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 to cancer. 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 <15 years of age. 90, 000 deaths/ year <15 years of age.

Introduction:
Childhood cancer is not a single disease, but includes a variety of malignancies in which abnormal cells divide in an uncontrolled manner. These cancer cells can invade nearby tissues and can migrate by way of

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 factors 5-15% 2. known environmental exposures and exogenous factors <5-10% 3. unknown factors 75-90% Risk factors: 1. External agents: a. Physical carcinogens: Ionizing radiation (x-rays) Non ionizing radiation (electromagnetic fields, ultraviolet) b. Biological carcinogens: Infections from viruses (Epstein Barr virus: Burkitts lymphoma and Hodgkins disease) c. Chemical carcinogens: Tobacco: mothers who smoke during pregnancy. Pesticides, asbestos: parental occupation. Aflatoxin, arsenic: food and drinking water contaminants.

Drugs and medication: pregnant women treatment. Dietary constituents. 2. Internal agents: Inherited factors Predisposition 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 tumor 4. Non- Hodgkins lymphoma and Hodgkins lymphoma 5. Rhabdo myosarcoma 6. Retino blastoma 7. Osteo sarcoma and Ewing sarcoma 8. Germ cell tumors 9. Pleura pulmonary blastoma 10. Hepato blastoma and hepato cellular carcinoma

Cancer in teenagers and young adults: Below are the most common types of cancers in teenagers, ages 15 to 19. 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 bodys production 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.

In general, leukemias are classified in to acute (rapidly d eveloping) 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 myelogenous leukemia (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 with leukemia 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 are defective, kids with leukemia may experience increased episodes of fevers and infections.

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, spread of 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 are given 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 higher dose 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 childhood leukemia include: vincristine, daunorubicin, doxorubicin, cytarabin, L-asparginase, etoposide, 6-mercaptopurine, 6thioguanine, 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:

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 bimodal distribution 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 or the 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.

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 cells intermix 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. High grade 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

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 epidermal growth 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 most commonly 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

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 cerebellar deficits. 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 with headache, 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 pouch in 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.

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 include school 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 confirm a 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)

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 a vein (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.

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 difference between 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

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 includescyclophosphamide, vincristine, doxorubiine, prednisone, cytarabin, methotrexate, L-asparginase, etoposide, 6mercaptopurine. Hodgkin lymphoma: Hodgkin lymphoma often occur in teenagers(age 15 to 19). Two types of childhood Hodgkin lymphoma are: a. Classical Hodgkin lymphoma This is divided in to four subtypes, based on how the cancer cells look under a microscope. They are

Lymphocyte-rich classical Hodgkin lymphoma Nodular sclerosis Hodgkin lymphoma Mixed cellularity Hodgkin lymphoma Lymphocyte-depleted Hodgkin lymphoma b. 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

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 trilateral retinoblastoma. 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.

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% of cases 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.

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 of heterozygosity 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

the distal femur or the proximal tibia. The proximal humerus is the next most common site. Children those with mutation in the RB1 gene, LiFraumeni syndrome or Rothmund-Thompson syndrome have 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 like normal 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 tumors Ewing tumors are the second most common malignant bone tumor in children. b. Benign(non-cancerous) bone tumors Treatment: Treatment for osteosarcoma includes surgery, chemotherapy, and radiation therapy. Drugs used to treat osteosarcoma include- methotrexate, doxorubicin,

cisplatin, etoposide, ifosfamide, epirubicin, gemcitabine. 8. Pleuropulmonary blastoma:

cylophosphamide,

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)

serum level. Treatment of HB combines Cisplatin-based chemotherapy and surgery.