The “long-tongue” sign: a new perspective on magnetic resonance imaging images of medullary ganglioglioma

Introduction

Ganglioglioma (GG) is a rare, typically low-grade central nervous system (CNS) tumor composed of dysplastic neuronal elements and neoplastic glial cells (1,2). It accounts for approximately 0.4–0.9% of all CNS tumors (3) and 1–7.6% of all primary brain neoplasms (2,4). Although most GGs arise in the supratentorial region, infratentorial involvement is relatively uncommon, comprising about 15% of cases, and typically involves the brainstem, cerebellum, or fourth ventricle (2,5,6). Among infratentorial GGs, those occurring in the medulla oblongata (medullary GGs) represent an exceptionally rare and distinct subgroup. The medulla’s dense concentration of vital cardiorespiratory centers and cranial nerve nuclei imposes significant challenges for safe surgical resection (7-9). Consequently, patients with medullary GG often experience a poorer prognosis compared to those with supratentorial lesions.

Early radiological recognition of medullary GG is crucial for guiding treatment strategies, especially given the anatomical constraints that limit surgical resection. In this multicenter retrospective study, we performed a systematic imaging analysis of 13 histopathologically confirmed cases and identified a distinctive imaging feature termed the “long-tongue” sign. Interestingly, this imaging marker showed a high rate of co-occurrence with the BRAF V600E mutation, suggesting potential utility both as a diagnostic hallmark and a predictor of response to targeted therapy. Recognition of this sign may prompt earlier molecular testing and facilitate timely initiation of BRAF inhibitor treatment, potentially improving clinical outcomes in this challenging patient population.

Methods

We retrospectively identified 13 patients with histopathologically confirmed medullary GG diagnosed between 2019 and 2024 from the Picture Archiving and Communication System (PACS) databases of 5 medical centers in China: Zhejiang Provincial Hospital of Traditional Chinese Medicine, Sanbo Brain Hospital of Capital Medical University, Beijing Tiantan Hospital of Capital Medical University, Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University, and the First Affiliated Hospital of Fujian Medical University. To maximize sensitivity in case retrieval, we used a broad range of search terms, including “medulla”, “medullary”, “brainstem”, “tumor”, “mass”, and “glioma”. Radiology reports and imaging studies matching these keywords were manually reviewed by 2 experienced neuroradiologists to identify lesions located specifically in the medulla oblongata. Final inclusion required both radiologic evidence of medullary involvement and histopathological confirmation of GG.

The inclusion criteria were as follows: (I) radiologically confirmed localization to the medulla oblongata; (II) histopathological diagnosis of GG; and (III) availability of complete preoperative magnetic resonance imaging (MRI) data. Patients with other intracranial tumors or inadequate imaging quality were excluded. This retrospective study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine) (No. 2025-KLS-320-01), and informed consent was provided by all included patients. All participating hospitals/institutions were informed of and agreed the study.

Demographic, clinical, and treatment information were obtained from electronic medical records. All patients underwent surgical resection, and the extent of resection was categorized as gross-total, near-total, subtotal, or partial, based on postoperative MRI or operative reports. Postoperative follow-up data were not uniformly available because many cases were referred from multiple institutions, and long-term outcome information was beyond the scope of this study. All tumors were evaluated using T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC), and contrast-enhanced T1-weighted MRI sequences. Imaging analysis focused on tumor location, morphology, signal characteristics, margins, and degree of contrast enhancement. Two board-certified neuroradiologists, each with over 10 years of experience, independently reviewed the MRI scans in a blinded manner. Discrepancies in interpretation were resolved by consensus after discussion. All patients underwent surgical resection, and histopathological confirmation was available for all cases.

Immunohistochemical (IHC) analysis was performed in 11 cases; among them, 8 were additionally tested for the BRAF V600E mutation by targeted sequencing of exon 15 of the BRAF gene. Each case was classified based on 2 binary variables: the presence or absence of the “long-tongue” sign and BRAF V600E mutation status, resulting in 4 possible combinations (L⁺B⁺, L⁺B⁻, L⁻B⁺, L⁻B⁻). Fisher’s exact test was used to evaluate the association between these 2 variables in the 8 genetically profiled cases.

Results

General parameters

The retrospective cohort included 13 patients (5 males and 8 females), ranging in age from 6 to 56 years [median: 22 years; mean ± standard deviation (SD): 24.6±17.3 years]. Clinical presentations varied based on tumor localization, with overlapping neurological symptoms observed. The most common symptoms included limb weakness (4/13, 30.8%), dysphagia with coughing (3/13, 23.1%), nausea and vomiting (3/13, 23.1%), hoarseness (2/13, 15.4%), gait instability (2/13, 15.4%), and dizziness (2/13, 15.4%). Preoperative systemic evaluations showed no evidence of distant metastasis in any patient. A summary of the clinical characteristics is provided in Table 1.

Imaging features

Tumor diameters ranged from 9 to 78 mm, with a median size of 29 mm. All lesions originated in the medulla oblongata, with varying degrees of anatomical extension: isolated medullary involvement (5/13), medulla and cervical spinal cord (3/13), medulla and pons (2/13), medulla, pons, and cervical spinal cord (1/13), and extension into the cerebellar hemisphere (2/13). The predominant growth pattern was mixed endophytic-exophytic in 12 of 13 patients (92.3%), typically presenting as rostral tumor extension from the dorsal medulla into the pons or cervical spinal cord, with secondary caudal and ventral infiltration within the brainstem (10,11). One case exhibited a purely exophytic pattern, protruding into the fourth ventricle and causing periventricular compression.

Lesions appeared as nodular or longitudinally infiltrative masses, primarily solid (10/13, 76.9%) and occasionally cystic-solid (3/13, 23.1%). On MRI, most tumors showed isointense or slightly hypointense signal on T1WI, hypointense or hyperintense signal on T2WI, and hyperintense or mildly hyperintense signal on FLAIR. On DWI, lesions typically demonstrated mildly hyperintense signal, with corresponding hyperintensity on ADC maps, indicating restricted diffusion in solid components. Cystic components exhibited slightly hypointense signal on T1WI and markedly hyperintense signal on T2WI. Calcifications were uncommon and clearly visible in only 1 case.

A distinct imaging feature, referred to as the “long-tongue” sign, was identified on contrast-enhanced sagittal T1WI in the majority of cases. This sign is defined as dorsal infiltration of the tumor along the medulla oblongata, presenting as ill-defined, patchy, and heterogeneous enhancement resembling an elongated tongue. It was observed in 11 of 13 patients (84.6%) and may serve as a potential imaging biomarker for medullary GG. Representative examples are shown in Figure 1A-1D.

Figure 1 T1-weighted contrast-enhanced MRI features of gangliogliomas. (A) A 22-year-old female with ganglioglioma involving the medulla oblongata, pons, cervical spinal cord, and right cerebellar hemisphere. A solid nodule with heterogeneous enhancement, more pronounced at the medullary margin. The white arrow indicates the “long-tongue” sign. (B) A 14-year-old female with ganglioglioma of the medulla oblongata and pons. A solid mass with patchy, heterogeneous enhancement and indistinct borders blending into adjacent tissue. The white arrow marks the “long-tongue” sign. (C) A 26-year-old female with a medullary ganglioglioma. A cystic-solid mass with irregular contours and heterogeneous enhancement; internal hypointense cystic regions are visible. The white arrow shows the “long-tongue” sign; the blue arrow indicates the hypointense cystic area. (D) A 45-year-old male with a medullary ganglioglioma. A cystic-solid lesion with mild enhancement and hypointense cystic components. The white arrows show the “long-tongue” sign; the blue arrow indicates the hypointense cystic area. All images are published with the patient’s consent. MRI, magnetic resonance imaging.

Histopathology

Grossly, the tumors appeared firm, with gray-white to gray-red cut surfaces. Histologically, all lesions demonstrated a biphasic composition of dysplastic neuronal elements and neoplastic glial components on hematoxylin and eosin (H&E) staining (Figure 2A). Diagnoses were established according to the “2021 World Health Organization (WHO) Classification of Tumors of the Central Nervous System”. According to this system, 11 cases (84.6%) were categorized as WHO grade 1. Two cases (15.4%) exhibited atypical histologic features characterized by proliferative glial cells with moderate-to-low cellular density, slender cytoplasmic processes, mild nuclear atypia, and absent mitotic activity. Focal areas contained scattered neurons or ganglion-like cells, and some regions were rich in collagen fibers, consistent with GG morphology. These tumors also demonstrated mild infiltrative growth and slightly poorer differentiation than typical WHO grade 1 GGs; therefore, they were designated as WHO grade 1/2.

Figure 2 Histopathological and IHC features of medullary ganglioglioma. (A) The tumor tissue showed a biphasic composition of clustered large multipolar neurons and surrounding glial cells (H&E staining, ×400). (B) IHC staining for CD34 demonstrated patchy positive expression (×400). CD34, cluster of differentiation 34; IHC, immunohistochemistry; H&E, hematoxylin and eosin.

IHC analysis revealed diffuse positivity for glial fibrillary acidic protein (GFAP) and scattered nuclear reactivity for neuronal nuclei (NeuN) across all 11 cases. Synaptophysin (Syn) and S-100 protein were expressed in 7 cases each, whereas oligodendrocyte lineage transcription factor 2 (Olig2) and cluster of differentiation 34 (CD34) were positive in 6 and 7 cases, respectively (representative CD34 immunostaining is shown in Figure 2B). The Ki-67 labeling index was low, ranging from 1% to 3%, indicating limited proliferative activity.

Among the 8 patients with available molecular data, 7 (87.5%) tested positive for BRAF V600E mutations. Of these, 6 (75%) also exhibited the “long-tongue” sign on MRI. Although Fisher’s exact test revealed no statistically significant association between BRAF mutation status and imaging sign manifestation (P>0.05), a high rate of co-occurrence was observed.

Discussion

In this retrospective study, we analyzed the clinical features, MRI characteristics, and histopathological findings of 13 patients with medullary GG. A distinctive imaging feature—the “long-tongue” sign—was consistently observed on sagittal contrast-enhanced T1WI. This sign reflects dorsally extending, irregular enhancement with poorly defined borders, and was present in 84.6% of cases. Notably, the majority of patients who underwent BRAF V600E genetic testing also exhibited this imaging feature, suggesting potential utility for both diagnosis and therapeutic stratification.

Clinical presentations of brainstem GG vary depending on tumor location, growth rate, and degree of involvement, as previously reported (10,12,13). In our cohort, symptoms included limb weakness, dysphagia with coughing, nausea and vomiting, hoarseness, gait instability, and dizziness. These nonspecific manifestations pose challenges for early clinical diagnosis, emphasizing the value of reliable imaging biomarkers.

Contrast-enhanced MRI remains the gold standard for radiologic evaluation of brainstem tumors (12). In our series, we introduce the concept of the “long-tongue” sign, which may indicate diffuse tumor infiltration along the dorsal medulla, likely resulting from blood-brain barrier disruption due to perivascular lymphatic sheath involvement. Similar dorsal enhancement patterns—such as the previously described “paintbrush” sign—have been observed in rare brainstem GG cases (14). Compared to the “paintbrush” description, the “long-tongue” sign not only depicts morphology but also implies a directional growth pattern extending rostrally and caudally along the medulla, offering an improvement in radiologic characterization.

The predilection for dorsal extension in medullary GG may be attributed to several anatomical and biological factors: (I) the relatively small volume of the medulla and constraints from surrounding bone structures limit lateral and ventral expansion, favoring dorsal growth; (II) fewer dorsal nerve fiber tracts and looser parenchymal tissue may facilitate infiltration (15); (III) GG arising in the medulla may behave more aggressively than supratentorial GG, showing glioma-like diffuse infiltration; and (IV) these tumors may originate from stem or progenitor cells located dorsally within the medulla, predisposing them to dorsal infiltration. In our study, the absence of the “long-tongue” sign in 2 cases may be explained by an exophytic growth pattern in 1 case—protruding into the fourth ventricle—and lack of contrast enhancement in the other, possibly due to the tumor’s microstructural composition.

Regarding differential diagnosis, medullary GGs exhibit imaging characteristics that help distinguish them from other medullary tumors. Pilocytic astrocytoma commonly affects children and adolescents, often presents as a cystic-solid lesion with prominent enhancement of the solid component, and typically shows unrestricted diffusion and low perfusion. Medulloblastoma is usually hypointense on T2WI and demonstrates restricted diffusion due to its high cellularity. Ependymoma, in contrast, often arises exophytically from the floor of the fourth ventricle and extends through the foramina of Luschka and/or Magendie (14). In our series, medullary GGs typically appeared as solid, expansile, and mildly infiltrative lesions with iso- to hypointense signal on T1WI and hyperintense signal on T2WI, frequently accompanied by the characteristic “long-tongue” enhancement sign. To our knowledge, this enhancement pattern has not been reported in other medullary tumor types, but further comparative studies with larger cohorts are warranted to verify its specificity.

Although both supratentorial and infratentorial GGs share some imaging similarities, infratentorial GGs are more likely to be solid, as confirmed by our findings and previous studies (13,14). These differences may reflect underlying biological variations based on tumor location, potentially supporting future refinement of GG classification.

BRAF V600E is a well-established therapeutic target in GG, with reported mutation frequencies ranging from 18% to 57% (16-19). The mutation results in constitutive kinase activation and downstream MEK/ERK pathway hyperactivation (16), contributing to tumorigenesis and being associated with an increased risk of recurrence (20-22). In our study, 87.5% (7/8) of genetically profiled patients harbored the BRAF V600E mutation, and 75% (6/8) exhibited both the mutation and the characteristic “long-tongue” sign on MRI. Although the association did not reach statistical significance (P>0.05), the high rate of concordance suggests a possible correlation between BRAF mutation status and this imaging feature, which warrants further investigation in larger cohorts.

Clinically, BRAF-targeted therapies such as dabrafenib and trametinib have shown benefit in patients with GG (16,19,23). However, BRAF V600E is not specific to GG and also occurs in other tumor types, including gliomas (24,25), thyroid cancer (26), and colorectal cancer (27). Given the strong prevalence of BRAF V600E in GG and its correlation trend with the “long-tongue” sign, this enhancement pattern may serve as a noninvasive imaging indicator suggestive of BRAF mutation status in medullary GG. Further prospective and multimodal studies are needed to validate this potential radiogenomic association and clarify its implications for individualized therapeutic decision-making.

In our study, all patients underwent surgical resection. Gross-total or near-total resection was achieved in most cases (10/13, 76.9%), but there were 3 patients (23.1%) who underwent partial removal due to tumor proximity to critical nuclei or fiber tracts. Low-grade GGs generally have a favorable prognosis, with reported overall survival rates of 100%, 88%, and 84% at 2, 5, and 10 years, respectively (28). Notably, subtotal resection of infratentorial GGs does not appear to result in worse outcomes or higher malignant transformation rates compared with their supratentorial counterparts (29). Previous studies have suggested that tumor size is not the primary determinant of resection extent (30), whereas anatomical location is a stronger prognostic factor (7). When lesions are adjacent to eloquent areas or lack clear borders, a more conservative surgical strategy may minimize the risk of neurological injury while still providing durable tumor control (28).

Radiotherapy plays a limited role in the management of brainstem GGs because of their low radiosensitivity and the long-term adverse effects in younger patients. Malignant transformation of either glial (31,32) or neuronal components (33) following radiation has been reported. Therefore, for incompletely resected diffuse or intrinsic brainstem GGs, close follow-up is preferred over radiotherapy (30).

Recent advances in microsurgical techniques have further improved the safety and precision of tumor resection. Robot-assisted cerebellar stereotactic surgery has been reported for posterior fossa tumors in children, offering a shorter surgical trajectory that traverses only 1 leptomeningeal surface while avoiding motor and sensory fiber tracts (34). However, further studies are needed to define its indications and clinical benefits. In addition, intraoperative MRI (ioMRI) and intraoperative ultrasound (ioUS) have emerged as valuable tools to facilitate complete tumor resection and real-time lesion visualization (35). Fluorescein sodium (FL)-guided surgery has also proven beneficial; in a multicenter series of 18 patients aged 3–78 years, complete tumor resection was achieved in 67% (12/18) of cases, and the fluorescence technique was considered helpful by surgeons in all procedures (35,36).

This study has several limitations. The retrospective design and small sample size reduce the statistical power and generalizability of the findings. Additionally, not all patients underwent BRAF testing, limiting the depth of molecular correlation. Future prospective studies with larger cohorts are warranted to validate the diagnostic and prognostic value of the “long-tongue” sign and its relationship with underlying molecular alterations.

In summary, this study identified the “long-tongue” sign as a characteristic imaging feature of medullary GG; its observed concordance with BRAF V600E mutation is preliminary and requires validation in larger, prospective cohorts.

Acknowledgments

None.

Footnote

Funding: This work was supported by the National Natural Science Foundation of China (Nos. 82402002 and 82402023 to S.W.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1498/coif). S.W. reports funding from the National Natural Science Foundation of China (Nos. 82402002 and 82402023). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This retrospective study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine) (No. 2025-KLS-320-01), and informed consent was taken from all the patients. All participating hospitals/institutions were informed of and agreed the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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