Successful treatment of an extensive oral verrucous hyperplasia with topical 5-aminolevulinic acid-mediated photodynamic therapy -case report HSIN-MING CHEN 1,2,3 CHUAN-HANG YU 4 JULIA YU-FONG CHANG 1,2 TSUIMIN TSAI 5 RU-CHENG KUO 1 CHUN-PIN CHIANG 1,2,3,4 1 Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC. 2 School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC. 3 Graduate Institute of Oral Biology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC. 4 Graduate Institute of Clinical Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC. 5 Graduate Institute of Biomedical Materials, Taipei Medical University, Taipei, Taiwan, ROC. Our previous studies showed successful treatment of 13 oral verrucous hyperplasia (OVH) lesions and an extensive oral verrucous carcinoma with a topical 5-aminolevulinic acid-mediated photodynamic therapeutic (topical ALA-PDT) protocol (with a fluence rate of 100 mw/cm 2 and a light exposure dose of 100 J/cm 2 ) using a 635-nm light-emitting diode (LED) light source. In this case report, we tested the efficacy of an enhanced topical ALA-PDT protocol (with a fluence rate of 200 mw/cm 2 and a light exposure dose of 200 J/cm 2 ) for an extensive OVH lesion on the right buccal mucosa of a 43-year-old male smoker and areca quid chewer. The OVH lesion showed complete regression after 18 treatments of this enhanced topical ALA-PDT. Severe post-treatment pain was noted after each of the initial 6 treatments, and the patient needed strong analgesics (30 mg codeine phosphate 3 times daily) to control the pain. No recurrence of the OVH lesion was found after a follow-up period of 20 months. We suggest that our enhanced topical ALA-PDT protocol is very effective for treating OVH lesions. The treatment course may be slightly shortened with this enhanced protocol. However, severe post-pdt pain was experienced by the patient when the regression of tumor volume was large between 2 treatments. (J Dent Sci, 2(4):216-220, 2007) Key words: 5-aminolevulinic acid, topical photodynamic therapy, oral verrucous hyperplasia. Oral verrucous hyperplasia (OVH) is a premalignant lesion that may transform into a verrucous carcinoma or a squamous cell carcinoma. Traditional treatment for an OVH is total surgical excision that always leads to scar formation for a large OVH lesion. Photodynamic therapy (PDT) is another effective treatment option for human premalignant and malignant lesions because it is noninvasive, is well Received: September 18, 2007 Accepted: November 4, 2007 Reprint requests to: Dr. Chun-Pin Chiang, Department of Dentistry, National Taiwan University Hospital, No. 1, Chang-Te Street, Taipei, Taiwan 10048, ROC. tolerated by patients, can be used repeatedly without cumulative side effects, and results in little scar formation 1. 5-Aminolevulinic acid (ALA) itself is not a photosensitizer but serves as the biological precursor of the photosensitizer, protoporphyrin IX (PpIX), in the heme biosynthesis pathway. PDT with topically applied ALA (topical ALA-PDT) has been used to treat human oral premalignant lesions with relatively good clinical outcomes 2-7. Topical ALA-PDT is an even better treatment modality for oral precancers than systemic ALA-PDT because systemic administeration of ALA to patients has the side effects of nausea, vomiting, and elevation of blood levels of bilirubin and liver enzymes (e.g., aspartate transaminase, AST) 8, 216
ALA-PDT for verrucous hyperplasia while the direct local application of ALA onto oral lesions produces none of those systemic side effects 9-11. In addition, because topical ALA-PDT for oral lesions uses only a small amount of ALA, it causes no cutaneous photosensitivity, even with exposure of the patients skin to the sun immediately after treatment. Our previous studies showed successful treatment of 13 OVH lesions and an extensive oral verrucous carcinoma (OVC) with a topical ALA-PDT protocol (with a fluence rate of 100 mw/cm 2 and a light exposure dose of 100 J/cm 2 ) using a 635-nm light-emitting diode (LED) light source 5-7,12. In this case report, we tested the efficacy of an enhanced topical ALA-PDT protocol (with a fluence rate of 200 mw/cm 2 and a light exposure dose of 200 J/cm 2 ) on an extensive OVH lesion on the right buccal mucosa of a 43-year-old male smoker and areca quid (AQ) chewer. CASE PRESENTATION This 43-year-old male patient came to our outpatient dental clinic and asked for treatment of a verrucous lesion on the right buccal mucosa by PDT. The verrucous lesion on the right buccal mucosa measured about 6 4 cm, and occupied approximately 5/6 of the surface area of the entire right buccal mucosa (Figure 1A). All major systemic diseases including diabetes mellitus and hypertension were denied by the patient. The patient had had the AQ chewing habit (120 quids per day) for 16 years and smoking habit (4 cigarettes per day) for 23 years. He began to notice a verrucous tumor on the right buccal mucosa 6 months previous. Although he had quit both the AQ chewing and smoking habits 4 months previous, the tumor continued to grow up to the present form and size. During the past 6 months, the patient had received no treatment. Based on the size and appearance of the lesion, the tentative clinical diagnosis was an OVC. However, an incisional biopsy taken from the tumor portion near the right mouth angle showed it to be an OVH (Figure 1B). Because only a small portion of the tumor was examined histologically, we still could not rule out the possibility of concomitant presence of an OVC in other parts of the lesion. For comparison in efficacy between a previously used protocol (with a fluence rate of 100 mw/cm 2 and a light exposure dose of 100 J/cm 2 ) and an enhanced topical ALA-PDT protocol (with a fluence rate of 200 mw/cm 2 and a light exposure dose of 200 J/cm 2 ), we decided to treat this patient with the latter protocol after informed consent was obtained from him. The anterior portion of the tumor near the right mouth angle was first treated by the enhanced topical ALA-PDT protocol followed by the posterior portion of the tumor on the right buccal mucosa. The treatment course for this patient was the same as that for our previous OVH or OVC patients as described previously 5-7,12 except that a 2-fold light exposure dose was given to the patient in this case. In brief, at the first visit of the treatment, an oral examination and incisional biopsy were performed. At the second appointment, we did the kinetics study of topical ALA by ALA-induced PpIX fluorescence spectroscopy and found that the PpIX reached its maximum level in the lesional epithelial cells 1.5 hours after local ALA application. Therefore, the subsequent light treatments were set at 1.5 hours after topical application of ALA to the lesion. The topical ALA-PDT treatment was performed once a week starting from the patient s third appointment. On the day of treatment, 0.8 ml of 20% ALA was applied to the anterior 1/4 of the tumor upon patient s arrival. The light treatment was composed of multiple 3-minute irradiations with an LED red light at 635 ± 5 nm separated by 3-minute rest periods for a total irradiance time of 1000 seconds (at a fluence rate of 200 mw/cm 2 and a light exposure dose of 200 J/cm 2 ) delivered 1.5 hour after topical ALA application. Light treatments were carried out under local anesthesia using 2% lidocaine with the patient completely conscious. The tip of the LED light device was kept as close to the surface of the lesion as possible. The OVH lesion showed complete regression after 18 treatments of the enhanced topical ALA-PDT (Figure 1C-H). The elongated right upper first and second molars were extracted after 17 treatments of ALA-PDT due to frequent irritation to the right buccal mucosa (Figure 1H). Because of the severe post-treatment pain, codeine phosphate (30 mg/tablet, 1 tablet 3 times a day) was prescribed to the patient for the former 6 treatments, while acetaminophen (500 mg/tablet, 1 tablet 4 times a day) was given to the patient for the latter 12 treatments after PDT. After completion of the entire treatment course, the patient was followed-up once a week in the first month and once a month thereafter. No recurrence of the lesion was found after a follow-up period of 20 months. 217
H.M. Chen, C.H. Yu, J.Y.F. Chang, et al. A B C D E F G H Figure 1. Clinical and histologic photographs of the patient. (A) The initial oral verrucous hyperplasia (OVH) lesion on the right buccal mucosa before treatment. (B) Incisional biopsy of the tumor portion near the right mouth angle showing OVH (hematoxylin and eosin stain; original magnification, 5). Clinical pictures of the OVH lesion after 2 (C), 4 (D), 6 (E), 8 (F), and 14 (G) treatments of the enhanced topical 5-aminovulinic acid photodynamic treatment (ALA-PDT) showing partial regression of the OVH lesion. (H) Clinical picture of the right buccal mucosa after 18 treatments of the enhanced topical ALA-PDT showing complete regression of the OVH lesion. A diffuse white lesion with submucous fibrosis was found on the right buccal mucosa, especially the posterior part of the buccal mucosa. Furthermore, the elongated right upper first and second molars were extracted after 17 ALA-PDT treatments. 218
ALA-PDT for verrucous hyperplasia DISCUSSION In this case report, we treated an extensive OVH lesion on the right buccal mucosa of a 43-year-old male smoker and AQ chewer with a new enhanced topical ALA-PDT protocol. The large OVH lesion showed complete regression after 18 treatments of topical ALA-PDT. In our previous studies, a topical ALA-PDT protocol was successfully used to treat 13 OVH lesions and an OVC lesion 5-7,12. The results of the present report confirm that our new enhanced topical ALA-PDT protocol is also very effective for treating an extensive OVH lesion. The clinical appearance and treatment course of this OVH lesion were comparable to those of an OVC lesion we previously reported 12. Both lesions were very extensive, were located on the right buccal mucosa, and showed complete response to topical ALA-PDT. The incubation period (the time needed for the transformation of ALA into PpIX) was 1.5 hours for this OVH lesion and 2 hours for the previous OVC C lesion. The difference could be due to the lesskeratotic surface of this OVH lesion which may have allowed more-rapid absorption of ALA into the lesional epithelial cells compared to the morekeratotic surface of the previous OVC lesion which might have retarded the absorption of ALA by epithelial cells. The total light exposure dose per treatment was doubled (200 J/cm 2 ) for this OVH lesion compared to that (100 J/cm 2 ) for the previous OVC lesion. This light dose difference resulted in a slightly shorter treatment E course (18 treatments) for this OVH lesion than for the previous OVC lesion (22 treatments). In addition, approximately 4/5 and 7/8 of the tumor volume of this OVH lesion were respectively cleared after 6 and 8 treatments with the enhanced topical ALA-PDT protocol. This suggests that doubling the light dose may slightly shorten the treatment course. However, more-severe post-pdt pain was experienced by this OVH patient than by the previous OVC patient. Therefore, stronger analgesics (codeine phosphate) were G needed for this OVH patient to control the post-pdt pain than for the previous OVC patient. PDT with topically applied ALA has been used to treat oral precancerous lesions like oral leukoplakia (OL) and OVH and cancerous lesions like OVC with promising clinical outcomes 2-7,12. Kubler et al. 2 treated 12 OL lesions with PDT after local application of 20% ALA cream and found a complete response (CR) in 5, a partial response (PR) in 4, and no response (NR) in 3. Sieron et al. 3,4 treated 17 OL lesions with PDT after topical application of 10% ALA ointment or emulsion in 2 separate studies. A CR was observed in 14 of 17 OL lesions. Our previous studies showed that complete regression of 13 OVH lesions and of an extensive OVC lesion was achieved with fewer than 6 and 28 treatments of topical ALA-PDT once a week, respectively 5-7,12. However, 24 OL lesions treated with topical ALA-PDT once a week demonstrated a CR in 3, a PR in 9, and NR in 12 7. Furthermore, 24 OL lesions treated with topical ALA-PDT twice a week showed a CR in 8 and a PR in 16. The twice-a-week treatment modality had a better clinical outcome for OL lesions than the once-a-week treatment modality 7. Although the response of OL lesions to topical ALA-PDT is not as good as the response of OVH lesions to the same treatment protocol in our studies, the results of above-mentioned investigations indicate that PDT with topical ALA may be an effective treatment modality for OVC, OVH, and OL lesions. Further studies are needed to assess whether the new enhanced topical ALA-PDT is more effective than the previous topical ALA-PDT for treating OL lesions. The successful clinical outcomes of OVH and OVC lesions treated by topical ALA-PDT may have been due to the ALA preparation, the specific topical ALA-PDT protocol used, and the characteristic features of the OVH or OVC lesion itself. The 20% ALA (w/w) preparation used in our studies is a liquid form at room temperature; it becomes a gel form at body temperature upon contacting the lesional oral mucosa due to a thermoresponsive sol-gel transition of the vehicle 5-7. The gel form of the ALA preparation is adhesive to the oral mucosa and partially resistant to dilution by saliva. This characteristic feature of our ALA preparation, in turn, facilitates ALA absorption from the lesional surface. Furthermore, the verrucous appearance of the OVH or OVC lesion provides a large area for good retention of ALA on the surface, and the less-keratotic epithelium of the OVH lesion than the OL lesion also provides a more-permeable surface layer for good absorption of ALA into oral epithelial cells. In addition, we divided the 1000- second light treatment course into 5 periods of 180 seconds and a final period of 100 seconds. These 6 periods of light treatment were interrupted by 5 periods of 3 minutes of rest each. Because an efficient 219
H.M. Chen, C.H. Yu, J.Y.F. Chang, et al. PDT needs a sufficient and continuous supply of new PpIX and oxygen, multiple 3-minute stops are supposed to provide an opportunity for oral epithelial cells to regenerate new PpIX and to obtain new oxygen. This, in turn, resulted in a successful clinical outcome for OVH and OVC lesions with this topical ALA-PDT protocol. In this case report, we succeeded in treating an extensive OVH with an enhanced protocol of topical ALA-PDT. Although further studies are needed to verify the actual efficacy of this enhanced treatment protocol, we suggest that our enhanced topical ALA-PDT protocol may be very effective in treating OVH lesions. The treatment course may be slightly shortened with this enhanced protocol. ACKNOWLEDGEMENTS The authors would like to thank Industrial Technology Research Institute of Taiwan for developing the light emitting diode source. REFERENCES 1. Dolmans DE, Fukumura D, Jain RK. Photodynamic therapy for cancer. Nat Rev Cancer, 3: 380-387, 2003. 2. Kubler A, Haase T, Rheinwald M, Barth T, Muhling J. Treatment of oral leukoplakia by topical application of 5-aminolevulinic acid. Int J Oral Maxillofac Surg, 27: 466-469, 1998. 3. Sieron A, Namyslowski G, Misiolek M, Adamek M, Kawczyk-Krupka A. Photodynamic therapy of premalignant lesions and local recurrence of laryngeal and hypopharyngeal cancers. Eur Arch Oto-Rhino-Laryngol, 258: 349-352, 2001. 4. Sieron A, Adamek M, Kawczyk-Krupka A, Mazur S, Ilewicz L. Photodynamic therapy (PDT) using topically applied δ-aminolevulinic acid (ALA) for the treatment of oral leukoplakia. J Oral Pathol Med, 32: 330-336, 2003. 5. Tsai JC, Chiang CP, Chen HM, Huang SB, Wang CW, Lee MI, Hsu YC, Chen CT, Tsai T. Photodynamic therapy of oral dysplasia with topical 5-aminolevulinic acid and lightemitting diode array. Lasers Surg Med, 34: 18-24, 2004. 6. Chen HM, Chen CT, Yang H, Kuo MYP, Kuo YS, Lan WH, Wang YP, Tsai T, Chiang CP. Successful treatment of oral verrucous hyperplasia with topical 5-aminolevulinic acidmediated photodynamic therapy. Oral Oncol, 40: 630-637, 2004. 7. Chen HM, Yu CH, Tu PC, Yeh CY, Tsai T, Chiang CP. Successful treatment of oral verrucous hyperplasia and oral leukoplakia with topical 5-aminolevulinic acid-mediated photodynamic therapy. Lasers Surg Med, 37: 114-122, 2005. 8. Fan KF, Hopper C, Speight PM, Buonaccorsi G, MacRobert AJ, Bown SG. Photodynamic therapy using 5-aminolevulinic acid for premalignant and malignant lesions of the oral cavity. Cancer, 78: 1374-1383, 1996. 9. Leunig A, Rick K, Stepp H, Gutmann R, Alwin G, Baumgartner R, Feyh J. Fluorescence imaging and spectroscopy of 5-aminolevulinic acid induced protoporphyrin IX for the detection of neoplastic lesions in the oral cavity. Am J Surg, 172: 674-677, 1996. 10. Leunig A, Betz CS, Mehlmann M, Stepp H, Arbogast S, Grevers G, Baumgartner R. Detection of squamous cell carcinoma of the oral cavity by imaging 5-aminolevulinic acid-induced protoporphyrin IX fluorescence. Laryngoscope, 110: 78-83, 2000. 11. Leunig A, Mehlmann M, Betz C, Stepp H, Arbogast S, Grevers G, Baumgartner R. Fluorescence staining of oral cancer using a topical application of 5-aminolevulininc acid: fluorescence microscopic studies. J Photochem Photobiol B: Biol, 60: 44-49, 2001. 12. Chen HM, Chen CT, Yang H, Lee MI, Kuo MYP, Kuo YS, Wang YP, Tsai TM, Chiang CP. Successful treatment of an extensive verrucous carcinoma with topical 5-aminolevulinic acid-mediated photodynamic therapy. J Oral Pathol Med, 34: 253-256, 2005. 220