Abstract
Background
Human Papillomavirus has been associated with oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC), involving several risk factors in different parts of the world. This study aimed to determine the prevalence of high-risk HPV 16 and HPV 18, and factors associated with this prevalence, among patients with oral and oropharyngeal squamous cell carcinoma who attended Mulago Hospital, Uganda, from 2010 to 2015.
Methods
This was a retrospective study in which 174 tissue blocks from individual patients, with confirmed oral and oropharyngeal squamous cell carcinoma, were retrieved from the archives. The corresponding medical charts of the patients were reviewed for demographic and clinical data. HE stained sections of the tissue blocks were reviewed for reconfirmation of OSCC& OPSCC. The samples were genotyped for HPV 16, 18 using Multiplex PCR techniques. The data was analysed using R.
Results
All 174 samples were confirmed positive for OSCC & OPSCC. HPV DNA was positive in 128 individuals (74%), 46 tested negative. HPV 16 alone occurred in 55 (32%) subjects and HPV 18 alone occurred in 37 (21%). Double infection was present in 36 individuals (21%). HIV was the only risk factor significantly associated with HPV 16 on OSCC& OPSCC (p = 0.018).
Conclusions
Overall, HPV 16 and 18 are key etiological factors in oral and oropharyngeal squamous cell carcinoma pathogenesis in the Ugandan population, with a high prevalence. The results suggest that HIV positive individuals are at a higher risk of acquiring HPV 16 associated OPSCC. Alcohol consumption and cigarette smoking are not factors associated with HPV associated OPSCC in this study population.
Keywords: Human papilloma virus (HPV), Oral and oropharyngeal squamous cell carcinoma (OSCC&OPSCC), HIV (Human immunodeficiency virus)
Background
Human papilloma viruses (HPVs) are a heterogeneous group of small non-enveloped DNA viruses that cause an epidemiologically and clinically distinct form of oropharyngeal squamous cell carcinoma (OSCC&OPSCC) [1–3]. More than 100 HPV genotypes have been fully sequenced [4]. Of the many types, HPV 16 and HPV 18 have consistently been most important epidemiologically and have been associated with squamous cell carcinoma [5, 6].
The reports about the factors associated with HPV related OSCC & OPSCC have been conflicting. Some studies report that HPV associated oral and oropharyngeal carcinoma patients show no history of tobacco use and alcohol consumption, and thus their disease is routinely attributed to HPV infection [5, 7, 8]. Therefore, the importance of HPV in oral squamous cell carcinoma causation is increasing exponentially, as reported by some authors [9]. Fortunately, reports show that HPV associated oral pharyngeal cancers have better prognostic outcomes compared to the cancers from the classical causes [9, 10].
The rising trend in HPV prevalence among individuals with OSCC and OPSCC has been attributed to sexual behaviour that exposes the oral cavity and pharynx to HPV, hence the oral HPV-16-positive tumors [11]. Oral sex, lifetime number of sexual partners, and open-mouth kissing are associated with the development of oral HPV infection and tumors [12, 13]. On the other hand, tobacco, alcohol use, and poor oral hygiene are associated with HPV-16-negative tumors [14]. As aforementioned, there are several reports on factors associated with HPV-related oral and oropharyngeal squamous cell carcinoma in different parts of the world [15].
However, studies to identify such associations are still limited in Uganda. A study reported high tobacco use and alcohol consumption in Uganda [16], but the association of these and other factors to HPV related OSCC and OPSCC has not yet been determined. We therefore set out to conduct a study with the aim of genotyping HPV 16 & 18 on archival specimens from oral and oropharyngeal squamous cell carcinoma cases in a Ugandan population.
Methods
Sample retrieval
We retrieved 174 Formalin Fixed Paraffin Embedded (FFPE) tissue blocks with corresponding medical history from the pathology department, Makerere University, in Kampala. Only those tissue blocks that had a histological diagnosis of oral and oropharyngeal squamous cell carcinoma with corresponding medical charts, containing sociodemographic information (2010–2015), were included in the analysis.
During retrieval and processing, 20 tissue blocks were disqualified because of inadequacy, an alternative diagnosis, and one tissue block was from the uterus. Other blocks were consecutively retrieved to replace these. Information from the medical charts was retrieved using a data collection form. Each form was assigned a unique identification number representing a FFPE tissue block of a particular case. The information from the medical charts included patient age, sex, alcohol consumption, cigarette smoking, tumor site, and HIV status.
The retrieved paraffin-embedded tissue blocks were re-embedded in fresh paraffin wax, and four sections (sandwich method) were cut for testing under strict conditions to avoid potential contamination at the Pathology laboratory. Two sections (the first and the last sections) were stained with Haematoxylin and Eosin (H&E) to confirm diagnosis and to ascertain the suitability of the tissue to continue for HPV genotyping. The sections in between were collected in a screw-top Eppendorf tube for HPV genotyping. A tissue-free paraffin block was cut after each study block to avoid any HPV carry-over from block to block. A new blade was used for each block, and the microtome was cleaned with a vacuum cleaner, Histoclear II, and 70% alcohol. To further control for contamination, blank paraffin blocks were simultaneously tested.
HPV DNA extraction
After confirmation of the blocks on H&E, they were prepared for transportation to the molecular biology lab of Makerere University for DNA extraction and genotyping by PCR. DNA extraction was performed according to the manufacturer’s instructions as described elsewhere [17]. Briefly, the residual cells in the preservative medium were centrifuged at 13,000 g for 15 min, and the cell pellets were resuspended in 50 ml of phosphate-buffered saline and centrifuged again at 13,000 g for 15 min. The washed cell pellets were added to a DNA purification column (Generation capture column kit; Gentra Systems, Inc., Minneapolis, MN). The concentration and the quality of the extracted DNA were determined by spectrophotometry. 5 µl of DNA solution was used as a template for PCR amplification.
HPV genotyping
HPV 16 and HPV 18 genotypes were determined as described elsewhere [17]. Briefly, HPV in positive samples was genotyped using a multiplex PCR assay targeting the 2 genotypes of high-risk HPV. We used 2 sets of genotype-specific primers that could amplify specific regions of both types of high-risk- HPV DNA (16 and 18). PCR was performed with a multiplex PCR kit (Qiagen) according to manufacturer’s instructions. Due to possible false negatives that could arise from DNA degradation due to over-fixing, we amplified a fragment of the human β-globin gene using a method and primers described elsewhere [18]. All β-globin-negative samples were excluded from further analysis.
Ethical approval for the reported study was obtained from the Higher Degrees Research and Ethics Committee (HDREC) of Makerere University School of Health Sciences, Kampala, Uganda.
Results
The socio-demographic characteristics of the study participants are shown in Table 1. A total of 174 archived samples were retrieved: of these, 117 (67%) were from males, and 57 (33%) were from females. The age of the patients ranged from 11 to 84 years mean ± SD, 53.98 ± 15.73 years. The Majority (80%) of the subjects were in the age group 31–70 years. About 52% of patients were cigarette smokers, and 49% were alcohol consumers. According to medical records, 144 subjects were HIV negative, while 30 (17.2%) were HIV seropositive.
Table 1.
Socio-demographic characteristics of the study subjects
| Characteristic | Category | n | (%) |
|---|---|---|---|
| Gender | Male | 117 | (67) |
| Female | 57 | (33) | |
| Total | 174 | (100) | |
| Age group | 11–20 years | 4 | (2) |
| 21–30 years | 9 | (5) | |
| 31–40 years | 23 | (13) | |
| 41–50 years | 34 | (19) | |
| 51–60 years | 41 | (24) | |
| 61–70 years | 41 | (24) | |
| 71–80 years | 17 | (10) | |
| 81–90 | 5 | (3) | |
| Total | 174 | (100) | |
| Cigarette Smoking | Smokers | 91 | (52) |
| Non-smokers | 83 | (48) | |
| Total | 174 | (100) | |
| Alcohol consumption | Consumers | 86 | (49) |
| Non-consumers | 88 | (51) | |
| Total | 174 | (100) | |
| HIV status | Positive | 30 (17) | (17) |
| Negative | 144 (83) | (83) | |
| Total | 174 (100) | (100) |
Socio-demographic characteristics of study participants. Values are presented as number (percentage) within each category
The tumors were described based on Histological differentiation, Site, and HPV genotype as shown in Table 2. Well-differentiated tumors were observed in 133 (76%) of the subjects, 15 (9%) of the tumors had moderate differentiation, and 26 (15%) of the tumors were poorly differentiated. The tongue and mandible were the commonest sites for OPSCC, contributing 78 (45%) and 50 (29%) of all the tumor sites, respectively. Each accounted for 3% of the tumor sites. HPV 16 was detected in 55 (32%) individuals, HPV 18 and double infections (HPV16 + HPV18) were each detected in 21% of individuals.
Table 2.
HPV type distribution by site and histological differentiation
| Characteristic | Category | n (%) | |
|---|---|---|---|
| Histological Differentiation | Poor | 26 (15) | |
| Moderate | 15 (9) | ||
| Well | 133 (76) | ||
| Total | 174 (100) | ||
| Site | Buccal | 11 (6) | |
| Mandible | 50 (29) | ||
| Maxilla | 24 (14) | ||
| Oral pharynx | 5 (3) | ||
| Palate | 6 (3) | ||
| Tongue | 78 (45) | ||
| Total | 174 (100) | ||
| Type of HPV | HPV 16 | 55 (32) | |
| HPV 18 | 37 (21) | ||
| HPV 16 AND HPV 18 | 36 (21) | ||
| NONE | 46 (26) | ||
| Total | 174 (100) |
HPV type distribution by histological differentiation and anatomical site of the tumour. Values are presented as number (percentage) within each category. HPV = human papillomavirus
We found a significant association between HIV sero-positivity and the occurrence of HPV 16-associated OPSCC (Table 3). However, no association was found between HIV positivity and HPV 18 only among subjects confirmed with OPSCC. Likewise, there was no significant association between HIV and having types HPV (16 &18); 16 &18 among those confirmed with OPSCC. Similarly, we found no association between the occurrence of HPV and the Histological differentiation of the tumor. There was insufficient evidence to suggest a significant relationship between alcohol consumption and HPV occurrence. Surprisingly, HPV genotypes had a higher frequency in non-alcohol consumers, as shown in Table 3. However, HPV 16 was the most frequent genotype among both alcohol consumers and non-consumers, detected in 26 and 29 individuals, respectively. In contrast, smoking was not associated with the presence of any HPV genotype.
Table 3.
Association between HPV and HIV
| HPV | P value | ||||
|---|---|---|---|---|---|
| 16 | 18 | 16 & 18 | |||
| HIV status | |||||
| Positive | 6 | 7 | 4 | 0.018 | |
| Negative | 49 | 30 | 32 | ||
| Alcohol consumption | |||||
| Yes | 26 | 19 | 18 | 0.583 | |
| No | 29 | 18 | 21 | ||
| Cigarette smoking | |||||
| Yes | 26 | 18 | 22 | 0.582 | |
| No | 29 | 19 | 14 | ||
| Age group | |||||
| 11–20 years | 2 | 0 | 0 | ||
| 21–30 years | 2 | 2 | 3 | ||
| 31–40 years | 7 | 9 | 5 | 0.271 | |
| 41–50 years | 13 | 2 | 8 | ||
| 51–60 years | 13 | 7 | 9 | ||
| 61–70 years | 14 | 8 | 9 | ||
| 71–80 years | 3 | 7 | 2 | ||
| 81–90 years | 1 | 1 | 1 | ||
| Site | |||||
| Buccal | 3 | 3 | 1 | ||
| Mandible | 15 | 12 | 13 | ||
| Maxilla | 5 | 5 | 6 | 0.781 | |
| Oral pharynx | 1 | 0 | 2 | ||
| Palate | 1 | 3 | 0 | ||
| Tongue | 25 | 13 | 15 | ||
Association between HPV subtypes (16, 18, and 16 & 18 co-infection) and selected demographic and behavioral factors, stratified by HIV status
Discussion
In this study, we determined the occurrence and established the factors associated with the presence of HPV genotypes 16 and 18, among patients diagnosed with oral and/or oropharyngeal squamous cell carcinoma. The overall prevalence of HPV 16 and 18 in oral and oropharyngeal squamous cell carcinoma was 74%.
This high prevalence tallies with a previous study from Uganda by Banura et al. who reviewed literature from Uganda and reported HPV in Uganda among different subgroups to range from 10 to 75% [19]. These studies, however, did not solely focus on OPSCC. Other studies from the continent, Senegal and Nigeria, for example, reported a low prevalence of HPV associated OPSCC of 3.4% 1.2% respectively [20]. Other East African countries like Kenya had either insufficient data on HPV associated prevalence in oral cancer or no data at all, making it hard to make a more geographically associated comparison [21].
This study didn’t find an association between gender and HPV occurrence in OPSCC confirmed subjects. This was true for both single and multiple infections of HPV 16 and 18. This finding is in agreement with most studies about risk factors associated with oral and oropharyngeal Squamous cell carcinomas [22, 23]. However, Combes et al. and Gillison et al., reported that HPV associated OPSCC is more common in men than women [24, 25]. The age group above 60 had the highest number of cases (40.8%), although it was not statistically significant in comparison to other age groups (P = 0.512). Studies from other continents have reported that HPV-positive patients were significantly younger, more likely to be male, and more likely to be white or of other races [26]. Our findings are in agreement with D’Souza et al., who found that age does not at all influence the risk of acquiring HPV associated oral and oropharyngeal squamous cell carcinomas [27].
Whereas the majority of head and neck cancers have been associated with high tobacco and alcohol consumption, patients with OPSCC have been reported by several groups not to have a history of tobacco or alcohol use [8]. Instead, their tumors are positive for oncogenic HPV types, particularly HPV 16, and their risks are mainly related to sexual history. Our findings are in agreement with these reports, as we didn’t find any association between HPV associated OPSCC with alcohol consumption or smoking.
HIV was the only risk factor that showed a significant association with HPV-associated OPSCC. Oral HPV prevalence has been associated with HIV infection and current CD4 cell count in several studies [28].
To the best of our knowledge, this is the first study in Uganda to report an association between any type of HPV associated OPSCC and HIV-1 infection. It has already been established that HIV-infected individuals are at a higher risk of developing oropharyngeal cancers [29, 30]. This is in agreement with our findings in this study. One explanation for this is the immunocompromised state of HIV-1-infected individuals, making them prone to several co-infections. However, with the current roll-out of ART (test and treat policy by WHO), most HIV infected individuals in the country are living healthy lives, and for longer. It would be crucial, therefore, to conduct a more in-depth investigation about this association. The medical charts had missing information about different HIV clinical parameters; for example, we couldn’t identify the CD4 count at the time of diagnosis, nor could we establish ART history of those who were HIV positive. Beachler et al. [31] already reported that HIV-infected individuals are living longer due to ART but have a high prevalence of oral HPV infection and have many of the currently determined risk factors for HPV-associated Head and Neck cancers. Also, it will be important for future studies to establish whether the distribution of HPV types in oropharyngeal cancers in HIV-infected individuals differs from that of the general population.
Our study was limited in certain aspects; a relatively small number of HIV positive cases warranted bigger studies to affirm the association reported here. The duration of fixation was not uniform and could have contributed to a misdiagnosis. Another limitation was inconsistency and gaps in records needed for sociodemographic data collection. We were also not able to genotype other HPV types as part of this study.
Further studies are necessary to genotype for all other HPV types to determine their respective contributions to oropharyngeal carcinomas. Sexual history couldn’t be established either from the charts, and we therefore couldn’t affirm the role of sexual behaviour and number of lifetime sex partners in HPV associated OPSCC in the study population. A higher statistically powered study will more clearly establish such associations in the future.
Conclusion
This study found a higher prevalence of HPV-associated OPSCC in a Ugandan population compared to reports from other regions, including Japan, Sweden, and Finland. The results support the role of HPV, particularly HPV 16, in the etiology of oral and oropharyngeal squamous cell carcinoma in this setting. HIV-positive individuals were found to be at a higher risk of HPV 16 16-associated disease, though no significant association was observed with HPV 18. No strong gender differences were detected in HPV-associated OSCC and OPSCC prevalence. These findings suggest that both males and females could be considered in future HPV vaccination strategies, but further research is needed to confirm these observations and to investigate factors contributing to the high prevalence observed.
Acknowledgements
We are grateful to Dr. Samuel Kyobe, Mr. Edgar Kigozi, and Mr. Fred Ashaba from the entire Molecular Biology department of Makerere University for their contribution to HPV genotyping and data collection. We thank Dr. Kyityamuwesi Richard for guidance during data collection and interpretation of results.
Abbreviations
- DNA
Deoxyribonucleic acid
- H&E
Haematoxilin and Eosin
- HIV
Human Immunodeficiency Virus
- HPV
Human papillomavirus
- PCR
Polymerase Chain Reaction
- OPSCC
Oropharyngeal squamous cell carcinoma
Author contributions
AMB was responsible for the concept drafting, full proposal development and getting approval from the ethics committees. CK was responsible for the specimen selection and data file cleaning. CK and AMB were responsible for the HPV DNA detection and quality control analysis. AMB and CK wrote the manuscript, and were responsible for the preparation of the manuscript for submission. CK generated the figures. AMB, MO, CK, EN, and AK Guided data analysis, interpreted data, and edited the paper. MO performed the histopathological evaluation. All authors reviewed the manuscript.
Funding
The study was partially supported by funds from the Ministry of Health, Uganda. The funder had no role in data collection, analysis or interpretation of results.
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This study was approved by the Institutional review board for the School of Health Sciences of Makerere University. The study adhered to the ethical principles outlined in the Declaration of Helsinki, and other relevant regulations.
Consent for publication
All authors have read and agreed to the published version of the manuscript.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.