Adamantinomatous Craniopharyngioma

Adamantinomatous Craniopharyngioma

craniopharyngioma with epithelium that forms stellate reticulum, wet keratin, and basal palisades. Up to 95% of cases of this variant shows CTNNB1 mutations and aberrant nuclear expression of beta-catenin 1).

Bimodal age distribution: childhood peak age 5–15 years, adult peak age 45–60 years 2).

The evolving characterization of the biological basis of adamantinomatous craniopharyngioma (ACP) has provided insights critical for novel systemically delivered therapies. While current treatment strategies for ACP are associated with low mortality rates, patients experience severely lowered quality of life due to high recurrence rates and chronic sequelae, presenting a need for novel effective treatment regimens. The identification of various dysregulated pathways that play roles in the pathogenesis of ACP has prompted the investigation of novel treatment options. Aberrations in the CTNNB1 gene lead to the dysregulation of the Wnt signaling pathway and the accumulation of nuclear β-catenin, which may play a role in tumor invasiveness. While Wnt pathway/β-catenin inhibition may be a promising treatment for ACP, potential off-target effects have limited its use in current intervention strategies. Promising evidence of the therapeutic potential of cystic proinflammatory mediators and immunosuppressants has been translated into clinical therapies, including interleukin 6 and IDO-1 inhibition. The dysregulation of the pathways of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), epidermal growth factor receptor (EGFR), and programmed cell death protein 1 and its ligand (PD-1/PD-L1) has led to identification of various therapeutic targets that have shown promise as clinical strategies. The Sonic Hedgehog (SHH) pathway is upregulated in ACP and has been implicated in tumorigenesis and tumor growth; however, inhibition of SHH in murine models decreased survival, limiting its therapeutic application. While further preclinical and clinical data are needed, systemically delivered therapies could delay or replace the need for more aggressive definitive treatments. Ongoing preclinical investigations and clinical trials of these prospective pathways promise to advance treatment approaches aimed to increase patients’ quality of life 3).

Early disease onset, clinical manifestation, histomorphology, and increased tendency to relapse distinguish the adamantinomatous craniopharyngioma (adaCP) from the more favorable papillary craniopharyngioma variant (papCP). A molecular hallmark of adaCP is the activated Wnt signaling pathway indicated by nuclear β-catenin accumulation in a subset of tumor cells. A mouse model recently illustrated that these cells are the driving force in tumorigenesis of adaCP. This observation and the peculiar growth pattern points to the existence of a specific tumor stem cell (TSC) population in human CP. Tumor stem cell-like characteristics of β-catenin accumulating cell clusters in adaCP, which may represent a tumor stem cell niche and might contribute to tumor recurrence. The potential impact of these special cell groups in regard to future CP management, including postoperative follow-up and additional treatment remains to be explored 4).

Osteogenic factor Bmp2 may play an important role in the calcification of adamantinomatous craniopharyngioma ACP via autocrine or paracrine mechanisms. Given the presence of osteogenic markers (Runx2 and Osterix), craniopharyngioma cells could differentiate into an osteoblast-like lineage, and the process of craniopharyngioma calcification resembles that which occurs in osteogenesis/odontogenesis 5).

Adamantinomatous and papillary craniopharyngiomas harbor mutations that are mutually exclusive and clonal. These findings have important implications for the diagnosis and treatment of these neoplasms 6).


1) , 2)

Louis DN, Ohgaki H, Wiestler OD, et al. WHO classification of tumors of the central nervous system. Lyon, France 2016

Hengartner AC, Prince E, Vijmasi T, Hankinson TC. Adamantinomatous craniopharyngioma: moving toward targeted therapies. Neurosurg Focus. 2020 Jan 1;48(1):E7. doi: 10.3171/2019.10.FOCUS19705. PubMed PMID: 31896087.

Hölsken A, Stache C, Schlaffer SM, Flitsch J, Fahlbusch R, Buchfelder M, Buslei R. Adamantinomatous craniopharyngiomas express tumor stem cell markers in cells with activated Wnt signaling: further evidence for the existence of a tumor stem cell niche? Pituitary. 2013 Dec 20. [Epub ahead of print] PubMed PMID: 24356780.

Song-Tao Q, Xiao-Rong Y, Jun P, Yong-Jian D, Jin L, Guang-Long H, Yun-Tao L, Jian R, Xiang-Zhao L, Jia-Ming X. Does the calcification of adamantinomatous craniopharyngioma resemble the calcium deposition of osteogenesis/odontogenesis? Histopathology. 2013 Jan 31. doi: 10.1111/his.12071. [Epub ahead of print] PubMed PMID: 24387671.

Brastianos PK, Taylor-Weiner A, Manley PE, Jones RT, Dias-Santagata D, Thorner AR, Lawrence MS, Rodriguez FJ, Bernardo LA, Schubert L, Sunkavalli A, Shillingford N, Calicchio ML, Lidov HG, Taha H, Martinez-Lage M, Santi M, Storm PB, Lee JY, Palmer JN, Adappa ND, Scott RM, Dunn IF, Laws ER Jr, Stewart C, Ligon KL, Hoang MP, Van Hummelen P, Hahn WC, Louis DN, Resnick AC, Kieran MW, Getz G, Santagata S. Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet. 2014 Jan 12. doi: 10.1038/ng.2868. [Epub ahead of print] PubMed PMID: 24413733.

Cystic craniopharyngioma

Cystic craniopharyngioma

Cystic craniopharyngiomas comprise more than 90% of the craniopharyngiomas.


Intracystic treatment options for cystic craniopharyngioma provide data suggestive of durable cyst shrinkage and benefit beyond a pure volume reduction due to repeated fluid aspirations. The effect however is limited to the cystic craniopharyngioma portion without an effect on the solid component. There are multiple challenges relating to technical practicalities: Multicystic occurrence may limit treatment to one cyst only and therefore this approach does not provide the clinical benefit as wished. The thickness of the cyst wall may not allow successful penetration of the scope/catheter into the cyst and different catheter designs make the correct intracystic positioning of the catheter and its holes difficult. Intraoperative ultrasound and computed tomography (CT) have aided to confirm the correct catheter position; however, volume changes during subsequent treatment may influence the intracystic catheter tip location.

Hence the prospect of a minimally invasive intervention – such as an endoscopic insertion of a catheter with a subcutaneous Ommaya reservoir – and subsequent instillation of substances inducing shrinkage of the craniopharyngioma cyst(s), seems a promising strategy 1).

Intracystic bleomycin

A search in electronic databases CENTRAL (2014, Issue 1), MEDLINE/PubMed (from 1966 to March 2014) and EMBASE/Ovid (from 1980 to March 2014) with pre-specified terms, Reference lists of relevant articles and reviews, conference proceedings (International Society for Paediatric Oncology 2005-2013) and ongoing trial databases (Register of the National Institute of Health and International Standard Randomised Controlled Trial Number (ISRCTN) register) in May 2014.

Randomized controlled trials (RCTs), quasi-randomized trials or controlled clinical trials (CCTs) comparing intracystic bleomycin and other treatments for cystic craniopharyngiomas in children (from birth to 18 years).

Two review authors independently performed the data extraction and ‘Risk of bias’ assessment. They used risk ratio (RR) for binary data and mean difference (MD) for continuous data. We planned that if one of the treatment groups experienced no events and there was only one study available for the outcome, we would use the Fischer’s exact test.

Zheng et al. could not identify any studies in which the only difference between the treatment groups was the use of intracystic bleomycin. They did identify a RCT comparing intracystic bleomycin with intracystic phosphorus 32 (n = 7 children). The trial had a high risk of bias. Survival could not be evaluated. There was no evidence of a significant difference between the treatment groups in cyst reduction (MD -0.15, 95% confidence interval (CI) -0.69 to 0.39, P value = 0.59), neurological status (Fisher’s exact P value = 0.429), 3rd nerve paralysis (Fischer’s exact P value = 1.00), fever (RR 2.92, 95% CI 0.73 to 11.70, P value = 0.13) or total adverse effects (RR 1.75, 95% CI 0.68 to 4.53, P value = 0.25). There was a significant difference in favour of the (32)P group for the occurrence of headache and vomiting (Fischer’s exact P value = 0.029 for both outcomes).

Since they identified no RCTs, quasi-randomised trials or CCTs of the treatment of cystic craniopharyngiomas in children in which only the use of intracystic bleomycin differed between the treatment groups, no definitive conclusions could be made about the effects of intracystic bleomycin in these patients. Only one low-power RCT comparing intracystic bleomycin with intracystic (32)P treatment was available, but no definitive conclusions can be made about the effectiveness of these agents in children with cystic craniopharyngiomas. Based on the currently available evidence, we are not able to give recommendations for the use of intracystic bleomycin in the treatment of cystic craniopharyngiomas in children. High-quality RCTs are needed 2).


Radioactive phosphorus 32 (P32) has been used as brachytherapy for craniopharyngiomas with the hope of providing local control of enlarging tumor cysts. Brachytherapy has commonly been used as an adjunct to the standard treatment of surgery and external beam radiation (EBR). Historically, multimodal treatment, including EBR, has shown tumor control rates as high as 70% at 10 years after treatment. However, EBR is associated with significant long-term risks, including visual deficits, endocrine dysfunction, and cognitive decline. Theoretically, brachytherapy may provide focused local radiation that controls or shrinks a symptomatic cyst without exposing the patient to the risks of EBR.

Ansari et al reviewed their experiences with craniopharyngioma patients treated with P32 brachytherapy as the primary treatment without EBR. The authors reviewed these patients’ records to evaluate whether this strategy effectively controls tumor growth, thus avoiding the need for further surgery or EBR.

Ansari et al performed a retrospective review of pediatric patients treated for craniopharyngioma between 1997 and 2004. This was the time period during which the authors’ institution had a relatively high use of P32 for treatment of cystic craniopharyngioma. All patients who had surgery and injection of P32 without EBR were identified. The patient records were analyzed for complications, cyst control, need for further surgery, and need for future EBR.

Thirty-eight patients were treated for craniopharyngioma during the study period. Nine patients (23.7%) were identified who had surgery (resection or biopsy) with P32 brachytherapy but without initial EBR. These 9 patients represented the study group. For 1 patient (11.1%), there was a complication with the brachytherapy procedure. Five patients (55.5%) required subsequent surgery. Seven patients (77.7%) required subsequent EBR for tumor growth. The mean time between the injection of P32 and subsequent treatment was 1.67 ± 1.50 years (mean ± SD).

In this small but focused population, P32 treatment provided limited local control for cyst growth. Brachytherapy alone did not reliably avert the need for subsequent surgery or EBR 3).

Case series

11 non-consecutive adult cystic craniopharyngiomas (7 recurrent lesions) have been treated with Ommaya Reservoir System (ORS), in two neurosurgical centers. ORS was placed in nine cases using minimally invasive procedures: six burr hole endoscopic insertion and three navigated electromagnetic placement; in the remaining two patients, the Ommaya reservoir was used as a shunt to prevent cyst recollection during a transcranial approach.

The main presenting symptoms were visual impairment (75%), cognitive and behavioral disorders (66.7%), hypopituitarism (38%), headache (30.8%) and hypothalamic obesity (8%). The median follow-up period was 41.4 months. In all patients, the visual function and intracranial hypertension improved after decompression. Local tumor control was accomplished in eight patients (72.7%), without the need of adjuvant treatments. The endoscopic vision carried similar rates of tumor control than the stereotaxy (75% vs 66.7%).

In selected patients, tailored procedures are required to achieve long-term tumor control and as well limit surgery-related morbidity. ORS could represent a safe and effective treatment option for cystic craniopharyngiomas, providing also reduced surgical related morbidity especially in recurrent lesions and in patients nonsuitable for radical surgery 4).



Bartels U, Laperriere N, Bouffet E, Drake J. Intracystic therapies for cystic craniopharyngioma in childhood. Front Endocrinol (Lausanne). 2012 Mar 27;3:39. doi: 10.3389/fendo.2012.00039. eCollection 2012. PubMed PMID: 22654864; PubMed Central PMCID: PMC3356106.

Zheng J, Fang Y, Cai BW, Zhang H, Liu W, Wu B, Xu JG, You C. Intracystic bleomycin for cystic craniopharyngiomas in children. Cochrane Database Syst Rev. 2014 Sep 19;9:CD008890. doi: 10.1002/14651858.CD008890.pub3. Review. PubMed PMID: 25233847.

Ansari SF, Moore RJ, Boaz JC, Fulkerson DH. Efficacy of phosphorus-32 brachytherapy without external-beam radiation for long-term tumor control in patients with craniopharyngioma. J Neurosurg Pediatr. 2016 Apr;17(4):439-45. doi: 10.3171/2015.8.PEDS15317. Epub 2015 Dec 18. PubMed PMID: 26684761.

Frio F, Solari D, Cavallo LM, Cappabianca P, Raverot G, Jouanneau E. OMMAYA RESERVOIR SYSTEM FOR THE TREATMENT OF CYSTIC CRANIOPHARYNGIOMAS: SURGICAL RESULTS IN A SERIES OF 11 ADULT PATIENTS AND REVIEW OF THE LITERATURE. World Neurosurg. 2019 Aug 7. pii: S1878-8750(19)32133-3. doi: 10.1016/j.wneu.2019.07.217. [Epub ahead of print] PubMed PMID: 31400528.

Craniopharyngioma Cyst Fluid

Craniopharyngioma Cyst Fluid

The dense oily fluid content of craniopharyngioma CPs is reported to cause brain tissue damage, demyelination and axonal loss in the hypothalamus; however, its exact effect on different cell types of CNS is still unexplored.

One cause of postoperative morbidity, and indeed mortality, is aseptic meningitis from spill-out of craniopharyngioma cyst contents.

Halliday and Cudlip from the John Radcliffe Hospital, developed a surgical technique for the management of large craniopharygngioma cysts extending into the third ventricle, to reduce this risk.

They described a technique of using an epidural catheter, inserted into the working channel of a neuroendoscope, to decompress the cystic portion of a craniopharyngioma cyst before opening the cyst wall widely, preventing spill-out of large volumes of cyst content into the ventricular system.

They had no cases of aseptic meningitis, nor any complications, from use of the described technique.

They believe that this is a safe and effective technique of decompression and fenestration of large suprasellar craniopharyngioma cysts that reduces rates of aseptic meningitis and the associated morbidity and mortality from this 1)

In a study, Ghosh et al. from Bangalore, collected CP cyst fluid (CCF) from mostly young patients during surgical removal and exposed it 9-10 days in vitro to the primary cultures derived from rat brain hypothalamus for 48 hours. A gradual decline in cell viability was noted with increasing concentration of CCF. Moreover, a distinct degenerative morphological transformation was observed in neurons and glial cells, including appearance of blebbing and overall reduction of the cell volume. Further, enhanced expression of Caspase-3 in neurons and glial cells exposed to CCF by immunofluorescence imaging, supported by Western blot experiment suggest CCF induced apoptosis of hypothalamic cells in culture.

They demonstrated the deleterious effects of the cyst fluid on various cell types within the tumors originating region of the brain and its surroundings for the first time. Taken together, this finding could be beneficial towards identifying the region specific toxic effects of the cyst fluid and its underlying mechanism 2).

Craniopharyngiomas (CPs) are cystic, encapsulated, slow-growing epithelial tumors. CPs can be aggressive forms invading and resorting surrounding structures of adjacent brain tissue, where Rosenthal fibers (RFs) are expressed. The aim of this study was to investigate the ultrastructure of these fibers in human biopsies and compare it with an experimental toxic model produced by the cortical infusion of the oil cyst fluid (“Oil machinery” fluid or OMF) from CPs to rats. For this purpose, the CPs from ten patients were examined by light and electron microscopy. OMF was administered to rats intracortically. Immunohistochemical detection of glial fibrillary acidic protein (GFAP) and vimentin was assessed. In both freshly obtained CPs and rat brain tissue, the presence of abundant cellular debris, lipid-laden macrophages, reactive gliosis, inflammation and extracellular matrix destruction were seen. Ultrastructural results suggest focal pathological disturbances and an altered microenvironment surrounding the tumor-brain junction, with an enhanced presence of RFs in human tumors. In contrast, in the rat brain different degrees of cellular disorganization with aberrant filament-filament interactions and protein aggregation were seen, although RFs were absent. Our immunohistochemical findings in CPs also revealed an enhanced expression of GFAP and vimentin in RFs at the peripheral, but not at the central (body) level. Through these findings we hypothesize that the continuous OMF release at the CPs boundary may cause tissue alterations, including damaging of the extracellular matrix, and possibly contributing to RFs formation, a condition that was not possible to reproduce in the experimental model. The presence of RFs at the CPs boundary might be considered as a major criterion for the degree of CPs invasiveness to normal tissue. The lack of RFs reactivity in the experimental model reveals that the invasive component of CPs is not present in the OMF, although the fluid per se can exert tissue damage 3).

Fifteen samples of cyst fluid and 14 samples of blood serum were collected from 14 patients with cystic forms of craniopharyngiomas and studied biochemically regarding total protein, albumin, immunoglobulins G and M contents, lactate and pH. Analysis of the data obtained for cyst fluids according to Felgenhauer and comparing them to those obtained for the corresponding blood sera led us to prove the hypothesis of blood-brain barrier impairment in patients with cyst formations in craniopharyngioma.

Arefyeva et al. have also revealed an elevated lactate content and decreased pH in cyst fluids compared with blood sera. Thus the pathogenesis of craniopharyngiomal cyst appears to be much more akin to those described for cysts accompanying other brain tumours than it was believed earlier 4).

A prospective study of cystic fluid in craniopharyngiomas in 10 patients was performed to correlate signal intensity on T1-weighted magnetic resonance (MR) images and biochemical analysis. Within 2 days before surgery, each patient underwent MR imaging before and after administration of gadopentetate dimeglumine. Five patients had cystic fluid lower in signal intensity than white matter, with protein levels less than 9,000 mg/dL (90.00 g/L) and no free methemoglobin. One of the five patients had the highest triglyceride concentration (84 mg/dL [0.95 mmol/L]) of all 10 patients; another of these five had the highest cholesterol concentration of all (270 mg/dL [6.98 mmol/L]). It is concluded that the increased signal intensity of cystic fluid in craniopharyngiomas on T1-weighted MR images can be caused by a protein concentration greater than or equal to 9,000 mg/dL (90.00 g/L), the presence of free methemoglobin, or both. In the ranges of concentrations measured in this study, cholesterol and triglyceride did not increase signal intensity 5).



Halliday J, Cudlip S. A new technique of endoscopic decompression of suprasellar craniopharyngioma cyst. Acta Neurochir (Wien). 2019 Aug 4. doi: 10.1007/s00701-019-04024-x. [Epub ahead of print] PubMed PMID: 31377958.

Ghosh M, Das S, Rao KVLN, Pruthi N, Ramesh VJ, Raju TR, Sathyaprabha TN. Effects of Craniopharyngioma Cyst Fluid on Neurons and Glial Cells cultured from rat brain hypothalamus. J Chem Neuroanat. 2018 Oct 16. pii: S0891-0618(18)30086-3. doi: 10.1016/j.jchemneu.2018.10.005. [Epub ahead of print] PubMed PMID: 30339791.

Tena-Suck ML, Morales-Del Ángel AY, Hernández-Campos ME, Fernández-Valverde F, Ortíz-Plata A, Hernández AD, Santamaría A. Ultrastructural characterization of craniopharyngioma at the tumor boundary: A structural comparison with an experimental toxic model using “oil machinery” fluid, with emphasis on Rosenthal fibers. Acta Histochem. 2015 Oct;117(8):696-704. doi: 10.1016/j.acthis.2015.09.006. Epub 2015 Oct 26. PubMed PMID: 26515050.

Arefyeva IA, Semenova JB, Zubairaev MS, Kondrasheva EA, Moshkin AV. Analysis of fluid in craniopharyngioma-related cysts in children: proteins, lactate and pH. Acta Neurochir (Wien). 2002 Jun;144(6):551-4; discussion 554. PubMed PMID: 12111487.

Ahmadi J, Destian S, Apuzzo ML, Segall HD, Zee CS. Cystic fluid in craniopharyngiomas: MR imaging and quantitative analysis. Radiology. 1992 Mar;182(3):783-5. PubMed PMID: 1535894.
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