Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Factors that may influence polymorphous low-grade adenocarcinoma growth


There is mounting evidence on the importance of some biological processes in tumor growth, such as vascular supply, apoptosis, autophagy, and senescence. We have investigated these processes in polymorphous low-grade adenocarcinoma (PLGA), in an attempt to identify those that are relevant for this particular lesion. We analyzed 31 cases of PLGA using immunohistochemistry to antibodies against CD34 and CD105 to detect blood vessels; against D2-40 to detect lymphatic vessels; against Bax, Bcl-2, and survivin to explore cell apoptosis; and against Beclin and LCB3 to investigate autophagy and against p21 and p16 to assess senescence. Our results showed that PLGA growth does not depend on newly formed vessels but only on preexisting vasculature. Furthermore, PLGA is promoted by autophagy, sustained by both anti-apoptotic and anti-senescence signals, and stimulated by Bcl-2 and survivin.

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

Fig. 1
Fig. 2


  1. 1.

    Luna MA, Wenig BM (2005) Polymorphous low-grade adenocarcinoma. In: Barnes L, Eveson JW, Reichart P, Sidransky D, Ed. Pathol. Genet. Head Neck Tumours. pp 223–224

  2. 2.

    Freedman PD, Lumerman H (1983) Lobular carcinoma of intraoral minor salivary gland origin. Oral Surgery, Oral Med Oral Pathol 56:157–165. doi:10.1016/0030-4220(83)90282-7

  3. 3.

    Batsakis JG, Pinkston GR, Luna MA et al (1983) Adenocarcinomas of the oral cavity: a clinicopathologic study of terminal duct carcinomas. J Laryngol Otol 97:825–835. doi:10.1017/S0022215100095062

  4. 4.

    El-Naaj IA, Leiser Y, Wolff A, Peled M (2011) Polymorphous low grade adenocarcinoma: case series and review of surgical management. J Oral Maxillofac Surg 69:1967–1972. doi:10.1016/j.joms.2010.10.010

  5. 5.

    Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257. doi:10.1038/35025220

  6. 6.

    Detmar M, Hirakawa S (2002) The formation of lymphatic vessels and its importance in the setting of malignancy. J Exp Med 196:713–718

  7. 7.

    Ouyang L, Shi Z, Zhao S et al (2012) Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 45:487–498. doi:10.1111/j.1365-2184.2012.00845.x

  8. 8.

    Townson JL, Naumov GN, Chambers AF (2003) The role of apoptosis in tumor progression and metastasis. Curr Mol Med 3:631–642

  9. 9.

    Roberg K, Jonsson A-C, Grénman R, Norberg-Spaak L (2007) Radiotherapy response in oral squamous carcinoma cell lines: evaluation of apoptotic proteins as prognostic factors. Head Neck 29:325–334. doi:10.1002/hed

  10. 10.

    Levine B (2007) Cell biology: autophagy and cancer. Nature 446:745–747. doi:10.1038/446745a

  11. 11.

    Lindqvist LM, Simon a K, Baehrecke EH (2015) Current questions and possible controversies in autophagy. Cell Death Discov 1:15036. doi:10.1038/cddiscovery.2015.36

  12. 12.

    Cosway B, Lovat P (2016) The role of autophagy in squamous cell carcinoma of the head and neck. Oral Oncol 54:1–6. doi:10.1016/j.oraloncology.2015.12.007

  13. 13.

    Burada F, Nicoli ER, Ciurea ME et al (2015) Autophagy in colorectal cancer: an important switch from physiology to pathology. World J Gastrointest Oncol 7:271–284. doi:10.4251/wjgo.v7.i11.271

  14. 14.

    Parkhitko AA, Favorova OO, Henske EP (2013) Autophagy: mechanisms, regulation, and its role in tumorigenesis. Biochemistry 78:355–367. doi:10.1134/S0006297913040044

  15. 15.

    Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740. doi:10.1038/nrm2233

  16. 16.

    Collado M, Serrano M (2010) Senescence in tumours: evidence from mice and humans. Nat Rev Cancer 10:51–57. doi:10.1038/nrc2772

  17. 17.

    Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24:2463–2479. doi:10.1101/gad.1971610

  18. 18.

    Michal M, Skálová A, Simpson RHW et al (1999) Cribriform adenocarcinoma of the tongue: a hitherto unrecognized type of adenocarcinoma characteristically occurring in the tongue. Histopathology 35:495–501. doi:10.1046/j.1365-2559.1999.00792.x

  19. 19.

    Skalova A, Sima R, Kaspirkova-Nemcova J et al (2011) Cribriform adenocarcinoma of minor salivary gland origin principally affecting the tongue: characterization of new entity. Am J Surg Pathol 35:1168–1176. doi:10.1097/PAS.0b013e31821e1f54

  20. 20.

    Weinreb I, Zhang L, Tirunagari LMS et al (2014) Novel PRKD gene rearrangements and variant fusions in cribriform adenocarcinoma of salivary gland origin. Genes Chromosom Cancer 53:845–856. doi:10.1002/gcc.22195

  21. 21.

    Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307. doi:10.1038/nature10144

  22. 22.

    Wong RSY (2011) Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30:87. doi:10.1186/1756-9966-30-87

  23. 23.

    Um H-D (2016) Bcl-2 family proteins as regulators of cancer cell invasion and metastasis: a review focusing on mitochondrial respiration and reactive oxygen species. Oncotarget 7:5193–5203. doi:10.18632/oncotarget.6405

  24. 24.

    Hirano H, Yamaguchi T, Yokota S et al (2015) Survivin expression in lung cancer: association with smoking, histological types and pathological stages. Oncol Lett 10:1456–1462

  25. 25.

    Ko YH, Roh SY, Won HS et al (2010) Survivin expression in resected adenoid cystic carcinoma of the head and neck. Head Neck Oncol 30:30

  26. 26.

    Ettl T, Stiegler C, Zeitler K et al (2012) EGFR, HER2, survivin, and loss of pSTAT3 characterize high-grade malignancy in salivary gland cancer with impact on prognosis. Hum Pathol 43:921–931. doi:10.1016/j.humpath.2011.08.006

  27. 27.

    Kondo Y, Kanzawa T, Sawaya R, Kondo S (2005) The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 5:726–734. doi:10.1038/nrc1692

  28. 28.

    El-Khattouti A, Selimovic D, Haikel Y, Hassan M (2013) Crosstalk between apoptosis and autophagy: molecular mechanisms and therapeutic strategies in cancer. J Cell Death 6:37–55. doi:10.4137/JCD.S11034

  29. 29.

    Beauséjour CM, Krtolica A, Galimi F et al (2003) Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 22:4212–4222. doi:10.1093/emboj/cdg417

  30. 30.

    Dimri GP (2005) What has senescence got to do with cancer? Cancer Cell 7:505–512. doi:10.1016/j.ccr.2005.05.025

Download references


The authors would like to thank Jeruza Bossonaro and Nadir Freitas for their technical expertise.

Authors’ contributions

All authors contributed equally to the preparation of the article.

Author information

Correspondence to Andresa Borges Soares.

Ethics declarations

This study was approved by the Ethics Committee of the São Leopoldo Mandic Institute and Research Center (number 916.794).


The authors are also extremely grateful to FAPESP (São Paulo Research Foundation) and CNPq for their financial support (FAPESP #2015/12418-5 and CNPQ #304031/2014-3).

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Soares, A.B., Martinez, E.F., Ribeiro, P.F.A. et al. Factors that may influence polymorphous low-grade adenocarcinoma growth. Virchows Arch 470, 437–443 (2017). https://doi.org/10.1007/s00428-017-2085-3

Download citation


  • Polymorphous low-grade adenocarcinoma
  • Angiogenesis
  • Apoptosis
  • Autophagy
  • Senescence
  • Bcl2
  • Survivin
  • LC3B