MR Imaging Characteristics of Wingless-Type–Subgroup Pediatric Medulloblastoma

Discussion

In this article, we describe the conventional MR imaging features and common locations of WNT-subgroup medulloblastomas by using an MR imaging–based descriptive approach to analyze pre- and postoperative images. Our results suggest that WNT-subgroup medulloblastomas are close to the midline yet are lateralized tumors originating from structures around the foramen of Luschka (superficial layers of the dorsolateral brain stem under the middle cerebellar peduncle and paramedian structures of the inferomedial cerebellar hemispheres). These findings advance our current understanding of the implications of tumor location in molecular medulloblastoma subgroups and correlate well with recent discoveries about the developmental origins of WNT-subgroup medulloblastoma and pertinent aspects of the WNT molecular signaling mechanism.^9,12

In the human embryo, the cerebellum, pons, and medulla oblongata develop from the primitive rhombencephalon. The rhombencephalon is initially formed by 8 rhombomeres, which are present by the end of the fourth fetal week of life, but the development of the cerebellum, in particular, continues even after birth. Each rhombomere has specific sets of transcription factors and receptors, and specific progenitor cell populations have been identified within each rhombomere, which give rise to various cell populations that form the future cerebellum or brain stem. SHH tumors originate from glutamatergic granule cell neuron precursor cells, which are derived from the upper rhombic lip. Conversely, WNT tumors originate from cells arising from the lower rhombic lip.⁹ The latter normally migrate along the anterior precerebellar extramural migratory stream (AES) to form nuclei within the posterior portion of the brain stem, but mutant cell populations may give rise to tumors such as WNT-subgroup medulloblastomas in childhood. WNT pathway derangements (somatic mutations of the β-catenin gene, CTNNB1) have been found in up to 10% of sporadic medulloblastomas, and WNT tumors represented approximately 11% of our cohort with available molecular data.^4,13

Conventional and DWI features of WNT-subgroup medulloblastomas are quite similar to those described in the literature.^14,15 Consistent with the high cell attenuation in embryonal tumors of the CNS, WNT-subgroup medulloblastomas have lower T2 signal than do other common pediatric posterior fossa tumors, such as juvenile pilocytic astrocytomas, ependymomas, and choroid plexus tumors. Our data suggest that the diagnostic value of precontrast T2WI and FLAIR imaging is not substantially different. The only potential diagnostic benefit of precontrast FLAIR imaging may be its ability to distinguish a tumor cyst and a sequestrated fourth ventricle space (both may appear quite similar in T2- and T1WI); but in clinical settings, this advantage may not affect disease management enough to justify the additional examination time. DWI remains the most valuable technique in the differentiation of medulloblastomas and all other nonembryonal tumors in the posterior fossa. It invariably shows more-or-less restricted diffusivity within solid tumor areas with corresponding low signal in ADC map images. Although quantitative analysis of ADC data could not be performed in our cohort, variations in ADC signal were recognized, but their significance is still unclear. Because all of our patients had histopathologically classic medulloblastoma, specific correlations between radiologic and histopathologic data were not sought in this cohort. Previous attempts at making such correlations have led to limited or controversial results.^16,17

Regarding the spatial distribution of WNT-subgroup medulloblastomas in the posterior fossa, our study provides new insights into the most common sites of predilection more precisely than is described in a recent report,¹⁸ which found that 75% of WNT-subgroup tumors occurred along the cerebellar peduncle and the cerebellopontine (CP) angle cistern. Our findings are concordant in that CP angle and foramen of Luschka locations (subtypes C and D in our spatial classification scheme) are highly characteristic of WNT tumors, but we found that the “off-midline” subtypes account for only 50% of the cases. In our experience, WNT tumors seem to develop along an oblique-curved triangle centered on the foramen of Luschka, with 1 peak extending ventrolaterally to the CP-angle cistern, another posteroinferomedially to the cisterna magna, and the third posterosuperomedially to the fourth ventricle (Fig 5).

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Fig 5.

Putative points of origins of WNT-subgroup medulloblastoma in sagittal, transverse, and coronal planes. Letters (A–D) indicate the theoretic epicenter of tumors in the different subtypes; however, the points of origin represent a continuum, and actual tumors may be centered anywhere along the dotted lines.

Consequently, MR imaging shows many of these tumors as clearly off-midline (subtypes C and D) and others as apparently midline (subtypes A and B). To investigate putative points of origin of the latter 2 subtypes, we developed an iterative evaluation process that takes into account pre- and postoperative imaging features indicating tumor invasion of specific anatomic regions and structures. The resultant LSs suggest laterality even in the apparent midline cases; therefore, we speculate that midline-intraventricular WNT-subgroup medulloblastomas may originate near the ventricular orifice of the foramen of Luschka (eg, lateral recess of the fourth ventricle) and spread upward along the lateral wall of the fourth ventricle, which would explain the high incidence of dentate nucleus invasion.

Most interesting, the LS, if based solely on the postoperative damage pattern, is relatively low and, by itself, does not much affect determinations of the laterality of the tumor. The most likely explanation for this phenomenon may be that the postoperative damage pattern may include a few inadvertent lesions (“collateral damage”); therefore, the resultant LS is somewhat reduced by those. Nonetheless, we found the meticulous evaluation of the postoperative damage pattern to be helpful in understanding typical tumor locations.

On the basis of the observed involvement patterns, we propose that 4 apparent topographic phenotypes may be distinguished in WNT-subgroup medulloblastomas: 1) midline-intraventricular; 2) midline-extraventricular (centered on the cisterna magna with possible extensions toward the foramen magnum and/or the foramen of Magendie); 3) off-midline–intraventricular (centered on the foramen of Luschka with systematic extension to the fourth ventricle and optional extension into the CP angle cistern); and 4) off-midline–extraventricular (centered on the CP angle cistern, with more-or-less involvement of the foramen of Luschka). The extreme forms in each subtype are fairly straightforward, but overall, these phenotypic subtypes exhibit spatial overlaps, representing a continuum rather than 4 distinct categories. We have reason to believe that “midline” tumors (subtypes A and B) in the WNT-subgroup are actually paramedian (ie, close to the midline but not originating from the vermis) as opposed to the usually more lateralized SHH-subgroup tumors. Given that SHH-subgroup medulloblastomas are usually hemispheric (with few originating from the vermis) and typically extraventricular, and if WNT-subgroup medulloblastomas are indeed paramedian, then the only true midline-intraventricular tumors may be group 3 and 4 medulloblastomas. Further studies are needed to examine this hypothesis.

The incidence of PICA territory infarction in our patient cohort was high. The infarctions did not include the retro-olivary area; therefore, we speculate that the increased surgical risk to these patients may have to do with the often-suggested possible engulfment of the artery in its retromedullary course. We speculate that WNT-subgroup medulloblastomas may be associated with an increased risk for PICA infarction at surgery.

The laterality in conjunction with the dominantly extraparenchymal location of WNT-subgroup medulloblastomas would suggest that these tumors originate from mutant precursor cells on one side of the lower rhombic lip that fail to migrate along the anterior precerebellar extramural migratory stream. As a function of other modulating factors, these precursors may subsequently undergo neoplastic transformation and spread from the foramen of Luschka toward adjacent CSF spaces along the surface of the cerebellum and brain stem. This scenario implies that WNT-subgroup medulloblastomas are not cerebellar tumors.

We found that in midline-intraventricular (subtype A) WNT medulloblastomas, an obvious laterality is usually difficult to recognize at preoperative diagnostic imaging evaluation, complicating the differential diagnosis between these and other midline-intraventricular tumors, including group 3 and 4 medulloblastomas, some ependymomas, and choroid plexus tumors. Conversely, a tumor with DWI evidence of hypercellularity in any of the other 3 locations (subtypes B–D) may be more suggestive of WNT-subgroup medulloblastoma, but overlaps may occur. The infravermian (subtype B) tumors are rare but fairly characteristic, as are tumors with a clearly unilateral foramen of Luschka epicenter (subtype C). These location subtypes, however, may overlap with the typically hemispheric SHH-subgroup medulloblastomas (if those are inferomedial) and with some of the posterior fossa ependymomas. The CP angle cistern is also a well-known location for atypical teratoid rhabdoid tumors, complicating the initial imaging differential diagnosis of subtype D WNT-subgroup medulloblastomas; however, the biologic behavior and prognosis of the 2 are different. Bilateral involvement of the foramina of Luschka and of the CP angle cisterns is common in ependymoma and is rare in WNT-subgroup medulloblastoma. Choroid plexus tumors arising from the fourth ventricle are often midline-intraventricular but may be lateralized to involve the foramen of Luschka; however, their DWI appearance usually differs from that of embryonal tumors.