Association Between Diabetes Mellitus and Head and Neck Cancer: An Umbrella Review of Systematic Reviews and Meta-Analyses

Abstract

Background/Objectives: Emerging evidence links diabetes to increased cancer risk. This study aimed to assess the association between diabetes mellitus (DM)(type 1, type 2, or gestational) and the development of head and neck cancer. Methods: An umbrella review was conducted using systematic searches in Cochrane, EBSCO, Wiley, ScienceDirect, and PubMed (January 2000–January 2024), registered in PROSPERO (CRD42024512151). Included were systematic reviews (SRs) and meta-analyses (MAs) of observational studies. Article selection followed the PRISMA guidelines; the quality and risk of bias of the selected studies were assessed with the Joanna Briggs Institute Checklist. The GROOVE tool was used to identify double counting. Two independent reviewers screened studies, with a third resolving disagreements. Results: Seven SRs were included. While DM has been widely examined in cancer research, few studies specifically targeted head and neck cancers. Of the 20 associations between various cancer sites and diabetes types, 9 (45%) showed a statistically significant positive correlation. The strongest evidence was for overall cancer risk (RR = 1.22, 95% CI: 1.16–1.29, p < 0.001). Oral cancer showed elevated risks (RRR = 1.13, p = 0.009; OR = 1.32, p < 0.001; HR = 1.73, p < 0.05; RR = 1.28, p < 0.05). Increased risks were also observed for oropharyngeal (RR = 1.18; HR = 1.53), head and neck (HR = 1.47), and nasopharyngeal cancer (OR = 1.40), all p < 0.05. Heterogeneity was low in two reviews, unreported in one, and high in four. Five SRs reported associated risk factors. Conclusions: While some associations between DM and cancer appear significant, evidence remains limited and inconsistent, particularly for oral cancer. Further standardized, high-quality research is needed to clarify the link across head and neck cancer subtypes.

1. Introduction

Oral cancer is a serious disease that affects the oral cavity and its surrounding structures, such as the lips, tongue, jugal mucosa, palate, and floor of the mouth, the tongue being the most affected area [1]. It can manifest itself in various ways, including persistent ulcers, abnormal white or red spots, swelling or unexpected lumps, persistent pain and difficulty in speaking, and swallowing or chewing [1,2,3]. It is more common in men aged 50 and over [4]. The treatment of oral cancer depends on several factors, including the stage of the disease, the location of the tumor, the patient’s general state of health and other individual factors [4]. Generally, treatment involves a multidisciplinary approach that can include surgery, radiotherapy, chemotherapy, and targeted therapies [1,3,5].

Head and neck cancers (HNCs) predominantly originate in the oral cavity, oropharynx, hypopharynx, and larynx, with squamous cell carcinoma being the most common histological subtype. Globally, over 500,000 new cases are diagnosed each year, ranking HNC as the sixth most prevalent type of cancer. Established risk factors include tobacco use, alcohol consumption, and human papillomavirus (HPV) infection, particularly in oropharyngeal cancers [6]. In addition to surgery, radiation therapy (RT) is a cornerstone of curative-intent treatment for both early and advanced stages of head and neck cancer. However, despite the use of multimodal strategies, clinical outcomes remain suboptimal, with approximately 50% of patients experiencing local recurrence within three years and a relatively high incidence of severe RT-associated toxicities [7].

Diabetes is a chronic condition that affects the body’s ability to regulate blood sugar levels. There are two main types of diabetes, as follows: type 1, which is an autoimmune condition in which the body does not produce insulin due to the self-destruction of the pancreas β cells [8], and type 2, which is more common and is characterized by the failure of pancreatic β-cell islets resulting from the body’s resistance to insulin, associated with a decrease in β-cell mass and function and an increase in glucagon secretion. Type 2 diabetes results from the interaction between individual genetic predisposition and environmental stimuli/exposure [9]. Both types of diabetes can increase the risk of various health complications and affects the treatment of certain diseases [10].

The relationship between head and neck cancer and diabetes is complex and multifactorial. Some studies suggest that diabetic patients may have a slightly increased risk of developing oral cancer, possibly due to factors such as chronic inflammation and a compromised immune system [11,12], as type 1 individuals have a lower risk than type 2 individuals [13]. In addition, inadequate control of blood sugar levels in diabetic patients may contribute to the growth and spread of oral cancer [14].

The primary aim of this study was to investigate whether there is a significant and positive relationship between the presence of diabetes mellitus—encompassing type 1 diabetes, type 2 diabetes, and gestational diabetes—and the subsequent development of head and neck cancer. This investigation seeks to explore the potential link between these conditions by examining their association in detail and evaluating whether individuals diagnosed with any form of diabetes mellitus are at an increased risk of developing head and neck cancer.

2. Materials and Methods

This study was prepared in accordance with the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines [15]. The umbrella review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the number CRD 42024512151.

The central question “Is there a relationship between diabetes mellitus and head and neck carcinoma?” is explained based on the PECO (Population, Exposition, Comparison, and Outcome) strategy shown in

Table 1. Explanation of the PECO.

Component	Explanation
Population	Any kind of patients
Exposure	Having diabetes
Comparison	Not having diabetes
Outcome	Probability of having head and neck cancer

.

2.1. Literature Search

A search was carried out independently by two reviewers (F.F. and A.A.), with a third reviewer consulted at a given selection stage (M.C.M.). The search was conducted separately for each database, covering the period from January 2000 to 15 January 2024. All searches were conducted on 15 January 2024, using the queries listed in

Table 2. Queries used per database.

Database	Query
PubMED	((“diabetes”[All Fields] OR “diabetes mellitus”[MeSH Terms] OR (“diabetes”[All Fields] AND “mellitus”[All Fields]) OR “diabetes mellitus”[All Fields] OR “diabetes”[All Fields] OR “diabetes insipidus”[MeSH Terms] OR (“diabetes”[All Fields] AND “insipidus”[All Fields]) OR “diabetes insipidus”[All Fields] OR “diabetic”[All Fields] OR “diabetics”[All Fields] OR “diabets”[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] OR (“carcinoma”[MeSH Terms] OR “carcinoma”[All Fields] OR “carcinomas”[All Fields] OR “carcinoma s”[All Fields]) OR (“neoplasms”[MeSH Terms] OR “neoplasms”[All Fields] OR “neoplasia”[All Fields] OR “neoplasias”[All Fields]) OR (“cysts”[MeSH Terms] OR “cysts”[All Fields] OR “cyst”[All Fields] OR “neurofibroma”[MeSH Terms] OR “neurofibroma”[All Fields] OR “neurofibromas”[All Fields] OR “tumor s”[All Fields] OR “tumoral”[All Fields] OR “tumorous”[All Fields] OR “tumour”[All Fields] OR “neoplasms”[MeSH Terms] OR “neoplasms”[All Fields] OR “tumor”[All Fields] OR “tumour s”[All Fields] OR “tumoural”[All Fields] OR “tumourous”[All Fields] OR “tumours”[All Fields] OR “tumors”[All Fields]) OR (“neoplasm s”[All Fields] OR “neoplasms”[MeSH Terms] OR “neoplasms”[All Fields] OR “neoplasm”[All Fields]) OR (“maligna”[All Fields] OR “malignas”[All Fields]) OR (“adenocarcinoma”[MeSH Terms] OR “adenocarcinoma”[All Fields] OR “adenocarcinomas”[All Fields] OR “adenocarcinoma s”[All Fields])) AND (“meta analysis”[Publication Type] OR “meta analysis as topic”[MeSH Terms] OR “meta analysis”[All Fields] OR (“systematic review”[Publication Type] OR “systematic reviews as topic”[MeSH Terms] OR “systematic review”[All Fields])) AND (“mouth”[MeSH Terms] OR “mouth”[All Fields] OR “oral”[All Fields] OR (“buccal”[All Fields] OR “buccally”[All Fields]) OR (“head”[MeSH Terms] OR “head”[All Fields]) OR (“neck”[MeSH Terms] OR “neck”[All Fields]))) AND ((meta-analysis[Filter] OR systematicreview[Filter]) AND (fft[Filter]) AND (humans[Filter]) AND (english[Filter]) AND (2000:2024[pdat]))
EBSCO	“((diabetes) AND (cancer OR carcinoma OR neoplasm OR tumour OR neoplasm OR malignant) AND (meta-analysis OR systematic review) AND (oral OR buccal OR head OR neck))” 2000-2024
Science Direct	“((diabetes) AND (cancer OR carcinoma OR neoplasm) AND (meta-analysis OR systematic review) AND (oral OR head))” 2000–2024
Wiley	“((diabetes) AND (cancer OR carcinoma OR neoplasm OR tumour OR neoplasm OR malignant) AND (meta-analysis OR systematic review) AND (oral OR buccal OR head OR neck)) 2000–2024 and open access only
Cochrane	“((diabetes) AND (cancer OR carcinoma OR neoplasm OR tumor OR neoplasm OR malignant) AND (meta-analysis OR systematic review) AND (oral OR buccal OR head OR neck))” 2000–2024

and applying the inclusion and exclusion criteria described in

Table 3. Eligible criteria.

Inclusion Criteria	Exclusion Criteria
Meta-analyses and systematic reviews	Types of cancer other than head and neck as an outcome
From the beginning of 2000 to the end of January 2024	Associations other than diabetes mellitus with oral cancer
English only	Studies with no original data or effect statistics reported. Results that cannot be interpreted/converted into categorical
Open access (in the case of Science Direct)
Human participants, regardless of age and gender	Human studies only: no in vivo, animal, or in vitro cell line studies
Study subjects must have type 1 or type 2 diabetes	Associations other than diabetes mellitus with oral cancer

. For Science Direct specifically, the search was performed with fewer keywords, as the platform only allows up to 8 Boolean expressions.

2.2. Selection of Studies and Eligibility

Duplicate articles were removed, and the reviewers screened the articles through the title and abstract and discussed the results based on the inclusion/exclusion criteria (Table 3).

The search using all six databases and the query (keywords) shown in Table 2 returned 15,957 papers, as can be seen in Figure 1. In the initial phase, 15,876 papers were removed (after analyzing the title and year), leaving 81 studies, and from those, 7 were removed due to duplication. The remaining 74 papers were screened and fully read by two authors (F.F. and A.A.) and later also approved by a third reviewer (M.C.M.). The reading led to the exclusion of a total of 69 papers, 44 because they were neither meta-analyses nor systematic reviews, 5 because diabetes mellitus was not the exposure of interest, 8 because they were Umbrella reviews, 2 because the association in question was not the one intended, and 10 because oral cancer (any location of oral cancer) was not the outcome of interest. This analysis gave five SR or MA papers to be included in the present umbrella.

In addition, 566 articles were identified for searching only for the words “Diabetes Mellitus and Oral Cancer”, or taken from the reference list of umbrellas that appeared in the previous search (564 belonging to eight umbrellas and 2 at random). Of those, 557 were excluded after analyzing the year of publication and title due to disagreement with the proposed objectives. After an evaluation by the two reviewers (FF and AA), three articles were excluded because they did not include associations within the scope of this study, one because oral cancer was not the outcome observed, and one because it was not in the format of a systematic review or meta-analysis. The standard Joanna Briggs Institute Critical Appraisal Checklist for Systematic Re-views and Research Synthesis was used [16,17].

From the two search strategies, the literature search on this topic resulted in seven papers [14,18,19,20,21,22,23] that were integrated in this umbrella review (Figure 1).

2.3. Data Extraction

From the papers that met the eligibility criteria and were included in this umbrella review, the following information was extracted for correct data analysis: (a) author and year of publication; (b) journal; (c) population; (d) outcome; (e) sample size (number of patients and studies); (f) guidelines used; (g) PROSPERO code; (h) search strategy and date; (h) eligibility criteria; (i) diagnostic criteria for diabetes or oral cancer conditions; (j) assessment of the risk of bias; (k) whether there was a meta-analysis or not; (l) associated risk factors; (m) conflict of interest; (n) type of association; (o) fixed or random RR; (p) fixed or random p-value and prediction interval; (q) Egger’s p-value; (r) I² and p-value; and (s) AMSTAR and classification of the evidence of the articles.

2.4. Risk of Bias

The selected systematic reviews were critically appraised independently by two reviewers (F.F. and A.A.), and when necessary, a third reviewer (M.C.M.) solved disagreements by consensus. The standard Joanna Briggs Institute Critical Appraisal Checklist for Systematic Reviews and Research Synthesis was used [16,17] and followed the JBI Reviewers’ Manual (2020) with 10 questions [17]. Whenever necessary, authors of the systematic reviews were contacted to request missing or additional information such as in Gormley et al. 2022 [23]. For the checklist appraisal, studies that were deemed of low quality (≤3 yes/10 questions) were excluded, while we included any that showed moderate quality (4–6 yes/10 questions) and high quality (7–10 yes/10 questions) [16,17].

2.5. Strategy for Data Synthesis

Study double counting in different systematic reviews was presented visually using the Graphical Representation of Overlap for OVErviews (GROOVE) tool, which is a methodological approach and a tool that facilitates the assessment of primary study overlap among multiple systematic reviews.

3. Results

3.1. Study Characteristics

Of the seven systematic reviews and meta-analysis included in this umbrella review (Table 4), including Gong et al. (2015) [14], Sona et al. (2018) [18], Ohkuma et al. (2018) [19], Ramos-Garcia et al. (2020) [20], Yan et al. (2021) [21], Dos Santos et al. (2022) [22], and Gormley et al. (2022) [23], there were associations of diabetes mellitus with risk of oral cancer overall (n = 7) [14,18,19,20,21,22], oral cavity (n = 2) [19,21], lip cancer (n = 1) [19], head and neck (n = 3) [19,21,22], nasopharynx (n = 2) [19,21], oropharyngeal (n = 4) [19,20,21,22], oral squamous cell carcinoma (n = 1) [20], and a mix between oral squamous cell carcinoma and oropharyngeal (n = 1) [20]. Although there was no restriction on the type of diabetes, there were two papers that focused just on diabetes mellitus type 2, one on diabetes mellitus type 1, and the remaining five focused on both types of diabetes mellitus, without making a distinction between types.

The number of studies overall was 350. We only considered the measures of association OR, RR, HR, or RRR, and excluded data on incidence or mortality rates. The lowest number of cases of oral cancer in a meta-analysis was 6465 in Gong et al. (2015) [14].

When it comes to the guidelines for the selection of studies, these were similar in five of the seven reviews [19,20,21,22,23], using the PRISMA method; one using MOOSE [14]; and the other used no specific guideline [18]. The Newcastle–Ottawa Quality Assessment Scale (NOS) was also used for critically appraising 4 of them [14,18,19,21], GRADE for just one [20], and ROBINS-E in another one [23] (Table 4). All of them were meta-analyses and only three had a PROSPERO code [20,22,23] (Table 4).

The risk of bias was evaluated with funnel plots and Begg’s and Egger’s tests in four of the seven reviews, the Joanna Briggs Institute was used in two [20,22], and ROBINS-E in one [23] (Table 5). There was only one systematic review that mentioned diagnostic criteria of diabetes mellitus for inclusion in the study [23]. The time frame of the reviewed studies ranges from 1961 to 2022 (Table 5). Two studies [19,20] did not consider any risk factors while conducting the review (Table 5). There was no funding disclosed for the seven papers in question.

The studies recruited patients from 29 countries, 47 studies conducted in Asia, 73 in Europe, 29 in America, 6 in Oceania, and 1 in Africa (Table 6).

3.2. Quantitative Evaluation

Of these seven reviews included (Table 7), 9 out of 20 (45%) significant associations of increased risk of cancer were found, meaning that the RR, OR, RRR, and HR confidence intervals were higher than 1, with significance when extrapolated to the population (where there is a significant association). For oral cancer, this significant increase was found in Ohkuma et al. (2018) [19], RRR = 1.13 (p = 0.009); Ramos-Garcia et al. (2020) [20], OR = 1.32 (p < 0.001); dos Santos et al. (2022) [22], HR = 1.73 (p < 0.05); Yan et al. (2021) [21], RR = 1.28 (p < 0.05). For oral squamous cell carcinoma, a significant increase was observed for Ramos-Garcia et al. (2020) [20], OR = 1.41 (p < 0.001). For oropharyngeal, a significant increase was depicted by Yan et al. (2021) [21], RR = 1.18 (p < 0.05), and dos Santos et al. (2022) [22], HR = 1.53 (p < 0.05). Regarding head and neck cancer, a significant increase was shown by dos Santos et al. (2022) [22], HR = 1.47 (p < 0.05). For nasopharyngeal, this was found by dos Santos et al. (2022) [22], OR = 1.40 (p < 0.05).

The most robust evidence was seen in Gormley et al. (2022) [23], for the relation with overall cancer (RR fixed effects = 1.22, 95%CI = 1.16–1.29, p < 0.001), with RR calculated using the fixed effects method (Table 7). The effect of the largest study included in each meta-analysis is also depicted in Table 6.

Regarding heterogeneity (using the Q test), there were two meta-analyses with low heterogeneity [14,18], one [19] with nothing being mentioned, and four with high heterogeneity [20,21,22,23].

The only study retrieved from dos Santos et al. (2022) [22] was the one of Tseng et al. (2014 ) [24] (where the OR estimative was extracted from), because it was the only one from which the author of the systematic review drew information about the target population of the present review, results, and association of interest (diabetes mellitus and head and neck cancer).

There was no evidence for the presence of small study effects according to Egger’s test (Table 7), except for the incidence of endometrial and hepatocellular cancer, where p < 0.10 with more conservative effects in the larger studies.

Table 4. Description of the 7 studies of diabetes mellitus and oral cancer association included in umbrella review, part I.

Authors (Year)	Population	Outcome	Sample Size (Patients)	Guidelines	PROSPERO Code	Search Strategy (Date)	Eligibility Criteria Restrictions
[14] Gong et al. (2015)	Patients with diabetes mellitus type 2	Oral cancer and precancerous lesions	17 studies total; 13 for oral cancer with 4,8 million participants and 6465 cases with oral cancer	MOOSE	ND	MEDLINE and EMBASE through 31 May 2014	(a) original data from case–control or cohort studies; (b) exposure was type 2 DM; (c) outcome was oral cancers or precancerous lesions; (d) studies should report either adjusted OR, RR, hazard ratio (HR), or standardized incidence/mortality ratios (SIR/SMR) with their 95% Cis (or data to calculate them).
[18] Sona et al. (2018)	Type 1 Diabetes mellitus patients	Various types of cancer including head and neck	15 observational studies with two case–control studies and 13 cohort studies from 11 articles	ND	ND	PubMed and EMBASE in April 2017	(a) case–control studies and prospective or retrospective cohort studies; (b) association between type 1 diabetes and the risk of cancer; (c) reporting measures of outcomes with adjusted odds ratios (Ors) or relative risks (RRs) and 95% confidence intervals (Cis); (d) data identical in more than one study or duplicated, the more comprehensive or first published study was included in the analysis.
[19] Ohkuma et al. (2018)	Diabetes of type 1 or type 2	Cancer, overall and by site	108 studies total, 19 million participants	PRISMA	ND	PubMed on 23 December 2016	(a) observational cohort studies if they had provided RR; (b) exclusion if they had not adjusted at least for age or did not provide information about the variability around the point estimate or if they only had data for one sex; (c) in duplicate reports from the same study, the one with the longest follow-up or the highest number of cases was included.
[20] Ramos-Garcia et al. (2020)	Diabetes of type 1 or type 2	Oral cancer or oral potentially malignant disorders	52 studies, 559,927 participants	PRISMA	CRD42020162848	PubMed; Embase, Web of Science; Scopus; until November 2019	(a) original studies, without language, publication date, sex, or age restrictions; (b) oral cancer in type 1 or type 2 DM; (c) cohort, case–control and cross-sectional studies; (d) exclusion of animal research or in vitro studies; (e) results from the same study where included the most recent or with more data.
[21] Yan et al. (2021)	Diabetes mellitus type 2	Head and neck cancer subtypes	27 studies, 1.4 million T2DM cases and 23,045 HNC cases	PRISMA	ND	PubMed, Web of Science and Embase, on 31 July 2020	(a) cohort or case–control study; (b) exposure of T2DM; (c) primary outcome was incidence of HNC, oral cancer, pharyngeal cancer, or laryngeal cancer; (d) reported the risk estimates OR, standard incidence ratio (SIR), RR or hazard ratio (HR), and 95% confidence intervals; (e) when multiple articles come from the same, we only include the longest duration of follow-up.
[22] Dos Santos et al. (2022)	Patients with systemic conditions	Oral squamous cell carcinoma	95 studies total, 14,442,487 participants	PRISMA—PECOS	CRD42021242702	PubMed; Scopus; Web of Science; Embase; Google Scholar; OpenGrey; ProQuest Dissertation & Theses Global; on 27 February 2021 and updated on 19 February 2022	(a) English articles; (b) with systemic conditions; (c) systemic conditions associated with increased risk to develop OSCC; (d) observational studies.
[23] Gormley et al. (2022)	Metabolic disorders	Head and neck cancer	36 studies total; 15 between diabetes type 2 and HNC	PRISMA	CRD42021250520	January 1966 to November 2021, including Cochrane Library, OVID SP versions of Medline and EMBASE; Cochrane Library, EthOS, Google Scholar, Open Grey and ClinicalTrials.gov (gray literature)	(a) participants over 18 years old, of either sex, from any ethnic background; (b) with T2D, obesity, dyslipidemia or hypertension; (c) outcome HNSCC which may be human papilloma virus (HPV) positive or negative and high-risk types HPV16, 18, 31 and 33 only will be included; (d) All studies published from January 1966 in the English language; (e) observational with head and neck squamous cell carcinoma; (f) with OR or risk ratio, or data which will allow to calculate

Table 4. Description of the 7 studies of diabetes mellitus and oral cancer association included in umbrella review, part I.

Authors (Year)	Population	Outcome	Sample Size (Patients)	Guidelines	PROSPERO Code	Search Strategy (Date)	Eligibility Criteria Restrictions
[14] Gong et al. (2015)	Patients with diabetes mellitus type 2	Oral cancer and precancerous lesions	17 studies total; 13 for oral cancer with 4,8 million participants and 6465 cases with oral cancer	MOOSE	ND	MEDLINE and EMBASE through 31 May 2014	(a) original data from case–control or cohort studies; (b) exposure was type 2 DM; (c) outcome was oral cancers or precancerous lesions; (d) studies should report either adjusted OR, RR, hazard ratio (HR), or standardized incidence/mortality ratios (SIR/SMR) with their 95% Cis (or data to calculate them).
[18] Sona et al. (2018)	Type 1 Diabetes mellitus patients	Various types of cancer including head and neck	15 observational studies with two case–control studies and 13 cohort studies from 11 articles	ND	ND	PubMed and EMBASE in April 2017	(a) case–control studies and prospective or retrospective cohort studies; (b) association between type 1 diabetes and the risk of cancer; (c) reporting measures of outcomes with adjusted odds ratios (Ors) or relative risks (RRs) and 95% confidence intervals (Cis); (d) data identical in more than one study or duplicated, the more comprehensive or first published study was included in the analysis.
[19] Ohkuma et al. (2018)	Diabetes of type 1 or type 2	Cancer, overall and by site	108 studies total, 19 million participants	PRISMA	ND	PubMed on 23 December 2016	(a) observational cohort studies if they had provided RR; (b) exclusion if they had not adjusted at least for age or did not provide information about the variability around the point estimate or if they only had data for one sex; (c) in duplicate reports from the same study, the one with the longest follow-up or the highest number of cases was included.
[20] Ramos-Garcia et al. (2020)	Diabetes of type 1 or type 2	Oral cancer or oral potentially malignant disorders	52 studies, 559,927 participants	PRISMA	CRD42020162848	PubMed; Embase, Web of Science; Scopus; until November 2019	(a) original studies, without language, publication date, sex, or age restrictions; (b) oral cancer in type 1 or type 2 DM; (c) cohort, case–control and cross-sectional studies; (d) exclusion of animal research or in vitro studies; (e) results from the same study where included the most recent or with more data.
[21] Yan et al. (2021)	Diabetes mellitus type 2	Head and neck cancer subtypes	27 studies, 1.4 million T2DM cases and 23,045 HNC cases	PRISMA	ND	PubMed, Web of Science and Embase, on 31 July 2020	(a) cohort or case–control study; (b) exposure of T2DM; (c) primary outcome was incidence of HNC, oral cancer, pharyngeal cancer, or laryngeal cancer; (d) reported the risk estimates OR, standard incidence ratio (SIR), RR or hazard ratio (HR), and 95% confidence intervals; (e) when multiple articles come from the same, we only include the longest duration of follow-up.
[22] Dos Santos et al. (2022)	Patients with systemic conditions	Oral squamous cell carcinoma	95 studies total, 14,442,487 participants	PRISMA—PECOS	CRD42021242702	PubMed; Scopus; Web of Science; Embase; Google Scholar; OpenGrey; ProQuest Dissertation & Theses Global; on 27 February 2021 and updated on 19 February 2022	(a) English articles; (b) with systemic conditions; (c) systemic conditions associated with increased risk to develop OSCC; (d) observational studies.
[23] Gormley et al. (2022)	Metabolic disorders	Head and neck cancer	36 studies total; 15 between diabetes type 2 and HNC	PRISMA	CRD42021250520	January 1966 to November 2021, including Cochrane Library, OVID SP versions of Medline and EMBASE; Cochrane Library, EthOS, Google Scholar, Open Grey and ClinicalTrials.gov (gray literature)	(a) participants over 18 years old, of either sex, from any ethnic background; (b) with T2D, obesity, dyslipidemia or hypertension; (c) outcome HNSCC which may be human papilloma virus (HPV) positive or negative and high-risk types HPV16, 18, 31 and 33 only will be included; (d) All studies published from January 1966 in the English language; (e) observational with head and neck squamous cell carcinoma; (f) with OR or risk ratio, or data which will allow to calculate

Table 5. Description of the 7 studies of diabetes mellitus and oral cancer association included in umbrella review, part II.

Authors (Year)	Diagnostic Criteria for Inclusion	Time Range of the Studies Included	Risk of Bias	Meta-Analysis	Risk Factors	Funding
[14] Gong et al. (2015)	ND	1994 to 2013	Funnel plots and the further Begg’s adjusted rank correlation and Egger’ regression asymmetry tests	Yes	Cigarette smoking, alcohol consumption, betel-quid chewing and some types of viral infections	ND
[18] Sona et al. (2018)	ND	1965 to 2014	funnel plots and the further Begg’s adjusted rank correlation and Egger’ regression asymmetry tests	Yes	Age; sex and age at onset of diabetes; alcohol; tobacco consumption; history of hepatitis; liver cirrhosis; BMI; history of cancer in first degree relatives; calendar year at follow-up; duration of diabetes and its status; period of diagnosis; socioeconomic status; region	ND
[19] Ohkuma et al. (2018)	ND	1982 to 2016	Funnel plots and Egger’s and Begg’s tests	Yes	ND	ND
[20] Ramos-Garcia et al. (2020)	ND	1983 to 2016	Joanna Briggs Institute, University of Adelaide, Australia; QUIPS	Yes	ND	ND
[21] Yan et al. (2021)	ND	1994 to 2018	Egger’s linear regression test and Begg’s test;	Yes	Smoking, alcohol use, or BMI/obesity.	ND
[22] Dos Santos et al. (2022)	ND	1961 to 2022	Joanna Briggs Institute; In the Diabetes Mellitus study the risk of Bias is LOW	Yes	Having systemic conditions	ND
[23] Gormley et al. (2022)	Symptoms such as polyuria or polydipsia, plus: A random blood plasma glucose concentration ≥ 11.1 mmol/L; A fasting plasma glucose concentration ≥ 7.0 mmol/L (whole blood ≥ 6.1 mmol/L); Two-hour plasma glucose concentration ≥ 11.1 mmol/L, two hours after 75 g anhydrous glucose in an oral glucose tolerance test; Glycated hemoglobin (HbA1c) 6.5% or more (48 mmol/mol and above).	1992 to 2021	ROBINS-E	Yes	Smoking, alcohol and presence of human papillomavirus	ND

Table 5. Description of the 7 studies of diabetes mellitus and oral cancer association included in umbrella review, part II.

Authors (Year)	Diagnostic Criteria for Inclusion	Time Range of the Studies Included	Risk of Bias	Meta-Analysis	Risk Factors	Funding
[14] Gong et al. (2015)	ND	1994 to 2013	Funnel plots and the further Begg’s adjusted rank correlation and Egger’ regression asymmetry tests	Yes	Cigarette smoking, alcohol consumption, betel-quid chewing and some types of viral infections	ND
[18] Sona et al. (2018)	ND	1965 to 2014	funnel plots and the further Begg’s adjusted rank correlation and Egger’ regression asymmetry tests	Yes	Age; sex and age at onset of diabetes; alcohol; tobacco consumption; history of hepatitis; liver cirrhosis; BMI; history of cancer in first degree relatives; calendar year at follow-up; duration of diabetes and its status; period of diagnosis; socioeconomic status; region	ND
[19] Ohkuma et al. (2018)	ND	1982 to 2016	Funnel plots and Egger’s and Begg’s tests	Yes	ND	ND
[20] Ramos-Garcia et al. (2020)	ND	1983 to 2016	Joanna Briggs Institute, University of Adelaide, Australia; QUIPS	Yes	ND	ND
[21] Yan et al. (2021)	ND	1994 to 2018	Egger’s linear regression test and Begg’s test;	Yes	Smoking, alcohol use, or BMI/obesity.	ND
[22] Dos Santos et al. (2022)	ND	1961 to 2022	Joanna Briggs Institute; In the Diabetes Mellitus study the risk of Bias is LOW	Yes	Having systemic conditions	ND
[23] Gormley et al. (2022)	Symptoms such as polyuria or polydipsia, plus: A random blood plasma glucose concentration ≥ 11.1 mmol/L; A fasting plasma glucose concentration ≥ 7.0 mmol/L (whole blood ≥ 6.1 mmol/L); Two-hour plasma glucose concentration ≥ 11.1 mmol/L, two hours after 75 g anhydrous glucose in an oral glucose tolerance test; Glycated hemoglobin (HbA1c) 6.5% or more (48 mmol/mol and above).	1992 to 2021	ROBINS-E	Yes	Smoking, alcohol and presence of human papillomavirus	ND

Table 6. Description of the 7 studies of diabetes mellitus and oral cancer association included in umbrella review, part III.

Authors (Year)	Association Between Diabetes and the Outcome:	Nº of Studies	Nº of Cases/Population	Countries in Each Revision
[14] Gong et al. (2015)	Oral cancer or precancerous lesions	17 studies total; 13 for oral cancer and 4 for precancerous lesions	More than 4.8 million patients and 6465 cases of oral cancer; 1407 cases with oral precancerous lesions (1137 with leukoplakia, 100 with erythroplakia and 170 with submucous fibrosis)	USA, Hungary, India, Poland, Germany, Italy, Japan, Switzerland, Denmark, England, Taiwan
[18] Sona et al. (2018)	All types of cancer, including head and neck	15 total, 2 with buccal cancer	31,893 cancer patients among a total of 1,915,179 participants	Sweden (n = 3), Australia (n = 2), UK (n = 2), Denmark (n = 2), Italy (n = 2), Finland (n = 1), Scotland (n = 1), US (n = 1) and Taiwan (n = 1)
[19] Ohkuma et al. (2018)	Lip, oral cavity, pharynx, head and neck, nasopharynx and oral cancer; and sex differences	108 total; 3 with lip, oral cavity and pharynx; 3 with head and neck; 2 with nasopharynx; 2 with oral cancer	108 total; 3 with lip, oral cavity and pharynx; 3 with head and neck; 2 with nasopharynx; 2 with oral cancer	USA, Japan, Italy, Denmark, Australia, Finland, Scotland, Sweden, Germany, Austria, Korea, China, Taiwan, Israel, UK, New Zealand, Singapore, Spain, Netherlands, Poland, France, Mauritius, Fiji, Nauru
[20] Ramos-Garcia et al. (2020)	Oral cancer in general or oral potentially malignant disorders	52; 28 studies only evaluated cancer; 23 reported data about prevalence and risk of oral cavity and oropharynx cancer	559,927	Asia (n = 21), Europe (n = 20), North America (n = 6), South America (n = 4) and Global Multicontinent (n = 1)
[21] Yan et al. (2021)	Oral cavity; pharynx; larynx; oral; head and neck general; specific squamous cell carcinoma; Nasopharyngeal	27 total; all with DM2	1.4 million T2DM cases and 23,045 HNC cases in 15 studies; 28,451 HNC cases in the remaining 12 studies	Europe (n = 11), East Asia (n = 8), North America (n = 6), and Brazil (n = 1)
[22] Dos Santos et al. (2022)	Oral squamous cell carcinoma	86 for qualitative synthesis; 9 for quantitative synthesis; 1 study with the diabetes mellitus condition	1,442,487 patients with systemic conditions; 89,089 with diabetes mellitus; Tseng: n(DM) = 89,530 and n(without DM) = 89,530	Japan, United States, Denmark, Taiwan and South Korea.
[23] Gormley et al. (2022)	Head and neck squamous cell carcinoma	36 total, 15 with diabetes mellitus type 2	39,002 total; 17,582 cases with diabetes mellitus	Sweden, UK, USA, Netherland, Other European Countries, Denmark, Israel, Taiwan, Scotland, Japan, Finland, Korea, China, Hawaii

Table 6. Description of the 7 studies of diabetes mellitus and oral cancer association included in umbrella review, part III.

Authors (Year)	Association Between Diabetes and the Outcome:	Nº of Studies	Nº of Cases/Population	Countries in Each Revision
[14] Gong et al. (2015)	Oral cancer or precancerous lesions	17 studies total; 13 for oral cancer and 4 for precancerous lesions	More than 4.8 million patients and 6465 cases of oral cancer; 1407 cases with oral precancerous lesions (1137 with leukoplakia, 100 with erythroplakia and 170 with submucous fibrosis)	USA, Hungary, India, Poland, Germany, Italy, Japan, Switzerland, Denmark, England, Taiwan
[18] Sona et al. (2018)	All types of cancer, including head and neck	15 total, 2 with buccal cancer	31,893 cancer patients among a total of 1,915,179 participants	Sweden (n = 3), Australia (n = 2), UK (n = 2), Denmark (n = 2), Italy (n = 2), Finland (n = 1), Scotland (n = 1), US (n = 1) and Taiwan (n = 1)
[19] Ohkuma et al. (2018)	Lip, oral cavity, pharynx, head and neck, nasopharynx and oral cancer; and sex differences	108 total; 3 with lip, oral cavity and pharynx; 3 with head and neck; 2 with nasopharynx; 2 with oral cancer	108 total; 3 with lip, oral cavity and pharynx; 3 with head and neck; 2 with nasopharynx; 2 with oral cancer	USA, Japan, Italy, Denmark, Australia, Finland, Scotland, Sweden, Germany, Austria, Korea, China, Taiwan, Israel, UK, New Zealand, Singapore, Spain, Netherlands, Poland, France, Mauritius, Fiji, Nauru
[20] Ramos-Garcia et al. (2020)	Oral cancer in general or oral potentially malignant disorders	52; 28 studies only evaluated cancer; 23 reported data about prevalence and risk of oral cavity and oropharynx cancer	559,927	Asia (n = 21), Europe (n = 20), North America (n = 6), South America (n = 4) and Global Multicontinent (n = 1)
[21] Yan et al. (2021)	Oral cavity; pharynx; larynx; oral; head and neck general; specific squamous cell carcinoma; Nasopharyngeal	27 total; all with DM2	1.4 million T2DM cases and 23,045 HNC cases in 15 studies; 28,451 HNC cases in the remaining 12 studies	Europe (n = 11), East Asia (n = 8), North America (n = 6), and Brazil (n = 1)
[22] Dos Santos et al. (2022)	Oral squamous cell carcinoma	86 for qualitative synthesis; 9 for quantitative synthesis; 1 study with the diabetes mellitus condition	1,442,487 patients with systemic conditions; 89,089 with diabetes mellitus; Tseng: n(DM) = 89,530 and n(without DM) = 89,530	Japan, United States, Denmark, Taiwan and South Korea.
[23] Gormley et al. (2022)	Head and neck squamous cell carcinoma	36 total, 15 with diabetes mellitus type 2	39,002 total; 17,582 cases with diabetes mellitus	Sweden, UK, USA, Netherland, Other European Countries, Denmark, Israel, Taiwan, Scotland, Japan, Finland, Korea, China, Hawaii

Table 7. Data on the associations found on the 7 studies of diabetes mellitus and oral cancer association included in umbrella review, and tools for bias and heterogeneity evaluation.

Authors (Year)	Association Between Diabetes Mellitus and the Outcome	Random Effects	Largest Study of Our Outcome	Random p-Value	Egger’s p-Value	I2; P-Value	Evidence of Reclassification (I-IV)	AMSTAR
[14] Gong et al. (2015)	oral cancer	SRR = 1.15 (95% CI: 1.02–1.29)	ORLS1 = 1.04 (0.63–1.63); ORLS2 = 0.95 (0.43–1.84)	p = 0.277	Egger’s p = 0.176; Begg’s p = 0.392	p = 0.277, I2 = 15.4%	The quality scores ranged from 5 to 9, with the median score 7. Most of the included studies (13/17) were of high quality (NOS score ≥ 7).	Newcastle–Ottawa quality assessment Scale (NOS)
[18] Sona et al. (2018)	buccal cancer	OR or RR = 1.79 (95% CI: 0.96–3.36)	ND	ND	p = 0.218	I2 = 0.0%	One of the studies was qualified as Low and another one High	Newcastle–Ottawa Scale (NOS)
[19] Ohkuma et al. (2018)	lip, oral cavity, pharynx cancer	RRR = 0.94 (95% CI: 0.68–1.32);	Oral OR = 1.13 (1.00–1.28)	ND	Egger’s p = 0.13; Begg’s p = 0.16	ND	Lower score (<7 points) = 1.02 (0.97–1.07) Higher score (≥7 points) = 1.07 (1.04–1.10)	Newcastle–Ottawa Quality Assessment Scale (NOS)
	head and neck cancer	RRR = 1.01 (95% CI: 0.59–1.72);		ND		ND
	nasopharynx cancer	RRR = 1.04 (95% CI: 0.92–1.18);		ND		ND
	oral cancer	RRR = 1.13 (95% CI: 1.00–1.28)		p = 0.009		ND
[20] Ramos-Garcia et al. (2020)	oral cancer	OR = 1.32 (95% CI: 1.12–1.56) I2 = 75.5%	Mixed OR = 1.21 (0.95–1.53)	p < 0.001	p = 0.492	I2 = 75.5%; p < 0.001	“low” quality of evidence for the association between oropharyngeal cancer development and diabetes; and “very low” quality of evidence for the rest of analyzed outcomes. The most influential domain was “inconsistency,” mainly due to the high heterogeneity found.	GRADE
	oral squamous cell carcinoma	OR = 1.41 (95% CI: 1.1–1.81) I2 = 83.2%		p < 0.001
	oropharyngeal cancer	OR = 1.17 (95% CI: 0.82–1.65) I2 = 32.2%		p = 0.229
	mixed	OR = 1.21 (95% CI: 0.95;1.53) I2 = 41.7%		p = 0.127
[21] Yan et al. (2021)	head and neck cancer	RR = 1.04 (95% CI: 0.88–1.23); p = 0.635;	head and neck squamous cell carcinoma: OR = 0.92 (0.88–0.96)	p < 0.10	Egger’s p = 0.437; Begg’s p = 0.951	p < 0.001; I2 = 83.2%	ND	Newcastle–Ottawa Quality Assessment Scale (NOS)
	oral cancer	RR = 1.28, (95% CI, 1.04–1.58);		p < 0.05			ND
	oropharyngeal cancer	RR = 1.18, (95% CI, 1.02–1.37)		p < 0.05			ND
[22] Dos Santos et al. (2022)	head and neck cancer	HR = 1.47 (95% CI: 1.30–1.66) *	ND	p < 0.05	ND	p < 0.01, I2 = 95%	87%, low risk of bias	Joanna Briggs Institute
	oral cancer	HR = 1.73 (95% CI: 1.46–2.05) *		p < 0.05
	oropharyngeal cancer	HR = 1.53 (95% CI: 1.01–2.31) *		p < 0.05
	nasopharyngeal carcinoma	OR = 1.40 (95% CI: 1.03–1.90) *		p < 0.05
[23] Gormley et al. (2022)	overall cancer	RRoverall = 1.13, (95% CI: 0.95–1.34); RRfixed effects = 1.22, (95% CI: 1.16- 1.29)	OR = 1.21 (1.13–1.30)	p < 0.001	ND	p < 0.0001, I2 = 80.0%	One study was rated as ‘Very high’ risk of bias (3.7%), 21 studies were rated as ‘High’ (77.8%), one study as ‘Some concerns’ (3.7%) and the remaining studies as ‘Low’ (14.8%) risk of bias	ROBINS-E tool
	oral cancer	RR = 1.13, (95% CI: 0.97–1.31)	OR = 1.10 (0.98–1.24)	ND
	oropharyngeal cancer	RR = 1.16, (95% CI: 0.73–1.83)	OR = 0.95 (0.84–1.08)	ND

* Data collected from the Tseng KS et al. (2014) [21]—paper within the initially selected one.

Table 7. Data on the associations found on the 7 studies of diabetes mellitus and oral cancer association included in umbrella review, and tools for bias and heterogeneity evaluation.

Authors (Year)	Association Between Diabetes Mellitus and the Outcome	Random Effects	Largest Study of Our Outcome	Random p-Value	Egger’s p-Value	I2; P-Value	Evidence of Reclassification (I-IV)	AMSTAR
[14] Gong et al. (2015)	oral cancer	SRR = 1.15 (95% CI: 1.02–1.29)	ORLS1 = 1.04 (0.63–1.63); ORLS2 = 0.95 (0.43–1.84)	p = 0.277	Egger’s p = 0.176; Begg’s p = 0.392	p = 0.277, I2 = 15.4%	The quality scores ranged from 5 to 9, with the median score 7. Most of the included studies (13/17) were of high quality (NOS score ≥ 7).	Newcastle–Ottawa quality assessment Scale (NOS)
[18] Sona et al. (2018)	buccal cancer	OR or RR = 1.79 (95% CI: 0.96–3.36)	ND	ND	p = 0.218	I2 = 0.0%	One of the studies was qualified as Low and another one High	Newcastle–Ottawa Scale (NOS)
[19] Ohkuma et al. (2018)	lip, oral cavity, pharynx cancer	RRR = 0.94 (95% CI: 0.68–1.32);	Oral OR = 1.13 (1.00–1.28)	ND	Egger’s p = 0.13; Begg’s p = 0.16	ND	Lower score (<7 points) = 1.02 (0.97–1.07) Higher score (≥7 points) = 1.07 (1.04–1.10)	Newcastle–Ottawa Quality Assessment Scale (NOS)
	head and neck cancer	RRR = 1.01 (95% CI: 0.59–1.72);		ND		ND
	nasopharynx cancer	RRR = 1.04 (95% CI: 0.92–1.18);		ND		ND
	oral cancer	RRR = 1.13 (95% CI: 1.00–1.28)		p = 0.009		ND
[20] Ramos-Garcia et al. (2020)	oral cancer	OR = 1.32 (95% CI: 1.12–1.56) I2 = 75.5%	Mixed OR = 1.21 (0.95–1.53)	p < 0.001	p = 0.492	I2 = 75.5%; p < 0.001	“low” quality of evidence for the association between oropharyngeal cancer development and diabetes; and “very low” quality of evidence for the rest of analyzed outcomes. The most influential domain was “inconsistency,” mainly due to the high heterogeneity found.	GRADE
	oral squamous cell carcinoma	OR = 1.41 (95% CI: 1.1–1.81) I2 = 83.2%		p < 0.001
	oropharyngeal cancer	OR = 1.17 (95% CI: 0.82–1.65) I2 = 32.2%		p = 0.229
	mixed	OR = 1.21 (95% CI: 0.95;1.53) I2 = 41.7%		p = 0.127
[21] Yan et al. (2021)	head and neck cancer	RR = 1.04 (95% CI: 0.88–1.23); p = 0.635;	head and neck squamous cell carcinoma: OR = 0.92 (0.88–0.96)	p < 0.10	Egger’s p = 0.437; Begg’s p = 0.951	p < 0.001; I2 = 83.2%	ND	Newcastle–Ottawa Quality Assessment Scale (NOS)
	oral cancer	RR = 1.28, (95% CI, 1.04–1.58);		p < 0.05			ND
	oropharyngeal cancer	RR = 1.18, (95% CI, 1.02–1.37)		p < 0.05			ND
[22] Dos Santos et al. (2022)	head and neck cancer	HR = 1.47 (95% CI: 1.30–1.66) *	ND	p < 0.05	ND	p < 0.01, I2 = 95%	87%, low risk of bias	Joanna Briggs Institute
	oral cancer	HR = 1.73 (95% CI: 1.46–2.05) *		p < 0.05
	oropharyngeal cancer	HR = 1.53 (95% CI: 1.01–2.31) *		p < 0.05
	nasopharyngeal carcinoma	OR = 1.40 (95% CI: 1.03–1.90) *		p < 0.05
[23] Gormley et al. (2022)	overall cancer	RRoverall = 1.13, (95% CI: 0.95–1.34); RRfixed effects = 1.22, (95% CI: 1.16- 1.29)	OR = 1.21 (1.13–1.30)	p < 0.001	ND	p < 0.0001, I2 = 80.0%	One study was rated as ‘Very high’ risk of bias (3.7%), 21 studies were rated as ‘High’ (77.8%), one study as ‘Some concerns’ (3.7%) and the remaining studies as ‘Low’ (14.8%) risk of bias	ROBINS-E tool
	oral cancer	RR = 1.13, (95% CI: 0.97–1.31)	OR = 1.10 (0.98–1.24)	ND
	oropharyngeal cancer	RR = 1.16, (95% CI: 0.73–1.83)	OR = 0.95 (0.84–1.08)	ND

* Data collected from the Tseng KS et al. (2014) [21]—paper within the initially selected one.

3.3. Risk of Bias

As can be seen in Table 8, all the studies were assessed with a score of high quality, three studies with 9 positive answers, two with all 10 positive questions, and two studies with 8 positive answers.

3.4. Strategy for Data Synthesis

Study double counting in different systematic reviews was presented visually using the Graphical Representation of Overlap for OVErviews (GROOVE) tool (Figure 2). This methodological approach facilitates the assessment of overlap of primary studies among multiple systematic reviews. It was observed that both Gong et al. (2015) [14] and Yan et al. (2021) [21] had the highest percentage of overlapping studies with Ramos-Garcia et al. (2019) [20] with 64.3% and 61.1%, respectively. On the other hand, Sona et al. (2018) [18] do not have any studies in common with the rest of the systematic reviews in question.

Table 8. Risk of bias evaluation with a critical appraisal checklist for the systematic reviews [16].

	[14] Gong et al. (2015)	[18] Sona et al. (2018)	[19] Ohkuma et al. (2018)	[20] Ramos-Garcia et al. (2020)	[21] Yan et al. (2021)	[22] Dos Santos et al. (2022)	[23] Gormley et al. (2022)
Is the review question clearly and explicitly stated?	Met	Met	Met	Met	Met	Met	Met
Were the inclusion criteria appropriate for the review question?	Met	Met	Met	Met	Met	Met	Met
Was the search strategy appropriate?	Met	Met	Met	Met	Met	Met	Met
Were the sources and resources used to search for studies adequate?	Met	Met	Met	Met	Met	Met	Met
Were the criteria for appraising studies appropriate?	Met	Met	Met	Met	Met	Met	Met
Was critical appraisal conducted by two or more reviewers independently?	Met	Met	Unclear	Met	Met	Met	Met
Were the methods used to combine studies appropriate?	Met	Met	Met	Met	Met	Met	Met
Was the likelihood of publication bias assessed?	Met	Met	Met	Met	Met	Met	Met
Were recommendations for policy and/or practice supported by the reported data?	Met	Unclear	Met	Met	Unclear	Met	Met
Were the specific directives for new research appropriate?	Met	Not met	Met	Met	Unclear	Not Met	Not met
Include?	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Low, Moderate or High quality?	High	High	High	High	High	High	High

Table 8. Risk of bias evaluation with a critical appraisal checklist for the systematic reviews [16].

	[14] Gong et al. (2015)	[18] Sona et al. (2018)	[19] Ohkuma et al. (2018)	[20] Ramos-Garcia et al. (2020)	[21] Yan et al. (2021)	[22] Dos Santos et al. (2022)	[23] Gormley et al. (2022)
Is the review question clearly and explicitly stated?	Met	Met	Met	Met	Met	Met	Met
Were the inclusion criteria appropriate for the review question?	Met	Met	Met	Met	Met	Met	Met
Was the search strategy appropriate?	Met	Met	Met	Met	Met	Met	Met
Were the sources and resources used to search for studies adequate?	Met	Met	Met	Met	Met	Met	Met
Were the criteria for appraising studies appropriate?	Met	Met	Met	Met	Met	Met	Met
Was critical appraisal conducted by two or more reviewers independently?	Met	Met	Unclear	Met	Met	Met	Met
Were the methods used to combine studies appropriate?	Met	Met	Met	Met	Met	Met	Met
Was the likelihood of publication bias assessed?	Met	Met	Met	Met	Met	Met	Met
Were recommendations for policy and/or practice supported by the reported data?	Met	Unclear	Met	Met	Unclear	Met	Met
Were the specific directives for new research appropriate?	Met	Not met	Met	Met	Unclear	Not Met	Not met
Include?	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Low, Moderate or High quality?	High	High	High	High	High	High	High

4. Discussion

This umbrella review aims to comprehensively explore and summarize all available information from systematic reviews (SRs) on a specific topic, outlined as follows: the potential association between diabetes mellitus and the subsequent development of head and neck cancer. By analyzing this relationship in detail and assessing whether individuals diagnosed with any form of diabetes mellitus face an increased risk of developing head and neck cancer, this review adheres to specific eligibility criteria. In doing so, it provides a state-of-the-art overview of this subject from January 2000 to 2024 (although the search was conducted on January 15, 2024, and some studies from 2024 may be missing), helping to identify the next steps for future scientific research.

This umbrella review incorporates seven SRs, which collectively analyzed data from 20 primary studies. However, in total, 350 different studies were included due to the lack of specific eligibility criteria in some SRs and errors in the study selection process.

Positive data was seen in nine out of the twenty associations presented in seven reviews, specifically those regarding oral cancer overall, yielding the highest number of correlations found and the most robust evidence. Although it was possible to see this association, studies, in general, cannot be compared because of the fact that the variables like the comorbidities or the countries from which the patients are originated are distinct between the papers in the reviews or are not even contemplated in the given data.

One limitation of this review is the exclusion of gray literature, which may introduce publication bias. Nevertheless, we consider the selected databases to be highly comprehensive, thereby increasing the likelihood that all relevant studies were included.

The fact that this association between the two conditions appears in some studies and not in others may be due to other limitations, such as smaller sample sizes when there is little to nonsignificant association, as well as the variability of the sample units within populations and the methods used to select the sample units; It may also be due to the difference in region/country of each study; In addition, the risk factors such as tobacco and alcohol usage increase susceptibility to developing cancer compared to patients with only diabetes and a high BMI.

Typically, umbrella reviews do not analyze primary studies included in SRs. However, due to the numerous limitations identified in the included SRs, a deeper individual assessment of these primary studies was deemed necessary. This analysis revealed that the majority of studies did not directly address the main objective of this umbrella review, for the reasons outlined in the Results section.

The mechanisms involved in this link (individuals diagnosed with any form of diabetes mellitus face an increased risk of developing head and neck cancer) are the following: a reduction in insulin sensitivity which induces hyperinsulinemia (due to an increase in the level of circulating insulin-like growth factors (IGF), which stimulates a mitogenic effect as well as protection against apoptotic stimuli and invasion in many organs increasing the risk of cancer) [25,26,27]; hyperglycemia (causes oxidative stress with DNA damage due to the release of free radicals) [28]; or chronic inflammation based on biological mechanisms, particularly hormonal, involving insulin resistance [13].

It would also be very important to point out that individuals with type 1 diabetes, who have an insulin deficit, have a lower risk of cancer than individuals with type 2 diabetes [27].

Several hypotheses have been proposed to explain this association. One suggests that elevated circulating insulin reduces hepatic hormone metabolism, resulting in increased bioavailability of estrogen and testosterone, both of which are associated with a higher risk of cancer [29,30].

Another hypothesis is based on the mechanism of adipose tissue producing factors such as interleukin-6 (IL-6) and tumor necrosis factor-α, which regulate malignant transformation or cancer progression by increasing the proliferation of cancer cells and suppressing the host’s anti-tumor immunity [29,31].

The relationship is bidirectional; diabetes can develop as a consequence of cancer, since cancers generally cause insulin resistance and subsequent hyperglycemia through the production of cytokines such as tumor necrosis factor-α, as mentioned above [32].

Hyperinsulinemia promotes oral cancer progression by upregulating cyclin D1 (CCND1), which enhances both cell proliferation and migration (Okumura et al., 2002). Additionally, hyperglycemia contributes to tumorigenesis through oxidative DNA damage and increased glucose uptake—known as the Warburg effect—driven by the activation of GLUT-1 and PKC-α [33].

In addition to an increased risk of cancer incidence, there is now considerable evidence in the literature suggesting that patients with diabetes have a lower cancer screening and survival rate than patients without. Barone et al. 2008 evaluated 23 studies and found that DM was associated with reduced cancer-specific survival [34].

As Giovannucci et al. (2010) [29] discuss, determining whether the association between diabetes and certain cancers is due to shared risk factors or to diabetes itself and its metabolic alterations is challenging. The study contextualizes the high heterogeneity observed in some of the systematic reviews included in this umbrella review, helps to understand why this heterogeneity is a significant limitation in interpreting the results, and suggests that variability in risk factors between primary studies may be one of the causes of this heterogeneity and could consequently affect confidence in the positive associations found.

The American Cancer Society study (n.d.) [30] posits that factors such as tobacco and alcohol consumption are prevalent risk factors for head and neck cancers. The article by Giovannucci and associates (2010) [29] elaborates on this, emphasizing that the association between diabetes and cancer may be indirect due to common risk factors such as obesity, poor diet, and physical inactivity. The study further underscores the necessity for future research to account for risk factors such as comorbidities and patients’ countries of origin, with the aim of isolating the impact of diabetes mellitus.

This umbrella review examined the current evidence from meta-analyses on the association between diabetes mellitus and head and neck cancer. Most articles demonstrated positive results for the risk being higher in people with diabetes rather than without.

As Giovannucci et al. (2010) [29] point out, there is a need for the better characterization of aspects of diabetes (e.g., duration, therapy, and glycemic control) in relation to cancer risk. They also discourage studies that explore links between diabetes and the risk of all cancers combined due to variable associations at specific sites. This underscores the necessity to standardize the collection of specific data on the type and duration of diabetes in head and neck cancer studies.

Therefore, the identification of a (positive) association, particularly in oral cancer cases, emphasizes the necessity for future research to adopt standardized methodologies and to exercise rigorous control over comorbidities. This research is encouraged to take place between diabetologists, oncologists, and other specialists with the objective of better understanding the underlying mechanisms and the development of more effective preventive and early detection strategies.

While this systematic review benefited from a comprehensive search strategy, the inclusion of multiple high-quality studies, and its thorough quality assessment of those, and rigorous data extraction methods, its limitations include potential publication bias, heterogeneity among study populations and methodologies, and the limited availability of long-term outcome data.

5. Conclusions

Regarding the question “Is there a relationship between diabetes mellitus and head and neck carcinoma?” the result of this umbrella review allows us to conclude there is support for listing diabetes mellitus as a risk factor associated with head and neck cancer, even though larger studies are needed to validate the scientific evidence in this regard.

Furthermore, given the limitations of the included quantitative systematic reviews, it is important to continue conducting studies and, collecting data, following the same structure for all types of head and neck cancer, but with better control of risk factors. Future articles and research should therefore follow the same guidelines, such as more effectively assessing type 2 diabetes itself, treatment duration, and circumstances like risk factors, to draw more precise conclusions on the topic.