Skip to main content

Advertisement

SpringerLink
Log in

Can tissue biomarkers reliably predict the biological behavior of craniopharyngiomas? A comprehensive overview

  • Published:
Pituitary Aims and scope Submit manuscript

“A physician is obligated to consider more than a diseased organ, more even than the whole man -he must view the man in his world.”

Harvey Cushing (1869–1939)

Quoted in “Thomson EH (1950) Harvey Cushing: Surgeon, Author, Artist. Henry Schuman, New York: p ix”

Abstract

Background

The growing interest in the molecular and genetic alterations of craniopharyngiomas (CPs) is embodied in recent studies revealing insights into the CP tumorigenesis and identifying novel molecular pathways amenable of targeted therapies. The actual impact of this new information, however, remains inconclusive.

Methods

We present a comprehensive review of the accumulated knowledge on molecular biology of CPs and a critical analysis on the strengths and weaknesses of the studies focused on CP molecular/genetic alterations published to date.

Results

A thorough analysis of the alterations of β-catenin/CTNNB1 and BRAF genes investigated in 1123 CP cases included in 27 studies, showed that, on average, CTNNB1 mutations were present in two-thirds of adamantinomatous CPs and BRAF mutations in 90% of papillary CPs. Their role as oncogenic drivers has not been well established. Although rare, coexistence of both mutations may occur. The involvement of pituitary stem cells in human CP tumorigenesis is still uncertain. Expression of stem markers in human CP samples predominantly occurred along the CP border in contact with brain tissue. Finally, none of the various molecular alterations which have been proposed as markers for CP recurrence can be used today as reliable predictors of the CP behavior.

Conclusions

The isolated evaluation of CPs’ molecular or genetic profiles that do not take into consideration fundamental pathological and therapeutic factors, specifically the tumor topography and the degree of tumor removal, may actually generate confusion regarding the reliability of some biomarkers to predict the CP biological behavior.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Reproduced with permission from Dr. Ronald Kim, University of California Irvine

Fig. 2

Similar content being viewed by others

Abbreviations

aCP:

Adamantinomatous CP

CP:

Craniopharyngioma

LI:

Labelling index

pCP:

Squamous papillary CP

References

  1. Apps JR, Martinez-Barbera JP (2016) Molecular pathology of admantinomatous craniopharyngioma: review and opportunities for practice. Neurosurg Focus 41:E4

    Article  PubMed  Google Scholar 

  2. Prieto R, Pascual JM, Castro-Dufourny I, Carrasco R, Barrios L (2017) Craniopharyngioma: surgical outcome as related to the degree of hypothalamic involvement. World Neurosurg 104:1006–1010

    Article  PubMed  Google Scholar 

  3. Prieto R, Pascual JM, Subhi-Issa I, Jorquera M, Yus M, Martínez R (2013) Predictive factors for craniopharyngioma recurrence: a systematic review and illustrative case report of a rapid recurrence. World Neurosurg 79:733–749

    Article  PubMed  Google Scholar 

  4. Brastianos PK, Taylor-Weiner A, Manley PE, Jones RT, Dias-Santagata D, Thorner AR et al (2014) Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet 46:161–165

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Rienstein S, Adams EF, Pilzer D, Aviram Goldring A, Goldman B, Friedman E (2003) Comparative genomic hybridization analysis of craniopharyngiomas. J Neurosurg 98:162–164

    Article  PubMed  CAS  Google Scholar 

  6. Sekine S, Shibata T, Kokubu A, Morishita Y, Noguchi M, Nakanishi Y et al (2002) Craniopharyngiomas of adamantinomatous type harbor beta-catenin gene mutations. Am J Pathol 161:1997–2001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Li Z, Xu J, Huang S, You C (2015) Aberrant membranous expression of β-catenin predicts poor prognosis in patients with craniopharyngioma. Ann Diagn Pathol 19:403–408

    Article  PubMed  Google Scholar 

  8. Ogawa T, Watanabe M, Tominaga T (2013) Ratke’s cleft cysts with significant squamous metaplasia: high risk of postoperative deterioration and close origins to craniopharyngioma. Acta Neurochir 155:1069–1075

    Article  PubMed  Google Scholar 

  9. Kato K, Nakatani Y, Hanno H, Inayama Y, Ijiri R, Nagahara N et al (2004) Possible linkage between specific histological structures and aberrant reactivation of the Wnt pathway in adamantinomatous craniopharyngioma. J Pathol 203:814–821

    Article  PubMed  CAS  Google Scholar 

  10. Buslei R, Nolde M, Hofmann B, Meissner S, Eyupoglu IY, Siebzehnrübl F et al (2005) Common mutations of β-catenin in adamantinomatous craniopharyngiomas but not in other tumors originating from the sellar region. Acta Neuropathol 109:589–597

    Article  PubMed  CAS  Google Scholar 

  11. Oikonomou E, Barreto DC, Soares B, De Marco L, Buchfelder M, Adams EF (2005) β-catenin mutations in craniopharyngiomas and pituitary adenomas. J Neuro Oncol 73:205–209

    Article  CAS  Google Scholar 

  12. Hofmann BM, Dreutzer J, Saeger W, Buchfelder M, Blümcke I, Fahlbusch R, Buslei R (2006) Nuclear β-catenin accumulation as reliable marker for the differentiation between cystic craniopharyngiomas and Rathke cleft cysts: a clinic-pathologic approach. Am J Surg Pathol 30:1595–1603

    Article  PubMed  Google Scholar 

  13. Campanini ML, Colli LM, Paixao B, Cabral TP, Amaral FC, Machado HR et al (2010) CTNNB1 gene mutations, pituitary transcription factor and microRNA expression involvement in the pathogenesis of adamantinomatous craniopharyngiomas. Horm Can 1:187–196

    Article  CAS  Google Scholar 

  14. Cao J, Lin JP, Yang LX, Chen K, Huang ZS (2010) Expression of aberrant β-catenin and impaired p63 in craniopharyngiomas. Br J Neurosurg 24:249–256

    Article  PubMed  CAS  Google Scholar 

  15. Cani CMG, Matushita H, Carvalho LRS, Soares IC, Brito LP, Almeida MQ, Mendoça BB (2011) PROP1 and CTNNB1 expression in adamantinomatous craniopharyngiomas with or without β-catenin mutations. Clinics 66:1849–1854

    PubMed  PubMed Central  Google Scholar 

  16. Garcia-Lavandeira M, Saez C, Diaz-Rodriguez E, Perez-Romero S, Senra S, Dieguez C et al (2012) Craniopharyngioma express embryonic stem cell markers (SOX2, OCT4, KLF4, and SOX9) as pituitary stem cells but do not coexpress RET/GFRA3 receptors. Endocrinol Metab 97:E80–E87

    Article  CAS  Google Scholar 

  17. Larkin SJ, Preda V, Karavitaki N, Grossman A, Ansorge O (2014) BRAF V600E mutations are characteristic for papillary craniopharyngioma and may coexist with CTNNB1-mutated adamantinomatous craniophryngioma. Acta Neuropathol 127:927–929

    Article  PubMed  PubMed Central  Google Scholar 

  18. Esheba GE, Hassam AA (2015) Comparative immunohistochemical expression of β-catenin, EGFR, ErbB2, and p63 in adamantinomatous and papillary craniopharyngiomas. J Egypt Natl Cancer Inst 27:139–145

    Article  Google Scholar 

  19. Gomes DC, Jamra SA, Leal LF, Colli LM, Campanini ML, Oliveira RS et al (2015) Sonic Hedgehog pathway is upregulated in adamantinomatous craniopharyngiomas. Eur J Endocrinol 172:603–608

    Article  PubMed  CAS  Google Scholar 

  20. Marucci G, de Biase D, Zoli M, Faustini-Fustini M, Bacci A, Pasquini E et al (2015) Targeted BRAF and CTNNB1 next-generation sequencing allows proper classification of nonadenomatous lesions of the sellar region in samples with limiting amounts of lesional cells. Pituitary 18:905–911

    Article  PubMed  CAS  Google Scholar 

  21. Schweizer L, Capper D, Hölsken A, Fahlbusch R, Flitsch J, Buchfelder M et al (2015) BRAF V600E analysis for the differentiation of papillary craniopharyngiomas and Rathke’s cleft cysts. Neuropathol Appl Neurobiol 41:733–742

    Article  PubMed  CAS  Google Scholar 

  22. Preda V, Larkin SJ, Karavitaki N, Ansorge O, Grossman AB (2015) The Wnt signaling cascade and the adherens junction complex in craniopharyngioma tumorigenesis. Endocr Pathol 26:1–8

    Article  PubMed  CAS  Google Scholar 

  23. Hölsken A, Sill M, Merkle J, Schweizer L, Buchfelder M, Flitsch J et al (2016) Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles. Acta Neuropathol Commun 4:20

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Liu Y, Wang CH, Li DL, Zhang SC, Peng YP, Peng JX et al (2016) TREM-1 expression in craniopharyngioma and Rathke’s cleft cyst: its possible implication for controversial pathology. Oncotarget 7:50564–50574

    PubMed  PubMed Central  Google Scholar 

  25. Bi WL, Greenwald NF, Ramkissoon SH, Abedalthagafi M, Coy SM, Ligon KL et al (2017) Clinical identification of oncogenic drivers and copy-number alterations in pituitary tumors. Endocrinology 158:2284–2291

    Article  PubMed  PubMed Central  Google Scholar 

  26. Chang CV, Araujo RV, Cirqueira CS, Cani CM, Matushita H, Cescato VA et al (2017) Differential expression of stem cell markers in human adamantinomatous craniopharyngioma and pituitary adenoma. Neuroendocrinology 104:183–193

    Article  PubMed  CAS  Google Scholar 

  27. Goschzik T, Gessi M, Dreschmann V, Gebhardt U, Wang L, Yamaguchi S et al (2017) Genomic alterations of adamantinomatous and papillary craniopharyngioma. J Neuropahtol Exp Exp Neurol 76:126–134

    Google Scholar 

  28. Guadagno E, de Divitis O, Solari D, Borreli G, Bracale UM, Di Somma A et al (2017) Can recurrences be predicted in craniopharyngiomas? B-catenin coexisting with stem cell markers and p-ATM in a clinicopathologic study of 45 cases. J Exp Clin Cancer Res 36:95

    Article  PubMed  PubMed Central  Google Scholar 

  29. Malguwar PB, Nambirajan A, Pathak P, Faruq M, Suri V, Sarkar C et al (2017) Study of β-catenin and BRAF alterations in adamantinomatous and papillary craniopharyngiomas: mutation analysis with immunohistochemical correlation in 54 cases. J Neurooncol 133:487–495

    Article  CAS  Google Scholar 

  30. Omay SB, Chen YN, Almeida JP, Ruiz-Treviño AS, Boockvar JA, Stieg PE et al (2017) Do craniopharyngioma molecular signatures corelate with clinical characteristics? J Neurosurg 14:1–6

    Article  Google Scholar 

  31. Yoshimoto K, Hatae R, Suzuki SO, Hata N, Kuga D, Akagi Y et al (2018) High-resolution melting and immunohistochemical analysis efficiently detects mutually exclusive genetic alterations of adamantinomatous and papillary craniopharyngiomas. Neuropathology 38:3–10

    Article  PubMed  CAS  Google Scholar 

  32. Prieto R, Pascual JM (2013) Craniopharyngiomas with a mixed histological pattern: the missing link to the intriguing pathogenesis of adamantinomatous and squamous-papillary varieties. Neuropahtology 33:682–686

    Google Scholar 

  33. Buslei R, Rushing EJ, Giangaspero F, Paulus W, Buger PC, Santaga S (2016) Craniopharyngiomas. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) WHO classification of tumors of the central nervous system, 4th edn. IARC Press, Lyon, pp 324–329

    Google Scholar 

  34. Petito CK, De Girolami U, Earle KM (1976) Craniopharyngiomas: a clinical and pathological review. Cancer 37:1944–1952

    Article  PubMed  CAS  Google Scholar 

  35. Szeifert GT, Sipos L, Horváth M, Sarker MH, Major O, Salomváry B et al (1993) Pathological characteristics of surgically removed craniopharyngiomas: analysis of 131 cases. Acta Neurochir 124:139–143

    Article  PubMed  CAS  Google Scholar 

  36. Erdheim J (1904) Über Hypophysengangsgeschwülste und Hirncholesteatome. Sitzungsb Kais Akad Wissen Math Naturw Klin 113:537–726

    Google Scholar 

  37. Gaston-Massuet C, Andoniaou CL, Signore M, Jayakody SA, Charolidini N, Kyeyune R et al (2011) Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans. Proc Natl Acad Sci USA 108:11482–11487

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hölsken A, Stache C, Schlaffer SM, Flitsch J, Fahlbusch R, Buchfelder M, Buslei R (2014) 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 17:546–556

    Article  PubMed  CAS  Google Scholar 

  39. Andoniadou CL, Matsushima D, Mousavy Gharavy SN, Signore M, Mackintosh AI, Schaeffer M et al (2013) Sox2 + stem/progenitor cells in the adult mouse pituitary support organ homeostasis and have tumor-inducing potential. Cell Stem Cell 13:433–445

    Article  PubMed  CAS  Google Scholar 

  40. Hölsken A, Buchfelder M, Fahlbusch R, Blümcke I, Buslei R (2010) Tumour cell migration in adamantinomatous craniopharyngiomas is promoted by activated Wnt-signalling. Acta Neuropathol 119:631–639

    Article  PubMed  CAS  Google Scholar 

  41. Apps JR, Carreno G, Gonzalez-Meljem JM, Haston S, Guiho R, Cooper JE et al (2018) Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAP/ERK pathways as a novel therapeutic target. Acta Neuropathol. https://doi.org/10.1007/s00401-018-1830-2

    Article  PubMed Central  PubMed  Google Scholar 

  42. Alywin SJ, Bodi I, Beaney R (2016) Pronounced response of papillary craniopharyngioma to treatment with vemurafenib, a BRAF inhibitor. Pituitary 19:544–546

    Article  Google Scholar 

  43. Brastianos PK, Shankar GM, Gill CM, Taylor-Weiner A, Nayya N, Panka DJ et al (2016) Dramatic response of BRAF V600E mutant papillary craniopharyngioma to targeted therapy. J Natl Cancer Inst 108:djv310

    Article  PubMed  CAS  Google Scholar 

  44. Rostami E, Witt Nystöm P, Libard S, Wikström J, Casar-Borota O, Gudjonsson O (2017) Recurrent papillary craniopharyngioma with BRAFV600E mutation treated with neoadjuvant-targeted therapy. Acta Neurochir 159:2217–2221

    Article  PubMed  PubMed Central  Google Scholar 

  45. Roque A, Odia Y (2017) BRAF-V600E mutant papillary craniopharyngioma dramatically responds to combination BRAF and MEK inhibitors. CNS Oncol 6:95–99

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Martinez-Barbera JP, Andoniaou CL (2016) Concise review: paracrine role of stem cell in pituitary tumors: a focus on adamantinomatous craniopharyngioma. Stem Cells 34:268–276

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Prieto R, Pascual JM, Rosdolsky M, Castro-Dufourny I, Carrasco R, Strauss S, Barrios L (2016) Craniopharyngioma adherence: a comprehensive topographical categorization and outcome-related risk stratification model based on the methodical examination of 500 tumors. Neurosurg Focus 41:E13

    Article  PubMed  Google Scholar 

  48. Haston S, Manshaei S, Martinez-Barbera JP (2018) Stem/progenitor cells in pituitary organ homeostasis and tumorigenesis. J Endocrinol 236:R1–R13

    Article  PubMed  Google Scholar 

  49. Scagliotti V, Avagliano L, Gualtieri A, Graziola F, Doi P, Chalker J et al (2016) Histopathology and molecular characterization of intrauterine diagnosed congenital craniopharyngioma. Pituitary 19:50–56

    Article  PubMed  CAS  Google Scholar 

  50. Thimsen V, John N, Buchfelder M, Flitsch J, Fahlbusch R, Stefanits H et al (2017) Expression of SRY-related HMG Box transcription factor (Sox) 2 and 9 in Craniopharyngioma subtypes and surrounding brain tissue. Sci Rep 20:15856

    Article  CAS  Google Scholar 

  51. Pascual JM, Prieto R, Carrasco R (2011) Infundibulo-tuberal or not strictly intraventricular craniopharyngioma: evidence for a major topographical category. Acta Neurochir 153:2403–2426

    Article  PubMed  Google Scholar 

  52. Sekine S, Takata T, Shibata T, Mori M, Morishita Y, Noguchi M et al (2004) Expression of enamel proteins and LEF1 in adamantinomatous craniopharyngioma: evidence for its odontogenic epithelial differentiation. Histopathology 45:573–579

    Article  PubMed  CAS  Google Scholar 

  53. Berstein ML, Buchino JJ (1983) The histologic similarities between craniopharyngioma and odontogenic lesions: a reappraisal. Oral Surg Oral Med Oral Pathol 56:502–511

    Article  Google Scholar 

  54. Pascual JM, Rosdolsky M, Prieto R, Strauβ S, Winter E, Ulrich W (2015) Jakob Erdheim (1874–1937): father of hypophyseal-duct tumors (craniopharyngiomas). Virchows Arch 467:459–469

    Article  PubMed  Google Scholar 

  55. VanGilder JC, Inukai J (1973) Growth characteristics of experimental intracerebrally transplanted oral epithelium. J Neurosurg 38:608–615

    Article  PubMed  CAS  Google Scholar 

  56. Nishi T, Kuratsu J, Takeshima H, Saito Y, Kochi M, Ushio Y (1999) Prognostic significance of the MIB-1 labeling index for patient with craniopharyngioma. Int J Mol Med 3:157–161

    PubMed  CAS  Google Scholar 

  57. Izumoto S, Suzuki T, Kinoshita M, Hahiba T, Kagawa N, Wada K et al (2005) Immunohistochemical detection of female sex hormone receptors in craniopharyngiomas: correlation with clinical and histologic features. Surg Neurol 63:520–525

    Article  PubMed  Google Scholar 

  58. Tena-Suck ML, Salinas-Lara C, Arce-Arellano RI, Rembao-Bojórquez D, Morales-Espinosa D, Sotelo J, Arrieta O (2006) Clinico-pahtological and immunohistochemical characteristics associated to recurrence/regrowth of craniopharyngiomas. Clin Neurol Neurosurg 108:661–669

    Article  PubMed  Google Scholar 

  59. Lefranc F, Mijatovic T, Decaestecker C, Kaltner H, Andre S, Brotchi J et al (2005) Monitoring the expression profiles of integrins and adhesion/ growth-regulatory galectins in adamantinomatous craniopharyngiomas: their ability to regulate tumor adhesiveness to surrounding tissue and their contribution to prognosis. Neurosurgery 56:763–776

    Article  PubMed  Google Scholar 

  60. Lubansu A, Ruchoux MM, Brotchi J, Salmon I, Kiss R, Lefranc F (2003) Cathepsin B, D and K expression in adamantinomatous craniopharyngiomas relates to their levels of differentiation as determined by the patterns of retinoic acid receptor expression. Histopathology 43:563–572

    Article  PubMed  CAS  Google Scholar 

  61. Xia X, Liu W, Li S, Jia G, Zhang Y, Li C et al (2011) Expression of matrix metalloproteinase-9, type IV collagen and vascular endothelial growth factor in adamantinomatous craniopharyngioma. Neurochem Res 36:2346–2351

    Article  PubMed  CAS  Google Scholar 

  62. Gong J, Zhang H, Xing S, Li C, Ma Z, Jia G et al (2014) High expression levels of CXCL12 and CXCR4 predict recurrence of adamanti-nomatous craniopharyngiomas in children. Cancer Biomark 14:241–251

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors especially wish to thank Eduard Winter and Verena Hofecker, from the Pathologic-Anatomical museum of Vienna, for their kind assistance to study the collection of craniopharyngiomas stored at the Narrenturm (Fools’ Tower). We are also grateful to George Hamilton for his critical review of the language and style of the manuscript.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Puerta de Hierro University Hospital, C/Manuel de Falla 1, Majadahonda, 28222, Madrid, Spain

    Ruth Prieto

  2. Department of Neurosurgery, La Princesa University Hospital, Madrid, Spain

    José M. Pascual

Authors
  1. Ruth Prieto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. José M. Pascual
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design: RP. Acquisition of data: RP and JMP. Drafting the article: RP and JMP. Critically revising the article: RP and JMP.

Corresponding author

Correspondence to Ruth Prieto.

Ethics declarations

Conflict of interest

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Prieto, R., Pascual, J.M. Can tissue biomarkers reliably predict the biological behavior of craniopharyngiomas? A comprehensive overview. Pituitary 21, 431–442 (2018). https://doi.org/10.1007/s11102-018-0890-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-018-0890-6

Keywords

Search

Navigation