Oral submucous fibrosis: a study of qualitative and analytical treatment using intralesional injections: placental extract versus combination of steroid with hyaluronidase

INTRODUCTION

Diseases in a human body are mainly due to changes in life style and habits. Oral submucous fibrosis (OSMF) is a chronic debilitating disease caused due to the habit of chewing arecanut, chillies, misri and tobacco in many forms resulting in marked rigidity and progressive decrease in mouth opening.¹

WHO in 1978 defined OSMF as a slowly progressive multifactorial disease in which multiple fibrotic bands are formed in oral mucosa ultimately leading to restriction of mouth opening and tongue movements, it mainly affects palate, cheek and facial pillars. The etiological role of chewing arecanut and its association with malignancy in OSMF has been noticed.^2,3 The factors are as follows.

Prolonged local irritation

Tobacco and its chemical constituents are irritants while nicotine had a synergistic effect with arecoline and both of them inhibits collagen phagocytosis and decreases the overall breakdown of collagen.^4,5 This results in increased fibrosis due to increased collagen synthesis.¹ OSMF remains active even after cessation of the chewing habit, suggesting that components of the arecanut initiate OSMF and then affect gene expression in the fibroblasts, which then produce greater amounts of normal collagen.⁶ Arecanuts have shown to have a high copper which stimulates fibrogenesis through up-regulation of copper dependent lysyl oxidase activity.^7,8

Genetic and immunologic process

This may be due to exogenous antigenic stimulation which increases frequency of HLA factors production and thus reduces antifibrotic activity leading to alteration of tissue architecture and may be the cause of OSMF.^6,9

Nutritional deficiencies

Deficiencies of iron, vitamin B complex, micro elements and antioxidants can precipitate fibrotic activity and affect the integrity of the oral mucosa.^10,11

Clinical features

The clinical stage depends on features of the disease as per the progression of lesion is proposed is by More et al in 2012.^12,13

Stage 1

Stomatitis and vesiculation, erythematous mucosa, ulcers, melanotic mucosal pigmentation and mucosal petechiae. Burning sensation in mouth for spicy food.

Stage 2

Ruptured vesicles and ulcers healed by fibrosis. Circular and vertical fibrous bands appear around lips, oropharyngeal mucosa (Figure 1). Buccal mucosa (98%) is most common site.¹⁴

Specific findings include trimus, stiff and small tongue, fibrotic and depigmented gingiva, rubbery soft palate, decreased salivation, atrophic tonsil, shrunken bud like uvula. The fibrosis involves pyriform fossa but larynx is free hence respiration is not affected.

Stage 3

Sequelae and complication of speech, dysphagia and hearing defects due to fibrosis of tongue, esophagus and eustachian tube openings respectively.

Stage 4

Any of the above stage along with other potentially malignant lesions seen in India like leukoplakia, erythroplakia, squamous cell carcinoma (SCC) 7.6% incidence is found with OSMF.¹³ As per one study the traumatized mucosa in addicted person may concentrate more carcinogen and more susceptible to SCC.¹⁵

Treatment

The etiopathology and curative solution is not clear even now to the present medical science.¹⁶ Management of OSMF depends on the degree and stage of disease. In very early cases cessation of chewing habit was sufficient.¹⁷ In mild to moderate cases medical management may be sufficient.

Medical treatment

Along with multivitamins, antioxidant tablets and intralesional injections like combination of steroids with hyaluronidase or placental extracts and IFN-γ etc.

Steroids

Anti-inflammatory and immunosuppressant properties helps to prevent mucosal damage in early and moderate cases. Commonly used ones are dexamethasone, triamcinolone acetonide and betamethasone. Triamcinolone is more preferred as intralesional therapy.¹⁸

Contraindication

Hypersensitivity, active bacterial and fungal infection.

Side effects

Risks of infections, adrenal insufficiency, hyperglycemia, osteonecrosis, myopathy, peptic ulcer, hypokalemia, psychosis etc.

Adult doses

Dexamethasone 4 mg i.v., triamcinolone 40-80mg intralesional.

Hyaluronidase

It stimulates hydrolysis of hyaluronic acid, one of the chief ingredients of tissue cement. Distensibility of the mucosa reported with injection hyaluronidase.

Contraindication

Hypersensitivity, safety in pregnancy not established. Avoid injecting to inflamed and cancerous areas.

Steroids along with hyaluronidase gives synergistic effect and also shows better long-term results in combination of steroids with hyaluronidase.^19,20

Placental extracts

It has a proposed anti-inflammatory action and thus prevents mucosal damage. Intralesional injection of aqueous extract of human placental extracts (PE) showed marked improvement of the condition as it has biogenic stimulator action and it stimulates metabolism, increases the vascularity, promotes regeneration and recovery of the tissue.^21,22

In severe cases, surgical excision of fibrotic bands with coronoidectomy and bilateral temporalis myotomy and split thickness skin grafting along with continuous post-op physiotherapy has proven successful outcomes.⁵

Physiotherapy

Regular jaw muscle stretching exercises with Heinster mouth gag is helpful to prevent further limitation of mouth opening especially after intralesional treatment or surgery.²³

Follow up and further care: every patient should have a regular visit for early detection of dysplasia or carcinoma. Biopsy should be done from doubtful lesions of fibrosis with leukoplakia.²⁴

Government has started public health awareness campaign and de-addiction affliated centre for awareness and knowledge of disadvantage of tobacco chewing habits and its association with malignancy. Its preventive and curative management for early cases and education regarding orodental hyegine and abstinence from various addictions.¹ All precaution needs to be taken for avoiding morbid conditions.

Aim of the study was to present the comparative therapeutic effect of placental extract vs the combination triamcinolone and hyaluronidase and also, to assess its efficacy in improvement of mouth opening, burning sensation of mouth in OSMF.

METHODS

We have done comparative study of 60 cases which was conducted in patients attending ENT OPD of tertiary care hospital from September 2015 to May 2019 by randomized clinical trial.

Inclusion criteria

60 cases who were clinically diagnosed as OSMF with age between 17-55 years were included. Interpretation was done with respect to measurement of inter incisor distance by measuring scale for the mouth opening and subjective grading of burning sensation in oral cavity before and after the course of intralesional agents.

Exclusion criteria

Patients who were having leukoplakia, erythroplakia, oral candidiasis and other causes of trismus like malignancy were excluded.

This study assessed the effectiveness of the given intralesional agents. After the clinical examination and provisional diagnosis, we had categorized the patients into two groups for treatment viz group A and B.

Group A

Consisted of first 30 patients who received combined injection triamcinolone 40 mg reconstituted with injection hyaluronidase (1500 IU).

Group B

Included other set of 30 patients who received 2 ml injection placental extract alone.

By using 2 ml syringe with a 26 G no needle injections were given intralesionally till blanching occurred. The same dose was repeated every 7^th day and a total of six doses were given. At the same time all patients received oral antioxidants twice daily for three months along with jaw stretching exercises every day.

We have measured the mouth opening of upper and lower central inter incisor distance pre and post therapy and tabulated their results. The inter incisor distance of mouth opening is categorized into: stage I (>3 cm), stage II (2-3 cm) and stage III (<2 cm).

The improvement in food intake was also recorded by subjective measurement scale which was defined as >75% = good, 50-75% = moderate and <50% = poor.

Patients were reviewed after 3 months of subsequent follow-up for the same parameters with the ancillary treatment modalities remaining the same.

Microsoft office 2007 was used to make tables and graphs. Descriptive statistical analysis like percentages, mean was used to interpret the data and conclude the results.

RESULTS

The 30 patients of each groups, after sixth course of intralesional injection were followed regularly once in a month till three months. The findings with improvements and side effects were noted by direct patient interview and observation.

Group A

Patients who received combination of triamcinolone with hyaluronidase injection

The 30 patients were treated with a combination of intralesional injections of triamcinolone 40 mg with hyaluronidase 1500 IU given in each sitting once a week for 6 weeks (Figure 2).

Improvement in mouth opening varied from 0.6-1.4 cm with an average of 1cm with good subjective improvement for burning sensation for hot and spicy food. Twenty-one patients showed more than 75% improvement and seven patients between 50-75%.

Among these thirty patients there were no side effects except for two patients (23 years and 40 years old female) who had complaints of slight facial puffiness after sixth dose which later subsided spontaneously.

Group B

Patients who received placental extract injection

For the other 30 patients; intralesional injection of one vial of 2 ml of placental extract in each sitting once a week for 6 weeks, the improvement in mouth opening varied from 0.4 to 1.0 cm with an average of 0.7 cm and also with good subjective improvement for burning sensation (Table 1). Fourteen patients showed more than 75% improvement and eleven patients between 50-75% improvement. In general, the results were tabulated as follows.

Age groups

The study groups patients vary from 17-55 years, with majority, 55% belongings to 17-30 age groups and 31.66% were of 31-45 age groups and 13.33% were of more than 45 year of age.

Sex

In these sixty patients; 43 were males and 17 were females. i.e. (71.66% and 28.33% respectively) were affected by OSMF. Some studies having conflicting result may be due to the in-chewing habits and oral hygiene among gender.

Major symptoms distribution, out of sixty patients, forty 66.67% had burning sensation and decreased mouth opening since, 1-3 years duration. Seventeen (28.33%) patients had complaints of more than 3 years. But three (5%) patients had history of less than 1 year.

Some of the patients were habituated to multiple chewing products. Almost all patients had exposure to these chewing habits for more than two years with an average of 4-5 times a day but out of these sixty only four patients had surprisingly history of chewing habits of less than one year.

DISCUSSION

Nowadays worldwide commercially available prepacked betelnut preparation can give rise to a greater number of cases than individually prepared tobacco. These commercial preparations are cheap, easily available in every nook and corner of India with no age restriction for its sale. Hence in our study the most common age group of presentation is 17-30 years 55%, compared to Pindborg et al 75% to be of 30-60 years while Aziz et al were 45-54 years as major age groups.^13,25

Out of the sixty patients 71.66% were males and 28.33% were females that is 2.53:1 ratio noted in this study, compared to Pindborg (1:1), Aziz (1:2.3).^13,25 Males were more predominantly affected than females and found in all socioeconomic strata may be due to outdoor stress with excessive chewing habits and longtime keeping intraoral quid at work.²⁶

It is noted in this study that many patients had long standing chewing habit with more with frequency more than 5-6 times per day developed OSMF earlier than four patients who had an exposure less than one year.

In our study, addiction of tobacco chewer 56.6% (34 patients), betelnut and its commercial prepacked preparation users 45% (27 patients), guthka 30% (18 patients) were users and 13.33% were (8 patients) MISRI users. There was no patient without any chewing habits. Due to its carcinogenic effect, it has chances of developing OSMF.

Both the groups were treated with oral antioxidants and physiotherapy simultaneously along with intralesional injections.

For the first group A thirty patients with combined injection of triamcinolone 40 mg with hyaluronidase 1500IU intralesionally like Shah et al study, we had improvement in mouth opening with an average of 1cm and with good subjective improvement for burning sensation for hot and spicy foods.²¹ Twenty-one patients showed more than 75% improvement for burning sensation with nearly similar effects in study of James et al.¹⁹ Only two female patients had facial puffiness after sixth dose of injection, which was subsided spontaneously in contrast with the study of Singh et al, in which no significant side effects were noted while study by Goswami et al noted post-injection pain reduced with analgesics.^27,28

The group B another thirty patients was given intralesional 2ml placental extract every 7^th day for six weeks. Gupta and others study came up with nearly same results as our study.^16,21,22 The improvement seen in our study in mouth opening after six courses of intralesional PE injection with an average of 0.7cm and also with good improvement in burning sensation for hot and spicy foods. Fourteen patients had more than 75% improvement. No side effects were noted in our and Gupta et al study.¹⁶

Although injection placental extract is reasonably cheaper than combined regimen injection triamcinolone and hyaluronidase. The effectiveness of both the injections showed not much difference which is also seen in study of Shah PH.²¹ Still we preferred comparatively superior therapeutic effect with i.e. combined intralesional regimen over placental extract.^19,28 In severe cases of trismus due to OSMF, surgery will be required.⁵

Every care should be taken for good nutrition and good orodental hygiene. Patients should be councilled regarding importance of discontinuing the chewing habits. Public health campaign and de-addiction government centers available to improve knowledge and awareness of side effects and reduction of chewing habits.

CONCLUSION

Oral submucous fibrosis is a precancerous condition of oral mucosa. OSMF purely lifestyle habit related condition which can be preventable. OSMF has no definitive treatment but comparatively effective improvement was seen in major symptoms more with a combined regimen of intralesional triamcinolone 40mg with hyaluronidase 1500IU intralesionally than placental extract. Added with continuous physiotherapy and oral antioxidants will helps in improvement of OSMF.

ACKNOWLEDGEMENTS

We are grateful to the Dean Sir, Dr R. N. Bharmal, TN Medical College and BYL Nair Charitable Hospital, Mumbai Central, Mumbai for allowing us to publish this article.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: The study was approved by the Institutional Ethics Committee

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