Central nervous system tumor guidelines

Central nervous system tumor guidelines

The NCCN Guidelines for Central nervous system tumor focus on the management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 Oligodendroglioma IDH-mutant and 1p/19q-codeleted, WHO grade 2-4 Astrocytoma IDH-mutants, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastasesleptomeningeal metastases, non-AIDS-related Primary central nervous system lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers is designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding molecular profiling of glioma1)

Evidence-based, clinical practice guidelines in the management of central nervous system tumors (CNS) continue to be developed and updated through the work of the Joint Section on Tumors of the Congress of Neurological Surgeons (CNS) and the American Association of Neurological Surgeons (AANS).

The guidelines are created using the most current and clinically relevant evidence using systematic methodologies, which classify available data and provide recommendations for clinical practice.

This update summarizes the Tumor Section Guidelines developed over the last five years for non-functioning pituitary adenomas, low-grade gliomas, vestibular schwannomas, and metastatic brain tumors 2).


1)

Horbinski C, Nabors LB, Portnow J, Baehring J, Bhatia A, Bloch O, Brem S, Butowski N, Cannon DM, Chao S, Chheda MG, Fabiano AJ, Forsyth P, Gigilio P, Hattangadi-Gluth J, Holdhoff M, Junck L, Kaley T, Merrell R, Mrugala MM, Nagpal S, Nedzi LA, Nevel K, Nghiemphu PL, Parney I, Patel TR, Peters K, Puduvalli VK, Rockhill J, Rusthoven C, Shonka N, Swinnen LJ, Weiss S, Wen PY, Willmarth NE, Bergman MA, Darlow S. NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022. J Natl Compr Canc Netw. 2023 Jan;21(1):12-20. doi: 10.6004/jnccn.2023.0002. PMID: 36634606.
2)

Redjal N, Venteicher AS, Dang D, Sloan A, Kessler RA, Baron RR, Hadjipanayis CG, Chen CC, Ziu M, Olson JJ, Nahed BV. Guidelines in the management of CNS tumors. J Neurooncol. 2021 Feb;151(3):345-359. doi: 10.1007/s11060-020-03530-8. Epub 2021 Feb 21. PMID: 33611702.

German Pituitary Tumor Registry

German Pituitary Tumor Registry

In 1996, the German Registry of Pituitary Tumors was founded by the Pituitary Section of the German Society of Endocrinology as a reference center for collection and consultant pathohistological studies of pituitary tumors.


The collection comprises a total of 16,283 cases up until the end of 2018. Of these cases, 12,673 originated from surgical and 3,610 from autopsy material. All specimens were fixed in formalin and embedded in paraffin. The sections were stained with H&E stain and PAS. Monoclonal (prolactinTSHFSHLH, and alpha subunit) or polyclonal (GH and ACTH) antibodies were used to detect pituitary hormones in the lesions. Since 2017, antibodies against the transcription factorPit-1T-Pit, and SF-1 has been used in difficult cases. The criteria of the The 2017 World Health Organization classification of tumors of the pituitary gland have been basic principles for classification since 2018 (Osamura et al. 2017). For differentiation of other sellar tumors, such as meningiomas, chordomas, or metastases, the use of additional antibodies was necessary. For these cases, it was possible to use a broad antibody spectrum. Autopsy pituitaries were generally studied by H&E and PAS sections. If any lesions were demonstrated in these specimens, additional immunostaining was performed.

Multiple tumorous lesions with more than one pituitary neuroendocrine tumor (PitNET) respectively adenoma make up 1.4% (232 cases) in our collection. Within the selected cases, synchronous multiple pituitary neuroendocrine tumors (PitNETs) account for 17.3%, PANCH cases (pituitary adenoma with neuronal choristoma) for 14.7%, PitNETs and posterior lobe tumors for 2.2%, PitNETs and metastases for 5.2%, PitNETs and mesenchymal tumors for 2.6%, PitNETs and cysts for 52.2%, and PitNETs and primary inflammation for 6.0%. The mean patient age was 53.8 years, with a standard deviation of 18.5 years. A total of 55.3% of the patients were female and 44.7% were male. From 1990 to 2018, there was a continuous increase in the number of multiple tumorous lesions.

From the studies, Schöning et al. concluded that considering possible tumorous double lesions during surgeries and in preoperative X-ray analyses is recommended 1).


Inflammatory pituitary lesions account for 1.8% of all specimens from the German Pituitary Tumor Registry. They occur in 0.5% of the autoptical specimens and in 2.2% of the surgical cases. Women are significantly more often affected than men and are often younger when first diagnosed. In general, primary and secondary inflammation can be distinguished, with secondary types occurring more frequently (75.1%) than idiopathic inflammatory lesions (15.4%). In primary inflammation, the lymphocytic type is more common (88.5%) than the granulomatous type of hypophysitis (11.5%). The most common causes of secondary inflammation are Rathke’s cleft cysts (48.6%), followed by tumors (17.4%) such as craniopharyngioma (9.1%), and adenoma (5.5%) or germinoma (2.0%). More causes are tumor-like lesions (7.1%) such as xanthogranuloma (3.5%) or Langerhans histiocytosis (3.5%), abscesses (5.5%), generalized infections (5.1%), spread inflammations (4.7%) and previous surgeries (4.0%). In 1.6% of all specimens, the reason for the inflammation remains unclear. The described classification of hypophysitis is important for specific treatment planning after surgery 2).


Searching the data bank of the German Pituitary Tumor Registry 12 double pituitary adenomas with diverse lineage were identified among 3654 adenomas and 6 hypophyseal carcinomas diagnosed between 2012 and 2020. The double adenomas were investigated immunohistochemically for the expression of hormones and lineage markers. In addition, chromosomal gains and losses as well as global DNA methylation profiles were assessed, whenever sufficient material was available (n = 8 PA).

In accordance with the literature, combinations of GH/prolactin/TSH-FSH/LH adenoma (4/12), GH/prolactin/TSH-ACTH adenoma (3/12), and ACTH-FSH/LH adenoma (3/12) were observed. Further, two out of 12 cases showed a combination of a GH/prolactin/TSH adenoma with a null-cell adenoma. Different expression patterns of hormones were confirmed by different expression of transcription factors in 11/12 patients. Finally, multiple lesions that were molecularly analyzed in 4 patients displayed distinct copy number changes and global methylation patterns.

The data confirm and extend the knowledge on multiple PAs and suggest that such lesions may originate from distinct cell types 3).


Between 1996 and 2020, 12,565 cases were enrolled in the German Registry of Pituitary Tumors including 10,084 PitNETs (10,067 adenomas and 19 carcinomas obtained surgically and 193 adenomas diagnosed at autopsy) as well as 69 spindle cell tumors of the neurohypophysis (64 surgical specimens and 5 autopsies). In six patients (1 post-mortem and 5 surgical specimens), PitNETs, as well as posterior lobe tumors, were found in the specimens. Two of the PitNETs were sparsely granulated prolactin-producing tumors, combined in one case with a granular cell tumor and in one case with a pituicytoma. One of the PitNETs revealed that the autopsy was a sparsely granulated GH tumor combined with a neurohypophyseal granular cell tumor. Two PitNETs were null cell adenomas combined with a pituicytoma and a spindle cell oncocytoma, respectively. Further, one Crooke cell tumor was combined with a spindle cell oncocytoma. In five cases, the PitNETs were larger than the posterior lobe tumors and accounted for the clinical symptoms. Previously, four cases of co-existing pituitary anterior and posterior lobe tumors were described in the literature, comprising two ACTH PitNETs, one gonadotrophic PitNET and one null cell PitNET, each in combination with a pituicytoma. PitNETs and concomitant granular cell tumor or spindle cell oncocytoma, as observed in our cohort, have not been reported before 4).


The first 10 years of this registry based on 4122 cases were reported by Saeger et al. The data supplement former collections of the years 1970-1995 with 3480 surgically removed tumors or lesions of the pituitary region. The cases were studied using histology, immunostainings, and in some cases also molecular pathology or electron microscopy. The adenomas were classified according to the current World Health Organization classification in the version of 2004. From 1996 on 3489 adenomas (84.6%), 5 pituitary carcinomas (0.12%), 133 craniopharyngiomas (3.2%), 39 meningiomas (0.94%), 25 metastases (0.6%), 22 chordomas (0.5%), 115 cystic non-neoplastic lesions (2.8%), and 46 inflammatory lesions (1.1%, 248 other lesions or normal tissue (6.0%)) were collected by us. The adenomas (100%) were classified into densely granulated GH cell adenomas (9.2%), sparsely granulated GH cell adenomas (6.3%), sparsely granulated prolactin (PRL) cell adenomas (8.9%), densely granulated PRL cell adenomas (0.3%), mixed GH/PRL cell adenomas (5.2%), mammosomatotropic adenomas (1.1%), acidophilic stem cell adenomas (0.2%), densely granulated ACTH cell adenomas (7.2%), sparsely granulated ACTH cell adenomas (7.9%), Crooke cell adenomas (0.03%), TSH cell adenomas (1.5%), FSH/LH cell adenomas (24.8%), null cell adenomas (19.3%), null cell adenoma, oncocytic variant (5.8%), and plurihormonal adenomas (1.3%). Following the WHO classification of 2004, the new entity ‘atypical adenoma’ was found in 12 cases in 2005. Various prognostic parameters and clinical implications are discussed 5)


1)

Schöning JV, Flitsch J, Lüdecke DK, Fahlbusch R, Buchfelder M, Buslei R, Knappe UJ, Bergmann M, Schulz-Schaeffer WJ, Herms J, Glatzel M, Saeger W. Multiple tumorous lesions of the pituitary gland. Hormones (Athens). 2022 Aug 10. doi: 10.1007/s42000-022-00392-9. Epub ahead of print. PMID: 35947342.
2)

Warmbier J, Lüdecke DK, Flitsch J, Buchfelder M, Fahlbusch R, Knappe UJ, Kreutzer J, Buslei R, Bergmann M, Heppner F, Glatzel M, Saeger W. Typing of inflammatory lesions of the pituitary. Pituitary. 2022 Feb;25(1):131-142. doi: 10.1007/s11102-021-01180-1. Epub 2021 Aug 31. PMID: 34463941; PMCID: PMC8821060.
3)

Hagel C, Schüller U, Flitsch J, Knappe UJ, Kellner U, Bergmann M, Buslei R, Buchfelder M, Rüdiger T, Herms J, Saeger W. Double adenomas of the pituitary reveal distinct lineage markers, copy number alterations, and epigenetic profiles. Pituitary. 2021 Dec;24(6):904-913. doi: 10.1007/s11102-021-01164-1. Epub 2021 Sep 3. PMID: 34478014; PMCID: PMC8550269.
4)

Saeger W, von Schöning J, Flitsch J, Jautzke G, Bergmann M, Hagel C, Knappe UJ. Co-occurrence of Pituitary Neuroendocrine Tumors (PitNETs) and Tumors of the Neurohypophysis. Endocr Pathol. 2021 Dec;32(4):473-479. doi: 10.1007/s12022-021-09677-y. Epub 2021 Jun 15. PMID: 34129177.
5)

Saeger W, Lüdecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S. Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol. 2007 Feb;156(2):203-16. doi: 10.1530/eje.1.02326. PMID: 17287410.

Dysembryoplastic neuroepithelial tumor differential diagnosis

Dysembryoplastic neuroepithelial tumor differential diagnosis

The differential diagnosis of DNET includes oligodendrogliomas, low-grade gliomas, gangliogliomas and pleomorphic xanthoastrocytomas (PXA). Clinical features, imaging findings, and histologic findings are key in making the diagnosis

Low-grade epilepsy-associated neuroepithelial tumors (LEATs) create a diagnostic challenge in daily practice and intraoperative pathological consultation (IC) in particular.


Specific DNT is a homogeneous group of tumours sharing characteristics of pediatric low-grade gliomas: a quiet genome with a recurrent genomic alteration in the RASMAPKsignalling pathway, a distinct DNA methylation profile, a good prognosis but showing progression in some cases. The “non-specific/diffuse DNTs” subgroup encompasses various recently described histo-molecular entities, such as PLNTY and Diffuse astrocytoma MYB or MYBL1 altered 1).


Intraoperative squash smear cytology are extremely useful for accurate diagnosis; however, the knowledge of cytopathologic features of LEATs is based on individual case reports. Kurtulan et al. discuss the 3 most common and well-established entities of LEATs: ganglioglioma (GG), dysembryoplastic neuroepithelial tumor (DNT), and papillary glioneuronal tumor (PGNT).

Thirty patients who underwent surgery for GG, DNT, and PGNT between 2001 and 2021 were collected. Squash smears prepared during intraoperative consultation were reviewed by 1 cytopathologist and an experienced neuropathologist.

Among the 30 tumors, 16 (53.3%) were GG, 11 (36.6%) DNT, and 3 (10%) PGNT. Cytomorphologically, all of the 3 tumor types share 2 common features such as dual cell population and vasculocentric pattern. GG smears were characteristically composed of dysplastic ganglion cells and piloid-like astrocytes on a complex architectural background of thin- to thick-walled vessels. DNT, on the other hand, showed oligodendroglial-like cells in a myxoid thin fibrillary background associated with a delicate capillary network. Common cytological features of PGNT were hyperchromatic cells with narrow cytoplasm surrounding hyalinized vessels forming a pseudopapillary pattern and bland cells with neuroendocrine nuclei dispersed in a neuropil background.

A higher diagnostic accuracy can be obtained when squash smears are applied with frozen sections. However, it is important to integrate clinical and radiologic features of the patient as well as to know the cytopathologic features of the LEAT spectrum in the context of differential diagnosis to prevent misinterpretation in the IC 2).


A 29-year-old male from Bolivia, who lived in Spain, presented seizures and a multicystic brain lesion, initially suspected to be a dysembryoplastic neuroepithelial tumor (DNET). He underwent gross total resection of the mixed solid/cystic lesion. Pathology revealed gliosis, multiple interconnected cystic cavities with fibrous walls, inflammatory cell infiltration and no necrotizing granulomatous reaction. Inside the cavities, a parasitic form was identified as the larva of the cestode Spirometra mansoni. At 1-year follow-up, the patient had no deficits and was seizure free. Clinicians should be alerted to the possible existence of this rare entity in Europe, especially in patients from endemic areas with a possible infection history as well as “wandering lesions” on the MRI 3).

14-year-old woman admitted due to a right temporal lobe tumor.

She was transferred from other Hospital after finding a right temporal lesion on MRI in the context of seizures.

Unprovoked focal seizure. Paroxysmal episodes of blank stare, unresponsiveness, Orofacial Dyskinesia, Guttural sounds, and hypersalivation lasting approximately 30 seconds. Transient global amnesia. He refers to a similar episode a month ago.

Cranial magnetic resonance imaging without and with intravenous contrast (8ml gadovist) was performed with the usual protocol: sagittal T1 TSE, axial T2 TSE, coronal T2 TSE, axial T2 FLAIR, axial T2 EG and axial diffusion.

A signal alteration centered on the anterior pole of the right temporal lobe of approx. 2.2×2.7×1.7cm (TxAPxCC) associates diffuse cortical thickening and the presence of a heterogeneous lesion with a solid and microcystic component that is hypointense in the T1 sequences and hyperintense in the T2 sequences, it also presents a hyperintensity of the peritumoral signal and an increase in diffusion in DWI sequences without presenting signal drop in the ADC. The perfusion sequences did not show an increase in cerebral perfusion at this level with ADC: 1.3. This lesion presents a heterogeneous contrast uptake, drawing attention to the presence of a solid pole adjacent to the dura that presents intense enhancement, but does not present dural enhancement. These findings may be related to a dysembryogenic neuroepithelial tumor (DNET) or to a Ganglioglioma as the main differential diagnoses. No microbleeds were seen in the gradient echo T2 sequence or calcifications. The rest of the cerebral, cerebellar and brainstem parenchyma show no morphological or signal alterations. Middle line centered. Free basal and perimesencephalic cisterns. Centered ventricular system with preserved ventricular size. The main arterial and intracranial venous vessels show a caliber and signal void within normality. Unoccupied paranasal sinuses and mastoid cells. Slight descent of the cerebellar tonsils not significant (2 mm).

Diagnostic impression:

Heterogeneous lesion centered on the anterior temporal pole of the right temporal lobe with a solid / cystic component and enhancement after contrast administration, with tumor characteristics suggesting a Dysembryoplastic neuroepithelial tumor (DNET) or a ganglioglioma as the main differential diagnoses.


1)

Pagès M, Debily MA, Fina F, Jones DTW, Saffroy R, Castel D, Blauwblomme T, Métais A, Bourgeois M, Lechapt-Zalcman E, Tauziède-Espariat A, Andreiuolo F, Chrétien F, Grill J, Boddaert N, Figarella-Branger D, Beroukhim R, Varlet P. The genomic landscape of dysembryoplastic neuroepithelial tumours and a comprehensive analysis of recurrent cases. Neuropathol Appl Neurobiol. 2022 Jul 14:e12834. doi: 10.1111/nan.12834. Epub ahead of print. PMID: 35836307.
2)

Kurtulan O, Bilginer B, Soylemezoglu F. Challenges in the Intraoperative Consultation of Low-Grade Epilepsy-Associated Neuroepithelial Tumors by Cytomorphology in Squash Preparations. Acta Cytol. 2022 Jan 11:1-7. doi: 10.1159/000521249. Epub ahead of print. PMID: 35016169.
3)

Lo Presti A, Aguirre DT, De Andrés P, Daoud L, Fortes J, Muñiz J. Cerebral sparganosis: case report and review of the European cases. Acta Neurochir (Wien). 2015 Sep;157(8):1339-43. doi: 10.1007/s00701-015-2466-9. Epub 2015 Jun 18. PubMed PMID: 26085111.

Obstructive hydrocephalus from posterior fossa tumor risk factors

Obstructive hydrocephalus from posterior fossa tumor risk factors

Saad et al. from the Emory University Hospital surveyed the CNS (Central Nervous System) Tumor Outcomes Registry at Emory (CTORE) for patients who underwent posterior fossa tumor surgery at 3 tertiary-care centers between 2006 and 2019. Demographic, radiographic, perioperative, and dispositional data were analyzed using univariate and multivariate models.

They included 617 patients undergoing PFT resection for intra-axial (57%) or extra-axial (43%) lesions. Gross total resection was achieved in 62% of resections. Approximately 13% of patients required permanent cerebrospinal fluid shunt. Only 31.5% of patients who required pre- or intraop external ventricular drain (EVD) placement needed permanent cerebrospinal fluid shunt. On logistic regression, Tumor size, transependymal edema, use of perioperative external ventricular drain, postoperative intraventricular hemorrhage (IVH), and surgical complications were predictors of permanent CSF diversion. Preoperative tumor size was the only independent predictor of postoperative shunting in patients with subtotal resection. In patients with intra-axial tumors, transependymal flow (P = .014), postoperative IVH (P = .001), surgical complications (P = .013), and extent of resection (P = .03) predicted need for shunting. In extra-axial tumors, surgical complications were the major predictor (P = .022).

The study demonstrates that the presence of preoperative hydrocephalus in patients with PFT does not necessarily entail the need for permanent CSF diversion. Saad et al. reported the major predictive factors for needing a permanent cerebrospinal fluid shunt for obstructive hydrocephalus 1).


Superior tumor extension (into the aqueduct) and failed total resection of tumor were identified as independent risk factors for postoperative hydrocephalus in patients with fourth ventricle tumor 2).


Cully and colleagues analyzed 117 patients and found the following factors to be associated with a higher incidence of postresection hydrocephalus (PRH): age <3 years, midline tumor location, subtotal resection, prolonged EVD requirement, cadaveric dural grafts, pseudomeningocele formation, and CSF infections 3).

Due-Tonnessen and Hleseth found that patients with medulloblastoma and ependymoma had much higher rates of postoperative shunt placement than astrocytomas 4). Kumar and colleagues in a study of 196 consecutive children found age <3 years, tumor histology of medulloblastoma/ependymoma and partial resections were associated with the increased chances of postresection hydrocephalus 5). A study noted that the only modifiable risk factor for the development of PRH was the presence of intraventricular blood in postoperative imaging 6).

Intraventricular blood can cause hydrocephalus either by the “snow globe effect” 7) or by other factors like impaired absorption of CSF by inflammation and fibrosis of the arachnoid granulations caused by blood degradation products 8).

Gopalakrishnan and colleagues noted the following risk factors for PRH: the need for CSF diversion in the pediatric population—children with symptomatology <3 months duration, severe hydrocephalus at presentation, tumor location in the midline, tumor histology, viz. medulloblastoma and ependymoma, use of intraoperative EVD, longer duration of EVD, postoperative meningitis, and pseudomeningocele 9). Similar findings were also reported by Bognar et al. who showed that the presence of EVD and the duration of EVD were associated with a significant increase in the incidence of postresection CSF diversion. In another recent study, Pitsika et al. 10) showed that patients who underwent EVD had a higher rate of postoperative VPS. They also noted a negative correlation between early EVD clamping and VPS indicating that clamping encourages the re-establishment of normal CSF flow when the obstructive tumor is removed 11). From 12).


Choroid plexus cysts (CPCs) are a type of neuroepithelial cysts, benign lesions located more frequently in the supratentorial compartment. Symptomatic CPCs in the posterior fossa are extremely rare and can be associated with obstructive hydrocephalus

Predictive factors for postoperative hydrocephalus has been identified, including young age (< 3 years), severe symptomatic hydrocephalus at presentation, EVD placement before surgery, FOHR index > 0.46 and Evans index > 0.4, pseudomeningocelecerebrospinal fluid fistula, and infection. The use of a pre-resection cerebrospinal fluid shunt in case of signs and symptoms of hydrocephalus is mandatory, although it resolves in the majority of cases. As reported by several studies included in the present review, we suggest CSF shunt also in case of asymptomatic hydrocephalus, whereas it is not indicated without evidence of ventricular dilatation 13).


1)

Saad H, Bray DP, McMahon JT, Philbrick BD, Dawoud RA, Douglas JM, Adeagbo S, Yarmoska SK, Agam M, Chow J, Pradilla G, Olson JJ, Alawieh A, Hoang K. Permanent cerebrospinal fluid shunt in Adults With Posterior Fossa Tumors: Incidence and Predictors. Neurosurgery. 2021 Nov 18;89(6):987-996. doi: 10.1093/neuros/nyab341. PMID: 34561703; PMCID: PMC8600168.
2)

Chen T, Ren Y, Wang C, Huang B, Lan Z, Liu W, Ju Y, Hui X, Zhang Y. Risk factors for hydrocephalus following fourth ventricle tumor surgery: A retrospective analysis of 121 patients. PLoS One. 2020 Nov 17;15(11):e0241853. doi: 10.1371/journal.pone.0241853. PMID: 33201889; PMCID: PMC7671531.
3)

Cully DJ, Berger MS, Shaw D, Geyer R. An analysis of factors determing the need for ventriculoperitoneal shunts after posterior fossa tumor surgery in children. Neurosurgery 1994;34:402-8.
4) , 8)

Due-Tonnessen B, Helseth E. Management of hydrocephalus in children with posterior fossa tumors: Role of tumor surgery. Pediatr Neurosurg 2007;43:92-6
5)

Kumar V, Phipps K, Harkness W, Hayward RD. Ventriculoperitoneal shunt requirement in children with posterior fossa tumors: An 11-year audit. Br J Neurosurg 1996:10:467-70.
6)

Abraham A, Moorthy RK, Jeyaseelan L, Rajshekhar V. Postoperative intraventricular blood: A new modifiable risk factor for early postoperative symptomatic hydrocephalus in children with posterior fossa tumors. Childs Nerv Syst 2019;35;1137-46.
7)

Tamburrini G, Frassanito P, Bianchi F, Massimi L, Di Rocco C, Caldarelli M. Closure of endoscopic third ventriculostomy after surgery for posterior cranial fossa tumor: The “Snow Globe effect”. Br J Neurosurg 2015;29:386-9.
9)

Gopalakrishnan CV, Dhakoji A, Menon G, Nair S. Factors predicting the need for cerebrospinal fluid diversion following posterior cranial fossa tumor surgery in children. Pediatr Neurosurg 2012;48:93-101
10)

Pitsika M, Fletcher J, Coulter IC, Cowie CJA. A validation study of the modified Canadian preoperative prediction rule for hydrocephalus in children with posterior fossa tumors. J Neurosurg. doi: 10.3171/2021.1.PEDS20887.
11)

Bognar L, Borgulya G, Benke P, Madarassy G. Analysis of CSF shunting procedure requirement in children with posterior fossa tumors. Childs Nerv Syst 2003;19:332-6.
12)

Muthukumar N. Hydrocephalus Associated with Posterior Fossa Tumors: How to Manage Effectively? Neurol India. 2021 Nov-Dec;69(Supplement):S342-S349. doi: 10.4103/0028-3886.332260. PMID: 35102986.
13)

Anania P, Battaglini D, Balestrino A, D’Andrea A, Prior A, Ceraudo M, Rossi DC, Zona G, Fiaschi P. The role of external ventricular drainage for the management of posterior cranial fossa tumours: a systematic review. Neurosurg Rev. 2021 Jun;44(3):1243-1253. doi: 10.1007/s10143-020-01325-z. Epub 2020 Jun 3. PMID: 32494987.

Atypical teratoid/rhabdoid tumor

Atypical teratoid/rhabdoid tumor

A malignant World Health Organization grading system IV embryonal tumor of the CNS comprised of poorly differentiated elements and rhabdoid cells and, by definition, includes inactivation of SMARCB1 (INI1) or (extremely rarely) SMARCA4 (BRG1). Histologically similar tumors lacking these molecular genetics should be classified as CNS embryonal tumors with rhabdoid features.

Many of these tumors were probably previously misdiagnosed as MDBs. Occurs primarily in infants and children (> 90% are < 5 years of age, with most age < 2 years). A minority are associated with primary renal rhabdoid tumor. The ratio of supratentorial to infratentorial AT/RTs is 4:3. Posterior fossa AT/RTs may occur in the cerebellar hemispheres, cerebellopontine angle (CPA) and brainstem. 33% have CSF spread at presentation. Althogh the prognosis is poor, not all AT/RTs have the same behavior, and at least 2 different molecular classes have been identified.


Atypical teratoid rhabdoid tumor (AT/RT) is a rare, highly malignant, true rhabdoid tumor in the central nervous system predominantly presenting in young children.

It was originally described a histological variant of Wilm’s tumor in 1978.


Atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In a study, Torchia et al., analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets.

They found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, they discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype 1).

AT/RT can occur anywhere in the central nervous system (CNS) including the spinal cord. About 60% will be in the posterior cranial fossa (particularly the cerebellum). One review estimated 52% posterior fossa, 39% sPNET (supratentorial primitive neuroectodermal tumors), 5% pineal, 2% spinal, and 2% multi-focal.

In the United States, three children per 1,000,000 or around 30 new AT/RT cases are diagnosed each year. AT/RT represents around 3% of pediatric cancers of the CNS.

Around 17% of all pediatric cancers involve the CNS; it is the most common childhood solid tumor.

see Adult sellar atypical teratoid rhabdoid tumor.

see Cerebellopontine angle atypical teratoid rhabdoid tumor.

Atypical Teratoid Rhabdoid Tumor of the Cauda Equina.

Atypical Teratoid Rhabdoid Tumor of the Conus Medullaris.

Typically shows rhabdoid cells which can also be seen in other tumors, but it is differentiated from other tumors by the specific genetic alteration involving the SMARCB1 gene. Only a few cases of AT/RT arising in low-grade glioma have been reported. A 13-year-old girl presented with headache, dizziness, nausea and vomiting.A 4.7 cm cerebellar mass was found on MRI.The mass was totally removed. Histologically, the tumor revealed two distinct morphologic appearances: central areas of AT/RT containing rhabdoid cells and sarcomatous component in the background of pleomorphic xanthoastrocytoma(PXA). Immunohistochemically, PXA areas retained nuclear expression of INI-1 and low Ki-67 proliferation index, whereas AT/RT component showed loss of INI-1 nuclear expression and markedly elevated Ki-67 proliferation index. Epithelial membrane antigen (EMA), smooth muscle actin (SMA), and p53 protein were positive only in AT/RT. BRAF V600E mutation was identified in PXA by real-time polymerase chain reaction.We report a rare case of AT/RT arising in PXA which is supposed to progress by inactivation of INI-1 in a pre-existing PXA 2).

Atypical teratoid rhabdoid tumor treatment.

Patient age at the time of diagnosis, supratentorial location of the mass and fewer complications with adjuvant treatments seem to be factors yielding good prognosis for AT/RT tumors.

AT/RT is a rare and highly progressive malignancy in the children population. This tumor aggressively grows after the first surgery. The INI-1 gene has been found as a diagnostic tumor marker in AT/RT. The characteristic of AT/RT is an absence of INI-1 staining in tumor cells. The treatment in AT/RT serves as palliative treatment, aiming to improve patient’s quality of life. The poor prognosis is associated with MR imaging evidence of disseminated leptomeningeal tumor 3).

Twenty-eight pediatric patients with CNS AT/RT who were treated with radiation therapy (RT) as part of multimodality treatment regimens at a single institution (1996-2015) were reviewed. Survival outcomes were analyzed in relation to possible prognostic factors.

The 28 patients analyzed were followed up for a median 48-month period. Median progression-free survival (PFS) was 11 months, and overall survival (OS) was 57 months. Patients < 3 years old had RT delayed for a longer period after surgery (p = 0.04), and the mean RT dose to tumor bed was lower (p < 0.01) than in patients ≥ 3 years old. In multivariate analysis, a higher primary tumor bed RT dose was identified as a favorable prognostic factor for both PFS (hazard ratio [HR] = 0.85 per gray, p < 0.01) and OS (HR = 0.92 per gray, p = 0.02). In addition, an interval between surgery and RT initiation > 2 months, with disease progression observed before RT, as compared with an interval ≤ 2 months without disease progression prior to RT, was associated with worse PFS (HR = 8.50, p < 0.01) and OS (HR = 5.27, p < 0.01).

Early and aggressive RT after surgery is critical for successful disease control in AT/RT patients. Conversely, a delay in RT until disease progression is observed that leads to unfavorable outcomes 4).


In a study, Torchia et al. analyzed 191 primary Atypical teratoid rhabdoid tumor ATRTs and 10 ATRT cell lines to define the genomics and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. They found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, they discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype 5).

A 7-years-old girl with recurrent tumor mass in the left parieto-occipital region after performing craniotomy surgical resection. The tumor mass aggressively grew within a month after surgery 6).


1) , 5)

Torchia J, Golbourn B, Feng S, Ho KC, Sin-Chan P, Vasiljevic A, Norman JD, Guilhamon P, Garzia L, Agamez NR, Lu M, Chan TS, Picard D, de Antonellis P, Khuong-Quang DA, Planello AC, Zeller C, Barsyte-Lovejoy D, Lafay-Cousin L, Letourneau L, Bourgey M, Yu M, Gendoo DM, Dzamba M, Barszczyk M, Medina T, Riemenschneider AN, Morrissy AS, Ra YS, Ramaswamy V, Remke M, Dunham CP, Yip S, Ng HK, Lu JQ, Mehta V, Albrecht S, Pimentel J, Chan JA, Somers GR, Faria CC, Roque L, Fouladi M, Hoffman LM, Moore AS, Wang Y, Choi SA, Hansford JR, Catchpoole D, Birks DK, Foreman NK, Strother D, Klekner A, Bognár L, Garami M, Hauser P, Hortobágyi T, Wilson B, Hukin J, Carret AS, Van Meter TE, Hwang EI, Gajjar A, Chiou SH, Nakamura H, Toledano H, Fried I, Fults D, Wataya T, Fryer C, Eisenstat DD, Scheinemann K, Fleming AJ, Johnston DL, Michaud J, Zelcer S, Hammond R, Afzal S, Ramsay DA, Sirachainan N, Hongeng S, Larbcharoensub N, Grundy RG, Lulla RR, Fangusaro JR, Druker H, Bartels U, Grant R, Malkin D, McGlade CJ, Nicolaides T, Tihan T, Phillips J, Majewski J, Montpetit A, Bourque G, Bader GD, Reddy AT, Gillespie GY, Warmuth-Metz M, Rutkowski S, Tabori U, Lupien M, Brudno M, Schüller U, Pietsch T, Judkins AR, Hawkins CE, Bouffet E, Kim SK, Dirks PB, Taylor MD, Erdreich-Epstein A, Arrowsmith CH, De Carvalho DD, Rutka JT, Jabado N, Huang A. Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors. Cancer Cell. 2016 Dec 12;30(6):891-908. doi: 10.1016/j.ccell.2016.11.003. PubMed PMID: 27960086.
2)

Jeong JY, Suh YL, Hong SW. Atypical teratoid/rhabdoid tumor arising in pleomorphic xanthoastrocytoma: a case report. Neuropathology. 2014 Aug;34(4):398-405. PubMed PMID: 25268025.
3) , 6)

Parenrengi MA, Permana GI, Suryaningtyas W, Fauziah D. The aggressive progression of primary intracranial atypical teratoid/rhabdoid tumor after surgical resection: A case report. Int J Surg Case Rep. 2022 Jan 24;91:106790. doi: 10.1016/j.ijscr.2022.106790. Epub ahead of print. PMID: 35086049.
4)

Yang WC, Yen HJ, Liang ML, Chen HH, Lee YY, Wong TT, Hu YW, Chen YW. Role of early and aggressive post-operative radiation therapy in improving outcome for pediatric central nervous system atypical teratoid/rhabdoid tumor. Childs Nerv Syst. 2019 Apr 13. doi: 10.1007/s00381-019-04126-y. [Epub ahead of print] PubMed PMID: 30982172.

Endodermal sinus tumor (EST)

Endodermal sinus tumor (EST)

Also known as yolk sac tumor (YST), is a member of the germ cell tumor group of cancers.

It is the most common testicular tumor in children under 3, and is also known as infantile embryonal carcinoma. This age group has a very good prognosis. In contrast to the pure form typical of infants, adult endodermal sinus tumors are often found in combination with other kinds of germ cell tumor, particularly teratoma and embryonal carcinoma. While pure teratoma is usually benign, endodermal sinus tumor is malignant.

The histology of EST is variable, but usually includes malignant endodermal cells. These cells secrete alpha-fetoprotein (AFP), which can be detected in tumor tissue, serum, cerebrospinal fluid, urine and, in the rare case of fetal EST, in amniotic fluid. When there is incongruence between biopsy and AFP test results for EST, the result indicating presence of EST dictates treatment.

This is because EST often occurs as small “malignant foci” within a larger tumor, usually teratoma, and biopsy is a sampling method; biopsy of the tumor may reveal only teratoma, whereas elevated AFP reveals that EST is also present. GATA-4, a transcription factor, also may be useful in the diagnosis of EST.

Diagnosis of EST in pregnant women and in infants is complicated by the extremely high levels of AFP in those two groups. Tumor surveillance by monitoring AFP requires accurate correction for gestational age in pregnant women, and age in infants. In pregnant women, this can be achieved simply by testing maternal serum AFP rather than tumor marker AFP. In infants, the tumor marker test is used, but must be interpreted using a reference table or graph of normal AFP in infants.

A combination of operation and chemotherapy might be the effective management for EST in the posterior cranial fossa.

While pure teratoma is usually benign, endodermal sinus tumor is malignant.

The serum alpha fetoprotein level is well correlated with the severity of the tumor.The prognosis of extragonadal intracranial EST is poor 1).

Adenocarcinoma Arising in a Yolk Sac Tumor of the Pineal Gland 2).


A 54-year-old Japanese man presented with disturbance of consciousness, Parinaud’s syndrome, and gait disturbance. Magnetic resonance imaging revealed a pineal mass lesion, and subtotal resection of the tumor was achieved. The histologic diagnosis was MGCT, consisting mainly of YST. Although he underwent 5 courses of chemotherapy and craniospinal irradiation after surgery, tumor dissemination could not be controlled, and he died 10 months postoperatively.

The present case highlights the need for clinicians to include YST in the differential diagnosis of acute progressive lesions around the pineal region, even in adult patients 3).


A case of a 6-year-old boy initially manifested symptoms of dizziness and vomiting. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a large irregular oval tumor in the cerebellar hemisphere. They subtotally removed the tumor by microsurgery through the left suboccipital approach. Immunohistochemical staining showed that alpha fetoprotein (AFP) was positive and the Ki-67 proliferation index was high (60%), suggesting a germ cell tumor. After 3 months of follow-up, neither recurrence of tumor nor complications were found in the patient. The diagnosis of YST should be confirmed on the basis of clinical manifestations, neuroimaging and pathological findings. Gross total resection (GTR) is an ideal treatment for YST. However, due to the location of the tumor, GTR is usually difficult, and the rate of postoperative complications is high. This reported case shows that subtotal resection can be a good treatment strategy for YST 4).


A patient with primary YST in the pineal region who achieved long term survival. Despite undergoing treatment, he experienced several recurrences over a 15-year period.

Brain magnetic resonance imaging (MRI) demonstrated the presence of space-occupying lesions in the pineal region and the medial tail of the left lateral ventricle. The tumors were excised, and the histological diagnosis suggested an intracranial YST.

The patient achieved long term survival after combined modality therapy including surgery, stereotactic radiosurgery (SRS)/intensity modulated radiation therapy (IMRT), chemotherapy, and targeted therapy.

The disease remained stable. However, the patient gave up treatment and passed away in October 2020, with a total survival of about 15 years.

To the best of our knowledge, this patient with intracranial YST had received a longer survival compared with other published reports 5).


Gkampeta et al. reported the case of a 3-year-old boy with a primary posterior mediastinal yolk sac tumor who was managed initially with surgery, followed by chemotherapy and had a favorable prognosis. In the literature on yolk sac tumors presenting as a mediastinal mass, pediatric germ cell tumors have been reported very rarely in the posterior mediastinum 6).


1) 

Fan MC, Sun P, Lin DL, Yu Y, Yao WC, Feng YG, Tang LM. Primary endodermal sinus tumor in the posterior cranial fossa: clinical analysis of 7 cases. Chin Med Sci J. 2013 Dec;28(4):225-8. PubMed PMID: 24382224.
2) 

Troy C, Gill BJA, Miller ML, Hickman RA, Canoll P, Zacharoulis S, Feldstein NA, Bruce JN. Adenocarcinoma Arising in a Yolk Sac Tumor of the Pineal Gland. J Neuropathol Exp Neurol. 2022 Feb 16:nlac002. doi: 10.1093/jnen/nlac002. Epub ahead of print. PMID: 35172008.
3) 

Uda H, Uda T, Nakajo K, Tanoue Y, Okuno T, Koh S, Onishi Y, Ohata H, Watanabe Y, Umaba R, Kawashima T, Ohata K. Adult-Onset Mixed Germ Cell Tumor Composed Mainly of Yolk Sac Tumor Around the Pineal Gland: A Case Report and Review of the Literature. World Neurosurg. 2019 Dec;132:87-92. doi: 10.1016/j.wneu.2019.08.079. Epub 2019 Aug 27. PMID: 31470154.
4) 

Wu N, Chen Q, Chen M, Ning J, Peng S, Zhang T, Zhong W, Duan S, Cheng C, Xie Y. Primary Yolk Sac Tumor in the Cerebellar Hemisphere: A Case Report and Literature Review of the Rare Tumor. Front Oncol. 2021 Nov 5;11:739733. doi: 10.3389/fonc.2021.739733. PMID: 34804928; PMCID: PMC8602065.
5) 

Xu ZN, Yue XY, Cao XC, Liu YD, Fang BS, Zhao WH, Li C, Xu S, Zhang M. Multidisciplinary treatment of primary intracranial yolk sac tumor: A case report and literature review. Medicine (Baltimore). 2021 May 14;100(19):e25778. doi: 10.1097/MD.0000000000025778. PMID: 34106610; PMCID: PMC8133229.
6) 

Gkampeta A, Tziola TS, Tragiannidis A, Papageorgiou T, Spyridakis I, Hatzipantelis E. Primary posterior mediastinal germ cell tumor in a child. Turk Pediatri Ars. 2019 Sep 25;54(3):185-188. doi: 10.14744/TurkPediatriArs.2019.88155. eCollection 2019. PubMed PMID: 31619931; PubMed Central PMCID: PMC6776447.

Choroid plexus tumor

Choroid plexus tumor

Choroid plexus tumors are rare intraventricular papillary neoplasms derived from choroid plexus epithelium.

They account for approximately 2% to 4% of intracranial tumors in children and

Choroid plexus tumors occur more frequently in children, comprising approximately 4% of all pediatric brain tumors. Up to 20% of these tumors occur during the first year of life.

They account for 0.5% of intracranial tumors in adults.

Choroid plexus tumors most commonly arise from the lateral ventricles (50%), followed by the fourth (40%) and the third ventricle (5%). Other locations are rare, including the cerebellopontine angle, supresellar region, brain parenchyma and the spine.

They include three histologies, choroid plexus papilloma (WHO grade I), atypical choroid plexus papilloma (WHO grade II) and choroid plexus carcinoma (WHO grade III). All together, they account for 0.4-0.6% of all brain tumors 1) 2).

Results support the role of aggresome as a novel prognostic molecular marker for pediatric choroid plexus tumors (CPTs) that was comparable to the molecular classification in segregating samples into two distinct subgroups, and to the pathological stratification in the prediction of patients’ outcomes. Moreover, the proteogenomic signature of CPTs displayed altered protein homeostasis, manifested by enrichment in processes related to protein quality control 3).

see Choroid plexus metastases.

On CT, choroid plexus tumors appear heterogeneous and isodense with calcifications and necrosis.

Amer et al. examined the presence of aggresomes in 42 patient-derived tumor tissues by immunohistochemistry and we identified their impact on patients’ outcomes. We then investigated the proteogenomics signature associated with aggresomes using whole-genome DNA methylation and proteomic analysis to define their role in the pathogenesis of pediatric CPTs.

Aggresomes were detected in 64.2% of samples and were distributed among different pathological and molecular subgroups. The presence of aggresomes with different percentages was correlated with patients’ outcomes. The ≥ 25% cutoff had the most significant impact on overall and event-free survival (p-value < 0.001) compared to the pathological and the molecular stratifications.

These results support the role of aggresome as a novel prognostic molecular marker for pediatric CPTs that was comparable to the molecular classification in segregating samples into two distinct subgroups, and to the pathological stratification in the prediction of patients’ outcomes. Moreover, the proteogenomic signature of CPTs displayed altered protein homeostasis, manifested by enrichment in processes related to protein quality control 4).

2015

A total of 349 patients with CPTs were identified (120 CPCs, 26 aCPPs, and 203 CPPs). Patients with CPC presented at a younger age (median 3, mean 14.8 years) relative to CPP (median 25, mean 28.4 years; p < 0.0001). Histology was a significant predictor of OS, with 5-year OS rates of 90, 77, and 58 % for CPP, aCPP, and CPC, respectively. Older age and male sex were prognostic for worse OS and CSS for CPP. Only extent of surgery had a significant impact on survival for CPC. The use of adjuvant RT in patients with CPC undergoing surgery was not associated with a significantly improved OS (p = 0.17). For patients undergoing GTR without RT as part of an initial course of therapy, estimated 5- and 10-year OS were 70 % (±7 %) and 67 % (±8 %), respectively. Prospective data are required to define the optimal combination of surgery with adjuvant therapies, including chemotherapy 5).


Seventeen childhood patients were recorded with CPT. Cases were distributed so that 9 cases were choroid plexus-papilloma (CPP) (52.9%), 2 cases atypical CPP (11.7%) and 6 cases choroid plexus-carcinoma (CPC) (35.2%). Age at diagnosis was less than 2 years in 14 of the 17 patients (82.3%) and the incidence was higher in males (82.3% of the cases). Gross total resection was performed in 16 patients (94.1%). Adjuvant treatment was used in 6 patients (all this cases with CPC) (35.2%). Two of the 17 patients died (11.7%), showing an incidence density of 0.01 deaths/year.

The case series is consistent with previous published in scientific literature regarding epidemiology, tumor grade, clinical presentation, radiological features and therapeutic approach. Gross total resection is considered the therapeutic gold standard for choroid plexus tumors. Chemotherapy and radiotherapy should be used as adjuvant treatment in CPC and recurrent or remaining atypical CPP 6).


1)

Fuller CE, Narendra S, Tolocica I. Choroid plexus neoplasm. Adesina AM, Tihan T, Fuller C, Young Poussaint T, editors. , Atlas of pediatric brain tumors. New York: Springer Publication; 2010. pp 269-279
2)

Gopal P, Parker JR, Debski R, Parker JC., Jr. Choroid plexus carcinoma. Arch Pathol Lab Med 2008;132:1350-4
3) , 4)

Amer N, Taha H, Hesham D, Al-Shehaby N, Mosaab A, Soudy M, Osama A, Mahmoud N, Elayadi M, Youssef A, Elbeltagy M, Zaghloul MS, Magdeldin S, Sayed AA, El-Naggar S. Aggresomes predict poor outcomes and implicate proteostasis in the pathogenesis of pediatric choroid plexus tumors. J Neurooncol. 2021 Jan 26. doi: 10.1007/s11060-020-03694-3. Epub ahead of print. PMID: 33501605.
5)

Cannon DM, Mohindra P, Gondi V, Kruser TJ, Kozak KR. Choroid plexus tumor epidemiology and outcomes: implications for surgical and radiotherapeutic management. J Neurooncol. 2015 Jan;121(1):151-7. doi: 10.1007/s11060-014-1616-x. Epub 2014 Oct 1. PubMed PMID: 25270349.
6)

Cuervo-Arango I, Reimunde P, Gutiérrez JC, Aransay A, Rivero B, Pérez C, Budke M, Villarejo F. [Choroid plexus tumour treatment at Hospital Infantil Niño Jesús in Madrid: Our experience over the last three decades.]. Neurocirugia (Astur). 2015 Feb 24. pii: S1130-1473(15)00005-6. doi: 10.1016/j.neucir.2015.01.001. [Epub ahead of print] Spanish. PubMed PMID: 25724620.

Cerebellopontine Angle Synchronous Tumor

Cerebellopontine Angle Synchronous Tumor

Synchronous cerebellopontine angle (CPA) tumors are a rare entity, heterogeneous lesions with a marked predisposition toward poor facial nerve outcomes, potentially attributable to a paracrine mechanism that simultaneously drives multiple tumor growth and increases invasiveness or adhesiveness at the facial nerve-tumor interface. Preceding nomenclature has been confounding and inconsistent; Graffeo et al. recommended classifying all multiple CPA tumors as “synchronous tumors,” with “schwannoma with meningothelial hyperplasia” or “tumor-to-tumor metastases” reserved for rare, specific circumstances 1).

Several publications refer to surgery for such tumors and their classification. Yet, there are no publications on upfront radiosurgery for synchronous CPA tumors.

Simultaneous and stepwise radiosurgery for synchronous CPA tumors seems to be safe and effective. There were no side effects or complications. To the best of our knowledge this is the first report on upfront radiosurgery for synchronous CPA tumors 2).

Mindermann and Heckl presented two patients with sporadic synchronous benign CPA tumors who underwent upfront radiosurgery. One patient had two separate schwannomas of the CPA and the other had a cerebellopontine angle schwannoma and a cerebellopontine angle meningioma. One patient underwent stepwise radiosurgery treating one tumor after another and the other patient underwent simultaneous radiosurgery for both tumors at the same time.

Simultaneous and stepwise radiosurgery for synchronous CPA tumors seems to be safe and effective. There were no side effects or complications. To the best of our knowledge this is the first report on upfront radiosurgery for synchronous CPA tumors 3).


A 64-year-old woman and a 42-year-old man presented with symptoms referable to the CPA. Magnetic resonance imaging in both patients revealed 2 separate contiguous tumors. Retrosigmoid craniotomy and tumor removal in each case confirmed VS and meningioma. Systematic literature review identified 42 previous English-language publications describing 46 patients with multiple CPA tumors. Based on Frassanito criteria, there were 4 concomitant tumors (8%), 16 contiguous tumors (33%), 3 collision tumors (6%), 13 mixed tumors (27%), and 11 tumor-to-tumor metastases (23%). Extent of resection was gross total in 16 cases and subtotal in 16 cases (50% each). Unfavorable House-Brackmann grade III-VI function was documented in 27% overall and in 33% of patients with VS and meningioma, a marked increase from the observed range in isolated VS 4).


A 57-year-old female patient presented with headache, speech disturbance, left facial numbness and deafness in the left ear. Magnetic resonance imaging demonstrated two different tumors in the left CPA. These tumors were not in continuity. The tumors were totally removed through the left suboccipital approach. Histopathological examination revealed that the large tumor was a vestibular schwannoma and the smaller was a meningioma. Neurofibromatosis was not diagnosed in the patient. No recurrence was observed at the end of 9 years after the operation. The simultaneous occurrence of vestibular schwannoma and meningioma in the CPA appears coincidental. This association must be kept in mind if two different tumors are detected radiologically in the same CPA 5).


1) , 4)

Graffeo CS, Perry A, Copeland WR 3rd, Giannini C, Neff BA, Driscoll CL, Link MJ. Synchronous Tumors of the Cerebellopontine Angle. World Neurosurg. 2017 Feb;98:632-643. doi: 10.1016/j.wneu.2016.11.002. Epub 2016 Nov 12. PMID: 27836701.
2) , 3)

Mindermann T, Heckl S. Radiosurgery for Sporadic Benign Synchronous Tumors of the Cerebellopontine Angle. J Neurol Surg A Cent Eur Neurosurg. 2020 Oct 21. doi: 10.1055/s-0040-1714424. Epub ahead of print. PMID: 33086420.
5)

Izci Y, Secer HI, Gönül E, Ongürü O. Simultaneously occurring vestibular schwannoma and meningioma in the cerebellopontine angle: case report and literature review. Clin Neuropathol. 2007 Sep-Oct;26(5):219-23. doi: 10.5414/npp26219. PMID: 17907598.

Glioma tumor microenvironment

Glioma tumor microenvironment

In a study, both U118 cell and GSC23 cell exhibited good printability and cell proliferation. Compared with 3D-U118, 3D-GSC23 had a greater ability to form cell spheroids, to secrete VEGFA, and to form tubule-like structures in vitro. More importantly, 3D-GSC23 cells had a greater power to transdifferentiate into functional endothelial cells, and blood vessels composed of tumor cells with an abnormal endothelial phenotype was observed in vivo. In summary, 3D bioprinted hydrogel scaffold provided a suitable tumor microenvironment (TME) for glioma cells and GSCs. This bioprinted model supported a novel TME for the research of glioma cells, especially GSCs in glioma vascularization and therapeutic targeting of tumor angiogenesis 1).


Important advances have been made in deciphering the microenvironment of GBMs, but its association with existing molecular subtypes and its potential prognostic role remain elusive. Jeanmougin et al. investigated the abundance of infiltrating immune and stromal cellin silico, from gene expression profiles. Two cohorts, including in-house normal brain and glioma samples (n=70) and a large sample set from The Cancer Genome Atlas (TCGA)(n=393), were combined into a single exploratory dataset. A third independent cohort (n=124) was used for validation. Tumors were clustered based on their microenvironment infiltration profiles, and associations with known GBM molecular subtypes and patient outcome were tested a posteriori in a multivariable setting. Jeanmougin et al. identified a subset of GBM samples with significantly higher abundances of most immune and stromal cell populations. This subset showed increased expression of both immune suppressor and immune effector genes compared to other GBMs and was enriched for the mesenchymal molecular subtype. Survival analyses suggested that the tumor microenvironment infiltration pattern was an independent prognostic factor for GBM patients. Among all, patients with the mesenchymal subtype with low immune and stromal infiltration had the poorest survival. By combining molecular subtyping with gene expression measures of tumor infiltration, the present work contributes to improving prognostic models in GBM 2).


Tumor-associated microglia and macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are potent immunosuppressors in the glioma tumor microenvironment (TME). Their infiltration is associated with tumor grade, progression and therapy resistance.

This resiliency of glioma stem cells (GSCs) is, in part, due to self-remodeling of their supportive niche also known as the tumor microenvironment 3) 4) 5) 6).

The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

The tumor microenvironment contributes to tumour heterogeneity.

Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms.

Solid cancers develop in dynamically modified microenvironments in which they seem to hijack resident and infiltrating nontumor cells, and exploit existing extracellular matrices and interstitial fluids for their own benefit. Glioblastoma (GBM), the most malignant intrinsic glial brain tumor, hardly colonizes niches outside the central nervous system (CNS). It seems to need the unique composition of cranial microenvironment for growth and invasion as the incidence of extracranial metastasis of GBM is as low as 0.5%. Different nontumor cells (both infiltrating and resident), structures and substances constitute a semiprotected environment, partially behind the well-known blood–brain barrier, benefitting from the relatively immune privileged state of the CNS. This imposes a particular challenge on researchers and clinicians who try to tackle this disease and desire to penetrate efficiently into this shielded environment to weaken the GBM cells and cut them off from the Hinterland they are addicted to. In this chapter, we focus on how GBM interacts with the different components of its tumor microenvironment (TME), how we can target this TME as a useful contribution to the existing treatments, how we could make further progress in our understanding and interaction with this environment as a crucial step toward a better disease control in the future, and what efforts have already been taken thus far 7).


To characterize the glioma tumor microenvironment, a mixed collective of nine glioma patients underwent [18F]DPA-714-PET-MRI in addition to [18F]FET-PET-MRI. Image-guided biopsy samples were immuno-phenotyped by multiparameter flow cytometry and immunohistochemistry. In vitro autoradiography was performed for image validation and assessment of tracer binding specificity.

They found a strong relationship (r = 0.84, p = 0.009) between the [18F]DPA-714 uptake and the number and activation level of glioma-associated myeloid cells (GAMs). TSPO expression was mainly restricted to HLA-DR+ activated GAMs, particularly to tumor-infiltrating HLA-DR+ MDSCs and TAMs. [18F]DPA-714-positive tissue volumes exceeded [18F]FET-positive volumes and showed a differential spatial distribution.

[18F]DPA-714-PET may be used to non-invasively image the glioma-associated immunosuppressive TME in vivo. This imaging paradigm may also help to characterize the heterogeneity of the glioma TME with respect to the degree of myeloid cell infiltration at various disease stages. [18F]DPA-714 may also facilitate the development of new image-guided therapies targeting the myeloid-derived TME. 8).

References

1)

Wang X, Li X, Ding J, et al. 3D bioprinted glioma microenvironment for glioma vascularization [published online ahead of print, 2020 Aug 10]. J Biomed Mater Res A. 2020;10.1002/jbm.a.37082. doi:10.1002/jbm.a.37082
2)

Jeanmougin M, Håvik AB, Cekaite L, Brandal P, Sveen A, Meling TR, Ågesen TH, Scheie D, Heim S, Lothe RA, Lind GE. Improved prognostication of glioblastoma beyond molecular subtyping by transcriptional profiling of the tumor microenvironment. Mol Oncol. 2020 Mar 14. doi: 10.1002/1878-0261.12668. [Epub ahead of print] PubMed PMID: 32171051.
3)

Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007;11(1):69-82.
4)

Cheng L, Huang Z, Zhou W, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 2013;153(1):139- 152.
5)

Lathia JD, Heddleston JM, Venere M, et al. Deadly teamwork: neural cancer stem cells and the tumor microenvironment. Cell Stem Cell. 2011;8(5):482- 485.
6)

Wang L, Rahn JJ, Lun X, et al. Gamma-secretase represents a therapeutic target for the treatment of invasive glioma mediated by the p75 neurotrophin receptor. PLoS Biol. 2008;6(11):e289.
7)

De Vleeschouwer S, Bergers G. Glioblastoma: To Target the Tumor Cell or the Microenvironment? In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 16. Available from http://www.ncbi.nlm.nih.gov/books/NBK469984/ PubMed PMID: 29251862.
8)

Zinnhardt B, Müther M, Roll W, Backhaus P, Jeibmann A, Foray C, Barca C, Döring C, Tavitian B, Dollé F, Weckesser M, Winkeler A, Hermann S, Wagner S, Wiendl H, Stummer W, Jacobs AH, Schäfers M, Grauer OM. TSPO imaging-guided characterization of the immunosuppressive myeloid tumor microenvironment in patients with malignant glioma. Neuro Oncol. 2020 Feb 12. pii: noaa023. doi: 10.1093/neuonc/noaa023. [Epub ahead of print] PubMed PMID: 32047908.