NEUROBLASTOMA

MODERATOR :- DR. SUDHIR .S. SINGH

PRESENTER :- DR.VIJAY.P.RATURI

EPIDEMIOLOGY :-

• 3rd m.c malignancy diagnosed in children.

• It’s m.c cancer diagnosed before 12 months.

• Median age at diagnosis is 2 years.

• Excretion of catecholamine metabolites in the urine of children with neuroblastoma has served as the basic of these screening tests. - qualitatively for VMA test - quantitatively for VMA & homovanillic acid (HVA)

• Screening dose not affect the mortality rate in N.B

NATURAL HISTORY :-

• N.B may arise from any site in sympathetic nervous system.

• M.c site of origin is adrenal medulla (30-40%) , paraspinal ganglia in abdomen & pelvis (25%).Thoracic (15%) and head and neck primary tumours (5%) are more common in infants than in older children.

• > 70% pt have metastasis at presentation.

• Most frequent site of mets are L.N , B.M , skin & liver, lung & CNS is rare site.

• Highest spontaneous remission usually by maturation to ganglioneuroma.

• Most potential N.B are never clinically manifested ,because of spontaneous remission.

CLINICAL PRESENTATION:-

• Pain is the m.c presentation , this is caused by bone, liver, or B.M mets other symptom include weight loss, anorexia, malaise & fever.

• Respiratory distress may accompany massive hepatomegaly.

• Spinal cord compression in N.B that originates along the sympathetic ganglia through adjacent foramina.

• Skin mets may have bluish tinge (“Blue berry muffin“ sign).

• Localized N.B unsually presents with opsoclonus- myoclonus syndrome , manifested by truncal ataxia & cerebellar encephalopathy.

DIAGNOSTIC WORKUP :-

• Diagnosis of N.B is establish by pathologic evaluation. tumour tissue is obtained from suspected primary tumour site or involved L.N by excision or incisional biopsy.

• Pathological evaluation of B.M is required for staging of neuroblastoma.

• Measurement of urinary catecholamine metabolites HVA or VMA , metabolite of dopa/N.E & epinephrine is elevated in >90% of pt with stage 4 N.B. ( ratio of VMA to HVA > 1.5 is asso with good prognosis)

• CBC ,serum ferritin , LDH & other liver function should be assayed routinely.

• MRI allows better evaluation of b.v encasement , intraspinal extension , B.M involvement .

• Radionuclide scan is a mandatory investigation.

• MIBG scan can be used to image primary & metastatic sites of N.B. ( labelled with I123 or I131 have sensitivity of 85-90% and specificity of 95% ).

• Long acting somatostatin analog octreotide labelled with I123 is used to image neuroblastoma , expression of S.R by N.B tissue is favourable prognostic factor.

STAGING :- M.c used staging system is INSS.

• STAGE 1:- Localized tumor with complete gross excision, without microscopic residual disease; representative ipsilateral LN negative for tumor microscopically (nodes attached to and removed with the primary tumor may be +ve)

• STAGE 2A:- Localized tumor with incomplete gross excision; representative ipsilateral nonadherent LNs -VE for tumor microscopically.

• STAGE 2B :- Localized tumor with or without complete gross excision, with ipsilateral nonadherent LNs positive for tumor. Enlarged contralateral LNs must be negative microscopically.

• STAGE 3 :- - Unresectable unilateral tumor infiltrating across the midline, with or without regional LN involvement; or localized unilateral tumor with contralateral regional LN involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by LN involvement.

• STAGE 4:- Any primary tumor with dissemination to distant LNs, bone, B.M, liver, skin, and/or other organs (except as defined for stage 4S).

• STAGE 4S:- Localized primary tumor as defined for stage 1, 2A, or 2B with dissemination limited to skin, liver, and/or B.M (limited to infants <1 year of age).

PATHOLOGICAL CLASSIFICATION :- three types of tumors, representing different degree of differentiation .

• GANGLIONEUROMA :- it consist of mature ganglion cells, schwann cells, & nerve bundle & is benign .its calcified form may represent mature N.B.

• GANGLIONEUROBLASTOMA:- it’s intermediate between ganglioneuroma & N.B . Both mature & undifferentiated neuroblast are evident.

• NEUROBLASTOMA :- it’s the undifferentiated end of spectrum of neural crest tumors.

• IHC stains helps in diagnosis of neuroblastoma , it stains +ve for NF , NSE , synaptophysin , chromogranin A.

• Grading system by shimada et al , it evaluate tumor specimen for stromal development , neuroblastic differentiation & mitosis karyorrhexis index.

PROGNOSTIC FACTORS :-

PROGNOSTIC FACTOR FAVOURABLE UNFAVOURABLE• age <2 YR > 2 YR• stage 1,2 , 4s 3,4• Pathology ( shimada) favourable unfavourable• Ferritin <143 ng/ml >143 ng/ml• NSE <100 > 100• Urine VMA/HVA <1 >1• N-myc single copy ampilified• DNA index > 1.1 1• 1p deletion no 1p deletion 1p deletion

GENERAL MANAGEMENT:-

LOW –RISK DISEASE :- • low stage resectable tumour (INS stage 1,2 or 3 with –ve nodes)

have an excellent prognosis after complete surgical excision.

• Unresectable tumors of low stages (INSS stage 1-3 with -ve LN) may require preoperative C.t & occasionally R.t to convert them into resectable status.

• Pt with n-myc amplification or low DNA index may require adjuvant therapy and should be enrolled in trials.

• In CCG trial 3381 with stage 1 disease , 4 yr EFS & OSR for children t/td with Sx alone were 93% &99%.

• With stage 2 4 yr EFS & OSR were 81% and 98%

INTERMEDIATE RISK DISEASE :-

• Locally advanced & regional metastatic tumors (INSS stage 2b – 3 with +ve LN) require intensive therapy .

• Infant <1 yr should undergo complete resection of primary tumor and receive adjuvant C.T

• In Unresectable cases, C.T may be administered initially & Sx can be done after response to sys.CT.

• In older children with LN metastases, adjuvant RT to primary & regional LN has improved DFS & OSR.

• De Bernardi et al failed to show a benefit from adding RT in children > 1yr with post op residual tumor or +ve LN.

• In pt with intraspinal extension of NB ,t/tnt with CT demonstrate 92% improvement in neurological deficit

avoiding neurosurgical decompression in >60% cases receiving courses of CARBOPLATIN & ETOPOSIDE alternating with CYCLOPHOSPHAMIDE, VINCRISTINE, DOXORUBICIN.

• On the basis of CCG & POG , pt with intermediate risk NB have 3yr survival between 75% & 98%

HIGH RISK DISEASE :-

• Aggressive t/t regimens is been used to prolong survival & achieve cure.

• Intensive high dose C.T regimens appear to be superior. Drugs used are CYCOPHOSPHAMIDE, CISPLATIN , DOXORUBICIN , ETOPOSIDE & TENIPOSIDE.

• Recent trials have sought to intensify t/t of metastatic NB through use of high dose myeloablative C.T with stem cell rescue or B.M transplantation.

• Pt reveiving the ABMT has a higher EFS than pt continuing on std CT.

• European NB study grp studied role of consolidated ABMT with high dose MELPHALAN Vs no further t/t following induction CT with OPEC REGIMEN in pt with stage 3 & 4. report shows inprovement in EFS (38% vs 27%) & OS ( 47% & 30%) for high dose melphalan arm.

• R.T plays an imp role in palliative Mx of pt with end stage symptomatic NB. Radiation doses ranged from 4- 24.4gy at a rate of 1 – 1.5gy /#.

R.T TECHNIQUE :- T/T PLANING & FIELD DESIGN :-

• R.T to primary tumor site should t/t gross residual tumor remaining after C.T with at least 2cm margin from the tumor to the block edge.

• Regional LN sites should be covered if LN were radiologicaly or pathological involved at any time during the course of disease.

• CT or MRI should be used to define full extent of disease.

• R.T of metastatic sites should include generous margin.

• Low dose TBI as a part of preparative regimen for pt undergoing BMT for high risk metastatic disease.

• NB is very radiosensitive tumor, neuroblast exhibits very little repair capacity between # .this make hyper# RT an option .

• Irradiation dose to control gross disease is age dependent < 1 yr -- dose 12gy 12- 48 month -- dose at least 25gy > 4 yr – dose of >25gy

• Sloan kettering CA center , reported that 21 gy of hyper# RT resulted in 90% primary site local control at 5 years.

• Haas hogan show the result of IORT in pt with high risk disease.Single # of 7-16gy( median 10gy) to primary tumor bed is asso with local Control rate of 100% in pt with gross total resection.

• Children t/td for palliative for symptomatic metastatic disease should receive adequate irradiation dose for tumor control if they have reasonable expectation of long survival.

• If likelihood of long survival is small , 5-20 gy in one or five daily # can give rapid palliation.

RESULTS OF THERAPY :-

LOW RISK DISEASE :- Survival rate after Sx alone is 85-90%

INTERMEIDATE RISK DISEASE :- - Children with large ,initialy unresectable tumor often respond to primary C.T with combinations of drugs.

- Children with unresponsive , unresectable gross residual tumor may require EBRT .

- Frequently this children can undergo resection of tumor at a second look operation & achieve a survival rate of 60 – 90%.

HIGH RISK DISEASE :- - children > 1yr with metastatic NB have poor prognosis with survival rate of <10-30%.

• Addition of cisplatin & teniposide to CT improved expected 4 yr survival rate from 7% to 28% .

• Addition of cis- retinoic acid was asso with a 47% EFS.

• In stage 4S survival rates can be as high as 75% to 90%. • In this pt goal of therapy should be limited to relief of

acute presenting symptoms.

• Local field #ted low dose RT < 12gy , minimal CT & supportive care is imp to achieve high survival rate.

SEQUELAE OF TREATMENT :-

EARLY COMPLICATION :- especially skin reaction & mucositis.

LATE COMPLICATION :- Depends on site of RT & total dose of both RT & CT .

- Age and time of t/t influence risk & severity of skeletal anomalies.

- Younger pt are more prone to develop late effect.

- Neve et al reported high rate of pulmonary function impairment in children receiving TBI as a part of conditioning regimen for ABMT.

LONG TERM SEQUELAE RELATED TO R.T (WASHINGTON UNIVERSITY) :-

• Scoliosis (severe) 8 – 30gy

• Bone & muscle pulmonary hypoplasia 28 – 30gy

• Lung fibrosis 48gy

• Liver fibrosis 39.5 gy

• Rib necrosis 48 gy

• Cataract 20gy

• Hypopituitarism 20gy

thank you…