Histopathology
From the foregoing account of pathogenesis, it is clear that on histological examination a periapical lesion may show a wide variety of features. Over 100 years ago Thoma (1917 ) described five types of lesion that may be encountered in association with a non‐vital tooth. To paraphrase his descriptions into contemporary terminology, the five lesions were periapical granuloma, periapical abscess, periapical granuloma with proliferating epithelium, periapical granuloma with early cyst formation, and radicular cyst. However, we should not regard these as individual lesions, but as a continuum of changes that reflect the pathogenic pathway, with a fully developed cyst as the end result.
Some have suggested that a diagnosis of a cyst can only be made after examination of multiple serial sections to confirm the presence of a true cavity with an epithelial lining (Simon 1980 ; Nair et al. 1996 ; Ricucci and Bergenholtz 2004 ), but this is not practical or sustainable in routine clinical practice. The diagnostic histopathologist rarely receives an intact specimen, or a specimen still in continuity with the offending root apex. This is because a periapical lesion is often surgically removed during an apicectomy operation, where the apex of the tooth and associated soft tissue are removed and a filling material is placed in the root canal, thus enabling preservation and restoration of the affected tooth. Therefore, the pathologist often receives the lesion as a fragmented or irregular curettage specimen from which the diagnosis of a cyst must be deduced, in the context of the orientation of the tissues and the clinical and radiological findings. An intact specimen may be a spherical or ovoid cystic mass, but often they are irregular and collapsed. Lesions are usually 10–15 mm in diameter and rarely exceed 30 mm. The walls vary from extremely thin to a thickness of about 5 mm. As with all cystic lesions, it is important to examine the inner surface of the cyst. This may be smooth or corrugated, but mural nodules or thickenings may be seen, which often represent accumulations of cholesterol or hyaline (Rushton) bodies projecting into the lumen. The fluid contents are usually watery and brown from the breakdown of blood, but when cholesterol crystals are present they impart a shimmering gold or straw colour. Pathologists must also recall that a radicular cyst is always associated with a non‐vital tooth. If this is not the case, then an alternative diagnosis must be sought, usually needing careful correlation with clinical and radiological findings.
On histological examination, the key diagnostic criterion is to identify a variably inflamed fibrous cyst wall lined wholly or in part by stratified squamous epithelium (Figure 3.12). The epithelial lining may be discontinuous and ranges in thickness from 1 to 50 cell layers. The majority are 6–20 cell layers thick. The nature of the lining may depend on the age or stage of development of the cyst, or on the intensity of the inflammation. In early cysts, the epithelial lining may be proliferative and show a characteristic arcading with an intense associated inflammatory process (Figure 3.12), but as the cyst enlarges the inflammation may subside and the lining becomes thin and regular, with a certain degree of differentiation to resemble a simple non‐keratinised stratified squamous epithelium. In well‐developed cysts, the lining may vary. At sites of heavy inflammation, often adjacent to the tooth root, the epithelium may be proliferative and thickened, but away from the tooth the wall is often less inflamed and the lining becomes thin and regular (Figure 3.11). Long‐standing cysts and residual cysts in particular may be lined by a thin, regular lining of stratified squamous epithelium (Figure 3.13).
Figure 3.12 Radicular cyst. The cyst has a thick fibrous wall. The lumen is lined by proliferating and arcading epithelium.
The inflammatory cell infiltrate in the cyst wall and the epithelial lining may vary considerably, since it reflects a single moment of the pathogenic pathway caught in a histological section. Thus any of the inflammatory cells involved in the development of the lesion may be seen. In early lesions the proliferating epithelial lining usually contains many PMNs, whereas the adjacent fibrous capsule is infiltrated mainly by chronic inflammatory cells (Shear 1963a , 1964 ; Cohen 1979 ; Matthews and Browne 1987 ). The proliferating epithelial lining shows a considerable degree of inter‐ and intraepithelial oedema or spongiosis.
The cyst wall is essentially composed of granulation tissue at various stages of maturation, depending on the age of the lesion and on the proximity to the source of the inflammation. The wall is therefore often zoned, with heavily inflamed granulation tissue adjacent to the epithelial lining, less inflamed maturing granulation tissue centrally, and collagenous fibrous tissue at the peripheral margin adjacent to the bone (Figure 3.12). Inflammation is also more prominent adjacent to the root apex – where accumulations of polymorphs may be seen, even in long‐standing lesions. The predominant cell population, however, is of chronic inflammatory cells, mostly lymphocytes; plasma cells are also seen, and on occasion may predominate or may form dense focal accumulations.
Figure 3.13 Quiescent epithelium lining a mature, long‐standing residual cyst.
Remnants of odontogenic epithelium and occasional satellite microcysts may be found in the fibrous capsule and there have been reports of examples where epithelial proliferation is so extensive that it resembles squamous odontogenic tumour (Wright 1979 ; Simon and Jensen 1985 ; Unal et al. 1987 ; Chrcanovic and Gomez 2018a ). These proliferations are reactive in nature and should not be interpreted as a co‐existent neoplasm. The behaviour is that of the cyst of origin and no further treatment is required if this observation is made during histological examination of the cyst wall (Chrcanovic and Gomez 2018a ).
Some cyst walls are markedly vascular. Haemorrhage is invariably present and haemosiderin deposits are seen in many specimens (Shear 1963c ). Calcifications of various kinds may also be seen. Dystrophic calcifications associated with necrotic and degenerative material in the cyst lumen are a particular feature of residual cysts that have been present for a long time (High and Hirschmann 1986 ). Hyaline bodies may also calcify either within the epithelial lining or among deposits that have extruded into the lumen or into the wall. In curettage specimens, trabeculae of reactive woven bone and occasionally lamellar bone are often found at the periphery of the lesion. Occasionally a well‐formed rim of woven bone may be seen.
Although well‐formed colonies of actinomycosis are well described in case reports, this is a rare finding. Hirschberg et al. (2003 ) found colonies of Actinomyces in only 17 of 936 (1.8%) periapical lesions examined, 4 of which were radicular cysts. Nair (2006 ) found a similar frequency in a review of the literature, and postulated that established colonies of Actinomyces may persist and be an important cause of endodontic failure and persistent or recurrent lesions. Ricucci and Siqueira (2008 ), however, found no evidence for this and suggested that provided the root canal was properly cleaned, the presence of actinomycosis was not associated with treatment failure.
Cellular and Metaplastic Changes
Radicular cysts may show variable histological features due to reactive changes and to metaplastic changes of the lining epithelium. These additional features are characteristic and occasionally assist in diagnosis (Table