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Pediatrics_Nelson. Pretreatment with diphenhydramine ± hydrocortisone 2. Volume reduction to reduce donor plasma 3. Washing cellular products to remove all donor plasma (for severe reactions) Adapted from Andreoli TE, Bennett JC, Carpenter CC, Plum F, et al: Cecil Essentials of Medicine, ed 4, Philadelphia, 1997, WB Saunders. HLA, Human leukocyte antigen; RBCs, red blood cells; WBC, white blood cell. *Normal saline is the compatible intravenous fluid. include graft-versus-host disease and infectious diseases such as hepatitis B (<1:250,000 units) and C (1:1,600,000units), human immunodeficiency virus (<1:1,800,000 units), malaria, syphilis, babesiosis, brucellosis, and Chagas disease. Patients who are chronically transfused are more prone to iron overload and alloimmunization to RBCs and platelets. Key NS, Negrier C, Klein HG, et al: Transfusion medicine 1, 2, 3, Lancet 370(9585):415–426, 2007, 427–438, 439–448


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Pediatrics_Nelson. Key NS, Negrier C, Klein HG, et al: Transfusion medicine 1, 2, 3, Lancet 370(9585):415–426, 2007, 427–438, 439–448 Kliegman RM, Stanton BF, St. Geme JW, et al: Nelson Textbook of Pediatrics, ed 19, Philadelphia, 2011, Saunders, p 1648–1722 Monagle P, Chan A, Goldenberg NA, et al: Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines, Chest 141(Suppl 2): 3737S–e801S, 2012. Neunert C, Lim W, Crowther M, et al: American Society of Hematology: The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia, Blood 117(16): 4190–4207, 2011 Scheinberg P: Aplastic anemia: therapeutic updates in immunosuppression and transplantation, 2012, Hematology Am Soc Hematol Educ Program 292–300, 2012


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Pediatrics_Nelson. Scheinberg P: Aplastic anemia: therapeutic updates in immunosuppression and transplantation, 2012, Hematology Am Soc Hematol Educ Program 292–300, 2012 Tolar J, Mehta PA, Walters MC: Hematopoietic cell transplantation for nonmalignant disorders, Biol Blood Marrow Transplant 18(Suppl 1): S166–S171, 2012 Thomas W. McLean and Marcia M. Wofford 21


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Pediatrics_Nelson. S166–S171, 2012 Thomas W. McLean and Marcia M. Wofford 21 Childhood cancer is rare; only about 1% of new cancer cases in the United States occur among children younger than 19 years of age. Hematopoietic tumors (leukemia, lymphoma) are the most common childhood cancers, followed by brain/central nervous system (CNS) tumors and sarcomas of soft tissue and bone (Fig. 153-1). There is wide variability in the age-specific incidence of childhood cancers. Embryonal tumors, such as neuroblastoma and retinoblastoma, peak during the first 2 years of life; acute lymphoblastic leukemia peaks during early childhood (ages 2 to 5 years); osteosarcoma peaks during adolescence; and Hodgkin disease peaks during late adolescence (Fig. 153-2). The overall incidence of cancer among white children is higher than that among other ethnic groups and is twice that of African American children in the United States.


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Pediatrics_Nelson. Many signs and symptoms of childhood cancer are nonspecific. Although most children with fever, fatigue, weight loss, or limp do not have cancer, each of these symptoms may be a manifestation of an underlying malignancy. Uncommonly a child with cancer will have no symptoms at all. An abdominal mass may be palpated on routine examination, or a complete blood count (CBC) may be unexpectedly abnormal. Some children have a genetic susceptibility to cancer and should be screened appropriately (Table 153-1).


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Pediatrics_Nelson. It is important to explore quality, duration, location, severity,and precipitating events of the chief complaint. A prominentlymph node that does not resolve (with or without antibiotics)may warrant a biopsy. A limp that does not improve within weeksshould prompt a CBC and a radiograph or a bone scan. Persistent headaches or morning vomiting should prompt a computed tomography (CT) or magnetic resonance imaging (MRI)scan of the head. Fever, night sweats, or weight loss should raisethe concern for lymphoma. In addition it is important to obtainthe birth history, medical and surgical history, growth history,developmental history, family history, and social history.


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Pediatrics_Nelson. Growth parameters and vital signs are important to obtain in all patients. Pulse oximetry should be obtained if respiratory symptoms are present. The overall appearance of the patient should be noted, particularly general appearance, pain, cachexia, pallor, and respiratory distress. Palpable masses should be measured. Lymphadenopathy and organomegaly should be quantified, if present. A thorough examination of the skin may reveal rashes, bruises, and petechiae. Careful neurologic and ophthalmologic examinations are crucial if headache or vomiting is present, because the vast majority of patients with CNS tumors have abnormal neurologic examinations. Available @ StudentConsult.com Visual Impairment and Leukocoria Vomiting Hepatomegaly Splenomegaly Headaches Lymphadenopathy Anemia Petechiae/Purpura Pancytopenia Fever of Unknown Origin


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Pediatrics_Nelson. Available @ StudentConsult.com Visual Impairment and Leukocoria Vomiting Hepatomegaly Splenomegaly Headaches Lymphadenopathy Anemia Petechiae/Purpura Pancytopenia Fever of Unknown Origin The most common manifestations of childhood cancer are fatigue, anorexia, malaise, pain, fever, abnormal lump ormass, pallor, bruising, petechiae, bleeding, headache, vomiting, visual changes, weight loss, and night sweats (Table 153-2). Lymphadenopathy and organomegaly are commonin leukemia, particularly with T-cell acute lymphoblasticleukemia (ALL) or non-Hodgkin lymphoma. Patients withsolid tumors usually have a palpable or measurable mass.Other signs and symptoms may include limp, cough, dyspnea, cranial nerve palsies, and papilledema. In generalmalignant masses are firm, fixed, and nontender, whereas masses that are infectious or inflammatory in nature are relatively softer, mobile, and tender to palpation.


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Pediatrics_Nelson. Neuroblastoma IV Retinoblastoma V Renal VI Hepatic VII Bone VIII Soft tissue IX Germ cell X Other malig. epithelial neo. XI Other XII Retinoblastoma Primitive neuroectodermal tumor (PNET) Sarcomas Osteosarcoma Ewing sarcoma Soft-tissue sarcoma Hodgkin disease Testicular cancer Ovarian cancer Acute lymphoid leukemia Non-Hodgkin lymphoma Glioma Birth 5 10 18 Age (yr) Figure 153-2 Incidence of the most common types of cancer in children by age. The cumulative incidence is shown as a dashed line. (Courtesy of Archie Bleyer, MD). Distinguishing a malignant process from another diseasecan be difficult. Ultimately a tissue diagnosis (from bonemarrow or solid tumor biopsy) with pathologic confirmation is required to confirm a diagnosis of cancer. Infection 7.8 3.1 6.3 2.2 9.2 12.4 11.9 16.9 0.5 47.1 43.1 25.1 0 10 20 30 40 50 60 Rate per 1,000,000


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Pediatrics_Nelson. Figure 153-1 Childhood Cancer: SEER Incidence Rates 2005–2009 by ICCC Group (includes myelodysplastic syndromes and Group III benign brain). Under 20 years of age, both sexes, all races. Source: SEER 18 areas (San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, Atlanta, San Jose-Monterey, Los Angeles, Alaska Native Registry, Rural Georgia, California excluding SF/SJM/LA, Kentucky, Louisiana, New Jersey, and Georgia, excluding ATL/RG). Rates are age-adjusted to the 2000 U.S. Std Population (19 age groups Census P25-1130). International Classification of Childhood Cancer is based on ICD-O-3. (Steliarova-Foucher E, Stiller C, Lacour B, et al: International Classification of Childhood Cancer, ed 3. Cancer 103(7):1457−1467, 2005.) *Rate for Group III (Brain/CNS) includes benign brain tumors.


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Pediatrics_Nelson. International Classification of Childhood Cancer, ed 3. Cancer 103(7):1457−1467, 2005.) *Rate for Group III (Brain/CNS) includes benign brain tumors. commonly masquerades as a potential malignancy. In particular Epstein-Barr virus, cytomegalovirus, and mycobacterial infections can mimic leukemia or lymphoma by causingfever, lymphadenopathy, organomegaly, weight loss, andabnormal blood counts. Trauma may produce swelling thatcan mimic solid tumors. Idiopathic thrombocytic purpuraand iron deficiency can produce thrombocytopenia and anemia, respectively. Immune deficiencies or irregularities (autoimmune hemolytic anemia or neutropenia) can also producecytopenias. Juvenile idiopathic arthritis and other collagenvascular disease can cause musculoskeletal pain and anemia,mimicking leukemia. Benign tumors are relatively commonin children, including mature germ cell tumors/hamartomas,hemangiomas or other vascular tumors, mesoblastic nephromas, and bone cysts.


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Pediatrics_Nelson. A CBC with differential and review of the peripheral blood smear is the best screening test for many pediatric malignancies. Leukopenia (with or without neutropenia), anemia, or thrombocytopenia may be present in leukemia or any cancer that invades the bone marrow (e.g., neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma). Leukemia may also produce leukocytosis, usually with blasts present on the peripheral blood smear. An isolated cytopenia (neutropenia, anemia, or thrombocytopenia) widens the differential diagnosis but still could be the only abnormal laboratory finding. Of note, a Table 153-1 Known Risk Factors for Selected Childhood Cancers CANCER TYPE RISK FACTOR COMMENTS Acute lymphoid leukemia Ionizing radiation Prenatal diagnostic x-ray exposure increases risk. Therapeutic irradiation for cancer treatment also increases risk.


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Pediatrics_Nelson. Genetic conditions Down syndrome is associated with an estimated 10to 20-fold increased risk. Neurofibromatosis 1, Bloom syndrome, and ataxia-telangiectasia, among others, are associated with an elevated risk. Acute myeloid leukemias Chemotherapeutic agents Alkylating agents and epipodophyllotoxins increase risk. Genetic factors Down syndrome and neurofibromatosis 1 are strongly associated. Familial monosomy 7 and several other genetic syndromes are also associated with increased risk. Patients treated with radiation therapy for other cancers. Brain cancers Therapeutic ionizing radiation to the head Genetic factors Neurofibromatosis 1 is strongly associated with optic gliomas and, to a lesser extent, with other central nervous system tumors. Tuberous sclerosis and several other genetic syndromes are associated with increased risk. Hodgkin disease Family history Monozygotic twins and siblings are at increased risk. Infections Epstein-Barr virus is associated with increased risk.


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Pediatrics_Nelson. Hodgkin disease Family history Monozygotic twins and siblings are at increased risk. Infections Epstein-Barr virus is associated with increased risk. Non-Hodgkin lymphoma Immunodeficiency Acquired and congenital immunodeficiency disorders and immunosuppressive therapy increase risk. Infections Epstein-Barr virus is associated with increased risk. Osteosarcoma Ionizing radiation Cancer radiation therapy and high radium exposure increase risk. Genetic factors Increased risk is apparent with Li-Fraumeni syndrome and hereditary retinoblastoma. Ewing sarcoma Race Incidence is about nine times higher in white children than in black children in the United States. Neuroblastoma Genetic factors Chromosome 6p22 variants and mutations in the ALK and PHOX genes are associated with increased risk. Retinoblastoma Genetic factors Mutations in the Rb gene on chromosome 14


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Pediatrics_Nelson. Retinoblastoma Genetic factors Mutations in the Rb gene on chromosome 14 Wilms tumor Congenital anomalies Aniridia, Beckwith-Wiedemann syndrome, and other congenital and genetic conditions are associated with increased risk. Renal medullary carcinoma Sickle cell trait Etiology is unknown. Rhabdomyosarcoma Congenital anomalies and Li-Fraumeni syndrome and neurofibromatosis 1 are associated with increased genetic conditions risk. Hepatocellular carcinoma Infections Hepatitis B virus infection increases risk. Malignant germ cell tumors Cryptorchidism Cryptorchidism is a risk factor for testicular germ cell tumors. Modified from Kliegman RM, Stanton BF, St. Geme JW III, editors: Nelson Textbook of Pediatrics, ed 19, Philadelphia, 2011, Saunders.


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Pediatrics_Nelson. Modified from Kliegman RM, Stanton BF, St. Geme JW III, editors: Nelson Textbook of Pediatrics, ed 19, Philadelphia, 2011, Saunders. patient with leukemia may also have a normal CBC. Lactate dehydrogenase and uric acid are often elevated in fast-growing tumors (leukemia or lymphoma) and occasionally in sarcomas or neuroblastoma. In many cases, it is appropriate to assess electrolytes and renal and hepatic function in the screening process. Elevated blood pressure, if confirmed by repeat measurements, should prompt a urine analysis, as should the palpation of an abdominal mass. A chest x-ray (CXR) (posteroanterior and lateral) is the bestscreening radiographic study for a patient with suspiciouscervical lymphadenopathy, fever, and weight loss. Mediastinalmasses and pleural effusions can often be detected on CXR.


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Pediatrics_Nelson. Abdominal signs or symptoms warrant an ultrasound or CT.Persistent headache, vomiting, or abnormal neurologic findings should lead to a head CT or MRI. For suspected bonetumors, plain radiographs are indicated and will usuallyreveal the lesion(s), if present. Radiographs may be normalwhen a bony pelvic lesion is suspected; a CT or MRI shouldbe obtained. Other imaging studies to delineate a mass and tosearch for suspected metastases are often indicated, but thesedecisions are usually best left to the pediatric oncology team.Table 153-3 shows the general use of diagnostic imaging following confirmation of a diagnosis of cancer, assessing the primary tumor and for metastases. Positron emission tomography(PET) has proved useful for staging and assessing response forsome pediatric cancers, especially lymphomas. Metaiodobenzylguanidine (mIBG) scans are useful for neuroblastoma.


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Pediatrics_Nelson. Table 153-2 Common Manifestations of Childhood Malignancies SIGN/SYMPTOM SIGNIFICANCE EXAMPLE Hematologic Pallor, anemia Bone marrow infiltration Leukemia, neuroblastoma Petechiae, thrombocytopenia Bone marrow infiltration Leukemia, neuroblastoma Fever, neutropenia Bone marrow infiltration Leukemia, neuroblastoma Systemic Bone pain, limp, arthralgia Primary bone tumor, metastasis Osteosarcoma, Ewing sarcoma, leukemia, to bone neuroblastoma Fever of unknown origin, weight loss, Lymphoreticular malignancy Hodgkin disease, non-Hodgkin lymphoma night sweats Painless lymphadenopathy Lymphoreticular malignancy, Leukemia, Hodgkin disease, non-Hodgkin lymphoma, metastatic solid tumor Burkitt lymphoma, thyroid carcinoma Cutaneous lesion Primary or metastatic disease Neuroblastoma, leukemia, Langerhans cell histiocytosis, melanoma Abdominal mass Abdominal/pelvic organ Neuroblastoma, Wilms tumor, lymphoma, hepatoblastoma, germ cell tumor


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Pediatrics_Nelson. Abdominal mass Abdominal/pelvic organ Neuroblastoma, Wilms tumor, lymphoma, hepatoblastoma, germ cell tumor Hypertension Sympathetic nervous system tumor Neuroblastoma, pheochromocytoma, Wilms tumor Soft tissue mass Local or metastatic tumor Ewing sarcoma, osteosarcoma, neuroblastoma, thyroid carcinoma, rhabdomyosarcoma, germ cell tumor Diabetes insipidus, galactorrhea, poor Neuroendocrine involvement of Adenoma, craniopharyngioma, prolactinoma, growth hypothalamus or pituitary gland Langerhans cell histiocytosis Emesis, visual disturbances, ataxia, Increased intrathecal pressure Primary brain tumor; metastasis headache, papilledema, cranial nerve palsies Miosis, ptosis, heterochromia Horner syndrome: Neuroblastoma compression of cervical Opsomyoclonus, ataxia Neurotransmitters (?) Neuroblastoma Autoimmunity (?) Exophthalmos, proptosis Orbital tumor Rhabdomyosarcoma, lymphoma Thoracic


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Pediatrics_Nelson. Opsomyoclonus, ataxia Neurotransmitters (?) Neuroblastoma Autoimmunity (?) Exophthalmos, proptosis Orbital tumor Rhabdomyosarcoma, lymphoma Thoracic Anterior mediastinal mass Cough, stridor, pneumonia, Germ cell tumor, T-cell lymphoma, Hodgkin disease, tracheal-bronchial compression primary mediastinal large B-cell lymphoma Posterior mediastinal mass Vertebral or nerve root compression; Neuroblastoma, ganglioneuroblastoma, dysphagia ganglioneuroma VMA, HVA mIBG scan Rhabdomyosarcoma Yes Yes Yes Yes Yes, for parameningeal tumors only Germ cell tumors Yes Yes AFP, β-hCG Consider brain MRI Yes, if MRI Yes (brain) ± Yes


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Pediatrics_Nelson. VMA, HVA mIBG scan Rhabdomyosarcoma Yes Yes Yes Yes Yes, for parameningeal tumors only Germ cell tumors Yes Yes AFP, β-hCG Consider brain MRI Yes, if MRI Yes (brain) ± Yes AFP, Alpha-fetoprotein; BMA/bx, bone marrow aspirate/biopsy; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; CXR, chest x-ray; β-hCG, beta-human chorionic gonadotropin; HVA, homovanillic acid; mIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; PET, positron emission tomography; Rb, retinoblastoma; VMA, vanillylmandelic acid. *Individual cases may require additional studies.


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Pediatrics_Nelson. The overall goal of pediatric oncology is to cure all patientswith minimal toxicity. Treatment for children with cancer isoften multimodal and may involve surgery, radiation therapy,and chemotherapy. Surgery and radiation are generally localtreatment modalities (an exception is total body irradiation as part of a bone marrow or stem cell transplant), whereas chemotherapy has both local and systemic effects.


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Pediatrics_Nelson. Primary prevention strategies for most pediatric malignancies are unknown. Two exceptions are the use of hepatitis Bvaccine to lower the rates of hepatocellular carcinoma and theuse of human papillomavirus vaccine to reduce the risk of cervical, vulvar, and vaginal cancers. Childhood malignancies arenot associated with tobacco or alcohol use, dietary factors, orsun exposure. Treatment with certain chemotherapy agents andradiation therapy increases the rate of second malignancies.Secondary prevention may be accomplished by screening the at-risk child (e.g., a child with Beckwith-Wiedemann syndromeor twin of a leukemia patient), but these opportunities are rare. Adverse effects of tumors and treatments may result in oncologic emergencies in children and adolescents (Table 154-1).


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Pediatrics_Nelson. Adverse effects of tumors and treatments may result in oncologic emergencies in children and adolescents (Table 154-1). Mediastinal masses from lymphoma can cause life-threatening airway obstruction. Tumors with a large tumor burden (e.g., lymphoma, leukemia) may affect renal function adversely from tubular deposition of uric acid crystals. Allopurinol or rasburicase can be administered before chemotherapy to minimize this effect. A common metabolic emergency is tumor lysis syndrome,often seen in treatment of leukemia and lymphoma. Large amounts of phosphate, potassium, and uric acid are released into the circulation from lysed cells. Overwhelming infection and spinal cord compression with neurologic compromise are other oncologic emergencies.


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Pediatrics_Nelson. Appropriate imaging (usually with computed tomography [CT] or magnetic resonance imaging [MRI]) for solidtumors presenting as a palpable mass or mass-relatedsymptoms (pain, respiratory distress, intestinal obstruction) should be obtained and followed by resection (whenpossible) or biopsy (if complete resection is not feasible).An exception to this is a suspected lymphoma, for which a biopsy may be needed. However, almost all pediatric lymphomas are chemosensitive and do not require surgicalresection. It is crucial to determine the amount of tissue required and the appropriate distribution of the tissue for testing so that all necessary studies are performed. A general oncologic surgery principle is to resect not just the tumor, but also, in most cases, a surrounding margin of normal tissue to ensure the entire tumor has been resected. Hyperuricemia Uric acid nephropathy; Tumor lysis syndrome Lymphoma, leukemia Allopurinol, hydration, gout


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Pediatrics_Nelson. Hyperuricemia Uric acid nephropathy; Tumor lysis syndrome Lymphoma, leukemia Allopurinol, hydration, gout Hyperkalemia Arrhythmias, cardiac arrest Tumor lysis syndrome Lymphoma, leukemia Kayexalate; sodium bicarbonate, glucose, and insulin Anemia Pallor, weakness, heart Bone marrow suppression Any with chemotherapy Packed red blood cell failure or infiltration; blood loss Thrombocytopenia Petechiae, hemorrhage Bone marrow suppression Any with chemotherapy Platelet transfusion or infiltration Disseminated Shock, hemorrhage Sepsis, hypotension, Promyelocytic leukemia, Fresh frozen plasma; intravascular coagulation tumor factors others platelets, treat infection Tracheal compression Respiratory distress Mediastinal mass Lymphoma Radiation therapy, compressing trachea CNS, Central nervous system; CT, computed tomography; G-CSF, granulocyte colony-stimulating factor; MRI, magnetic resonance imaging.


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Pediatrics_Nelson. CNS, Central nervous system; CT, computed tomography; G-CSF, granulocyte colony-stimulating factor; MRI, magnetic resonance imaging. CHEMOTHERAPY tumors. For patients with localized solid tumors, chemo-Because most pediatric solid tumors have a high risk for therapy administered after removal of the primary tumor is micrometastatic disease at the time of diagnosis, chemo-referred to as adjuvant therapy. Chemotherapy administered therapy is used in almost all cases (Table 154-2). Exceptions while the primary tumor is still present is referred to as neoinclude low-stage neuroblastoma and Wilms tumor (particu-adjuvant chemotherapy. Neoadjuvant chemotherapy has larly in infants) and low-grade central nervous system (CNS) a number of potential benefits, including an early attack on


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Pediatrics_Nelson. Methotrexate Folic acid Hepatic Renal, 50%–90% ALL, lymphoma, Myelosuppression (nadir 7–10 antagonist; inhibits excreted medulloblastoma, days), mucositis, dermatitis, dihydrofolate unchanged; biliary osteosarcoma hepatitis, renal and CNS reductase effects with high-dose administration; prevent with hydration and leucovorin, monitor levels 6-Mercaptopurine Purine analog Hepatic Renal ALL Myelosuppression; hepatitis; mucositis; allopurinol increases toxicity myopathy, osteoporosis, infection, peptic ulceration, irritability, psychosis, hunger, fluid retention Chapter 154 u Principles of Cancer Treatment 541 Table 154-2 Cancer Chemotherapy—cont’d DRUG* ACTION METABOLISM EXCRETION INDICATION ACUTE TOXICITY Antimetabolites Hormones Prednisone Direct lymphocyte cytotoxicity Hepatic Renal ALL; Hodgkin disease, lymphoma Cushing syndrome, cataracts, diabetes, hypertension, Carboplatin Inhibits DNA — Renal Same as for cisplatin Myelosuppression synthesis


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Pediatrics_Nelson. Carboplatin Inhibits DNA — Renal Same as for cisplatin Myelosuppression synthesis Etoposide (VP-16) Topoisomerase-— Renal ALL, lymphoma, germ Myelosuppression, secondary inhibitor cell tumor, sarcoma leukemia, allergic reaction ADH, Antidiuretic hormone; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CNS, central nervous system. *Many drugs produce nausea and vomiting during administration, and many cause alopecia with repeated doses. presumed micrometastatic disease, shrinkage of the primary tumor to facilitate local control, and additional time to plan for definitive surgery.


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Pediatrics_Nelson. presumed micrometastatic disease, shrinkage of the primary tumor to facilitate local control, and additional time to plan for definitive surgery. Resistance to a particular chemotherapeutic agent can develop in a number of ways: decreased influx into or increased efflux of the chemotherapeutic agent from the malignant cell; mutation in the target tissue so that it cannot be inhibited by the drug; amplification of a drug target to overcome inhibition; and blockade of normal cellular processes leading to programmed cell death or apoptosis. Because mutation is an ongoing process in malignant tumors, it follows that certain subpopulations of tumor cells within a tumor may be more or less sensitive to any particular chemotherapy drug. Given this fact, combinations of chemotherapy drugs are used, as opposed to sequential single agents, to treat the various forms of childhood cancer.


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Pediatrics_Nelson. The blood-brain barrier prevents the penetration of chemotherapeutic drugs into the CNS; instillation of the chemotherapeutic agent directly into the cerebrospinal fluid (by lumbar puncture) may be necessary. Radiation therapy also circumvents the blood-brain barrier. Radiation therapy is the process of delivering ionizing radiationto malignant cells in order to kill them directly or, more commonly, prevent them from dividing by interfering with DNAreplication. Conventional radiation therapy uses photons, butatomic particles such as electrons, protons, and neutrons canalso be used. Not all tumors are radiosensitive, and radiation therapy is not necessary in all tumors that are radiosensitive.


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Pediatrics_Nelson. Certain cancers have been treated with cytokines, biologic response modifiers, or monoclonal antibodies in addition to standard treatments. Targeted therapies specifically target the tumor cells, sparing normal host cells. Imatinib mesylate is a protein kinase inhibitor that targets the effects of the t(9;22) translocation of chronic myeloid leukemia and acute lymphoblastic leukemia. Rituximab is a monoclonal antibody directed against the cell surface antigen CD20 expressed in some lymphomas. Ch14.18 is an anti-GD2 monoclonal antibody used for neuroblastoma. Supportive care also plays an important role in pediatric oncology, including the use of appropriate antimicrobial agents, blood products, nutritional support, intensive care, and integrative therapies.


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Pediatrics_Nelson. Because chemotherapy agents are cellular toxins, numerous adverse effects are associated with their use. Bone marrow suppression, immunosuppression, nausea, vomiting, and alopecia are general adverse effects of commonly used chemotherapy drugs. Each chemotherapy drug also has specific toxicities. Doxorubicin can cause cardiac damage; cisplatin can cause renal damage and ototoxicity; cyclophosphamide and ifosfamide can cause hemorrhagic cystitis; and vincristine can cause peripheral neuropathy. Radiation therapy produces many adverse effects such as mucositis, growth retardation, organ dysfunction, and the later development of secondary cancers. Significant therapy-related late effects may develop in pediatric cancer patients (Table 154-3).


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Pediatrics_Nelson. Alkylating agents; radiation Second cancers Genetic predisposition; radiation; alkylating agents, etoposide, topoisomerase II inhibitors Sepsis Splenectomy Hepatotoxicity Methotrexate, 6-mercaptopurine; radiation Hepatic venoocclusive High-dose, intensive chemotherapy disease (busulfan, cyclophosphamide) ± bone marrow transplant Scoliosis Radiation Pulmonary (fibrosis) Radiation; bleomycin, busulfan Cardiomyopathy Doxorubicin, daunorubicin; radiation Leukoencephalopathy Cranial radiation ± methotrexate Cognition/intelligence Cranial radiation ± methotrexate Pituitary dysfunction Cranial radiation (growth hormone deficiency, panhypopituitarism) Psychosocial Stress, anxiety, death of peers; conditioned responses to chemotherapy


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Pediatrics_Nelson. The etiology of childhood leukemia is unknown and is probably multifactorial. Genetics and environmental factors play important roles. There are many recurrent nonrandom chromosomal translocations in leukemia cells. A translocation may lead to the formation of a new gene, whose expression may lead to a novel protein with transforming capabilities. In chronic myelogenous leukemia (CML) and some cases of acute lymphoblastic leukemia (ALL), a translocation between chromosomes 9 and 22 results in a fusion gene incorporating parts of two genes, BCR and ABL. The protein formed by this novel gene plays an important role in the development of the leukemias. In addition, certain constitutional genotypes can predispose a child to the development of acute leukemia. Patients with Down syndrome, Fanconi anemia, Bloom syndrome, ataxia-telangiectasia, Wiskott-Aldrich syndrome, and neurofibromatosis 1 all have an increased risk of acute leukemia. Siblings of children with leukemia are at increased


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Pediatrics_Nelson. anemia, Bloom syndrome, ataxia-telangiectasia, Wiskott-Aldrich syndrome, and neurofibromatosis 1 all have an increased risk of acute leukemia. Siblings of children with leukemia are at increased risk of developing leukemia (approximately twofold to fourfold above the childhood population). This risk increases for twin siblings (up to 25% for monozygotic twins). In certain patients with leukemia, the unique antigen receptor gene rearrangement or the specific chromosomal translocation characterizing the patient’s leukemic clone can be demonstrated in cord blood cells and neonatal blood spots used for screening for metabolic diseases, suggesting a possible in utero etiology. There are reports of familial leukemia. Environmental factors that may increase the risk of leukemia include ionizing radiation and exposure to certain chemotherapy agents, particularly the topoisomerase II inhibitors.


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Pediatrics_Nelson. Each year 2500 to 3500 new cases of childhood leukemia occur in the United States. The disease affects about 40 per 1 million children under the age of 15 years. ALL accounts for approximately 75% of cases. Acute myelogenous leukemia (AML)accounts for 15% to 20%, and CML accounts for less than 5% of cases. Other chronic leukemias, including juvenile myelomonocytic leukemia, chronic myelomonocytic leukemia, and chronic lymphocytic leukemia, are rare in childhood.


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Pediatrics_Nelson. ALL and AML are classified according to the World Health Organization system (Table 155-1), although many clinicians and pathologists still use the French-American-British system for AML. ALL is classified according to cell lineage as either B-lineage or T-lineage. The incidence of ALL peaks at 2 to 5 years of age and is higher in boys than in girls. T-cell ALL, in particular, is associated with male predominance as well as an older age of peak incidence. In the United States, ALL is more common in white than in African American children.The incidence of AML is relatively high in the neonatal period then drops and stabilizes until adolescence when there is a slight increase, which continues into adulthood, especially beyond 55 years of age. Males and females are equally affected by AML. Hispanic and African American children have slightly higher incidence rates than white children. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Signs and symptoms of acute leukemias are related to the infiltration of leukemic cells into normal tissues, resulting in either bone marrow failure (anemia, neutropenia, thrombocytopenia) or specific tissue infiltration (lymph nodes, liver, spleen, brain, bone, skin, gingiva, testes). Common presenting symptoms are fever, pallor, petechiae or ecchymoses, lethargy, malaise, anorexia, and bone or joint pain. Physical examination frequently reveals lymphadenopathy and hepatosplenomegaly. The testes and central nervous system (CNS) are common extramedullary sites for ALL; neurologic symptoms or a painless enlargement of one or both testes may be seen. Patients with T-cell ALL often have high white blood cell (WBC) counts, anterior mediastinal masses, bulky disease ALL, B cell—L3 morphology (i.e., Burkitt leukemia)


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Pediatrics_Nelson. ALL, B cell—L3 morphology (i.e., Burkitt leukemia) AMLs with recurrent cytogenetic translocations AML with t(8;21)(q22; q22), AML1(CBF-alpha)/ETO Acute promyelocytic leukemia—AML with t(15;17)(q22; q11–12) and variants, PML/RAR-alpha) (i.e., M3*) AML with abnormal bone marrow eosinophils—inv(16) (p13q22) or t(16;16)(p13; q11), CBFb/MYH11 AML with 11q23/MLL abnormalities AML with multilineage dysplasia With prior myelodysplastic syndrome Without prior myelodysplastic syndrome AML and myelodysplastic syndromes, therapy-related Alkylating agent-related Epipodophyllotoxin-related (some may be lymphoid) Other types AML not otherwise categorized AML minimally differentiated (M1) AML without maturation (M0) AML with maturation (M2) Acute myelomonocytic leukemia (M4) Acute monocytic leukemia (M5) Acute erythroid leukemia (M6) Acute megakaryocytic leukemia (M7) Acute basophilic leukemia Acute panmyelosis with myelofibrosis


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Pediatrics_Nelson. Modified from World Health Organization Classification. MLL, Mixed lineage leukemia. *The designations M0 to M7 are those of the French-AmericanBritish classification system for AML, which predated the World Health Organization system and is still used by many clinicians and pathologists. with cervical lymphadenopathy, hepatosplenomegaly, and CNS involvement. In patients with AML, extramedullary softtissue tumors may be found in various sites.


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Pediatrics_Nelson. The diagnosis of acute leukemia is confirmed by findings of immature blast cells on either the peripheral blood smear, bone marrow aspirate, or both. Most patients have abnormal blood counts; anemia and thrombocytopenia are common. The WBC count may be low, normal, or high; 15% to 20% of patients have a WBC count greater than 50,000/mm3. Definitive diagnosis requires the evaluation of cell surface markers (immunophenotype) by flow cytometry and evaluation of cytochemical staining patterns. Cytogenetic analysis should be undertaken in all cases of acute leukemia. Certain types of both lymphoid and myeloid leukemias have specific chromosomal abnormalities. In ALL, the t(12;21) translocation is most common (approximately 20% of all cases) and is associated with a favorable prognosis. The t(9;22) translocation occurs in less than 5% of cases and is associated with a poor prognosis. The t(4;11) translocation (and other translocations involving the MLL gene on chromosome 11) often occurs in


Pediatrics_Nelson

Pediatrics_Nelson. translocation occurs in less than 5% of cases and is associated with a poor prognosis. The t(4;11) translocation (and other translocations involving the MLL gene on chromosome 11) often occurs in infants and patients with secondary AML and is generally associated with a poor prognosis. Fluorescent in situ hybridization or polymerase chain reaction techniques are now used in most cases of leukemia because many chromosomal abnormalities may not be apparent on routine karyotypes. DNA microarray techniques are gaining relevance and will likely become standard in the future. A lumbar puncture should always be performed at the time of diagnosis to evaluate the possibility of CNS involvement. A chest x-ray should be obtained in all patients to exclude an anterior mediastinal mass, which is commonly seen in T-cell ALL. Electrolytes, calcium, phosphorus, uric acid, and renal and hepatic function should be monitored in all patients.


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Pediatrics_Nelson. The differential diagnosis of acute leukemia includes nonmalignant and malignant diseases. Infection is probably the most common mimicker of acute leukemia, particularly the Epstein-Barr virus infection. Other infections (cytomegalovirus, pertussis, mycobacteria) also can produce signs and symptoms common to leukemia. Noninfectious diagnostic considerations include aplastic anemia, histiocytosis, juvenile rheumatoid arthritis, immune thrombocytopenic purpura, and congenital or acquired conditions that lead to neutropenia or anemia. Several malignant diagnoses also can mimic leukemia, including neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma. Newborns with trisomy 21 may have a condition known as transient myeloproliferative disorder, which produces elevated WBC counts with peripheral blasts, anemia, and thrombocytopenia. It usually resolves with supportive care only, but these children have a significantly increased risk (30%) of developing true acute leukemia (ALL or AML)within


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Pediatrics_Nelson. blasts, anemia, and thrombocytopenia. It usually resolves with supportive care only, but these children have a significantly increased risk (30%) of developing true acute leukemia (ALL or AML)within the next few months and years of life.


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Pediatrics_Nelson. Patients with ALL generally receive threeor four-agent induction chemotherapy based on their initial risk group assignment. Lowand standard-risk patients receive vincristine, prednisone, and L-asparaginase for 4 weeks; high-risk patients also receive an anthracycline (daunorubicin or doxorubicin). During induction, intrathecal instillation of some combination of methotrexate, cytarabine, and hydro-cortisone is given to treat existing CNS leukemia or prevent its development. Following induction of successful remission, which is achieved in nearly all patients with ALL, the remission is consolidated along with CNS-directed therapy. The intensity of therapy depends on risk factors with higher risk patients receiving more intensive chemotherapy. For patients with CNS disease detected at diagnosis and those with T-cell ALL, cranial radiation therapy is usually provided, although the omission of radiation therapy for all pediatric leukemia patients holds great promise. All patients receive


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Pediatrics_Nelson. and those with T-cell ALL, cranial radiation therapy is usually provided, although the omission of radiation therapy for all pediatric leukemia patients holds great promise. All patients receive continuation therapy for a total duration of therapy of 2 to 3 years. Continuation therapy generally consists of intermittent vincristine and short courses (5 to 7 days) of oral corticosteroid therapy, plus daily oral 6-mercaptopurine, and weekly methotrexate (orally or intramuscularly).


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Pediatrics_Nelson. The treatment of AML is quite different from that of ALL because nonmyelosuppressive drugs (vincristine, prednisone, and asparaginase) are not effective. Several cycles of extremely intensive myelosuppressive chemotherapy are necessary to cure childhood AML; there is little evidence that low-dose continuation therapy is helpful in AML (with the exception of acute promyelocytic leukemia). Induction therapy for AML usually consists of cytarabine, daunomycin, and etoposide (or 6-thioguanine). If a patient has an HLA-matched sibling donor, most experts recommend a stem cell transplantation in the first remission, except in patients with Down syndrome and those with relatively favorable cytogenetics such as inv(16), t(15;17), and t(8;21). Bortezomib, sorafenib and haploidentical natural killer cell transplantation are being studied as an adjuvant therapy for newly diagnosed childhood AML.


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Pediatrics_Nelson. Major short-term complications associated with the treatment of leukemia result from bone marrow suppressioncaused by chemotherapy. Patients may have bleeding andsignificant anemia that necessitates transfusion of plateletsor blood. Neutropenia with fewer than 500 neutrophils/mm3, and especially fewer than 100 neutrophils/mm3, greatly predispose the patient to significant bacterial and fungal infection. Cell-mediated immunosuppression increases the risk ofPneumocystis jiroveci (carinii) pneumonia. Prophylaxis withoral trimethoprim-sulfamethoxazole or aerosolized pentamidine is recommended. Prophylaxis with antibiotics andantifungal agents is under investigation. Long-term sequelaeof therapy are less common than in previous treatment erasbut are prevalent in long-term survivors treated in the 1980sand earlier. These sequelae include neurocognitive impairment, short stature, obesity, cardiac dysfunction, infertility,second malignant neoplasms, and psychosocial problems(see Table 154-3).


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Pediatrics_Nelson. Patients with ALL are classified into four prognostic risk groups (low, standard, high, and very high) based on age, initial WBC count, genetic characteristics, and response to induction therapy. Classification systems are complex and evolving (Table 155-2). In general low-risk patients are 1 to 9 years old with an initial WBC count less than 50,000/mm3 and favorable cytogenetic findings such as t(12;21). High-risk patients are younger than 1 year of age or 10 years of age and older, have an initial WBC count greater than 50,000/mm3, have CNS or testicular disease at diagnosis, or have unfavorable cytogenetics such as t(4;11). Very high-risk patients have a hypodiploid DNA index, a t(9;22) translocation, or fail to achieve remission after 4 weeks of therapy. All other patients are considered to have standard-risk ALL. Immunophenotype, minimal residual disease, and early response to therapy are other factors that influence risk stratification. Infants with ALL generally have a highly


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Pediatrics_Nelson. to have standard-risk ALL. Immunophenotype, minimal residual disease, and early response to therapy are other factors that influence risk stratification. Infants with ALL generally have a highly undifferentiated immunophenotype, often have a 1–9.99 years <1 or >10 years Initial WBC count <50,000/mm3 >50,000/mm3 CNS disease at Absent Present diagnosis DNA index >1.16 <1.16 Cytogenetics t(12;21) t(4;11), t(9;22) Response to therapy Rapid Slow


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Pediatrics_Nelson. CNS, Central nervous system; WBC, white blood cell. translocation involving the mixed lineage leukemia gene (e.g., t(4;11)), and have a poor prognosis. The overall cure rate for childhood ALL with current therapy approximates 80%. Relapse of ALL occurs most commonly in the bone marrow but also may occur in the CNS, testes, or other extramedullary sites. If relapse occurs while the patient is still receiving treatment, the prognosis is worse than if relapse occurs after discontinuation of therapy. Stem cell transplant from a matched sibling donor, matched unrelated donor, or cord blood currently is recommended for patients who have a relapse while receiving initial chemotherapy. The current overall cure rate for childhood AML is approximately 50%. It is slightly higher for patients who receive a matched sibling stem cell transplant in first remission than for patients treated with chemotherapy alone. The prognosis for relapsed AML is poor.


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Pediatrics_Nelson. Lymphomas, or malignancies of lymphoid tissues, are the third most common malignancy in childhood, behind leukemias and central nervous system (CNS) tumors. There are two major types of lymphoma: Hodgkin disease and non-Hodgkin lymphoma (NHL). The etiologies are unknown, but evidence in many cases suggests that the Epstein-Barr virus (EBV) plays a causal role in both conditions. Almost all cases of NHL in childhood are diffuse, highly malignant, and show little differentiation. NHL has three histologic subtypes: small noncleaved cell (Burkitt lymphoma), lymphoblastic, and large cell. For simplicity, these may be regarded as B cell, T cell, and large cell (which may be of either B-cell or T-cell origin) (Table 156-1). Chromosomal translocation may move an oncogene from its normal site to a new, unregulated site, leading to increased expression. In Burkitt lymphoma, translocation occurs


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Pediatrics_Nelson. Chromosomal translocation may move an oncogene from its normal site to a new, unregulated site, leading to increased expression. In Burkitt lymphoma, translocation occurs Large cell T-cell, B-cell, or indeterminate Lymph nodes, skin, soft tissue, bone t(2;5)(p23;q35) between chromosome 8 (c-myc oncogene) and the immunoglobulin gene locus on chromosome 2, 14, or 22, such that the c-myc oncogene comes to reside next to an immunoglobulin gene. The c-myc gene turns on the immunoglobulin gene, leading to a malignant B-cell lymphoma.


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Pediatrics_Nelson. The incidence of Hodgkin disease has a bimodal distribution with peaks in the adolescent/young adult years and again after age 50; it is rarely seen in children younger than 5 years of age. In children, boys are affected more commonly than girls; in adolescents, the gender ratio is approximately equal. The incidence of NHL increases with age. It is more common in whites than in African Americans and in males than in females. NHL has been described in association with congenital or acquired immunodeficiency states and after organ or stem cell transplantation. Burkitt lymphoma commonly is divided into two forms: a sporadic form commonly seen in North America and an endemic form commonly seen in Africa, which has a strong association to EBV. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com The most common clinical presentation of Hodgkin disease is painless, firm lymphadenopathy often confined to one or two lymph node areas, usually the supraclavicular and cervical nodes. Mediastinal lymphadenopathy producing cough or shortness of breath is another frequent initial presentation. The presence of one of three B symptoms has prognostic value: fever (>38° C for 3 consecutive days), drenching night sweats, and unintentional weight loss of 10% or more within 6 months of diagnosis. The sporadic (North American) form of Burkitt lymphoma more commonly has an abdominal presentation (typically with pain), whereas the endemic (African) form frequently presents with tumors of the jaw. The anterior mediastinum and cervical nodes are the usual primary sites for T-cell lymphomas. These lymphomas may cause airway or superior vena cava obstruction, pleural effusion, or both.


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Pediatrics_Nelson. The diagnosis of lymphoma is established by tissue biopsy orexamination of pleural or peritoneal fluid. Systemic symptoms,such as fever and weight loss, may be present and are particularly prominent in patients with anaplastic large cell lymphoma,which can be insidious in onset. If the bone marrow contains 25% or greater blasts, the disease is classified as acute leukemia (either B-cell acute lymphoblastic leukemia [ALL] or T-cellALL). This distinction makes little prognostic or therapeuticdifference because both require aggressive, systemic therapy inaddition to CNS-directed therapy.


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Pediatrics_Nelson. Patients suspected to have lymphoma should have a complete blood count, erythrocyte sedimentation rate, and measurement of serum electrolytes, calcium, phosphorus, lactate dehydrogenase, and uric acid. A chest x-ray assesses for a mediastinal mass (Fig. 156-1). The diagnosis ultimately requires a pathologic confirmation from tissue or fluid sampling. For staging purposes, a bone marrow aspirate, bone scan, and positron emission tomography or gallium scan also are indicated. The pathologic hallmark of Hodgkin disease is the identification of Reed-Sternberg cells. Histopathologic subtypes in childhood Hodgkin disease are similar to those in adults; 10% to 15% have lymphocyte predominant, 50% to 60% have nodular sclerosis, 30% have mixed cellularity, and less than 5% have lymphocyte depletion. All subtypes are responsive to treatment. Staging of Hodgkin disease is according to the Ann Arbor system. Staging laparotomy is no longer used in children because computed tomography scans often


Pediatrics_Nelson

Pediatrics_Nelson. All subtypes are responsive to treatment. Staging of Hodgkin disease is according to the Ann Arbor system. Staging laparotomy is no longer used in children because computed tomography scans often identify abdominal (lymph nodes, liver, spleen) involvement.


Pediatrics_Nelson

Pediatrics_Nelson. The differential diagnosis for lymphomas in children includes leukemia, rhabdomyosarcoma, nasopharyngeal carcinoma, germ cell tumors, and thymomas. Nonmalignant diagnoses include infectious mononucleosis (EBV infection), branchial cleft and thyroglossal duct cysts, cat scratch disease (Bartonella henselae), bacterial or viral lymphadenitis, mycobacterial infection, toxoplasmosis, and even tinea capitis, all of which can produce significant lymphadenopathy that can mimic lymphoma. Patients with acute abdominal pain from Burkitt lymphoma may be misdiagnosed as having appendicitis.


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Pediatrics_Nelson. The generally accepted treatment for childhood Hodgkin disease is a combination of chemotherapy and low-dose, involved-field radiation therapy. Chemotherapy usually consists of some combination of cyclophosphamide, vincristine, procarbazine, doxorubicin, bleomycin, vinblastine, prednisone, and etoposide. In general four to six courses of combination chemotherapy are given. Selected low-risk patients may be cured with chemotherapy alone, without radiation therapy. Figure 156-1 Chest x-ray of a 15-year-old boy demonstrating a large superior anterior mediastinal mass (large arrows) compressing the trachea and deviating it rightward (arrowheads). Biopsy revealed non-Hodgkin lymphoma. Distant, noncontiguous metastases are common in childhood NHL. Systemic chemotherapy is mandatory and should be administered to all children with NHL, even those with clinically localized disease at diagnosis.


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Pediatrics_Nelson. T-cell lymphoblastic lymphoma and anaplastic large cell lymphoma generally are treated with aggressive multidrug regimens similar to the regimens used in ALL. The main drugs used in the treatment of mature B-cell NHL are cyclophosphamide, moderateto high-dose methotrexate, cytarabine, doxorubicin, ifosfamide, and etoposide. Surgery and radiation therapy rarely are used because the disease is rarely localized and is highly sensitive to chemotherapy. The short-term complications from the treatment of lymphoma are similar to other pediatric malignancies and commonly include immunosuppression, related sequelae from myelosuppression, nausea, vomiting, and alopecia. Late adverse effects include second malignant neoplasms (acute myeloid leukemia or myelodysplasia, thyroid malignancies, and breast cancer), hypothyroidism, impaired soft tissue and bone growth, cardiac dysfunction, and pulmonary fibrosis.


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Pediatrics_Nelson. Children and adolescents with Hodgkin disease are classified as low, intermediate, or high risk according to stage andnodal bulk. The prognosis is generally excellent. There is an approximately 90% 5-year overall survival rate, approaching 100% for low-risk patients and 70% to 90% for high-riskpatients. For NHL prognosis also is related to stage. The overall3-year survival rates for B-cell, T-cell, and large cell NHL are70% to 90%.


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Pediatrics_Nelson. Most central nervous system (CNS) tumors in children and adolescents are primary tumors that originate in the CNS and include low-grade astrocytomas or embryonic neoplasms (medulloblastoma, ependymoma, germ cell tumor). In contrast CNS tumors in adults are high-grade astrocytomas or secondary tumors that are metastatic from other carcinomas. CNS tumors also may arise in patients previously treated with radiation therapy. CNS tumors are likely multifactorial in etiology. The classification of CNS tumors is complex and evolving, with the World Health Organization classification being the most complete and accurate system.


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Pediatrics_Nelson. CNS tumors are the most common solid tumors in children and are second to leukemia in overall incidence during childhood. About 1700 new cases occur each year in the United States; the rate is approximately 33 cases per 1 million children under 15 years of age. The incidence peaks before age 10 years and then decreases until a second peak after age 70. For medulloblastoma and ependymoma, males are more affected than females; for other tumor types, no gender differences exist. In the first 2 to 3 years of life, whites are affected more than multiracial children; otherwise incidence rates are essentially equal for whites and multiracial children. Children with certain inherited syndromes, including neurofibromatosis (types 1 and 2), Li-Fraumeni syndrome, tuberous sclerosis, Turcot syndrome, and von Hippel-Lindau syndrome, have an increased risk for developing a CNS tumor. Most CNS tumors arise in children with no known underlying disorder or risk factor.


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com Abnormal Head Size, Shape, and Fontanels Visual Impairment and Leukocoria Vomiting Headaches


Pediatrics_Nelson

Pediatrics_Nelson. Brain tumors can cause symptoms by impingement on normal tissue (usually cranial nerves) or by an increase in intracranial pressure caused either by obstruction of cerebrospinal fluid (CSF) flow or by a direct mass effect. Tumors that obstruct the flow of CSF become quickly symptomatic. Symptoms of increased intracranial pressure are lethargy, headache, and vomiting (particularly in the morning on awakening). Irritability, anorexia, poor school performance, and loss of developmental milestones all may be signs of slow-growing CNS tumors. In young children with open cranial sutures, an increase in head circumference may occur. Optic pathway tumors may lead to loss of visual acuity or visual field defects. Inability to abduct the eye as the result of sixth cranial nerve palsy is a common sign of increased intracranial pressure. Cranial nerve deficits other than sixth nerve palsy suggest involvement of the brainstem. Seizures occur in 20% to 50% of patients with supratentorial tumors;


Pediatrics_Nelson

Pediatrics_Nelson. sign of increased intracranial pressure. Cranial nerve deficits other than sixth nerve palsy suggest involvement of the brainstem. Seizures occur in 20% to 50% of patients with supratentorial tumors; focal weakness or sensory changes also may be seen. Pituitary involvement produces neuroendocrine effects (galactorrhea with prolactinoma, excessive growth with growth hormone secretory tumors, precocious puberty). Cerebellar tumors are associated with ataxia and diminished coordination. A history and physical examination are fundamental for evaluation, which should include a careful neurologic assessment, including visual fields and a funduscopic examination.


Pediatrics_Nelson

Pediatrics_Nelson. If an intracranial lesion is suspected, magnetic resonance imaging (MRI) is currently the examination of choice (Fig. 157-1). Examination of CSF by cytocentrifuge histologic testing is essential to determine the presence of metastatic disease in primitive neuroectodermal tumors, germ cell tumors, and pineal region tumors. A lumbar puncture should not be performed before imaging has been obtained to evaluate for evidence of increased intracranial pressure. If a tumor is Figure 157-1 Magnetic resonance imaging scan of a 9-year-old boy showing a heterogeneously enhancing fourth ventricular mass (arrow). It was resected, and pathology revealed medulloblastoma.


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Pediatrics_Nelson. Figure 157-1 Magnetic resonance imaging scan of a 9-year-old boy showing a heterogeneously enhancing fourth ventricular mass (arrow). It was resected, and pathology revealed medulloblastoma. suspected to have metastatic potential (medulloblastoma), MRI of the entire spine should be obtained before surgery to assess for neuraxial dissemination. A postoperative MRI study of the brain should be obtained within 24 to 48 hours of surgery to assess the extent of resection. During follow-up, magnetic resonance spectroscopy can help distinguish recurrent tumor from radiation necrosis. The differential diagnosis of a CNS mass lesion includes malignant tumor, benign tumor, arteriovenous malformation, aneurysm, brain abscess, cysticercosis, granulomatous disease (tuberculosis, sarcoid), intracranial hemorrhage, pseudotumor cerebri, vasculitis, and, rarely, metastatic tumor.


Pediatrics_Nelson

Pediatrics_Nelson. The therapy for children with CNS tumors is individualized and depends on the tumor type, location, size, and associatedsymptoms. High-dose dexamethasone often is administered immediately to reduce tumor-associated edema. Surgical objectives are complete excision, if possible, and maximal debulkingif a complete excision is not possible. In children, radiationtherapy often is combined with chemotherapy; in young children, radiation therapy may be delayed or avoided altogether.Primitive neuroectodermal tumors (including medulloblastoma) and germ cell tumors are sensitive to chemotherapy; gliomas are less sensitive to chemotherapy. Chemotherapy playsan especially important role, particularly in infants in whomthe effects of high-dose CNS radiation may have devastatingeffects on growth and neurocognitive development.


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Pediatrics_Nelson. Short-term adverse effects of therapy include nausea, vomiting, anorexia, fatigue, immunosuppression, and cushingoid features. Long-term adverse effects include neurocognitive deficits, endocrinologic sequelae, decreased bone growth, ototoxicity, renal insufficiency, cataracts, infertility, and second malignant neoplasms (including myelodysplasia). The neurocognitive deficits can be significant, particularly in infants and young children, and are the primary reason for the continued search for the lowest efficacious radiation therapy dose and the most conformal delivery methods for the radiation therapy boosts. Cerebellar mutism syndrome occurs in 25% of patients after resection of a posterior fossa tumor and is characterized by an acute decrease in speech (often mutism), behavioral changes (e.g., irritability, apathy, or both), diffuse cerebellar dysfunction, and other neurologic abnormalities. It may begin within hours to days of surgery and is usually self-resolving within weeks to


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Pediatrics_Nelson. (e.g., irritability, apathy, or both), diffuse cerebellar dysfunction, and other neurologic abnormalities. It may begin within hours to days of surgery and is usually self-resolving within weeks to months; cerebellar ataxia and dysmetria often persist. Somnolence syndrome, which is characterized by excessive fatigue and sleepiness, may occur in the months after completion of radiation therapy and is self-limited. Posterior fossa syndrome manifests as headache and aseptic meningitis days to weeks after surgery in this area.


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Pediatrics_Nelson. Improvements in neurodiagnosis, neurosurgical techniques, chemotherapy regimens, and radiation therapy techniques Table 157-1 Location, Incidence, and Prognosis of CNS Tumors in Children LOCATION INCIDENCE (%) 5-YEAR SURVIVAL (%)


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Pediatrics_Nelson. Table 157-1 Location, Incidence, and Prognosis of CNS Tumors in Children LOCATION INCIDENCE (%) 5-YEAR SURVIVAL (%) Infratentorial (posterior fossa) 55–60 Astrocytoma (cerebellum) 20 90 Medulloblastoma 20 50–80 Glioma (brainstem) 15 High grade: 0–5; low grade: 30 Ependymoma 5 50–60 Supratentorial (cerebral 40–55 hemispheres) Astrocytoma 15 50–75 Glioblastoma multiforme 10 0–5 Ependymoma 2.5 50–75 Choroid plexus papilloma 1.5 95 Midline Craniopharyngioma 6 70–90 Pineal (germinoma) 1 65–75 Optic nerve glioma 3 90 have improved overall outcome. The 5-year overall survival rate associated with all childhood CNS tumors is approximately 50% to 60%, resulting in large measure from the high curability of cerebellar astrocytomas and the increasing cure rate for patients with medulloblastoma (Table 157-1). Intrinsic brainstem gliomas and glioblastoma multiforme have extremely poor prognoses.


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Pediatrics_Nelson. Neuroblastoma is derived from neural crest cells that form the adrenal medulla and the sympathetic nervous system. The cause is unknown. Most cases occur in young children, thus it is likely that neuroblastoma results from prenatal and perinatal events. Neuroblastoma may rarely (1% to 2% of cases) be hereditary. Mutations in the ALK and PHOX2B genes are associated with most familial cases. In sporadic cases, several genetic mutations have been identified. Neuroblastoma is the most common extracranial solid tumor of childhood and the most common malignancy in infancy. The median age at diagnosis is 20 months. There are approximately 650 new cases of neuroblastoma in the United States each year. The incidence is estimated to be 1 in 7000 live births. The tumor usually occurs sporadically, but, in 1% to 2% of cases, there is a family history of neuroblastoma. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Neuroblastoma is remarkable for its broad spectrum of clinical prognosis ranging from spontaneous regression to rapidprogression and metastasis resulting in death. Childrenwith localized disease are often asymptomatic at diagnosis,whereas children with metastases often appear ill and havesystemic complaints, such as fever, weight loss, and pain.The most common presentation is abdominal pain or mass.The mass is often palpated in the flank and is hard, smooth,and nontender. In the abdomen, 45% of tumors arise in the adrenal gland, and 25% arise in the retroperitoneal sympathetic ganglia. Other sites of origin are the paravertebralganglia of the chest and neck. Paraspinal tumors may invadethrough the neural foramina and cause spinal cord compression. Horner syndrome sometimes is seen with neck orapical masses. Several paraneoplastic syndromes, including secretory diarrhea, profuse sweating, and opsomyoclonus (dancing eyes and dancing feet), are associated with neuroblastoma.


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Pediatrics_Nelson. Neuroblastoma may metastasize to multiple organs, including the liver, bone, bone marrow, and lymph nodes. Periorbital ecchymoses is a sign of orbital bone involvement. A unique category of neuroblastoma, stage 4S, is defined in infants (<1 year old) with a small primary tumor and metastasis limited to skin, liver, or bone marrow. It is associated with a favorable outcome.


Pediatrics_Nelson

Pediatrics_Nelson. A complete blood count and plain films may help identify patients with neuroblastoma. Calcification within abdominal neuroblastoma tumors is often observed on plain films of the abdomen.About 90% of neuroblastomas produce catecholamines (Vanillylmandelic acid; Homovanillic acid) that can be detected in the urine. Definitive diagnosis of neuroblastoma requires tissuefor light microscopic, electron microscopic, and immunohistologic examination. A computed tomography (CT) scan of thechest, abdomen, and pelvis; a bone scan and/or metaiodobenzylguanidine scan; bilateral bone marrow aspiration and biopsies;and urinary catecholamines complete the evaluation.


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Pediatrics_Nelson. The abdominal presentation of neuroblastoma must be differentiated from Wilms tumor, which also presents as an abdominal flank mass. Ultrasound or CT examination usually differentiates the tumors. Periorbital ecchymoses from orbital metastases sometimes are mistaken for child abuse. Because children with bone marrow involvement may have anemia, thrombocytopenia, or neutropenia, leukemia is often considered in the differential.


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Pediatrics_Nelson. Treatment of neuroblastoma is based on surgical staging and biologic features (Table 158-1). Complete surgical excision is the initial treatment of choice for localized neuroblastoma. Children with favorable biology who undergo a gross total resection require no further therapy. In patients with advanced disease, combination chemotherapy usually is given after confirmation of the diagnosis. The most commonly used agents are vincristine, cyclophosphamide, doxorubicin, cisplatin, and etoposide. Delayed resection of the primary tumor is undertaken after numerous courses of chemotherapy. Radiation therapy often is administered to the primary tumor bed and areas of metastatic disease. High-dose chemotherapy with autologous stem cell rescue has improved the outcome for patients with high-risk neuroblastoma. Survival has also improved with the addition of cis-retinoic acid (isotretinoin) and anti-GD2 monoclonal antibody therapy after maximal reduction of tumor burden with chemotherapy,


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Pediatrics_Nelson. neuroblastoma. Survival has also improved with the addition of cis-retinoic acid (isotretinoin) and anti-GD2 monoclonal antibody therapy after maximal reduction of tumor burden with chemotherapy, surgery, and radiation therapy.


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Pediatrics_Nelson. Spinal cord compression from neuroblastoma may cause an irreversible neurologic deficit and is an oncologic emergency. Children with the opsomyoclonus syndrome may suffer from developmental delay or mental retardation. The aggressive chemotherapy and radiation therapies currently used to treat high-risk neuroblastoma may result in complications such as ototoxicity, nephrotoxicity, growth problems, and second malignancies.


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Pediatrics_Nelson. The prognosis for survival is affected by age at diagnosis, stage, primary site, presence or absence of metastasis, cytogenetics, DNA ploidy, MYCN status, and histopathology. Currently children with neuroblastoma can be divided into three groups: low, average, and high risk. Unfavorable biologic factors include lack of cell differentiation, amplification (>10 copies/cell) of the MYCN oncogene, lack of hyperdiploidy, and mutations of chromosome 1p, 11q, or 6p22. Patients with favorable biology tend to be younger and often have localized disease. Patients under 1 year of age generally have a better prognosis than older patients. Older patients with stage 4 disease most commonly have unfavorable biology, and more than 50% will relapse due to drug-resistant residual disease. Although neuroblastoma represents only 8% of cases of childhood cancer, it is responsible for 15% of cancer deaths in children.


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Pediatrics_Nelson. Table 158-1 Proposed Children’s Oncology Group Neuroblastoma Risk Stratification Schema, by Stage STAGE AGE MYCN PLOIDY HISTOLOGY OTHER RISK GROUP 1 Low 2A/2B Not amplified >50% resection Low From Maris JM, Hogarty MD, Bagatell R, et al: Neuroblastoma, Lancet 369:2106–2120, 2007. DI, DNA index. Wilms tumor is thought to arise from primitive, metanephric blastema, the precursor of a normal kidney. Nephrogenic rests are foci of embryonal cells that may be rarely (<1%) found in normal infant kidneys and are commonly (25% to 40%) found in Wilms tumor-bearing kidneys. They may be perilobar, intralobar, or both, and are widely considered to be precursors to Wilms tumors. Although the cause of Wilms tumor is unknown, children with certain congenital anomalies or genetic conditions are at increased risk of developing the disease.


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Pediatrics_Nelson. Multiple Wilms tumor or WT genes have been identified. The WT1 gene at chromosomal band 11p13 is important in a minority of tumors, and other genes at 11p15, 16q, and 1p are also involved. The identification of several genes involved in the etiology or progression of Wilms tumor and the loss of heterozygosity (LOH) in normal tissues of some patients demonstrate that the genetic predisposition to Wilms tumor is heterogeneous.


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Pediatrics_Nelson. Wilms tumor is the most common malignant renal tumor of childhood, with approximately 500 new cases per year in the United States. The mean age at diagnosis is 3 to 3.5 years of age, and no gender predilection is apparent. A hereditary form of Wilms tumor may be associated with bilateral presentation and younger age at onset. Many congenital anomalies are associated with Wilms tumor, including sporadic aniridia, hemihypertrophy, and genitourinary abnormalities. Patients with the WAGR (Wilms tumor, aniridia, genitourinary malformation, mental retardation) syndrome have Wilms tumor as a manifestation of the syndrome itself, resulting from a germline deletion at chromosome 11p. Patients with Beckwith-Wiedemann syndrome and some other overgrowth syndromes are at increased risk for developing Wilms tumor and should be screened with periodic renal imaging. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Most children with Wilms tumor are brought to medical attention because they have an abdominal mass that is discovered by their parents. Although many children do not have complaints at the time that the mass is first noted, associated symptoms may include abdominal pain, fever, hypertension, and hematuria.


Pediatrics_Nelson

Pediatrics_Nelson. An abdominal ultrasound or computed tomography (CT) scan can usually distinguish an intrarenal mass from a mass in the adrenal gland or other surrounding structures. Evaluation of the inferior vena cava is crucial because the tumor may extend from the kidney into the vena cava. A complete blood count, urinalysis, liver and renal function studies, and a chest radio-graph (to identify pulmonary metastases) should be obtained. In most cases, a CT scan of the chest, abdomen, and pelvis is obtained. The diagnosis is confirmed by histologic examination of the tumor. Although most cases of Wilms tumor are classified as favorable histology, the presence of anaplasia is predictive of a worse prognosis and is considered unfavorable.


Pediatrics_Nelson

Pediatrics_Nelson. The differential diagnosis of Wilms tumor includes hydronephrosis and polycystic disease of the kidney; benign renal tumors, such as mesoblastic nephroma and hamartoma; and other malignant tumors, such as renal cell carcinoma, neuroblastoma, lymphoma, and retroperitoneal rhabdomyosarcoma.


Pediatrics_Nelson

Pediatrics_Nelson. The timing of nephrectomy for unilateral, resectable Wilms tumor remains controversial. The North American approach is for immediate nephrectomy followed by adjuvant chemotherapy, whereas the European approach is to make a diagnosis by imaging and sometimes a biopsy, give neoadjuvant chemotherapy followed by surgery and then adjuvant chemotherapy (plus radiation therapy, as indicated). The overall survival is comparable regardless of the approach. The Children’s Oncology Group protocols for Wilms tumor with favorable histologic findings generally include vincristine and actinomycin, with or without doxorubicin. Radiation therapy is reserved for a minority of patients depending on stage, presence of metastases, response to therapy, and LOH status.


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Pediatrics_Nelson. Bilateral Wilms tumor is present in about 5% of children on initial presentation, whereas recurrent disease affects the opposite kidney in 4% to 5% of patients. Treatment for patients with bilateral Wilms tumor should be individualized to retain as much normal kidney as possible. Survivors of Wilms tumor are at risk for several late effects, including cardiomyopathy, scoliosis, hypertension and prehypertension, renal and bladder insufficiency, pulmonary dysfunction, hepatic dysfunction, infertility, and second malignancies. Patients with bilateral Wilms tumor are sometimes left with renal insufficiency or failure. Female survivors may have complicated pregnancies and deliveries.


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Pediatrics_Nelson. In general the prognosis for patients with Wilms tumor isvery good. Prognostic factors include stage and histologic features. Anaplastic variants of Wilms tumor have a significantlyworse outcome than classic Wilms tumor. In addition LOH at chromosomes 1p or 16q confers an increased risk of relapseand death compared to tumors without LOH at either site. The 4-year relapse-free survival of patients with tumors of favorable histologic picture is directly related to stage. Curerates for patients with localized Wilms tumor at diagnosis aregreater than 85%, whereas patients with pulmonary metastases have event-free survival rates of approximately 70% to 80%.


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Pediatrics_Nelson. Sarcomas are divided into soft tissue sarcomas and bone cancers. Soft tissue sarcomas arise primarily from the connective tissues of the body, such as muscle tissue, fibrous tissue, and adipose tissue. Rhabdomyosarcoma, the most common soft tissue sarcoma in children, is derived from mesenchymal cells that are committed to skeletal muscle lineage. Less common soft tissue sarcomas include fibrosarcoma, synovial sarcoma, and extraosseous Ewing sarcoma. The most common malignant bone cancers in children are osteosarcoma and Ewing sarcoma. Osteosarcomas derive from primitive bone-forming mesenchymal stem cells. Ewing sarcomas are thought to be of neural crest cell origin.


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Pediatrics_Nelson. The cause is unknown for most children diagnosed with sarcoma, although a few observations have been made regarding risks. Individuals with Li-Fraumeni syndrome (associated with a germline p53 mutation) and neurofibromatosis (associated with NF1 mutations) have an increased risk of softtissue sarcomas. There is a 500-fold increased risk for osteosarcoma for individuals with hereditary retinoblastoma. Prior treatment for childhood cancer with radiation therapy or chemotherapy, specifically alkylating agents, or both, increases the risk for osteosarcoma as a second malignancy.


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Pediatrics_Nelson. In the United States, 850 to 900 children and adolescents under 20 years of age are diagnosed with soft tissue sarcomas each year; approximately 350 are rhabdomyosarcoma. The incidence of rhabdomyosarcoma peaks in children 2 to 6 years old and in adolescents. The early peak is associated with tumors in the genitourinary region, head, and neck; the later peak is associated with tumors in the extremities, trunk, and male genitourinary tract. Boys are affected 1.5 times more often than girls. Of the 650 to 700 U.S. children and adolescents under 20 years of age diagnosed with bone tumors each year, approximately two thirds have osteosarcoma and one third have Ewing sarcoma. Osteosarcoma most commonly affects adolescents; the peak incidence occurs during the period of maximum growth velocity. The incidence of Ewing sarcoma peaks between ages 10 and 20 years but may occur at any age. Ewing sarcoma affects primarily whites; it rarely occurs in African American children or Asian children.


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Pediatrics_Nelson. Available @ StudentConsult.com The clinical presentation of rhabdomyosarcoma varies, depending on the site of origin, subsequent mass effect, and presence of metastatic disease. Periorbital swelling, proptosis, and limitation of extraocular motion may be seen with an orbital tumor. Nasal mass, chronic otitis media, ear discharge, dysphagia, neck mass, and cranial nerve involvement may be noted with tumors in other head and neck sites. Urethral or vaginal masses, paratesticular swelling, hematuria, and urinary frequency or retention may be noted with tumors in the genitourinary tract. Trunk or extremity lesions tend to present as rapidly growing masses that may or may not be painful. If there is metastatic disease to bone or bone marrow, limb pain and evidence of marrow failure may be present.


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Pediatrics_Nelson. Osteosarcoma often is located at the epiphysis or metaphysis of anatomic sites that are associated with maximum growth velocity (distal femur, proximal tibia, proximal humerus), but any bone may be involved. It presents with pain and may be associated with a palpable mass. Because the pain and swelling often are initially thought to be related to trauma, radio-graphs of the affected region frequently are obtained, which usually reveal a lytic lesion, often associated with calcification in the soft tissue surrounding the lesion. While 75% to 80% of patients with osteosarcoma have apparently localized disease at diagnosis, the majority of patients are believed to have micrometastatic disease as well. Although Ewing sarcoma can occur in almost any bone in the body, the femur and pelvis are the most common sites. In addition to local pain and swelling, clinical manifestations may include systemic symptoms, such as fever and weight loss.


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Pediatrics_Nelson. Tissue biopsy is needed for a definitive diagnosis of sarcomas. Selection of the biopsy site is important and has implications for future surgical resection and radiation therapy. Under light microscopy, rhabdomyosarcoma and Ewing sarcoma appear as small, round, blue cell tumors. Osteosarcomas are distinguishable by the presence of osteoid substance.


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Pediatrics_Nelson. Immunohistochemical staining for muscle-specific proteins, such as actin and myosin, helps confirm the diagnosis of rhabdomyosarcoma. Two major histologic variants exist for rhabdomyosarcoma: embryonal and alveolar. Embryonal histologic variant is most common in younger children with head, neck, and genitourinary primary tumors. Alveolar histologic variant occurs in older patients and is seen most commonly in trunk and extremity tumors. Alveolar rhabdomyosarcoma often is characterized by specific translocations: t(2;13) or t(1;13). Metastatic evaluation for patients with rhabdomyosarcoma should include a computed tomography (CT) scan of the chest, abdomen, and pelvis; a bone scan; and bone marrow aspiration and biopsy. A lumbar puncture is required in patients with a parameningeal primary site.


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Pediatrics_Nelson. Definitive diagnosis of osteosarcoma often is establishedby carefully placed needle biopsy. The presence of osteoidand immunohistochemical analysis confirms the diagnosisof osteosarcoma. The extent of the primary tumor shouldbe delineated carefully with magnetic resonance imaging(MRI) before starting chemotherapy. Osteosarcoma tends tometastasize to the lung, most commonly, and rarely to otherbones. Metastatic evaluation includes a chest CT scan and a bone scan. The diagnosis of Ewing sarcoma is established with immunohistochemical analysis and cytogenetic and molecular diagnostic studies of the biopsy material. Ewing sarcoma is characterized by a specific chromosomal translocation, t(11;22), which is seen in 95% of tumors. MRI of the primary lesion should be performed to delineate extent of the lesion and any associated soft tissue mass. Metastatic evaluation involves a bone scan, chest CT scan, and bone marrow aspiration and biopsy.


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Pediatrics_Nelson. Patients with Ewing sarcoma may be misdiagnosed as having osteomyelitis; children with osteogenic sarcoma often are thought initially to have pain and swelling related to trauma. The differential diagnosis for rhabdomyosarcoma depends on the location of the tumor. Tumors of the trunk and extremities often present as a painless mass and may be initially thought to be benign tumors. Periorbital rhabdomyosarcoma may be misdiagnosed as orbital cellulitis, and other head and neck rhabdomyosarcoma may be confused with chronic infection of ears or sinuses. The differential diagnosis for intra-abdominal rhabdomyosarcoma includes other abdominal malignancies, such as Wilms tumor or neuroblastoma.


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Pediatrics_Nelson. Treatment of rhabdomyosarcoma is currently based on a staging system that incorporates both the primary site and histologic picture. The staging system also involves a local tumor group assessment based on the extent of disease and surgical result. In the intergroup rhabdomyosarcoma studies, the most common chemotherapy agents used are cyclophosphamide, vincristine, and actinomycin. Doxorubicin, etoposide, ifosfamide, topotecan, and irinotecan are also active against rhabdomyosarcoma. Radiation is administered to patients who have residual disease after initial surgery or who have only had a primary biopsy of the tumor.


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Pediatrics_Nelson. The current treatment of osteosarcoma involves neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy. Agents effective against osteosarcoma are doxorubicin, cisplatin, high-dose methotrexate, ifosfamide, and etoposide. The treatment for Ewing sarcoma is similar to that for osteosarcoma; preoperative chemotherapy is given, followed by local control measures, and then further chemotherapy. In contrast to osteosarcoma, Ewing sarcoma is radiation sensitive. Chemotherapy includes vincristine, cyclophosphamide, ifosfamide, etoposide, and doxorubicin.


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Pediatrics_Nelson. In addition to the risk of late effects from the chemotherapy, children with sarcomas have potential complications related to local control of the tumor. If the local disease is controlled with surgery, the long-term sequelae may include loss of limb or limitation of function. If local control is accomplished with radiation therapy, the late effects depend on the dose of radiation given, the extent of the site radiated, and the development of the child at the time of radiation therapy. Irradiating tissues interfere with growth and development, so significant adverse consequences may occur in young children.


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Pediatrics_Nelson. For all children with sarcoma, presence or absence of metastatic disease at presentation is the most important prognostic factor. The outlook remains poor for patients who have distant metastasis from Ewing sarcoma, rhabdomyosarcoma, or osteosarcoma at diagnosis. Patients with localized rhabdomyosarcomas in favorable sites have an excellent prognosis when treated with surgery followed by vincristine and actinomycin. In patients with osteosarcoma and Ewing sarcoma, another important prognostic factor is the degree of tumor necrosis after preoperative chemotherapy. In general, patients whose tumor specimens show a high degree (>90%) of necrosis following preoperative chemotherapy have an event-free survival rate greater than 80%. Patients who still have large amounts of viable tumor after presurgical chemotherapy have a much worse prognosis. The cure rate for patients with localized osteosarcoma and Ewing sarcoma is approximately 60% to 70%. Patients who have lung metastasis at


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Pediatrics_Nelson. after presurgical chemotherapy have a much worse prognosis. The cure rate for patients with localized osteosarcoma and Ewing sarcoma is approximately 60% to 70%. Patients who have lung metastasis at diagnosis have a cure rate of approximately 30% to 35%. Patients with metastases to other bones have a poor prognosis.


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Pediatrics_Nelson. Arndt CA, Rose PS, Folpe AL, et al: Common musculoskeletal tumors of childhood and adolescence, Mayo Clin Proc 87:475–487, 2012 Davenport KP, Blanco FC, Sandler AD: Pediatric malignancies: neuroblas toma, Wilms tumor, hepatoblastoma, rhabdomyosarcoma and sacrococ cygeal teratoma, Surg Clin North Am 92:745–767, 2012 Kopp LM, Gupta P, Pelayo-Katsanis L, et al.: Late effects in adult survivors of pediatric cancer: a guide for the primary care physician, Am J Med 125:636–641, 2012 Packer RJ, MacDonald T, Vezina G: Central nervous system tumors, Pediatr Clin North Am 55:121–145, 2008 Pui CH, Mulligan CG, Evans WE, et al: Pediatric acute lymphoblastic leuke mia: where are we going and how do we get there? Blood 120:1165–1174, John D. Mahan and Hiren P. Patel 22


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Pediatrics_Nelson. Pui CH, Mulligan CG, Evans WE, et al: Pediatric acute lymphoblastic leuke mia: where are we going and how do we get there? Blood 120:1165–1174, John D. Mahan and Hiren P. Patel 22 The kidneys preserve homeostasis through multiple mechanisms: maintain fluid and electrolyte balance, excrete metabolic waste products through glomerular filtration and tubular secretion, generate energy (gluconeogenesis), and produce important endocrine hormones (renin, vitamin D metabolites, erythropoietin). Renal disorders, by disturbing homeostasis, can affect growth and development and result in a variety of clinical manifestations (Table 161-1). Renal disorders in children may represent intrinsic renal diseases or derive from systemic conditions (Table 161-2).


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Pediatrics_Nelson. Fetal urine production contributes to amniotic fluid volume, lung maturation, and somatic development. Congenital renal disorders may be associated with reduced (oligohydramnios) or increased amniotic fluid volume (polyhydramnios). Pulmonary hypoplasia and fetal maldevelopment of the face and extremities may result from insufficient amniotic fluid (Potter syndrome) (see Chapters 58 and 60). Risk factors for renal disease (e.g., perinatal hypoxia-ischemia, acute tubular necrosis, renal vein thrombosis) can be detected by a careful history. A detailed family history may identify hereditary renal conditions. Poor growth and/or feeding, abnormal fluid intake and/or output may indicate underlying renal dysfunction. Other common manifestations of renal and/or urinary tract disorders are listed in Table 161-1.


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Pediatrics_Nelson. Renal diseases in children may be initially asymptomatic and detected during routine visits. Abnormal growth, hypertension (HTN), dehydration, or edema may suggest occult renal disease (see Chapter 33). Abnormal facial features may suggest syndromes associated with renal disorders (fetal alcohol syndrome, Down syndrome). Preauricular tags, deformities of the external ear, or ophthalmologic abnormalities (keratoconus, aniridia, iridocyclitis, cataracts) can be associated with congenital renal defects. Abdominal examination may reveal renal masses. Bladder distention may suggest a urine-concentrating defect or urinary tract obstruction.


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Pediatrics_Nelson. Normal renal function depends on intact glomerular filtration and tubular function (proximal tubule [PT], loop of Henle, and distal tubule [DT]) that results in urine formation (Fig. 161-1). The net glomerular pressure favors movement of fluid out of the capillaries into Bowman’s space. Intraglomerular pressure is regulated by afferent and, particularly, efferent arteriolar tone. Renin is generated by cells in the juxtaglomerular apparatus, located at the base of each glomerulus in proximity to the afferent/efferent arterioles and DT of that nephron and released in response to glomerular flow and perfusion.


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Pediatrics_Nelson. The PT conducts isosmotic reabsorption (see Fig. 161-1)to reabsorb two thirds of the filtered volume, sodium, and chloride. Glucose, amino acids, potassium, and phosphate are almost completely reabsorbed. Approximately 75% of filtered bicarbonate is reabsorbed in the PT. When filtered bicarbonate exceeds the PT threshold, bicarbonate is spilled into the urine. The PT also secretes compounds such as organic acids, penicillins, and other drugs. The most potent vitamin D analog—1,25(OH)2-cholecalciferol (calcitriol)—is produced by PT cells in response to parathyroid hormone and intracellular calcium/phosphorus concentrations. The loop of Henle is the site of reabsorption of 25% of sodium chloride filtered in the glomerulus (see Fig. 161-1).Active chloride transport drives the countercurrent multiplier and composes the medullary interstitial hypertonic gradient required for urinary concentration.


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Pediatrics_Nelson. The DT is composed of the distal convoluted tubule (DCT) and collecting ducts (CD). The DCT is water impermeable and contributes to urine dilution by active sodium chloride absorption. The CD is the primary site of antidiuretic hormone (vasopressin) response, which leads to urine concentration. Sodium-potassium and sodium-hydrogen exchange in the CD is regulated by aldosterone. Active hydrogen ion secretion, which is responsible for the final acidification of the urine, also occurs in the CD. Renal ammonia production and intraluminal generation of ammonium (NH4+) facilitate urine hydrogen ion excretion. Urinary NH4+ is not measured easily but can be inferred by calculation of the urinary anion gap. The gap between measured anions and cations largely consists of NH4+. Problems with renal acid excretion or ammonia production decrease the


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Pediatrics_Nelson. Table 161-1 Common Manifestations of Renal Disease by Age FINDING SIGNIFICANCE NEONATE Flank mass Multicystic dysplasia, urinary tract obstruction (hydronephrosis), polycystic disease, tumor Hematuria Acute tubular/cortical necrosis, urinary tract malformation, trauma, renal vein thrombosis Anuria and oliguria Renal agenesis, obstruction, acute tubular necrosis, vascular thrombosis CHILD/ADOLESCENT Cola red-colored urine Hemoglobinuria (hemolysis); myoglobinuria (rhabdomyolysis); pigmenturia (porphyria, urate, beets, drugs); hematuria (infection, glomerulonephritis, Henoch-Schönlein purpura, hypercalciuria, stones) Gross hematuria Infection, glomerulonephritis, trauma, benign hematuria, nephrolithiasis, tumor Edema Nephrotic syndrome, glomerulonephritis, acute/chronic renal failure, cardiac/liver disease Hypertension Acute glomerulonephritis, acute/chronic renal failure, obstruction, cysts, dysplasia, coarctation of the aorta, renal artery stenosis


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Pediatrics_Nelson. Hypertension Acute glomerulonephritis, acute/chronic renal failure, obstruction, cysts, dysplasia, coarctation of the aorta, renal artery stenosis Polyuria Diabetes mellitus, central and nephrogenic diabetes insipidus, obstruction, dysplasia, hypokalemia, hypercalcemia, psychogenic polydipsia, sickle disease/trait, polyuric renal failure, diuretic abuse Oliguria Dehydration, acute tubular necrosis, acute glomerulonephritis, interstitial nephritis, hemolytic uremic syndrome Dysfunctional voiding/urgency Neurogenic bladder, urinary tract infection, vaginitis, hypercalciuria, foreign body Polycystic kidney disease Cystinosis, oxalosis Renal/urinary tract tumor Galactosemia, hereditary fructose intolerance Extrarenal malignancy (leukemia, lymphoma) urinary anion gap. A urinary gap of approximately 1 mEq/kg body weight is reasonable in normal children.


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Pediatrics_Nelson. The maximum urinary concentrating capacity in a preterm newborn (∼400 mOsm/L) is less than that in afull-term newborn (600 to 800 mOsm/L), which is less thanthat in older children and adults (∼1200 mOsm/L). Neonates can dilute urine similar to adults (75 to 90 mOsm/L),but, because the glomerular filtration rate (GFR) is lower,the capacity to excrete a water load is less in infants. GFRreaches adult levels by 1 to 2 years of age. Tubular reabsorption of sodium, potassium, bicarbonate, and phosphateand excretion of hydrogen are all reduced in infants relative to adults. These functions mature independently andat different ages, so a neonate rapidly develops the abilityto reabsorb sodium efficiently, but it takes 2 years for bicarbonate reabsorption to mature. Erythropoietin is secreted by interstitial cells in the renal medulla in response to lowoxygen delivery and helps regulate bone marrow red bloodcell production. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Renal disorders can be classified as primary or secondary (due to systemic illnesses) (see Table 161-2). Renal diseases may present with obvious signs, such as hematuria oredema, or with subtle signs detected on screening examinations (abdominal or flank mass, HTN, proteinuria). Fever, irritability, and vomiting may be presenting symptoms inneonates and infants with urinary tract infections (UTIs),whereas frequency and dysuria suggest UTI in older children.Chronic kidney disease often is associated with poor growthand feeding but may be first detected on screening examinations (HTN, hematuria). An abnormal urine stream mayindicate posterior urethral valves, other bladder disorders, orobstructive lesions.


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Pediatrics_Nelson. The GFR is measured most accurately by infusion of a substance that is freely filtered by the glomerulus but is not metabolized, reabsorbed, or secreted in or by the tubules. The GFR is calculated as follows: where [U] is urine concentration, [P] is serum concentration of a substance (mg/dL) used to measure clearance, and V is urine flow rate (mL/min). By convention, GFR is corrected to a body surface area of 1.73 m2 to allow comparison between different sized individuals. In a full-term newborn, an uncorrected GFR of 4 to 5 mL/min corrects to approximately 40 mL/min/1.73 m2. GFR increases rapidly during the first 2 years of life when it achieves adult values (100 to 120 mL/min/1.73 m2). After that, GFR and body size increase proportionately, and GFR remains stable.


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Pediatrics_Nelson. Plasma creatinine reflects muscle mass, increases with age, and is used to approximate GFR. Creatinine is also secreted by PT, resulting in a less accurate measurement of GFR with immature kidneys or with decreased renal function. Blood Figure 161-1 Major transport functions of each nephron segment, including representative osmolalities in vasa recta, interstitium, and tubule at different levels within the kidney. ADH, Antidiuretic hormone; Glu, glucose; OA, organic acid. (From Andreoli TE, Carpenter CCJ, Plum F, et al, editors: Cecil Essentials of Medicine, Philadelphia, 1986, WB Saunders.) urea nitrogen is affected by renal function but is greatly altered by hydration, nutrition, catabolism, and tissue breakdown. The correlation between creatinine and GFR can be used to estimate GFR. The revised Schwartz formula is the following: 0.413×Ht


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Pediatrics_Nelson. Height is measured in centimeters. Serum creatinine is measured in milligram per deciliter. This formula is most useful when body habitus and muscle mass are reasonably normal andwhen renal function is relatively stable. This formula may bemost accurate in the range of 15 to 75 mL/min per 1.73 m2. Values greater than 75 should be reported as such rather than as aspecific number. Creatinine clearance ([UCr]V/[PCr]) estimatesGFR but overestimates GFR when renal function is decreased.


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Pediatrics_Nelson. Urinalysis is a useful screen for renal abnormalities. In addition to urine color and turbidity, macroscopic urinalysis uses a urine dipstick for pH and the presence of protein, glucose, ketones, blood, and leukocytes. Dilute urine may result in a false-negative result for protein; false-positive results may occur with extremely alkaline or concentrated urine or if there is a delay in reading the test. Dipsticks are exquisitely sensitive to the presence of hemoglobin (or myoglobin); there are few false-negative test results but many false-positive results. Glucose is detected via a glucose oxidase-peroxidase reaction, and leukocytes are detected via a leukocyte esterase reaction. The nitrite test may detect bacteriuria if the bacteria reduce nitrate to nitrite and have long contact time with the urine. False-negative results occur with frequent voiding, low urine bacterial count, urinary tract obstruction, and infection with bacteria unable to generate nitrite. Gross hematuria or


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Pediatrics_Nelson. with the urine. False-negative results occur with frequent voiding, low urine bacterial count, urinary tract obstruction, and infection with bacteria unable to generate nitrite. Gross hematuria or prolonged contact (uncircumcised boys) may result in a false-positive nitrite test. Microscopic urinalysis is used to confirm pyuria and hematuria and detect casts and crystals.


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Pediatrics_Nelson. Proteinuria can be further defined by determination of a spot urine protein/creatinine (UPr/Cr) in a single urine specimen.This unit-less value correlates very well with 24-hour urine protein excretion: spot UPr/Cr approximates 24-hour urine protein/ m2/day (normal <0.20; nephrotic range >2.0 in children). Ultrasound reliably assesses kidney size, determines degree of dilation, and differentiates cortex and medulla. The bladder also can be visualized. Pulsed Doppler studies assess arterial and venous blood flow and can be used to calculate the kidneys’ resistive index. A voiding cystourethrogram involves repeated filling of the bladder to detect vesicoureteral reflux and to evaluate the urethra. Computed tomography and magnetic resonance imaging have mostly replaced the intravenous pyelogram to evaluate kidney structure and function. Radionuclide studies can define renal size, scars, and renal function/excretion.


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Pediatrics_Nelson. Small amounts of protein are found in the urine of healthy children (<4 mg/m2/hour or UPr/Cr <0.2). Nephrotic proteinuria in children is defined as protein greater than 40 mg/m2/hour or U Pr/Cr >2.0. Proteinuria between these levels is mildly to moderately elevated but not nephrotic. Proteinuria may be transient or persistent, asymptomatic or symptomatic, and orthostatic (present in the upright position but not in the recumbent position) or fixed (present in all positions). Proteinuria may be glomerular (disruptions of the normal glomerular barrier to protein filtration) or tubular (increased filtration, impaired reabsorption, or secretion of proteins).


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Pediatrics_Nelson. Nephrotic syndrome (NS) is characterized by persistent heavy proteinuria (mainly albuminuria) (>2 g/m2/24 h);hypoproteinemia (serum albumin <3.0 g/dL); hypercholesterolemia (>250 mg/dL); and edema. Age, race, and geography affect the incidence of NS. Certain HLA types (HLA-DR7, HLA-B8, and HLA-B12) are associated with an increased incidence of NS. Increased glomerular permeability is due to alterations in the normal glomerular cellular and basement membrane barrier that restrict filtration of serum proteins. The resultant massive proteinuria leads to decreased serum proteins, especially albumin. Plasma oncotic pressure is diminished, leading to fluid shifts from vascular to interstitial compartments and plasma volume contraction. Renal syndrome Primary focal Henoch-Schönlein purpura, glomerulosclerosis Wegener and other vasculitides Membranoproliferative Chronic infections (hepatitis B, glomerulonephritis hepatitis C, malaria, human


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Pediatrics_Nelson. Membranoproliferative Chronic infections (hepatitis B, glomerulonephritis hepatitis C, malaria, human Congestive heart failure, constrictive blood flow and the glomerular filtration rate are not usually diminished. Edema results from reduction in effective circulating blood volume and increase in tubular sodium chloride reabsorption secondary to activation of the renin-angiotensin-aldosterone system. Hypoproteinemia stimulates hepatic lipoprotein synthesis and diminishes lipoprotein metabolism, leading to elevated serum lipids (cholesterol, triglycerides) and lipoproteins.