Jottrtial of Oral Pathology 1975: 4: 31-46 Review Article

The pathogenesis of odontogenic

cysts: a review
R. M. BROWNE
Department of Oral Pathology, University of Birmingham, England

Abstract. The pathogenesis of the three common forrns of odontogenic cyst is discussed. It
is concluded that the dental cyst arises from proliferation of the epithelial rests of Malassez
in a focus of inflammation stimulated by pulpal necrosis of the associated tootli. It enlarges
by unicentric expansion from the hydrostatic pressure of its contents.
The dentigerous cyst arises from pooling of inflammatory exudate, which is derived frotn
the obstructed follicular veins of an unerupted tooth and accumulates between Ihe reduced
enamel epithelium and the crown of the tooth. It enlarges by unicentric expansion from the
hydrostatic pressure of its contents.
The odontogenic keratocyst arises by proliferation of the residues of the dental lamina,
possibly as a hamartomatous abnormality. It enlarges by both multicentric expansion due
to the proliferation of localized groups of epithelial cells in the lining and by unicentric
expansion from the hydrostatic pressure of its contents.

Received IS Novetnber 1974, accepted for publicatioti 3 March 1975

There has been a great increase in know-
ledge of the pathology of odontogenie eysts
in recent years, so it is ati opportune mo-
ment to review the advatices that have been
made. It is not possible to define the reason
for this upsurge in interest, but if there is
one observatioti that has spurred if on, it
must be the evaluation of the significance of
the structure of the epithelial lining of
odotitogenic cysts, pattieularly the presetice
or absenee of a keratin layer.
The significance of keratin formation iti
the epithelial lining of odontogenic eysts is
two-fold: firstly, the great majority of these
cysts fall into a category, the odontogenic
keratoeyst, whieh exhibits a more trouble-
some pattern of clinical behavior than fhe
other eysts (Pindborg & Hansen 1963, Bram-
ley & Browne 1967, Toller 1967) and se-
condly a keratinizing cyst lining is more
common in cysts which have undergone
earcinomatous change (Browne & Gough
1972), _
Classification
Because of the importance of the structure
of the lining of these cysts, a logical clas-
sification must be based primarily on their
histological features and histogenesis, and
the clinical atid radiological features must
be seeondary consideratiotis.
There is no advantage to be gained from
reviewing the many previous elassifieations

This paper is based on a lecture of the same title delivered in the series The Scientific Basis
of Dentistry of the British Postgraduate Medical Foundation, April 1974,
32 BROWNE

CLASSIFICATION OF ODONTOGENIC CYSTS

GROUP MAIN TYPE SUB TYPE

DENTAL CYST RADICULAR CYST

RESIDUAL CYST
DEVELOPMENTAL CYSTS
LATERAL PERIODONTAL CYST GINGIVAL CYST

<
' DENTIGEROUS CYST ERUPTION CYST

PRIMORDIAL CYS)
•. -•• - . ... ODONTOGENIC KERATOCYST
Fig. 1. A classification of odontogenic cysts.

that have been proposed. In any classifica-
tion exceptions may be pointed out, but
these exceptions form only a very small
proportion of the whole and are best omitted.
The most satisfactory classification is the
simplest, providing of course that it is ac-
curate; a suitable classification, similar
to that proposed by Toller (1972), is pre-
sented in Fig. 1.
A dental cyst is usually lined by stratified
squamous cpithcliutn and arises in a focus
of inflammation in the periodontal ligament
caused by pulpal necrosis of an associated
tooth. This most commonly occurs periapi-
cally, but if the tooth has a lateral root
canal, i( tnay occur laterally to the tooth.
In either position it is referred to as a radi-
cular cyst. If the cyst persists following the
removal of the causative tooth, it becomes
a lcsidual cyst.
A lateral periodontal cyst is usually lined
by stratified squatnous epithelium and arises
in a focus of inflammation in the periodon-
tium caused by irritation from the marginal
periodontium. The cyst most commonly
arises within the bone but occasionally may
occur in the gingiva, where it may be refer-
red to as a gingival cyst. As has already
been pointed out, tio simple classification
can be comprehensive, and there are oc-
casional cysts, lined by non-keratinizing
epithelium and arising in the site of a lat-
eral periodontal cyst or gingival cyst, which
arc apparently not of inflammatory origin.
It should be emphasized, however, that al-
though there may be no evidence of inflam-
mation at the time of examination of the
specimen, no definite conclusion may be
reached as to whether such changes were
present at the initiation of cyst formation.
As cysts of this type are extremely rare and
thus there are few data upon which to base a
mechanism of their origin, they are not in-
cluded separately in the present classifica-
tion.
A dentigerous cyst is usually lined by a
layer of stratified squamous epithelium
which encloses the crown of an associated
uneruptcd tooth. It arises as a result of the
itnpeded eruption of the associated tooth.
This usually occut"s within (he bone bu( oc-
casionally takes place in the overlying soft
tissue, where it is called an eruption cyst.
An odontogenic keratocyst is always lined
 ODONTOGENIC CYSTS: A REVIEW 33

by a layer of stratified epithelium whieh is after the initiation of root dentinogenesis;

keratinized and has a characteristic struc-
ture. It is not assoeiated with a tooth in an
etiologieal relationship. Unerupted teeth are
frequently displaced by odontogenie kerato-
cysts, which thus may clinically resemble
dentigerous eysts. Occasionally odontogenic
keratoeysts arise in place of teeth. Sueh
cysts were originally deseribed as primor-
dial cysts (Shafer et al. 1974), although
several authors (Shear 1960, Soskolne &
Shear 1967, Pindborg et al. 1971) use this
latter term in a wider eonnotation synonym-
ously with odontogenic keratoeyst. In the
author's view the term primordial cyst
should be used in its original sense and sueh
cysts, which all have a lining of keratinizing
epithelium, form a stnall subgroup of the
odontogenic keratoeysts. Indeed, the odont-
ogenic keratoeyst may clinically and radio-
logically mimic any of the other types of
odontogenic cysts. It is likely that this has
contributed to much of the confusion in the
past.
The epithelial lining of odontogenie cysts
is derived from the epithelial residues of the
tooth-forming organ. There are three kinds:
1. the epithelial rests of Malassez, left behind
in the periodontal ligament by the break-
down of the epithelial root sheath of Hertwig
2. the reduced etiamel epithelium, which
covers the cotnpletely formed crown of an
unerupted tooth and which is derived from
the enamel organ, and 3. the epithelial
tests or glands of Serres, whieh persist
after the dissolution of the dental lamina.
The evidence indicates that each of these
rests is primarily respotisible for the origin
of a particular eategory of odontogenic
eyst. The rests of Malassez ate responsible
for inflammatory eysts, i.e. dental and la-
teral periodontal eysts, the redueed enamel
epithelium for dentigerous cysts and the
residues of the dental latnina for odonto-
genie keratocysts (Fig. 2). Although oe-
casionally epithelial rests may give rise to
types of eyst other than those indicated, in
the author's view there is no firm evidence
for these alternatives and thus they are not
ineluded.
Therefore, to understand the pathogene-
sis of each type of odontogenic eyst, it is
tiecessary to study the epithelial residues
from whieh they arise and to eompare them
with the epithelium of the eysts to whieh
they give origin.
Rests of Malassez
In man, epithelial rests of Malassez are

EMBRYOLOGICAL DERIVATION OF ODONTOGENIC CYSTS

EMBRYOLOGICAL STRUCTURE EPITHELIAL RESIDUE ODONTOGENIC CYST

DENTAL LAMINA EPITHELIAL COILS

ODONTOGENIC KERATOCYST
(GLANDS OF SERRES)

ENAMEL ORGAN REDUCED ENAMEL

DENTIGEROUS CYST
EPITHELIUM

EPITHELIAL ROOT • •' " EPITHELIAL RESTS DENTAL CYST

SHEATH OF HERTWIG ' - ^- OF MALASSEZ LATERAL PERIODONTAL CYST
Fig. 2 The embryological derivation of the epithelium in odontogenic cysts.
 BROWNE
present in the periodontal ligament as a
network of cells enmeshing the roots of the
teeth (Simpson 1964). In section they ap-
pear as islands close to the cementum sur-
face of tbe tooth (Sicher 1962).
Their gradual decrease in number with
age (Reeve 1960, Reitan 1961), together
with an absence of mitotic figures, suggests
that these cells are indeed resting. This view
is supported by histochemical (Ten Cate
1963, 1965) and ultrastructural (Valderhaug
& Nylen 1966, Morgenroth & Morgenroth
1966) observations. The presence of glyco-
gen granules and enzyme pathways indi-
cative of pentose shunt and anaerobic gly-
colytic activity led Ten Cate (1965) to the
conclusion that they are cells undergoing a
metabolism requiring little energy.
The reason for their survival into adult-
hood and old age therefore remains a my-
stery. To solve this problem, previous work-
ers have ascribed a secretory (Black 1899,
Robinson 1926, Higaki 1932) or protective
(Waerhaug 1958, Loe & Waerbaug 1961)
function to them. However, their paucity of
rough endoplasmic reticulum and absence
of a developed Golgi complex (Valderbaug
& Nylen 1966) make it unlikely that they
undertake any synthesis of secretory pro-
teins and there is, as yet, no evidence tbat
they play any functional role.
In tbe formation of dental and lateral
periodontal cysts the rests are stimulated to
proliferate by changes in their environment
occasioned by the development of foci of
inflammation in the periodontium. Whether
their lack of mitotic activity under physio-
logical circumstances is due to the presetice
of intracellular, inhibitory cbalone-adrenalin
complexes, as demonstrated in the skin
(Bullough & Laurence 1964) and gingival
epithelium (Hansen 1967), is not known,
but it would be reasonable to anticipate
that this may be so. Tbus tbe altered
environment of the periapical granuloma
would permit the release of these itihibitors
from the affected cells and lead to a renewal
of mitotic activity. This telease of the
epithelial rests from mitotic inhibition in
periapical granulomas is presumably similar
to that observed in explants of these cells
grown in tissue culture (Grupe et al. 1967,
Nylen & Grupe 1969). In both situations
the epithelial cells undergo an increase in
cytoplasmic/nuclear ratio accompanied by
increased pentose shunt tnetabolism and
ribonucleoprotein synthesis. This change in
metabolic activity is also a feature of oral
epithelium involved in non-specific inflam-
matory lesions, as in wound healing (Ten
Cate 1966), where tbe epithelial prolifera-
tion meets a biological need to restore the
continuity of the body's outer integument
(Ten Cate 1972). But in a periapical granul-
oma, although such a need is also present
because tbe periapical tissue is in effect ex-
posed to the external environment through
the pulp cavity of the non-vital tooth, the
epithelial ptoliferation is unable to achieve
its objective. This failure is a sequel of the
deep anatomical situation in which the pro-
liferation occurs and because the causative
agents are able to persist in tbe root canal
safe from tbe body's defense mechanisms.
As a result, epithelial proliferation continues
and dental cyst formation may ensue.
Although necrosis of tbe dental pulp is a
frequent event and periapical granulomas
forrn thereafter, the factors which deter-
mine why cystic transformation occurs in a
granuloma are not clear. There is an opin-
ion that some persons have a greater poten-
tial for forming cysts than others, although,
apart from Oehler's study (1970), there is
little evidence to support this.
Dental Cysts
Cyst formation arises either by the degenera-
tion of the central cells in thickening pro-
cesses of non-vascular epithelium (Turner
1898, Hill 1930, Shear 1963, Ten Cate
1972) or by the degeneration of areas of
 ODONTOGENIC CYSTS: A REVIEW
granulation tissue which have becotne sur-
rounded by the proliferating epithelial cells
(Stones 1951), Although both mechanisms
probably play a role in the initiation of
dental eyst formation, it would seem that
epithelial degeneration is the predominant
one.
Thus the newly formed dental cyst emer-
ges, at first lined by an irregular layer of
stratified squamous epithelium whieh, as
the lesion matures, beeomes more ordered.
Ultrastructural studies show that, whereas
these cells have the same basie features as
those in the oral mucosa, they Iaek the or-
derly sequence of structural changes observed
from the basal layers to the surface layers
of this latter epitheliutn (Frithiof & Hagg-
lund 1966, Kobeyasi & Hansen 1970, Hor-
nova et al. 1972). The persistenee of large
numbers of eytoplasmic organelles and the
largely membrane-bound distribution of
aeid phosphatase in the surface epithelial
eells of dental eysts suggest that they are
shed itito the cavity by autolysis rather than
by maturation and desquamation (Kobeyasi
& Hansen 1970). This view is supported by
the examination of smears of dental eyst
fluids which contain large nutnbers of in-
flammatory eells and only occasional de-
generate epithelial cells.
The autolysis of the surface epithelium
contributes eell breakdown produets to the
fluid oeeupying the eyst cavity. As a result,
the cyst contains large numbers of osmoti-
cally active moleeules and so is hypertonic
compared with serum (Toller 1970). Becau-
se of the semi-permeable nature of the cyst
wall and thus of the limited lymphatic
drainage from the cyst (Toller 1966b), the
moleeules disseminate only slowly, and as
a result water is attraeted into the cyst
cavity. This fluid tnovemetit provides a hy-
drostatic force to the cyst contents (Toller
1948) which provides the unicentric, bal-
looning pattern of expansion characteristic
of this lesion. This hydrostatic meehanism
35
of eyst growth has been fully discussed by
Main (1970a) and Toller (1972). As a result
of the cyst growth, osteoclastie bone resorp-
tion is stimulated to aeeommodate the ex-
panding mass. Whether the raised hydro-
statie pressure of the cyst contents is trans-
mitted through the cyst wall direetly to the
bone surface to stimulate the osteoelasis is
not known. It has been suggested that the
large amounts of librinolytic cytokitiase
present in the endothelium of the blood
vessels in cyst capsules (Harris 1970, Bjor-
lin et al. 1971) is there to aetivate the plas-
minogen system and thus prevent the ves-
sels, which may be partially occluded by the
eyst pressure, from beeoming totally oe-
eluded by blood clot. In any event, there is
now evidence to suggest that stimulation of
the osteoclasts is chetnically mediated by the
release of prostaglandins, partieularly PGEo,
in the capsule (Harris & Goldhaber 1973,
Harris et al. 1973, Harris 1974),
As well as cell breakdown products, other
substatices are added to the cyst fluid. As a
result of metaplasia, the epithelial cells tnay
become mucus seereting or form keratin
(Browne 1972). Mucus metaplasia occurs in
at least 40 % of dental eysts and there is
evidence to suggest that mueus cells beeome
more prevalent the longer the cyst has been
present (Stoelinga 1971, Browne 1972). As
a result it is likely that mucin is added to
the eyst eontetits and in increasing amoutits
with age, although whether secretion is pos-
sible against the pressure gradient of the
cyst cotitents has been questioned (Main
1970a). The metaplastic keratinization, like
tnueus eell metaplasia, starts as clones of
eells scattered in the cyst lining undergoing
keratinization and may beeome generalized
so that mueh and occasionally all the epi-
thelium is itivolved. This is a far less com-
mon event than mucus metaplasia, only
2 % of dental cysts exhibiting it, but again
there is evidence to suggest that it is a
change which becomes more comtnon the
 BROWNE

Dental Cyst readily these proteins gain access from the

TOTAL PERCENTAGE
capsule to the cyst cavity is not clear. It has
PROTEIN la A lg G 1B H OF ALBUM[N been shown that cyst walls are relatively
16,0 2000"
impermeable to the outward diffusion of
protein molecules when introduced into the
cyst cavity (Toller 1966a) despite the fre-
quent presence of discontinuities in (he lin-
1500" 120 -
ing epithelium (Toller 1966a) and therefore
it is likely that diffusion in the opposite
direction will be similarly slow. Further,
analysis of these proteins indicates that the
percentage of albumin present (Mean
I lui 48.3% Skaug & Hol'stad 1973, 49.1%
t.
s
Browne 1974) is less than in autologous
# serum and that of (he y globulins is corres-
t,
#
pondingly greater. These findings itidicate
that the proteins in the cyst fluid cannot be
• 500- • HI) —
derived simply as a filtrate of the exudate
I
by the semi-permeable capsule but that the
exudate must be actively modified in some
I way.
Estimation of the thtee main serum im-
Fig. 3. A summary of the total protein content, munoglobulin fractions, IgA, IgG and IgM
IgA, IgG and IgM levels and percentage of (Fig. 3) indicates that the former two are
albumin content of 30 dental cysts.
significantly higher in cyst fluid than in
serum (Toller & Holborrow 1969, Browne
longer the cyst has been present (Browne 1974), and levels of IgA up to 20 times
1972). that in scrum have been reported (Toller
In addition to mucin and keratin, cho- & Holborrow 1969). It has been shown by
lesterol (Browne 1971a, Trott et al. 1973), immunofluorescent techniques that immuno-
hyaluronic acid (Hansen & Kobeyasi 1970a, globulins arc produced locally by the plas-
Skaug & Hofstad 1973) and serum proteins ma cells in (he cyst wall and there is evi-
(Toller 1970, Skaug & Hofstad 1973, Skaug dence that they are actively transported by
1973a, b, Browne 1974) arc added to the the formative cells through the lining epithe-
cyst contents. All groups of serum proteins, lium. The nature of the antigenic stimulus
even the large macrotnolcculcs iti the a2 glo- to the local formatioti of antibodies is un-
bulin group, are usually ptcscnt in the cyst known and the evidence has been reviewed
fluid, so soluble protein levels at least as tecently by Toller (1971b). It is interesting
great as and often higher than those of au- that the level of y globulin (2.46 g/100 ml)
tologous serum are found (Fig. 3). Mean in residual cysts is slightly higher than that
levels of 7.5 g/100 ml (Skaug 1973a) and in apical cysts (2.05 g/100 ml) (Skaug
6.3 g/100 ml (Browne 1974) have been re- 1973a). Although this difference was not
ported. This suggests that (heir main source statistically significant, it docs raise the pos-
is from the plasma (Skaug 1973b) and, as sibility that the fluid contents of dental
the cyst fluid is rich in y globulins, that it is cysts may vary with age in respect of their
derived as an inflammatory exudate. How immunoglobulin content also. • • .,
 ODONTOGENIC CYSTS: A REVIEW
Fig. 4. Autoradiographs of explants of cyst
linings following incubation in 20 (ic tritiated
thymidine for 2 h. A: dental cyst, B: odont-
ogenic keratocyst, • v
Although evidence is slight, the rate of
expansion is generally considered to be slow
and the accompanying epithelial activity of
a correspondingly low otder. This low
epithelial aetivity has been eonsistently re-
ported whether from mitotic counts in hist-
ological seetions (Main 1970b) or from stu-
dies of the uptake of tritiated thymidine in
explants of eyst epithelium (Toller 1971a)
(Fig. 4).
There is thus good evidenee that dental
eysts arise by reactivation of the epithelial
rests of Malassez in a foeus of inflamma-
tory change. However, once established the
epithelium plays a less important role iti the
mechanism of growth. The fluid cotitents of
the eyst have many characteristics of an
inflamtnatory exudate but one modified by
the activities of the epithelium and capsular
cells, the effects of which appear to become
more marked with age.
37
Redticed Ettatnel Epithelium
The reduced enamel epithelium covers the
anatomieal ctown of a fully formed yet
still unerupted tooth (Sicher 1962). As the
erown of the assoeiated tooth projeets into
the cavity of a dentigerous cyst, the wall of
which is attached to the neck of the tooth,
it is generally believed that this lesion deve-
lops by the accumulation of fluid between
the redueed enamel epithelium and the
tooth surface.
After ctown formation the cells of the
redueed enamel epithelium consist of an
inner layer of cuboidal or columnar cells
derived from the ameloblasts, the redueed
ameloblasts, and an outer layer of polyhed-
ral cells which may be more than one eell
thiek and is derived from the other layers
of the enamel organ. Whereas the redueed
ameloblasts undergo no mitosis, the cells iti
the outer layer, although normally similarly
inactive, exhibit eonsiderable mitotie acti-
vity during the proeess of fusion of this
epithelium with that of the oral mueosa
during eruption (McHugh 1963, Schroeder
& Listgarten 1971). During the proeess of
eruption the reduced ameloblasts assume an
inereasingly inclined angle to the tooth sur-
face (Provenza & Sisca 1970, Schroeder &
Listgarten 1971) and so acquire a more
squamoid appearance.
ln the event of a tooth beeoming impac-
ted and failing to erupt, this squamoid
ehaiige beeomes more marked so the epi-
thelium assutnes the characteristies of a layer
of stratified squamous epithelium. There is
evidence to suggest that the attachment of
the redueed enamel epithelium to the tooth
surface becomes weaker as it changes to
squamous type. The tneehanical separatioti
of the follicle frotn around the crown of an
unerupted tooth removed from a patient not
older than the nonnal age limit of the erup-
tioti of that tooth, rarely leaves a continuous
epithelial layer on the enamel surface of the
follicle (Ussing 1955, Stanley et al. 1965),
 38
Dentigerous Cyst
TOTAL
PROTEIN
16,0 2000
12.0- 6000 600-
1000 -
Fig. 5. A summary of the total protein content,
IgA, IgG and IgM levels and percentage albu-
min content of 12 dentigerous cysts.
suggesting tbat the cells are more firmly
attached to tbe enamel than to each other
and tbe surrounding connective tissue (List-
garten 1966). On tbe other band, in patients
older than the normal age limit of eruption
when tbe squamoid change is complete, a
continuous epithelial covering is usually
present (Stanley et al. 1965) suggesting that
the attachment to the enamel is now tbe
weaker.
Dentigerous Cysts
It might be expected therefore that as den-
tigerous cyst formation is a sequel to im-
peded eruption it would be more likely to
occur after tbis squamoid change has taken
place. Although most of the standard text-
books consider that dentigerous cysts are
more common fn early adulthood, some
data (Browne 1972) indicate an increasing
BROWNE
prevalence up to tbe fifth decade. Tbe pre-
vious, probably erroneous, conclusion has
PERCENTAGE
OF ALBUMIN arisen from the confusion of odontogenic
160
keratocysts with dentigerous cysts. In pre-
vious studies (Killey & Kay 1966, Cabrlni
et al. 1970) odontogenic keratocysts were
not classified separately and more den-
120 ~ tigerous cysts were reported in the second
and third decades than in later ones. As
odontogenic keratocysts closely mimic den-
tigerous cysts clinically and radiologically,
particularly in tbe younger age groups
(Browne 1970), it is likely that if odont-
ogenic keratocysts had been classified se-
parately, a different distribution for den-
tigerous cysts would bave been reported.
Tbe stimulus for epithelial proliferation
in these lesions has not been determined.
Inflammatory changes in tbe cyst wall are
not marked and they are less likely to form
the proliferative stimulus, despite the fact
that the mitotic activity in the epithelium
lining of dentigerous cysts is low, just like
that in dental cysts (Main 1970a). The low
mitotic rate in both dental and dentigerous
cysts is more probably a reflection of tbeir
derivation from epithelial rests which are
in a state of low metabolic activity. This low
epithelial activity and tbe frequent epithelial
discontinuities in tbe lining of dentigerous
cysts bave led to tbe bypotbesis that the
epithelium plays little if any role in the path-
ogenesis of this cyst. Main (1970b) suggested
tbat "venous obstruction subsequent upon
compression of its follicle by tbe impacted
tooth, induces transudation across tbe vessel
walls. The increased hydrostatic pressure of
this pooling transudate separates the follicle
from tbe crown, witb or witbout reduced
enamel epithelium, and in time leads to an
increased permeability of the vessels so that
the extravasation more resetnbles an
exudate".
Analysis of the protein composition of
dentigerous cyst fluids would support this
view (Fig. 5). The total soluble protein
 ODONTOGENIC CYSTS: A REVIEW
eotitent is rather less than iti dental cysts,
although the difference is not statistically
significant, and thus the fluid mote elosely
approximates serutn. Mean figures of 6.8
g/100 ml (Skaug 1973a) and 5.5 g/100
ml (Browne 1974) have been reported.
The albumin/globulin ratio (Skaug & Hof-
stad 1973) or albumin percentage (Browne
1974) is similar to that of serum and thus
the fluid resembles an inflammatory ex-
udate. Analysis of the immunoglobulin levels
shows these to be similar to serum also,
exeept that the IgA levels are sometimes
slightly raised (Browne 1974), These results
suggest therefore that in dentigerous cysts
the fluid arises as an exudate from the ves-
sels in the capsule and is only little tnodified
by any loeal immunoglobulin synthesis in
the cyst wall. This conclusion is supported
by the relative paucity of inflammatory cells
in many dentigerous cysts.
The fluid in dentigerous eysts is modified
by the aetivities of cells in the cyst wall
(Browne 1972), in the same way as in the
dental cyst. Thus it is hypettonic in com-
parisoti with serum and so provides the driv-
ing force for the expansion of the cyst.
Although the frequent presence of epithelial
discontinuities (Gorlin 1957, Toller 1966a)
and the large intereellular spaces between
the cells in the epithelial lining (Hansen &
Kobeyasi 1970a, Hornova et al. 1972),
where it is present, suggest that the presenee
of epithelium is not essential for the cyst
wall to act as a dialysing membrane, it
would seem likely that the ptesence of the
reduced enatnel epithelium is neeessary to
provide a potential space between it and
either the crown of the tooth or the adjacent
connective tissue, to allow the poolitig of the
fluid transudate in the initiation of the cyst.
Thereafter a unicentrie, hydrostatic gtowth
force allows the lesion to expand. The
epithelial proliferation ean be regarded as
a manifestation of its inherent property to
cover a "raw" connective tissue surface. As
39
the cyst expatids there will be compensa-
tory epithelial proliferation to cover the
greater surfaee of eonnective tissue, but the
stimulus to growth is slight, as eonfirmed by
the low mitotic rate and, as exetnplified by
the epithelial discontitiuities, it frequently
does not achieve its aim.
Epithelial Rests of the Detital Latttina
The availability of human fetal material has
permitted a thorough evaluation of the chan-
ges in the dental lamina which give rise to
the primary teeth and their successors. The
fragmentation of the lamina eonsequent
upon the initiation of tooth germ formation
and the presence of discrete epithelial rests
in the ridge mucosa overlying the developing
teeth is well doeutnented (Sicher 1962),
Some of these rests undergo tnieroeyst for-
mation with the accumulation of keratin
centrally in the cyst cavity. These may form
macroscopic nodules (Bohn's nodules) on
the edentulous ridge of the neonate (Saun-
ders 1972). The cysts are short-lived and
terminate their growth during the first year
of life by fusing with the overlying mueosal
epithelium and thus disgorging their eon-
tents into the otal cavity. The histologic
similarity of these mieroeysts and satellite
cysts in the walls of odotitogenic keratoeysts
has led several authors (Soskolne & Shear
1967, Toller 1967, Browne 1969) to postul-
ate the origin of odontogenie keratoeysts
from these residues of the dental lamina.
This histologie similarity, together with the
observation of transitional stages of eyst
developtnent frotn residues in the walls of
established cysts (Soskolne & Shear 1967),
affords strong circumstantial evidence.
Ultrastrueturally, the cells of the oral end
of the proliferating dental lamina contain
a better developed cytoskeleton of tono-
filaments than the cells in the zone of
epithelial rest formation (Provenza & Sisca
1970). This might indicate that the odont-
ogenic keratocyst derives frotn the oral
 40 BROWNE

epitbelium rather than tbe rests of tbe dental Odontogenic Keratocyst

lamina, a point emphasized by Stoelinga
TOTAL PERCENTAGE
(1971), wbo reported "the often firm ad- PROTEIPJ lg A OF ALBUMIN

hesion of the cyst wall with tbe overlying

160 - 1
mucosa". However, no primary odontogenic
keratocysts bave been reported in soft tis-
sues rather than in bone. Further, although
tbe deeper rests show little evidence of ker-
atin formation normally, the development 12.0- 1500- 6000-
of an odontogenic keratocyst is an abnormal
event in wbich they may undergo sucb a
cbange in activity.
Rather less is known about tbe fate of tbe
dental lamina giving rise to the permanent
molars. Tbis lamina presumably fragments
in a fasbion similar to that associated with
the primary dentition and residues remain
within tbe bone of the jaws. Such residues
1.0- 500- 2000- t 200 -
would not normally undergo keratin micro-
cyst formation as occurs in tbe edentulous
alveolus because, at least in tbe rnandible,
there is no nearby epithelial surface with
wbich they might fuse and tbus regress.
Such a conclusion is supported by the ultra-
Jt
structural studies referred to earlier (Proven- Fig. 6. A summary of the total protein content,
IgA, IgG and IgM levels and percentage albu-
za & Sisca 1970). Should sucb a microcyst min content of 26 odontogenic keratocysts.
form, it is likely tbat it will lead to clinical
cyst formation.
that they expand more rapidly than the
Odontogenic Keratocysts other types of odontogenic cyst, their growth
Many observations suggest that the odont- rate must still be relatively slow. Tbus, even
ogenic keratocyst is a developmental ab- when diagnosed in tbe second and third
normality. It is most prevalent during the decades of life, the cysts have probably al-
second and third decades of life, although ready been present for a number of years. In
many lesions are not diagnosed until later other words, they are presumed to form in
(Toller 1967, Browne 1970). However, this adolescetice.
lesion grows largely through the medullary There is no evidence that odontogenic
spaces of the jaws in a predominantly antero- keratocysts arise in foci of inflammation as
posterior direction, rather like tbe amelobla- do, for example, dental cysts. Tbeir walls
stoma (Kramer 1963), so tbat it bas fre- are characteristically free from inflamma-
quently achieved a large size before pro- tory cells, apart from the presence of scat-
ducing clinical symptoms. For this reason, tered foci (Browne 1971b). Analysis of tbe
it is likely that many lesions not diagnosed cyst fluids reveals low quantities of soluble
until later in life have been present for protein (Mean 2.5 g/100 ml Toller 1972,
many years. Their rate of expansion is un- mean 2.1 g/100 ml Browne 1974) composed
known and, although it bas been suggested predominantly of albumin witb only small
 ODONTOGENIC CYSTS: A REVIEW
quantities of globulins (Fig. 6), inconsistent
with its derivation as an inflammatory exu-
da(e. Indeed, (he conten(s of these cysts are
frequently semi-solid, cotnposed predomi-
nantly of desquamated kera(in.
Akhough (he epi(hclial lining of odonto-
genic keratocysts has a characteristic ap-
pearance under the light mictoscope (Phil-
lipsen 1956, Shear 1960, Browne 1971b), in
particular a flattened basement tnetnbranc,
a regular row of colutnnar basal cells with
palisaded nuclei and an abtupt transition
between the deeper cells and the surface
layer of parakeratosis, no unusual features
have been observed electron microscopic-
ally. A gradual diminution in the tiutnbcrs
of cytoplasmic organdies is accompanied by
an increase in the number of tonofilament
bundles as the cells pass toward the surface,
which is largely similar to what happens in
stratified squatnous epithelium in the oral
mucosa (Hansen & Kobeyasi 1970b). The
cellular control docs not appear to be as
well organized as in oral tnucosa and num-
bers of non-keratinized cells are prcsctit iti
the surface epithelium. However, the process
of epithelial shedding into (he cyst cavity is
essentially one of maturation and dcsquatn-
ation as in the oral epithelium, as confirmed
by the presence of both intercellular and
intracellulat, membtanc-bound acid phos-
phatase in the surface layers (Kobeyasi &
Hansen 1970). Thus smears of keratocyst
fluid contain many epithelial squames (Kra-
mer 1970) which distinguishes (hctn from
dental and dentigerous cysts. Unlike these
latter types of cyst also, mucous metaplasia
is rare (Browne 1972).
The origin of the odontogenic kera(ocysts
is a subject of considerable discussion. The
view has been expressed that they are essen-
tially hollow benign neoplasms (Toller
1972). Their epithelium is far more active
than in the other types of odontogenic cysts,
whether assessed on the basis of mitotic
counts in histological sections (Main 1970b,
41
Browne 1971b) or from thytnidinc uptake
in cxplants of cyst lining (Toiler 1971a)
(Fig. 4).
In addition (here is a high ra(e of recur-
rence following surgical treatment compared
with other forms of odontogenic cyst. On
average, 40 % (Browne 1969) of odontogenic
k:era(ocys(s recur. In par(icular, occasional
recurrences are particularly aggressive and
can present great pt obletns of tnanagctnent if
these arise in the soft tissues (Emerson et al.
1972) or in botic grafts (Schoficid 1971).
However, there are also features of the
odontogenic keratocyst which permit the
view that it could be a hamartoma. Firsdy,
(heir predominance in adolescence is con-
sistent with this view.
Secondly, these lesions may be single or
multiple. They are mos( cotnmon in the
matidible, particularly in the ramus (Browne
1970), a distribution different from the other
odontogenic cysts, and when multiple are
cotnmonly bilateral. This patterti of occur-
ring either as isolated or tnultiple lesions is
cotnmon to other hamar(omas such as he-
mangioma and fibrous dysplasia.
Thirdly, (hey may arise as part of a synd-
rome of abnormalities. This syndrome, first
recognised by Gorlin & Goltz (1960) and
now referred to as the tnultiple ncvoid basal
cell carcinoma syndrome, has numerous
manifestations which have been fully re-
viewed elsewhere (Gorlin & Sedano 1971,
Rittersma 1972).The most important features
are multiple ncvoid basal cell carcinoma of
the skin, multiple odontogenic keratocysts,
various abnormalities affecting particularly
(he ribs, vettebrae and bones of the skull,
and abnormalities of calcium and phosphate
metabolism manifested by mineralizations in
the cerebral incninges, subcutaneously and
in the walls of the cysts (Browne 1972) and
by a lack of phosphate diuresis following
administration of parathormonc. Again, this
association of the lesion with other develop-
mental abnormalities is in common with
 BROWNE
otber bamartomas sucb as tbe bemangioma,
for example, in Sturge-Weber syndrome and
fibrous dysplasia in Albright's syndrome.
The nevoid basal cell carcinoma synd-
rome is inherited as an autosomal dominant
trait, which has marked penetrance and
variable expressivity (Gorlin & Sedano
1971). Tbe variable expressivity has promp-
ted the suggestion that patients with odont-
ogenic keratocysts alone may in fact be suf-
fering from the syndrome in one of its least
expressed forms (Browne 1969, Rittersma
1972).
Finally, there are frequently groups of
epithelial cells apparently derived from tbe
dental lamina in the capsules of odontogenic
keratocysts. Tbese often form satellite cysts,
suggesting tbat there is a clone of epithelial
remnants of the dental lamina wbicb are
genetically abnormal and prone to exuberant
proliferation. The importance of this epi-
thelial proliferation in the growth of tbe
odontogenic keratocyst is confirmed by tbeir
multilocular and loculated radiograpbic out-
lines (Browne 1970), wbicb are difficult to
interpret on tbe basis of unicentric hydro-
static expansion alone. Rather, this form of
cyst outline suggests a multicentric pattern
of cyst growth brought about by tbe proli-
feration of local groups of epitbelial cells
against the semi-solid cyst contents (Kramer
1974).
Whether tbe primary defect is in the
epithelial cells themselves or in tbe adjacent
mesencbyme is not known. However, tbere
is evidence that the mesenchyme of the cyst
wall is also abnormal. The capsule is less
densely fibrous and more cellular tbati those
of dental and dentigerous cysts (Browne
1971b) and, particularly in patients witb tbe
nevoid basal cell carcinoma syndrome, may
form a prominent part of the lesion (Wal-
dron 1969). Under these latter circumstan-
ces, the tissue may be rich in mucopolysac-
charides. Further, there is a greater prev-
alence of mineralization in the capsules of
odontogenic keratocysts compared with den-
tal and dentigerous cysts (Browne 1972). i
Tbere is some evidence that the meso- ';
derm beneath nevoid basal cell carcinomas
is similarly abnormal and in this way differs
from other basal cell carcinomas. Tbe j
nevoid tumors may be distinguisbed by tbe
bigh composition of sulfated acid muco-
polysaccbarides (Graham et al. 1965) in the 1
underlying mesoderm and by a tendency •
towards ossification and calcification in this
tissue (Maddox et al. 1964, Graham et al.
1965, Murphy 1969). The basal proliferation |
of tbese tumors is mimicked to some extent '
by tbe epithelium of odontogenic kerato-
cysts. Particularly in patients witb multiple I
cysts, witb or without tbe full syndrome, |
basal sprouting of tbe epitbelium of tbe lin-
ing may be present. In some instances tbere
is evidence tbat satellite cyst formation may
arise in this way, altbougb tbe principal
origin of tbe satellite cysts is by proliferation
in adjacent remnants of tbe dental larnina.
Tbis basal sprotiting bas led sotne authors
(Waldron 1969, Panders & Hadders 1969)
to conclude that tbese cysts are different
from tbe isolated lesions, but basal sprouting
may occur in isolated lesions too.
Tbese similarities between the adjacent
mesenchyme of nevoid basal cell carcinomas
and odontogenic keratocysts raise the pos-
sibility that there may be some common
mesencbymal defect in patients witb tbis
syndrome. Tbere is some evidence tbat cul-
tures of fibroblasts from tbe connective tis-
sue beneatb nevoid basal cell carcinomas
possess a larger number of cbromosomal
abnormalities than of cells frotn normal
cultures (Happle et al. 1971, Happle & Kup-
ferschmid 1972, Happle & Hoehn 1973) but
no observations bave yet been rnade on fib-
roblast cultures frotn odontogetiic kerato-
cyst walls.
Tbere is tbus some evidence in support of
botb views. The possibility that odontogenic
keratocysts are cystic neoplasms is not sup-
 ODONTOGENIC CYSTS: A REVIEW
ported by the observation that they reeur
no more frequently following the leaving
behind of portions of cyst lining in tnar-
supialization than in other situations (Brow-
ne 1969). Further preliminary observations
on the growth of epithelial cells from odont-
ogenic keratocysts iti tissue culture suggest
that their growth is inhibited by contact of
one cell with atiother (Toller 1972). Such
contact inhibition is not a feature of neo-
plastic cells.
On the other hand, the gtowth of odont-
ogenic keratocysts after the cessatioti of
general body growth does not, at first, seem
to support a hamartomatous origin. How-
ever, as they are cystic lesions, they are
likely to continue to grow because, in com-
mon with other cysts, they will he suhject
to the same hydrostatic growth mechanisms.
The presence of a continuous epithelial lin-
ing (Browne 1970) cotnposed of cells with
narrow intercellular spaces (Hatisen & Ko-
beyasi 1970b) and a surface keratin layer
makes the walls of these cysts a more effi-
cient semipermeable metnbrane. This is
demonstrated by the slower outward dif-
fusion rate of radioactive tnarkers intro-
duced into the cyst cavity (Toller 1966b)
and the greater osmolality of the cyst con-
tents (Toller 1970) compared with other
odontogenic cysts. Thus, unlike other hamar-
tomas, odontogenie keratocysts would be
expected to continue to expand after the ces-
sation of general body growth. The studies
on mitotic activity iti the epithelial cells of
odontogenic keratocysts so far reported
(Main 1970a, Toller 1971a, Browne 1971b)
have not determined whether there is any
correlatioti between the rate of cell division
and the age of the patient from whom the
cyst was retnoved. It is thus necessary to
collect more evidence before any conclu-
sions can be reached.
Although these cysts occasionally appear
in place of a tooth of the normal series
(Shear 1960), i.e. as pritnordial eysts, there
43
is no positive evidenee that they are derived
frotn the enamel organ as such. Likewise,
there is no evidence that they are derived as
pritnordial cysts from supernumerary tooth
gertns (Browne 1969). Thus, primordial
cysts should be tegarded as just one of the
many clinical forms of odontogenic kerato-
cysts.
In summary, it is suggested that the
odontogenic keratocyst is derived from the
dental lamina, possibly as a hamartoma. As
such, the proliferation of the epithelial cells
lining the cyst plays a more aetive role in
its growth. Although hydrostatic growth
forces supervene onee the cyst has formed,
epithelial proliferatioti plays as great or
even greater a role in cyst growth, at least
until general body growth has ceased. The
soluble protein of the eyst fluid resembles a
transudate of serum, with a very small local
production of immunoglohulins, even if the
cyst becotnes infected.
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Address:
R. M. Browne
Department of Oral Pathology
Detttal School
St. Chad's Queetisway
Birtnitigham B4 6NN
Englatid