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The Gulf Journal of Oncology is published with the financial supportfrom the Kuwait Foundation for the Advancement of Sciences
Table of Contents
Original ArticlesSpectrum of Breast Diseases: Histopathological and Immunohistochemical Study from North India...................................................06Sumyra Khurshid Qadri, Pranjali Sejwal, Rashmi Priyadarshni, Milan Jaiswal, Ruchi Khandewal, Manisha Khanna, Tanu Agarwal, Hema Pant, Ratana Saxena
Concurrent Paclitaxel and Radiotherapy for Node Positive Breast Cancer ..............................................................................................14Asmaa Ali Hassan, Noha Yehia Ibrahim, Mohamed Abdel Rahman Kassem, Abdel Aziz Mostafa Toeama
Cancer Control Priorities and Challenges in Saudi Arabia: A Preliminary Projection of Cancer Burden ................................................22Maha T. Alattas
A Novel Approach to Obtain Follow-up Data on the Vital Status of Registered Cancer Patients: The Kuwait Cancer Registry Experience....................................................................................................................................................31Eiman Alawadhi, Ahmed Al-Awadi, Amani Elbasmi, Michel P. Coleman, Claudia Allemani
Cancer survival trends in Kuwait, 2000-2013: A population-based study .............................................................................................39Eiman Alawadhi, Ahmed Al-Awadi, Amani Elbasmi, Michel P. Coleman, Claudia Allemani
Triple Negative Breast Cancer: 10-Year Survival Update of The Applied Treatment Strategy in Kuwait ...............................................53Salah Fayaz, Gerges A. Demian, Mustafa El-Sherify, Heba Eissa, Mary Aziz, Sadeq Abuzallouf
Early Calcium Supplementation After Total Thyroidectomy Can Prevent Symptomatic Hypocalcemia - Findings from a Retrospective Study .....................................................................................................................................................60Manu Santhosh, Sajith Babu Thavarool, Sandeep Vijay, Adharsh Anand, Guru Charan Sahu,v Satheeshan Balasubramaniam
Association between nodal metastasis and histopathological factors in postoperative gingivo-buccal complex squamous cell carcinoma: A Retrospective Study .....................................................................................................................66Sweta Soni, Tej Prakash Soni, Nidhi Patni
Review ArticlesImpact of HPV on the Pathobiology of Cancers .........................................................................................................................................72Ritesh Kumar, Pranay Tanwar, Angel Rajan Singh, Showket Hussain, G.K. Rath
Cancer Immunotherapy: An Updated Overview of Current Strategies and Therapeutic Agents .............................................................76Osama Abu-Shawer, Tariq Bushnaq, Mohammad Abu-Shawer
Case ReportsExtremely Giant Ovarian Mucinous Cystadenoma ....................................................................................................................................83Abdulaziz Alobaid, Heba Elamir, Mohammed Abuzaid, Ahmed Abu-Zaid
Hemorrhagic Brain Metastasis as the Initial Manifestation of Esophageal Adenocarcinoma ................................................................87Hussein Algahtani, Bader Shirah, Yehya Seddeq, Hatim Al-Maghraby
Conference Highlights/Scientific Contributions• News Notes............................................................................................................................................................................................91
• Advertisements .....................................................................................................................................................................................94
• ScientificeventsintheGCCandtheArabWorldfor2019 ..................................................................................................................95
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Corresponding Author: Dr. Pranay Tanwar, Associate Professor, Laboratory Oncology Unit,
Dr BRAIRCH, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
Emails: [email protected], [email protected]
IntroductionHuman papilloma Virus (HPV) is a circular double
stranded deoxyribonucleic acid (DNA) virus. This virus belongs to family Papillomaviridae that comprises of non-enveloped, small, double-stranded deoxyribonucleic acid (DNA) viruses [1] HPV is related to approximately 610,000 new cancer cases per year worldwide. [2] The impact of viruses especially HPV on the dynamic phenomenon of neoplasia has been studied for long. HPV- induced cancer research has led to the development of high risk HPV testing. The strategy has been utilized in the cervical cancer screening program and positively helped development of HPV-related vaccines.
In category of infection induced carcinogenesis, viruses are playing an important etiological predominant role. According to de Martel et al, HPV is causative agent for 100% of cervical cancers, 88% of anal cancers, 70% of vaginal cancers, 50% of penile cancers and 43% of vulvar cancers.[2] Most of the HPV induced carcinoma is due to high Risk HPV 16 and 18.[3] According to World Health Organization International Agency for Research on Cancer (IARC) , the persistent infection of HPV 16 and 18 are the main cause of multiple cancers primarily cervical cancer and a section of oropharyngeal, anal and penile cancer.[4] European Research Organization on Genital Infection and Neoplasia (EUROGIN) in along with other scientific societies are highlighting importance and relevance of research on HPV in the form of many upcoming papers and presentations
Abstract
Human papilloma virus (HPV) associated cancers represents a special subgroup of cancers which are potential targets of screening strategy to reduce the burden of HPV-associated cancers. The viruses have different molecular pathways which ultimately lead to the immortalization of cells. The unique pathobiology and detailed discovery of molecular signaling pathways have paved the new dimensions and advancements in
both early detection and development of newer treatment strategy in terms sensitivity towards radiotherapy in HPV-induced cancers versus others. Their clinical behavior suggests good prognosis when compared to Non-HPV positive group cancers. The better prognosis between HPV positive and Non-HPV positive cancer demands a timely diagnosis of HPV status to stratify high risk cases to promote personalized management.
Keywords: HPV, pathology of cancers.
Review Article
Impact of HPV on the Pathobiology of CancersRitesh Kumar1, Pranay Tanwar2, Angel Rajan Singh3, Showket Hussain4, G.K. Rath1
1 Department of Radiotherapy, Dr. BRAIRCH, AIIMS, New Delhi-29, India 2 Laboratory Oncology Unit- Dr. BRAIRCH, AIIMS, New Delhi-29, India
3 Department of Hospital Administration, AIIMS, New Delhi-29, India 4 National Institute of Cancer Prevention & Research, Noida, India
in their annual meetings. The rate limiting step of timely diagnosis of HPV infection has to be overcome to run and implement a successful cancer screening program. There has been reduction in incidence of cervical cancer in countries with effective screening program [5]
Impact of HPV in promoting Neoplasia Apart from affecting human beings, the infection of
HPV has also reported in snakes, birds and tortoises. [6-7] A huge number of approximately 170 types of HPVs which have been completely sequenced and there are further 200 more are under process. [8] HPV 16 belongs to the family Papillomavirida is a non-enveloped virus which is icosa-hedral shaped double stranded circular DNA virus. The size of this virus is only 55nm [Figure 1]. Six proteins which are namely (E1, E2, E4, E5, E6, E7) are expressed early while two late proteins (L1 and L2) are expressed later then early proteins in HPV life cycle. [9]
The early proteins have their specific function in overall pathobiology which promotes the immortalization of cell.
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Viral DNA replication is supported by E1 and E2. Post transcriptional modification of virus is being guided by E4. E5 promotes upgradation of growth factor receptors and transformation of cell. [9] The Ubiquitin mediated degradation of tumor suppressor protein (p53) which ultimately make the cell resistant to apoptosis is done by E6. Degradation of retinoblastoma protein (Rb) promoted by E7 binds leading downstream signaling of E2F factor promoting uncontrolled cell division by early entry of cell to synthesis phase (S-phase). The simultaneous action of both E6/E7 oncoprotein together results in immortalization of the virus infected cell. [10] The viral capsid formation is done by L1 major protein and L2 promotes the entry of viral DNA to genome of host cell. [11] Once, the host cell is infected by virus it leads to increased expression of all early and late viral proteins by progressive cell divisions. This results in degradation of host tumor suppressor protein such as p53 and Rb. This infected cell continues to remain in prolonged cell cycle with failure of apoptotic mechanism. Finally, it results in unstable genome and immortalization. [12]
The Surrogate Marker of HPV: P16 Expression
The p16 protein expression in tumor act as surrogate marker for HPV. [13] The p16 protein inhibits Rb protein phosphorylation which is mediated by CDK4 and cyclinD1. Hence the expression of p16 increases when Rb is degraded by HPV E7 oncoprotein as a result of feedback loop mechanism. [14]
Cancer Screening: A Molecular Diagnostics approach
The involvement of HPV in cancer other than cervical cancer has broadened its horizon to other tumors. HPV is also involved in specific group of head and neck cancer, oropharyngeal, anal canal, vulvo-vaginal cancers. This may be as a result altered sex habits and co-infection/prior infection of other viruses. Though, different site of tumors, molecular patho-biology and persistent neoplastic insults appears to be similar in all tumors. [15] There has been drastic improvement in diagnostic technique which has significantly contributed in improving the sensitivity of HPV detection rates.
The diagnostics of HPV for cancer screening has been classified on their basic techniques utilized or target amplification. The DNA based methods includes polymeric chain reaction (PCR) mostly utilizing L1 region primer for amplification. The Hybrid Capture II (HC2; Qiagen, Gaitherberg, MD) is the first of all FDA-approved test for screening of High-Risk HPV DNA. This Test uses Hybrid Capture II technology as a nucleic acid hybridization assay with signal amplification that utilizes microplate chemiluminescent detection. The next generation test has come up which are based on mRNA ie, Aptima which can detect mRNA of 12 high risk HPV virus. Many of the studies have been done, which declares this test as equally sensitive but more specific for HPV detection when compared with DNA based HC-II test. [16-17]
Cancer Cervix
HPV is the single most important causative agent in cancer of cervix, accounting for more than 95% of cases. [2] In an Indian population-based study, the high-risk HPV (hr HPV) was found in 87.8% of squamous cell carcinomas (SCC) of cervix. [18] The HPV infection initially causes in CIN1 (Cervix Intraepithelial Neoplasia–1), which in most of the cases undergoes spontaneous regression. However, in patients with HPV16 or 18 infections or with a high viral load, the CIN might persist for a longer duration and eventually progress to CIN2/3. HPV16 viral loads are a stronger predictor for the persistence of lesions than other strains. [19] Wang et al. evaluated the prognostic value of HPV genotypes in 327 cervical cancer patients who underwent treatment with radiotherapy alone or concurrent chemo-radiation.22 different genotypes of HPV were detected in 98.8% patients and the most common genotypes were HPV 16, 58, 18, and 33. There was a significant improvement in response and cure rates in patients with HPV 18 and HPV 58 positive tumors receiving chemoradiotherapy. [20]
Figure 1: HPV genome (The figure is being declared as free to be published under GNU Free Documentation License. The same figure can be confirmed at link below. www.commons.wikimedia.org/wiki/File:HPV-16_genome_organization.png
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Impact of HPV on Pathobiology of Cancers, Ritesh Kumar, et. al.
Vulvovaginal Cancer
Vulvovaginal cancers are also associated with HPV, though the degree of association is not as strong as that in cancer cervix. HPV is associated with 70% of vaginal cancers and 43% of vulvar cancers. [2] An increase in the incidence of vulvar cancers reported mainly in younger women has been attributed to HPV and mechanisms similar to those of cervical cancer development have been documented. The role of HPV-related vaccine seems encouraging and the studies have shown a significant reduction of HPV-related anogenital diseases in young females. [21]
Anal Cancer
The association of HPV in the development of anal cancers is well-documented in literature. HPV is associated with 88% of anal cancers. [2] There is an increase in the incidence of anal cancer over the last few decades mainly attributed in homosexual men and Human immunodeficiency virus (HIV) positive groups. [22] There is emerging evidence that anal intra epithelial neoplasia (AIN) is a precursor of anal cancer and unlike cervical cancer, the evidence is mainly from small studies with a follow-up duration of only 5–10 years. [22]
Head and Neck Cancer
HPV is recognized as an independent cause of oropharyngeal cancer. Sixty-three percent of oropharyngeal cancers each year are associated with HPV infection.[2] Base of the tongue and the tonsils are the common primary site with HPV-associated oropharyngeal cancers.[23] Hong et al showed that patients with HPV-positive cancers had a better outcome when treated with radical radiotherapy ± chemotherapy or surgery and adjuvant radiation.[24] Sathish et al. showed that HPV oropharyngeal cancer have a higher likelihood of a complete response to treatment. [25] HPV associated cancers have favorable treatment outcomes and thus generate a hypothesis of de-escalating the intensity of treatment to reduce long term treatment related toxicities.
Cancer Penis
HPV is associated with cancer Penis in 50% of cases. As cancer penis is very rare, there is a paucity of literature. However, HPV 16 is the most common subtype. [26]
ConclusionsHPV associated cancers represents a special subgroup
of cancers. HPV integrate with the host tissue and causes carcinogenesis in a phased manner. With vaccination, the incidence of HPV associated cancers can be decreased. With the use of different HPV based screening tests, they
can be detected early. Overall, HPV associated cancers have a good prognosis as compared to the non-HPV subtype and there is a growing thought on treatment de-escalation in these tumors to decrease long term treatment related toxicities.
References1. McNamara M, Batur P, Walsh JM, Johnson KM. HPV
Update: Vaccination, Screening, and Associated Disease. Journal of general internal medicine. 2016 May 16:1-7.
2. de Martel C, Ferlay J, Franceschi S, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol 2012; 13:607–15.
3. Arbyn M, de Sanjose S, Saraiya M, et al. EUROGIN 2011 roadmap on prevention and treatment of HPV-related disease. Int J Cancer 2012;131: 1969–82.
4. Anna R. Giuliano, Alan G. Nyitray, Aimmee R et al. EUROGIN 2014 roadmap: Differences in human papillomavirus infection natural history, transmission and human papillomavirus-related cancer incidence by gender and anatomic site of infection 2015;136(12):2752-60.
5. Peto J, Gilham C, Fletcher O, et al. The cervical cancer epidemic that screening has prevented in the UK. Lancet 2004; 364:249–56.
6. Herbst LH, Lenz J, Van Doorslaer K, et al. Genomic characterization of two novel reptilian papillomaviruses, Chelonia mydas papillomavirus 1 and Caretta caretta papillomavirus1. Virology. 2009 Jan 5;383(1):131-5
7. Lange CE, Favrot C, Ackermann M, et al. Novel snake papillomavirus does not cluster with other non-mammalian papillomaviruses Virol J. 2011 Sep 12;8:436.
8. Chouhy D, Bolatti EM, Pérez GR et al. Analysis of the genetic diversity and phylogenetic relationships of putative human papillomavirus types. J Gen Virol. 2013 Nov;94(Pt 11):2480-8
9. Yugawa T, Kiyono T. Molecular mechanisms of cervical carcinogenesis by high-risk human papillomaviruses: novel functions of E6 and E7 oncoproteins. Reviews in medical virology. 2009 Mar 1;19(2):97-113.
10. B. Ruttkay-Nedecky, A.M. Jimenez Jimenez, L. Nejdl, D. Chudobova, J. Gumulec, M. Masarik, V. Adam, R. Kizek, Relevance of infection with human papillomavirus: the role of the p53 tumor suppressor protein and E6/E7 zinc finger proteins (Review), Int J Oncol, 43 (2013) 1754-1762.
11. R. Pereira, I.I. Hitzeroth, E.P. Rybicki, Insights into the role and function of L2, the minor capsid protein of papillomaviruses, Arch Virol, 154 (2009) 187-197.
12. J. Maxwell, S. Khan, R. Ferris, The Molecular Biology of HPV-Related Head and Neck Cancer, in: C. Fakhry, G. D’Souza (Eds.) HPV and Head and Neck Cancers, Springer India, Place Published, 2015, pp. 51-63.
75
G. J. O. Issue 29, 2019
13. E. Benson, R. Li, D. Eisele, C. Fakhry, The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas, Oral Oncol, 50 (2014) 565-574. [48]
14. H. Rayess, M.B. Wang, E.S. Srivatsan, Cellular senescence and tumor Suppressor gene p16, Int J Cancer, 130 (2012) 1715-1725. [47]
15. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Human papillomaviruses (2005) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 90. Lyon: IARC
16. Reid JL, Wright Jr TC, Stoler MH, et al. Human papillomavirus oncogenic mRNA testing for cervical cancer screening: baseline and longitudinal results from the CLEAR Study. Am J Clin Pathol. (2015) 144(3): 473–483.
17. Iftner T, Becker S, Neis KJ, et al. Head-to-head comparison of the RNA-based aptima human papillomavirus (HPV) assay and the DNA-based hybrid capture 2 HPV test in a routine screening population of women aged 30 to 60 years in Germany. J Clin Microbiol. (2015) 53: 2509–2516.
18. Nandakumar A, Ramnath T, Chaturvedi M. The magnitude of cancer cervix in India. Indian J Med Res. 2009 Sep; 130:219-21.
19. Dalstein V, Riethmuller D, Prétet JL, Le Bail Carval K, Sautière JL, Carbillet JP, Kantelip B, Schaal JP, Mougin C. Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French cohort study. International journal of cancer. 2003 Sep 1;106(3):396-403.
20. Wang S, Wei H, Wang N, Zhang S, Zhang Y, Ruan Q, Jiang W, Xiao Q, Luan X, Qian X, Zhang L. The prevalence and role of human papillomavirus genotypes in primary cervical screening in the northeast of China. BMC cancer. 2012 May 1;12(1):1.
21. Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S, Tang GW, Ferris DG, Steben M, Bryan J, Taddeo FJ. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. New England Journal of Medicine. 2007 May 10;356(19):1928-43.
22. Stanley MA, Winder DM, Sterling JC, Goon PK. HPV infection, anal intra-epithelial neoplasia (AIN) and anal cancer: current issues. BMC cancer. 2012 Sep 8; 12(1):1.
23. De Stefani A, Boffano P, Averono G, Ramella A, Pia F, Bongioannini G. Prevalence and characteristics of HPV infection in oropharyngeal cancer. Journal of Craniofacial Surgery. 2013 Jan 1;24(1): e40-3.
24. Hong AM, Dobbins TA, Lee CS, Jones D, Harnett GB, Armstrong BK, Clark JR, Milross CG, Kim J, O’Brien CJ, Rose BR. Human papillomavirus predicts outcome in oropharyngeal cancer in patients treated primarily with surgery or radiation therapy. British journal of cancer. 2010 Nov 9;103(10):1510-7.
25. Sathish N, Wang X, Yuan Y. Human Papillomavirus (HPV)-associated Oral Cancers and Treatment Strategies. Journal of Dental Research. 2014 Jul;93 (7 Suppl):29S.
26. Bezerra AL, Lopes A, Santiago GH, Ribeiro KC, Latorre MR, Villa LL. Human papillomavirus as a prognostic factor in carcinoma of the penis. Cancer. 2001 Jun 15;91(12):2315-21.
