RESEARCH

 

Mapping oral cancer research in South Africa

 

 

P.J. Botha^I; A. Schoonees^II; C.C. Pontes^III

^IBChD, PDD, MChD(Oral Med/Perio), MSC Med Sci.(ClinEpi). Specialist in Oral Medicine and Periodontology, Private Practice, 3 Zinnia Street, Bloemhof, Bellville, Cape Town, South Africa. Contribution: Principal Researcher 65%
^IIMSc Med Sci. (Clin Epi). Centre for Evidence-based Health Care, Division of Epidemiology and Biostatistics, Department of Global Health Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa. Contribution: Advisor 20%
^IIIBDS, MSc (Periodontology) PhD(Health Sciences). Specialist in Periodontology, Independent Researcher 38C Higgo Crescent, Gardens, Cape Town, South Africa. Contribution: Scientific writing 15%

Correspondence

 

 

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ABSTRACT

The aim of the present study was to review the scope of oral squamous cell carcinoma (OSCC) research in South Africa, including its epidemiology, diagnosis, associated risk factors and management. All publications relating to OSCC on the South African population were sought. A total of 72 studies were included and classified into seven categories; most studies were case reports or case series. Risk factors and epidemiology were the most investigated categories while early detection and diagnosis was the least explored. All the main ethnic groups in South Africa were investigated. The highest incidence of OSCC in South Africa was reported for males of mixed ancestry; there was a male predominance in all ethnic groups except for Asians. There is a high prevalence of OSCC in younger individuals in comparison with the global average. Future research about early detection and diagnosis, risk factors, premalignant lesions, management and disease progression is suggested. Educational programmes are necessary and should include schools and tertiary education institutions to reach adolescents and young adults.

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INTRODUCTION

OSCC ranks amongst the ten most prevalent cancers in the world; being associated with high morbidity and mortality, it constitutes a public health problem.^1,2 As in several low and middle-income countries, lack of access to oral health care can delay diagnosis of OSCC and ultimately decreases survival rates.³

It has been recognised that cancers in the oral cavity and oropharynx present wide geographical heterogeneity. In South Africa, OSCC derives from a wide geographical area.⁴ OSCC in South Africa is the fifth most common cancer in males and the tenth most common cancer in females.⁵ Globally, 6% of oral cancers occur before the age of 45; in South Africa, 7.3% of oral cancers occur in males in this age group, and 7.8% in females.⁶ Lifestyle-related factors like smoking, alcohol, betel nut and spices consumption, together with other risk factors such as the human papillomavirus (HPV) and persistent inflammation in the oral cavity, are associated with the aetiology of OSCC.⁷

The aim of the present paper is to map archived material of OSCC in South Africa, including research on its epidemiology, aetiology, pathology, diagnosis, associated risk factors and management. Results from this review could help in defining and refining knowledge and voids relating to OSCC research in South Africa.

 

METHODS

This report draws on the Arksey and O'Malley methodological framework for scoping reviews.⁸

Inclusion criteria used to identify potential studies:

1. Anatomical sites: oral, oropharyngeal, or both.

2. Fields of study: premalignant and malignant lesions, leukoplakia, eryhthroplakia, combined leukoplakia/ erythroplakia, proliferative verrucous hyperplasia, carcinoma-in-situ, verrucous carcinoma, and oral squamous cell carcinoma (OSCC).

3. Study design: laboratory studies, case reports, case series, case-control studies, cross-sectional studies (including diagnostic accuracy studies), surveys, cohort studies, randomised controlled trials (RCTs) and other clinical trials, screening studies (using Toluidine Blue, chemiluminescence, brush biopsy, and tissue fluorescence imaging) and qualitative studies.

4. Population: South African population samples. International multicentre studies where one or more sites in South Africa were included were also eligible.

Secondary research (e.g. literature reviews) as well as primary studies where the focus was on oral tumours of odontogenic origin, salivary gland origin, tumours of intra-osseous origin, lymphomas, Kaposi's sarcoma and lesions of melanocyte origin were excluded. Studies on lip cancer were also excluded.

Identification of studies for inclusion

A Medline electronic search (accessed via PubMed) was performed in October 2012 and updated in January 2014 and 2017, according to the search terms displayed in Table 1. Furthermore, hand searching of reference lists of potentially eligible studies was performed during the screening and data extraction process. The heads of the departments of South African universities in the disciplines of Otolaryngology (eight departments), Oral Medicine and Periodontology (four departments), Oral Pathology (four departments), and Maxillofacial and Oral Surgery (three departments) were contacted via email and asked to send any additional studies that could have been missed by the electronic search.

 

 

Selection of studies and extraction of data

Two authors independently reviewed the titles from the electronic search results and selected potentially eligible studies. Disagreements were resolved by discussion until a consensus was reached. The articles sent by the heads of departments were screened for their eligibility.

The following data were extracted from the included articles: category (case reports & case series, prevalence & incidence, risk factors, early detection and diagnosis; premalignant lesions; treatment; and progression of disease); study period; study design, sample size, demographics (gender, age, ethnicity), aim/objectives and main findings. Missing data were described as 'not reported'.

 

RESULTS

The search results and selection process are displayed in Figure 1. In summary, four-hundred-and-two articles were identified through the Medline search, of which 70 were identified as potentially eligible during the screening process. The 19 emails sent out to heads of departments resulted in 46 articles received, of which 22 were included as potentially eligible. Scrutiny of the full texts resulted in 72 studies that met the eligibility criteria. The included studies were classified into seven categories, as displayed in Table 2. Early detection and diagnosis, premalignant lesions and disease progression were the least investigated categories. The earliest included study included was performed in 1964 and the latest was performed in 2014. All the extracted data were summarised in Tables 3 to 10.

 

 

 

 

Only one of the included studies was a randomised controlled trial (RCT). Due to the higher prevalence of OSCC among older people, most studies included adults and elderly. All main ethnic groups in South Africa (Whites, Blacks, Asians and people with Mixed ancestry, also referred to as "Coloured", according to the Population Registration Act n.30 of 1950, repealed in 199 1⁸⁰) have been investigated in relation to OSCC, which is important due to the potential influence of ethnicity on OSCC.

Several of the included studies lacked clear objectives; amongst those that explicitly stated the objectives, in many instances the design of the study was not ideal to address the objective. For the studies on risk factors for example, most were case series or cross-sectional, which offer limited information on the topic. Similarly, for the treatment category, only one out of the nine included studies was a RCT, which is the most suited design to evaluate the efficacy of an intervention.⁶⁷

 

DISCUSSION

Case reports/case series

The several case reports and case series highlighted the importance of the biopsy for abnormal lesions in the oral cavity in order to avoid delays in the diagnosis of OSCC. Most cases were associated with tobacco use and alcohol consumption; however, a few cases of OSCC were reported in younger patients in the absence of traditional risk factors.^12,17 Reports on oral cancer in HIV-infected and discoid lupus erythematous patients suggest a possible role for these conditions in relation to OSCC.^14,15 With the alarming statistics for HIV in South Africa, 12.7% of the population is HIV-positive (Government Statistical Release 2016⁸¹); the development of non-AIDS related cancers requires further attention.⁸²

Prevalence and incidence

In South Africa, the National Cancer Registry (NCR) compiles pathology- based data on cancer in the country. The most recent studies on prevalence and incidence of oral cancer in South Africa relies on data extracted from the NCR database. Globally, oral cavity and oropharynx cancers combined account for approximately 5% of all cancers in males and 2% of all cancers in females; the number of new cases per year for both genders is estimated at 310.000.⁸³ In South Africa, from 1997-2001, 5% of all cancers in males and 0.6% of all cancers in females were oral cancers; 0.6% and 0.1% were cancers in the oropharynx of males and females, respectively.^6,21,22

The average age standardized incidence rate (ASIR) for oral cancer in South Africa from 1996-2001 was 6.2/100.000/ year for men and 1.6/100.000/year for women.⁶ The combined ASIR for both genders was 4.5/100.000/ year²⁹, which is not far from the global average ASIR of 5.1/100.000/year from the Globocan database.¹

Differences among ethnic groups were observed, with Coloured males having the highest ASIR for oral cancer (10.2/100.000/year), followed by white males (6.9/100.000/ year). Asian women had the highest ASIR amongst females (3.4/100.000/year), followed by Coloured and White women (both 2.8/100.000/year). The only ethnic group where females had higher ASIR than males was the Asian group. In subjects under 45 years of age, there was no male prevalence.^6,21

The majority of oral cancers were diagnosed at the end of the sixth decade; the population average age at time of diagnosis was 57.8 years.²⁹ In South Africa, the incidence of cancers in the oral cavity and oropharynx in males (7.3%) and females (7.8%) younger than 45 years is higher than the global average (6%).⁶ Rural populations seem to present lower incidence of OSCC as compared with urban groups.²⁶

Oral cancer in Sub-Saharan Africa presents estimated mortality rate of 2.8/100.000/year for males and of 1.0/100.000/year for females for cancer of the lip and oral cavity combined.⁴ A global estimate from the US for the 5-year relative survival rates for oral cancer is based on the clinical stage at diagnosis, with 82% for localized lesions, 52% for regional lymph node involvement and 27% for patients with metastasis.⁸⁴ It must be pointed out that, since only cancers diagnosed histologically are included in the NCR, the real burden of oral cancer in South Africa can be worse than hitherto reported.²¹

Risk factors

Traditional risk factors such smoking and alcohol consumption play a crucial role in the aetiology and pathogenesis of OSCC worldwid.⁷ Globally, oral cancer is more prevalent in males and so is smoking; in South Africa the gap among genders is large, while 32% of adult men smoke, only 8% of adult women are smokers (WHO report 2015).⁸⁵

The use of potentially carcinogenic leaf products such as areca nut, associated or not with tobacco, adds to the complexity of aetiological factors for oral cancer in South Africa.⁴ The habit of chewing areca nut can maybe explain the higher prevalence of oral cancer in female South Africans of Indian heritage as compared to male Indian South Africans.^26,35,37 It has been reported that up to 93% of adult South African Indian women chew areca nut/quid.³⁷

The potential role of infection with HPV16 and 18 infection in OSCC has been investigated worldwide, especially in non-smoker younger patients.^86,87 Neither HPV nor Epstein-Barr virus were associated with OSCC in South African subjects.^34,40,51 One case series investigated alterations in chromosome 3 in relation to OSCC and suggested that mutations in the short arm of chromosome 3 may play a role in the progression of OSCC.⁴²

Globally, low socio economic status has been associated with increased odds ratio for development of oral cancer (OR up to 2.4), measured as low income, educational level and social class.⁸⁸ Furthermore, a pooled analysis of 16 studies showed that each portion of fruit or vegetables consumed per day decreases the risk for oral cancer (OR 0.5).89 In a country with much inequity such as South Africa, it is surprising that no study has evaluated the role of low socio economic status and dietary deficiency for oral cancer.

Early detection and diagnosis, premalignant lesions and disease progression

Despite advances in research and surgical techniques, the 5-year survival rate for OSCC remains low, with a rough estimate of 50%.¹ The high morbidity and mortality rates emphasize the importance of screening programmes and techniques for early detection of malignancy. Although exfoliative cytology has been investigated as a pre-screening alternative,⁵³ the gold standard for diagnosis of cancer of the oral cavity and oropharynx remains the biopsy.⁹⁰ Visual examination is still the best screening tool; guidelines from the American Dental Association suggest that cytology can be useful for patients with suspicious lesions that refuse to undergo biopsy.^91,92

Leukoplakia is the most common premalignant lesion, the overall risk for malignant transformation in oral leukoplakia lesions is estimated at 2%. The majority of leukoplakia (80%) reported in South Africa affects white subjects.⁶⁸ Oral submucous fibrosis is another recognized premalignant condition, with an estimated malignancy transformation rate of 3.7%.⁹³ Chewing of areca nut, a common habit among Indian and Indian-descendant women, is a significant risk factor for developing oral submucous fibrosis.^57,61 More studies are necessary to better understand the carcinogenesis of those premalignant lesions.

It is estimated that in approximately 40% of patients with OSCC, the disease progresses through metastases in cervical lymph nodes, which worsen prognosis and survival rates.⁹⁴ Submandibular and axillary lymph nodes are rarely affected, but should be examined routinely.^74,75 Studies have suggested that DNA flow cytometry can help identify the risk for metastasis in primary OSCC tumours.^73,76,77 Understanding the progression of the disease and its metastatic potential can help improve survival rates.

The search for prognostic markers of disease progression for OSCC in South African subjects has not yet been successful according to studies on the expression of E-cadherin and b-catenin.⁷⁸ Fhit protein has been investigated as a potential prognostic factor, since the tumour suppressant FHIT gene seems to be inactivated in severe dysplastic OSCC lesions.⁷⁹ Prognosis of tongue cancer has been reported as worse when this protein is under expressed; however the clinical application of this finding is still to be determined.⁹⁵

Treatment

Surgical techniques for oral cancer treatment have been the primary focus of studies on OSCC management in South African subjects, highlighting that most lesions are diagnosed at a late stage.³ Surgery is the main treatment strategy for oral cancer patients worldwide, especially in advanced stages. A study from 1992 reported a 50% survival rate at 3 years and 25% at 5 years for South Africans submitted to major surgery for OSCC.⁶⁶

Radiotherapy is usually used as an adjunctive treatment after surgery for advanced lesions. Chemotherapy has not been commonly used for oral cancer treatment, however, there has been a trend for its use combined with surgery and radiation in advanced or recurrent cases.⁹⁶ The use of molecular targeted drugs holds promise on less debilitating treatment options for OSCC patients worldwide.⁹⁷

 

CONCLUSIONS

OSCC is a significant problem in South Africa, resulting in morbidity and mortality. Ethnic and gender variations are present, with males of mixed ancestry, having the highest incidence rate of OSCC in the country. Smoking and alcohol consumption are strong risk factors for OSCC in the general population. The prevalence of OSCC in young subjects (<45 years) in South Africa is higher than the global average and not always associated with traditional risk factors.

Generally, there is a paucity of information on premalignant lesions, early diagnosis, traditional and non-traditional risk factors, disease progression and management of cancers of the oral cavity and oropharynx in South Africa. Although there seems to be enough information on the epidemiology of OSCC in the country, an underestimation of the incidence and prevalence cannot be excluded.

Various studies mention the need for educational programmes and public health policies targeting risk factors and early identification of lesions, which ideally should translate into less invasive treatment, better quality of life and lower mortality rates. Educational programmes should include schools and tertiary education institutions to reach adolescents and young adults.

 

Acknowledgements

We thank Ms Eunice Turawa for participating in locating the full text articles for us, as well as for Dr Olatunji Adetokunboh for his assistance with the results tables.

 

ACRONYMS

HPV: human papillomavirus

NCR: National Cancer Registry

OSCC: oral squamous cell carcinoma

RCT: randomised controlled trials

 

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Correspondence:
Dr Paul J Botha
Specialist in Oral Medicine and Periodontology, Private Practice.
Tel: 021 910 3330, Fax: 021 910 3331
E-mail: p.mbotha@mweb.co.za