Medulloblastoma in children

20118/10/59

Paul N. KongkhamCynthia HawkinsJames T. Rutka

Outline• Epidemiology• Genetics• Pathology• Clinical finding• Diagnostic imaging• Staging and prognostic factors• Treatment• Surveillance imaging and disease recurrence

Epidemiology

• The most common malignant pediatric posterior fossa tumor• Median age 6 to 9 years(during first decade)• Can occur in adulthood• Midline cerebellum, in the region of the mid and inferior vermis• May spread along the cerebellar peduncles and extend upward

through the tentorial hiatus or downward into the cervical spinal canal• All patient must be evaluated for “drop mets”

Genetics

• Granule cell precursor (GCP) cell

Familial cancer syndromesGorlin’s syndrome• AD• PTCH1 gene• multiple cutaneous basal cell

carcinomas• 5%

Turcot’s syndrome• heritable disorder• adenomatous polyposis coli (APC)

gene• multiple colorectal neoplasm • central nervous system tumors(GBM,

AA, MB, pineoblastoma, ganglioglioma, ependymoma)

Familial cancer syndromes• Li-Fraumeni syndrome• mutations of the p53 tumor suppressor gene

• Rubenstein-Taybi• Aicardi’s syndrome

Molecular biology• Non-random chromosomal abnormalities

• consistent deletion of 17p markers

• Information from gene profiling• ZIC and NSCL1

• Abnormalities in signal transduction pathways• neurotrophin signaling pathway (important in cerebellar development) or Sonic

hedgehog (Shh)

Pathology• All MB are WHO grade IV

• Gross• pinkish gray to purple mass, commonly arising from the medullary velum• most of its blood supply from the posterior inferior cerebellar artery• firm, discrete• “sugar-coated” appearance of the cerebellar surface

Pathology• 1.classic (90%)• small, densely packed undifferentiated cells with hyperchromatic nuclei, scant cytoplasm• inconstant cell clusters in Homer-Wright rosettes• sometimes called “blue tumor” (monotonous appearance)

• 2. Desmoplastic (6%)• similar to classic type with “glomeruli” AKA pale islands (collagen bundles

and scattered, less cellular areas)• Marked tendency for neuronal differentiation• More common in adults• Prognosis controversi11al: may be the same or less aggressive than classic MB

Pathology• 3. large cell (4%)• large, round, and/or pleomorphic nucleoli, higher mitotic activity• In the few case reports, all were male• More aggressive than classic• Resembles atypical teratoid/rhabdoid tumors of cerebellum , but has

different phenotype and cytogenic features

H&E : 200x H&E : 100xDesmoplastic MB

Desmoplastic MBReticulin stain

H&E : 400xAnaplastic MBnuclear pleomorphism, nuclear molding, cell-cell wrapping high mitotic index

H&E : 400xLarge-cell MBlarge nuclei with prominent nucleolinuclear moldingabundant cytoplasm

Clinical finding

• Most common triad : headache, lethargy, and vomiting• Short clinical history : 1.5 Mo, 3 Mo• Infants and young children• irritability, loss of appetite, weight loss, and failure to thrive• increased intracranial pressure, including lethargy, drowsiness, vomiting,

sunsetting, a full fontanelle, or an increasing head circumference

• Older children• headache, neck stiffness, dizziness, or diplopia

Clinical finding• Neurological examination• truncal or appendicular ataxia, dysmetria, nystagmus, or cranial nerve palsies• A head tilt, signifying descent of the cerebellar tonsils into the foramen

magnum with compression of the C1 or C2 nerve roots• Not specific • Ddx : other posterior fossa lesions such as astrocytoma, ependymoma, or

cystic mass lesions

Diagnostic imaging

• CT• Non-contrast : homogeneous hyperdense midline mass within the posterior

fossa• Contrast : homogeneous enhancement• Peritumoral edema and hydrocephalus• Minimal : Calcification, necrosis, cystic degeneration, and hemorrhage

Diagnostic imaging• MRI• Brain and spine• Early post operative MRI : residual tumor• T1 : hypointense to isointense• T2 : isointense to hyperintense• T1 c Gd : typically robust but may appear homogeneous or slightly

heterogeneous• DWI : restricted diffusion

Chang Classification

Prognosis• Average-risk patients• Children 3 years and older• Without evidence of gross or microscopic metastatic disease at diagnosis• And with less than 1.5 cm2 of residual tumor after surgical resection

• High-risk patients• younger than 3 years or any patient• With evidence of metastatic tumor spread• Or significant residual tumor (>1.5 cm2) after surgery

Treatment• Surgery• Radiation• Chemotherapy

Surgery

• Goal• obtaining a tissue diagnosis• achieving maximal safe tumor resection• relieving critical structures from mass effect• addressing any associated hydrocephalus

Symptomatic hydrocephalus• Decision must be made whether to treat the hydrocephalus

beforehand or at the time of tumor resection• Temporary CSF diversion : external ventricular drain (EVD), diversion

through a ventriculoperitoneal shunt (VPS), diversion via endoscopic third ventriculostomy (ETV)• 10-40% require permanent CSF diversion after resection of the tumor• Factor• more severe hydrocephalus at diagnosis• younger patient age• larger preoperative tumor size

Surgery• Midline suboccipital approach• Inferior telovelar approach• If an EVD was placed : gradual weaning• MRI is performed within 48 hours postoperatively : Significant

residual tumor (>1.5 cm2) should prompt consideration of early repeat resection• Unless the procedure was stopped early because of problems with

hemostasis or invasion of tumor into critical structures

Postoperative complications• Cranial nerve palsies, ataxia, dysmetria, or bulbar symptoms : If

potential for recovery, it typically occurs within 6 months after surgery• Infection, aseptic meningitis, CSF leak, pseudomeningocele, and

persistent hydrocephalus.• Cerebellar mutism

Cerebellar mutism• unique postoperative complication seen in children after resection of a posterior

fossa mass lesion• result from splitting of the vermis and exertion of pressure on the medial cerebellum• 10% to 25%• 1 to 2 days after surgery• Mutism and ataxia are typically the most significant symptoms• Emotional lability, hypotonia• Resolving week to month• Improvements in affect and oral intake ability occur before resolution of the speech

difficulties

Radiation

• Craniospinal irradiation (CSI)• Average-risk patient and High-risk patients• Highly radiosensitive• Short-term side effects

• hair loss, fatigue, weakness, nausea, and vomiting

• Long-term adverse effects• Neurologic, cognitive, and endocrine abnormalities• Hypothalamic-pituitary axis dysfunction secondary to CSI may result in obesity,

hypothyroidism, precocious puberty, and growth retardation• Short stature or scoliosis (or both)

Chemotherapy

• Adjuvant chemotherapy• Average-risk patient and High-risk patients• Moderate chemosensitive• No standard regimen• Lomustine(CCNU), Cisplatin, Vincristine(VCR)

Chemotherapy• Platinum based agent : SNHL• Alkylating agent : acute myelogenous leukemia• Complication • Myelocompression• Fatigue,nausea,vomiting,loss of apetite,stomatitis, infection• Nephrotoxicity,hepatotoxicity,cardiomyopathy,urinary bladder and pulmonary

fibrosis

Surveillance imaging and disease recurrence

• After resection,postopeararive MRI within 48 hr• accurately assess the degree of residual disease• baseline for assessing response to subsequent adjuvant therapy• disease recurrence on follow-up imaging studies

• Long-term follow-up imaging• repeat MRI every 3 to 6 months for the first 2 years after treatment• Surveillance imaging has not been shown to detect a significant proportion of

asymptomatic disease recurrence in some studies

Surveillance imaging and disease recurrence• Recurrence at the primary site is most common• Metastasis outside the nervous system is uncommon• Despite adjuvant treatment, up to 60% of patients will display evidence of

disseminated disease at relapse• Patients with recurrent disease who were initially treated with adjuvant

radiation therapy and chemotherapy : salvage therapy with either repeat chemotherapy or focal stereotactic radiotherapy (or both)• Patients treated initially with surgery and chemotherapy alone, long-term

disease control after local recurrence: salvage high-dose chemotherapy followed by autologous stem cell rescue combined with radiotherapy

Surveillance imaging and disease recurrence• Collins’ law• Period of risk of recurrence(PRR)• Age at diagnosis plus 9 month• Patients that remain free of recurrence beyond the PRR have a much lower

risk of recurrence