Chronic inflammatory periapical diseases: a Brazilian multicenter study of 10,381 cases and literature review

The aim of this study was to investigate the epidemiological and clinical characteristics of chronic inflammatory periapical diseases in different regions of Brazil and to compare with data from the literature. A multicenter study was carried out in four Brazilian referral centers in oral diagnosis. Histopathological records were reviewed, and all cases diagnosed microscopically as periapical granuloma, radicular cyst, and periapical abscess were included. Demographic and clinical data were collected. Descriptive statistics and Pearson’s chi-square test were performed. A total of 10,381 cases of chronic inflammatory periapical diseases were found (13.8% of 74,931 archived specimens) over a period of 65 years. Radicular cysts were the most common lesion (59.9%). Women (56.1%) with a mean age of 37.01 years old (range 13 to 100 ± 14.42) and people of white skin color (59.2%) were the most affected individuals by chronic inflammatory periapical diseases. The lesions were generally asymptomatic (28.1%), located in the maxilla (60.1%), and posterior region (49.8%). The radicular cysts were larger when compared to periapical granulomas (p < 0.001). The disagreement between the clinical and histopathological diagnoses was higher when the final diagnosis was a periapical granuloma (p < 0.001). Chronic inflammatory periapical diseases continue to be common lesions affecting mainly adults. This should be a consequence of the burden of untreated caries in permanent teeth. Women are more affected and radicular cyst was the most common lesion.


Introduction
In recent years, the global prevalence of untreated caries in permanent teeth has stagnated worldwide. 1 However, dental caries remains the most common oral disease affecting the world population. 2 This situation is not different in Brazil, even though significant advances in dental caries prevention and control has taken place. 3 The main consequence of untreated caries is pulp necrosis. 4 Therefore, along with periodontitis, dental caries is the main cause of tooth loss in adult patients. 5 Periapical disease is an inflammatory disease around the apex of the root of a tooth caused by an infection in the root canal. 6,7 Although trauma and iatrogenic factors may lead to this outcome, dental caries is the main cause Declaration of Interests: The authors certify that they have no commercial or associative interest that represents a conflict of interest in connection with the manuscript. of pulp infection. 4,8 Periapical disease is characterized by local inflammation, bone and tissues destruction resulting in periapical lesions, usually classified in accordance with their histological structure in periapical granulomas, radicular cysts, and periapical abscesses. 6,9 Briefly, periapical granulomas are histopathologically constituted by "presence of a granulomatous tissue predominantly infiltrated with lymphocytes, plasma cells and macrophages" 6 and "may be non-epithelialized or epithelialized." 6 Radicular cysts are constituted by "a distinct epithelium-lined pathological cavity." 6 Periapical abscesses are lesions constituted by "presence of a distinct collection of polymorphonuclear leukocytes" and may be epithelialized or non-epithelialized. 10 Epidemiological clinical studies in different populations show periapical disease as a widespread condition in many countries. 11,12,13,14,15 However, there is an expressive variability in the results, particularly in relation to the frequency of these lesions. Considering that Brazil is a continental country, with marked social differences among regions and inequalities associated with oral health care, 3 a multicenter study in this country may depict the epidemiological and clinical aspects of chronic inflammatory periapical disease more appropriately. In addition, this study may contribute to the knowledge of specific features of periapical disease and the association of this outcome with demographic and clinical characteristics of the affected population.
Thus, the aim of this multicenter study was to investigate the epidemiological and clinical characteristics of chronic inflammatory periapical diseases including periapical granulomas, radicular cysts, and periapical abscesses in a sample of Brazilians, and to compare these features with data retrieved in a literature review.

Sample
Histopathological records (n = 74,931) of oral and maxillofacial lesions registered at the Oral and Maxillofacial Pathology services of all the participating institutions were reviewed without any date restrictions. All cases with a microscopic diagnosis of a periapical granuloma, radicular cyst, or periapical abscess 6 were selected. The terms used for this study were periapical granuloma, apical granuloma, dental granuloma, radicular granuloma, dental radicular granuloma, radicular cyst, periapical cyst, apical periodontal cyst, dental cyst, apical cyst, dental radicular cyst, residual cyst, residual radicular cyst, residual periapical cyst, residual dental radicular cyst, periapical abscess, dental radicular abscess, dental abscess, and dentoalveolar abscess. Cases without a histopathological diagnosis were excluded, as well as cases affecting individuals ≤ 12 years because of the mixed dentition, for which a separate analysis is more appropriate.

Statistical analysis of data
The statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software, version 22.0 (SPSS Inc., Armonk, USA). Descriptive statistics and bivariate analyses using Pearson's Chi-square test were carried out. The z-test to compare the proportions in the columns and the Bonferroni correction were employed for variables with more than two categories. P values < 0.05 were considered statistically significant.

Literature review Eligibility criteria
A literature review was carried out to retrieve retrospective studies investigating the frequency of periapical diseases microscopically diagnosed in Oral and Maxillofacial Pathology services. Inclusion criteria were: studies assessing cases with a microscopic diagnosis of periapical granuloma, radicular cyst, or periapical abscess and studies in English, Portuguese, or Spanish published within the last 20 years (1999-2019). Case reports or series with less than 10 cases, in vitro studies, immunohistochemistry and microbiology studies, animal studies, studies with cadaver, prospective studies, studies that included restricted age groups (for example children/adolescents or older people), studies that did not report the total sample size, reviews, editorials, letters, abstracts of scientific meetings, and book chapters were excluded.

Information source
The electronic search was performed in PubMed (National Library of Medicine), in September/2019 using the following search strategy: apical periodontitis OR periapical periodontitis OR periapical lesion OR apical lesion OR periapical granuloma OR apical granuloma OR dental granuloma OR radicular granuloma OR dental radicular granuloma OR radicular cyst OR periapical cyst OR apical periodontal cyst OR dental cyst OR apical cyst OR dental radicular cyst OR residual cyst OR residual radicular cyst OR residual periapical cyst OR residual dental radicular cyst OR periapical abscess OR dental radicular abscess OR dental abscess OR dentoalveolar abscess AND histopathological OR histopathologic OR microscopic OR microscopy OR slide.

Study selection
The selection of studies performed by two reviewers (AMC and LGA) was divided into two phases. In Phase 1, titles/abstracts that fulfilled the eligibility criteria were included. In case of doubt, the full text was retrieved for evaluation in Phase 2 to determine whether the reference would be included or not.

Data extraction
Data extracted from the included articles were: authors, year of publication, country where the study was conducted, period of investigation (in years), sample size (total), group of oral lesions included, frequency of periapical diseases -periapical granuloma, radicular cyst and periapical abscess -(% total), and frequency of periapical diseasesperiapical granuloma, radicular cyst, and periapical abscess -(% in group of oral lesions included).

Multicenter study
Among the 74,931 records, 13.8% (10,381 samples) were cases of chronic inflammatory periapical diseases in individuals ≥ 13 years old. Considering the specific diagnosis, radicular cysts represented 8.2%, periapical granulomas represented 5.4%, and periapical abscesses, 0.07% of all records. The cases of periapical diseases were distributed within the institutions as follows: 286 in UEPB, 903 in UFG, 4,388 in UFMG, and 4,804 in UFPel. Table 1 shows the frequency of periapical diseases per institution and in general. Agreement between the clinical and histopathological diagnoses occurred in 5,865 (56.5%) cases, disagreement in 1,933 (18.6%), missing clinical diag nostic information in 1,006 (9.7%) cases, and 1,577 (15.2%) of the cases had a non-specific clinical diagnosis, making the analysis unfeasible. Table 3 shows the clinical diagnoses of the cases, for which there was disagreement with the histopathological diagnosis. For the cases in which the histopathological diagnosis was a periapical granuloma, the most frequent diagnostic hypothesis was a radicular cyst [ Bivariate analyses results comparing periapical granulomas and radicular cysts are shown in Table 4. There was a significantly higher frequency of women diagnosed with periapical granulomas and radicular cysts (p < 0.001) and a significantly higher frequency of radicular cysts diagnosed in patients aged 13-19 and 50-59 years in relation to periapical granulomas (p < 0.001).
Although uncommon, symptomatology was more frequently reported among cases of cysts than among cases of granulomas (p < 0.027). Cysts were also bigger than granulomas (p < 0.001). The mean size of periapical granulomas was 7.22 mm Table 3. Clinical diagnosis of cases with disagreement between the clinical and histopathological diagnosis (n = 1,933).

Discussion
This multicenter study showed that chronic inflammatory periapical diseases are common, representing 13.8% of the lesions diagnosed in the referral centers where data for the present study were collected. Radicular cysts accounted for 8.29%, periapical granulomas accounted for 5.48%, and periapical abscesses accounted for 0.07%. The frequency of lesions was higher in the southern region (19.5%). In agreement with these results, most studies included in the literature review also demonstrated an expressive frequency of periapical diseases in Oral and Maxillofacial Pathology services. The association of dental caries with periapical disease is helpful in the understanding of these results. 4 Although dental caries may develop later in life with a reduction in childhood prevalence, there is a burden among adults with economic and social consequences. 1 Therefore, effective allocation of resources in preventive or therapeutic actions aiming to tackle dental caries in individuals of all ages would prevent the development of chronic periapical disease in Brazil and elsewhere.
In the present study, radicular cysts (59.9%) were more frequent than periapical granulomas (39.6%) agreeing with what has been described in other studies. 11,15,28 Radicular cysts were the most frequent chronic inflammatory periapical disease. Probably, conventional endodontic treatment is more successful for periapical granulomas than for radicular cysts 15 and after periapical surgery, the radicular cysts are the periapical lesions that present worse prognosis. 29 Therefore, surgical treatment with posterior histopathologic exam is employed more frequently for the treatment of radicular cysts 15 , explaining the frequency results of this study. However, there are also studies describing periapical granulomas as the most common periapical disease. 30,31 Comparisons among studies are difficult due to differences in sample size, type of study, nomenclature, and histopathological criteria in the differentiation of radicular cysts and periapical granulomas. [11][12][13][14][15]32 Finally, in this study, periapical abscesses were extremely uncommon lesions, similar to findings published elsewhere. 12,14 Another interesting aspect is the tendency to surgically remove larger lesions, while minor lesions are usually treated without surgery. 33 Usually, larger lesions are radicular cysts. 34 Indeed, in this study, a significantly higher frequency of radicular cysts measuring more than 10 mm was observed. Most periapical granulomas (87.4%) had a mean size of 10 mm and cysts were approximately double the size of granulomas as observed by other authors. 15 It is interesting to observe that the results were quite similar among the referral centers. In all Oral and Maxillofacial Pathology facilities, women were more affected by chronic inflammatory periapical disease than men. Periapical granulomas and radicular cysts, analyzed separately, had higher frequency among women, which is similar to the findings of another Brazilian study. 15 Other studies, though, showed that radicular cysts had a predilection for males. 12,35 The fact that chronic inflammatory periapical diseases are more frequent in women does not necessarily reflect a genetic predisposition for the development of these lesions or the influence of sex. The most likely explanation is the greater concern of women regarding their oral health, which ultimately has an impact on their treatment seeking. 36 The mean age of the patients affected by chronic inflammatory periapical disease was 37.01 years old. The mean age varies across studies, but there is a predominance of cases affecting individuals in their third and fourth decades of life. 11,13,15,31 These Table 5. findings are possibly associated with the highest prevalence of untreated dental caries in young adults, leading to the development of periapical disease. 1 On the other hand, as observed by other authors, these lesions are rare among adults older than 60 years. 37 This probably occurs because tooth extraction, as an alternative to conventional endodontic treatment, is carried out more frequently in the elderly than in younger patients. 37 Mo st pat ie nt s d i ag no s e d w it h c h r on ic inflammatory periapical disease were white. However, since the vast majority of cases were from the South (46.3%) and Southeast of Brazil (42.3%), these data may be overestimated since the population of those regions is predominantly white. 38 However, it is important to emphasize that the concentration of cases in the south and southeast regions (88.6%) may also reflect a situation of inequality in the access to oral health services in Brazil. This reinforces the need for public policies that make access to this type of treatment universal in all regions of the country.
Regarding clinical characteristics, most cases of chronic inflammatory periapical disease had a long evolution, with a duration of more than one year and absence of symptomatology. The symptomatic cases of the study (13.8%) occurred due to an acute exacerbation of inflammation. 8 It is interesting to observe that the occurrence of symptoms was higher in radicular cysts compared to periapical granulomas. Radicular cysts are bigger than periapical granulomas and can cause bone expansion, pain, and discomfort. 15,39 The permanent first molars are the teeth most affected by dental caries. 40 In this sense, molars and teeth with dental caries are at a higher risk for periapical disease. 41 In the present study, most cases of periapical granulomas and radicular cysts had a predilection for the posterior region. Permanent molars are the first teeth to erupt and this makes them more susceptible to dental caries, pulp infection, and periapical disease. 41 On the other hand, other authors reported that the most common region for periapical granulomas and radicular cysts was the anterior maxilla. 11,15 Aesthetic reasons can explain these results since patients are concerned in maintaining their anterior teeth, even though endodontic therapy was unsatisfactory. 42 In present study, agreement analyses between clinical and histopathological diagnoses had three outcomes: disagreements within the spectrum of periapical inflammatory diseases (for example, cysts diagnosed as granulomas or granulomas diagnosed as cysts); periapical diseases diagnosed as other bone pathologies including cysts and tumors; and periapical diseases diagnosed as lesions of the mucosa. All these situations denote failure in the diagnosis based only in one aspect of the disease; clinical or radiographic. However, for the establishment of the initial diagnosis of any lesion, the correlation of both aspects is necessary. 43 Pulp vitality test is fundamental in the establishment of a diagnosis of periapical disease 44 and unfortunately, this tool is frequently ignored by practitioners. In most cases, the initial diagnosis was conducted only by radiographic exam. Although periapical radiolucency can be interpreted as many different lesions, the inflammatory lesion of endodontic origin is the most common and continues to be the first hypothesis. 45 The diagnostic agreement was higher when the histopathological diagnosis was a radicular cyst. Despite this finding, the radiographic differentiation of inflammatory periapical disease is difficult, particularly when represented by small and poorly defined radiolucent areas. 46 Thus, the most appropriate diagnostic tool to differentiate among these lesions is biopsy followed by a histopathological evaluation. 12,47 This study has limitations. Although the study included referral centers of different geographic regions of Brazil, these data may not be representative of the entire country. Thus, caution is required in extrapolating the findings to the rest of the population. 48 In addition, a possible social bias may have occurred since the samples were obtained from public Brazilian universities, where individuals of a lower socioeconomic level seek treatment. Moreover, the histological slides were not reviewed to confirm diagnosis.
The present study evaluated the epidemiological and clinical characteristics of chronic inflammatory periapical disease. The strengths of this study are the long period of investigation, the multicenter approach, including different geographic regions of Brazil, and the large sample size.

Conclusions
Chronic inflammatory periapical diseases were common in the Brazilian Oral and Maxillofacial Pathology services. Women, young adults, and people of white skin color were the most affected patients.
Radicular cysts were the most frequent lesion. Chronic inflammatory periapical diseases were asymptomatic, with maxilla and posterior region being the most affected anatomical locations.