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

Abstract

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.

Periapical Diseases; Periapical Granuloma; Radicular Cyst; Periapical Abscess; Epidemiology

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.⁴Therefore, 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 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.⁶,⁹Briefly, 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.

Methodology

Multicenter study

Ethical issues and study design

A multicenter retrospective study (1952–2017) was conducted in four institutional referral centers in oral diagnosis in different geographic regions in Brazil: Universidade Estadual da Paraíba (UEPB, northeast region), Universidade Federal de Goiás (UFG, mid-west region), Universidade Federal de Minas Gerais (UFMG, southeast region) and Universidade Federal de Pelotas (UFPel, southern region). The study was approved by the Committee of Ethics on Research of the Universidade Federal de Minas Gerais (protocol CAAE 87761518.7.1001.5149). Patient’s anonymity was guaranteed according to the Helsinki Declaration.

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 abscess⁶ 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.

The following demographic and clinical data were collected from the patient records: sex (female or male), age (13–19, 20–29, 30–39, 40–49, 50–59, or ≥ 60), skin color (white or non-white), symptoms (asymptomatic or symptomatic), lesion duration (0–6 months, 7–12 months, or more than 1 year), lesion size (≤ 10 mm or > 10 mm), lesion location (maxilla or mandible and anterior, posterior, or both) and agreement between the clinical and histopathological diagnoses (disagreement, agreement, or nonspecific clinical diagnosis).

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 diseases - periapical granuloma, radicular cyst, and periapical abscess - (% in group of oral lesions included).

Results

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.

Table 1
Frequency of chronic inflammatory periapical diseases.

Institution (geographical region of Brazil)	Period investigated	Biopsied lesions in the studied period	Number of diagnosis
			n (%)
UEPB (northeast)	2011-2017	2,793	286 (10.2)
UFG (mid-west)	1996-2017	10,958	903 (8.2)
UFMG (southeast)	1952-2017	36,61	4,388 (11.9)
UFPel (south)	1959-2017	24,57	4,804 (19.5)
Total		74,931	10,381 (13.8)

• UEPB: Universidade Estadual da Paraíba; UFG: Universidade Federal de Goiás; UFMG: Universidade Federal de Minas Gerais; UFPel: Universidade Federal de Pelotas.

Clinical and demographic data of lesions are presented in Table 2. In all referral centers, women [(5,821 cases (56.1%)] were more affected than men. The mean age of the patients was 37.01 years old (±14.42) and ranged between 13 and 100 years. A total of 2,376 (22.9%) cases occurred in individuals between 30 and 39 years old. In all referral centers, the predominant skin color of the affected individuals was white [6,148 cases (59.2%)], except for UEPB, where non-white individuals were the most affected [159 cases (68.2%)].

Table 2
Distribution of the clinical and demographic features of 10,381 cases of chronic inflammatory periapical disease.

Variables	n (%)
Sex
Female	5,821 (56.1)
Male	4,321 (41.6)
Missing	239 (2.3)
Age (years)
13–19	999 (9.6)
20–29	2,258 (21.8)
30–39	2,376 (22.9)
40–49	1,886 (18.2)
50–59	1,175 (11.3)
≥ 60	722 (7.0)
Missing	965 (9.3)
Skin color
White	6,148 (59.2)
Non-white	2,616 (25.2)
Missing	1,617 (15.6)
Histopathological diagnosis
Periapical granuloma	4,110 (39.6)
Radicular cyst	6,215 (59.9)
Periapical abscess	56 (0.5)
Symptoms
Asymptomatic	2,921 (28.1)
Symptomatic	1,431 (13.8)
Missing	6,029 (58.1)
Lesion duration
0–6 months	493 (4.7)
7–12 months	508 (4.9)
More than 1 year	1,378 (13.3)
Missing	8,002 (77.1)
Size
≤ 10 mm	2,617 (25.2)
> 10 mm	1,270 (12.2)
Missing	6,494 (62.6)
Lesion location I
Maxilla	6,241 (60.1)
Mandible	3,440 (33.1)
Missing	700 (6.7)
Lesion location II
Anterior	3,719 (35.8)
Posterior	5,172 (49.8)
Both	569 (5.5)
Missing	921 (8.9)
Agreement between clinical and histopathological diagnosis
Disagreement	1,933 (18.6)
Agreement	5,865 (56.5)
Nonspecific clinical diagnosis	1,577 (15.2)
Missing	1,006 (9.7)

The frequency of lesions in the referral centers followed the same tendency. The most frequent lesions were radicular cysts [6,215 cases (59.9%)], followed by periapical granulomas [4,110 cases (39.6%)]. Periapical abscesses represented only 0.5% of the total sample. Among the 6,215 cases of radicular cysts, 602 (5.8%) were residual cysts. The lesions were predominantly asymptomatic [2,921 cases (28.1%)] with a duration of more than one year [1,378 cases (13.3%)], and a size of ≤ 10 mm [2,617 cases (25.2%)]. The mean lesion size was 12.58 mm (±13.68) and ranged between 0.1 mm and 150.0 mm. Regarding the anatomical location, the maxilla [6,241 cases (60.1%)] and the posterior region [5,172 cases (49.8%)] had the highest frequency of cases.

Agreement between the clinical and histopathological diagnoses occurred in 5,865 (56.5%) cases, disagreement in 1,933 (18.6%), missing clinical diagnostic 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 [1,278 cases (94.7%)]. For the cases of a radicular cyst, the most frequent hypothesis was a periapical granuloma [352 cases (62.4%)] and an odontogenic keratocyst [62 cases (11.0%)]. Finally, for cases of a periapical abscess, the most frequent hypothesis was a radicular cyst [12 cases (60.0%)].

Table 3
Clinical diagnosis of cases with disagreement between the clinical and histopathological diagnosis (n = 1,933).

Variable	Histopathological diagnosis
	Periapical granuloma (n = 1,349)	Radicular cyst (n = 564)	Periapical abscess (n = 20)
	n (%)	n (%)	n (%)
Clinical diagnosis
Periapical granuloma	-	352 (62.4)	4 (20.0)
Radicular cyst	1,278 (94.7)	-	12 (60.0)
Periapical granuloma or radicular cyst	-	-	4 (20.0)
Periapical abscess	22 (1.6)	25 (4.4)	-
Osteomyelitis	4 (0.3)	12 (2.1)	0 (0.0)
Bone sequestration	1 (0.1)	2 (0.4)	0 (0.0)
Bisphosphonate associated osteonecrosis	0 (0.0)	1 (0.2)	0 (0.0)
Foreign body reaction	1 (0.1)	0 (0.0)	0 (0.0)
Periodontal lesion	2 (0.1)	5 (0.9)	0 (0.0)
Endodontic-periodontal lesion	3 (0.2)	6 (1.1)	0 (0.0)
Pyogenic granuloma	0 (0.0)	6 (1.1)	0 (0.0)
Granulomatous epulis	1 (0.1)	0 (0.0)	0 (0.0)
Central Giant Cell Granuloma	1 (0.1)	2 (0.4)	0 (0.0)
Dentigerous cyst	7 (0.5)	20 (3.5)	0 (0.0)
Odontogenic keratocyst	6 (0.4)	62 (11.0)	0 (0.0)
Periodontal cyst	9 (0.7)	25 (4.4)	0 (0.0)
Paradentary cyst	1 (0.1)	6 (1.1)	0 (0.0)
Globule-maxillary cyst	3 (0.2)	5 (0.9)	0 (0.0)
Nasopalatine duct cyst	1 (0.1)	3 (0.5)	0 (0.0)
Median palatine cyst	0 (0.0)	1 (0.2)	0 (0.0)
Median mandibular cyst	0 (0.0)	2 (0.4)	0 (0.0)
Maxillary sinus cyst	0 (0.0)	1 (0.2)	0 (0.0)
Mucous retention cyst	0 (0.0)	2 (0.4)	0 (0.0)
Epidermoid cyst	1 (0.1)	0 (0.0)	0 (0.0)
Simple bone cyst	0 (0.0)	2 (0.4)	0 (0.0)
Fibrous dysplasia	1 (0.1)	1 (0.2)	0 (0.0)
Cemento-osseous dysplasia	0 (0.0)	2 (0.4)	0 (0.0)
Central odontogenic fibroma	1 (0.1)	0 (0.0)	0 (0.0)
Neurofibroma	0 (0.0)	1 (0.2)	0 (0.0)
Ameloblastoma	4 (0.3)	9 (1.6)	0 (0.0)
Squamous odontogenic tumor	0 (0.0)	1 (0.2)	0 (0.0)
Odontoma	0 (0.0)	2 (0.4)	0 (0.0)
Odontogenic myxoma	0 (0.0)	4 (0.7)	0 (0.0)
Cementoma	0 (0.0)	1 (0.2)	0 (0.0)
Brown Tumor	0 (0.0)	1 (0.2)	0 (0.0)
Papilloma	1 (0.1)	0 (0.0)	0 (0.0)
Blastomycosis	1 (0.1)	2 (0.4)	0 (0.0)

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).

Table 4
Bivariate analyses of 10,325* periapical granulomas and radicular cysts.

Variables	Histopathological diagnosis
	Periapical granuloma (n = 4,110)	Radicular cyst (n = 6,215)	p-value**
	n (%)	n (%)
Sex
Female	2,528 (63.3)	3,258 (53.5)
Male	1,468 (36.7)	2,833 (46.5)	< 0.001
Age (years)
13–19	431 (11.6)a	558 (9.9)b
20–29	927 (24.9)	1,314 (23.3)
30–39	966 (25.9)	1,402 (24.9)
40–49	725 (19.5)	1,154 (20.5)
50–59	414 (11.1)a	755 (13.4)b
≥ 60	262 (7.0)	457 (8.1)	< 0.001
Skin color
White	2,435 (69.6)	3,678 (70.5)
Non-white	1064 (30.4)	1538 (29.5)	0.364
Symptoms
Asymptomatic	1,044 (65.0)	1,863 (68.3)
Symptomatic	561 (35.0)	863 (31.7)	0.027
Lesion duration
0–6 months	185 (20.2)	303 (20.9)
7–12 months	188 (20.5)	319 (22.0)
More than 1 year	545 (59.4)	830 (57.2)	0.548
Size
≤ 10 mm	1,215 (87.4)	1,386 (55.9)
> 10 mm	175 (12.6)	1,094 (44.1)	< 0.001
Lesion location I
Maxilla	2,475 (65.3)	3,734 (63.9)
Mandible	1,314 (34.7)	2,108 (36.1)	0.163
Lesion location II
Anterior	1,443 (38.1)	2,257 (40.1)
Posterior	2,283 (60.3)a	2,859 (50.8)b
Both	58 (1.5)a	511 (9.1)b	< 0.001
Agreement between clinical and histopathological diagnosis
Disagreement	1,349 (36.7)a	564 (10.0)b
Agreement	1,537 (41.8)a	4,320 (76.5)b
Nonspecific clinical diagnosis	792 (21.5)a	763 (13.5)b	< 0.001

• *56 cases of periapical abscesses were not included in the bivariate analyses because of their low frequency (0.5%). **Pearson Chi-square test (Significance level p < 0.05). Different letters indicate a statistical difference using the z-test and Bonferroni correction (significance level of p < 0.05).

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 (± 8.24) and ranged between 0.2 mm and 150.0 mm, while the mean size of the cysts was 15.62 mm (±15.16) and ranged between 0.1 mm and 150.0 mm. The posterior region of the jaw was the most frequent location of both periapical granulomas and radicular cysts, with cysts outnumbering granulomas (p < 0.001). The disagreement between clinical and histopathological diagnoses was more common when the histopathological diagnosis was a periapical granuloma (p < 0.001).

Literature review

In the literature review, 1,786 articles were retrieved. The eligibility criteria were applied and 13 articles were selected.¹²,¹⁶-²⁷ Considering the total sample of the studies, the frequency of periapical granuloma varied between 0.007²⁰ and 17.3%,¹⁹ radicular cyst between 0.03²⁰ and 22.7%,¹⁹ and periapical abscess between 0.4²⁵ and 0.5%.¹²

The frequency of radicular cysts in studies that included jaw lesions ranged from 24.7²⁵ to 29.9%.¹⁹ Considering jaw intraosseous lesions, that frequency ranged from 17.8²⁰ to 19.6%¹⁶ and between odontogenic cysts ranged from 35.1²³ to 54.1%.¹⁷Considering the radiolucent inflammatory jaw lesions, the frequency of periapical granuloma was 59.7% and of radicular cyst 29.2%¹² (Table 5).

Table 5
Reported frequency of periapical diseases in the literature.

Authors, year and country	Period (years)	Sample size (total)	Group of oral lesions included (n)	Frequency of periapical diseases (% total)	Frequency of periapical diseases (% in group of oral lesions included)
Present study	1952 to 2017	74,931	Periapical diseases (n = 10,381)	Periapical granuloma (n = 4,110, 5.4%);	Periapical granuloma (n = 4,110, 39.6%);
				Radicular cyst (n = 6,215, 8.2%);	Radicular cyst (n = 6,215, 59.9%);
				Periapical abscess (n = 56, 0.07%)	Periapical abscess (n = 56, 0.5%)
Farias et al., 2019,16 Brazil	2006 to 2017	2,051	Intraosseous lesions of the stomatognathic complex (n = 290)	Periapical granuloma (n = 26, 1,2%*)	Periapical granuloma (n = 26, 8.9%*)
				Radicular cyst (n = 57, 2.7%*)	Radicular cyst (n = 57, 19.6%*)
Villasis-Sarmiento et al., 2017,17 Mexico	2000 to 2013	10,97	Odontogenic cysts (n = 753)	Radicular cyst (n = 408, 3.7%);	Radicular cyst (n = 408, 54.1%);
				Residual cyst (n = 18, 0.1%*)	Residual cyst (n = 18, 2.3%)
Deepthi et at., 2016,18 India	1998 to 2012	7,117	Odontogenic cysts and tumors (n = 1,177)	Radicular cyst: (n = 655, 9.2%*);	Radicular cyst: (n = 655, 55.6%*);
				Residual cyst (n = 44, 0.6%*)	Residual cyst (n = 44, 3.7%*)
Peker et al., 2016,19 Turkey	2008 to 2013	1,938	Jaw lesions (n = 1,473)	Periapical granuloma (n = 337, 17.3%*);	Periapical granuloma (n = 337, 22.9%);
				Radicular cyst (n = 440, 22.7%*);	Radicular cyst (n = 440, 29.9%);
				Residual cyst (n = 76, 3.9%*)	Residual cyst (n = 76, 5.2%)
Jamshidi et al., 2015,20 Iran	1990 to 2010	142,865	Jaw intraosseous	Periapical granuloma (n = 11, 0.007%*)	Periapical granuloma (n = 11, 3.8%)
			lesions (n = 284)	Radicular cyst (n = 51, 0.03%*);	Radicular cyst (n = 51, 17.8%);
				Residual cyst (n = 3, 0.002%*)	Residual cyst (n = 3, 1.0%)
Akinyamoju et al., 201421, Nigeria	1990 to	1,877	Periapical lesions (endodontic and non-endodontic)	Periapical granuloma (n = 71, 3.7%*);	Periapical granuloma (n = 71, 68.3%);
	2012		(n = 104)	Radicular cyst (n = 31, 1.6%*)	Radicular cyst (n = 31, 29.8%)
Alcantara et al., 2013,22 Brazil	2000 to 2010	3,446*	Radicular cyst	Radicular cyst (n = 214, 6.2%)	Not applicable
					(Only one group included)
Khosravi et al., 2013,23 Iran	1988 to 2010	7,412	Odontogenic cysts (n = 1,603)	Radicular cyst (n = 563, 7.5%*)	Radicular cyst (n = 563, 35.1%);
				Residual cyst (n = 208, 2.8%*)	Residual cyst (n = 208, 12.9%)
Butt et al., 2011,24 Kenya	1991 to 2010	4,257	Odontogenic and nonodontogenic cysts (n = 194)	Radicular cyst (n = 43, 1.0%*)	Radicular cyst (n = 43, 22.1%)
Ali, 2011, 25 Kwait	2004 to 2009	1,28	Jaw lesions (n = 385)	Chronic apical periodontitis (n = 59, 4.6%*);	Chronic apical periodontitis (n = 59, 15.3%);
				Radicular cyst (n = 95, 7.4%*);	Radicular cyst (n = 95, 24.7%);
				Residual cyst (n = 8, 0.6%*);	Residual cyst (n = 8, 2.0%*);
				Dental abscess (n = 6, 0.4%*)	Dental abscess (n = 6, 1,5%*)
Becconsall-Ryan et al., 2010,12 New Zeland	1986 to 2006	17,038	Radiolucent inflammatory jaw lesions (n = 3,626)	Periapical granuloma (n = 2,165, 12.7%*);	Periapical granuloma (n = 2,165, 59.7%);
				Radicular cyst (n = 1,057, 6.2%*);	Radicular cyst (n = 1,057, 29.2%);
				Periapical abscess (n = 88, 0,5%*)	Periapical abscess (n = 88, 2.4%)
Núñez-Urrutia et al., 2010,26 Spain	1997 to 2006	1,235	Odontogenic cysts (n = 418)	Radicular cyst (n = 210, 17.0%*);	Radicular cyst (n = 210, 50.2%);
				Residual cyst (n = 18, 1.4%*)	Residual cyst (n = 18, 4.3%)
Ledesma-Montes, et al., 2000,27 Mexico	1986 to 1996	3,865	Odontogenic cysts (n = 304)	Radicular cyst (n = 118, 3.0%*);	Radicular cyst (n = 118, 38.8%);
				Residual cyst (n = 15, 0.3%*)	Residual cyst (n = 15, 4.9%)

• *Calculated according to the data presented in the article.

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 cysts¹⁵and 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 cysts¹⁵, 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.¹¹-¹⁵,³² 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.³⁴Indeed, 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.¹⁵Other studies, though, showed that radicular cysts had a predilection for males.¹²,³⁵The 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 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

Most patients diagnosed with chronic 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.³⁸However, 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 disease⁴⁴ 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.⁴⁸In 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.

Acknowledgements

This work was supported by Pró-Reitoria de Pesquisa da Universidade Federal de Minas Gerais (PRPq-UFMG), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Financial Code 001), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil.

References

• ¹
  Kassebaum NJ, Bernabé E, Dahiya M, Bhandari B, Murray CJ, Marcenes W. Global burden of untreated caries: a systematic review and metaregression. J Dent Res. 2015 May;94(5):650-8. https://doi.org/10.1177/0022034515573272
  » https://doi.org/10.1177/0022034515573272
• ²
  Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, Brown A, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016 Oct;388(10053):1545-602. https://doi.org/10.1016/S0140-6736(16)31678-6
  » https://doi.org/10.1016/S0140-6736(16)31678-6
• ³
  Ardenghi TM, Piovesan C, Antunes JL. [Inequalities in untreated dental caries prevalence in preschool children in Brazil]. Rev Saude Publica. 2013 Dec;47 Suppl 3:129-37. Portuguese. https://doi.org/10.1590/S0034-8910.2013047004352 PMID:24626589
  » https://doi.org/10.1590/S0034-8910.2013047004352
• ⁴
  Zero DT, Zandona AF, Vail MM, Spolnik KJ. Dental caries and pulpal disease. Dent Clin North Am. 2011 Jan;55(1):29-46. https://doi.org/10.1016/j.cden.2010.08.010
  » https://doi.org/10.1016/j.cden.2010.08.010
• ⁵
  Jepsen S, Blanco J, Buchalla W, Carvalho JC, Dietrich T, Dörfer C, et al. Prevention and control of dental caries and periodontal diseases at individual and population level: consensus report of group 3 of joint EFP/ORCA workshop on the boundaries between caries and periodontal diseases. J Clin Periodontol. 2017 Mar;44 Suppl 18:S85-93. https://doi.org/10.1111/jcpe.12687
  » https://doi.org/10.1111/jcpe.12687
• ⁶
  Nair PN. Apical periodontitis: a dynamic encounter between root canal infection and host response. Periodontol 2000. 1997 Feb;13(1):121-48. https://doi.org/10.1111/j.1600-0757.1997.tb00098.x
  » https://doi.org/10.1111/j.1600-0757.1997.tb00098.x
• ⁷
  Abbott PV. The periapical space: a dynamic interface. Aust Endod J. 2002 Dec;28(3):96-107. https://doi.org/10.1111/j.1747-4477.2002.tb00399.x
  » https://doi.org/10.1111/j.1747-4477.2002.tb00399.x
• ⁸
  Nair PN. Pathogenesis of apical periodontitis and the causes of endodontic failures. Crit Rev Oral Biol Med. 2004 Nov;15(6):348-81. https://doi.org/10.1177/154411130401500604
  » https://doi.org/10.1177/154411130401500604
• ⁹
  Peters E, Lau M. Histopathologic examination to confirm diagnosis of periapical lesions: a review. J Can Dent Assoc. 2003 Oct;69(9):598-600.
• ¹⁰
  Ramachandran Nair PN, Pajarola G, Schroeder HE. Types and incidence of human periapical lesions obtained with extracted teeth. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996 Jan;81(1):93-102. https://doi.org/10.1016/S1079-2104(96)80156-9
  » https://doi.org/10.1016/S1079-2104(96)80156-9
• ¹¹
  Safi L, Adl A, Azar MR, Akbary R. A twenty-year survey of pathologic reports of two common types of chronic periapical lesions in Shiraz Dental School. J Dent Res Dent Clin Dent Prospects. 2008;2(2):63-70. https://doi.org/10.5681/joddd.2008.013
  » https://doi.org/10.5681/joddd.2008.013
• ¹²
  Becconsall-Ryan K, Tong D, Love RM. Radiolucent inflammatory jaw lesions: a twenty-year analysis. Int Endod J. 2010 Oct;43(10):859-65. https://doi.org/10.1111/j.1365-2591.2010.01751.x
  » https://doi.org/10.1111/j.1365-2591.2010.01751.x
• ¹³
  Lin HP, Chen HM, Yu CH, Kuo RC, Kuo YS, Wang YP. Clinicopathological study of 252 jaw bone periapical lesions from a private pathology laboratory. J Formos Med Assoc. 2010 Nov;109(11):810-8. https://doi.org/10.1016/S0929-6646(10)60126-X
  » https://doi.org/10.1016/S0929-6646(10)60126-X
• ¹⁴
  Diegues LL, Colombo Robazza CR, Costa Hanemann JA, Costa Pereira AA, Silva CO. Correlation between clinical and histopathological diagnoses in periapical inflammatory lesions. J Investig Clin Dent. 2011 Aug;2(3):184-6. https://doi.org/10.1111/j.2041-1626.2011.00053.x
  » https://doi.org/10.1111/j.2041-1626.2011.00053.x
• ¹⁵
  Tavares DP, Rodrigues JT, Santos TC, Armada L, Pires FR. Clinical and radiological analysis of a series of periapical cysts and periapical granulomas diagnosed in a Brazilian population. J Clin Exp Dent. 2017 Jan;9(1):e129-35. https://doi.org/10.4317/jced.53196
  » https://doi.org/10.4317/jced.53196
• ¹⁶
  Farias JG, Souza RC, Hassam SF, Cardoso JA, Ramos TC, Santos HK. Epidemiological study of intraosseous lesions of the stomatognathic or maxillomandibular complex diagnosed by a Reference Centre in Brazil from 2006-2017. Br J Oral Maxillofac Surg. 2019 Sep;57(7):632-7. https://doi.org/10.1016/j.bjoms.2019.05.003
  » https://doi.org/10.1016/j.bjoms.2019.05.003
• ¹⁷
  Villasis-Sarmiento L, Portilla-Robertson J, Melendez-Ocampo A, Gaitan-Cepeda LA, Leyva-Huerta ER. Prevalence and distribution of odontogenic cysts in a Mexican sample: a 753 cases study. J Clin Exp Dent. 2017 Apr;9(4):e531-8. https://doi.org/10.4317/jced.53627
  » https://doi.org/10.4317/jced.53627
• ¹⁸
  Deepthi PV, Beena VT, Padmakumar SK, Rajeev R, Sivakumar R. A study of 1177 odontogenic lesions in a South Kerala population. J Oral Maxillofac Pathol. 2016 May-Aug;20(2):202-7. https://doi.org/10.4103/0973-029X.185897
  » https://doi.org/10.4103/0973-029X.185897
• ¹⁹
  Peker E, Öğütlü F, Karaca İR, Gültekin ES, Çakır M. A 5 year retrospective study of biopsied jaw lesions with the assessment of concordance between clinical and histopathological diagnoses. J Oral Maxillofac Pathol. 2016 Jan-Apr;20(1):78-85. https://doi.org/10.4103/0973-029X.180945
  » https://doi.org/10.4103/0973-029X.180945
• ²⁰
  Jamshidi S, Shojaei S, Roshanaei G, Modabbernia S, Bakhtiary E. Jaw intraosseous lesions biopsied extracted from 1998 to 2010 in an Iranian population. Iran Red Crescent Med J. 2015 Jun;17(6):e20374. https://doi.org/10.5812/ircmj.17(5)2015.20374
  » https://doi.org/10.5812/ircmj.17(5)2015.20374
• ²¹
  Akinyamoju AO, Gbadebo SO, Adeyemi BF. Periapical lesions of the jaws: a review of 104 cases in ibadan. Ann Ib Postgrad Med. 2014 Dec;12(2):115-9.
• ²²
  Alcantara BA, Carli ML, Beijo LA, Pereira AA, Hanemann JA. Correlation between inflammatory infiltrate and epithelial lining in 214 cases of periapical cysts. Braz Oral Res. 2013 Nov-Dec;27(6):490-5. https://doi.org/10.1590/S1806-83242013005000023
  » https://doi.org/10.1590/S1806-83242013005000023
• ²³
  Khosravi N, Razavi SM, Kowkabi M, Navabi AA. Demographic distribution of odontogenic cysts in Isfahan (Iran) over a 23-year period (1988-2010). Dent Res J (Isfahan). 2013 Mar;10(2):162-7. https://doi.org/10.4103/1735-3327.113325
  » https://doi.org/10.4103/1735-3327.113325
• ²⁴
  Butt FM, Ogeng’o J, Bahra J, Chindia ML. Pattern of odontogenic and nonodontogenic cysts. J Craniofac Surg. 2011 Nov;22(6):2160-2. https://doi.org/10.1097/SCS.0b013e3182323fbe
  » https://doi.org/10.1097/SCS.0b013e3182323fbe
• ²⁵
  Ali MA. Biopsied jaw lesions in Kuwait: a six-year retrospective analysis. Med Princ Pract. 2011;20(6):550-5. https://doi.org/10.1159/000330023
  » https://doi.org/10.1159/000330023
• ²⁶
  Nuñez-Urrutia S, Figueiredo R, Gay-Escoda C. Retrospective clinicopathological study of 418 odontogenic cysts. Med Oral Patol Oral Cir Bucal. 2010 Sep;15(5):e767-73. https://doi.org/10.4317/medoral.15.e767
  » https://doi.org/10.4317/medoral.15.e767
• ²⁷
  Ledesma-Montes C, Hernández-Guerrero JC, Garcés-Ortíz M. Clinico-pathologic study of odontogenic cysts in a Mexican sample population. Arch Med Res. 2000 Jul-Aug;31(4):373-6. https://doi.org/10.1016/S0188-4409(00)00069-2
  » https://doi.org/10.1016/S0188-4409(00)00069-2
• ²⁸
  Fierro-Garibay C, Almendros-Marqués N, Berini-Aytés L, Gay-Escoda C. Prevalence of biopsied oral lesions in a Department of Oral Surgery (2007-2009). J Clin Exp Dent. 2011;3(2):e73-7. https://doi.org/10.4317/jced.3.e73
  » https://doi.org/10.4317/jced.3.e73
• ²⁹
  Carrillo C, Peñarrocha M, Bagán JV, Vera F. Relationship between histological diagnosis and evolution of 70 periapical lesions at 12 months, treated by periapical surgery. J Oral Maxillofac Surg. 2008 Aug;66(8):1606-9. https://doi.org/10.1016/j.joms.2007.12.014
  » https://doi.org/10.1016/j.joms.2007.12.014
• ³⁰
  Stockdale CR, Chandler NP. The nature of the periapical lesion: a review of 1108 cases. J Dent. 1988 Jun;16(3):123-9. https://doi.org/10.1016/0300-5712(88)90004-8
  » https://doi.org/10.1016/0300-5712(88)90004-8
• ³¹
  Croitoru IC, CraiToiu Ş, Petcu CM, Mihailescu OA, Pascu RM, Bobic AG, et al. Clinical, imagistic and histopathological study of chronic apical periodontitis. Rom J Morphol Embryol. 2016;57(2 Suppl):719-28.
• ³²
  Ricucci D, Pascon EA, Ford TR, Langeland K. Epithelium and bacteria in periapical lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006 Feb;101(2):239-49. https://doi.org/10.1016/j.tripleo.2005.03.038
  » https://doi.org/10.1016/j.tripleo.2005.03.038
• ³³
  Natkin E, Oswald RJ, Carnes LI. The relationship of lesion size to diagnosis, incidence, and treatment of periapical cysts and granulomas. Oral Surg Oral Med Oral Pathol. 1984 Jan;57(1):82-94. https://doi.org/10.1016/0030-4220(84)90267-6
  » https://doi.org/10.1016/0030-4220(84)90267-6
• ³⁴
  Zain RB, Roswati N, Ismail K. Radiographic evaluation of lesion sizes of histologically diagnosed periapical cysts and granulomas. Ann Dent. 1989;48(2):3-5.
• ³⁵
  Lo Muzio L, Mascitti M, Santarelli A, Rubini C, Bambini F, Procaccini M, et al. Cystic lesions of the jaws: a retrospective clinicopathologic study of 2030 cases. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017 Aug;124(2):128-38. https://doi.org/10.1016/j.oooo.2017.04.006
  » https://doi.org/10.1016/j.oooo.2017.04.006
• ³⁶
  Georgopoulou MK, Spanaki-Voreadi AP, Pantazis N, Kontakiotis EG. Frequency and distribution of root filled teeth and apical periodontitis in a Greek population. Int Endod J. 2005 Feb;38(2):105-11. https://doi.org/10.1111/j.1365-2591.2004.00907.x
  » https://doi.org/10.1111/j.1365-2591.2004.00907.x
• ³⁷
  Berlinck T, Tinoco JM, Carvalho FL, Sassone LM, Tinoco EM. Epidemiological evaluation of apical periodontitis prevalence in an urban Brazilian population. Braz Oral Res. 2015;29(1):51. https://doi.org/10.1590/1807-3107BOR-2015.vol29.0051
  » https://doi.org/10.1590/1807-3107BOR-2015.vol29.0051
• ³⁸
  Instituto Brasileiro de Geografia e Estatística – IBGE. Tabela 2094 - População residente por cor ou raça e religião; 2010. [Cited 2019 May 21]. Available from: https://sidra.ibge.gov.br/tabela/2094#/n1/all/n2/all/n3/all/v/1000093/p/last%201/c86/allxt/c133/0/d/v1000093%201/l/v,p+c86,t+c133/resultado
  » https://sidra.ibge.gov.br/tabela/2094#/n1/all/n2/all/n3/all/v/1000093/p/last%201/c86/allxt/c133/0/d/v1000093%201/l/v,p+c86,t+c133/resultado
• ³⁹
  Diwan A, Bhagavaldas MC, Bagga V, Shetty A. Multidisciplinary approach in management of a large cystic lesion in anterior maxila: a case report. J Clin Diagn Res. 2015 May;9(5):ZD41-3. https://doi.org/10.7860/JCDR/2015/13540.5992
  » https://doi.org/10.7860/JCDR/2015/13540.5992
• ⁴⁰
  Constante HM, Souza ML, Bastos JL, Peres MA. Trends in dental caries among Brazilian schoolchildren: 40 years of monitoring (1971-2011). Int Dent J. 2014 Aug;64(4):181-6. https://doi.org/10.1111/idj.12103
  » https://doi.org/10.1111/idj.12103
• ⁴¹
  Vengerfeldt V, Mändar R, Nguyen MS, Saukas S, Saag M. Apical periodontitis in southern Estonian population: prevalence and associations with quality of root canal fillings and coronal restorations. BMC Oral Health. 2017 Dec;17(1):147. https://doi.org/10.1186/s12903-017-0429-7
  » https://doi.org/10.1186/s12903-017-0429-7
• ⁴²
  Ochsenius G, Escobar E, Godoy L, Peñafiel C. Odontogenic cysts: analysis of 2,944 cases in Chile. Med Oral Patol Oral Cir Bucal. 2007 Mar;12(2):E85-91.
• ⁴³
  Mohanty S, Gulati U, Mediratta A, Ghosh S. Unilocular radiolucencies of anterior mandible in young patients: a 10 year retrospective study. Natl J Maxillofac Surg. 2013 Jan;4(1):66-72. https://doi.org/10.4103/0975-5950.117885
  » https://doi.org/10.4103/0975-5950.117885
• ⁴⁴
  Petersson K, Söderström C, Kiani-Anaraki M, Lévy G. Evaluation of the ability of thermal and electrical tests to register pulp vitality. Endod Dent Traumatol. 1999 Jun;15(3):127-31. https://doi.org/10.1111/j.1600-9657.1999.tb00769.x
  » https://doi.org/10.1111/j.1600-9657.1999.tb00769.x
• ⁴⁵
  Koivisto T, Bowles WR, Rohrer M. Frequency and distribution of radiolucent jaw lesions: a retrospective analysis of 9,723 cases. J Endod. 2012 Jun;38(6):729-32. https://doi.org/10.1016/j.joen.2012.02.028
  » https://doi.org/10.1016/j.joen.2012.02.028
• ⁴⁶
  Rózyło-Kalinowska I. Digital radiography density measurements in differentiation between periapical granulomas and radicular cysts. Med Sci Monit. 2007 May;13 Suppl 1:129-36.
• ⁴⁷
  Rosenberg PA, Frisbie J, Lee J, Lee K, Frommer H, Kottal S, et al. Evaluation of pathologists (histopathology) and radiologists (cone beam computed tomography) differentiating radicular cysts from granulomas. J Endod. 2010 Mar;36(3):423-8. https://doi.org/10.1016/j.joen.2009.11.005
  » https://doi.org/10.1016/j.joen.2009.11.005
• ⁴⁸
  Van der Veken D, Curvers F, Fieuws S, Lambrechts P. Prevalence of apical periodontitis and root filled teeth in a Belgian subpopulation found on CBCT images. Int Endod J. 2017 Apr;50(4):317-29. https://doi.org/10.1111/iej.12631
  » https://doi.org/10.1111/iej.12631

Publication Dates

• Publication in this collection
  15 Mar 2021
• Date of issue
  2021

History

• Received
  8 June 2020
• Accepted
  22 Oct 2020
• Reviewed
  26 Nov 2020