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��ࡱ�>��	�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������y�	�R���bjbj��F��{�{BF%�������jj������������8Lg4�T9���"���'''8��8�8�8�8�8�8$;��=��8Q�'''''�8����T9'V����8'8�N0�2�����`w��������}f�0�7$90T91�>���>(22�>�*2�'''''''�8�8y'''T9''''���������������������������������������������������������������������>'''''''''j+�:	Incidence of Benign and Malignant Eyelid Tumors in Japan


Hiroshi Toshida1*, Naoki Mamada2, Takuro Fujimaki2, Toshinari Funaki2, Nobuyuki Ebihara2, Akira Murakami2), Shigekuni Okisaka2,3

1 Department of Ophthalmology, Juntendo University Shizuoka Hospital, Shizuoka, 410-1129, Japan
2 Department of Ophthalmology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan
3 Laboratory of Ophthalmic Pathology Education, Tokyo, 156-0043, Japan


(Running title: Incidence of Eyelid Tumors in Japan)


Manuscript category: original article
Word count for Abstract: 188
Word count for main text: 1942
No. of references: 21
No. of figures: 0
No. of tables: 4


Authors certify that no portion of this manuscript has been previously published, and reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. We all agree for publication.


Corresponding author: Hiroshi Toshida. M.D., Ph.D.; 
Address: Department of Ophthalmology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2295, Japan.
Tel.: +81-55-948-3111. 
Fax: +81-55-948-3351. 
E-mail;  HYPERLINK "mailto:toshida@juntendo.ac.jp" toshida@juntendo.ac.jp
Abstract
Purpose: To report incidence of eyelid tumors and tumor-like lesions that were examined histopathologically. 
Methods: We reviewed retrospectively 118 eyelid tumors that were examined histopathologically at the Department of Ophthalmology of Juntendo University School of Medicine over a 15-year period. The incidence of each disease and the rate of malignancy were investigated.
Results: The subjects included 47 males and 71 females, with an average age at removal of lesions 47.8�23.7 years old. There were 106 benign tumors (89.8%), with the most common cases being 23 nevi, followed by 18 squamous cell papilloma, 14 seborrheic keratosis, 10 epidermal cysts. Among 12 cases (10.2%) with malignant tumors, the number of male was 4 and female 8. The average age at removal of the malignant tumors was 53.1�20.7 years old, although the males were significantly younger than the females (33.8�24.0 years old versus 62.8�10.2 years old) (t-test, p<0.05). The malignant tumors consisted of basal cell carcinoma (4 cases), malignant lymphoma (3 cases), squamous cell carcinoma and sebaceous carcinoma (2 cases each), and Bowen�s disease (1 case). 
Conclusions: Malignant tumors accounted for 10.2%, and the age at removal was younger in male. 

Key words: tumor, eyelid tumor, incidence, eye, adnexa















Introduction
	Benign eyelid tumors are more common than malignant ones and are the decision making is important in ophthalmic practice. Macroscopic decision making is difficult, and definitive histopathological examination is required [1]. Therefore, the knowledge of the incidence of tumors is helpful for the clinical practice. Especially, the incidence is important for diagnosis, and there are differences among countries, races and time when the investigation was done, even though it depends on the geographic location and genetic background of the population surveyed and its socioeconomical status and access to medical care [2].
	Although there have been many reports about eyelid tumors in Japan [3-6], most have covered malignant tumors and few have also included benign eyelid tumors. In the present study, we investigated histopathologically the incidence of eyelid tumors examined at the Department of Ophthalmology, Juntendo University School of Medicine over a 15-year period. 

Materials & Methods
	The materials were 118 consecutive cases of eyelid tumors that were histopathologically examined between January 1993 and December 2007. The subjects included 47 males and 71 females. These were all retrospectively reviewed and diagnosed by the same ophthalmologist (S.O.) in accordance with the tumor classification based on the 2006 edition of the AFIP atlas of tumor pathology [7] basically, except inflammatory lesions. Eyelid tumors of the palpebral conjunctiva, recurrent tumors and chalazion were not included in the present study, except and tumors of the palpebral conjunctiva. 
	We first categorized the eyelid tumors as benign or malignant, and then examined the incidence, the average age at removal and gender. We also examined predilection site of benign and malignant tumors by categorizing the tumor sites into four regions: upper eyelid, lower eyelid, outer canthus, and inner canthus. We combined Meibomian gland carcinoma and Zeis gland carcinoma as sebaceous carcinoma.

Results
1. Incidence of tumors
	Of 118 tumors that were removed and examined, 106 (89.8%) were benign and 12 (10.2%) were malignant. There were no differences in incidence between benign and malignant lesions (unpaired t-test). The most frequent histopathological diagnosis among 106 benign lesions was nevus in 23 cases (21.7% of all benign lesions), included intradermal nevus (9 cases), pigmented nevus (7 cases), nevocellular nevus (5 cases) and compound nevus (2 cases). Squamous cell papilloma in 18 cases (17.0%), seborrheic keratosis in 14 cases (13.2%), epidermal cyst in 10 cases (9.4%), dermoid cyst in 7 cases (6.6%) and verruca vulgaris in 6 cases (5.7%) were followed [Table 1]. The malignant tumors were as follows: basal cell carcinoma in 4 cases (33.3% of all malignant lesions), malignant lymphoma in 3 cases (25.0%), squamous cell carcinoma in 2 cases (16.7%), sebaceous carcinoma in 2 cases (16.7%) and Bowen�s disease in 3 cases (8.3%) [Table 2].  

2. Age
	The ages of the 118 patients ranged from 1 to 94 years old, with an average age of 47.8 � 23.7 years old. The average ages of the 107 patients with benign lesions were 47.8 � 23.2 years old, and 12 patients with malignant lesions 53.1 � 20.7 years old. There were no statistical differences in ages between benign and malignant lesions. In the review of age distribution for each lesion, notable trends were the relatively even distribution for nevi between 2 and 77 years old (average: 46.7 � 18.7 years old).  Squamous cell papilloma was distributed between 6 and 90 years old (average: 50.8 � 22.9 years old) and the peak occurrence between 50 and 70 years old. All cases of seborrheic keratosis were shown 40 years old or older, and approximately 40% in their 70s or older (average: 64.1 � 15.9 years old).  Epidermal cysts were common both in patients in their 60s and 30s or younger (average: 43.7 � 30.3 years old). Most of patients with verruca vulgaris were 50 years old or older (average: 50.7 � 22.3 years old) except one female.
	The average age at removal of the malignant tumors was 53.1 � 20.7 years. Basal cell carcinoma was common among patients who were aged 50 years old or older, except one patient was a 7-year-old male. Malignant lymphoma was shown in patients aged 45, 61 and 65 years old. Squamous cell carcinoma was shown at different ages, including patients aged 22 and 59 years old. Sebaceous carcinoma was shown in patients aged 49 and 74 years old. Patient with Bowen�s disease was appeared in 63 years old.

3. Gender
	We examined differences in the frequency of tumors between males and females. Although the number of female patients with both benign and malignant tumors was higher, there was no statistical significant [Tables 1 and 2]. Among 12 cases with malignant tumors, the number of male was 4 and female 8. The average age at removal of the malignant tumors was 53.1 � 20.7 years old as described above, although the males were significantly younger than the females (33.8�24.0 years old versus 62.8�10.2 years old) (unpaired t-test, p<0.05). In the malignant tumors, basal cell carcinoma (1 male, 3 females), sebaceous carcinoma (no males, 2 females) and Bowen�s disease (no males, 1 female) occurred more frequently in women.

4. Sites of tumor
	Table 3 shows the results of major benign tumors, and there was a trend to occur most frequently on the upper eyelid, followed by the lower eyelid, the inner canthus, and then the outer canthus, commonly. Most of malignant tumors were also appeared on the upper eyelid and on the lower eyelid [Table 4]. One basal cell carcinoma involved both the lower eyelid and inner canthus. 

Discussion
	Malignant tumors are commonly needed to excise medically. In contrast, most of benign tumors are excised by patient's wish for cosmetics. In addition, there are many cases which surgical resections are not carried out in patients with benign tumors. For these reasons, the difference of the histopathological results and practical generating frequency exists. In previous reports, the frequency of malignant eyelid tumors was between 14 and 27% [2,4,8-11], especially, 27% was in Japan [4]. Although the percentage of malignancy in our series was 10.2%, there was likely to be a problem in judging that the frequency of the malignant tumor decreased because of reasons described below. We excluded inflammatory lesions, chalazion and conjunctiva originated tumors were included in a total changes with papers as previous report [2,12]. It might influence a little. There are commonly differences in the incidence of eyelid tumor among regions, countries, races and time [2]. In addition, medical circumstance, such as the number of hospitals and doctors per population, has a difference by the area. For example, in Tokyo, many university hospitals and its branch hospitals are located more than 20. In addition, there are also national cancer center and cancer institute hospital. There is a possibility that the patients with malignant tumor are distributed to them, since there are many hospitals, or concentrating on national cancer center and cancer institute hospital. Although we reviewed eyelid tumors that were surgically resected at our department and all specimens were examined histopathologically by an ophthalmologist over the past 15 years, it may not be reflecting the actual condition in Tokyo.
0In the present study, more than half of all benign tumors consisted of nevi, squamous cell papilloma, or seborrheic keratosis. These results were similar to previous reports.  
From Japan and other countries that most frequent were primarily nevi, cysts, seborrheic keratosis, and papilloma [2,4,8]. In our series, women had a significantly higher incidence of benign tumors. This may be because women are more conscious of cosmetic concerns and therefore are more likely to request surgery. For example, frequency of seborrheic keratosis is higher in male than in female [2], but were more common among women in the present study. It can be assumed the male to female ratios for other benign tumors might be influenced by the number of patients who request surgery for cosmetic reasons, as well as by how physicians establish the indications for surgery. The incidence rate of benign eyelid tumors is also particularly affected by certain factors at each institution or country, such as how much histopathological detail the surgeons request and how the indications for surgery are established. 
0	The most common site for benign tumors, apart from nevus, was the upper eyelid and second the lower, whereas malignant tumors showed little difference with regard to occurrence on the upper or lower eyelid [Tables 3 and 4].0
	Among malignant tumors in the present study, basal cell carcinoma, malignant lymphoma, squamous cell carcinoma, sebaceous carcinoma and Bowen�s disease were shown, even though there are small numbers of the malignant tumors. According to previous reports, the majority of eyelid malignancies are basal cell carcinomas, squamous cell carcinomas and sebaceous carcinomas [2,3,5-8,10,12,14-17].   
	In general, it is known that there are differences in the incidence of malignant eyelid tumor among regions, countries, races, time and among area, especially even within Asia. 
	As all cases of malignant lymphoma were diagnosed before 2001, when WHO classification was renewed [18]. In the present study, one case was defined as T-cell lymphoma shown in 45-year.old male, located in upper eyelid. Other 2 cases were B-cell lymphoma. One was 61-year old male located in upper eyelid, another was 65-year old female of mantle cell lymphoma located in lower eyelid. The incidence of malignant lymphoma was 25% (3 of 12 malignant tumors), which percentage seemed to be higher comparing to previous reports [2,3] including report from north area of Japan (2.6%) [3]. However, it is difficult to judge whether it does not match those previous studies. Because the other studies from different area in Japan reported that the frequency was not low. For example, Obata et al reported that 4 of 24 malignant eyelid tumors (16.7%) were malignant lymphoma and Kawana et al reported 11 of 60 (18.3%), both done in Tokyo and in Kanto district that included Tokyo. The area might be related to incidence of malignant lymphoma even inside of Japan.
	While the average age at removal of eyelid malignancy was 53.1 � 20.7 years in the present study, the frequent age at removal of eyelid malignancy was the 60s in the previous studies [12,14,15], and studies from other Japanese institutions reported that the average age or the peak was in patients in 68 years older higher [3-6].  In addition, the average age in male and female was 33.8�24.0 years old and 62.8�10.2 years old respectively. The youngest case was 7-year .old boy with basal cell carcinoma and 22-year.old male with squamous cell carcinoma was followed. After tumor extraction, the recurrence is not accepted in both cases. Such younger cases are rare and it is not easy to find the reason of development of malignant tumors in young male. Reviews since the 1940s have reported patients younger than 11 years with eyelid malignancy (basal cell carcinoma) [19], including a 5-year-old patient.  The youngest such patient in Japan was 26 years old [20]. As the age at removal of eyelid malignant tumors tended to be younger than that of benign tumors significantly described above, although number of our cases were a few. 
	Another reason for this younger onset is assumed to be the small number of sebaceous carcinomas in the present series, since these are usually more common in the elderly. Other institutions have reported an average age of 60 years or older for eyelid malignancies as described above. Basically in recent years, cases of malignant tumors in the eye and adnexa occurring at a younger age have been consistently reported [12,19]. Furthermore, eyelid malignancy tended to occur at a younger age, and we have previously reported that keratoconjunctival malignant tumors also occurred at a younger age [21]. Further studies are needed to elucidate the causes of young-onset eyelid malignancy. 













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