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South African Journal of Agricultural Extension

On-line version ISSN 2413-3221
Print version ISSN 0301-603X

S Afr. Jnl. Agric. Ext. vol.41 n.1 Pretoria Jan. 2013

 

Characterised by rapid localisation to bone and a short half-life the diphosphonates are therefore favourable markers of bone turnover and bone perfusion.3 Lesions can be detected when there is a 5-10% change in bone turnover and the diagnostic value of bone scintigraphy can thus be appreciated when one considers that between 30-50% of alteration to bone content is necessary for detection on conventional radiographs.4 The high sensitivity does however come at the expense of specificity. Any pathology invoking an osteoblastic response such as infection, inflammation, primary or secondary tumours, metabolic bone disease, or trauma will manifest as increased uptake on a bone scan. Fortunately, in the vast majority of cases, a definitive diagnosis can often be made based on a clinical-pathological correlation. Image acquisition involves a computed gamma camera that records the emitted gamma rays and subsequently generates an image that is displayed and processed on an advanced workstation. Normal scintigraphic findings are described as a symmetric distribution of activity throughout the skeletal system in healthy adults.

Urinary bladder activity, faint renal activity, and minimal soft-tissue activity are also normally present.2 Areas of increased bone metabolism are scintigraphically demonstrated as areas of increased tracer uptake and are referred to as "hot spots". Decreased uptake, referred to as "cold spots" are associated with metabolically inactive bone, lack of osteogenesis, or an absent vascular supply.4 Bone-imaging techniques include standard bone scan (whole body scanning), three-phase bone scan, SPECT and SPECT/CT.1,4

The power of the bone scan as a diagnostic modality is most widely appreciated in oncology where it is employed in the detection of primary skeletal tumours and osseous metastases, but other applications include the assessment of bone grafts, acute infection, osteonecrosis of the jaw and condylar hyperplasia. These applications are discussed in more detail below. Malignant bone lesions most frequently present scintigraphically as one or more randomly distributed "hot spots". The presence of multiple, randomly distributed areas of increased uptake of varying shape, size and intensity are highly suggestive of bone metastases. While these "hot spots" are not specific, their location, intensity, and pattern of distribution are analysed to exclude other causes such as traumatic injury and osteoporosis. The success of osseointegrated dental implants is largely dependent on the quality and amount of bone available for osseous integration. Bone is often grafted to support implants or to replace parts of the jaw marred by periodontal disease, trauma, tumour infiltration, cystic lesions, or congenital defects. Three-phase positive bone scans have been shown to correlate with viable bone grafts thus enhancing prognostication and planning.5

In unviolated bone, a three-phase bone scan has high diagnostic accuracy for the detection of acute osteomyelitis and is often positive days or weeks before any changes may be appreciated on plain radiographs. However, in the setting of any underlying bone pathology, the sensitivity of the scan remains high, but the specificity becomes limited.4 In such cases, second-line infection imaging needs to be performed. In current clinical practice, this involves the use of radiolabelled autologous white blood cells (WBCs), the rationale being that the bio-distribution of activated white cells can be imaged due to their active accumulation at sites of infection or inflammation.

WBCs may be radiolabelled in vitro - white blood cells are isolated from a sample of the patients' blood and radiolabelled under aseptic conditions, or targeted in vivo with radiolabelled antibodies that bind to antigens expressed by activated neutrophils. The use of regular bone scans as routine investigations for disease progression makes the bone scan an attractive predictive imaging tool for osteone-crosis of the jaw which may be caused by infection, external beam irradiation (osteoradionecrosis), or medication-related (MRONJ).6

Osteoradionecrosis (ORN) is defined as irradiated bone that fails to heal over a period of 3 months without evidence of residual or recurrent tumour.7 The incidence of ORN is increasing in tandem with the rise in oropharyngeal cancers. The mean time for the development of ORN following irradiation ranges between 22 and 47 months.8 Biphosphonate induced osteonecrosis may remain asymptomatic for many weeks or months. Bisphosphonates are often used in conjunction with chemotherapy for the treatment of hypercalcaemia associated with malignancy, lytic bone metastasis, and multiple myeloma. Biphosphonates are also frequently prescribed for osteoporosis.

Bisphosphonates bind to osteoclasts in areas of active bone resorption to reduce osteoclastic recruitment; longevity and activity. During the early stages of MRONJ, areas of reduced uptake are consistent with the decreased vascularity of diseased bone.

As the disease progresses, bone scintigraphy can show areas of radionuclide uptake reflective of osteoblastic hyperactivity in a subchondral location.9 Scintigraphy is thus proposed as a screening tool by some authors to detect subclinical osteonecrosis in patients receiving bisphosphonates (see figure 1).9,10 Condylar hyperplasia (CH) is a rare bone disorder that is characterised by excessive growth of the condylar process of the mandible. It is typically a unilateral disorder (UCH), with resultant facial asymmetry, deformity, and malocclusion. It usually presents predominantly in female patients during adolescence. UCH is classified as a self-limiting condition and is characterised by a stationary and active phase. UCH is best managed during the stationary phase to prevent further deformity and unnecessary disruption of the TMJ. Functional imaging is uniquely able to differentiate between the two phases based on a qualitative and quantitative assessment of the uptake on the affected side, which will be asymmetrically higher during the active phase with a return to normal during the stationary phase.

 

Lymphoscintigraphy and Sentinel Node Mapping

Nodal involvement is one of the most important prognostic factors in head and neck cancer. Sentinel lymph node(s) (SLN) refer to the first lymph node(s), in a lymph node group, to receive lymphatic drainage and metastasis from a tumour.

Functional imaging in the form of lymphoscintigraphy utilising radiolabelled nano-particles can identify the SLN, both preoperatively through imaging, and intraoperatively by using a hand-held gamma probe. The aim of lympho-scintigraphy is to 'map' or identify the SLN for intraoperative frozen section and pathological evaluation. If the SLN biopsy is negative, the remaining nodes may not require routine resection which reduces operative and anaesthetic time, intra- and postoperative morbidity, and recovery times. 99mTc nanocolloid is injected around the tumour and will be carried by lymph to a regional lymph node group and subsequently retained in the SLN. Regional imaging following injection allows for the preoperative delineation of lymphatic pathways and the SLN. SPECT/CT is particularly useful in SLN mapping with the SPECT component providing the high sensitivity for SLN detection and the CT allowing for anatomical localisation of the lymph node (see figure 2).

 

PET

PET is principled on the use of positron-emitting radioisotopes. Following intravenous administration and subsequent in-vivo localisation of a radiopharmaceutical, the PET radioisotope undergoes radioactive decay and emits a positron. The positron travels a short distance from the point of decay and interacts with an electron in the orbit of an atom in its path.

The positron and electron undergo an 'annihilation reaction' and produce two gamma photons that travel in opposite directions, which are detected by a PET camera. PET imaging has several inherent advantageous over SPECT. Higher image resolution, sensitivity, and quantification is achieved with PET because of higher energy gamma photons, electronic (rather than physical collimation) and the use of hybrid PET/CT and PET/MR scanners which allow for attenuation correction. Hybrid scanners also improve specificity through accurate localisation of tracer accumulation, tissue characterisation, distinguishing physiologic from pathologic uptake, and verifying a suspicious finding on one modality by confirmation on the other. Commonly utilised PET radioisotopes include 11C, 13N, 15O, 18F, 64Cu, 124I, and 89Zr. These radioisotopes may be used to label more organic compounds (such as glucose, amino acids, neurotransmitters, DNA nucleosides, antibodies etc.), which permit non-invasive, whole body molecular imaging of tumour biology. Molecular imaging has ensconced itself as an essential tool in both the preclinical and clinical setting in oncology, cardiology, neurology, neuroscience and pharma-cology.However, the cost and availability of PET/CT remain a challenge, particularly in resource-constrained environments.

Most clinical applications of PET employ the use of flourineflourine18-labeled flouro-2-deoxyglucose (18F-FDG), a radiolabelled glucose analogue.11 The uptake of 18F-FDG is based on the 'the Warburg effect' - neoplastic cells do not obey normal homeostatic control mechanisms that regulate growth and metabolism, thus they consume large amounts of glucose to fuel their growth and hypermetabolism.12 18F-FDG PET/CT is now a key diagnostic tool in oncology, including in (H&N) head and neck cancer (see figure 3).

Initial staging: (see figure 4) As with any cancer, accurate initial staging plays a vital role in management and prognostication. While cross-sectional CT and MRI remain the primary imaging modalities for tumour (T) staging, 18F-FDG PET/CT plays an important role in nodal (N) and metastatic disease (M) evaluation, particularly in more advanced disease or tumours with a high metastatic risk (such as naso- or hypopharyn-geal tumours).13 Furthermore, PET/CT may be beneficial in the setting of metallic artefacts caused by dental restorative materials which may severely degrade the interpretability and diagnostic localisation of CT.14 The strength of PET/CT in N and M staging lies in its ability to detect disease in normal-sized organs (including lymph nodes), and routine whole body scanning with the capability of detecting clinically and/ or radiologically occult distant disease. Accurate N staging is especially important in oral cancer, as the presence of metastatic spread to regional lymph nodes correlates strongly with a poor overall prognosis, an increased risk of distant metastasis and a reduction in 5-year survival rates by approximately 50%.14,15

Detection of synchronous cancers:18F-FDG PET/CT is more accurate than than conventional imaging in the detection of second primary malignancies and should be considered in selected cases where conventional imaging is negative or equivocal.16,17

Detection of recurrence: It may be difficult to differentiate between post-treatment anatomical changes (such as fibrosis or necrosis) and residual and/or recurrent tumour on conventional imaging. 18F-FDG PET/CT imaging relies on a metabolic signal from viable tumour cells. It is therefore reported to be more accurate than anatomical imaging in this setting, especially if conventional modalities are equivocal.18,19

Radiotherapy planning: Imaging plays an increasingly important role in radiotherapy planning. There is a growing body of evidence that advocates for the use of 18F-FDG PET/ CT to more precisely define tumour volumes, especially in intensity-modulated radiotherapy, where accurate delineation of disease is critical.20-23 Metabolic data from the PET/CT facilitates the determination of a biological target volume. Modulated therapy can be applied in accordance with metabolic activity within the target volume.24

Therapy response evaluation: Accurate assessment of treatment response is essential in the management of patients with H&N cancer. Treatment-associated oedema, hyperaemia, scarring, and the loss of facial planes may make it difficult to differentiate between residual and/or recurrent disease and post-therapy changes on conventional CT or MRI.25 Conventional imaging relies on size as the most important criterion for response assessment. Limitations in using size include inaccurate response assessment in the setting of residual tumour necrosis and/or fibrosis. Conversely, metabolic response to therapy may be assessed using 18F-FDG PET/CT, where cellular viability is determined from a metabolic signal that is independent of size.

 

Table I

 

Prognostic value: A meta-analysis assessing the effectiveness of intra- and post-therapy FDG PET/CT in predicting long-term survival outcomes in patients treated for H&N squamous cell carcinoma found that interim and post-therapy PET/CT could accurately predict the risk of death or disease progression after two years and three to Ave years, respectively.26

Detection of recurrence / follow-up: (see figure 5) In patients with H&N squamous cell carcinoma, early and accurate post-therapy diagnosis of recurrence offers the best opportunities for salvage treatment and prognostic prediction. Due to its ability to detect local, regional nodal and distant recurrence, FDG PET/CT is a useful modality for follow-up in these patients.16'27,28 High cost and limited availability restrict the routine use of PET/CT in this setting, but the study should be considered in patients with a high clinical suspicion in whom conventional imaging is negative or equivocal.

Carcinoma of Unknown Primary (CUP): Despite extensive clinical examination, pan-endoscopy, CT and MRI, the primary tumour may not be detected in 5-10% of patients who present with cervical nodal squamous cell cancer metastases. PET/CT offers an additional 25% detection rate when compared to conventional workup.29 Lesion detection may be complicated in small volume disease in the primary tumour, normal biodistribution of FDG in the H&N and some tumours have inherently low FDG uptake.30

 

PET/MRI

Hybrid PET/MRI is now approved and commercially available, although current installations are limited due to the high cost and complicated installation. Early studies suggest that PET/MRI performs as well as PET/CT in the staging and restaging of H&N cancer and in radiation therapy planning. The MRI component has the advantages of high spatial resolution and soft tissue characterisation, which may assist in therapy planning, coupled with no ionising radiation, which reduces the radiation burden to the patient.31,32

 

CONCLUSION

Bone scintigraphy, lymphoscintigraphy, SPECT and PET are but a few of the physiological imaging modalities that serve the fundamental purposes of detection, characterisation, and potential staging of disease. Each modality plays a specific role in the diagnostic arena and is best appreciated as a diagnostic tool that is selected to best complement other clinical and laboratory findings. South African public health sector patients often present at initial consultation with advanced disease that is often complicated by infective conditions. Within this resource and financially constrained sector it becomes imperative that oral health care practitioners appreciate the value of appropriate advanced imaging to facilitate cost-effective and efficient treatment. Accurate interpretation of advanced imaging studies requires additional expertise to recognise both normal and abnormal processes in a somewhat larger field of view than in traditional dental imaging systems.33 In light of advancing diagnostic and treatment methodologies and the interdisciplinary management of patients, it is essential that the dental professional appreciates the applicability of nuclear medicine within his scope of practice.

 

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Correspondence:
Dr Sandeepa Rajbaran Singh
Telephone: (012) 521 4902
Email: sandeepa.singh@smu.ac.za

 

 

The role played and the respective contribution:
1 . Dr Sandeepa Rajbaran Singh: First author - contributed to the write-up and editing of the text and images: 50%
2 . Dr Aadil Abdulaziz Gutta: Second author - contributed to the write-up and editing of the text and images: 50%

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REVIEW
http://dx.doi.org/10.17159/2519-0105/2021/v76no10a8

 

Oral and Oropharyngeal HPV prevalence in South Africa. A systematic review and meta-analysis

 

 

NH WoodI; PD MotlobaII; LN MakwakwaIII; JP BogersIV

IDepartment of Periodontology and Oral Medicine, School of Oral Health Sciences, Sefako Makgatho Health Sciences University, Pretoria, South Africa, Neil.wood@smu.ac.za ORCID: 0000-0001-8950-7999
IIDepartment of Community Dentistry, School of Oral Health Sciences, Sefako Makgatho Health Sciences University, Pretoria, South Africa, Pagollang.Motloba@smu.ac.za ORCID: 0000-0003-1379-7576
IIIClinical Manager, Lecturer, School of Oral Health Sciences, Sefako Makgatho Health Sciences University, Pretoria, South Africa, Nokukhanya.Makwakwa@smu.ac.za
IVFaculty of Medicine and Health Sciences, Applied Molecular Biology Research Group (AMBIOR), Laboratory of Cell Biology and Histology, University of Antwerp, Belgium. jpbogers@ambior.org; ORCID: 0000-0001-9107-132X

Correspondence

 

 


ABSTRACT

BACKGROUND: Prevalence data for HPV infection in the head and neck in Southern African populations is lacking. In addition to cervical cancer, this sexually transmitted oncogenic virus is responsible for a subset of head and neck cancer and is transmitted via oral sexual routes, and through other forms of intimate contact between anatomical sites lined by mucosa. This systematic review and meta-analyses aimed to synthesize data for the prevalence of head and neck HPV infection in South Africa. Original research papers from South Africa reporting on the prevalence of HPV in the head and neck was systematically reviewed using PubMed, Ovid Medline, Embase and the Cochrane Library. A meta-analysis on the prevalence data was conducted for 16 papers that met the inclusion criteria.
MAIN TEXT: This systematic review and meta-analysis reports a pooled prevalence for head and neck HPV infection of 11%. The study shows both a shortage of, and a data lag for HPV prevalence studies in the head and neck of Southern African populations. Technological improvement over time, differences in data collection methodology, differences in laboratory analysis processes and differences in the selection of study populations including various population risk levels all influence the prevalence measurement outcome.
CONCLUSION: Prevalence reporting for head and neck HPV in South Africa is lagging with only a few reports in existence over a 25-year period. The overall pooled prevalence of 11% is slightly higher than global averages. Populations comprising higher risk groups exhibit higher HPV prevalence rates which is in part influenced by the existence of comorbidities in these groups. Methodologic and study design consistencies and standardization will improve prevalence reporting in this geographic region.

Key words: HPV prevalence, oropharynx, oral, HPV, human papillomavirus


 

 

INTRODUCTION

The Human papillomavirus (HPV) is classified as oncogenic to humans (group 1 infectious agent) and the oropharynx is an anatomic site associated with high-risk (HR)-HPV-induced epithelial transforma-tion.1 This is the most common sexually-transmitted pathogen that includes oro-genital and oral-oral transmission routes.2 The virus infects exposed basal keratinocytes of a micro-lacerated or abraded mucosal surface.3

Clinically productive HPV infection of the skin or mucosae result in benign or malignant lesions. The benign HPV-induced lesions are typically single exophytic proliferations often described as having a cobblestone-like surface or finger-like projections. These lesions are usually of a normal mucosal coloring unless traumatized or secondarily infected.3 There are also reports that describe HPV association with oral leukoplakic lesions that exhibit dysplastic change, with oral lichen planus and with erythropla-kia, although these may represent incidental findings. Associations with malignancies have been reported for cases of verrucous carcinomas.4-6 However, a subset of head-and-neck carcinomas driven by HPV infection as seen in younger, sexually active individuals is now well recognized.7-10

It appears that some HPV types exhibit stronger gender bias than others11-13, although this association may be artefactual or biased, as many HPV-prevalence studies focus purely on the cervix. In a study from the US, men had three times higher asymptomatic HPV infection than women.14 The reasons for this gender disparity remain unclear.9

High-risk HPV-types may be found in benign HPV-associated oral lesions and low-risk (LR)-HPV types may be identified in malignant HPV-associated lesions like oropharyngeal SCC (OPSCC).15 Some view the presence of HPV in the mouth as beig an oral HPV carrier, or as a passenger infection16-18; and these individuals are probable transmitters of the virus19 through oral sex practices and through open mouth kissing among others.2

The prevalence of HPV in the mouth and oropharynx has been studied globally, but there is an apparent lack of substantial data from sub-Saharan Africa, and specifically, South Africa. A 2012 systematic review and meta-analysis that reported findings on malignancies resultant from infectious agents also found a significant lack of prevalence studies from developed areas.20 Only 3 South African studies were included in a 2018 systematic review9, and the Human papillomavirus and related diseases report cited only two South African studies, both dealing with oral/oropharyngeal squamous cell carcinoma.21

Given the epidemiologic shift in HR-HPV infection of the head and neck and its closer association with OPSCC9, it becomes even more urgent to estimate the burden of HPV infection of South Africans in terms of incidence and persistence. The systematic synthesis of these epidemiologic data would improve our understanding of the diseases and of its natural course in this geographic setting.

 

METHODOLOGY

Search strategy

The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) was adopted in conducting this meta-analysis. The CoCoPop (Condition, Context and Population) framework was adopted to generate the following keywords -Condition - Oral HPV, oropharyngeal HPV; Context - South Africa, English language; Population - Human subjects. Two authors (NHW and LNM) performed searches of PubMed, EBSCOhost, MEDLINE and Embase. For additional articles, grey literature, conference proceedings and reference lists from previously published research were reviewed. To augment the search, MeSH and Emtree subject headings were used individually and in combination.

Study selection

Studies were included if they satisfied the following criteria: (i) human subjects, (ii) described the incidence, prevalence of oral or oropharyngeal HPV (ii) South African population. The following studies were excluded (i) systematic reviews, (ii) meta-analyses, (iii) case control studies, (iv) case studies, (v) studies of nonhuman subjects.

Quality Assessment

The study quality was assessed using the Critical Appraisal Checklist for Studies Reporting Prevalence Data published by the JBI. The tool scores the studies on a total score of 9 points, with higher scores indicative of better design and quality. Two researchers (NHW and LNM) blindly performed assessed the studies and assigned a rating of "poor" (<3), "fair" (4-7), or "good" (>8) to each study. Only studies achieving a rating of good by both reviewers were included in the analysis. Any disagreement was resolved through discussion between the researchers, or by third reviewer (DPM).

Data Extraction

A form specially developed for this study was used by two independent authors to extract information. The variables of interest included: authors and date of publication; characteristics of the study population (gender, age, sexual orientation); site of sample collection (oral cavity, oropharynx), method of sample collection (oral brush, rinse and gargle, and tissues blocks), prevalence of HPV (crude prevalence and population size).

Data analysis

The measure of effect size (Prevalence of HPV) was computed using the Metaprop command for the meta-analysis of proportions in Stata®. Metaprop is appropriate for proportions, which range from 0 or 100% and guarantees that CIs remain within the 0 to 1 range. This stability is achieved by using the binomial distribution to model within-study variability. In this study, the effect size was calculated together with the corresponding 95% CI using the Wald method executed with the cimethod (score) command. Forest plot was generated to show the individual and pooled effects size, 95% CI, the author's name, publication year and study weights (both for primary studies and this systematic review/meta-analysis), based on subgroups. The random effects model was used to compute the overall estimate of prevalence and the 95% confidence interval. The Cochran's I2 index was calculated to measure heterogeneity among studies, with p < 0.05 indicative of heterogeneity. The I2 values of <25%, between (25% and 50%), and of >50% reflected, mild, moderate and high heterogeneity respectively.

Subgroup analysis was performed to assess sources of heterogeneity among the studies. Variables included in the subgroup analysis included publication date, site and method of sample collection. Additional sensitivity analysis was done using the "leave-one-out" approach to evaluate the robustness of the pooled results. By removing one study at a time, the weighted or disproportional influence of a single study on the overall prevalence was evaluated. Publication bias was checked by visual inspection of funnel plots of prevalence and precision and statistical tests.

 

RESULTS

A total of 239 records were obtained from a comprehensive literature search. After the screening of 70 abstracts and titles, 20 full texts were reviewed, of which 16 satisfied the inclusion and exclusion criteria and were included in the analysis (Figure 1). The 16 studies were published between 1995 and 2020 with the total sample size of 2478 and 230 confirmed cases of HPV (Table 1). Larger heterogeneity was anticipated for the small South African data pool.

 

Figure 2

 

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