NEPHROBLASTOMA:Management and challenges in tropical settings.

Dr. Ahmed I.M.Dept. of paediatrics

ABUTH Zaria.

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

Definition Malignant embryonal tumor of renal tissue First described in 1899 by Max Wilms as

“Mischgeschwülste der Niere” (mixed tumors

of the kidney)

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.

INCIDENCE

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.

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.

Nigerian experience

WILMS` TUMOURIncidence(Cases /106 children under 15 years of age/year

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

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%)

Incidence of Congenital Anomalies in Patients with Wilms’ Tumor

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

CHROMOSOMAL ASSOCIATION

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)

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

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

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

Pathology

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

Microscopic features

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

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.

CLINICAL MANIFESTATIONS

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

Sign/symptom %

Palpable abdominal mass 60Hypertension 25Haematuria 15Obstipation 4Weight loss 4UTI 3Diarrhoea 3Previous trauma 3Other signs 8

Initial Signs and Symptoms of Wilms’ Tumor in Order of Frequency

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.

DIAGNOSIS

History

Physical examination

Complete blood count

Urinalysis

Blood chemistries

Assessment of coagulation factors

Diagnosis contd

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

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

Investigations :

1. Plain X-Ray.2. I.V.U.

Chest X-ray

.

4. Selective Renal angiogram.

5. MRI

6. Ultrasound.

7. Biopsy: In the advanced stage.

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

Radiological Diagnosis

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

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)

Differential Diagnosis

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

DDX contd

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

National Wilms Tumor Study Group staging system

TREATMENT

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

Chemotherapy

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)

Stage I favorable or anaplastic histology or stage II favorable histology

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

Stages III and IV favorable histology or stage II–IV unfavorable histology

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.

SURGERY

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.

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

Surgical procedures

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.

Treatment of Tumors Considered Inoperable Because of Size

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.

Radiation Therapy

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.

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.

POST-THERAPY FOLLOW-UP

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.

Treatment of Relapse

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

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.

BILATERAL WILMS’ TUMOR

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.

Prognostic Factors

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

Mgnt of BWM

Favorable histology Survival 94–100% Standard histology Survival 90% Unfavorable histology Survival 70%

Prognosis according to stage

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

Prognosis

– Diffuse anaplasia – Viable malignant cells after preoperative

chemotherapy – Infiltration of tumor capsule – Invasion of tumor cells into vessels – Nonradical surgical resection of tumor

Unfavorable factors:

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

  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

 Wilms Tumor: Survival by Histology and Stage

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

Current advances

Cost Issue

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

Wilm's TumorProblems in Management

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

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

Problems with Immediate Nephrectomy

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

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

Poverty and cancer

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

Recommendations

Conclusion

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?

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.

References

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.

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 rescue in children with nephroblastoma. Bone Marrow Transpl 2002;30:893–8.

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.

THANK YOU.