Nonmalignant nonendodontic lesions mimicking periapical lesions of endodontic origin: A systematic review.

The objective of the study is to describe the clinical and radiographic features of nonmalignant nonendodontic periapical lesions (NMNPLs) mimicking lesions of endodontic cause. Five electronic databases, PubMed, Web of Science, Scopus, Embase, and ProQuest, were searched (till July 2021) for case reports, case series, and cross-sectional studies, in English language, reporting NMNPLs, which were clinically and/or radiographically simulating periapical pathosis of endodontic origin. Data extraction was done followed by quality assessment of the included articles using the Joanna Briggs Institute tool for case reports and case series. Seventy-three articles comprising 176 cases were included. Sixty-one articles were case reports, nine articles were case series, and three articles were retrospective studies. Male:female ratio was 1.5:1, with a higher prevalence of lesions occurring in the fourth and second decades of life. The majority of the lesions were located in the anterior maxilla. Radiographically, most of the lesions were well defined, radiolucent, and unilocular. Histologically, 29 different types of NMNPLs were reported, with the most common ones being odontogenic keratocyst (25.56%), dentigerous cyst (17.61%), ameloblastoma (11.36%), nasopalatine duct cyst (10.79%), and adenomatoid odontogenic tumor (5.68%). As all the included studies were observational, the quality of available evidence is considered low. Various features such as loss of tooth vitality, history of trauma, and presence of periapical radiolucency may lead to misdiagnosis of NMNPLs and must be considered during diagnosis of the lesion. Additional imaging modalities and histopathology can aid in right diagnosis. Copyright:

INTRODUCTION

Periapical lesions caused due to infections in the root canal system are most often present as radiolucency at the apex of the teeth on radiographs.[1] Cysts, granuloma, and abscess account for about 90% of all such lesions that occur in the periapical region.[2] They are diagnosed through clinical examination, pulp sensibility testing, and radiographic examination. Periapical lesions of endodontic origin usually heal after nonsurgical root canal treatment, and the cases that do not heal require endodontic retreatment or surgical intervention.[3]

However, other lesions such as benign cysts and tumors of odontogenic and nonodontogenic origin, malignant lesions, and infectious diseases can also occur in the periapical region. Sirotheau Corrêa Pontes et al. reported that out of all the cases that were initially misdiagnosed as periapical lesions of endodontic origin, 66% of them were benign lesions while 29% were malignant.[4] In a recent systematic review on malignant nonendodontic periapical lesions (MNPLs), it was reported that metastatic jaw lesions of primary tumors occurring elsewhere in the body (lungs and breast) and salivary gland malignancies represent 26.6% and 25% of all the malignant lesions. They emphasized the importance of correct diagnosis at the initial stages of the lesion, which will allow for early treatment and prevention of complications.[5]

In a recent multicenter study, 4.22% of the periapical lesions were of nonendodontic origin, among which 34.9% of the lesions were odontogenic keratocyst (OKC), 15.6% were dentigerous cyst (DC), and 9.15% were nasopalatine duct cyst (NPDC).[6] Previous studies in the literature have reported that 0.65%–6.7% of lesions with a histopathological diagnosis of nonendodontic cause were clinically diagnosed as endodontic lesions.[78]

Differentiating between an endodontic and nonendodontic periapical lesion is of paramount importance. A wrong diagnosis may result in an unwanted endodontic treatment, nonhealing of the lesion, and persistence of signs and symptoms. Tsesis et al. in 2020 determined the accuracy of clinical diagnosis of periapical cystic lesions in comparison with histologic findings and found that nonendodontic cysts were clinically diagnosed correctly only in 41.7% of the cases.[9] Thus, it becomes pertinent for the clinicians to be familiar with periapical lesions that might be arising due to nonendodontic causes to enable correct diagnosis and hence proper treatment. To date, no systematic review has been done on nonmalignant nonendodontic lesions mimicking endodontic lesions. Hence, this systematic review aims at describing clinical and radiographic features of nonmalignant nonendodontic periapical lesions (NMNPLs) that mimic lesions of endodontic pathosis.

MATERIALS AND METHODS

Eligibility criteria

Research question

What are the clinical and radiographic features of nonmalignant nonendodontic lesions that mimic lesions of endodontic origin?

The review was formulated based on PICOS format (P – Population, I – Intervention, C – Comparison, O – Outcome, S – Study design).

P – Human deciduous and/or permanent teeth/tooth with periapical lesions

I – Clinical and/or radiographic features mimicking endodontic cause

C – Not applicable

O – Histopathological diagnosis of NMNPLs

S – Observational studies (case reports, case series, and cross-sectional studies).

Inclusion criteria

Clinical studies, in English language, reporting cases with NMNPLs that were clinically and/or radiographically mimicking periapical pathosis of endodontic origin or any incidental findings confirmed by the histological analysis were included in this review.

Exclusion criteria

Clinical studies that did not present radiographic features or histological diagnosis, anatomical landmarks or deformities that were misinterpreted as endodontic pathology, animal studies and laboratory-based studies, letters to editor, book chapters, narrative/literature reviews, and abstracts of conferences were all excluded.

Information sources and search strategy

The following five electronic databases were searched, without any filters, till July 2021: PubMed, Web of Science, Scopus, Embase, and ProQuest. The search strategy was developed for each electronic database using the following keywords: periapical diseases, benign lesion, and diagnostic errors. The search strategy aimed at identifying all the published case reports/case series/retrospective studies pertaining to the subject of this review. Detailed search strategies were formulated and utilized for each database to identify the relevant studies by four reviewers (K.M., R.P., S.E., and P.K.), which was further validated by two senior reviewers (B.A. and N.V.). The subject search used a combination of MeSH words using the Boolean method [Supplemental Table 1]. A manual search was conducted by going through the references of all the relevant articles. In addition, three peer-reviewed Endodontic journals (Journal of Endodontics, International Endodontic Journal, and Australian Endodontic Journal) were also manually searched for relevant articles.

Supplemental Table 1

Search strategy

Database	Search strategy
PubMed	(“Periapical diseases”[MeSH] OR periapical patho* OR apical periodontitis OR periapical granuloma OR radicular cyst OR periapical cyst OR endodontic periapical lesion OR periapical abscess OR dentoalveolar abscess) AND (benign lesion OR benign patho* OR benign tumor OR non endodontic lesion OR non odontogenic OR odontogenic cyst) AND (“diagnostic errors”[MeSH] OR “diagnosis, differential/diagnosis”[MeSH] OR mimic*)
Scopus	TITLE-ABS-KEY (“periapical disease” OR “periapical patho*” OR “apical periodontitis” OR “periapical granuloma” OR “radicular cyst” OR “periapical cyst” OR “endodontic periapical lesion” OR “periapical abscess” OR “dentoalveolar abscess”) AND (“benign lesion” OR “benign pathosis” OR “benign tumor” OR “non endodontic lesion” OR “non endodontic lesion” OR “non odontogenic” OR “odontogenic cyst”) AND (“diagnostic error” OR “differential diagnosis” OR “mimic*”)
Embase, Web of Science, ProQuest	(Periapical diseases OR periapical pathosis OR apical periodontitis OR periapical granuloma OR radicular cyst OR periapical cyst OR endodontic periapical lesion OR periapical abscess OR dentoalveolar abscess) AND (benign lesion OR benign pathosis OR benign tumor OR non endodontic lesion OR non odontogenic OR odontogenic cyst) AND (diagnostic errors OR differential diagnosis OR mimic)

Study selection

The lists of articles from search results were transferred to Zotero reference management software (Zotero 5.0 for Windows, Centre for History and New Media, George Mason University, Fairfax, Virginia, USA). Duplicates were identified and eliminated. Titles and abstracts were independently screened by four reviewers (K.M., R.P., S.E., and P.K.). Full-text article evaluation was done and articles fulfilling the inclusion criteria were included for the final qualitative assessment. Any disagreements were resolved by discussion with two senior reviewers (B.A. and N.V.).

Data extraction

Data were extracted using custom-designed Excel spreadsheet (Microsoft Excel, Redmond, WA 2016) by four reviewers (K.M., R.P., S.E., and P.K.) which was further verified by the two senior reviewers (B.A. and N.V.). The data extraction sheet included the following:

Study characteristics: Author, year of publication, study design

Demographic details: Country, patient age, and sex

Clinical features: Clinical signs and symptoms, tooth number, location, tooth mobility

Diagnostic tests: Pulp sensibility or vitality tests, other tests

Radiographic features: Type of radiographic imaging, radiographic appearance, radiographic lesion borders, image pattern, root resorption, cortical bone resorption, radiographic extent

Diagnosis: Provisional/differential diagnosis, histopathological diagnosis

Intervention and follow-up.

Quality assessment of included articles

All the included articles were independently assessed by four reviewers (K.M., R.P., S.E., and P.K.) for quality using the Joanna Briggs Institute (JBI) tool for case series[10] and case reports.[11] Retrospective studies were also assessed using the JBI tool for case series as the questions in the checklist better suited the included retrospective studies in this review. The JBI tool for case reports and case series consists of 8 and 10 questions, respectively. Each question was answered with either “yes,” “no,” “unclear,” or “not applicable.” The tenth question (“Was statistical analysis appropriate?”) in the JBI tool for case series was not applicable for any of the included articles, and hence, the question was not considered for quality assessment. Any disagreements were discussed and resolved by the two senior reviewers (B.A. and N.V.).

Risk of bias (RoB) for individual articles was calculated based on the number of positive responses (yes), out of a maximum score of 8 for case reports and 9 for case series. The final score was categorized as high (score equal or lower than 49%), moderate (50%–69%), or low (higher than 70%).[12]

Quality of evidence

To rate the quality of evidence in this review, the JBI levels of evidence was used.

RESULTS

The search flow diagram is presented in Figure 1. A total of 1087 articles were identified from the initial search of the databases. After the title and abstract screening and removal of duplicates, 880 articles were excluded. After full-text reading of the remaining 86 articles, 66 articles were selected for the review. Hand searching of the journals and references of included articles resulted in the inclusion of additional seven articles, accounting for a total of 73 articles. The 73 included articles comprised 61 case reports, 9 case series (24 cases), and 3 retrospective studies (95 cases), accounting for a total of 176 cases.

Figure 1

Literature search flow diagram

Study characteristics

There were 14 case series in the included articles. Among these, in five case series, only one of the cases fulfilled the inclusion criteria. Hence, these five articles were considered as case reports. The reason for exclusion of other cases in the case series and articles excluded[468913141516171819 2021222324252627] during full-text reading is provided in Supplemental Table 2.

Supplemental Table 2

Excluded articles and cases with reasons

Author, year	Reason for exclusion
Neville, 1996 Islam et al., 2008 Kamal P, 2010 Bains, 2016	Full text article not available
Kuc, 2000 Ali and Baughman, 2003 Ortega, 2007 Morais, 2011 Pontes, 2015 Kontogiannis, 2015 Huang, 2016 Vierra, 2020 Tsesis, 2020	Radiographic features not mentioned
Cases excluded from case series Xia, 2011 (case 1, 2, 5) Philipsen, 1992 (case 1 and 3); Natarajan, 2016 (case 2); Daviet Noual, 2017 (case 1 and 2); Patil, 2019 (case 2) Brody, 2019 (case 2)	Radicular cyst mimicking odontogenic cyst (cases 1 and 2); cancer metastasis (case 5) Not misdiagnosed or mimicking periapical pathology of endodontic origin No histopathological diagnosis mentioned

The 176 included cases were reported from five continents with 66.47% (115/176) from Asia, 13.06% (23/176) in South America, 12.5% (22/176) in North America, 6.81% (12/176) in Europe, and the remaining 1.13% (2/176) from Australia. The age of the patients ranged from 8 to 81 years. Patients in the fourth (40–49 years) and second decades of life (10–19 years) were most commonly affected with the prevalence of 20.5% each (21/102) [Figure 2]. Among the included cases, 60.7% (62/102) were male and 39.2% (40/102) were female, with male-to-female ratio of 1.5:1 [Figure 2].

Figure 2

Pie charts representing prevalence of (a) gender, (b) age, and (c) site of the lesions. These results do not include the age, gender, and site of one retrospective study Kosanwat et al., 2021

Twenty-nine different types of NMNPLs were found in this review, with the majority being OKC (25.56%) followed by DC (17.61%), ameloblastoma (11.36%), NPDC (10.79%), and adenomatoid odontogenic tumor (AOT, 5.68%) [Figure 3]. They were most commonly located in the anterior region of the maxilla (28.43%) followed by the posterior region of the mandible (27.45%) [Figure 2]. In 78.43% (80/102) of the cases, the patients presented with symptoms, while in 21.56% (22/102) cases, the patients were asymptomatic. The number of cases with the involved teeth either responding normally or not responding to pulp sensibility tests was equal (38.18%; 21/55) each. Previously, root canal-initiated/treated teeth were 9.09% (5/55).

Figure 3

Nonmalignant nonendodontic periapical lesions and their frequency

For radiographic evaluation, various types of modalities were used such as intraoral periapical radiograph, orthopantomogram, occlusal radiograph, or a combination of these. In addition to the two-dimensional radiographic imaging, in 13 cases, cone-beam computed tomography (CBCT) was used, computerized tomography scan (CT scan) was used in five articles, and one article used magnetic resonance imaging (MRI). Fine needle aspiration cytology was carried out in five cases. Radiographically, 94.88% (167/176) were radiolucent, 90.64% (126/139) were unilocular, and 96.32% (121/136) had well-defined borders. Furthermore, 52.5% (21/40) cases reported cortical bone perforation, 30% (12/40) showed expansion of cortical bone, and 50% (17/34) had pathological root resorption.

The follow-up of cases ranged from 2 weeks to 8 years. The overall percentages of all the characteristics of all the included articles are given in Table 1, and data extraction of all the individual cases is provided in Supplemental Tables 3 and 4.

Table 1

Results of the included articles

Variable	n (%)
Geographic region (n=176)
Asia	117 (66.47)
South America	23 (13.06)
North America	22 (12.5)
Europe	12 (6.81)
Australia	2 (1.13)
Appearance (n=176)
Radiolucent	167 (94.88)
Mixed	8 (4.5)
Radiopaque	1 (0.56)
Borders (n=136)
Ill defined	5 (3.67 )
Well defined	131 (96.32)
Pattern (n=139)
Unilocular	126 (90.64)
Multilocular	13 (9.35)
Symptoms (n=102)
Symptomatic	80 (78.43)
Asymptomatic	22 (21.56)
Bone (n=40)
Perforation	21 (52.5)
Expansion	12 (30)
Expansion+perforation	2 (5)
No	5 (12.5)
Root resorption (n=34)
Yes	17 (50)
No	17 (50)
Pulp sensibility (n=55)
Normal response	21 (38.18)
No response	21 (38.18)
Combination of normal and no response	7 (12.72)
Previously root canal initiated/treated	5 (9.09)
Inconclusive	1 (1.81)
Case reports	61 cases
Case series	9 articles; 24 cases
Retrospective studies	3 articles; 95 cases
Total	73 articles; 176 cases

Supplemental Table 3

Data extraction of the included articles

Supplemental Table 4

Preferred reporting items for systematic reviews and meta-analysis checklist 2020

Section and topic	Item#	Checklist item	Location where item is reported
Title
Title	1	Identify the report as a systematic review	0
Abstract
Abstract	2	See the PRISMA 2020 for Abstracts checklist	1 and 2
Introduction
Rationale	3	Describe the rationale for the review in the context of existing knowledge	3 and 4
Objectives	4	Provide an explicit statement of the objective(s) or question(s) the review addresses	3 and 4
Methods
Eligibility criteria	5	Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses	4
Information sources	6	Specify all databases, registers, websites, organizations, reference lists, and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted	5
Search strategy	7	Present the full search strategies for all databases, registers and websites, including any filters and limits used	5 and Supplemental Table 1
Selection process	8	Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process	5, 32
Data collection process	9	Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process	5
Data items	10a	List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g., for all measures, time points, analyses), and if not, the methods used to decide which results to collect	5
	10b	List and define all other variables for which data were sought (e.g., participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information	5
Study risk of bias assessment	11	Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process	6
Effect measures	12	Specify for each outcome the effect measure(s) (e.g., risk ratio, mean difference) used in the synthesis or presentation of results	-
Synthesis methods	13a	Describe the processes used to decide which studies were eligible for each synthesis (e.g., tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5))	4, 5
	13b	Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions	5
	13c	Describe any methods used to tabulate or visually display results of individual studies and syntheses	5
	13d	Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used	-
	13e	Describe any methods used to explore possible causes of heterogeneity among study results (e.g., subgroup analysis, meta-regression)	-
	13f	Describe any sensitivity analyses conducted to assess robustness of the synthesized results	-
Reporting bias assessment	14	Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases)	-
Certainty assessment	15	Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome	-
Results
Study selection	16a	Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram	6, 32
	16b	Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded	6 and Supplemental Table 2
Study characteristics	17	Cite each included study and present its characteristics	7
Risk of bias in studies	18	Present assessments of risk of bias for each included study	8, 33, 34
Results of individual studies	19	For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g., confidence/credible interval), ideally using structured tables or plots	7, 8, 30, 31, 35, 36, Supplemental Table 3
Results of syntheses	20a	For each synthesis, briefly summarize the characteristics and risk of bias among contributing studies	7, 8, 30, 31
	20b	Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g., confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect	-
	20c	Present results of all investigations of possible causes of heterogeneity among study results	-
	20d	Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results	-
Reporting biases	21	Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed	-
Certainty of evidence	22	Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed	-
Discussion
Discussion	23a	Provide a general interpretation of the results in the context of other evidence	9-16
	23b	Discuss any limitations of the evidence included in the review	9, 16
	23c	Discuss any limitations of the review processes used	16
	23d	Discuss implications of the results for practice, policy, and future research	15, 16, 37
Other information
Registration and protocol	24a	Provide registration information for the review, including register name and registration number, or state that the review was not registered	17
	24b	Indicate where the review protocol can be accessed, or state that a protocol was not prepared	17
	24c	Describe and explain any amendments to information provided at registration or in the protocol	-
Support	25	Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review	17
Competing interests	26	Declare any competing interests of review authors	17
Availability of data, code and other materials	27	Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review	-

Source.[121] For more information, visit: http://www.prisma-statement.org/. PRISMA: Preferred reporting items for systematic reviews and meta-analysis

Quality analysis

On quality assessment of the case reports using the JBI tool, 49 articles had a low RoB and 12 had moderate RoB. Of the included case series and retrospective studies, two had low RoB, six had moderate RoB, and four had high RoB [Figures 4 and 5]. The majority of the included articles were case series/reports, and hence, a quantitative analysis was not possible.

Figure 4

Graphical representation of scientific merit assessment of included articles using the Joanna Briggs Institute tool: (a) case reports; (b) case series. Green indicates “low risk of bias,” yellow indicates “some risk of bias,” and red indicates “high risk of bias”

Figure 5

Scientific merit assessment scoring of individual articles using the Joanna Briggs Institute tool: (a-i and a-ii) case reports; (b) case series. “+” indicates yes, “−” indicates no, and “?” indicates unclear response

As all the articles included in this review were case series, case reports, and retrospective studies, the JBI level of evidence falls in 4a category. Performing clinical trials on this topic will be extremely difficult, and hence, the currently available evidence from the existing case reports/series and retrospective studies is highly relevant.

DISCUSSION

With a wide range of benign odontogenic and nonodontogenic cysts and tumors in the periapical region simulating those of endodontic origin, it becomes imperative for clinicians to understand the prevalence, presentation, and diagnostic features of these lesions for making a correct diagnosis. To the best of our knowledge, this is the first systematic review to describe features of NMNPLs mimicking lesions of endodontic pathosis. Using strict inclusion and exclusion criteria, the present systematic review analyzed 73 articles (61 case reports, 9 case series, and 3 retrospective studies) of NMNPLs mimicking endodontic periapical lesion.

Quality assessment of the included articles was done using the JBI tool for case reports and case series.[1011] Majority of the case reports had low RoB while the case series had moderate RoB as the adverse events were not described in most of the cases.

The majority of the included cases were from Asia occurring most frequently in the second and fourth decades of life [Figure 2], with a higher male predilection. Clinically, NMNPLs were most commonly seen in the anterior region of the maxilla and posterior region of the mandible. However, the age, gender, and location of the lesion from one retrospective study[28] were not included in the results of this review due to an unclear distinction between the cases with and without the description of their radiographic features. In more than half the cases, the patients were symptomatic with the most common symptom being swelling, either with or without pain. In the previous systematic review on MNPLs, findings for the location of the lesion were different, with the posterior region of the mandible being the most commonly affected site.[5] The majority of the patients were symptomatic in their review although the description of the symptoms was not specified.[5]

Radiographically, a vast majority of NMNPLs had a unilocular radiolucency. This is similar to the previous review on MNPLs.[5] Only a small fraction of the included articles in this review exhibited multilocularity and/or mixed radiographic appearance. Besides this, 93% of NMNPLs had well-defined borders in radiographs, while only 21.8% of the MNPLs were well defined in the previous systematic review.[5]

The most commonly reported NMNPLs in this review were OKC, DC, NPDC, ameloblastoma, and AOT, in the descending order. OKC had the highest frequency accounting for 29.5% of all the NMNPLs. Previous studies reported frequencies of 14%, 32.2%, 34.6%, 34.9%, and 42.3%, respectively.[68192029]

OKCs are benign intraosseous lesions of odontogenic origin, accounting for about 10% of all jaw cysts.[30] They are characterized by an aggressive behavior with a relatively high recurrence rate.[31] In this review, there were a total of ten case reports,[32333435363738394041] two case series,[4243] and two retrospective studies[2844] on OKC. It showed a high male predilection with a majority of the patients in the third decade of life 31–40 years. This is in accordance with the previous literature.[31454647] The lesions were more commonly located in the anterior maxillary region.[32394042] The most common clinical presentation was swelling with/without purulent discharge.[35373839404243] Two cases were incidental findings.[3243] Radiographically, OKC appears as a well-defined unilocular or multilocular radiolucency bounded by corticated margins.[45] While most of the cases in this review were unilocular,[343637394344] two articles reported cysts that were multilocular[4044] and another article reported a cyst appeared as two separate “sister lesions,” with one located apically and the other along the lateral aspect of the root.[44] When a small unilocular OKC occurs in the anterior region of the maxilla, it may simulate other odontogenic and nonodontogenic cysts, such as radicular cyst, lateral periodontal cyst, or NPDC.[1548] When a periapical lesion exhibits an aggressive nature or abnormally large size, clinicians must consider OKC in the differential diagnosis.[45] In this review, one of the cases exhibited root resorption[40] and one case series and two cases reported perforation of buccal/labial cortical plate.[344143]

DCs were the second most common lesion in this review. DCs are developmental cysts that account for about 20% of all odontogenic cysts.[49] They are most commonly found enclosing the crown of an unerupted tooth at the level of the cementoenamel junction.[50] In this review, 17.61% of the cases had a histopathological diagnosis of DC,[2229515253] and the affected teeth were permanent successors with the cyst seeming to involve the roots of the overlying primary teeth, thus mimicking periradicular pathosis of the primary teeth. In accordance with the literature evidence,[49] the age of all the affected individuals in this review was within the first two decades of life, and the majority of them were male. The posterior mandible was more affected, and all the reported lesions were unilocular and radiolucent. Three cases and one retrospective study (24 cases) described the borders of the lesion as well defined.[22295253] Expansion of the buccal cortical plate was observed in one case.[22] Since DCs are found in relation to unerupted or impacted teeth, these are relatively easier to diagnose and differentiate from endodontic lesions. However, when associated with a permanent successor, like in the included cases, it can pose a diagnostic challenge. In such a scenario, DC can be distinguished by an intact lamina dura of the primary tooth and excessively widened follicular space of the erupting tooth on radiographs.[51]

Ameloblastoma is a locally aggressive odontogenic tumors, comprising 10% of all the tumors of the jaws. They clinically present as a painless swelling that may cause facial asymmetry.[54] In this review, three cases, one case series (two cases), and two retrospective studies (15 cases) were diagnosed with ameloblastoma.[12955565758] In the retrospective study by Gondak et al, two cases were asymptomatic while three cases presented with swelling and/or pain.[58] Additionally, two case reports and one case series also presented with similar symptoms.[15557] One case had a history of trauma with nonvital tooth and pus discharge.[56] Similar to the previous literature,[59] all the cases of ameloblastoma had a well-defined radiolucency, and most of them occurred in the posterior mandible.[5558] Due to their aggressive nature, they may exhibit root resorption and bony expansion with “egg shell crackling” on palpation. “Soap bubble appearance” on radiograph is a classic feature of the multilocular variant.[60] These characteristics should lead to a suspicion of ameloblastoma in the periapical region. However, radiographic appearance of unicystic variant is difficult to distinguish from endodontic periapical lesion. Locularity of the lesion in this review was mentioned only in two cases wherein both were unilocular.[5556] Root resorption was present in one case report and the retrospective study (three cases),[5558] and bony expansion was mentioned in two cases.[156]

NPDCs are developmental, epithelial, and nonodontogenic cysts found on the palate behind the maxillary anterior teeth. It develops due to the proliferation of epithelial remnants of the nasopalatine ducts[61] stimulated by irritation, local trauma, or infections.[6263] NPDC prevalence ranges from 2.2% to 11.6%,[646566] and in this review, it accounted for 10.79% of all the lesions.[67686970717273] It showed higher male predilection which is in accordance with previous literature.[626374] The patient is usually asymptomatic, and it is an accidental radiographic finding.[61] In this review, two cases presented with swelling,[6872] three cases had a history of trauma,[697173] and one case each complained of discomfort during palpation,[69] pain,[67] and ill-fitting denture.[70] Teeth involved in all the cases either responded normally to pulp sensibility tests or were previously endodontically treated. NPDC should be suspected when a radiolucency involving the anterior maxilla is associated with vital teeth. On CBCT examination, the lesion has shown to be involving the nasopalatine canal[697173] or extending into the nasal cavity.[70] Hence, when a lesion at this site is associated with a nonvital or endodontically treated tooth, CBCT should be considered to aid in diagnosis. Radiographically, most of the cases were unilocular well-defined radiolucent lesions which are in agreement with the literature.[75] Cortical bone resorption, which is an uncommon finding, was found in two case series (two cases each) and one case report.[697073]

AOT is a slow-growing, noninvasive, benign lesion with a prevalence of 2.2%–7.1% of all odontogenic tumors.[76] Of the ten cases of AOT in this review, eight were of extrafollicular variant[2377787980818283] and one case series (two cases) was of follicular type.[84] In agreement with the previous literature,[76] there were clear female predilection and higher prevalence in the second decade of life. AOTs were located mainly in the anterior region of the jaws. Radiographically, the lesions were unilocular with well-defined borders and most of them appeared radiolucent.[237880818284] Four cases exhibited root resorption[23798183] and three cases had cortical bone perforation[808183] which are uncommon in AOT.[76] In 70/% of the AOTs, small radiopacities are seen within the radiolucency.[85] This feature can be used to differentiate an AOT from a periapical lesion of endodontic origin, which usually does not have any opacities. AOTs are usually asymptomatic or may present as a painless, slow-growing swelling.[85] In this review, three cases were incidental findings,[788283] four cases and one case series (two cases) had a painless swelling,[2379808184] whereas one case presented with pain[77] and only three cases had flecks of radiopacities in the radiolucency.[798384] Two cases had a history of trauma,[7982] out of which one case had a nonvital tooth in relation to the AOT, leading to misdiagnosis of radicular cyst.[79]

In addition to the above-mentioned lesions, five cases of cemento-osseous dysplasia,[27868789] five cases of glandular odontogenic cyst,[2528909192] one case series (3 cases) of surgical ciliated cyst,[93] one case and one retrospective study (2 cases) of traumatic bone cyst,[2894] two cases each of calcifying odontogenic tumor,[9596] central giant cell granuloma,[9798] central giant cell lesion,[99100] schwannoma,[101102] paradental cyst,[28103] lateral periodontal cyst,[28104] and osteomyelitis,[105106] and one case each of ossifying fibroma,[107] osseous dysplasia,[26] osteoblastoma,[108] lymphangioma,[109] cemental dysplasia,[24] eosinophilic granuloma,[110] central odontogenic fibroma,[111] cemento-osseous fibroma,[24] foreign body reaction,[28] squamous odontogenic tumor,[112] plasmacytoma,[113] tuberculosis,[24114] and actinomycosis[115] were also reported in the included articles [Supplemental Table 3].

Adverse or unanticipated events were not clearly described in most of the cases. One case reported an incomplete root fracture after the initial treatment.[35] Bone sequestration during extraction procedure,[106] inaccessibility and poor visibility to perform surgical root canal treatment after flap elevation,[111] and intraoperative hemorrhage with the sectioned root apex lost in the bleeding tissue[97] were some of the unanticipated events reported during surgical procedures. In addition, postoperatively, paresthesia with suppuration[55] and an emergency visit to the dental clinic due to pain[88] were also reported.

Other NMNPLs such as globulomaxillary cyst, median palatine/mandibular cyst, aneurysmal bone cyst, osteoclastoma, calcifying epithelial odontogenic tumor, squamous odontogenic tumor, and periapical scar have not been reported in any of the included articles in this review. Clinicians should also be aware that persistence of radiolucency after nonsurgical root canal treatment or periapical surgery can be a periapical scar.[2] These cases can be radiographically interpreted as failures. Histologically, this area consists of dense, fibrous connective tissue with no sign of inflammation.[116] Therefore, if the patient is asymptomatic or there is no increase in size of the lesion, periapical scar tissue formation should also be considered in differential diagnosis.

Presence of an undamaged crown, no history of trauma, tooth responding to pulp sensibility tests, intact lamina dura in radiographs, and abnormally large lesion are few indicators of the lesion being NMNPLs. Lesions such as NPDC, median palatine/mandibular cyst, and globulomaxillary cyst have a specific area of occurrence which makes it easier for the clinicians to diagnose. Previous history of periradicular surgery or trauma can hint to the possibility of surgical ciliated cyst or traumatic bone cyst. A cyst or tumor of nonendodontic origin expanding in the periapical region of a tooth may severe off the blood supply to the associated tooth, leading to loss of its vitality and misdiagnosis of the periapical lesion.

Anatomic landmarks such as maxillary sinus and mental foramen and the presence of thick cortical bone in the mandible may complicate radiographic interpretation. Currently, the use of limited field of view CBCT in endodontics for diagnosis of nonodontogenic pathoses or in patients with nonspecific signs and/or symptoms is recommended.[117118] In the included articles, additional imaging modalities such as CBCT, CT, and MRI were also used to aid in diagnosis of the lesion. Musu et al. used ultrasonography in the diagnosis of OKC, AOT, DC, and central giant cell granuloma.[119] Future studies should consider exploring the use of ultrasonography in the diagnosis of NMNPLs.

A guideline that would help arrive at the correct final diagnosis of all types of periapical lesions with respect to their origin is provided in Figure 6.

Figure 6

Guideline for diagnosis of periapical lesions

The strengths of this review are that a strict inclusion criterion was followed, and only articles with both radiographic examination and histopathological diagnosis were included. This review provides a comprehensive summary of cases that provided the presentation, diagnosis, and management of NMNPLs, mimicking lesions of endodontic origin which always pose a diagnostic challenge for the clinicians.

Inconsistent and incomplete reporting in some included articles is one of the limitations of this review. Besides this, seven retrospective studies were excluded due to lack of radiographic details [Supplemental Table 2]. In addition, there is a difficulty in addressing various other potential NMNPLs due to their rarity in occurrence. The results of prevalence of the lesions in this review [Figure 3] must be viewed with caution because these data are pertaining only to cases of NMNPLs that have been reported. The actual prevalence could differ. Lack of long-term follow-up and missing details on adverse/unanticipated events are the other limitations of this review.

In future cases, complete details of the patient's history and treatment with follow-up should be provided following the Case Report Guidelines.[120] Retrospective studies should provide more data on the clinical and radiographic findings. Thorough clinical examination along with interpretations of different diagnostic tests (CBCT, CT, ultrasound, or MRI) should be correlated for provisional diagnosis and confirmed using histopathological examination.

CONCLUSION

This systematic review has highlighted the various clinical and radiographic features of several NMNPLs that mimic endodontic pathosis. They should be considered as a part of differential diagnosis of periapical lesions. Detailed medical and dental history-taking, thorough extraoral and intraoral clinical examination, appropriate diagnostic tests, and a sound knowledge of various NMNPLs will help clinicians in correct diagnosis and ultimately improve prognosis and treatment outcomes of such lesions. In cases of nonhealing periapical lesions of endodontically treated teeth, definitive diagnosis should be based on histopathological evaluation.

Other information

Protocol and registration

This systematic review was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analysis checklist.[121] The protocol was registered in International Prospective Register of Systematic Reviews (CRD42021237990).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.