Skip to main content
SpringerLink
Log in

Histopathological investigation of the 1p/19q-codeleted gliomas resected following alkylating agent chemotherapy

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Purpose

Lower grade gliomas with 1p/19q codeletion are often responsive to chemotherapy, and several of these have been treated using upfront chemotherapy and subsequent resection following tumor volume decrease. This study aimed to elucidate the histological changes and the mechanism of recurrence after alkylating agent chemotherapy in 1p/19-codeleted gliomas.

Methods

Fourteen 1p/19q-codeleted gliomas resected following tumor volume decrease after alkylating agent chemotherapy were included and compared with their pre-chemotherapy specimens. Histological changes were investigated using hematoxylin–eosin staining, and changes in proliferative activity, status of glioma stem cells (GSCs), and tumor-infiltrating macrophages were assessed using immunohistochemistry for Ki-67/MIB-1, CD68 as a pan-macrophage/monocyte marker, CD163 as a presumed marker of M2 polarity, and nestin and CD133 as markers of GSCs.

Results

The most frequent histological findings following chemotherapy included a sparse glial background and abundant foamy cell infiltration. The Ki-67/MIB-1 index decreased and the number of CD68 + cells increased after chemotherapy. The increasing rate of CD68 + cells in the post-/pre-chemotherapy specimens was inversely correlated with patient prognosis but not tumor response. The number of CD163 + cells, M2/M1 + M2 ratio, and the ratio of GSCs to total tumor cells increased after chemotherapy, and those in the post-chemotherapy specimens were negatively correlated with patient prognosis. There was a correlation between the M2/M1 + M2 ratio and the ratio of GSCs in both pre- and post-chemotherapy specimens.

Conclusion

GSCs in conjunction with M2 macrophages constitute the mechanism of resistance to and recurrence after alkylating agent chemotherapy in 1p/19q-codeleted gliomas.

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
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

Raw data of the findings of the study are available in Table S1.

Code availability

The code is available from the corresponding author, upon reasonable request.

References

  1. Darnton SJ, Allen SM, Edwards CW, Matthews HR (1993) Histopathological findings in oesophageal carcinoma with and without preoperative chemotherapy. J Clin Pathol 46(1):51–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Langer R, Ott K, Feith M, Lordick F, Siewert JR, Becker K (2009) Prognostic significance of histopathological tumor regression after neoadjuvant chemotherapy in esophageal adenocarcinomas. Mod Pathol 22(12):1555–1563

    Article  CAS  PubMed  Google Scholar 

  3. Kurosumi M, Akashi-Tanaka S, Akiyama F et al (2008) Histopathological criteria for assessment of therapeutic response in breast cancer (2007 version). Breast Cancer 15(1):5–7

    Article  PubMed  Google Scholar 

  4. Schiffer D, Giordana MT, Buoncristiani P, Paoletti P (1978) Human malignant gliomas treated with chemotherapy: a pathological study. Neurosurgery 3(3):344–347

    Article  CAS  PubMed  Google Scholar 

  5. Schiffer D, Giordana MT, Paoletti P, Soffietti R, Tarenzi L (1980) Pathology of human malignant gliomas after radiation and chemotherapy. Acta Neurochir 53(3–4):205–216

    Article  CAS  PubMed  Google Scholar 

  6. Fischer I, Cunliffe CH, Bollo RJ et al (2008) High-grade glioma before and after treatment with radiation and Avastin: initial observations. Neuro Oncol 10(5):700–708

    Article  PubMed  PubMed Central  Google Scholar 

  7. DeLay M, Jahangiri A, Carbonell WS et al (2012) Microarray analysis verifies two distinct phenotypes of glioblastomas resistant to antiangiogenic therapy. Clin Cancer Res 18(10):2930–2942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Woo JY, Yang SH, Lee YS, Lee SY, Kim J, Hong YK (2015) Continuous low-dose temozolomide chemotherapy and microvessel density in recurrent glioblastoma. J Korean Neurosurg Soc 58(5):426–431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tamura R, Tanaka T, Miyake K et al (2016) Histopathological investigation of glioblastomas resected under bevacizumab treatment. Oncotarget 7(32):52423–52435

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sasaki H, Hirose Y, Yazaki T et al (2015) Upfront chemotherapy and subsequent resection for molecularly defined gliomas. J Neurooncol 124(1):127–135

    Article  CAS  PubMed  Google Scholar 

  11. Louis DN, Ohgaki H, Wiestler OD, et al. (2016) WHO classification of tumours of the central nervous system. Revised 4th edn. Lyon: International Agency for Research on Cancer

  12. Kitamura Y, Sasaki H, Kimura T et al (2013) Molecular and clinical risk factors for recurrence of skull base chordomas: gain on chromosome 2p, expression of brachyury, and lack of irradiation negatively correlate with patient prognosis. J Neuropathol Exp Neurol 72(9):816–823

    Article  CAS  PubMed  Google Scholar 

  13. Cui L, Rashdan NA, Zhu D et al (2017) End stage renal disease-induced hypercalcemia may promote aortic valve calcification via annexin VI enrichment of valve interstitial cell derived-matrix vesicles. J Cell Physiol 232(11):2985–2995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Strojnik T, Røsland GV, Sakariassen PO, Kavalar R, Lah T (2007) Neural stem cell markers, nestin and musashi proteins, in the progression of human glioma: correlation of nestin with prognosis of patient survival. Surg Neurol 68(2):133–143

    Article  PubMed  Google Scholar 

  15. Zhang M, Song T, Yang L et al (2008) Nestin and CD133: valuable stem cell-specific markers for determining clinical outcome of glioma patients. J Exp Clin Cancer Res 27(1):85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. van den Bent MJ, Wefel JS, Schiff D et al (2011) Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol 12(6):583–593

    Article  PubMed  Google Scholar 

  17. Blumenthal DT, Aisenstein O, Ben-Horin I et al (2015) Calcification in high grade gliomas treated with bevacizumab. J Neuro-Oncol 123(2):283–288

    Article  CAS  Google Scholar 

  18. Sethi D, Sen R, Parshad S, Khetarpal S, Garg M, Sen J (2012) Histopathologic changes following neoadjuvant chemotherapy in various malignancies. Int J Appl Basic Med Res 2(2):111–116

    Article  PubMed  PubMed Central  Google Scholar 

  19. Liu G, Yuan X, Zeng Z et al (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67

    Article  PubMed  PubMed Central  Google Scholar 

  20. Fillmore CM, Kuperwasser C (2008) Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 10(2):R25

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tanei T, Morimoto K, Shimazu K et al (2009) Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res 15(12):4234–4241

    Article  CAS  PubMed  Google Scholar 

  22. Aomatsu N, Yashiro M, Kashiwagi S et al (2012) CD133 is a useful surrogate marker for predicting chemosensitivity to neoadjuvant chemotherapy in breast cancer. PLoS ONE 7(9):e45865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dell’Albani P (2008) Stem cell markers in gliomas. Neurochem Res 33(12):2407–2415

    Article  PubMed  Google Scholar 

  24. Dahlrot RH, Hermansen SK, Hansen S, Kristensen BW (2013) What is the clinical value of cancer stem cell markers in gliomas? Int J Clin Exp Pathol 6(3):334–348

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Wu B, Sun C, Feng F, Ge M, Xia L (2015) Do relevant markers of cancer stem cells CD133 and Nestin indicate a poor prognosis in glioma patients? A systematic review and meta-analysis. J Exp Clin Cancer Res 34(1):44

    Article  PubMed  PubMed Central  Google Scholar 

  26. Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6:13

  27. Tamura R, Tanaka T, Yamamoto Y, Akasaki Y, Sasaki H (2018) Dual role of macrophage in tumor immunity. Immunotherapy 10(10):899–909

    Article  CAS  PubMed  Google Scholar 

  28. Zeiner PS, Preusse C, Golebiewska A et al (2019) Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas. Brain Pathol 29(4):513–529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hao NB, Lü MH, Fan YH, Cao YL, Zhang ZR, Yang SM (2012) Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol 2012:948098

    Article  PubMed  PubMed Central  Google Scholar 

  30. Chanmee T, Ontong P, Konno K, Itano N (2014) Tumor-associated macrophages as major players in the tumor microenvironment. Cancers 6(3):1670–1690

    Article  PubMed  PubMed Central  Google Scholar 

  31. Zhou W, Ke SQ, Huang Z et al (2015) Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat Cell Biol 17(2):170–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Ms. Naoko Tsuzaki at the Department of Neurosurgery, Keio University School of Medicine for her technical assistance with laboratory work.

Funding

This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science [15K10343, 19K09490 to H.S.].

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Tokunori Kanazawa, Masato Nakaya, Kazunari Yoshida & Hikaru Sasaki

  2. Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Kentaro Ohara

  3. Department of Neurosurgery, Tokyo Saiseikai Central Hospital, 1-4-17 Mita, Minato-ku, Tokyo, 108-0073, Japan

    Yohei Kitamura

Authors
  1. Tokunori Kanazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kentaro Ohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yohei Kitamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masato Nakaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kazunari Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hikaru Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception, design, and development of methodology: T.K. and H.S. Data acquisition, experiment, analysis, and interpretation: T.K., K.O., Y.K., M.N., and H.S. Writing of the manuscript: T.K., K.O., and H.S. Study supervision: K.Y. and H.S.

Corresponding author

Correspondence to Hikaru Sasaki.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the Institutional Review Board of the Keio University School of Medicine (Approval Numbers 20050002, 20130250).

Consent to participate

Written informed consent was obtained from all patients included in the study.

Consent to publication

Waived.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1368 kb)

Supplementary file2 (XLSX 14 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kanazawa, T., Ohara, K., Kitamura, Y. et al. Histopathological investigation of the 1p/19q-codeleted gliomas resected following alkylating agent chemotherapy. J Neurooncol 155, 235–246 (2021). https://doi.org/10.1007/s11060-021-03855-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-021-03855-y

Keywords

Search

Navigation