A seminar presentation on benign kidney malignancy in children-Nephroblastoma, siting management and challenges in the tropical setting.

1. Management and challenges in tropical settings.
Dr. Ahmed I.M.
Dept. of paediatrics
ABUTH Zaria.

2.  INTRODUCTION
 DEFINITION
 EPIDEMIOLOGY/INCIDENCE
 PATHOLOGY
 CLINICAL MANIFESTATIONS
 DIAGNOSIS
 DIFFERENTIAL DIAGNOSES
 TREATMENT
 CURRENT ADVANCES IN TREATMENT
 CHALLENGES IN MANAGEMENT
 PROGNOSIS
 RECOMMENDATIONS
 CONCLUSION
 REFERENCES

3.  Definition
 Malignant embryonal tumor of renal tissue
 First described in 1899 by Max Wilms as
“Mischgeschwülste der Niere” (mixed tumors
of the kidney)

4.  6% of all childhood cancers.
 4th most common childhood malignancy in
the United States. Occurs in 1 out of 10,000
children less than 15 years of age.
 Nine new cases per million children
diagnosed annually in the United States.
 Male:female ratio 0.92:1.00 in unilateral
disease and 0.6:1.00 in bilateral disease.

5.  Seventy-eight percent of children are
diagnosed at 1–5 years of age.
 Peak incidence occurring between 3 and 4
years of age.
 Median age of presentation is 44 months in
unilateral disease, 32 months in bilateral
disease.
 Usually sporadic, but 1% of cases are familial.

6.  The peak age incidence was 2–5 years with a
male:female ratio of 1.1:1
◦ 22 children (52.3%) had stage III disease,
◦ 13 (31.0%) had stage IV,
◦ 7 (16.7%) children had stage II. (Enugu)
◦ Wilms' tumour (1.6%) in Port Harcourt.

7.  USA 7.8
 UK (Manchester) 5.1
 Australia (Queensland) 7.2
 Sweden 8.3
 The Netherland 6.5
 Italy (Turin) 6.5

8.  Genitourinary anomalies: horseshoe kidney, dysplasia of
kidney, cystic disease of kidney, hypospadias,
cryptorchidism, duplication of collecting system (4.4%)
 Congenital aniridia (1.1%)
 Congenital hemihypertrophy (2.9%)
 Musculoskeletal anomalies: clubfoot, rib fusion, distal
phocomelia, hip dislocation (2.9%)
Hamartomas: hemangiomas, “birthmarks,” multiple nevi,
café-au-lait spots (7.9%)

9.  Association with chromosomal parts responsible
for growth functions
Chromosomal association:
◦ Chromosome 11p13 with WT1 in 10–30% of
nephroblastomas
◦ Chromosome 11p15 with WT2
◦ Chromosome 17q with familial FWT-1 (chromosomal
association in familial Wilms tumor)
◦ Chromosome 19q with familial FWT-2
◦ Chromosomes 16q, 1p, 7p und 17q with TP53 mutations

10.  Association with congenital anomalies
 WAGR syndrome (Wilms tumor, aniridia, genital
malformations, mental retardation):
◦ Genital malformations: cryptorchidism, hypospadias,
pseudohermaphroditism, gonadal dysgenesis
◦ Deletion of chromosome 11p13
 Denys-Drash syndrome:
 – Pseudohermaphroditism
 – Glomerulopathy
 – Mutation of chromosome 11p (only one allele
of WT1 with mutation)

11.  Beckwith-Wiedemann syndrome (BWS)
 – Hemihypertrophy
 – Macroglossia
 – Omphalocele
 – Visceromegaly
 – Associated with WT2 on chromosome
11p15 at a rate of 15%
 Isolated hemihypertrophy
 In neurofibromatosis, Perlman syndrome,
Simpson-Golabi-Behmel syndrome

12.  Familial occurrence:
◦ 1–2 % of nephroblastomas with chromosomal
anomalies and familial gene loci (familial WT-1,
familial WT-2; see below)
◦ Sometimes bilateral nephroblastoma
◦ Increased risk in homozygous twins

13.  Macroscopic features
 High variation in tumor size and tissue
morphology
 Tumor often with lobular structure of gray to
pink color and with a capsule
 Occasionally with cysts and hemorrhages
 Tumor growth in the renal vein
 Bilateral 5–7.5%, multifocal 12% spread in one
kidney

14.  Mostly mixed form of epithelial blastemic and
stromal cellular components as well as with
various degrees of cell differentiation.
 In well-differentiated forms glandular acini or
glomerular structures separated by stroma
elements which arrange cells in cords or
nests.
 Stroma with fibroblastic or myxomatous
components containing smooth muscle,
skeletal muscle, cartilage and fatty tissue

15.  Favorable:
◦ good prognosis
◦ blastema, epithelia, and stroma devoid of ectopia or
anaplasia
 Unfavorable:
◦ Poor prognosis
◦ marked enlargement of the nuclei, hyperchromatism of
the enlarged nuclei, and multipolar mitotic figures
◦ Areas of anaplasia may be focal or diffuse

16.  Abdominal mass is the most common
presenting symptom and sign.
 Occasionally, there is abdominal pain,
especially when hemorrhage occurs in the
tumor following trauma.
 Hematuria is not common but is more often
seen microscopically.

17.  Hypertension(25% ) due to elaboration of
renin by tumor cells or, less compression of
renal vasculature.
 Polycythemia is occasionally present.
Erythropoietin levels are usually increased but
can also be normal.
 Bleeding diathesis is due to the presence of
acquired von Willebrand disease

18. Sign/symptom %
Palpable abdominal mass 60
Hypertension 25
Haematuria 15
Obstipation 4
Weight loss 4
UTI 3
Diarrhoea 3
Previous trauma 3
Other signs 8

19.  OBJECTIVES:
◦ Presence of a functioning kidney on the other side
◦ Presence of lung metastases
◦ Presence of bone or brain metastases if indicated
by history or physical examination
◦ Presence of thrombi in inferior vena cava.

20.  History
 Physical examination
 Complete blood count
 Urinalysis
 Blood chemistries
 Assessment of coagulation factors

21.  Assessment of cardiac status:
electrocardiogram and echocardiogram
 Abdominal ultrasound
 Abdominal CT scan with special attention to:
◦ Presence and function of the opposite kidney
◦ Evidence of bilateral involvement
◦ Evidence of involvement of blood vessels with
tumor
◦ Lymph node involvement
◦ Liver infiltration

22.  Chest radiograph (posteroanterior and lateral)
 Chest CT scan: helps recognize small metastases
that may be hidden behind ribs, diaphragm,
 Skeletal scintigram:
 Magnetic resonance imaging and/or CT scan of
brain.
 Angiography may be indicated in bilateral
nephroblastoma.
 Peripheral blood for chromosomal analysis

23.  Investigations :
1. Plain X-Ray.
2. I.V.U.

24. .

25. 4. Selective Renal angiogram.
5. MRI
6. Ultrasound.
7. Biopsy: In the advanced stage.

28.  Conventional abdominal radiography:
intestinal displacement by tumor mass with
punctuated calcifications (in 2–3%)
 Ultrasound, computed tomography (CT)
and/or magnetic resonance imaging (MRI;
with contrast urography) of the abdomen
including the hepatic area (metastases) and
chest CT
 Angiography may be indicated in bilateral
nephroblastoma

29.  Radioisotope scans and/or skeletal survey in
patients with suspected skeletal metastases
 Central nervous system (CNS) MRI in patients
with clear-cell sarcoma or rhabdoid kidney
sarcoma and in patients with possible brain
metastases

30.  Multicystic kidney, hydronephrosis, cystic
nephroma
 Renal abscess
 Cyst of ductus choledochus or mesenteric cyst
 Neuroblastoma, rhabdomyosarcoma,
hepatoblastoma
 Other solid tumors in retroperitoneal area
 In neonates: congenital mesoblastic nephroma
(fetal hamartoma)

31.  Lymphoma of the kidney (rare)
 Renal cell carcinoma
 Rhabdoid tumor of the kidney
 Nephroblastomatosis
 Clear cell sarcoma of the kidney

32.  Stage I:
 Tumor is limited to kidney and is completely
excised.
 Stage II:
 Tumor extends beyond kidney but is completely
excised.
 Stage III:
 Residual non-hematogenous tumor confined to
the abdomen.
 Stage IV:
 Deposits beyond stage III (e.g., lung, liver, bone,
brain).
 Stage V:
 Bilateral renal involvement at diagnosis

34. TREATMENT

35.  Preoperative chemotherapy: vincristine and
actinomycin D; in children with primary
metastases addition of anthracycline
 Postoperative chemotherapy: duration and
drug combination according to stage and
histology
 Toxicity: veno-occlusive disease (VOD) of the
liver especially in infants and small children

36.  WEEK 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
 A A A A A A
A
 V V V V V V V V V V V V V
 A − Dactinomycin (15 μg/kg, IV)
 V − Vincristine (0.05 mg/kg, IV)
 V* − Vincristine (0.067 mg/kg, IV)

37.  WEEK 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
24
A D+ A D+ A D* A D*
A
 V V V V V V V V V V V* V* V* V*
V*
 XRT
 A − Dactinomycin (15 μg/kg, IV)
 D* − Doxorubicin (1.0 mg/kg, IV)
 D+ − Doxorubicin (1.5 mg/kg, IV)
 V − Vincristine (0.05 mg/kg, IV)
 V* − Vincristine (0.067 mg/kg, IV)
 XRT − Radiation therapy

38.  Complete exploration of the abdomen,
including the liver and the contralateral
kidney, should be done.
 All lymph nodes removed should be identified
and the site marked.
 If no abnormal lymph nodes are identified,
one or more apparently normal lymph nodes
should be removed.

39.  Radical excision is advised so that all tumor
tissue can be completely removed.
 The junction of suspicious abnormal areas
with normal kidney should be removed to
facilitate the accurate diagnosis of small
lesions.

40.  Transabdominal tumor resection with
abdominal exploration including liver and
contralateral kidney
 Biopsy of suspected tissue especially lymph
nodes
 Where there is large tumor mass:
preoperative chemotherapy, probably
radiotherapy

41.  The chemotherapy regimen should be administered.
 An abdominal computed tomography (CT) scan should be
performed after approximately 5 weeks of therapy.
 Radiation therapy should be given if there is no reduction
in the size of the tumor from chemotherapy.
 The suggested radiation dose is 1200–1260 cGy (150
cGy/day for 8 days or 180 cGy/day for 7 days). During
radiation therapy, vincristine should be continued at
weekly intervals.

42.  Nephroblastoma is radiosensitive
 Radiation therapy (RT) is usually begun
shortly after surgery (within 10 days), with
the aim of eradicating tumor cells that may
have spilled during surgery.
 The size of the field depends on the findings
at surgery, but in all cases, the liver, spleen,
and opposite kidney should be carefully
shielded.

43.  Whole abdominal radiotherapy is unnecessary
for patients with tumor spills confined to the
flank or for those who had prior biopsy of the
neoplasm.
 Metastatic disease to lungs visible on chest
x-ray require whole-lung RT 1200 cGy.
 Stages III and IV favorable histology (FH) and
stages II, III, and IV unfavorable histology (UH)
at a dose of 1080 cGy as determined by the
preoperative radiologic findings.

44.  Chest radiographs should be performed every 3
months during the first and second years and
every 6 months for 5 years thereafter.
 In patients with pulmonary disease at diagnosis,
chest CT scans should be performed at the same
intervals.
 Abdominal ultrasonography should be performed
every 3 months during the first and second years
post-therapy and then every 6 months until 5
years posttherapy.

45.  Treatment of relapse is determined by the
following factors:
 Group I
 Favorable factors are as follows:
◦ Histology favorable at diagnosis
◦ Stage I at time of diagnosis
◦ Treatment initially with only dactinomycin and
vincristine
◦ Recurrence only in the lungs OR
◦ Recurrence in the abdomen when radiotherapy was
not initially given OR
◦ Recurrence 12 months or more after diagnosis.

46.  Group II
 Unfavorable factors are as follows:
 Unfavorable histology at diagnosis (anaplastic
clear cell and rhabdoid subtypes), regardless
of other factors
 Favorable histology at diagnosis, previously
treated with dactinomycin, vincristine, and
doxorubicin or tumor recurs in the abdomen
after radiotherapy or in other nonpulmonary
sites

47.  Presentation: abdominal mass synchronously
(simultaneously) or metachronously
(sequentially).
 Associated findings: hypertension, aniridia,
and genitourinary anomalies; may arise from
renal dysplasia or nodular or diffuse
nephroblastomatosis.
 Histology: usually favorable.

48.  Diagnosis at an early age (<2 years of age)
carries a better prognosis (survival 70–75%)
than diagnosis at more than 2 years of age
(survival 20–45%).
 Survival is better for patients with stage I or II
disease (85%) compared to stage III or IV
disease (0%).
 Synchronous tumors have a better outlook
than metachronous tumors.

49.  A laparotomy and biopsy of both kidneys should be
performed for purposes of staging and histology
 The chemotherapy
 Evaluation and abdominal CT scan should be carried
out at week 5:
 Postoperative chemotherapy should be adapted to
renal function abnormalities

50.  Favorable histology Survival 94–100%
 Standard histology Survival 90%
 Unfavorable histology Survival 70%

51.  Before era of radiotherapy and chemotherapy,
surgery only: survival rate 20–40%
 After multidisciplinary approaches according
to tumor stage and standard therapy 85–90%
cure rate
 Prognosis depends on stage and histology

52.  – Diffuse anaplasia
 – Viable malignant cells after preoperative
chemotherapy
 – Infiltration of tumor capsule
 – Invasion of tumor cells into vessels
 – Nonradical surgical resection of tumor

53.  Lymph node involvement
 – Tumor rupture (also after biopsy)
 – Metastatic spread
 – Large tumor volume
 – Histology: rhabdoid tumor
 – Molecular genetics: alteration of loss of
heterozygosity on 1p, 11q, 16q, and 22q;
p53 mutations

54. SURVIVAL
HISTOLOGY/STAGE 2 Yr (%) 4 Yr (%)
Favorable I 98 97
Favorable II 96 94
Favorable III 91 88
Favorable IV 88 82
Anaplastic I 89 89
Anaplastic II–IV 56 54

55.  Combinatio nof vincristine, actinomycin D,
doxorubicin, ifosfamide, carboplatin,
cyclophosphamide and etoposide.
 Salvage chemotherapy with ifosfamide,
carboplatin and etoposide.
 High-dose chemotherapy regimes autologous
hemopoietic stem-cell rescue
 Role of molecular biologic markers in
stratifying patients.

 G-CSF 5–10 μg/kg SC

56.  The treatment cost is high compared to
other pediatric cancers
 Does not need high tech lab
 The main drugs vincristine, actinomycin
and doxorubicin are cheaper drug
 The treatment is mainly out-patient

57.  Lack of multidisciplinary approach
 Initially seen and treated by surgeons
 No uniform protocol
 Late referrals and advanced staged
disease
 Poor Performance status
 Inability to afford treatment.
 Lost to follow up

58.  poverty, ignorance, inadequate drug supply
and lack of collaboration.
 poor communication between the doctor and
patients
 Lack of facilities and qualified personnel
needed for early diagnosis

59.  Pretreatment workup is incomplete
 Surgical details are not available
 Surgical staging is not done
 Post surgery follow up is poor
 Incomplete surgery
 Operative complications

60.  Worse Sanitary conditions.
 Higher mortality.
 Lower survival rates of cancer,
 Shorter life expectancy in developing
countries
 Occupational risks are becoming a serious
problem in developing countries

61.  Improving health funding and health information
in the health care delivery system.
 Free health care for children with malignancy is
advocated.
 Collaboration with institutions in the privileged
parts of the world may help.
 Collaborative efforts among surgeons,
pathologists, pediatricians and radiation
oncologists

62.  Wilms tumor is curable in majority even
within constrained resources
 Multidisciplinary approach with good team
work of Surgeon, Pediatric Oncologist,
pathologist and Radiotherapist is essential
 Adherence to a standard protocol
 SIOP Approach may be more suitable for
developing countries?

63.  Abu-Gosh AM, Krailo MD, Goldman SC, Slack RS,
Davenport V, Morris E, Laver JH, Reaman GH,
Cairo W. Ifosfamide, carboplatin and etoposide in
children with poor risk relapsed Wilms tumor: a
Children’s Cancer Group report. Ann Oncol
2002;13:460–9.
 Beckwith JB, Zuppan CE, Browning NG, Moksness
J, Breslow NE. Histological analysis of
aggressiveness and responsiveness in Wilms’
tumor. Med Pediatr Oncol 1996;27:422–8.
 Nelson Textbook of Paediatrics. 18th ed.

64.  Current challenges in Wilms' tumor management.
Gommersall LM, Arya M, Mushtaq I, Duffy P.
Great Ormond Street Hospital, London, UK.
 Poverty and cancer. Tomatis L. Istituto
dell'infanzia, Trieste, Italy.
 Current management of Wilms' tumor in children.
Ko EY, Ritchey ML. Mayo Clinic College of
Medicine, Phoenix, AZ, USA.
 The challenge of nephroblastoma in a developing
country S. O. Ekenze*, N. E. N. Agugua-Obianyo
& O. A. Odetunde Sub-Department of Paediatric
Surgery, University of Nigeria Teaching Hospital,
Enugu, Nigeria.

65.  Recent advances in the management of wilms
tumour. S Agarwala. Indian journal of medical
and paediatric oncology. Vol. 25 No. 3, 2004.
 Dome JS, Coppes MJ. Recent advances in
Wilms’ tumor genetics. Curr Opin Pediatr
 2002;14:5–11.
 Kremens B, Gruhn B, Klingebiel T, Hasan C,
Laws HJ, Koscielniak E, Hero B, Selle B,
Niemeyer G, Finckenstein FG, Schulz A,
Wawer A, Zinti F, Graf N. High dose
chemotherapy with autologous stem cell
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66.  Renal disorders in children: a Nigerian study.
Eke FU, Eke NN. Department of Paediatric
Nephrology, University of Port Harcourt
Teaching Hospital, Port Harcourt, Rivers
State.

67. THANK
YOU.