introduction - tumor otak, kanker otak, gejala tumor otak
TRANSCRIPT
Presenter:AsadullahAdvisor:Dr. dr. Joni Wahyuhadi, SpBS (K)Dr. dr. Rahadian Indarto S. SpBS (K)dr. Irwan Barlian I. H, SpBS (K) 0
Introduction
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
1
Introduction
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
2
20% dari seluruh kasus tumor susunan sarafpusat pada anak
Pertama kali diperkenalkan oleh Harvey Cushing dan Percival Bailey pada tahun 1925
Berpotensi untuk menyebar melalui celah sub arachnoid dan bahkan pada beberapa kasus
dapat bermetastasis keluar dari susunan sarafpusat
Epidemiologi
• Insiden medulloblastoma
Usia 0-3 : 12%
Usia 4-9 : 44%
Usia 10-16 : 23%
Usia >16 : 21%
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
3
Sales
0-3th 4-9th 10-16th >16th
Epidemiologi
• Central Brain Tumor Registry (CBTRUS) high grade glioma (secaratotal) > medulloblastoma
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
4
History
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
5
• Cushing mendeskripsikan medulloblastoma sebagai tumor yang tumbuh dari vermis cerebellum dan dapat bermetastasis ke lokasiyang jauh serta lebih cenderung terjadi pada laki-laki usia muda
History
• Based on histological similarity between medulloblastomas and other small round blue cell tumors arising in areas outside of the posterior fossa, it was proposed that these tumors be classified together under the umbrella group of primitive neuroectodermal tumors (PNETs)
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
6
History
• We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
7
Etiology
• Non-fresh peaches and similar fruits (OR = 0.5, 95% CI: 0.3, 0.8), non-chocolate candy (OR = 1.7, 95% CI: 1.0, 3.0), french fries (OR = 2.4, 95% CI: 1.2, 4.9) and chili peppers (OR = 1.8, 95% CI: 1.0, 3.0) were associated with medulloblastoma/PNET.
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
8
Etiology
• Neurotropic JC virus (JCV) is able to induce cerebellar neoplasms in rodents that exhibit a phenotype similar to that of human medulloblastomas
• By using PCR techniques we demonstrate that 11 of 23 samples of tumor tissue contain DNA sequences corresponding to three different regions of the JCV genome
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
9
Etiology
• HCMV encodes proteins that provide immune evasion strategies and promote oncogenic transformation and oncomodulation
• HCMV induces COX-2 expression; STAT3 phosphorylation; production of PGE2, vascular endothelial growth factor, and IL-6; and tumorformation in vivo
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
10
Etiology
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
11
Histology
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
12
Klasik Medulloblastoma Desmoplastik Nodular
Large-cell Anaplastic Melanotic
Medullomyoblastoma
Histology
• Klasik medulloblastoma (70%)
Sel pada tumor tampak sangat padat dengan nukleus berbentuk bulatatau oval dengan gambaran hiperkromatik
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
13
Histology
• Desmoplastic-Nodular (15%)
• Tumor memiliki gambaran retikulen-free nodul dengan densitas lebihrendah pada daerah internodular. Desmoplasia terjadi pada daerahinternodular.
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
14
Histology
• Large-cell anaplastic (10%)
• Sel yang berukuran besar dengan nucleus bulat dan prominen sertaproporsi sitoplasma yang lebih banyak dari jenis klasik
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
15
Patofisiologi
• Cusing melihat adanya sel neural dan glia pada medulloblastoma yang mengesankan bahwa medulloblastoma berasal dari sel yang lebihprimitif yaitu embryonic neuroepithelial cell yang kemudiandinamakan “medulloblast”
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
16
Patofisiologi
• Cancer stem cell
Self renewal
Differentiation
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
17
Patofisiologi
• Cerebellum berasal dari beberapa regio termasuk bagian atasrhombic lip dan zona ventricular di sekeliling ventrikel empat yang berkembang selama fase embrio dan mencapai maturase pada beberapa bulan setelah kelahiran
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
18
Patofisiologi
• Transcriptional profiling studies of medulloblastoma cohorts from several research groups around the globe have suggested the existence of multiple distinct molecular subgroups that differ in their demographics, transcriptomes, somatic genetic events, and clinical outcomes
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
19
Sonic Hedgeog
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
20
Sonic Hedgeog
• Gli1 dan Gli2 berperan penting pada pembentukan dan regulasipembelahan sel pada cancer
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
21
Wingless
• Adanya TCF menyebabkanaktivasi transkripsi gen c-mycdan Cylin D1 yang berperandalam proliferasi gen dan bersifat proto-oncogenes
22Ilmiah Divisi Neuro-Onkologi
Departemen Bedah SarafFK UNAIR – RSUD dr Soetomo
Patofisiologi
• Aktivasi berlebihan pada kedua jalur diatas baik Shh dan Wnt dapat memicuterjadinya medulloblastoma akibat terbentuknya proto oncogene dan kegagalan seluntuk keluar dari kondisiproliferative dan masukpada proses deferensiasi
23Ilmiah Divisi Neuro-Onkologi
Departemen Bedah SarafFK UNAIR – RSUD dr Soetomo
Classification (Histology)
• More than 70% of patients have classic MB
• Their response to treatment is highly variable
• Histological classification may have limited prognostic value.
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
24
Histological Sub-Type
Anaplastic
Large cell
Classic
Extensive nodular
Desmoplastic
Classification (Risk Stratification)
• High risk
Residual tumors (>1.5 cm2)
<3 years of age at diagnosis
presence of metastatic disease
• Average risk
Other
Cure rates of average and high-risk patients are 85 and 70%
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
25
Age at diagnosis
Metastatic status
Extend of resection
Average risk
High risk
Classification (Molecular)
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
26
Anamnesis
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
27
Physical diagnostik
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
28
Work-up
Imaging
Sitologi
Screening extra cranial metastasis
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
29
Imaging
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
30
Cranio-axis MRI Not AvailableCranio-axis MRI 2
week post op
Radiogenomic
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
31
Sitologi CSF
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
32
• With the use of either CSF cytology or spinal MRI alone, LMD would be missed in up to 14% to 18% of patients with medulloblastoma or PNET
• 3:1 male/female ratio
• Bone was the most frequent site of metastases in adults (77%) and children (78%) Followed by lymph nodes (33%) in both children and adults. Lung metastases were more common in adults (17%), but liver metastases occurred more frequently in children (15%)
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
33
Sign of metastasis (abnormality blood count)
High Risk (under 3 year)
Screening (ex. Bone Scan)
Session 2
34Ilmiah Divisi Neuro-Onkologi
Departemen Bedah SarafFK UNAIR – RSUD dr Soetomo
Management
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
35
Surgery
RadiotherapyChemoterapy
Targetted ??
History
• Pembedahan pada medulloblastoma di era Cushing awalnya memilikitingkat mortalitas yang sangat tinggi (>30%)
• Selain mortalitas akibat pembedahan yang tinggi prognosis pada pasien medulloblastoma juga buruk karena angka rekurensi dan metastasis yang tinggi
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
36
Extend of tumor resection
Better survival outcome
Evolution in neurosurgical
technique
Poor prognosis
History
• Prognosis pasien dengan medulloblastoma tetap buruk sampaidiperkenalkannya radiasi kraniospinal oleh Paterson dan Farr pada tahun 1953 (survival rate 3th mencapai 65% )
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
37
History
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
38
Survival rate ↑↑Efek sampingradioterapi
Gangguanneurokognitif
Disfungsi endokrin
Tumor sekunder
History
Reduction in the IQ score as high as 40 points
Endocrine deficits occurred in 45%
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
39
History
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
40
Improve Survival + Minimal
side effect
Surgery
KemoterapiRadioterapi
History
• 5-year overall survival was 85% (95% CI 75-94) in patients in the average-risk group and 70% (54-84) in those in the high-risk group(p=0.04); 5-year event-free survival was 83% (73-93) and 70% (55-85)
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
41
History
• 5-year overall survival ± SE and progression-free survival ± SE for M+ patients treated at the RP2D on regimen A was 82% ± 9% and 71% ±11% versus 68% ± 10% and 59% ± 10% on regimen B (P = .36)
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
42
History
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
43
Improve Survival + Minimal
side effect
Surgery
Kemoterapi
Radioterapi
Targeted
History
• Despite the body of literature describing the molecular subgroups, these findings have yet to translate directly to the clinical realm. Standard of care treatment remains maximal up front surgical resection followed by radiation and chemotherapy.
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
44
Surgery
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
45
Gross Total Resection Near Total Resection
High Risk
Surgical approach
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
46
Transcortical
Cerebellum
Transvermian
Telovelar
Ventricle IV
Transvermian/Median Sub-Occipital
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
47
• Splitting the inferior vermis on the sub-occipital surface. The incision extends a variable distance through the uvula, pyramid, tuber, and folium of the vermis, depending on the location and size of the lesion
• Retracting the two halves of the lower vermis laterally, then opening the telachoroidea and the inferior medullary velum, exposing the full length of the floor from the aqueduct to the obex
Telovelar
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
48
• Examine the access to the fourth ventricle achieved by opening the tela choroidea and inferior medullary velum without incising or removing part of the cerebellum.
Telovelar
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
49
• The medullotonsillar space of the cerebellomedullary fissure and the uvulotonsillar space are sharply dissected to release the tonsils from the uvula and the medulla oblongata bilaterally.
• The two cerebellar tonsils are then retracted laterally to expose the floor of the fissure. The telachoroidea is incised from the foramen of the magendie and then followed laterally to the foramen of the luschka on both sides
Recommendation
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
50
• The transvermian approach has a higher risk of postoperative cerebellar mutism syndrome particularly in children
Radioteraphy
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
51
• This strategy of brief intensive chemotherapy for young children with non-metastatic medulloblastoma eliminated the need for craniospinal irradiation 52% of the patients, and may preserve QoL and intellectual functioning.
Radioteraphy
• Patient > 3th average-risk
36 Gy craniospinal irradiation (dose-reduction to 18 Gy in children aged 3 to 7 years), and a boost to the posterior fossa for a total dose of 54 G
• Patient > 3th high-risk
36 Gy craniospinal irradiation with a boost to both the posterior fossa and focal sites of metastatic disease to 55.8 Gy
52Ilmiah Divisi Neuro-Onkologi
Departemen Bedah SarafFK UNAIR – RSUD dr Soetomo
Chemoteraphy
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
53
Targeted terapy
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
54
Targeted terapy
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
55
Targetted terapy
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
56
• Our findings suggest that norcantharidin has potential therapeutic applications in the treatment of medulloblastoma as a result of its ability to cross the blood-brain barrier and its impairment of Wnt-β-catenin signaling
Targetted terapy
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
57
• Group 3 medulloblastomas are characterized by frequent amplifications of the oncogene MYC
• Genomic profiling of Group 3 medulloblastoma cells treated with alsterpaullone confirmed inhibition of cell cycle-related genes, and down-regulation of MYC.
Complication
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
58
Complication
Surgery
RadiotherapyChemotherapy
Targeted
Surgery
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
59
• Cerebellar mutism: decreased speech, hypotonia, ataxia and emotional instability
• First presented at the 13th Annual Meeting of Japanese Society for Paediatric
• Pathophysiology of cerebellar mutism has not been well clarified yet
• Incidence is 11%–29%
Posterior fossa syndrome
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
60
Cerebellar Mutism
Brain stem invasion
Midline Tu
Aggressive surgery
Radiotherapy
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
61
• Low IQ
• Endocrine dysfunction
• Secondary neoplasm
• Radiation necrosis
• Behavior abnormalities
• Stroke
• Steno-occlusive disease
• Vascular malformation
Chemotherapy
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
62
• Ototoxicity
• Renal toxicity
• Hepatotoxicity
• Pulmonary fibrosis
• Gastrointestinal disturbance
Prognosis
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
63
• With current means of therapy, children with nondisseminatedmedulloblastoma 80% or more will be alive 5 years after diagnosis and treatment, with many free of the disease
Prognosis 5yr Survival
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
64
Average Risk: 80%
High Risk: <40%
<3th: 30-70%
Issue
Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf
FK UNAIR – RSUD dr Soetomo
65
Goal
Improve Survival at Any CostOld
New Improve Survival +
Quality of Life
Terimakasih
66Ilmiah Divisi Neuro-Onkologi
Departemen Bedah SarafFK UNAIR – RSUD dr Soetomo