Presenter: Asadullah Advisor: Dr. dr. Joni Wahyuhadi, SpBS (K) Dr. dr. Rahadian Indarto S. SpBS (K) dr. Irwan Barlian I.

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Advisor:

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Introduction

20% dari seluruh kasus tumor susunan saraf pusat 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 saraf

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Epidemiologi

• Insiden medulloblastoma Usia 0-3 : 12% Usia 4-9 : 44% Usia 10-16 : 23% Usia >16 : 21% Sales

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Epidemiologi

• Central Brain Tumor Registry (CBTRUS) high grade glioma (secara total) > medulloblastoma

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History

• Cushing mendeskripsikan medulloblastoma sebagai tumor yang tumbuh dari vermis cerebellum dan dapat bermetastasis ke lokasi yang jauh serta lebih cenderung terjadi pada laki-laki usia muda

(7)

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)

(8)

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

(9)

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.

(10)

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

(11)

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 tumor

(12)

(13)

Histology

Klasik Medulloblastoma Desmoplastik Nodular Large-cell Anaplastic Melanotic

(14)

Histology

• Klasik medulloblastoma (70%)

Sel pada tumor tampak sangat padat dengan nukleus berbentuk bulat atau oval dengan gambaran hiperkromatik

(15)

Histology

• Desmoplastic-Nodular (15%)

• Tumor memiliki gambaran retikulen-free nodul dengan densitas lebih rendah pada daerah internodular. Desmoplasia terjadi pada daerah internodular.

(16)

Histology

• Large-cell anaplastic (10%)

• Sel yang berukuran besar dengan nucleus bulat dan prominen serta proporsi sitoplasma yang lebih banyak dari jenis klasik

(17)

Patofisiologi

• Cusing melihat adanya sel neural dan glia pada medulloblastoma yang mengesankan bahwa medulloblastoma berasal dari sel yang lebih

primitif yaitu embryonic neuroepithelial cell yang kemudian dinamakan “medulloblast”

(18)

Patofisiologi

• Cancer stem cell Self renewal

(19)

Patofisiologi

• Cerebellum berasal dari beberapa regio termasuk bagian atas

rhombic lip dan zona ventricular di sekeliling ventrikel empat yang berkembang selama fase embrio dan mencapai maturase pada

(20)

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

(21)

(22)

Sonic Hedgeog

• Gli1 dan Gli2 berperan penting pada pembentukan dan regulasi pembelahan sel pada cancer

(23)

• Adanya TCF menyebabkan aktivasi transkripsi gen c-myc dan Cylin D1 yang berperan dalam proliferasi gen dan bersifat proto-oncogenes

(24)

• Aktivasi berlebihan pada kedua jalur diatas baik Shh dan Wnt dapat memicu

terjadinya medulloblastoma akibat terbentuknya proto oncogene dan kegagalan sel untuk keluar dari kondisi

proliferative dan masuk pada proses deferensiasi

(25)

Classification (Histology)

• More than 70% of patients have classic MB

• Their response to treatment is highly variable

• Histological classification may have limited

prognostic value. Histological Sub-Type Anaplastic Large cell Classic Extensive nodular Desmoplastic

(26)

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

Age at diagnosis Metastatic status Extend of resection

Average risk High risk

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Work-up

Imaging

Sitologi

(31)

Imaging

(32)

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Sitologi CSF

• 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

(34)

• 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%)

Sign of metastasis (abnormality blood count)

High Risk (under 3 year)

(35)

(36)

Management

Surgery

Radiotherapy

Chemoterapy Targetted ??

(37)

History

• Pembedahan pada medulloblastoma di era Cushing awalnya memiliki tingkat mortalitas yang sangat tinggi (>30%)

• Selain mortalitas akibat pembedahan yang tinggi prognosis pada pasien medulloblastoma juga buruk karena angka rekurensi dan metastasis yang tinggi

Extend of tumor resection Better survival outcome Evolution in neurosurgical technique Poor prognosis

(38)

History

• Prognosis pasien dengan medulloblastoma tetap buruk sampai

diperkenalkannya radiasi kraniospinal oleh Paterson dan Farr pada tahun 1953 (survival rate 3th mencapai 65% )

(39)

History

Survival rate ↑↑ Efek samping radioterapi

Gangguan neurokognitif Disfungsi endokrin

(40)

Reduction in the IQ score as high as 40 points

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History

Improve Survival + Minimal side effect Surgery Kemoterapi Radioterapi

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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

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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)

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History

Improve Survival + Minimal side effect Surgery Kemoterapi Radioterapi Targeted

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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.

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Surgery

Gross Total Resection Near Total Resection

(47)

Surgical approach

Transcortical

Cerebellum

Transvermian

Telovelar

Ventricle IV

(48)

Transvermian/Median Sub-Occipital

• 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

(49)

Telovelar

• Examine the access to the fourth ventricle achieved by opening the tela choroidea and inferior medullary velum without incising or

(50)

Telovelar

• 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

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Recommendation

• The transvermian approach has a higher risk of postoperative cerebellar mutism syndrome particularly in children

(52)

• 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.

(53)

• 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

(54)

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Targetted terapy

• 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

(58)

Targetted terapy

• 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.

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Complication

Complication Surgery Radiotherapy Chemotherapy Targeted

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Surgery

• 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%

(61)

Posterior fossa syndrome

Cerebellar Mutism

Brain stem invasion Midline Tu Aggressive surgery

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Radiotherapy

• Low IQ • Endocrine dysfunction • Secondary neoplasm • Radiation necrosis • Behavior abnormalities • Stroke • Steno-occlusive disease • Vascular malformation

(63)

Chemotherapy

• Ototoxicity • Renal toxicity • Hepatotoxicity • Pulmonary fibrosis • Gastrointestinal disturbance

(64)

Prognosis

• With current means of therapy, children with nondisseminated

medulloblastoma 80% or more will be alive 5 years after diagnosis and treatment, with many free of the disease

(65)

Prognosis 5yr Survival

Average Risk: 80%

High Risk: <40%

(66)

Issue

Goal

Improve Survival at Any Cost

Old

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