the cyst increases in size by mechanisms that are discussed later.
Most information regarding cyst formation is taken from histological observation of biopsy specimens taken from humans and there are very few longitudinal studies. In experiments that have not been repeated, Valderhaug (1972 ) induced radicular cysts in monkeys. Because of the rarity of such experiments, it is worth considering some of the details of his findings. He induced pulpal necrosis sequentially in 39 teeth in 4 animals and was able to histologically examine periapical inflammation and cyst formation for up to 360 days after the pulps were removed. Of interest is that he did not observe any cysts until after 200 days, although proliferating epithelium was observed in earlier lesions. In lesions examined after 200 days, 11 of 16 (69%) developed cysts. Even after 300 days, 3 of 8 lesions showed no inflammation, but 4 had developed into cysts. Of relevance to the proposed mechanisms of cyst formation is that he did not see evidence of intraepithelial degeneration with formation of microcysts, but observed long strands of proliferating epithelium lining surfaces of granulation tissue, or arcades surrounding cores of vascularised or degenerating granulation tissue. These observations support the merging epithelial strands theory (theory 3). However, in most cases Valderhaug also observed that the proliferating epithelium was associated with PMNs, but he did not describe frank abscess formation. He also showed that in most cysts the epithelial lining was closely connected to the roots around the apical foramen, supporting the notion that the epithelium is reforming an intact integument, and that the cysts are pocket or bay cysts. In a very similar study, Valderhaug (1974 ) examined 52 primary teeth, and although periapical inflammation was common, he found small cysts only in ‘a few cases with long observation periods’. Of relevance to the theories of cyst formation is that he found that abscess formation, often with oral fistulas, was common and more frequently seen than in his previous study on permanent teeth (Valderhaug 1972 ). His findings, however, did not support the abscess theory, since ‘proliferating epithelium was not observed in the periapical area in connection with abscess formation’.
Figure 3.8 Sheet of epithelial cells in a periapical lesion. A distinct cleft has formed and this may initiate a radicular cyst.
Despite this, as described previously, there is good evidence that PMNs are a prominent feature of periapical granulomas and are associated with epithelial proliferation (Valderhaug 1972 ; Shear 1963a , 1964 ; Cohen 1979 ; Johannessen 1986 ; Marton and Kiss 2014 ). In their examination of 256 periapical lesions, Nair et al. (1996 ) showed that 90 (35%) were an ‘abscess’ and that two‐thirds of these contained epithelium. However, the definition of an abscess was of a collection of PMNs in a pre‐existing periapical granuloma – making distinction of a primary abscess from a collection of PMNs in a necrotic lesion difficult. In support of the abscess theory, Nair et al. (2008 ) were able to demonstrate that epithelium implanted into experimentally induced abscesses could form cysts. However, the relevance of these experiments is uncertain, since the abscesses were induced in the skin of experimental rats, and cysts only developed in 2 of 16 animals (6%). In addition, it is known that implanted epithelium may cause cysts even in the absence of infection or abscess formation. Nevertheless, we have seen cases of abscess formation in periapical granulomas where the abscess cavity has become encased in epithelium to form a cyst filled with PMNs (Figure 3.10). This supports the abscess theory, but not to the exclusion of the other possible mechanisms.
Figure 3.9 Degeneration of cells in the centre of a mass of proliferating epithelium in a periapical granuloma. There is an intense infiltration of lymphocytes and polymorphonuclear leukocytes. Accumulations of intercellular fluid coalesce to form a microcyst.
It seems, therefore, that there is little difference between the three proposed mechanisms – cyst formation occurs due to a ‘walling‐off’ of inflamed connective tissue by a process of epithelial proliferation similar to healing at an epithelial surface. This is due to the innate property of epithelium to form an external protective integument. The cyst lumen therefore represents the external environment, and in the case of a pocket or bay cyst (see later in this chapter) is continuous with the outside through the root canal. All three theories are thus tenable and not mutually exclusive. There is good observational or experimental evidence for each but, conversely, there is little evidence to refute any of them.
Figure 3.10 A periapical granuloma at the apex of a molar tooth root. There is a central focal accumulation of polymorphonuclear leukocytes that has become surrounded by epithelium (inset).
Growth and Enlargement of the Radicular Cyst
Role of Hydrostatic Pressure
The third phase in the pathogenesis of the radicular cyst is its growth and enlargement, which must involve a mechanism for expansion and for resorption of alveolar bone. Almost without exception, radicular cysts, especially when small, are seen as round or spherical radiolucencies on radiographs and on 3D imaging (CT or CBCT). This implies that growth of the cyst is regular and centripetal, and it is widely accepted that hydrostatic pressure, due to osmosis, provides the slow and evenly distributed forces necessary to achieve this growth pattern. This was first noted by Warwick James in 1926 in an address to the Royal Society of Medicine. He also reported that he had measured the increased pressure in cysts and was probably the first to suggest that ‘The increase in tension may be partly due to osmosis’ (Warwick James 1926 ). (Many of these very early papers are freely available online and are recommend for their clarity, insight, and the quality of the scientific observations.) The evidence for this was provided by early experiments carried out by Paul Toller, more than half a century ago, which have never been repeated or bettered (Toller 1948 , 1966b , 1967 , 1970a , 1970b ). In his first paper, Toller noted that early surgeons had observed that when opened, jaw cysts appeared to be under pressure, and that marsupialisation checked further growth and led to a reduction in size of the lesions (Toller 1948 ). He quoted Potts, who in 1927 had noted that cysts displaced the roots of teeth ‘as if by pressure’. This led to his experiments to measure the hydrostatic pressure in jaw cysts. Using a cannula and a manometer, he showed that the intracystic pressure in radicular and dentigerous cysts averaged 65–70 cm of water, which was considerably higher than capillary blood pressure, which was estimated to be lower than 10 cm of water (Toller 1948 ). In the same paper, he suggested that this increased pressure was a result of ‘osmotic tension’ and then went on to test whether the cyst lining acted as a semi‐permeable membrane. He used freshly dissected walls from radicular cysts and clamped them between two cylinders of Ringer's solution with 5% albumin added to one side. In all cases fluid passed through the cyst wall towards the albumin, showing that the wall acted as a semi‐permeable membrane.
In later studies, Toller (1970b ) showed that the mean osmolality of the fluid from 21 apical and residual cysts was 290 ± 14.93 mOsm and was greater than the mean serum osmolality of 279 ± 4.68 mOsm (P < 0.01). Lytic products of the epithelial and inflammatory cells in the cyst cavity provided the great numbers of smaller molecules that raised the osmotic pressure of the cyst fluid. Toller believed that the upper limit of permeability in most cysts was close to the molecular size of albumin (molecular weight 69 kDa) and that particles of larger size would find difficulty in diffusing across a cyst lining. These findings were confirmed by Skaug (1976a ), who conducted similar experiments and showed that the
