Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling

Abstract

MNTI is a rare tumor of indeterminate histogenesis and molecular signature. We performed methylation and copy number variation (CNV) profiles in patients with MNTI (n = 7) and PAT (n = 1) compared to the methylation brain tumor classifier v11b4 (BT-C) and the medulloblastoma (MB) classifier group 3/4 v1.0 (MB3/4-C). The patients’ mean age was 8 months (range: 4–48). The BT-C classified five MNTIs and one PAT (relapse) as class family MB-G3/G4, subclass group 3 (score: >0.9). The remaining two MNTIs and PAT (primary) were classified as class family plexus tumor, subclass pediatric (scores: >0.45). The MB3/4-C classified all MNTIs as high-risk MB-G3, Subtype II (score: >0.45). The primary PAT was classified as subtype III (score: 0.99) and its relapse as subtype II/III. MNTI and PAT clustered close to MB-G3. CNV analysis showed multiple rearrangements in one PAT and two MNTIs. The median follow-up was 54 months (four MNTIs in remission, one PAT died). In conclusion, we demonstrated that MNTI shares a homogenous methylation profile with MB-G3, and possibly with PAT. The role of a multipotent progenitor cell (i.e., early cranial neural crest cell) in their histogenesis and the influence of the anatomical site, tumor microenvironment, and other cytogenetic events in their divergent biologic behavior deserve further investigation.

Two cases of pineal anlage tumor with molecular analysis

“…PAT has been described mainly in single case reports 1,2,4,[10][11][12][13][14][15][16][17][18] (see also Supporting Table S4). PAT occurs primarily in children under 2 years of age, and causes symptoms due to mass effect and hydrocephalus.…”

“…Limited molecular analysis of PAT has been reported, comprising methylation classification in three patients and fluorescence in situ hybridization in one. [2][3][4] We present two cases of PAT that underwent next-generation sequencing targeting a panel of 340 cancer-related genes to identify point mutations and copy number alterations. 5 These cases also demonstrate the longest reported follow-up of PAT.…”

“…Many institutions in the United States treat PAT and PB similarly, incorporating surgical resection, radiation, and chemotherapy. Limited molecular analysis of PAT has been reported, comprising methylation classification in three patients and fluorescence in situ hybridization in one 2–4 . We present two cases of PAT that underwent next‐generation sequencing targeting a panel of 340 cancer‐related genes to identify point mutations and copy number alterations 5 .…”

Melanotic neuroectodermal tumor of infancy in the mandible

“…Immunohistochemistry can be used as a diagnostic aid, where biopsy specimens reveal a neuroblast-like morphology and expression of neuronal markers such as neuron-specific enolase, synaptophysin, and chromogranin A can confirm the neuroblastic origin of the small cells. [ 9 ] The large cells have a lightly eosinophilic or vacuolated cytoplasm, an oval bright nucleus with small nucleoli, and are of ectodermal origin, which can be confirmed by epithelial membrane antigen, cytokeratin, and HMB-45 positivity. This heterogeneity of cellular phenotypes is probably explained by the morphological features of the mesoderm and ectoderm displayed by neural crest cells at different stages of their ontogeny.…”

“…More than 500 cases of MNTI have been reported worldwide by Rachidi et al In addition to the 472 cases reported between 1918 and 2013 as a part of the largest retrospective study, [ 5 ] we found 49 cases reported between January 2014 and June 2021 by searching PubMed. [ 3 , 4 , 9 – 32 , 36 – 38 ] In a systematic review of 472 MNTI cases, [ 5 ] most cases developed within 1 year of age, with more than 90% of cases occurring in the craniofacial region, such as the maxilla (60.3%), skull (18.1%), and mandible (10.3%). On the other hand, to summarize the reported cases since 2014, 27 (87.1%) cases of MNTI developed within 1 year of age, and 32 (65.3%) cases occurred in the maxilla, 4 (8.2%) in the mandible, and 1 (2%) in the hard palate, while 12 (24.5%) cases occurred outside the oral cavity, such as the cranial bone, middle ear, upper arm, fibula, and ovary.…”