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Neuroblastoma
- 2. CASE HISTORY • 8 year boy from Jumla • Presented with – Sudden onset of increased frequency of urine in Asar 26, 2068 – Relieved by foley’s catheterisation • Referal – Jumla- Nepaljung- KMC- TUTH- Bir Hospital
- 3. EXAMINATION • GPE- unremarkable • Per Abdomen: – Midline suprapubic mass, 4cmx4cm, illdifined firm,fixed, nontender – Bulge in the perineum • Investigation – Blood count – Urine – PSA – Imaging (USG,IVU,MRI,Cx-R) – cystoscopy – Biopsy
- 5. BIOPSY Small round cell tumor STAGE III DISEASE
- 7. NEUROBLASTOMA MODERATOR Prof. Dr. RV/ Dr. PMS/ Dr. AS Presenter: Bikash Bk Thapa
- 8. INTRODUCTION • Spectrum of neuroblastic tumors that arise from primitive sympathetic ganglion cells. »neuroblastoma, »ganglioneuroblastoma and » ganglioneuromas
- 10. EPIDEMIOLOGY • 97 % of neuroblastic tumor • Heterogeneous • Broad spectrum of clinical behavior • Third most common childhood tumor • Most common below 1 year • Most common extracranial solid malignancy
- 11. 1 in 10,000 17.3 months 15 % overall mortality
- 12. Risk factors • Maternal – Opiate consumption – Folate deficiency • Toxic exposure – Alcohol, sex hormones, diuretics, hair color, electromagnetic • Congenital abnormalites – Down syndrome, leukaemia, pyloric stenosis, GTDM – Urogenital and cardiac anamolies • Genetic factors – Girls with turners syndrome, hirschsprungs’s, NF-I • Familial neuroblastoma – 2 % , autosomal dominant
- 13. Pathogenesis • Embryogenesis – Develop from residual microscopic neuroblastic nodules, – Origin of extraadrenal neuroblastomas is unknown • Molecular – Chromosomal deletion (1p, 11q, 14p)- 50% – Over expression of the oncogene MYCN ( n-myc)- 25% – Gain of chromosome 17q material (trisomy 17q) – Alterations in total DNA content – Expression of neurotrophic factors: • NGF and BDNF and receptors
- 14. Genetic model of neuroblastoma development
- 15. PATHOLOGY • Tumors of neuroblastic origin are classified according to the balance between neural-type cells and Schwann-type cells • Neuroblastomas are the most aggressive – undifferentiated, poorly differentiated, or differentiating • Neuroblastomas distinguished by – -neuron-specific enolase , synaptophysin, chromogranin, and S100
- 16. SPREAD • LYMPHATC-35% – Regional – disseminated • HAEMATOGENOUS – bone, bone marrow, liver,brain, lung
- 17. CLINCAL PRESENTATION – Adrenal gland-40% – Abdominal-25% – Thoracic-15% – Cervical-5% – Pelvic sympathetic-5%
- 18. Clincal features • Abdominal mass • Abdominal pain or constipation • Horner syndrome • Localized back pain, weakness • Scoliosis • Bladder dysfunction • Heterochromia iridis • Opsoclonus myoclonus ataxia syndrome • Unexplained secretory diarrhea • Hypertension • Systemic symptoms (fever, weight loss) • Bone pain • Anemia • Proptosis • Periorbital ecchymoses ("raccoon eyes", • Palpable nontender subcutaneous nodules • Unilateral nasal obstruction
- 19. Abdominal tumors “organs of Zuckerkandl” • Abdominal pain, fullness, mass • Intestinal obstruction • Compression of bowel or bladder • Constipation, reduced bladder capacity, enuresis • Vascular compression • Scortal edema, LL edema • Incidental mass- nontender, fixed and firm
- 20. Differential diagnosis • Wilm’s tumor • Hepatoblastoma • Lymphoma, germ cell tumour, infection • Lymphoma, small round cell osteosarcoma, Ewings sarcoma • Rhabdomyosarcoma • Infantile myofibromatosis • Dermoid cyst
- 21. DIAGNOSTIC EVALUATION • CLINICAL • LAB • IMAGING • BIOPSY
- 22. LAB – Routine blood count – RFT n Electrolytes – LFT – Serum / urine cathchecholamines metabolites: vanillylmandelic acid, homovanillic acid – Serum ferritin (>142ng/ml) – Serum LDH(>1500 IU/ml) – Neuron specific enolase (>100ng/ml)
- 23. IMAGING • USG • CT-SCAN • MRI • RADIONUCLEIDE BONE SCAN – technetium radionuclide scan or I123-MIBG scan BIOPSY • BIOPSY (HPE, IMMUNOHISTOCHEMISTRY) • BONE MARROW BIOPSY/ASPIRATE
- 24. DIAGNOSTIC CRITERIA • An unequivocal histologic diagnosis from tumor tissue by light microscopy, with or without immunohistochemistry, electron microscopy, or increased urine (or serum) catecholamines or their metabolites. • Evidence of metastases to bone marrow on an aspirate or trephine biopsy with concomitant elevation of urinary or serum catecholamines or their metabolites.
- 25. STAGING WORKUP • Bone marrow biopsy • Radionuclide scan or I123- MIBG scan • CT/MRI abdomen • CxR • CT /MRI chest • CT-head
- 26. SCREENING • Urinary cantchecholamines • Not recommended • Positive family history
- 27. STAGING • International neuroblastoma staging system (INSS) – Resectability – Lymph nodes – Distant mets – Age at diagnosis • International Neuroblastoma Risk Group Staging system (INRGSS) – Multiple pretreatment imaging paratmeters
- 28. INTERNATIONAL NEUROBLASTOMA STAGING SYSTEM 1986/1993
- 29. The International Neuroblastoma Pathology Classification (INPC) system,, favorable tumors include those that are: • Poorly differentiated or differentiating neuroblastoma, with low or intermediate mitosis-karyorrhexis index (MKI),patient age ≤1.5 years • Differentiating neuroblastoma and low MKI tumors in patients 1.5 to 5.0 years • Ganglioneuroblastoma, intermixed, regardless of age • Ganglioneuroma, regardless of age Unfavorable tumors include those that are: • Undifferentiated or high MKI tumors in patients of any age • Poorly differentiated / intermediate MKI tumors in patients 1.5 to 5.0 years o • Any grade of differentiation and any MKI class in patients ≥5 years of age • Nodular ganglioneuroblastoma, regardless of age
- 30. TREATMENT • Patients are classified into low-, intermediate-, and high-risk » Stage of the disease » Patient age » Histologic appearance of the tumor » Quantitative DNA content of the tumor (DNA index or ploidy) » Presence or absence of amplification of the MYCN oncogene
- 31. TREATMENT MODALITES • SURGERY • CHEMOTHERPAY – cyclophosphamide, carboplatin or cisplatin, etoposide or teniposide, and doxorubicin. • RADIOTHERAPY • OBSERVATION • Autologous hematopoietic stem cell rescue
- 32. COG risk strata for TREATMENT
- 33. NEWER MODALITIES »Immunotherapy »Neuroblastoma Vaccine »Angiogenesis Inhibitor • fenretinide »Iodine-131-metaiodobenzylguanidine (MIBG), in conjunction with hematopoietic cell transplantation
- 34. PROGNOSTIC FACTORS »TUMOR STAGE »AGE AT DIAGNOSIS »CYTOGENETICS AND MOLECULAR GENETICS »PATHOLOGICAL RISK CLASSIFICATION
- 35. References • Sabiston textbook of surgery 18th edn • Schwartz’s principle of surgery 9th edn • Uptodate 2011
- 36. THANK YOU
Editor's Notes
- Neuroblastoma refers to spectrum of tumors that arises fom primitive sympathetic ganglion cells…thatis neural crest cell….and it comprises tumor of wide histological ranges….neuroblastoma, ganlioneuroblastoma and ganlioneuromas
- Neuroblast is the primitive sympathetic ganglion cells that originate from neural crest cells….other tumors of neural crest origin are pheochromocytoma and paraganglioma
- 97% of neuroblastic origin..and heterogenous in respect to its location, HPE and biological bhehaviours Similarly it present itself with broad spectrum of clinical behaviour ….spontantous regress…transform in to benign form or disseminated metastatic disease
- Overall incidence is 1 in 10,000 The median age at diagnosis is 17.3 months, 40 % below 1 year and < 5% above 10 yrs Common in white boys 15 percent of all pediatric cancer fatalities
- such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) along with their receptors
- Morphologically, the appearance is similar to that of other small round blue cell tumors involving bone and soft tissue, including lymphoma, small cell osteosarcoma, mesenchymal chondrosarcoma, the Ewing sarcoma family of tumors, primitive neuroectodermal tumors (PNETs), and undifferentiated soft tissue sarcomas such as rhabdomyosarcoma [90]. (See "Epidemiology, pathology, and molecular genetics of the Ewing sarcoma family of tumors".)
- metaiodobenzylguanidine (MIBG)
- Bilateral iliac crest bone marrow aspirate and biopsy; core biopsies must contain at least 1 cm of marrow, excluding cartilage, to be considered adequate. Bone radiographs and either technetium radionuclide scan or I123-MIBG scan. Abdominal imaging by CT or MRI scan with three-dimensional tumor measurements. Chest radiograph [AP] and lateral); Chest CT or MRI are necessary only if the chest radiograph is positive or if abdominal mass or lymph node disease extend into the chest. Head CT should be considered for patients presenting with proptosis, periorbital ecchymoses or as clinically indicated Among patients with known neuroblastoma, I123 MIBG has a sensitivity of approximately 90 percent [42]. For these patients, I123 MIBG is preferred to technetium scan, given its higher sensitivity and specificity for detection of metastatic disease
- Screening led to more neuroblastomas being diagnosed in the screened population; however, the additional tumors were mainly low-stage tumors with favorable biologic features. Many of these tumors presumably would have undergone spontaneous regression and never would have been diagnosed clinically.There was no decrease in the incidence of high-risk tumors in children beyond the age of screening (ie, older than one year of age).Mortality was not lower in the screened populations.
- Intermidate risk Surgery plus moderatly intesive chemotherapy and radiotherapy indicated only for progressive disease…adjuvant radiotherapy is not recommended …owing to lack of any benefit High risk aggressive multimodality approach that includes chemotherapy, surgical resection, high-dose chemotherapy with hematopoietic stem-cell rescue, and radiation therapy [
- Low risk Surgery alone is the primary treatment for low-risk tumors [23-27]. Resectability is determined by tumor location and mobility, relationship to major nerves and blood vessels, the presence of distant metastases, and patient age. Avoid sacrificing vital organs Chemotherapy is for them:cannot be resected or who have threatening symptoms of spinal cord compression or respiratory or bowel compromise. Radiotherpay is for unrescetable tumor or progressive despite chemotherapy ,life threatening complications, neurologic compromise, or tumor-related organ dysfunction unresponsive to emergency chemotherapy Observation for those in 4S except age less than 2 months, diploid, n-myc amplification and undifferentiated tumor
- Tumor stage– influenced greatly by distant mets..not much by regional or adjacent lymph node and age … outcome in 4S is good except infants below 4 weeks Five year survival is 83, 55, and 40 percent for children younger than one year, one to four years, and five to nine years, respective , five-year event-free survival (EFS) was more than three times greater among children with favorable compared to unfavorable disease (90 versus 27 percent) including MYCN (N-myc) amplification, DNA content (ploidy), and gain or loss of certain chromosomes.