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## 3. Diagnostic Spectrum |
### 3.1. Adult-Type Diffuse Gliomas |
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, remains the archetype of the phenotype herein discussed. Typical histology includes uniform round nuclei, clear cytoplasm, delicate branching “chicken-wire” vasculature, microcysts, and calcifications (Figure 1A). However, definitive diagnosis requires the demonstrati... |
IDH-mutant astrocytoma may show focal oligodendroglioma-like areas, especially in higher-grade tumors. In contrast to oligodendroglioma, these tumors usually show ATRX loss and strong diffuse p53 expression, reflecting ATRX and TP53 alteration [1,2]. Homozygous deletion of CDKN2A/B defines CNS WHO grade 4 in IDH-mutant... |
IDH-wildtype glioblastoma may represent a particularly treacherous mimic when it displays small-cell or oligodendroglioma-like morphology. Glioblastomas harboring FGFR3::TACC3 fusion can show oligodendroglioma-like morphology with monomorphic cytology, compact growth, and limited necrosis in small samples, thereby mimi... |
### 3.2. Ependymal Tumors |
Clear-cell morphology may occur in ependymomas and can closely simulate oligodendroglioma, particularly in supratentorial ependymomas with ZFTA fusion, while it is more unusual in YAP1-fused subgroup. Ependymomas with clear-cell (oligodendroglioma-like) morphology may show compact growth, uniform polygonal cells, and o... |
This group illustrates a key diagnostic principle: a cortical or frontal lesion with oligodendrocyte-like cells in a young patient is not automatically an oligodendroglioma. Ependymal differentiation must be actively excluded when morphology, location, or immunophenotype are discordant. |
### 3.3. Pediatric-Type Low-Grade and Glioneuronal Tumors |
Several pediatric-type low-grade and glioneuronal tumors may feature oligodendrocyte-like cells. These lesions are especially common in the setting of long-term epilepsy-associated tumors, where clinical presentation, cortical location, and radiological circumscription are essential diagnostic clues [17]. |
Although pilocytic astrocytoma (PA) classically demonstrates a conventional biphasic architecture with Rosenthal fibers and eosinophilic granular bodies, rare cases may exhibit extensive oligodendroglioma-like morphology [17]. In such cases, the distinction from “true” oligodendroglioma may be challenging, particularly... |
Dysembryoplastic neuroepithelial tumor (DNT) is an epilepsy-associated tumor, histologically characterized by oligodendrocyte-like cells arranged within a mucin-rich matrix and associated with floating neurons (Figure 2B). It is IDH-wildtype, is typically ATRX retained, and is frequently driven by FGFR1 alterations [17... |
Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters is defined by a distinct DNA methylation profile, and is characterized by glioneuronal differentiation, nuclear clusters, presence of multinucleated cells, and absence of IDH1/2 mutation, along with recurrent monosomy 14 [20,21,22]. Di... |
Rosette-forming glioneuronal tumor (Figure 4A,B), papillary glioneuronal tumor, and multinodular and vacuolating neuronal tumor may also enter the differential diagnosis when focal clear-cell or oligodendroglioma-like morphology is present, but their architecture, location, and molecular alterations usually provide dec... |
### 3.4. Neurocytic Tumors |
Central neurocytoma and extraventricular neurocytoma may closely resemble oligodendroglioma because of uniform round nuclei of neurocytic cells, which also feature perinuclear halos (Figure 5A). However, the presence of neuropil islands, along with diffuse NeuN (Figure 5B) and Synaptophysin (Figure 5C) expression; abse... |
Cerebellar liponeurocytoma is another rare neurocytic tumor that often contains clear or lipidized cells and shows biphenotypic neuronal and glial differentiation (Figure 6A–C). Although generally indolent, it has potential for late recurrence and should not be mistaken for an oligodendroglioma [32]. |
### 3.5. Other Neoplastic Mimics with Clear-Cell Morphology |
Metastatic renal cell carcinoma and hemangioblastoma may also enter in the differential diagnosis of clear-cell CNS lesions. Metastatic renal cell carcinoma may closely mimic primary clear-cell CNS tumors and requires epithelial and renal lineage markers such as cytokeratins, PAX8, and CAIX [38]. |
Hemangioblastoma combines stromal clear cells with a prominent vascular network (Figure 7A) and may be confused with metastatic renal cell carcinoma or other clear-cell lesions. Inhibin alpha (Figure 7B); S100; vascular markers; and clinical correlation, including possible von Hippel–Lindau disease, assist in classific... |
### 3.6. Non-Neoplastic Mimics |
Non-neoplastic lesions represent one of the most important sources of misdiagnosis. Subacute infarcts, tumefactive demyelinating lesions (Figure 7C), and inflammatory conditions may contain macrophage-rich areas, reactive oligodendroglial hyperplasia, vacuolated cells, or fixation artifacts that simulate low grade glio... |
CD68 and CD163 staining can highlight macrophage-rich inflammatory or ischemic lesions and prevent misinterpretation as neoplastic clear-cell populations. This point is clinically crucial because overcalling a non-neoplastic mimic as glioma may expose the patient to unnecessary surgery, radiotherapy, or chemotherapy. |
## 4. Practical Integrated Diagnostic Workflow |
A practical diagnostic approach begins with the recognition that morphology establishes a hypothesis, not a conclusion. The diagnostic sequence should proceed from clinical and radiological triage to morphology, immunohistochemistry, tiered molecular testing, and, when necessary, DNA methylation profiling (Table 2). Fi... |
### 4.1. Clinico-Radiological Triage |
Age and location often provide the first diagnostic filter. A cortical temporal lesion associated with long-standing epilepsy suggests a glioneuronal tumor more strongly than a diffuse adult-type glioma. An intraventricular lesion raises the possibility of central neurocytoma or ependymoma. A dural-based clear-cell les... |
MRI features can further refine the differential diagnosis. T2 FLAIR mismatch favors IDH-mutant astrocytoma in the appropriate setting. A multinodular or “soap bubble” cortical lesion supports DNT or related epilepsy-associated tumors. Open-ring enhancement may suggest tumefactive demyelination. Marked diffusion restri... |
### 4.2. First-Line Immunohistochemistry |
A minimal first-line immunohistochemical panel should be tailored to the differential diagnosis generated by age, site, and morphology. In most adult-type diffuse glioma cases, IDH1 R132H, ATRX, p53, OLIG2, and Ki67 are essential. In clear-cell or oligodendroglioma-like lesions with possible neuronal or glioneuronal di... |
Immunohistochemistry should not be interpreted mechanically. ATRX retention supports oligodendroglioma only in the proper molecular setting, and p53 overexpression suggests astrocytoma but must be considered with morphology and IDH status. OLIG2 positivity is not exclusive to oligodendroglioma. Similarly, focal neurona... |
### 4.3. Tiered Molecular Testing |
Molecular testing should answer the most clinically relevant diagnostic question first. In an adult-type diffuse gliomas, the initial priority is to define IDH status and 1p/19q codeletion. If IDH is wildtype, testing for molecular features of glioblastoma, including TERT-promoter mutation, EGFR amplification, and comb... |
In pediatric-type or glioneuronal tumors, MAPK pathway alterations, FGFR1 or FGFR2 alterations, BRAF fusion or mutation, PDGFRA p.K385 mutation, and selected gene fusions may be more informative than anadult diffuse glioma panel. For clear-cell ependymal tumors, ZFTA fusion assessment or validated surrogate markers (i.... |
### 4.4. When DNA Methylation Profiling Becomes Essential |
Genome-wide DNA methylation profiling has transformed CNS tumor diagnostics by identifying biologically coherent epigenetic classes across histologically overlapping entities [2,3,42]. It is particularly valuable when morphology, immunophenotype, anatomical site, and limited molecular data do not converge on a single d... |
Practical indications include unusual patient age; atypical location; discordant immunohistochemistry; lack of expected molecular alterations; small biopsies with limited diagnostic architecture; suspected methylation-defined entities, such as DGONC; and tumors with ambiguous glioneuronal, neurocytic, or embryonal feat... |
## 5. Discussion |
### 5.1. Why a True Oligodendroglioma May Be Misdiagnosed |
The main diagnostic risk of oligodendroglioma-like morphology is not semantic but clinical, because “true” oligodendrogliomas, IDH-mutant and 1p/19q-codeleted, may benefit from targeted therapies and often show a more indolent course. The main reason an oligodendroglioma fails to be recognized and correctly diagnosed i... |
### 5.2. Minimal Diagnostic Panel in Routine Practice |
In routine practice, a rational minimum panel can prevent most major errors (Box 1). For adult-type diffuse gliomas, IDH1 R132H, ATRX, p53, OLIG2, and Ki67 should be considered first-line markers, followed by IDH sequencing and 1p/19q testing when indicated. If IDH-wildtype status is confirmed, molecular testing for gl... |
For lesions in children, young adults, or epilepsy-associated cortical locations, the panel should expand toward neuronal and glioneuronal markers, including Synaptophysin, NeuN, MAP2, and CD34, with subsequent molecular evaluation of MAPK pathway alterations. For clear-cell lesions with possible ependymal differentiat... |
In a recent AOSNP-ADAPTR consensus, the authors proposed a resource-stratified diagnostic framework for adult-type diffuse gliomas to facilitate the implementation of the 2021 WHO CNS classification in laboratories with varying access to molecular testing [43]. The recommendations advocate a stepwise approach integrati... |
### 5.3. Molecular Diagnostics and Methylation Profiling |
Molecular diagnostics should be tiered according to diagnostic probability. A broad molecular panel may be ideal, but in many centers, it is neither immediately available nor cost-neutral. The practical alternative is a staged approach in which morphology and immunohistochemistry define the next most informative test. ... |
DNA methylation profiling is increasingly important when conventional workup remains unresolved. Its greatest strength is the ability to classify histologically overlapping tumors into biologically coherent entities and to reveal unexpected diagnoses. Its limitation is that it requires adequate tissue, appropriate qual... |
### 5.4. Practical Implications |
The integrated approach proposed here supports a shift from descriptive morphology to predictive morphomolecular diagnosis. In daily practice, this means that the pathologist should avoid ending the report at the level of “oligodendroglioma-like tumor” unless the case is explicitly unresolved and further testing is pen... |
This approach is also relevant for multidisciplinary discussion. Radiologists can identify patterns that argue against conventional oligodendroglioma; neurosurgeons can provide information about sampling and lesion boundaries; and oncologists need an integrated diagnosis to select surveillance, radiotherapy, chemothera... |
## 6. Conclusions |
Oligodendroglioma-like morphology remains one of the most recognizable patterns in CNS pathology, but it is not synonymous with oligodendroglioma. In the current WHO era, its correct interpretation requires integration of morphology with clinical setting, imaging, immunohistochemistry, targeted molecular testing, and, ... |
9802f6f55064d980f1c2fb32fccfb0aefaed85d980b7552eedf4239968fb565b pmc13513445.txt |
PMCID: PMC13564585 |
TITLE: Diagnostic Pitfalls of Oligodendroglioma-like Morphology: Integrated Reappraisal of 23 Non-Oligodendroglial Central Nervous System Tumors |
LICENSE: https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. |
ABSTRACT: Background/Objectives: Oligodendroglioma-like morphology may generate diagnostic uncertainty in central nervous system tumors, although oligodendroglioma is defined by the integrated presence of IDH mutation and whole-arm 1p/19q codeletion. This study aimed to evaluate the diagnostic pitfalls of oligodendrogl... |
## 1. Introduction |
Oligodendroglioma has historically been recognized by a characteristic histopathological appearance, including uniform round nuclei, perinuclear clearing, delicate branching capillary networks, and frequent calcifications. However, in the current molecular era, these morphological features are no longer sufficient for ... |
Oligodendroglioma-like morphology may be encountered in a broad spectrum of non-oligodendroglial central nervous system tumors, either as a predominant pattern or as a focal component within an otherwise more characteristic tumor architecture. Diffuse astrocytomas may show areas with small round cells and perinuclear c... |
Several low-grade glioneuronal and epilepsy-associated tumors may also enter the differential diagnosis of oligodendroglioma. Dysembryoplastic neuroepithelial tumors may contain oligodendroglial-like cells, microcystic architecture, and neuronal elements, particularly in cortically based lesions associated with epileps... |
Beyond diffuse gliomas and low-grade glial or glioneuronal tumors, other entities may also simulate oligodendroglioma on routine hematoxylin and eosin sections. Central neurocytoma may show uniform round cells with perinuclear halos and a delicate capillary network, particularly in intraventricular lesions [16]. Suprat... |
This morphological overlap has practical diagnostic implications. In routine neuropathology practice, oligodendroglioma-like features may generate a broad range of initial microscopic impressions, including low-grade glial tumor, high-grade glial tumor, DNET, ependymoma, astroblastoma, oligodendroglioma, metastatic epi... |
Although individual oligodendroglioma mimics have been described in the literature, fewer studies have focused on the diagnostic process generated by oligodendroglioma-like morphology in routine practice. In particular, limited data are available on how initial microscopic impressions are refined or redirected by immun... |
## 2. Materials and Methods |
### 2.1. Study Design and Case Selection |
This study was designed as a single-center, retrospective, case-based diagnostic reappraisal study rather than a hypothesis-driven comparative diagnostic accuracy study. The archives of the Department of Pathology, Ankara Etlik City Hospital, were searched for central nervous system tumors diagnosed between 2022 and 20... |
Oligodendroglioma-like morphology was defined by the presence of one or more of the following features: small monotonous round nuclei, perinuclear clearing or halo formation, delicate branching or chicken-wire-like capillary vasculature, calcification, microcystic background, and/or a histological pattern raising the d... |
Cases with a final integrated diagnosis of oligodendroglioma, IDH-mutant and 1p/19q-codeleted were excluded. Additional exclusion criteria were insufficient tissue for histopathological review, lack of essential clinicopathological data, and absence of evaluable oligodendroglioma-like histomorphological features. |
A total of 23 non-oligodendroglial central nervous system tumors fulfilled the inclusion criteria and were included in the final cohort. |
### 2.2. Clinical and Radiological Data |
Clinical and demographic data were obtained from electronic medical records, pathology reports, and available clinical documentation. The recorded parameters included age at diagnosis, sex, tumor location, available presenting clinical information, type of surgical procedure, postoperative follow-up status, residual or... |
Preoperative radiological descriptions were retrieved from available radiology reports and clinical records. Radiological variables included tumor location, cortical or subcortical involvement, intraventricular localization, cystic or necrotic components, calcification, contrast enhancement pattern, edema, hemorrhagic ... |
### 2.3. Histopathological Evaluation |
All available hematoxylin and eosin-stained slides were retrospectively reviewed. Histopathological evaluation focused on the presence and distribution of oligodendroglioma-like features, including small monotonous round nuclei, perinuclear clearing or halo formation, delicate chicken-wire-like capillary vasculature, c... |
For each case, the initial microscopic impression recorded during the diagnostic process was documented. These initial impressions included categories such as low-grade glial tumor, high-grade glial tumor, dysembryoplastic neuroepithelial tumor, ependymoma, astroblastoma, oligodendroglioma, central neurocytoma, dysplas... |
Final diagnoses were assigned according to the current integrated diagnostic approach for central nervous system tumors, incorporating histopathological, immunohistochemical, molecular, cytogenetic, and clinicoradiological findings when available. |
### 2.4. Immunohistochemistry |
Immunohistochemical findings were retrieved from pathology reports and, when necessary, reviewed on available stained slides. The antibody panel varied according to the original diagnostic work-up of each case. Evaluated markers included, when available, IDH1 R132H, ATRX, p53, Olig2, GFAP, synaptophysin, NeuN, CD34, EM... |
IDH1 R132H positivity was interpreted as cytoplasmic and/or nuclear staining in tumor cells. ATRX loss was defined as loss of nuclear expression in tumor cells with retained internal positive control staining in non-neoplastic cells. p53 expression was assessed according to the observed nuclear staining pattern. Ki-67 ... |
The diagnostic contribution of immunohistochemistry was assessed descriptively according to whether the marker profile supported astrocytic, glioneuronal, neuronal, ependymal, circumscribed glioma, or metastatic epithelial/renal differentiation. |
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