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 intracystic pressure ranged from 25 to 66 mmHg and that these pressures were restored 3–7 days after aspiration, suggesting that there was constant movement of fluid into the cyst lumen.
This pioneering work on the role of hydrostatic pressure in the growth of odontogenic cysts was mostly undertaken during the 1970s, but it has not been superseded or refuted by more contemporary experiments. Nair (1998 , 2004 ) has suggested that osmotic pressure as a factor in the development of radicular cysts has been ‘eliminated’. As evidence for this he cites the fact that the lumen of pocket or bay cysts is open to the root canal, and cannot therefore sustain an increased internal pressure. He suggests that cyst growth is sustained by molecular mechanisms. This is undoubtedly correct – a cascade of biological factors underpins the processes of epithelial proliferation, extracellular matrix destruction, and bone resorption, but there is still good evidence that there is increased pressure within the cyst lumen, and that osmosis is the driving force. This does not exclude other factors, although it should be noted that even in pocket cysts it is unlikely that the root canal remains empty and that the lumen is truly open to the oral cavity. It is also well recognised that release of this pressure, through decompression, has long been and still is a common and effective form of treatment (Castro‐Núñez 2016 ). More recently this issue has been re‐evaluated, but the outcome remains that hydrostatic pressure is still considered to be of primary importance in the growth of all cyst types. Kubota et al. (2004 ) measured the intracystic fluid pressure of odontogenic keratocysts, dentigerous cysts, and radicular cysts. They confirmed the earlier results of Toller (1970b ) and Skaug (1976a ), that the pressure was greater than the local blood pressure and that there were no differences between the three cyst types. They also measured cyst volume and showed that volume correlated to the area of the cysts measured on panoramic radiographs. They correlated the pressure to the areas of the cysts and found pressures of 337.6 ± 126.0, 258.2 ± 160.9, and 254 ± 157.3 mmHgcm−2 for keratocysts, dentigerous cysts, and radicular cysts, respectively. Furthermore, these authors showed that the intracystic pressure in all cyst types was inversely correlated to the cyst size. They therefore concluded that increased pressure played a pivotal part in early cyst growth.
Ward et al. (2004 ) used mathematical modelling to simulate odontogenic cyst growth. They assumed a spherical cyst lined by a semi‐permeable membrane and with a central osmotic pressure as a result of accumulation of degraded cellular material. The model supported the conclusions of the early experimental work, that osmotic pressure played an important part in cyst growth. Interestingly, the model also confirmed the findings of Kubota et al. (2004 ), and suggested that as the cyst became larger, osmotic pressure played a lesser part and cell proliferation became more important.
Osmotic pressure must be maintained by a high concentration of soluble proteins in the cyst fluid. Electrophoretic studies (Toller and Holborow 1969 ; Toller 1970a ) demonstrated that radicular cyst fluids contained small molecular‐sized albumin and β1‐globulin in quantities comparable with the patient's serum, but had fewer, if any, of the larger protein molecules. α‐ and β2‐ globulins were greatly diminished or absent, and γ‐globulins (mainly immunoglobulins) varied greatly in quantity, but were most often found in inflamed cysts. They showed that more than half display levels of immunoglobulins much higher than the patient's own serum. In 19 cyst fluids in which levels of IgG, IgA, and IgM were measured independently, all three were significantly raised in most of the non‐keratinising cysts. Immunofluorescent staining showed that lymphoid cell aggregates in the walls of radicular cysts often included numerous plasma cells.
Skaug (1973 , 1974 , 1976b , 1977 ) confirmed that fluid from non‐keratinising jaw cysts contained high concentrations of proteins, including immunoglobulins, but supported the view that accumulation of cyst fluid resulted essentially from inadequate lymphatic drainage of the cyst cavity. He suggested that plasma protein exudate and hyaluronic acid, as well as the products of cell breakdown, contributed to the high osmotic pressure of the cyst fluid.
These data suggest that the accumulation of proteins in the cyst lumen is a combination of a serum exudate, an inflammatory exudate, and breakdown products of cells, including luminal epithelial cells and inflammatory cells. It is likely therefore that the luminal pressure, necessary for cyst expansion, is greatest when the cyst is most inflamed, at earlier stages of development. As a cyst gets larger and matures, inflammation may subside, the rate of growth will slow, and a state of equilibrium may be reached. This is supported by the study of Kubota et al. (2004 ) and the model proposed by Ward et al. (2004 ), who both show that pressure and the rate of growth decrease with size of the lesion.
Although osmotic pressure may provide the stimulus for expansion, it does not operate alone and, as mentioned above, a complex cascade of molecular events is responsible for growth.