Embryonal Tumors

Main Text

Preamble

The rapidly evolving molecular classification of brain tumors has fundamentally changed the understanding of embryonal neoplasms. In the 2021 WHO schema, the classification of the largest group of embryonal neoplasms—medulloblastoma—was revised to reflect clinically relevant molecular subgroups.

The 2021 WHO classification recognizes two general categories of embryonal tumors: (1) Medulloblastoma (MB) (relatively common) and (2) other CNS embryonal tumors (rare). The term primitive neuroectodermal tumor (PNET) was previously removed from the diagnostic lexicon in the 2016 classification scheme. The tumors formerly included in this now-obsolete category have recently been redefined using molecular data and are now included in the “other CNS embryonal tumors.”

We begin this chapter with an in-depth discussion of MB that follows the 2021 WHO, 5th edition presentation of this biologically heterogeneous neoplasm. We conclude the chapter with a brief discussion of the less common embryonal tumors.

Medulloblastoma

Histology and Genetics

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 account for ~ 20% of childhood CNS neoplasms.

MB is not a single tumor entity but a heterogeneous cluster of multiple distinct, clinically relevant molecular subgroups. International consensus now recognizes five molecular subgroups, each differing in its demographics, recommended treatments, and clinical outcomes.

All MBs are designated CNS WHO grade 4 even though certain molecular groups and subgroups (e.g., WNT-activated tumors) have a good therapeutic response and cure is possible in some cases.

Medulloblastoma, Histologically Defined

MBs consist of densely packed small round poorly differentiated (“blue”) cells. Moderate nuclear pleomorphism and a high mitotic index (MIB-1 or Ki-67) are characteristic.

The 2021 WHO classification recognizes four morphologic subtypes of medulloblastoma: (1) Classic MB, (2) desmoplastic/nodular (D/N) MB, (3) MB with extensive nodularity (MBEN), (4) large cell/anaplastic (LC/A) MB. All MBs are currently designated as CNS WHO grade 4 neoplasms.

Classic MBs are typically located in the cerebellar midline and involve the fourth ventricle (24-1). D/N MBs may arise both in the cerebellar hemisphere and vermis. D/N MBs in adults often arise in the lateral cerebellum (24-2). MBENs are typically located in the vermis and frequently involve both cerebellar hemispheres (24-9). LC/A MBs usually involve the fourth ventricle, brainstem, and adjacent cerebellum (24-3).

Medulloblastoma, Genetically Defined

MB is a genetically heterogeneous disease with five main molecular subgroups: (1) WNT-activated, (2) SHH-activated and TP53-wildtype, (3) SHH-activated and TP53-mutant, (4) non-WNT/non-SHH, group 3and (5) non-WNT/non-SHH, group 4. Groups 3 and 4—the non-WNT/non-SHH MBs—are further divided by DNA methylation profiling into eight subgroups.

All MB subtypes have different origins, preferred anatomic locations, and demographics, as well as different prognosis and therapeutic implications. Each of these subtypes has been further subdivided into distinctive molecular subgroups, adding more precision to patient-based risk stratification.

WNT-Activated Medulloblastomas

WNT-activated MB (WNT-MB) is the smallest molecular subgroup (10%) and appears strikingly different from the other MBs in origin, appearance, and prognosis. WNT-MBs are lateralized tumors that arise from the lower rhombic lip in the dorsolateral primitive brainstem around the foramen of Luschka and cerebellar peduncle (24-3).

WNT-MBs are very rare in infants and usually affect older children and young adults. They almost always exhibit classic histology. Childhood patients with WNT-MBs have a favorable prognosis (five-year survival > 90%) and reduced intensity; risk-adapted therapies are often utilized.

Germline mutations in the WNT pathway inhibitor, APC, predispose individuals to develop MB in the setting of Turcot syndrome.

SHH-Activated and TP53-Wildtype Medulloblastomas

Overall, the two SHH-activated subgroups (distinguished by mutant or wildtype TP53) account for 25-30% of MBs. Both subgroups of SHH-activated MBs (SHH MBs) arise from granule neuron precursor cells, which are found in the external granular layer of the cerebellum. SHH MBs (both TP53- wildtype and TP53-mutant) comprise four provisional molecular subgroups (designated SHH-1 through 4) that can be demonstrated by DNA methylation or transcriptome profiling.

SHH MBs in infants frequently involve the vermis. In older children and young adults, SHH MBs are most often located laterally within the cerebellar hemispheres (24-2).

The majority of SHH MBs are TP53-wildtype. There is a high incidence of germline mutations (~ 40%) in SHH MBs, including basal cell nevus (Gorlin) syndrome.

Compared with other subgroups, SHH-activated TP53-wildtype MBs are more likely to have desmoplastic or nodular pathology.

All four clinical subtypes of SHH MB may have TP53-wildtype status. TP53-wildtype SHH MBs have an intermediate prognosis that is generally better than those with TP53mutations. However, specific gene alterations may alter the prognosis of patients within this subgroup.

SHH-Activated and TP53-Mutant Medulloblastomas

Non-WNT/Non-SHH Medulloblastoma

By definition, non-WNT/non-SHH MBs lack activation of the WNT and SHH signaling pathways.

Non-WNT/non-SHH MBs cluster into two groups (group 3 and group 4) and comprise eight molecular subgroups, as demonstrated by DNA methylation profiling. These MBs arise almost exclusively in the cerebellum, usually in the midline. Most exhibit classic histopathology. LC/A tumors can belong to either group.

Group 3 is the third largest MB subgroup (20-25%) and has the worst outcome. Group 3 tumors are common in infants but exceedingly rare in adults. MYC amplification is common, and ~ 50% of patients present with metastases at initial diagnosis (24-8). NOTCH1 has been identified as a pivotal driver of group 3 MB metastasis and self-renewal.

Group 4 is the largest (~ 35%) of the four molecular MB subgroups. Most group 4 MBs exhibit classic histology. Group 4 MBs affect all ages but are most common in children. The M:F ratio is 2:1. A minority of group 4 MBs present with metastasis. Overall prognosis is intermediate but poor in adults.

In both groups 3 and 4, MYC amplification plays an important role in prognosis, with those tumors expressing increasing MYC having a poorer prognosis.

Pathology, Clinical, and Imaging Features

Pathology

Location

While any histologic type can be found in any location, > 85% of classic, group 3, and group 4 MBs arise in the midline. They typically fill the fourth ventricle, displacing and compressing the pons anteriorly (24-1). Posteroinferior extension into the cisterna magna is common. Unlike ependymoma, lateral extension into the cerebellopontine angle is uncommon.

WNT-MBs are also found at the cerebellopontine angle and along the lateral recess of the fourth ventricle. SHH MBs are most often located in the cerebellar hemispheres. Occasionally, MB occurs as a diffusely infiltrating lesion without a focal dominant mass (24-3).

Microscopic Features

MBs are highly cellular tumors (small round blue cell tumor). Neuroblastic (Homer Wright) rosettes—radial arrangements of tumor cells around fibrillary processes—are found in 40% of cases.

Clinical Issues

Epidemiology and Demographics

Most MBs occur before the age of 10 years old; median patient age at diagnosis is nine years. There is a second, smaller peak in adults aged 20-40 years with up to 25% of MBs occurring in adults.

MBs occur in the setting of several inherited cancer syndromes, including nevoid basal cell carcinoma (Gorlin) syndrome with SUFU and PTCH1 mutations, TP53 mutations (Li-Fraumeni syndrome), and APC (familial adenomatous polyposis), among others.

Presentation

The most common clinical manifestations of MB are vomiting (90%) and headache (80%). Because of their location, MBs tend to compress the fourth ventricle and cause obstructive hydrocephalus.

Natural History

Risk varies with the molecular subgroup. For example, almost all WNT-MBs exhibit classic histology and are considered low-risk neoplasms.

Poor prognostic factors include metastatic disease at time of diagnosis, TP53 mutation, MYC amplification, non-WNT/non-SHH and LC/A histologies.

Imaging

The three main standard imaging phenotypes that can help predict MB molecular subgroups are (1) anatomic location (24-3), (2) enhancement pattern, and (3) metastasis. Radiomics and machine learning approaches have recently been reported as significantly improving the prediction of the MB subgroup in individual cases.

As 40-50% of MBs have CSF dissemination at the time of initial diagnosis, preoperative contrast-enhanced MR of the entire neuraxis is recommended.

CT Findings

NECT scans show a moderately hyperdense, relatively well-defined mass in the midline posterior fossa (classic MB) (24-4A), around the foramen of Luschka (WNT-subgroup MB) (24-7)or lateral cerebellum (SHH). Cyst formation (40%) and calcification (20-25%) are common (24-4B) (24-5A). Gross hemorrhage is uncommon. Enhancement patterns are variable.

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

MR Findings

Almost all MBs are hypointense relative to gray matter on T1WI (24-8A) and hyperintense on T2WI (24-5B). Peritumoral edema is present in 1/3 of cases. Obstructive hydrocephalus with periventricular accumulation of CSF is common and best delineated on FLAIR.

Because of their dense cellularity, MBs often show moderate restriction on DWI (24-6B), helping distinguish them from other posterior fossa tumors. pMR shows low rCBV and increased permeability. MRS typically reveals a small taurine peak, high Cho peak, decreased NAA peak, and increased Cho:Cr and Cho:NAA ratios.

Enhancement patterns show striking variation. 2/3 of MBs show marked enhancement, whereas 1/3 show only subtle (24-7B), marginal, or linear enhancement (24-5C). Multinodular and gyriform tumor masses that enhance strongly and uniformly can be seen in MBs with extensive nodularity (24-10B)(24-11).

Group 4 MBs often exhibit minimal or no enhancement. Enhancing leptomeningeal metastases at initial diagnosis are common (“sugar icing”) (24-12) and typically occur with groups 3(24-8) and 4(24-13).

Differential Diagnosis

The main differential diagnoses in children are atypical teratoid/rhabdoid tumor (AT/RT), ependymoma, and pilocytic astrocytoma. AT/RT is a cellular rhabdoid tumor and is often indistinguishable from MB on imaging studies.

Ependymoma is also typically centered in the fourth ventricle but more often demonstrates lateral extension through the foramina of Luschka into the adjacent cisterns, sometimes described as a plastic appearance. The majority of ependymomas do not exhibit restricted diffusion.

The vast majority of pilocytic astrocytomas arise in the cerebellar hemispheres. The main differentiating factor from MB is the hypocellularity of the solid pilocytic tumor components, which are typically very bright on T2 and ADC.

The differential diagnosis of MB in adults differs. The most common parenchymal posterior fossa mass in adults is metastasis. A newly described neoplasm, high-grade astrocytoma with piloid features (HGAP), occurs throughout the neuraxis but is most common in the cerebellum (75% of cases). Unlike pilocytic astrocytomas, HGAPs are more common in young and middle-aged adults but rare in the pediatric population.

Other CNS Embryonal Tumors

Preamble

CNS embryonal neoplasms other than medulloblastoma (MB) are a rare, aggressive and heterogeneous group of poorly differentiated tumors composed of immature cells that resemble neural progenitors. They are mostly—but not exclusively—neoplasms of childhood. In contrast to MBs (which arise in the posterior fossa), these embryonal tumors may arise throughout the neuraxis.

This group now consists of five specific pathologic entities: Embryonal tumor with multilayered rosettes (ETMR), AT/RT, cribriform neuroepithelial tumor (CRINET), CNS neuroblastoma, FOXR2-activated, CNS tumor with BCOR internal tandem duplication, and CNS embryonal tumor, not elsewhere classified/not otherwise classified (NEC/NOS). DNA methylation profiling provides an indispensable tool in distinguishing these rare neoplasms.

Embryonal Tumor With Multilayered Rosettes

Terminology

ETMRs are aggressive CNS embryonal tumors that are characterized histologically by multilayered rosettes. ETMRs have three morphologic patterns: (1) Embryonal tumor with abundant neuropil and true rosettes, (2) ependymoblastoma, and (3) medulloepithelioma. Once considered separate entities, they now comprise a single clinicopathologic entity based on common molecular alterations.

Pathology

Approximately 70% of ETMRs are supratentorial masses that appear relatively well demarcated with little surrounding edema. Tumors are highly variable in size but often reach > 5 cm in diameter when located in the cerebral hemispheres (24-14). The cerebellum and brainstem are the primary site in 30% of cases.

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.

ETMRs harbor either C19MC alterations (most common) or DICER1 mutation (rare). ETMR corresponds histologically to CNS WHO grade 4.

Clinical Issues

Almost all ETMRs occur under the age of four years with the majority occurring in the first two years of life. Increasing head circumference and signs of elevated intracranial pressure are common. ETMRs are extremely aggressive neoplasms, and the clinical prognosis is dismal with poor overall survival.

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 (24-15).

CT Findings

A complex, heterogeneously iso- to hyperdense mass is typical on NECT. When large, they often become more heterogeneous and frequently develop cystic components. Hemorrhage and dystrophic calcifications may occur, especially in larger lesions.

MR Findings

Conventional sequences show T2/FLAIR iso-/hyperintensity of solid components (24-16). With increasing size of tumor, signal characteristics typically become more heterogeneous, and T2-hyperintense cystic areas and areas of T1 hyperintensity and T2*/SWI signal loss consistent with hemorrhage are often seen. 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 (24-15B).

Because of their relatively dense cellularity, C19MC-altered ETMRs solid components typically show moderately restricted diffusion (24-15C)(24-16E). pMR shows areas of elevated rCBV and vascular permeability.

Enhancement varies from none (24-16F) to solid or rim enhancement.

Differential Diagnosis

The differential diagnosis of C19MC-altered ETMR in infants and children includes other bulky hemispheric masses, including AT/RT, supratentorial ependymoma (ZFTA or YAP1 fusion-positive), astroblastoma (MN1-altered), pediatric-type diffuse high-grade gliomas, such as infant-type hemispheric glioma, CNS neuroblastoma (FOXR2-altered), and CNS tumor with internal tandem duplication (BCOR).

Atypical Teratoid/Rhabdoid Tumor

Atypical teratoid/rhabdoid tumor (AT/RT) occurs at a younger age and is associated with a worse prognosis than MB. Although it accounts for just 1-2% of pediatric CNS tumors, it is the most common of the “other CNS embryonal neoplasms.” AT/RTs occur at a younger age than MB.

Terminology

AT/RT is a rare, highly malignant CNS embryonal tumor composed of poorly differentiated elements and a variable number of malignant rhabdoid cells.

Etiology

AT/RT is a genetically defined tumor characterized by deletions and biallelic inactivating mutations of the SMARCB1 (a.k.a. hSNF5 or INI1) gene. Loss of the SMARCB1 protein in AT/RT results in unopposed expression of LIN28B (a key gene in embryonic development and for maintaining pluripotency in stem cells).

Molecular profiling has identified three molecularly and clinically distinct AT/RT subgroups, currently designated as ATRT-TYR, ATRT-SHH, and ATRT-MYC.

Pathology

Location

AT/RTs occur throughout the neuraxis, in both the supra-(24-17) and infratentorial compartments (24-18). Spinal cord AT/RTs are rare. Location is strongly correlated with molecular subgroup.

Slightly more than 1/2 of all AT/RTs are supratentorial, usually occurring in the cerebral hemispheres (24-17), although cases in other sites (including the suprasellar cistern, ventricles, and pineal gland) have been reported. Most supratentorial AT/RTs are ATRT-MYC or ATRT-SHH subtypes.

Posterior fossa AT/RTs preferentially occur in the cerebellar hemispheres (24-18A), although they can occur in the fourth ventricle, where they mimic MB. Although ATRT-MYC and ATRT-SHH subtypes occasionally occur here, the posterior fossa is the site of ~ 75% of ATRT-TYR neoplasms.

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. Nuclear loss of SMARCB1 (INI1) protein expression is a highly sensitive marker for the diagnosis of AT/RT.

Clinical Issues

Epidemiology

AT/RT accounts for just 1-2% of all pediatric brain tumors but up to 20% of patients under three years of age. 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 syndrome characterized by a markedly increased risk of developing malignant rhabdoid tumors—including AT/RT—caused by loss or inactivation of the SMARCB1 gene (less commonly, the mutation involves the SMARCA4 gene).

Children with RTPS and AT/RT are even younger, have more extensive disease, and experience more rapid progression compared to sporadic tumors. 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 6-8 months despite aggressive therapy. Survival in adults is somewhat better, averaging two years.

ATYPICAL TERATOID/RHABDOID TUMOR: 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)

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

Approach to Congenital Malformations Choroid Plexus Tumors Approach to Toxic, Metabolic, Degenerative, and CSF Disorders Vascular Neurocutaneous Syndromes Toxic Encephalopathy Congenital, Acquired Pyogenic, and Acquired Viral Infections

Stay updated, free articles. Join our Telegram channel

Join