PAEDIATRIC ONCOLOGY

Lecture notes, prepared by Dr. Jamal A. RASHID

INTRODUCTION:

The incidence of malignant diseases in general is 1 in 600 children younger than 15 years.

The majority of cancers occur sporadically. They may rarely be associated with some chromosomal, familial, immunodeficiency disorders or various known syndromes. Virus infection & environmental factors have also been implicated.

In most of the developed countries malignant diseases are considered the 2nd cause of death, after trauma, while in the developing countries malignancy rank 4th or 5th among causes of death in children. Organs which are involved in neoplastic disorders in children differ from those in adults; nephroblastoma, neuroblastoma&retinoblastoma are exclusive to childhood.

Acute leukemia is the most common malignancy in children followed by brain tumors.

%frequency of various forms of malignancies in children:

LEUKEMIAS; 35%:

ALL 27, AML 6% , CML 2%

BRAIN &SPINAL CORD ; 23%:

Astrocytoma ; 7%

Ependymoma ; 3%

Medulloblastoma; 5%

All others; 8%

LYMPHOMAS; 10%:

Hodgkins; 5%

Non Hodgkins; 5%

NEUROBLASTOMA ; 7%

NEPHROBLASTOMA ; 6%

OSTEOSARCOMA; 5%

SOFT TISSUE SARCOMA; 4%

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RETINOBLASTOMA; 3%

GERM CELL TUMOR; 2%

HEPATOBLASTOMA; 1%

ALL OTHERS; 4%

AETIOLOGICAL CAUSES OF CHILDHOOD MALIGNANCIES:

The cause of childhood cancer is often unknown, however genetic disorders, immunodeficiency disorders, viral infections, various chromosomal disorders&syndromes in addition to various environmental factors may predispose to certain cancers.

1/ familial disorders; 10-15% of cancers have some association with genetic disorders. Some tumors may occur in more than one member of a family e.g. brain tumors, Hodgkins disease, NHL, leukemia, neuroblastoma, retinoblastoma & Wilms tumor.

Some genetically determined diseases may predispose the affected individuals to certain malignancy e.g. ataxia telangiectasia; to lymphoma, leukemia & sarcoma. Xeroderma pigmentosa; predisposes to melanoma & other skin cancers. Neurofibromatosis; to brain tumor, lymphoma, leukemia, malignant schwanoma & acaustic neuroma . Fanconi anemia to leukemia. Beckwith- Wiedemann syndrome;toWilms,hepatoblastoma,rhabdomyosarcoma&adrenocortical carcinoma.

Tyrosinemia&adenomatous polyposis to hepatoblastoma.

2/ immune deficiencies; as severe combined immunodeficiency, Wiskott-Aldrich syndrome & XL lymphoproliferative disease associated with EBV infection may predispose to lymphoma.

3/chromosomal disorders:

Down syndrome predisposes to ALL & AML.

Turner syndrome to gonadoblastoma.

Trisomy 13 to leukemia & teratoma.

Trisomy 18 to Wilms tumor& neurogenic malignancies.

Klinefelter syndrome predisposes to leukemia, breast cancer & germ cell tumors.

4/Viral infections; e.g. EBV & HIV are associated with Burkitts lymphoma & Kaposi sarcoma respectively.

5/Environmental factors;such as previous chemotherapy & ionizing radiation.

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FEATURES WITH WHICH CHILDHOOD MALIGNANCIES MAY PRESENT:

1/Prolong fever especially when associated with weight loss or night sweat.

2/Masses:

Abdominal masses should always be considered malignant until proved otherwise.

Wilms tumor, neuroblastoma & lymphoma are the common abdominal malignancies.

Mediastinal masses e.g. Hodgkins & NHL ( anterior mediastinum) , neuroblastoma (posterior mediastinum). ALL, Ewing sarcoma from chest wall…..etc.

Mediastinal obstruction causes orthopnea, chest discomfort, cough, hoarseness, stridor, congested, swollen, plethoric face, neck & upper chest.

Trunk & extremity masses: may be caused by rhabdomyosarcoma or bone tumor.

3/ Bone pain; may indicate bone metastasis, leukemic infiltration of B.M, bone or connective tissue tumor.

4/Supra clavicular lymphadenopathy , which is non tender but firm, may occur in leukemia, lymphoma & may indicate metastasis from abdomen & chest.

5/Early morning headache & vomiting or ataxia; may indicate intracranial tumor with raised intracranial pressure.

6/Bruising, petechiae & pallor.

7/Leukocoria (white papillary reflex) may indicate retinoblastoma.

8/Hypertention; may indicate pheochromocytoma, neuroblastoma or wilms tumor.

LEUKEMIAAcute leukemia is the most common childhood malignancy.

ALL represents 85% of childhood leukemias.

The peak age is 2-6years & ALL is more common in males.

ALL is classified according to cell (lymphoblast) morphology in to L1, L2 & L3.

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L1: small lymphoblasts, little cytoplasm & indistinc nucleoli.

L3: large lymphoblasts with one or more nucleoli.

ALL is also classified immunophenotypically to:

T- cell phenotype 25% , B-cell phenotype 5% & pre B-cell phenotype 70%

Clinical picture:

The most common form of presentation of ALL is as acute or subacute pallor associated with bruising, hepatosplenomegaly & lymphadenopathy. F ever & bone or joint pain may be another form of presentstion. Other features include fatigue, epistaxis, testicular pain & swelling.

Diagnosis:

It is important to keep in mind that a normal C.B.C. & blood film does not exclude leukemia.

But C.B.C.& film in most cases of leukemia may show anemia, thrombocytopenia & increased white cells with a variable proportion of lymphoblasts.

Diagnosis of leukemia can only be confirmed or excluded by B.M examination.

Prognosis:

The favorable prognostic factors for ALL include:

Age: 1-9 years

Sex: female

Race: white

WBC; less than 50.000/c.mm

Ploidy: hyperploidy (more than 53 chromosomes within lymphoblasts)

No organ involvement (organomegaly,CNS involvement or mediastinal masses)

Immunophenotype: CALLA;+ve (Common, Acute, Lymphocytic , Leukemia, Antigen)

Chromosomal translocation: none

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With proper treatment at good centers approximately 70% of children with ALL are expected to be cured.

The prognosis after relapse depends on the timing of relapse. Children with late relapse (more than 2 years after remission) have a better prognosis.

Treatment; Involves 3 stages: induction, consolidation & maintenance.

1/induction of remission: aims to destroy as many cancer cells as possible to induce remission.

Remission is defined as resolution of organomegaly & adenopathy + normal peripheral C.B.C. + no evidence of leukemia on B.M. examination (less than 5% blasts) & normal C.S.F.

With appropriate therapy 98% of ALL patients are expected to achieve complete remission within 4 weeks of starting therapy.

The most commonly used protocol for induction include: I.V. vincristine, steroid (prednisolone or dexamethazone) & L-asparaginase as well as C.N.S. treatment with methotrexate , cytarabine & hydrocortisone delivered directly in to C.S.F

Some additional drugs may be added in high risk patients.

2/ consolidation: the aim of this phase is to consolidate the gains of remission by further eliminating remaining leukemia cells using cycles of high dose methotrexate as intermittent pulses of L-asparaginase & doxorubicin.

This phase also includes prophylactic regimens to prevent C.N.S involvement because systemic chemotherapy poorly penetrates the B.B.B.

Intrathecal methotrexate is continued during consolidation & in the high risk children older than 5 years of age cranial radiation may rarely be indicated.

3/maintenance therapy involves weekly methotrexate & daily 6-MP with intermittent pulses of vincristine & prednisolone to complete a total of 2-3 years of therapy.

Bone marrow transplant: may be done for the very high risk children & for those who have relapsed. The most common site of ALL relapse is the B.M (indicated by the appearance of leukemia blast cells on the peripheral blood smear).

Extramedullary sites of relapse include C.N.S (indicated by leukemia blast cells in the C.S.F.) & testes (indicated by diffuse enlargement or as an isolated palpable testicular mass).

Supportive care &treatment & prevention of infection:

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These are extremely important in all immune-compromised & especially in children with leukemia.

Supportive care includes management of anemia & thrombocytopenia with appropriate blood products.

Infection associated with neutropenia (absolute neutrophil count less than 500/c.mm) is potentially life threatening.

Opportunistic infections with herpes virus, pneumocystis carinii & fungi are always possible.

Metabolic complications from spontaneous or therapy induced cell lysis (cell- lysis syndrome):

Hyperuricemia may cause acute renal failure

Hyperkalemia

Hyperphosphatemia which may also cause hypocalcemia.

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