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Immunohistochemical analysis of glassy cell carcinoma of the cervix reveals robust lymphocyte infiltrate and the expression of targetable inhibitory immune checkpoints

  • Gynecologic Oncology
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Objective

To validate our previous findings of high-level EGFR expression in GCCC using an expanded cohort of specimens and to further examine the molecular and cellular features of this aggressive malignancy to identify potentially actionable therapeutic targets.

Methods

The SEER database was queried to obtain the epidemiological data regarding the current national survival trends for GCCC. Immunohistochemistry (IHC) was used to examine the expression of EGFR, PD-1, and PD-L1. CiberSort analysis was used to analyze a previously published RNA-sequencing dataset obtained from a single patient diagnosed with GCCC.

Results

In comparison to squamous cell carcinomas and adenocarcinoma/adenosquamous carcinomas, GCCC was observed in younger patients (p < 0.001) and demonstrated inferior survival (p < 0.001). All (100%) of the specimens (8/8) exhibited immunoreactivity when stained for CD3ε (T-cell marker), EGFR, PD-1, and PD-L1 whereas CTLA4 expression was not detected. Analysis of RNA-sequencing data revealed that cetuximab and erlotinib altered the chemokine profile, lymphocyte abundance, and expression of inhibitory immune checkpoints in a single patient when combined with cytotoxic chemotherapy in a single patient.

Conclusions

The data from this descriptive study suggests that immune checkpoint blockade, whether single agent or in combination, may be a suitable therapeutic option for a disease for which targeted approaches do not currently exist.

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Data availability

Data and material available for review upon request.

References

  1. Hopkins MP, Morley GW (2004) Glassy cell adenocarcinoma of the uterine cervix. Am J Obstet Gynecol 190(1):67–70. https://doi.org/10.1016/s0002-9378(03)00928-1 (Epub 2004/01/30, PubMed PMID: 14749637)

    Article  PubMed  Google Scholar 

  2. Zolciak-Siwinska A, Jonska-Gmyrek J (2014) Glassy cell carcinoma of the cervix: a literature review. Eur J Obstet Gynecol Reprod Biol 179:232–235. https://doi.org/10.1016/j.ejogrb.2014.03.035 (Epub 2014/05/06, PubMed PMID: 24792540)

    Article  CAS  PubMed  Google Scholar 

  3. Guitarte C, Alagkiozidis I, Mize B, Stevens E, Salame G, Lee YC (2014) Glassy cell carcinoma of the cervix: a systematic review and meta-analysis. Gynecol Oncol 133(2):186–191. https://doi.org/10.1016/j.ygyno.2014.01.048 (Epub 2014/02/08, PubMed PMID: 24503463)

    Article  PubMed  Google Scholar 

  4. Jung YY, Nahm JH, Kim HS (2016) Cytomorphological characteristics of glassy cell carcinoma of the uterine cervix: histopathological correlation and human papillomavirus genotyping. Oncotarget 7(45):74152–74161. https://doi.org/10.18632/oncotarget.12361 (Epub 2016/10/07, PubMed PMID: 27708230; PubMed Central PMCID: PMCPMC5342042)

    Article  PubMed  PubMed Central  Google Scholar 

  5. Littman P, Clement PB, Henriksen B, Wang CC, Robboy SJ, Taft PD et al (1976) Glassy cell carcinoma of the cervix. Cancer 37(5):2238–2246. https://doi.org/10.1002/1097-0142(197605)37:5%3c2238::aid-cncr2820370513%3e3.0.co;2-d (Epub 1976/05/01, PubMed PMID: 1260713)

    Article  CAS  PubMed  Google Scholar 

  6. Kuroda H, Toyozumi Y, Masuda T, Ougida T, Hanami K, Kyoko K et al (2006) Glassy cell carcinoma of the cervix: cytologic features and expression of estrogen receptor, progesterone receptor and Her2/neu protein. Acta Cytol 50(4):418–422. https://doi.org/10.1159/000325985 (Epub 2006/08/12, PubMed PMID: 16901007)

    Article  PubMed  Google Scholar 

  7. Chung JH, Koh JS, Lee SS, Cho KJ (2000) Glassy cell carcinoma of the uterine cervix. Cytologic features and expression of estrogen and progesterone receptors. Acta Cytol 44(4):551–556. https://doi.org/10.1159/000328529 (Epub 2000/08/10, PubMed PMID: 10934948)

    Article  CAS  PubMed  Google Scholar 

  8. Yoon N, Kim JY, Kim HS (2016) Clinical outcomes of advanced-stage glassy cell carcinoma of the uterine cervix: a need for reappraisal. Oncotarget 7(48):78448–78454. https://doi.org/10.18632/oncotarget.12905 (Epub 2016/10/30, PubMed PMID: 27793022; PubMed Central PMCID: PMCPMC5346652)

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gray HJ, Garcia R, Tamimi HK, Koh WJ, Goff BA, Greer BE et al (2002) Glassy cell carcinoma of the cervix revisited. Gynecol Oncol 85(2):274–277. https://doi.org/10.1006/gyno.2001.6523 (Epub 2002/04/26, PubMed PMID: 11972387)

    Article  PubMed  Google Scholar 

  10. McEachron TA, Sender LS, Zabokrtsky KB, Kaltenecker B, Holmes WN, Cherni I et al (2016) Molecular genetic profiling of adolescent glassy cell carcinoma of the cervix reveals targetable EGFR amplification with potential therapeutic implications. J Adolesc Young Adult Oncol 5(3):297–302. https://doi.org/10.1089/jayao.2015.0068 (Epub 2016/03/15, PubMed PMID: 26974246)

    Article  PubMed  Google Scholar 

  11. Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481

    Article  Google Scholar 

  12. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y et al (2015) Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 12(5):453–457. https://doi.org/10.1038/nmeth.3337 (Epub 2015/03/31, PubMed PMID: 25822800; PubMed Central PMCID: PMCPMC4739640.)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lin A, Wei T, Meng H, Luo P, Zhang J (2019) Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations. Mol Cancer 18(1):139. https://doi.org/10.1186/s12943-019-1062-7 (Epub 2019/09/19, PubMed PMID: 31526368; PubMed Central PMCID: PMCPMC6745797)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jia Y, Li X, Jiang T, Zhao S, Zhao C, Zhang L et al (2019) EGFR-targeted therapy alters the tumor microenvironment in EGFR-driven lung tumors: implications for combination therapies. Int J Cancer 145(5):1432–1444. https://doi.org/10.1002/ijc.32191 (Epub 2019/02/21, PubMed PMID: 30784054)

    Article  CAS  PubMed  Google Scholar 

  15. Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R et al (2019) Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 37(17):1470–1478. https://doi.org/10.1200/jco.18.01265 (Epub 2019/04/04, PubMed PMID: 30943124)

    Article  CAS  PubMed  Google Scholar 

  16. Teng MW, Ngiow SF, Ribas A, Smyth MJ (2015) Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 75(11):2139–2145. https://doi.org/10.1158/0008-5472.can-15-0255 (Epub 2015/05/16, PubMed PMID: 25977340; PubMed Central PMCID: PMCPMC4452411)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sznol M, Chen L (2013) Antagonist antibodies to PD-1 and B7–H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res 19(5):1021–1034. https://doi.org/10.1158/1078-0432.ccr-12-2063 (Epub 2013/03/06, PubMed PMID: 23460533; PubMed Central PMCID: PMCPMC3702373)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Angell H, Galon J (2013) From the immune contexture to the immunoscore: the role of prognostic and predictive immune markers in cancer. Curr Opin Immunol 25(2):261–267. https://doi.org/10.1016/j.coi.2013.03.004 (Epub 2013/04/13, PubMed PMID: 23579076)

    Article  CAS  PubMed  Google Scholar 

  19. Li Q, Cheng X, Ji J, Zhang J, Zhou X (2014) Gene amplification of EGFR and its clinical significance in various cervical (lesions) lesions using cytology and FISH. Int J Clin Exp Pathol 7(5):2477–2483 (Epub 2014/06/27, PubMed PMID: 24966959; PubMed Central PMCID: PMCPMC4069959)

    PubMed  PubMed Central  Google Scholar 

  20. Li Q, Tang Y, Cheng X, Ji J, Zhang J, Zhou X (2014) EGFR protein expression and gene amplification in squamous intraepithelial lesions and squamous cell carcinomas of the cervix. Int J Clin Exp Pathol 7(2):733–741 (Epub 2014/02/20, PubMed PMID: 24551297; PubMed Central PMCID: PMCPMC3925921)

    PubMed  PubMed Central  Google Scholar 

  21. Conesa-Zamora P, Torres-Moreno D, Isaac MA, Perez-Guillermo M (2013) Gene amplification and immunohistochemical expression of ERBB2 and EGFR in cervical carcinogenesis. Correlation with cell-cycle markers and HPV presence. Exp Mol Pathol 95(2):151–155. https://doi.org/10.1016/j.yexmp.2013.06.011 (Epub 2013/07/06, PubMed PMID: 23827764)

    Article  CAS  PubMed  Google Scholar 

  22. Bumrungthai S, Munjal K, Nandekar S, Cooper K, Ekalaksananan T, Pientong C et al (2015) Epidermal growth factor receptor pathway mutation and expression profiles in cervical squamous cell carcinoma: therapeutic implications. J Transl Med 13:244. https://doi.org/10.1186/s12967-015-0611-0 (Epub 2015/07/26, PubMed PMID: 26209091; PubMed Central PMCID: PMCPMC4513684)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL et al (2013) Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov 3(12):1355–1363. https://doi.org/10.1158/2159-8290.cd-13-0310 (Epub 2013/10/01, PubMed PMID: 24078774; PubMed Central PMCID: PMCPMC3864135)

    Article  CAS  PubMed  Google Scholar 

  24. Azuma K, Ota K, Kawahara A, Hattori S, Iwama E, Harada T et al (2014) Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. Ann Oncol 25(10):1935–1940. https://doi.org/10.1093/annonc/mdu242 (Epub 2014/07/11, PubMed PMID: 25009014)

    Article  CAS  PubMed  Google Scholar 

  25. Thumallapally N, Parylo S, Vennepureddy A, Ibrahim U, Sokoloff A (2018) Synchronous presence of EGFR, ALK driver mutations along with PD L1 overexpression in a resected early stage non-small cell lung cancer: a case report and review of literature. World J Oncol 9(2):50–55. https://doi.org/10.14740/wjon1090e (Epub 2018/05/16, PubMed PMID: 29760833; PubMed Central PMCID: PMCPMC5942208)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Jean Richardson for support of the USC Department of Obstetrics & Gynecology Gynecologic Tissue and Fluid Repository and the Norris Comprehensive Cancer Center Translational Pathology Core (NIH P30CA014089).

Funding

Funded by USC Department of Gynecologic Oncology Research Fund.

Author information

Authors and Affiliations

  1. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA

    Erin A. Blake, Koji Matsuo & Lynda Roman

  2. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Malcolm S. Ross & Sarah Taylor

  3. Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO, USA

    Megan E. Ross

  4. Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA

    Emily T. Silverstein

  5. Hyundai Cancer Genomics Center, Children’s Hospital of Orange County, Orange, CA, USA

    Lilibeth R. Torno

  6. Department of Pediatrics, School of Medicine, University of California-Irvine, Orange, CA, USA

    Lilibeth R. Torno

  7. Division of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Rohit Bhargava

  8. Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA

    Miriam D. Post

  9. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, USA

    Diane M. Da Silva

  10. Department of Laboratory Medicine and Pathology, Department of Gynecologic Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Saloni Walia

  11. Department of Gynecologic Oncology, University of Southern California, 2020 Zonal Ave., Room 522, Los Angeles, CA, 90033, USA

    Erin A. Blake

  12. Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Troy A. McEachron

Authors
  1. Erin A. Blake
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  2. Malcolm S. Ross
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Contributions

EB: principal investigator and manuscript author; TM: senior author, project concept and execution; MR: UMPC principal investigator; MR: University of Colorado Principal Investigator; RB: pathologist at UMPC; MP: pathologist at University of Colorado; SW: pathologist at USC, reviewed all samples for consistency; KM: SEER database analysis and figures; DdS: basic science advisory role; LR: Gyn Onc faculty supervisor; LT: basic science contributor; ES: logistical support.

Corresponding author

Correspondence to Erin A. Blake.

Ethics declarations

Conflict of interest

Erin Blake: none; Troy McEachron: none; Malcolm Ross: none; Megan Ross: none; Rohit Bhargava: none; Miriam Post: none; Saloni Walia: none; Koji Matsuo: Chugai (honorarium 2016), Springer (textbook editorial expense 2018), VBL Therapeutics (investigator meeting attendance expense 2019); Diane da Silva: Venn Biosciences (grant researching ovarian cancer biomarkers), Quantum screening (consulting fees); Lynda Roman: Tempus Lab (consultant > 2 years ago, none relevant to submission), Quantgene (consultant, not relevant to submission); Lilibeth Torno: none; Emily Silverstein: none.

Ethical approval

USC Health Sciences Institutional Review Board approved (HS-18-00266). Approval letter available upon request.

Informed consent

Informed consent was not necessary for this study.

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Supplementary Information

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404_2021_6164_MOESM1_ESM.pdf

Supplementary file1 Expression of CD3ε, CD8, PD-L1, PD1, and EGFR in cervical tissue unaffected by disease (PDF 13404 KB)

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Blake, E.A., Ross, M.S., Ross, M.E. et al. Immunohistochemical analysis of glassy cell carcinoma of the cervix reveals robust lymphocyte infiltrate and the expression of targetable inhibitory immune checkpoints. Arch Gynecol Obstet 305, 439–447 (2022). https://doi.org/10.1007/s00404-021-06164-x

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  • DOI: https://doi.org/10.1007/s00404-021-06164-x

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