CONSERVATIVE TREATMENT OF CHOLESTEATOMA BY 5-FU OINTMENT

Tomomi Yamamoto-Fukuda,1,2 Haruo Takahashi2

1Department of Histology and Cell Biology, Unit of Basic Medical Science; 2Department of Otolaryngology-Head and Neck Surgery, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

Introduction

It is well known that middle-ear cholesteatoma is characterized by the presence of a keratinizing epithelium which is believed to have hyper-proliferative properties. In 1985, Smith1 used 5-Fluorouracil (5-FU) for treating cholesteatoma as an agent suppressing its abnormal proliferation, and reported its clinical effect. 5-FU is a pyrimidine analog developed in 1957.2 It is an effective inhibitor of both RNA function and the synthesis of thymidylate.3 5-FU is recognized as an anti-neoplastic agent effective especially for skin tumors.4 Wright et al.5 confirmed its efficacy in animal experiments, and Sala et al.6 reconfirmed its clinical efficacy and safety. We have also tried this treatment for cholesteatoma using commercially available 5-FU topical cream, and reported its usefulness.7

In this lecture, we introduce: how we perform this 5-FU topical cream therapy, the clinical efficacy of 5-FU topical cream on various types of cholesteatoma, the influence of 5-FU topical cream treatment on inner ear function in guinea pigs and the cell-biological effect of 5-FU cream on middle-ear cholesteatoma.

Method

We use 5-FU topical cream produced by Kyowa Hakko and Kirin Pharma. After cleaning the debris within or on the surface of the cholesteatoma as much as possible, two to three mm3 of 5% 5-FU topical cream should be meticulously applied on the outer surface of cholesteatoma transmeatally under the microscope (Fig. 1). The application of 5-FU topical cream is done two to five times with an interval of two weeks on an outpatient basis. The cream should not harm healthy skin. Treatment should be continued until the debris disappears.

Results

In the previous study,7 we investigated the clinical efficacy of commercially available 5-FU topical cream on 50 cases of various types of cholesteatoma. In total, 59% of the cholesteatomas showed good effect, 29% of them showed fair effect, and the effect was poor in the remaining 12%. It was particularly effective in cholesteatomas in the external auditory canal (EAC) (good effect was 84%)(Fig. 2), attic cholesteatomas with an aerated mastoid (good and fair effect was 43% and 36%), and in recurrent type cholesteatoma (good effect was 72%). Particularly in attic type cholesteatoma, a long-term follow up and periodical computed tomography (CT) check up are required for several years after this treatment, because this type of cholesteatoma may have a risk to recur even if it showed a good effect just after treatment. There was no serious side effect observed. No patient recognized hearing loss or tinnitus during or after this treatment, and skin erosion was not seen in any patients. Just in one patient, bone-conduction hearing loss occurred, but the air-conduction threshold remained unchanged and the patient did not complain of a hearing problem. The results of this clinical study indicated that 5-FU treatment is good for the early-stage or EAC-type cholesteatoma, and also for patients who refuse or cannot have surgery for various reasons such as serious underlying diseases, only hearing ear, etc.

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Fig. 1. 5-FU treatment of attic cholesteatoma. a: Step 1, we check the volume of debris, with or without perforation, infection and middle ear effusion before treatment; b: Step 2, cleaning the debris within or on the surface of the cholesteatoma as much as possible. If the patient has inflammation, we use eardrops containing antibiotics, steroids or anti-fungal agents; c: Step 3, 5-FU topical cream is applied exactly on the surface of cholesteatoma. Circle indicates retraction pockets after cleaning the debris. Arrows indicate 5-FU topical cream.

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Fig. 2. Ear findings of a representative case with external auditory canal (EAC)-type cholesteatoma showing good effect. Comparing with before treatment, the EAC condition (*) remained clean without debris or infection after treatment, leaving only bone resolution.

The influence of 5-FU topical cream treatment on inner ear function in guinea pigs

One of our colleagues8 studied the side effects of 5-FU in animal experiments. One week after 5-FU ointment application to the external or middle ear in guinea pigs, the endocochlear DC potential (EP) was measured. When 5-FU ointment was applied on the EAC, there was no significant difference between the EP values of the experimental side and the control side, in other words, inner-ear damage did not occur. When 5-FU ointment was applied on the round window membrane through myringotomy, there was a statistically significant difference between the 5-FU treatment ear and the control ear (p < 0.05, Fig. 3). 5-FU ointment application to the external ear appears to be safe but its application to the middle ear may pose some risk of ototoxicity.

The cell-biological effect of topically applied 5-FU on middle ear cholesteatoma

In previous studies, we focused on the possible involvement of both keratinocyte growth factor (KGF) and its receptor (KGFR) in enhanced epithelial cell proliferative activity and recurrence of cholesteatoma,9 and we examined the effect of 5-FU on the expression of KGF, KGFR and epithelial cell proliferative activity (Ki-67) in attic cholesteatomas by immunohistochemistry.10 The study subjects consisted of 77 ears with attic cholesteatoma under 5-FU treatment (n = 12) or not (n = 65). The results showed that the percentage of the KGF-positive cases was significantly lower in the 5-FU group than in the control group (58.3% vs. 90.5%, p < 0.05). But the percentage of the KGF-receptor-positive cases in the 5-FU group (50%) was almost the same as that in the controls (60.7%). The Ki-67 labeling index was significantly lower in the 5-FU group than in the control group (37.5 ± 0.2% vs. 49.5 ± 0.2%, t = 2.00, p < 0.05). In the cholesteatoma tissue, 5-FU put on the surface of the epithelium may down regulate the expression of KGF in stromal cells, and may reduce the proliferative activity of epithelial cells through the paracrine action of KGF.

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Fig. 3. There was a significant difference between the 5-FU treated ears and control ears (P < 0.05). (Reproduced with modification with permission from Iwanaga T et al.8)

Conclusion

5-FU cream was effective in cholesteatomas particularly in those in the EAC and the attic with an aerated mastoid, and in recurrent-type cholesteatomas. There was no serious side effect observed in this treatment. However, we should use this treatment carefully, and should not put the cream into the middle ear to prevent sensori neural hearing loss. It seems, therefore, recommended to refrain from using it on ears with eardrum perforation. We also found that this agent down-regulated the expression of KGF in stromal cells and reduced the proliferative activity of epithelial cells of cholesteatoma.

References

1.Smith MFW. The topical use of 5-fluorouracil in the ear in the management of cholesteatoma and excessive mucous secretion. Laryngoscope 95:1202–1203, 1985

2.Dushinsky R, Pleven E, Heidelberger C. The synthesis of 5-fluoropyrimidines. J Am Chem Soc 79:4559–4560, 1957

3.Hartman KU, Heidelberger C. Studies on fluorinate pyrimidines. XIII. Inhibition of thymidylate synthetase. J Biol Chem 236:3006–3013, 1961

4.Goldman L. The response of skin cancer to topical therapy with 5-fluorouracil. Cancer Chemother Rep 28:49–52, 1963

5.Wright CG, Bird LL, Meyerhoff WL. Effect of 5-fluorouracil in cholesteatoma development in an animal model. Am J Otolar-yngol 12:133–138, 1991

6.Sala DT. Topical applications of 5-fluorouracil in the medical treatment of cholesteatoma of the middle ear. Ear-Nose-Throat-J 73:412–414, 1994

7.Takahashi H, et al. Clinical efficacy of 5- fluorouracil (5-FU) topical cream for treatment of Cholesteatoma. Auris Nasus Larynx 32(4):353–357, 2005

8.Iwanaga T, et al. Does topical application of 5-fluorouracil ointment influence inner ear function? Otolaryngol Head Neck Surg 134: 961–965, 2006

9.Yamamoto-Fukuda T, Aoki D, Hishikawa Y , Kobayashi T, Takahashi H, Koji T. Possible involvement of keratinocyte growth factor and its receptor in enhanced epithelial-cell proliferation and acquired recurrence of middle-ear cholesteatoma. Lab Invest 83(1):123–136, 2003

10.Yamamoto-Fukuda T, Terakado M, Hishikawa Y , Koji T, Takahashi H. Topical application of 5-fluorouracil on attic cholesteatoma results in downregulation of keratinocyte growth factor and reduction of proliferative activity. Eur Arch Otorhinolaryngol 265:1173–1178, 2008


Address for correspondence: Tomomi Yamamoto-Fukuda, MD, PhD, Department of Histology and Cell Biology, Unit of Basic Medical Science, Nagasaki University Graduate School of Biomedical Sciences, 1–12-4 Sakamoto, Nagasaki 852–8523, Japan. tomomiYF@nagasaki-u.ac.jp

Cholesteatoma and Ear Surgery – An Update, pp. 151–154

Edited by Haruo Takahashi

2013 © Kugler Publications, Amsterdam, The Netherlands