NEUROBLASTOMA.pptx

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A quick review

1. NEUROBLASTOMA Eretare C Odjugo

2. OUTLINE Introduction Developmental anatomy Epidemiology Aetiology /Genetics Pathology Clinical presentation Diagnosis Biochemistry Radiology Histology Staging

3. OUTLINE Grading Screening Treatment Prognosis Current and future trends Loco-regional issues Follow-up Conclusion

4. Introduction Neuroblastomas are the second most common solid tumors of childhood after brain tumors It’s also the most diagnosed tumor in infancy Over 90% of cases are diagnosed by 5 years It’s has varied clinical features and at diagnosis is believed to have metastasized in over 70% of cases Mean age at diagnosis is ~18months Despite advances in diagnosis and treatment, outcomes for aggressive disease remains poor

5. Developmental anatomy Arise as derivative of neural crest cells These migrate to final organs and tissues The tumor can arise at any site where these cells are found Adrenal medulla 50% Paraspinal ganglia and retroperitoneal 25% Posterior mediastinum 20% Pelvic ganglia <5% Cervical <5% Metastasis – Liver, bone and bone marrow, lymph node, skin

6. Loco-regional epidemiology In a 6-month period 15 December 2021 to 14 June 2022 (UBTH) Paediatric oncology admissions – 48 Neuroblastoma – 3 (6.25%) Ibadan 13 year study of childhood tumors Lymphoma 59% Neuroblastomas – 2.6% Kano Retinoblastoma – 30.6% Burkitts lymphoma – 19.9% Neuroblastoma – 2.7%

7. epidemiology Found in 1 in 7500 to 10,000 live births 10% of all childhood tumors with 15% of deaths are attributable to it 1.2:1 Male to female ratio Racial predeliction in Caucasians and Asians. Not as common in Africans and people of African descent

8. Aetiology /genetics The exact aetiology is unknown in most cases i.e they are spontaneous Familial cases account for 1 – 2% and are usually associated with younger age at diagnosis (median age 9 months) as well as PHOX2B and ALK gene mutations BARD2 gene is said to also be a risk factor No single environmental factor has been linked to the disease MYCN (n-MYC) gene amplification is seen in 20% of tumors and is indicative of advanced disease and confers a worse prognosis Ploidy: Hyperdiploidy when found in children less than 1 year confers a good prognosis Loss of heterozygosity at 1p, 11q, and 14q as well as a 17q gain confer a worse prognosis However, complete gain of chromosome 17 gives a better outcome

9. Aetiology /genetics Neuroblastoma has been observedin infants with Beckwith-Wiedemann syndrome, Neurofibromatosis (von Recklinghausen disease), Hirschsprung disease, C entral hypoventilation syndrome ( Ondine’s curse), F etal alcohol syndrome, and I n offspring of mothers taking phenytoin (fetal hydantoin syndrome) for seizure disorders. In twins, concordance in younger aged twins and divergence in older twins indicates a familial or spontaneous mutation respectively

10. pathology Classic subtypes Neuroblastoma Ganglion neuroblastoma Ganglion neuroma Neuroblastoma Small round blue uniform cells with hyperchromatic nuclei and scanty cytoplasm Homer-Wright pseudorosette Necrosis Calcification

11. Clinical presentation Very heterogenous clinical presentation and course Spontaneous regression Aggressive tumors Presentation may be as Mass effect of the tumors at site(s) Metabolic abnormalities Evidence of metastatic disease Constitutional symptoms Anorexia Weight loss Malaise Fever

12. Clinical presentation Abdominal swelling and pain Failure to thrive Respiratory distress Displacement of the diaphragm by a large intra-abdominal tumor or liver Thoracic inlet partially occluded (cough, breathlessness) Horner’s syndrome Neurologic deficits Urinary retention Severe diarrhoea Bone or joint pain Protopsis and peri-orbital ecchymoses Opsoclonus-Myoclonus syndrome Multi-vectorial eye movements Twitching of muscle groups Ataxia Hypokalemia Cytopenias Blueberry muffin sign Paroxysmal hypertension Tumor lysis syndrome

13. diagnosis Laboratory evaluation Full blood count Renal function test Liver function test Urinalysis Urine assay for catecholamines [ Homovanillic acid (HVA) and Vanillylmandellic acid (VMA)] Tumor markers Neuron specific enolase Chromogranin A Ferritin

14. radiology Ultrasound First line investigation Plain radiographs Can show calcified tumors in abdomen and posterior mediastinum CT scan MRI Radionuclide scan Bone scan

15. CT scans Can delineate tumors properly and are useful when assessing image derived risk factors Calcification easily noted Helps in distinguishing neuro- from nephroblastoma Nodal status may be assessed

16. MRI Excellent for visualizing intra-spinal extensions of the tumors Also good for delineating vascular arrangements Absence of radiation is a benefit

17. MIBG scan Based on the selective uptake of meta- iodobenzylguanidine by the neuroblastoma Also a great too for monitoring response to treatment Iodine-123 is used for investigative purposes

18. Bone scan Uses Technetium 99 Useful only in MIBG positive cases Helps detect cortical bone involvement

19. biopsy Tissue diagnosis is essential Needle biopsy Bone marrow biopsy or aspiration Needle biopsies are image guided with several cores collected from different areas of the tumor Immunohistiochemistry and cytogenetics are an important part of diagnosis, treatment planning and prognostication MYCN amplification (~30%) DNA ploidy 11q deletions and other variants

20. Bone marrow aspiration and biopsy

21. staging

22. staging

23. grading

24. Grading

25. grading

26. screening This is done in several developed countries like Japan Urine assays for Vanillylmandellic acid (VMA) and Homovanillic acid (HVA) are the commonest screening tools Its role is controversial Supporters say the good prognosis for those diagnosed early and the high rate of metastasis at the time of diagnosis Opponents: No survival benefits with screening as found in a large randomized trial. Screen detected disease are usually those with a favourable outcome while screening negative cases that subsequently develop the disease have an unfavourable histology Screening was halted in 2004 after studies in Canada and Germany showed no reduction in deaths due to neuroblastoma, but rather caused an increase in diagnoses that would have disappeared without treatment, subjecting those infants to unnecessary surgery and chemotherapy.

27. treatment Multi-modal Surgery Chemotherapy including immunotherapy Radiotherapy Multidisciplinary and includes but not limited to Surgeon Paediatric oncologist Nurses Radiologic oncologist/radiotherapist Psychologists Neurologist

28. surgery Aims at Establishing a diagnosis Staging the tumor Excision (if localized and resectable ) Provision of tissue for further evaluation Excision is the mainstay of INSS 1, 2 and 4S patients Lymph node sampling is done at surgery Care to be taken to avoid undue morbidity Radical excision is avoided Sacrifice of major organs like kidneys and spleen should be avoided especially in children < 1 year old Approach varies based on location of tumor A liver biopsy is done for 4S cases

29. chemotherapy Neoadjuvant or adjuvant Multi-agent therapy May be low, moderate or high intensity chemotherapydependent on the stage and the risk stratification Indications Respiratory distress Spinal cord compression Progressive disease Recurrence Common agents used Cisplatin Carboplatin Etoposide Cyclophosphamide Vincristine Doxorubicin Others are Thiotepa Mephalan Topotecan busulphan

30. chemotherapy

31. radiotherapy Neuroblastomas are radio-sensitive Radiation exposure and dosage may be kept to a minimum due to good long-term survival Very useful in down-staging a large rapidly enlarging tumor with mass effect Also a part of palliative care in symptomatic patients with end-stage disease May be used pre-op, intra-op or post-op Dosage administered depends on the risk stratification Typically delivered as external beam radiation Usually avoided in spinal cord lesions due to effect on growth of the spine

32. Low risk (50%) Observation Asymptomatic 4S disease Small adrenal masses in newborns Surgery Primary mode of treatment Sufficient for most cases 5 year Survival >95% Radiotherapy Usually not indicated Chemotherapy Short cause usually for symptomatic cord compression May be given prior to surgery to debulk prior to resection Adjuvant chemo may be given in cases of MYCN amplification

33. Intermediate risk (10 – 15%) Surgery Primary resection where possible Chemotherapy Multi-agent moderately intensive chemotherapy. 4 cycles for favourable histology, 8 for unfavourable . Neoadjuvant chemo for unresectable tumor or tumors with intraspinal extension Radiotherapy Given when there’s disease progression despite surgery and chemotherapy

34. High risk Induction Intensive chemotherapy (8 months) Shrinks primary tumor and helps with metastasis Local control Attained by surgery and radiotherapy Surgery is planned for 13 – 18 weeks post induction Radiation of the tumor bed helps prevent recurrence Consolidation High dose chemotherapeutic agents plus melphalan or busalfan ( myelo -ablative therapy) Autologous haematopoietic stem cell rescue + GM CSF therapy Maintenance Aims to manage minimal residual disease 13 cis-Retinoic acid given every 14 days for 6 months Anti-GD2 antibody and IL-2 give better outcomes than retinoic acid alone

35. outcomes Survival probability of 2196 patients with neuroblastoma treated using the COG and POG guidelines

36. Current/future trends PET scans are been evaluated for use vs CT and MIBG scans Pros Indicates activity Excellent at identifying tissues of interest Great contrasts Cons Expensive High radiation dose Not readily available Resolution and details still poor

37. Current/future trends High doses of 131-iodinated MIBG is being trialled in the treatment of neuroblastoma due to its preferential uptake. Good responses Challenges with side effects and toxicity Targeted anti-ALK therapy ( crizitinib , Lorlatinib ) Targeted autologous T-cells (NK cells) Use of anti-angiogenic agents (Bevacizumab) Apoptosis inducers ( Fenretinide )

38. Follow-up Post treatment tumors can increase in size by Maturation Progression Histology of new tumor is needed to differentiate both Recurrence/relapse Low risk Intermediate risk High risk Prognostication

39. Treatment options for recurrence

40. Treatment options for recurrence High risk: Candidates for clinical trials Palliative care Treat as high risk disease Palliation

41. locoregional Late presentation Financial challenges Poor infracstructure Religious beliefs

42. conclusion Neuroblastoma despite being the most common extra-cranial solid tumor is a rare tumor. It is a treatable malignancy with a long life expectancy if diagnosed early and treated appropriately Surgery remains the mainstay of treatment with chemo- and radiotherapy being supportive pillars Late presentation results in especially poor outcomes in our environment Despite advances in knowledge and treatment, outcomes are still poor in those with unfavourable histology

43. references Coran GA et al (editors); Paediatric surgery; Seventh edition (1)- 441 - 458 Ochicha , O., Gwarzo , A. K., & Gwarzo , D. (2012).  Pediatric malignancies in Kano, Northern Nigeria. World Journal of Pediatrics, 8(3), 235–239. Williams, A. O. (1975).  Tumors of childhood in Ibadan, Nigeria. Cancer, 36(2), 370–378. Neuroblastoma – Wikipedia accessed 10/06/22 at 22:35 Neuroblastoma (image-defined risk factors) | Radiology Reference Article | Radiopaedia.org Sci-Hub | Immunotherapeutic Strategies for Neuroblastoma: Present, Past and Future. Vaccines, 9(1), 43 | 10.3390/vaccines9010043 International Neuroblastoma Risk Group Task Force (inrgdb.org)

44. references Neuroblastoma Cancer | American Cancer Society Sci-Hub | Revision of the International Neuroblastoma Pathology Classification. Cancer, 98(10), 2274–2281 | 10.1002/cncr.11773