ORIGINAL ARTICLE
High-risk human papillomavirus enhances the expression of COX-2 VEGF, EGFR, ProEx-C, and TERT proteins in
human papillomavirus-related multiphenotypic sinonasal carcinoma through activation of PI3K/Akt, pRb, and TERT
signalling pathways
1
Department of Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2
Department of Pathology, Faculty of Medicine, University of Benghazi, Benghazi, Libya
3
Department of Clinical Oncology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
4
Department of Medical Oncology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
5
Department of Otorhinolaryngology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
6
Department of Histology and Cell Biology, Faculty of Medicine, Tanta University, Tanta, Egypt
7
Department of Biology, College of Science, University of Jeddah, Jeddah, Kingdom of Saudi Arabia
Submission date: 2022-11-22
Acceptance date: 2022-12-09
Publication date: 2023-03-20
Corresponding author
Mohamed Ali Alabiad
Mohamed Ali Alabiad, MD Lecturer of Pathology Faculty of Medicine Zagazig University 44519 Zagazig, Egypt
Mohamed Ali Alabiad, MD Lecturer of Pathology Faculty of Medicine Zagazig University 44519 Zagazig, Egypt
Pol J Pathol 2022;73(4):283-298
KEYWORDS
TOPICS
ABSTRACT
Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is a new type of sinonasal tumour that frequently drops out of accurate diagnosis. Human papillomavirus related multiphenotypic sinonasal carcinoma was previously known as HPV-related sinonasal carcinoma with adenoid cystic characteristics, and it is connected to high-risk HPV (HR-HPV) strains whose prognosis is unknown. We aim to evaluate PI3K/Akt, pRb, and h telomerase reverse transcriptase (TERT) signalling pathway activation through the expression of proteins cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), ProEx-C, and TERT and their prognostic and clinicopathological value in HMSC patients.
Sections of the 40 paraffin blocks of HMSC were recovered, and all samples were evaluated for the presence of a cocktail of HR-HPV, and the absence of MYB, NFIB, and MYBL1 fusions using fluorescence in situ hybridization; the presence of myoepithelial markers; S100, actin; the presence of squamous differentiation markers; calponin, p40, and p63 using PCR-based assays; and COX-2,VEGF, ProEx-C, and TERT using immunohistochemical staining. All patients were monitored for around 54 months, until death, or the last known surviving data (range 20–60 months).
A statistically significant relationship exists between COX-2 expression was significantly related to the old age group, tumour extent, relapse, mortality, and poor DFS; (p = 0.001), (p = 0.01), (p = 0.002), and (p = 0.035), respectively. While VEGF, ProEx-C, and TERT expression with the old age group, tumour extent, lymph node metastasis, advancedstaging, relapse, mortality, poor disease free survival (DFS), and overall survival (p = 0.001).
Human papillomavirus-related multiphenotypic sinonasal carcinoma is a unique sinonasal neoplasm with a strong link to HR-HPV strains. Expression of COX-2, VEGF, EGFR, ProEx-C, TERT was linked to poor prognosis, survival, and aggressive malignant behaviours such as proliferation, local recurrence, and lymph node metastasis, making them novel beneficial biomarkers and targeted therapies for HMSC patients.
Sections of the 40 paraffin blocks of HMSC were recovered, and all samples were evaluated for the presence of a cocktail of HR-HPV, and the absence of MYB, NFIB, and MYBL1 fusions using fluorescence in situ hybridization; the presence of myoepithelial markers; S100, actin; the presence of squamous differentiation markers; calponin, p40, and p63 using PCR-based assays; and COX-2,VEGF, ProEx-C, and TERT using immunohistochemical staining. All patients were monitored for around 54 months, until death, or the last known surviving data (range 20–60 months).
A statistically significant relationship exists between COX-2 expression was significantly related to the old age group, tumour extent, relapse, mortality, and poor DFS; (p = 0.001), (p = 0.01), (p = 0.002), and (p = 0.035), respectively. While VEGF, ProEx-C, and TERT expression with the old age group, tumour extent, lymph node metastasis, advancedstaging, relapse, mortality, poor disease free survival (DFS), and overall survival (p = 0.001).
Human papillomavirus-related multiphenotypic sinonasal carcinoma is a unique sinonasal neoplasm with a strong link to HR-HPV strains. Expression of COX-2, VEGF, EGFR, ProEx-C, TERT was linked to poor prognosis, survival, and aggressive malignant behaviours such as proliferation, local recurrence, and lymph node metastasis, making them novel beneficial biomarkers and targeted therapies for HMSC patients.
REFERENCES (65)
2.
Barnes L, Eveson J, Reichart P, Sidransky D. Tumours of the nasal cavity and paranasal sinuses. WHO Classification of Tumours 2005, 3rd ed.
3.
Demers PA, Kogevinas M, Boffetta P, et al. Wood dust and sino-nasal cancer: pooled reanalysis of twelve case-control studies. Am J Ind Med 1995; 28: 151-166.
4.
Slack R, Young C, Rushton L. Occupational cancer in Britain: nasopharynx and sinonasal cancers. Br J Cancer 2012; 107: S49.
5.
Laco J, Sieglová K, Vošmiková H, et al. The presence of high-risk human papillomavirus (HPV) E6/E7 mRNA transcripts in a subset of sinonasal carcinomas is evidence of involvement of HPV in its etiopathogenesis. Virch Arch 2015; 467: 405-415.
6.
Singhi AD, Westra WH. Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience. Cancer 2010; 116: 2166-2173.
7.
Bishop JA, Ogawa T, Stelow EB, et al. Human papillomavirus-related carcinoma with adenoid cystic-like features: a peculiar variant of head and neck cancer restricted to the sinonasal tract. Am J Surg Pathol 2013; 37: 836.
8.
Rooper LM, Mccuiston AM, Westra WH, Bishop JA. SOX10 immunoexpression in basaloid squamous cell carcinomas: a diagnostic pitfall for ruling out salivary differentiation. Head Neck Pathol 2019; 13: 543-547.
9.
Ahn B, Kim E, Oh H, et al. Human papillomavirus – related multiphenotypic sinonasal carcinoma with late recurrence. J Pathol Transl Med 2019; 53: 337.
10.
Bishop JA, Guo TW, Smith DF, et al. Human papillomavirus- related carcinomas of the sinonasal tract. Am J Surg Pathol 2013; 37: 185.
11.
Chen J. Signaling pathways in HPV-associated cancers and therapeutic implications. Rev Med Virol 2015; 25: 24-53.
12.
Ramakrishnan S, Partricia S, Mathan G. Overview of high-risk HPV’s 16 and 18 infected cervical cancer: pathogenesis to prevention. Biomed Pharmacother 2015; 70: 103-110.
13.
Beccati MD, Buriani C, Pedriali M, Rossi S, Nenci I. Quantitative detection of molecular markers ProEx C (minichromosome maintenance protein 2 and topoisomerase IIa) and MIB-1 in liquid-based cervical squamous cell cytology. Cancer Cytopathol 2008; 114: 196-203.
14.
Shi J, Liu H, Wilkerson M, et al. Evaluation of p16INK4a, minichromosome maintenance protein 2, DNA topoisomerase II, ProEX C, and p16INK4a/ProEX C in cervical squamous intraepithelial lesions. Hum Pathol 2007; 38: 1335-1344.
15.
Bala R, Pinsky BA, Beck AH, Kong CS, Welton ML, Longacre TA. P16 is superior to ProEx C in identifying high-grade squamous intraepithelial lesions (HSIL) of the anal can. Am J Surg Pathol 2013; 37: 659.
16.
Guraya SY, London N, Guraya SS. Ethics in medical research. J Microsc Ultrastruct 2014; 2: 121-126.
17.
Andreasen S, Bishop JA, Hansen TVO, et al. Human papillomavirus-related carcinoma with adenoid cystic-like features of the sinonasal tract: clinical and morphological characterization of six new cases. Histopathol 2017; 70: 880-888.
18.
Jacobs M, de Roda Husman A, van den Brule A, Snijders P, Meijer C, Walboomers J. Group-specific differentiation between high-and low-risk human papillomavirus genotypes by general primer-mediated PCR and two cocktails of oligonucleotide probes. J Clin Microbiol 1995; 33: 901-905.
19.
Hagmar B, Johansson B, Kalantari M, Petersson Z, Skyldberg B, Walaas L. The incidence of HPV in a Swedish series of invasive cervical carcinoma. Med Oncol Tumor Pharmacother 1992; 9: 113-117.
20.
Bishop JA, Andreasen S, Hang JF, et al. HPV-related multiphenotypic sinonasal carcinoma: an expanded series of 49 cases of the tumor formerly known as HPV-related carcinoma with adenoid cystic carcinoma-like features. Am J Surg Pathol 2017; 41: 1690.
21.
Alabiad MA, Elderey MS, Shalaby AM, Nosery Y, Gobran MA. The usefulness of 4 immunoperoxidase stains applied to urinary cytology samples in the pathologic stage of urothelial carcinoma: a study with histologic correlation. Appl Immunohistochem Mol Morphol 2021; 29: 422-32.
22.
Khayal EE, Alabiad MA, Elkholy MR, Shalaby AM, No- sery Y, El-Sheikh AA. The immune modulatory role of marjoram extract on imidacloprid induced toxic effects in thymus and spleen of adult rats. Toxicology 2022; 471: 153174.
23.
Alabiad MA, Harb OA, Hefzi N, et al. Prognostic and clinicopathological significance of TMEFF2, SMOC-2, and SOX17 expression in endometrial carcinoma. Exp Mol Pathol 2021; 122: 104670.
24.
Shalaby AM, Alabiad MA, El Shaer DF. Resveratrol ameliorates the seminiferous tubules damages induced by finasteride in adult male rats. Microsc Microanal 2020; 26: 1176-86.
25.
Tawfeek SE, Shalaby AM, Alabiad MA, Albackoosh AA, Albakoush KM, Omira MM. Metanil yellow promotes oxidative stress, astrogliosis, and apoptosis in the cerebellar cortex of adult male rat with possible protective effect of scutellarin: a histological and immunohistochemical study. Tissue Cell 2021; 73: 101624.
26.
Alabiad MA, Harb OA, Taha HF, El Shafaay BS, Gertal- lah LM, Salama N. Prognostic and clinic-pathological significances of SCF and COX-2 expression in inflammatory and malignant prostatic lesions. Pathol Oncol Res 2019; 25: 611-624.
27.
Elsalam SA, Mansor AE, Sarhan MH, Shalaby AM, Gobran MA, Alabiad MA. Evaluation of apoptosis, proliferation, and adhesion molecule expression in trophoblastic tissue of women with recurrent spontaneous abortion and infected with Toxoplasma gondii. Int J Gynecol Pathol 2021; 40: 124-133.
28.
Ahmed MM, Gebriel MG, Morad EA, et al. Expression of immune checkpoint regulators, cytotoxic T-lymphocyte antigen-4, and programmed death-ligand 1 in Epstein-Barr virus-associated nasopharyngeal carcinoma. Appl Immunohistochem Mol Morphol 2021; 29: 401-408.
29.
Khayal EE, Ibrahim HM, Shalaby AM, Alabiad MA, El-Sheikh AA. Combined lead and zinc oxide-nanoparticles induced thyroid toxicity through 8-OHdG oxidative stress-mediated inflammation, apoptosis, and Nrf2 activation in rats. Environ Toxicol 2021; 36: 2589-604.
30.
Shalaby AM, Aboregela AM, Alabiad MA, El Shaer DF. Tramadol promotes oxidative stress, fibrosis, apoptosis, ultrastructural and biochemical alterations in the adrenal cortex of adult male rat with possible reversibility after withdrawal. Microsc Microanal 2020; 26: 509-523.
31.
Shamloo N, Taghavi N, Yazdani F, Azimian P, Ahmadi S. Evaluation of VEGF expression correlates with COX-2 expression in pleomorphic adenoma, mucoepidermoid carcinoma and adenoid cystic carcinoma. Dent Res J 2020; 17: 100.
32.
Ward ML, Kernig M, Willson TJ. HPV-related multiphenotypic sinonasal carcinoma: a case report and literature review. Laryngoscope 2021; 131: 106-110.
33.
Rupp NJ, Camenisch U, Seidl K, et al. HPV-related multiphenotypic sinonasal carcinoma: four cases that expand the morpho- molecular spectrum and include occupational data. Head Neck Pathol 2020; 14: 623-629.
34.
Shah AA, Lamarre ED, Bishop JA. Human papillomavirusrelated multiphenotypic sinonasal carcinoma: a case report documenting the potential for very late tumor recurrence. Head Neck Pathology 2018; 12: 623-628.
35.
Bergbrant I, Samuelsson L, Olofsson S, Jonassen F, Ricksten A. Polymerase chain reaction for monitoring human papillomavirus contamination of medical personnel during treatment of genital warts with CO2 laser and electrocoagulation. Acta Dermat Venereol 1994; 74: 393-395.
36.
Kofoed K, Norrbom C, Forslund O, et al. Low prevalence of oral and nasal human papillomavirus in employees per- forming CO 2-laser evaporation of genital warts or loop electrode excision procedure of cervical dysplasia. Acta Derm Venereol 2015; 95: 173-176.
37.
Hang JF, Hsieh MS, Li WY, et al. Human papillomavirus- related carcinoma with adenoid cystic-like features: a series of five cases expanding the pathological spectrum. Histopathology 2017; 71: 887-896.
38.
Geraets D, Alemany L, Guimera N, et al. Detection of rare and possibly carcinogenic human papillomavirus genotypes as single infections in invasive cervical cancer. J Pathol 2012; 228: 534-543.
39.
Thompson LD. HPV-related multiphenotypic sinonasal carcinoma. Ear Nose Throat J 2020; 99: 94-95.
40.
Lee SK, Kwon MS, Lee YS, et al. Prognostic value of expression of molecular markers in adenoid cystic cancer of the salivary glands compared with lymph node metastasis: a retrospective study. World J Surg Oncol 2012; 10: 1-9.
41.
Yu F, Jiang X, Chen W, Zhao Y, Zhou X. Microvessel density and expression of vascular endothelial growth factor in ade- noid cystic carcinoma of salivary gland. Shanghai Kou Qiang Yi Xue 2003; 12: 443-446.
42.
Lim JJ, Kang S, Lee MR, et al. Expression of vascular endo- thelial growth factor in salivary gland carcinomas and its relation to p53, Ki-67 and prognosis. J Oral Pathol Med 2003; 32: 552-561.
43.
Li Z, Tang P, Xu Z. Clinicopathological significance of microvessel density and vascular endothelial growth factor expression in adenoid cystic carcinoma of salivary glands. Zhonghua Kou Qiang Yi Xue 2001; 36: 212-214.
44.
Park S, Nam SJ, Keam B, et al. VEGF and Ki-67 overexpression in predicting poor overall survival in adenoid cystic carcinoma. Cancer Res Treat 2016; 48: 518.
45.
Branco KFCC, Ribeiro ALR, de Mendonça RP, et al. Abnormal activation of the Akt signaling pathway in adenoid cystic carcinoma. Eur Arch Otorhinolaryngol 2018; 275: 3039-3047.
46.
Akrish S, Peled M, Ben-Izhak O, Nagler RM. Malignant salivary gland tumors and cyclo-oxygenase-2: a histopathological and immunohistochemical analysis with implications on histogenesis. Oral Oncol 2009; 45: 1044-1050.
47.
Haymerle G, Schneider S, Harris L, et al. Minor salivary gland carcinoma: a review of 35 cases. Eur Arch Otorhinolaryngol 2016; 273: 2717-2726.
48.
Li Z, Yang H, Yang B. Molecular markers in head and neck cytology. Molecular cytopathology. Springer 2016.
49.
Panta P, Manavathi B, Nagini S. Genetics and molecular mechanisms in oral cancer progression. Oral cancer detection. Springer 2019.
50.
Saida K, Murase T, Ito M, et al. Mutation analysis of the EGFR pathway genes, EGFR, RAS, PIK3CA, BRAF, and AKT1, in salivary gland adenoid cystic carcinoma. Oncotarget 2018; 9: 17043.
51.
Ettl T, Schwarz S, Kleinsasser N, Hartmann A, Reichert T, Driemel O. Overexpression of EGFR and absence of C-KIT expression correlate with poor prognosis in salivary gland carcinomas. Histopathology 2008; 53: 567-577.
52.
Conesa-Zamora P, Domenech-Peris A, Ortiz-Reina, S, et al. Immunohistochemical evaluation of ProEx C in human papillomavirus-induced lesions of the cervix. J Clin Pathol 2009; 62: 159-162.
53.
Alabiad MA, Alsayed AA, Mohamed AS, Shalaby AM, No- sery Y, Gobran MA. TERT promoter mutation and proEx C are useful as a screening tool to predict the malignant behavior of thyroid tumors of uncertain malignant potential. Pol J Pathol 2021; 71: 314-327.
54.
Alabiad MA, Elderey MS, Shalaby AM, Nosery Y, Gobran MA. The usefulness of 4 immunoperoxidase stains applied to urinary cytology samples in the pathologic stage of urothelial carcinoma: a study with histologic correlation. Appl Immunohistochem Mol Morphol 2021; 29: 422-432.
55.
Wang WC, Wu TT, Chandan VS, Lohse CM, Zhang L. Ki-67 and ProExC are useful immunohistochemical markers in esophageal squamous intraepithelial neoplasia. Human Pathol 2011; 42: 1430-1437.
56.
Chrisostomos S, Andria P, Sevasti M. Significance of biomarkers in primar detection of cervical intraepithelial neoplasia lesions – review of the literature. J Clin Res Oncol 2020; 3: 1-5.
57.
Elfeky M, Harb O, Gertallah L. Panel of villin, pro-ex-c, estrogen receptor and progesterone receptor expressions could help in differentiation between endocervical and endometrioid adenocarcinoma. Turk Patoloji Derg 2017; 1: 29-40.
58.
Kungoane T. The prognostic significance of proliferation markers Ki-67 and MCM2 and p53 protein expression in salivary gland neoplasms. Available from: https://www.semanticscholar.or... paper/The-prognostic-significance-of-proliferation-Ki-67-Kungoane/ 03fe6c46b5a03c88f57788e7f0526059894e55d4.
59.
Vargas P, Cheng Y, Barrett A, Craig G, Speight P. Expression of Mcm-2, Ki-67 and geminin in benign and malignant salivary gland tumours. J Oral Pathol Med 2008; 37: 309-318.
60.
Jaehne M, Roeser K, Jaekel T, Schepers JD, Albert N, Lö- ning T. Clinical and immunohistologic typing of salivary duct carcinoma: a report of 50 cases. Cancer 2005; 103: 2526-2533.
61.
Savera AT, Sloman A, Huvos AG, Klimstra DS. Myoepithelial carcinoma of the salivary glands: a clinicopathologic study of 25 patients. Am J Surg Pathol 2000; 24: 761-774.
62.
Ghazy SE, Helmy IM, Baghdadi HM. Maspin and MCM2 immunoprofiling in salivary gland carcinomas. Diagn Pathol 2011; 6: 1-8.
63.
Vivatvakin S, Ratchataswan T, Leesutipornchai T, et al. MCM-2, Ki-67, and EGFR downregulated expression levels in advanced stage laryngeal squamous cell carcinoma. Sci Rep 2021; 11: 1-12.
64.
Stoeber K, Tlsty TD, Happerfield L, et al. DNA replication licensing and human cell proliferation. J Cell Sci 2001; 114: 2027-2041.
65.
Shigeishi H, Sugiyama M, Tahara H, et al. Increased telomerase activity and hTERT expression in human salivary gland carcinomas. Oncol Lett 2011; 2: 845-850.
Share
RELATED ARTICLE
| eISSN: | 2084-9869 |
| ISSN: | 1233-9687 |
We process personal data collected when visiting the website. The function of obtaining information about users and their behavior is carried out by voluntarily entered information in forms and saving cookies in end devices. Data, including cookies, are used to provide services, improve the user experience and to analyze the traffic in accordance with the Privacy policy. Data are also collected and processed by Google Analytics tool (more).
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
