Multinodular and Vacuolating Neuronal Tumor – Challenges and Perspectives

INTRODUCTION

First described in 2013, multinodular and vacuolating neuronal tumor (MVNT) was classified as a benign ganglion cell grade I tumor, potentially associated with seizures, with a specific molecular marker, as outlined in the WHO 2016 and 2021 classification [1-3]. The discovery of MVNT is often accidental, and it is frequently asymptomatic [1,2]. Studying MVNT is of utmost significance in neurooncology. Understanding the molecular mechanisms underlying the development and progression of MVNT can provide insights into potential therapeutic targets and treatment strategies.

Typically identified in adults, MVNTs seem to appear during neurogenesis and present as subcortical clusters of nodular lesions within the cortex and superficial subcortical white matter [4]. Structure abnormalities in the cortex may be present with it [4,5]. Initially classified as either neoplastic or malformation, recent research on MVNTs emphasizes their stable nature over time, suggesting that they are “leave me alone” lesions with minimal changes in volume, thus underscoring the potential for less frequent imaging surveillance [6,7]. Whether the nodules of vacuolar neurons are a definite neoplastic transformation or aberrant development is still up for debate [6]. Overall, these insights contribute to a nuanced understanding of MVNTs, highlighting the complexities and diagnostic considerations surrounding these distinct neuronal tumors. Moreover, the purpose of this research is to shed light on the challenges and perspectives surrounding MVNT.

MATERIALS AND METHODS

A narrative review was conducted through five electronic databases (PubMed, CINAHL, Google Scholar, Cochrane, Web of Science/Clarivate), using as keywords “multinodular and vacuolating neuronal tumor” AND “diagnosis” OR “pathogen*” OR “imaging” OR “treatment”. All primary and secondary reports found from the inception of the respective databases up to July 2024 were explored for relevant data. Only papers that addressed explicitly the pathogenesis, diagnosis methods, and treatment strategies of MVNT were included in the secondary analysis .

RESULTS

Based on the literature search, 34 primary and secondary reports were reviewed in detail. The results were classified according to the three areas of interest, i.e., (1) pathogenesis and classification of MVNT, (2) imaging characteristics, and (3) diagnosis and treatment.

Classification and pathogenic characteristics of MVNT

Recent studies have highlighted the challenge of defining and classifying MVNT. Due to its rarity and unique histopathological features, there is ongoing debate within the scientific community regarding its precise definition and classification. Some researchers argue that MVNT should be considered a separate entity from other neuronal tumors due to its distinct morphological characteristics and clinical behavior. On the other hand, some propose classifying it under the umbrella of neuronal and mixed neuronal-glial tumors based on its neurocytic differentiation and immunohistochemical profile.

The purely neuronal tumors in the 2021 WHO classification include multinodular and vacuolating neuronal tumors, gangliocytoma, extraventricular neurocytoma, central neurocytoma, dysplastic cerebellar gangliocytoma, and cerebellar liponeurocytoma.

The mixed glioneuronal tumors include dysembryoplastic neuroepithelial tumor, diffuse glioneuronal tumor with oligodendrogliomalike features and nuclear clusters, ganglioglioma, desmoplastic infantile ganglioglioma/astrocytoma, papillary glioneuronal tumor, rosette-forming glioneuronal tumor, myxoid glioneuronal tumor, and diffuse leptomeningeal glioneuronal tumor [13].

There is a consensus on the need for standardized diagnostic criteria to identify and classify MVNT cases accurately. This would facilitate better communication among pathologists and clinicians, improving management strategies and outcomes for patients with MVNT.

The WHO 2016 classification defines MVNT as a benign ganglion cell tumor with specific pathologic hallmarks [2]. These nodular lesions are typically located in specific brain regions and can present differently across age groups, emphasizing the importance of histopathological examination for accurate diagnosis [1,14,15].

Histopathological analysis of MVNT reveals several distinctive features that aid in their diagnosis and differentiation from other neuronal tumors. One of the hallmark features of MVNT is the presence of numerous vacuoles within the tumor cells. This vacuolation can create a “floating” appearance of the cells and is a critical diagnostic criterion. MVNT typically exhibits a multinodular architecture. The tumor forms distinct nodules, which may vary in size, often surrounded by a gliotic background. Such detailed histopathological analyses are essential for elucidating the distinct features of MVNT and guiding effective clinical management strategies. Nevertheless, no histopathological evidence is available to confirm the diagnosis since only a small percentage of patients with suspected MVNT undergo surgery [10].

Immunohistochemical markers play a crucial role in the diagnosis and classification of MVNT. Various markers have been studied, differentiating MVNT from other tumors with similar histological features, such as dysembryoplastic neuroepithelial tumor (DNT) or ganglioglioma [16,17]. So, immunohistochemistry (IHC) is a crucial tool in the diagnosis and characterization of MVNT, establishing the neuronal nature of MVNT, as seen with positive staining for neuronal markers [18]. MVNT typically shows positivity for several neuronal differentiation markers: NeuN, a neuronal nuclear antigen typically expressed in mature neurons, β-III tubulin, which is highly expressed in neuronal cells and can help confirm the tumor’s neuronal lineage. Synaptophysin, a protein associated with synaptic vesicles, indicates neuroendocrine differentiation and is often used to demonstrate the presence of neurons. Although MVNT is primarily neuronal, some glial markers may also be expressed, reflecting maybe the mixed composition of the tumor. GFAP (Glial Fibrillary Acidic Protein) positivity can indicate a glial component in the tumor. Phenotypic analyses may also include checking for markers that indicate low proliferation rates, which can help distinguish MVNT from more aggressive tumors. Markers like Ki-67 are occasionally assessed but typically show low proliferation in MVNT. The absence of expression for markers associated with high-grade tumors, such as p53 or other markers linked to aggressive histology, reinforces its benign nature [18,19].

Understanding the molecular pathogenesis of Multinodular Vacuolating Neuronal Tumors (MVNT) presents a significant challenge due to the tumor’s unique histological features and clinical behavior. MVNTs are characterized by vacuolated tumor nodules with glial and neuronal differentiation, primarily affecting the cerebrum in adults. The pathognomonic radiological features, such as the soapbubble morphology and lack of enhancement post-gadolinium injections, provide important clues for differential diagnosis and management strategies [4,11,20,21]. The molecular mechanisms driving its formation and growth remain elusive. Further research is warranted to elucidate the genetic alterations and signaling pathways involved in the development of MVNT. The MAP (MitogenActivated Protein) kinase signaling pathway is a critical cellular signaling pathway that regulates various cellular processes, such as growth, proliferation, differentiation, survival, and apoptosis. This pathway is activated by various extracellular signals, including growth factors, cytokines, and environmental stresses. MAP kinase signaling pathway possibly sheds light on targeted therapeutic approaches [22].

Research has identified specific genetic mutations that may contribute to the development of MVNTs. For instance, missense mutations in the BRAF gene or HRAS gene have been linked to the pathogenesis of tumors [22,23]. Vacuolization and neuronal differentiation in MVNTs are characterized by vacuolated neurons. This cellular morphology suggests that disruptions in normal neuronal differentiation and cellular homeostasis may be due to genetic and epigenetic factors. Investigating the presence of other oncogenes and tumor suppressor genes may provide further insights. In exploring the molecular underpinnings of MVNT, a deeper understanding of its pathogenesis may pave the way for personalized treatment strategies and improved patient outcomes in the future. Like many tumors, MVNTs may exhibit altered vascularization patterns [24]. The tumor microenvironment, including the interaction between tumor cells and surrounding glial cells, immune cells, and extracellular matrix components, plays a crucial role in tumorigenesis [25,26]. Studying these interactions can show how the tumor ecosystem supports MVNT growth and survival.

MAPK- Mitogen-Activated Protein Kinase; CT – computer tomography; MRI- magnetic resonance imaging; T2 FLAIR – space inversion recovery with fluid attenuation; FDGPET/CT- fluorodeoxyglucose positron emission tomography/computed tomography; CD34 – transmembrane phosphoglycoprotein encoded by the CD34 gene; IDH1-isocitrate dehydrogenase; ATRX- chromatin remodeling · nucleosome assembly; p53- tumor suppressor gene; Ki67 – a nuclear nonhistone protein present in all active phases of cell cycle; GFAP – Glial fibrillary acidic protein responsible for astroglial cytoskeleton and is not found outside the CNS

Imaging Characteristics of MVNT

Imaging characteristics of MVNT reveal distinctive features that aid in their diagnosis and differentiation from other brain tumors. Described as low-grade lesions primarily found in the cerebrum, MVNT presents as clustered multinodular structures within the cortex and subcortical regions (Table 1). The brain MRI revealed multinodular T2-hyperintense lesions in both the deep cortex and superficial white matter of the frontal lobes or temporal lobes, exhibit a unique soap-bubble morphology, hyperintensity on T2 FLAIR sequences, and minimal or absent contrast enhancement [10,16,27]. Based on the signals from T1, T2, and T2 FLAIR, the nodules have nonhomogeneous signal intensity due to low T1, high T2, and low FLAIR vacuole aspects. Confluent T2/FLAIR hyperintensity overlying cortex was present in some cases [4]. The larger nodules have an inner core that is hypointense, a rim that is hyperintense, and areas with a high signal intensity that connect the nodules. The smaller nodules exhibit a signal intensity that is not uniform, with a central dot of low-intensity [11]. The nodules’ periphery shows high signal intensity on FLAIR because of high protein content and neuronal demyelination [11].

Sometimes MR spectroscopy indicates an increase in the choline peak and a decrease in the N-acetyl aspartate peak, and tractography shows a partial disruption of the typical structure caused by the absence of lesional cortical layers [11,28]. No increase in perfusion was observed by perfusion-weighted imaging in another study, and abnormal peaks were not detected by MR spectroscopy [10]. Despite their benign nature, the pathologic hallmark of MVNT, questions their neoplastic or malformative origin and potential association with seizures [29]. Cases of a spinal cord lesion resembling cerebral MVNT of unknown significance were named MVNTlike spinal cord lesions. With intramedullary cystic ovoid nodules within the white matter, some immediately contiguous to the grey matter, this lesion was stable in a follow-up [9,30]. The presence of well-delineated intramedullary cystic ovoid nodules within the spinal cord raises questions about the underlying pathophysiology of MVNT [9]. A comprehensive MR protocol has been suggested to increase the diagnostic confidence of MVNT [10].

Diagnostic and treatment of MVNT

Despite advancements in imaging and molecular techniques, MVNT can present with various clinical manifestations, posing diagnostic challenges. Usually, MVNT is revealed as an incidentaloma [31]. The clinical presentation is nonspecific, with symptoms such as seizures, headaches, or focal neurological deficits, often mimicking other more common brain tumors or epilepsy syndromes [1,14]. Additionally, the radiological features of MVNT on MRI can be subtle and easily overlooked, leading to misdiagnosis. The lack of specific diagnostic criteria for MVNT further complicates accurate identification, underscoring the need for histopathological examination for definitive diagnosis [16,32]. Biopsy remains the gold standard for confirming MVNT, highlighting the importance of integrating clinical, radiological, and pathological findings to navigate the diagnostic challenges posed by this rare entity in neurooncology. Additionally, the classification of MVNT as a benign neuronal tumor, possibly associated with seizures, further complicates the understanding of its neurological manifestations, especially in young patients [33].

Distinguishing MVNT from entities such as dysembryoplastic neuroepithelial tumor (DNET), ganglioglioma, extraventricular neurocytoma, and low-grade glioma is sometimes challenging [34]. The bright diffusion sign and absence of cortical involvement could differentiate MVNT from DNET [35]. Moreover, incorporating genetic and molecular analyses can further aid in narrowing down the list of differential diagnoses and confirming the diagnosis of MVNT. Immunohistochemical analysis for neural and glial markers are also helpful (Table 2). Antibodies against neuronal protein HuC/HuD (HuC/HuD), pan-neurofilament (pan-NF), neurofilament 200 KD (NF200 KD), chromogranin, and antibodies against glial fibrillary acidic protein (GFAP), nestin, CD3, CD45, CD68, CD34, human leukocyte antigen-DR (HLA-DR), isocitrate dehydrogenase1 (IDH1), calbindin, parvalbumin, calretinin, Ankyrin-G, p62 and Ki67, BRAF(V600E) enhance diagnostic accuracy [8,19]. Immunopositivity for HuC/HuD and Olig2 proves that MVNT appears during neuronal development [4].

The latest WHO tumor brain classification has classified MVNTs as grade I, and the mitogen-activated protein kinase (MAPK) is considered a molecular marker [3,8]. The MAPK is a key signaling pathway that transmits signals from the cell surface to the nucleus and regulates various cellular processes, including growth, proliferation, differentiation, and survival. Further research in this area, particularly investigating specific diagnostic markers and biomarkers, is warranted to refine the differential diagnosis process for MVNT.

Factors such as tumor size, location, and the presence of associated neurologic deficits can influence treatment strategies and prognosis.

One of the foremost challenges in the preoperative diagnosis of MVNT is the difficulty in distinguishing them from other neoplastic or malformative lesions to avoid unnecessary surgical interventions [36]. The characteristic imaging features of MVNT, such as the subcortical nodular lesions with unique signal properties on MRI, can often be mistaken for more aggressive tumors due to their atypical presentation in younger patients. The rarity of MVNT in young individuals poses a diagnostic dilemma, questioning the classification of these lesions as true neoplasms or malformative anomalies [22,31,21].

Imaging modalities and treatment strategies play pivotal roles in managing epileptic patients, especially those with drug-resistant epilepsy considered for neurosurgery. Utilizing advanced imaging techniques such as the Harmonized Neuroimaging of Epilepsy Structural Sequences (HARNESS-MRI) protocol and 7-Tesla MRI can aid in identifying previously occult epileptogenic lesions and improving surgical outcomes [37,38]. Additionally, the development of MRI postprocessing techniques and functional imaging modalities like EEG-functional MRI contribute to enhanced sensitivity in lesion detection and focus localization [39].

Surgery is often considered the primary treatment option for multinodular vacuolating neuronal tumors (MVNTs) under several circumstances. If the MVNT is causing neurological symptoms (such as seizures, headaches, or focal neurological deficits), surgical intervention may be necessary to alleviate these symptoms, when the tumor is accessible and can be safely resected without causing significant damage to surrounding brain tissue. Histological confirmation by surgical resection can provide a definitive diagnosis through the histopathological exam, which is crucial for confirming the nature of the tumor and ruling out other possible lesions. However, the precise location of the tumor within the brain can sometimes pose challenges in obtaining a biopsy sample. In such cases, advanced imaging techniques and neurosurgical expertise are indispensable in ensuring accurate sampling for an accurate diagnosis and subsequent management of MVNT. It is essential that surgical decisions are made in consultation with a team of specialists, including neurosurgeons and oncologists, who can evaluate the risks and benefits specific to each patient’s condition and tumor characteristics. Functional MRI is as accurate as WADA testing, for determining language dominance [40].

The management of asymptomatic MVNT often involves careful observation rather than immediate intervention. However, a strategy of active surveillance can be appropriate for asymptomatic or minimally symptomatic MVNT. This involves regular follow-up through serial neurological examinations and imaging studies (usually MRI) every 6-12 months .

DISCUSSION

Advancements in diagnostic technologies have shown promise in addressing the challenges associated with diagnosing MVNTs. One emerging technology that holds potential is liquid biopsy, an innovative and non-invasive diagnostic tool that analyzes biomarkers (circulating tumor cells and genetic material) from bodily fluids (such as blood, urine, or cerebrospinal fluid) to provide information about tumors [41-46]. Circulating Tumor DNA (ctDNA) from the blood allows for the detection of genetic mutations and alterations associated with MVNT. Liquid biopsy is less invasive than traditional tissue biopsy, making it a more feasible option for patients, especially in complex cases where surgical options may be limited. It allows for repeated sampling without the risks associated with multiple surgical procedures, enabling ongoing monitoring.

Additionally, the development of radiomics, a method that extracts quantitative data from medical images to provide detailed insights into tumor characteristics, could aid in distinguishing MVNTs from other brain tumors with similar radiographic features [44-46]. These innovative diagnostic technologies have the potential to revolutionize the current diagnostic landscape for MVNTs, allowing for earlier detection, accurate classification, and personalized treatment strategies. Furthermore, integrating these technologies into clinical practice could improve patient outcomes and enhance our understanding of MVNT biology.

More studies are needed to elucidate the genetic mutations and molecular pathways involved in the development of MVNT. This would not only provide valuable insights into the underlying mechanisms of this rare brain tumor but also potentially identify novel therapeutic targets. Additionally, clinical research focusing on the efficacy of different monitoring modalities is crucial for optimizing patient outcomes .

CONCLUSION

Based on the results of this narrative review, emerging technologies allow for a re-conceptualization of the MVNT diagnosis and treatment. Although data regarding the validity of the new imaging and molecular techniques are still gathering, the fact that WHO includes MAPK as a marker for MVNT indicates the need for further refinement of the differential diagnosis based on molecular explorations in this pathology. The references in the literature related to genetic mutations and alterations associated with MVNT suggest new research directions congruent with the paradigm of personalized medicine.

Conflicts of interest and sources of funding

The authors declare no conflict of interest. This research received no external funding.

Acknowledgment

The current manuscript does not contain previously published materials or self-generated AI text.

Authors’ contribution

Conceptualization, M.M., O.V., and O.M.S.; methodology, O.V., A.P., and O.M.S.; software, M.M., A.P., and O.M.S.; validation, M.M., O.V., and A.P.; formal analysis, O.V.; investigation, M.M.; resources, A.P., and O.M.S.; data curation, O.V.; writing—original draft preparation, M.M., O.V., and O.M.S.; writing—review and editing, M.M., O.V., and O.M.S. All authors have read and agreed to the published version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

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