Skip to main content

Advertisement

SpringerLink
Log in

Vascular density and inflammatory infiltrate in primary oral squamous cell carcinoma and after allogeneic hematopoietic stem cell transplantation

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Hematopoietic stem cell transplantation (HSCT) recipients have been reported to have an increased risk of chronic graft versus host disease (cGVHD) and hematological and solid cancers. Oral manifestations are the first signs of cGVHD observed in the majority of patients, and oropharyngeal cancer is the most frequent secondary malignancy occurred after HSCT. In this study, we have evaluated the inflammatory infiltrate cell content and correlated with the vascular density in patients affected by primary oral squamous cell carcinoma (OSCC) from previous healthy controls and OSCC after cGVHD. Results have demonstrated that patients with OSCC after GVHD show a more consistent inflammatory infiltrate as compared with the OSCC ones. In detail, the inflammatory background composed of CD3-positive T cells, tryptase-positive mast cells, CD31-positive endothelial cells, and CD68-positive macrophages may be more pronounced in the setting of GVHD + OSCC than in the control group. By contrast, CD20-positive B cells and CD1a-positive dendritic cells were more abundant in the latter population. Finally, a positive correlation was found as between vascular density and inflammatory cell infiltration in both GVHD + OSCC and OSCC groups. Overall, these results confirm the role played by immune cells in enhancing tumor progression and angiogenesis and suggest a potential therapeutic strategy involving inhibition of recruitment of immune cells to the tumor microenvironment and blockade of pro-tumoral effects and pro-angiogenic functions.

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

References

  1. Danylesko I, Shimoni A (2018) Second malignancies after hematopoietic stem cell transplantation. Curr Treat Options in Oncol 19(2):9. https://doi.org/10.1007/s11864-018-0528-y

    Article  Google Scholar 

  2. Qian L, Dima D, Berce C, Liu Y, Rus I, Raduly LZ, Liu Y, Petrushev B, Berindan-Neagoe I, Irimie A, Tanase A, Jurj A, Shen J, Tomuleasa C (2018) Protein dysregulation in graft versus host disease. Oncotarget 9(1):1483–1491. https://doi.org/10.18632/oncotarget.23276

    Article  PubMed  Google Scholar 

  3. Dander E, Balduzzi A, Zappa G, Lucchini G, Perseghin P, Andre V et al (2009) Interleukin-17-producing T-helper cells as new potential player mediating graft-versus-host disease in patients undergoing allogeneic stem-cell transplantation. Transplantation 88(11):1261–1272. https://doi.org/10.1097/TP.0b013e3181bc267e

    Article  CAS  PubMed  Google Scholar 

  4. Zeiser R, Sarantopoulos S, Blazar BR (2018) B-cell targeting in chronic graft-versus-host disease. Blood 131(13):1399–1405. https://doi.org/10.1182/blood-2017-11-784017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Majhail NS, Brazauskas R, Rizzo JD, Sobecks RM, Wang Z, Horowitz MM, Bolwell B, Wingard JR, Socie G (2011) Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning. Blood 117(1):316–322. https://doi.org/10.1182/blood-2010-07-294629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Inamoto Y, Shah NN, Savani BN, Shaw BE, Abraham AA, Ahmed IA, Akpek G, Atsuta Y, Baker KS, Basak GW, Bitan M, DeFilipp Z, Gregory TK, Greinix HT, Hamadani M, Hamilton BK, Hayashi RJ, Jacobsohn DA, Kamble RT, Kasow KA, Khera N, Lazarus HM, Malone AK, Lupo-Stanghellini MT, Margossian SP, Muffly LS, Norkin M, Ramanathan M, Salooja N, Schoemans H, Wingard JR, Wirk B, Wood WA, Yong A, Duncan CN, Flowers MED, Majhail NS (2015) Secondary solid cancer screening following hematopoietic cell transplantation. Bone Marrow Transplant 50(8):1013–1023. https://doi.org/10.1038/bmt.2015.63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Atsuta Y, Suzuki R, Yamashita T, Fukuda T, Miyamura K, Taniguchi S, Iida H, Uchida T, Ikegame K, Takahashi S, Kato K, Kawa K, Nagamura-Inoue T, Morishima Y, Sakamaki H, Kodera Y, Japan Society for Hematopoietic Cell Transplantation (2014) Continuing increased risk of oral/esophageal cancer after allogeneic hematopoietic stem cell transplantation in adults in association with chronic graft-versus-host disease. Ann Oncol 25(2):435–441. https://doi.org/10.1093/annonc/mdt558

    Article  CAS  PubMed  Google Scholar 

  8. Demarosi F, Lodi G, Carrassi A, Soligo D, Sardella A (2005) Oral malignancies following HSCT: graft versus host disease and other risk factors. Oral Oncol 41(9):865–877. https://doi.org/10.1016/j.oraloncology.2005.02.001

    Article  PubMed  Google Scholar 

  9. Adhikari J, Sharma P, Bhatt VR (2015) Risk of secondary solid malignancies after allogeneic hematopoietic stem cell transplantation and preventive strategies. Future Oncol 11(23):3175–3185. https://doi.org/10.2217/fon.15.252

    Article  CAS  PubMed  Google Scholar 

  10. Gallagher G, Forrest DL (2007) Second solid cancers after allogeneic hematopoietic stem cell transplantation. Cancer 109(1):84–92. https://doi.org/10.1002/cncr.22375

    Article  PubMed  Google Scholar 

  11. Leisenring W, Friedman DL, Flowers ME, Schwartz JL, Deeg HJ (2006) Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol 24(7):1119–1126. https://doi.org/10.1200/JCO.2005.02.7052

    Article  PubMed  Google Scholar 

  12. Rizzo JD, Curtis RE, Socie G, Sobocinski KA, Gilbert E, Landgren O, Travis LB, Travis WD, Flowers MED, Friedman DL, Horowitz MM, Wingard JR, Deeg HJ (2009) Solid cancers after allogeneic hematopoietic cell transplantation. Blood 113(5):1175–1183. https://doi.org/10.1182/blood-2008-05-158782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Noce CW, Gomes A, Copello A, Barbosa RD, Sant’anna S, Moreira MC et al (2011) Oral involvement of chronic graft-versus-host disease in hematopoietic stem cell transplant recipients. Gen Dent 59(6):458–462 quiz 463–454

    PubMed  Google Scholar 

  14. Imanguli MM, Pavletic SZ, Guadagnini JP, Brahim JS, Atkinson JC (2006) Early and late features of chronic graft-versus-host disease of oral mucosa: review of available therapies. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 101(2):175–183. https://doi.org/10.1016/j.tripleo.2005.08.028

    Article  PubMed  Google Scholar 

  15. Gomes AO, Torres SR, Maiolino A, Santos CW, Junior AS, Correa ME et al (2014) Not available. Rev Bras Hematol Hemoter 36(1):43–49. https://doi.org/10.5581/1516-8484.20140012

    Article  PubMed  PubMed Central  Google Scholar 

  16. Weng X, Xing Y, Cheng B (2017) Multiple and recurrent squamous cell carcinoma of the oral cavity after graft-versus-host disease. J Oral Maxillofac Surg 75(9):1899–1905. https://doi.org/10.1016/j.joms.2017.02.012

    Article  PubMed  Google Scholar 

  17. de Araujo RL, Lyko Kde F, Funke VA, Torres-Pereira CC (2014) Oral cancer after prolonged immunosuppression for multiorgan chronic graft-versus-host disease. Rev Bras Hematol Hemoter 36(1):65–68. https://doi.org/10.5581/1516-8484.20140016

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353–364

    Article  CAS  PubMed  Google Scholar 

  19. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186. https://doi.org/10.1056/NEJM197111182852108

    Article  CAS  PubMed  Google Scholar 

  20. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964. https://doi.org/10.1126/science.1129139

    Article  CAS  PubMed  Google Scholar 

  21. Tamma R, Guidolin D, Annese T, Tortorella C, Ruggieri S, Rega S, Zito FA, Nico B, Ribatti D (2017) Spatial distribution of mast cells and macrophages around tumor glands in human breast ductal carcinoma. Exp Cell Res 359(1):179–184. https://doi.org/10.1016/j.yexcr.2017.07.033

    Article  CAS  PubMed  Google Scholar 

  22. Penack O, Socie G, van den Brink MR (2011) The importance of neovascularization and its inhibition for allogeneic hematopoietic stem cell transplantation. Blood 117(16):4181–4189. https://doi.org/10.1182/blood-2010-10-312934

    Article  CAS  PubMed  Google Scholar 

  23. Laishram D, Rao K, Devi HSU, Priya NS, Smitha T, Sheethal HS (2017) Mast cells and angiogenesis in malignant and premalignant oral lesions: an immunohistochemical study. J Oral Maxillofac Pathol 21(2):229–238. https://doi.org/10.4103/jomfp.JOMFP_111_15

    Article  PubMed  PubMed Central  Google Scholar 

  24. Stasikowska-Kanicka O, Wagrowska-Danilewicz M, Danilewicz M (2017) Association of infiltrating cells with microvessel density in oral squamous cell carcinoma. Pol J Pathol 68(1):40–48. https://doi.org/10.5114/pjp.2017.67614

    Article  PubMed  Google Scholar 

  25. Ringden O, Brazauskas R, Wang Z, Ahmed I, Atsuta Y, Buchbinder D et al (2014) Second solid cancers after allogeneic hematopoietic cell transplantation using reduced-intensity conditioning. Biol Blood Marrow Transplant 20(11):1777–1784. https://doi.org/10.1016/j.bbmt.2014.07.009

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sloand EM, Pfannes L, Ling C, Feng X, Jasek M, Calado R, Tucker ZCG, Hematti P, Maciejewski J, Dunbar C, Barrett J, Young N (2010) Graft-versus-host disease: role of inflammation in the development of chromosomal abnormalities of keratinocytes. Biol Blood Marrow Transplant 16(12):1665–1673. https://doi.org/10.1016/j.bbmt.2010.07.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Beachy PA, Karhadkar SS, Berman DM (2004) Tissue repair and stem cell renewal in carcinogenesis. Nature 432(7015):324–331. https://doi.org/10.1038/nature03100

    Article  CAS  PubMed  Google Scholar 

  28. Mashhadiabbas F, Fayazi-Boroujeni M (2017) Correlation of vascularization and inflammation with severity of oral leukoplakia. Iran J Pathol 12(3):225–230

    PubMed  PubMed Central  Google Scholar 

  29. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867. https://doi.org/10.1038/nature01322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899. https://doi.org/10.1016/j.cell.2010.01.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ribatti D, Crivellato E (2009) Immune cells and angiogenesis. J Cell Mol Med 13(9A):2822–2833. https://doi.org/10.1111/j.1582-4934.2009.00810.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ribatti D, Vacca A (2008) Overview of angiogenesis during tumor growth. In: Figg WD, Folkman J (eds) Angiogenesis. Springer, Boston

    Google Scholar 

  33. Nelson BH (2010) CD20+ B cells: the other tumor-infiltrating lymphocytes. J Immunol 185(9):4977–4982. https://doi.org/10.4049/jimmunol.1001323

    Article  CAS  PubMed  Google Scholar 

  34. Shen M, Sun Q, Wang J, Pan W, Ren X (2016) Positive and negative functions of B lymphocytes in tumors. Oncotarget 7(34):55828–55839. https://doi.org/10.18632/oncotarget.10094

    Article  PubMed  PubMed Central  Google Scholar 

  35. Yang C, Lee H, Pal S, Jove V, Deng J, Zhang W, Hoon DSB, Wakabayashi M, Forman S, Yu H (2013) B cells promote tumor progression via STAT3 regulated-angiogenesis. PLoS One 8(5):e64159. https://doi.org/10.1371/journal.pone.0064159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mor F, Quintana FJ, Cohen IR (2004) Angiogenesis-inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J Immunol 172(7):4618–4623

    Article  CAS  PubMed  Google Scholar 

  37. Carvalho MI, Pires I, Dias M, Prada J, Gregorio H, Lobo L et al (2015) Intratumoral CD3+ T-lymphocytes immunoexpression and its association with c-Kit, angiogenesis, and overall survival in malignant canine mammary tumors. Anal Cell Pathol (Amst) 2015:920409. https://doi.org/10.1155/2015/920409

    Article  CAS  Google Scholar 

  38. Yu JL, Rak JW (2003) Host microenvironment in breast cancer development: inflammatory and immune cells in tumour angiogenesis and arteriogenesis. Breast Cancer Res 5(2):83–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bosisio D, Ronca R, Salvi V, Presta M, Sozzani S (2018) Dendritic cells in inflammatory angiogenesis and lymphangiogenesis. Curr Opin Immunol 53:180–186. https://doi.org/10.1016/j.coi.2018.05.011

    Article  CAS  PubMed  Google Scholar 

  40. Blois SM, Piccioni F, Freitag N, Tirado-Gonzalez I, Moschansky P, Lloyd R et al (2014) Dendritic cells regulate angiogenesis associated with liver fibrogenesis. Angiogenesis 17(1):119–128. https://doi.org/10.1007/s10456-013-9382-5

    Article  CAS  PubMed  Google Scholar 

  41. Qu Z, Liebler JM, Powers MR, Galey T, Ahmadi P, Huang XN, Ansel JC, Butterfield JH, Planck SR, Rosenbaum JT (1995) Mast cells are a major source of basic fibroblast growth factor in chronic inflammation and cutaneous hemangioma. Am J Pathol 147(3):564–573

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lee HS, Myers A, Kim J (2009) Vascular endothelial growth factor drives autocrine epithelial cell proliferation and survival in chronic rhinosinusitis with nasal polyposis. Am J Respir Crit Care Med 180(11):1056–1067. https://doi.org/10.1164/rccm.200905-0740OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cimpean AM, Tamma R, Ruggieri S, Nico B, Toma A, Ribatti D (2017) Mast cells in breast cancer angiogenesis. Crit Rev Oncol Hematol 115:23–26. https://doi.org/10.1016/j.critrevonc.2017.04.009

    Article  PubMed  Google Scholar 

Download references

Funding

This work was supported in part by Fellowship FIRC-AIRC 1-year fellowship “Laura Bassi” id. 20879 to TA.

Author information

Author notes

  1. Gianfranco Favia and Giorgina Specchia equally contributed to this work.

Authors and Affiliations

  1. Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Piazza Giulio Cesare, 11, 70124, Bari, Italy

    Roberto Tamma, Tiziana Annese & Domenico Ribatti

  2. Department of Interdisciplinary Medicine, Section of Odontostomatology, University of Bari Medical School, Bari, Italy

    Luisa Limongelli, Angela Tempesta, Saverio Capodiferro & Gianfranco Favia

  3. Department of Emergency and Transplantation, Pathology Section, University of Bari Medical School, Bari, Italy

    Eugenio Maiorano, Eliano Cascardi, Mauro G. Mastropasqua & Claudia Covelli

  4. Department of Emergency and Transplantation, Hematology Section, University of Bari Medical School, Bari, Italy

    Domenico Pastore, Paola Carluccio & Giorgina Specchia

  5. Oral Medicine and Oral Oncology Unit, Department of Oncology, University of Turin Medical School, Turin, Italy

    Monica Pentenero

Authors
  1. Roberto Tamma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luisa Limongelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eugenio Maiorano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Domenico Pastore
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eliano Cascardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Angela Tempesta
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paola Carluccio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mauro G. Mastropasqua
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Saverio Capodiferro
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Claudia Covelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Monica Pentenero
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tiziana Annese
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Gianfranco Favia
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Giorgina Specchia
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Domenico Ribatti
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors have seen and approved the manuscript being submitted.

Corresponding author

Correspondence to Domenico Ribatti.

Ethics declarations

Full ethical approval and signed informed consent from individual patients were obtained to conduct the study. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tamma, R., Limongelli, L., Maiorano, E. et al. Vascular density and inflammatory infiltrate in primary oral squamous cell carcinoma and after allogeneic hematopoietic stem cell transplantation. Ann Hematol 98, 979–986 (2019). https://doi.org/10.1007/s00277-018-3575-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-018-3575-3

Keywords

Search

Navigation