the right kidney (18 of 28 or 64%) and without any distinct capsule (14 of 24 or 58%). Other, more unusual features included cystic components (7 of 24 cases or 29%), tumor calcifications (3) and increased vascularity (6). None of these characteristics allowed one to distinguish between CMN and WT. One or more complications were identified in 20 of the 28 cases (71%) during the prenatal period, at birth or during the postoperative course. Prenatal complications. As defined by an increased amniotic fluid index above the 95th percentile for gestation, polyhydramnios was observed in 11 cases (39%). Two of these neonates had hypercalcemia at birth. Polyhydramnios was significantly associated with pre-term labor and prematurity. Patients with polyhydramnios were born at a median term of 33 WG (range 29 to 37) compared to 36 WG (range 32 to 39) for those with a normal amniotic fluid index (p ⬍0.01).
Submitted for publication March 30, 2004. * Correspondence: Service de Chirurgie Infantile-Urologie Pe´diatrique, Hoˆpital Me`re-Enfant, Centre Hospitalier Universitaire de Nantes, 44093 Nantes, Cedex 01, France (telephone: ⫹33 2 40 08 35 85; FAX: ⫹33 2 40 08 35 46; e-mail: [email protected]). 186
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OUTCOME OF FETAL RENAL TUMORS
Nonimmune fetal hydrops was observed in 2 cases. The first patient was a female fetus with a renal tumor diagnosed at 30 WG. Two weeks later US revealed polyhydramnios and extensive subcutaneous edema suggestive of hydrops. Further scans showed worsening of polyhydramnios and hydrops, leading to the decision to perform cesarean section at 34 WG. Respiratory distress at birth required intubation and mechanical ventilation. The neonate underwent nephrectomy at 7 days of life, allowing complete resection of a 70 mm Wilms tumor of the right kidney. She was discharged home at 30 days of life and followup was uneventful. The second patient was a female diagnosed at 29 WG with a 100 mm right solid renal tumor that had high intratumoral vascular signal intensity on Doppler examination. US showed polyhydramnios, hydrops fetalis with subcutaneous edema, ascites, pleural effusions and evidence of high output heart failure. After urgent cesarean section and adequate resuscitation in the neonatal intensive care unit the newborn was still unstable and surgery was performed at 1 day of life. A large CMN (cellular variant) was removed with major blood loss. Despite full supportive care the infant died on day 2. Acute fetal distress occurred in 7 fetuses (25%) at a median term of 31 WG (range 29 to 34). Persistent decelerations on cardiotocograph monitoring in these cases led to the decision to perform emergency delivery by cesarean section. One fetus died in utero before delivery at 34 WG, 2 weeks after the diagnosis of a renal tumor associated with oligohydramnios. As defined by birth at or before 34 WG, prematurity was observed in 13 newborns (46%). Of these premature newborns 11 had 1 or more previously detailed prenatal complications. Median age at birth of the 27 neonates born alive was 35 WG (range 29 to 39). Birth. Patients in this study were born by vaginal delivery (15), cesarean section (12) and unknown (1). The indication for cesarean section was a worsening condition in 7 fetuses, obstetric reasons in 3 and a large, noncomplicated abdominal mass in 2. Median birth weight was 3,080 gm (range 1,700 to 3,980). Except for the 2 patients with hydrops fetalis all newborns had a birth weight within the normal range ⫾ 2 SD when matched for gestational age. There were no cases of in utero growth retardation. Postnatal complications. Three newborns with severe fetal distress presented after emergency extraction with hemodynamic instability and required cardiocirculatory resuscitation. Two of them underwent emergency surgical procedure for resection of the abdominal mass. Eight newborns (30%) who presented at birth with severe respiratory distress syndrome required mechanical ventilation. The median term of birth was 32 WG (range 30 to 36). Arterial hypertension, requiring specific anti-hypertensive treatment was noted at birth in 6 neonates (22%), of whom 3 had documented, increased plasma renin activity and aldosterone. Two of the 6 newborns with hypertension had prenatal polyhydramnios and hypercalcemia at birth. In all cases blood pressure and calcemia returned to normal values after nephrectomy. Surgery. All neonates born alive underwent complete surgical resection of the renal tumor at a median age of 7 days (range 0 to 38). The surgical procedure was performed via a transperitoneal transverse approach in all except 1 case. Median operative time was 80 minutes (range 50 to 180). The overall rate of surgical complication was 26% (7 of 27 cases). There were 2 major intraoperative complications, which occurred in the 2 patients who underwent surgery in the first hours of life for hemodynamic instability. In 1 case partial rupture of the tumor capsule occurred, resulting in intraperitoneal tumor spillage of a classic form of CMN. This child had no evidence of recurrent disease at a followup of 2 years. The second complication was intraoperative bleeding in the patient with fetal hydrops who died during the postoperative course. Postoperative complications developed in 5 patients (19%), namely ischemic colonic perforation with
peritonitis at day 2 in 1, an adhesive intestinal obstruction requiring surgery at day 36 in 1, postoperative necrotizing enterocolitis in a full-term 3,040 gm male newborn with long-term neurological sequelae, septicemia from a central venous line in 1 and a sacral bedsore requiring further plastic surgery in 1. On histological examination 26 renal tumors were diagnosed as CMN, of which 5 (19%) were a cellular variant of CMN. The remaining 2 patients had International Society of Paediatric Oncology stage I favorable histology Wilms tumor. None of the children of this series had received adjuvant therapy. As of August 2003, the median followup was 42 months (range 2 to 105). At the current followup 26 of the 27 patients born alive had no evidence of recurrent disease. The 2 children with WT were in complete remission 42 and 64 months after diagnosis, respectively.
DISCUSSION
To our knowledge this multicenter study is the first large series describing the outcome of prenatally diagnosed renal tumors. It confirms the excellent oncological outcome but shows a high incidence of perinatal complications of fetal renal tumors. Mesoblastic nephroma represents approximately 2% to 3% of pediatric renal tumors3 but most cases occur within the neonatal period. CMN is a mesenchymal tumor that is histologically characterized by the proliferation of spindleshaped cells arranged in fascicles that dissect into the normal renal parenchyma.2, 3 The main differential diagnoses of CMN are Wilms tumor and malignant rhabdoid tumor of the kidney, which are rare in neonates. It seems difficult to differentiate reliably between CMN and WT based on prenatal US. Experience with WT in infancy and childhood shows that WT is frequently a well encapsulated, heterogeneous tumor, whereas CMN is often reported to have an homogenous solid aspect on ultrasonography4, 5 and it lacks a welldefined capsule because tumor proliferation blends with the adjacent renal parenchyma. However, several ultrasonographic variants have also been described,6, 7 as confirmed in this series by tumors with microcalcifications or hypoechoic (cystic) components. Other imaging modalities, such as magnetic resonance imaging, may help make a more precise diagnosis, especially in poor sonographic conditions such as obesity of the mother or oligohydramnios. Polyhydramnios is reported to be a frequent clinical feature of CMN.8 In the current study it was observed in almost 40% of the fetuses. The physiopathology of polyhydramnios in renal tumors is still debated and several mechanisms have been suggested, including excessive fetal urine production and impaired gastrointestinal function due to bowel compression.5, 6 Fetal polyuria could be related to renal hyperperfusion, impaired renal concentrating ability and hypercalcemia.9 Nonimmune fetal hydrops had already been observed in CMN10, 11 and Wilms tumor.12 In the context of a renal tumor hydrops fetalis may be attributable to the compression of major infradiaphragmatic vessels by a large abdominal mass12 or the consequence of prenatal high output heart failure due to vascular shunting in a large angiomatous lesion, as in 1 patient in the current series. The poor outcome in patients with fetal hydrops11, 12 justifies close monitoring after prenatal diagnosis of a renal tumor. This report underlines the high risk of prematurity in fetal renal tumors because almost half of the newborns were delivered before week 34 of gestation. Of the 13 premature newborns 11 presented with polyhydramnios and repeat therapeutic amniocenteses may have contributed to the onset of pre-term labor and amniotic membrane rupture. Alterations in fetal condition were also an important factor of
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prematurity since 25% of the fetuses showed evidence of acute fetal distress and were delivered prematurely. The neonatal morbidity of congenital renal tumors may be related to prematurity and/or to the tumor itself. A large renal tumor appears to be a life threatening condition because 3 newborns needed immediate resuscitation at birth and 1 fetus died in utero with acute fetal distress. Eight infants in the current study required ventilatory support at birth for respiratory distress syndrome as a consequence of delayed maturation of the lungs or diaphragmatic compression by the abdominal mass. Hypertension has long been recognized as a presenting feature of CMN since Malone et al reported an association of hypertension, plasmatic hyperreninism and a distinctive pattern of immunoreactive renin staining within the tumor.13 Hypertension was found in 22% of the neonates in the current study with hyperreninism in 3. Blood pressure in neonates with a renal tumor should be monitored and controlled before surgery to avoid perioperative fluctuations. The high rate of surgical complications in this study was related to several factors, such as complications of an emergency procedure performed in infants in poor condition (major bleeding and subsequent death, and tumor rupture), complications of major abdominal and oncological surgery (necrotizing enterocolitis, bowel ischemic perforation and intestinal obstruction) or complications of neonatal nursing (septicemia and a sacral bedsore). Safe resection of abdominal neonatal tumors may be challenging in cases of large and fragile tumors with rich peripheral neovascularization. In their study of 51 infants or children with CMN Howell et al reported 12 (23%) with intraoperative rupture and tumor spillage or incomplete resection for local extension.14 Wilms tumor is extremely rare in neonates with an incidence lower than 0.2% in the experience of the National Wilms’ Tumor Study.15, 16 In neonates Ritchey et al reported an outcome comparable to that in the older population with WT with some risk of relapse when treated without adjuvant therapy, and a high incidence of nephrogenic rests with the subsequent risk of metachronous tumor formation.16 They concluded that neonates could benefit from de-escalation in adjuvant therapy but they require close and prolonged surveillance. In a report from the National Wilms Tumor Study-5 protocol Green et al observed that children younger than 24 months with stage 1 favorable histology WT treated with surgery alone had an 86.5% 2-year disease-free survival rate, which was marginally inferior to that in children treated with adjuvant chemotherapy.17 When considering the potential risks of chemotherapy (central venous line complications and hepatic toxicity), it seems that surgery only is an acceptable strategy in neonates, although it is not the standard of care. In contrast to WT, CMN has benign biological behavior and a more favorable outcome if adequate surgical resection is achieved.14, 18 Metastatic spread of CMN is extremely rare, although recurrence and distant metastases in the brain, heart and lungs have been reported.19 The cellular variant is a potentially more aggressive form of CMN but a positive surgical margin seems to be the only prognostic factor related to tumor recurrence.18 The data in the current study confirm the excellent outcome after treatment of congenital renal tumors with an overall survival rate of 96% and no recurrence in a population with 27 renal tumors, including 2 WTs and 5 cellular variants of CMN. The optimal perinatal management of fetal renal tumors includes a multidisciplinary approach involving obstetricians, pediatricians, pediatric surgeons and oncologists. The good outcome of these tumors may help parental counseling before birth. Data in this study regarding morbidity provide support for careful, continuous observation of the fetus when a renal tumor is diagnosed during routine prenatal US. Maternal referral to a perinatal care center should be considered, and close US followup and maternal-fetal monitoring
should be performed to detect fetal complications. Considering the high incidence of polyhydramnios and the influence of prematurity in perinatal complications, control of polyhydramnios is essential.20 When severe fetal complications are detected, pre-term delivery should be balanced with the morbidity of consented prematurity. With the eventuality of severe cardiocirculatory or respiratory distress at birth maternal transportation for induced elective delivery at a pediatric tertiary care center may be considered in some cases. APPENDIX
Main investigators at the departments of pediatric urology at the following institutions participated in the study on behalf of the Groupe d’Etude en Urologie Pe´diatrique: L. Coupris, Centre Hospitalier Universitaire (CHU) d’Angers, Angers, F. Sauvat and F. Gauthier, CHU de Biceˆtre, Biceˆtre, E. Dobremez and P. Vergnes, CHU de Bourdeaux, Bordeaux, P. Ravasse, CHU de Caen, Caen, E. Sapin, CHU de Dijon, Dijon, J. F. Colombani, CHU de Fort-de-France, Fort-deFrance, C. Piolat and J. F. Dyon, CHU de Grenoble, Grenoble, D. Weil, Centre Hospitalier de Le Mans, Le Mans, L. Fourcade, CHU de Limoges, Limoges, M. D. Leclair and Y. Heloury, CHU de Nantes, Nantes, H. Steyaert, Hoˆpital Lenval, Nice, A. El-Ghoneimi, A. Bonnard and Y. Aigrain, Hoˆpital Robert Debre´, A. Lironi and C. Fekete, Hoˆpital des Enfantes Malades and M. Williamson and G. Audry, Hoˆpital d’Enfants Armand Trousseau, Paris, G. Levard, CHU de Poitiers, Poitiers, F. Lefebre, CHU de Reims, Reims, O. Azzis and B. Fremond, CHU de Rennes, Rennes, D. Eurin and A. Liard, CHU de Rouen, Rouen, F. Varlet, CHU de SaintEtienne, Saint-Etienne, and F. Lemasson and J. Moscovici, CHU de Toulouse, Toulouse, France; J. M. Joseph, CHU de Lausanne, Lausanne, Switzerland; and C. Esposito, Universita` di Napoli Federico II, Naples, Italy. REFERENCES
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