Uncommon low-grade brain tumors

Abstract

The 2016 World Health Organization (WHO) classification of primary central nervous system (CNS) tumors includes numerous uncommon (representing ≤1% of tumors) low-grade (grades I–II) brain neoplasms with varying clinical behaviors and outcomes. Generally, gross tumor or maximal safe resection is the primary treatment. Adjuvant treatments, though their exact role is unknown, may be considered individually based on pathological subtypes and a proper assessment of risks and benefits. Targetable mutations such as BRAF (proto-oncogene B-Raf), TRAIL (tumor necrosis factor apoptosis inducing ligand), and PDGFR (platelet derived growth factor receptor) have promising roles in future management.

Primary central nervous system (CNS) tumors constitute a heterogeneous group of neoplasms with varying clinical behaviors and outcomes. The World Health Organization (WHO) 2016 classification includes some uncommon low-grade (grades I–II) tumors, representing ≤1% of all primary CNS tumors.¹ Due to their rarity, there is no consensus on their optimal management. These tumors may be categorized based on their presentation as long-term epilepsy-associated tumors (LEAT) or non-LEAT. We therefore summarize the characteristics and current management of these tumors.

Long-Term Epilepsy-Associated Tumors

LEAT comprise a heterogeneous group of slow-growing low-grade cortical brain lesions of varying cells of origin, often seen in younger patients investigated for prolonged (≥2 y) drug-resistant epilepsy.² Gangliogliomas and dysembryoplastic neuroepithelial tumors (DNETs) are the most common of these tumors.

Neuronal and Mixed Neuronal-Glial Tumors

Gangliocytoma and ganglioglioma

These are low-grade neoplasms with neuronal differentiation (gangliocytoma) or both neuronal and glial differentiation (ganglioglioma). They are the commonest neoplasms associated with epilepsy and occur between 10 and 30 years of age. Over 80% occur in the temporal lobe, and raised intracranial pressure (ICP) may be a presenting feature.

MRI in gangliocytoma reveals a cortically based tumor consisting of solid T1-hypointense, T2-hyperintense components which enhance with gadolinium. Cyst formation is often appreciated on CT and MRI.³ Radiological appearances of gangliogliomas are varied but classically show a cyst with a mural nodule in around 50%. Other manifestations include a solid mass with low to intermediate T1-weighted (T1W) and high T2W signal or a predominantly T1 hyperintense mass. Contrast enhancement of the solid component is variable. Mass effect or surrounding edema is rarely seen, although peripherally located gangliogliomas can cause scalloping of the overlying calvaria due to slow growth resulting in bone remodeling. These tumors frequently contain calcification.

Histologically, gangliocytomas are composed of well-differentiated neuronal (ganglion) cells that display architectural disarray and cytological dysmorphism (Fig. 1A), including binucleate forms. Eosinophilic granular bodies, Rosenthal fibers, and perivascular lymphocytes are common features. Gangliogliomas are similar but by definition contain an additional neoplastic glial population. Histological differential diagnoses include DNET, pilocytic astrocytoma, and diffuse gliomas. Genetic events which characterize astrocytomas are absent in ganglion cell tumors.

Fig. 1.

Histopathology of uncommon low-grade brain tumors (all hematoxylin and eosin stains. Scale bars 100 μm unless otherwise stated). (A) Ganglion cell tumor: nests of abnormal ganglion cells are a feature of ganglion cell tumors, which may also have a neoplastic glial element. Less specific features include eosinophilic granular bodies and perivascular lymphocytes. (B) Dysembryoplastic neuroepithelial tumors are characterized by large pyramidal neurons “floating” in pools of mucin. This feature is unusual in oligodendroglioma, the main histological differential diagnosis. (C) Desmoplastic infantile astrocytomas/gangliogliomas have an attachment to the overlying dura as seen in this low power image as the thick fibrous tissue at the top of the image. (D) Desmoplastic infantile gangliogliomas combine a compact spindle cell element, with astrocytic features, with occasional small ganglioid cells with features intermediate between astrocytes and ganglion cells (arrow). (E) Angiocentric gliomas are characterized by an infiltrative growth pattern of slender, monomorphic, bipolar cells that form angiocentric rosettes and accumulate under the pial surface. (F) Pleomorphic xanthoastrocytomas combine spindle shaped astrocytes and large, multinucleated, pleomorphic cells (arrows). Lipid vacuoles, eosinophilic granular bodies, and perivascular lymphocytes are also common features. (G) Rosette-forming glioneuronal tumors are characterized by bland neurocytes forming rosettes with core of neuropil-like material that is immunoreactive for synaptophysin (not shown). (H) Chordoid glioma: cords of epithelioid cells embedded in a myxoid background lend a chordoma-like quality to this neoplasm. Nuclei are bland and mitotic figures infrequent. (I) Astroblastoma: extensive sclerosis of blood vessels is common in this neoplasm. Tumor cells are oriented around the central vessel, defining the astroblastic rosette. (J) Choroid plexus papilloma: a papillary architecture composed of epithelium overlying fibrovascular cores. Mitotic figures are rare in this grade I example. Atypical examples display raised mitotic activity and variable loss of the papillary pattern. (K) Dysplastic gangliocytoma of the cerebellum is best appreciated at low magnification where the thickening of the affected cerebellar cortex and loss of the darkly staining granular layer are most apparent. Compare with the normal cortex in the top right of the image. (L) Neurocytoma: neurocytic cells with uniformly round nuclei are typical features. Occasional poorly formed rosettes may feature as in this example. Immunoreactivity for synaptophysin would be expected. (M) Subependymal giant cell astrocytoma. Large cells with features intermediate between ganglion cells and astrocytes characterize this lesion, which is strongly associated with tuberous sclerosis complex.

Gross tumor resection (GTR) is the treatment of choice, resulting in 5-year overall survival (OS) of >90%. The role of adjuvant radiotherapy is unclear. In a retrospective study of 402 patients with gangliogliomas, the 10-year local control rates were 89% after GTR, 90% after GTR plus radiotherapy, 52% after subtotal resection (STR), and 65% after STR plus radiotherapy.⁴ The corresponding 10-year OS rates were 95%, 95%, 62%, and 74%, respectively (P < 0.001). Radiotherapy after STR significantly improved local control (P = 0.004) but not OS (P = 0.22) but improved neither local control nor OS after GTR.

Posterior cranial fossa gangliogliomas usually have an infiltrative brainstem component which limits resection. In children, GTR was achieved in only 58.3% of brainstem tumors compared with 68% in other sites.⁵ In data from the Surveillance, Epidemiology, and End Results program, brainstem location is associated with a 5-year OS of 80.6%.⁵ Surgical attempts to remove well-circumscribed enhancing components of gangliogliomas improve long-term outcome. When resection is not feasible, ventriculostomy to relieve intracranial pressure followed by observation is appropriate. Radical radiotherapy (potentially curative doses of ≥54 Gy given for inoperable or macroscopic residual disease) should be considered for symptomatic progression.

Recurrences are generally managed with further surgery. BRAF V600E mutation has been described in 20–60% of gangliogliomas and reports suggest that vemurafenib, a BRAF inhibitor, can lead to sustained clinical improvement for 6 months to 2 years.⁶

DNET

Dysembryoplastic neuroepithelial tumors are the second most common tumors in patients undergoing surgery for intractable epilepsy. Mean age of onset of seizures was 8.1 years and >90% of patients have had an episode of seizures (generally complex partial) before 20 years.

These tumors are located in the cortex and vary on imaging⁷ (Fig. 2A–E). Type 1 tumors are strongly hypointense cystic or polycystic well-delineated lesions on T1W MRI. Type 2 tumors are nodular with mixed-signal intensity, whereas type 3 are iso- or hypointense on T1W MRI.⁸ They do not show perilesional edema or mass effect.

Fig. 2.

Dysembryoblastic neuroepithelial tumor (A–E) on CT (A), on T2W (B), and on FLAIR MRI (C) shows a multicystic lesion in the left medial temporal lobe. It is predominantly hypodense, T2 hyperintense, and with suppression on FLAIR. No surrounding edema. Magnetic resonance (MR) fast spoiled gradient echo (D) and post-contrast T1W (E) images on coronal plane demonstrate the hippocampal involvement with no contrast enhancement. Desmoplastic infantile ganglioglioma (F–I) on T2W MR (F) and FLAIR (G) shows a lesion centered on the right frontal lobe that contains cystic (confirmed with FLAIR suppression) and solid areas (isointense to gray matter). There is mass effect with shift of the midline structures and compression of the right lateral ventricle. Post-contrast T1W MRIs (H–I) show avid enhancement of the solid components at the lateral aspect as well as a broad dural tail/attachment.

Specific features include a wedge-shaped lesion pointing toward the ventricle, or a multicystic lesion. More recently described findings are a rim of high fluid-attenuated inversion recovery (FLAIR) signal at the lesional border and high apparent diffusion coefficient values within the lesion.

Histologically, DNETs are multinodular intracortical neoplasms. They can be divided into simple and complex variants. Both have a specific glioneuronal element with oligodendroglial-like cells in columns and patterned intracortical mucin-rich nodules with characteristic “floating neurones” (Fig. 1B). Complex variants also show glial nodules which may be indistinguishable from pilocytic astrocytoma. Mutations of isocitrate dehydrogenase (IDH) and loss of heterozygosity 1p/19q are not seen. BRAF V600E mutations (4–51%) and activation of the pathways of mammalian target of rapamycin (mTOR) (90%) and mitogen-activated protein kinase (MAPK) (50%) have been reported.

Excision of the lesion, which controls seizures, is often sufficient.⁹ Although an earlier study did not report tumor recurrence following GTR (median follow-up, 21.6 mo),¹⁰ a recent series (n = 51) reported recurrence in 3 of 30 patients post GTR and tumor growth in 6 of 18 patients post STR at a mean follow-up of 4.5 years.¹¹ There are reports of malignant transformation of DNET to astrocytoma or oligodendroglioma, particularly following STR.¹¹

In summary, GTR followed by routine follow-up is recommended for DNET. The role of adjuvant treatment after STR is unclear. Patients with recurrence should have further surgery.¹²

Desmoplastic infantile astrocytoma/ganglioglioma (DIA/DIG)

These are supratentorial, durally based, cystic tumors occurring predominantly in male infants, generally in the first 2 years of life.^13,14 The classical presentation is increase in head size with a bulging fontanelle, and 25% present with seizures. Children can also present with developmental delay.¹³

MRI shows a mass expanding more than one lobe with a large cystic and smaller solid component attached to the meninges with dural enhancement (Fig. 2F–I). Radiological differentials include pleomorphic xanthoastrocytoma, ganglioglioma, and primitive neuroectodermal tumor.

Microscopically, these tumors have a distinct leptomeningeal component composed of spindle cells with associated collagenous desmoplasia (Fig. 1C). They also have a neuroepithelial component featuring small neoplastic neuronal cells and dysplastic ganglion cells (Fig. 1D) which can be clustered or isolated within the desmoplastic region. Mutations of p53 and deletions of 1p/19q are not encountered.¹⁵ BRAF mutations have been detected in some tumors.

Even though these tumors can be easily differentiated from brain tissue perioperatively, GTR was possible in only 54% of tumors because of extensive disease and/or tumor involving deep structures.^13,15 The reported recurrence-free interval following GTR ranged from 6 months to 19 years. Malignant transformation to glioblastoma has been reported.¹⁶

In summary, GTR is standard of care for DIA/DIG. The role of adjuvant radiotherapy following STR is unknown. Recurrent tumors are treated with re-excision, chemo, and BRAF inhibitors (eg, vemurafenib). Radiotherapy is generally avoided to prevent diencephalic dysfunction.

Papillary glioneuronal tumor (PGNT)

These tumors can occur in both sexes, with the median age at presentation being 23 years.^17,18 They are usually hemispheric, mainly in the temporal lobe, but also can involve the paraventricular white matter. Clinical presentation is nonspecific, with headache and seizures common.¹⁸ Radiologically, they are comparable to gangliogliomas, being cystic lesions with a mural nodule that may enhance with contrast and can be located close to the ventricles.^17,19

Histologically, they are defined by the presence of pseudopapillary structures composed of a central fibrovascular core with a layer of spindled to cuboidal cells strongly immunoreactive for glial fibrillary acidic protein (GFAP). There is also typically an interpapillary population of synaptophysin-positive neurocytic cells. Molecular studies suggest that PGNTs have a dysregulation of the MAPK pathway. Fusion of solute carrier family 44 member 1 and protein kinase C alpha (SLC44A1-PRKCA), detectable by fluorescence in situ hybridization, is emerging as a specific characteristic of PGNT with a high diagnostic value.

GTR is the treatment of choice. In the largest series of 71 patients, GTR was possible in 52 (73.2%).¹⁸ At median follow-up of 1.5 years (range, 0.2 to 19 y), OS and progression-free survival (PFS) were 80%. This study did not assess the effect of resection on survival. Adjuvant radiotherapy following surgery has limited evidence and therefore is not recommended.

Other Gliomas

Angiocentric glioma (AG)

These tumors mainly affect children and young adults (median age, 16 y). They are usually located in the frontal and temporal lobes but have been reported in the midbrain, hippocampus, and amygdala.²⁰ The most common presentation is epilepsy (up to 88%) followed by headache and visual symptoms.²⁰

MRI shows a well-demarcated, non-enhancing lesion, hyperintense on T2W and hypointense on T1W. There is a characteristic T1W hyperintense rim and stalk-like extension toward the ventricles.

Histologically AG demonstrates both ependymal and astrocytic characteristics (Fig. 1E). These tumors consist of monomorphous bipolar giant cells which accumulate along vascular structures to form pseudorosettes. Differential diagnoses include astroblastoma, ependymoma, and papillary glioneuronal tumors.²¹ Tumor cells do not harbor IDH or BRAF mutations, and the presence of either would suggest an alternative diagnosis. There is one report of malignant transformation to anaplastic ependymoma.²²

GTR is associated with better tumor control. The role of adjuvant radiotherapy after STR is unknown. In a review (n = 88), only 1 (2.7%) of the 37 patients post-GTR had seizure recurrence, whereas 44% of the 16 patients post-STR did.²⁰ In this series, 83 patients were followed up for a median of 24 months and only 5 had tumor recurrence (3 post-GTR, 1 STR, 1 unknown). Time to recurrence ranged from 6 months to 12 years. Adjuvant radiotherapy was used in 5 patients (3 post-GTR and 2 post-biopsy). One patient’s tumor recurred post-GTR and radiotherapy within 6 months, but that tumor had high-grade histological features. Both of the patients who had radiotherapy following biopsy showed tumor regression on follow-up MRI.

In summary, GTR is the recommended treatment. After STR or biopsy, patients should have regular imaging; there is no role for routine adjuvant treatment.

Other Astrocytic Tumors

Pleomorphic xanthoastrocytoma (PXA)

PXAs are rare grade II tumors of children and young adults, with median age at presentation of 26 years.²³ The most common location is the temporal lobe and they usually present with headache and seizures.

The classic radiological manifestation is a cystic tumor that is adjacent to the peripheral leptomeninges with a strongly enhancing mural nodule (Fig. 3A–D). PXAs are usually avascular on angiography. A reactive dural tail means it may mimic meningioma. Perilesional edema is common.

Fig. 3.

Pleomorphic xanthoastrocytoma. (A–D) Pre- and post-contrast CT (A, B) images show an isodense, partially solid, and cystic lesion within the right occipital lobe with small amount of calcification. There is avid contrast enhancement of the solid component with the cystic component showing a rim of peripheral enhancement. The adjacent lateral ventricular atrium is compressed. T2W and post-contrast T1W MRIs (C, D) illustrate the cystic (hyperintense on T2W) and solid (isointense to gray matter on T2W) components of the well-circumscribed lesion which abuts the leptomeninges medially. The areas of low T2W signal represent calcification and blood degradation products. There is adjacent vasogenic edema in the occipital and parietal white matter. Rosette-forming glioneural tumor (E–H): T1W (E) and post-contrast T1W MRI (F) show an isointense lesion filling and expanding the aqueduct and fourth ventricle, which has a heterogeneous ring like enhancement with gadolinium. There is a well-defined border without invasion into surrounding structures. FLAIR images (G–H) illustrate a midline lesion in the fourth ventricle at the level of the middle cerebellar peduncle. There are enhancing nodules more superiorly lining the ependymal surfaces of the lateral ventricles.

Histologically, PXAs are characterized by spindled astrocytic or mesenchymal-like areas, xanthomatous cells, eosinophilic granular bodies, and large cells with bizarre-looking, pleomorphic multinucleated cells (Fig. 1F). Malignant transformation to a higher-grade glioma has been described.

GTR is recommended and the extent of resection correlates with OS.²³ Local recurrence can occur in 15–20% of cases, and the role of adjuvant treatment is unknown. Adjuvant radiotherapy may be offered for residual tumors with high MIB index (>5%).²⁴

BRAF V600E mutation is detected in 60% to 70% of tumors and is associated with better outcomes. Four patients with recurrence after resection, adjuvant radiation, and alkylating chemotherapy received 4 weeks of vemurafenib with median PFS of 5 months and median OS of 8 months.²⁵ Recent reports also highlight the efficacy of BRAF inhibitors in PXA.^26,27

Non-Long-Term Epilepsy-Associated Tumors

Neuronal and Mixed Neuronal-Glial Tumors

Rosette-forming glioneuronal tumors (RGNTs)

These were originally described in the fourth ventricle but have been reported in the chiasm, suprasellar region, pineal gland, and spinal cord.²⁸ Commoner in females, mean age at diagnosis is 29 years.²⁸ The commonest presentation is headache followed by ataxia and nystagmus. Due to the long-standing nature of the tumor, hydrocephalus may be chronic.

On MRI, they appear hypointense on T1W and iso- or hyperintense on T2W images (Fig. 3F–H) and are relatively well circumscribed, heterogeneous, and variably contrast enhancing. Pilocytic astrocytoma is a differential diagnosis. The recently described “green bell pepper sign” is based on the post-contrast appearances of RGNTs—central hypointensity surrounded by thin/no enhancement with an enhancing ring.²⁹ The central component is typically hypointense on diffusion-weighted imaging, which may aid in differentiation from high-grade tumors.

Histologically, there are 2 components, neural and glial (Fig. 1G), with the latter predominating. The neural component consists of small uniform neurocytes forming Homer Wright and perivascular rosettes. The glial component often resembles pilocytic astrocytoma. GFAP is positive in the glial component, and the neurocytes express synaptophysin.

Surgery is recommended. Because of the indolent nature of this tumor, STR and relief of hydrocephalus may be sufficient. In a review of 58 cases, there were 4 recurrences; time to recurrence was 10 years in 2 cases and 9 and 4 years in another 2.²⁸ Regular long-term follow-up is necessary. The role of adjuvant treatment is unknown.

Other Gliomas

Chordoid glioma of the third ventricle (CG)

The age at presentation of these grade II tumors is approximately 46 years, with female predominance.³⁰ Only 80 cases are reported, with 3 in children.³¹ They are located in the anterior third ventricle but may occur elsewhere.

Presenting symptoms include headache, nausea, visual disturbance, and limb weakness. This is due to mass effect or invasion of adjacent structures, and 25% present with hydrocephalus.^32,33 Hypopituitarism and syndrome of inappropriate antidiuretic hormone secretion have been reported.

On MRI, a CG tumor appears as a well-defined ovoid mass in the third ventricle, hyperintense on T2 and hypointense on T1 with avid uniform contrast enhancement (Fig. 4A–D). Occasionally there are small peripheral cystic changes.

Fig. 4.

Astroblastoma (A–D). CT (A) and T2W MRI (B) show a lesion centered on the right inferior frontal gyrus, involving the right insular and subinsular cortex, the right temporal stem, and the right medial temporal gyrus. The lesion contains solid components with areas of cystic degeneration and small foci of calcification and there is adjacent edema resulting in mild compression of the right lateral ventricle. Contrast-enhanced T1W MRI (C, D) shows a predominantly hypointense lesion with minimal heterogeneous contrast enhancement. Dysplastic cerebellar gangliocytoma (E–H): T2W MRI (E, F) shows a lesion within the left superior cerebellar cortex with apparent widening of the cerebellar folia seen as hyper- and isointense striations relative to gray matter. There is no evidence of compression of the fourth ventricle. T1W MRI (G, H) demonstrates a slightly smaller left cerebellar hemisphere, which is more easily appreciated on coronal images.

Histologically CG tumors are composed of cords and clusters of epithelioid cells on a mucoid stroma (Fig. 1H), often with an associated lymphoplasmacytic infiltrate.³⁴ High-grade features are absent. Histopathological differentials include chordoma and chordoid meningioma. Immunohistochemically, the tumor cells are positive for GFAP, vimentin, CD34, and thyroid transcription factor 1. Genetic mutations in epidermal growth factor receptor, murine double minute 2, and cyclin-dependent kinase 4 are absent, suggesting a distinct origin from other gliomas and meningiomas.

GTR is recommended but is achievable in only 44% of patients.³⁵ Postoperative mortality may be as high as 33%, and pulmonary embolism (42%) and infection, including meningitis, were leading causes of death.³⁰ Postoperative morbidities include diabetes insipidus, hypothermia, hyponatremia, hypotension, weight gain, severe short-term memory loss, and psychosis.^20,36

After STR, tumors enlarge slowly, although rapid growth has been reported. Adjuvant fractionated radiotherapy (54 Gy in 30 fractions) or radiosurgery (marginal dose of 12 Gy) may be considered after biopsy or incomplete resection; the exact benefit of such an approach is unknown because of small numbers.²⁰

Astroblastoma

Astroblastoma typically occurs in the frontoparietal region in children and young adults (median age range, 16–35 y).^37,38 Presenting symptoms include raised ICP, focal neurology, or seizures. Radiologically, they are large, well-defined peripheral solid tumors with multiple intratumoral cysts giving a “bubbly” appearance. They are hypointense to isointense on T1W and hyperintense on T2W and enhance heterogeneously with contrast, often as a rim. Calcification within the tumor is consistently reported, most often punctate. Peritumoral edema is described as a risk factor for early recurrence or progression.

Histologically, astroblastomas are composed of spindle-shaped cells with short, broad processes arranged around vessels to form pseudorosettes (Fig. 1I), often with vascular sclerosis. Cells stain for vimentin, S-100, GFAP, epithelial membrane antigen, cytokeratin, and oligodendrocyte transcription factor but not IDH1/2. While astroblastoma is generally considered to be low grade, higher grade is indicated by increased mitotic rate, cellular atypia, and necrosis.

GTR is recommended and feasible in 75–84 % of cases. Reported 5-year OS is 48.5% and GTR is associated with an improved 5-year PFS (83% vs 55%, P = 0.011) compared with STR.^37–39 Adjuvant radiotherapy has been used after STR but its benefit is unclear.^37,39 Re-excision, radiotherapy, and chemotherapy are used at recurrence, and up to 30% had transformed to higher grade at salvage surgery.³⁷

Choroid Plexus Tumors

Choroid plexus papilloma (CPP) and atypical choroid plexus papilloma (aCPP)

Choroid plexus tumors are rare and occur mostly in children, nearly half of them under 2 years.⁴⁰ Most CPPs are sporadic but some are associated with Li–Fraumeni syndrome. In children, the commonest site is the lateral ventricle (43%), while in adults it is the posterior fossa.⁴¹ The majority of supratentorial CPPs present at <20 years, with features of raised ICP in infants.

CT scan shows an iso- or hyperdense mass with calcification present in 4–20%.^41,42 On MRI, they are cauliflower- or mulberry-like lesions which are iso- or hypointense on T1W. T2W images show hyperintense or mixed signal with occasional flow voids with avid contrast enhancement.⁴¹ They are very vascular tumors with high risk of intraoperative hemorrhage. Heterogeneous enhancement, irregular contours, and parenchymal invasion may suggest choroid plexus carcinoma (CPC). Imaging of the entire neuraxis is warranted with all choroid plexus tumors to exclude disseminated disease.^42,43

Choroid plexus tumors have been subclassified into CPP (defined as <2/10 mitoses per high-powered field [HPF], WHO grade I) (Fig. 1J), atypical CPP (2–5 mitoses per HPF, WHO grade II), and CPC with hallmarks of malignancy such as nuclear pleomorphism, necrosis, and >5 mitoses per HPF. However, all choroid plexus tumors may disseminate throughout the neuraxis or undergo malignant transformation, and therefore are best considered as a spectrum from CPP to CPC. The biggest diagnostic challenge is to identify a truly benign CPP from an aCPP that has the potential to recur, and studies need to be done to identify suitable molecular markers.

Outcomes following maximal safe resection of CPP are excellent. An intermediate analysis of the Choroid Plexus Tumor SIOP 2000 study of the International Society of Paediatric Oncology reported 5-year OS of 100% and 5-year event-free survival of 92% for 39 patients with CPP. The 5-year OS was 89% and 5-year event-free survival was 83% for 24 patients with aCPP.⁴⁴ Patients with CPP and completely resected aCPP are therefore observed postoperatively. Patients with incompletely resected aCPP, CPCs, and metastatic tumors irrespective of histology receive postoperative chemotherapy using etoposide and vincristine combined with either carboplatin or cyclophosphamide for 6 cycles. Patients >3 years with incompletely excised aCPP or CPC who respond to chemotherapy have focal radiotherapy (54 Gy in 30 fractions). Those who do not respond to chemotherapy or metastatic tumor irrespective of histology are treated with craniospinal irradiation (CSI) to a dose of 35.2 Gy in 22 fractions with a boost to residual tumor to 54 Gy. One study suggested that patients with CPC treated with CSI had a better 5-year PFS than patients receiving focal or whole-brain radiotherapy (44.2% vs 15.3%, P = 0.031).⁴⁵ Late recurrences (>5 y after initial treatment) are reported, so MRI surveillance is essential.

Neuronal and Mixed Neuronal-Glial Tumors

Dysplastic gangliocytoma of the cerebellum (Lhermitte–Duclos disease)

This occurs predominantly in young adults (median age, 34 y) and >200 cases have been described.⁴⁶ It is strongly associated with Cowden syndrome (a multiple hamartoma neoplasia complex associated with mutations in phosphatase and tensin homolog [PTEN]) and so may also be a hamartoma. Most patients have a germline loss of one PTEN allele and somatic loss of the remaining allele allowing for abnormal growth.

Lhermitte–Duclos

disease usually presents with features of a posterior cranial fossa mass such as cranial nerve palsies and ataxia and rarely as obstructive hydrocephalus.

Imaging alone may be sufficient to make this diagnosis as the radiological findings are so specific and compelling that no realistic differential diagnosis exists.⁴⁷ The characteristic appearance on MRI is of a cerebellar mass with typical striations of alternating hypo- and hyperintense bands on T1W and T2W MRI, a “tiger-striped folial” pattern⁴⁸ (Fig. 4E–H). CT features are of a hypo- or iso-attenuating lesion compared with cortex, making it difficult to appreciate. Most tumors do not enhance, and mass effect causing fourth-ventricular obstruction is common.

Histologically there is disruption of the cerebellar cortex and replacement of the granular layer with large dysplastic ganglion cells (Fig. 1K). Features of malignancy are absent.⁴⁹

Resection is the treatment of choice but may require shunt placement prior to maximal safe tumor resection. GTR may be difficult because tumor definition is difficult perioperatively,⁵⁰ but should be attempted because of the possibility of recurrence or malignant transformation. Patients thus require long-term follow-up.

Central neurocytoma (CN)

These grade II tumors represent 0.1–0.5% of primary brain tumors and arise from the septum pellucidum and the wall of the lateral ventricles.^51,52 Median age at presentation is 34 years. Clinical presentation relates to raised ICP, most commonly papilledema and ataxia.⁵³

On imaging, CN appears as a well-defined, hyperdense mass attached to the lateral ventricles and close to the foramen of Monro. Lesions are iso-/hypointense on T1W MRI and hyperintense on T2W MRI. Calcification and cystic areas are common with moderate contrast enhancement. Prominent flow voids are seen on T2W imaging, and formal angiography shows a tumor blush with supply from the choroidal arteries.⁵⁴ The common differentials are ependymoma and oligodendroglioma.

Histology shows small cells with uniform round nuclei on a fine fibrillary matrix (Fig. 1L). Definitive diagnosis requires demonstration of synaptophysin and neuronal markers on immunohistochemistry. Central neurocytomas are classified as typical (tCN) or atypical (aCN) (defined as tumors with MIB-1 index of >2%, or with atypical features such as increased mitosis, focal necrosis, and vascular proliferation).

GTR is achieved in 30–50% of patients. In an analysis of 520 cases of central neurocytomas, atypia was associated with a worse prognosis.⁵⁵ In this study, the 10-year OS and PFS were 97% and 72%, respectively, for tCN (n = 351), while the 10-year OS and PFS for aCN were 70% and 46%, respectively. For tCN, GTR (n = 137) was associated with better 10-year OS (100% vs 90%) and 10-year PFS (76% vs 43%) compared with STR (n = 90). For both tCN and aCN, adjuvant radiotherapy post GTR did not improve 5-year OS or PFS, but adjuvant radiotherapy post STR improved 5-year local control and OS for both histological subtypes. While 54 Gy is adequate for tCN, radiation dose of 55–60 Gy was associated with better 5-year local control in aCN. Adjuvant radiation is therefore recommended for atypical tumors and after incomplete resection.⁵⁶ Long-term side effects of radiotherapy, particularly in patients with typical tumors, should be weighed against the potential benefits.

Stereotactic radiosurgery (SRS) may also be an adjuvant option.⁵⁷ An analysis of 64 cases showed that adjuvant SRS results in a tumor control rate of 91% at a median of 59.3 months.⁵⁸ SRS has also been proposed as an alternative to surgery in smaller tumors without hydrocephalus. In a series of 14 patients treated to a mean tumor margin dose of 12.1 Gy there was a mean reduction in tumor volume by 69% at 65 months with neither tumor recurrence nor radiotherapy toxicity.^59,60

In patients with recurrent disease not suitable for further surgery or radiotherapy, chemotherapy may be an option using combinations of platinum, etoposide, topotecan, and cyclophosphamide.⁵³

Extraventricular neurocytoma (EVN)

This is a counterpart to central neurocytomas arising in the extraventricular parenchymal tissue and representing 0.1–0.4% of CNS tumors.⁶¹ It is more common in the Asian population and mean age at presentation is 27 years (range, 2–75 y). Around 100 cases, including <20 in children, have been reported.^62,63 The commonest site is the frontal lobe, but it can occur in other lobes as well as the thalamus, cerebellum, pons, and spinal cord.

Clinical presentation is usually with features of raised ICP, sometimes disproportionate to the size of the lesion. Frontal lobe tumors present with gait disturbance and behavioral/emotional changes, while temporal lobe tumors present with seizures. The average duration of onset of clinical symptoms to diagnosis was approximately 32.5 months in one series.⁶²

EVNs are generally well-defined lesions which are hypointense on T1W and hyperintense on T2W images, with heterogeneous contrast enhancement. There may be associated cystic degeneration, calcification, and perilesional edema. They occasionally involve the cortex, which can lead to these tumors being misinterpreted as oligodendrogliomas or gangliogliomas.⁶⁴

Histological features are similar to oligodendroglioma: both have regular round nuclei but the monotonous neoplastic cells in EVN are embedded in a matrix of neuropil. EVN is less invasive and shows greater positivity for synaptophysin. Histologically they differ from central neurocytoma in higher rate of ganglion and glial differentiation. The absence of IDH mutations and 1p/19q codeletion differentiates EVN from oligodendroglioma.

GTR is treatment of choice. Approximately 27% of tumors are typical and are more common in ages >50 years as well as <18 years. Atypical tumors (having necrosis, vascular proliferation, and >3 mitoses per 10 HPF) are associated with a high risk of local recurrence and worse prognosis irrespective of extent of resection.⁶¹ In a review of 85 cases, the median time to recurrence after initial treatment was 48 months (range, 6–216 mo) for typical tumors and 21 months (range, 5–94 mo) for atypical tumors. Rate of recurrence was 68% and mortality was 44% for atypical tumors, whereas the similar figures for typical tumors were 36% and 4%.⁶⁵ For typical tumors, both GTR and STR followed by radiotherapy were associated with reduced risk of recurrence (less than 5% and 17%, respectively). For atypical tumors, the rate of recurrence following GTR with or without radiotherapy was 33–50%, STR followed by radiotherapy was 50%, and STR alone was 100%. However, the number of patients with atypical tumors was small (n = 23) and GTR was achieved in only 13% of tumors—therefore, a definite recommendation regarding adjuvant radiotherapy is difficult.

Cerebellar liponeurocytoma

This tumor is composed of neurocytic cells with variable degrees of lipidization; >40 cases have been reported. It occurs predominantly in those aged >30 years. Most tumors occur in the cerebellum; but they can occur in supratentorial locations. Clinical presentation is with features of raised ICP or cerebellar or brainstem signs.

On imaging, these are well-circumscribed lesions located in the cerebellar hemispheres. They may be seen in the paramedian region or vermis and cause mass effect on the cerebellopontine angle. Variable signal characteristics have been described. There is often hypo/isointensity on T1W images and hyperintensity on T2W images, with heterogeneous contrast enhancement. Focal areas of T1 hyperintensity are variable and correspond to areas of high lipid content which become hypointense on fat-suppressed sequences.^66,67

Histology shows small neurocytic cells similar to a central neurocytoma but with the addition of areas where cells resemble adipocytes. Mitotic activity is low. Necrosis and vascular proliferation are rare, but if present suggest a more aggressive course.

GTR is the treatment of choice, although in one tumor series 6 of 15 patients received adjuvant radiotherapy to a dose of 50 to 59 Gy.⁶⁸

The reported 5-year OS of 48% should be interpreted with caution given the rarity of the tumor.⁶⁹ Patients have prolonged recurrence-free intervals with surgical resection alone. In one study the average time to recurrence following resection was 10.6 years. Given the potential for late recurrence, radiotherapy has a role; but it is unclear whether it should be given immediately or delayed until recurrence. Since there are no reports of spinal metastases, adjuvant radiotherapy is given only to the posterior cranial fossa.

Other Astrocytic Tumors

Subependymal giant cell astrocytoma (SEGA)

SEGA is a tumor of >0.5 cm arising near the foramen of Monro, most common in patients with tuberous sclerosis complex (TSC).⁷⁰ It appears in the first 2 decades of life and the common presentations are features of raised ICP, focal neurology, and seizures.

Tumor location is one of the main differentiating factors for the diagnosis. It occurs when a subependymal nodule at the foramen of Monro transforms into a SEGA. On imaging, these are well-circumscribed masses with calcification and cyst formation which are iso/hypointense on T1W and iso/hyperintense on T2W images with heterogeneous contrast enhancement.

Histology shows a neoplasm composed of large cells with features intermediate between ganglion cells and astrocytes, having abundant glassy eosinophilic cytoplasm, large vesicular nuclei, and prominent nucleoli (Fig. 1M). Conventional high-grade features are not encountered.

Surgery is indicated in symptomatic disease or with documented increase in the volume of tumor or enlargement of the ventricles.⁷⁰ Incomplete resection is associated with tumor progression. Inhibition of mTOR is the treatment of choice for patients ≥3 years with inoperable tumors. In the placebo-controlled phase III trial EXIST-1, everolimus resulted in at least 50% reduction in the tumor volume in 35% of patients treated.⁷¹ The 5-year analysis of a previous phase II trial reported ≥50% reduction in the volume of the tumor in 52% and ≥30% reduction in volume in 61% of patients.⁷² An expanded access program of everolimus (EFFECTS) reported 67.5% partial response and 29.2% stable disease with acceptable toxicity in a cohort of 120 patients.⁷³ The EMINENTS study showed that low-dose maintenance therapy after 12 months of standard dose everolimus is effective and leads to less frequent side effects of reduced severity.⁷⁴ While studies report reduction in size of the tumor after SRS, the response is delayed and therefore the procedure is not an option for symptomatic patients.

Mesenchymal, Nonmeningothelial Tumors

Solitary fibrous tumor (SFT)/hemangiopericytoma (HPC)

These are dural-based tumors, but SFT can rarely arise in the lateral ventricles and spinal cord. In the 2016 classification, SFT and HPC, which have overlapping pathological characteristics, including “patternless” sheets of uniform spindle cells, collagen fibers, and prominent, thin-walled ectatic blood vessels, are grouped together as these tumors exhibit a unique fusion of NAB2 (nerve growth factor-inducible protein A binding protein 2) and STAT6 (signal transducer and activator of transcription 6). The age at diagnosis is the mid-30s and males are more frequently affected. These tumors can be of grades I–III. Grade I tumors were previously diagnosed as SFT, grade II tumors as HPC. Grade III tumors (anaplastic HPC) are characterized by ≥5 mitoses/10 HPF and a higher risk (20–25%) of extracranial recurrence.⁷⁵

Grade I tumors are well-circumscribed extra-axial masses arising from the dura with similar appearances to meningioma. They are typically isodense to hyperdense, may have calcifications, and can erode adjacent bone. These tumors are T1 isointense and T2 hypointense with heterogeneous enhancement. Grade II tumors are mixed iso-hypointense or isointense on T1W and mixed iso-hyperintense or isointense on T2W. The tumors may be uniform or heterogeneously enhancing with areas of necrosis and cystic changes, and the “dural tail” sign may be seen.

GTR is the treatment of choice and 14% of grade I tumors recur. Grades II–III tumors have a higher rate of recurrence, and case series suggest that adjuvant radiotherapy may improve PFS but not OS. Grade II tumors have a higher risk of recurrence even after GTR (>80%) and therefore, adjuvant radiotherapy is advised in tumors with malignant features and after STR.⁷⁶

Hemangioblastoma

Hemangioblastomas account for 2% of intracranial tumors and is associated with von Hippel–Lindau syndrome.⁷⁷ It commonly occurs in patients aged 20–40 years. The commonest site is the posterior fossa, particularly the cerebellum. Presentations are with cerebellar symptoms or features of hydrocephalus. Histologically, they are composed of large vacuolated stromal cells with degenerate nuclear atypia and a rich capillary network. On imaging, these are well-defined tumors consisting of a cyst with non-enhancing walls, except for an enhancing mural nodule. The solid component, which abuts the pia mater, is T1 hypo- or isointense, T2 hyperintense.

GTR is the standard of care, and the reported local recurrence rate is 3–10%. Patients need long-term follow-up.⁷⁷

Conclusion

Table 1 summarizes the features and management of uncommon low-grade tumors. Primary surgery followed by close follow-up remains the standard of care. The role of adjuvant treatment is unclear. However, adjuvant treatment may be considered after STR for tumors with a significant risk of recurrence and where further surgery risks morbidity. Chemotherapy regimens are similar to those for other low-grade gliomas. Some of these tumors exhibit BRAF V600E mutation and there are reports of clinical benefit with BRAF inhibitors.⁷⁸ Importantly, all these tumors should have a structured molecular evaluation as proposed by Jones et al in 2018 to identify potentially targetable genetic alterations.⁷⁹

Table 1.

Summary of features and management of uncommon low-grade tumors*

Type of Tumor		Age, y	Presentation	MRI Features	Primary Treatment	Role of Adjuvant Treatment	Survival/Prognosis	Treatment of Recurrence/Malignant Transformation	Targetable Mutations, If Any
Gangliocytoma and ganglioglioma3–5 (WHO grade I)	0.5% of all CNS tumors	10–30	Epilepsy and raised intracranial pressure	Gangliocytoma: solid hypointense mass on T1W with enhancement on gadolinium and hyperintense on T2W Ganglioglioma: variable and non-specific	GTR if feasible or maximal surgical resection	Adjuvant RT after STR improves local control but not OS. Adjuvant chemotherapy not studied	10-year OS >90%	Surgery if feasible or radical radiotherapy	1. BRAF mutation in 20–60%, BRAF inhibitor 2. TLE4-NTRK2 fusion—Trk inhibitor, eg, entrectinib
DNET9,10 (WHO grade I)	1% of all CNS tumors	8–20	Epilepsy	Variable based on the type. Type 1: well-delineated hypointense cyst or polycystic lesion on T1W; type 2: nodular with mixed signal intensity and type 3: iso- or hypointense on T1W	Excision of the lesion	No proven role	0–10% recurrence after GTR and 34% recurrence after STR	Re-excision if recurs. Possible malignant transformation to astrocytoma/oligodendroglioma after STR	BRAF mutation in 4–51% and activation of mTOR (90%) and MAPK (50%) pathways, BRAF inhibitors, mTOR inhibitors. and MAPK inhibitors
DIA/DIG12,14 (WHO grade I)	0.1–0.3% of all CNS tumors	0–2	Increase in head size, bulging fontenelle, and seizures	Tumor with large cystic and small solid component attached to meninges with dural enhancement	Surgical excision (GTR feasible only in 50%)	No proven role	Median recurrence-free interval <1 y‒19 y	Re-excision, chemotherapy similar to LGG. Radiotherapy not given to avoid diencephalic dysfunction	In one study, 2 out of 16 DIG and 1 out of 2 DIA showed BRAF mutation—BRAF inhibitors
PGNT18 (WHO grade I)	Less than 100 cases reported	Any age, median 23	Nonspecific: headache and seizures	Cystic lesion with an enhancing mural nodule. Calcification common	GTR (feasible in 73%)	No proven role	OS of 80% at a median follow-up of 1.5 years	Re-excision, chemotherapy, radiotherapy	None so far
Angiocentric glioma20 (WHO grade I)	<100 cases reported	Median age 16	Epilepsy, headache and visual symptoms	Well-defined non-enhancing lesion, T1W hypointense and T2W hyperintense. Characteristic T1W hyperintense rim	GTR or maximal safe resection	No proven role	3% recurrence after GTR and 44% recurrence after STR	Re-excision, chemotherapy, radiotherapy. Malignant transformation to ependymoma	MYB-QKI fusion
Pleomorphic xanthoastrocytoma23–25 (WHO grade II)		Median age 26	Headache and seizure	Cystic tumors with strongly enhancing mural nodule adjacent to peripheral leptomeninges	GTR or maximal safe resection	No proven role	Local recurrence in 10–20% 5-year OS 74%	Re-excision if feasible, radical radiotherapy, or chemotherapy. Malignant transformation in 15–20%	BRAF mutation in 60–70%—BRAF inhibitors
RGNT28 (WHO grade I)	Less than 200 cases reported	Mean age 29	Headache, ataxia, and nystagmus	Well-circumscribed hypointense on T1W with variable contrast enhancement. Hyperintense on T2W. “Green bell pepper sign”	Surgical excision	No proven role	Indolent and subtotal excision may be sufficient, regular long-term follow-up	Re-excision, radiotherapy, chemotherapy	PI3CA and FRFR1 mutations—PI3 kinase inhibitors
Choroid glioma of the third ventricle32,35 (WHO grade II)	Less than 50 cases	Median age 46 y, common in females	Variable— headache, visual disturbances, weakness of limbs	Well-defined ovoid mass which is hypointense on T1W with avid contrast enhancement. Hyperintense on T2W	GTR (feasible in only 44%) or maximal safe resection	Adjuvant radiotherapy may be considered after STR/biopsy as risk of further surgery is high	High postoperative mortality rate	High risk of local recurrence. Radiotherapy and SRS	None so far
Astroblastoma37,38 (not graded; range from 1–3)	1% of all CNS tumors	16–35 y	Raised intracranial tension, focal neurology, or seizure	Well-defined solid tumor with intratumoral cyst (“bubbly,”) which is hypo-or isointense on T1W with heterogeneous contrast enhancement and hyperintense on T2W	GTR (feasible in 75–84%) or maximal safe resection	No proven role	5-year OS 48.5% and GTR is associated with better 5-year PFS (83%) compared with STR (55%)	Re-excision, radiotherapy, and chemotherapy. Up to 30% show malignant transformation on salvage surgery	BRAF mutation in 38%—BRAF inhibitors
Choroid plexus tumors41,44,45 (WHO grades I–II)	04-0.6% of all CNS tumors	<20 y	Raised intracranial tension	Cauliflower-like vascular tumors with avid contrast enhancement. T1 iso or hypointense, T2 hyperintense. Flow voids reflect vascularity. MR spectroscopy: markedly increased choline and decreased N-acetyl aspartate	GTR or maximal safe resection	Incompletely excised aCPP and may be considered for adjuvant chemotherapy (<3 y) or radiotherapy (>3 y)	5-year event-free survival of 92% for CPP, and 83% for aCPP.	Re-excision, radiotherapy, or chemotherapy	Methylation of ligand-induced apoptosis pathway (TRAIL) and upregulation of transcription factor TWIST 1 in CPP
Dysplastic gangliocytoma of cerebellum46 (WHO grade I)	>200 cases reported	Median 34	Posterior fossa cranial nerve palsies, ataxia	Cerebellar tumor—alternating hypo- and hyperintense striations—“tiger striped folial” pattern. MR spectroscopy: reduced N-acetyl to choline and N-acetyl to creatine ratio. This may be due to lack of mature neuronal architecture and favoring a hamartomatous aetiology	GTR or maximal safe resection	No role for adjuvant treatment	Re-excision, chemotherapy	Risk of malignant transformation and late recurrence	PTEN mutation
Central neurocytoma53,55,57,58 (WHO grade II)	0.1–0.5% of all CNS tumors	Median 34	Raised intracranial pressure and ataxia	Well-defined T1 hypo, T2 hyperintense tumor with moderate enhancement. Calcification and cysts common. MR spectroscopy: glycine and choline peaks. Usually non-FDG avid but increase in FDG activity may indicate increased risk of recurrence.	GTR (feasible in 30–50%) or maximal safe resection	Adjuvant radiotherapy improves local control after incomplete resection but not survival	10-year OS 100% with GTR and 93% with STR	Re-excision if feasible, radiotherapy, or chemotherapy	Overexpression or mutation of N-Myc, PTEN, PDGF-D, and NRG-2
Extraventricular neurocytoma61,63 (WHO grade II)	0.1–0.4% of brain tumors	Mean age 27	Raised intracranial pressure	Heterogeneously enhancing T1 hypo, T2 hyperintense tumor. Variable enhancement	GTR or maximal safe resection	No proven role for adjuvant treatment	36% recurrence with typical tumors and 68% recurrence with atypical	Malignant transformation to anaplastic ganglioglioma reported	None so far
Cerebellar liponeurocytoma67,69 (WHO grade II)	>40 cases reported	>30	Raised intracranial pressure or cerebellar symptoms	Well-defined cerebellar tumor with T1 hypo and T2 hyperintensity. Foci of T1 hyperintensity = lipid components. No tracer uptake on FDG-PET but increased tracer uptake on methionine-PET	GTR or maximal safe resection	No proven benefit	5-year OS 48%	Re-excision if feasible, radiotherapy. 40% recurrence	None so far
SEGA70,73,74 (WHO grade I)	<1% of all CNS tumors; 5–14% in tuberous sclerosis	<20 y	Raised intracranial pressure, focal neurology, or seizure	Tumor location a main differentiating factor—a subependymal nodule at the foramen of Monro. T1 hypointense, T2 hyperintense with heterogeneous enhancement	Surgery. If surgery not feasible, mTOR inhibitor (everolimus) if >3 y	Maintenance everolimus	Everolimus leads to 68% partial response and 29% stable disease	SRS if no response with everolimus—may promote malignant transformation	Mutations in TSC1 and TSC2 leading to hyperactivation of mTOR signaling—mTOR inhibitors, eg, everolimus, sirolimus
Solitary fibrous tumor/hemangiopericytoma75 (WHO grades I–III)	<1% of CNS tumors	Mid-30s	Raised intracranial pressure, focal neurology, and altered mental status	Grade I: T1 isointense and T2 hypointense with heterogeneous enhancement. Grade II tumors are mixed iso-hypointense or isointense or on T1W and mixed iso-hyperintense or isointense on T2W. Uniform or heterogeneous enhancement with areas of necrosis and cystic changes	GTR	Adjuvant radiotherapy improves local control in grade II tumor with no improvement in OS. Radiotherapy considered after STR.	14% recurrence in grade I and 80% in grade II	Re-excision or radiotherapy	None
Hemangioblastoma77 (WHO grade I)	1–2%	30s	Cerebellar symptoms or features of raised intracranial tension	Well-defined tumor comprising a cyst with non-enhancing walls, except for an enhancing mural nodule. The solid component is T1 hypo or isointense, T2 hyperintense.	GTR	No role for adjuvant treatment	3–10% recurrence	Re-excision, radiotherapy (60–90% local control)	Anti-angiogenic agents (eg, anti-VEGF)

*See online supplement for full list of references.

Abbreviations: FDG = fluorodeoxyglucose; RT = radiotherapy; LGG = low-grade glioma; TLE4 = transducin like enhancer of split 4; NTRK2 = neurotrophic receptor tyrosine kinase; Trk = tropomyosin receptor kinase; MYB = myeloblastosis; QKI = quaking homolog, KH domain RNA binding (mouse); NRG-2 = neuregulin 2; PDGF-D = platelet derived growth factor D; VEGF = vascular endothelial growth factor.

Search Strategy and Selection Criteria

An initial search of PubMed used the broad search terms “brain tumors,” “low-grade,” “radiotherapy,” “chemotherapy,” “surgery,” and “treatment” from January 1990 to March 2018. A subsequent focused search was undertaken using the names of individual histological subtypes of low-grade brain tumors as in the 2016 WHO classification. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this review.

Supplementary Material

A full list of references as supplementary data are available at Neuro-Oncology online.

(see appendix for full list of references)