Oncology: Epidemiology, Etiology, Diagnosis, Therapy & Long-Term Sequelae

Incidence & prevalence · Causation & survival · Inherited predisposition & genetic susceptibility · Environmental factors · Diagnostic principles (pathology, radiology, biochemical markers, cytogenetics, bone marrow) · Principles of therapy · Tumor resistance · Surgery & irradiation · Monitoring response · Specific treatment effects · Long-term sequelae
🧬 Key concepts: Annual incidence ~160/million children; 5-year survival >80% in resource-rich countries. Inherited syndromes (Li-Fraumeni, RB1, APC, NF1, WT1). Environmental factors (radiation, chemotherapy). Diagnostic workup: histology, cytogenetics, molecular markers. Treatment: multimodal (chemo, surgery, radiotherapy). Late effects: cardiotoxicity, secondary malignancies, endocrine, neurocognitive.

📖 Epidemiology, etiology, therapy & late effects

📊 Incidence & survival
~1 in 500 children develops cancer before 15y. 5-year survival now >80% in high-income countries (ALL ~90%, Wilms ~90%, Hodgkin >95%). Improvements due to risk-adapted therapy and supportive care.
🧬 Inherited predisposition & genetics
Li-Fraumeni (TP53), RB1 (retinoblastoma), APC (FAP), NF1, WT1 (Wilms), DICER1. Susceptibility genes: CHEK2, PALB2, BRCA2. Somatic mutations drive tumorigenesis.
🌍 Environmental factors
Ionising radiation (secondary cancers), chemotherapy (alkylators → leukemia), in utero radiation, Epstein-Barr virus (lymphoma), HIV (Kaposi), pesticides (limited evidence).
🔬 Diagnosis & markers
Pathology (gold standard), radiology (CT/MRI/US), biochemical markers (AFP, β-hCG, catecholamines, LDH), cytogenetics (translocations, ploidy), bone marrow aspirate (leukemia/lymphoma).
💊 Therapy & resistance
Multimodal: surgery, chemotherapy, radiotherapy, immunotherapy, HSCT. Drug resistance mechanisms: MDR1 (P-gp), altered drug targets (topoisomerase), DNA repair. Monitoring response: imaging (RECIST), MRD (flow/PCR).
⚠️ Late effects (survivorship)
Cardiomyopathy (anthracyclines), secondary malignancies (etoposide/alkylators, radiation), endocrine (GH deficiency, hypothyroidism, infertility), neurocognitive (cranial RT), psychosocial, dental, pulmonary.
⚠️ Red flags for inherited cancer predisposition: Early age at diagnosis, bilateral/multiple primary tumors, family history of cancer (especially young age), unusual tumors (e.g., adrenocortical carcinoma, choroid plexus carcinoma), multiple affected family members.

🩺 Diagnostic principles & inherited predisposition workup

1
Tissue diagnosis (biopsy) – Gold standard. Histology, immunohistochemistry (e.g., MYCN, CD99, synaptophysin).
2
Radiologic staging – Ultrasound (abdominal), CT (chest, abdomen, pelvis), MRI (brain, bone, soft tissue), MIBG (neuroblastoma), PET/CT (lymphoma).
3
Biochemical markers – AFP (hepatoblastoma, yolk sac), β-hCG (germ cell), HVA/VMA (neuroblastoma), LDH (lymphoma, leukemia).
4
Cytogenetics & molecular – Karyotype, FISH, microarray, PCR. Risk stratification based on ploidy, translocations (t(11;22), t(12;21), BCR-ABL), MYCN status.
5
Bone marrow examination – Aspirate and biopsy for staging (neuroblastoma, lymphoma, leukemia). MRD monitoring.
6
Inherited cancer predisposition evaluation – Detailed family history (three-generation pedigree). Genetic counseling and testing (TP53, RB1, APC, WT1, NF1, DICER1). Surveillance protocols (e.g., Li-Fraumeni syndrome).
📌 Clinical pearl: Elevated AFP in a child with a liver tumor suggests hepatoblastoma (neonates/ infants) or yolk sac tumor. Normal AFP does not exclude malignancy.

📋 Principles of therapy, resistance, monitoring & late effects

1
Multimodal therapy – Chemotherapy (induction, consolidation, maintenance), surgery (complete resection when possible), radiotherapy (cranial, spinal, local), immunotherapy (anti-GD2, CAR-T).
2
Tumor cell resistance mechanisms – Multidrug resistance (MDR1/P-gp), altered drug targets (topoisomerase mutations), increased DNA repair, drug inactivation (GST), altered apoptosis (BCL2).
3
Surgery & irradiation considerations – Gross total resection improves survival (neuroblastoma, Wilms). Radiation to critical structures (brain, heart, breast) limited due to late effects. Proton therapy reduces scatter.
4
Monitoring tumor response – Imaging (RECIST criteria: CR, PR, SD, PD). MRD (flow cytometry/PCR). Tumor markers (AFP, β-hCG, catecholamines).
5
Specific treatment effects (acute) – Myelosuppression, mucositis, nausea, alopecia, tumor lysis, cardiotoxicity (anthracyclines), neuropathy (vincristine), hemorrhagic cystitis (cyclophosphamide/ifosfamide).
6
Long-term sequelae (survivorship care plan) – Cardiac (echo every 2-5y), endocrine (growth, thyroid, fertility), secondary malignancies (breast cancer surveillance after chest RT), neurocognitive (educational support), psychosocial, pulmonary (bleomycin), renal (ifosfamide, platinum).
🚨 Common acute toxicities requiring urgent intervention: Febrile neutropenia (antibiotics), tumor lysis syndrome (rasburicase), hypersensitivity reactions (asparaginase), vincristine ileus/neuropathy (support care).

🧠 Reflex prompts: epidemiology, genetics, resistance, late effects

📊 What is the approximate 5-year overall survival for childhood cancer in high-income countries?
>80% (exceeds 90% for ALL, Wilms, Hodgkin lymphoma).
🧬 Name three inherited cancer predisposition syndromes and associated genes.
Li-Fraumeni (TP53), Familial retinoblastoma (RB1), Familial adenomatous polyposis (APC), Neurofibromatosis type 1 (NF1), Beckwith-Wiedemann (11p15), DICER1.
🧪 Which biochemical marker is elevated in hepatoblastoma and yolk sac tumors?
Alpha-fetoprotein (AFP).
🔬 What is the most common mechanism of multidrug resistance in cancer cells?
P-glycoprotein (MDR1/ABCB1) efflux pump overexpression.
💊 Which chemotherapeutic agent causes dose-dependent cardiomyopathy?
Anthracyclines (doxorubicin, daunorubicin, epirubicin). Risk increases with cumulative dose.
🩺 What is the standard tool to monitor minimal residual disease (MRD) in childhood ALL?
Multiparametric flow cytometry or real-time PCR for clonal rearrangements (Ig, TCR).
🌍 What environmental factor is most clearly linked to childhood leukemia?
Ionising radiation (pre-natal/post-natal). High-dose radiation increases risk. No consistent link with EMF/pesticides.
🧬 Which translocation is associated with Ewing sarcoma?
t(11;22)(q24;q12) EWSR1-FLI1.
💥 What is the most common long-term cardiac complication after anthracycline therapy?
Dilated cardiomyopathy (systolic dysfunction); risk lifelong.
🩺 What is the recommended surveillance for female survivors after chest radiation for Hodgkin lymphoma?
Annual breast MRI starting at age 25 (or 8 years after RT) and mammography.