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Association between tonsillectomy and risk of oropharyngeal cancer: a systematic review
Abstract
Objective. Studies have demonstrated that tonsillectomy may alter the risk of oropharyngeal cancer (OPC). We systematically reviewed the evidence and pooled data to examine such an association.
Methods. PubMed, Embase, and Scopus were searched up to 25th April 2023. Studies reporting an association between tonsillectomy and oropharyngeal cancer risk at any site were included.
Results. Five studies were eligible. All examined the risk of tonsillar and base of the tongue (BOT) cancer with prior history of tonsillectomy. On meta-analysis of the data, prior history of tonsillectomy was associated with a significantly decreased risk of tonsillar cancer. The second meta-analysis showed that history of tonsillectomy did not significantly alter the risk of BOT cancer. However, after exclusion of one study, the results showed an increased risk of BOT cancer with a history of tonsillectomy.
Conclusions. The scarce data available in the literature suggests that tonsillectomy may reduce the risk of tonsillar cancer but does not alter the risk of BOT cancer. Further studies are needed to explore the association between tonsillectomy and the risk of OPC.
Introduction
Oropharyngeal cancer (OPC) is a common malignancy affecting the upper aerodigestive tract and consists of tumours of the tonsils, soft palate, pharyngeal walls, and base of the tongue (BOT). The GLOBOCAN database has shown that, in 2020, 98,400 new cases of OPC were diagnosed causing 48,100 deaths 1. OPC is significantly more common in men and its incidence varies in different geographical regions 2. Indeed, an association between tobacco and alcohol consumption and the risk of OPC is well known. However, the worldwide rise in human papillomavirus (HPV) infections due to changing sexual behaviors has led to an HPV epidemic and significantly increased the incidence of OPC 3. HPV-related OPC is seen in younger individuals who frequently have no history of smoking or alcohol 4,5. Compared to non-HPV cases, the number of HPV-related OPC is rising significantly and is expected to be the most common HPV-associated malignancy in the future by overtaking cervical cancer 2.
Tonsillectomy is a common surgery frequently carried out in children to treat hypertrophic tissue, obstructive sleep disorders, or chronic infections 6. In the past few years, there has been research linking tonsillectomy with the risk of cancer. Sun et al. in a population-based study from Taiwan suggested that tonsillectomy could marginally increase the risk of cancer 7. A recent meta-analysis of eight studies found that prior history of tonsillectomy is associated with an increased risk of breast cancer 8. Similarly, there has been research linking tonsillectomy with OPC. In one of the first studies, Fakhry et al. 9 analysed the Danish cancer registry and found that prior history of tonsillectomy decreased the risk of tonsillar cancer, but had no impact on other OPC sites. However, other authors report different results 10. Given the inconsistencies among studies, this systematic review was designed to analyse if tonsillectomy alters the risk of OPC.
Materials and methods
Literature source and search strategy
The systematic review protocol was uploaded on PROSPERO before the commencement of the literature search (CRD42023415250). PRIMA guidelines were followed 11. Peer-reviewed published articles were searched on the electronic databases of PubMed, Embase, and Scopus. Two reviewers performed the search separately which was completed on 25th April 2023. The databases were examined with keywords consisting of “tonsillectomy”, “tonsils”, “cancer”, “oropharyngeal cancer”, and “oropharyngeal carcinoma” in different combinations. Details of the search are listed in Supplementary Table 1. All search results were congregated and deduplicated electronically. The titles and abstracts of all articles were screened to identify relevant studies. Non-relevant articles were excluded, and the remaining underwent full-text analysis. The reviewers carefully screened these studies based on the following criteria for further inclusion. Any disagreements were resolved by consensus. We also examined the reference lists of the included studies for additional articles.
Inclusion criteria
The criteria for inclusion were as follows:
- All types of studies (cohort, cross-sectional, or case-control) examining the association between prior tonsillectomy and risk of any OPC.
- Studies reporting adjusted effect size with 95% confidence intervals (CI) of the association.
The exclusion criteria were:
- Studies including patients undergoing tonsillectomy for prior malignancies.
- Studies not reporting adjusted outcomes.
- Review articles, editorials, and non-English language studies.
Extracted data and outcomes
The studies underwent data extraction using a preformatted Table. Two reviewers independently retrieved data on the author’s name, year of publication, database for the study, location, study type, sample size, type and proportion of cancer evaluated, gender details, record of tonsillectomy, effect size, and adjusted factors. Study details were then cross-matched, and any discrepancies were resolved in discussion with the third author.
The outcomes of the review were the risk of any OPC based on the history of tonsillectomy. Finally, based on the availability of data, we examined the association between tonsillectomy and the risk of tonsillar cancer and BOT cancer.
Risk of bias analysis
Two reviewers judged the study’s quality based on Newcastle-Ottawa Scale (NOS) 12. The NOS has three domains: representativeness of the study cohort, comparability, and measurement of outcomes. Points are given based on the preformatted questions. The final score of a study can range from 0-9.
Statistical analysis
We used “Review Manager” (RevMan, version 5.3; Nordic Cochrane Centre [Cochrane Collaboration], Copenhagen, Denmark; 2014) for combining data from included studies. Data were combined to generate pooled outcomes as odds ratio (OR) with 95% CI in a random-effects model. Due to limited data, funnel plots were not generated. The I2 statistic was the tool to determine inter-study heterogeneity. I2 < 50% meant low and > 50% meant substantial heterogeneity. A leave-one-out analysis was performed to check for any change in the results on the exclusion of any study.
A p value < 0.05 was considered statistically significant.
Results
Figure 1 shows the results obtained at each step of the literature search. Of the 9162 articles searched, 6248 were duplicates. The remaining studies underwent screening and 16 were selected for full-text review. Of these, five 9,10,13-15 were included in the systematic review and meta-analysis.
Table I represents the details extracted from included studies. Two were cohort studies, two were case-control and one was a cross-sectional study. The studies were from Italy, Denmark, Sweden, France, and USA. The two cohort studies were large sample size studies including 227,996 and 3,859,867 individuals, while the other studies included < 4000 individuals. The history of tonsillectomy was assessed by either patient records or was self-reported. Tonsillar and BOT cancer were examined in all studies, while two studies also examined the risk of other OPC. Age and gender were common variables adjusted in the studies. The NOS score of the studies was between 6 to 7.
On meta-analysis of the data, prior history of tonsillectomy was associated with a significantly decreased risk of tonsillar cancer (OR: 0.24, 95% CI: 0.11, 0.51 I2 = 88%) (Fig. 2). The results did not change during sensitivity analysis indicating that no study was an outlier.
The second meta-analysis showed that the history of tonsillectomy did not significantly alter the risk of BOT cancer (OR: 0.89, 95% CI: 0.24, 3.24 I2 = 97%) (Fig. 3). However, on the exclusion of the study of Alharbi et al. 10, the results showed an increased risk of BOT cancer with a history of tonsillectomy (OR: 1.64, 95% CI: 1.24, 2.17 I2 = 0%).
The two studies which examined tonsillectomy and the risk of other OPC demonstrated non-significant results.
Discussion
This is the first meta-analysis using pooled data from five studies to demonstrate that prior history of tonsillectomy is associated with a significantly reduced risk of tonsillar cancer. The results were consistent across all included studies with the pooled analysis showing a 76% reduction of tonsillar cancer among those who had undergone tonsillectomy. This was expected as a large amount of tonsillar tissue is removed during the procedure, thereby reducing the overall risk of carcinoma. Chaturvedi et al. 15 have shown that tonsillectomy reduces the risk of tonsillar cancer in both HPV-associated and tobacco/alcohol-associated cancer. However, Zevallos et al. 13 in a sub-group analysis of their cohort observed different results. In their study, the authors showed that tonsillectomy was associated with a significant reduction in the risk of only HPV-related tonsillar cancer, while the risk of non-HPV-associated tonsillar cancer remained unchanged. Such a non-significant association between the two could be because nonlymphoid tissues in the tonsillar region, i.e. the faucial pillars and tonsillar fossa, are still susceptible to non-HPV associated malignancy even with prior tonsillectomy. Indeed, the tonsils constitute a major reservoir of HPV in the oropharyngeal region and their removal leads to a significant reduction in the risk of oral HPV infections 16. The lining of the tonsillar tissue and the tonsillar crypts permit direct inoculation of HPV into the lymphatic system. In case of failure of the immune system to clear the viral infection, the pathogen causes a monoclonal response leading to invasive cancer. The virus can also migrate to the entire Waldeyer’s ring from a single inoculation site causing cancer in other regions as well 17,18. Hence, their removal could justify the major reduction in the risk of HPV-related malignancy which, however, still needs to be examined by further analyses.
In the second part of the analysis, we noted that prior history of tonsillectomy did not alter the risk of BOT. However, there were variations in the results of individual studies. The study by Zevallos et al. 13 found a significantly higher risk of BOT cancer with tonsillectomy. In contrast, Alharbi et al. 10 found a significantly reduced risk of BOT cancer among patients who had undergone tonsillectomy. The remaining three studies noted no significant association between the two. In sensitivity analysis, after exclusion of the study of Alharbi et al. 10, the pooled results found an increased risk of BOT cancer with tonsillectomy. Indeed, these results have created a conundrum that is difficult to decipher. The differences in study designs, sample size, and importantly the factors adjusted while determining the association could be major reasons for the variations. Zevallos et al. 13 interpreted the high risk of BOT cancer with the increased incidence of lingual tonsillar hypertrophy noted in tonsillectomy patients. About one-third of children undergoing tonsillectomy demonstrate enlargement of the lingual tonsil resulting in increased lymphoid tissue in the BOT 19. This could increase the risk of BOT cancer. On the other hand, the reduced risk of BOT cancer could not be explained by Alharbi et al. 10 and their contrasting results could be a statistical artifact due to the small number of BOT cancer patients in their study. Nevertheless, given the scarce and contrasting data, further large-scale cohort studies need to be conducted to further explain a potential association between tonsillectomy and BOT cancer.
Given that all studies noted a significant reduction in the risk of tonsillar cancer with tonsillectomy, the latter could be potentially a secondary preventive strategy to reduce the risk of OPC. Nevertheless, tonsillectomy is not a minor surgery and is associated with several adverse complications. Subramanyam et al. in a review of major complications reported that bleeding is among the most common post-tonsillectomy complications along with other adverse events such as anoxia events, opioid toxicity, and even death 20. Also, the low prevalence of OPC is another major reason that precludes routine use of tonsillectomy as a prophylactic measure. Secondly, the upcoming HPV vaccine could provide a safer and more effective way for the prevention of OPC 21,22.
There are several limitations to this meta-analysis. The small number of studies should not be discounted while interpreting the results. The current scarce evidence was limited to a few regions around the world and needs to be supplemented by further data for conclusive evidence. Secondly, there were only two large cohort studies, while the others were cross-sectional and case-control in design which further downgrades the credibility of the evidence. In a few studies, tonsillectomy was self-reported while in others it was verified by medical records. Recall bias and errors in data entry could be a possible source of bias in such scenarios. Thirdly, the factors adjusted by the studies to derive the effect size were not comprehensive. Key factors like tobacco use, alcohol use, HPV status, sexual history, tumour stage, treatment status, etc. were unavailable in most studies. Hence, the possibility of residual confounding cannot be negated. Lastly, data could be quantitatively assessed only for tonsillar and BOT cancer. It is still unclear if tonsillectomy alters the risk of OPC at other sites.
Conclusions
The scarce data from the available literature suggests that tonsillectomy may reduce the risk of tonsillar cancer, but does not alter the risk of BOT cancer. Limitations in study design and residual confounding hamper the credibility of current evidence. Further studies are needed to explore the association between tonsillectomy and risk of OPC.
Conflict of interest statement
The authors declare no conflict of interest.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author contributions
CB, MH, SL, JL, LZ: developed the concept for this review; CB, MH, LZ, YZ: designed the study; SL, JL, FC, LZ: data collection and analysis; YZ: interpreted the results; CB, YZ: creation of figures; LZ, MH, YZ: wrote the article; CB, YZ: edited final draft. All authors approved the final manuscript.
Ethical consideration
Not applicable.
Figures and tables
Figure 1.Study flow-chart.
Figure 2.Meta-analysis of the risk of tonsillar cancer based on history of tonsillectomy.
Figure 3.Meta-analysis of BOT cancer based on history of tonsillectomy.
| Study | Database | Location | Type | Sample size | Record of tonsillectomy | Types of cancer studied | Male gender (%) | Proportion of cancer | Effect size (95% CI) | Adjusted factors | NOS score |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Alharbi, 2023 10 | University of Florida patient registry | USA | CS | 3620 | Medical records | Tonsillar | 81 | 27.5 | 0.086 (0.066, 0.113) | Age, sex, race | 6 |
| BOT | 79 | 26.6 | 0.117 (0.079, 0.174) | ||||||||
| Other OP | 24 | 45.9 | 1.031 (0.921, 1.154) | ||||||||
| Combes, 2021 14 | 11 university hospitals | Italy | CC | 1145 | Patient-reported or surgeon evaluated | Tonsillar | 71.8 | 7.4 | 0.4 (0.2, 0.8) | Age, gender, region, and education | 7 |
| BOT | 84.2 | 6.6 | 1.8 (1.1, 3.1) | ||||||||
| Other OP | 75.3 | 17.6 | 1.2 (0.9, 1.7) | ||||||||
| Zevallos, 2016 13 | North Carolina Central Cancer Registry | France | CC | 1739 | Patient-reported | Tonsillar | 83.3 | 11.4 | 0.22 (0.13, 0.36) | Age, race, sex, smoking, insurance status, education, alcohol, and number of sexual partners | 7 |
| BOT | 88 | 6.2 | 1.95 (1.25, 3.06) | ||||||||
| Chaturvedi, 2016 2 | National registry | Sweden | Cohort | 227,996 | Medical records | Tonsillar | NR | NR | 0.31 (0.08, 0.79) | Age, gender, calendar year, and county | 7 |
| BOT | 1.31 (0.42, 3.05) | ||||||||||
| Fakhry, 2015 9 | Danish cancer registry | Denmark | Cohort | 3,859,867 | Medical records | Tonsillar | NR NR | 54.5* 14.8 | 0.4 (0.2, 0.7) | Age, calendar period, education, and gender | 7 |
| BOT | 1.1 (0.6, 2.1) | ||||||||||
| NOS: Newcastle-Ottawa Scale; BOT: base of tongue; OP: oropharyngeal; CC: case control; CS: cross-sectional; CI: confidence intervals; NR: not reported. * of total oropharyngeal cancers. | |||||||||||
| Query | Search details |
|---|---|
| (tonsillectomy) AND (cancer) | (“tonsillectomy”[MeSH Terms] OR “tonsillectomy”[All Fields] OR “tonsillectomies”[All Fields]) AND (“cancer s”[All Fields] OR “cancerated”[All Fields] OR “canceration”[All Fields] OR “cancerization”[All Fields] OR “cancerized”[All Fields] OR “cancerous”[All Fields] OR “neoplasms”[MeSH Terms] OR “neoplasms”[All Fields] OR “cancer”[All Fields] OR “cancers”[All Fields]) |
| (tonsillectomy) AND (oropharyngeal carcinoma) | (“tonsillectomy”[MeSH Terms] OR “tonsillectomy”[All Fields] OR “tonsillectomies”[All Fields]) AND (“oropharyngeal neoplasms”[MeSH Terms] OR (“oropharyngeal”[All Fields] AND “neoplasms”[All Fields]) OR “oropharyngeal neoplasms”[All Fields] OR (“oropharyngeal”[All Fields] AND “carcinoma”[All Fields]) OR “oropharyngeal carcinoma”[All Fields]) |
| ((tonsils) AND (surgery)) AND (oropharyngeal cancer) | (“palatine tonsil”[MeSH Terms] OR (“palatine”[All Fields] AND “tonsil”[All Fields]) OR “palatine tonsil”[All Fields] OR “tonsil”[All Fields] OR “tonsils”[All Fields] OR “tonsilitis”[All Fields] OR “tonsillitis”[MeSH Terms] OR “tonsillitis”[All Fields] OR “tonsillitides”[All Fields] OR “tonsills”[All Fields]) AND (“surgery”[MeSH Subheading] OR “surgery”[All Fields] OR “surgical procedures, operative”[MeSH Terms] OR (“surgical”[All Fields] AND “procedures”[All Fields] AND “operative”[All Fields]) OR “operative surgical procedures”[All Fields] OR “general surgery”[MeSH Terms] OR (“general”[All Fields] AND “surgery”[All Fields]) OR “general surgery”[All Fields] OR “surgery s”[All Fields] OR “surgerys”[All Fields] OR “surgeries”[All Fields]) AND (“oropharyngeal neoplasms”[MeSH Terms] OR (“oropharyngeal”[All Fields] AND “neoplasms”[All Fields]) OR “oropharyngeal neoplasms”[All Fields] OR (“oropharyngeal”[All Fields] AND “cancer”[All Fields]) OR “oropharyngeal cancer”[All Fields]) |
| ((tonsils) AND (surgery)) AND (oropharyngeal carcinoma) | (“palatine tonsil”[MeSH Terms] OR (“palatine”[All Fields] AND “tonsil”[All Fields]) OR “palatine tonsil”[All Fields] OR “tonsil”[All Fields] OR “tonsils”[All Fields] OR “tonsilitis”[All Fields] OR “tonsillitis”[MeSH Terms] OR “tonsillitis”[All Fields] OR “tonsillitides”[All Fields] OR “tonsills”[All Fields]) AND (“surgery”[MeSH Subheading] OR “surgery”[All Fields] OR “surgical procedures, operative”[MeSH Terms] OR (“surgical”[All Fields] AND “procedures”[All Fields] AND “operative”[All Fields]) OR “operative surgical procedures”[All Fields] OR “general surgery”[MeSH Terms] OR (“general”[All Fields] AND “surgery”[All Fields]) OR “general surgery”[All Fields] OR “surgery s”[All Fields] OR “surgerys”[All Fields] OR “surgeries”[All Fields]) AND (“oropharyngeal neoplasms”[MeSH Terms] OR (“oropharyngeal”[All Fields] AND “neoplasms”[All Fields]) OR “oropharyngeal neoplasms”[All Fields] OR (“oropharyngeal”[All Fields] AND “carcinoma”[All Fields]) OR “oropharyngeal carcinoma”[All Fields]) |
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© Società Italiana di Otorinolaringoiatria e chirurgia cervico facciale , 2024
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