Embryonal Neoplasms

Introduction

Embryonal tumors of the CNS are poorly differentiated malignant neoplasms that preferentially affect children. Categories of embryonal CNS neoplasms recognized by the World Health Organization (WHO) include medulloblastoma; CNS neuroblastoma; CNS ganglioneuroblastoma; embryonal tumor with multilayered rosettes (ETMR), C19C-altered; medulloepithelioma; CNS-embryonal tumor, NOS; and atypical teratoid/rhabdoid tumor (AT/RT) (1). Additional NOS categories are present when confirmatory diagnostic testing is unavailable or cannot be performed for technical reasons. Notably missing from the classification is the term primitive neuroectodermal tumor (PNET), which has been abandoned in the 2016 WHO update. Pineoblastomas are also malignant tumors that may have an embryonal phenotype, yet are usually addressed with other pineal parenchymal tumors (see Chapter 12). As a group, these lesions are treated aggressively, with both craniospinal radiation and multiagent chemotherapy. Although response to therapy and survival varies among the different entities, all embryonal tumors of the CNS are malignant and considered WHO grade IV.

Medulloblastoma (WHO Grade IV)

General

The concept of medulloblastoma has undergone a foundational shift since the 2007 WHO classification in which the entire disease spectrum was described and categorized by three histopathologic patterns. Since then, a number of large-scale genetic investigations have elucidated the biology of medulloblastoma and provided an objective genetic framework with which to classify them, separating them into four major separate tumor types with further subtyping of one of those groups (2,3). The result has been a hybrid medulloblastoma classification that provides criteria for both the genetic and histomorphologic categories, with the latter having been more or less subsumed as patterns within the larger genetic context, allowing for an “integrated” approach that improves prognostic and therapeutic precision.

Demographics and Clinical Context

Medulloblastomas tend to occur in children, in whom they are the most common primary CNS malignancy. Most cases occur in the first 4 years of life, with incidence becoming progressively lower through young adulthood (4). Although rare, medulloblastomas may occur in older patients, up to the seventh decade, so patient age alone cannot rule it out as a diagnostic consideration. The male to female ratio is about 1.5:1 (5).

Medulloblastomas present with histories similar to those of other posterior fossa masses, particularly ependymoma. Infants may present with an enlarging head due to increased intracranial pressure with incompletely fused cranial sutures, whereas slightly older children will often experience increased intracranial pressure and hydrocephalus with headaches, nausea/vomiting, dizziness, and ataxia.

FIGURE 10-1 T1-weighted magnetic resonance imaging showing a midline cerebellar vermis mass extending into the fourth ventricle, the classic imaging appearance of medulloblastoma.

By definition, medulloblastomas occur in the posterior fossa. Most cases are centered in the midline cerebellum, or vermis, and extend into the fourth ventricle, sometimes causing obstruction of cerebrospinal fluid flow (Figure 10-1). The older the age at presentation, the more likely the tumor will arise in the lateral cerebellum, where it may display a “grape-like” pattern of nodularity that corresponds to the extent of nodularity in the histologic pattern, discussed later (6,7). Nodular/desmoplastic medulloblastoma in early childhood suggests the presence of Gorlin syndrome. On imaging, medulloblastomas are usually ring-enhancing or have a heterogeneous pattern with contrast and tend to be solid with discrete circumscription. Distant seeding of the subarachnoid space may
be identified on neuroimaging and is associated with decreased rates of survival. Extensive or geographic necrosis is uncommon on radiographic examination.

Prognosis by Clinical Factors

The outlook for patients with medulloblastoma can be stratified by clinical and radiologic factors into two groups, poor (high) risk and average, or standard, risk (8). The single most predictive clinical factor is the presence of leptomeningeal dissemination or “drop” metastases at the time of diagnosis. This is evaluated both by magnetic resonance imaging (MRI) of the brain and spinal cord and lumbar puncture for cytologic evidence of metastasis. In one series, given combination of radio- and chemotherapy, patients with evidence of tumor dissemination at diagnosis have around a 67% 5-year survival rate, in contrast to a 90% 5-year survival in patients with no evidence of spread (9). Patient age is the other major risk factor, with those younger than 3 years being at higher risk. Not surprisingly, extent of surgical resection plays a role in patient survival. Compared with other embryonal CNS malignancies, survival in cases of medulloblastoma is high overall, up to almost 80% at 5 years, when treated with radiation and multiagent chemotherapy (9). Occasionally, medulloblastomas will metastasize outside of the CNS, usually to bone but also occasionally to solid organs and soft tissue (10).

Histopathology

Classic Medulloblastoma

Most medulloblastomas fit the “classic” pattern, composed of sheets of monotonous, embryonal cells with minimal cytoplasm. In addition to sheet-like growth, other patterns such as palisading, prominent rosettes, and perivascular clearing can be seen. Fibrillar, or neuroblastic, rosettes (Homer Wright) (Figure 10-2) are present in fewer than half of cases and are not specific to medulloblastoma, thus are not a necessary diagnostic criterion; however, their presence heavily favors a lesion of immature neuronal differentiation. Foci of necrosis are common, although they usually make up only a small fraction of the tumor bulk. The nuclei are typically hyperchromatic with smooth chromatin and range from round and regular to angular with some nuclear molding. Nucleoli are usually inconspicuous, if identifiable at all. These cells often extend along the surface of the cerebellum underneath the leptomeninges and into the parenchyma along the perivascular spaces of penetrating arteries (Figure 10-3). Occasionally, tumor cells may encircle and arrange themselves around blood vessels, creating structures similar to the perivascular pseudorosettes seen in ependymomas.

Occasionally, one will receive a biopsy from a previously treated medulloblastoma patient that shows almost complete transition from small blue cells to large, mature ganglion cells (Figure 10-4) (11,12,13). These could represent maturation of residual medulloblastoma cells induced by radiation and chemotherapy or dysplasia of native cerebellar granular neurons.

FIGURE 10-2 Homer Wright rosettes often dot the sheets of poorly differentiated cells in classic medulloblastoma, but they are not necessary for the diagnosis.

Desmoplastic/Nodular Pattern

FIGURE 10-3 Medulloblastoma extending through the subarachnoid space and along perivascular spaces.

Conceptually, this pattern represents a medulloblastoma with foci of increased neuronal differentiation. The prototype consists of circumscribed, round, reticulin-poor nodules composed of well-spaced tumor cells in a neuropil-like background, separated by more cellular strands of tumor with a reticulin-rich background (Figures 10-5 and 10-6). The pale nodules show increased synaptophysin and neurofilament expression, more uniform nuclear features, and decreased proliferation.
Maturing or mature ganglion cells may reside within nodules. In contrast, the internodular tissue is less differentiated, more pleomorphic, and more proliferative. Occasionally, nodules are so prominent that they abut each other with virtually no intervening tissue. When this pattern forms the entirety of the lesion, it can be categorized as medulloblastoma with extensive nodularity (MBEN) (Figures 10-7 and 10-8) according to WHO 2016 classification. MBEN is associated with infant patients and Gorlin syndrome.

FIGURE 10-4 Posttreatment biopsies of medulloblastoma occasionally show mature ganglion cells in places suspected to be recurrence.

FIGURE 10-5 The “pale islands” of nodular/desmoplastic medulloblastoma give an impression of lymph node tissue at low magnification.

FIGURE 10-6 Reticulin staining marks the internodular tissue in nodular/desmoplastic medulloblastoma and spares the nodule contents.

FIGURE 10-7 When the nodules constitute the vast majority of the tissue and there is only a scant internodular element, it is a medulloblastoma with extensive nodularity.

In some cases, desmoplasia presents as a solid background of dense collagen impregnated with small files of tumor cells (Figure 10-9). Although technically desmoplastic, this feature does not constitute a desmoplastic/nodular pattern by itself and is most likely a reactive fibrosis due to activation of leptomeningeal fibroblasts (14). Similarly, one may see pale nodules
without reticular, internodular reticular desmoplasia that also do not qualify a tumor as desmoplastic/nodular; both elements must be present. Absence of evidence for SHH-activation (sonic hedgehog) can be taken as evidence that a medulloblastoma is not desmoplastic/nodular (see below). Cases with nodules but no internodular desmoplasia (Figure 10-10) have
been termed “biphasic” and shown to behave clinically more like classic medulloblastomas (15). Such biphasic cases are not of the SHH-activated group and should be considered histologically classic.

FIGURE 10-8 Linear streaming of neurocytic tumor cells within nodules is common on medulloblastoma with extensive nodularity.

FIGURE 10-9 Pale nodules appear in classic and large cell/anaplastic histologies without internodular reticular desmoplasia (inset). Such lesions do not qualify as desmoplastic/nodular.

FIGURE 10-10 Dense, sclerotic collagen containing scant tumor cells is a reactive phenomenon and is not relevant to the desmoplastic/nodular histologic pattern.

Large Cell/Anaplastic Pattern

These tumors have a higher degree of cytologic atypia and larger cell size, and retain a sheetlike growth pattern. The term anaplastic is applied where large, pleomorphic, and hyperchromatic nuclei mold to each other in a pattern similar to mosaic tiles (Figure 10-11). In contrast, the “large cell” nucleus is more round with open or vesicular chromatin, a prominent nucleolus, and a thin rim of eosinophilic cytoplasm (Figure 10-12). Both patterns show increased mitoses, frequent apoptotic debris, and cell–cell wrapping. Although originally described as separate entities, large cell and anaplastic medulloblastoma are thought to represent similarly aggressive phenotypes, more prone to metastasis, and less amenable to treatment (16).

Heterologous Elements

Several heterologous elements have been reported in otherwise classic or anaplastic medulloblastomas, including cartilage (17), muscle, fat (18), and melanocytes (19,20,21). Myogenic and melanocytic are the two most common types and cases with them were formerly classified as separate entities. However, now such examples are merely considered rare morphologic variants with nondistinctive clinical behavior. It is unclear as to whether medulloblastomas with heterologous elements tend to fall into any specific molecular category; they have been reported in WNT-activated (22) and non-WNT/non-SHH (23,24). In the case of medulloblastoma with adipocytic differentiation, one should proceed with caution to prevent confusion with a less aggressive
tumor, cerebellar liponeurocytoma, discussed in Chapter 6 with neuronal and glioneuronal tumors.

FIGURE 10-11 Angular large nuclei mold to form mosaic tile patterns in anaplastic medulloblastoma.

Medulloblastoma Genetic Groups

Medulloblastoma, WNT-Activated

Clinical Context

FIGURE 10-12 Large round nuclei with open chromatin and prominent nucleoli are the signature features of purely large cell medulloblastoma.

This group accounts for the fewest of any medulloblastoma molecular group, around 10% (Table 10-1). Patients with

WNT-activated medulloblastomas are typically children or young adults, infant cases being rare, and are equally likely to be male or female. Although rare, medulloblastomas that arise within the context of familial adenomatous polyposis (germline APC mutation; Turcot syndrome, type 2) are presumably in the WNT-activated group by virtue of gene’s involvement in the same pathway (26). WNT-activated medulloblastomas rarely present with metastases and have an excellent prognosis overall, with greater than 95% 5-year survival, although adult patients may not fare as well (27).

FIGURE 10-13 Nuclear accumulation of beta-catenin, which can be focal and subtle, identifies WNT-activated medulloblastomas.

TABLE 10-1 Clinically Relevant Medulloblastoma Molecular Groups (WHO 2016)

		SHH-activated		Non-WNT/non-SHH
	WNT-activated	TP53 Wild Type	TP53 Mutant	Group 3	Group 4
Ages	Mostly children, some adults	Bimodal: infants and adults	Children	Children, some infants	Mostly children, few infants and adults
Histology	Classic, rare LCA	Desmoplastic, MBEN, classic, LCA	Classic, LCA	Classic or LCA	Classic > LCA
Chromosomal Abnormalities	Monosomy 6 (∼85–90%)	del9q (∼50%), occasional MYCN amp	MYCN amp., GLI2 amp. del17p	i17q, MYC amp, 1q+	i17q (>50%), occasional MYCN amp
Gene Mutations	CTNNB1 (95%), DDX3X, SMARCA4, TP53	PTCH, SUFU, SMO	TP53	None consistent	None consistent
Immunohistochemistry	Nuclear β-catenin, YAP1+; GAB1 neg	GAB1, YAP1 +	p53, GAB1, YAP1+	GAB1, YAP1 neg	GAB1, YAP1 neg
Prognosis	Very good	Infants good, others intermediate	Poor	Poor	Intermediate
Percent of total (approx.)	15%	20%	5%	20%	40%
Modified from (25) and (2).

Histopathology

Almost all cases from the WNT-activated group have the classic histology and very rarely will have a LC/A histology. Immunostaining for beta-catenin is an important surrogate marker for WNT-activated tumors, it showing nuclear accumulation that is usually focal (Figure 10-13) in a majority of cases (28). Like SHH-activated cases, WNT group tumors also express YAP1 in most cases, but not GAB1. One recent series suggests that ALK immunostaining may be useful in identifying WNT-activated medulloblastomas (29).

Genetics

Around 90% of tumors from this group have inactivating point mutations in CTNNB1, the gene for beta-catenin (30), making it the most common genetic feature. Almost as many also have monosomy 6, which has long been known to be a marker of WNT-driven biology and good prognosis in medulloblastomas (31). Other mutations are common in WNT-driven medulloblastomas, such as in DDX3X or SMARCA4, yet their exact roles are unknown (32). TP53 mutations are seen, but do not convey the poor prognosis that they do in the SHH group. Occasional WNT-driven medulloblastomas may have MYC amplification (33).

Medulloblastoma, SHH-Activated (TP53-Wild Type and TP53-Mutant)

Clinical Context

SHH-activated medulloblastomas may occur at any age and form a bimodal distribution, with the younger peak from birth to about 4 years and the older peak rising from adolescence to adulthood. Whereas tumors from the other genetic groups tend to occur in the midline, SHH-driven ones are more likely to be laterally situated. Given a medulloblastoma in a lateral cerebellar hemisphere, the likelihood of it being SHH-group is high. Several tumor syndromes are associated with SHH medulloblastomas, including Gorlin syndrome (34), Li-Fraumeni syndrome (35), and Fanconi anemia (36). Gorlin-associated cases tend to present before the age of 3 years, be extensively nodular, and have an excellent prognosis (34,37).

As a group, SHH-driven medulloblastomas have an age-dependent prognosis, with those in younger children having better outcomes and those in adults having intermediate outcomes. The main dichotomy in prognosis is between cases that are TP53-wild type and TP53-mutant, the latter associated so strongly with poor survival that TP53 mutation constitutes a separate subcategory of SHH medulloblastoma in the 2016 WHO (1). MYCN and GLI2 amplification are thought to be associated with poor survival.

Histopathology

All desmoplastic/nodular and extensively nodular medulloblastomas are SHH-driven, but the converse is not true. Given an SHH tumor, only half of the time will it be D/N, with the remaining cases being mostly classic and a few anaplastic (28). Immunohistochemistry is a convenient method to classify a medulloblastoma as SHH-driven and can involve any of a number of markers, including GAB1, YAP1, and SFRP1 (28,38). Immunostaining for p53 provides useful surrogate for TP53 mutation testing, showing strong nuclear accumulation in the vast majority of cases where mutations are present (39).

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