Pediatric Nephrology
PediatrNephrol (1992) 6:358- 364 9 IPNA 1992
Practical pediatric nephrology Wilms' tumor R. P. Warrier and Osvaldo Regueira
Departnaentof Pediatrics,LSU MedicalCenter, 1542TulaneAvenue,New Orleans,LA 70112, USA ReceivedMarch27, 1992and acceptedApril7, 1992 Abstract. In the last 2 decades, important advances in the treatment of Wilms' tumor have been made. The remarkable improvement in survival in these patients has been the product of new surgical techniques, classification of the tumors into prognostic stages upon initial presentation and the tailoring of chemotherapy and radiation therapy thus permitted. A brief historical perspective is presented with a review of the current treatment and ongoing studies. Key words: Nephroblastoma - Wilms' tumor - Nepronsparing surgery - National Wilms' Tumor Study
Historical perspective
Originally classified as a renal neoplasm by Rance [4] in 1814, it was the subject of a classic monograph by the surgeon Max Wilms in 1899 [5]. During the years that followed, the results of various therapies were dismal. Ladd and White [6] reported very poor results for surgical therapy alone at Boston Children's Hospital at the turn of the century. By the 1940s the survival rate was close to 50%, this being credited to the addition of postoperative irradiation [7]. The effectiveness of chemotherapy, especially actinomycin D, enhanced the result of surgery and radiation, and further improved the results of treatment and survival [8-10].
Introduction Epidemiology
Cancer is the most common cause of death due to disease in children between 1 and 15 years of age [1]. Approximately 6,000-7,000 children under 16 years develop cancer every year [2], acute leukemias and brain tumors being the most common malignancies in the pediatric population. Wilms' tumor is the second most common malignant retroperitoneal tumor in children, affecting approximately 350 children every year in the United States, with an annual incidence of 10.9. per million black children and 8.5 per million white children [3]. Progress in the therapy of Wilms' tumor and the dramatic improvements in survival have been the results of multimodal therapy developed and refined by cooperative efforts of surgeons, radiation therapists, pediatric oncologists and other members of oncology teams in organized national study groups. Comprehensive supportive care with better therapy for infants, abundance of blood products, improvements in radiation therapy and advances in postoperative care have played a major role in this success story.
Correspondence to: R. E Warrier
Wilms' tumor is the most common malignant renal tumor in both children and adolescents [11]. No significant geographical variations have been noted and a 1 : 1 sex ratio is seen in most studies [12]. The median age at diagnosis of unilateral tumors is 36 months for males and 42.5 months for females [13]. The median age at diagnosis for bilateral tumors is 30 months [14], and they represent less than 6% of Wilms' tumors. An increased propensity in family members of patients with Wilms' tumor has been suggested by Knudson [15], however, the absence of cases amongst the siblings of successfully treated patients [16] indicates the role of additional factors. While Kantor et al. [17] indicated a higher risk for children whose fathers were exposed to lead, parental occupation did not appear to have any significant correlation to Wilms' tumor in other studies [18]. Familial cases reported in the literature had an increased incidence of bilaterality and occurred in younger age groups when compared with sporadic cases [18]. Since Wilms' tumor rarely occurs after the 2nd decade, a prenatal origin has been suggested. There is a lack of convincing evidence supporting involvement of environmental factors in the causality of Wilms' tumors [19].
359
Fig. 1 A - C. An 8-month-old infant presented with a mass in the right flank. A Plain X-ray, B abdominal ultrasound and C computed tomographic (CT) scan
Congenital anomalies
Clinical presentation and diagnostic evaluation
Miller et al. [20] reported the association of Wilms' tumor with aniridia, hemihypertrophy and other congenital malformations. The most frequently encountered associations are with aniridia and genitourinary anomalies [21-23]. Miller et al. [20] found that aniridia occurred at a rate of 1 in 73 patients in Wilms' tumor, compared with 1 in 50 000 in the general population. With sporadic aniridia, 33% of the patients develop Wilms' tumor and, due to this high risk, routine ultrasound scanning every 6 months is indicated, until age 5 years [22]. Association of aniridia, mental retardation and ambiguous genitalia has been observed with a specific chromosome deletion of band 1 lp [15, 16, 24] in the short arm of chromosome 11 [25]. Hyperdiploidy and nonrandom trisomies have been recently described in a series of 133 Japanese patients. Trisomy 12 was present in 27% of the patients and was followed in frequency by trisomies of chromosomes 6, 7, 8, 9, 10, 13, 18 and 20, which occurred in at least 10% of patients. No significant difference was found between this series and the European and United States counterparts [26]. Hemihypertrophy occurs in 0.003 per 100 normal children [27] but increases to 2.1 per 100 in children with Wilms' tumor.
An accurate history and thorough physical examination, with attention to associated congenital anomalies and metastasis, followed by a complete blood count, differential white cell count, hepatic and renal function tests and urinalysis should be the starting point. Approximately 83% of children with Wilms' tumor present with a palpable abdominal mass, first noted by the mother or during a routine pediatric checkup A supine plain X-ray of the abdomen will demonstrate a bulging flank and the presence of a mass of homogeneous density with displacement of the bowel gas pattern. An intravenous pyelogram will show distortion and displacement of the urinary collecting system (Fig. 1). Fever, abdominal pain, hematuria and hypertension are other relatively common manifestations. The incidence of hypertension varies from 25% to 63% [28] and has been attributed to an increase in renin activity [29]. Ramsay et al. [30] described patients with abdominal pain, rapid distention of the abdomen, anuria, hypertension and sometimes fever associated with a subcapsular hemorrhage. Rupture of the tumor with acute abdominal pain and peritonitis may present a diagnostic problem [31]. Ascites, hepatomegaly and superficial venous engorgement, secondary to obstruction of the inferior vena cava, represent another clinical variant [32].
360
Fig. 2. CT scan of chest of a 4-year-old child with numerous pulmonary metastases
Fig. 3. Bilateral Wilms' tumor with small calcification in left tumor
Ultrasound scan of the abdomen is probably the most informative yet easily available and noninvasive test [33]. Ultrasound and computed tomographic (CT) scan help establish and delineate the renal mass and the normality of the other kidney, and to document the patency of the inferior vena cava as well as the presence or absence of lung metastasis. Evidence of subdiaphragmatic lymphadenopathy, the relation of tumor to adjoining structures and the presence of cystic and necrotic areas within the kidneys are well detected by these techniques. A carefully perform-
ed ultrasound and CT scan provide most of the information required. Magnetic resonance imaging is noninvasive and demonstrates the anatomy well, but does not provide evidence of function and requires sedation. Arteriography is not usually done initially, but may be of value in cases of bilateral tumor in which partial nephrectomy is contemplated [34-40]. The use of CT scan often detects pulmonary nodules otherwise undetectable by chest X-ray (Fig. 2). Fernback and Pick [36] have shown that not all the nodules are
Fig. 4. A 4-year-old child with right-sided tumor extending into the vena cava and right atrium (counter clockwise)
361 Table 1. National Wilms' Tumor Study staging of Wilms' tumor Stage Description
I
Tumor limited to kidney and completelyexcised. Surfaceof renal capsuleintact. Tumor not rupturedbefore or during removal. No residual tumor apparentbeyond margins of resection
II
Tumor extendsbeyond kidneybut is completelyexcised. Regional extension(i. e., penetrationthrough outer surfaceof renal capsuleinto perirenal soft tissues). Vessels outside kidney surfacesinfiltratedor contain tumor thrombus. Tumor may have been examinedon biopsy, or there has been local spillage of tumor confinedto flank. No residual tumor apparent at or beyond margins of excision Residual nonhematogenoustumor confinedto abdomen. Any of the followingoccur:
III
A. Lymphnodes on biopsy found to be involvedin hilus, periaorticchains, or beyond B. Diffuseperitonealcontaminationby tumor such as spillage of tumor beyond flank before or during surgeryor by tumor growth that has penetratedthrough peritonealsurface C. Implantsfound on peritonealsurfaces D. Tumorextendsbeyond surgical margins either microscopicallyor grossly E. Tumor not completelyexcisablebecauseof local infiltrationinto vital structures IV V
Hematogenousmetastases. Depositsbeyond stage III (i. e., lung, liver, bone, brain) Bilateralrenal involvementat diagnosis. Attempts shouldbe made to stage accordingto the above criteria on the basis of extent of disease before biopsy
From ref [49]
metastatic malignancy, and this results in questions regarding the need for biopsy of these lesions for appropriate staging and tailoring of chemotherapy and possible radiotherapy [41]. Although CT scan is probably the most sensitive modality for detection of nephroblastomatosis, small microscopic foci may not be visualized (Fig. 3). Rarely foci of calcification may be seen and extension of the tumor into the inferior vena cava can be documented (Fig. 4). Of interest is the observed increased levels of hyaluronic acid and hyaluronic acid-activating activity [42]. This may prove to be a useful marker for tumor recurrence and may also be indicative of more aggressive tumor behavior.
Therapy of Wilms' tumor patients Multi-institutional and cooperative group studies by the National Wilms' Tumor Study Committee (NWTS) in the United States and Canada, the Medical Research Council in Great Britain and the International Society for Pediatric Hematology-Oncology in Europe have resulted in refinements of the anatomical staging, histological clarification of prognostic types, establishment of guidelines for radiotherapy, as well as type and duration of chemotherapy [14, 43 -45].
Su~e~ Accurate surgical staging has been the basis on which NWTS has been devised. The current staging system is outlined in Table 1. An attempt at total excision of the Wilms' tumor by a wide transabdominal incision, as described by Mixter [43], is preferred as it permits en bloc resection of the tumor and involved kidney, and allows for appropriate inspection and palpation of the contralateral kidney. Biopsies of the liver, periaortic nodes and any suspicious area on the contralateral kidney also may be performed. Isolation of the tumor, while avoiding spillage and careful handling of the renal vein and inferior vena cava, are essential. The inferior vena cava is involved by tumor thrombus in 4 % - 1 0 % of patients, but right atrial involvement is rare. Use of preoperative chemotherapy lasting several weeks has resulted in a 50% reduction in the size of the original tumor as well as complete resolution of the caval-atrial extensions [46]. Bilateral partial nephrectomy or less complete surgical excision of the tumor to preserve renal parenchyma and function may be indicated in bilateral tumors. Needle biopsy, preoperative chemotherapy and radiation therapy, followed by second-look surgery and partial nephrectomy, have been used w i t h success in bilateral Wilms' tumors [47-51]. A growing trend is that of nephron-sparing surgery for maximal preservation of renal tissue and function. Focal intraoperative radiation therapy in situ or ex vivo can thus be given to involved areas selectively. This is especially important in those patients with bilateral Wilms' tumors who would otherwise require bilateral nephrectomy, with the need for subsequent hemodialysis and renal transplantation, that carries an overall poor prognosis [52].
Chemotherapy Surgical excision with appropriate clinicopathological staging is the first and most important phase of planning therapy for renal tumors. Children with late stages of disease and with histology can be given more aggressive chemotherapy and for a longer duration with the addition of radiation therapy if indicated. Beckwith and Palmer [48] separated all renal tumors into those with favorable (FH) and unfavorable (UFH) histology: In addition, studies are under way to determine if the nuclear morphology of a Wilms' tumor cell can predict the response to chemotherapy at the time of evaluation of the patient [53]. The aim of the cooperative trials, especially NWTS, has been to standardize the staging and histological classification and recognize prognostic significance of age, stage and histology on the outcome of therapy. Staging with the identification of prognostic groups led to tailoring of chemotherapy [ 4 8 - 51 ]. Results of NWTS I and II showed that children with stage I FH Wilms' tumor can be treated with an 11-week regimen of vincristine and actinomycin D without irradiation, with a 4-year relapse-free survival (RFS) of 89%. The 4-year survival for stage 1I FH patients treated with vincristine and actinomycin D with no abdominal
362
radiation was 91%, with RFS of 87.4% [54]. Addition of Adriamycin (doxorubicin hydrochloride, Adria Laboratories, Columbus, Ohio, USA) or radiation therapy to the tumor bed did not statistically improve RFS. NWTS III treated stage I/I patients with vincristine, actinomycin D and Adriamycin or this regimen plus cyclophosphamide. The children had undergone immediate total nephrectomy followed by abdominal and lung irradiation. This resulted in a 5-year RFS of 71.9%. The addition of cyclophosphamide did not improve the RFS [49]. Patients with tumors that contained one or more areas of anaplastic histology (UFH) were randomized to treatment with vincristine, Adriamycin and actinomycin D or this regimen plus cyclophosphamide. Preliminary results from NWTS III suggest that patients with stage II-IV anaplastic Wilms' tumor may benefit by the addition of cyclophosphamide [46]. All those patients received abdominal irradiation and the 4-year RFS was 82.5%.
Radiation therapy Administration of postoperative irradiation to the flank was reported to have improved the survival rate of unstaged children in 1949. Later reports have documented the importance of stage in survival of patients treated with nephrectomy and postoperative abdominal irradiation, with results of: stage I, 61%; stage II, 47%; stage III, 11%; stage IV, 0%; stage V, 0%. The data from NWTS showed that 2,000 rad may be sufficient for the patients that require postoperative irradiation and those that do not have gross residual disease. NWTS IV recommends abdominal irradiation for stage I - I V UFH Wilms' tumors and stage III, IV and V FH tumors [55-60]. Radiation therapy has also been given to lung fields in cases of metastatic disease. A recent observation by NWTS III suggests that no significant statistical difference in 4-year survival post pulmonary relapse has been noted in patients undergoing either resection of metastatic nodules or whole lung radiation [61 ].
Long-term sequelae Patients registered in NWTS have been closely monitored for tumor recurrence, damage to normal tissues and organs resulting from radiotherapy, development of second neoplasms and quality of survival. A 2-year RFS and a 5-year survival after nephrectomy are considered to be equivalent to cure for a patient with Wilms' tumor. With the excellent prognosis for the majority of patients with Wilms' tumor, significant attention is being directed to sequelae of treatment. Acute and chronic liver toxicity, secondary to radiation in right-sided Wilms' tumor, is not uncommon [56, 57]. Radiation damage to axial skeleton, pelvis, thorax, lungs and other organs has been reported in long-term survivors. Kyphosis, scoliosis, unilateral pelvic hypoplasia and unilateral thoracic hypoplasia are all potential complications
[58-60]. Damage to the normal contralateral kidney from radiation and chemotherapy, infection, or antibiotic-induced injury or chronic increase in renal load should be monitored [62]. Several recent reports have described serious abnormafities of cardiac function in patients treated with anthracyclines for various childhood cancers [63, 64]. Development of second neoplasms is another delayed complication in survivors of Wilms' tumor. Li et al. [65] reported that in 487 patients treated between 1927 and 1981 there were 30 patients who developed second neoplasms. Of these, 11 were malignant, with 10 of the 11 being located within the radiation field. The cumulative probability of a second neoplasm in this series was 6% after 20 years and 80% after 39 years. Studies of offspring of persons treated for childhood Wilms' tumor have not shown an increase in congenital anomalies [66]. A study of 118 women treated for Wilms' tumor between 1931 and 1979 [67] showed an increased perinatal morbidity rate as well as an increase in low birth weight infants. Offspring of patients with Wilms' tumor and associated congenital anomalies should be closely monitored [68]. Minimizing the toxicity of chemotherapy, by using less toxic therapy for a shorter duration for children with lowrisk, good-prognosis tumors, and the selective use of radiation therapy, without altering the outcome, continue to be major goals of Wilms' tumor therapy. The model of multimodality, multigroup therapy as started in Wilms' tumor is now spreading to other childhood solid tumors and has attained a goal that could not have been realized by single institutions or smaller groups. The role of limited surgery to spare renal parenchyma, alternatives to anthracyclines for stages II-IV and the role of preoperative chemotherapy are other questions that are being raised in the context of possible limitations of longterm sequelae. Refinements in surgical techniques, elimination of as much chemotherapy as possible with substitution by less toxic drugs for a shorter duration, along with limiting and decreasing radiation therapy, should continue to offer excellent survival rates with better preservation of functional renal tissue and less long-term sequelae. Advances in supportive care, including blood banking, antibiotics, nutritional support and psychosocial advances, should decrease the toxicity and enhance the quality of life for these children. Acknowledgement.The authors wish to thank Dr. J. Smith (LSUMC) for allowing the use of his radiographic teaching collection.
References 1. Cancer Statistics 1984. CA 34:7-23 2. Young JL, Miller RW (1975) Incidence of malignant tumors in U. S. children. J Pediatr 86:254-258 3. Stiller CA, Parkin DM (1990) International variations in the incidence of childhood tumors. Br J Cancer 62: 1026-1030 4. Rance TF (1814) Causes of lung hematodes of the kidneys. Med Phys J 132:19 5. Wilms M (1899) Die Mischgeschwulste der Nieren. Arthur Georgi, Leipzig, pp 1-90 6. Ladd WE, White RR (1938) Embryoma of the kidney (Wilms' tumor). Ann Surg 108:885-902
363 7. Gross RE, Neuhauser EBD (1950) Treatment of mixed tumors of the kidney in childhood. Pediatrics 6: 843-852 8. Farber S (1966) Chemotherapy in the treatment of leukemia and Wilms' tumor. JAMA 198:826-836 9. Farber S, Toch R, Sears EM, Pinkel MD (1956) Advances in chemotherapy of cancers in man. Adv Cancer Res 4 : 1 - 7 1 10. Hammond GD (1986) The cure of childhood cancers. Cancer 58: 407-413 11. Parkin DM, Stiller CA, Draper NJ (1988) International incidence of childhood cancer. International Agency for Research in Cancer, Lyon, p 357 12. Breslow NE, Langholz B (1983) Childhood cancer incidence, geographical and temporal variations. Int J Cancer 32:703 -716 13. Breslow N, Beckwith JB, Ciol M, Sharpies K (1988) Age distribution of Wilms' tumor. Report from the National Wilms' Tumor Study. Cancer Res 48:1653 - 1657 14. Gaynow PS, Nachman J, Wolf J (1984) Chemotherapy of Wilms' tumor. In: Pochedly C, Baun ES (eds) Wilms' tumor, clinical and biological manifestations. Elsevier, New York, p 327 15. Knudson AG (1976) Genetics and the etiology of childhood cancers. Pediatr Res 10:513-517 16. Green DM, Fine WE, Li FP (1982) Offspring of patients treated for unilateral Wilms' tumor in childhood. Cancer 49: 2285-2288 17. Kantor A, McCrea CMG, Meigs JW (1979) Occupation of fathers of patients with Wilms' tumor. J Epidemiol Community Health 33: 253-256 18. Fabia J, Thy JD (1974) Occupation of the father at the time of birth of children dying of malignant disease. Br J Prev Soc Med 28: 98-100 19. Matsunaga E (1981) Genetics of Wilms' tumor. Hum Genet 57: 231-247 20. Miller RW, Fraumeni JR, Manning MD (1964) Association of Wilms' tumor with aniridia, hemihypertrophy and other congenital anomalies. N Engl J Med 270:922-927 21. Ledlie EM, Mynor s LS, Draper GJ, Gorbach PD (1970) Natural history and the treatment of Wilms' tumor. An analysis of 335 cases occurring in England and Wales 1962-1966. BMJ 4:195-200 22. Breslow NE, Beckwith JB (1982) Epidemiological features of Wilms' tumor, results of the National Wilms' Tumor Study. J Natl Cancer Inst 68:429-436 23. Sotelo-Avila C, Gonzalez-Crussi F, Starling K (1980) Wilms' tumor in a patient with an incomplete form of Beckwith Wiedemann syndrome. Pediatrics 66:121 -122 24. Drash A, Sherman F, Hattman WA, Blizzard RM (1970) A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension,.and degenerative renal disease. J Pediatr 76:585 -593 25. Riccardi VM, Sujansky E, Smith AC, Franeke U (1978) Chromosomal imbalance in the aniridia-Wilms' tumor association 1lp interstitial deletion. Pediatrics 61: 604 - 610 26. Kaneko Y, Homma C, Maseki N, Sakurai M, Hata J (1991) Correlation of chromosome abnormalities with histological and clinical features in Wilms' and other childhood renal tumors. Cancer Res 51: 5937-5942 27. Myrianthopolou NC, Chung CS (1974) Congenital.malformation in singletons. Epidemiological survey. Birth Defects 10:1 - 5 8 28. Sukarochana K, Tolentino W, Kiesewetter W (1972) Wilms' tumor and hypertension. J Pediatr Surg 7:573 -578 29. Gonzalez A, Gribble J, Tune B (1973) Renin secretin Wilms' tumor; report of a case and brief review of renin secretion in humans. Ann Intern Med 79:835-837 30. Ramsay NKC, Dehner LP, Coccia F, D'Angio GJ, Nesbit M (1977) Acute hemorrhage into Wilms' tumor. J Pediatr 91:763-765 31. Rosenfeld M, Rodgers BM, Talbert L (1977) Wilms' tumor with acute abdominal pain. Arch Surg 112: 1080-1082 32. Clayman RV, Sheldon CA, Gonzales R (1982) Wilms' tumor, an approach to vena cava intrusion. Prog Pediatr Surg 15: 285-305 33. Teele RL (1977) Ultrasonography of the genitourinary tract. Radiol Clin North Am 15:109-128 34. Green MD (1985) The diagnosis and management of Wilms' tumor. Pediatr Clin North Am 32:735-754
35. Bell TH, Cohen MD, Smith JA (1986) MRI of Wilms' tumor: proraise as the primary imaging method. Am J Radiol 146:955-961 36. Femback D, Pick T (1989) The role of computerized tomography in the clinical staging of Wilms' tumor, a report from the National Wilms' Tumor study. Proc SIOP 16:5 37. Miller JH (1985) Imaging in pediatric oncology. Williams and Wilkins, Baltimore 38. Grossman H (1976) Evaluating common intraabdominal masses in children, a systematic radiographic approach. CA 26:219-235 39. Appell G, Brandes W, Georgi M (1982) Radiographic and scintigraphic appearance of bone metastazing Wilms' tumor, problems in confirming diagnosis. Ann Radiol (Paris) 25: 14-18 40. Cormier PJ, Donaldson JS, Gonzales-Cmssi (1988) Nephroblastomatosis, missed diagnosis. Radiology 169:737-738 41. Wollstein M (1927) Renal neoplasms in young children. Arch Pathol 3:1-13 42. Stem M, Longaker MT, Adzick S, Harrison M, Stem R (1991) Hyaluronidase levels in urine from Wilms' tumor patients. J Natl Cancer Inst 83: 1569-1574 43. Mixter CG (1932) Malignant tumors of the kidney in infancy and childhood. Ann Surg 96: 1017-1027 44. Ganick DJ (1987) Wilms' tumor in cancer in children. Hematol Oncol Clin North Am 1: 695-719 45. Kay R, Tank E (1986) The current management of bilateral Wilms' tumor. J Urol 135:983-985 46. Oberholzer H, Falkson G, De Jager LC (1992) Successful management of inferior vena cava and right atrial nephroblastoma tumor thrombus with preoperative chemotherapy. Med Pediatr Oncol 20: 61-63 47. White JJ, Golladay ES, Kaizer H, Pinney JD, Haller JA (1976) Conservative aggressive management with bilateral Wilms' tumor. J Pediatr Surg 11:859-865 48. Beckwith JB, Palmer NF (1978) Histopathology and prognosis of Wilms' tumor. Cancer 41: 1937-1948 49. D'Angio GJ, Breslow N, Beckwith JB, Evans A, Baum E, Lorimer A, Fembach D, Hrabovsky E, Jones B, Kelalis P, Othersen B, Tefft M, Thomas PRM (1989) Treatment of Wilm's tumor. Results of the Third National Wilms' Tumor Study. Cancer 69: 349-360 50. Green DM, Finkelstein JZ, Breslow NE, Beckwith JB (1991) Remaining problems in the treatment of patients with Wilms' tumor. Solid tumors in children. Pediatr Clin North Am 38:475-488 51. Green DM, Jaffe N (1978) Wilms' tumor, model of a curable pediatric malignant solid tumor. Cancer Treat Rev 5: 143-172 52. Longaker M, Harrison M, Adzick S, Crombleholme TM, Langer JC, Duncan B, Halberg FE, Salvatierra O (1990) Nephron sparing approach to bilateral Wilms' tumor: in situ or ex vivo surgery and radiation therapy. J Pediatr Surg 25:411-414 53. Gearhart JP, Partin A, Leventhal B, Beckwith JB, Epstein I (1992) The use of nuclear morphometry to predict response to therapy in Wilms' tumor. Cancer 69: 804-808 54. D'Angio GJ, Tefft M, Breslow N (1978) Radiation therapy of Wilms' tumor - results according to dose, field, post operative timing and histology. Int J Radiat Oncol Biol Phys 4:769-780 55. Thomas PRM, Tefft M, D'Angio GJ (1983) Relapse pattern in irradiated Second National Wilms' Tumor Study (NWTS 2) (abstract). Proc ASCO 2:69 56. Bamard JA, Marshall GS, Neblett WW, Gray G, Ghishan FK (1986) Noncirrhotic portal fibrosis after Wilms' tumor therapy. Gastroenterology 90: 1054-1056 57. Bjork O, Eklof O, Willis U (1985) Veno-occlusive disease and peliosis of the liver complicating the course of Wilms' tumor. Acta Radio126:589-597 58. D'Angio GJ (1982) The child cured of cancer, a problem for the internist. Semin Oncol 9:143 - 149 59. Kinsella JP, Brasch RC, Ablin AS (1985) Unilateral hypoplasia of the hemithorax causing "pseudo scoliosis" after lung irradiation in a child with Wilms' tumor. Pediatr Radiol 15:340-342 60. Smith R, Davidson JK, Flatman GE (1982) Skeletal effects of orthovoltage and megavoltage therapy following treatment of nephroblastoma. Clin Radio133:601-613
364 61. Green DM, Breslow NE, Li Y, Grundy P, Schochat S, Takashima J, D'Angio GJ (1991) The role of surgical excision in the management of relapsed Wilms' tumor patients with pulmonary metastases: a report of the National Wilms' Tumor Study. J Pediatr Surg 26: 728-733 62. Welch TR, Mc Adams AJ (1986) Focal glomerulosclerosis as a late sequela of Wilms' tumor. J Pediatr 108: 105-109 63. Lipshultz SE, Colan SD, Sanders S, Sallan SEP (1987) Late cardiac effects of doxorubicin in childhood ALL (abstract). Blood 70:234 a 64. Steinherz L, Steinherz P, Tan C, Murphy L (1989) Cardiac toxicity 4 - 2 0 years after completing anthracycline therapy (abstract). Proc Am Soc Clin Oncol 8:296
65. Li FP, Yan JC, Sallan S, Cassady JR, Danahy J, Fine W, Gelber GR, Green DM (1983) Second neoplasms after Wilms' tumor in childhood. J Natl Cancer Inst 71: 1205-1209 66. Li FP, Fine W, Jaffe N (1979) Offspring of patients treated for cancer in childhood. J Natl Cancer Inst 62:1193 - 1197 67. Li FP, Gimbrere K, Gelber RD (1986) Adverse pregnancy outcome after radiotherapy for childhood Wilms' tumor. Proc ASCO 5:202 68. Cordero JF, Li FP, Holmes LB, Geral PS (1980) Wilms' tumor in five cousins. Pediatrics 66:716-719
Literature abstracts Kidney Int (1991) 40: 107-114
Global glomerular sclerosis and glomerular arteriolar hyalinosis in insulin dependent diabetes Ralph D. Harris, Michael W. Steffes, Rudolf W. Bilous, David E. R. Sutherland, and S. Michael Mailer We studied the lesions of global glomerular sclerosis and arteriolar hyalinosis in 43 (29 females) insulin-dependent diabetes mellitus (IDDM) patients whose creatinine clearance (Ccr) was _>45ml/ mirdl.73 m 2 and whose renal biopsies had at least 20 glomeruli available for study.__These patients, ages 17 to 55 years, had IDDM for 7. to 32 (20___6, X + S D ) years. Ccr ranged from 47 to 139 (91-+-25) ml/min/1.73 m 2 and urinary albumin excretion (UAE) from 5 to 3386 (median = 127) mg/24 hrs. Eighteen patients were hypertensive. Thus, these patients represented a broad clinical range from normal renal function through overt diabetic nephropathy. The percent of glomeruli which were globally sclerosed was strongly correlated with Ccr (r =-0.64, P
PediatrNephrol (1992) 6:358- 364 9 IPNA 1992
Practical pediatric nephrology Wilms' tumor R. P. Warrier and Osvaldo Regueira
Departnaentof Pediatrics,LSU MedicalCenter, 1542TulaneAvenue,New Orleans,LA 70112, USA ReceivedMarch27, 1992and acceptedApril7, 1992 Abstract. In the last 2 decades, important advances in the treatment of Wilms' tumor have been made. The remarkable improvement in survival in these patients has been the product of new surgical techniques, classification of the tumors into prognostic stages upon initial presentation and the tailoring of chemotherapy and radiation therapy thus permitted. A brief historical perspective is presented with a review of the current treatment and ongoing studies. Key words: Nephroblastoma - Wilms' tumor - Nepronsparing surgery - National Wilms' Tumor Study
Historical perspective
Originally classified as a renal neoplasm by Rance [4] in 1814, it was the subject of a classic monograph by the surgeon Max Wilms in 1899 [5]. During the years that followed, the results of various therapies were dismal. Ladd and White [6] reported very poor results for surgical therapy alone at Boston Children's Hospital at the turn of the century. By the 1940s the survival rate was close to 50%, this being credited to the addition of postoperative irradiation [7]. The effectiveness of chemotherapy, especially actinomycin D, enhanced the result of surgery and radiation, and further improved the results of treatment and survival [8-10].
Introduction Epidemiology
Cancer is the most common cause of death due to disease in children between 1 and 15 years of age [1]. Approximately 6,000-7,000 children under 16 years develop cancer every year [2], acute leukemias and brain tumors being the most common malignancies in the pediatric population. Wilms' tumor is the second most common malignant retroperitoneal tumor in children, affecting approximately 350 children every year in the United States, with an annual incidence of 10.9. per million black children and 8.5 per million white children [3]. Progress in the therapy of Wilms' tumor and the dramatic improvements in survival have been the results of multimodal therapy developed and refined by cooperative efforts of surgeons, radiation therapists, pediatric oncologists and other members of oncology teams in organized national study groups. Comprehensive supportive care with better therapy for infants, abundance of blood products, improvements in radiation therapy and advances in postoperative care have played a major role in this success story.
Correspondence to: R. E Warrier
Wilms' tumor is the most common malignant renal tumor in both children and adolescents [11]. No significant geographical variations have been noted and a 1 : 1 sex ratio is seen in most studies [12]. The median age at diagnosis of unilateral tumors is 36 months for males and 42.5 months for females [13]. The median age at diagnosis for bilateral tumors is 30 months [14], and they represent less than 6% of Wilms' tumors. An increased propensity in family members of patients with Wilms' tumor has been suggested by Knudson [15], however, the absence of cases amongst the siblings of successfully treated patients [16] indicates the role of additional factors. While Kantor et al. [17] indicated a higher risk for children whose fathers were exposed to lead, parental occupation did not appear to have any significant correlation to Wilms' tumor in other studies [18]. Familial cases reported in the literature had an increased incidence of bilaterality and occurred in younger age groups when compared with sporadic cases [18]. Since Wilms' tumor rarely occurs after the 2nd decade, a prenatal origin has been suggested. There is a lack of convincing evidence supporting involvement of environmental factors in the causality of Wilms' tumors [19].
359
Fig. 1 A - C. An 8-month-old infant presented with a mass in the right flank. A Plain X-ray, B abdominal ultrasound and C computed tomographic (CT) scan
Congenital anomalies
Clinical presentation and diagnostic evaluation
Miller et al. [20] reported the association of Wilms' tumor with aniridia, hemihypertrophy and other congenital malformations. The most frequently encountered associations are with aniridia and genitourinary anomalies [21-23]. Miller et al. [20] found that aniridia occurred at a rate of 1 in 73 patients in Wilms' tumor, compared with 1 in 50 000 in the general population. With sporadic aniridia, 33% of the patients develop Wilms' tumor and, due to this high risk, routine ultrasound scanning every 6 months is indicated, until age 5 years [22]. Association of aniridia, mental retardation and ambiguous genitalia has been observed with a specific chromosome deletion of band 1 lp [15, 16, 24] in the short arm of chromosome 11 [25]. Hyperdiploidy and nonrandom trisomies have been recently described in a series of 133 Japanese patients. Trisomy 12 was present in 27% of the patients and was followed in frequency by trisomies of chromosomes 6, 7, 8, 9, 10, 13, 18 and 20, which occurred in at least 10% of patients. No significant difference was found between this series and the European and United States counterparts [26]. Hemihypertrophy occurs in 0.003 per 100 normal children [27] but increases to 2.1 per 100 in children with Wilms' tumor.
An accurate history and thorough physical examination, with attention to associated congenital anomalies and metastasis, followed by a complete blood count, differential white cell count, hepatic and renal function tests and urinalysis should be the starting point. Approximately 83% of children with Wilms' tumor present with a palpable abdominal mass, first noted by the mother or during a routine pediatric checkup A supine plain X-ray of the abdomen will demonstrate a bulging flank and the presence of a mass of homogeneous density with displacement of the bowel gas pattern. An intravenous pyelogram will show distortion and displacement of the urinary collecting system (Fig. 1). Fever, abdominal pain, hematuria and hypertension are other relatively common manifestations. The incidence of hypertension varies from 25% to 63% [28] and has been attributed to an increase in renin activity [29]. Ramsay et al. [30] described patients with abdominal pain, rapid distention of the abdomen, anuria, hypertension and sometimes fever associated with a subcapsular hemorrhage. Rupture of the tumor with acute abdominal pain and peritonitis may present a diagnostic problem [31]. Ascites, hepatomegaly and superficial venous engorgement, secondary to obstruction of the inferior vena cava, represent another clinical variant [32].
360
Fig. 2. CT scan of chest of a 4-year-old child with numerous pulmonary metastases
Fig. 3. Bilateral Wilms' tumor with small calcification in left tumor
Ultrasound scan of the abdomen is probably the most informative yet easily available and noninvasive test [33]. Ultrasound and computed tomographic (CT) scan help establish and delineate the renal mass and the normality of the other kidney, and to document the patency of the inferior vena cava as well as the presence or absence of lung metastasis. Evidence of subdiaphragmatic lymphadenopathy, the relation of tumor to adjoining structures and the presence of cystic and necrotic areas within the kidneys are well detected by these techniques. A carefully perform-
ed ultrasound and CT scan provide most of the information required. Magnetic resonance imaging is noninvasive and demonstrates the anatomy well, but does not provide evidence of function and requires sedation. Arteriography is not usually done initially, but may be of value in cases of bilateral tumor in which partial nephrectomy is contemplated [34-40]. The use of CT scan often detects pulmonary nodules otherwise undetectable by chest X-ray (Fig. 2). Fernback and Pick [36] have shown that not all the nodules are
Fig. 4. A 4-year-old child with right-sided tumor extending into the vena cava and right atrium (counter clockwise)
361 Table 1. National Wilms' Tumor Study staging of Wilms' tumor Stage Description
I
Tumor limited to kidney and completelyexcised. Surfaceof renal capsuleintact. Tumor not rupturedbefore or during removal. No residual tumor apparentbeyond margins of resection
II
Tumor extendsbeyond kidneybut is completelyexcised. Regional extension(i. e., penetrationthrough outer surfaceof renal capsuleinto perirenal soft tissues). Vessels outside kidney surfacesinfiltratedor contain tumor thrombus. Tumor may have been examinedon biopsy, or there has been local spillage of tumor confinedto flank. No residual tumor apparent at or beyond margins of excision Residual nonhematogenoustumor confinedto abdomen. Any of the followingoccur:
III
A. Lymphnodes on biopsy found to be involvedin hilus, periaorticchains, or beyond B. Diffuseperitonealcontaminationby tumor such as spillage of tumor beyond flank before or during surgeryor by tumor growth that has penetratedthrough peritonealsurface C. Implantsfound on peritonealsurfaces D. Tumorextendsbeyond surgical margins either microscopicallyor grossly E. Tumor not completelyexcisablebecauseof local infiltrationinto vital structures IV V
Hematogenousmetastases. Depositsbeyond stage III (i. e., lung, liver, bone, brain) Bilateralrenal involvementat diagnosis. Attempts shouldbe made to stage accordingto the above criteria on the basis of extent of disease before biopsy
From ref [49]
metastatic malignancy, and this results in questions regarding the need for biopsy of these lesions for appropriate staging and tailoring of chemotherapy and possible radiotherapy [41]. Although CT scan is probably the most sensitive modality for detection of nephroblastomatosis, small microscopic foci may not be visualized (Fig. 3). Rarely foci of calcification may be seen and extension of the tumor into the inferior vena cava can be documented (Fig. 4). Of interest is the observed increased levels of hyaluronic acid and hyaluronic acid-activating activity [42]. This may prove to be a useful marker for tumor recurrence and may also be indicative of more aggressive tumor behavior.
Therapy of Wilms' tumor patients Multi-institutional and cooperative group studies by the National Wilms' Tumor Study Committee (NWTS) in the United States and Canada, the Medical Research Council in Great Britain and the International Society for Pediatric Hematology-Oncology in Europe have resulted in refinements of the anatomical staging, histological clarification of prognostic types, establishment of guidelines for radiotherapy, as well as type and duration of chemotherapy [14, 43 -45].
Su~e~ Accurate surgical staging has been the basis on which NWTS has been devised. The current staging system is outlined in Table 1. An attempt at total excision of the Wilms' tumor by a wide transabdominal incision, as described by Mixter [43], is preferred as it permits en bloc resection of the tumor and involved kidney, and allows for appropriate inspection and palpation of the contralateral kidney. Biopsies of the liver, periaortic nodes and any suspicious area on the contralateral kidney also may be performed. Isolation of the tumor, while avoiding spillage and careful handling of the renal vein and inferior vena cava, are essential. The inferior vena cava is involved by tumor thrombus in 4 % - 1 0 % of patients, but right atrial involvement is rare. Use of preoperative chemotherapy lasting several weeks has resulted in a 50% reduction in the size of the original tumor as well as complete resolution of the caval-atrial extensions [46]. Bilateral partial nephrectomy or less complete surgical excision of the tumor to preserve renal parenchyma and function may be indicated in bilateral tumors. Needle biopsy, preoperative chemotherapy and radiation therapy, followed by second-look surgery and partial nephrectomy, have been used w i t h success in bilateral Wilms' tumors [47-51]. A growing trend is that of nephron-sparing surgery for maximal preservation of renal tissue and function. Focal intraoperative radiation therapy in situ or ex vivo can thus be given to involved areas selectively. This is especially important in those patients with bilateral Wilms' tumors who would otherwise require bilateral nephrectomy, with the need for subsequent hemodialysis and renal transplantation, that carries an overall poor prognosis [52].
Chemotherapy Surgical excision with appropriate clinicopathological staging is the first and most important phase of planning therapy for renal tumors. Children with late stages of disease and with histology can be given more aggressive chemotherapy and for a longer duration with the addition of radiation therapy if indicated. Beckwith and Palmer [48] separated all renal tumors into those with favorable (FH) and unfavorable (UFH) histology: In addition, studies are under way to determine if the nuclear morphology of a Wilms' tumor cell can predict the response to chemotherapy at the time of evaluation of the patient [53]. The aim of the cooperative trials, especially NWTS, has been to standardize the staging and histological classification and recognize prognostic significance of age, stage and histology on the outcome of therapy. Staging with the identification of prognostic groups led to tailoring of chemotherapy [ 4 8 - 51 ]. Results of NWTS I and II showed that children with stage I FH Wilms' tumor can be treated with an 11-week regimen of vincristine and actinomycin D without irradiation, with a 4-year relapse-free survival (RFS) of 89%. The 4-year survival for stage 1I FH patients treated with vincristine and actinomycin D with no abdominal
362
radiation was 91%, with RFS of 87.4% [54]. Addition of Adriamycin (doxorubicin hydrochloride, Adria Laboratories, Columbus, Ohio, USA) or radiation therapy to the tumor bed did not statistically improve RFS. NWTS III treated stage I/I patients with vincristine, actinomycin D and Adriamycin or this regimen plus cyclophosphamide. The children had undergone immediate total nephrectomy followed by abdominal and lung irradiation. This resulted in a 5-year RFS of 71.9%. The addition of cyclophosphamide did not improve the RFS [49]. Patients with tumors that contained one or more areas of anaplastic histology (UFH) were randomized to treatment with vincristine, Adriamycin and actinomycin D or this regimen plus cyclophosphamide. Preliminary results from NWTS III suggest that patients with stage II-IV anaplastic Wilms' tumor may benefit by the addition of cyclophosphamide [46]. All those patients received abdominal irradiation and the 4-year RFS was 82.5%.
Radiation therapy Administration of postoperative irradiation to the flank was reported to have improved the survival rate of unstaged children in 1949. Later reports have documented the importance of stage in survival of patients treated with nephrectomy and postoperative abdominal irradiation, with results of: stage I, 61%; stage II, 47%; stage III, 11%; stage IV, 0%; stage V, 0%. The data from NWTS showed that 2,000 rad may be sufficient for the patients that require postoperative irradiation and those that do not have gross residual disease. NWTS IV recommends abdominal irradiation for stage I - I V UFH Wilms' tumors and stage III, IV and V FH tumors [55-60]. Radiation therapy has also been given to lung fields in cases of metastatic disease. A recent observation by NWTS III suggests that no significant statistical difference in 4-year survival post pulmonary relapse has been noted in patients undergoing either resection of metastatic nodules or whole lung radiation [61 ].
Long-term sequelae Patients registered in NWTS have been closely monitored for tumor recurrence, damage to normal tissues and organs resulting from radiotherapy, development of second neoplasms and quality of survival. A 2-year RFS and a 5-year survival after nephrectomy are considered to be equivalent to cure for a patient with Wilms' tumor. With the excellent prognosis for the majority of patients with Wilms' tumor, significant attention is being directed to sequelae of treatment. Acute and chronic liver toxicity, secondary to radiation in right-sided Wilms' tumor, is not uncommon [56, 57]. Radiation damage to axial skeleton, pelvis, thorax, lungs and other organs has been reported in long-term survivors. Kyphosis, scoliosis, unilateral pelvic hypoplasia and unilateral thoracic hypoplasia are all potential complications
[58-60]. Damage to the normal contralateral kidney from radiation and chemotherapy, infection, or antibiotic-induced injury or chronic increase in renal load should be monitored [62]. Several recent reports have described serious abnormafities of cardiac function in patients treated with anthracyclines for various childhood cancers [63, 64]. Development of second neoplasms is another delayed complication in survivors of Wilms' tumor. Li et al. [65] reported that in 487 patients treated between 1927 and 1981 there were 30 patients who developed second neoplasms. Of these, 11 were malignant, with 10 of the 11 being located within the radiation field. The cumulative probability of a second neoplasm in this series was 6% after 20 years and 80% after 39 years. Studies of offspring of persons treated for childhood Wilms' tumor have not shown an increase in congenital anomalies [66]. A study of 118 women treated for Wilms' tumor between 1931 and 1979 [67] showed an increased perinatal morbidity rate as well as an increase in low birth weight infants. Offspring of patients with Wilms' tumor and associated congenital anomalies should be closely monitored [68]. Minimizing the toxicity of chemotherapy, by using less toxic therapy for a shorter duration for children with lowrisk, good-prognosis tumors, and the selective use of radiation therapy, without altering the outcome, continue to be major goals of Wilms' tumor therapy. The model of multimodality, multigroup therapy as started in Wilms' tumor is now spreading to other childhood solid tumors and has attained a goal that could not have been realized by single institutions or smaller groups. The role of limited surgery to spare renal parenchyma, alternatives to anthracyclines for stages II-IV and the role of preoperative chemotherapy are other questions that are being raised in the context of possible limitations of longterm sequelae. Refinements in surgical techniques, elimination of as much chemotherapy as possible with substitution by less toxic drugs for a shorter duration, along with limiting and decreasing radiation therapy, should continue to offer excellent survival rates with better preservation of functional renal tissue and less long-term sequelae. Advances in supportive care, including blood banking, antibiotics, nutritional support and psychosocial advances, should decrease the toxicity and enhance the quality of life for these children. Acknowledgement.The authors wish to thank Dr. J. Smith (LSUMC) for allowing the use of his radiographic teaching collection.
References 1. Cancer Statistics 1984. CA 34:7-23 2. Young JL, Miller RW (1975) Incidence of malignant tumors in U. S. children. J Pediatr 86:254-258 3. Stiller CA, Parkin DM (1990) International variations in the incidence of childhood tumors. Br J Cancer 62: 1026-1030 4. Rance TF (1814) Causes of lung hematodes of the kidneys. Med Phys J 132:19 5. Wilms M (1899) Die Mischgeschwulste der Nieren. Arthur Georgi, Leipzig, pp 1-90 6. Ladd WE, White RR (1938) Embryoma of the kidney (Wilms' tumor). Ann Surg 108:885-902
363 7. Gross RE, Neuhauser EBD (1950) Treatment of mixed tumors of the kidney in childhood. Pediatrics 6: 843-852 8. Farber S (1966) Chemotherapy in the treatment of leukemia and Wilms' tumor. JAMA 198:826-836 9. Farber S, Toch R, Sears EM, Pinkel MD (1956) Advances in chemotherapy of cancers in man. Adv Cancer Res 4 : 1 - 7 1 10. Hammond GD (1986) The cure of childhood cancers. Cancer 58: 407-413 11. Parkin DM, Stiller CA, Draper NJ (1988) International incidence of childhood cancer. International Agency for Research in Cancer, Lyon, p 357 12. Breslow NE, Langholz B (1983) Childhood cancer incidence, geographical and temporal variations. Int J Cancer 32:703 -716 13. Breslow N, Beckwith JB, Ciol M, Sharpies K (1988) Age distribution of Wilms' tumor. Report from the National Wilms' Tumor Study. Cancer Res 48:1653 - 1657 14. Gaynow PS, Nachman J, Wolf J (1984) Chemotherapy of Wilms' tumor. In: Pochedly C, Baun ES (eds) Wilms' tumor, clinical and biological manifestations. Elsevier, New York, p 327 15. Knudson AG (1976) Genetics and the etiology of childhood cancers. Pediatr Res 10:513-517 16. Green DM, Fine WE, Li FP (1982) Offspring of patients treated for unilateral Wilms' tumor in childhood. Cancer 49: 2285-2288 17. Kantor A, McCrea CMG, Meigs JW (1979) Occupation of fathers of patients with Wilms' tumor. J Epidemiol Community Health 33: 253-256 18. Fabia J, Thy JD (1974) Occupation of the father at the time of birth of children dying of malignant disease. Br J Prev Soc Med 28: 98-100 19. Matsunaga E (1981) Genetics of Wilms' tumor. Hum Genet 57: 231-247 20. Miller RW, Fraumeni JR, Manning MD (1964) Association of Wilms' tumor with aniridia, hemihypertrophy and other congenital anomalies. N Engl J Med 270:922-927 21. Ledlie EM, Mynor s LS, Draper GJ, Gorbach PD (1970) Natural history and the treatment of Wilms' tumor. An analysis of 335 cases occurring in England and Wales 1962-1966. BMJ 4:195-200 22. Breslow NE, Beckwith JB (1982) Epidemiological features of Wilms' tumor, results of the National Wilms' Tumor Study. J Natl Cancer Inst 68:429-436 23. Sotelo-Avila C, Gonzalez-Crussi F, Starling K (1980) Wilms' tumor in a patient with an incomplete form of Beckwith Wiedemann syndrome. Pediatrics 66:121 -122 24. Drash A, Sherman F, Hattman WA, Blizzard RM (1970) A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension,.and degenerative renal disease. J Pediatr 76:585 -593 25. Riccardi VM, Sujansky E, Smith AC, Franeke U (1978) Chromosomal imbalance in the aniridia-Wilms' tumor association 1lp interstitial deletion. Pediatrics 61: 604 - 610 26. Kaneko Y, Homma C, Maseki N, Sakurai M, Hata J (1991) Correlation of chromosome abnormalities with histological and clinical features in Wilms' and other childhood renal tumors. Cancer Res 51: 5937-5942 27. Myrianthopolou NC, Chung CS (1974) Congenital.malformation in singletons. Epidemiological survey. Birth Defects 10:1 - 5 8 28. Sukarochana K, Tolentino W, Kiesewetter W (1972) Wilms' tumor and hypertension. J Pediatr Surg 7:573 -578 29. Gonzalez A, Gribble J, Tune B (1973) Renin secretin Wilms' tumor; report of a case and brief review of renin secretion in humans. Ann Intern Med 79:835-837 30. Ramsay NKC, Dehner LP, Coccia F, D'Angio GJ, Nesbit M (1977) Acute hemorrhage into Wilms' tumor. J Pediatr 91:763-765 31. Rosenfeld M, Rodgers BM, Talbert L (1977) Wilms' tumor with acute abdominal pain. Arch Surg 112: 1080-1082 32. Clayman RV, Sheldon CA, Gonzales R (1982) Wilms' tumor, an approach to vena cava intrusion. Prog Pediatr Surg 15: 285-305 33. Teele RL (1977) Ultrasonography of the genitourinary tract. Radiol Clin North Am 15:109-128 34. Green MD (1985) The diagnosis and management of Wilms' tumor. Pediatr Clin North Am 32:735-754
35. Bell TH, Cohen MD, Smith JA (1986) MRI of Wilms' tumor: proraise as the primary imaging method. Am J Radiol 146:955-961 36. Femback D, Pick T (1989) The role of computerized tomography in the clinical staging of Wilms' tumor, a report from the National Wilms' Tumor study. Proc SIOP 16:5 37. Miller JH (1985) Imaging in pediatric oncology. Williams and Wilkins, Baltimore 38. Grossman H (1976) Evaluating common intraabdominal masses in children, a systematic radiographic approach. CA 26:219-235 39. Appell G, Brandes W, Georgi M (1982) Radiographic and scintigraphic appearance of bone metastazing Wilms' tumor, problems in confirming diagnosis. Ann Radiol (Paris) 25: 14-18 40. Cormier PJ, Donaldson JS, Gonzales-Cmssi (1988) Nephroblastomatosis, missed diagnosis. Radiology 169:737-738 41. Wollstein M (1927) Renal neoplasms in young children. Arch Pathol 3:1-13 42. Stem M, Longaker MT, Adzick S, Harrison M, Stem R (1991) Hyaluronidase levels in urine from Wilms' tumor patients. J Natl Cancer Inst 83: 1569-1574 43. Mixter CG (1932) Malignant tumors of the kidney in infancy and childhood. Ann Surg 96: 1017-1027 44. Ganick DJ (1987) Wilms' tumor in cancer in children. Hematol Oncol Clin North Am 1: 695-719 45. Kay R, Tank E (1986) The current management of bilateral Wilms' tumor. J Urol 135:983-985 46. Oberholzer H, Falkson G, De Jager LC (1992) Successful management of inferior vena cava and right atrial nephroblastoma tumor thrombus with preoperative chemotherapy. Med Pediatr Oncol 20: 61-63 47. White JJ, Golladay ES, Kaizer H, Pinney JD, Haller JA (1976) Conservative aggressive management with bilateral Wilms' tumor. J Pediatr Surg 11:859-865 48. Beckwith JB, Palmer NF (1978) Histopathology and prognosis of Wilms' tumor. Cancer 41: 1937-1948 49. D'Angio GJ, Breslow N, Beckwith JB, Evans A, Baum E, Lorimer A, Fembach D, Hrabovsky E, Jones B, Kelalis P, Othersen B, Tefft M, Thomas PRM (1989) Treatment of Wilm's tumor. Results of the Third National Wilms' Tumor Study. Cancer 69: 349-360 50. Green DM, Finkelstein JZ, Breslow NE, Beckwith JB (1991) Remaining problems in the treatment of patients with Wilms' tumor. Solid tumors in children. Pediatr Clin North Am 38:475-488 51. Green DM, Jaffe N (1978) Wilms' tumor, model of a curable pediatric malignant solid tumor. Cancer Treat Rev 5: 143-172 52. Longaker M, Harrison M, Adzick S, Crombleholme TM, Langer JC, Duncan B, Halberg FE, Salvatierra O (1990) Nephron sparing approach to bilateral Wilms' tumor: in situ or ex vivo surgery and radiation therapy. J Pediatr Surg 25:411-414 53. Gearhart JP, Partin A, Leventhal B, Beckwith JB, Epstein I (1992) The use of nuclear morphometry to predict response to therapy in Wilms' tumor. Cancer 69: 804-808 54. D'Angio GJ, Tefft M, Breslow N (1978) Radiation therapy of Wilms' tumor - results according to dose, field, post operative timing and histology. Int J Radiat Oncol Biol Phys 4:769-780 55. Thomas PRM, Tefft M, D'Angio GJ (1983) Relapse pattern in irradiated Second National Wilms' Tumor Study (NWTS 2) (abstract). Proc ASCO 2:69 56. Bamard JA, Marshall GS, Neblett WW, Gray G, Ghishan FK (1986) Noncirrhotic portal fibrosis after Wilms' tumor therapy. Gastroenterology 90: 1054-1056 57. Bjork O, Eklof O, Willis U (1985) Veno-occlusive disease and peliosis of the liver complicating the course of Wilms' tumor. Acta Radio126:589-597 58. D'Angio GJ (1982) The child cured of cancer, a problem for the internist. Semin Oncol 9:143 - 149 59. Kinsella JP, Brasch RC, Ablin AS (1985) Unilateral hypoplasia of the hemithorax causing "pseudo scoliosis" after lung irradiation in a child with Wilms' tumor. Pediatr Radiol 15:340-342 60. Smith R, Davidson JK, Flatman GE (1982) Skeletal effects of orthovoltage and megavoltage therapy following treatment of nephroblastoma. Clin Radio133:601-613
364 61. Green DM, Breslow NE, Li Y, Grundy P, Schochat S, Takashima J, D'Angio GJ (1991) The role of surgical excision in the management of relapsed Wilms' tumor patients with pulmonary metastases: a report of the National Wilms' Tumor Study. J Pediatr Surg 26: 728-733 62. Welch TR, Mc Adams AJ (1986) Focal glomerulosclerosis as a late sequela of Wilms' tumor. J Pediatr 108: 105-109 63. Lipshultz SE, Colan SD, Sanders S, Sallan SEP (1987) Late cardiac effects of doxorubicin in childhood ALL (abstract). Blood 70:234 a 64. Steinherz L, Steinherz P, Tan C, Murphy L (1989) Cardiac toxicity 4 - 2 0 years after completing anthracycline therapy (abstract). Proc Am Soc Clin Oncol 8:296
65. Li FP, Yan JC, Sallan S, Cassady JR, Danahy J, Fine W, Gelber GR, Green DM (1983) Second neoplasms after Wilms' tumor in childhood. J Natl Cancer Inst 71: 1205-1209 66. Li FP, Fine W, Jaffe N (1979) Offspring of patients treated for cancer in childhood. J Natl Cancer Inst 62:1193 - 1197 67. Li FP, Gimbrere K, Gelber RD (1986) Adverse pregnancy outcome after radiotherapy for childhood Wilms' tumor. Proc ASCO 5:202 68. Cordero JF, Li FP, Holmes LB, Geral PS (1980) Wilms' tumor in five cousins. Pediatrics 66:716-719
Literature abstracts Kidney Int (1991) 40: 107-114
Global glomerular sclerosis and glomerular arteriolar hyalinosis in insulin dependent diabetes Ralph D. Harris, Michael W. Steffes, Rudolf W. Bilous, David E. R. Sutherland, and S. Michael Mailer We studied the lesions of global glomerular sclerosis and arteriolar hyalinosis in 43 (29 females) insulin-dependent diabetes mellitus (IDDM) patients whose creatinine clearance (Ccr) was _>45ml/ mirdl.73 m 2 and whose renal biopsies had at least 20 glomeruli available for study.__These patients, ages 17 to 55 years, had IDDM for 7. to 32 (20___6, X + S D ) years. Ccr ranged from 47 to 139 (91-+-25) ml/min/1.73 m 2 and urinary albumin excretion (UAE) from 5 to 3386 (median = 127) mg/24 hrs. Eighteen patients were hypertensive. Thus, these patients represented a broad clinical range from normal renal function through overt diabetic nephropathy. The percent of glomeruli which were globally sclerosed was strongly correlated with Ccr (r =-0.64, P
