The incisive canal is located between and apical to the roots of the maxillary central incisors. It is generally accepted that a diameter of 6 mm is the upper limit of the normal size for the incisive canal, so that a radiolucency of 6 mm or smaller in this area is usually considered a normal foramen unless there are clinical signs or symptoms (e.g., swelling, pain, drainage) present [37]. Lesions larger than 6 mm are usually considered as an incisive canal cyst. The incisive canal or the incisive canal cyst usually appears as a symmetrical, well-defined radiolucent lesion between the roots of the upper central incisors, showing a “heart”-like-shaped outline due to its superimposition on the anterior nasal spine. However, occasionally, the canal or its cystic variant is asymmetrical, lying only on one side of the midline, overlapping the apex of the adjacent central incisor, thus mimicking a periapical pathosis. In this case, in particular when the lesion is larger than 6 mm, an occlusal radiograph will aid in determining the spatial relation between the seemingly unilateral “periapical” pathosis and the status of the LD and width of the periodontal ligament of the adjacent tooth [37].

The mental foramen may also have a radiographic appearance of a periapical pathosis in the area of the lower second premolars. If doubts are raised in regard to the true nature of the lesion, then additional periapical x-rays should be taken from different angles in order to analyze changes in the position of the “periapical” finding [37].

The anatomical depression at the angle of the mandible below the inferior alveolar nerve canal, in which part of the submandibular salivary gland or muscle tissue or fibro-fatty tissue resides and has a radiographic appearance of a cyst-like lesion, is known as the mandibular lingual salivary gland depression/Stafne defect/static bone cyst [37]. In a minority of cases, this anatomical mandibular defect has been found more anteriorly, namely, starting from the symphysis area to the premolars. This anterior variation of “Stafne bone defect” is filled by sublingual salivary gland tissue and has the appearance of a periapical pathosis [42].

Anecdotal cases of atypical anatomy of the maxillary sinus with an extension seen on conventional panoramic x-rays as a unilocular, well-defined corticated radiolucency in the second premolar-first molar location were reported [43]. With the aid of adequate CT imaging, when indicated, it could provide valuable information for an exact diagnosis.

Another rare anatomical variation is the canalis sinuosus that carries the anterior superior dental nerve and associated blood vessels [44]. It can rarely take an aberrant route between the medial aspect of the alveolar bone of the maxillary canine and the nasal cavity and as such be interpreted as a periapical pathosis of the canine tooth. Close examination of periapical x-rays will reveal the intact periodontal ligament space of the canine upon which the radiolucency of the canalis sinuosus is superimposed.

A true cyst is defined as a pathologic cavity lined by epithelium and filled with fluid or semisolid material [37]. Cysts rarely develop within bones for the simple reason that it is unusual to find epithelium in these locations. The jawbones, however, are a marked exception to this rule, and cysts occur in this region more frequently than in any other bone in the body. The source of epithelium in the jawbones is both odontogenic and non-odontogenic. Corresponding to this epithelium, two major types of bone cysts, odontogenic and non-odontogenic, arise within the jaws. The odontogenic cysts can be further classified as developmental (part originates from the rests of dental lamina and part from reduced enamel epithelium) and as inflammatory (originates from the rests of Malassez) [37]. Cysts of jawbone are well-defined, totally or predominantly radiolucent, sometimes expansile lesions.

The lateral periodontal cyst (LPC) is a rare developmental odontogenic cyst that typically occurs on the lateral surface of a canine or a premolar tooth, predominantly in the lower jaw [37]. Adjacent teeth are vital and as such the LD and periodontal ligament space are expected to be intact. Radiographically, LPC is a well-defined radiolucency on the lateral aspects of the tooth roots with a diameter of ~1 cm. These clinical and radiographic parameters should be enough to distinguish a LPC from a LRC. However, LPC type of lesions can be present in association with a non-vital tooth or with what seems to be lack of healing of an endodontically treated tooth [37]. Upon submitting the lesion to microscopic examination the diagnosis of LPC has to be supported by the typical features of the lining epithelium (that are expected to be preserved, at least in part, even if the cyst is inflamed).

Another rare odontogenic developmental cyst reported at the apex of a non-vital tooth is the orthokeratinized odontogenic cyst [45] that usually has no characteristic clinical or radiographic features to distinguish it from other inflammatory cysts.

Odontogenic tumors arise from epithelial and/or mesenchymal components of the developing odontogenic apparatus and are almost always confined to the jaws. These tumors are usually benign but vary widely in their behavior.

Radiographically, they may manifest as totally radiolucent or radiopaque lesions or as mixed radiolucent-radiopaque lesions. The lesions are diagnosed and classified on the basis of their histologic features, usually correlating the clinical and radiographic features.

The keratocystic odontogenic tumor (KCOT), formerly known as odontogenic keratocyst, is a developmental odontogenic lesion, now believed to represent a cystic tumor [37]. KCOT may demonstrate a radiographic picture that, among other possibilities, can mimic that of a PAG/PAC [37]. In fact, when large series of periapical biopsies taken from teeth with clinically necrotic pulps were analyzed, KCOTs were found in a frequency ranging from 0 % [38, 46, 47] to 0.27 % [40], 0.3 % [48], 0.53 % [49], and up to 0.7 % [50]. Comparing KCOT to other periapical noninflammatory types of lesions, it seems that KCOT is the most frequently encountered. In a study of 239 KCOTs, 21 (9 %) were located periradicularly and 12 (57 %) were associated with non-vital teeth or endodontically treated teeth and therefore were considered to be of endodontic origin [51]. Interestingly, in the latter lesions, two-thirds were symptomatic, the mandible-to-maxilla ratio was almost 1:1, 90 % were associated with teeth anterior to the molars, mainly anterior teeth, and the mean age of the patients was 56 years. These features are different than those that characterize the classical non-periapical, non-vital tooth-related KCOT, in terms of location and age of patients [37]. Periapical lesions that fail to heal after good-quality endodontic treatment require further investigation, in particular if lesions continue to enlarge and/or present aggravating symptomatology during follow-up. A 4-year follow-up period has been suggested in order to assess success or failure [52]. Assuming that the nonhealing periapical lesion could be a KCOT, it is likely that during this follow-up period it would continue to advance and change the radiographic picture, thus demanding a biopsy procedure and a definite microscopic diagnosis. A case of KCOT mimicking a periapical lesion is seen in Fig. 2.2. The treatment of KCOT must take into consideration the tendency for recurrence, and therefore the surgical approach is usually more aggressive than for other developmental cystic lesions nonetheless periapical inflammatory pathoses and usually comprises of removal of the lesion followed by peripheral ostectomy of the bony cavity and/or chemical cauterization. Exceptionally, locally aggressive KCOTs demand local resection and bone grafting [37].

Anecdotal cases of solid ameloblastoma appearing as a periapical, cyst-like radiolucency associated with non-vital teeth have been reported [53, 54]. Similarly, unicystic ameloblastoma adjacent to vital and non-vital teeth was reported [36, 55]. A case of a “periapical” unicystic ameloblastoma considered to be an inflammatory periapical lesion that remained untreated for about 10 years is illustrated in Fig. 2.3. The treatment approach for solid, multicystic ameloblastoma and for unicystic ameloblastoma with mural proliferation is quite aggressive because the tumor infiltrates into the adjacent cancellous bone, beyond the apparent radiographic margins [37]. The most conservative treatment is removal of the tumor after careful study of the CT scans followed by peripheral ostectomy. Escalation of the surgical procedure to marginal resection followed by reconstructive surgery might be mandatory depending on tumor size and pattern of expansion, yet a 15 % recurrence rate still occurs. The other types of unicystic ameloblastoma (i.e., the luminal and intraluminal) are treated as “conventional” cysts by enucleation and close follow-up as recurrence rates of 10–20 % were reported [37]. Additional types of rare odontogenic tumors in a periapical location were published, either as single-case reports or as part of case series on periapical inflammatory lesions, and these include adenomatoid odontogenic tumor, calcifying cystic odontogenic tumor, ameloblastic fibroma, squamous odontogenic tumor, calcifying epithelial odontogenic tumor, and odontogenic myxoma [38, 40, 56, 57]. Part of these reported lesions were not accompanied with photomicrographs of the histopathological findings, so that the accuracy of the diagnoses cannot be always confirmed.

In conclusion, the key to an accurate diagnosis in case of a periapical lesion, even if it looks to be of inflammatory nature, is the collection of all available clinical data and radiographic findings and sufficient follow-up period in those doubtful cases.

This is a diverse group of lesions of varied etiologies; we will presently focus on two entities that radiologically have features of a radicular cystic lesion, namely, central giant cell granuloma (CGCG) and fibro-osseous lesions.

CGCGs appearing as small periapical lesions constituted 9 % of all examined CGCG cases (N = 75) in one study [58]. Furthermore, the largest retrospective study on CGCG (N = 79) found in a periapical location (PA-CGCG) revealed that 20 % of the lesions were associated with teeth with necrotic pulps and that the majority of these necrotic teeth had been endodontically treated [59]. In addition, PA-CGCG was encountered in patients older than 30 years of age, while the non-PA-CGCG is usually diagnosed in younger patients; ~50 % of the PA-CGCGs were in the posterior area of the mandible; in regard to the PA-CGCG found in the maxilla, there was a similar distribution between the anterior and posterior areas. Single cases of PA-CGCG or small case series were also reported [38, 40, 60–62]. All these studies emphasized the need for careful analysis of the radiographic findings in order to decide the lesion-tooth supporting structures relations, both at the initial presentation and during the follow-up period, if teeth were endodontically treated in equivocal cases. Whenever surgical specimens are taken, submission to microscopic evaluation is mandatory. A case of CGCG mimicking a periapical lesion is seen in Fig. 2.4. CGCGs are usually treated by thorough curettage although recurrence rates of 11 % and up to 50 % were reported, with the higher values being attributed to those lesions that are defined as biologically aggressive and which are characterized by a tendency to recur, especially in young patients [37]. Recurrent CGCGs may be treated by curettage or by a more radical surgical approach, depending on the clinical findings, with optional addition of different pharmacological agents.

Fibro-osseous lesions of the focal or periapical type [focal cemento-osseous dysplasia (FCOD) and periapical cemental dysplasia (PCD)] can be confused with PAGs/PACs in their early, radiolucent stage [63, 64], although, at least PCD, rarely affect only one tooth. Whenever diagnosis based on clinical and radiographic information is doubtful, biopsy of the periapical lesion should be considered before starting a redundant endodontic treatment.

This subgroup includes cases of traumatic bone cyst [65, 66], central schwannoma [67, 68], and lymphangioma [69