•Treatment of tumor-associated increased ICP. •Dexamethasone, ± mannitol or hyperventilation. •Ventriculoperitoneal shunting or third ventricu- lostomy may be required. • Late effects include neurocognitive morbidity, growth failure, neurobehavioral abnormalities, endocrinopathies, focal neurologic deficits, and psy- chosocial effects. 103 LEUKEMIA Elaine R. Morgan EPIDEMIOLOGY • Most common childhood extracranial malignancy. • Incidence 4–6 per 100,000 children. • Peak age range 3–6. •M F = increased incidence in identical twin if one child has leukemia (20–50%) within 1 year. PREDISPOSING CONDITIONS •Down syndrome—acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL). • Human immunodeficiency virus (HIV) infection— ALL • Ataxia, telangiectasia—T-cell ALL • Bloom syndrome •Kostman syndrome •Fanconi syndrome AML •Medically treated AA • Myelodysplasia • Prior chemotherapy INITIAL PRESENTING SYMPTOMS AND SIGNS • Most common presentations include fever, bone pain, fatigue, pallor, bleeding, and respiratory distress sec- ondary to mediastinum mass. •Physical findings may include lymphadenopathy and hepatosplenomegaly. • Rarely may present with central nervous system (CNS) symptoms, mass lesions/testicular involvement, skin lesions, gingival hypertrophy, renal insufficiency, dis- seminated intravascular coagulation (DIC), and intractable bleeding. INITIAL WORKUP • Initial workup includes routine and specialized labo- ratory studies. • Laboratory studies: Complete blood count (CBC), chemistry panel, uric acid, coagulation studies, and bacterial cultures. • Chest x-ray • LP with cytospin. • Bone marrow (BM) aspirate. • Specialized studies for classification include flow cy- tometry, cytochemical stains, cytogenetics, ± molecular testing for chromosomal abnormalities. CLASSIFICATION • One to two percent of childhood leukemias are classic metaphyseal lesions (CML), 15% are ANLL, and 85% are ALL. • ANLL is subclassified histologically and cytogeneti- cally into eight subtypes (M 0 → M 7 ). The M 3 (promye- locytic) subtype is treated differently. • ALL is subclassified by immunophenotype: B precur- sor (85%); T cell (13%); mature B cell (1–2%). •T and B cell types are associated with a worse prog- nosis. • B-precursor leukemias can be separated into two to five risk categories (low, standard, high, very high, and infant) based on clinical and laboratory findings. •Very high-risk features: Chromosomal translocation t 9;22; hypodiploidy; age <1 year. • High-risk features: Age >10 years, white blood cell (WBC) at diagnosis >50,000, chromosomal transloca- tions t 4;11 t 1;19. •Low-risk features: Hyperdiploidy; trisomies 4&10; tel/acute myelogenous leukemia (AML) gene rearrangement. • Possible prognostic findings: Sex, ethinicity, CNS status. •Patients with rapid initial response have a more favor- able prognosis. INITIAL MANAGEMENT • Diagnostic workup. •Transfusions of packed red blood cells (PBRCs) and platelets as needed. • Hydration. • Management/prophylaxis of hyperuricemia alkalin- ization and allopurinol or uricase. •Preemptive broad spectrum antibiotics if febrile. 376 SECTION 13 • MALIGNANCIES CHAPTER 104 • LYMPHOMA 377 CML • Initial presentation: Splenomegaly, leukocytosis; ±leuko- stasis (cerebrovascular accident [CVA], pulmonary priaprism). • Diagnosis confirmed by 9;22 translocation or molec- ular studies (BCR/abl). •Treatment: Gleevec PO vs. hydroxyurea ± bone marrow transplant (BMT). • Survival: Eighty percent with BMT unknown with Gleevec. ANLL • Risk analysis limited: (a) Low risk—promyelocytic leukemia (APL), Down syndrome; (b) high risk—sec- ondary leukemia, monosomy 5 or 7; and (c) possible lower risk factors: WBC <25,000; chromosomes: t 8;21, inversion 16. • CNS disease uncommon. TREATMENT • APL—ATRA (all transretinoic acid) + anthracycline + maintenance. •Down syndrome—Modified • All patients receive one to two intensive inpatient sequential courses including anthracycline, cytosine arabinoside (AraC) ± other. • Remission rate: Eighty percent • Consolidation with either three to five courses of intensive chemotherapy including high-dose Ara-C ± bone marrow transplant. • Maintenance is controversial. •Treatment of relapse is difficult. • Complications: Twenty percent induction death rate due to infection, bleeding, resistant disease, continued risk of infection, and bleeding during consolidation. • Outcome: APL and Down syndrome 80–90% event free survival (EFS). •Other: Thirty to forty percent EFS with chemother- apy, 60–70% EFS with BMT. • Survival after relapse: <20%. ALL • B-ALL is treated with short (~6 months) intensive chemotherapy • EFS 60% (CNS+) to 80% (CNS−). • Relapse occurs early, usually BM, CNS. Survival after relapse is rare. CNS involvement common. •T-ALL may be associated with mediastinal mass. A variety of protocols available that use intensive mul- tidrug treatments ± cranial irradiation. Remission rate ~80% EFS—60–70%. Treatment duration ~2 years. Relapses occur in BM, CNS usually within 2 years of diagnosis. Survival after relapse—poor. CNS involve- ment more common than B-precursor ALL. • B-precursor ALL is most common type of leukemia. Treatment with multidrug chemotherapy; risk based. Irradiation is used for CNS disease. Treatment duration 2–3 years. BMT used for very high-risk patients. Remission achieved in 80–95% of patients, usually within 28 days of diagnosis. EFS overall 70–85%. Relapses may occur early or late. Bone marrow most common site; CNS <10%; testicular <5%. Treatment of relapse may be successful. Survival depends on dura- tion of first remission, initial R x , and site of relapse. Treatment includes alternative chemotherapy ± BMT. COMPLICATIONS • Leukostasis secondary to hyperleukocytosis. Metabolic/ problems secondary to tumor lysis. Infection—bacterial, fungal, viral, Pneumocystis carinii pneumonia (PCP). Bleeding and anemia. Chemotherapy side effects. 104 LYMPHOMA Elaine R. Morgan and Maureen Haugen EPIDEMIOLOGY •Twelve percent of all pediatric cancers; third most common childhood cancer in the United States; 1 per 100,000 children. Forty percent Hodgkin disease and 60% non-Hodgkin lymphoma (NHL). • Fifty percent of childhood cancers in Africa. HODGKIN DISEASE EPIDEMIOLOGY • Rare under 5 years of age; increased incidence in ado- lescents and young adults. • Predisposing conditions: Family history, immuno- deficiency. SIGNS/SYMPTOMS •Painless, firm lymphadenopathy; cervical supracla- vicular 60–90%. • Respiratory symptoms • Systemic symptoms: Pruritis “B” symptoms, weight loss, fevers, night sweats 30%. • Histologic subtypes: Lymphocytic predominant, nodu- lar sclerosing, mixed cellularity, lymphocyte depleted. INITIAL WORKUP • Chest x-ray (CXR), computed tomography (CT) scan (neck to pelvis). • Complete blood count (CBC), chemistry panel, erythrocyte sedimentation rate (ESR), copper, ferritin. • Bone marrow aspirate and biopsy. •± Gallium scan or positron emission tomography (PET) scan. STAGING • I: Single lymph node region. • II: Two or more lymph node regions on the same side of the diaphragm. • III: Lymph node regions/on both sides of the diaphragm. •IV: Disseminated extra lymphatic sites: Bones, bone marrow, lungs, liver. TREATMENT • Combined modality treatment: Chemotherapy and radiation. • Stem-cell transplant after relapse. • Prognosis 70–90% 5-year disease free survival (DFS). • Adverse indicators: Stage III or IV disease, B symp- toms, bulky tumor. NON-HODGKIN LYMPHOMA EPIDEMIOLOGY • Rare, less than 2 years of age, peak age is 7–11 years. • Predisposing conditions: Immunosuppressive therapy, Wiskott-Aldrich syndrome, Chediak-Higashi syn- drome, X-linked lymphoproliferative disorder, ataxia- telangiectasia, Epstein-Barr virus (EBV) (African type NHL), human immunodeficiency virus (HIV). SIGNS/SYMPTOMS • Respiratory symptoms, chest pain, superior vena cava syndrome. •Lymphadenopathy, painless. • Abdominal pain, nausea, vomiting, gastrointestinal (GI) symptoms or bleeding, ascites, abdominal dis- tention. • Skin/scalp masses, testicular mass. • Bone pain. • Renal failure. • CNS symptoms. INITIAL WORKUP • CBC, chemistry panel, uric acid, lactic dehydrogenase (LDH). • Bone marrow aspirate ± biopsy. • Lumbar puncture with cytospin. • CXR, CT scan, bone scan, gallium scan. HISTOLOGY • Small, noncleaved, diffuse, poorly differentiated (B cell) •Lymphoblastic (usually T cell) • Large cell (B cell, T cell, or non-T; non-B) •Lymphoproliferative (usually B cell) polyclonal or monoclonal (commonly occurs posttransplant). STAGING (MURPHY SYSTEM) •I:Localized • II: Regional • III: Above and below diaphragm. •IV: CNS or BM involvement. TREATMENT • Radiation: For emergency relief of symptoms; treat- ment of CNS disease. • Chemotherapy: B cell—intensive, repetitive, short duration. •T cell—similar to ALL for 18–24 months. • Stem-cell transplant: For refractory or relapsed dis- ease; limited success. •Lymphoproliferative disease: Reduction in immuno- suppressive therapy; consider monoclonal antibody and/or chemotherapy for nonresponsive disease. PROGNOSIS—80% DFS • Adverse indicators: Advanced stage, high LDH, Stage IV disease. 378 SECTION 13 • MALIGNANCIES CHAPTER 105 • NEUROBLASTOMA 379 105 NEUROBLASTOMA Susan L. Cohn and Kelly Coyne EPIDEMIOLOGY • There are approximately 600 new cases of neuroblas- toma (NBL) in the United States each year (1 per 7000 births). • Most common tumor in children <1-year-old; median 2 years; 90% <5 years. • Eight to ten percent of all pediatric cancers and 15% of pediatric cancer-related deaths. • One to two percent familial. CLINICAL PRESENTATION • Neural crest origin; adrenal or parasympathetic ganglia. • Signs and symptoms reflect both the location of the primary tumor and the extent of disease. • Specific associated findings include paraneoplastic syndromes (opsoclonus-myoclonus; intractable diar- rhea secondary to vasoactive intestinal protein (VIP). • Metastatic disease (approximately 50% of cases). •Lymphadenopathy, hepatomegaly, pallor, exophthal- mos, eyelid ecchymosis, skull mass, bone pain, skin nodules, and purpura. • Systemic symptoms: Fever, weight loss, fatigue, and hypertension. • This clinical diversity correlates closely with numer- ous clinical and biologic factors including tumor stage, patient age, tumor histology, and genetic abnor- malities. DIAGNOSTIC STUDIES AND TESTS DIAGNOSTIC CONFIRMATION •Pathologic diagnosis from tumor tissue or bone marrow aspirate with neuroblastoma tumor cells and increased urinary catecholamines. • Clinical and biologic studies are critical for risk- group classification (see below). CLINICAL STUDIES • Urinary catecholamines—elevated in >90% of those diagnosed. • Bilateral bone marrow biopsies and aspirates. • Computed tomography (CT) of the chest, abdomen, and pelvis; ± head CT. • MIBG (metaiodobenzylguanidine) scan—adrenergic tissue-specific scan. • Bone scan. • Magnetic resonance imaging (MRI) if potential intraspinal extension. TUMOR BIOLOGY STUDIES • MYCN protooncogene copy number. •Tumor cell ploidy. • Histopathology. THE INTERNATIONAL NEUROBLASTOMA STAGING SYSTEM (INSS) • Stage 1: Localized tumor with complete gross exci- sion. • Stage 2A: Localized tumor with incomplete gross excision, nonadherent lymph nodes negative. • Stage 2B: Localized tumor with or without complete gross excision, with nonadherent ipsilateral nodes positive. • Stage 3: Tumor involvement across the midline. • Stage 4: Disseminated tumor. • Stage 4S: Infants <1 year with primary tumor (as defined in Stages I and II) with dissemination limited to skin, liver, and/or bone marrow (<10% tumor cells and MIBG scan negative in the marrow). RISK-GROUP STRATIFICATION SYSTEM • Based on clinical and biologic studies. • Assignment to low-, intermediate-, and high-risk cat- egories based on age at diagnosis, INSS stage, histopathology, MYCN amplification status, and deoxyribonucleic acid (DNA) index. • Survival: <30% (high risk) to >90% (low risk). RISK-BASED TREATMENT •Low-risk patients. • Require minimal therapy, perhaps resection alone. •Newborns and infants with low-risk disease may have spontaneous regression. INTERMEDIATE RISK PATIENTS •Tumor biology impacts response to therapy and out- come. •Treated with moderate intensity chemotherapy, sur- gery ± irradiation. HIGH-RISK PATIENTS • Dose intensity has been shown to correlate strongly with both response and progression-free survival. •Treatment includes high dose chemotherapy with stem cell rescue. • Preliminary data suggest that biologic agents may also be clinically effective in the setting of minimal residual disease. •More effective therapy is needed for high-risk neu- roblastoma patients. 106 WILMS TUMOR Morris Kletzel EPIDEMIOLOGY •Affects 1–10,000 children younger than 15 years of age. • Approximately 400 new cases are reported yearly in the United States. • Incidence is higher among African-Americans and lower among Asian-Americans. GENETICS •Wilms tumor is associated with multiple congenital abnormalities and in some cases with identified syn- dromes. 1. Aniridia (1%) 2. WAGR (Wilms tumor, aniridia, genitourinary mal- formation, and mental retardation) 3. Deny Drash syndrome (Wilms tumor, pseudoher- maphroditism and glomerulopathy) 4. Beckwith-Wiedemann syndrome (BWS) (macro- glosia, gigantism, umbilical hernia) 5. Trisomy 18 6. Genitourinary anomalies (5%) 7. Hemihypertrophy • Mutations in the WT1 gene located on chromosome 11p13 and WT2 gene (11p15) result in the develop- ment of Wilms tumor. CLINICAL PRESENTATION • Mean age at diagnosis is 3.4–4.0 years and for bilat- eral tumors is 2.5 years. • Most common presenting symptoms are abdominal mass ± abdominal pain. • Less frequent symptoms: Hypertension, fever, hema- turia, and anemia. • Acquired Von Willibrand disease has been associated with Wilms tumor. DIAGNOSTIC IMAGING • Abdominal ultrasound and/or computed tomography (CT) of the abdomen. • Chest CT STAGING • Stage I: Tumor limited to the kidney and completely excised. • Stage II: Tumor beyond the kidney but completely excised. • Stage III: Residual nonhematogenous tumor confined to the abdomen. •Stage IV: Hematogenous metastases (lung, liver, bone, brain). • Stage V: Bilateral involvement at diagnosis. PATHOLOGY • Subtypes are favorable (trilineage) or unfavorable (anaplasia, sarcoma). THERAPY • Highly successful. • Includes surgery, chemotherapy, and irradiation. • The treatment is based on the stage and histologic type and over the past 20 years has evolved according to clinical trials develop by the National Wilms Tumor Study Group. OUTCOME • Based on the National Wilms Tumor Study #3, the 4-year survivals are Stages I, II, and III with favorable histology: 96.5, 92.2, and 86.8%, respectively; high- risk patients (Stage IV or unfavorable histology): 73%. Stage V ( bilateral tumor): 70%. 380 SECTION 13 • MALIGNANCIES CHAPTER 107 • PEDIATRIC BONE TUMORS 381 107 PEDIATRIC BONE TUMORS Laurie MacDonald, David O. Walterhouse, and Robert L. Satcher BENIGN BONE TUMORS STAGING BY PATHOLOGIC AGGRESSIVENESS • Stage 1 (latent); Stage 2 (active); Stage 3 (aggressive). •Treatment: Stage 1 (observation); Stage 2 (intrale- sional excision); Stage 3 (marginal or wide excision). MALIGNANT BONE TUMORS OSTEOSARCOMA • Primary malignant tumor of bone produces osteoid. EPIDEMIOLOGY •Four hundred cases/year in children <20 years. Peak incidence occurs in the second decade of life during the adolescent growth spurt. • Associations: Radiation; retinoblastoma; Li-Fraumeni familial cancer syndrome. CLINICAL PRESENTATION •Pain, soft tissue mass. • Site: Usually metaphyses of long bones (lower extremity more common); other bony sites are rare. • Fifteen to twenty percent present with metastatic dis- ease; lungs most common. STAGING WORKUP • Plain films; magnetic resonance imaging (MRI) of primary. • Computed tomography (CT) of chest • Bone scan ± thallium scan ± positron emission tomo- graphy (PET) scan. UNFAVORABLE PROGNOSTIC FACTORS • Metastasis at presentation. • Primary site in axial skeleton. •Tumor size >5 cm. • Poor initial response to chemotherapy. TREATMENT • Chemotherapy generally administered both presurgi- cally (neoadjuvant) and postsurgically. •Surgery includes amputation (local recurrence <5%) or limb salvage (local recurrence rate 5–10%; more postoperative complications). • Radiation therapy only for unresectable tumors. OUTCOME • ~60–65% disease-free survival with nonmetastatic osteosarcoma of the extremity; 20% with metastatic disease. • Relapses occur early (<3 years): 85% pulmonary, 15–30% bone; 10–20% of disease-free survival after relapse. EWING SARCOMA/PNET (PERIPHERAL NEUROECTODERMAL TUMOR) E PIDEMIOLOGY •Four hundred new cases/year. • Ninety-six percent of patients White. Male:Female = 1.3–1.6:1. BIOLOGY • Chromosomal translocations: t(11;22)(q24;q12); seen in 85–95% of cases. PATHOLOGY/DIAGNOSIS • Small round blue cell tumor. 1. Ewing sarcoma is a primitive tumor without differ- entiation; PNET has neural differentiation. CLINICAL PRESENTATION • Primary site: (bony or soft tissue) 53% extremities and 47% central (pelvis, chest wall, spine, and head or neck); 74% of PNETs are central, mainly chest. SIGNS AND SYMPTOMS •Pain, palpable mass, pathologic fracture; back pain, cord compression. • Constitutional: Fever, weight loss, increased erythro- cyte sedimentation rate (ESR). •Twenty percent present with metastatic disease: Lung (38%), bone (31%), and bone marrow (11%). S TAGING •Workup same as osteosarcoma and bone marrow aspi- rate and biopsy. U NFAVORABLE PROGNOSTIC FACTORS • Metastasis at presentation. • Primary site in axial skeleton. •Tumor size >10 cm. •Viable tumor postchemotherapy at time of surgery. TREATMENT • Local control with surgery or irradiation. • Chemotherapy: 1. All patients require chemotherapy. 2. The majority of treatment failures are distant. • Bone marrow transplant: May play a role in high-risk or relapsed patients. 108 SOFT TISSUE SARCOMA David O. Walterhouse and Peter E. Zage • Sarcomas are malignant tumors arising from mes- enchyme-derived cells. • Soft tissue sarcomas (STS) include rhabdomyosar- coma (RMS)/undifferentiated sarcoma and nonrhab- domyosarcomatous STS. RHABDOMYOSARCOMA/UNDIFFEREN- TIATED SARCOMA INCIDENCE AND EPIDEMIOLOGY • RMS is the most common soft tissue sarcoma, accounting for approximately 50% of soft tissue sar- comas in children <15 years old. • Sixth most common form of cancer during childhood (5–8% of all childhood cancer) with 4.6 cases per mil- lion children (less than 15 years of age) per year in the United States or 250–350 new cases diagnosed each year. • The peak age of onset is <5 years old. • May occur in Li-Fraumeni familial cancer syndrome, (p53 gene mutation). BIOLOGY AND PATHOLOGY • RMS demonstrates some degree of skeletal muscle differentiation. • Subtypes are embryonal (70%), alveolar (20%), and undifferentiated (10%). • Chromosomal translocation t(2;13) (q 35; q 14) in alveolar variant. CLINICAL PRESENTATION • Most common sites: Head and neck, genitourinary (GU), extremities. • Usually presents as a mass, ± pain ± organ obstruction ± local invasion. •Ten to twenty percent of patients present with metastatic disease (bone marrow, lung, lymph nodes, bone, or liver). WORKUP • Computed tomography (CT) or magnetic resonance imaging (MRI) of primary tumor, chest and abdomi- nal CT, chest x-ray (CXR), bone scan, bone marrow aspiration and biopsy, lumbar puncture (LP) if para- meningeal, and ± regional lymph node sampling. IMPORTANT PROGNOSTIC FACTORS DEFINE RISK GROUPS • Site of origin (favorable sites include the head and neck, some genitourinary; unfavorable sites include para- meningeal, bladder, prostate, extremities, and trunk). • Stage (defined by primary site, local invasiveness, regional lymph node involvement, and metastatic spread). • Group (defined by the extent of tumor remaining after initial surgery). • Histologic subtype (alveolar and undifferentiated his- tologies are considered unfavorable). TREATMENT AND OUTCOME • Multimodality approach (surgery, radiation therapy, and chemotherapy). • The Intergroup Rhabdomyosarcoma Study (IRS) Group was formed in 1972 and has conducted sequen- tial therapeutic trials. •Five-year survival has increased from 55% on the IRS-I protocol (1972–1978) to approximately 71% on the IRS-III (1984–1991) and IRS-IV (1991–1997) protocols. NONRHABDOMYOSARCOMATOUS SOFT TISSUE SARCOMAS INCIDENCE, EPIDEMIOLOGY, AND PATHOLOGY • Fifty percent of STS. • Subtypes: Synovial sarcoma, fibrosarcoma, malignant peripheral nerve sheath tumor, malignant fibrous his- tiocytoma, hemangiopericytoma, leiomyosarcoma, alveolar soft part sarcoma, and liposarcoma. 382 SECTION 13 • MALIGNANCIES CHAPTER 109 • HEPATIC TUMORS 383 • The peak age of onset is during late adolescence. • Infants develop a distinctive set of soft tissue sarco- mas. • Associated with the Li-Fraumeni syndrome, neurofi- bromatosis, and prior irradiation. CLINICAL PRESENTATION • Most common sites are the extremities, trunk, head, and neck. • Metastatic sites most commonly include lungs, lymph nodes, and bones. WORKUP • CT or MRI of the primary tumor, CXR, chest and abdominal CT, and bone scan. IMPORTANT PROGNOSTIC FACTORS • Resectability or group (complete resection or micro- scopic residual disease are considered favorable). •Tumor size (<5 cm has a favorable outcome) •Tumor pathologic grade; low grade (grades I or II) favorable. TREATMENT AND OUTCOME •Surgery represents the mainstay of therapy: Excision may be curative. • Radiation therapy for local control for patients with residual tumor. • The role of chemotherapy remains controversial. • Outcome remains poor for patients with unresectable or metastatic tumors. 109 HEPATIC TUMORS Howard M. Katzenstein GENERAL • 0.5–2% of all pediatric malignancies; tenth most com- mon pediatric malignancy. • Malignant liver tumors include hepatoblastoma, hepa- tocellular carcinoma, sarcoma, germ cell tumors, lym- phoma, rhabdoid tumor, and metastatic tumors. • Benign liver tumors include hemangioendothelioma, hemangioma, hamartoma, focal nodular hyperplasia, and adenoma. EPIDEMIOLOGY • Hepatoblastoma: Usually less than 3 years of age: Median 1 year. • Hepatocellular carcinoma has a wide age range at presentation (median 12 years). • Increased incidence of hepatoblastoma in premature and low birthweight infants with Beckwith-Wiedemann syndrome, familial adenomatous polyposis, and hemi- hypertrophy. • Increased incidence of hepatocellular carcinoma is seen in hepatitis B and C; anabolic steroids, tyrosine- mia, a-1 antitrypsin deficiency, type I glycogen stor- age disease, and cirrhosis. CLINICAL FEATURES •Liver tumors most commonly present as an asympto- matic abdominal mass. • Hepatoblastoma is usually unifocal. Additional symp- toms include abdominal pain, anorexia, weight loss, emesis isosexual precocious puberty in patients with tumors that secrete b-hCG (3%) and osteopenia. • Hepatocellular carcinoma often presents as a multifo- cal lesion and can occur with jaundice (25%), hemo- peritoneum, and splenomegaly. •Metastatic disease: Twenty percent of patients at diag- nosis, usually the lungs or lymph nodes. DIAGNOSTIC WORKUP • Computed tomography (CT) scan of chest, abdomen, and pelvis. • Bone scan if clinically indicated. • Alpha feto-protein (AFP) is elevated in virtually all or the majority of hepatoblastomas and 70% of hepato- cellular carcinoma. STAGING (UNITED STATES SYSTEM) • Stage I: No metastases, tumor completely resected. • Stage II: No metastases, tumor grossly resected with microscopic residual disease. • Stage III: No distant metastases, gross residual tumor or positive lymph nodes. • Stage IV: Distant metastases, regardless of the extent of liver involvement. • The PRETEXT staging system for hepatoblastoma used in Europe is based on the extent of liver involve- ment at diagnosis. PROGNOSTIC VARIABLES (ADVERSE) • Metastatic, unresectable or recurrent disease. • Slow rate of decline of AFP in response to chemother- apy. •Low AFP (normal) in hepatoblastoma (anaplastic variant). TREATMENT •Surgery is essential for cure: At diagnosis 50% of hepatoblastomas and 25% of hepatocellular carcino- mas are resectable. •Liver transplantation used for unresectable liver tumors. • Chemotherapy effective in the treatment of hepato- blastoma; unproven in hepatocellular carcinoma. • Radiation therapy used for palliation. 110 LANGERHANS CELL HISTIOCYTOSIS Elaine R. Morgan and Jacquie Toia INTRODUCTION • Spectrum of clinical behaviors ranging from lesions that will spontaneously regress to a multisystem, life- threatening disorder. • Langerhans cell histiocytosis (LCH) is distinct from both the malignant histiocytic disorders, such as malignant histiocytosis and hemophagocytic lympho- histiocytosis (HLH). •Pathogenesis is obscure. NOMENCLATURE • LCH has had many names during the past decades including the following: 1. Eosinophilic granuloma 2. Hand-Schuller-Christian disease 3. Letterer-Siwe disease 4. Hashimoto-Pritzker disease 5. Histiocytosis X (self-healing, pure cutaneous) 6. Langerhans cell or eosinophilic granulomatosis 7. Type II histiocytosis 8. Nonlipid reticuloendotheliosis EPIDEMIOLOGY • LCH is rare and sometimes undiagnosed. • Actual incidence is difficult to establish: It is esti- mated that four to five children per million under the age of 15 years will be diagnosed with LCH each year. • LCH may occur at any age; peak incidence 1–3 years. • Multisystem LCH occurs most often in the first 2 years of life. CLINICAL PRESENTATION • Symptoms include fever, weight loss, fatigue, and organ-specific symptoms. • Many systems involved; skin rash, bone lesions, and chronic otitis are common. WORKUP • Biopsy with immunohistochemistry, electron micros- copy. •Skeletal survey; radiographs of involved areas. • Complete blood count (CBC), liver chemistries. TREATMENT • Approaches to treatment of LCH vary widely. • Localized disease may resolve, be surgically excised or respond to local therapy. • Multisystem disease requires systemic chemotherapy. PROGNOSIS • Disease confined to bone or lymph nodes are associ- ated with a good prognosis. • Multisystem disease is associated with a poor progno- sis. •Very young infants with extensive disease involving multiple organs statistically have the worst outcomes. • Recurrence is common and may occur early or late. • Late effects are more common in patients with multi- system disease, in those that receive long treatment courses and in children diagnosed at an early age. 384 SECTION 13 • MALIGNANCIES CHAPTER 111 • LATE EFFECTS 385 111 LATE EFFECTS Elaine R. Morgan RISK FACTORS FOR LATE EFFECTS GENETICS, TREATMENT, AGE OF TREATMENT •Young age may increase organ damage, especially central nervous system (CNS). •Familial cancer syndromes, genetic predisposition increase second malignant neoplasm (SMN) risk. • Higher intensity treatment, combination therapy (C, I). • Increased incidence over time from diagnosis. • Infertility risk may be higher in children treated after puberty. • Late effects are drug and modality specific. SYSTEM-SPECIFIC EFFECTS HEENT Cataracts, dry eyes, small orbits (I) Hearing loss (I, P) Dry mouth, dental loss, and caries (I) Facial asymmetry (I) Cardiopulmonary Cardiomyopathy (I, A, AA), restrictive pericarditis (I) Pulmonary fibrosis (C, I, AA), radiation pneumonitis (I) GI Hepatitis—medication–induced infections (AM, E) Hepatic fibrosis/cirrhosis (C) Malabsorption, radiation enteritis (I) GU Bladder fibrosis, incontinence (I) Hemorrhagic cystitis (AA, I) RENAL Renal insufficiency (M, IF, I, P) Renal Fanconi syndrome, tubular dysfunction (IF, P) MUSCULOSKELETAL Scoliosis, kyphosis, musculoskeletal asymmetry (I) Limb loss (S, I) Osteomyelitis, osteonecrosis, fracture (I) Avascular necrosis (S, M) Osteoporosis (S, M, I) Breast hypoplasia (I) METABOLIC Diabetes mellitus (C, after BMT) Hyperlipidemia (C, I) Obesity (C, I) NEUROLOGIC/NEUROPSYCHIATRIC Paralysis/paresis secondary to cord compression (D) Peripheral neuropathy, autonomic dysfunction (C) Leukoencephalopathy (M, I) Learning disability (M, I) ENDOCRINE Hypo/hyperthyroidism (I) Growth hormone failure (I) Precocious puberty (I, C) Premature menopause (I, AA) Reproductive Hormone deficiency (AA, I) Amenorrhea (AA, I) Infertility (C, I) SECONDARY NEOPLASIA Leukemia, myelodysplasia occur 2–4 years after treatment (AA, T, I) Sarcomas occur late (I) Lymphomas—secondary to immunosuppression (C, I, D) Benign tumors secondary to XRT (I) Carcinoma—breast most common; also colon, lung (I) PSYCHOSOCIAL Cognitive delays Insurance, employment, military discrimination Adjustment disorders A BBREVIATIONS:P = platinum; I = irradiation; C = chemotherapy; A = anthracycline; T = topoisomerose inhibitors; AA = alkylating agents; AM = antimetabolite; IF = ifosfamide; S = steroids; M = methotrexate; S = surgery; D = disease related; BMT = bone marrow transplant; XRT = radiotherapy. FOLLOW-UP CARE • Requires multidisciplinary approach including med- ical specialties, reproductive evaluation, psychosocial, educational, surgical specialties, PT, OT. • Multidisciplinary follow-up clinics, including adult practitioners are effective. •Patients require annual medical evaluation into adult- hood. • Preventive medicine is essential. • Screening tests are disease and treatment specific and may include the following: 1. Mammograms 2. Echocardiograms 3. Organ system evaluation 4. Metabolic evaluation 5. Bone mineral density • Other cancer screening. BIBLIOGRAPHY Altman AS, Schwartz AD. Malignant Diseases of Infancy, Childhood and Adolescence. Renal Tumors. Philadelphia, PA: W.B. Saunders, 1983, Chap. 16. [...]... bacteria to the blood The polysaccharide capsule (a virulence factor of the bacteria) is important for its survival in the bloodstream The capsule allows the bacteria to evade the complement and phagocytic activity of the polymorpholeukocytes (PMNs) and allows the bacteria to replicate • The bacteria most commonly gain access to the meninges by crossing the blood-CSF barrier of the choroid plexus Once they... abscess The abscess is usually located in the right paracolic gutter; however, there can be spread to the left paracolic gutter, the pelvis, or the subphrenic space E coli is the most common aerobic organism isolated, and Bacteroides species are the most common anaerobic organisms • Liver abscesses in the United States are typically of a bacterial etiology; however, in many parts of the world, the most... within hours to days The forehead and cheeks are flushed, and the area around the mouth is pale (circumoral pallor) The rash has a sandpaper texture and generally fades on pressure and ultimately desquamates Deep red, nonblanching, or petechial lesions may be present in the folds of the joints (Pastia’s lines) or other parts of the extremities • Early in the illness, the dorsum of the tongue may have... and the development of pain, fever, overlying warmth, and redness of the joint Swelling of the joint space results in increased pressure which can compromise the blood supply of the head of the femur or the humerus if the hip or shoulder joints are involved • Infection of the joint may result in necrosis of the articular cartilage and thickening and scarring of the synovium ETIOLOGIC AGENTS • There... early and partially-treated meningitis (2) Rapid CSF antigen tests (e.g., enzyme-linked immunosorbent assays [ELISA], latex agglutination) are more sensitive than the Gram’s stain (88% to 100%) These tests are especially helpful in partially-treated cases where the low number of bacteria will cause both the Gram’s stain and the culture to be negative Bacterial antigens should also be tested in the urine,... antibiotic(s) should be given Otherwise, the initial empiric therapy should be decided by the age of the patient and the known local susceptibilities of the pathogens In neonates, the combination of cefotaxime with ampicillin or ampicillin with gentamicin (or other aminoglycoside) are the drugs of choice In children older than 6 weeks, ceftriaxone (or cefotaxine) with vancomycin is the preferred combination... and the bacteria becomes encased within the vegetation • In congenital heart disease, endothelial damage can occur as a result of abnormal high-velocity blood flow Thus, left-sided (high pressure) lesions are more commonly seen The most common congenital lesions in IE are tetralogy of Fallot and ventricular septal defects • In the presence of venous catheters, the catheter itself causes trauma to the. .. species and Aspergillus most frequently occurs in the immunocompromised host or in the premature infant who have a central venous catheter or are receiving prolonged antimicrobial therapy CLINICAL SIGNS AND SYMPTOMS • In children, the clinical findings of osteomyelitis differ with the age of the patient, the duration of the process, and the location of the infection • In newborns and infants, classic... fontanelle, separation of the sutures) are found TREATMENT • There is no direct relationship between prompt administration of antibiotics and the outcome Therefore, therapy can be delayed for a short period of time (to rule out ICP, await results of the LP to document bacterial etiology or to better tailor the antibiotic therapy) • If the Gram’s stain or rapid antigen tests identify the etiologic agent,... year of age, the disease is usually monoarticular and involves the large joints The clinical findings may be subtle and include swelling, tenderness, and erythema of the skin overlying the joint Guarding, limitation of movement of the affected extremity, limp, or pain on passive manipulation may also be found In the neonate and young infant, pseudoparalysis of the affected limb may be the only clinical . present in the folds of the joints (Pastia’s lines) or other parts of the extremities. • Early in the illness, the dorsum of the tongue may have a white coating, through which the papillae pro- trude. trials. •Five-year survival has increased from 55% on the IRS-I protocol (1 972 –1 978 ) to approximately 71 % on the IRS-III (1984–1991) and IRS-IV (1991–19 97) protocols. NONRHABDOMYOSARCOMATOUS SOFT TISSUE. necessary. SINUSITIS CONJUNCTIVITIS EPIDEMIOLOGY • The conjunctiva of the eye is a mucous membrane covering the front part of the eye lining the inner sur- face of the eyelid. It is divided into the bulbar and palpebral portions.