Article Childhoood Cancer

8/12/2019 Article Childhoood Cancer

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Pediatric cancers

Abstract:

The body is made up of trillions of living cells. Normal cells grow, divide,

and die in an orderly fashion. Cancer begins when cells in a part of the

body start to grow out of control. Cancer cell growth is different from

normal cell growth. Instead of dying, cancer cells continue to grow and

form new, abnormal cells. Possibly as many as 30% of cancers are

caused by smoking, while another 30% are diet related. Activation of

proto-oncogenes, inactivation of tumor suppression genes leads tocancer. These genetic defects leads to cellular defects like abnormal

signalling pathway, insensitivity to growth-inhibitory signals,

abnormalities in cell cycle regulation, evasion of programmed cell

death, limitless cell division, ability to develop new blood vessels, tissue

invasion and metastasis. Recent U.N organized surveys performed in

multiple countries have found the average percentage of people who

suffer from some sort of cancer is 31%.

Global incidence of childhood cancer is

160, 000 new cases/ year


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the blood or lymph system to other parts of body. The forms of cancer

that are more common vary according to age.

Cancer in childhood is quite rare compared with cancer in

adults, but it still causes more deaths than any factor, other than

injuries, among children from infancy to age 15 years. The annual

incidence of childhood cancer has increased slightly over the last 30

years; however, mortality has declined significantly for many cancers

due largely to improvements in treatments.

Causes of childhood cancers:

1. Identified familial and genetic factors5-15%

2.known environmental exposures and exogenous factors


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Drugs and medication: pregnant women treatment.

Dietary constituents.

2. Internal agents:Inherited factorsPredisposition to particular familial diseases

Genetically determined features

Types of pediatric cancers:

1.Leukemia(accounts for about 34% of childhood cancer cases)Acute lymphoblastic leukemia (ALL)

Acute myeloid leukemia (AML)2.Brain and CNS tumors(27%, including tumors of spinal cord)

Astrocytoma

Brain stem glioma

Craniopharyngioma

Desmoplastic infantile ganglioglioma

Ependymoma

High- grade glioma

Medulloblastoma

Atypical teratoid rhabdoid tumor

Neurobastoma

3.Wilms tumor4.Non- Hodgkins lymphoma and Hodgkins lymphoma5.Rhabdo myosarcoma6.Retino blastoma7.Osteo sarcoma and Ewing sarcoma8.Germ cell tumors9.Pleura pulmonary blastoma10. Hepato blastoma and hepato cellular carcinoma


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Cancer in teenagers and young adults:

Below are the most common types of cancers in teenagers, ages 15 to19.

1.Hodgkins lymphoma(16%) and Non-Hodgkins lymphoma(8%)2.Germ cell tumors including testicular cancer and ovarian cancer

(16%)

3.CNS tumors (10%)4.Thyroid cancer (7%)5.Acute lymphoblastic leukemia (6%)6.Melanoma (7%)7.Soft tissue carcinoma (7%)8.Osteo sarcoma (5%)9.Acute myeloid leukemia (5%)10. Ewing sarcoma (2%)11. Other cancers (12%)

1. Leukemia:

The term leukemia refers to the cancers of the white blood cells.

When a child has leukemia, a large number of abnormal white

blood cells are produced in the bone marrow. These abnormal

white cells crowd the bone marrow, but they cant perform their

proper role of protecting the body against disease because they are

defective. As leukemia progresses, the cancer interferes with bodysproduction of other types of blood cells including red blood cells

and platelets. This results in anaemia and bleeding problems, in

addition to the increased risk of infection caused by the white cell

abnormalities.


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In general, leukemias are classified in to acute (rapidly developing)

and chronic (slowly developing) forms. In children, about 98% of

leukemias are acute. Acute childhood leukemias are also divided in

to acute lymphoblastic leukemia (ALL) and acute myelogenousleukemia (AML). AML attacks myeloblast cells, making it develop

immaturely, while ALL attacks the white blood cells.

The ALL form of the disease most commonly

occurs in younger children ages 2-8, with a peak incidence at age 4.

Kids have a 20- 25% chance of developing ALL or AML if they have

an identical twin who was diagnosed with illness before age 6. In

general, non identical twins and other siblings of children withleukemia have 2-4 times the average risk of developing this illness.

Children who have inherited certain genetic

problems- such as Li-Fraumeni syndrome, Down syndrome,

Kleinfelter syndrome, neurofibromatosis, Fancosis anaemia- have a

higher risk of developing leukemia, as do kids who are receiving

medical drugs to suppress their immune system after organ

transplants.

Children who have received prior radiation or

chemotherapy for other types of cancers also have a higher risk of

leukemia, usually with in the first eight years after treatment. Most

leukemias arise from non inherited mutations in the genes of

growing blood vessels.

Symptoms:

a.Because of their infection- fighting white blood cells aredefective, kids with leukemia may experience increased episodes

of fevers and infections.


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b.Children with leukemia might bruise and bleed very easily,experience frequent nose bleeds, or bleed for an unusually long

time after even a minor cut because leukemia destroys the bone

marrows ability to produce clot-forming platelets.c. Other symptoms of leukemia include: pain in the bones or joints,

swollen lymph nodes, an abnormality tired feeling.

d.In about 12% of kids with AML and 6% of those with ALL, spreadof leukemia to the brain causes headaches, seizures, balance

problems or abnormal vision.

Chemotherapy for childhood leukemia:

a.Chemotherapy is treatment with anti-cancer drugs that aregiven in to a vein, in to a muscle, in to the cerebrospinal fluid

or taken by mouth as pills.

b.In general, treatment for acute myeloid leukemia uses higherdose of chemo over a shorter period of time, and acute

lymphocytic leukemia treatment uses lower doses of chemo

over a longer period of time (usually 2-3 years).

c. Some of the drugs commonly used to treat childhoodleukemia include: vincristine, daunorubicin, doxorubicin,

cytarabin, L-asparginase, etoposide, 6-mercaptopurine, 6-

thioguanine, methotrexate, mitoxantrone, cyclophosphamide,

prednisone, and dexamethasone.

2.Brain tumors:

Approximately one-half of all childhood brain tumors arise in

the posterior fossa. The suprasellar and pineal regions are

relatively frequent sites for supratentorial childhood brain

tumors.

Medulloblastoma:


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Medulloblastoma which by definition arises in the posterior

fossa, is the most common malignant brain tumor of

childhood. Medulloblastomas usually are diagnosed in

children less than 15 years of age, and they have a bimodaldistribution peaking at 3-4 years of age and then again

between 8-9 years of age. For unknown reasons, there is a

male predominance.

Medulloblastoma is thought to

originate from a primitive cell type in the cerebellum, arising

from one of the two cerebellar germinal zones, the ventricular

zone that forms the innermost boundary of the cerebellum orthe external germinal layer that lines the outside of the

cerebellum. Various genes and signaling pathways have been

identified as active in medulloblastoma and support

progenitor therapies. The nevoid basal cell carcinoma

syndrome, which is caused by an inherited germ line mutation

of the patched tumor suppressor gene (PCTH) on

chromosome 22, encodes the sonic hedge hog (SHH) receptor

patched1 (PCT1), which normally represses the SHH signaling.

Somatic mutation of PTC1 has been

associated predominantly with desmoplastic variant, possibly

from external granular layer precursor, and this pathway is

likely a potential therapeutic target for 10% to 20% of

medulloblastomas. Another signaling pathway that has been

identified in a subset of patients with medulloblastoma has

been the -catenin pathway (Wnt pathway), which is aberrant

in Turcotts syndrome.


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Suprtentorial primitive neuroectodermal tumors:

Supratentorial primitive neuroectodermal tumors are characterized

by undifferentiated or poorly differentiated neuroepithelial cells

that may show some degree of differentiation.Pineoblastomas:

They represent approximately 25% of tumors that occur in pineal

region.

Atypical teratoid or rhabdoid tumors:

These lesions, which predominantly occur in children younger than

3 years, but may be first diagnosed in older children and

adolescents, histologically are characterized by rhabdoid cellsintermix with a variable component of primitive neuroectodermal,

mesenchymal, and epithelial cells.

The rhabdoid cell is a medium- sized round-to-oval

cell with distinct borders, an eccentric nucleus, and a prominent

nucleolus. The primitive neuroectodermal component of atypical

teratoid rhabdoid tumor (AT/RT) is indistinguishable from that

found in other forms of primitive neuroectodermal tumors.

Immunohistochemical studies demonstrated that AT/RTS were

different from medulloblastomas, because the rhabdoid

component of the tumor characteristically stained positive for

epithelial membrane antigen, vimentin, cytokeratin, glial fibrillary

acidic protein, and, at times, smooth muscle actin and

neurofilament protein.

Highgrade glioma (HGG):

These tumors present most frequently between 5 and 10 years of

age. Patients may present with headaches, motor weakness,

personality changes and seizures. On CT and MRI, high grade


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gliomas typically appear as irregularly shaped lesions with partial

contrast enhancement and peritumoral edema with or without

mass effect. A more recent expression for profiling study of

childhood HGG revealed increased expression of the epidermalgrowth factor receptor(EGFR)/ hypoxia inducible factors(HIF)/

insulin growth factor binding protein2(IGFBP2) pathway. The tumor

protein53(TP53) gene is mutated in 34% of HGG in children younger

than 3 years and only 12% of HGG in children older than 3 years.

Low-grade gliomas(LGG):

Most low-grade cortical gliomas in children are juvenile polycytic

astrocytoma(JPA) or diffuse fibrillary astrocytoma. LGG mostcommonly present with headache and seizure. On CT, diffuse

astrocytomas appear ill-defined, homogeneous masses of low

density without contrast enhancement.

Chaismatic gliomas:

Gliomas of the visual pathway, which also may extend to the

hypothalamus and thalamus, comprise a relatively common form of

childhood glioma. 20% of children who have neurofibromatosis

type-1(NF-1) syndrome will develop visual pathway tumors,

predominantly juvenile polycytic astrocytoma. Visual pathway

tumors may cause visual loss, strabismus, nystagmus and proptosis.

Brainstem glioma (BSG):

BSGs comprise 10% to 15% of all pediatric CNS tumors and

generally uncommon in adult population. Peak incidence in

between 5 and 9 years of age, but may occur any time during

childhood. BSGs most commonly arise in the Pons, in which location

they typically resemble adult glioblastomas multiforme (GBM) and

have an almost uniformly dismal prognosis. In contrast, those


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arising from mid brain or medulla are likely to be low-grade lesions

that have a more common indolent course and better outcome.

BSGs commonly present with multiple cranial nerve deficits,

especially 6th

and 7th

nerve palsies, long track signs, and cerebellardeficits.

Cerebellar gliomas:

Cerebellar glioma is found almost exclusively in children, occurring

most frequently between ages 4 and 9. JPA is the most common

subtype, accounting for 85% of cerebellar gliomas. Diffuse

astrocytoma is the next most common, while malignant

astrocytoma is rare in this location. Children typically present withheadache, papilledema and gait disturbances.

Ependymomas:

Ependymomas comprise 5% to 10% of all childhood brain tumors.

Most (70% to 80%) arise in the posterior fossa and, because of a

relative predilection for the cerebellopontine angle and lateral

portion of the lower brain stem, often cause multiple cranial nerve

deficits including 6th and 7th nerve palsies, hearing loss, and

swallowing difficulties.

Craniopharyngiomas:

Cranipharyngiomas account for 5% to 10% of all childhood brain

tumors and are believed to arise from embryonic remnants of

Rathkes pouchin the sellar region. Symptoms may be secondary to

blockage of cerebrospinal fluid and resultant increased intra cranial

pressure or direct charismatic or hypothalamic damage from the

solid tumor and associated cyst. Visual symptoms are variable and

may include decreased visual acuity in one or both eyes and visual

field deficits.


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Germ cell tumors:

Germ cell tumors, which comprise approximately 2% to 5% of all

childhood tumors, arise predominantly in the pineal and suprasellar

region, but may occur throughout the brain. Symptoms includeschool difficulties, polyuria, and behavioral problems, occur in up to

one-third of patients. Germinomas and mixed germ cell tumors

account for approximately 60% of all pineal region masses.

Germinomas may present in both the pineal region and the

suprasellar region in 10% to 20% patients. Elevated cerebrospinal

fluid and, in selected cases, blood levels of -Fento protein(AFP)

and -human chorionic gonadotropin(HCG) can be used to confirma mixed germ cell tumor. Highly elevated levels of -HCG alone are

diagnostic of a choriocarcinoma.

Choroid plexus tumor:

Tumors of the choroid plexus are relatively uncommon,

contributing 1% to 5% of all pediatric tumors. Choroid plexus

papillomas, because of their intraventricular location and

associated cerebrospinal fluid over production, and blockage of

cerebrospinal fluid reabsorbtion pathways, predominantly result in

hydrocephalus.

Spinal cord tumors:

Spinal cord tumors may be extremely difficult to diagnose in young

children who may present with delays in walking, in older patients,

who develop difficult-to-characterize gait disturbances. Back pain is

frequent but often non specific and initially non localizing, and

sensory abnormalities are often hard to characterize in children. In

total, spinal cord tumors account for less than 10% of all

neoplasms. Patients who have NF-1(neurofibromatosis type-1)


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syndrome are prone to develop intramedullary astrocytomas, and

are at high risk for extrinsic cord compression by neurofibromas.

Chemotherapy for CNS tumors:

Chemotherapy uses anti-cancer drugs that are usually given in to avein (IV) or taken by mouth. Chemotherapy is most often used

along with other types of treatment such as surgery and radiation

therapy. Drugs used in chemotherapy are: carboplatin, carmustine,

cisplatin, cyclophosphamide, etoposide, lomustine, methotrexate,

temozolamide, thiotepa, and vincristine.

3.Wilms tumors:Wilms tumors are cancers that can start anywhere in the kidneys.Most wilms tumors are unilateral, which means they affect only

one kidney. Most often there is only one tumor, but 5% to 10% of

children with wilms tumors have more than one tumor in the same

kidney. About 5% of children with wilms tumors have bilateral

disease (cancer in both kidneys).

Germ line wilms tumor1 suppressor gene (WT1)

mutations predispose to wilms tumors. WT1 encodes a zinc finger

transcription factor that is critical to normal development of the

kidneys and gonads. Wilms tumors are most common in young

children, with the average age being about 3 to 4 years. The risk of

wilms tumors is slightly higher in girls than in boys.

Children with WAGR syndrome (wilms tumor

aniridia genitourinary anomalies, and mental retardation) have

about a 30% to 50% chance of having a wilms tumor. Children with

Beckwith wiedemann syndrome have about a 5% to 10% risk of

having wilms tumors. Children with Denys- drash syndrome have

risk of wilms tumors.


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The first sign is usually swelling or a hard mass in the abdomen,

which parents may notice while bathing or dressing the child. Some

children with wilms tumor may also have fever, nausea, loss of

appetite, shortness of breath, constipation or blood in urine.Treatment:

Treatment includes surgery, chemotherapy and radiation therapy.

Drugs used in chemotherapy are Actinomycin D, vincristine.

4.Hodgkin and Non-Hodgkin lymphomas:Lymphoma is a cancer of the lymph system. Lymphoma usually

begins when cells in the lymph system change and grow

uncontrollably which may form tumor. The major differencebetween Hodgkin lymphoma and Non-Hodgkin lymphoma is the

presence of Reed-Sternberg cells in the Hodgkin lymphoma, and

absent in the other type of cancer. Common symptoms for both

types of lymphomas includes swelling of lymph nodes, fever,

unexplained weight loss, sweating, chills, lack of energy and itching.

Non-Hodgkin lymphoma:

Children with Wiskott-Aldrich syndrome, severe combined

immunodeficiency syndrome (SCID), common variable immune

deficiency, Bloom syndrome, X-linked lymphoproliferative

syndrome have high risk of developing Non-Hodgkin lymphoma.

The combination of immune deficiencies (from inherited

conditions, drug treatment or HIV infection) and Epstein-Barr virus

infection can cause some types of Non-Hodgkin lymphoma.

Types of Non-Hodgkin lymphoma in children:

a.Burkitt lymphoma:This type of B-cell lymphoma commonly affects the bone

marrow and central nervous system. Burkitt lymphoma is one of


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the fastest growing types of cancers. It most often develops in

the abdomen and may often spread to the other organs,

including brain.

Large cell Non-Hodgkin lymphoma (LCL):This may develop in throat, abdomen, lymph tissue of the neck,

or near the thymus. LCL is further classified in to subtypes. The

most common subtypes of LCL include Large B-cell lymphoma

(15%), which develops from B-cells, and Anaplastic cell

lymphoma (ALCL,10%) ,which commonly develops from T-cells

but can arise rarely from B-cells.

Lymphoblastic lymphoma (LBL):LBL accounts for about 30% of all childhood Non-Hodgkin

lymphoma. It most often develops in the breast bone and can

spread to the surface of the brain, the bone marrow, other

lymph nodes, and the membranes surrounding the heart and

lungs.

Treatment:

Treatment includes surgery, radiation therapy and

chemotherapy. Drugs used in chemotherapy includes-

cyclophosphamide, vincristine, doxorubiine, prednisone,

cytarabin, methotrexate, L-asparginase, etoposide, 6-

mercaptopurine.

Hodgkin lymphoma:

Hodgkin lymphoma often occur in teenagers(age 15 to 19). Two

types of childhood Hodgkin lymphoma are:

a.Classical Hodgkin lymphomaThis is divided in to four subtypes, based on how the cancer

cells look under a microscope. They are


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Lymphocyte-rich classical Hodgkin lymphoma

Nodular sclerosis Hodgkin lymphoma

Mixed cellularity Hodgkin lymphoma

Lymphocyte-depleted Hodgkin lymphomab.Nodular lymphocyte- predominant Hodgkin lymphoma

Treatment:

Treatment includes radiation therapy, chemotherapy. Drugs

used for chemotherapy includes-mechlorethamine,

vincristine, procarbazine, prednisone, doxorubicin, bleomycin,

vinblastine and dacarbazine.

5.Retinoblastoma:Retinoblastoma is a cancer that starts in the retina, the very

back part of the eye. It is the common type of eye cancer in

children. Rarely, children have other kinds of eye caners, such

as medulloepithelioma. Most children diagnosed with

retinoblastoma are younger than 3 years old. Most congenital

or hereditary retinoblastomas are found during the first year

of life, while non-inherited retinoblastomas tend to diagnosed

in 1-and 2-year-olds. Retinoblastomas are rare in older

children and adults.

Retinoblastoma develops as a result of mutation in the

gene called the Retinoblastoma (RB or RB1) gene. Depending

on when and where the change in the RB1 gene occurs, two

different types of retinoblastoma can result.

a.Congenital (hereditary) retinoblastoma:Every person has two RB1 genes but passes only 1 on to

each of their children. The odds that a parent who had


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hereditary retinoblastoma will pass the mutated gene on to

his or her child are 1 out of 2.

In about 1 out of 3 retinoblastoma, the abnormality

in the RB1 is congenital and is in all the cells of the body.This includes all of the cells of both retinas. Children born

with a mutation in the RB1 gene usually develop

retinoblastoma in both eyes and they are multifocal

retinoblastoma. A small number of children with this form

of retinoblastoma will develop another tumor in the brain,

usually in the pineal gland at the base of the brain

(pineoblastoma). This is also known as trilateralretinoblastoma.

Sporadic (non-hereditary) retinoblastoma:

In about 2 out of 3 cases of retinoblastoma, the

abnormality in the RB1 gene develops on its own in only

one cell in one eye. A child who has sporadic

retinoblastoma develops only one tumor in one eye. This

type of retinoblastoma is often found at a larger age than

the hereditary form.

Medulloepithelioma:

These tumors are very rare. Most medulloepitheliomas are

malignant, but they rarely spread outside of eye. They

usually cause eye pain and loss of vision.

Signs and symptoms:

White pupillary reflex and strabismus are the signs of

retinoblastoma. Other symptoms include vision problems,

eye pain, redness of the white part of the eye, bleeding in

the front part of the eye.


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Treatment:

Treatment includes surgery, radiation therapy,

photocoagulation, cryotherapy, thermotherapy, and

chemotherapy.Drugs used for chemotherapy are

carboplatin, cisplatin, vincristine, etoposide, teniposide,

cyclophosphamide, and doxorubicin.

6.Rhabdomyosarcoma:Rhabdomyosarcoma (RMS) is a malignant tumor of

mesenchymal origin that thought to arise from cells

committed to a skeletal lineage. Approximately 65% ofcases are diagnosed in children less than six years of age

with remaining cases noted in the 10-to-18-year old age

group.

Most cases of RMS appear to be sporadic in

nature, but the disease has been associated with familial

syndromes such as neurofibromatosis and the Li-Fraumeni

syndrome (LFS). RMS has also been observed in association

with Beckwith-wiedemann syndrome, a fetal overgrowth

syndrome associated with abnormalities on chromosome

11P15, where the gene for insulin-like growth factor is

located.

The two histological subtypes of RMS, embryonal

and alveolar, have been found to have distinct genetic

alterations that may play a role in the pathogenesis of

these tumors. Alveolar RMS has been demonstrated to

have a characteristic translocation between the long arm of

chromosome 2 and the long arm of chromosome 13.


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Alveolar RMS exhibits small, round, densely appearing cells

lined up along spaces reminiscent of pulmonary alveoli,

giving rise to the term Alveolar RMS.

Embryonal RMS is known to have loss ofheterozygosity at the 11p15 locus with loss of maternal

genetic information and duplication of paternal genetic

information. The embryonic subtype is characterized by

spindle-shaped cells with a stroma-rich appearance. Both

alveolar and embryonal RMS appear to over produce IGF-2,

a growth factor that has been shown to stimulate RMS

tumor cell growth.Treatment:

Treatment approaches to RMS incorporate surgery,

radiation therapy, and chemotherapy.

Chemotherapy includes vincristine, actinomycin D,

doxorubicin, cyclophosphamide, ifosfamide, and etoposide.

7.Osteosarcoma:Osteosarcoma is the most common type of cancer that

develops in bone. Like the osteoblasts in normal bone, the

cells that form this cancer make bone matrix. But the bone

matrix of an osteosarcoma is not as strong as that of

normal bones. Most osteosarcomas occur in children and

young adults. Teens are the most commonly affected age

group, but osteosarcoma can occur at any age group.

In children and young adults, osteosarcoma

usually develops in areas where the bone is growing

quickly, such as near the ends of the long bones. Most

tumors develop in the bones, around the knee, either in


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the distal femur or the proximal tibia. The proximal

humerus is the next most common site.

Children those with mutation in the RB1 gene, Li-

Fraumeni syndrome or Rothmund-Thompson syndromehave high risk of developing osteosarcoma.

Pain in the affected bone the most common symptom of

osteosarcoma.

Subtypes of the oteosarcoma:

a.High-grade osteosarcoma:These are the fastest growing types of osteosarcoma.

When seen under microscope, they do not look likenormal bone and have many cells in the process of

dividing in to new cells. Most osteosarcomas that occur

in children and teens are high-grade.

b.Low-grade osteosaroma:These are the slowest growing osteosarcomas. The

tumors look more like normal bone and have few

dividing cells when seen under a microscope.

Other types of bone tumors:

a.Malignant(cancerous) bone tumorsEwing tumors are the second most common malignant

bone tumor in children.

b.Benign(non-cancerous) bone tumorsTreatment:

Treatment for osteosarcoma includes surgery,

chemotherapy, and radiation therapy. Drugs used to

treat osteosarcoma include- methotrexate, doxorubicin,


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cisplatin, etoposide, ifosfamide, cylophosphamide,

epirubicin, gemcitabine.

8.Pleuropulmonary blastoma:Pleuropulmonary blastoma is a rare aggressive

malignant tumor of infancy and early childhood. The

tumor arises in the lung and pleura. The tumor affects

mainly in children with ages ranges from 1 month to 12

years. Most cases are diagnosed before 4 years of age.

Males and females are equally affected.

There are three types of Pleuropulmonary blastoma

with distinct macroscopic features.

Treatment:

Drugs used to treat pleuropulmonary blastoma include

vincristine, dactinomycin, cylophosphamide, ifosfamide,

doxorubicin, and actinomycin-D.

9.Hepatoblastoma (HB):HB is a rare tumor but represents the commonest

primary malignant tumor of the liver in childhood. The

onset of HB occurs at a median age of 18-24 months.

Serum -Fetoprotein levels are frequently elevated. HB

may be associated with Beckwith-wiedemann syndrome

and familial adenomatous polyposis. HB may be also

associated with increased platelet count and, rarely,

with elevated -human chorionic gonadotropin (-HCG)


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serum level. Treatment of HB combines Cisplatin-based

chemotherapy and surgery.

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Article Childhoood Cancer