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Selected References

Pineal Region Anatomy and Histology

Shoja MM et al: History of the pineal gland. Childs Nerv Syst. 32(4):583-6, 2016

Jiménez-Heffernan JA et al: Cytologic features of the normal pineal gland of adults. Diagn Cytopathol. 43(8):642-5, 2015

Gross Anatomy

Matsuo S et al: Midline and off-midline infratentorial supracerebellar approaches to the pineal gland. J Neurosurg. 126(6):1984-1994, 2017

Meyer FB et al: Introduction to microsurgery of the third ventricle, pineal region, and tentorial incisura. Neurosurg Focus. 40 Video Suppl 1:1, 2016

Normal Imaging

Galluzzi P et al: MRI-based assessment of the pineal gland in a large population of children aged 0-5 years and comparison with pineoblastoma: part I, the solid gland. Neuroradiology. 58(7):70512, 2016

Sirin S et al: MRI-based assessment of the pineal gland in a large population of children aged 0-5 years and comparison with pineoblastoma: part II, the cystic gland. Neuroradiology. 58(7):71321, 2016

Whitehead MT et al: Physiologic pineal region, choroid plexus, and dural calcifications in the first decade of life. AJNR Am J Neuroradiol. 36(3):575-80, 2015

Pineal Parenchymal Tumors

Tamrazi B et al: Pineal region masses in pediatric patients. Neuroimaging Clin N Am. 27(1):85-97, 2017

Mottolese C et al: Incidence of pineal tumours. A review of the literature. Neurochirurgie. 61(2-3):65-9, 2015

Ostrom QT et al: CBTRUS Statistical Report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro Oncol. 17 Suppl 4:iv1-iv62, 2015

Pineocytoma

Nakazato Y et al: Pineocytoma. In: Louis DN et al (eds), WHO Classification of Tumours of the Central Nervous System. Lyon, France: International Agency for Research on Cancer, 2016, pp. 170-172

Pineal Parenchymal Tumor of Intermediate Differentiation

Raleigh DR et al: Histopathologic review of pineal parenchymal tumors identifies novel morphologic subtypes and prognostic factors for outcome. Neuro Oncol. 19(1):78-88, 2017

Amato-Watkins AC et al: Pineal parenchymal tumours of intermediate differentiation - an evidence-based review of a new pathological entity. Br J Neurosurg. 30(1):11-5, 2016

Kang YJ et al: Integrated genomic characterization of a pineal parenchymal tumor of intermediate differentiation. World Neurosurg. 85:96-105, 2016

Pineoblastoma

Bueno MT et al: Pediatric imaging in DICER1 syndrome. Pediatr Radiol. ePub, 2017

Parikh KA et al: Pineoblastoma-the experience at St. Jude Children's Research Hospital. Neurosurgery. ePub, 2017

Gener MA et al: Clinical, pathological, and surgical outcomes for adult pineoblastomas. World Neurosurg. 84(6):1816-24, 2015

Papillary Tumor of the Pineal Region

Heim S et al: Papillary tumor of the pineal region: a distinct molecular entity. Brain Pathol. 26(2):199-205, 2016

Germ Cell Tumors

Overview of Germ Cell Tumors

Fukushima S et al: Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas. Acta Neuropathol. 133(3):445-462, 2017

Wu CC et al: MRI features of pediatric intracranial germ cell tumor subtypes. J Neurooncol. ePub, 2017

Germinoma

Pérez-Ramírez M et al: Pediatric pineal germinomas: epigenetic and genomic approach. Clin Neurol Neurosurg. 152:45-51, 2017

Ichimura K et al: Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy. Acta Neuropathol. 131(6):889-901, 2016

Rosenblum MK et al: Germ cell tumors. In: Louis DN et al (eds), WHO Classification of Tumours of the Central Nervous System. Lyon, France: International Agency for Research on Cancer, 2016, pp. 286-291

Teratoma

Algahtani H et al: Teratoma of the nervous system: a case series. Neurocirugia (Astur). ePub, 2017

Nariai H et al: Prenatally diagnosed aggressive intracranial immature teratoma-clinicopathological correlation. Fetal Pediatr Pathol. 35(4):260-4, 2016

Robles Fradejas M et al: Fetal intracranial immature teratoma: presentation of a case and a systematic review of the literature. J Matern Fetal Neonatal Med. 1-8, 2016

DasGupta S et al: Central nervous system teratomas in infants: a report of two cases. Indian J Pathol Microbiol. 58(1):89-92, 2015

Other Germ Cell Neoplasms

Murray MJ et al: A pipeline to quantify serum and cerebrospinal fluid microRNAs for diagnosis and detection of relapse in paediatric malignant germ-cell tumours. Br J Cancer. 114(2):15162, 2016

Zhang S et al: Clinical and radiologic features of pediatric basal ganglia germ cell tumors. World Neurosurg. 95:516-524.e1, 2016

Jinguji S et al: Long-term outcomes in patients with pineal nongerminomatous malignant germ cell tumors treated by radical resection during initial treatment combined with adjuvant therapy. Acta Neurochir (Wien). 157(12):2175-83, 2015

"Other Cell" Pineal and Pineal Region Neoplasms

Lensing FD et al: Pineal region masses--imaging findings and surgical approaches. Curr Probl Diagn Radiol. 44(1):76-87, 2015

Smith AB et al: From the archives of the AFIP: lesions of the pineal region: radiologic-pathologic correlation. Radiographics. 30(7):2001-20, 2010

Chapter 21

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Embryonal Neoplasms

Malignant brain tumors are the second leading cause of death in pediatric cancer patients. The most common of these tumors are the embryonal neoplasms, a heterogeneous group of primitive neoplasms with protean histopathologic manifestations.

The rapidly evolving molecular classification of brain tumors has fundamentally changed the understanding of embryonal neoplasms. In the 2016 World Health Organization schema, the classification of the largest group of embryonal neoplasms—medulloblastoma—was revised to reflect both recognized histopathologic variants and clinically relevant molecular subgroups.

Embryonal neoplasms other than medulloblastomas have also undergone substantial changes. The term primitive neuroectodermal tumor (PNET) has been removed from the diagnostic lexicon, and the tumors formerly included in this category have been redefined using molecular data.

The 2016 WHO classification now recognizes three general categories of embryonal tumors: (1) medulloblastoma, (2) other (non-medulloblastoma) embryonal tumors, and (3) atypical teratoid/rhabdoid tumor. All three are discussed in this chapter.

Medulloblastoma

Medulloblastoma Overview

Medulloblastoma (MB) is the most common malignant CNS neoplasm of childhood and the second most common overall pediatric brain tumor (after astrocytoma). As a group, MBs accounts for approximately 20% of childhood CNS neoplasms.

It is now recognized that the pathologically defined entity historically known as MB is not a single tumor entity but a heterogeneous clustering of multiple distinct, clinically relevant molecular subgroups based on transcriptome or methylome profiling. International consensus now recognizes four molecular subgroups. Three of the four subgroups have at least one further level of hierarchy. Each distinct MB molecular subgroup differs in its demographics, recommended treatments, and clinical outcomes (see below).

In addition to genetically defined MBs, the 2016 WHO retained a histopathologic MB classification because of its clinical utility when molecular (i.e., genetic) analysis is either limited or unavailable. We discuss both systems below.

Medulloblastoma	635
Medulloblastoma Overview	635
Classic Medulloblastoma	638
Medulloblastoma With Extensive	641
Nodularity
Desmoplastic/Nodular	641
Medulloblastoma
Large Cell/Anaplastic	642
Medulloblastoma
Other CNS Embryonal Tumors	643
Embryonal Tumor With
Multilayered Rosettes, C19MC-	643
Altered
Other CNS Embryonal Tumors	647
New Molecularly Defined	652
Embryonal Neoplasms
Malignant Rhabdoid Tumors	652
Atypical Teratoid/Rhabdoid	652
Tumor
Other CNS Neoplasms With	657
Rhabdoid Features

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Histologically Defined Classification of Medulloblastoma

MB is defined as an embryonal neuroepithelial tumor that arises in the cerebellum or dorsal brain stem and consists of densely packed small round undifferentiated ("blue") cells. Moderate nuclear pleomorphism and a high mitotic index (MIB-1 or Ki-67) are characteristic.

The 2016 WHO classification recognizes classic medulloblastoma and three medulloblastoma histopathologic variants: (1) desmoplastic/nodular medulloblastoma, (2) medulloblastoma with extensive nodularity, and (3) large cell/anaplastic medulloblastoma.

All MBs are designated as WHO grade IV neoplasms irrespective of their histologic or genetic subtype.

Classic Medulloblastoma. Classic MBs account for approximately 70% of all MBs. They exhibit highly cellular

(21-1A) Classic medulloblastomas (MBs) are formed of sheets of small, uniform "round blue cells" with little nuclear pleomorphism. Mitoses are relatively few although this is a WHO grade IV neoplasm. (From DP: Neuropathology, 2e.) (21-1B) Homer-Wright (neuroblastic) rosettes with fibrillar cores are characteristic of classic MBs. (From DP: Neuropathology, 2e.)

(21-2) The desmoplastic/nodular MB variant contains palestaining reticular-laden islands surrounded by the darker blue, less differentiated background of extranodular tissue. (From DP: Neuropathology, 2e.) (21- 3) Large cell/anaplastic MBs contain large anaplastic-appearing cells with prominent nucleoli. (From DP: Neuropathology, 2e.)

sheets and lobules of uniform small round "blue cells" with neuroblastic (Homer-Wright) rosettes and perivascular pseudorosettes. Mitotic figures are variable (21-1).

Desmoplastic/Nodular Medulloblastoma and Medulloblastoma With Extensive Nodularity. The term "desmoplastic" refers to the growth of fibrous or connective tissue. The desmoplastic/nodular MB variant accounts for 1520% of MBs. This variant is characterized by abundant islands of reticulin fibers interspersed in a background of less differentiated small round blue cells (21-2). In instances in which the nodules predominate, the variant is known as medulloblastoma with extensive nodularity (MBEN).

Large Cell/Anaplastic Medulloblastoma. The large cell/anaplastic MB variant accounts for approximately 10% of MBs. Large anaplastic-appearing cells with nuclear pleomorphism, high mitotic activity, and abundant apoptosis are characteristic (21-3).

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(21-4) Autopsy specimen demonstrates a large medulloblastomanearly filling the fourth ventricle with some sparing of the uppermost aspect of the ventricle . Pons is compressed anteriorly . (Courtesy R. Hewlett, MD.)

Genetically Defined Classification of

Medulloblastomas

Molecular classification is redefining the risk stratification of patients with MB. MB is a genetically heterogeneous disease with four main molecular subgroups. All four MB subtypes have different origins, preferred anatomic locations, and demographics, as well as dramatically different prognosis and therapeutic implications.

The two named pathways are the WNT-activated and SHHactivated pathways. Two non-WNT, non-Shh groups are designated as simply "group 3" and "group 4."

WNT-Activated Medulloblastomas. WNT-activated medulloblastoma (WNT-MB) is the smallest molecular subgroup (10%) and appears strikingly different from the other MBs. WNT MBs are lateralized tumors that arise from the lower rhombic lip in the dorsolateral primitive brainstem around the foramen of Luschka (21-12).

Loss of chromosome 6 and activating mutations in the WNT signaling pathway are typical. Almost 90% of WNT-MBs have somatic mutations in the CTNNB1 gene. Germline mutations in the WNT pathway inhibitor, APC, predispose individuals to develop MB in the setting of Turcot syndrome.

WNT MBs are very rare in infants but more common in children (7-14 years of age) and young adults. They almost always exhibit classic histology. Childhood patients with WNT MBs consistently show a favorable prognosis (5-year survival > 90%), and reduced intensity risk-adapted therapies are currently being studied.

(21-5) CSF spread is from MB. Cut section shows in situ tumor expanding, filling 4th ventricle . Glistening, translucent "sugar icing" metastases coat cerebellum ; "drop" metastases along spinal cord , cauda equina . (Courtesy R. Hewlett, MD.)

SHH-Activated MBs. The SHH subgroup accounts for 25-30% of MBs. SHH-activated MBs arise from granule neuron precursor cells (GNPCs), which are found in the external granular layer of the cerebellum until early in the second postnatal year. GNPC proliferation is dependent on SHH signaling pathway activation. Because of their rhombic lip origin, SHH MBs are often located laterally within the cerebellar hemispheres (21-6). The vermis is the second most common site.

SHH-MBs have significantly enriched desmoplastic or nodular pathology compared with all other subgroups. TP53 mutations, MYCN amplifications, and large cell anaplastic histology are significantly more frequent in childhood SHH MBs compared with SHH MBs in infants in whom desmoplastic/nodular and classical histologies predominate.

For risk stratification purposes in patients younger than 16, SHH-activated MB is now split into two age-dependent subgroups: infants (< 4.3 years) and children (> 4.3 years).

SHH-MBs associated with MYCN and GLI1 amplifications or TP53 mutation have a poor prognosis even when treated with high-dose craniospinal radiation and adjuvant chemotherapy.

Individuals with germline mutations in the SHH receptor

PTCH1 have basal cell nevus (Gorlin) syndrome and are predisposed to develop SHH-activated MBs.

Non-WNT/Non-SHH Medulloblastoma. Non-WNT/non-SHH MBs are classic or large cell/anaplastic tumors that cluster into two groups ("group 3" and "group 4") defined by transcriptome, methylome, and microRNA profiles. There is significant clinicobiological overlap between the two groups.

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(21-6A) Autopsy specimen from an adult shows desmoplastic medulloblastoma as a firm, fibrous-appearing, somewhat lobular and laterally located mass in the cerebellar hemisphere. (Courtesy R. Hewlett, MD.)

MEDULLOBLASTOMA CLASSIFICATION

Histologically Defined Medulloblastomas

•Classic medulloblastoma

•Medulloblastoma variants

○Desmoplastic/nodular medulloblastoma

○Medulloblastoma with extensive nodularity

○Large cell/anaplastic medulloblastoma

Genetically Defined Medulloblastomas

•WNT-activated medulloblastoma

•SHH-activated medulloblastomas

○TP53 mutant

○TP53 wild-type

•Non-WNT/non-SHH medulloblastomas

○Group 3 medulloblastoma

○Group 4 medulloblastoma

Group 3 is the third largest MB subgroup (20-25%). Group 3 tumors are common in infants but exceedingly rare in adults. There is a 2:1 M:F predominance. Most exhibit classical histopathology. MYC amplification is common, and approximately 50% of patients present with metastases (2110).

Group 3 MBs have the worst outcome of all four molecular subtypes. MYC amplification is the only risk factor significantly associated with progression-free survival in this group.

Group 4 is the largest (about 35%) of the four molecular MB subgroups. Most Group 4 MBs exhibit classic histology. Large cell/anaplastic variants do occur but are uncommon, whereas desmoplastic histology is rare. Group 4 MBs affect all ages but are most common in children. The M:F ratio is 2:1. A minority

(21-6B) Cut section shows the classic desmoplastic medulloblastoma located in the lateral cerebellar hemisphere. Most tumors in this location are SHH-activated. (Courtesy R. Hewlett, MD.)

of Group 4 MBs present with metastasis. Prognosis is intermediate.

Classic Medulloblastoma

Pathology

Location. More than 85% of classic MBs (CMBs) arise in the midline (21-4). They are located within the fourth ventricle and focally infiltrate the dorsal brainstem and vermis.

Occasionally, CMB occurs as a diffusely infiltrating lesion without a focal dominant mass (21-7).

Posteroinferior extension into the cisterna magna is common. Unlike ependymoma, lateral extension into the cerebellopontine angle is rare.

Size and Number. CMBs vary in size. Most tumors are between 2 and 4 cm at the time of initial diagnosis.

Gross Pathology. CMBs are relatively well-defined pink or grayish masses that typically fill the fourth ventricle, displacing and compressing the pons anteriorly (21-4). Small scattered foci of necrosis and hemorrhage may be present.

Microscopic Features. CMBs are highly cellular tumors. Dense sheets of uniform cells with round or oval hyperchromatic pleomorphic nuclei surrounded by scanty cytoplasm are the typical appearance ("small round blue cell tumor") (21-1A). Neuroblastic (Homer-Wright) rosettes—radial arrangements of tumor cells around fibrillary processes—are found in 40% of cases (21-1B).

CLASSIC MEDULLOBLASTOMA

Terminology

• Classic medulloblastoma (CMB)

Etiology

•All four molecular subtypes represented

○Almost all WNT-activated MBs are CMBs

•CMBs from dorsal midbrain → fourth ventricle

Pathology

•Midline (> 85%, fourth ventricle)

•"Small round blue cell tumor"

•Neuroblastic (Homer-Wright) rosettes

•WHO grade IV

Clinical Features

•MB = 20% of all pediatric brain tumors

•CMBs = 70% of all MBs

•Most common malignant posterior fossa childhood neoplasm

•Most CMBs in patients < 10 years

○Second peak in patients 20-40 years

•Low risk if WNT activated

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(21-7) (Upper left) Graphic depicts classic medulloblastoma in the midline fourth ventricle with CSF spread. All molecular subgroups and all histologies can be located here, but the most common subtypes are groups 3 and 4 (compare to Figure 21-9). (Upper right) Graphic depicts a medulloblastoma in the cerebellar peduncle/CPA cistern. This location is classic for WNT medulloblastoma (compare to Figures 21-10 and 21-12). (Lower left) Graphic depicts a medulloblastoma in the lateral cerebellar hemisphere. This is the classic location for desmoplastic medulloblastoma, SHH molecular subtype (compare to Figure 21-11). (Lower right). Graphic depicts a nonfocal, diffusely infiltrating medulloblastoma (compare to Figure 21-13). Groups 3 and 4 can be diffusely infiltrating with no dominant mass. Group 4 MBs are sometimes characterized by exhibiting minimal or no enhancement on T1 C+ FS (compare to Figure 21-9).

Clinical Issues

Epidemiology and Demographics. MBs cause 10% of all pediatric brain tumors and are the most common malignant posterior fossa childhood neoplasm. CMBs account for 70% of MBs. Most occur before age 10 years. There is a second, smaller peak in adults aged 20-40 years.

Presentation. The most common clinical manifestations of MB are vomiting (90%) and headache (80%). Psychomotor regression, ataxia, strabismus, and spasticity are common. The median interval between symptom onset and diagnosis is 2 months.

Because of their location, MBs tend to compress the fourth ventricle and cause obstructive hydrocephalus. In one-third of children younger than 3 years, the diagnosis is made only after life-threatening signs of intracranial hypertension appear.

Natural History. CMBs occur in all four principal molecular subgroups. Risk varies with subgroup. Almost all WNTactivated MBs exhibit classic histology and are considered lowrisk neoplasms. Overall survival is excellent with surgical resection and adjuvant chemotherapy. SHH-activated TP53- mutant MBs with classic histology are considered standard risk.

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(21-8A) NECT shows a mostly hyperdense midline posterior fossa mass with intratumoral cysts.

(21-8B) The solid portion enhances strongly on CECT, whereas the cyst does not. Note the mild enlargement of the temporal horns .

(21-8C) Sagittal CECT shows the obstructing midline mass causes moderate hydrocephalus. This is classic MB, WHO IV, standard risk.

Imaging

General Features. CMBs have relatively defined margins on imaging studies. Despite this appearance, 40-50% have CSF dissemination at the time of initial diagnosis (21-5). Preoperative contrast-enhanced MR of the entire neuraxis is recommended.

CT Findings. NECT scans show a moderately hyperdense, relatively welldefined mass in the midline posterior fossa (21-8A) or around the foramen of Luschka (WNT-subgroup MB). Cyst formation (40%) and calcification (2025%) are common (21-9A). Gross hemorrhage is rare. Strong but heterogeneous enhancement is seen on CECT (21-8B).

If dense tentorial or falcine calcifications are present, the patient should be evaluated for basal cell nevus (Gorlin) syndrome.

MR Findings. Almost all CMBs are hypointense relative to gray matter on T1WI and hyperintense on T2WI (21-9B). Peritumoral edema is present in one-third of cases. Obstructive hydrocephalus with periventricular accumulation of CSF is common and best delineated on FLAIR.

Enhancement patterns show striking variation, ranging from minimal to patchy to marked. Two-thirds of CMBs show marked enhancement, whereas one-third show only subtle, marginal, or linear enhancement (21-9D).

Occasionally, CMBs present as diffusely infiltrating cerebellar masses with multifocal scattered T2/FLAIR hyperintensities and minimal or no enhancement (21-13).

Because of their dense cellularity, CMBs often show moderate restriction on DWI (21-9C). pMR shows low rCBV and increased permeability on K2 maps.

CLASSIC MEDULLOBLASTOMA: IMAGING AND DIFFERENTIAL DIAGNOSIS

CT

•Hyperdense on NECT

•Cysts (40%)

•Ca++ (20-25%)

•Hemorrhage rare

•Enhances strongly, heterogeneously

MR

•Hypoon T1, hyperintense on T2

•Often restricts on DWI

•Enhancement: none to strong

Differential Diagnosis

•Medulloblastoma variant

•Atypical teratoid/rhabdoid tumor

•Lhermitte-Duclos disease (adults)

Differential Diagnosis

The major differential diagnosis of CMB in children is a medulloblastoma variant. A posterior fossa atypical teratoid/rhabdoid tumor (AT/RT) may be indistinguishable from CMB on imaging studies alone.

Choroid plexus papilloma (CPP) of the fourth ventricle is rare in children but can be hyperdense on NECT and enhance strongly on CECT. The front-like papillary configuration is often apparent on MR, and looking for a myoinositol peak on MRS can provide helpful distinguishing features.

Lhermitte-Duclos disease (LDD) can be seen in children but is more common in young adults. LDD and desmoplastic MB may resemble one

another although the striated pattern of LDD is quite characteristic.

The differential diagnosis of MB in adults differs. The most common parenchymal posterior fossa mass in adults is metastasis.

Medulloblastoma With Extensive

Nodularity

MBs with extensive nodularity (MBENs) occur almost exclusively in infants, and most all are Shh pathway MBs. The expanded lobular ("nodular") architecture of MBENs is the major histologic feature that differentiates them from CMB and desmoplastic MB.

Imaging studies demonstrate striking nodularity. Off-midline or paramidline location is more common. T1 C+ MR scans show multifocal grape-like tumor masses that enhance strongly and uniformly.

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Desmoplastic/Nodular Medulloblastoma

Desmoplastic MB (DMB) is an MB variant characterized by nodules of neuronal maturation in a dense intercellular reticulin fiber network. There is a strong association between desmoplastic histology and Shh subtype; almost all adult and 90% of infant DMBs belong to the Shh subgroup.

DMBs account for 15-20% of MBs, but prevalence varies significantly with patient age. DMBs cause about 40% of MBs in infants but only 10% of adult MBs.

The vermis is the customary location in children. Adult DMBs are often located laterally within the cerebellar hemispheres (21-11). DMBs have a somewhat better prognosis than classic, anaplastic, or large cell MBs.

(21-9A) NECT in an 8y boy with confusion, headache, and 3 weeks of vomiting shows a mildly hyperdense mass in the midline posterior fossa that fills the fourth ventricle . Obstructive hydrocephalus and a small focus of calcification in the mass are present. (21-9B) Sagittal T2WI shows that the mass fills the fourth ventricle and extends posteroinferiorly through the foramen of Magendie into the cisterna magna .

(21-9C) Axial DWI in the same case shows that the mass exhibits uniformly restricted diffusion. (21-9D) Axial T1 C+ FS shows mild irregular enhancement in the center of the mass. This is group 4, classic histology, WHO grade IV, standard risk.

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Imaging findings that suggest DMB include off-midline location (adults), multiple peripheral small cysts, and focal areas of T2/FLAIR isoor hypointensity that enhance on T1 C+.

Large Cell/Anaplastic

Medulloblastoma

Large cell MB (LCMB) is the rarest histologic variant, accounting for just 2-4% of cases. LCMBs have considerable cytologic overlap with anaplastic MBs and are often grouped together as "large cell/anaplastic medulloblastoma" (LC/A MB). LC/A MBs are generally Shh, group 3, or group 4 molecular subtypes. Both LCMBs and anaplastic MBs have a dismal prognosis.

Marked but inhomogeneous enhancement is typical. There are no reported imaging features that distinguish LCMB from anaplastic MB.

(21-10A) Sagittal T1WI in a 4y boy with vomiting and bulging fontanelle shows a mixed isoand hypointense mass in the midline posterior fossa. (21-10B) Sagittal T2WI in the same case shows that the mass bulges into the 4th ventricle and is isoto mildly hyperintense compared with gray matter.

(21-10C) Sagittal T1 C+ shows strong but patchy enhancement in the mass. Note subtle pial enhancement along the tectum, in the hemispheric sulci, and coating the spinal cord . (21-10D) Sagittal T2WI (L) shows thickened nodular "lumpybumpy" hyperintensity along the distal spinal cord. Sagittal T1 C+ (R) shows that these are enhancing pial metastases. This is group 3 MB with CSF dissemination at initial presentation.

MEDULLOBLASTOMA VARIANTS

Desmoplastic Medulloblastoma

•SHH-activated

•Young children, second peak in young adults

•Off-midline location in adults, vermis in children

Medulloblastoma With Extensive Nodularity (MBEN)

•Infants

•Off-midline or paramidline > midline

•Multifocal grape-like tumor masses

Large Cell/Anaplastic Medulloblastoma (LC/A)

•All molecular subtypes represented except WNTactivated (very rare)

○Most group 3, SHH/TP53-mutant MBs

○Generally high-risk tumors (early CSF spread)

•No distinctive imaging features

Other CNS Embryonal

Tumors

CNS embryonal neoplasms other than medulloblastoma (MB) are a heterogeneous group of tumors composed of poorly differentiated cells that may express neuronal and/or glial markers. These non-MB embryonal tumors have undergone substantial alterations in classification, with deletion of the term primitive neuroectodermal tumor (PNET) and the recognition that many embryonal neoplasms display amplification of the C19MC region on chromosome 19.

In addition to many pediatric CNS embryonal tumors that were formerly designated as PNETs, the new group of

C19MC-amplified embryonal tumors (ETMRs) includes entities variously called ETANTR (embryonal tumor with

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abundant neuropil and true rosettes), ependymoblastoma, and medulloepithelioma.

Embryonal Tumor With Multilayered

Rosettes, C19MC-Altered

Terminology

ETMRs are aggressive CNS embryonal tumors that are characterized histologically by multilayered rosettes and genetically by amplification or fusion in the C19MC locus at 19q13.42.

Pathology

Approximately 70% of ETMRs are supratentorial masses that appear relatively well demarcated with little surrounding edema. Tumors are often more than 5 cm in diameter, and some are massive lesions that occupy much of the cerebral

(21-11A) Axial T1WI in a

24y woman with headaches and dizziness shows a mildly hypointense mass in the right cerebellar hemisphere. (21-11B) T2WI in the same case shows that the mass is hyperintense compared with cortex.

(21-11C) T1 C+ FS in the same case shows strong, uniform enhancement in the solid, lobulatedappearing mass . (2111D) DWI shows that the mass restricts strongly and uniformly . Desmoplastic medulloblastoma was found at surgery. Most desmoplastic medulloblastomas in the lateral cerebellum are SHH-activated, low-risk tumors of children and adults.

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(21-12A) Axial T1WI in a

22y woman with headaches shows an illdefined hyperintense massin the left brachium pontis. (21-12B) T2WI in the same case shows that the mass is heterogeneously hyperintense and compresses and displaces the lateral recess of the fourth ventricle but does not invade it.

(21-12C) Axial DWI in the same case shows that the mass restricts strongly. Surgery disclosed classic histology, WNT-activated. This is considered a lowrisk tumor. The patient is alive and well 5 years later. (21-12D) Axial T1 C+ FS shows mild enhancement in the brachium pontis mass .

(21-12E) More inferior axial T1 C+ FS shows an enhancing mass near the left foramen of Luschka. Note pial enhancement , suggesting CSF metastases. (21-12F) Coronal T1 C+ shows that the enhancing mass is immediately adjacent to the foramen of Luschka. This is WNT medulloblastoma, classic histology. The patient is alive 3 years after initial diagnosis.

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(21-13A) Axial T1WI in a

32y man with ataxia shows expansion and deformity of the right pons and brachium pontis. Note mass effect on the 4th ventricle and ill-defined hypointensities in the right cerebellar hemisphere and vermis. (21-13B) Axial T2WI in the same case shows multifocal patchy hyperintensities in both cerebellar hemispheres, the vermis, and the pons.

(21-13C) FLAIR in the same case shows the extensive patchy hyperintensities , misshapen right pons, and brachium pontis . (2113D) T1 C+ FS shows no enhancement.

(21-13E) DWI shows no evidence for restricted diffusion. (21-13F) Axial ADC shows patchy foci of T2 "shine through" without evidence for restricted diffusion. This is biopsy-proven classic histology medulloblastoma, WHO IV. Molecular profile was not obtained. Occasionally a diffusely infiltrating medulloblastoma presents without a dominant enhancing mass.

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hemispheres. The cerebellum and brainstem are the primary site in 30% of cases.

On cut section, ETMRs are soft grayish pink to purplish masses that frequently contain areas of necrosis (21-14). Intratumoral cysts and hemorrhage are common.

Microscopically, ETMRs contain abundant neuropil and true rosettes with a pseudostratified neuroepithelium surrounding a central round or slit-like lumen. Mitoses are frequent, and CSF dissemination is common. Most ETMRs exhibit high LIN28A protein expression, considered a potent diagnostic immunohistochemical marker for this neoplasm.

C19MC-altered ETMR corresponds histologically to WHO grade IV.

(21-14) Autopsy (L) and antemortem FLAIR scan

(R) in an 8m infant with a supratentorial embryonal neoplasm show a large, aggressive-looking hemispheric mass with confluent areas of necrosis and hemorrhage. There is relatively little peritumoral edema. (Courtesy R. Hewlett, MD.) (21-15A) Axial T1WI in an infant with macrocephaly shows a very large right frontal mass with areas of necrosis and hemorrhage .

(21-15B) T2WI in the same patient shows that the mass is relatively well demarcated and mostly hyperintense with heterogeneously hypointense foci of hemorrhage . (21-15C) The lesion restricts on DWI . This is a supratentorial embryonal neoplasm (formerly designated as PNET). (Courtesy G. Hedlund, DO.)

Clinical Issues

Almost all ETMRs occur under the age of 4 years, with the majority occurring in the first 2 years of life. Increasing head circumference and signs of elevated intracranial pressure are common. Headache, nausea, vomiting, and visual disturbances are typical presenting symptoms.

Imaging

General Features. ETMRs grow rapidly and are often very large, heterogeneous-appearing masses that cause gross distortion and effacement of the underlying brain architecture

(21-15).

CT Findings. A complex, heterogeneously isoto hyperdense mass with mixed cystic and solid components is typical on NECT. Necrosis and intratumoral hemorrhages are common, as are dystrophic calcifications. CECT scans show moderate but heterogeneous enhancement.

MR Findings. All sequences exhibit heterogeneous signal intensity with T1 shortening (21-15A) and T2* blooming secondary to intratumoral hemorrhage. T2/FLAIR hyperintensity in cystic or necrotic segments and isointensity in the solid portions of the mass are typical. Peritumoral edema is typically minimal or absent (21-16).

Because of their relatively dense cellularity, C19MC-altered ETMRs may show foci of moderately restricted diffusion (2115C) (21-16D). pMR shows areas of elevated rCBV and vascular permeability.

Heterogeneous enhancement with solid and rim enhancement is typical (21-17) (21-18).

Differential Diagnosis

The differential diagnosis of C19MC-altered ETMR in infants and children includes other bulky hemispheric masses, including AT/RT, RELA fusion-positive ependymoma,

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astroblastoma, glioblastoma, and the rare CNS neuroblastoma or ganglioneuroblastoma.

Other CNS Embryonal Tumors

To date, medulloblastoma, C19MC-altered ETMRs, and atypical teratoid/rhabdoid tumor (AT/RT) are the only genetically defined CNS embryonal neoplasms in the 2016 WHO.

Several rare CNS embryonal tumors without current molecular classification in the 2016 WHO include medulloepithelioma, CNS neuroblastoma (NB), and CNS ganglioneuroblastoma. Embryonal tumors that lack the specific histopathologic features or molecular alterations that define other CNS neoplasms are designated as CNS embryonal tumor, NOS.

(21-16A) Axial T1WI in a

2y girl shows a large mass of mixed signal intensitythat occupies most of the right cerebral hemisphere. (21-16B) Axial T2 FS MR in the same case shows that the mass is very heterogeneously hyperintense and relatively well demarcated. There is no discernible surrounding edema.

(21-16C) Axial T1 C+ MR shows mild to moderate patchy enhancement in some portions of the mass, whereas others show little or no enhancement . (2116D) ADC map shows that solid portions of the tumor exhibit restricted diffusion. Embryonal tumor with multilayered rosettes, C19MC-altered, was documented. (Courtesy M. Warmuth-Metz, MD.)

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Medulloepithelioma

Medulloepithelioma (ME) is an embryonal tumor characterized by papillary tubular arrangements of neoplastic neuroepithelium that mimic the embryonic neural tube. C19MC alterations are rare or absent. Mitotic figures are common with MIB-1 often exceeding 50%.

Almost all patients are younger than 5 years at the time of diagnosis. Half are under the age of two. Symptoms of elevated intracranial pressure are the typical presentation.

MEs are often massive tumors that replace much of the affected hemisphere and appear very heterogeneous on both CT and MR. Cysts, calcification, and sometimes hemorrhagic foci are common. There are no imaging features that distinguish MEs from C19MC-altered ETMRs.

(21-17A) Axial T2WI in 3y child shows large, very heterogeneous left frontal lobe mass with both solid, mixed cystic/solid , and cystic-appearing portions . (21-17B) T1 C+ FS shows minimal enhancement in solid portions of mass. Histologic diagnosis was ETANTR. In new 2016 WHO, this would either be C19MC-amplified embryonal tumor or designated as CNS embryonal tumor, NOS. (Courtesy T. Poussaint, MD.)

(21-18A) T2WI in newborn with macrocrania, nystagmus, periodic breathing, and bulging fontanelle shows predominantly necrotic, partially hemorrhagic hemisphere mass with hemosiderin staining around mass and over the cerebrum. (21-18B) This T1WI C+ shows the rim of the tumor enhances . Note enhancement over the pia and around the ventricular ependyma . This is CNS embryonal neoplasm, NOS. (Courtesy G. Hedlund, DO.)

CNS Neuroblastoma

Craniocerebral NB can be either secondary or primary. Secondary disease is far more common than primary CNS NB and so is discussed first. NB is notorious for its diverse manifestations (one of the "great mimickers") and can masquerade as primary neurologic disease in a child with an unexplained neurologic disorder.

Secondary (Metastatic) Neuroblastoma. NB is a neuroendocrine tumor that arises from neural crest elements, usually within the adrenal gland or sympathetic nervous system. It is the most common extracranial solid cancer in childhood and the most common overall cancer of infants. NB accounts for 10-15% of all childhood malignancies, following leukemia and primary brain tumors in prevalence.

Clinical Issues. Metastases are present in almost 70% of NB patients at the time of initial diagnosis. Skeletal metastases are the most common manifestation. Approximately 25%

occur in the orbit, calvaria, and skull base. The classic clinical manifestation of orbital metastatic NB is a child with proptosis and "raccoon eyes."

CNS involvement by metastatic NB is uncommon and generally occurs as a late complication of stage IV disease (3- year risk = 8%). CNS NB metastases are usually detected at the time of disease recurrence rather than initial diagnosis.

Imaging. NECT shows one or more hyperdense soft-tissue masses with orbit, skull, scalp, and/or extradural components. Bone CT shows fine "hair on end" spicules of the periosteal bone that project from the skull or greater sphenoid wings (21-19). Multiple bilateral lesions involving both the inner and outer tables of the skull are typical. Lytic defects and widened indistinct sutures are other common findings.

MR shows an extraaxial mass that is heterogeneously hypointense to brain on both T1and T2WI. Strong enhancement following contrast administration is typical.

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Linear hypointensities that represent the "hair on end" bony spicules can sometimes be identified within the strongly enhancing masses (21-20).

CNS lesions are uncommon, appearing as a parenchymal (2121), an intraventricular, or even a spinal cord mass. Disseminated leptomeningeal disease is rare.

Nuclear medicine studies are helpful in the early evaluation of NB. Metaiodobenzylguanidine (MIBG) imaging is the most sensitive and specific imaging modality to determine primary and metastatic disease. F18 FDG PET is helpful in depicting stage I and II NB.

The major imaging differential diagnosis of NB metastatic to the calvaria is leukemia. Both often have duraor calvariabased masses, but parenchymal lesions are much more common with leukemia than with NB.

(21-19A) Axial bone CT is of a 9m boy with proptosis, stage IV suprarenal neuroblastoma identified on abdominal CT (not shown). Note the striking orbital spiculated periostitis with adjacent soft tissue masses . (Courtesy S. Blaser, MD.) (21-19B) More cephalad scan in the same patient shows the classic "hair on end" appearance of metastatic neuroblastoma. (Courtesy S. Blaser, MD.)

(21-20A) T1 C+ FS in metastatic neuroblastoma shows bilateral enhancing soft tissue masses and "hair on end" neoplastic periostitis . (21-20B) Coronal T1 C+ FS shows metastases with striking "hair on end" neoplastic periosteitis . (Courtesy C. Y. Ho, MD.)

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Other lesions that can present with lytic bone lesions include

Langerhans cell histiocytosis (LCH). Both can present with dura-based masses, but the spiculated periosteal reaction of metastatic NB is absent in LCH.

Primary CNS Neuroblastoma. Primary CNS NB is much less common than secondary disease. If a supratentorial embryonal neoplasm displays only neuronal differentiation, then by definition it is a cerebral NB. Imaging findings are indistinguishable from those of other PNETs, i.e., a large hemispheric mass with necrosis, hemorrhage, and strong but heterogeneous enhancement following contrast administration.

Esthesioneuroblastoma

Terminology. Esthesioneuroblastoma (ENB)—also known as olfactory neuroblastoma—is a rare malignant neuroectodermal tumor that arises in the superior nasal cavity (21-22). ENBs are a type of "small round blue cell tumor" that

(21-21A) Sagittal T1WI in a 3y girl with seizures and systemic metastases from an extensive retroperitoneal neuroblastoma shows a hyperintense cysticappearing parietal masswith a solid hypointense mural nodule. (21-21B) Axial T2WI in the same case shows that the cyst contents are hyperintense , whereas the irregularly shaped nodule is hypointense compared with adjacent cortex.

(21-21C) DWI in the same case shows facilitated diffusion in the cyst and restricted diffusion in the hypercellular tumor nodule . (21-21D) Sagittal T1 C+ SPGR shows that the tumor nodule demonstrates mild enhancement . Note diffuse sulcal enhancement from CSF metastases . Parenchymal metastases from extracranial neuroblastoma are rare.

may be difficult to differentiate from other tumors such as lymphoma and Ewing sarcoma.

Etiology. ENBs are tumors of neural crest origin that probably arise from basal cells of the olfactory epithelium. There are no known risk factors.

ENBs and other sinonasal neuroendocrine tumors (sinonasal neuroendocrine carcinoma, sinonasal undifferentiated carcinoma) overexpress ASCL1. The neurotrophin receptors TrkA and TrkB are also strongly expressed in almost all ENBs. TrkB overexpression participates in tumorigenesis through ERK and Akt pathway activation.

Pathology. As they are primarily extracranial neoplasms, ENBs are not graded according to WHO criteria. ENBs appear grossly as submucosal lobulated, moderately vascular masses.

The modified Kadish classification is used for staging and recognizes four stages: stage A, tumors that are localized to

the nasal cavity; stage B, nasal cavity and paranasal sinuses; stage C, orbital and intracranial extension; stage D, cervical and distant metastases.

Histologic grading uses the Hyams system with grades I-IV based on nuclear pleomorphism, mitoses, and necrosis. ENBs are divided into low-grade (Hyams I-III) and high-grade (Hyams IV) tumors.

Low-grade ENBs feature a lobular architecture with neurofibrillary intercellular matrix and pseudorosette formation. Mild nuclear pleomorphism with infrequent mitoses is typical. Electron microscopy demonstrates neurosecretory granules. To date, no studies clearly prove molecular differences between lowand high-grade ENBs.

Clinical Issues. ENBs account for approximately 2-3% of all nasal cavity tumors.

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ENBs have a wide age range with a bimodal peak in the second and sixth decades of life. ENB is usually not a diagnostic consideration in children.

The most common symptoms are nasal obstruction and epistaxis. ENBs with intracranial extension may present with headache, proptosis, and cranial neuropathies.

Overall 5-year survival rate is approximately 75% but varies with Kadish stage. Five-year survival ranges from over 90% (Kadish A) to under 35% (Katish D). Local recurrence is common (30%). Nodal and/or distant metastases to lung, bone, and liver develop in 10-30% of patients.

Imaging. The typical finding in ENB is a superior nasal cavity mass at the cribriform plate. A "dumbbell" shape—the upper portion in the anterior cranial fossa and the lower portion in the nose with the narrowest aspect at the cribriform plate—is seen with large masses (21-22).

(21-22) Coronal graphic depicts esthesioneuroblastoma (ENB) as a large nasal mass with cephalad intracranial extension through the cribriform plate . (21-23) Coronal bone CT shows an ENB filling the upper nasal cavity and ethmoid sinuses . The lesion extends through the anterior skull base . The right lamina papyracea is thinned and laterally displaced . (From DI: Head and Neck, 3e.)

(21-24A) Coronal T2 FS in a 47y woman shows a classic ENB filling the nasal cavity and ethmoid sinuses. The lesion extends superiorly into the anterior cranial fossa and laterally into the right orbit . Note cysts at the tumor-brain interface , a common finding with ENBs. (21-24B) Coronal T1 C+ FS in the same case shows the ENB enhances strongly, moderately uniformly. Note tumor-associated cysts , obstructed right maxillary sinus .

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CT Findings. Bone CT shows expansile bone remodeling mixed with bone destruction, especially of the cribriform plate (21-23). Speckled intratumoral calcification is unusual. A homogeneously enhancing mass on CECT is typical.

MR Findings. ENB is hypoto isointense compared with brain on T1WI and isoto hyperintense on T2WI. Areas of cystic degeneration and intratumoral hemorrhage are common. Some large ENBs that extend intracranially have benign nonneoplastic tumor-associated cysts around their superior and lateral margins at the tumor-brain interface. ENBs generally enhance strongly and relatively uniformly (21-24).

ENB spread to cervical lymph nodes is common, typically spreading first to level II nodes, with frequent involvement of level I, level III, and retropharyngeal nodal groups at later stages. Nodes harboring metastatic disease are predominantly solid and demonstrate avid contrast enhancement.

PET/CT. 18F FDG PET/CT is a useful adjunct to conventional imaging in the initial staging or subsequent restaging of ENB. Nodal and distant metastatic disease, as well as local recurrence obscured by treatment changes on standard imaging, can be depicted. PET/CT changes previously assigned disease stage and alters patient management in nearly 40% of cases with more than one-third of tumors upstaged.

Differential Diagnosis. The major differential diagnoses of ENB with intracranial extension are sinonasal squamous cell carcinoma (SCCa) and sinonasal neuroendocrine carcinoma

(SNEC). Sinonasal SCCa is more common in the maxillary antrum than in the nose and does not enhance as intensely as ENB. SNECs develop in the superior or posterior nasal cavity, often extending into the maxillary or ethmoid sinuses. Patients with sinonasal adenocarcinoma often have a history of occupational or wood dust exposure.

Sinonasal undifferentiated carcinoma (SNUC) may be difficult to distinguish from ENB on imaging alone. Sinonasal non-Hodgkin lymphoma is typically hyperdense on NECT, restricts on DWI, and rarely extends directly superiorly into the skull base and anterior fossa. Sinonasal melanoma favors the lower nasal cavity as its site of origin (septum, turbinates). T1 hyperintensity and T2 hypointensity are classic MR findings.

Anterior skull base (cribriform plate) meningioma typically causes hyperostosis and exhibits a "sunburst" pattern of vascularity with the central tumor supplied by dural branches of the carotid arteries. Peritumoral cysts are not a distinguishing feature, as they occur with both meningiomas and ENBs.

New Molecularly Defined Embryonal

Neoplasms

A significant proportion of tumors originally diagnosed as CNS-PNETs demonstrate ambiguous small-cell morphology, making it difficult to classify on the basis of histology alone and highlighting the diagnostic necessity of utilizing molecular markers.

In addition to the well-recognized molecularly defined CNS embryonal neoplasms, recent studies have identified four new tumor entities with specific genetic alterations and distinct histopathologic and clinical features. These new molecularly defined entities have been designated as CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2), CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC), CNS highgrade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1), and CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR).

All these tumors are rare, WHO grade IV malignant neoplasms that tend to affect infants and young children although they may also occur in adolescents and adults. They typically present as large, bulky supratentorial hemispheric masses that are characterized by imaging findings that are indistinguishable from other CNS embryonal neoplasms.

Malignant Rhabdoid

Tumors

Malignant rhabdoid tumors (MRTs) are aggressive tumors that were first described in the kidneys and soft tissues of infants and young children. Cranial rhabdoid tumors were subsequently recognized as a distinct pathologic entity and termed atypical teratoid/rhabdoid tumor (AT/RT). AT/RTs are separated from other CNS embryonal neoplasms and nonCNS MRTs by distinct immunohistochemical, histopathologic, and molecular features.

Atypical Teratoid/Rhabdoid Tumor

Terminology

AT/RT is a malignant CNS embryonal tumor composed of poorly differentiated elements and malignant rhabdoid cells.

Etiology

AT/RT is now a genetically-defined tumor characterized by deletions and biallelic inactivating mutations of the SMARCB1/SNF5 gene. Loss of the SMARCB1 protein in AT/RT results in unopposed expression of LIN28B (a key gene in embryonic development and for the maintenance of pluripotency in stem cells) and related oncogenes such as CCND1.

AT/RT is not a homogeneous disease even though these tumors are all characterized by the prototypic loss of expression of SMARCB1 (or SMARCA4 in the rare SMARCB1 wild-type cases). Molecular profiling has identified three epigenetically and clinically distinct AT/RT subgroups, currently designated as ATRT-TYR, ATRT-SHH, and ATRT-MYC.

ATRT-TYRs have broad SMARCB1 deletions exhibiting overexpression of melanosomal genes. ATRT-SHH tumors have focal SMARCB1 aberrations with overexpression of SHH pathway. ATRT-MYCs also have focal SMARCB1 deletions but overexpress the MYC and HOX clusters.

Pathology

Location. AT/RTs occur in both the supraand infratentorial compartments. Location is correlated with epigenetic subgroup.

Slightly more than half of AT/RTs are supratentorial, usually occurring in the cerebral hemispheres (21-25) although cases in other sites (including the suprasellar cistern, ventricles (2126), and pineal gland (21-27)) have been reported. Most supratentorial AT/RTs are ATRT-MYC or ATRT-SHH subtypes.

Posterior fossa AT/RTs preferentially occur in the cerebellar hemispheres (21-28) although they can occur in the fourth ventricle, where they mimic medulloblastoma (21-29). Other less frequent sites include the cerebellopontine angle and brainstem. All three molecular subgroups can occur in the infratentorial compartment although the posterior fossa is the site of almost 75% of ATRT-TYR neoplasms.

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AT/RT: ETIOLOGY AND PATHOLOGY

Etiology

•Loss of expression of SMARCB1 protein (INI1) required for diagnosis

○SMARCB1 wild-type has SMARCA4 mutations

•Loss of part or all of chromosome 22

•3 epigenetically distinct AT/RT subgroups

○ATRT-TYR, ATRT-SHH, ATRT-MYC

Pathology

•Supratentorial ~ 50%

○Most are ATRT-MYC or ATRT-SHH

•Infratentorial ~ 50%

○All 3 subgroups (75% of ATRT-TYR)

•Poorly differentiated neuroepithelial elements + rhabdoid cells

•WHO grade IV

(21-25A) NECT in an 18m girl with vomiting for 1-2 weeks shows a mixed, mostly hyperdense right frontal mass with marked vasogenic edema. (21-25B) T2WI shows that the mass has mixed, mostly hypoand isointense signal intensity.

(21-25C) T1 C+ shows diffuse but very heterogeneous enhancement. (21-25D) ADC map shows marked diffuse restriction due to the high cellularity of the tumor. MRS (not shown) demonstrated elevated Cho and lactate. Histologic diagnosis was atypical teratoid/rhabdoid tumor (AT/RT). (Courtesy B. Jones, MD.)

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Gross Pathology. The gross appearance—a large, soft, fleshy, hemorrhagic, necrotic mass—is similar to that of other CNS embryonal neoplasms.

Microscopic Features. AT/RTs are composed of poorly differentiated neural, epithelial, and mesenchymal elements together with prominent rhabdoid cells. Loss of nuclear staining for INI1 is diagnostic of AT/RT.

Clinical Issues

Epidemiology. AT/RT accounts for 1-2% of all pediatric brain tumors. Most occur in children under 5 years of age. Peak incidence is between birth and 2 years, and some investigators suggest that AT/RT accounts for at least 10% of all CNS neoplasms in infants. AT/RT does occur in adults but is rare. There is a moderate male predominance.

AT/RT can occur sporadically or in rhabdoid tumor predisposition syndrome (RTPS). RTPS is a familial cancer

(21-26A) Sagittal T1WI in an 18m girl with vomiting and lethargy shows a large lobulated, mixed- signal-intensity mass in the third ventricle. (2126B) Axial T2WI in the same case shows that the mass is heterogeneously hyperintense and extends into the frontal horns of both lateral ventricles , causing severe obstructive hydrocephalus.

(21-26C) Axial DWI in the same case shows that the mass exhibits strong diffusion restriction. (2126D) Axial T1 C+ FS in the same case shows that the mass enhances moderately but quite heterogeneously. AT/RT was found at surgery. The patient survived 11 months.

syndrome characterized by a markedly increased risk of developing MRTs—including AT/RT—caused by loss or inactivation of the SMARCB1 gene (less commonly, the mutation involves the SMARCA4 gene). Pedigree analysis supports an autosomal-dominant inheritance pattern with incomplete penetrance.

Patients with RTPS may develop an AT/RT with a synchronous renal or extrarenal MRT. Children with RTPS and AT/RT are even younger, have more extensive disease, and experience more rapid progression. Other CNS tumors associated with RTPS include choroid plexus carcinoma and rhabdoid meningioma.

Natural History. AT/RT is a highly malignant tumor with generally poor prognosis. Median survival is around 17 months. Most children die within 6 to 8 months despite aggressive therapy. Survival in adults is somewhat better, averaging 2 years.

AT/RT: CLINICAL ISSUES

Epidemiology

•1-2% of pediatric brain tumors

○Children < 5 years, most < 2 years

○10% of CNS neoplasms in infants

○Occasionally occur in adults (rare)

Rhabdoid Tumor Predisposition Syndrome

•Malignant rhabdoid tumors

•Choroid plexus carcinoma

Imaging

General Features. AT/RT shares many imaging features with other embryonal tumors, i.e., they are densely cellular neoplasms that frequently contain hemorrhage, necrosis, cysts, and calcifications. A moderately large, bulky tumor with

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mixed solid and cystic components and heterogeneous density/signal intensity is typical.

CSF dissemination is common, so the entire neuraxis should be imaged prior to surgical intervention.

CT Findings. NECT scan shows a mildly to moderately hyperdense mass with cysts and hemorrhagic foci (21-25A) (21-27). Calcification and obstructive hydrocephalus—especially with posterior fossa AT/RT—are common (21-29A). Enhancement is typically strong but heterogeneous.

MR Findings. AT/RTs are heterogeneously hypoto isointense to brain on T1WI and isoto hyperintense on T2WI (21-25). "Blooming" foci on T2* (GRE, SWI) are common. Mild to moderate diffusion restriction is present (21-25D). MRS shows elevated Cho and decreased or absent NAA.

(21-27A) Axial NECT in a

4y girl with a 1-month history of headache and vomiting shows a hyperdense mass in the pineal region, causing severe obstructive hydrocephalus. (21-27B) Sagittal T2WI in the same case shows a pineal gland mass that appears isointense with the adjacent brain.

(21-27C) Sagittal T1 C+ in the same case shows that the mass enhances strongly but slightly heterogeneously. (2127D) Axial DWI shows the mass exhibits restricted diffusion. Preoperative diagnosis was pineoblastoma. AT/RT was found at surgery. The patient is alive 11 months after surgery with adjuvant chemotherapy.

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Enhancement on T1 C+ is strong but heterogeneous (21-26). Leptomeningeal spread is present in 15-20% of cases at the time of initial imaging.

Differential Diagnosis

The major differential diagnosis for supratentorial AT/RT includes C19MC-altered embryonal neoplasm, RELA-fusion ependymoma, teratoma, and malignant astrocytoma. As all of these may be bulky—even massive—tumors with very heterogeneous imaging appearance, definitive diagnosis requires biopsy and SMARCB1 (INI1) staining.

The major differential diagnosis for posterior fossa AT/RT is medulloblastoma. These tumors can look virtually identical on imaging studies (21-29) (21-30).

(21-28A) NECT in a 4m boy with vomiting, head tilt, and bulging fontanelle shows a partially solid , partially cystic-appearingposterior fossa mass that exhibits focal calcifications . (21-28B) Axial T1WI in the same case shows that the massis mixed iso- /hypointense compared with gray matter.

(21-28C) Coronal T2WI in the same case shows that the mixed solid , cysticmass is causing severe obstructive hydrocephalus. (21-28D) Axial T1 C+ FS shows the solid components of the mass enhancing strongly but heterogeneously. The cysts exhibit rim enhancement . This is AT/RT, WHO grade IV.

AT/RT: IMAGING AND DIFFERENTIAL DIAGNOSIS

Imaging

•Heterogeneous, hyperdense on NECT

•Heterogeneous on both T1, T2

•Enhances strongly but heterogeneously

•CSF spread in 15-20% at diagnosis

•Restricts on DWI

Differential Diagnosis

•DDx of supratentorial AT/RT

○CNS embryonal tumor, C19MC-altered

○RELA-fusion ependymoma, teratoma, malignant astrocytoma

•DDx of posterior fossa AT/RT

○Medulloblastoma (midline AT/RT may be indistinguishable)

Other CNS Neoplasms With

Rhabdoid Features

CNS embryonal tumor with rhabdoid features is a highly malignant neoplasm composed of poorly differentiated elements and rhabdoid cells with SMARCB1 or SMARCA4 expression. These extremely rare tumors correspond histologically to WHO grade IV.

Rhabdoid meningioma is an uncommon WHO grade III meningioma subtype that contains sheets of rhabdoid cells. Most have high proliferative indices and exhibit other cytologic features of malignancy. Rhabdoid meningiomas are very rare in infants and retain INI1 staining, which differentiates them histopathologically from AT/RT.

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CNS NEOPLASMS WITH RHABDOID FEATURES

Rhabdoid Glioblastoma

•GBM + rhabdoid cells (SMARCB1 loss)

•Younger than typical GBM

•Extracranial metastases common

Embryonal Neoplasm With Rhabdoid Features

•WHO IV tumor with differentiated rhabdoid cells

•SMARCB1/4 mutation

Rhabdoid Meningioma

• Rhabdoid features without SMARCB1 mutation

Rhabdoid Predisposition Syndrome

•SMARCB1 germline mutation/deletion

•AT/RT, choroid plexus carcinoma, medulloblastoma

(21-29A) NECT in a 3y boy with morning emesis for 4-6 weeks shows a hyperdense mass in the fourth ventricle. Note intratumoral calcifications . There is no evidence for obstructive hydrocephalus. (21-29B) T1 C+ shows that the mass enhances heterogeneously. Preoperative diagnosis was medulloblastoma. Histologic examination revealed AT/RT, WHO grade IV.

(21-30A) Sagittal T2WI in a 6m girl with lethargy and vomiting shows a heterogeneous-appearing mass in the fourth ventricle causing severe obstructive hydrocephalus. (21-30B) Sagittal T1 C+ in the same case shows that the massenhances very heterogeneously. Preoperative diagnosis was medulloblastoma. AT/RT was found at surgery. Imaging findings of posterior fossa AT/RTs can be indistinguishable from MB.