Pediatric Oncology

Non-modifiable — germline predisposition (~10% of cases)

• RB1 (retinoblastoma): two-hit loss of a tumor suppressor; germline carriers develop bilateral/multifocal disease at younger age and carry lifelong risk of osteosarcoma and trilateral retinoblastoma (pineoblastoma)
• TP53 (Li-Fraumeni): loss of the guardian of the genome → adrenocortical carcinoma, rhabdomyosarcoma, osteosarcoma, choroid plexus carcinoma
• 11p15 imprinting defects (Beckwith-Wiedemann) and WT1 (WAGR, Denys-Drash): overgrowth/dysregulated nephrogenesis with persistent nephrogenic rests → Wilms tumor; hepatoblastoma also increased. A consensus surveillance approach endorsed by the AAP and the American Association for Cancer Research uses serial abdominal ultrasound (plus AFP for hepatoblastoma risk) in early childhood
• Trisomy 21: markedly increased risk of both ALL and acute megakaryoblastic leukemia, often preceded by transient abnormal myelopoiesis with GATA1 mutation
• RASopathies and phakomatoses: NF1 (optic pathway glioma, juvenile myelomonocytic leukemia), tuberous sclerosis (subependymal giant cell astrocytoma), Gorlin syndrome (PTCH1 → SHH medulloblastoma), APC/*Turcot* (medulloblastoma)
• Genomic instability/DNA-repair syndromes: Fanconi anemia, ataxia-telangiectasia, Bloom syndrome, constitutional mismatch repair deficiency → leukemia, lymphoma, brain tumors
• Familial neuroblastoma: germline ALK or PHOX2B mutations (rare); somatic MYCN amplification drives aggressive sporadic disease

Acquired / potentially modifiable

• Prior cytotoxic therapy: alkylating agents cause therapy-related MDS/AML with chromosome 5q/7q loss after several years; topoisomerase II inhibitors (etoposide, anthracyclines) cause *KMT2A (11q23)*-rearranged AML with a shorter latency and no myelodysplastic prodrome
• Ionizing radiation: therapeutic and diagnostic radiation exposure raises risk of thyroid cancer, CNS tumors, and sarcomas within the radiation field — the rationale for ALARA imaging practices
• Immunosuppression and oncogenic viruses: EBV in the setting of HIV or post-transplant immunosuppression → post-transplant lymphoproliferative disorder and Burkitt lymphoma
• Distractor to resist: routine population screening for childhood cancer is not recommended by the USPSTF; surveillance is syndrome-directed only

• Embryonal origin: Pediatric tumors arise from primitive germinal tissues and developing organs, explaining why most are sarcomas (rhabdomyosarcoma, Ewing sarcoma) or neural tumors (neuroblastoma, medulloblastoma) rather than carcinomas
• Genetic predisposition vs. sporadic: Most pediatric cancers are sporadic, but germline mutations (TP53, RB1, BRCA1/2, DNA mismatch repair genes) increase risk; familial cancer syndromes account for ~10% of cases
• Chromosomal translocations: Hallmark molecular features include t(9;22) in CML (BCR-ABL), t(12;21) in ALL (ETV6-RUNX1, favorable prognosis), t(8;14) in Burkitt lymphoma (MYC deregulation), and t(11;22) in Ewing sarcoma (EWS-FLI1)
• Clonal evolution: Cancer develops through sequential acquisition of oncogenic mutations and loss of tumor suppressors; children have shorter latency periods for biologically aggressive tumors
• Microenvironment factors: Unlike adults, the pediatric tumor microenvironment has less established vasculature and different immune cell composition, affecting therapeutic response and metastatic potential

• Systemic B symptoms: Fever, night sweats, and weight loss are classic for lymphomas and leukemias; their presence indicates advanced disease and guides staging
• Masses and swelling: Painless lymphadenopathy (>1 cm in supraclavicular/posterior cervical regions is concerning), abdominal masses (neuroblastoma, Wilms tumor), or bone swelling (osteosarcoma, Ewing sarcoma) are common presenting complaints
• Cytopenias and bleeding: Pallor, fatigue, petechiae, and easy bruising indicate bone marrow involvement; these are the most common initial signs of leukemia
• Neurological symptoms: Headaches, vomiting, ataxia, and vision changes suggest CNS involvement (medulloblastoma, brainstem gliomas); these often present acutely and are emergencies
• Pain syndromes: Bone pain (especially at night in osteosarcoma/Ewing sarcoma) or abdominal pain should raise suspicion in children with constitutional symptoms
• Organ-specific symptoms: Hematuria (Wilms tumor), proptosis/periorbital ecchymosis (retinoblastoma), or respiratory symptoms (mediastinal masses in lymphoma/T-cell ALL)
• Clinical pearl: Never attribute lymphadenopathy or hepatosplenomegaly in a child to simple viral infection lasting >2 weeks without appropriate imaging

• Complete blood count (CBC) with differential: Essential first test; reveals cytopenias (blasts in leukemia), absolute lymphocytosis (ALL), or mature cell involvement (CML, lymphomas affecting blood)
• Bone marrow aspiration and biopsy: Gold standard for leukemias; provides morphology, immunophenotyping (flow cytometry), cytochemistry, cytogenetics, and molecular studies (critical for prognostication and treatment decisions)
• Imaging modality selection: Chest X-ray (mediastinal masses, pleural effusion), CT (staging, surgical planning), MRI (CNS penetration, spinal involvement), PET-CT (lymphomas, metastatic disease assessment)
• Histopathology and immunohistochemistry: Essential for solid tumors; immunophenotyping and light microscopy define entity (e.g., small round blue cell tumors differentiated by CD99+/EWS-FLI1+ Ewing vs. desmin+/myogenin+ rhabdomyosarcoma)
• Lumbar puncture (LP) with CNS prophylaxis assessment: Indicated in ALL, lymphomas, and medulloblastoma to detect leptomeningeal disease; CNS-positive disease requires intensified therapy
• Tumor markers: Alpha-fetoprotein (AFP) in germ cell tumors and hepatoblastoma, beta-hCG in choriocarcinoma, catecholamine metabolites (VMA, HVA) in neuroblastoma, lactate dehydrogenase (LDH) elevation in lymphomas
• Molecular/cytogenetic studies: Chromosomal translocations and gene expression profiles are critical for prognosis and treatment stratification (e.g., ETV6-RUNX1 in ALL = better prognosis; MYC rearrangements = worse prognosis)
• Diagnostic pearl: Never delay treatment while pursuing unnecessary testing; empiric therapy is justified if clinical suspicion is high while waiting for confirmatory studies

• Multimodal approach (chemotherapy, surgery, radiation): Most pediatric cancers require combination therapy tailored to histology and risk stratification; chemotherapy is the backbone for most malignancies
• Acute lymphoblastic leukemia (ALL) - first-line: Induction phase (vincristine, daunorubicin, asparaginase, prednisone/dexamethasone) followed by consolidation, intensification, and maintenance phases over 2-3 years; CNS prophylaxis (intrathecal methotrexate) is mandatory; risk stratification determines intensity
• Acute myeloid leukemia (AML) - first-line: Intensive chemotherapy (cytarabine + daunorubicin or other anthracyclines); allogeneic stem cell transplant (ASCT) in first remission for high-risk disease; generally more aggressive chemotherapy than ALL
• Lymphomas: Hodgkin lymphoma treated with ABVD or similar regimens with radiation for localized disease; non-Hodgkin lymphoma (NHL) including Burkitt lymphoma requires intensive multiagent chemotherapy (e.g., HyperCVAD, LMB protocols); CNS prophylaxis in high-grade NHL
• Solid tumors: Osteosarcoma (neoadjuvant + postoperative chemotherapy ± surgical resection); Ewing sarcoma (intensive multiagent chemotherapy ± surgery ± radiation); rhabdomyosarcoma (chemotherapy, surgery, ± radiation based on stage/grade); neuroblastoma (surgery, chemotherapy, immunotherapy, radiation, and stem cell transplant for high-risk disease)
• Retinoblastoma: Intraocular disease managed with chemotherapy ± enucleation; metastatic disease requires systemic therapy; globe-salvaging chemotherapy protocols (intra-arterial carboplatin, intravitreal chemotherapy) increasingly used
• Wilms tumor (nephroblastoma): Preoperative chemotherapy followed by surgical nephrectomy and postoperative chemotherapy ± radiation; low-risk (stage I, favorable histology) requires minimal therapy
• Targeted therapy and immunotherapy: Tyrosine kinase inhibitors (imatinib for BCR-ABL+ CML, dasatinib alternatives); monoclonal antibodies (rituximab for B-cell lymphomas); CAR-T cell therapy for relapsed/refractory ALL (tisagenlecleucel FDA-approved); check point inhibitors emerging for select pediatric malignancies
• Stem cell transplantation: ASCT or allogeneic HSCT indicated for high-risk disease, relapsed disease, or as part of multimodal therapy (neuroblastoma, high-risk AML, lymphomas)
• Supportive care: Aggressive supportive care including hematopoietic growth factors, infection prophylaxis (PCP prophylaxis with TMP-SMX for ALL patients in remission), transfusions, and nutritional support is essential for treatment tolerance
• Special populations: Infants <1 year have worse prognosis for most malignancies and often require modified, less intensive chemotherapy; adolescents may be treated on adult vs. pediatric protocols (enrollment in pediat

Oncologic emergencies (act before confirmatory testing)

• Tumor lysis syndrome: massive cell turnover in Burkitt lymphoma, T-ALL, or hyperleukocytosis releases potassium, phosphate, and nucleic acids → hyperkalemia, hyperphosphatemia with secondary hypocalcemia, hyperuricemia, and AKI. Signals: rising creatinine, peaked T waves, tetany. Aggressive IV hydration plus urate-lowering therapy (allopurinol for prophylaxis; rasburicase when uric acid is high or risk is high) — rasburicase is contraindicated in G6PD deficiency (hemolysis, methemoglobinemia)
• Febrile neutropenia: mucosal barrier injury plus neutropenia permits gram-negative bacteremia. IDSA guidance is blood cultures then empiric antipseudomonal beta-lactam monotherapy (cefepime or piperacillin-tazobactam) without waiting for the ANC
• Anterior mediastinal mass / SVC syndrome: T-cell ALL or lymphoblastic lymphoma compresses trachea and great vessels; facial plethora, orthopnea, and stridor. Supine positioning and general anesthesia can precipitate cardiorespiratory collapse — obtain tissue by the least invasive route awake
• Obstructive hydrocephalus: posterior fossa tumors (medulloblastoma) block the fourth ventricle → morning headache, vomiting, papilledema. Neuroimaging precedes lumbar puncture
• Spinal cord compression and hyperleukocytosis with leukostasis are likewise time-critical

Disease-specific

• Wilms tumor: hypertension from renin, acquired von Willebrand disease, tumor thrombus extending into the IVC; percutaneous biopsy risks upstaging
• Neuroblastoma: opsoclonus-myoclonus paraneoplastic syndrome, VIP-mediated secretory diarrhea, Horner syndrome, cord compression from dumbbell tumor

Treatment toxicity (drives COG Long-Term Follow-Up surveillance)

• Anthracyclines: cumulative dose-dependent cardiomyopathy — serial echocardiography; dexrazoxane is cardioprotective
• Cisplatin: ototoxicity and tubular magnesium wasting; vincristine: neuropathy, ileus, SIADH; cyclophosphamide/ifosfamide: hemorrhagic cystitis (mesna), Fanconi syndrome, encephalopathy
• Asparaginase: pancreatitis and thrombosis from depleted antithrombin; methotrexate: mucositis, nephrotoxicity, leukoencephalopathy (leucovorin rescue)
• Late effects: secondary malignancy, infertility, growth hormone deficiency and neurocognitive decline after cranial radiation, avascular necrosis from corticosteroids

• Leukocoria = retinoblastoma until proven otherwise: absent red reflex or cat's eye pupil, ± strabismus. Best next step is urgent dilated ophthalmologic exam under anesthesia, not biopsy — needle biopsy risks orbital seeding. Bilateral disease implies a germline RB1 mutation and lifelong osteosarcoma risk; the classic association tested is trilateral retinoblastoma (pineoblastoma)
• Crosses the midline, calcified, and the child looks sick = neuroblastoma; smooth, unilateral, and the child looks well = Wilms tumor. Neuroblastoma gives elevated urinary HVA/VMA, raccoon eyes from orbital metastases, blueberry muffin skin nodules, and dancing eyes–dancing feet. Wilms presents with painless hematuria and hypertension; the distractor is ordering a percutaneous biopsy, which upstages the tumor — go to nephrectomy or preoperative chemotherapy per Children's Oncology Group protocols
• MYCN amplification is the single prognostic marker examiners test in neuroblastoma; infants with stage MS/4S disease and liver/skin/marrow involvement may regress spontaneously despite metastases
• ALL is the most common childhood malignancy, peaking around ages 2–5, with bone pain, fever, and cytopenias; blasts are TdT+ and CD10+. t(12;21) ETV6-RUNX1 is favorable; hypodiploidy and KMT2A rearrangement are unfavorable. The distractor is diagnosing juvenile idiopathic arthritis in a child with bone pain plus cytopenias — check a CBC with differential and smear
• Posterior fossa tumor with truncal ataxia and morning vomiting = medulloblastoma; it seeds CSF as drop metastases, so stage with MRI of the entire neuraxis and CSF cytology. Do not perform lumbar puncture before imaging when ICP is elevated
• Fever plus neutropenia in a child on chemotherapy is an emergency: cultures, then broad empiric antipseudomonal coverage promptly, per IDSA — never wait for a source or for counts to recover
• High tumor burden Burkitt/T-ALL before therapy: anticipate tumor lysis; hydrate and give rasburicase in high-risk patients, checking G6PD status first