Is Systemic Immunosuppression a Risk Factor for Oral Cancer? A Systematic Review and Meta-Analysis.

1. Introduction

According to official data from the World Health Organization (WHO, Geneva, Switzerland), 377,713 new cases of oral and lip cancer were diagnosed in 2020, making it the 16th most common cancer in the world. It still has a severe prognosis today, as approximately 50% of oral and lip cancer patients will die in the 5 years following diagnosis, while the remaining 50% have aesthetic and functional relics that make their quality of life rather low. Historically, the main risk factors for this neoplasm are being male, having a diet low in vitamins, having MPDs, past/present viral infections, radiation exposure, having genetic predispositions and immunodeficiencies, and engaging in luxuriant habits such as smoking and alcohol and betel consumption [ 1 ].

Oral cancer treatment is challenging and requires a multidisciplinary approach with a team of specialists, which includes head and neck surgeons, radiation oncologists, medical oncologists, and oral oncologists [ 2 ].

Although surgery is the most common initial definitive treatment for the majority of oral cancers, adjunctive radiotherapy (RT), with or without chemotherapy (CT) may be performed [ 3 ].

The immune system performs numerous functions, among which its primary functions are defense against infections, self-control and immunosurveillance at the onset and during the proliferation of solid and liquid cancers, identifying and suppressing genetically modified cells that have already passed the normal checkpoints, and the intracellular control of proliferation. The possible role of the immune system in the development of cancers has been defined in the theory of “immune surveillance”, which configures the active role of the immune system in preventing the onset of cancers [ 4 ].

Immune surveillance against cancer is the process in which the immune system identifies cancerous and/or precancerous cells and eliminates them.

According to the most recent findings, the immune system can play a role in preventing tumors, throughout different mechanisms. First, the virus-induced tumors can be prevented when a functioning immune system can eliminate or suppress viral infections. Second, this action against pathogens may cause a prompt resolution of inflammation, preventing the establishment of an inflammatory environment, which is a risk factor for carcinogenesis [ 5 ]. Third, the immune system can identify and eliminate tumor cells on the basis of their expression of tumor-specific antigens. Therefore, the theory of immunosurveillance is essentially based on two generally accepted claims: (I) most cancers are antigenic (an obvious requirement for immunological recognition) and (II) such antigenic differences can, “under appropriate conditions”, elicit an immune response [ 4 ].

Despite immune surveillance, cancers develop even in the presence of a functioning immune system, and therefore, currently, we speak of “cancer immunoediting”, a term which is used to describe the evolution of tumors, wherein tumor cells become less effectively recognized and killed by the immune system [ 6 , 7 ].

A first consideration concerns the definition that is used for patients with disorders of the immune system. The terms immunosuppression and immunodeficiency are often used interchangeably. This confusion is related to the subtle nuance that separates them. It could be specified that immunosuppression identifies a medical condition of a general malfunction of the immune system. Immunodeficiency, on the other hand, classifies the severity of this physical deficit according to two categories: primary and secondary.

Immunosuppression is a pathological condition characterized by the inhibition of one or more components of the immune system, whether natural or acquired, resulting in the impossibility of a person’s immune system to function properly. However, currently, there is no description illustrating the relationship between immunoediting and immunosuppression. The incorrect functioning of the immune system can favor the development of autoimmune and allergic diseases or neoplasms. Immunodeficiencies are divided into primary (if they are derived from congenital defects) and secondary (if they are derived from infections or pharmacological treatments) classifications. This condition involves the onset of infections that develop and recur very often, manifesting themselves in a more serious and longer-lasting form.

Among the many alterations of the immune system, immunodeficiency can be caused by numerous and different causes, and it can involve acquired or innate immunity, both in the humoral and cellular components, as follows: innate pathologies (e.g., agammaglobulinemia linked to the X sex chromosome, one common variable immunodeficiency, severe combined immunodeficiency, DiGeorge syndrome, and congenital hypogammaglobulinemia), systemic diseases (e.g., autoimmune diseases, diabetes, chronic infections, and solid and liquid malignancies, such as leukemia, lymphoma, and multiple myeloma), and pharmacological therapies (e.g., chemotherapy, antirheumatics, immunosuppressants, and glucocorticoids), which are the main causes of immunodeficiency [ 8 , 9 ].

By definition, immunodeficiency is characterized by a functional deficit of the immune system (either congenital or acquired). Immunosuppression is a pathological condition characterized by the inhibition of one or more components of the immune system (natural or acquired), and it occurs following an intercurrent disease or autoimmune pathologies [ 10 ]. Immunosuppression also refers to pharmacological treatment with immunosuppressive drugs capable of inhibiting an immune system response [ 11 ]. Therefore, immunocompromised patients have a reduced ability to fight infections and other diseases.

Numerous studies have shown that in immunosuppressed subjects, there is a higher incidence of cancers than in a population with normal immunity [ 12 ]. The increased susceptibility to infections (i.e., HPV, candida, Helicobacter pylori, etc.) and the reduced immune response to infections in immunosuppressed subjects could represent a further mechanism that favors the onset of neoplasms. Furthermore, immunosuppression is, at the same time, one of the risk factors for the onset of oncological pathologies, but it is also a condition that could favor the loco-regional and distant growth and spread of cancers. In fact, the literature shows that immunosuppression is not only a risk factor for the genesis of a cancer but also a factor for the prognosis of its course [ 13 ].

Although the relationship between immunosuppression and the increased incidence of systemic cancers is now well documented, currently, it is not clear how much the risk of developing oral cancer increases in immunosuppressed subjects and what effect immunosuppression has on prognosis in terms of survival. The purpose of this systematic review was, therefore, to evaluate the association and the possible correlation between the state of depression of the immune system and the development of oral cancer through the evaluation of the incidence of oral cancer in patients with systemic immunosuppression and to compare that to data from official databases (Globocan, WHO), which lacked precise data on non-immunosuppressed subjects.

2. Materials and Methods

In the present systematic review, the adopted protocol followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The review protocol was registered in PROSPERO database (CRD42021243898).

2.1. PICOS Question

The following question was developed according to the population, intervention, comparison, outcome, and study design (PICOS).

Population: immunosuppressed patients who later developed oral cancer were included in this systematic review.

Intervention: patients with systemic immunodepression due to various factors (immunodepression, malnutrition, infections, autoimmune diseases, genetic immunosuppression, immunosuppression as a consequence of immunosuppressive therapy or radiotherapy, and oncologic immunosuppression) who subsequently developed oral cancer were considered.

Comparison: the rates of development of oral cancer in non-immunosuppressed patients and the rates of development of oral cancer in immunosuppressed patients were compared.

Outcome: the primary outcome was to evaluate the incidence of oral carcinoma in immunosuppressed patients.

Study design: cohorts, case controls, cross-sectional studies, and randomized clinical trials (RCTs) with no fewer than 10 patients were included. All case reports, case series with less than 10 patients, in vitro or in vivo studies based on animals, systematic reviews, letters to the editor, cases of oral cancer related to human papilloma virus (HPV), and articles published in languages other than Italian, English, and Spanish were excluded.

2.2. Focused Question

The question on which attention was focused was formulated on the basis of the PICOS criteria: “Do immunosuppressed patients have a higher rate of development of oral cancer than healthy patients?”.

2.3. Research

The research was conducted on three databases (MEDLINE via OVID, Scopus, and Web of Science) from the start of their activity in May 2022, using a combination of key words and MeSH terms as follows: ((immunosuppression OR malnutrition OR infections OR autoimmune disease OR X-linked agammaglobulinemia OR common variable immunodeficiency OR selective immunoglobulin A deficiency OR hyper IgM syndrome OR DiGeorge syndrome OR severe combined immunodeficiency OR Wiskott–Aldrich syndrome OR acquired immunodeficiency syndrome OR AIDS OR immunosuppressive therapy OR radiotherapy OR “other systemic cancers” OR leukaemia OR lymphoma) AND “Oral Cancer”), (“Oral Carcinoma” AND (immunosuppression OR malnutrition OR infections OR autoimmune disease OR X-linked agammaglobulinemia OR common variable immunodeficiency OR selective immunoglobulin A deficiency OR hyper IgM syndrome OR DiGeorge syndrome OR severe combined immunodeficiency OR Wiskott–Aldrich syndrome OR acquired immunodeficiency syndrome OR AIDS OR immunosuppressive therapy OR radiotherapy OR “other systemic cancers” OR leukaemia OR lymphoma)), and (“Oral Neoplasms” AND (immunosuppression OR malnutrition OR infections OR autoimmune disease OR X-linked agammaglobulinemia OR common variable immunodeficiency OR selective immunoglobulin A deficiency OR hyper IgM syndrome OR DiGeorge syndrome OR severe combined immunodeficiency OR Wiskott–Aldrich syndrome OR acquired immunodeficiency syndrome OR AIDS OR immunosuppressive therapy OR radiotherapy OR “other systemic cancers” OR leukaemia OR lymphoma)). The date of the last search was 28 April 2023.

2.4. Manual Search

A manual search of articles published between 2002 and 2022 in the following peer-reviewed journals was performed: Oral Oncology , Oral Diseases , Lancet Oncology, and Journal of Hematology and Oncology .

2.5. Search of Unpublished Articles

Unpublished literature was searched in the U.S. National Institutes of Health clinical trials registry and the European Multidisciplinary Database to identify incumbent studies and grey literature. In addition, bibliographic references of all included articles and reviews were similarly checked to identify additional potentially relevant studies and increase the sensitivity of the search.

2.6. Study Selection

Based on the inclusion criteria, two authors independently and in duplicate (D.M. and F.S.) analyzed the titles and abstracts of the articles found. The authors retrieved the full versions of articles whose titles and abstracts appeared to meet the inclusion criteria or those, which reported insufficient data to make a clear decision. Next, the two authors independently read the full texts to determine whether the articles met these criteria. In cases where the two authors disagreed, agreement was sought through a comparison between the two, and when a solution could not be reached, a third senior author (R.P.) stepped in.

To calculate the agreement between the reviewers, Cohen’s kappa coefficient was used. The level of agreement was considered excellent when k was greater than 0.75, fair to good when it was between 0.40 and 0.74, and poor when it was less than 0.4 [ 14 ].

All articles that met the inclusion criteria were subjected to data extraction and quality assessments. All irrelevant articles were excluded, and the reasons for exclusion were as described.

2.7. Extraction Data

The data were collected using a purpose-built data extraction form. In cases where the publication did not provide all the necessary data, the corresponding author was contacted by e-mail to obtain the missing data. In the event that the two authors disagreed about one of the publications, a discussion was opened, which, in cases of disagreement, required the intervention of the third author.

In cases of redundant publications, the most recent article and the one with the largest follow-up were included.

2.8. Quality Assessment

The risk of bias in the included studies was independently assessed in duplicate by two authors as part of the data extraction process.

An assessment of risk of bias was undertaken using the Newcastle–Ottawa Scale (NOS) [ 15 ]. The presence of each parameter was recorded with a green mark, while absence was recorded with a red mark (0). Papers with 1–3 green marks were classified as high risk of bias, those with 4–6 green marks were classified as medium risk, and those with 7–9 green marks were classified as low risk. A supplemental analysis was performed independently by the two examiners regarding the overall quality of the evidence for any performed meta-analysis using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system [ 16 ]. Any disagreement between the two reviewers (D.M. and F.S.) was solved by discussion with the author supervisor (R.P.).

Publication bias was assessed through a funnel plot, which was made using Excel software (Microsoft Excel ® ).

2.9. Heterogeneity Assessment

The OpenMeta software was used for assessing the heterogeneity of the studies included in any conducted meta-analysis (OpenMeta, Inc.©, Zug, Zug, Switzerland). The authors calculated the comparability of the observed proportions across the results with chance alone using the I2 test. In cases where the p -value was <0.1, the heterogeneity was considered significant. Moreover, the same test was considered as a measure of heterogeneity across studies, following the subsequent scheme [ 17 ]: 0–40%, negligible; 30–60%, moderate; 50–90%, substantial; and 75–100%, considerable.

2.10. Data Analysis

Descriptive characteristics of the studies are expressed as means/medians and/or frequencies, as appropriate, depending on the variables.

Meta-analyses were performed only when there were studies comparing similar groups and reporting the same outcomes. In such cases, the meta-analyses were performed with a fixed-effect model. A random-effect model was used only in the case of not-negligible heterogeneity across the included studies (>50%).

A forest plot was created to illustrate the effects on the meta-analysis of individual studies and the overall estimate. OpenMeta-analyst [ 18 ] was used to perform all analyses. The cut-off value of significance was set at p < 0.05.

3. Results

3.1. Study Selection

A flowchart of the search strategy and study selection is shown in Figure 1 .

A total of 2843 articles was identified, with 2796 found through electronic searches and 47 found through other sources. Out of the 2709 studies that resulted after removal of the duplicates, 2470 were excluded as a result of title and abstract reading (inter-reader agreement, k = 0.78). Eventually, out of the 239 articles that remained to be evaluated in the full-text, 44 met the inclusion criteria and were included in either the qualitative or quantitative analyses (meta-analysis); in contrast, 195 were excluded. All information about full-text articles excluded, with reasons are included in the Supplementary Materials File (Table S1) .

3.2. Study Characteristics

The characteristics of the included studies are summarized in Table 1 .

Both prospective (five studies) and retrospective (nine studies) cohort studies were included in the review. Twenty-four studies presented data from national registries, and therefore, they were analyzed separately. In addition, six studies presented results related to a single immunosuppression condition, namely, graft-versus-host disease, and for this reason, they were analyzed separately, as this condition is, itself, a potentially malignant disorder of the oral cavity. All studies were conducted in an institutional environment.

3.3. Assessment of the Risk of Bias

The risk of bias is summarized in Figure 2 and Figure 3 . The methodological quality of the included studies was high for 12 studies [ 19 , 22 , 24 , 25 , 28 , 31 , 32 , 33 , 36 , 51 , 53 , 58 ], moderate for 26 studies [ 20 , 21 , 23 , 25 , 26 , 29 , 30 , 32 , 34 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 52 , 54 , 55 , 56 , 57 , 60 , 61 , 62 ], and low for six studies [ 23 , 26 , 27 , 35 , 48 , 59 ].

The results regarding publication bias are presented in Figure 4 , Figure 5 and Figure 6 . Significant publication bias was found in the studies that presented results related to Graft Versus Host Disease (GVHD) and the national registries. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system provided information on the certainty of the conclusions and the strength of the evidence ( Table 2 ). Although the meta-analyses drew conclusions from cohort studies, which are considered to be among the best-available evidence, they were considered to have only moderate strength of evidence because of the presence of at least one study with a high risk of bias and very wide confidence intervals.

3.4. Results of the Meta-Analyses

As reported earlier, three separate meta-analyses were conducted. The meta-analysis related to the national registries ( Figure 7 ) was conducted on 23 studies with a total of 5,227,567 patients and found an “untransformed proportion” (PR) of 0.2% (95% CI: 0.002–0.003) ( p -value of <0.001).

The meta-analysis concerning data not derived from the national registries ( Figure 8 ) was conducted on 15 studies with a total of 6997 patients and found an “untransformed proportion” (PR) of 1% (95% CI: 0.006–0.014) ( p -value of <0.001).

The meta-analysis regarding data about GVHD ( Figure 9 ) was conducted on six studies with a total of 49,285 patients and found an “untransformed proportion” (PR) of 0.3% (95% CI: 0.001–0.005) ( p -value of < 0.001).

The meta-analyses conducted on the three groups of patients revealed a general increased risk of developing an oral cancer in immunosuppressed populations. Such risk ranges from 0.2% to 1% depending on whether data from national registries are considered. In immunosuppressed patients, this evidence emphasizes the need to provide for a careful follow-up of suspicious lesions and potentially malignant disorders of the oral cavity.

4. Discussion

4.1. Summary of the Main Findings

The close relationship between the immune system and cancer immunoediting has been documented for many years for numerous cancers, including oral carcinoma, and this systematic review highlighted an incidence of oral carcinoma in immunosuppressed patients of 200 new cases per 100,000. If this is compared to data from registries on the incidence of oral cancer in the general population, which is approximately 4.1 per 100,000 subjects (ASR incidence = 4.1 per 100,000), immunosuppressed subjects have a risk of developing oral cancer that is 50 times higher than the general population. These raw data emphasize the need to establish clinical protocols for primary prevention and screening in all immunosuppressed subjects, likely with tailor-made protocols that depend on the cause of immunosuppression and the severity of the immunosuppression.

Some considerations of a methodological nature that emerged from this systematic review should be made in light of the literature. A first consideration concerns the definition that is used for patients with disorders of the immune system. The terms immunosuppression and immunodeficiency are often used interchangeably. This confusion is related to the subtle nuance that separates them. It could be specified that immunosuppression identifies a medical condition involving a general malfunction of the immune system, whereas immunodeficiency classifies the severity of this deficit into primary and secondary in relation to the cause. Furthermore, an aspect still unresolved concerns the identification of clinical and/or instrumental parameters that can identify the state of immunosuppression (considering both innate and acquired immunity, both cellular and humoral) and classify it in relation to the severity of the immunosuppression.

The present systematic review demonstrated that immunosuppression should be considered a risk factor for the development of oral cancer, with a percentage of increased risk ranging from 0.2% to 1% (95% CI: 0.2% to 1.4%). Considering the main causes of immunosuppression reported in the selected articles, there are some interesting considerations. In fact, in this systematic review, the authors decided to divide the results from the included papers into three main groups: the results derived from the literature analysis of the main reasons for immunosuppression (not from national registries), those from articles related to GVHD, and those from the registry analysis, which depict an increased risk of 1% (95% CI: 0.6% to 1.4%), of 0.3% (95% CI: 0.1% to 0.5%), and of 0.2% (95% CI: 0.2% to 0.3%), respectively. Articles referring to states of malnutrition were not included in this review, as they did not report adequate information regarding immune status.

4.2. Organ Transplantation

Organ transplantation, in particular, kidney transplantation, represents one of the main causes of immunosuppression most frequently associated with the onset of oral cavity neoplasms. The increased life expectancy of transplant recipients exposes them to prolonged immunosuppressive therapy (mainly cyclosporine), which is necessary to avoid the phenomenon of transplant rejection. In the study conducted by López-Pintor [ 62 ], 500 kidney transplant patients were recruited, and during follow-up, six cases of oral cancer were reported out of 500 patients (incidence of 1 patient per 100 subjects).

The same trend was seen for patients undergoing heart transplantation (HTx). Due to new techniques introduced in transplant surgery, survival after heart transplantation has improved significantly in recent decades. In the study conducted by Jääma-Holmberg (2019) [ 25 ], the risk of oral cancer after organ transplantation was two to four times higher than that of the general population, becoming one of the main long-term complications in this group of patients. Furthermore, it would appear that oral cancer occurs with a higher frequency in subjects who have undergone thoracic organ transplantation rather than those who have undergone abdominal organ transplants (i.e., liver and kidney). This different risk of oral cancer in relation to the type of organ transplanted could be partly related to the different pharmacological regimens adopted and partly linked to the underlying pathologies that lead to the need for transplants. Further studies should stratify the risk of oral cancer in relation to the type of organ transplanted.

4.3. Other Cancers

Another cause of immunosuppression associated with a greater risk of developing oral cavity cancer is represented by the treatment of thyroid neoplasms. The number of newly diagnosed cases of thyroid cancer has increased in recent years due to technological advances and the spread of cytological tests for early diagnosis. Patients who underwent partial or total thyroidectomy and those who received radio-iodine treatment for the treatment of thyroid cancer reported an increased risk of developing oral cancer. The study by Hsu et al. (2014) [ 40 ] showed an increased association between thyroid cancer and subsequent head and neck cancer. This association found that its biochemical-molecular explanation was related to the intrinsic carcinogenic action of radio-iodine, which can possibly be enhanced by pre-existing molecular genetic mutations in a framework of immunological impairment linked to the partial or total removal of the thyroid.

4.4. Infectious Agents

Other known causes of immunosuppressive states are infectious agents (i.e., HCV, HIV, and HPV). This literature review reported only one study, which was conducted by Su et al. [ 49 ] that highlighted an incidence of 698 cases of carcinoma out of 147,962 patients. The risk of oral cancer appears to be lower in HCV patients receiving pegylated interferon (PEG-IFN) therapy than that of untreated HCV patients. Further studies should investigate the role of HCV infection in oral cancer oncogenesis, with particular attention paid to the type of therapy administered to patients.

Studies investigating the role of HIV as a cause of immunosuppression were not included in this review. In fact, it is known that HIV infection causes a depletion of CD4+ T lymphocytes, with consequent impairment of the immune system. Acquired immunodeficiency could, therefore, lead to an increased risk of oral cancer. The study conducted by Precious K. Motlokwa et al. (2022) on an oral cancer population in sub-Saharan Africa did not show an increased risk of carcinogenicity in a group of HIV-infected patients [ 63 ]. This could be partly explained by new antiretroviral therapies, which allow clinicians to gain control of HIV infections and, therefore, reduce the impairment of patients’ immune systems. Further studies are needed to evaluate whether there is a real risk in HIV-positive patients and whether there are associated risk factors (CD4 T lymphocyte count or traditional antiretroviral therapies vs HAART).

4.5. Hematopoietic Stem Cell Transplantation (HSC)

Within the selected articles, it was possible to identify a group of articles conducted on patients undergoing hematopoietic stem cell transplantation (HSC), which now represents an essential therapy for the treatment of various haemato-lymphoproliferative diseases and other benign conditions (multiple myeloma, lymphomas, autoimmune disorders, etc.). In the study conducted by Santarone et al. (2020) [ 56 ], patients undergoing HSC transplantation reported the incidence of developing a malignancy at double the rate of the general population. In support of this, Dyer and colleagues [ 54 ] also found a similar incidence rate in patients undergoing HSC transplantation, underlining the importance of regular follow-ups with patients.

Furthermore, GVHD is among the adverse events associated with HSC transplantation. This clinical condition represents an adverse immunological phenomenon following HSC transplantation. GVHD oral lesions are among the so-called potentially malignant disorders, as they have a greater risk of neoplastic degeneration than healthy mucosa. Furthermore, the most frequently used therapy in the treatment of GVHD involves the use of immunosuppressive agents (e.g., both topical and high potency systemic corticosteroids and calcineurin inhibitors), which, although they reduce the inflammatory component of GVHD lesions, could increase the risk of developing a secondary malignancy. The risk of developing malignancy in patients with chronic GVHD was significantly increased compared with the general population, with a standard incidence ratio (SIR) of 1.8 and a 95% confidence interval (95% CI) of 1.5–2.0. The risk is much higher for cancer of the oral cavity (SIR = 15.7, 95% CI, 12.1–20.1), cancer of the esophagus (SIR = 8.5, 95% CI, 6.1–11.5), colon cancer (SIR = 1.9, 95% CI, 1.2–2.7), skin cancer (SIR = 7.2, 95% CI, 3.9–12.4), and cancers of the nervous system (SIR = 4.1, 95% CI, 1.2–8.4). The risk of developing oral, esophageal, or skin cancer appears to have a maximum incidence 1 year after transplantation [ 61 ].

4.6. Strengths and Limitations of the Present Systematic Review

Finally, the data obtained from this systematic review were partly extrapolated from the analysis of national registers from China, Japan, Republic of Korea, India, Taiwan, and Nordic Scandinavian countries. As these databases have a large amount of data, they can lead to significant statistical variations capable of creating very significant discrepancies in the results. In light of this, a meta-analysis dedicated solely to the analysis of the data obtained from these registries was conducted in this systematic review. It is also known that cancer of the oral cavity has a notably high incidence in the aforementioned countries (e.g., China and India) due to the different cultural and social habits. The funnel plot shown in Figure 4 revealed the presence of some studies with particularly discrepant data with respect to the confidence interval of the meta-analysis. Specifically, the study conducted by Levi et al. was discrepant to the funnel plot, and for this reason, it was removed from the statistical analysis and presented only in a qualitative form.

From a methodological point of view, all the studies included in this review had the main objective of investigating the incidence of cancer in other sites. Therefore, further prospective observational studies evaluating the occurrence of oral cancers in immunosuppressed patients as the main outcome while also taking into account the main risk factors of oral cancer that may influence this association (e.g., smoking, candida, HPV, and alcohol) are required. Moreover, it is essential to consider adequate follow-ups to avoid an underestimation of the real incidence of oral carcinomas. The time factor certainly plays an important role in the carcinogenic process, considering that a prolonged state of immunosuppression can increase the risk of the onset of neoplasms.

5. Conclusions

The results obtained from the systematic review indicated that immunosuppression is to be considered a risk factor for the development of oral cancer.

Particular attention and accurate follow-ups with all immunosuppressed patients are, therefore, essential in order to intercept clinical situations at an early stage that could evolve into oral cancer.

Further studies are needed to investigate the effective role of immunosuppression in carcinogenesis and to identify any risk factors.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers15123077/s1 , Table S1. Full-text articles excluded, with reason [ 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 ].

Click here for additional data file.

Author Contributions

Conceptualization, C.L.; methodology, R.P.; validation, C.L., M.A.D. and R.P.; formal analysis, G.G.; data curation, F.S. and D.M.; writing—original draft preparation, R.P., F.S. and D.M.; writing—review and editing, C.L. and R.P.; visualization, C.R. and M.A.D.; supervision, M.C. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are available upon request to the corresponding author.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Rivera C. Essentials of oral cancer Int. J. Clin. Exp. Pathol. 2015 8 11884 11894 26617944 PMC4637760

2. Liu J. Kaplon A. Blackman E. Miyamoto C. Savior D. Ragin C. The Impact of the Multidisciplinary Tumor Board on Head and Neck Cancer Outcomes Laryngoscope 2020 130 946 950 10.1002/lary.28066 31095740 PMC7868105

3. Shanti R.M. O’Malley B.W. Surgical Management of Oral Cancer Dent. Clin. N. Am. 2018 86 77 86 10.1016/j.cden.2017.08.005 29126495

4. Burnet M. Immunological factors in the process of carcinogenesis Br. Med. Bull. 1964 20 154 158 10.1093/oxfordjournals.bmb.a070310 14168097

5. Swann J.B. Smyth M.J. Immune surveillance of tumors J. Clin. Investig. 2007 117 1137 1146 10.1172/JCI31405 17476343 PMC1857231

6. Bird L. Innate surveillance Nat. Rev. Immunol. 2016 16 132 133 10.1038/nri.2016.20 26875829

7. Lodish H. Molecular Biology of the Cell 5th ed. Macmillan New York, NY, USA 2004

8. Chinen J. Shearer W.T. Secondary immunodeficiencies, including HIV infection J. Allergy Clin. Immunol. 2010 125 S195 S203 10.1016/j.jaci.2009.08.040 20042227 PMC6151868

9. Notarangelo L.D. Bacchetta R. Casanova J.L. Su H.C. Human inborn errors of immunity: An expanding universe Sci. Immunol. 2020 5 eabb1662 10.1126/sciimmunol.abb1662 32651211 PMC7647049

10. Rice J.M. Immunosuppression Tumour Site Concordance and Mechanisms of Carcinogenesis IARC Scientific Publications (No. 165) Baan R.A. Stewart B.W. Straif K. International Agency for Research on Cancer Lyon, France 2019 Chapter 16 33979073

11. Geisser E.K. Immunosuppression Cancer Treat. Res. 2009 146 23 43 19415191 10.1007/978-0-387-78574-5_4

12. Kumar M. Oral cancer: Etiology and risk factors: A review J. Cancer Res. Ther. 2016 12 458 463 10.4103/0973-1482.186696 27461593

13. Vial T. Descotes J. Immunosuppressive drugs and cancer Toxicology 2003 185 229 240 10.1016/S0300-483X(02)00612-1 12581698

14. Landis J.R. Koch G.G. The measurement of observer agreement for categorical data Biometrics 1977 33 159 174 10.2307/2529310 843571

15. Wells G.A. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised studies in Meta-Analyses Eur. J. Epidemiol. 2014 25 603 605 10.1007/s10654-010-9491-z 20652370

16. Guyatt G.H. GRADE: An emerging consensus on rating quality of evidence and strength of recommendations BMJ 2008 336 924 10.1136/bmj.39489.470347.AD 18436948 PMC2335261

17. Higgins J.P.T. Measuring in consistency in meta-analyses BMJ 2003 327 557 560 10.1136/bmj.327.7414.557 12958120 PMC192859

18. Wallace B.C. Closing the Gap between Methodologists and End-Users: R as a Computational Back-End J. Stat. Softw. 2012 49 1 15 10.18637/jss.v049.i05

19. Spolidorio L.C. Oral health in renal transplant recipients administered cyclosporin A or tacrolimus Oral Dis. 2006 12 309 314 10.1111/j.1601-0825.2005.01200.x 16700742

20. Jiang Y. Villeneuve P.J. Wielgosz A. Schaubel D.E. Fenton S.S. Mao Y. The incidence of cancer in a population-based cohort of Canadian heart transplant recipients Am. J. Transpl. 2010 10 637 645 10.1111/j.1600-6143.2009.02973.x 20121725

21. Derk C.T. Rasheed M. Spiegel J.R. Jimenez S.A. Increased incidence of carcinoma of the tongue in patients with systemic sclerosis J. Rheumatol. 2005 32 637 641 15801018 PMC6744938

22. Da Silva L.C. de Almeida Freitas R. de Andrade M.P. Jr. Piva M.R. Martins-Filho P.R. de Santana Santos T. Oral lesions in renal transplant J. Craniofac. Surg. 2012 23 e214 e218 10.1097/SCS.0b013e31824de388 22627437

23. Öhman J. Rexius H. Mjörnstedt L. Gonzalez H. Holmberg E. Dellgren G. Hasséus B. Oral and lip cancer in solid organ transplant patients—A cohort study from a Swedish Transplant Centre Oral. Oncol. 2015 51 146 150 10.1016/j.oraloncology.2014.11.007 25497104

24. Narayan G. Carcinoma of the Tongue in Renal Transplant Recipients: An Unusual Spectrum of De Novo Malignancy at a Tertiary Care Center in India over a Period of 26 Years Indian J. Nephrol. 2018 28 119 126 29861562 10.4103/ijn.IJN_354_16 PMC5952450

25. Jäämaa-Holmberg S. Salmela B. Lemström K. Pukkala E. Lommi J. Cancer incidence and mortality after heart transplantation—A population-based national cohort study Acta. Oncol. 2019 58 859 863 10.1080/0284186X.2019.1580385 30821595

26. Laprise C. Cahoon E.K. Lynch C.F. Kahn A.R. Copeland G. Gonsalves L. Madeleine M.M. Pfeiffer R.M. Engels E.A. Risk of lip cancer after solid organ transplantation in the United States Am. J. Transpl. 2019 19 227 237 10.1111/ajt.15052 30074684 PMC6310619

27. Lin N.C. Chen Y.L. Tsai K.Y. Head and neck cancer in living donor liver transplant recipients: Single center retrospective study Medicine 2019 98 PMC6709202 10.1097/MD.0000000000016701 PMC6709202 31374062

28. Johns M.E. Shikhani A.H. Kashima H.K. Matanoski G.M. Multiple primary neoplasms in patients with salivary gland or thyroid gland tumors Laryngoscope 1986 96 718 721 10.1288/00005537-198607000-00002 3724320

29. Gutman M. Are malignant melanoma patients at higher risk for a second cancer? Cancer 1991 68 660 665 10.1002/1097-0142(19910801)68:3<660::AID-CNCR2820680337>3.0.CO;2-5 2065289

30. Lishner M. Second malignant neoplasms in patients with non Hodgkin’s lymphoma Hematol. Oncol. 1991 9 169 179 10.1002/hon.2900090308 1937408

31. Hiyama T. Hanai A. Fujimoto I. Second primary cancer after diagnosis of stomach cancer in Osaka, Japan Jpn. J. Cancer Res. 1991 82 762 770 10.1111/j.1349-7006.1991.tb02700.x 1908843 PMC5918547

32. Spitz M.R. Sider J.G. Schantz S.P. Newell G.R. Association between malignancies of the upper aerodigestive tract and uterine cervix Head Neck 1992 14 347 351 10.1002/hed.2880140502 1399566

33. Rabkin C.S. Biggar R.J. Melbye M. Curtis R.E. Second primary cancers following anal and cervical carcinoma: Evidence of shared etiologic factors Am. J. Epidemiol. 1992 136 54 58 10.1093/oxfordjournals.aje.a116420 1329500

34. Levi F. Randimbison L. La Vecchia C. Erler G. Te V.C. Incidence of invasive cancers following squamous cell skin cancer Am. J. Epidemiol. 1997 146 734 739 10.1093/oxfordjournals.aje.a009349 9366621

35. Levi F. Randimbison L. Te V.C. La Vecchia C. Second primary cancers in patients with lung carcinoma Cancer 1999 86 186 190 10.1002/(SICI)1097-0142(19990701)86:1<186::AID-CNCR25>3.0.CO;2-3 10391579

36. Levi F. Randimbison L. Maspoli M. Te V.C. La Vecchia C. Second neoplasms after oesophageal cancer Int. J. Cancer 2007 121 694 697 10.1002/ijc.22744 17417783

37. Chuang S.C. Hashibe M. Scelo G. Brewster D.H. Pukkala E. Friis S. Tracey E. Weiderpass E. Hemminki K. Tamaro S. Risk of second primary cancer among esophageal cancer patients: A pooled analysis of 13 cancer registries Cancer Epidemiol. Biomark. Prev. 2008 17 1543 1549 10.1158/1055-9965.EPI-07-2876 18559572

38. Brown A.P. Neeley E.S. Werner T. Soisson A.P. Burt R.W. Gaffney D.K. A population-based study of subsequent primary malignancies after endometrial cancer: Genetic, environmental, and treatment-related associations Int. J. Radiat. Oncol. Biol. Phys. 2010 78 127 135 10.1016/j.ijrobp.2009.07.1692 19910129

39. Zhu G. Chen Y. Zhu Z. Lu L. Bi X. Deng Q. Chen X. Su H. Liu Y. Guo H. Risk of second primary cancer after treatment for esophageal cancer: A pooled analysis of nine cancer registries Dis. Esophagus 2012 25 505 511 10.1111/j.1442-2050.2011.01273.x 22067063

40. Hsu C.H. Huang C.L. Hsu Y.H. Iqbal U. Nguyen P.A. Jian W.S. Co-occurrence of second primary malignancy in patients with thyroid cancer QJM 2014 107 643 648 10.1093/qjmed/hcu051 24623860

41. Robsahm T.E. Karagas M.R. Rees J.R. Syse A. New malignancies after squamous cell carcinoma and melanomas: A population-based study from Norway BMC Cancer 2014 19 210 10.1186/1471-2407-14-210 24645632 PMC3994878

42. Davis E.J. Beebe-Dimmer J.L. Yee C.L. Cooney K.A. Risk of second primary tumors in men diagnosed with prostate cancer: A population-based cohort study Cancer 2014 120 2735 2741 10.1002/cncr.28769 24842808 PMC4195444

43. Bae S.H. Other primary systemic cancers in patients with melanoma: Analysis of balanced acral and nonacral melanomas J. Am. Acad. Dermatol. 2016 72 333 340 10.1016/j.jaad.2015.09.047 26584878

44. Krilaviciute A. Vincerzevskiene I. Smailyte G. Basal cell skin cancer and the risk of second primary cancers: A cancer registry-based study in Lithuania Ann. Epidemiol. 2016 26 511 514 10.1016/j.annepidem.2016.05.003 27262816

45. Schlieve T. Heidel R.E. Carlson E.R. Second Primary Head and Neck Cancers after Non-Head and Neck Primary Cancers J. Oral. Maxillofac. Surg. 2016 74 2515 2520 10.1016/j.joms.2016.05.009 27292523

46. Adjei Boakye E. Wang M. Sharma A. Jenkins W.D. Osazuwa-Peters N. Chen B. Lee M. Schootman M. Risk of second primary cancers in individuals diagnosed with index smoking- and non-smoking- related cancers J. Cancer Res. Clin. Oncol. 2020 146 1765 1779 10.1007/s00432-020-03232-8 32356175 PMC11804670

47. Wu X. Zhang X. Tao L. Chen P. Risk of second primary malignancy in adults with pulmonary high-grade neuroendocrine carcinoma (HGNEC) BMC Cancer 2020 20 719 10.1186/s12885-020-07224-2 32746796 PMC7398247

48. Song C. Lv J. Liu Y. Chen J.G. Ge Z. Zhu J. Dai J. Du L.B. Yu C. Guo Y. Virus Infection and Risk of All Cancer Types JAMA Netw. Open. 2019 2 6 10.1001/jamanetworkopen.2019.5718 PMC6575146 31199446

49. Su T.H. Tseng T.C. Liu C.J. Chou S.W. Liu C.H. Yang H.C. Chen P.J. Chen D.S. Chen C.L. Kao J.H. Antiviral therapy against chronic hepatitis C is associated with a reduced risk of oral cancer Int. J. Cancer 2020 147 901 908 10.1002/ijc.32840 31853972

50. Mahale P. Ugoji C. Engels E.A. Shiels M.S. Peprah S. Morton L.M. Cancer risk following lymphoid malignancies among HIV-infected people AIDS 2020 34 1237 1245 10.1097/QAD.0000000000002528 32287068 PMC7382023

51. Yokota A. Ozawa S. Masanori T. Akiyama H. Ohshima K. Kanda Y. Takahashi S. Mori T. Nakaseko C. Onoda M. Secondary solid tumors after allogeneic hematopoietic SCT in Japan Bone Marrow Transpl. 2012 47 95 100 10.1038/bmt.2011.23 21358690

52. Curtis R.E. Metayer C. Rizzo J.D. Socié G. Sobocinski K.A. Flowers M.E. Travis W.D. Travis L.B. Horowitz M.M. Deeg H.J. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: An international case-control study Blood 2005 105 3802 3811 10.1182/blood-2004-09-3411 15687239 PMC1895092

53. Majhail N.S. Brazauskas R. Rizzo J.D. Sobecks R.M. Wang Z. Horowitz M.M. Bolwell B. Wingard J.R. Socie G. Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning Blood 2011 117 316 322 10.1182/blood-2010-07-294629 20926773 PMC3037753

54. Dyer G. Brice L. Schifter M. Gilroy N. Kabir M. Hertzberg M. Greenwood M. Larsen S.R. Moore J. Gottlieb D. Oral health and dental morbidity in long-term allogeneic blood and marrow transplant survivors in Australia Aust. Dent. J. 2018 63 312 319 10.1111/adj.12627 29878377

55. Anak S. Yalman N. Bilgen H. Sepet E. Deviren A. Gürtekin B. Tunca F. Başaran B. Squamous cell carcinoma development in Fanconi anemia patients who underwent hematopoietic stem cell transplantation Pediatr. Transpl. 2020 24 e13706 10.1111/petr.13706 32255560

56. Santarone S. Natale A. Angelini S. Papalinetti G. Vaddinelli D. Di Bartolomeo A. Di Bartolomeo P. Secondary oral cancer following hematopoietic cell transplantation Bone Marrow Transpl. 2021 56 1038 1046 10.1038/s41409-020-01147-z 33235350

57. Bensing S. Brandt L. Tabaroj F. Sjöberg O. Nilsson B. Ekbom A. Blomqvist P. Kämpe O. Increased death risk and altered cancer incidence pattern in patients with isolated or combined autoimmune primary adrenocortical insufficiency Clin. Endocrinol. 2008 69 697 704 10.1111/j.1365-2265.2008.03340.x 18727712

58. Zhang W. Feng S. Yan S. Zhao Y. Li M. Sun J. Zhang F.C. Cui Q. Dong Y. Incidence of malignancy in primary Sjogren’s syndrome in a Chinese cohort Rheumatology 2010 49 571 577 10.1093/rheumatology/kep404 20040528

59. Katsanos K.H. Roda G. McBride R.B. Cohen B. Colombel J.F. Increased Risk of Oral Cancer in Patients with Inflammatory Bowel Diseases Clin. Gastroenterol. Hepatol. 2016 14 413 420 10.1016/j.cgh.2015.09.041 26499929

60. Rautemaa R. Hietanen J. Niissalo S. Pirinen S. Perheentupa J. Oral and oesophageal squamous cell carcinoma—A complication or component of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I) Oral Oncol. 2007 43 607 613 10.1016/j.oraloncology.2006.07.005 16997613

61. Atsuta Y. Suzuki R. Yamashita T. Fukuda T. Miyamura K. Taniguchi S. Iida H. Uchida T. Ikegame K. Takahashi S. Continuing increased risk of oral/esophageal cancer after allogeneic hematopoietic stem cell transplantation in adults in association with chronic graft-versus-host disease Ann. Oncol. 2014 25 435 441 10.1093/annonc/mdt558 24399081

62. López-Pintor R.M. Hernández G. de Arriba L. de Andrés A. Lip cancer in renal transplant patients Oral Oncol. 2011 47 68 71 10.1016/j.oraloncology.2010.10.017 21112239

63. Motlokwa P.K. Tsima B.M. Martei Y.M. Ralefala T. Galebole F. Stephens-Shields A.J. Grover S. Gross R. Disparities in Oral Cancer Stage at Presentation in a High HIV Prevalence Setting in Sub-Saharan Africa JCO Glob. Oncol. 2022 8 e2100439 10.1200/GO.21.00439 35981280 PMC9812499

64. Whiteside T.L. Immunobiology and immunotherapy of head and neck cancer Curr Oncol Rep. 2001 3 46 55 10.1007/s11912-001-0042-3 11123869

65. Wen B.W. Tsai C.S. Lin C.L. Chang Y.J. Lee C.F. Hsu C.H. Kao C.H. Cancer risk among gingivitis and periodontitis patients: A nationwide cohort study QJM 2014 107 283 290 10.1093/qjmed/hct248 24336850

66. Gupta B. Ariyawardana A. Johnson N.W. Oral cancer in India continues in epidemic proportions: Evidence base and policy initiatives Int. Dent. J. 2013 63 12 25 10.1111/j.1875-595x.2012.00131.x 23410017 PMC9374955

67. Dickenson A.J. Currie W.J. Avery B.S. Screening for syphilis in patients with carcinoma of the tongue Br. J. Oral Maxillofac. Surg. 1995 33 319 320 10.1016/0266-4356(95)90046-2 8555151

68. Mohd Bakri M. Mohd Hussaini H. Rachel Holmes A. David Cannon R. Mary Rich A. Revisiting the association between candidal infection and carcinoma, particularly oral squamous cell carcinoma J. Oral Microbiol. 2010 21 2 10.3402/jom.v2i0.5780 PMC3084579 21523221

69. Garrote L.F. Herrero R. Reyes R.M. Vaccarella S. Anta J.L. Ferbeye L. Muñoz N. Franceschi S. Risk factors for cancer of the oral cavity and oro-pharynx in Cuba Br. J. Cancer 2001 85 46 54 10.1054/bjoc.2000.1825 11437401 PMC2363910

70. Hassona Y. Scully C. Almangush A. Baqain Z. Sawair F. Oral potentially malignant disorders among dental patients: A pilot study in Jordan Asian Pac. J. Cancer Prev. 2014 15 10427 10431 10.7314/APJCP.2014.15.23.10427 25556487

71. Ben-David Y. Leiser Y. Kachta O. El-Naaj I.A. Does long-term treatment with Doxil® predispose patients to oral cancer? Int. J. Clin. Oncol. 2013 18 554 555 10.1007/s10147-012-0400-1 22430199

72. Fahmy M.S. Sadeghi A. Behmard S. Epidemiologic study of oral cancer in Fars Province, Iran Community Dent. Oral Epidemiol. 1983 11 50 58 10.1111/j.1600-0528.1983.tb01354.x 6572124

73. Sankaranarayanan R. Nair M.K. Mathew B. Balaram P. Sebastian P. Dutt S.C. Recent results of oral cancer research in Kerala, India Head Neck. 1992 14 107 112 10.1002/hed.2880140206 1601646

74. Warnakulasuriya S. Kovacevic T. Madden P. Coupland V.H. Sperandio M. Odell E. Møller H. Factors predicting malignant transformation in oral potentially malignant disorders among patients accrued over a 10-year period in South East England J. Oral Pathol. Med. 2011 40 677 683 10.1111/j.1600-0714.2011.01054.x 21762430

75. Túri K. Barabás P. Csurgay K. Léhner G.Y. Lőrincz A. Németh Z.S. An analysis of the epidemiological and etiological factors of oral tumors of young adults in a Central-Eastern European population Pathol. Oncol. Res. 2013 19 353 363 10.1007/s12253-013-9628-y 23645516

76. Gorsky M. Epstein J.B. Oakley C. Le N.D. Hay J. Stevenson-Moore P. Carcinoma of the tongue: A case series analysis of clinical presentation, risk factors, staging, and outcome Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2004 98 546 552 10.1016/j.tripleo.2003.12.041 15529126

77. Hsue S.S. Wang W.C. Chen C.H. Lin C.C. Chen Y.K. Lin L.M. Malignant transformation in 1458 patients with potentially malignant oral mucosal disorders: A follow-up study based in a Taiwanese hospital J. Oral Pathol. Med. 2007 36 25 29 10.1111/j.1600-0714.2006.00491.x 17181738

78. Saira Ahmed R. Malik S. Khan M.F. Khattak M.R. Epidemiological and clinical correlates of oral squamous cell carcinoma in patients from north-west Pakistan J. Pak. Med. Assoc. 2019 69 1074 1078 31431755

79. Yao J.G. Gao L.B. Liu Y.G. Li J. Pang G.F. Genetic variation in interleukin-10 gene and risk of oral cancer Clin. Chim. Acta 2008 388 84 88 10.1016/j.cca.2007.10.012 17980158

80. De Benedittis M. Petruzzi M. Giardina C. Lo Muzio L. Favia G. Serpico R. Oral squamous cell carcinoma during long-term treatment with hydroxyurea Clin. Exp. Dermatol. 2004 29 605 607 10.1111/j.1365-2230.2004.01586.x 15550132

81. Tsai C.W. Chang W.S. Lin K.C. Shih L.C. Tsai M.H. Hsiao C.L. Yang M.D. Lin C.C. Bau D.T. Significant association of Interleukin-10 genotypes and oral cancer susceptibility in Taiwan Anticancer Res. 2014 34 3731 3737 24982395

82. Abhinav R.P. Williams J. Livingston P. Anjana R.M. Mohan V. Burden of diabetes and oral cancer in India J. Diabetes Complicat. 2020 34 107670 10.1016/j.jdiacomp.2020.107670 32651032

83. Satheeshkumar P.S. Mohan M.P. Oral Helicobacter pylori infection and the risk of oral cancer Oral Oncol. 2013 49 e20 e21 10.1016/j.oraloncology.2013.02.007 23481311

84. Krüger M. Hansen T. Kasaj A. Moergel M. The Correlation between Chronic Periodontitis and Oral Cancer Case Rep. Dent. 2013 2013 262410 10.1155/2013/262410 23936684 PMC3725788

85. Hermsen M.A. Xie Y. Rooimans M.A. Meijer G.A. Baak J.P. Plukker J.T. Arwert F. Joenje H. Cytogenetic characteristics of oral squamous cell carcinomas in Fanconi anemia Fam. Cancer 2001 1 39 43 10.1023/A:1011528310346 14574014

86. Moura L.K.B. Mobin M. Matos F.T.C. Monte T.L. Lago E.C. Falcão C.A.M. Ferraz M.Â.A.L. Santos T.C. Tapety F.I. Nunes C.M.C.L.L. Bibliometric Analysis on the Risks of Oral Cancer for People Living with HIV/AIDS Iran J. Public Health 2017 46 1583 1585 29167779 PMC5696700

87. Singh P.K. Ahmad M.K. Kumar V. Gupta R. Kohli M. Jain A. Mahdi A.A. Bogra J. Chandra G. Genetic polymorphism of interleukin-10 (-A592C) among oral cancer with squamous cell carcinoma Arch. Oral Biol. 2017 77 18 22 10.1016/j.archoralbio.2016.12.011 28157558

88. Tarvainen L. Suojanen J. Kyyronen P. Lindqvist C. Martinsen J.I. Kjaerheim K. Lynge E. Sparen P. Tryggvadottir L. Weiderpass E. Occupational Risk for Oral Cancer in Nordic Countries Anticancer Res. 2017 37 3221 3228 28551668 10.21873/anticanres.11684

89. Soulier J. Fanconi anemia Hematol. Am. Soc. Hematol. Educ. Program. 2011 2011 492 497 10.1182/asheducation-2011.1.492 22160080

90. Sun C. Hu Z. Zhong Z. Jiang Y. Sun R. Fei J. Xi Y. Li X. Song M. Li W. Clinical and prognostic analysis of second primary squamous cell carcinoma of the tongue after radiotherapy for nasopharyngeal carcinoma Br. J. Oral Maxillofac. Surg. 2014 52 715 720 10.1016/j.bjoms.2014.06.015 25085271

91. Hashibe M. Ritz B. Le A.D. Li G. Sankaranarayanan R. Zhang Z.F. Radiotherapy for oral cancer as a risk factor for second primary cancers Cancer Lett. 2005 220 185 195 10.1016/j.canlet.2004.10.023 15766594

92. Santos A.M. Marcu L.G. Wong C.M. Bezak E. Risk estimation of second primary cancers after breast radiotherapy Acta Oncol. 2016 55 1331 1337 10.1080/0284186X.2016.1185150 27379458

93. Rafferty M.A. O’Dwyer T.P. Secondary primary malignancies in head and neck squamous cell carcinoma J. Laryngol. Otol. 2001 115 988 991 10.1258/0022215011909567 11779329

94. Lee K.D. Lu C.H. Chen P.T. Chan C.H. Lin J.T. Huang C.E. Chen C.C. Chen M.C. The incidence and risk of developing a second primary esophageal cancer in patients with oral and pharyngeal carcinoma: A population-based study in Taiwan over a 25 year period BMC Cancer 2009 9 373 10.1186/1471-2407-9-373 19843324 PMC2770571

95. Shanmugham J.R. Zavras A.I. Rosner B.A. Giovannucci E.L. Alcohol-folate interactions in the risk of oral cancer in women: A prospective cohort study Cancer Epidemiol. Biomark. Prev. 2010 19 2516 2524 10.1158/1055-9965.EPI-10-0499 20841386 PMC2952069

96. De Araújo R.L. Lyko Kde F. Funke V.A. Torres-Pereira C.C. Oral cancer after prolonged immunosuppression for multiorgan chronic graft-versus-host disease Rev. Bras. Hematol. Hemoter. 2014 36 65 68 10.5581/1516-8484.20140016 PMC3948669 24624039

97. Rosenquist K. Wennerberg J. Schildt E.B. Bladström A. Göran Hansson B. Andersson G. Oral status, oral infections and some lifestyle factors as risk factors for oral and oropharyngeal squamous cell carcinoma. A population-based case-control study in southern Sweden Acta Otolaryngol. 2005 125 1327 1336 10.1080/00016480510012273 16303683

98. Douglas C.M. Jethwa A.R. Hasan W. Liu A. Gilbert R. Goldstein D. De Almedia J. Lipton J. Irish J.C. Long-term survival of head and neck squamous cell carcinoma after bone marrow transplant Head Neck. 2020 42 3389 3395 10.1002/hed.26402 32820585

99. Farrar M. Sandison A. Peston D. Gailani M. Immunocytochemical analysis of AE1/AE3, CK 14, Ki-67 and p53 expression in benign, premalignant and malignant oral tissue to establish putative markers for progression of oral carcinoma Br. J. Biomed. Sci. 2004 61 117 124 10.1080/09674845.2004.11732655 15462255

100. Hsu H.J. Yang Y.H. Shieh T.Y. Chen C.H. Kao Y.H. Yang C.F. Ko E.C. TGF-β1 and IL-10 single nucleotide polymorphisms as risk factors for oral cancer in Taiwanese Kaohsiung J. Med. Sci. 2015 31 123 129 10.1016/j.kjms.2014.12.003 25744234 PMC11916862

101. Danylesko I. Shimoni A. Second Malignancies after Hematopoietic Stem Cell Transplantation Curr. Treat. Options Oncol. 2018 19 9 10.1007/s11864-018-0528-y 29423555

102. Adhikari J. Sharma P. Bhatt V.R. Risk of secondary solid malignancies after allogeneic hematopoietic stem cell transplantation and preventive strategies Future Oncol. 2015 11 3175 3185 10.2217/fon.15.252 26551415

103. Demarosi F. Lodi G. Carrassi A. Soligo D. Sardella A. Oral malignancies following HSCT: Graft versus host disease and other risk factors Oral Oncol. 2005 41 865 877 10.1016/j.oraloncology.2005.02.001 16084755

104. Manavoğlu O. Orhan B. Evrensel T. Karabulut Y. Ozkocaman V. Ozyardimci C. Second primary cancer due to radiotherapy and chemotherapy J. Environ. Pathol. Toxicol. Oncol. 1996 15 275 278 9216821

105. Takeuchi Y. Onizawa K. Wakatsuki T. Yamagata K. Hasegawa Y. Yoshida H. Tongue cancer after bone marrow transplantation Oral Oncol. 2006 42 251 254 10.1016/j.ooe.2006.04.001

106. Tomihara K. Dehari H. Yamaguchi A. Abe M. Miyazaki A. Nakamori K. Hareyama M. Hiratsuka H. Squamous cell carcinoma of the buccal mucosa in a young adult with history of allogeneic bone marrow transplantation for childhood acute leukemia Head Neck 2009 31 565 568 10.1002/hed.20931 18972418

107. Kawano K. Goto H. Takahashi Y. Kaku Y. Oobu K. Yanagisawa S. Secondary Squamous Cell Carcinoma of the Oral Cavity in Young Adults after Hematopoietic Stem Cell Transplantation for Leukemia: Report of Two Cases with Human Papillomavirus Infection Oral Sci. Int. 2007 4 110 116 10.1016/S1348-8643(07)80005-X

108. Inamoto Y. Shah N.N. Savani B.N. Shaw B.E. Abraham A.A. Ahmed I.A. Akpek G. Atsuta Y. Baker K.S. Basak G.W. Secondary solid cancer screening following hematopoietic cell transplantation Bone Marrow Transplant. 2015 50 1013 1023 10.1038/bmt.2015.63 25822223 PMC4989866

109. Hernández G. Arriba L. Jiménez C. Bagán J.V. Rivera B. Lucas M. Moreno E. Rapid progression from oral leukoplakia to carcinoma in an immunosuppressed liver transplant recipient Oral Oncol. 2003 39 87 90 10.1016/S1368-8375(02)00009-X 12457727

110. Torres-Pereira C.C. Stramandinoli-Zanicotti R.T. Amenábar J.M. Sassi L.M. Galbiatti Pedruzzi P.A. Piazzetta C.M. Bonfim C. Oral squamous cell carcinoma in two siblings with Fanconi anemia after allogeneic bone marrow transplantation Spec. Care Dentist 2014 34 212 215 10.1111/scd.12058 24274144

111. Alotaiby F. Song F. Boyce B.J. Cao D. Zhao Y. Lai J. Unusual Papillary Squamous Cell Carcinoma of the Tip of Tongue Presenting in a Patient Status Post Heart Transplant Anticancer Res. 2018 38 4203 4206 10.21873/anticanres.12715 29970551

112. Shiboski C.H. Schmidt B.L. Jordan R.C. Tongue and tonsil carcinoma: Increasing trends in the U.S. population ages 20–44 years Cancer 2005 103 1843 1849 10.1002/cncr.20998 15772957

113. Weng X. Xing Y. Cheng B. Multiple and Recurrent Squamous Cell Carcinoma of the Oral Cavity After Graft-Versus-Host Disease J. Oral Maxillofac. Surg. 2017 75 1899 1905 10.1016/j.joms.2017.02.012 28322198

114. Sharma R.N. Oral Carcinoma: A Clinical Study Of 122 Cases J. Indian Med. Assoc. 1964 43 263 268 14198372

115. Fu X. Chen S. Chen W. Yang Z. Song M. Li H. Zhang H. Yao F. Su X. Liu T. Clinical analysis of second primary gingival squamous cell carcinoma after radiotherapy Oral Oncol. 2018 84 20 24 10.1016/j.oraloncology.2018.06.018 30115471

116. García-Martín J.M. Varela-Centelles P. González M. Seoane-Romero J.M. Seoane J. García-Pola M.J. Epidemiology of oral cancer Oral Cancer Detection Panta P. Springer Cham, Switzerland 2019

117. Tao Y. Sturgis E.M. Huang Z. Sun Y. Dahlstrom K.R. Wei Q. Li G. A TGF-β1 genetic variant at the miRNA187 binding site significantly modifies risk of HPV16-associated oropharyngeal cancer Int. J. Cancer 2018 143 1327 1334 10.1002/ijc.31530 29663347 PMC6120756

118. Madrid C. Scully C. Oral cancer: Comprehending the condition, causes, controversies, control and consequences. 17. Osteonecrosis Dent. Update 2012 39 377 379 10.12968/denu.2012.39.5.377 22852516

119. Dhanuthai K. Rojanawatsirivej S. Thosaporn W. Kintarak S. Subarnbhesaj A. Darling M. Kryshtalskyj E. Chiang C.P. Shin H.I. Choi S.Y. Oral cancer: A multicenter study Med. Oral Patol. Oral Cir. Bucal. 2018 23 e23 e29 10.4317/medoral.21999 29274153 PMC5822535

120. Geng F. Wang Q. Li C. Liu J. Zhang D. Zhang S. Pan Y. Identification of Potential Candidate Genes of Oral Cancer in Response to Chronic Infection With Porphyromonas gingivalis Using Bioinformatical Analyses Front Oncol. 2019 9 91 10.3389/fonc.2019.00091 30847302 PMC6394248

121. Pisani L.P. Estadella D. Ribeiro D.A. The Role of Toll Like Receptors (TLRs) in Oral Carcinogenesis Anticancer Res. 2017 37 5389 5394 28982847 10.21873/anticanres.11965

122. Okubo M. Kioi M. Nakashima H. Sugiura K. Mitsudo K. Aoki I. Taniguchi H. Tohnai I. M2-polarized macrophages contribute to neovasculogenesis, leading to relapse of oral cancer following radiation Sci Rep. 2016 6 27548 10.1038/srep27548 27271009 PMC4897643

123. Dewan K. Kelly R.D. Bardsley P. A national survey of consultants, specialists and specialist registrars in restorative dentistry for the assessment and treatment planning of oral cancer patients Br. Dent. J. 2014 216 E27 10.1038/sj.bdj.2014.544 24970541

124. Mukhopadhyaya R. Rao R.S. Fakih A.R. Gangal S.G. Detection of circulating immune complexes in patients with squamous cell carcinoma of the oral cavity J. Clin. Lab. Immunol. 1986 21 189 193 3494132

125. Adewole R.A. Alcohol, smoking and oral cancer. A 10-year retrospective study at Base Hospital, Yaba West Afr. J. Med. 2002 21 142 145 12403038

126. Kashyap T. Pramanik K.K. Nath N. Mishra P. Singh A.K. Nagini S. Rana A. Mishra R. Crosstalk between Raf-MEK-ERK and PI3K-Akt-GSK3β signaling networks promotes chemoresistance, invasion/migration and stemness via expression of CD44 variants (v4 and v6) in oral cancer Oral Oncol. 2018 86 234 243 10.1016/j.oraloncology.2018.09.028 30409306

127. Moore S. Johnson N. Pierce A. Wilson D. The epidemiology of lip cancer: A review of global incidence and aetiology Oral Dis. 1999 5 185 195 10.1111/j.1601-0825.1999.tb00300.x 10483063

128. Ueda N. Kamata N. Hayashi E. Yokoyama K. Hoteiya T. Nagayama M. Effects of an anti-angiogenic agent, TNP-470, on the growth of oral squamous cell carcinomas Oral Oncol. 1999 35 554 560 10.1016/S1368-8375(99)00031-7 10705089

129. Chen Y. Wang X. Fang J. Mesenchymal stem cells participate in oral mucosa carcinogenesis by regulating T cell proliferation Clin. Immunol. 2019 198 46 53 10.1016/j.clim.2018.12.001 30528889

130. Kikuchi K. Noguchi Y. de Rivera M.W. Detection of Epstein-Barr virus genome and latent infection gene expression in normal epithelia, epithelial dysplasia, and squamous cell carcinoma of the oral cavity Tumour Biol. 2016 37 3389 3404 10.1007/s13277-015-4167-7 26449822

131. Lenouvel D. González-Moles M.Á. Talbaoui A. An update of knowledge on PD-L1 in head and neck cancers: Physiologic, prognostic and therapeutic perspectives Oral Dis. 2020 26 511 526 10.1111/odi.13088 30866171

132. Brown A.M. Lally E.T. Frankel A. Harwick R. Davis L.W. Rominger C.J. The association of the IGA levels of serum and whole saliva with the progression of oral cancer Cancer 1975 35 1154 1162 10.1002/1097-0142(197504)35:4<1154::AID-CNCR2820350421>3.0.CO;2-D 803867

133. Johnson N.W. Az oralis carcinomák etiológiája és rizikófaktorai, különös tekintettel a dohányzásra és az alkoholfogyasztásra [Aetiology and risk factors for oral cancer, with special reference to tobacco and alcohol use] Magy Onkol. 2001 45 115 122 12050703

134. Adams S. Lin J. Brown D. Shriver C.D. Zhu K. Ultraviolet Radiation Exposure and the Incidence of Oral, Pharyngeal and Cervical Cancer and Melanoma: An Analysis of the SEER Data Anticancer Res. 2016 36 233 237 26722048

135. Kurokawa H. Tsuru S. Okada M. Nakamura T. Kajiyama M. Evaluation of tumor markers in patients with squamous cell carcinoma in the oral cavity Int. J. Oral Maxillofac. Surg. 1993 22 35 38 10.1016/S0901-5027(05)80353-4 7681461

136. Talamini R. Vaccarella S. Barbone F. Oral hygiene, dentition, sexual habits and risk of oral cancer Br. J. Cancer 2000 83 1238 1242 10.1054/bjoc.2000.1398 11027440 PMC2363583

137. La Rosa G.R.M. Gattuso G. Pedullà E. Rapisarda E. Nicolosi D. Salmeri M. Association of oral dysbiosis with oral cancer development Oncol. Lett. 2020 19 3045 3058 10.3892/ol.2020.11441 32211076 PMC7079586

138. Das D. Ghosh S. Maitra A. Epigenomic dysregulation-mediated alterations of key biological pathways and tumor immune evasion are hallmarks of gingivo-buccal oral cancer Clin. Epigenetics 2019 11 178 10.1186/s13148-019-0782-2 31796082 PMC6889354

139. Rajkumar T. Sridhar H. Balaram P. Oral cancer in Southern India: The influence of body size, diet, infections and sexual practices Eur. J. Cancer Prev. 2003 12 135 143 10.1097/00008469-200304000-00007 12671537

140. Khanna S. Immunological and biochemical markers in oral carcinogenesis: The public health perspective Int. J. Environ. Res. Public Health 2008 5 418 422 10.3390/ijerph5050418 19151437 PMC3700002

141. Engku Nasrullah Satiman E.A.F. Ahmad H. Ramzi A.B. Wahab R.A. Kaderi M.A. Harun W.H.A.W. Dashper S. The role of Candida albicans candidalysin ECE1 gene in oral carcinogenesis J. Oral Pathol. Med. 2020 49 835 841 10.1111/jop.13014 32170981

142. Wu T.S. Tan C.T. Chang C.C. B-cell lymphoma/leukemia 10 promotes oral cancer progression through STAT1/ATF4/S100P signaling pathway Oncogene. 2015 34 1207 1219 10.1038/onc.2014.43 24681956

143. Malinowska K. Morawiec-Sztandera A. Majsterek I. Kaczmarczyk D. TC2 C776G polymorphism studies in patients with oral cancer in the Polish population Pol. J. Pathol. 2016 67 277 282 10.5114/pjp.2016.63780 28155977

144. Leuci S. Coppola N. Blasi A. Oral Dysplastic Complications after HSCT: Single Case Series of Multidisciplinary Evaluation of 80 Patients Life 2020 10 236 10.3390/life10100236 33050268 PMC7600275

145. Anqi C. Takabatake K. Kawai H. Oo M.W. Yoshida S. Fujii M. Omori H. Sukegawa S. Nakano K. Tsuijigiwa H. Differentiation and roles of bone marrow-derived cells on the tumor microenvironment of oral squamous cell carcinoma Oncol. Lett. 2019 18 6628 6638 10.3892/ol.2019.11045 31807176 PMC6876317

146. Furquim C.P. Pivovar A. Amenábar J.M. Bonfim C. Torres-Pereira C.C. Oral cancer in Fanconi anemia: Review of 121 cases Crit. Rev.Oncol. Hematol. 2018 125 35 40 10.1016/j.critrevonc.2018.02.013 29650274

147. Shah A.T. Wu E. Wein R.O. Oral squamous cell carcinoma in post-transplant patients Am. J. Otolaryngol. 2013 34 176 179 10.1016/j.amjoto.2012.11.004 23332408

148. Elad S. Zadik Y. Zeevi I. Miyazaki A. de Figueiredo M.A. Or R. Oral cancer in patients after hematopoietic stem-cell transplantation: Long-term follow-up suggests an increased risk for recurrence Transplantation 2010 90 1243 1244 10.1097/TP.0b013e3181f9caaa 21119507

149. Abdelsayed R.A. Sumner T. Allen C.M. Treadway A. Ness G.M. Penza S.L. Oral precancerous and malignant lesions associated with graft-versus-host disease: Report of 2 cases Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2002 93 75 80 10.1067/moe.2002.119736 11805779

150. González-Moles M.Á. Ruiz-Ávila I. González-Ruiz L. Ayén Á. Gil-Montoya J.A. Ramos-García P. Malignant transformation risk of oral lichen planus: A systematic review and comprehensive meta-analysis Oral Oncol. 2019 96 121 130 10.1016/j.oraloncology.2019.07.012 31422203

151. Nagao Y. Sata M. Fukuizumi K. Harada H. Kameyama T. Oral cancer and hepatitis C virus (HCV): Can HCV alone cause oral cancer?—A case report Kurume Med. J. 1996 43 97 100 10.2739/kurumemedj.43.97 8709566

152. Nagao Y. Sata M. Noguchi S. Detection of hepatitis C virus RNA in oral lichen planus and oral cancer tissues J. Oral Pathol. Med. 2000 29 259 266 10.1034/j.1600-0714.2000.290604.x 10890556

153. Nagao Y. Sata M. Tanikawa K. Itoh K. Kameyama T. High prevalence of hepatitis C virus antibody and RNA in patients with oral cancer J. Oral Pathol. Med. 1995 24 354 360 10.1111/j.1600-0714.1995.tb01199.x 7500291

154. Nagao Y. Sata M. Oral verrucous carcinoma arising from lichen planus and esophageal squamous cell carcinoma in a patient with hepatitis C virus-related liver cirrhosis-hyperinsulinemia and malignant transformation: A case report Biomed. Rep. 2013 1 53 56 10.3892/br.2012.14 24648893 PMC3956769

155. Gandolfo S. Richiardi L. Carrozzo M. Risk of oral squamous cell carcinoma in 402 patients with oral lichen planus:A follow-up study in an Italian population Oral Oncol. 2004 40 77 83 10.1016/S1368-8375(03)00139-8 14662419

156. Wang L.Y. You S.L. Lu S.N. Risk of hepatocellular carcinoma and habits of alcohol drinking, betel quid chewing and cigarette smoking: A cohort of 2416 HBsAg-seropositive and 9421 HBsAg-seronegative male residents in Taiwan Cancer Causes Control 2003 14 241 250 10.1023/A:1023636619477 12814203

157. Kao C.H. Sun L.M. Liang J.A. Chang S.N. Sung F.C. Muo C.H. Relationship of zolpidem and cancer risk: A Taiwanese population-based cohort study Mayo Clin. Proc. 2012 87 430 436 10.1016/j.mayocp.2012.02.012 22560522 PMC3498427

158. Tandle A.T. Sanghvi V. Saranath D. Determination of p53 genotypes in oral cancer patients from India Br. J. Cancer 2001 84 739 742 10.1054/bjoc.2000.1674 11259085 PMC2363816

159. Shih L.C. Li C.H. Sun K.T. Association of Matrix Metalloproteinase-7 Genotypes to the Risk of Oral Cancer in Taiwan Anticancer Res. 2018 38 2087 2092 29599326 10.21873/anticanres.12448

160. Chiu C.F. Tsai M.H. Tseng H.C. Wang C.L. Tsai F.J. Lin C.C. Bau D.T. A novel single nucleotide polymorphism in ERCC6 gene is associated with oral cancer susceptibility in Taiwanese patients Oral Oncol. 2008 44 582 586 10.1016/j.oraloncology.2007.07.006 17933579

161. Park J.Y. Schantz S.P. Stern J.C. Kaur T. Lazarus P. Association between glutathione S-transferase pi genetic polymorphisms and oral cancer risk Pharmacogenetics 1999 9 497 504 10780269

162. Hatagima A. Costa E.C. Marques C.F. Koifman R.J. Boffetta P. Koifman S. Glutathione S-transferase polymorphisms and oral cancer: A case-control study in Rio de Janeiro, Brazil Oral Oncol. 2008 44 200 207 10.1016/j.oraloncology.2007.02.001 17418613

163. Misra C. Majumder M. Bajaj S. Ghosh S. Roy B. Roychoudhury S. Polymorphisms at p53, p73, and MDM2 loci modulate the risk of tobacco associated leukoplakia and oral cancer Mol Carcinog. 2009 48 790 800 10.1002/mc.20523 19204927

164. Sartor M. Steingrimsdottir H. Elamin F. Role of p16/MTS1, cyclin D1 and RB in primary oral cancer and oral cancer cell lines Br. J. Cancer 1999 80 79 86 10.1038/sj.bjc.6690505 10389982 PMC2363027

165. Chiang C.T. Chang T.K. Hwang Y.H. A critical exploration of blood and environmental chromium concentration among oral cancer patients in an oral cancer prevalent area of Taiwan Environ. Geochem. Health 2011 33 469 476 10.1007/s10653-010-9346-2 20978824

166. Chen W.C. Chen M.F. Lin P.Y. Significance of DNMT3b in oral cancer PLoS ONE 2014 9 e89956 10.1371/journal.pone.0089956 24625449 PMC3953114

167. Kang D. Gridley G. Huang W.Y. Microsatellite polymorphisms in the epidermal growth factor receptor (EGFR) gene and the transforming growth factor-alpha (TGFA) gene and risk of oral cancer in Puerto Rico Pharmacogenet. Genom. 2005 15 343 347 10.1097/01213011-200505000-00010 15864136

168. Rao A.K.D.M. Manikandan M. Arunkumar G. Revathidevi S. Vinothkumar V. Arun K. Tiwary B.K. Rajkumar K.S. Prevalence of p53 codon 72, p73 G4C14-A4T14 and MDM2 T309G polymorphisms and its association with the risk of oral cancer in South Indians Gene Rep. 2017 7 106 112 10.1016/j.genrep.2017.03.003

169. Yen C.Y. Liu S.Y. Chen C.H. Tseng H.F. Chuang L.Y. Yang C.H. Lin Y.C. Wen C.H. Chiang W.F. Ho C.H. Combinational polymorphisms of four DNA repair genes XRCC1, XRCC2, XRCC3, and XRCC4 and their association with oral cancer in Taiwan J. Oral Pathol. Med. 2008 37 271 277 10.1111/j.1600-0714.2007.00608.x 18410587

170. Ramachandran S. Ramadas K. Hariharan R. Rejnish Kumar R. Radhakrishna Pillai M. Single nucleotide polymorphisms of DNA repair genes XRCC1 and XPD and its molecular mapping in Indian oral cancer Oral Oncol. 2006 42 350 362 10.1016/j.oraloncology.2005.08.010 16324877

171. Shukla D. Dinesh Kale A. Hallikerimath S. Vivekanandhan S. Venkatakanthaiah Y. Genetic polymorphism of drug metabolizing enzymes (GSTM1 and CYP1A1) as risk factors for oral premalignant lesions and oral cancer Biomed. Pap. Med. Fac. Univ. Palacky Olomouc. Czech Repub. 2012 156 253 259 10.5507/bp.2012.013 22660220

172. Park J.Y. Muscat J.E. Ren Q. CYP1A1 and GSTM1 polymorphisms and oral cancer risk Cancer Epidemiol. Biomark. Prev. 1997 6 791 797 9332761

173. Cha I.H. Park J.Y. Chung W.Y. Choi M.A. Kim H.J. Park K.K. Polymorphisms of CYP1A1 and GSTM1 genes and susceptibility to oral cancer Yonsei Med. J. 2007 48 233 239 10.3349/ymj.2007.48.2.233 17461521 PMC2628133

174. Carneiro N.K. Oda J.M. Losi Guembarovski R. Ramos G. Oliveira B.V. Cavalli I.J. Ribeiro E.M.d.S.F. Goncalves M.S.B. Watanabe M.A.E. Possible association between TGF-β1 polymorphism and oral cancer Int. J. Immunogenet. 2013 40 292 298 10.1111/iji.12037 23442056

175. Wang L.-H. Ting S.-C. Chen C.-H. Tsai C.-C. Lung O. Liu T.-C. Lee C.-W. Wang Y.-Y. Tsai C.-L. Lin Y.-C. Polymorphisms in the apoptosis-associated genes FAS and FASL and risk of oral cancer and malignant potential of oral premalignant lesions in a Taiwanese population J. Oral Pathol. Med. 2010 39 155 161 10.1111/j.1600-0714.2009.00873.x 20359312

176. Chung T.T. Pan M.S. Kuo C.L. Impact of RECK gene polymorphisms and environmental factors on oral cancer susceptibility and clinicopathologic characteristics in Taiwan Carcinogenesis 2011 32 1063 1068 10.1093/carcin/bgr083 21565829

177. Shukla D. Dinesh Kale A. Hallikerimath S. Yerramalla V. Subbiah V. Mishra S. Association between GSTM1 and CYP1A1 polymorphisms and survival in oral cancer patients Biomed. Pap. Med. Fac. Univ. Palacky Olomouc. Czech Repub. 2013 157 304 310 10.5507/bp.2013.028 23681307

178. Gunduz E. Gunduz M. Ouchida M. Genetic and epigenetic alterations of BRG1 promote oral cancer development Int. J. Oncol. 2005 26 201 210 10.3892/ijo.26.1.201 15586241

179. Merrill R.M. Isakson R.T. Beck R.E. The association between allergies and cancer: What is currently known? Ann. Allergy Asthma Immunol. 2007 99 102 150 10.1016/S1081-1206(10)60632-1 17718097

180. Li G. Sturgis E.M. Wang L.E. Association of a p73 exon 2 G4C14-to-A4T14 polymorphism with risk of squamous cell carcinoma of the head and neck Carcinogenesis 2004 25 1911 1916 10.1093/carcin/bgh197 15180941

181. Twu C.W. Jiang R.S. Shu C.H. Lin J.C. Association of p53 codon 72 polymorphism with risk of hypopharyngeal squamous cell carcinoma in Taiwan J. Formos. Med. Assoc. 2006 105 99 104 10.1016/S0929-6646(09)60330-2 16477330

182. Katoh T. The frequency of glutathione-S-transferase M1 (GSTM1) gene deletion in patients with lung and oral cancer Sangyo Igaku. 1994 36 435 439 10.1539/joh1959.36.6_435 7844900

183. Wang Z. The role of COX-2 in oral cancer development, and chemoprevention/ treatment of oral cancer by selective COX-2 inhibitors Curr. Pharm. Des. 2005 11 1771 1777 10.2174/1381612053764887 15892674

184. Liu F. Liu L. Li B. p73 G4C14-A4T14 polymorphism and cancer risk: A meta-analysis based on 27 case-control studies Mutagenesis 2011 26 573 581 10.1093/mutage/ger018 21502193

185. Singh A.P. Shah P.P. Ruwali M. Mathur N. Pant M.C. Parmar D. Polymorphism in cytochrome P4501A1 is significantly associated with head and neck cancer risk Cancer Investig. 2009 27 869 876 10.1080/07357900902849657 19639480

186. Shillitoe E.J. The role of viruses in squamous cell carcinoma of the oropharyngeal mucosa Oral Oncol. 2009 45 351 355 10.1016/j.oraloncology.2008.08.001 18952492

187. Beppu M. Ikebe T. Shirasuna K. The inhibitory effects of immunosuppressive factors, dexamethasone and interleukin-4, on NF-kappaB-mediated protease production by oral cancer Biochim. Biophys. Acta 2002 1586 11 22 10.1016/S0925-4439(01)00080-1 11781145

188. Van der Meij E.H. Epstein J.B. Hay J. Ho V. Lerner K. Sweet’s syndrome in a patient with oral cancer associated with radiotherapy Eur. J. Cancer B Oral Oncol. 1996 32B 133 136 10.1016/0964-1955(95)00070-4 8736177

189. Uittamo J. Siikala E. Kaihovaara P. Salaspuro M. Rautemaa R. Chronic candidosis and oral cancer in APECED-patients: Production of carcinogenic acetaldehyde from glucose and ethanol by Candida albicans Int. J. Cancer 2009 124 754 756 10.1002/ijc.23976 18975379

190. Shillitoe E.J. The role of immunology in the diagnosis, prognosis and treatment planning of oral cancer Proc. R. Soc. Med. 1976 69 747 749 186794 10.1177/003591577606901007 PMC1864661

191. Meurman J.H. Infectious and dietary risk factors of oral cancer Oral Oncol. 2010 46 411 413 10.1016/j.oraloncology.2010.03.003 20381409

192. Sanjaya P.R. Gokul S. Gururaj Patil B. Raju R. Candida in oral pre-cancer and oral cancer Med. Hypotheses 2011 77 1125 1128 10.1016/j.mehy.2011.09.018 21978967

193. Morris L.G. Patel S.G. Shah J.P. Ganly I. Squamous cell carcinoma of the oral tongue in the pediatric age group: A matched-pair analysis of survival Arch. Otolaryngol. Head Neck Surg. 2010 136 697 701 10.1001/archoto.2010.94 20644066 PMC3005582

194. Hara H. Ozeki S. Nagata T. Okamoto M. Sasaguri M. Tashiro H. Jingu K. Pulmonary tuberculosis in patients with oral cancer Gan No Rinsho. 1988 34 1647 1653 3193609

195. Laprise C. Shahul H.P. Madathil S.A. Periodontal diseases and risk of oral cancer in Southern India: Results from the HeNCe Life study Int. J. Cancer. 2016 139 1512 1519 10.1002/ijc.30201 27215979

196. Arantes D.A. Costa N.L. Mendonça E.F. Silva T.A. Batista A.C. Overexpression of immunosuppressive cytokines is associated with poorer clinical stage of oral squamous cell carcinoma Arch. Oral Biol. 2016 61 28 35 10.1016/j.archoralbio.2015.10.013 26513679

197. Hwang P.H. Lian L. Zavras A.I. Alcohol intake and folate antagonism via CYP2E1 and ALDH1: Effects on oral carcinogenesis Med. Hypotheses 2012 78 197 202 10.1016/j.mehy.2011.10.023 22100631 PMC3250228

198. Mun M. Yap T. Alnuaimi A.D. Adams G.G. McCullough M.J. Oral candidal carriage in asymptomatic patients Aust. Dent. J. 2016 61 190 195 10.1111/adj.12335 25912248

199. Krogh P. Hald B. Holmstrup P. Possible mycological etiology of oral mucosal cancer: Catalytic potential of infecting Candida albicans and other yeasts in production of N-nitrosobenzylmethylamine Carcinogenesis 1987 8 1543 1548 10.1093/carcin/8.10.1543 3652390

200. Yakin M. Gavidi R.O. Cox B. Rich A. Oral cancer risk factors in New Zealand N. Z. Med. J. 2017 130 30 38 28253242

201. Sheu J.J. Keller J.J. Lin H.C. Increased risk of cancer after Bell’s palsy: A 5-year follow-up study J. Neurooncol. 2012 110 215 220 10.1007/s11060-012-0954-9 22890970

202. Ma’aita J.K. Oral cancer in Jordan: A retrospective study of 118 patients Croat. Med. J. 2000 41 64 69 10810170

203. Mäkinen A. Nawaz A. Mäkitie A. Meurman J.H. Role of Non-Albicans Candida and Candida Albicans in Oral Squamous Cell Cancer Patients J. Oral Maxillofac. Surg. 2018 76 2564 2571 10.1016/j.joms.2018.06.012 30509395

204. Menicagli R. Bolla G. Menicagli L. Esseridou A. The Possible Role of Diabetes in the Etiology of Laryngeal Cancer Gulf. J. Oncolog. 2017 1 44 51 28272002

205. Bhattathiri N.V. Bindu L. Remani P. Chandralekha B. Nair K.M. Radiation-induced acute immediate nuclear abnormalities in oral cancer cells: Serial cytologic evaluation Acta Cytol. 1998 42 1084 1090 10.1159/000332093 9755662

206. D’Costa J. Saranath D. Sanghvi V. Mehta A.R. Epstein-Barr virus in tobacco-induced oral cancers and oral lesions in patients from India J. Oral Pathol. Med. 1998 27 78 82 10.1111/j.1600-0714.1998.tb02098.x 9526734

207. Jin X. Lu S. Xing X. Wang L. Mu D. He M. Huang H. Zeng X. Chen Q. Thalidomide: Features and potential significance in oral precancerous conditions and oral cancer J. Oral Pathol. Med. 2013 42 355 362 10.1111/jop.12004 22978368

208. Gall F. Colella G. Di Onofrio V. Rossiello R. Angelillo I.F. Liguori G. Candida spp. in oral cancer and oral precancerous lesions New Microbiol. 2013 36 283 288 23912870

209. Vijayakumar T. Sasidharan V.K. Ankathil R. Remani P. Kumari T.V. Vasudevan D.M. Incidence of hepatitis B surface antigen (HBsAg) in oral cancer and carcinoma of uterine cervix Indian J. Cancer 1984 21 7 10 6510943

210. Li M.H. Ito D. Sanada M. Odani T. Hatori M. Iwase M. Nagumo M. Effect of 5-fluorouracil on G1 phase cell cycle regulation in oral cancer cell lines Oral Oncol. 2004 40 63 70 10.1016/S1368-8375(03)00136-2 14662417

211. Mawardi H. Elad S. Correa M.E. Stevenson K. Woo S.B. Almazrooa S. Haddad R. Antin H.J. Soiffer R. Treister H. Oral epithelial dysplasia and squamous cell carcinoma following allogeneic hematopoietic stem cell transplantation: Clinical presentation and treatment outcomes Bone Marrow Transplant. 2011 46 884 891 10.1038/bmt.2011.77 21460866 PMC3111881

212. Gruter M.O. Brand H.S. Oral health complications after a heart transplant: A review Br. Dent. J. 2020 228 177 182 10.1038/s41415-020-1244-0 32060460

213. Sankaranarayanan R. Dinshaw K. Nene B.M. Cervical and oral cancer screening in India J. Med. Screen. 2006 13 (Suppl. 1) S35 S38 17227640

214. Nagasaka M. Zaki M. Kim H. PD1/PD-L1 inhibition as a potential radiosensitizer in head and neck squamous cell carcinoma: A case report J. Immunother. Cancer 2016 4 83 10.1186/s40425-016-0187-0 27895920 PMC5109767

215. Kapoor V. Aggarwal S. Das S.N. 6-Gingerol Mediates its Anti- Tumor Activities in Human Oral and Cervical Cancer Cell Lines through Apoptosis and Cell Cycle Arrest Phytother. Res. 2016 30 588 595 10.1002/ptr.5561 26749462

216. Ha N.H. Park D.G. Woo B.H. Porphyromonas gingivalis increases the invasiveness of oral cancer cells by upregulating IL-8 and MMPs Cytokine 2016 86 64 72 10.1016/j.cyto.2016.07.013 27468958

217. Ahmed H.G. Aetiology of oral cancer in the Sudan J. Oral Maxillofac. Res. 2013 4 e3 10.5037/jomr.2013.4203 24422031 PMC3886112

218. Lucchese A. Viruses and Oral Cancer: Crossreactivity as a Potential Link Anticancer Agents Med. Chem. 2015 15 1224 1229 10.2174/1871520615666150716105654 26179264