Diffuse Leptomeningeal Glioneuronal Tumor With Initial Diagnosis of Pilocytic Astrocytoma With Anaplasia: A Case Study

ABSTRACT

Diffuse leptomeningeal glioneuronal tumor is a rare central nervous system tumor with imaging findings including leptomeningeal enhancement and nodular/cystic lesions. This case highlights how patients can have differing imaging features, requiring whole‐genome DNA methylation profiling for diagnosis, and demonstrates successful treatment after initial descriptive diagnosis of pilocytic astrocytoma with anaplasia.

1. Introduction

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare tumor arising from glial or neuronal cells in the central nervous system (CNS) [1]. It is a newer tumor type first described in 2016 by the World Health Organization (WHO) [2]. DLGNTs occur more often in the pediatric population with a male predominance, but cases can be noted in the adult population as well [1, 3]. Clinical symptoms that patients experience include seizures, headaches, and imbalance with walking [1]. Clinical behavior of DLGNT is very diverse with majority of tumors growing relatively slowly but some displaying rapid progression resulting in poor outcomes. Due to the rarity of the tumor, the diverse molecular and radiological features, and tumor evolution, the 2021 version of WHO CNS classification has not yet graded this tumor.

Lab testing includes lumbar puncture as well as autoimmune markers and infectious workup if etiologies such as encephalitis or meningitis are suspected [2]. Diagnosis involves head imaging with magnetic resonance imaging (MRI) as well as spinal MRI and positron emission tomography‐computed tomography (PET‐CT) scan if indicated [1, 2]. Common imaging findings include leptomeningeal nodules spreading throughout the brain with supratentorial or infratentorial involvement; other findings can include intraparenchymal spinal lesions or enhancement of the leptomeninges near the spinal cord, posterior fossa, and basal cisterns [1]. Pathology and genetic analysis help to identify tumors with markers including S100, MAP2, OLIG2, synaptophysin, and glial fibrillary acidic protein (GFAP); genetic changes include chromosome 1p deletions or fusion of BRAF genes [1].

Treatment of DLGNTs may include surgery, chemotherapy, and radiation therapy (RT) [1]. Due to the rarity of DLGNTs, optimal treatment regimens have not been formalized. Here, we present a case study of a patient with an initial descriptive diagnosis of “pilocytic astrocytoma (PA) with anaplasia” due to the presence of focal Rosenthal fibers, brisk mitotic activity, and gain of BRAF (7q34) on biopsy. Her pathology and genetic analysis also indicated diffuse positivity for Olig2, reactivity for GFAP and synaptophysin, a chromosome 1p19q codeletion, and a PDE4B::NTRK3 fusion. These findings, along with later DNA methylation profiling, determined a formal diagnosis of DLGNT. This case study underlines an example of DLGNT with an initial diagnosis of PA with anaplasia that was successfully treated with surgery followed by adjuvant sequential radiotherapy and chemotherapy.

2. Case History/Examination

A 20‐year‐old female with no significant past medical history initially presented to the emergency department with a four‐month history of headache and vertigo, 2 months prior to her presentation in the radiation oncology clinic. She had been experiencing frontal headaches that were intermittent, aching, and worsened with movement. No associated paresthesia, weakness, or other triggers for headaches were noted. The patient denied changes to hearing or vision, imbalance, falls, or trauma. She had previously been treated with Epley maneuvers for her vertigo and ibuprofen for her headaches with minimal improvement.

On her physical exam, the patient was alert with no deficits in strength, sensation, or gait. Horizontal nystagmus was noted on leftward gaze for both eyes.

3. Differential Diagnoses, Investigations, and Treatments

CT scan of the head from an outside institution showed a large cerebellar cystic mass. A brain MRI scan showed a 4.7 cm hemorrhagic cystic cerebellar mass with irregular rim contrast enhancement and prominent nodular irregularity in the posterior lobular component (Figure 1). Associated findings include mass protrusion into the fourth ventricle, mass effect on the pons and cerebellar hemispheres, and obstructive hydrocephalus.

FIGURE 1.

Images of MRI brain T1 + C (A) and T2 (B) demonstrating a hemorrhagic and cystic cerebellar mass.

With these imaging findings, initial differential diagnoses included hemangioblastoma, medulloblastoma, and glioma. The next day, interventional radiology (IR) placed a right frontal ventricular drain and conducted a CNS angiogram prior to surgical operation. The angiogram findings showed a lesion with its vascular supply from the posterior inferior cerebellar artery (PICA) and superior cerebellar artery (SCA).

Two days after her initial presentation, Neurosurgery conducted a suboccipital craniotomy and a gross total resection of the cerebellar lesion. Pathology results from the resected tissue indicated a glioma with brisk mitotic activity; the diagnosis of PA with anaplasia was favored due to focal Rosenthal fibers and gain of BRAF (7q34). Other findings included diffuse positivity for Olig2, reactivity for GFAP, and focal reactivity for synaptophysin (Figure 2). Despite identification of a 1p/19q codeletion as usually seen with oligodendrogliomas, no IDH mutation, BRAF V600E, or H3K27M mutation was identified by immunohistochemistry (IHC) or next‐generation sequencing. No EGFR amplification, gain of chromosome 7, or monosomy 10 were noted on fluorescence in situ hybridization (FISH). High‐grade morphological features included focal incipient necrosis as well as nine to ten mitoses per 10 high‐power fields.

FIGURE 2.

Pathology slides from resected tumor showing diffuse positivity for Olig2, reactivity for glial fibrillary acidic protein (GFAP), and focal reactivity for synaptophysin. The tumor cells were negative for IDH1 R132H, BRAF V600E, and H3K27M, with retained ATRX expression. A subset of tumor cells was positive for p53, consistent with a wildtype pattern. Neurofilament (NF) highlighted focal infiltration at the tumor periphery. Ki‐67 labeling index was 5%–10%.

On her presentation to the radiation oncology clinic 2 months following hospital discharge, she noted intermittent headaches with improvement while on dexamethasone. Her vertigo resolved following tumor resection. In addition, the patient noted mild left lower extremity numbness after tumor resection that increased when tapering off dexamethasone. She denied any blurriness or other changes including vision changes, hearing changes, cafe au lait spots, or axillary and groin freckling suggestive of neurofibromatosis I, fever, chills, night sweats, or unexpected long‐term weight loss. On physical exam, cranial nerves were intact with no deficits in vision, hearing, sensation, strength, or gait.

Her tumor type was determined to be similar to the severity of a Grade 2 to 3 glioma in concordance with perusal of available medical literature. As such, the adjuvant treatment regimen was determined to be 54 Gray in 30 fractions with intensity‐modulated radiation treatment (IMRT) of her localized tumor followed by six cycles of temozolomide for chemotherapy.

Prior to the start of therapy, the patient underwent oocyte retrieval for in vitro fertilization (IVF). She tolerated radiotherapy and chemotherapy with nausea controlled on ondansetron and prochlorperazine.

4. Long‐Term Outcome and Updated Diagnosis

Since completion of therapy, the patient has continued to follow with her oncologist every 6 months with no signs of tumor recurrence on imaging at the most recent clinic visit. During her most recent presentation to the oncology clinic 6 years and 4 months following surgery, she denied any headaches, vertigo, changes to vision or hearing, or changes to strength, sensation, or gait. On her physical exam, there were no deficits noted in vision, hearing, cranial nerves, sensation, strength, or gait. MRI scan of the brain showed postoperative changes with no signs of tumor recurrence (Figure 3). Whole‐genome DNA methylation profiling was performed to further classify this tumor and demonstrated a high‐confidence match to DLGNT, methylation class (MC)‐1 subtype.

FIGURE 3.

Images of MRI brain T1 + c (A) and T2 (B) showing postoperative changes in the posterior fossa with no signs of residual contrast‐enhancing tumor or recurrence.

5. Discussion

Cases of DLGNT are more prevalent in the pediatric population compared to the adult population but have been noted in the young adult population [1]. For our patient, she is outside of the typical age range for DLGNTs, making her tumor a rare occurrence.

In the literature, common findings of diffuse leptomeningeal enhancement, nodular and cystic lesions throughout the brain, and hydrocephalus are noted [1]. For our patient, her tumor did have cystic features with hydrocephalus but lacked enhancement of the leptomeninges. Lack of enhancement of the leptomeninges is a finding that has been noted in other case studies, with some patients never developing leptomeningeal enhancement during their disease course [4]. The location of the patient's tumor was primarily infratentorial, differing from the more common pattern seen in case studies.

When examining the pathology of DLGNTs, tumor markers and FISH results for chromosomal abnormalities prove to be helpful. With their origin from glial cells and neuronal cells, DLGNTs may express synaptophysin and GFAP; genetic deletions for chromosome 1p and KIAA1549:BRAF gene fusions have been noted as well [5]. Our patient had co‐deletions of 1p/19q and a gain of BRAF (7q34), but no BRAF gene fusions were noted. Instead, our tumor harbored a rare PDE4B::NTRK3 fusion that, to our knowledge, has not previously been reported in DLGNTs.

While DLGNTs are noted in the literature to not consistently have typical imaging findings of leptomeningeal involvement, reports also note tumors sharing genetic alterations and histological features with other tumor types, making accurate diagnoses difficult [1]. In previously published case reports, occasionally DLGNTs were reported to be diagnosed in pediatric patients previously diagnosed of PA tumors [6]. Although the two neoplasms share common features with both frequently harbor common MAPK pathway alterations, especially KIAA1549::BRAF fusions, the phenotypes of the two types of tumors differ significantly [6]. Tumor cells in PAs exhibit a glial morphology and are positive for GFAP, while those in DLGNT display both glial and neuronal differentiation and are characteristically positive for OLIG2, MAP2, and S100 with variable expression for synaptophysin and GFAP [7]. As such, methylation profiling is highly crucial to achieving final diagnosis. Current classification separates DLGNTs into methylation Classes 1 (DLGNT‐MC‐1) and 2 (DLGNT‐MC‐2) with shared features such as deletions of 1p and KIAA1549:BRAF gene fusions; features such as co‐deletions of 1p/19q were noted to be more indicative of Class 1 while gain of 1q and chromosome 8 were more commonly seen in Class 2 [7]. DLGNT‐MC‐1 patients are usually younger than MC‐2 (median 5 vs. 14 years). DLGNT‐MC‐2 subtype tumors demonstrate a significantly more aggressive clinical course with five‐year overall survival being 43% versus 100% in DLGNT‐MC‐1 [7]. It is noted that our patient was diagnosed of MC‐1 subtype at much older age than average.

Treatment regimens of DLGNTs continue to be defined. If possible, surgical resection can be attempted, but may not be the best course of treatment in cases of leptomeningeal involvement [8]. Chemotherapy options include carboplatin and vincristine, temozolomide, and vinblastine and vinorelbine, with chemotherapy playing an important role in the control of disease progression [3, 8]. Radiotherapy options include localized radiation for individual tumors and craniospinal irradiation (CSI) with diffuse spread [9, 10]. Currently, use of radiation in the treatment of DLGNTs depends on clinical picture and judgment with the goal of stable disease or cure; localized disease often receives localized radiation in contrast to more advanced disease with signs of leptomeningeal dissemination being more likely to receive CSI [5, 9, 10]. Radiation treatment earlier on in the clinical course can play an important role in increasing progression‐free survival and achieving stable disease and cure; however, determination of localized radiation versus CSI requires further investigation in combination with other therapies [5, 11, 12]. The treatment decision in the era of methylation classification may be more personalized with the emerging information of the much benign/indolence clinical course of DLGNT‐MC‐1 tumors than MC‐2 which may be treated with chemotherapy or RT only [3]. In our case, with localized disease and tumor being MC‐1 subtype, local RT rather than CSI is justifiable as demonstrated by our patient's good long‐term outcomes, considering the young age of this type of tumors.

Due to the fact that her tumor was diagnosed prior to the methylation test becoming available, she was treated with the combination of localized radiation treatment and chemotherapy with temozolomide as for low grade gliomas which proved to be successful in treating her tumor and preventing disease progression and metastases. Retrospectively speaking, the treatment she received could be lessened to chemotherapy only, RT only, or potentially considering targeted therapy such as trametinib, a MEK inhibitor, that has been shown with some efficacy in DLGNT although lower than chemotherapy or RT [3].

Our patient in this case study reinforces the importance of methylation profiling to accurately reach a diagnosis of DLGNT. More importantly, her case demonstrates a scenario where the patient's tumor had been treated as a PA with anaplasia or Grade 2 gliomas with no recurrence after completion of treatment. This example provides possibilities for future examination of treatment regimens for DLGNTs with now subtyping becoming available with methylation classifications.

Author Contributions

Anita Zhou: conceptualization, data curation, writing – original draft, writing – review and editing. Joseph Carmicheal: conceptualization, data curation, writing – original draft, writing – review and editing. Jie Chen: conceptualization, data curation, writing – review and editing. Chi Zhang: conceptualization, data curation, supervision, writing – original draft, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

According to UNMC IRB guideline 45 CFR 46.102, a single case report does not meet the regulatory definition of human subject research; therefore, consent was not required per university IRB guidelines (https://guides.unmc.edu/books/hrpp‐policies‐and‐procedures).

Consent

Verbal and written informed consent for publication was obtained from the patient for this case study.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data from this case study is available on request due to privacy and ethical concerns.