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Effectiveness of Interventions to Improve Oral Cancer Knowledge: a Systematic Review

• Published: 27 January 2021
• Volume 37 , pages 479–498, ( 2022 )

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• Nikhil A. Ahuja 1 ,
• Satish K. Kedia   ORCID: orcid.org/0000-0002-7114-5843 1 ,
• Kenneth D. Ward 1 ,
• Latrice C. Pichon 1 ,
• Weiyu Chen 1 ,
• Patrick J. Dillon 2 &
• Hitesh Navaparia 3  

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Oral cancer is prone to late-stage diagnosis, and subsequent low five-year survival rates. A small number of interventions or campaigns designed to enhance knowledge of risk factors and symptoms associated with oral cancer have been attempted in the UK, US, and some other countries. The purpose of this systematic review is to assess the effectiveness of interventions designed to improve oral cancer knowledge. We searched five databases to identify randomized controlled trials (RCTs) and non-randomized/quasi-experimental (NR/QE) studies targeting the general population or high-risk groups (tobacco users or alcohol consumers), aged ≥15 years, and reporting the outcomes of individual and/or community level interventions. Two co-authors independently identified relevant studies, extracted data, and assessed the risk of bias. Adhering to PRISMA guidelines, 27 (eight RCTs and 19 NR/QE studies) of the 551 studies identified from the five databases met the inclusion criteria. All RCTs and nine NR/QE studies used either printed materials, health education sessions, multimedia aids, or some combinations of these tools. The other ten NR/QE studies were community-based and used mass media campaigns to increase oral cancer awareness. Overall, the majority of studies significantly improved oral cancer knowledge; however, heterogeneity in study design and variation in measurement tools made it difficult to compare outcomes. Findings suggest that individual and/or community level interventions are generally effective in increasing knowledge of oral cancer risk factors, signs and symptoms, and/or its early diagnosis and prevention strategies among the general population or high-risk groups. However, the long-term benefits of these interventions are understudied.

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Nikhil A. Ahuja, Satish K. Kedia, Kenneth D. Ward, Latrice C. Pichon & Weiyu Chen

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All authors have read and approved the submitted version of the paper. The specific contributions were as follows: NA: conceptualization, literature search, data extraction, synthesis and analysis, writing—original draft, review and editing; SK: conceptualization, supervision, and writing—review and editing, KW: supervision and writing—review and editing; LP: supervision and writing—review & editing; WC: literature search, data extraction and analysis; PD: writing—review and editing and HN: data extraction, synthesis, and analysis.

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Ahuja, N., Kedia, S., Ward, K.D. et al. Effectiveness of Interventions to Improve Oral Cancer Knowledge: a Systematic Review. J Canc Educ 37 , 479–498 (2022). https://doi.org/10.1007/s13187-021-01963-x

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Accepted : 13 January 2021

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DOI : https://doi.org/10.1007/s13187-021-01963-x

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The cost of oral cancer: A systematic review

Contributed equally to this work with: Rejane Faria Ribeiro-Rotta, Eduardo Antônio Rosa, Vanessa Milani, Nadielle Rodrigues Dias, Ana Laura de Sene Amâncio Zara

Roles Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation School of Dentistry, Universidade Federal de Goiás (UFG), Goiânia, Goiás, Brazil

Roles Conceptualization, Data curation, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing

Roles Investigation, Writing – review & editing

Roles Conceptualization, Methodology, Supervision, Validation, Writing – review & editing

¶ ‡ DM and ENS also contributed equally to this work.

Affiliation Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

Roles Conceptualization, Investigation, Methodology, Supervision, Validation, Writing – review & editing

Affiliation Universidade de Brasília (UnB), Brasília, Federal District, Brazil

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• Rejane Faria Ribeiro-Rotta, 
• Eduardo Antônio Rosa, 
• Vanessa Milani, 
• Nadielle Rodrigues Dias, 
• Danielle Masterson, 
• Everton Nunes da Silva, 
• Ana Laura de Sene Amâncio Zara

• Published: April 21, 2022
• https://doi.org/10.1371/journal.pone.0266346
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Although clinical and epidemiological aspects of oral cancers (OC) are well-documented in the literature, there is a lack of evidence on the economic burden of OC. This study aims to provide a comprehensive systematic assessment on the economic burden of OC based on available evidence worldwide. A systematic review was conducted. The population was any individual, who were exposed to OC, considered here as lip (LC), oral cavity (OCC), or oropharynx (OPC) cancer. The outcome was information on direct (medical and non-medical) and indirect (productivity loss and early death) costs. The data sources included Scopus, Web of Science, Cochrane, BVS, and NHS EED. A search of grey literature (ISPOR and INAHTA proceedings) and a manual search in the reference lists of the included publications were performed (PROSPERO no. CRD42020172471). We identified 24 studies from 2001 to 2021, distributed by 15 countries, in 4 continents. In some developed western countries, the costs of LC, OCC, and OPC reached an average of Gross Domestic Product per capita of 18%, 75%, and 127%, respectively. Inpatient costs for OC and LC were 968% and 384% higher than those for outpatients, respectively. Advanced cancer staging was more costly (from ~22% to 373%) than the early cancer staging. The economic burden of oral cancer is substantial, though underestimated.

Citation: Ribeiro-Rotta RF, Rosa EA, Milani V, Dias NR, Masterson D, da Silva EN, et al. (2022) The cost of oral cancer: A systematic review. PLoS ONE 17(4): e0266346. https://doi.org/10.1371/journal.pone.0266346

Editor: Antoine Eskander, University of Toronto, CANADA

Received: October 3, 2021; Accepted: March 19, 2022; Published: April 21, 2022

Copyright: © 2022 Ribeiro-Rotta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All data files are available from the Figshare database (accession number https://figshare.com/s/f7eb4990efeb5021f131 ).

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Detection of oral cancer does not demand elaborate screening tests such as breast, prostate, and colon cancers. Oral cancer can be easily and effectively detected early with oral inspection during routine dental consultations and integrated in primary care [ 1 ]. To achieve this goal, current efforts must include target programs to educate high-risk persons and primary care providers about the main aspects of early detection [ 2 ]. Oral cancer staging plays an important role in survival rate, with early-stage (I and II) and advanced-stage (III and IV) lesions having a 5-year survival rate of 80% and 50% or less, respectively [ 3 ]. Additionally, advanced stages require more aggressive combined interventions, and consequently more expensive treatments. There are also equity concerns about oral cancers, since they asymmetrically affect different population groups and countries. Older, heavier male users of tobacco and alcohol, and people from low socioeconomic strata, as well as those who have a poor dietary intake are populations who are at a high risk of developing oral cancer [ 4 ]. Regarding geographical locations, the highest incidence rates occur in three low- and middle-income countries (Pakistan, Brazil, and India) [ 4 ]. There is also a growing incidence of oral and oropharynx cancer among young patients (<45 years), particularly in Africa, the Middle East, and Asia [ 5 ].

Although clinical and epidemiological aspects of oral cancers are well-documented in the literature, there is a lack of evidence on the economic burden of oral cancers worldwide. Cost-of-illness studies can provide information on the monetary consequences of a disease or condition, including healthcare costs and productivity losses, and its impact on societal or public health expenditure [ 6 ]. This information can be used to estimate avoidable costs if policies/programmes are implemented to reduce the prevalence of this disease. When available, it also can inform costs stratified by stages of the disease. In the United Kingdom, average treatment cost for oral cancer can range from I$ 3,343 in the early stages to I$24,890 in the advanced stages [ 7 ]. Cost-of-illness can also be used to inform priority setting, by providing estimates of how big a problem is in terms of costs [ 8 ]. Moreover, gathering information on costs may encourage decision makers to implement strategies for detecting and screening populations at high-risk of developing oral cancer, particularly by comparing costs at different stages of the disease. To the best of our knowledge, up to now there are no systematic reviews that synthesize evidence on the economic burden of oral cancer. The objective of this study is to provide a comprehensive systematic assessment of the economic burden of oral cancer based on available evidence worldwide.

A systematic review of studies revealing the costs of lip cancer (LC), oral cavity cancer (OCC), and oropharyngeal cancer (OPC) was conducted, taking into account any cost perspective (societal, third-party players, public systems). The method used was guided by the concepts of the Joanna Briggs Institute (JBI) [ 9 ] and in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [ 10 ]. A systematic review protocol can be found as a preprint on Research Square ( https://www.researchsquare.com/article/rs-34637/v1 ). This protocol was reformulated, and the final version can be found in Prospero (CRD42020172471).

Problem specification

What is the economic burden of oral cancer, including direct and indirect costs?

The question was framed using the acronym PEO (Population, Exposure, Outcome), which was used to define the search strategy. The population (P) considered for publication searching was any individual (human) or groups of individuals, without restriction of age, sex, race, or socioeconomic status, who were exposed (E) to oral cancer, considered here as LC, OCC, or OPC. The outcome (O) required from the publications was information on direct (medical and non-medical) and indirect (productivity loss and early death) costs.

Eligibility criteria

Original studies on the cost of oral cancer, which included direct and/or indirect costs, or that provided estimates per patient (average cost or by clinical stage) or economic burden as percentage of GDP or national healthcare expenditure were included in the review. No language or year of publication restriction was established.

Publications that met the following criteria were excluded:

• Types of study such as: editorial, letters to the editor, systematic and non-systematic reviews of the literature, meta-analyses, case reports, case series, clinical trials.
• Studies that estimated specific item components of oral cancer cost (e.g., only surgery or medication, etc).
• Studies that addressed specific analyses, such as cost-effectiveness, cost-utility, cost-benefit, cost-minimization.

Information sources

A systematic literature search was carried out through a comprehensive search of databases in PubMed, Scopus, Web of Science, BVS (Biblioteca Virtual em Saúde) and NHS Economic Evaluation Database up to March 31, 2021. We also manually searched the references of the articles included for additional studies. Additionally, our search was supplemented by gray literature, with the search of abstracts of conference proceedings from annual meetings of the following societies: International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and International Network of Agencies for Health Technology Assessment (INAHTA) [ 11 ] (accessed March 31, 2021).

Design of search strategy

To identify relevant cost-of-illness studies for LC, OCC, and OPC, appropriate disease-related MeSH terms were used (Additional file 1, available via https://figshare.com/s/f7eb4990efeb5021f131 ). To determine the search strategy, descriptors were selected by building a table (concept mapping). The table rows were allocated for each item of the acronym PEO and the columns for PubMed controlled vocabulary terms (Medical Subject Headings–MeSH), their subcategories (entry terms; see also), and uncontrolled vocabulary (free terms) usually obtained from titles and abstracts of the main publications, books, and gray literature on the research theme. After the PubMed MeSH controlled vocabulary tree was explored, terms were tested in the PubMed database and the most relevant descriptors were selected, and a search strategy was built (Additional file 2, available via https://figshare.com/s/f7eb4990efeb5021f131 ). The search strategy defined for PubMed was adapted for searches in the other databases.

All publications identified in the databases were exported to the Mendeley Reference Manager (Mendeley®, Elsevier, version 1.19.5/20019) for duplicate removal. After that, all publications were exported to Rayyan® software (Rayyan QCRI, Qatar Computing Research Institute–Data Analytics) [ 12 ] for the selection process.

Selection process

The stages of the selection process included at least one reviewer from each of the following fields of knowledge: oral cancer (EAR; VM; NRD; RFRR); epidemiology (ALSAZ); and / or health economics (ENS). Three reviewers (EAR; VM; NRD) read the title and abstract of publications using the software Rayyan (Rayyan QCRI). Kappa statistic was calculated to assess agreement between reviewers, in pairs, in the eligibility stage, with a significance level of 5% (p<0.05). The scale of Kappa value interpretation was as following: <0 no agreement; 0–0.20 slight; 0.21–0.40 fair; 0.41–0.60 moderate; 0.61–0.80 substantial and 0.81–1.0 perfect. All studies identified were screened based on the eligibility criteria and were forwarded for full-text review. Contact with the authors was established for the screened studies not available in full text. Two reviewers (EAR; ENS) independently read the full text for inclusion. Additional reviewers (RFRR; ALSAZ) were consulted for consensus in case of disagreement between the first two (EAR; ENS). Reviewers underwent training prior to the publication selection process, which was performed using 100 screened publications.

Data collection

An instrument was built to extract the relevant data on cost methodologies, designs, and approaches, using Research Electronic Data Capture (REDCap) [ 13 ]. This instrument included the following variables:

• Study identification: first author; country; journal and year of publication.
• Main study design characteristics: type of study (cost-of-illness study or another type of study that provides cost-of-illness information of oral cancer); epidemiological approach (longitudinal or cross-sectional or case control); sample (number, age, type of cancer, cancer anatomical site and stage); retrospective or prospective data gathering; data source; perspective of the analysis (societal, government, health insurance provider, hospital); time horizon; presence of a control group (patients not affected by oral cancer); location/setting (country, state, or city); cost-of-illness based approach (prevalence-based or incidence-based); estimation of resources and costs (single study-based or model-based); assumptions adopted (structural or other assumptions underpinning the study); year of cost estimation; currency; sensitivity analysis; use of discount rate; funding sources; conversion; data source (primary or secondary database). The perspective of studies was defined as: i) societal, which includes direct and indirect costs and/or out-of-pocket costs from patient point of view; ii) government (public payer), includes direct costs only; iii) health insurance provider (private payer), which includes direct costs reimbursed by the private health insurers; and iv) hospital, which includes direct cost charged by just one hospital, unless the authors explicitly reported the government or health insurer perspectives.
• Type of cost estimated: direct healthcare costs (hospitalization, surgery, chemotherapy, radiotherapy, intensive care unit, emergency room, physical therapists, speech therapists, medication, laboratory tests, imaging diagnosis and follow-up); direct non-healthcare costs (social services and transportation costs), indirect costs (productivity loss, early death).
• Primary study outcomes: costs related to oral cancer in patients, reported in monetary units or economic burden as a percentage of Gross Domestic Product (GDP) or national healthcare expenditure.
• Additional outcome: if the studies provided a specific breakdown of costs, this information was reported as a secondary outcome (outpatient and inpatient costs; cost by clinical stage; primary and recurrent tumor cost). We also calculated the economic burden of OC at individual level, by dividing the OC costs per patient by the GDP per capita of the country under investigation. This measure would indicate how catastrophic those costs could be for an average citizen (GDP per capita).

Data extraction was carried out by at least two of four reviewers (ALSAZ; EAR; ENS; RFRR), in a double-blind process, and disagreements were decided by consensus.

Data synthesis

All studies meeting the eligibility criteria were included in the study and critically appraised using the Larg & Moss’s guide [ 14 ] for assessing cost-of-illness. This checklist includes three domains: analytical framework; methodology and data; analysis and reporting. The method for assessing quality of individual studies was done at both the outcome and study level, independently, and in duplicate (EAR, ENS), and discrepancies were resolved by consensus. We provided a global score for the quality of each study by calculating the total number of points rated as “yes” and “not applicable (NA)”. Percentage intervals were established for meeting the items of the quality assessment instrument applied to the included studies: >80%; between 79% and 50%; and less than 50%. The average and standard deviation (SD) of the scores were calculated. The average of the scores were compared between study design groups (longitudinal studies, cross-sectional and case control studies, and cross-sectional studies based on information system data) and by domains, using a one-way analysis of variance (ANOVA) (p<0.05), by Open-Source Epidemiologic Statistics for Public Health (OpenEpi), version 3.01 [ 15 ]. In this section, this was considered the risk of bias information obtained from each study.

To calculate the percentage of the burden of the cost of oral cancer, GDP per capita of the countries where the studies were carried out was considered and converted to International Dollars (I$) by Purchasing Power Parity—PPP (2019) [ 16 ].

The results were presented in narrative form, using the Synthesis Without Meta-Analysis (SWiM) reporting guideline [ 17 ], and the main results were presented in tables.

The search procedure is shown in the PRISMA flow diagram [ 10 ] ( Fig 1 ). The systematic literature search identified 12,391 potentially relevant articles. After removal of duplicates, 6,864 studies were screened for inclusion ( Fig 1 ). Following title and abstract review, full-text articles were assessed (n = 44) and excluded (n = 20) for the following reasons—they were not an oral cancer cost study, did not include a specific intervention cost, there was a head and neck cancer cost study that did not present oral cancer cost separately, only proceedings available and there were no abstracts. The author or co-authors were contacted by email for the nine studies which were unobtainable, and for which only the abstracts or the title was available. There was only one answer from all of these authors, stating that they had not published the full study. Overall, 24 studies met all the eligibility criteria and were included in the systematic review.

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In the eligibility stage, Kappa coefficient was 0.83 (perfect) between the EAS and VM reviewers; 0.78 (substantial) between EAS and NRD and 0.78 (substantial) between VM and NRD.

Study characteristics

The study characteristics are summarized in Tables 1 and 2 . The studies identified were published from 2001 to 2021 and distributed by continent as follows: Europe (n = 9), Asia (n = 7), America (n = 6), Oceania (n = 1), and 1 global study stratified by region and income of 195 countries. The study population size ranged from a minimum of 69 (Sri Lanka) [ 18 ] to a maximum of 62,265 (Korea) [ 19 ]. Four studies [ 20 – 22 ] estimated costs by procedures and not per individual. The studies included investigated a wide variety of anatomical sites of the head and neck region, using a non-standardized terminology to identify them ( Table 1 ).

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The 24 included studies were stratified by study design, which revealed five longitudinal studies [ 23 – 27 ] with a time horizon varying from one to five years. Of the 18 cross-sectional studies, 10 were cost-of-illness [ 18 – 22 , 28 – 32 ], 8 cost analysis [ 33 – 40 ] and one was a case control study [ 41 ]. The 24 studies used primary and/or secondary data sources, of which four were based on information system data [ 20 – 22 , 28 ]. The most frequent perspective of the studies was hospital (n = 7) [ 21 , 32 , 33 , 35 , 37 – 39 ]. Two studies used estimation of resources and cost based on mathematical models [ 31 , 35 ] ( Table 2 ).

Quality assessment

The global quality score of the studies, considered as the percentage rate of compliance to the items of the quality evaluation instrument, was 47.8% (SD = 10.9). The quality score varied from 38% [ 20 , 32 ] to 66% [ 19 ] ( Table 3 ). Regarding the study designs, the average of quality scores was 49.1% (SD = 9.9) for longitudinal studies, 47.3% (SD = 5.8) for cross-sectional and case control studies, and 46.0% (SD = 7.2) for studies based on information system data. No statistically significant difference was found among the average scores by study design (p = 0.796). Considering all studies, the Analytical Framework domain had an average score of 68.8% (SD = 15.0), the Methodology and Data domain 42.9% (SD = 10.1), and the Analysis and Reporting domains 43.8% (SD = 16.1), presenting a statistically significant difference among the average scores (p<0.001). The average of the quality scores of cross-sectional studies and those studies based on system data differed among domains (respectively p<0.001 and p = 0.001). The Analytical Framework domain had the highest average score in each included publication, when compared to the other two domains.

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Cost components

Fourteen studies [ 18 , 19 , 21 – 23 , 25 – 27 , 32 , 34 , 35 , 37 , 39 , 41 ] evaluated all components of direct medical costs (surgery, chemotherapy, radiotherapy, follow-up, medications, exams), and only six [ 18 , 19 , 22 , 29 , 30 , 39 ] investigated non-medical costs. Regarding indirect costs, three studies [ 18 , 28 , 30 ] evaluated absenteeism costs, two evaluated both [ 19 , 29 ] absenteeism and early death, and one investigated early death costs [ 31 ]. None of them estimated presenteeism costs ( Table 4 ).

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Studies that met the inclusion criteria presented the estimates of oral cancer cost according to a wide variety of aspects: cost per patient, monthly cost, total cost in a period, cost per treatment or procedure, from the payer’s perspective, cost components, outpatient and inpatient cost, services, by International Classification of Diseases, Tenth Revision (ICD-10) separately or in aggregate, by disease stage, follow-up, and disease recurrence ( Table 5 ).

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The OC cost comparison among studies was not possible. The set of anatomical sites investigated varied widely, in addition to the different measurement and costing methods. Only one of the studies included presented costs, separately, related to the sites considered as oral cancer in this systematic review (lip, oral cavity, and oropharynx) [ 22 ]. Most of the studies investigated lip, oral cavity, and oropharynx cancers together with other types of cancers from head and neck region ( Table 5 ).

Only two studies [ 22 , 23 ] investigated the cost of lip cancer separately from other ICD-10. The cost of lip cancer was estimated at GBP5,790 pounds per patient, over a five-year follow-up in the UK. In Brazil, the total expenditure of lip cancer was I$22.7 million in the period of nine years, from which I$18.1 million for inpatient costs and I$4.6 million for outpatient costs [ 22 ] ( Table 5 ).

Three studies [ 23 , 26 , 35 ] showed the cost of oral cavity cancer per patient, estimated at GBP25,311 pounds in five years of follow-up in the UK [ 23 ]; EUR18,462 in two years of follow-up [ 26 ] in Italy; and EUR35,541 in a mathematical model estimated for 10 years in the Netherlands [ 35 ]. Two studies [ 20 , 30 ] estimated oral cavity cancer cost per hospitalization, by information system data, with an average of THB29,531 [ 20 ] for Thailand and EUR6,482 for Germany [ 28 ], both over a one-year follow-up. One Brazilian study presented the expenditure of oral cavity cancer, in 9 years, as I$257.1 million: on average I$139.1 million for inpatients and I$118.0 million for outpatients [ 22 ] ( Table 5 ).

Three studies [ 26 , 35 , 41 ] showed the cost of oropharynx cancer per patient, estimated at EUR24,253 euros after two years of follow-up in Italy [ 26 ], EUR35,642 in a probabilistic mathematical model estimated for 10 years [ 35 ] in the Netherlands, which presented the health state after year 2, after year 4 and after years 5–10, calculated from the date of the primary diagnosis, and USD134,454 over a period of two years in the USA [ 41 ]. Three studies [ 20 , 22 , 28 ] estimated oropharynx cancer per hospitalization, by information system data, with an average of THB26,331 [ 20 ] in Thailand and EUR4,268 in Germany [ 28 ], both over a one-year follow-up, and I$1,338 in Brazil over nine years [ 22 ] ( Table 5 ).

Only four studies showed the costs of OC by cost components (direct and indirect costs) [ 28 – 30 ]. In France (2018) [ 30 ], the direct medical cost of head and neck cancer was EUR49,954 per patient, considering outpatient and inpatient care, public hospitals services, and private for-profit hospitals services. The indirect cost was EUR2,989 per patient for disability and sick leave. In Germany (2008) [ 28 ], the direct medical cost of oral cancer was approximately EUR113 million, and the indirect cost was EUR18 million (sick leave). The direct medical cost of oropharyngeal cancer was approximately EUR83 million, and the indirect cost was EUR16 million (sick leave) [ 28 ]. In Iran [ 29 ], the cost of lip cancer, and for other and unspecified parts of tongue, the floor of the mouth, and buccal cancers was approximately USD27 million, USD5 million, and USD32 million for direct and direct non-medical and indirect costs, respectively [ 29 ]. The direct medical costs in Taiwan (2018) [ 27 ] were USD19,644 per patient and indirect costs for morbidity and mortality were USD1,286 and USD35,570 per patient, respectively, in a follow-up over 2.3 years ( Table 5 ).

The LC burden of cost was 18.3% of UK GDP per capita [ 23 ]. Regarding the OCC cost, the burden was 79.8%, 64.9%, and 79.8% of UK, Italian, and the Netherlands’ GDP per capita, respectively [ 23 , 26 , 35 ]. The OPC burden of cost was 85.2%, 80.3%, 215.0% of Italy, the Netherlands, and the USA GDP per capita, respectively [ 26 , 35 , 41 ] ( Table 6 ).

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Five studies showed outpatient and inpatient costs [ 22 , 23 , 25 , 30 , 41 ]. In general, inpatient costs are higher than outpatient costs, with a coefficient of variation of 93% [ 30 ] to 967.5% [ 23 ]. Outpatient costs exceeded inpatient costs in those studies in which chemotherapy and radiotherapy procedures were performed as outpatient costs [ 22 , 41 ] ( Fig 2A ).

Oral cancer burden of cost and difference of costs (%) according to types of patient care (A) and clinical stage of the disease (B). Difference (%) = [(inpatient cost–outpatient cost)/outpatient cost x 100]. Currency: Kim,2011: Pounds; Lairson, 2017, Rezapour, 2018, Amarasinghe, 2019, Zavras, 2002, Epstein, 2008: US dollars; Pollaers, 2019: Australian dollars; Lafuma, 2019: Euros; Milani, 2021: International dollars (million); Goyal, 2014: rupees.

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Regarding the resource quantification, most of the included studies used a top-down approach (18 studies), generally obtained by allocating portions of a known total expenditure to a specific disease stratified by type of cost. Only 6 studies relied on individual data (bottom-up approach), generally obtained by multiplying the unit costs by quantities.

Advanced staging was more expensive (from 21.9% to 373.3%) than early cancer staging [ 18 , 25 , 29 , 34 , 37 ], despite the lack of a clinical stage standard definition of the disease and the different sets of head and neck tumors studied ( Fig 2B ).

The treatment of recurrent squamous cell carcinoma of the floor of mouth, tongue, and alveolar trigone was 51% more expensive than the treatment of primary tumors, in a two-year follow-up study [ 25 ].

Our systematic review highlights the economic impact of oral cancer as a rising burden from a worldwide perspective. In a resource‐scarce healthcare environment, with an aging population and an increasing number of new diagnoses of oral cancer, this new knowledge is imperative in guiding resource allocation for oral cancer care provision and research funding. Deployment of interventions to improve outcomes for patients should be measured not only in terms of clinical outcome, but also in terms of economic impact. Furthermore, the analysis uncovers the large heterogeneity of cost of illness studies (COI) focused on oral cancer.

In some western countries, the economic burden of OCC and OPC is more than 60% of GDP per capita [ 23 , 26 , 35 ], reaching 215% of US GDP per capita (OPC) [ 41 ]. Considering that the GDP per capita corresponds to the average income of families [ 16 ], it is a cost that the individual cannot, in most cases, bear alone, and which requires the support of governments. Governments and health insurance providers are supposed to be the organizations supplying support to the population in order to face the high cost of chronic diseases. Nevertheless, oral cancer has a 90% chance of being cured, if detected early [ 42 , 43 ].

The development of effective public policies is crucial for reducing these health expenditures. Oral cancer is confirmed as a public health problem and was a concern of at least 17 countries on 4 continents, based on the studies included in this review.

The main characteristics that qualify a COI study are expressed in its methodological definition. These include, among other aspects, the epidemiological approach, costing method and data collection. Incidence-based COI studies should include both direct and indirect costs throughout the life course to outcome. Prevalence-based COIs also include direct and indirect costs over a given period from any stage of the disease. For an acute illness, these two approaches would estimate similar costs. However, for a chronic disease, such as oral cancer, longitudinal incidence-based studies would provide more accurate estimates of the costs of this disease overt time. Considering the costing method for identifying and measuring resources, the COI approach can be micro (bottom up) or macro costing (top down). Using the micro-costing method, costing components and items are measured at the most detailed level possible, with estimated costs per individual, and the selection of a representative sample is recommended to allow external validity or generalizability of the results to a broader population. In macro costing, the total aggregate cost is divided by the number of individuals and can be expressed as an average value. Generally, COI studies that use micro-costing are more accurate, but less generalizable. Regarding data collection, retrospective studies represent a challenge because the data are secondary, generally intended for other purposes (epidemiological or surveillance) and may not be sufficient for a COI study. Most of the studies included in this systematic review did not meet all the items of the instrument used for quality assessment.

Although the economic burden of oral cancer was substantial, this systematic review showed that the costs may be underestimated, and only one [ 19 ] of the 24 studies considered all components of cost-of-illness simultaneously. In addition, from the six studies that analyzed indirect costs [ 18 , 19 , 28 – 31 ], only three studies [ 19 , 29 , 31 ] included costs of early death related to the disease, which is one of the most expensive items for society [ 44 ]. Further longitudinal studies with higher quality are needed, not only methodologically, but in their data analysis and reporting of results. These studies should include, not only direct medical costs, but also direct non-medical and indirect costs, so that more accurate estimates can contribute to cost evaluation of health promotion and disease management programs.

The wide heterogeneity of COI studies was identified in both the aspects related to disease characterization and those related to economic issues. Regarding the disease, the main sources of heterogeneity were the characteristics of the samples; the lack of standardization in the definition of the clinical stage of the disease, and the different sets of head and neck tumors studied. The heterogeneity related to economic issues of the studies were found in their design, perspective, time horizon, sources of information, components and costing items, the health system of each country, currency, and reporting of cost results. The World Health Organization (WHO) recommendation is that the results of COI studies be reported in international dollars according to the PPP, to better support country-to-country comparisons of costs [ 45 ]. The development of protocols for the cost evaluation of oral cancer should be encouraged, as it has been by the Pan American Health Organization (PAHO) with the protocol for calculating the cost of hospital infections [ 46 ], since these analyses are complex and depend on the objectives of the studies. Protocols may contribute to the reduction of heterogeneity, favoring the comparison between different regions and health systems, in order to obtain a more accurate calculation of oral cancer cost.

In general, inpatient costs are higher than outpatient costs. However, this depends on the provision of health resources in each healthcare unit of the health system in each country. For example, in the USA [ 41 ], outpatient costs were higher than inpatient costs because most patients were treated with radiotherapy in outpatient care, which is one of the most expensive treatments for oral cancer management.

The costs of oral cancer in advanced clinical staging were higher than those at early stages, which occurred regardless of the heterogeneous characteristics of the studies. Most cases of oral cancer have been diagnosed in advanced staging for almost two decades [ 47 ] which in addition to compromising patient survival, determines high-cost treatments and suggests flaws in policies to promote preventive measures/strategies and early detection and diagnosis. This reinforces the importance of public policies that prioritize actions in the context of primary care, including health education for the population, qualification of professionals for the early detection of the disease, and the monitoring of the population at risk through opportunistic screening [ 7 , 48 ].

The main limitation of this review was the difficulty of finding average cost results per patient from cancer sites, defined here as oral cancer (ICD-10 C01-C06, C09, and C10). These difficulties are possibly associated with the presentation of study results as aggregate costs of head and neck cancer and, also as a result of the absence of an international standardization defining which anatomical sites should characterize oral cancer. The heterogeneity of studies in other aspects of the disease characteristics, method, and economic issues may also have impacted on our findings, which did not allow a meta-analysis.

Decision makers increasingly require economic evidence to inform health policies [ 49 , 50 ] and systematic reviews of economic evaluations (COI and cost-effectiveness) have grown accordingly [ 51 – 55 ]. This study provides a comprehensive and critical overview of the COI analyses conducted around the world, which highlights the magnitude of the financial impact of oral cancer on societal or public health expenditure. This evidence can contribute to priority setting, particularly in the context of scarce resources. Our results can also be used by several other key stakeholders, such as international organizations (WHO and World Bank), health insurance companies, and health providers (health facilities and health workers).

This systematic review can also provide relevant insights for the health technology assessment field, particularly for economic evaluation studies. COI studies represent the first step towards complete economic analysis (e.g., cost-effectiveness analysis) and can also support budgetary impact analysis, by identifying, measuring, and valuing costs related to a specific disease or health condition [ 56 ].

This systematic review shows that the economic burden of oral cancer is substantial and underestimated. The cost of LC, OCC, and OPC reach an average of 18%, 75%, and 127% of GDP per capita, respectively, in some western countries. Further high-quality COI studies are needed, especially with robust methodological design and those that include, in addition to direct medical costs, the direct non-medical and indirect costs. Standardization of the terminology of the types of cancer and clarity in reporting the sources of cost information are crucial to consider in the COI studies. Also, if COI studies present international dollars as the unit price to reflect the economic cost of goods, and allow inter-country comparison of costs, this could support policy makers to identify major cost drivers of oral cancer and to make decisions regarding a more effective public policy for the prevention of oral cancer.

Supporting information

S1 checklist. prisma 2020 checklist..

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• Open access
• Published: 05 September 2022

Knowledge, attitudes, and practices of oral cancer prevention among dental students and interns: an online cross‑sectional questionnaire in Palestine

• Rola Muhammed Shadid 1 , 2 ,
• Mohammad Amid Abu Ali 3 &
• Omar Kujan 4  

BMC Oral Health volume  22 , Article number:  381 ( 2022 ) Cite this article

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Oral cancer is frequently characterized with an aggressive behavior and an unfavorable prognosis; however, it is generally associated with promising prognosis if detected early. Therefore, this study aimed to assess knowledge, practices, and attitudes toward oral cancer prevention among dental students and interns; and to investigate the factors that influence their practices of oral cancer screening or prevention.

Material and methods

A cross-sectional questionnaire-based survey was conducted between March and April of 2022 on the fourth- and fifth-year undergraduate dental students and interns in the College of Dentistry at Arab American University in Palestine. A 48-item questionnaire which has 4 sections: demographics, knowledge, practices, and attitudes toward oral cancer prevention and early detection was sent to all eligible participants (N = 570).

The response rate was 68.7% (N = 351). About 66.8% of the respondents had poor knowledge about oral cancer and its risk factors, and 85.5% had a poor practice of oral cancer early detection and prevention; however, the majority of the respondents (81.1%) had shown favorable attitudes toward oral cancer prevention. Interns had significantly better knowledge and attitude scores compared to the undergraduate dental students ( P  < 0.05). Lack of training, time, confidence, and effectiveness were stated among the barriers to oral cancer screening.

Conclusions

Most of the participants surveyed in this study appeared to lack adequate knowledge and skills in oral cancer prevention and early detection; however, they seemed to have good motivation and a good attitude toward oral cancer prevention training.

Peer Review reports

Lip and oral cavity cancers are considered a main global health problem representing the 16th most common neoplasm globally, with almost 377,713 new cases and about 177,757 deaths registered in 2020 [ 1 ]. However, most of the new cases of oral cancers are reported in the developing countries [ 2 ]. Kujan et al. based on GLOBOCAN 2012 projection, estimated that the number of new cases and the mortality rate of oral cancer will duplicate in the Middle East and North Africa (MENA) region, where most countries in this region are from the developing world, by the year 2030. This contrasts with the incidence and mortality rate of the oral cancer globally where it is estimated to increase by only 50% in the same time span [ 3 ].

In Palestine as part of the MENA region, the newly reported cases of oral cavity and oropharyngeal cancer were estimated at around 90 and the associated deaths were 35 in 2012 [ 4 ].

Squamous cell carcinoma has been found to be the most common type of the lip and oral cavity cancers representing about 90% [ 5 ], and it is regarded to be a multifactorial disease [ 6 , 7 ]. Heavy tobacco smoking, alcohol drinking, viral infection by human papilloma virus (HPV), and genetic instability are considered to be the main risk factors in the MENA region [ 7 , 8 , 9 , 10 , 11 ]. Dietary, occupational, and environmental risk factors might also contribute to oral cancer development [ 12 ]. However, tobacco smoking that is an endemic habit in the MENA region is considered the most significant risk factor. For example, the prevalence of tobacco smoking among the Palestinian male population is about 40% [ 12 ].

Oral cancers are most prevalent on the lower lip, lateral border of the tongue, and floor of the mouth. They affect mainly the middle-aged and elderly men with the highest occurrence in the sixth to eighth decades of life [ 3 ]. Although oral cancers are frequently characterized with an aggressive behavior and unfavorable prognosis [ 13 , 14 ], they are generally associated with promising prognosis if detected early [ 15 ]. These lesions can be prevented by either lessening exposure to risk factors or detection and surveillance of oral potentially malignant disorders [ 16 ]. Unfortunately, a recent systematic review demonstrated that oral cancers are commonly ignored by healthcare providers and the resulting delay in referrals is a major contributor to disease’s advanced stages [ 17 ]. General dental practitioners play a vital role in the prevention and early detection of oral cancer due to their forefront contact with patients [ 18 ].

Several studies worldwide investigated oral cancer awareness, knowledge, practices, and attitudes among qualified practicing and future dentists [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. Some of these studies revealed poor or inadequate level of knowledge, attitudes, or practices of oral cancer prevention [ 22 , 30 , 31 , 32 ], implying the need for improving the oral cancer curricula in undergraduate and graduate dental courses and for conducting more continuing education programs for healthcare professionals to improve the knowledge and attitudes toward oral cancer prevention and early detection.

Since the incidence of oral cancer is increasing in the MENA region [ 3 ] due to incremental trends of highly associated risk factors such as smoking and alcohol consumption [ 12 ], and owing to the vital role played by the general dental practitioners in the prevention and detection of oral cancer lesions at early stages, and because no study till now was conducted in Palestine to assess the dentist’s oral cancer awareness, this cross-sectional study aimed to assess the knowledge, practices, and attitudes toward oral cancer prevention among students and interns in the College of Dentistry at the Arab American University (AAUP); and to investigate the factors that influence their practices of oral cancer prevention or early detection.

This cross-sectional questionnaire-based study was conducted and reported in accordance with CHERRIES guidelines [ 33 ] between March and April of 2022, and targeted the fourth- and fifth-year undergraduate dental students and interns in the College of Dentistry at AAUP. A total of 511 undergraduate students and 59 interns were deemed as eligible participants. The study was approved by the Institutional Review Board (IRB), College of Dentistry, Arab American University (2022/A/3/N), and was conducted in agreement with the Declaration of Helsinki guidelines. All participants provided informed consent. The 48- item questionnaire used in the current study was established after reviewing previous studies [ 18 , 23 , 29 ], and it was pilot tested on a group of 20 undergraduate students and interns to verify its clarity and simplicity. The questionnaire content validity was evaluated by an expert in Oral Medicine and it was pre-validated in previous research work [ 18 ]. Reliability was assessed using the test–retest method in which 20 students and interns completed the questionnaire twice within two weeks. Outcomes of the two times were compared using Pearson’s correlation coefficient that has shown a significant stability coefficient suggesting a good test–retest reliability.

Regarding internal consistency between items in the survey, it was measured using the coefficient alpha "Cronbach’s alpha”. A Cronbach α = 0.785 was attained, entailing acceptable internal consistency.

The questionnaire was created online using Google Drive and a link was emailed and shared with all eligible participants in closed groups on social media. A cover letter accompanying the questionnaire explained the study aims, the methods of the study, and assured that the participation was voluntary, anonymous, and all information given would be confidential and used for research purposes only.

The questionnaire consisted of 47 close-ended questions and one open-ended question which were categorized into 4 sections: demographics, knowledge, practices, and attitudes toward oral cancer prevention and early detection. The first section included information about the demographics such as age, sex, and education level. The second section included questions about participants’ knowledge regarding oral cancer signs, symptoms, and risk factors (22 questions). A score of “1” was given for each correct answer on the questions, so the overall knowledge score ranged from 0–22. The current study used (13.2 /22) 60% as cut-off points [ 32 ], > 13.2 points was considered to have good knowledge and ≤ 13.2 points was considered to have poor knowledge of oral cancer.

The third part of the questionnaire included 12 questions about practices of oral cancer prevention and detection and one question about the claimed barriers for regular oral cancer screening. The best practice score was 12 while 7.2 represented a cut-off score; > 7.2 was regarded as good practice and ≤ 7.2 as poor practice.

In the final part of the questionnaire, participants were questioned about their attitudes and opinions about oral cancer prevention by responding to 10 statements using “strongly agree”, “agree”, “disagree”, and “strongly disagree”. A score of 1 designated positive attitude, while a score of 0 designated negative attitude, with 10 represented the maximum score. Six was set as cut-off score; > 6 was considered as a favorable attitude and ≤ 6 as unfavorable.

Statistical analysis

Responses were assembled using the Google Drive Excel document, and data were analyzed statistically using the Statistical Package for Social Sciences (SPSS), version 22.0. Descriptive statistics of the mean, standard deviation and percentages were calculated for all continuous variables. The level of statistical significance was considered at P  < 0.05.

The influence of sex and age on the knowledge, practice, and attitude scores was evaluated using independent samples t-test, and the influence of education level on the abovementioned variables was tested using One Way Analysis of Variance (ANOVA).

Of the 511 undergraduate dental students who were requested to participate, 351 completed the survey with a response rate of 68.7%; and 41 interns from 59 filled the survey with a 69.5% response rate. This represents an overall response rate of 68.8%. Most of the respondents were females (64.3%), ≤ 30 years old (94.1%), and undergraduate dental students (98.5%; Table 1 ).

Table 2 shows the number and percentage of undergraduate dental students and interns who correctly answered the knowledge questions. Table 3 shows the number and percentage of undergraduate dental students and interns who recognized high-risk factors for oral cancer. Table 4 reveals the number and percentage of undergraduate dental students and interns who claimed good practice and experience with oral cancer screening and referral at College of Dentistry. Table 5 demonstrates the number and percentage of undergraduate dental students and interns who exhibited positive attitudes toward oral cancer prevention.

Concerning the assessed knowledge of oral cancer and its risk factors, 66.8% of the respondents had a poor knowledge with an 11.86 (3.56) overall mean among the responding participants. About 85.5% of the responding participants had a poor practice of oral cancer prevention and early detection with an overall mean of 4.44 (2.75). However, most respondents (81.1%) had favorable attitudes toward oral cancer prevention with an overall mean of 7.48 (2.15) (Table 6 ).

Regarding if the participant’s age, sex, or education level had a significant effect on the level of knowledge, practice, and attitudes toward oral cancer prevention, an independent t-test and ANOVA showed that sex was significantly associated with oral cancer practice in the College of Dentistry at AAUP ( P  < 0.05). Male responders (4.94 ± 2.86) had better practice scores compared to females (4.16 ± 2.65). Education level was also significantly related to knowledge, practice, and attitudes toward oral cancer prevention in the College of Dentistry at AAUP ( P  < 0.05). Interns had significantly better knowledge (13.68 ± 2.43) and attitude scores (8.68 ± 1.68) toward oral cancer prevention compared to undergraduate dental students; however, fourth-year dental students had significantly better practice scores (4.93 ± 2.90) when compared to fifth-year students and interns (Table 7 ).

Regarding the perceived barriers to oral cancer screening among undergraduate dental students and interns at AAUP, more than half of the respondents (57.2%) believed that insufficient training was a barrier. Other claimed barriers included lack of time (19.3%), lack of confidence (12.9%), and lack of effectiveness (10.6%; Table 8 ).

This cross-sectional study sought to assess the knowledge, practices, and attitudes toward oral cancer prevention and early detection among students and interns in the College of Dentistry at AAUP; and to investigate the factors that influence their practices of oral cancer screening or prevention.

There was an 68.8% response rate, which is higher compared to other analogous studies from Saudi Arabia (56.4%, 54.2%) [ 27 , 32 ].

The current study revealed that the level of oral cancer knowledge among most of the surveyed participants is regarded as poor. This result is comparable to the results of previous studies conducted in Saudi Arabia [ 31 , 32 ], Kuwait [ 30 ] and United Arab Emirates [ 34 ], but it is in contrast to those of other studies in Saudi Arabia [ 18 , 28 ] and India [ 25 ] that revealed good to excellent knowledge of oral cancer and its associated risk factors among dental students and interns.

Regarding the level of the practice of oral cancer prevention and early detection, the present survey demonstrated a poor level of practice among the surveyed participants. This is in accordance with the results of a recent cross-sectional study in Saudi Arabia [ 32 ]; however, it is in contrary to the results of studies in India [ 25 ] and Brazil [ 24 ] that demonstrated good practices of oral cancer prevention and screening among undergraduate dental students. Might be the poor level of oral cancer knowledge in the current study justifies the poor level of practice among the responding participants.

In addition, the present study demonstrated that the attitude toward oral cancer prevention among the participants was favorable. This agrees with the results of other studies in Saudi Arabia [ 31 ], India [ 25 ] and Brazil [ 24 ], but contrasts with those of a recent cross-sectional study conducted in Saudi Arabia [ 32 ].

The current study concluded that the level of education positively affected the knowledge and attitude scores; since the interns in the College of Dentistry at AAUP had significantly better knowledge and attitude scores toward oral cancer prevention compared to the undergraduate dental students. This finding is in accordance with that demonstrated by Shubayr et al. [ 32 ], but it is in contrast to the results of a study in Turkey [ 19 ] that demonstrated no significant association between the year of study in the dental college and the level of knowledge of oral cancer risk factors.

Regarding the practice of oral cancer prevention and early detection, why fourth-year dental students had significantly better practice scores compared to fifth-year students and interns might be explained by their application of freshly educated topics since they start to take these topics at fourth-year level.

Concerning the perceived barriers to oral cancer prevention and screening among the undergraduate dental students and interns at AAUP, lack of training was the most prevalent, followed by lack of time, lack of confidence, and lack of effectiveness. These findings are in accordance with the results of a study [ 26 ] undertaken in Australia that reported that lack of training, confidence, time, and financial incentives were seen as barriers to performing oral mucosal screening to at least some degree by the responding participants. The lack of training could be managed by enhancing the dental undergraduate curricula and by making continuous educational programs and training on oral cancer prevention and early detection. In the United States, the CODA (Commission on Dental Accreditation) specifies that all USA dental students should be experienced in screening for head and neck cancer and in identification of its risk factors [ 35 ]. It is worth noting that the studies published before the recent modifications of the CODA academic standard had revealed that American dental students and dentists considered themselves undertrained in oral cancer screening and detection [ 20 , 21 ].

Undergraduate dental students in AAUP are sensitized to the subject of oral cancer starting from the third year of curriculum. During this year, the students in oral pathology course are exposed to risk factors and carcinogenesis of oral cancer and potentially malignant oral disorders. This course is given in the form of lectures, structured interactive sessions, and evaluation of histopathological slides. By the fourth and fifth years, the students in oral medicine courses get the theoretical basics of diagnosis and treatment of malignant and potentially malignant oral lesions in the form of lectures, structured interactive sessions, and seminars. These sessions are guided by oral medicine and oral surgery specialists. Clinically, the students in the fifth year have an oral medicine clinic where potentially malignant oral lesions and oral cancer cases are referred to and the students practice examining, diagnosing, and treating like these cases.

It appears that the present study is the first in Palestine to assess the knowledge, practice, and attitudes toward oral cancer prevention and early detection among future and current dentists.

This study gains its importance from being a cross-sectional, low-cost, and prompt method that provides useful information on the adequacy of the dental curriculum of oral cancer prevention in this dental school, and also gives insight into the need for continuous education programs to train students and practitioners in oral cancer prevention theoretically and practically.

However, caution should be taken when interpreting the results of the current study due to some methodological limitations. The study was a questionnaire-based survey and all data were self-reported and subjective; therefore, the responses may not appropriately reproduce the real levels of knowledge and attitudes. In addition, this study included only dental students and interns in the College of Dentistry at AAUP; this may limit the generalizability of the findings to all students and dentists practicing in Palestine. Finally, the relatively low response rate (68.8%) that could introduce a nonresponse bias should be taken into consideration. However, this study shed the light on the necessity of enhancing the educational undergraduate curricula and on conducting continuous training activities for dental students and dentists about oral cancer prevention and early detection both theoretically and practically. Numerous oral cancer screening cases should be part of dental students’ clinical requirements. Dental schools should be the leader in heading like these training programs for oral health providers; therefore, oral cancer cases will be early detected leading to an increase in oral cancer survival rates and a decrease of morbidity rates [ 36 , 37 ].

According to the findings of this survey, it was concluded that dental students and interns at Arab American University in Palestine appeared to have a good attitude and a good motivation toward oral cancer prevention and early detection. However, they lacked the adequate knowledge and training. Interns had higher knowledge and attitude scores toward oral cancer prevention compared to the undergraduate dental students. More efforts and further research are needed to fill the gap in oral cancer knowledge and training by enhancing the undergraduate curricula and by organizing periodic, continuous training activities for dental students and dentists with regard to oral cancer prevention and early detection at the AAUP College of Dentistry.

Availability of data and materials

The data that support the findings of this study are submitted with the manuscript.

Abbreviations

Arab American University

Middle East and North Africa

One way analysis of variance

Commission on dental accreditation

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Acknowledgements

The authors would like to take this opportunity to thank Dr. Nada H. M. Ahmed who shared her questionnaire that helped in making the current questionnaire and are grateful to Dr. Lubna Sabbah for helping in questionnaire’s distribution. The authors also thank all participants who took part in this survey.

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Department of Prosthodontics, College of Dentistry, Arab American University, P.O. Box: 240, Jenin, Palestinian Territory, Palestinian Territory

Rola Muhammed Shadid

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Department of Oral and Maxillofacial surgery, College of Dentistry, Arab American University, Jenin, Palestinian Territory

Mohammad Amid Abu Ali

Lead Discipline in Oral Pathology, UWA Dental School, University of Western Australia, Nedlands, WA, Australia

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R.S. conceived, designed, implemented the study, completed the data collection, wrote the manuscript, and approved the final version. M.A. implemented the study and approved the final version. O.K. designed the study, reviewed, edited, and approved the final version. All authors read and approved the final manuscript.

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Correspondence to Rola Muhammed Shadid .

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The study was approved by the Institutional Review Board (IRB), College of Dentistry, Arab American University (2022/A/3/N), and was conducted in agreement with the Declaration of Helsinki guidelines. Informed consent was obtained from all probable participants for contribution in the present study.

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Shadid, R.M., Abu Ali, M.A. & Kujan, O. Knowledge, attitudes, and practices of oral cancer prevention among dental students and interns: an online cross‑sectional questionnaire in Palestine. BMC Oral Health 22 , 381 (2022). https://doi.org/10.1186/s12903-022-02415-8

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• Published: 08 April 2000

oral cancer

Oral cancer in young adults: report of three cases and review of the literature

• R J Oliver 1 ,
• J Dearing 2 &
• I Hindle 3  

British Dental Journal volume  188 ,  pages 362–366 ( 2000 ) Cite this article

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Metrics details

Oral cancer chiefly affects older adults.

In younger adults, oral cancer is often not considered because of its relative infrequency which may lead to late referral for treatment.

Young adult patients who develop oral cancer often are not exposed to the traditional risk factors of tobacco and alcohol.

Oral cancer in young adults is fortunately uncommon in the UK. However, since it is so rare, when cases present they are often misdiagnosed and inappropriately treated leading to delay in definitive treatment. This may, in turn, lead to a poorer prognosis for these patients. It is debatable if oral cancer in younger adults carries an inherently poor prognosis and presents with more aggressive tumours. Three cases of oral cancer in young adults, aged under 30 years are presented and the literature reviewed with respect to oral cancer in this group of patients.

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Oral cancer (ICD 141, 143-146) continues to be a serious problem in the UK with a steadily rising incidence in certain birth cohorts. 1 Despite this, oral cancer remains primarily a disease of older patients. Cases occurring in younger adults are uncommon, in the region of 1% of oral cancers in England and Wales; 2 arbitrarily a younger age group is referred to as less than 30 or 40 years. However, in the majority of reports as in the present, a group of otherwise apparently healthy young adult patients often without any of the usual risk factors for the development of oral cancer are identified. However, even when young patients have indulged in the risk factors of tobacco and alcohol, it is for considerably shorter periods compared with the older age group. Patients in this younger age group are claimed by some to have a more aggressive disease with a higher incidence of local recurrence or regional lymph node involvement after treatment and a higher mortality rate compared with older patients 3 , 4 while others do not support this notion. 5 , 6 , 7 , 8

We are reporting a series of cases of oral cancer occurring in three apparently healthy Caucasian adult patients aged 20, 24 and 26 years old who presented to one consultant in a 12-month period.

Case reports

A 26-year-old married male presented for routine examination with his general dental practitioner, complaining of a sore area on the left side of his tongue, present for about 1 week. There was no relevant medical history, and the patient was a non-smoker who drank around 10 units of beer per week. The practitioner diagnosed a traumatic ulcer, prescribed triamcinolone in carmellose and a chlorhexidine mouthwash. Reviewing the patient 1 week later, the ulceration was found to have healed, leaving an area of leukoplakia tender to palpation. At review 1 month later the white patch had become nodular and the patient was referred. At presentation 3 days later the symptoms of pain from the left side of the tongue continued, exacerbated by spicy foods but not relieved by empirical treatments received from the practitioner. Intraorally, a 25 mm diameter white, verrucous area extended from the left lateral margin of the tongue into the sublingual area which was tender to palpation. The tissue proximal to the lesion was erythematous and atrophic in appearance.

The lesion was biopsied and histopathological examination revealed a well differentiated squamous cell carcinoma. The patient underwent total excision of the lesion with reconstruction using a split skin graft. At 5-year follow-up the patient remained free from disease.

A 24-year-old married female was referred urgently having presented to her general medical practitioner complaining of a lump under her tongue of about 3 weeks duration. On presentation, she admitted to a lump on the right side of her tongue which had previously been asymptomatic but had begun to cause occasional discomfort as it increased in size. The lump was interfering with the patients ability to eat. Previous medical history revealed that the patient had undergone cervical diathermy to remove severely dysplastic cells, which had been diagnosed as CIN III (cervical intra-epithelial neoplasia grade III). Otherwise her medical history was clear, and the patient was teetotal but smoked up to 20 cigarettes per day. Extraoral examination revealed the presence of right hand side jugulodigastric lymphadenopathy. Intraorally there was evidence of swelling on the right lower lateral border of the tongue extending into the floor of the mouth, which was tender and indurated ( Figure 1 ). There was no fixation of the mass to the mandible. An incisional biopsy was performed and histopathologically demonstrated well differentiated squamous cell carcinoma.

Lesion on the right lateral border of the tongue of Case 2 (24-year-old female)

Bone scans and chest computed tomogram (CT) were clear. CT revealed two abnormal nodes in the right jugulodigastric region and one on the left which were needle biopsied; the left hand side node was negative but the right nodes showed metastatic squamous cell carcinoma. Following surgery and radiotherapy the patient was still alive and well with no evidence of recurrent disease more than 5 years after presentation. She subsequently gave birth to her first child.

A 20-year-old female, was referred by her general dental practitioner regarding a 20 mm by 3 mm asymptomatic ulcerative lesion on the right lateral border of the tongue. This had been present for 3 weeks and had gradually reduced in size. The patient was unaware of the lesion, which had never caused any symptoms. There was no relevant medical history. The patient consumed minimal alcohol and smoked up to 30 cigarettes per day. Her paternal uncle had died from laryngeal carcinoma. Intraorally an erosive lesion of the right lateral margin of the tongue with surrounding areas of hyperkeratinisation was noted. Incisional biopsy of the lesion was performed providing a histopathological diagnosis of erosive lichen planus with no evidence of neoplasia.

The patient was reviewed at monthly intervals. Six months post-biopsy she attended her general dental practitioner complaining of a lump on her tongue, was reassured and dismissed. A further 2 months later the patient attended her local accident and emergency department for treatment of a sudden haemorrhage from the right side of her tongue. The haemorrhage was arrested and the patient discharged with no advice to seek further assistance. Two days later she presented suffering from marked dysarthria and dysphagia. Extraoral examination revealed a tender, hard, enlarged right jugulodigastric lymph node. Intraoral examination demonstrated a large, tender, indurated ulcer on the right lateral border of the tongue ( Figure 2 ). The patient was admitted and incisional biopsy of the lesion was performed which histopathologically was squamous cell carcinoma. Magnetic resonance imaging (MRI) showed that the lesion extended mesially to the midline of the tongue, inferiorly to the muscles of the floor of the mouth and posteriorly to the fauces without tonsillar involvement. Isotope bone scan and chest CT were clear, but MRI demonstrated abnormalities in the right jugulodigastric lymph nodes.

Ulcerated lesion on the right lateral border of the tongue of Case 3 (20-year-old female) illustrating that the lesion was haemorrhaging prior to taking the biopsy

Despite radical surgery and radiotherapy the patient died 5.5 months after presentation.

Oral cancer in young adults is uncommon and therefore case reports claiming its aggressiveness can be regarded as little more than anecdotal because of insufficient numbers to prove this hypothesis scientifically. The incidence of oral cancer is increasing in some cohorts of patients towards the younger end of the group of patients who develop oral cancer (those more than 40 years); 1 the numbers of cases in young adults less than 40 years of age are so few it is not possible at the present time to say if the incidence in this age group is actually increasing. Clinical experience tells us that young adults presenting with and treated for this disease often have extensive primary tumours and develop recurrences locally or in regional lymph nodes, often succumbing to their disease rapidly. However, this is not always the case, as illustrated in the present series. Summarised data of previous studies of oral cancer in young adults is presented in Table 1 .

Sarkaria and Harari reviewed a total of 152 cases of oral cancer in patients less than 40 years of age reported in the literature. 3 These authors concluded from this significant number that 57% experienced failure above the clavicles and that 47% of patients died from their cancer.However, recent statistics reveal that the 5-year survival for oral cancer in general is in the region of 39%. 9

In contrast to the above review of 14 papers, 3 Rennie and McGregor reported a series of 13 cases of oral cancer in patients less than 40 years of age and concluded that younger patients had a prognosis similar to older patients. 8 However, the age range of this group was between 33 and 39 years, with 11 out of 13 cases being smokers, 11 out of 13 being drinkers including 2 alcoholics; only one of their cases neither consumed alcohol nor smoked and this patient was alive and well after 4 years. In a similar vein, Lipkin et al . presented a series of head and neck cancers which included 15 cases in the oral cavity. 10 These authors concluded that oral cancer in young adults could be associated with heavy smoking and alcohol consumption with an average consumption of 63 pack/years of tobacco. However, their cohort of patients was largely in the 35 to 40 year age group which some would not classify as truly 'young' adults.

Lund and Howard reviewed head and neck tumours in the under 35 year olds during a 22-year period which included 14 tumours of the tongue, 6 of the palate and 3 in the floor of the mouth. 4 Detailed data were only available for the tongue tumours, all of which were squamous cell carcinomas. These authors noted a delayed presentation of these patients who had often been falsely reassured by other practitioners prior to referral. This fact may have accounted for their reported 75% mortality rate in this group. Their report, however, concluded that there was no increase in the rate of presentation in the younger patients. Indeed, in Case 3 of the present series, the patient was dismissed on two occasions when it was likely the carcinoma was present.

In a review of squamous cell carcinomas of the upper aerodigestive tract, Burzynski et al . included nine cases of the oral cavity with only two patients who died of disease, 6 one patient was lost to follow-up and one died of other causes. These cases were all treated with surgery in the first instance. They reported that 91% of the whole group (23 patients) were current or previous tobacco users, however, data was not presented for the individual patients with oral cancer. Two of the patients in the present report were smokers, interestingly, both female. Smoking is strongly associated with the development of oral cancer in older patients 11 but is not generally considered to be a significant aetiological agent in patients of the younger age group despite many of the reported cases showing this habit in these patients.

Assuming smoking and alcohol not to be significant in the aetiology of oral cancer in the young, the genetic events underlying the disease are difficult to account for. The tumour suppressor gene, p53, has been extensively studied and is the most consistently altered gene in oral cancer to date where it is particularly associated with heavy smoking. 12 In oral cancer of the young, p53 mutations have been reported as being absent in non-smoking and non-drinking patients. 13 Many young patients with oral cancer have a history of smoking, as two of the cases in the present report, so for these p53 may play a role but in the remainder of patients there is likely to be some other, as yet undetermined, genetic change. An increased susceptibility to carcinogenic agents has been reported in younger adult patients who have developed oral cancer, the details of which are outside the scope of this article and have been reviewed in a recent paper. 14

A family history of oral cancer has been reported 15 and positive family history of other cancers has been reported for young patients with oral cancer but this was not considered to be significant. 16 Mork et al . recently reported a significantly increased odds ratios for developing head and neck squamous cell carcinoma in female patients, aged less than 45 years, who had first degree relatives with cancer. 14

The role of viruses, particularly human papilloma virus (HPV), in oral cancer development is a much researched and debated area of study. Miller and White concluded in a review of the literature that HPV was a relatively ubiquitous virus and that its demonstration in a significant number of normal oral mucosae as well as in oral cancer was an effect rather than a cause. 17 The link between HPV and cervical cancer, however, is stronger 18 and it could be speculated there was a link in Case 2 between the development of CIN and oral cancer caused by HPV.

Some studies 3 , 4 have claimed oral cancer in younger patients is more aggressive than in older patients and on the basis of this advocate more aggressive therapy. 3 However, others have not reported any significant difference between the two groups. 5 , 6 , 7 , 8 Von Doersten et al . using multivariate analysis investigated recurrence in head and neck cancer patients comprising nearly half of the oral cavity. 19 They concluded that there was no significant difference between recurrence in the younger age group (15 to 39 years old) compared with the older age group and that more aggressive treatment was not necessary. In patients less than 40 years of age with squamous cell carcinoma of the head and neck, including 21% of tumours in the mouth, Clarke and Stell reported crude survival 10% better in younger patients than older adults. 7

Interestingly, one of the patients of the present series (Case 3) had histologically proven lichen planus which clinically presented in an erosive form. There is considerable controversy within the literature over the cancerous potential of lichen planus. Barnard et al . presented a series of cases of patients who developed squamous cell carcinoma in existing lichen planus and reviewed previously reported cases. 20 These authors concluded that there was up to a 5% increase in the risk of developing carcinoma in lichen planus. Most reports of malignant change are in those lesions which are atrophic or erosive which could also be expected to be more susceptible to carcinogens. However, lesions of lichen planus occurring in the high risk sites of the lateral border of the tongue and floor of the mouth should still be regarded with some suspicion. Zhang et al . 21 recently concluded that if malignant transformation occurred in lichen planus the genetic changes that took place were different from those of other precancerous lesions such as leukoplakia.

Conclusions

Oral cancer occurring in young adults is not common but nevertheless should always be considered in such patients when they present with persistent ulceration, leukoplakia, erythroplakia or swellings with no obvious local cause, particularly in the high-risk sites of the tongue and floor of the mouth. For any such lesion, a 'fast-track' referral is recommended by telephone to the nearest specialist centre accompanied by a letter, usually sent with the patient. This will ensure prompt investigation and initiation of treatment which may increase the chances of successful treatment.

It remains unproven if oral cancer in younger patients is inherently more aggressive with a worse prognosis than the disease in older individuals. Personal encounters with such patients may be clouded by the potential emotional aspects of such a deadly disease occurring in younger patients.

With so few cases of oral cancer in younger adults it is still not possible to demonstrate a rising incidence. Improved registration of oral cancer should enable this aspect to be investigated further.

The aetiology of oral cancer in the younger adult remains unclear. It is likely there is some degree of genetic predisposition; genetic linkage studies of affected individuals and their families may prove useful investigating this. In some of the young adult patients, possibly those with an inherent genetic defect, smoking may have a role in the aetiology of oral cancer.

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Senior Lecturer, Oral Surgery Unit, University Dental Hospital of Manchester, Higher Cambridge Street, Manchester, M15 6FH

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Oliver, R., Dearing, J. & Hindle, I. Oral cancer in young adults: report of three cases and review of the literature. Br Dent J 188 , 362–366 (2000). https://doi.org/10.1038/sj.bdj.4800481

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Received : 15 June 1999

Accepted : 22 November 1999

Published : 08 April 2000

Issue Date : 08 April 2000

DOI : https://doi.org/10.1038/sj.bdj.4800481

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Oral tongue cancer: literature review and current management.

Rodrigo Arrangoiz

Sociedad Quirurgica S.C., American British Cowdray Medical Center, Mexico

E-mail : aa

Fernando Cordera

Eduardo Moreno

Enrique Luque de Leon

Manuel Munoz

DOI: 10.15761/CRR.1000153

In 2018, it is estimated that about 51, 540 new cases of oral cavity and pharyngeal cancer will develop, which represent approximately 3-5% of all cancers in the United States. During the same time period it is estimated that there will be approximately 10, 030 deaths. Incidence rates are more than twice as high in men as in women (Male cases–37,160, Female cases–14,380). From 2006 to 2010 incidence rates remained stable in men and have decreased by 0.9% per year in women. Oral tongue cancer requires a multidisciplinary approach to treat it that includes a surgical oncologist, a medical oncologist, a radiation oncologist, speech therapists and physical rehabilitation as well as emotional support through the help of psychologists or social workers. In this review paper we will discuss current management of these complex tumor.

oral cancer, oral tongue cancer, squamous cell carcinoma, diagnosis and treatment of oral tongue cancer

Introduction

In 2018, it is estimated that about 51, 540 new cases of oral cavity and pharyngeal cancer will develop, which represent approximately 3-5% of all cancers in the United States [1,2]. During the same time period it is estimated that there will be approximately 10, 030 deaths [1,2]. Incidence rates are more than twice as high in men as in women (Male cases–37,160, Female cases–14,380) [1]. From 2006 to 2010 incidence rates remained stable in men and have decreased by 0.9% per year in women [1]. From 2005 to 2014, incidence rates decreased by more than 2% per year among blacks, but increased by about 1% per year among whites, largely driven by rising rates for a subset of cancers associated with human papillomavirus (HPV) infection that arise in the oropharynx.

Death rates have been decreasing over the past three decades; from 2006 to 2010, rates decreased by 1.2% per year in men and by 2.1% per year in women [1]. In 2018, it is estimated that 17,110 new cases of oral tongue cancer will occur, of this 12,490 will occur in men and 4620 will develop in women (one third of the cases will develop in women). The estimated death rate from oral tongue cancer in 2018 is 2,510 deaths (1750 in males and 760 in females) (Table 1) [1]. Most head and neck cancers present with metastatic disease at the time of diagnosis, with regional nodal involvement and distant metastatic disease in 43% and 10% of the cases, respectively [3].

Table 1. Estimated new cases and mortality for the year 2018 in the United States [1]

Head and neck cancer patients often develop second primary tumors, this is because they share common risk factors [4]. These second primary tumors develop at an annual rate of 3-7% and 50-75% of these new cancers are located in upper aero digestive tract or lungs [3].

Surgical anatomy of the oral cavity

• Boundaries of the oral cavity:
• Superior border-from the vermillion border to the junction of the hard and soft palates.
• Inferior border-from the vermillion border to the circumvallate papillae of the oral tongue.
• The lateral border-is the mucosa of the mouth up to the anterior tonsillar pillars.

The oral cavity includes the lips, buccal mucosa, upper and lower alveolar ridges, gingiva, retromolar trigone, floor of mouth, hard palate and the anterior two thirds of the tongue ("oral tongue”). The main lymphatic drainage is to level IA (submental triangle), IB (submandibular triangle) and II (upper deep jugular nodes) [5].

Tongue anatomy

The tongue which is located in the oral cavity and oropharynx is a mass of muscle that is almost completely covered by a thick mucous membrane. The primary function of the tongue is taste sensation, but it also assists with mastication, deglutition, articulation, and oral cleansing [6]. The complex innervation of this multifunctional organ is provided by five cranial nerves [7].

The embryologic origins of the tongue first appear at 4 weeks' gestation [7,8]. The first branchial arch is responsible for the development of the tongue derivatives. It gives rise to two lateral lingual swellings and one median swelling (known as the tuberculum impar) [7,8]. The two lateral lingual swellings grow over the tuberculum impar and merge, forming the anterior two thirds of the tongue [8]. Portions of the second, third, and fourth branchial arches give rise to the base of the tongue [9]. The intrinsic musculature of the tongue derives from occipital somites which give rise to myoblasts [8].

Macroscopically from anterior to posterior, the tongue has three surfaces: tip, body, and the base. The tip of the tongue is the highly mobile, pointed, anterior portion of the tongue. Behind to the tip lies the body of the tongue, which has a dorsal (superior) and a ventral (inferior) surfaces. The median sulcus of the tongue separates the body into left and right halves. The terminal sulcus is a V-shaped furrow that separates the body of the tongue from the base of the tongue. At the tip of this sulcus is the foramen cecum, a remnant of the proximal thyroglossal duct. The base of tongue contains the lingual tonsils, the inferior most portion of Waldeyer’s ring [7-9].

The body of the tongue derives its characteristic surface appearance from the presence of lingual papillae, which are projections of lamina propria covered with epithelium [6]. Four different types of lingual papillae exist: circumvallate (vallate), foliate, filiform, and fungiform [6]. The circumvallate papillae are flat, prominent papillae that are surrounded by troughs. There are approximately eight to 12 circumvallate papillae, located directly anterior to the terminal sulcus. The ducts of the lingual glands of von Ebner secrete lingual lipase into the surrounding troughs to begin the process of lipolysis [10]. On the lateral surface of the tongue foliate papillae are identified, they are small folds of mucosa. The filiform papillae are thin and long and they are the most abundant papillae in the tongue. They are located along the entire dorsum of the tongue, but they are not involved in taste sensation [6]. The mushroom shaped papillae and called the fungiform papillae. They are scattered most densely along the tip and lateral surfaces of the tongue. The human tongue has roughly 200 to 300 fungiform papillae.

Each circumvallate, foliate, and fungiform papilla contains taste buds (250, 1000, and 1600 taste buds, respectively) [6], innervated by multiple nerve fibers. All taste buds can perceive the five different taste qualities: salt, sweet, bitter, acid, and umami. The taste bud consists of a taste receptor, basal cell, and edge cell. When a taste molecule binds to a taste receptor, the receptor cell depolarizes, causing an influx of Ca++, which results in the release of an unidentified neurotransmitter [6]. Following the depolarization, the afferent neural pathway depends on the location of the taste bud that was stimulated. In the anterior two thirds of the tongue, the chorda tympani branch of the facial nerve (cranial nerve VII) is stimulated [6,11]. The lingual-tonsillar branch of the glossopharyngeal nerve (cranial nerve IX) relays taste information from the posterior third of the tongue [6,11].

The tongue has four intrinsic and four extrinsic muscles [7,9,11]. The muscles on each side of the tongue are separated by a fibrous lingual septum. The extrinsic muscles are so named because they originate outside the tongue and insert within it and the intrinsic muscles are within the substance of the organ and do not insert on bone. Though the muscles do not act in isolation, intrinsic muscles generally alter the shape of the tongue, whereas extrinsic muscles alter its position [7]. The extrinsic muscles of the tongue are the genioglossus, hyoglossus, styloglossus, and palatoglossus [7]. The hypoglossal nerve provides the motor innervation to all muscles of the tongue except the palatoglossus, which is supplied by the pharyngeal plexus [7,11].

The arterial supply to the tongue and floor of the mouth is derived from the dorsal lingual, sublingual, and deep lingual branches of the lingual artery [11]. The venous drainage of the tongue is into the lingual veins, which drain into the facial and retromandibular veins, which join to form the common facial vein.

The oral cavity is continuously, been exposed to inhaled and consumed carcinogens, and thus it is the most common site for the origin of malignant epithelial neoplasms in the head and neck region. The most common location for a malignant tumor of the oral cavity is the anterior two thirds of the tongue. Known carcinogens in the oral cavity include those present in tobacco, alcohol, and betel nuts. The relationship of human papilloma virus (HPV) with oral cancer is not as well established as in oropharyngeal cancers. Primary tumors of the oral cavity may arise from the surface epithelium, minor salivary glands, submucosal soft tissue, and tumors of dento-alveolar origin [11]. More than 90% of cancers in the oral cavity are squamous cell in origin and we will be focusing our review on these neoplasms.

Epidemiology

Malignant neoplasm of the tongue are by far more common in men than in women (66-95% of cases), this is similar to the rest of the oral cavity [1]. The incidence by gender varies depending on the anatomic location and has been changing due to the increase in the number of women who smoke. The male to female ratio is currently 3:1 [1]. The incidence of oral cavity and tongue cancer increases with age, especially after age 50. Most patients are between 50 and 70 years but can also occur in younger patients [3].

There are large differences in the incidence of oral cavity cancer among different geographical regions. The highest incidence of this disease is found in Asia and is believed to reflect the prevalence of certain risk factors, such as chewing betel nut [12,13] and the use of smokeless tobacco (snuff) [14]. In the United States, in urban areas the high incidence among men is thought to reflect exposure to snuff and alcohol. Among women in rural areas in the United States the increase risk of oral cavity cancer is associated with the use of smokeless tobacco (snuff) [1].

Etiology and risk factors

One of the most important risk factors for the development of squamous cell carcinoma (SCC) of the tongue is tobacco. Smoking cigarettes, cigars, or pipes; chewing tobacco; and using snuff are the single largest risk factors for all head and neck cancer including the tongue. Eighty-five percent (85%) of head and neck cancers are linked to tobacco use [15,16]. Secondhand smoke may also increase a person’s risk of developing a head and neck cancer [17].

Based on epidemiologic studies, cigar smoking is an important risk factors for oral cavity tumors and the only difference between cigarette smoking and cigar smoking is that it instigates a change in the usual anatomic location for these tumors [1,18]. The use of smokeless tobacco is also associated with an increased incidence of cancer of the oral cavity [1,2]. Chewing snuff is the leading cause of SCC of the oral cavity and oropharynx in India, part of Southeast Asia, China, and Taiwan, especially when consumed with betel containing areca nut [19].

Alcohol by itself is a risk factor for the development of tongue and oral cavity cancer, although it is less potent carcinogen than tobacco [20,21]. People who use tobacco and alcohol, these risk factors appear to be synergistic and result in a multiplicative increase in risk, 30 to 36 times higher for people who smoke and drink heavily [22].

Edentulous patients and poor oral hygiene can be risk factors for cancer of the oral cavity [23,24]. The use of mouthwashes that have high alcohol content could be a risk factor for tongue and oral cavity SCC (unproven) [24,25]. The consumption of the tea beverage, mate (consumed by South Americans), has been associated with an increased risk of cancer of the oral cavity [26] .

Epidemiologic studies suggest that the intake of vitamin A, β-carotene, and α -tocopherol may reduce the risk of developing oral cavity cancers [27-32]. Certain syndromes caused by inherited defects (mutations) in certain genes have a very high risk of developing cancer of the oral cavity and tongue. Fanconi anemia is a disease that can be caused by inherited defects in several genes that contribute to DNA repair. People with this syndrome often have hematologic problems an early age, which can lead to leukemia or aplastic anemia. They also have a risk of developing cancer of the oral cavity, especially tongue cancer [33,34]. Dyskeratosis congenita is a genetic syndrome that can cause aplastic anemia, skin rashes, and nail abnormalities of the hands and feet; they also increase the risk of developing oral cavity cancer [35,36].

Mechanisms of carcinogenesis

The development of tongue and oral cavity SCC is a multistep progression that involves changes related to specific genes, epigenetic events, and signal transduction within the cell [37]. Tobacco smoke contains agents that may act as mutagens. Also, tobacco smoke extract has been shown to activate the epidermal growth factor receptor (EGFR) in vitro and EGFR activation has been shown, in turn, to increase the production of prostaglandins, including PGE2 which may act in a positive feedback fashion by increasing EGFR signal transduction. Cyclin-D1 is frequently overexpressed in head and neck cancer and increased cyclin-D1 activity is a downstream event triggered by EGFR activation [38].

An important epigenetic event in the progression to cancer is the silencing of gene promoter regions through hypermethylation [39], which has been shown to affect the tumor suppressors p16, DAP-kinase, and E-cadherin. Also, the gene for retinoic acid receptor-beta (RAR-beta) is silenced by methylation of its promoter [40].

Genetic alterations that are present early in the course of carcinogenesis are mutations or deletions of chromosome 3p and 9p. Telomerase activation also occurs early in carcinogenesis. Mutations or deletions at chromosome 17p (involving the p53 tumor suppressor gene), and chromosome 13q and chromosome 18q generally are seen later in the process. Patients whose tumors contain HPV mRNA have a significantly lower rate of deletions of chromosomes 3p, 9p, and 17p, suggesting an alternate molecular mechanism in these patients. The viral proteins E6 and E7 have been shown to cause deregulation of the cell cycle by inactivating p53 and retinoblastoma protein, which may be the mechanism of HPV-mediated carcinogenesis [41].

In addition to deletions or mutations of individual genes, evidence exists demonstrating that numeric chromosomal imbalances, known as aneuploidy, may be a cause rather than a consequence of malignant transformation [42]. Aneuploidy may occur as a result of mutations in genes controlling chromosome segregation during mitosis and centrosome abnormalities.

The need for a rapid diagnosis and referral of patients to a skilled physician with expertise in the management of tumors of the head and neck is very important because early diagnosis can lead to a reduction in mortality [3]. The risk factors mention on the etiology section of this paper, including history of tobacco and alcohol use should be interrogated. Any adult patient with symptoms attributable to the upper aero digestive tract lasting more than two weeks or an asymptomatic cervical (neck) tumor should undergo a full examination with a high index of suspicion for malignancy [3].

The physical examination is the best way to detect lesions of the upper aero digestive tract. Often the initial assessment also indicates the severity and chronicity of the disease. Due to the frequent occurrence of synchronous primary tumors in patients with head and neck cancers (approximately 5%), a careful evaluation of the entire upper aero digestive tract is required at the time of diagnosis [43].

Tongue cancers usually cause symptoms related to the upper aero digestive tract, including changes in swallowing, speech, hearing and breathing. During the interrogation the physician must give emphasis to the following symptoms: tongue pain, non-healing ulcer on the tongue, and changes in the ability to form words. A complete physical examination should be performed on every patient with specific emphasis on the head and neck exam (inspection, palpation, otoscopic exam, indirect laryngoscopy, and when indicated nasopharyngolaryngoscopy) and a neurological exam with emphasis on cranial nerves V, through XII. The most common presenting complaint of patients with tongue tumors is a sore or lump. Cancer of the tongue mucosa may present as an indurated ulcer with raised edges (Figure 1) or as an exophytic growth. Bleeding from the surface of the lesion is a characteristic of malignancy and immediately raises suspicion for a neoplastic process. Approximately one third of the patients come in to the office with a neck lump [44].

Figure 1. Ulcerated lesion of the tongue

Biopsy of the tongue lesion can often be performed in the office or as an outpatient surgery depending on the anatomic site and patient preference. One can perform the biopsy in the office setting using a punch biopsy or using biopsy forceps (Figure 2). The biopsy should be obtained from the edge of the lesion, away from areas of obvious necrosis or excess keratinization.

Figure 2. Punch biopsy and forceps to perform the biopsy

Fine needle aspiration (FNA) is a useful diagnostic modality [45-47] for differentiating benign from malignant lymph nodes in the neck. A fine gauge needle (#23 gauge) makes multiple passes over the lesion while continues suction is applied. Suction must be released before removing the needle of the lesion. This procedure has a false negative rate of 7% [47]. Cytology is particularly useful to distinguish metastatic SCC from other malignant histology’s. However, a negative result should not be interpreted as " absence of disease" when the clinical scenario is highly suspicions for malignancy. A core needle biopsy should not be performed in a lump in the neck, with the exception of an already diagnosed lymphoma. Martin Hayes in a communication to the medical profession in general stated “not only to the needlessness but also to the possible harmfulness of excisional lymph node biopsy as the first or even as an early step in the diagnosis of cancer” [48]. Open biopsies should be done only when the diagnosis has not been made after extensive clinical evaluation and after at least two non-diagnostic FNA’s. The surgeon performing the open biopsy should be prepared to perform a definitive surgical treatment at that moment in time, which may involve a formal neck dissection if the diagnosis turns out to be a SCC.

Computed tomography (CT) is probably the most informative test in the evaluation of tumors of the oral cavity and tongue [49]. It can help define the extent of disease and the presence and extent of lymph node involvement. CT provides high spatial resolution, can discriminate between fat, muscle, bone and other soft tissues. CT out performs magnetic resonance imaging (MRI) in detecting bone erosion (Figure 3) [50], has a sensitivity of 100% and specificity of 85% [51]. MRI can provide accurate information on the size, location and extent of the tumor involvement of the soft tissues. It is not very reliable to provide information regarding bone extension, unless, there is full involvement of the medullary cavity. The MRI has a relatively higher sensitivity than CT but has lower specificity [49-52]. PET has been evaluated in primary and recurrent carcinomas of the head and neck. In a multicenter, prospective study of patients newly diagnosed with a tumor of the head and neck region the results were discrepant when PET was compared with CT in 43% of cases, and the therapeutic plan was altered in 14 % of patients [53]. PET should not be routinely used in the diagnosis or evaluation of patients with early tumors of the oral cavity.

Figure 3. CT of the head and neck showing bone erosion

Pathology and histologic grade of tongue and oral cavity tumors

Over 90% of head and neck cancers (including the oral cavity tumors) are SCC. The World Health Organization classifies squamous tumors of the head and neck in different histologic subtypes [54,55]:

-Conventional

- Verrucous

- Papillary

- Spindle Cell (Sarcomatoid)

- Acantholytic

- Adenosquamous

- Cuniculatum

Each of these variants can develop in any of the different regions of the head and neck with the exception of the Cuniculatum subtype, that only develops in the lining of the oral cavity [56]. Variants of SCC frequently arise within the mucosa of the upper aero digestive tract, accounting for up to 15% of SCCs in these areas. The most common variants include verrucous, exophytic or papillary, spindle-cell (sarcomatoid), basaloid and adenosquamous carcinoma. Each of these variants has a unique histomorphologic appearance, which raises a number of different differential diagnostic considerations, with the attendant clinically relevant management decisions. Stage for stage each one of these different subtypes of SCC has the same prognosis and are management identically.

Broder’s grading system was the first of the systems, which initiated quantitative grading of cancer. This classification system was based on the estimated ratio of differentiated to undifferentiated elements in the tumor. There are four histologic grades based on the amount of keratinization [56,57]:

• Well-differentiated tumor-> 75% keratinization.
• Moderately differentiated tumor-50-75% keratinization.
• Poorly differentiated tumor-25-50% keratinization.
• Anaplastic or undifferentiated tumor-< 25% keratinization.

Histologic grade is not a consistent predictor of clinical behavior. The characteristics that predict aggressive behavior include perineural infiltration, lymphatic invasion, and tumor extension beyond the capsule of the lymph nodes [56,58].

Immunohistochemical studies may be useful in poorly differentiated lesions to help make the diagnosis because SCC’s express epithelial markers such as cytokeratin’s. Squamous cells are immune-positive for certain cytokeratin’s such as AE1/AE3 and pancytokeratin’s. CK5/CK6 and p63 are also excellent markers for squamous differentiation [59].

Concept of field cancerization (field defect)

It is an important concept related to the natural history of oral cavity cancer. The term describes diffuse injury of the epithelium of the head and neck region, lung and esophagus resulting from chronic exposure to carcinogens [60]. Clinically field cancerization manifests by the frequent occurrence of abnormalities of the mucosa, such as leukoplakia and dysplasia, beyond the margins of an oral cavity cancer or second primary tumors in this field. The lifetime risk of a patient with oral cavity cancer to develop a new cancer is 20-40% [61].

TNM classification of tumors of the head and neck

The TNM staging system of the AJCC maintains uniformity in the staging of head and neck tumors and is based on the best estimate of the extent of disease prior to treatment (Tables 2-5). Assessment of the primary tumor is based on inspection and palpation when possible, by indirect mirror examination and direct endoscopy when necessary [62].

Table 2. TNM classification of oral cavity cancer - primary tumor (T) [62]

Table 3. TNM classification of oral cavity cancer - lymph nodes (N) [62]

Table 4. TNM classification of oral cavity cancer - distance metastasis (M) [62]

Table 5. Anatomical staging and prognostic groups [62]

The prognosis is strongly correlated with the stage of the disease at diagnosis. Survival of patients with stage I disease exceeds 80% [2]. For patients with locally advanced disease at the time of diagnosis (i.e., stage III and IV), survival drops below 40% [63]. The development of metastases in lymph nodes reduces the survival of a patient with a small primary tumor by 50% [2,3]. Most patients with head and neck cancers at the time of diagnosis are found to be stage III or IV [62,64].

Patterns of relapse

Despite aggressive treatment of the primary most relapses occur within the same region of the primary oral cavity tumor. Local and regional recurrences represent approximately 80% of primary treatment failures [65]. Distant metastases increase as the disease progresses and more frequently include the lungs, and to a lesser extent, bone and liver. This is a reason to use PET/CT for assessing the distant spread of the cancer in patients with disease recurrence of progression . In 10-30% of patients distant metastases are detected at the time of death [63].

Treatment options

Management of tongue cancers requires a multidisciplinary team made up of a surgical oncologist specialized in head and neck cancers, dentist, prosthodontist, plastic reconstructive surgeons, medical oncologist, radiation oncologist, speech therapist, fiscal rehabilitation therapist, social worker, and psychologist.

The treatment depends on the site, the extent of the primary tumor, and lymph node status, and may include [49,63,66]:

• Surgery alone.
• Radiation therapy alone.
• A combination of the above.

The best therapeutic approach for the primary tumor depends on the anatomic site. Most early cancers of the tongue can be treated equally well with surgery or radiation therapy, therefore the method chosen to treat the neck is based on the mode that has been selected for the primary tumor. When the primary tumor is treated with radiation, regional lymph nodes "at risk" are incorporated into the field of treatment [3]. Patient factors and experience should influence the choice of treatment. Due to the lower morbidity of primary surgical resection of oral tongue tumors compared to primary radiation therapy most international guidelines recommend surgery as the primary modality [67]. Larger cancers may require composite resections with reconstruction of the defect by pedicle flaps and often require adjuvant therapy with radiation and chemotherapy [68,69].

The classical surgical principles of oncology are applied to tongue cancers. Complete en bloc resection is necessary. Ensuring adequate margins can be challenging due to the important structures in this area [70]. The reconstruction after surgery is complex after resection of tumors of the tongue because the surgical procedure may have an important impact on speech and swallowing. Experienced surgeons should perform the decisions regarding the extent of resection. Prosthodontic rehabilitation is important, especially in the early stages of cancer, to ensure better quality of life.

For lesions of the oral tongue, surgery should revmove all macroscopic evidence of the disease keeping in mind the possibility of microscopic extension. If regional nodes are positive, cervical lymph node dissection is usually done in the same procedure. Neck dissection must be standardized (i.e. complete anatomical dissections, instead of random biopsies) in these situations to prevent incomplete surgery. Elective neck dissection is recommended for patients who have a oral cavity tumors with a minimum thickness of 4 mm [3], although some researchers believe that tumor thickness of 2-3 mm would be a more appropriate cut off [71,72] (Table 6).

Table 6. Thickness of oral cancer predicts survival and failure [72]

Supraomohyoid neck dissection is recommended in patients with a clinical stage N0 who are treated surgically. There is evidence of skip metastases through the levels of the neck [73] and in some cases just involving level IV without involving the first levels. Therefore some authors recommend extended supraomohyoid neck dissection [73]. Bilateral neck dissection is performed if the tumor is close to or abutting the midline.

Sentinel lymph node (SLN) biopsy is another new option to standard elective neck dissection for identifying an occult cervical metastasis in patients with an early (T1 or T2) oral tongue cancer in centers where expertise for this procedure exists [74,75]. Patients who are found to have metastatic disease in their SLN’s must undergo a completion neck dissection while those without a positive SLN can be observed with close follow up. The precision of the SLN biopsy for staging of the neck in early oral cavity cancer has been tested at length in multiple single-center trials and in two mutli-institutional studies against the reference standard of elective neck dissection with a pooled estimated sensitivity of 0.93 and negative predictive value ranging from 0.88 to 1 [74-79]. This is a technically demanding procedure that has a steep learning curve in which the success rate is dependent on the experience and expertise of the surgeon. Up to know a direct comparison with the policy of elective neck dissection is lacking [77], so we recommend using this procedure very selectively. For example, very early carcinomas of the oral cavity (T1 or may be T2), excluding floor of the mouth tumors because the accuracy in the studies we have up to date is inferior to other anatomical sites within the oral cavity such as the tongue [74,76], that have a tumor thickness less than 4 mm.

Radiation therapy for cancer of the oral cavity may be administered as external beam radiotherapy (EBRT) or interstitial implantation alone. It is difficult getting enough dose to primary with brachytherapy while still delivering adequate dose to the regional nodes, so for many sites using both modalities produces better control and better functional outcomes [80]. Small superficial cancers can be treated very successfully by local implantation using any of the various radioactive sources (intraoral cone therapy, or electrons) [81]. Larger lesions are frequently managed using external beam radiotherapy, which includes the primary site and regional lymph nodes (even if not clinically affected) [63]. Supplementation with interstitial radiation sources may be required to achieve adequate doses for bulky large primary tumors and / or lymph node metastases. A review of published clinical results of radical radiation therapy for head and neck tumors suggests a significant loss of local control when the administration of radiation therapy was prolonged, therefore, lengthening of standard treatment programs should be avoided whenever possible [82,83].

Radiation therapy with curative intent usually involves daily treatment for 6 to 7 weeks (total dose: 60-70 Gy) [67]. Although there is no loss of tissue with radiation therapy as with surgery, potential complications include dry mouth, tissue fibrosis, trismus, bone necrosis, hypothyroidism, and dysphagia [84-86]. Some of these problems are common and debilitating enough to require significant attention during treatment planning. Surgery often results in less morbidity in the oral cavity, while radiation therapy causes less morbidity in other regions such as the oropharynx, larynx and nasopharynx.

The definitive indications for postoperative radiotherapy are positive margins, multiple positive nodes with metastatic disease, and extra capsular nodal extension [66,87]. Less certain indications include lymphovascular space invasion, perineural spread, single encapsulated positive lymph node, and thick tumors [87]. Tumors with a thickness between 3 to 9 mm have 44% subclinical node positivity and a 7% local recurrence rate and tumors with a thickness greater than 9 mm thickness have 53% subclinical node positivity and a 24% local recurrence rate [87].

Postoperative radiotherapy (60 to 70 Gy in 6-7 weeks) reduces the rate of local and regional recurrence from 50-15% for tumors with pathologic features that predict a high local and regional failure rates [81,88,89]. The indications for postoperative radiotherapy are well established and are outlined in Table 7.

Table 7. Possible Indications for postoperative radiotherapy

Two randomized clinical trials were conducted to determine whether adding chemotherapy to radiation therapy improves local /regional control and survival in high-risk patients with head and neck cancers after definitive surgical resection. The results of these trials were published in 2004 [88,90] (Table 8).

Table 8. Results from the EORTC 22931 and RTOG 9501 Studies

In a comparative analysis of the two trials, the presence of extracapsular extension and / or microscopically involved surgical margins were the only risk factors for the positive impact that chemo radiation had over improved survival [91]. The adjuvant treatment for patients with oral tongue cancers is summarized in Table 9.

Table 9. Summary of adjuvant treatment of oral cavity cancers

Recently the results of the RTOG-0234 examining concurrent chemoradiotherapy and cetuximab in the postoperative treatment of patients with head and neck squamous cell carcinoma (HNSCC) with high-risk pathologic features was published [92]. The study recruited 238 patients were with stage III to IV HNSCC with gross total resection showing positive margins and/or extracapsular nodal extension and/or two or more nodal metastases. Patients were randomly assigned to 60 Gy radiation with cetuximab once per week plus either cisplatin 30 mg/m2 or docetaxel 15 mg/m2 once per week. With a median follow-up of 4.4 years, 2-year overall survival (OS) was 69% for the cisplatin arm and 79% for the docetaxel arm; 2-year disease-free survival (DFS) was 57% and 66%, respectively. DFS in this study was compared with that in the chemoradiotherapy arm of the RTOG-9501 trial, which had a hazard ratio of 0.76 for the cisplatin arm versus control (P=0.05) and 0.69 for the docetaxel arm versus control (P=0.01), reflecting absolute improvement in 2-year DFS of 2.5% and 11.1%, respectively. The delivery of postoperative chemoradiotherapy and cetuximab to patients with HNSCC is possible and tolerated with predictable toxicity. The docetaxel regimen shows favorable outcome with improved DFS and OS relative to historical controls and has commenced formal testing in a phase II/III trial (RTOG 1216).

The recommendations for follow-up are based on the risk of relapse, second primaries, treatment sequelae, and toxicities includes a history and physical (including a complete head and neck exam; mirror and fiberoptic examinations as clinically indicated every 1 to 3 months for the first year, every 2-6 months for the second year, every 4 to 8 months years 3 to 5, and every 12 months after 5 years. To facilitate this our group sees the patient every three months for the first five years. Post-treatment baseline imaging of the primary (and neck, if treated) is recommended within 6 months of treatment, further imaging is indicated based on signs and symptoms (but is not routinely recommended without worrisome manifestations). Chest imaging as clinically indicated for patients with a smoking history. If the neck was radiated, the NCCN guidelines recommend thyroid stimulating hormone (TSH) testing every 6 to 12 months. Smoking and alcohol counseling as clinically indicated [67].

Cancer of the oral tongue requires a multidisciplinary team approach to their management that includes a surgical oncologist, medical oncologist, radiation oncologist, dentist, oral maxillary surgeon, prosthodontist, rehabilitation therapists, rehabilitation speech therapist, as well as of emotional support by psychologists or social workers. Early referral to a center that has the expertise in the management of these complex tumors has been shown to improve outcomes and is highly encouraged.

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Editorial Information

Editor-in-chief.

Dung-Fang Lee University of Texas

Article Type

Review Article

Publication history

Received date: April 22, 2018 Accepted date: May 10, 2018 Published date: May 14, 2018

© 2018 Arrangoiz R. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Arrangoiz R, Cordera F, Caba D, Moreno E, de Leon EL, et al. (2018) Oral tongue cancer: Literature review and current management. Cancer Rep Rev 2: doi: 10.15761/CRR.1000153

Corresponding author

Rodrigo arrangoiz ms, md, facs.

Sociedad Quirurgica S.C. at the American Britihs Cowdray Medical Center, Av. Carlos Graef Fernandez # 154-515, Colonia Tlaxala, Delegacion, Cuajimalpa, Mexico, Tel: 1664 7200

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• Published: 12 April 2024

Partial recovery of peripheral blood monocyte subsets in head and neck squamous cell carcinoma patients upon radio(chemo)therapy is associated with decreased plasma CXCL11

• Christian Idel 1 ,
• Jonas Fleckner 1 ,
• Kirstin Plötze-Martin 1 ,
• Lotte Werner 1 ,
• Dirk Rades 2 ,
• Marie-Nicole Theodoraki 3 , 4 ,
• Linda Hofmann 3 ,
• Diana Huber 3 ,
• Anke Leichtle 1 ,
• Thomas K. Hoffmann 3 ,
• Karl-Ludwig Bruchhage 1   na1 &
• Ralph Pries 1   na1  

BMC Cancer volume  24 , Article number:  459 ( 2024 ) Cite this article

Metrics details

Head and neck squamous cell carcinoma (HNSCC) represents a common and heterogeneous malignancy of the oral cavity, pharynx and larynx. Surgery and radio(chemo)therapy are the standard treatment options and also have great influence on the composition of the tumor microenvironment and immune cell functions. However, the impact of radio(chemo)therapy on the distribution and characteristics of circulating monocyte subsets in HNSCC are not fully understood.

Expression patterns of adhesion molecules and chemokine receptors CD11a (integrin-α L; LFA-1), CD11b (integrin-α M; Mac-1), CD11c (integrin-α X), CX3CR1 (CX3CL1 receptor) and checkpoint molecule PD-L1 (programmed cell death ligand-1) were investigated upon radio(chemo)therapeutic treatment using flow cytometry. Furthermore, comprehensive analysis of plasma cytokines was performed before and after treatment using ELISA measurements.

Our data reveal a partial recovery of circulating monocytes in HNSCC patients upon radio(chemo)therapeutic treatment, with differential effects of the individual therapy regimen. PD-L1 expression on non-classical monocytes significantly correlates with the individual plasma levels of chemokine CXCL11 (C-X-C motif chemokine 11).

Conclusions

Further comprehensive investigations on larger patient cohorts are required to elucidate the meaningfulness of peripheral blood monocyte subsets and chemokine CXCL11 as potential bioliquid indicators in HNSCC with regard to therapy response and the individual immunological situation.

Peer Review reports

Introduction

Head and neck squamous cell carcinoma (HNSCC) is a common tumor entity of the oral cavity, pharynx, larynx and paranasal sinuses with a poor prognosis [ 1 , 2 ]. Besides surgery, radiation therapy with or without concomitant chemotherapy are currently the primary standard therapeutic options for HNSCC patients [ 3 , 4 ].

Furthermore, research advancements in tumor biology led to the development of novel promising approaches such as immune checkpoint inhibitors (ICIs) of checkpoint molecules PD-1 (programmed death 1) and PD-L1 (programmed death ligand 1) in order to prevent T-cell anergy and exhaustion [ 5 , 6 , 7 ]. However, it is well known that radio(chemo)therapy often fails due to different immunostimulatory as well as immunosuppressive effects [ 8 ]. For example, dying tumor cells in response to radiation may stimulate anti-tumor activities of different immune cells such as dendritic cells or cytotoxic T-cells [ 9 , 10 ], but radiotherapy can also result in a counteracting myelosuppression, which is defined as a decrease in the ability of the bone marrow to produce blood cells and which is also the major dose-limiting factor of chemotherapy [ 11 , 12 ]. These differential immunological consequences of radio(chemo)therapeutic treatment are not fully understood and need to be investigated more thoroughly.

Especially cells from the monocytic differentiation line are known to be important regulators of cancer development and progression [ 13 ]. In this context, radio(chemo)therapy has been shown to significantly enhance the proportion of rectal cancer-infiltrating CD8 + T cells and the percentage of tumor necrosis factor α (TNFα) producing monocytes [ 14 ]. It has recently been shown for locally advanced rectal cancer, that PD-L1 expression on monocytes suppresses the cell-mediated immunity and is inversely correlated with the individual response to preoperative radio(chemo)therapy [ 15 ].

However, a detailed understanding of the distribution of peripheral blood monocyte subsets and expression patterns of cytokines and proteins required for adhesion, invasion and immune regulation in HNSCC patients upon radio(chemo)therapeutic treatment remains incomplete.

Following the development in the bone marrow, monocytes circulate in the peripheral blood stream, and around three days later, they migrate to peripheral tissues, as a consequence of homeostasis and inflammation [ 16 ]. Circulating monocytes are capable of pro- as well as anti-tumor immune functions and act as progenitors of tumor infiltrating macrophages [ 13 ]. Monocytes can be classified into three different subpopulations based on their CD14 and CD16 expression, namely “classical” monocytes (CD14 ++ CD16 - ), “intermediate” monocytes (CD14 + CD16 + ) and “non-classical” monocytes (CD14 dim+ CD16 + ) [ 17 , 18 , 19 ]. All peripheral monocyte subsets are able to acquire macrophage morphology and characteristics, but the exact differentiation potential of the different subsets remains incomplete [ 20 ].

Our recent data revealed that increased percentages of circulating non-classical monocytes significantly correlated with elevated levels of overall monocytic PD-L1 in HNSCC patients, all of which were analyzed prior to any surgical or therapeutic treatment [ 21 ].

Aim of this study was to analyze the individual distribution of circulating monocyte subsets in HNSCC patients as well as associated expression levels of adhesion molecules and chemokine receptors CD11a (integrin-α L; LFA-1), CD11b (integrin-α M; Mac-1), CD11c (integrin-α X), CX3CR1 (CX3CL1 receptor) and checkpoint molecule PD-L1 (programmed cell death ligand-1) using flow cytometry, all of which are known to be differentially expressed in response to different environmental conditions [ 22 ]. Furthermore, comprehensive evaluation of expression patterns of plasma cytokines was carried out, in correlation with the immunological situation before and after radio(chemo)therapeutic treatment.

The study aimed to better understand the interplay between the individual treatment regimen and the peripheral immunologic consequences on circulating monocytes as a potential prognostic biomarker for therapy response assessment in patients with HNSCC.

Monocyte subset distribution upon radio(chemo)therapy

Whole blood flow cytometric measurements were performed to investigate the individual abundances of peripheral blood monocyte subsets and associated expression levels of different adhesion molecules upon radio(chemo)therapy of patients with HNSCC. Gating of monocyte subsets was conducted as described previously [ 23 ]. In short, CD45 was used as a pan leukocyte marker to facilitate whole blood measurement and monocytes were first roughly gated by their FSC/SSC characteristics and the positivity for CD14 and CD16. Neutrophil granulocytes, NK-cells and B-cells were excluded by means of HLA-DR which is specific for monocytes. Remaining monocytes were then subgated into CD14 ++ CD16 - (classical), CD14 ++ CD16 + (intermediate) and CD14 dim+ CD16 + (non-classical) monocytes (Fig.  1 ).

Flow cytometric analysis of peripheral blood monocyte subsets. A  Representative example gating scheme of monocyte subset analysis with regard to the forward scatter (FSC)/sideward scatter (SSC) characteristics and the B  CD14/CD16 expression levels. C  Percentages of circulating classical (CM), intermediate (IM) and non-classical monocytes (NCM) in the peripheral blood of HNSCC patients that unfortunately ‘died’ during the course of treatment, patients that received ‘no therapy’ and patients that were able to receive radio(chemo)therapeutic treatment (RCT). D  Monocyte subset abundances of HNSCC patients before (pre RCT) and after (post RCT) radio(chemo)therapeutic treatment compared to healthy donors (HD). *: p  < 0.05; **: p  < 0.01; ***: p  < 0.001

From our initial cohort of 29 HNSCC patients, we were able to investigate 17 patients before and after about 6 month of radio(chemo)therapeutic treatment, because five patients unfortunately died during the course of treatment and seven patients’ condition did not allow radio(chemo)therapeutic treatment. Thus, first we subdivided our initial cohort into three groups (died, no therapy, therapy) with regard to the percentages of peripheral blood monocyte subsets. Data revealed significantly redistributed abundances of all three monocyte subsets in patients who unfortunately died during the course of treatment compared to healthy donors (Fig.  1 C). These data of course have to be interpreted with caution due to different causes of dead, but nevertheless may add important information to an overall picture. Data of Results must be presented in with caution considering the limited sample size Moreover, significantly increased percentages of intermediate monocytes could be detected in the analysed cohorts compared to healthy donors (Fig.  1 C). Furthermore, subset abundances of HNSCC patients before and after radio(chemo)therapeutic treatment were investigated. Our data revealed no overall significant differences between the pre and post treatment situation, but a smaller spread of percentage values of classical (CM) and intermediate (IM) monocytes upon radio(chemo)therapy (Fig.  1 D).

Monocytic adhesion molecules upon radio(chemo)therapy

Expression levels of adhesion molecules and chemokine receptors CD11a (integrin-α L; LFA-1), CD11b (integrin-α M; Mac-1), CD11c (integrin-α X), and CX3CR1 (CX3CL1 receptor) on peripheral blood monocyte subsets from HNSCC patients before and after radio(chemo)therapeutic treatment were analyzed using flow cytometry and compared to healthy donors (Fig.  2 ).

Adhesion molecules on peripheral blood monocyte subsets (CM: classical monocytes; IM: intermediate monocytes; NCM: non-classical monocytes) before and after radio(chemo)therapeutic treatment (RCT). Measurements revealed significant alterations of A  CX3CR1 and B  CD11a expression on intermediate and non classical monocytes prior to RCT treatment compared to healthy donors (HD), respectively. Measurements of adhesion molecules C  CD11b and D  CD11c revealed no significant differences. *: p  < 0.05; **: p  < 0.01; ***: p  < 0.001. MFI: mean fluorescence intentsity

Measurements revelaled significantly increased pre-therapeutic expression levels of adhesion molecule CX3CR1 on classical ( p  = 0.0351) and non-classical monocytes ( p  = 0.0047) compared to healthy donors and a significantly decreased expression in response to therapeutic treatment in all three subsets (CM: p  = 0.0301; IM: p  = 0.0038; NCM: p  = 0.0347) (Fig.  2 A). Increased pre-therapeutic expression levels were also found for adhesion molecule CD11a in intermediate ( p  = 0.0093) and non-classical monocytes ( p  < 0.001) (Fig.  2 B). Overall, expression levels of adhesion molecules CD11b and CD11c revealed no significant differences with regard to the analyzed conditions, whereas elevated levels of CD11b could be observed in all monocyte subsets before therapeutic treatment compared to healthy donors and the after treatment situation by tendency (Fig.  2 C, D).

Plasma cytokines of HNSCC patients upon radio(chemo)therapy

To screen for potential factors which might be responsible for the observed partial recovery of the circulating monocyte subsets, plasma levels of 105 different cytokines and chemokines in two HNSCC patients (RC3, RC4) were measured before and after radio(chemo)therapeutic treatment using a membrane based human cytokine antibody array (Fig.  3 A).

Cytokine screening upon radio(chemo)therapy of HNSCC patients. A  Raw images of membrane based cytokine arrays of plasma samples of two HNSCC patients (RC3, RC4) before (pre RCT) and after (post RCT) radio(chemo)therapeutic treatment. Decreased expression patterns of certain cytokines (1: BDNF; 2: DKK1; 3: CD30; 4: PDGF-AA; 5: PDGF-AB; 6: TARC; 7: CXCL11) were identified in response to radio(chemo)therapeutic treatment. B  Semiquantitative analysis was performed by measuring the density of the CXCL11 dots and revealed differential expression levels in the analyzed plasma samples of HNSCC patients RC3 and RC4 before and after radio(chemo)therapeutic treatment

Decreased expression patterns of certain cytokines in response to radio(chemo)therapeutic treatment such as DKK1 (Dickkopf WNT Signaling Pathway Inhibitor 1), CD30 (TNF-Rezeptor 8), PDGF-AA/AB ( platelet-derived growth factor) , TARC (thymus and activation related chemokine), and CXCL11 (C-X-C motif chemokine 11) could be identified (Fig.  3 A).

Among these factors, chemokine CXCL11 caught our particular interest, because it has recently been shown, that CXCL11 is involved in tumor lymphatic cross talk and the regulation of checkpoint molecule PD-L1 (CD274) in cancer tissues [ 24 , 25 ]. Semiquantitative analyses were performed by measuring the density of the CXCL11 dots and revealed differential expression levels in the analyzed plasma samples of HNSCC patients RC3 and RC4 before and after radio(chemo)therapeutic treatment (Fig.  3 B). In order to quantify the individual plasma CXCL11 levels in our patient cohort, ELISA measurements were performed. Data revealed significantly increased CXCL11 levels in patients who unfortunately died during the course of treatment as well as in patients who received no therapy due to a bad health condition compared to healthy donors (Fig.  4 A).

Plasma CXCL11 in HNSCC patients upon radio(chemo)therapy ( n  = 17). A  ELISA measurements revealed significantly increased CXCL11 levels in patients that unfortunately ‘died’ during the course of therapy ( n  = 5) and in patients that received ‘no therapy’ due to a bad health condition ( n  = 7) compared to healthy donors ( n  = 10). B  CXCL11 measurements revealed no significant differences between the pre and post therapy situation or healthy donors. C  Individual plasma CXCL11 pre and post therapy values (ng/ml) revealed decreases as well as increases upon radio(chemo)therapeutic treatment. D  CXCL11 levels of HNSCC patients that received only radiotherapy (RT) vs. HNSCC patients that received radiochemotherapy (RCT). Our data revealed that radiotherapy resulted in increased CXCL11 levels in some HNSCC patients, whereas radiochemotherapy resulted only in decreased CXCL11 levels. E  Plasma CXCL11 levels of HPV positive vs. HPV negative HNSCC patients. Data revealed significantly increased CXCL11 levels in HPV + patients compared to healthy donors, but not in HPV negative individuals. F  Plasma CXCL11 levels of HNSCC patients that received only RTC therapy vs. HNSCC patients that received RTC therapy + surgery. *: p  < 0.05; **: p  < 0.01. ns: not significant

The treatment cohort (RCT) revealed no significant differences to the post therapy situation or healthy donors, due to widely spread measurement values (Fig.  4 A, B). A look at the individual plasma CXCL11 pre and post therapy values of our patient cohort revealed decreases as well as increases upon radio(chemo)therapeutic treatment (Fig.  4 C). Next, we compared plasma CXCL11 levels of HNSCC patients that received only radiotherapy vs. HNSCC patients that received radiochemotherapy. Our data revealed that radiotherapy resulted in increased CXCL11 levels in some HNSCC patients, whereas radiochemotherapy resulted only in decreased CXCL11 levels (Fig.  4 D). Furthermore, we compared plasma CXCL11 levels of HPV positive vs. HPV negative HNSCC patients. Our data revealed significantly increased CXCL11 levels in HPV + patients compared to healthy donors, but not in HPV negative individuals (Fig.  4 E). To analyze the potential influence of surgical treatment, plasma CXCL11 levels of HNSCC patients that received only RTC therapy vs. HNSCC patients that received RTC therapy + surgery were compared. Our data revealed no significant differences (Fig.  4 F).

Due to the potential impact of chemokine CXCL11 on the regulation of checkpoint molecule PD-L1, expression levels on peripheral blood monocyte subsets were analyzed in our initial patient cohort as well as before and after radio(chemo)therapeutic treatment. Data revealed significantly increased PD-L1 on all three monocyte subsets in patients that unfortunately died during the course of treatment compared to healthy donors (Fig.  5 A). Moreover, there were significantly increased PD-L1 expression levels on intermediate monocytes in the cohort of treated patients but no significant differences between the pre and post therapy situation (Fig.  5 B).

Flow cytometric analysis of PD-L1 on peripheral blood monocyte subsets. A  PD-L1 expression levels of circulating classical (CM), intermediate (IM) and non-classical monocytes (NCM) in the peripheral blood of HNSCC patients that unfortunately ‘died’ during the course of treatment, patients that received ‘no therapy’ and patients that were able to receive radio(chemo)therapeutic treatment (RCT) compared to healthy donors (HD). B  PD-L1 expression levels on monocyte subsets of HNSCC patients before (pre RCT) and after (post RCT) radio(chemo)therapeutic treatment compared to healthy donors (HD). C  PD-L1 expression levels on monocyte subsets of HNSCC patients before RCT and after radio-therapeutic treatment (post radio) and radiochemo-therapeutic treatment (post radiochemo) compared to healthy donors (HD). D  To analyze the potential influence of surgical treatment, we compared the PDL-1 levels on the different monocyte subsets of HNSCC patients that received only RTC therapy vs. HNSCC patients that received RTC therapy + surgery. *: p  < 0.05; **: p  < 0.01; ***: p  < 0.001. MFI: mean fluorescence intensity. ns: not significant

In order to further elucidate these measurements, the cohort of treated patients was further subdivided into patients who received only radiation-therapy (post radio) and patients who received radio- and chemo-therapeutic treatment (post radiochemo). Our data revealed significantly increased PD-L1 expression levels on classical ( p  = 0.0454) and intermediate ( p  = 0.0295) monocytes in response to radiation-therapy. Patients who received radio- and chemo-therapeutic treatment revealed significantly lower PD-L1 expression levels on classical (( p  = 0.0106) and intermediate ( p  = 0.0471) monocytes compared to only radiation treated patients (Fig.  5 ). In order to investigate the potential influence of surgery treatment, we compared the PDL-1 levels on the different monocyte subsets of HNSCC patients that received only RTC therapy vs. HNSCC patients that received RTC therapy + surgery (Fig.  5 D). Our data revealed no significant differences. An acknowledged limitation of results is the relatively small number of analyzed patients.

Next, correlation analyses were performed in order to analyze whether the differential effects of radio(chemo) therapeutic treatment on monocytic PD-L1 and plasma CXCL11 levels of cancer patients might be associated. Data revealed a significant positive correlation ( p  = 0.0404) between plasma CXCL11 and PD-L1 expression on non-classical monocytes after radio(chemo) therapeutic treatment, which indicates an association of these two molecular bioliquid parameters (Fig.  6 ).

Correlation analysis between the PD-L1 expression of circulating classical (CM), intermediate (IM) and non-classical monocytes (NCM) and plasma levels of chemokine CXCL11 (ng/ml) of HNSCC patients after radio(chemo) therapeutic treatment. The correlation coefficient (r), spearman (rho) correlation coefficient (rs), and p values are given for each correlation. p  < 0.05 was considered as significant. MFI: mean fluorescence intensity

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors and standard radio(chemo) therapeutic treatment is applied for over 60% of newly diagnosed cancer patients [ 26 , 27 ]. It is well known that radio(chemo)therapy exerts a multifaceted systemic immune regulatory influence by inducing the release of inflammatory mediators and immune cells [ 28 ]. However, the impact of radio(chemo)therapy on the abundances and cellular characteristics of circulating monocyte subsets in HNSCC is still mostly unclear.

In cancer, monocyte subsets possess diverse activities that contribute to both pro- and anti-tumoral immune response and the dynamics of the subset abundances have been investigated in different studies [ 29 , 30 , 31 ]. For instance, increased abundances of classical monocytes were measured during the first 5 cycles of chemotherapy in breast cancer patients, which recovered during the subsequent cycles [ 32 ].

In this study, we have shown a partial recovery of peripheral blood monocyte subsets from HNSCC patients upon radio(chemo)therapy compared to the pre-treatment situation. It is well known, that circulating monocytes encounter various tumor derived factors during the time they spend in the blood stream, which affects their behaviors and differentiation [ 33 , 34 ]. In this context, radio(chemo)therapy can diminish tumor immune escape mechanisms and restore anti-tumor immune response [ 35 , 36 , 37 ]. Investigations on the impact of radiation on different blood cell populations revealed that monocytes are more resistant compared to lymphocytes and granulocytes [ 38 ].

Our data revealed significantly increased pre-therapeutic expression levels of adhesion molecules CD11a and CX3CR1 on monocyte subsets compared to healthy donors, both of which significantly decreased upon radio(chemo)theraupeutic treatment. Moreover, elevated pre-therapeutic levels of CD11b were measured in circulating monocytes compared to healthy donors.

Integrins CD11a and CD11b are well established leukocyte adhesion molecules, that are expressed on dendritic cells, monocytes and granulocytes and can bind various ligands such as complement factors, collagen or lipopolysaccharide [ 39 , 40 ]. They are involved in the adhesion of monocytes to the vessel wall and extravasation upon inflammatory processes, such as in patients with coronary artery disease [ 41 ]. CX3CR1 is well known to be associated with atherosclerosis and vascular inflammation [ 42 , 43 ] and is also involved in the monocyte-endothelial interaction and enables leukocytes to crawl along the blood vessels [ 44 ]. Elevated levels of CX3CL-1 (CX3C-chemokine ligand 1) receptor CX3CR1 are distinctive markers for CD16 + monocytes in both men and mice [ 44 ]. These data corroborate different studies that revealed a reduced recruitment of peripheral blood monocytes due to an attenuated chemotactic activity of tumor cells upon therapeutic treatment. It has been shown that radiation as well as chemotherapy modify the migratory ability of monocytes in a drug- and cell-type-specific manner via systemic alteration of chemoattractant factors [ 45 , 46 , 47 , 48 ].

Next, measurements of pre- and post therapy plasma levels of different cytokines and chemokines revealed decreased expression patterns of certain cytokines such as DKK1 (Dickkopf WNT Signaling Pathway Inhibitor 1), CD30 (TNF-Rezeptor 8), TARC (thymus and activation related chemokine), and PDGF-AA/AB ( platelet-derived growth factor) in response to therapeutic treatment .

DKK1 is an important factor of the immunosuppressive tumor microenvironment in head and neck squamous cell carcinoma and parcticipates in the development of resistance to radiotherapy and immunotherapy [ 49 ].

Elevated pre-therapeutic plasma levels of CD30 and TARC have also been reported in patients with classical Hodgkin lymphoma and decreased upon treatment [ 50 ]. Furthermore, platelet-derived growth factors have been shown to be correlated with tumorigenensis and poor prognosis in oral squamous cell carcinoma and decreased levels were observed in response to chemotherapy [ 51 , 52 ]. However, it has recently been shown that PDGF does not act as a monocyte chemoattractant [ 53 ].

Of note, plasma levels of chemokine CXCL11 (C-X-C motif chemokine 11) were found to be decreased in the majorioty of HNSCC patients upon radio(chemo)therapy, but also increased values were identified in some patients. It has been shown in colorectal cancer that decreased CXCL11 levels were associated with an inhibition of cancer cell growth and epithelial-mesenchymal transition [ 54 ]. Elevated CXCL11 also increases the aggressiveness of breast cancer cells [ 55 ]. Furthermore, CXCL11 is involved in tumor lymphatic cross talk and the regualtion of checkpoint molecule PD-L1 (CD274) in cancer tissues [ 24 , 25 ]. In contrast, it has recently been shown in glioblastoma, that CXCL11 had a potent antitumor effect and reprogrammed the immunosuppressive tumormicroenvironment [ 56 ]. We further compared plasma CXCL11 levels of HNSCC patients that received only radiotherapy vs. HNSCC patients that received radiochemotherapy. Our data revealed that radiotherapy resulted in increased CXCL11 levels in some HNSCC patients, whereas radiochemotherapy resulted only in decreased CXCL11 levels. These data go along with another study, where it has been shown that radiotherapy stimulates tumor cells and stromal cells to produce chemokines, such as CXCL9, CXCL10, CXCL11 and CXCL16, which lead to the infiltration of DCs, macrophages and T cells, further promoting inflammatory tumor microenvironment. In an actual publication, it has been shown in glioblastoma, that CXCL11 had a potent antitumor effect and reprogrammed the immunosuppressive tumor microenvironment, in which increased infiltration of CD8 T cells, NK cells and M1 macrophages, but decreased abundances of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2-polarized macrophages were observed [ 57 ]. Furthermore, we compared the plasma CXCL11 levels of HPV positive vs. HPV negative HNSCC patients. Our data revealed significantly increased CXCL11 levels in HPV + patients compared to healthy donors, but not in HPV negative individuals. Despite the relatively small sample size of our cohort, these data are go along with an actual publication which has recently shown that antiviral treatment significantly reduces the levels of plasma CXCL11 [ 58 ].

Checkpoint molecule PD-L1 is involved in the immune regulation of different immune cells and the interaction of PD-1/PD-L1 attenuates immune responses and thus supports tumor immune escape mechanisms [ 59 , 60 , 61 , 62 ]. PD-L1 is known to be involved in different aspects of immune regulation and expressed in different types of immune cells including B cells, T cells, dendritic cells and monocytes [ 63 , 64 , 65 , 66 ]. Myeloid cells in particular are important regulators of cancer development and progression, and PD-L1 expression on myeloid cells has been correlated with poor prognosis of tumor patients [ 67 , 68 , 69 ]. PD-L1 overexpression on monocytes was found to promote cancer progression in lung adenocarcinoma [ 70 ].

With regard to monocytic PD-L1, we further subdivided our cohort into patients who received only radiation-therapy and patients who received radio- and chemo-therapy. Data revealed significantly increased PD-L1 expression levels on classical and intermediate monocytes in response to radiation-therapy, but significantly decreased PD-L1 expression levels upon radio- and chemo-therapeutic treatment. The population of peripheral blood monocytes is renewed about every 5 days and it is well known that chemo-therapy induces the proliferation of progenitors and the subsequent entry of naïve monocytes into the blood stream, which are less influenced by the tumor microenvironment [ 36 , 37 , 71 ] and therefore might reveal a normal PD-L1 expression level. It has been shown in different studies, that radiotherapy can affect the entire tumor microenvironment and might induce the expression immunosuppressive molecules PD-L1 [ 72 ].

Correlation analyses revealed a significant correlation between plasma CXCL11 levels and PD-L1 expression on non-classical monocytes, which corroborates earlier studies that have shown the involvement of CXCL11 in the regulation of checkpoint molecule PD-L1 in human cancers [ 24 , 25 ]. In summary, our study suggests a partial recovery of circulating monocytes in HNSCC patients upon radio(chemo)therapeutic treatment, with differential effects of the individual therapy regimen. Significant correlations were identified between PD-L1 expression on peripheral blood monocytes and plasma CXCL11 levels, both of which could provide helpful information concerning therapy response and the individual immunologic situation. An acknowledged limitation of our study is the relatively small number of patients. Further comprehensive investigations on larger patient cohorts in correlation with the specific individual therapy regimen, therapy response, and patient survival are required to elucidate the meaningfulness of peripheral blood monocyte subsets and chemokine CXCL11 as potential bioliquid indicators in HNSCC.

Materials and methods

Ethics statement.

All patients were treated at the Department of Otorhinolaryngology, University Hospital Schleswig-Holstein, Campus Luebeck, and have given their written informed consent. The study was approved by the local ethics committee of the University of Luebeck (approval number 16–278) and conducted in accordance with the ethical principles for medical research formulated in the WMA Declaration of Helsinki.

Tumor material, blood collection and patient data

We evaluated a cohort of 29 HNSCC patients prior and post radio(chemo)therapy in terms of the peripheral blood monocyte subset distribution and expression of PD-L1 and different monocytic adhesion molecules. The patients were diagnosed in the Institute for Pathology at the University Hospital Schleswig-Holstein in Luebeck. The clinical data of the HNSCC patients were obtained from clinical and pathological records and afterward anonymized. TNM stages were assessed by the 8th edition of the TNM classification for HNSCC. All blood donors have signed a written consent, and were informed about the aims of the study and the use of their samples. Blood was drawn by venipuncture into a sodium citrate containing S-Monovette (Sarstedt; Nümbrecht, Germany). Blood samples were collected from healthy donors ( n  = 10; 6 female/4 male; mean age of 59) from HNSCC patients ( n  = 29; mean age of 67). The clinicopathological characteristics of the patients are listed in Table  1 .

Staining of monocyte subsets in whole blood

Within 4 h after blood collection, 20 µl of citrate blood was diluted in 80 µl PBS. Blood cells were stained with following antibodies: CD45-PE, CD14-FITC, CD16-BV-510, HLA-DR-APC-Cy7, CX3CR1-BV421, CD11b-BV421 and CD3-PerCP (all from Biolegend, San Diego, USA). After 25 min staining in the dark, 650 µl RBC Lysis Buffer (Biolegend) were added to the samples and incubated for another 20 min. Subsequently, suspension was centrifuged at 400 x g for 5 min and supernatant was discarded. Cell pellet was resuspended in 100 µl fresh PBS and used for FACS analysis.

FACS analysis

Flow cytometry was performed with a MACSQuant 10 flow cytometer (Miltenyi Biotec, Bergisch-Gladbach, Germany) and data were analyzed using the FlowJo software version 10.0 (FlowJo, LLC, Ashland, USA). All antibody titrations and compensations were performed in beforehand. For whole blood measurements, at least 100 000 CD45 + leukocytes were analyzed. Gating of monocyte subsets was performed as described before [ 23 ].

Cytokine analysis

To determine plasma cytokine expression patterns upon radio(chemo)therapeutic treatment of HNSCC patients, cytokine arrays were performed. Supernatants from cell cultures were collected after incubation and instantly frozen with liquid nitrogen and preserved at -80 °C. Proteome Profiler ™ Human XL cytokine arrays (R&D Systems, Minneapolis, MN, USA) were hybridized with the cell culture medium as recommended by the supplier. Expression was visualized using an enhanced chemiluminescence detection kit (R&D Systems, Minneapolis, United States). Semiquantitative analysis was performed by measuring the density of the bands using an iBright CL 1000 biomolecular imager (Invitrogen, Carlsbad, CA, USA).

Plasma concentrations of chemokine CXCL11 were assessed from citrate-plasma samples and were determined by enzyme-linked immunosorbent assays (ELISA) according to manufacturer’s protocols (R&D Systems, Minneapolis, MN, USA).

Statistical analysis

Statistical analyses were performed with GraphPad Prism Version 7.0 f. The mean and standard error (SEM) are presented. The differences between groups were determined after testing for normal distribution and applying parametric (student`s t-Test), or non − parametric 1-way Anova with Bonferroni post hoc test. The correlation between parameters was calculated using multivariate regression with the Pearson correlation coefficient and the spearman (rho) correlation coefficient. p  < 0.05 (*), p  < 0.01 (**), and p  < 0.001 (***). Additional statistical details are given in the respective figure legends, when appropriate.

Availability of data and materials

No datasets were generated or analysed during the current study.

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Acknowledgements

We are grateful to all members of the involved Departments for supporting sample collection and helpful discussions.

Open Access funding enabled and organized by Projekt DEAL. This study has been supported by a grant of the Walter-Schulz-Foundation to MNT and RP.

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Karl-Ludwig Bruchhage and Ralph Pries contributed equally to this work.

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Department of Otorhinolaryngology and Head & Neck Surgery, University of Luebeck, Luebeck, 23538, Germany

Christian Idel, Jonas Fleckner, Kirstin Plötze-Martin, Lotte Werner, Anke Leichtle, Karl-Ludwig Bruchhage & Ralph Pries

Department of Radiation Oncology, University of Luebeck, Luebeck, 23538, Germany

Department of Otorhinolaryngology and Head & Neck Surgery, Ulm University Medical Center, Ulm, 89075, Germany

Marie-Nicole Theodoraki, Linda Hofmann, Diana Huber & Thomas K. Hoffmann

Department of Otorhinolaryngology, Technical University Munich, Munich, Germany

Marie-Nicole Theodoraki

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CI, JF, KPM, LW, and RP carried out the molecular studies and performed the statistical analysis. CI, DR, MNT, LH, DH, AL, TKH, KLB and RP participated in the design and co-ordination of the study and helped to draft the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ralph Pries .

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All patients were treated at the Department of Otorhinolaryngology, University Hospital Schleswig-Holstein, Campus Luebeck, and have given their written informed consent. The study was approved by the local ethics committee of the University of Luebeck (approval number 16–278).

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Idel, C., Fleckner, J., Plötze-Martin, K. et al. Partial recovery of peripheral blood monocyte subsets in head and neck squamous cell carcinoma patients upon radio(chemo)therapy is associated with decreased plasma CXCL11. BMC Cancer 24 , 459 (2024). https://doi.org/10.1186/s12885-024-12177-x

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CDK7 in breast cancer: mechanisms of action and therapeutic potential

• Ying Gong 1 &
• Huiping Li 1  

Cell Communication and Signaling volume  22 , Article number:  226 ( 2024 ) Cite this article

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Cyclin-dependent kinase 7 (CDK7) serves as a pivotal regulator in orchestrating cellular cycle dynamics and gene transcriptional activity. Elevated expression levels of CDK7 have been ubiquitously documented across a spectrum of malignancies and have been concomitantly correlated with adverse clinical outcomes. This review delineates the biological roles of CDK7 and explicates the molecular pathways through which CDK7 exacerbates the oncogenic progression of breast cancer. Furthermore, we synthesize the extant literature to provide a comprehensive overview of the advancement of CDK7-specific small-molecule inhibitors, encapsulating both preclinical and clinical findings in breast cancer contexts. The accumulated evidence substantiates the conceptualization of CDK7 as a propitious therapeutic target in breast cancer management.

Introduction

Breast cancer remains the most ubiquitous carcinoma worldwide, constituting approximately 30% of oncological diagnoses in females [ 1 ]. This pathology presents as an array of molecularly distinct subtypes, categorized by hormonal receptor and HER2 statuses—namely hormone receptor-positive (HR+), human epidermal growth factor receptor 2-positive (HER2+), and triple-negative breast cancer (TNBC). HR+/HER2- breast cancer, typified by the expression of estrogen and/or progesterone receptors and the lack of HER2 gene amplification, constitutes approximately 65–70% of all breast cancer cases [ 2 ]. As a central therapeutic approach for both early and late-stage manifestations of this disease, endocrine treatment focuses on strategies encompassing the reduction of estrogen synthesis, modulation of signaling through the ER, and antagonism or degradation of the ER itself [ 3 ]. The integration of CDK4/6 inhibitors with endocrine therapy has been sanctioned as a first-line approach in the metastatic setting. Three distinct orally administered CDK4/6 inhibitors, namely palbociclib, ribociclib, and abemaciclib, have been found to enhance progression-free survival (PFS) in conjunction with endocrine therapy. Nevertheless, extended administration of CDK4/6 inhibitors inevitably leads to drug resistance. TNBC, characterized by the absence of estrogen and progesterone receptors and HER2 overexpression, accounts for approximately 15% of all primary breast cancer diagnoses. TNBC represents the most virulent subtype of breast cancer, manifesting a markedly higher rate of recurrence and truncated overall survival. Increasingly, TNBC is recognized as a diverse and heterogeneous collection of diseases, the underlying biology of which remains enigmatic. This complexity has contributed to a lag in the development of targeted therapies for TNBC when compared to other breast cancer subtypes. In the current therapeutic landscape, cytotoxic chemotherapy endures as the cornerstone of standard care for this challenging category of breast cancer [ 4 ]. The advent of monoclonal antibodies, tyrosine kinase inhibitors, and antibody–drug conjugates targeting HER2 has markedly enhanced the therapeutic outcomes for HER2-positive breast cancer patients [ 5 ]. However, the clinical landscape is marred by instances of patient non-responsiveness or initial responsiveness followed by the eventual emergence of resistance.

Approximately 70–80% of patients diagnosed with early-stage, non-metastatic breast cancer experience curative outcomes [ 6 ]. In stark contrast, advanced breast cancer characterized by distant organ metastases remains a therapeutic conundrum, typically considered incurable with contemporary therapeutic strategies. Despite declining mortality rates attributed to advancements in early detection and innovative treatment regimens, contentious issues persist in the realms of therapeutic selection. These quandaries involve the formulation of optimal treatment paradigms for HR+/HER2- metastatic conditions that have developed resistance to conventional endocrine and CDK4/6 inhibitor regimens. Similarly, the challenges extend to identifying viable mechanisms for counteracting resistance to anti-HER2 interventions and optimizing the potency of immunotherapeutic approaches in TNBC. Addressing these clinical conundrums necessitates the identification of relevant biomarkers to augment a tailored treatment approach, thereby postponing the commencement of chemotherapy. A compelling candidate in this context is CDK7, a cyclin-dependent kinase-activating kinase that is integral to cell cycle progression and gene transcription [ 7 ]. Targeting CDK7 via various modalities, such as small interfering RNA (siRNA) or pharmacological inhibitors, has yielded encouraging antineoplastic results [ 8 , 9 ]. Recent advancements have ushered in a cadre of CDK7 inhibitors into phase I/II clinical trials for breast cancer [ 10 ]. In this comprehensive review, we illuminate the multifaceted role of CDK7 in maintaining malignant phenotypes and fostering drug resistance across diverse molecular subtypes of breast cancer. Moreover, we provide an exhaustive overview of ongoing clinical trials targeting CDK7, corroborating its potential as a viable therapeutic target. Thus, our findings advocate for the strategic exploration of anti-CDK7 therapy as a promising avenue in breast cancer management.

The biologic function of CDK7

CDK7, a serine/threonine kinase composed of 346 amino acids, has a predicted molecular mass of 39 kDa. Structurally, CDK7 exhibits a classical kinase fold, comprising the N-terminal cyclin H-binding lobe (residues 13–96), primarily consisting of β sheets and one α helix, and a C-terminal MAT1 binding lobe (residues 97–311), predominantly composed of α helices. The N-terminal residues 1–12 and the C-terminal residues 312–346 encompass a putative nuclear localization sequence [ 11 ], as detailed in Fig.  1 a. Within the cellular context, CDK7 forms a complex primarily with cyclin H and MAT1 to constitute the CDK-activating kinase (CAK) complex [ 12 ]. The CDK7 and cyclin H tandem establishes a canonical CDK-cyclin pair, while MAT1 assumes the role of a CAK assembly factor, heightening CAK activity toward target CDKs [ 13 , 14 ]. Additionally, MAT1 serves to anchor the CAK to the core of general transcription factor IIH (TFIIH) (XPD, XPB, P8, P44, P62, P34, P52) during the transcription initiation process carried out by this 10-subunit complex [ 15 , 16 ]. Notably, specific regions such as the RING domain and helical segments proximal to the MAT1 N-terminus, as well as the CAK anchor near the MAT1 C-terminus, engage with the TFIIH central complex and CDK7-cyclin H, respectively [ 17 ], as outlined in Fig.  1 b.The CAK complex functions as a crucial promoter of cell cycle transition, achieving this by phosphorylating the T-loop of key cell cycle CDKs, including CDK1, 2, 4, and 6 (Fig.  2 a). Essential to both the activation and complex formation of CDK1/cyclin-B during the G2-M phase transition, CDK7 is similarly vital for the activation of CDK2/cyclins in the G1-S phase transition [ 18 , 19 , 20 ]. Further, CDK7’s phosphorylation of CDK4/6 at Thr172 and Thr177 during the G1 phase initiates DNA synthesis, a process that responds to mitogen stimuli [ 20 , 21 ]. In addition to its well-documented role in cell cycle regulation, CDK7 serves as an integral part in transcriptional regulation. As a component of the TFIIH, CDK7 catalyzes the phosphorylation of Ser5 and Ser7 within the RNA Pol II C-terminal domain (CTD) [ 22 , 23 , 24 ], an essential step in driving the clearance of the polymerase from the promoter. This phosphorylation event facilitates the release of RNA Pol II from the mediator, initiating transcription (Fig.  2 b). Additionally, CDK7 phosphorylates CDK9, a core element of the positive transcription elongation factor b (P-TEFb), which subsequently phosphorylates the Ser2 residue of the RNA Pol II CTD, thereby promoting transcription elongation [ 25 ]. The regulatory landscape is further complexified with the response to DNA damage. During DNA repair, the initial recognition of damage is orchestrated by XPC-RAD23B, followed by the recruitment of TFIIH. Upon TFIIH loading, XPB initiates the unwinding of the DNA, enabling TFIIH to tilt against the DNA and positioning XPD to bind the damaged strand 5’ to the lesion. The binding event is closely monitored by MAT1, which signals to CAK to disengage from TFIIH, thereby allowing the progression of the repair process [ 26 , 27 ]. Following the completion of DNA repair, CAK reassociates with TFIIH, and the complex resumes its transcriptional role. The tumor suppressor protein p53, recognized as a transcriptional activator, plays a pivotal role in mediating cellular responses to DNA damage by inducing apoptosis and cell cycle arrest. The CAK complex interacts with p53 and activates it through phosphorylation at Ser-33. In a reciprocal manner, p53 downregulates CAK kinase activity [ 28 , 29 ]. This intricate feedback mechanism may lead to a cessation of both the cell cycle and transcription, thereby facilitating cell recovery or triggering apoptosis, as depicted in Fig.  2 c. Thus, CDK7 emerges as a multifaceted regulatory protein, involved in cell cycle control, RNA polymerase II-mediated RNA transcription, and DNA repair processes.

Structure of CAK and TFIIH. (a) CDK7, an enzyme comprising 346 amino acids. The N-terminal cyclin H-binding lobe (residues 13–96) primarily consists of β sheets and one α helix, while the C-terminal MAT1 binding lobe (residues 97–311) is predominantly composed of α helices. The N-terminal residues 1–12 and C-terminal residues 312–346 feature a putative nuclear localization sequence. (b) The structural of the MAT1 includes the RING domain and helical regions in the MAT1 N-terminus, and the CAK anchor in the MAT1 C-terminus.

Role of CDK7 in regulating the cell cycle (a) , transcription (b) and DNA repair (c) . (a) The CAK complex phosphorylates the T-loop of key cell cycle CDKs, including CDK1, 2, 4, and 6. (b) As a component of TFIIH, CDK7 catalyzes the phosphorylation of Ser5 and Ser7 within the RNA Pol II C-terminal domain. (c) In DNA repair, the dislodgement of MAT1 from its binding sites on the TFIIH core complex results in the release of the 3-subunit CAK module. The CAK complex interact and the activate p53 through phosphorylating at Ser-33. In a reciprocal manner, p53 downregulates CAK kinase activity.

CDK7 in cancer

CDK7’s vital role in the preservation of malignant phenotypes across various cancer cells is underscored by substantial evidence [ 30 ]. Comparative analysis reveals elevated CDK7 expression in tumor tissues across a spectrum of neoplasms, including but not limited to breast. Notably, increased CDK7 expression correlates with a dismal prognosis [ 31 ]. Targeting CDK7 has revealed pronounced effects on cancer cell proliferation, migration, invasion, stemness, and drug resistance across malignancies such as breast cancer [ 32 ], lung cancer [ 33 ], hepatocellular carcinoma [ 34 ], thyroid cancer [ 35 ], glioblastoma [ 36 ], gastric cancer [ 37 ], pancreatic cancer [ 38 ], gallbladder cancer [ 39 ], colorectal cancer [ 40 ], osteosarcoma [ 41 ], lymphomas [ 42 ], leukemia [ 43 ], among others. In recent years, a range of specific small molecular inhibitors targeting CDK7 has been synthesized and classified, as detailed in Table  1 . The set encompasses reversible ATP-binding site inhibitors such as BS-181 [ 44 ], CT7001 [ 45 ], LDC4297 [ 46 ], QS1189 [ 42 ], SY-5609 [ 47 ]. Additionally, the development of ATP-competitive covalent inhibitors has further expanded this field, with notable examples including THZ1 [ 48 ], THZ2 [ 49 ], SY-1365 [ 50 ], YKL-5-124 [ 51 ], and YKL-1-116 [ 52 ]. The specific CDK7 small molecular inhibitors have yielded promising results in suppressing malignant phenotypes across over 23 cancer types, especially in breast cancer. Importantly, nine specific CDK7 inhibitors, CT7001, SY5609, Q901, SY1365, XL102, TY-2699a, GTAEXS-617, EOC237, LY3405105, have now have reached Phase I/II clinical trials, reflecting an evolving therapeutic landscape (Table  1 ).

Investigations into the molecular mechanisms underlying anti-tumor effects of targeting CDK7 have primarily implicated its role in cell cycle arrest and the suppression of CDK7-dependent gene transcription [ 53 ]. CDK7 suppression with inhibitors or siRNA fosters apoptosis, increasing the G2/M cell population [ 54 , 55 , 56 ] and shRNA-mediated silencing of CDK7 leads to an impairment in T-loop phosphorylation of CDKs, thereby arresting the cell cycle and impeding cell proliferation [ 57 ]. Clusters of transcriptional enhancers driving expression of genes that define cell identity have been defined super-enhancers (SEs) [ 58 ]. The intricate interplay between transcriptional regulators, including CDK7, and SEs is further highlighted by the observation that cancer cells exhibit transcriptional addiction, demanding higher transcription levels to maintain growth [ 59 ]. Consequently, the targeting of transcription regulators like CDK7 has emerged as a strategy to dismantle this transcription boost [ 60 ], with THZ1 and THZ2 showing particular efficacy against cancers that rely on SE-driven genes including C-MYC , RUNX2 , STAT , SOX2 , MITF , SOX9 [ 32 , 33 , 48 , 49 , 61 , 62 , 63 , 64 ]. Recently, our team revealed a new function of CDK7 in mediating metabolic process of esophageal cancer. We discovered that CDK7 phosphorylated YAP at S127 and S397 sites in the nucleus and enhanced D-lactate dehydrogenase protein expression, therefore helping esophageal cancer stem cells escape from ferroptosis [ 65 ]. Overall, these findings underscore CDK7 as a critical mediator in cancer pathogenesis and opens avenues for targeted therapeutic interventions, thus heralding a new frontier in cancer research.

The expression of CDK7 and its prognostic value in breast cancer

In an examination of CDK7’s abundance within normal breast epithelium and a cohort of 12 breast cancer cell lines, immunoblotting analysis distinctly revealed elevated CDK7 protein expression within malignant counterparts as opposed to normal breast epithelium [ 66 ]. This observation was further corroborated through a comprehensive analysis of CDK7 mRNA levels within breast cancer patients, utilizing an array of public databases including METABRIC microarray [ 67 ], Oncomine, GEPIA2, Human Protein Atlas (HPA) database [ 68 ], and the GENT database [ 69 ]. Moreover, a detailed investigation based on a tissue array encompassing 140 patients and an expansive dataset exceeding 4,000 samples sourced from the bc-GenExMiner database provided additional insights. It highlighted that CDK7 protein levels were significantly higher within HR-positive and HER2-positive breast cancer subtypes, as contrasted with the TNBC subtype [ 69 ].

The prognostic significance of CDK7 in breast cancer remains a matter of considerable debate. One study, utilizing publicly available transcriptomic data from a specific group of TNBC patients ( n  = 383) and the METABRIC TNBC dataset ( n  = 217), identified that elevated CDK7 mRNA levels were synonymous with reduced relapse free survival (RFS) and poor breast cancer specific survival (BCSS). This association extended to higher CDK7 protein expression and unfavorable prognosis within the RATHER TNBC TMA cohort ( n  = 109) and METABRIC TNBC TMA cohort ( n  = 203) [ 70 ]. However, in an unstratified BreastMark and METABRIC cohort, no significant correlation between CDK7 expression and prognosis was observed [ 70 ], leading to the hypothesis that CDK7 might serve as a predictive factor specifically within the TNBC subgroup, rather than across breast cancer in general.

Contrarily, another study demonstrated that elevated CDK7 expression correlated with worse RFS across a broad and unselected cohort of breast cancer patients ( n  = 3,951), representing multiple subtypes [ 71 ]. This observation was further strengthened within specific subtypes, including HR+/HER2-, HER2+ breast cancer and TNBC, where higher CDK7 mRNA levels were associated with diminished RFS [ 71 ]. Such findings intimate that CDK7 could serve as a universal target for breast cancer treatment, irrespective of subtype. In alignment with the latter study, additional research utilizing platforms such as UALCAN, TCGA portal, and Kaplan-Meier Plotter underscored the connection between elevated CDK7 mRNA expression and poorer RFS and overall survival (OS) in breast cancer patients [ 68 , 69 ]. Remarkably, another study presented an opposing viewpoint, revealing that increased CDK7 protein levels were indicative of a more favorable prognosis. Analyzing breast cancer TMAs for CDK7 ( n  = 945), the study found that patients with high-grade and extensive tumors, or those with recurrent disease, exhibited lower CDK7 expression. Elevated CDK7 levels were instead associated with extended BCSS and prolonged time to distant metastasis [ 67 ].

This landscape of disparate findings illustrates the complexity of CDK7’s role within breast cancer prognosis and highlights the necessity for further refined and targeted investigations. An essential avenue for future exploration involves investigating whether the efficacy of CDK7 targeting therapy is contingent upon the expression level of CDK7. Furthermore, the question arises as to whether CDK7 expression should be routinely assessed in the treatment of advanced breast cancer with CDK7 small-molecule inhibitors.

CDK7 in ER-positive breast cancer

Analysis of TCGA ER-positive (ER+) breast cancer samples has revealed a positive correlation between CDK7 and ER mRNA levels, and high CDK7 expression has been associated with notably shorter OS for ER+ breast cancer patients [ 72 ]. Experimental approaches targeting CDK7 through specific small molecular inhibitors, such as THZ1 [ 72 ], LDC4297 [ 73 ], ICEC0942 [ 45 ], SNS-032 [ 74 ], and roscovitine [ 75 ], have proven effective in suppressing ER+ breast cancer cells. Specifically, these treatments have been demonstrated to inhibit the proliferation of ER+ breast cancer cells, induce apoptosis, and suppress the growth of breast cancer xenografts in murine models [ 45 , 72 , 73 , 74 ]. Most remarkably, the combination of CDK7 inhibitors with known therapeutic agents like fulvestrant [ 45 ] or tamoxifen [ 72 , 75 ] has shown enhanced efficacy in inhibiting tumor growth compared to either single agent, highlighting the potential therapeutic advantage of these combinations.

Mechanisms of endocrine treatment resistance have been described in previous studies. ER becomes an activated transcription factor upon estrogen binding and dimerization. A positive correlation has been identified between the expression of pERα-S118 and poorer disease-free and overall survival in HR+/HER2- breast cancer patients, as well as resistance to tamoxifen [ 76 , 77 ]. Studies indicate that CDK7 activates ER phosphorylation at Ser118, enhancing MYC transcription and mediating tamoxifen resistance in ER+ breast cancer [ 72 ]. Targeting CDK7 via inhibitors like THZ1 or roscovitine has been found to abolish this phosphorylation, thereby preventing ER activation and the expression of target genes such as MYC [ 78 , 79 ]. Specifically, mutations in the ER result in constitutive ER activity even in the absence of estrogen, thereby altering the transcriptional dynamics of the ER pathway and contributing to the complex landscape of endocrine resistance [ 79 , 80 , 81 , 82 ]. Interestingly, THZ1 treatment effectively prevented ER mutants (e.g., Y537S, Y537N, and D538G) phosphorylation in MCF7 and T47D cells, and the key pathways that inhibited by THZ1 were related to the ErbB/PI3K/mTOR pathway [ 83 ], suggesting that THZ1 is targeting the ER mutant transcriptional network. In addition, emerging research highlights estrogen treatment increases tumorsphere formation capacity, and tamoxifen-resistant cell lines exhibit higher number of cancer stem cell (CSC) populations [ 84 , 85 ]. Targeting CDK7 has proven effective in inhibiting tumorsphere formation and CSC biomarkers in MCF-7 and LCC2 cells [ 86 ]. Previous studies confirm mutation in PIK3CA-AKT1-mTORC pathway is the main factor mediating resistance of CDK4/6 targeted therapy [ 87 ]. Recently, a marked increase in the expression of CDK7 and other kinases, has been observed in palbociclib-resistant MCF-7 cells. Intriguingly, THZ1 could effectively inhibit the survival of palbociclib-resistant cell lines [ 88 ]. These findings further suggesting the therapeutic potential of CDK7 targeting in reversing drug resistance of endocrine or CDK4/6 targeted therapy in HR+/HER2- breast cancer. Based on the comprehensive results of the above studies, we can observe that CDK7 inhibitors are not only effective as monotherapy but also exhibit efficacy in combination with endocrine therapy. They are effective not only against endocrine-sensitive ER+ cells but also against ER+ cells that are resistant to both endocrine and CDK4/6 inhibitors. Therefore, in the future, it is necessary to clarify the timing of CDK7 inhibitor application—whether it should be used in combination with endocrine therapy from the outset or deferred until resistance develops.

Subsequent investigations have been conducted to elucidate the underlying mechanisms of acquired resistance to CDK7 inhibitors, ICEC0942 and THZ1, within the context of breast cancer treatment. Resistant MCF7 cell lines were synthetized via extended culture in the presence of either ICEC0942 or THZ1. Detailed analysis revealed that ABCB1 upregulation could instigate resistance to both ICEC0942 and THZ1, whereas upregulation of ABCG2 resulted in specific resistance to THZ1, while maintaining sensitivity to ICEC0942. The resistance could be counteracted by employing a competitive inhibitor of ABCB1, verapamil, or a non-competitive inhibitor, tariquidar, thereby restoring cellular responsiveness to both drugs [ 89 ]. In a related development, functional enhancement of p53 was discovered to augment the sensitivity of MCF-7 cells to THZ1 treatment. The synergistic use of THZ1 in combination with nutlin-3 or alternative strategies to boost p53 expression facilitated a considerable enhancement in the anticancer efficacy of THZ1, resulting in significant breast cancer cell lethality [ 90 ].

CDK7 in triple-negative breast cancer

A series of investigations have shed light on the potential of targeting CDK7 in the treatment of TNBC. Utilizing small molecular inhibitors such as THZ1 [ 32 , 70 , 91 ], BS-181 [ 92 ], LDC4297 [ 93 ], and N76-1 [ 94 ], researchers have effectively inhibited the malignant phenotypes of TNBC cells. Interestingly, TNBC cells displayed heightened sensitivity to CDK7 inhibition when compared to HR+ breast cancer cells [ 93 ]. Therapeutic application of THZ1 was further shown to inhibit patient-derived xenografts (PDXs) of TNBC [ 32 ], underscoring the potential of CDK7 inhibition as a promising avenue for the management of this aggressive cancer subtype. Emerging research has unveiled a phenomenon of “transcriptional addiction” within cancer cells, supporting their uncontrolled proliferation and other functional needs. Tumor cells were found to be highly reliant on transcriptional machinery [ 59 ], with CDK7 mediating this addiction to a critical cluster of genes in TNBC. Genes such as SOX9 , MYC , FOXC1 , EGFR , and FOSL1 , essential for TNBC tumorigenicity and frequently associated with super-enhancers, demonstrated particular sensitivity to CDK7 inhibition [ 32 ]. Consistently, transcription factors including SOX9 [ 95 ], FOXC1, MYC [ 96 ], and KLF5 [ 91 ] were observed to promote cell proliferation, migration, and stemness in TNBC cells. Elevated expression levels of these genes corresponded with poor prognosis in TNBC patients. Additionally, CDK7 was instrumental in maintaining chromatin sublooping, mediating the transcription of several condensin subunits, such as structural maintenance of chromosomes 2. Inhibition of CDK7 led to the prolongation of mitosis and induced chromatin bridge formation, DNA double-strand breaks, and abnormal nuclear features. Notably, the regulation of condensin subunit gene expression by CDK7 was found to be independent of super-enhancers [ 97 ].

Immunotherapy has been observed to confer significant benefits to patients with TNBC, outperforming other breast cancer subtypes in therapeutic efficacy. Clinically, the presence of programmed death ligand 1 (PD-L1) or programmed death 1 (PD-1) within the tumor microenvironment has been identified as a marker for predicting responsiveness to immunotherapy in TNBC patients [ 98 ]. The KEYNOTE-522 and KEYNOTE-355 trials have collectively demonstrated that the integration of the PD-1 inhibitor pembrolizumab with standard chemotherapy augments pathological complete remission rates or OS in early-stage or metastatic TNBC patients when compared to chemotherapy alone [ 4 ]. A preclinical investigation revealed that a combination of THZ1 with an anti-PD-L1 antibody surpassed the single administration group in terms of inhibiting tumor growth within a TNBC xenograft mouse model [ 96 ]. In a separate innovation, EGFR-targeted chimeric antigen receptor (CAR) T cells have been proven potent and specific in suppressing TNBC growth both in vitro and in vivo [ 99 , 100 ]. Despite initial success, a subset of mice promptly developed resistance. This resistance was mitigated through a combination therapy involving THZ1 and EGFR CAR T cells, which suppressed immune resistance in human MDA-MB-231 cell-derived and TNBC patient-derived xenografts by inhibiting the expression of CAR T-cell-induced immunosuppressive genes [ 101 ]. Consequently, the exploration of CDK7 inhibitors as immunoregulators has garnered attention. However, the compelling immunomodulatory potential inherent in CDK7’s role in the anti-tumor immune response is presently in its nascent stages. A comprehensive understanding of the direct impacts of CDK7 inhibition on both stromal and immune cells is imperative for nuanced analysis within the framework of breast cancers.

In addition to its pivotal role in orchestrating transcriptional machinery, CDK7 has been identified as having a direct oncogenic function through protein-protein interaction. Specifically, CDK7 interacts with C-terminal binding protein 2 (CtBP2), a protein known to promote tumor progression by enhancing epithelial-mesenchymal transition (EMT) and inhibiting apoptosis in cancer cells. Within this complex, CDK7 competes with the tumor repressor HIPK2 for CtBP2 binding. This interaction consequently inhibits the phosphorylation and dimerization of CtBP2, leading to its degradation in MDA-MB-231 cells. Thus, CDK7 serves to stabilize CtBP2 positively. The novel insights into the CDK7-CtBP2 axis provide a foundation for exploring this pathway as a potential anti-tumor strategy in TNBC [ 102 ].

The cumulative evidence from preclinical and clinical investigations underscores the potential of CDK7 inhibition as a promising strategy for managing TNBC. However, a significant obstacle to this approach is the likelihood of recurrent disease stemming from acquired resistance. Recognizing and targeting the underlying mechanisms of CDK7 inhibitor resistance will be instrumental in the forward development of therapies capable of bypassing this resistance. Recent research has revealed that both ABCG2 and phosphorylation of SMAD3 were upregulated in THZ1-resistant MDA-MB-468 cells. By employing either siRNA or small molecular inhibitors to suppress ABCG2 or SMAD4 (a transcriptional partner of SMAD3), researchers were able to resensitize resistant cells to CDK7 inhibitor [ 103 ]. These findings unveil the TGF-β/Activin-ABCG2 pathway as a potential target for both preventing and overcoming resistance to CDK7 inhibitors, thereby paving the way for further exploration in the context of TNBC treatment.

CDK7 in HER2-positive breast cancer

Numerous intrinsic or acquired resistance mechanisms to HER2-targeted therapy have been delineated, including mutations within the HER family of receptors that induce activation of downstream signaling cascades such as the PI3K-AKT and RAS-MAPK pathways, and the overactivation of compensatory elements like CDK2 and Cyclin D1 [ 104 ]. Such a complex matrix of resistance underlines the urgent necessity for innovative treatments targeting aberrant kinome activation that underpins resistance to HER2-targeted therapy. Intriguingly, recent investigations have illuminated the role of CDK7, whose expression is augmented by AKT in human HER2 inhibitor-resistant breast cancer cells. Functioning as a transcriptional cofactor, CDK7 induces aberrant gene upregulation that facilitates resistance to HER2 inhibition. Demonstrated both in vitro and in vivo, THZ1 has exhibited potent synergistic effects with the HER2 inhibitor lapatinib in HER2 inhibitor-resistant breast cancer cells [ 105 ]. This body of evidence fortifies the conceptualization of CDK7 inhibition as a viable additional therapeutic pathway, specifically targeting the activation of genes involved in the resistance fostered by multiple HER2 inhibitor-resistant kinases.

The specific CDK7 inhibitors in breast cancer clinical trails

A suite of oral specific CDK7 inhibitors, including SY5609, CT7001, XL102, TY-2699, GTAEXS-617 and intravenous specific CDK7 inhibitors such as Q901, SY1365, have made strides into phase I/II breast clinical trials (Table  2 ). As shown in Table  2 , the specific CDK7 inhibitors are predominantly assessed in patients with locally advanced or metastatic HR+/HER2- breast cancer, who exhibited failure in prior treatment with a CDK4/6 inhibitor in combination with hormonal therapy. Recently, the results of a clinical trial (ClinicalTrials.gov: NCT03363893) evaluating the safety and efficacy of the CT7001 in advanced breast cancer were published [ 106 ]. The trial determined a maximum tolerated dose of CT7001 to be 360 mg once daily, with a half-life of approximately 75 hours. The most common adverse events were low-grade nausea, vomiting, and diarrhea. Among the evaluated patients, one partial response (PR) (duration 337 days) and a clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) were achieved in locally advanced and/or metastatic TNBC patients administered CT7001 at 360 mg once daily. A cohort of 31 patients with post-CDK4/6 inhibitor HR+/HER2- advanced breast cancer received CT7001 in combination with fulvestrant, resulting in 3 patients achieving PR with a CBR of 36.0% (9/25) [ 106 ]. These findings underscore the therapeutic potential of CT7001, particularly in addressing the unmet medical needs of patients whose disease has progressed on CDK4/6 inhibitors.

Discussion and conclusion

CDK7, a pivotal component of theCAK complex, assumes a dual functional role. Firstly, it phosphorylates various CDKs, thereby facilitating the progression of the cell cycle. Additionally, CDK7 targets the CTD of RNA Polymerase II, a crucial process in gene transcription. Notably, certain investigations have indicated that CDK7 phosphorylates Ser5 and Ser7 within the CTD. However, it is worth noting that the inhibition of CDK7 using YKL-5-124, which apparently exhibits improved selectivity, does not effectively suppress the expression of Ser5 and Ser7 of CTD, as indicated in specific investigations [ 51 ]. Interestingly, murine embryonic fibroblasts lacking CDK7 expression demonstrate unaltered Pol II CTD Ser5 phosphorylation and a primarily unchanged gene expression program [ 57 ]. These results challenge the conventional understanding of CDK7 as the CTD kinase and consequently as a transcriptional regulator. It is plausible that both CDK7 and another CDK could fulfill the role of the CTD Ser5 kinase. In light of this possibility, it would be worthwhile to individually or in combination deplete other potential CDKs using CRISPR-Cas9 to determine which ones could complement the specific CDK7 inhibitors in blocking CTD Ser5 phosphorylation [ 107 ].

In this manuscript, we provide a comprehensive overview of the contemporary research landscape surrounding CDK7 within the domain of breast cancer. As delineated in Fig.  3 , the intricate involvement of CDK7 is underscored in fostering the processes of proliferation, invasion, migration, and resistance to apoptosis in breast cancer cells. Further mechanisms studies found inhibiting CDK7 impaired the abnormal phosphorylation of ER, weekend the self-renewal ability of cancer stem cells, and reversed endocrine drug resistance in ER+ breast cancer cells. Current investigations predominantly focus on HR-positive and triple-negative breast cancer, with scant data on HER2-positive variants. Only one research showed that CDK7 inhibitor THZ1 exhibited potent synergistic effects with the HER2 inhibitor lapatinib in HER2 inhibitor-resistant breast cancer cells. Due to the lack of effective biomarkers, the development and appliance of targeted therapy is limited in TNBC. Inhibiting CDK7 suppressed the survival of triple negative breast cancer cells and patient-derived xenografts. CDK7 has been implicated in sustaining malignant phenotypes by mediating transcriptional addiction dependent of super-enhancers, maintaining chromatin sublooping independent of super-enhancers, and inhibiting the degradation of oncogenic protein in a manner of protein-protein interaction. Moreover, preliminary findings suggest that CDK7 inhibitors could potentiate immunotherapy responses, thereby laying the groundwork for future therapeutic strategies.

A pattern diagram of CDK7 in breast cancer

Evolutionary studies suggest that CDKs are divided into cell-cycle-related CDKs such as CDK1, CDK2, CDK4 and CDK6 and transcriptional CDKs including CDK7, CDK8, CDK9 and CDK11 [ 108 , 109 ]. The recent FDA endorsement of CDK4/6 inhibitors for managing HR+/HER2- breast cancer indicates the burgeoning interest in CDK-targeted therapies. However, an established continuum of care remains elusive for patients with advanced HR+/HER2− breast cancer experiencing disease progression following CDK4/6 inhibition. Present therapeutic strategies gravitate toward mTOR inhibition with everolimus and PI3K inhibition with alpelisib. Insight from the phase I/II TRINITI study, involving a regimen of exemestane, ribociclib, and everolimus, revealed a CBR of 41% at week 24 and a median PFS of 5.7 months in a population where 92% had prior CDK4/6 inhibitor exposure [ 110 ]. Alpelisib’s application, albeit potent, is confined to patients harboring a PIK3CA mutation, representing approximately 40% of the cohort, achieving a median PFS of 7.3 months post-CDK4/6 inhibition, with a significant caveat of induced hyperglycemia necessitating anti-diabetic intervention [ 111 ]. Furthermore, preliminary data from DESTINY-Breast04 [ 112 ] and TROPiCS-02 [ 113 , 114 ] trials highlight the potential of Trastuzumab deruxtecan and Sacituzumab govitecan, the HER2-targeted antibody-drug conjugate, delineating a novel therapeutic avenue for patients with advanced HR+/HER2− breast cancer following CDK4/6 inhibitor treatment. The specific CDK7 inhibitor, CT7001, in conjunction with fulvestrant, demonstrates a competitive clinical benefit rate (CBR of 39%) and acceptable adverse effects in advanced HR+/HER2− breast cancer patients. Notably, preclinical and clinical evidence underscores the utmost promise of targeting CDK7 in the subset of advanced HR+/HER2− breast cancer cases that have experienced disease progression following prior treatment with a CDK4/6 inhibitor in combination with hormonal therapy. Despite these encouraging findings, it is imperative to acknowledge the limited availability of only phase I/II clinical trial data, necessitating the imperative acquisition of phase III clinical data to affirm the safety and efficacy of CDK7 inhibitors in future clinical practice. Furthermore, pivotal head-to-head comparative trials are indispensable for the comprehensive evaluation of the efficacy of CDK7 inhibitors in treating advanced HR+/HER2− breast cancer in relation to established therapeutic modalities such as everolimus, alpelisib, sacituzumab govitecan, and others. Such comparative analyses aim to delineate the optimal management paradigm for this patient cohort. Additionally, there exists a compelling need for further investigations to ascertain the most promising combination strategies for CDK7 inhibitor therapy. Evolutionary insights, as gleaned from phylogenetic analyses, illuminate the structural similarity between CDK family members. Given the high structural resemblance among subtypes, CDK7 blockers inherently exhibit off-target activity towards other isoforms, thereby engendering potential risks of side effects. Notably, the CDK7 covalent inhibitor THZ1 exemplifies this phenomenon by displaying inhibitory activity on other kinases, including CDK12/13. Consequently, the termination of the clinical trial of the CDK7 covalent inhibitor SY-1365 underscores the challenges associated with achieving both efficient anti-tumor effects and safety. The ongoing discourse hinges upon the advantages conferred by highly selective inhibitors that may concurrently exhibit some degree of off-target activity, prompting a nuanced consideration in the continued development of CDK7 inhibitors.

Abbreviations

chimeric antigen receptor T cells

CDK-activating kinase

clinical benefit rate

Cyclin-dependent kinase 7

hormone receptor

human epidermal growth factor receptor 2

nucleotide excision repair OS,overall survival

positive transcription elongation factor b

patient-derived xenograft

programmed death ligand 1

programmed death 1

progression-free survival

partial response

small interfering RNA

triple-negative breast cancer

general transcription factor IIH

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Gong, Y., Li, H. CDK7 in breast cancer: mechanisms of action and therapeutic potential. Cell Commun Signal 22 , 226 (2024). https://doi.org/10.1186/s12964-024-01577-y

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Signs and Symptoms of Oral Cancer

Oral cancer is cancer of the mouth that affects the tissues in the throat, gums, lips, under the tongue, and at its base. This cancer doesn't always cause symptoms in the early stages, but cancer cells can spread quickly. If you develop symptoms, common signs of this condition include the development of growths, sores, or white patches in the mouth.  

This condition becomes especially dangerous if it spreads (or “metastasizes”) to other parts of the body—which happens in about 3% to 7% of oral cancer cases. Fortunately, most cases of oral cancer are treatable, as long as you receive a diagnosis and treatment in a timely manner.

Common Symptoms 

If oral cancer goes untreated, symptoms can get worse. As with other cancers, healthcare providers such as periodontists (dentists specializing in oral disease) or otolaryngologists (specialists in the ears, nose, and throat) stage the disease based on the severity of your condition and how far it’s spread.

Across these stages, the most common warning signs of oral cancer include:

• Persistent sores on the tissues of the mouth, gums, tongue, throat, or lips
• Red or white patches in the throat
• Numbness in parts of the mouth or tongue
• Bleeding in the gums, tongue, and lips
• Sore throat , hoarseness, or loss of voice
• Pain or difficulty with chewing, swallowing, or talking
• Feeling a lump in your neck
• Difficulty moving the tongue or jaw
• Jaw swelling

Stage 0 Symptoms

When staging oral cancer, healthcare providers follow classification systems, such as the TNM system set by the American Joint Committee on Cancer (AJCC). This system stages cancer from 0 to 4 (stage 4 being the most severe), based on three criteria: tumor growth (T), the extent of spread to the neck’s lymph nodes (N), and metastasis (M), or whether the cancer has spread to other parts of the body.   

Also known as carcinoma in situ, stage 0 is a pre-symptomatic stage of oral cancer, and there’s no spread of cancer cells to the lymph nodes (known as metastasic). Though there aren’t symptoms, healthcare providers can detect abnormal squamous cells—the cells that line the mouth, tongue, and throat. These cells have the potential to become cancerous (or “malignant”).        

Stage I Symptoms 

In the first stage of oral cancer, the tumors are less than 2 centimeters (cm) in diameter and are 5 millimeters (mm) or less deep. Malignant cells in this stage are found in the tissues of the mouth, lips, or throat but haven’t spread to surrounding tissues, lymph nodes, or organs in other parts of the body, such as the lungs.

Stage II Symptoms 

According to the AJCC, there are two definitions of stage II oral cancer. In these cases, the cancerous tumors are either between 2 and 4 cm in diameter and between 5 and 10 millimeters (mm) deep. In this stage, cancer cells haven’t started growing into other tissues, so they aren’t present in the lymph nodes or other organs. But you may start noticing symptoms that affect your mouth, throat, or lips.

Stage III Symptoms 

In stage III, oral cancer has advanced considerably, becoming prominent in the mouth and in some cases starting to spread to the lymph nodes. As with stage 2, there are two definitions:

• Tumors are larger than 4 cm in diameter in the mouth or the base of the tongue , with no sign of spread to lymph nodes or other parts of the body
• Tumors of any size in tissues surrounding the throat and spreading to one lymph node, which swells to 3 mm or less, but nowhere else  

If the oral cancer spreads to your lymph nodes, it can lead to symptoms like painful swallowing and feeling a lump in the neck.

Stage IV Symptoms 

If you have stage IV—the most advanced stage of oral cancer—the cancer has started to spread to surrounding tissues, lymph nodes, and more distant organs. In the TNM classification, this stage can cause one or more of the following:

• Tumors of any size that may or may not actively spread into surrounding tissues, such as the bones of the jaw or face, the voice box (larynx), muscles, sinuses , and skin on the face or nose affected. Swelling in a nearby lymph node is common.
• Tumors spread into tissues as well as one lymph node on the same or opposite side. The lymph node usually swells to over 3 cm in diameter.
• Tumors have spread not only to surrounding structures and lymph nodes but also to other parts of the body, such as the lungs.

When to Contact a Healthcare Provider 

If you suspect oral cancer, it’s critical to get help as soon as possible, as this disease can progress rapidly. Early detection of this condition vastly improves outcomes. In one study, 90% of those who detected the issue in stage I and got treatment were still alive five years later; this number dropped to 45% among those with stage IV.

If you experience any symptoms of oral cancer for longer than two weeks, call your healthcare provider. Persistent sores or swollen, discolored spots, lumps in the neck, and other typical signs of the condition can mean you need help.

Oral cancer can become a medical emergency due to complications or severe side effects of treatments. Call 911, if you experience any of the following:

• Worsening side effects from radiation or chemotherapy , such as nausea and vomiting
• Shortness of breath
• Severe headache
• Neck stiffness
• Bloody urine

Questions to Ask Your Provider

When seeking care for oral cancer, think about asking the periodontist or specialist the following questions:

• What stage of oral cancer do I have, and what does that mean for treatment?
• What side effects can I expect from treatment and what I can do about them?
• What lifestyle changes can I adopt to improve my outcome?
• Will I need to change what I eat because of my symptoms?
• Will I need surgery to treat oral cancer?

A Quick Review 

Oral cancer causes tumors or growths in the tissues of the mouth, tongue, gums, or throat. This condition, if left untreated, worsens over time and can cause cancer cells to spread to the lymph nodes, surrounding tissues, and distant organs. If you're experiencing symptoms of oral cancer, get medical care as soon as you can to improve symptoms and survival outcomes.

Frequently Asked Questions

What is the survival rate for oral cancer?

Several factors influence the survival rate of oral cancer, such as whether you receive treatment and how severe your condition is. Without treatment, the prognosis is poor.

In one study, 31% of those who had stage I without treatment survived after five years, something which only 12.6% of stage IV patients managed. But with timely treatment, the picture improves. At five years, studies found survival rates after five years were 90% for people in stage I and nearly 50% for stage IV.

How long can you have oral cancer without knowing?

The early stages of this cancer don’t always cause symptoms. Some types, such as verrucous carcinoma, progress more slowly, making it harder to detect earlier signs. But squamous cell oral carcinoma, the most common type, moves more quickly, spreading to the lymph nodes or surrounding tissues within as little as three months or less.

Can a dentist detect oral cancer?

Though specialists like periodontists or otolaryngologists (ear, nose, and throat doctors) guide the treatment of oral cancer, dentists can diagnose the condition. During routine cleanings and check-ups, dentists look for tumors, growths, or other symptoms. Dentists may also perform additional screening methods, such as using a screening light or using a dye to detect growths or other signs.

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Role of Poor Oral Hygiene in Causation of Oral Cancer-a Review of Literature

Affiliation.

• 1 Dept. of Head and Neck Surgery, Tata Memorial Centre, Parel, Mumbai 400012 India.
• PMID: 30948897
• PMCID: PMC6414580
• DOI: 10.1007/s13193-018-0836-5

Oral squamous cell carcinomas (OSCC) are among the commonest cancers in South East Asia and more so in the Indian subcontinent. The role of tobacco and alcohol in the causation of these cancers is well-documented. Poor oral hygiene (POH) is often seen to co-exist in patients with OSCC. However, the role of poor oral hygiene in the etio-pathogenesis of these cancers is controversial. We decided to evaluate the available literature for evaluating the association of POH with OSCC. A thorough literature search of English-language articles in MEDLINE, PubMed, Cochrane Database of Systematic Reviews, and Web of Science databases was conducted, and 93 relevant articles were short-listed. We found that POH was strongly associated with oral cancers. It aids the carcinogenic potential of other known carcinogens like tobacco and alcohol. Even on adjusting for known confounding factors like tobacco, alcohol use, education, and socio-economic strata, presence of POH exhibits higher odds of developing oral cancer.

Keywords: Dental visits; Missing teeth; Mouth neoplasm; Oral cancer; Poor oral hygiene; Tooth brushing.

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• v.318(7190); 1999 Apr 17

Fortnightly review

Oral cancer.

The survival of patients with oral cancer remains poor despite recent surgical advances. About 30-40% of patients with intra-oral cancers will survive five years; the short survival time is caused, largely, by late detection. 1 Public awareness of oral cancer as compared with other cancers is low and this contributes to delays in diagnosis. 2 However, the mouth can be examined by healthcare professionals with much greater ease and accuracy than many other parts of the body. All healthcare workers need to be aware that a patient with an ulcer or white patch that persists beyond three weeks should be referred for further evaluation to an oral physician or to an oral and maxillofacial surgeon. Tobacco use is a major cause of oral cancer , and doctors and other health professionals can contribute to primary prevention by making patients aware that tobacco, in all forms, predisposes them to oral cancer.

Summary points

• The incidence of squamous cell carcinoma of the oral cavity is increasing
• The use of tobacco, in all forms, is major risk factor for squamous cell carcinoma; tobacco acts synergistically with alcohol
• Squamous cell carcinoma presents intra-orally as a non-healing ulcer, or a white or red patch
• A biopsy done under local anaesthesia is the single most important investigation in diagnosing oral cancer
• Five year survival rates for cancer of the lip are good but are low for other forms of mouth cancers, especially if the lesions are large at the time of diagnosis

The majority of references in this article were obtained from a personal collection built during 10 years of work in this subject and during a study of screening for oral cancer. A Medline search of articles published between 1966 and 1998 using the terms “mouth” and “neoplasms” yielded 20 664 articles. Adding the keywords “systematic” and “review” did not identify any systematic reviews. The Cochrane database does not list any protocols or completed systematic reviews of randomised controlled trials of head and neck surgery. 3 Searching the Cochrane Controlled Trials Register identified 11 randomised controlled trials, mainly on the use of chemotherapy. The American College of Physicians Journal Club and Evidence-Based Medicine database (1991-1997) lists no articles relating to mouth neoplasms. 4

Main types of oral cancers

Squamous cell

 Verrucous

 Spindle cell

 Adenoid squamous

Malignant melanoma

Odontogenic

Primary bone tumours

Salivary gland tumours

Mucoepidermoid

Acinic cell

Adenocarcinoma

Haemopoietic

Lymphoreticular

Metastases from other sites

Definition and classification

Neoplasms of the mouth are defined as neoplasms involving the oral cavity, which begins at the lips and ends at the anterior pillar of the fauces. The most common intra-oral malignancy is squamous cell carcinoma. Tumours of the salivary gland have different risk factors and are relatively rare. The major types of carcinomas encountered in the mouth are shown in the box.

Epidemiology and risk factors

Oral cancer is relatively rare in the United Kingdom—2000 new cases are diagnosed each year—but this is rising, especially among men. 5 Worldwide it is estimated to be the sixth most common cancer, prevalence being highest in India. 6 An increase in incidence has also been reported in central and eastern Europe, especially among younger men. 7 Mortality remains high and although the prognosis for cancer of the lip is good, the prognosis for intra-oral squamous cell carcinoma remains poor. 5 There is good evidence that tobacco in all forms, including the tobacco in snuff and betel quid (a mixture of ingredients including betel leaf, areca nut, slaked lime, and tobacco, which is wrapped in a betel leaf and chewed), is carcinogenic in the upper aerodigestive tract, which includes the mouth. 8 There is fairly convincing evidence that alcohol is also a carcinogen and acts synergistically with tobacco. 9 There is little convincing evidence that mouthwash use, poor oral hygiene, or oral infections of viral origin play an important role in the aetiology. 10 , 11 Consuming fruit and vegetables may have a protective effect. It has been suggested that lichen planus and oral submucosal fibrosis are associated with an increased risk of intra-oral malignancy. Wide variations in the malignant potential of these lesions have been reported. There is a slight familial risk for oral cancer which may be related to the similar exposures to tobacco and alcohol which occur among family members. 12 Patients who have had renal transplants have a higher incidence of cancer of the lip which may be due to immunosuppression. 13

Although a premalignant lesion (epithelial dysplasia) is recognised, many oral cancers do not go through a premalignant stage. Not all premalignant lesions become malignant, and some regress. 14 There is insufficient evidence to determine which features reliably predict malignant potential, but the degree of dysplasia may be a factor.

Primary prevention involves stopping the use of tobacco. Regression of premalignant lesions has been reported in former smokers. 15 , 16 In the Indian subcontinent and in areas with large populations of Asian migrants, reducing the use of betel quid may also be beneficial. The prevalence of betel quid use remains high in immigrant populations in the United Kingdom. 17

Early identification of premalignant lesions and small oral cancers will allow patients to be treated earlier. Screening for oral cancer is simple. It does not require any laboratory support; at the most it requires a good light source. Mass screening in the United Kingdom is not recommended because it does not fulfil the principles for screening suggested by Wilson and Jungner. 18 , 19 However, dentists should be encouraged to screen patients opportunistically especially if patients are males, smokers, and over 40 years old.

Public campaigns are necessary, however, to make patients aware of oral cancer; patients often delay seeking professional advice for over three months. 20 , 21 The 1992 US National Health Interview Survey showed that the 15% of adults who had had an oral examination were likely to be better educated about and more aware of the risks of oral cancer than those who had not had such an examination. 22

Clinical features

Oral squamous cell carcinoma presents in a variety of ways but most early lesions are asymptomatic. Premalignant and early malignant lesions may present as painless white or red patches. Lesions that look speckled—that is, non-homogeneous—or those that exhibit erythroplasia are more likely to have evidence of severe dysplasia on histological examination than homogeneous white patches. Some malignant lesions present as small, indolent ulcers. Many premalignant lesions regress if tobacco use is stopped. Lesions of intermediate malignancy may present as persistent ulceration with fixation to underlying tissues and regional lymph node enlargement. Late stage oral malignancy may result not only in large, indurated, crater-like ulcers with rolled margins but also in bony destruction, leading to mobile teeth, loss of teeth, or even pathological fractures. These may be associated with pain, numbness, or paraesthesia.

Figure ​ Figure1 1 shows a white homogeneous patch in the floor of the mouth of a smoker. A biopsy of this showed mild epithelial dysplasia. Figure ​ Figure2 2 shows a speckled white patch in the buccal mucosa of a male smoker. Figure ​ Figure3 3 shows an erythematous lesion on the lower alveolus near the wisdom tooth area. Biopsies of the lesions in figures ​ figures2 2 and ​ and3 3 confirmed the presence of squamous cell carcinoma. Figure ​ Figure4 4 shows a typical late stage squamous cell carcinoma.

Homogeneous white patch in mouth of a smoker. Biopsy of the lesion showed mild epithelial dysplasia

Speckled white patch in buccal mucosa of male smoker. Identified by biopsy as squamous cell carcinoma

Erythematous lesion on lower alveolus near wisdom tooth area. Identified on biopsy as squamous cell carcinoma

Typical late stage squamous cell carcinoma

Details of how rarer types of cancers present are shown in the table.

Investigations

The most useful investigations for suspected oral malignancy are representative biopsies, which may be taken from more than one area. These are usually done under local anaesthesia but occasionally an examination under general anaesthesia is useful. Intra-oral radiographs, orthopantomograms (radiographs of both jaws), and computed tomography scans may help define the extent of the lesion and any bony or nodal involvement.

In the United Kingdom, upper aerodigestive tract neoplasms are treated by ear, nose, and throat specialists; oral and maxillofacial surgeons; plastic surgeons; and oncologists. 23 There is no systematic collection of basic data, there are few combined clinics, and the use of other support services is variable. 23

Treatment for oral cancer is principally surgical. Few patients are treated solely with radiotherapy and even fewer with chemotherapy. Radiotherapy and chemotherapy are often used for adjuvant and adjunctive therapy. The factors that affect the choice of treatments for individual patients are beyond the scope of this article.

The aim of surgical management is to excise the entire lesion to eliminate possible channels of spread, such as the lymphatic system, nerves, and blood vessels. This ablative surgery is followed by reconstructive surgery which is used to improve healing and restore function and improve the patient’s quality of life. Debulking surgery is used as a palliative measure for incurable tumours. Some surgical procedures only involve soft tissues. Others involve both hard and soft tissues. The patient in figure ​ figure3, 3 , for example, had an excision of the maxillary alveolus. Neck dissection is frequently required, with a consequent increase in postoperative morbidity. Reconstruction may involve not only skin grafts and flaps, but also bony grafts and implants.

Radiotherapy is rarely used as a primary treatment; it is used either to debulk the tumour before surgery or to prevent recurrences and eliminate residual tissue after an incomplete resection. The complications of radiotherapy include oral mucositis and osteoradionecrosis, which present difficult management problems. Radiotherapy is also used if extracapsular spread is thought to have occurred; in this case, it is done within six weeks of surgery.

Chemotherapy is used nearly exclusively as a palliative treatment when there has been a local recurrence or metastases. However a meta-analysis of 42 randomised controlled trials involving 5079 patients has shown that adjuvant chemotherapy for squamous cell carcinomas of the head and neck results in a significant improvement in survival (relative hazard ratio of dying 0.89) but at the cost of a significant increase in morbidity (toxicity was increased with a relative proportion of 2.17). 24

The principles of the treatment of oral cancer and its sequelae are well described in the specialist literature. 25 Few studies have assessed the quality of life and coping strategies of patients who have undergone surgery. 25 – 28

A systematic review of the management of oral neoplasms is needed to provide the information required for patients and their medical advisers to make more informed choices about treatment.

The prognosis for large oral neoplasms remains poor. Healthcare professionals can make a large impact on the morbidity and mortality caused by oral cancer by referring patients with possible early or premalignant oral lesions for a specialist opinion as soon as possible. Raising public awareness of oral cancer may also assist in early diagnosis. A successful public health campaign to reduce the use of tobacco would also reduce the incidence of this condition, as has been shown in India. 16

Rarer types of oral cancer

Acknowledgments

I thank Dr Martin Underwood for his constructive comments.

Competing interests: None declared.