G Model JORMAS-785; No. of Pages 5 J Stomatol Oral Maxillofac Surg xxx (2019) xxx–xxx Available online at ScienceDirect www.sciencedirect.com Original article Surgical management of oral submucous fibrosis with ‘‘Seagull-nasolabial flap’’ combined with short-term oral pentoxifylline for preventing relapse Y. Kholakiya a, A. Jose b,*, A. Rawat b, S.A. Nagori c, S. Jacob d, A. Roychoudhury a a Department of oral and maxillofacial surgery, All India institute of medical sciences, New Delhi, India Division of oral and maxillofacial surgery, Army dental centre research and referral, New Delhi, India 21 CDU, Bhopal c/o 56 AP, India d Meerut, India b c A R T I C L E I N F O A B S T R A C T Article history: Received 6 October 2019 Accepted 18 December 2019 The aim of the study was to evaluate the effectiveness of seagull-shaped nasolabial flap (NLF) along with adjunctive short-term oral pentoxifylline in the surgical reconstruction of oral sub mucous fibrosis (OSMF) following fibrotomy. We retrospectively evaluated 18 patients with grade IV oral sub mucous fibrosis treated by NLF. There were 3 females and 15 males. All patients were classified as stage IV OSMF with a mean preoperative mouth opening of 8.11  3.38 mm. Postoperatively, patients were administered 400 mg of pentoxifylline (PTX) thrice daily for 3 months. Patients were followed up at one month, six months and one year. Mouth opening, presence or absence of malignant transformation, relapse and complications were recorded at each follow-up. We found statistically significant increase in mouth opening from 8.11  3.3 to 37.67  3.74 in the postoperative period. The complications associated with NLF were very minimal. The PTX was well tolerated by all the patients. There was no incidence of relapse or rebound fibrosis seen in our series. To the best of our knowledge, this is the first time that oral pentoxifylline has been administered along with surgical treatment of oral submucous fibrosis to prevent relapse. The use of oral PTX as an adjunct along with surgical reconstruction in OSMF improves mouth opening, reduces burning sensation and relapse. C 2019 Published by Elsevier Masson SAS. Keywords: Nasolabial flap Oral submucous fibrosis Pentoxifylline 1. Introduction Pindborg in 1956 defined oral submucous fibrosis (OSMF) as ‘‘an insidious chronic disease affecting any part of the oral cavity and sometimes the pharynx’’ [1]. It is always associated with juxtaepithelial inflammatory reaction, followed by a fibroblastic change in the lamina propria, with epithelial atrophy, leading to stiffness of the oral mucosa and causing trismus [1]. This potentially malignant condition was first reported by Schwartz in 1952 in five Indian females from Kenya when he coined the term atropica idiopathica mucosae oris [2]. This condition is primarily seen in the Indian subcontinent and Southeast Asia owing to increased consumption of areca nut and betel quid in these regions. In India, prevalence range is 0.2–0.5% with female predominance which varies between 1.2–4.5%. In Indian males, prevalence rate is about 0.2–2.3% [3]. * Corresponding author. E-mail address: ansonjoseaj@gmail.com (A. Jose). Once the disease has initiated, it does not reverse back even after cessation of habit. Management of this chronic progressive condition is based on the stage of the disease. However, OSMF has been refractory to most of the medical treatment modalities tried. Surgical modalities are reserved for more progressive and advanced stages. The nasolabial flap (NLF) is one of the most commonly used flaps in the management of OSMF. In 1921, Essar described the use of inferiorly based nasolabial flap for closure of palatal fistula [4]. This flap has undergone various modifications since then and has been used extensively for reconstruction of buccal mucosa, upper & lower lips, tongue, and floor of the mouth. This flap is a simple, safe and effective flap with minimum donor site morbidity and is in close proximity to the defect when used for management of OSMF [5]. Pentoxifylline (PTX) is a vasodilator with anti-fibrotic activity widely used for the conservative management of oral sub mucous fibrosis. The present study evaluates the efficacy of concomitant administration of PTX in preventing recurrence and rebound https://doi.org/10.1016/j.jormas.2019.12.015 2468-7855/ C 2019 Published by Elsevier Masson SAS. Please cite this article in press as: Kholakiya Y, et al. Surgical management of oral submucous fibrosis with ‘‘Seagull-nasolabial flap’’ combined with short-term oral pentoxifylline for preventing relapse. J Stomatol Oral Maxillofac Surg (2020), https://doi.org/10.1016/ j.jormas.2019.12.015 G Model JORMAS-785; No. of Pages 5 Y. Kholakiya et al. / J Stomatol Oral Maxillofac Surg xxx (2019) xxx–xxx 2 fibrosis after surgical reconstruction of grade IV OSMF using seagull NLF. 2. Materials and methods An institutional ethical committee approved retrospective review of patients diagnosed with OSMF between 2015–2018. All patients were treated in the same hospital by a single surgeon by NLF and PTX. Informed written consent was obtained from all patients. Institutional ethical committee approval was obtained. Diagnosis of OSMF was based on clinical examination and histopathological confirmation. All patients were counselled and encouraged to quit areca nut chewing before the surgical procedure. 3. Surgical technique All patients were operated under general anaesthesia administered by fibre optic intubation. An intra-oral incision was placed starting 1 cm posterior to the corner of mouth extending up to the faucial pillars. Care was taken to place the incision below the level of Stenson’s duct. Using blunt dissection, all fibrous bands were excised. After achieving an intra-operative mouth opening of at least 35 mm, third molars were extracted and coronoidectomy was performed through the same incision. Bilateral NLF were then outlined slightly lateral to the nasolabial fold extending from the alar facial grove to the lower border of mandible. The flap is raised in a ‘‘seagull wing’’ fashion with one wing above and one below pedicle at the modiolus (Fig. 1). The average length of the flap was 8–10 cm while width was 2–4cm. The NLF was raised in a supra-muscular plane as an axial flap. The flap is raised from the superior to inferior direction leaving a 1–1.5 cm pedicle of soft tissue at corner of the mouth (Fig. 2). A medial tunnel was then prepared and the flap was rotated and sutured it into the fibrotomy defect using resorbable sutures (Fig. 3). The donor site defect was then closed in layers. Fig. 2. 90-degree rotation of flap into the oral cavity through the mucosal tunnel. Fig. 3. Flap inset and suturing. Periodic flap evaluation was carried out at 6 hours, 24 hours, and 48 hours. Postoperatively, patients were administered 400 mg PTX thrice daily for 3 months. Postoperative physiotherapy started one week after the surgery with Heister’s mouth opener 20–25 times a day, and was continued till the end of 6 months after surgery. Patients were followed up at one month, six months and one year. Mouth opening, presence or absence of malignant transformation and complications were recorded at each followup visit. 4. Data analysis Fig. 1. Design of seagull nasolabial flap. Data on patient demographics, duration of habit, OSMF grade, post-operative mouth opening and complications were extracted for the purpose of this study. We compared preoperative and postoperative mouth opening using Student’s t-test. Results were considered significant for P < 0.05. Success was defined as postoperative mouth opening of >30 mm after at least one year of follow-up. Please cite this article in press as: Kholakiya Y, et al. Surgical management of oral submucous fibrosis with ‘‘Seagull-nasolabial flap’’ combined with short-term oral pentoxifylline for preventing relapse. J Stomatol Oral Maxillofac Surg (2020), https://doi.org/10.1016/ j.jormas.2019.12.015 G Model JORMAS-785; No. of Pages 5 Y. Kholakiya et al. / J Stomatol Oral Maxillofac Surg xxx (2019) xxx–xxx 3 Table 1 Baseline data and outcome of OSMF patients. Patient no Age Gender Duration of habit (years) Preoperative mouth opening (mm) Mouth opening at discharge (mm) Follow-up (months) Mouth opening at last follow-up (mm) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 36 52 33 36 56 38 37 33 28 28 37 46 35 43 26 24 31 56 M M M M M F M M M M M M M F M M F M 10 26 11 10 20 12 15 14 08 05 16 28 10 22 04 05 10 30 04 12 08 07 05 03 05 05 10 12 06 07 15 8 13 11 08 07 40 38 40 32 35 35 40 38 40 35 38 35 42 40 35 32 35 40 24 24 18 24 36 24 24 18 12 18 36 24 24 18 12 12 18 24 42 37 36 33 38 35 39 42 40 32 39 40 42 41 30 35 35 42 M: male; F: female; mm: millimetre. Fig. 5. Functional adaptation and mucosalisation of the graft at 1 year follow-up. Fig. 4. Postoperative passive mouth opening and inconspicuous scar of nasolabial region. 5. Results A total of 18 patients with an age range of 24–56 years were included in the study (Table 1). There were 3 females and 15 males. All patients reported areca nut chewing habit. Mean duration of habit was 14.2  7.95 years. All patients were classified as stage IV OSMF with a mean preoperative mouth opening of 8.11  3.38 mm. Preoperative histopathological evaluation of all patients was negative for malignancy. An intra-operative mouth opening of >35 mm was achieved in all cases. There were no major intra-operative complications. Mean mouth opening at the time of discharge was 37.22  3.02 mm. There was no case of partial/complete flap failure, infection or suture dehiscence. In the immediate postoperative period, 3 patients developed ecchymosis over the neck, which subsided spontaneously after two weeks. PTX was well tolerated by all patients. Two patients developed headache 2 weeks after the administration of PTX. Symptoms, however, reduced with dose reduction. No allergic reactions were noted with the drug. Five patients complained of intra-oral hair growth, however the density of hair decreased after 6 months and the remaining hair was removed by depilation. No hypertrophic scar or keloid formation was seen. There was no evidence of malignant transformation during the study period. After a follow-up period of 21.67  6.87 months, mean mouth opening was 37.67  3.74 (Fig. 4). As compared to preoperative values, increase in mouth opening was statistically significant (P < 0.0001) (Fig. 5). Success rate was 100% with no case of recurrence. 6. Discussion OSMF is an insidious, chronic, progressive disorder that affects the oral cavity and oropharynx with the clinical manifestation of reduced mouth opening [1,6]. A number of different terminologies have been suggested for this entity like ‘‘atrophia idiopathies mucosae oris’’, ‘‘diffuse oral submucous fibrosis’’, ‘‘idiopathic scleroderma of the mouth’’, ‘‘idiopathic palatal fibrosis’’, and ‘‘sclerosing stomatitis’’ [2,6]. Clinically the disease is characterised by trismus, loss of pigmentation, blanching, palpable fibrous bands in faucial pillars, soft palate, pterygomandibular raphe and buccal mucosa. In advanced cases, restriction in tongue movements and Eustachian tube dysfunction is also seen [1]. As this potentially malignant condition cannot be reversed once it is initiated, long- Please cite this article in press as: Kholakiya Y, et al. Surgical management of oral submucous fibrosis with ‘‘Seagull-nasolabial flap’’ combined with short-term oral pentoxifylline for preventing relapse. J Stomatol Oral Maxillofac Surg (2020), https://doi.org/10.1016/ j.jormas.2019.12.015 G Model JORMAS-785; No. of Pages 5 4 Y. Kholakiya et al. / J Stomatol Oral Maxillofac Surg xxx (2019) xxx–xxx standing cases suffer from poor oral hygiene, speech difficulty and malnutrition [1]. The malignant transformation rate of OSMF ranges from 7.6–33% [3,7]. The malignancy associated with oral submucous fibrosis is mainly seen on buccal mucosa at the molar region and retro molar region. This is probably due to secondary factors like chronic irritation of the genetically altered buccal mucosa by teeth and pericoronitis around third molar. The aetiology of OSMF is elusive. However, a significant association of OSMF is seen with areca nut chewing. Additionally, factors like capsaicin, deficiency of macro and micronutrients like iron and zinc may be some other etiological factors [7,8]. Similarly, a possible genetic aetiology cannot be ruled out [2,6]. Nevertheless, in developing Southeast Asian countries, there is an overwhelming evidence for areca nut chewing as the single most common aetiology [8]. Owing to its complex aetiology and varying clinical behaviour, an array of medical, adjunctive and surgical treatment modalities have been tried with inconsistent results [9]. The medical treatments are purely symptomatic and help to prevent further progression of the disease. The surgical treatment is the mainstay treatment of OSMF [10]. The surgical protocol includes fibrotomy, coronoidectomy and removal of all third molars [10]. Adequate surgical release of fibrous bands results in bilateral defects in buccal mucosa, which tends to contract and shrink if left to heal by secondary intention. Thus, the resulting soft tissue defect requires reconstruction with a well-vascularised tissue to prevent recurrence. For the reconstruction of defects, a variety of interpositional flaps have been tried in literature which includes buccal fat pad, temporoparietal fascia, nasolabial flap, platysma flap, palatal flap and tongue flap [2,9,10]. Apart from these local and regional flaps, various microvascular flaps like radial forearm and anterolateral thigh flaps have also been tried [11,12]. The success of surgical modality depends on complete fibrotomy and interposition of the gap with a material that prevents the reattachment of fibrosed juxta-epithelial layers. Postoperative vigorous physiotherapy also plays a crucial role in preventing recurrence. Amongst a wide array of surgical options available, the use of NLF for reconstruction of defects after fibrotomy has proved to be worthwhile [4,13]. NLF has traditionally been described as axial pattern flaps based on facial artery, however majority of flaps have random pattern blood supply. In the nasolabial region, artery runs deep to the mimetic muscles and gives vertically oriented perforators to the subcutaneous tissue. For the reconstruction of OSMF defects, elliptical shaped flaps raised in supra muscular plane are used [4]. The advantages of NLF are its versatility in design, reliable and rich vascularity, proximity to the defect, ease of flap elevation, and supple skin, thereby aiding in increased mouth opening with minimal aesthetic deformity [13]. Kavarana and Bhathena [14] were the first to use NLF for closure of surgical defect of OSMF. They had used inferiorly based flaps in 3 patients and adequate mouth opening was achieved in all the patients. In the present study, 36 flaps in 18 patients were used after fibrotomy and satisfactory results were achieved in all the 18 patients. All patients reported reduction in burning sensation after two months of administration of PTX. Objectively, a gradual increase in mouth opening was noted postoperatively. At 12 months follow-up, no recurrence was seen and surprisingly, there was total conversion of the epithelial part of NLF flap into oral mucosa. The authors believe that the metaplasia of epithelium of NLF flap into oral mucosa is accelerated by PTX administration. Shah and Tauro [15] had conducted a clinical and histopathological study to determine the basis of use of NLF in OSMF. Fourteen patients, in whom fibrotomy defect was reconstructed with NLF, reported adequate mouth opening, relief from trismus and no recurrence of fibrosis in 10 years of follow-up. The histological examination of biopsy sample of inset flap did not reveal fibrotic changes or inflammatory cells indicating that skin being a foreign tissue to oral cavity can be a reliable option for management of this debilitating condition. In a comparative study, Agarwal et al. [13] compared NLF with BFP in 32 patients with less than 25 mm mouth opening and noted sudden increase in mouth opening in BFP group at 1–2 weeks postoperatively, which gradually decreased until 6 months. In contrast to this, NLF group demonstrated slow, but progressive increase in mouth opening till 6 months. The authors concluded that NLF was a better option compared to BFP in terms of mouth opening. Even though surgery is the most accepted treatment modality in the advanced stages of OSMF, the postoperative outcome is very unpredictable. The chances of recurrence after surgery are very common [16]. The recurrence is mainly due to rebound fibrosis secondary to surgical trauma. The rebound fibrosis can be attributed to reduced oxygen supply to the fibrotic tissue and depletion of glycogen in masticatory muscles due to atrophy secondary to reduced vascularity [2,10]. Thus, increasing the local vascularity is very essential for preventing the further progression and recurrence of the disease. Owing to its vasodilating and anti-fibrotic properties, PTX will increase the blood supply and oxygenation of the affected tissues and reduces the postoperative fibrosis. Various authors have reported the effectiveness of PTX in the conservative management of OSMF [17–19]. The progressive loss of vascularity of the oral mucosa and submucosa is considered to play a crucial role in the pathogenesis in the disease. This is the rationale behind the use of vasodilators like nylidrin hydrochloride and PTX in the management of OSMF [20]. The vasodilators ensure adequate blood supply and oxygenation to the affected tissues. PTX is a vasodilator with antioxidant, anti-inflammatory and immune modulatory properties. It also increases the rheological properties of red blood cells, thereby increasing the deformability of the cells [18]. Moreover, the alteration in fibroblast physiology by PTX results in increased collagenase activity and decreased collagen production by inhibiting interleukin-induced proliferation of fibroblast [18]. All these factors invariably result in decreased fibrosis and increased tissue perfusion, thus making the drug suitable in the management of OSMF. In the present study, the authors have noted significant improvement in mouth opening and reduction in burning sensation one month after the use of PTX. Mouth opening increased from 8.11  3.3 to 37.67  3.74 in postoperative period, which was found to be statistically significant. There was no evidence of relapse or fibrosis in all the cases. The complications associated with NLF were very minimal. Most common complication was intra-oral hair growth (5 patients). The density of hair growth was reduced at the end of 3 months. The remaining hair was eliminated by mechanical depilation after 6 months. No evidence of hypertrophic scar and keloid was seen in any patients. The other complications reported in literature like flap necrosis, fish mouth deformity, widening of oral aperture, infection and orocutaneous fistula were not encountered in the present series. PTX was well tolerated by all of our patients and its side effects were minimal. Two patients in our series developed headache after two weeks of administration. Dose reduction was carried out in those two patients. Overall, PTX is a safe drug [19]. The main side effects of PTX are headache and dizziness. Other minor side effects include dryness of the mouth, nasal congestion and blurred vision. There are no contraindications for the use of PTX except hypersensitivity to the drug, cardiovascular and cerebrovascular accidents [20]. To the best of our knowledge, this is the first time that oral PTX has been used as an adjunct to surgery in reducing postoperative fibrosis and hence relapses in OSMF. As per our experience, NLF along with oral PTX is an excellent reconstructive option for the management of OSMF demonstrating adequate functional and aesthetic results. Though the results were entertaining, more such studies with large sample size are required before arriving at a valid conclusion. Please cite this article in press as: Kholakiya Y, et al. Surgical management of oral submucous fibrosis with ‘‘Seagull-nasolabial flap’’ combined with short-term oral pentoxifylline for preventing relapse. J Stomatol Oral Maxillofac Surg (2020), https://doi.org/10.1016/ j.jormas.2019.12.015 G Model JORMAS-785; No. of Pages 5 Y. Kholakiya et al. / J Stomatol Oral Maxillofac Surg xxx (2019) xxx–xxx Disclosure of interest The authors declare that they have no competing interest. References [1] Pindborg JJ, Sirsat SM. Oral submucous fibrosis. Oral Surg Oral Med Oral Pathol 1966;22:764–779.4. [2] Arakeri G, Brennan PA. 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[19] Mehrotra R, Singh HP, Gupta SC, Singh M, Jain S. Pentoxifylline therapy in the management of oral submucous fibrosis. Asian Pac J Cancer Prev 2011;12:971–4. [20] Liu J, Chen F, Wei Z, Qiu M, Li Z, Dan H, et al. Evaluating the efficacy of pentoxifylline in the treatment of oral submucous fibrosis: a meta-analysis. Oral Dis 2018;24(5):706–16. Please cite this article in press as: Kholakiya Y, et al. Surgical management of oral submucous fibrosis with ‘‘Seagull-nasolabial flap’’ combined with short-term oral pentoxifylline for preventing relapse. J Stomatol Oral Maxillofac Surg (2020), https://doi.org/10.1016/ j.jormas.2019.12.015