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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 32  |  Issue : 4  |  Page : 323-329

Therapeutic effect of proton pump inhibitor (Omeprazole) on homogenous leukoplakia with clinico-fractal analysis: A pilot study


Department of Oral Medicine and Radiology, Tamil Nadu Government Dental College and Hospital, Chennai, Tamil Nadu, India

Date of Submission27-Jul-2020
Date of Decision14-Oct-2020
Date of Acceptance19-Oct-2020
Date of Web Publication28-Dec-2020

Correspondence Address:
Dr. Nivethitha Nagarajan
Department of Oral Medicine and Radiology, Tamil Nadu Government Dental College and Hospital, Chennai - 600 003, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaomr.jiaomr_160_20

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   Abstract 


Background: Oral leukoplakia is a white patch or plaque that cannot be characterized clinically or pathologically as any other disease and is not associated with any physical or chemical causative agent except the use of tobacco. The prevalence of leukoplakia in India varies from 0.2% to 4.9% with variable clinical pattern and tendency towards malignant transformation. Current treatment strategies for oral leukoplakia include chemotherapeutic and surgical approaches. Aim and Objective: The study was done to compare the clinical and therapeutic effects of proton pump inhibitor therapy and vitamin-A therapy in oral leukoplakia. Setting and Design: Hospital based in-vivo prospective study. Materials and Method: The study compared two treatment groups; Proton pump inhibitor therapy-(Omeprazole - 20 mg) and vitamin-A therapy (200000 I.U.). The clinical assessment (size and surface texture), salivary pH and fractal dimension values were compared in pre-treatment and post-treatment periods. Statistical Analysis: SPSS® 25.0 (Statistical Package for the Social Sciences) was used for statistical analysis. Mean, standard deviation and independent t test were calculated. Results: The clinical assessment of pre-treatment and post-treatment revealed reduction in size and surface roughness in both the groups. The salivary pH and fractal dimension showed significant alterations in post treatment period of both groups but the P value (0.949) was not significant between the groups. Conclusion: This study demonstrated the efficacy of proton pump inhibitor therapy for oral leukoplakia in comparison with vitamin-A therapy. The study revealed reduction in the size, roughness of oral leukoplakia and alteration of salivary pH with proton pump inhibitor therapy.

Keywords: Fractal, leukoplakia, omeprazole, vitamin-A


How to cite this article:
Nagarajan N, Jayachandran S. Therapeutic effect of proton pump inhibitor (Omeprazole) on homogenous leukoplakia with clinico-fractal analysis: A pilot study. J Indian Acad Oral Med Radiol 2020;32:323-9

How to cite this URL:
Nagarajan N, Jayachandran S. Therapeutic effect of proton pump inhibitor (Omeprazole) on homogenous leukoplakia with clinico-fractal analysis: A pilot study. J Indian Acad Oral Med Radiol [serial online] 2020 [cited 2021 Jan 27];32:323-9. Available from: https://www.jiaomr.in/text.asp?2020/32/4/323/305270




   Introduction Top


Leukoplakia is derived from two Greek words: Leucos means white and Plakia means patch. The name was first coined in 1877 by a Hungarian dermatologist, Schwimmer.[1] In 1978 the oral leukoplakia was defined by World Health Organization (WHO) as “a white patch or plaque that cannot be characterized clinically or pathologically as any other disease.”[2],[3] Etiologically, leukoplakia is due to tobacco usage and may regress if tobacco habits are discontinued.[3],[4] The prevalence of oral leukoplakia in south Asian population is 4.11%[5] with a malignant transformation rate of 0.06 to 0.3%.[6],[7],[8] It predominantly occurs in middle aged adults with a strong male predominance. Tobacco cessation, topical therapy, surgical excision, cryosurgery and laser surgery are the current treatment modalities for oral leukoplakia. It has a variable clinical pattern with tendency towards malignant transformation and is classified under potentially malignant lesion.[4],[6] Hence early diagnosis and prompt treatment is necessary to eliminate the potential risk of malignancy. This study developed a new modality of treatment for oral leukoplakia and was undertaken to evaluate the clinical effectiveness of proton pump inhibitor therapy on oral leukoplakia.


   Materials and Method Top


The study was carried out in the department of Oral Medicine and Radiology, Tamil Nadu Government Dental College and Hospital. The study was approved by the Institutional Review Board (IRB), Tamil Nadu Government Dental College and Hospital (Institutional review board reference No: 4/IRB/2019 dated 22/08/2019) and followed all the recommendations of Helsinki Declaration (2013). This study was conducted over a period of six months from August 2019 to January 2020. It was an in-vivo prospective study conducted in a tertiary care centre and the prevalence/reported cases of the homogenous leukoplakia(without any dysplasia) was taken into consideration during the sample size calculation and n=10 was chosen as a pilot study.

The clinical diagnostic criteria for oral leukoplakia by World Health Organization (WHO) 1997 – “A predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion” and World Health Organization (WHO) 1980 – “Homogenous leukoplakia - Lesion that was uniformly white and unscrapable; Non-homogenous leukoplakia - Lesion predominantly white and speckled with red” was followed.[1] Pre treatment diagnostic LSCP criteria assessment was done for the clinical and histopathological staging of the disease. The LSCP criterion includes the examination lesion size (L) lesion site (S), clinical aspect (C) and histopathology (P). The lesion size was designated from L0 to L3, the lesion site was designated as S1 or S2, the clinical aspect was designated as C1 or C2 and the histopathological features from P1 to P4. The staging is concluded from the above four criteria and included into any of the four stages (Stage I, II, III and IV).[9]

Clinically and histopathologically proven new cases of oral leukoplakia at any intra oral site in patients aged between 20 to 60 years with history of tobacco usage and who were willing to participate in the study, were included for the study. Patients with history of any other systemic medications were excluded from the study to eliminate systemic interaction of the drugs. Histopathological dysplastic changes, verrucous leukoplakia, speckled leukoplakia and nodular leukoplakia types were excluded from the study. Patients with a history of systemic diseases/disorders and patients not willing to participate were not included in the study. Patients with other oral potentially malignant disorders, oral cancer and other white lesions (Eg: Candidiasis, Lichen planus) were excluded from the study. Patients with lesions adjacent to sharp teeth were not included in the study to decrease confounding bias as an etiological factor and to eliminate further risk of malignant transformation. Previously treated cases of oral leukoplakia or any other potentially malignant disorders were excluded from the study [Figure 1].
Figure 1: CONSORT flow diagram

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   Methodology Top


Patients attending the Oral Medicine clinic at Tamil Nadu Government Dental College and Hospital, satisfying the inclusion criteria/diagnostic criteria were thoroughly examined and a total of ten patients were recruited for the study. The history and clinical findings were documented in the study proforma. The treatment plan was explained elaborately and informed consent/photography consent were obtained individually from each patient. Tobacco cessation counselling and oral hygiene measures were performed. The patients were kept under observation for 2 weeks to notice any changes or reversal of lesions and to decrease the confounding bias caused due to tobacco cessation. The patients with no response were provisionally diagnosed with oral leukoplakia. Incisional biopsy was performed following the clinical diagnosis to eliminate dysplastic changes, to eliminate other specific disorders and for pre-treatment LSCP staging.

Pre-treatment LSCP staging was done; the clinically and histopathologically proven cases of oral leukoplakia (n = 10) were randomly allocated into two groups. Group-A (n = 5) received proton pump inhibitor therapy. The patients were given a proton pump inhibitor: Capsule Omeprazole of 20 mg, twice daily (morning and night) half an hour before food for 4 weeks. Group B (n = 5) received vitamin A therapy. The patients were given capsule vitamin A 200000 International Units (I.U.) once a week for 4 weeks.

Pre-treatment photograph [Figure 2]a was made using a digital camera (Canon- EOS 1300D, Lens MACRO 0.25m/0.8ft, EFS 18-15 mm, Program AE-White Balance mode, ISO 800). Patients were motivated to take the drug and therapy for both the groups was continued for a period of 4 weeks. The patients were advised with a normal diet and monitored regularly for 4 weeks. The post treatment photograph was taken after the treatment period using the same photographic specifications [Figure 2]b.
Figure 2: The figure reveals pretreatment photograph (a) and post treatment follow up photograph (b) after 4 weeks of proton pump inhibitor therapy

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The assessment of the leukoplakia treatment included: Clinical assessment, salivary pH and fractal analysis. The clinical assessment included size and surface texture. The salivary pH (Hydrogen ion concentration) was measured using a digital pH meter for both the groups; group A (n = 5) and group B (n = 5). Saliva was collected for the estimation of salivary pH as per the “Common Minimal Technical Standards and Protocols” by the World Health Organization/International Agency for Research on Cancer guideline.[10] The saliva was collected in the morning between 10.00-11.00 am after an overnight fasting. The patients were refrained from drinking or eating one hour before the sample collection. Prior to the sample collection the patients were given drinking water (bottled) and asked to rinse their mouth out well (without drinking water). Five minutes after the rinse, the patients were asked to spit whole saliva by dropping down the head and allowing the saliva run naturally to the front of the mouth. The pH of the saliva was immediately measured in order to prevent any deterioration of the sample.[10] Three values were measured with the same sample and the mean was obtained to eliminate observer and instrument error. The pH value was assessed by the end of first, second, third and fourth weeks.

The clinical photographs of the lesion were taken during the first day of the first week of therapy (pre-treatment photograph) and last day of the fourth week of the therapy (post- treatment photograph) for the fractal analysis.[11],[12] The photographs were taken using a digital camera with same pixels (86*124) and were analyzed by the ImageJ software [1.46r (National Institute of Health, USA – Java 1.6.0_20, 32-bit)] using a computer with configuration including Windows 7 operating system, Intel Core i3-380M. The images were converted to 8-bit type [Figure 3]a, [Figure 3]i and blurred by Gaussian filters [Figure 3]b, [Figure 3]j with a diameter of 35 pixels. This step removed all the fine-scale and medium-scale structures and retained only larger variations in density. The resulting image was blur type and was subtracted from the original image [Figure 3]c, [Figure 3]k. A 128 value was added to the image at pixel location [Figure 3]d, [Figure 3]l which generated an image of value 128 regardless of the initial image intensity. The image was transformed to binary [Figure 3]e, [Figure 3]m and the resultant image was eroded to reduce noise [Figure 3]f, [Figure 3]n. The image was dilated and skeletonised [Figure 3]g, [Figure 3]o. The fractal dimension (FD) of all the skeletonised images were calculated using a fractal box count method which included box values (C2, C3, C4, C6, C8, C12, C16, C32 and C64). A graph was obtained between box count and box size in log values which showed the fractal dimension value [Figure 3]h, [Figure 3]p. The pre and the post treatment values were obtained and compared.
Figure 3: The images were converted to 8-bit type (a, i) and blurred by Gaussian filter (b, j). The resulting image was subtracted (c, k). 128 value was added to the image (d, l) at pixel location. The image was transformed to binary (e, m) and the resultant image was eroded to reduce noise (f, n). The image was dilated and skeletonised (g, o). The fractal dimension (FD) of all the skeletonised images was calculated using fractal box count method. A graph was obtained between box count and box size in log values which showed the fractal dimension value (h, p)

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The measurements were analyzed using SPSS® 25.0 (Statistical Package for the Social Sciences) was used for statistical analysis. Descriptive analysis was calculated as mean and standard deviation. Independent t test was used to compare the values of pH and statistical significance was measured. The t-value, mean difference, standard error of difference, 95% confidence interval of the difference and P value were calculated. The level of significance was set at 5% for all the tests.


   Results Top


Ten patients were recruited for the study in which all were male. The mean age of the patients at the time of diagnosis was 43.1 (range 36–52). All the patients in the study were smokers and two patients consumed alcohol. The pretreatment LSCP staging for all the patients was stage – I as the only homogenous type with no dysplasia was included. The common site of occurrence of oral leukoplakia in the study: buccal mucosa (60%), commissure of lip (20%) and vestibular region (20%).

The clinical comparison (size and roughness) of pre-treatment and post-treatment therapies revealed a reduction in the size and surface roughness of three patients in group-A [Table 1]. The mean pH of the group-A during week 1, week 2, week 3 and week 4 was 6.66, 6.72, 6.9 and 6.96 respectively. Four patients in group-A showed significant reduction in the FD values during post treatment.
Table 1: Pre-treatment and post-treatment comparison of size, roughness, pH and fractal dimension in group A and group B

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The clinical comparison (size and roughness) of pre-treatment and post-treatment therapies revealed a reduction in the size and surface roughness of two patients in group-B [Table 1]. The mean pH of the group-B during week 1, week 2, week 3 and week 4 was 6.64, 6.68, 6.76 and 6.76 respectively. Four patients in group-B showed reduction in the FD values during post treatment.

The mean pH of group A revealed an alteration from 6.6 to 6.9 by the end of the therapy while the group B revealed an alteration from 6.6 to 6.7. The standard deviation values of the group-A were lower in all four weeks than the group-B suggestive of high variation of pH values in group-B [Figure 4]. The pH values in individual patients showed significant alterations towards the neutral zone during the fourth week in group-A.
Figure 4: Comparison of mean values of pH between group-A and group-B

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The FD values were compared between the groups pre and post treatment. The comparison of the pre-treatment and post-treatment fractal dimension values suggested a decrease in complexity/keratinisation of the lesion following treatment in both the groups. The independent sample t test was used and the t values were 0.877 (pre treatment) and -0.066 (post treatment). The P value was found to be 0.406 (pre treatment) and 0.949 (post treatment) which was not significant between the groups [Table 2].
Table 2: Comparison of Fractal Dimension between the groups before and after treatment using independent t test

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   Discussion Top


Oral leukoplakia was described as “a white patch or plaque that cannot be characterized clinically or pathologically as any other disease and is not associated with any physical or chemical causative agent except the use of tobacco” by the first international conference (1984) Malmo, Sweden.[13] The annual incidence rate attributable to leukoplakia was between 6.2 and 29.1 cases per 100,000 people worldwide and 2.1 per 1,000 among men/1.3 per 1000 among women in India.[4],[14] The worldwide prevalence was high in the age-group of 51–60 years and sex distribution showed a male: female ratio of 3.2:1.[15] Smoking tobacco, smokeless tobacco, alcohol, fungal infection (Candida albicans), viral infections, chronic trauma and vitamin deficiencies are the major attributable etiological factors.[3]

Toluidine blue staining, Lugol”s iodine staining, Vizilite, 5-Aminolevulinic acid mediated fluorescence endoscopic imaging, 5-Aminolevulinic acid mediated digitized fluorescence endoscopic imaging, autofluorescence spectroscopy, exfoliative cytology, and biopsy are the diagnostic modalities for oral leukoplakia.[1] Management and treatment of leukoplakia remain challenging especially for large lesions and verrucous lesions. Current strategies for oral leukoplakia include a “watch-and- see” approach, medical treatment and surgical approach.[16] Beta carotene, lycopene, vitamin C, aminolevulinic acid, phytoene, 13-cis retinoic acid, fenretinide, podophyllin, bleomycin, celecoxib, erlotinib, selenium and recombinant human adenovirus p53 are few chemotherapeutic agents used for the treatment of leukoplakia. Vitamin A is a common chemotherapeutic approach used for the treatment of leukoplakia due to its keratolytic and antioxidant properties. They induce apoptosis which lead to normal maturation of dividing cells, maintain differentiation of many tissues, and suppress carcinogenesis.[17]

The oral mucosa is thin and susceptible to various irritants like the laryngeal mucosa and hence the oral leukoplakia has correlating mechanisms with laryngeal leukoplakia. The proton pump inhibitor has been used in the treatment of laryngeal leukoplakia and proven to improve laryngeal mucosal damage.[18] The Proton pump inhibitor aids in irreversible blockage of the hydrogen/potassium adenosine tri phosphatase enzyme system (H+/K + ATPase) of the gastric parietal cells and inhibits acid secretion. Proton pump inhibitors have the ability to chemosensitize different cells through a normalization of extracellular pH hydrogen ion concentration.

In this study, five patients with oral leukoplakia were under omeprazole therapy for 4 weeks. Three patients of group-A showed decrease in the lesion size of oral leukoplakia. Three patients showed significant changes in pH towards the neutral zone at the end of fourth week of therapy. Four patients had decreased in the fractal dimension during the end of the therapy which revealed a decrease in the complexity/keratinisation of oral leukoplakia. The P value was statistically insignificant between the groups due to smaller sample size.

Many tumor cells secrete lysosomal enzymes that participate in the degradation of the extracellular matrix required for metastatic invasion.[19] These enzymes have a low optimal pH and it is V-ATPases that are responsible for acidifying the microenvironment. Several human tumor cells are characterized by increased V-ATPase expression and activity, and pre treatment with proton pump inhibitors (PPIs) has been found to sensitize tumor cell lines to the effect of different chemotherapy drugs.[20] There is evidence that points out the role of V-ATPase in tumor invasion and multidrug resistance in breast cancer, oral squamous cell carcinoma, esophageal carcinoma, hepatocellular and pancreatic carcinoma, lung carcinoma, sarcoma and solid tumors.[21]

One of the major hurdles in chemoprevention clinical trials has been the toxicity associated with medical interventions. Because only one third of all oral leukoplakia undergo malignant transformation, it is essential that the interventions should be less toxic.[22] Omeprazole is a common proton pump inhibitor which is safe and well tolerated by oral and laryngeal mucosal regions. In an earlier study, proton pump inhibitor therapy (Omeprazole) was used to treat the vocal cord lesions.[23] In another study a patient with vocal cord leukoplakia was treated with proton pump inhibitor therapy for two years and showed complete response with no recurrence.[24] A study included 178 patients with vocal cord leukoplakia who were treated with proton pump inhibitor therapy (20 mg omeprazole twice daily) alongside chinese medication for 6 weeks in which 127 patients showed complete/partial responses.[25] One study was performed with 24 patients of vocal cord leukoplakia who were treated with rabeprazole and 79.2% of patients had complete or partial responses after 6 months.[18]

In the present study, we report that proton pump therapy (Omeprazole 20 mg, twice daily) can be a clinically effective in treating oral leukoplakia and previous studies revealed that the proton pump inhibitor may be used efficiently as a chemopreventive agent for oral squamous cell carcinoma. Hence this therapy can decrease the malignant potentiality and development of dysplasia from oral leukoplakia. The dosage and duration of the drug used for this study was within standard range and no adverse drug reactions were noticed in patients throughout the study.

Limitations and Future Prospects

The limitations of this study are smaller sample size and short follow-up period. The study included only lesions without dysplasia as proton pump inhibitor therapy is a newer treatment modality for oral leukoplakia and the effects of the drug on epithelial dysplasia is still under research. Different drug dosages, delivery methods and duration of the drug schedules have to be improvised by further research for efficient treatment. Hence longer follow up period, increased sample size, different types of leukoplakia and post treatment biopsy is required for significant results and further research.


   Conclusion Top


Leukoplakia is a potentially malignant disorder of the oral cavity. The treatment options vary from non invasive to invasive modalities but there is no standardised treatment modality or algorithm for oral leukoplakia and there is no definitive clinical or microscopic method to identify the malignant potential. Hence early non-invasive intervention is mandatory for elimination of the risk of malignant transformation. This study demonstrated the efficacy of proton pump inhibitor therapy for oral leukoplakia in comparison with vitamin-A therapy. The study revealed reduction in the size, roughness of oral leukoplakia and alteration of salivary pH with proton pump inhibitor therapy. Proton pump inhibitor therapy may aid in early intervention of oral leukoplakia in a non invasive way. This modality of treatment is new for oral leukoplakia and the study evaluated proton pump inhibitor therapy and observed good treatment results. Larger sample size with longer follow up and further research is needed to support this evidence.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
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