Open Journal of Stomatology, 2011, 1, 212-217 doi:10.4236/ojst.2011.14033 Published Online December 2011 (http://www.SciRP.org/journal/ojst/ OJST ). Published Online December 2011 in SciRes. http://www.scirp.org/journal/OJST A clinico-pathological and cytological study of oral candidiasis Kayo Kuyama1,2, Yan Sun1, Chieko Taguchi3, Hiroyasu Endo4, Masanobu Wakami5, Masahiko Fukumoto6, Takanori Ito4, Hirotsugu Yamamoto1,2 1Department of Oral Pathology, Nihon University School of Dentistry at Matsudo, Chiba, Japan; 2Department of Diagnostic Pathology, Hospital of Nihon University School of Dentistry at Matsudo, Chiba, Japan; 3Department of Social Dentistry, Nihon University School of Dentistry at Matsudo, Chiba, Japan; 4Department of Oral Diagnosis, Nihon University School of Dentistry at Matsudo, Chiba, Japan; 5Department of Crown and Bridge Prosthodontics, Nihon University School of Dentistry at Matsudo, Chiba, Japan; 6Department of Laboratory Medicine for Dentistry, Nihon University School of Dentistry at Matsudo, Chiba, Japan. Email: kuyama.kay o@nihon-u.ac.jp Received 14 October 2011; revised 22 November 2011; accepted 3 December 2011. ABSTRACT Candidiasis of the oral mucosa arises chiefly as a re- sult of infection with Candida albicans. Many clinico- pathological analyses of macroscopic findings have been described, although the clinical findings of oral candidiasis vary considerably and the conditions are complex. The present study analyzes the distribution, clinical, cytological and histological diagnoses of oral candidiasis, associated complex diseases and the di- agnostic value of cytology. The ratio of Candida in- fection was 28.9% among 1551 study participants. Females were infected significantly more often than men (p < 0.01) and the affected age range was 60 - 79 years (61.0%, p < 0.01). The predominantly affected areas were the tongue (48.3%, p < 0.01) and gingiva (20.0%, p < 0.01), and occurrence at multiple loci was seen in 43 (9.6%) patients. The typical clinical find- ings of oral candidiasis were ulcerative/erythematous lesions (33.2%, p < 0.01) and pseudomembranous candidiasis (31.6%, p < 0.01). A histopathological dia- gnosis of candidiasis based on biopsy specimens from 26 lesions in patients with Candida infection indicated by cytology was confirmed from cultures. The break- down of a cytological to a definite diagnosis was 6 positive (SCC 4, verrucous carcinoma 1, moderate to severe dysplasia 1), 6 suspected positive (mild dyspla- sia, 2; moderate to severe dysplasia, 2; papilloma, 1 and SCC, 1) and 14 negative (epulis, 3; papilloma, 3; granulation tissue, 2; fibrosis, 2 and others, 4). Exfo- liative cytology can easily judge the presence of Can- dida species, although experience is necessary for the presumptive diagnosis of an oral mucosal disease. The application of exfoliative cytology using the Pe- riodic acid-Schiff reaction is helpful for the earlier detection of oral candidiasis with various macrosco- pic findings. Keywords: Candidiasis; Oral Exfoliative Cytology; Cli- nico-Pathology 1. INTRODUCTION Candidiasis in the oral mucosa is usually caused by Candida albicans, which is an indigenous fungus in the oral cavity of healthy individuals. However, oral can- didiasis can develop as a result of decreased host immu- nity, that is, as an opportunistic infection. The causes of oral candidiasis include being elderly or being an infant, having AIDS or diabetes, various drugs and local factors such as wearing dentures, steroid preparations and xeros- tomia. Many macroscopic findings of clinico-pathologi- cal analyses have been reported, although oral candidi- asis has a variable clinical presentation and thus can be difficult to precisely diagnose. Exfoliative cytology to screen for oral mucosal disease has been performed for 30 years at our hospital and all specimens are checked for Candida. Additionally, the accuracy of detecting Can- dida by exfoliative cytology has already been proven by simultaneous culture testing [1]. The present study analyzes the distribution of oral candidiasis screened by exfoliative cytology according to sex, location, age and clinical findings. Clinical, cy- tological, histological diagnoses and complicated dis- eases associated with oral candidiasis and the effective- ness of cytology as a diagnostic tool are examined and discussed. 2. MATERIALS AND METHODS We initially enrolled 1551 patients who presented main- ly due to oral mucosal abnormalities, and who were di- agnosed with a Candida infection by exfoliative cytol- ogy between April 2008 and March 2009 at the Depart- ment of Diagnostic Pathology at the Hospital of Nihon University School of Dentistry at Matsudo. All cytologi-
K. Kuyama et al. / Open Journal of Stomatology 1 (2011) 212-217 213 cal specimens were examined by Papanicolaou (Pap) staining and the Periodic acid-Schiff (PAS) reaction, and reconfirmed by an internationally qualified cytological screener and three specialists in oral cytopathology. Can- dida infection was diagnosed when spores, pseudohy- phae and/or mycelia were confirmed by PAS reaction. Candida infection in those with only detectable spores was confirmed by colony formation and culture (Nissui Pharmaceutical Co. Ltd., Tokyo, Japan). Six cases per- formed biopsy immediately among 12 cases in which the malignant tumor was suspected, cytological and clini- cally. The 6 remaining cases transferred to another hos- pital at the patient’s requests. The 437 cases except these 12 cases were performed intraoral re-examination after they had removed Candida. Biopsies were obtained from those with consistent macroscopic findings and diseases were histopathologically diagnosed by three oral pa- thologists using hematoxylin and eosin staining (H.E.) to determine more complex diseases. Histopathological di- agnoses followed the diagnostic criteria of the World Health Organization WHO [2]. Data were analyzed ac- cording to the age, location, clinical diagnosis, cytologi- cal diagnosis, histopathological diagnosis and disease complexity. The Ethics committee of Hospital of Nihon University School of Dentistry at Matsudo approved this study, and all patients provided written, informed con- sent to participate in all procedures associated with the study. All data were statistically analyzed using the Chi- square test (SPSS). 3. RESULTS 3.1. Candida Infection Rate Among 1551 (male 576, female 975) patients who pre- sented at our hospital with an oral mucosa disorder as the chief concern, 449 (28.9%; male, 156 (34.7%); fe- male 293 (65.3%)) of them were infected with Candida. 3.2. Distribution of Patients Significantly more women than men (p < 0.01) were infected. The retrieval of information according to age excluded 2 men and 10 women of unknown age. Table 1 shows the age distribution of individuals with oral candi- diasis. Most of the infected individuals were aged 60 - 79 years (61.0%, p < 0.01). Tabl e 2 lists the locations of oral candidiasis. Most lesions were on the tongue (48.3%, p < 0.01), followed by the gingiva (20.0%, p < 0.01), cheek (11.1%), lips (5.3%), palate (4.2%) and oral floor (1.3%). The tongue was further sub-classified as the do- rsum (43.8%, p < 0.01), margin (40.5%, p < 0.01), apex (7.4%), inferior aspect (4.6%), root (1.4%) and the entire tongue 5 (2.3%). Maxillo-mandibular infections were located in the gingiva (7.8%; 4/90), lip (8.3%; 2/24), right and left margin of the tongue (5.7%; 5/88), and cheek (22.0%; 11/50), and 43 (9.6%) patients had lesions at multiple loci. 3.3. Clinical Manifestations The clinical manifestations of patients with oral candi- diasis (Table 3) comprised ulcerative/erythematous le- sions (33.2%, p < 0.01), pseudomembranous candidiasis (31.6%, p < 0.01), white patch/leukoplakia (12.2%), denture stomatitis (8.9%), erythema (7.1%), lichen pla- nus (4.2%), nodules (2.2%) and angular cheilitis (0.4%). Table 1. Distribution of the patients of oral candidiasis. Age No.% Male % Female% 0 - 9 2 0.4 0 0.0 2 0.7 10 - 19 4 0.9 3 1.9 1 0.3 20 - 29 6 1.3 2 1.3 4 1.4 30 - 39 12 2.7 6 3.8 6 2.0 40 - 49 28 6.2 14 9.0 14 4.8 50 - 59 55 12.2 19 12.2 36 12.3 60 - 69 10222.7** 30 19.2 72 24.6 70 - 79 17238.3** 62 39.7 110 37.5 80 - 89 46 10.2 17 10.9 29 9.9 90 - 99 10 2.2 1 0.6 9 3.1 Unknown12 2.7 2 1.3 10 3.4 Total No.449100.0 156 100.0 293 100.0 **: A significant difference (p < 0.01) was observed among all the age groups by chi-square test. Table 2. The location of oral candidiasis. LocationNo.% No.% Gingiva 9020.0Lower 50 55.6** Upper 36 40.0** Upper & lower 4 4.4** Palate 194.2 Hard 16 84.2** Soft 3 15.8* Lip 245.3 Upper 12 50.0 Lower 8 33.3 Angle 2 8.3 Upper & lower 2 8.3 Oral floor6 1.3 Tongue 21748.3*Dorsum 95 43.8** Margin 83 38.2** Apex 16 7.4 Inferior aspect 10 4.6 Root 3 1.4 Right & left margin 5 2.3 Entire tongue 5 2.3 Cheek 5011.1*Cheek 39 78.0* Right & left cheek 11 22.0* Multiple439.6 *Cytological study of oral candidiasis. Significant differences (**: p < 0.01,*: <0.05) was observed among all the age. C opyright © 2011 SciRes. OJST
K. Kuyama et al. / Open Journal of Stomatology 1 (2011) 212-217 Copyright © 2011 SciRes. 214 OJST Table 3. Clinical diagnoses of oral candidiasis. No. % Pseudo membranous 142 31.6** Acute forms Erythematous 32 7.1 Leukoplakia 55 12.2 Lichen planus 19 4.2 Ulcerative/erythematous 149 33.2** Chronic forms Nodular 10 2.2 Denture stomatitis 40 8.9 Angular cheilitis 2 0.4 Median rhomboid glossitis 0 0.0 Candida-associated lesions Linear gingival erythema 0 0.0 **: A significant difference (p < 0.01) was observed among all the age groups by chi-square test. 3.4. Cytological and Histopathological Diagnoses Cytology with the PAS reaction detected Candida infec- tion with 100% precision. That is, Candida infection was confirmed by mycelia growth in all of the cultures that tested positive by PAS. Table 4 shows the cytological and oral biopsy findings. Cytological diagnoses were negative in 395 (88.0%), suspected positive in 39 (8.7%) and positive in 15 (3.3%) cases. The estimated negative diagnoses comprised inflammatory lesions (67.9%; 305/ 395) and hyperkeratosis (20.0%; 90/395), and the esti- mated positive diagnoses were verrucous (0.2%; 1/15) and squamous cell carcinoma (SCC, 3.1%; 14/15). We histopathologically diagnosed 26 lesions from 24 pa- tients in whom Candida infection was identified cyto- logically and confirmed by cultures. The breakdown of cytologically confirmed diagnoses is as follows. Six were confirmed as positive (SCC, (n = 4)); verrucous carcinoma, (n = 1); moderate to severe dysplasia, (n = 1), 6 suspected positive with mild (n = 2) and moderate to severe (n = 2) dysplasia; papilloma, (n = 1) and SCC (n = 1), and 14 were confirmed as negative, and having epulis (n = 3), papilloma (n = 3), granulation tissue (n = 2), fibrosis (n = 2) and others (n = 4). Candida infection was accompanied by benign and malignant diseases in 20 (76.9%) and 6 (23.1%) patients, respectively. 3.5. Treatment for Candida Infection The 437 patients in whom Candida infection was cyto- logically diagnosed were treated with an antifungal drug. These strategies resulted in the disappearance of the fungal mycelia from 432 cases (98.9%). 4. DISCUSSION Oral candidiasis is a common opportunistic infection in individuals with decreased immunity. Physiological factors Table 4. Result of cytology, treatment and biopsy. Cytological diagnosis No. % Estimate diagnosis No%No. of A.D.*No. of C.C.** No. of Biopsy Definite diagnosis No. Negative 395 88.0 Inflammatory change 30567.9305 305 14 Epulis 3 Hyperkeratosis 9020.090 86 Papilloma 3 Granulation tissue 2 Fibrosis 2 Fibro-epithelial polyp 1 Pyogenic granuloma 1 Capillry hemangioma 1 Sjögren syndrom 1 Suspicious of positive 39 8.7 Dysplasia 398.739 38 5 Mild dysplasia 2 Moderate to severe dysplasia2 Papilloma 1 Squamous cell carcinoma1 Positive 15 3.3 Verrucous carcinoa 1 0.20 0 7 Squamous cell carcinoma4 SCC*** 143.13 3 Verrucous carcinoma 1 Moderate to severe dysplasia1 A.D.*: Antifungal drug; C.C.**: Cured Candidiasis; SCC***: Squamous cell carcinoma.
K. Kuyama et al. / Open Journal of Stomatology 1 (2011) 212-217 215 that predispose individuals to oral candidiasis comprise pregnancy, immune defects, drugs and malnutrition, and local factors including trauma, denture-associated prob- lems and oral cancer [3]. Most reports have relied on macroscopic observation by dental clinicians, although many reports have described clinico-pathological studies of oral candidiasis. The present epidemiological study examined oral candidiasis detected by exfoliative cytol- ogy and by visible cultures. We also identified the value of oral exfoliative cytology for diagnosing oral candidi- asis. 4.1. Ratio of Candidiasis Candida species comprise the most common opportunis- tic fungal pathogens in humans, with C. albicans being the most prevalent cause of mucosal and systemic infec- tion. C. albicans has been described as the most frequent- ly encountered oral fungal commensal with detection rates of 40% to 65% in healthy adults [4]. The ratio of oral candidiasis in the present study was 28.9%, which was similar to the reported 24% of outpatients at a dental clinic [5] and 24.5% in a review of eight publications [6]. On the other hand, the rate of candidiasis was 14.09% in a large-scale Brazilian study of 1586 randomly selected individuals [7]. However, the detection rates were very low when Candida infection was determined only from interviews and macroscopic observations. 4.2. Epidemiological Features Infection rates were influenced by age and removable prostheses in a Brazilian study [7]. Age-matched statis- tical analysis in the present study found a significantly higher infection rate among 60 - 79-year-olds than in any other age group. Many factors have been investigated, such as an impaired host defense causing deceased Sali- vary flow [8], an increase in the morbidity rate of diabe- tes [9], wearing dentures [10], and taking medicine to treat chronic [11] and auto-immune diseases such as Sjögren syndrome [8]. The prevalence rate of oral candi- diasis among children with oral mucosal diseases was the highest among those aged 0 - 12 years (28.4%) [12], which was similar to findings from other countries [13- 15]. The ratio of 0 - 19-year-olds was very small in the present study. Rare symptoms of oral candidiasis in chil- dren might have been one of the causes. The higher pre- valence of candidiasis among women in the present stu- dy is in agreement with the findings of other studies [16, 17]. In fact, 62.9% of the patients who presented with the chief concern of oral mucosal abnormalities were female in the present study Furthermore, xerostomia and autoimmune diseases that cause oral candidiasis are pre- valent among women. Half of our patients with a Can- dida infection had lesions that were concentrated mostly on the dorsum and edges of the tongue. The dorsal sur- face is the main ecological niche for Candida in the oral cavity [4,8,11,18]. Presumably, chronic contact with den- tures [10] and relationships with oral mucosal diseases such as leukoplakia and injuries might explain the high frequency of infections being located on their edges. Moreover, since multiple symptoms were quite abundant (15.6%), we considered that factors such as age, drugs and immune defects were involved. 4.3. Clinical Manifestations The clinical classification of candidiasis is highly com- plex because the findings are diverse. Therefore, we categorized candidiasis into acute, chronic and Can- dida-associated lesions based on Lakshman’s classifica- tion [3]. We concentrated on the ulcerative/erythematous and pseudomembranous types. An inflammatory reaction was obvious in ulcerative/erythematous and Can dida- associated lesions. The hyphae of C. albicans tightly adhere to epithelial cells, and proteinases secreted by the hyphae damage the oral mucosa [19]. Schaller et al. as- sert that C. albicans proteinase causes tissue damage and increasing vascular permeability leads to an inflamma- tory reaction and clinical symptoms [20]. Chronic ery- thematous candidiasis is associated with corticosteroids, antibiotics and HIV infection. Dentists often treat stoma- titis with triamcinolone acetonide, which is routinely available at Japanese drugstores and prolonged use of this drug can become problematic [21]. In addition, can- didiasis can be a side effect of the inhaled steroids that are used to treat asthma [22] and allergosis. Because erythematous candidiasis is similar to a non-specific inflammatory reaction, it should be cytologically diag- nosed as soon as possible. The reported ratio of denture- related stomatitis (DRS) ranges from 11% to 67% [23]. A removable prosthesis is the most common cause of the growth and pathogenicity of Candida species [4,18,24]. Angular cheilitis is also associated with yeasts and bac- teria in relation to wearing dentures [3]. Candida species proliferate by contact with the resin [10], and Candida counts significantly correlate with the intensity of den- ture plaque scores [25]. The rate of hyperplastic candi- diasis that macroscopically presented like leukoplakia was 12.2% in the present study, and the malignant trans- formation rate was high [26]. Simultaneous Candida infection and several etiological factors seemed to play a role in malignant transformation [27]. Candida species were identified in 43.7% of the patients with lichen planus and leukoplakia in their oral cavities [28]. The reported prevalence of oral candidiasis varies between 8% and 94% in patients with advanced cancer, because of differences in diagnostic criteria, diagnostic methods and the study population [29]. Whether a condition de- pends only on a Candida infection or such infection with coexistent mucous membrane diseases should be deter- mined as soon as possible. Macroscopic classification is C opyright © 2011 SciRes. OJST
K. Kuyama et al. / Open Journal of Stomatology 1 (2011) 212-217 216 limited as most epidemiological surveillance concerning oral candidiasis considers the candidiasis, DRS and chei- litis as separate entities [17,30]. 4.4. Accuracy of Exfoliative Cytology Information about investigating Candida infection of the cervical area using Pap smears is very scarce [31]. Can- dida species have been detected based on the growth of hyphae on PAS smears [4,6]. The high accuracy of de- tecting oral candidiasis by exfoliative cytology was de- monstrated here, as well as by others [1]. The cytolo- gical detection of candidiasis is simple, inexpensive, ac- curate and painless. As for oral candidiasis, it is clini- cally variegated to present the findings of leukoplakia or intractable ulcerative lesion, etc. In this result, the abbre- viation half of oral candidiasis was occupied by these confusing clinical view. Therefore, discovery of candi- diasis by cytology was useful for avoiding unnecessary biopsy. In addition, as a result of giving antifungal drug immediately, as for candidiasis detected by cytological diagnosis, the fungal mycelia disappeared with 98.9% of these cases. However, Candida can be over- and under- diagnosed when other mucosal diseases coexist, espe- cially dysplasia and SCC. The size and shape of oral epi- thetlial cells infected with Candida significantly change [1,32]. Judgment of changes between atypia by Candida and dysplastic change should be required experience. In that case, judgment becomes possible by carrying out observation of a macro-scopic view, and exfoliative cy- tology after antifungal drug. In Japan, there is a custom which applies triamcinolone acetonide easily to stomata- tis. 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