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The origin of cholesterol in odontogenic cysts in man
Arch oral Elol. Vol. 16, pp. 107-113, 1971. Pergamon Press. Printed in Great Britain.
THE ORIGIN OF CHOLESTEROL IN ODONTOGENIC CYSTS IN MAN R. M. BROWNE Department of Oral Pathology, The Dental School, St. Mary’s Row, Birmingham 4, England Summary-A histological study was made of 537 odontogeuic cysts and the presence of cholesterol clefts and haemosiderin recorded.Cholesterol clefts were preseut iu 43.5 per cent of dental cysts, 39.0 per cent of dentigerous cysts and 17.1 per cent of odontogenic keratocysts. There was statistically significant correlation (p < O-01) between the preseuce of cholesterol and haemosideriu in odontogenic cysts. These findings support the hypothesis that the origin of cholesterol in odontogenic cysts is haemotogenous.
THE presence of cholesterol crystals in the fluid aspirated from the cavities of dental cysts has been recognized as a characteristic clinical feature for many years. Despite this, there is surprisingly little statistical information concerning their presence. The only figures are those from histological studies: DARLINGTON(1933) found cholesterol in 28 (17 *7 per cent) of 158 dental cysts and SHEAR(1963) in 57 (28 *5 per cent) of 200 dental cysts. It is not surprising therefore that the origin of the cholesterol crystals is still largely hypothetical and based upon little factual information. There are basically two schools of thought. On the one hand, it is postulated that cholesterol accumulates in the tissues as a result of the degeneration and disintegration of cells, in particular epithelial cells (COUNSELL, 1932; DARLINGTON, 1933; THOMAand GOLDMAN, 1960). On the other hand, it is suggested that the cholesterol is of haematogenous origin (JACOBSand STONE, 1940; FAIRHURST,1944; SHEAR, 1963).
The present study was undertaken to investigate the incidence of cholesterol crystals in different types of odontogenic cyst and to correlate its presence with that of other products of haematogenous origin. MATERIALS
AND METHODS
This study was carried out on a series of 537 consecutive odontogenic cysts that were examined microscopically in the Department of Oral Pathology, University of Birmingham. These were composed of 402 dental cysts, 77 dentigerous cysts, 41 odontogenic keratocysts, 15 lateral periodontal cysts, 1 gingival cyst and 1 calcifying odontogenic cyst. The cyst capsules were tixed in neutral buffered formalin and demineralized in 10 per cent formic acid for one day. Random sections were prepared from each specimen and stained with haematoxylin and eosin and by Perl’s method. 107
108
R. M. BROW
The presence of cholesterol clefts, haemosiderin deposits, foam cells and inflammation was noted. RESULTS
As there were only 1 gingival cyst and 1 calcifying odontogenic cyst in this series the results in these two groups are not considered in detail. TABLE 1. THE INCIDENCE OF CHOLESTEROL CLEFIS AND HAEMOSJDERIN IN ODONTOGENIC
CYSTS
Cholesterol
Total
Del&d Dentigerous Lateral periodontal Odontogenic keratocyst Calcifying odontogenic Gingival
175(43 - 5 %) 3Ou9.0 F)
402 77 15 41 1 1 537
Haemosiderin present
present
o
247(61*4x) 39(50-7 %) 5(33 *3 %) lO(24.4 %) 0
216(:0*2 %)
301(:6-l %)
;E;:;$; 0
The incidence of cholesterol clefts and haemosiderin deposits in the different types of odontogenic cyst is recorded in Table 1. The incidence is greatest in the dental cysts (cholesterol 43 *5 per cent, haemosiderin 61.4 per cent) and least in the odontogenie keratocysts (cholesterol 17 - 1 per cent, haemosiderin 24 ‘4 per cent). In all types of cyst, the incidence of haemosiderin is greater than that of cholesterol clefts. The correlation between the presence of cholesterol clefts, both in the cyst capsule and cavity, and haemosiderin in the capsule, is recorded in Table 2. In all but two of the TABLE 2. TIZ RELATIONSHIP BETWEEN THE PRESENCE OF CHOLESTEROL CLEFTS AND HAEMOSIDERIN IN ODONTOCiENIC CYSTS
No haemosiderin no cholesterol Dental
No haemosiderin cholesterol
Haemosiderin no cholesterol
Haemosiderin cholesterol
x2
P
141
14
86
161
122.14
35
3
12
27
30.44
9
1
2
3
4.26
co.05
30
1
4
6
17.21
Calcifying odontogenic
1
0
0
0
Gingival
1
0
0
0
217
19
104
197
181.25
>O*Ol
Dentigerous Lateral periodontal Odontogenic
keratocyst
THE ORIGIN OF CHOLESTEROLIN
ODONTOGENIC
CYSTS
109
183 cysts when cholesterol clefts were present in the cyst capsule, deposits of haemosiderin were closely related to them (Fig. 1). In all types of cyst the occurrence together of haemosiderin and cholesterol clefts, either in the cyst capsule or in the cavity was most frequent. Next in order of frequency came haemosiderin in the absence of cholesterol clefts and in only a very few cysts were cholesterol clefts present in the absence of haemosiderin. Analysis by the x2 test showed this correlation to be statistically significant at the 1 per cent level in all types of cyst except the lateral periodontal cyst where it was significant at the 5 per cent level. The position of the cholesterol clefts in the capsule or cavity of the cyst and its correlation with inflammation, foreign body giant cells and foam cells is summarized in Table 3. Of those cysts which contained cholesterol clefts, clefts were more frequently TABLE 3.
THE INCIDENCEOFCHOLESTEROL,GIANTCELLS,FOAMCELLSAND INFLAMMATIONINODONTOGENICCYSTS
Cholesterol Giant cells
Foam cells
30
140
24
174
7
1
28
2
29
3
0
1
3
1
4
5
1
1
6
2
6
Number
Capsule alone
Capsule and cavity
Cavity alone
175
75
70
Dentigerous
30
22
Lateral periodontal
4
Odontogenic keratocyst
7
Dental
Inflammation
present in the capsule (183 cysts, 84.7 per cent) than in the cavity (111 cysts, 51.4 per cent). Foreign body giant cells were closely adapted to the surface of the cholesterol clefts (Fig. 2) in the cyst capsules of 177 of the 183 cysts in which they were present. Only 3 of the 216 cysts which contained cholesterol clefts did not show inflammatory changes and, in all three, the clefts were in the cyst cavity and not in the capsule. Only 29 of the 216 odontogenic cysts with cholesterol clefts also contained foam cells; on the other hand, these cells were also present in 35 of the 321 cysts without cholesterol clefts. DISCUSSION
From the evidence of this study, the incidence of cholesterol crystals in dental cysts (43 -5 per cent) is higher than that (28 -5 per cent) reported by SHEAR (1963) but is still not as great as is generally believed from clinical practice. However, it should be stressed that in the present study only random sections were examined and, if serial sections were taken, it is likely that the incidence would be found to be greater. In addition, it is found that in some cysts the cholesterol clefts were present only in the cavity. As in many cysts the contents are lost in the preparation of the sections, again it is likely that the incidence is really much greater. Chemical analysis of cyst fluids by
110
R. M. BROWNE
HIRSCH (1952, 1956) has demonstrated the presence of cholesterol in all instances, usually in greater concentration than in serum. However, the incidence of cholesterol in crystalline form is not evident from these studies. There are three important findings arising from the present study which support the hypothesis that cholesterol in odontogenic cysts takes its origin from haemorrhage at sites of inflammation in the cyst capsule. The first observation is the different incidence of cholesterol in the various types of odontogenic cyst. The dental cyst invariably arises from epithelial proliferation within a periapical inflammatory lesion and hence is always associated with inflammation during its development and expansion. The capsule of the dental cyst usually contains an inflammatory infiltrate throughout. In the present series inflammation was present in the cyst capsule in all but one of the dental cysts which contained cholesterol. Dentigerous cysts arise either from the breakdown of the reduced enamel epithelium covering the crown of the unerupted tooth, or from the migration of a dental cyst in the apical region of an erupted tooth on to the crown of an underlying unerupted tooth. In either case, some degree of inflammatory change is usually present in the cyst capsule. In the present series, inflammation was present in the cyst capsule in all but one of the dentigerous cysts which contained cholesterol. The proportion of cysts containing cholesterol was very similar in both the dental and dentigerous cysts, namely 43 *5 and 39 -0 per cent respectively. On the other hand, the odontogenic keratocyst is developmental in origin (SOSKOLNEand SHEAR, 1967; TOLLER, 1967; BROWNE,1969) and only shows occasional areas of focal inflammation in the capsule. Although such foci were present in the cyst capsule in all but one of the odontogenic keratocysts which contained cholesterol, the proportion of them containing cholesterol was much lower, namely 17 - 1 per cent. The fact that cholesterol is more common in odontogenic cysts of inflammatory origin than in those of other origins in which inflammatory changes are less frequent suggests a close relationship between the two. The second observation is that the incidence of cholesterol in the cyst capsule is greater than that in the cyst cavity. This finding confirms that of SHEAR(1963) and suggests that in the first instance the cholesterol is deposited in the cyst capsule. Support for this hypothesis arises from the fact that cholesterol crystals are not infrequently found in periapical granulomas and abscesses in the absence of cyst formation. As has been mentioned, the dental cyst invariably arises from such lesions. The third observation is the close correlation between the presence of cholesterol clefts and haemosiderin. Haemosiderin is frequently found in sites of chronic inflammation. In such sites, minute haemorrhages into the tissues are likely to occur. Whereas in many parts of the body the iron released from the breakdown of haemoglobin from the red blood corpuscles is stored in the tissues as haemosiderin, the other components of the haemorrhage, in particular cholesterol, are removed from the site by macrophages and the lymphatic vessels. Hence cholesterol clefts are not often observed. However, chronic inflammatory and cystic lesions arising within bone may be relatively inaccessible to its normal lymphatic drainage (TOLLER,1967). This being so, in addition to the usual deposition of haemosiderin, the extravasated cholesterol would stagnate in the tissues and eventually crystallize. Presumably once the process
111
THEORIGtNOPCHOLESTEROLINODONTOGENICCYSTS
of crystallization had commenced it would be self-propagating. Such a hypothesis may explain the frequent occurrence of cholesterol clefts in periapical granulomas and dental cysts in the mandible and maxilla and in granulomas of the middle ear in the temporal bone. Several authors have put forward the hypothesis that the cholesterol in cholesterol granulomas of the middle ear arises from repeated haemorrhages (SIMPSON,1954; RANGER, 1949; ALTES,1966). They have suggested that the cholesterol released from disintegrating red blood cells is in a form that would more readily crystallize in the tissues. Some support for this hypothesis arises from the close correlation between the presence of haemosiderin and cholesterol found in the present Chronic
Hemorrhage
mto
m+lamma?ory _-...p
-_ tlssuc
Cholesterol
bodv
inflammatory
crystals lymg cyst cavity
Cryslallisatlon wth foreiqn
qiant
cells
in cyst wa!l body reaction
in
Exfoliation
of
foreiqn
body
FIG. 3. A diagrammatic summary of the hypothesis for the origin of cholesterol in odontogenic cysts.
study. It may also explain the lack of correlation between the level of the serum cholesterol and the presence of cholesterol both in periapical granulomas and dental cysts (HERTZ, 1963) and in cholesterol granulomas of the middle ear (SIMPSON,1954; DA& 1967), although Kmsc~ (1956) states that in most instances of jaw cysts the serum cholesterol is raised. On the basis of these observations, it is possible to form the following hypothesis, which is summarized in Fig. 3. At sites of inflammation in the walls of odontogenic cysts there are repeated small haemorrhages. The extravasated red blood corpuscles undergo breakdown and haemosiderin is deposited in the tissues. In addition cholesterol both from the erythrocyte breakdown and also from the serum accumulates in
112
R. M. BROWN@
the tissues because of its relative inaccessibility from normal lymphatic drainage. Thereafter the cholesterol crystallizes and forms the characteristic clefts. Because of its close association with haemosiderin, it is suggested that it is the cholesterol released from the erythrocytes rather than that in the extravasated serum which is the most important source. Once the crystals have formed, the body reacts to them as it does to any crystalline foreign body and a foreign body reaction develops around them. This is characterized on microscopical section by the presence of multinucleate giant cells which lie against the clefts left by dissolved crystals (Fig. 2). In addition, the body attempts to exfoliate the crystals on to the nearest external surface. In this respect, the cavity of a cyst can be considered to be an external surface which is separated from the body by its epithelial lining. By a combination of the proliferation of the epithelium around the crystals and its breakdown over their surface (Fig. 4), the crystals together with the intervening tissue are eventually shed into the cyst cavity. Large masses in the process of exfoliation can be observed macroscopically on the cyst walls (Fig. 5). Such masses or mural nodules are composed of large numbers of cholesterol clefts among which there are numerous multinucleate giant cells and chronic inflammatory cells (Fig. 6). As the final stage in the cycle, the cyst lumen contains the cholesterol crystals lying free in the cyst fluid. On aspiration of the cyst contents, these are present as the characteristic rhomboid-shaped crystals (Fig. 7) which contribute to its shimmering appearance. Thus, depending on the stage of development of the cycle, cholesterol clefts may be present in the capsule of the cyst alone, in both the capsule and the cavity or in the cavity alone, This hypothesis is similar to that put forward by SHEAR(1963) except that in the present one it is postulated that the cholesterol arises predominantly from the red blood cells rather than from the plasma. It is of interest to draw attention to the similar arguments which have been put forward for the accumulation of cholesterol in the intima of large blood vessels in atherosclerosis. In his review, FRENCH (1962) stresses the importance of the relative inaccessibility of the intima of large arteries to lymphatic access. However ,unlike the odontogenic cyst, the majority of the lipid in this lesion is present in the cytoplasm of macrophages and it is only in advanced lesions that free cholesterol crystals are present. It may be that its suspected predominant origin from the plasma rather than from the red blood cells accounts for this difference. The evidence presented in this paper does not discount the possible origin of cholesterol from epithelial or tissue cell-breakdown. For instance, the greater incidence of cholesterol in dental and dentigerous cysts compared with the odontogenic keratocyst may be explained on the basis that in the former the epithelial cells degenerate while in the latter they undergo maturation to form keratin. On the other hand, there is no real support for such a hypothesis and the positive correlations between the presence of haemosiderin and cholesterol clefts demonstrated in this study form strong support for the haematogenous origin of cholesterol in odontogenic cysts.
THEOIUOINOFCHOLlZ.WROLIN ODONTOGENICCYSTS
113
(1)
Une &de histologique est r&disc% au niveau de 537 kystes odonto&nes et la pr&xnce d’inclusions de cholest&ol et d’h&mosid&ine a &te &xii&z. (2) Des inclusions de cholest&ol sont visibles dans 43,5 pour cent des kystes dentaires, dans 39,0 pour cent de kystes dentigkres et dans 17,l pour cent de kystes odontogkniques & &olution corn&. (3) une corr&lation statistiquement significative (P < 0,Ol) a tt8 constat& entre le cholest&ol et l’h6mosid&ine des kystes odontog&nes. (4) L’ensemble des r&ultats semble indiquer que le chol&erol des kystes odontog&es est hkmatog&ne. Zusammenfassung(1) 537 odontogene Zysten wurden histologisch untersucht und das Vorkommen von Cholesterinnadeln und Haemosiderin beobachtet. (2) Cholesterinnadeln waren bei 43,5 Prozent der Zahnzysten, 39,0 Prozent der Zahnkeimzysten und 17,l Prozent der odontogenen Keratozysten vorhanden. (3) Zwischen der Gegenwart von Cholesterin und Haemosiderin in odontogenen Zysten gab es eine statistisch signi6kante Korrelation (P < 0,Ol). (4) Auf der Grundlage dieser Ergebnisse wird die Hypothese unterstiitzt, daD das Cholesterin in odontogenen Zysten haematogenen Ursprungs ist.
REFERENCES ALTas, A. J. K. 1966. Cholesterol granuloma in the tympanic cavity. J. Luryng. 80,690-698. BROW, R. M. 1969. The pathogen&s of the odontogenic keratocyst. CouNsELL, A. C. 1932. The pathology of dental cysts. Br. dent. J. 53,69-75. DARLIN~T~N, C. C. 1933. So-called tumours of special interest to the dentist. Dent. Cosmos. 75, 652-662. DA& G. N. 1967. Chronic ear disease in the state of Orissa. J. Luryng. 81, 1099-1108. FAIRHURST,R. 1944.The rootgranuloma, dental or radicular, and dentigerous or follicular cysts. Dent. Rec. 64,223-233. FRENCH,J.E. 1962.Atherosclerosis in General Pathology, (Edited by FUIREY, Sir H.) Third Edn, pp. 4184l8. Lloyd-Luke Ltd., London. HERTZ, R. S. 1963. An investigation into the relationship between blood serum cholesterol and the cholesterol content of periapical dental lesions. J. sth. Culif. St. dent. Ass., 51,41-46. JACOBS,M. H. and STONE,H. 1940. Cysts of the jaws. Am. J. Orthod. 26,690-711. -xxi, T. 1952. Uber die Beziehungen des Cholesterinspiegels in Blut mm Cholesteringehalt in Kieferzysten und fiber das Verhalten des Blutspiegels nach operativer Behandhmg der Zysten. Dt. zahniirtzl. Z 7, 630-637. HIRSCH,T. 1956. Uber das Verhalten des Cholesterinspiegels im Blut nach operativer Behandlung von Kieferzysten. Stoma 9,115-124. RANGER, D. 1949. Idiopathic “haemotympanum’. J. Luryng. 63,672-681. SHBAR,M. 1963. Cholesterol in dental cysts. Oral Surg. 16,1464-1473. SIMPSON,R. R. 1954. The heritage of British otology. Proc. R. Sot. Med. 47,205-214. SOSKOLNE,W. A. and SHEAR, M. 1967. Observations on the pathogenesis of primordial cysts. Br. dent. J. 321-326. THOMA, K. H. and GOLDMAN,H. M. 1960. Oral Pathology, Fifth edition p. 418. C. V. Mosby, St. Louis. TOLLER,P. A. 1967. Origin and growth of cysts of the jaws. Ann. R. CON. Surg. 40,306-336.
PLAW
A.O.B. 16/l-~
1 AND 2 OVERLEAP
THE ORIGIN OF CHOLESTEROL
IN ODONTOGENIC
CYSTS
FIG. I. Part
of the capsule of a dental cyst demonstrating the close relationship between cholesterol clefts and the black granules of haemosiderin. Per-l’s method x 80 FIG. 2. Part of the capsule of a dental cyst demonstrating the multinucleate giant cells closely opposed to the surfaces of the cholesterol clefts. Haematoxylin and eosin. x 325 FIG. 4. A part of the capsule of a dental cyst illustrating epithelial proliferation among a group of cholesterol clefts. Haematoxylin and eosin. :: 42 PLATE
A.O.B.
I
f.p. I I4
FIG. 5. A part of the capsule of a dental cyst with a mural nodule. in Fig. 5, showing it to contain FU3. 6. A section through the mural nodule illustrated large numbers of cholesterol clefts. Haematoxylin and eosin. x 9 crystals in the aspirated fluid of a dental cyst viewed under transFrc T. 7. Cholesterol mitted (left) and polarised (right) light. x 80 PLATE 2
THE ORIGIN OF CHOLESTEROL IN ODONTOGENIC CYSTS IN MAN R. M. BROWNE Department of Oral Pathology, The Dental School, St. Mary’s Row, Birmingham 4, England Summary-A histological study was made of 537 odontogeuic cysts and the presence of cholesterol clefts and haemosiderin recorded.Cholesterol clefts were preseut iu 43.5 per cent of dental cysts, 39.0 per cent of dentigerous cysts and 17.1 per cent of odontogenic keratocysts. There was statistically significant correlation (p < O-01) between the preseuce of cholesterol and haemosideriu in odontogenic cysts. These findings support the hypothesis that the origin of cholesterol in odontogenic cysts is haemotogenous.
THE presence of cholesterol crystals in the fluid aspirated from the cavities of dental cysts has been recognized as a characteristic clinical feature for many years. Despite this, there is surprisingly little statistical information concerning their presence. The only figures are those from histological studies: DARLINGTON(1933) found cholesterol in 28 (17 *7 per cent) of 158 dental cysts and SHEAR(1963) in 57 (28 *5 per cent) of 200 dental cysts. It is not surprising therefore that the origin of the cholesterol crystals is still largely hypothetical and based upon little factual information. There are basically two schools of thought. On the one hand, it is postulated that cholesterol accumulates in the tissues as a result of the degeneration and disintegration of cells, in particular epithelial cells (COUNSELL, 1932; DARLINGTON, 1933; THOMAand GOLDMAN, 1960). On the other hand, it is suggested that the cholesterol is of haematogenous origin (JACOBSand STONE, 1940; FAIRHURST,1944; SHEAR, 1963).
The present study was undertaken to investigate the incidence of cholesterol crystals in different types of odontogenic cyst and to correlate its presence with that of other products of haematogenous origin. MATERIALS
AND METHODS
This study was carried out on a series of 537 consecutive odontogenic cysts that were examined microscopically in the Department of Oral Pathology, University of Birmingham. These were composed of 402 dental cysts, 77 dentigerous cysts, 41 odontogenic keratocysts, 15 lateral periodontal cysts, 1 gingival cyst and 1 calcifying odontogenic cyst. The cyst capsules were tixed in neutral buffered formalin and demineralized in 10 per cent formic acid for one day. Random sections were prepared from each specimen and stained with haematoxylin and eosin and by Perl’s method. 107
108
R. M. BROW
The presence of cholesterol clefts, haemosiderin deposits, foam cells and inflammation was noted. RESULTS
As there were only 1 gingival cyst and 1 calcifying odontogenic cyst in this series the results in these two groups are not considered in detail. TABLE 1. THE INCIDENCE OF CHOLESTEROL CLEFIS AND HAEMOSJDERIN IN ODONTOGENIC
CYSTS
Cholesterol
Total
Del&d Dentigerous Lateral periodontal Odontogenic keratocyst Calcifying odontogenic Gingival
175(43 - 5 %) 3Ou9.0 F)
402 77 15 41 1 1 537
Haemosiderin present
present
o
247(61*4x) 39(50-7 %) 5(33 *3 %) lO(24.4 %) 0
216(:0*2 %)
301(:6-l %)
;E;:;$; 0
The incidence of cholesterol clefts and haemosiderin deposits in the different types of odontogenic cyst is recorded in Table 1. The incidence is greatest in the dental cysts (cholesterol 43 *5 per cent, haemosiderin 61.4 per cent) and least in the odontogenie keratocysts (cholesterol 17 - 1 per cent, haemosiderin 24 ‘4 per cent). In all types of cyst, the incidence of haemosiderin is greater than that of cholesterol clefts. The correlation between the presence of cholesterol clefts, both in the cyst capsule and cavity, and haemosiderin in the capsule, is recorded in Table 2. In all but two of the TABLE 2. TIZ RELATIONSHIP BETWEEN THE PRESENCE OF CHOLESTEROL CLEFTS AND HAEMOSIDERIN IN ODONTOCiENIC CYSTS
No haemosiderin no cholesterol Dental
No haemosiderin cholesterol
Haemosiderin no cholesterol
Haemosiderin cholesterol
x2
P
141
14
86
161
122.14
35
3
12
27
30.44
9
1
2
3
4.26
co.05
30
1
4
6
17.21
Calcifying odontogenic
1
0
0
0
Gingival
1
0
0
0
217
19
104
197
181.25
>O*Ol
Dentigerous Lateral periodontal Odontogenic
keratocyst
THE ORIGIN OF CHOLESTEROLIN
ODONTOGENIC
CYSTS
109
183 cysts when cholesterol clefts were present in the cyst capsule, deposits of haemosiderin were closely related to them (Fig. 1). In all types of cyst the occurrence together of haemosiderin and cholesterol clefts, either in the cyst capsule or in the cavity was most frequent. Next in order of frequency came haemosiderin in the absence of cholesterol clefts and in only a very few cysts were cholesterol clefts present in the absence of haemosiderin. Analysis by the x2 test showed this correlation to be statistically significant at the 1 per cent level in all types of cyst except the lateral periodontal cyst where it was significant at the 5 per cent level. The position of the cholesterol clefts in the capsule or cavity of the cyst and its correlation with inflammation, foreign body giant cells and foam cells is summarized in Table 3. Of those cysts which contained cholesterol clefts, clefts were more frequently TABLE 3.
THE INCIDENCEOFCHOLESTEROL,GIANTCELLS,FOAMCELLSAND INFLAMMATIONINODONTOGENICCYSTS
Cholesterol Giant cells
Foam cells
30
140
24
174
7
1
28
2
29
3
0
1
3
1
4
5
1
1
6
2
6
Number
Capsule alone
Capsule and cavity
Cavity alone
175
75
70
Dentigerous
30
22
Lateral periodontal
4
Odontogenic keratocyst
7
Dental
Inflammation
present in the capsule (183 cysts, 84.7 per cent) than in the cavity (111 cysts, 51.4 per cent). Foreign body giant cells were closely adapted to the surface of the cholesterol clefts (Fig. 2) in the cyst capsules of 177 of the 183 cysts in which they were present. Only 3 of the 216 cysts which contained cholesterol clefts did not show inflammatory changes and, in all three, the clefts were in the cyst cavity and not in the capsule. Only 29 of the 216 odontogenic cysts with cholesterol clefts also contained foam cells; on the other hand, these cells were also present in 35 of the 321 cysts without cholesterol clefts. DISCUSSION
From the evidence of this study, the incidence of cholesterol crystals in dental cysts (43 -5 per cent) is higher than that (28 -5 per cent) reported by SHEAR (1963) but is still not as great as is generally believed from clinical practice. However, it should be stressed that in the present study only random sections were examined and, if serial sections were taken, it is likely that the incidence would be found to be greater. In addition, it is found that in some cysts the cholesterol clefts were present only in the cavity. As in many cysts the contents are lost in the preparation of the sections, again it is likely that the incidence is really much greater. Chemical analysis of cyst fluids by
110
R. M. BROWNE
HIRSCH (1952, 1956) has demonstrated the presence of cholesterol in all instances, usually in greater concentration than in serum. However, the incidence of cholesterol in crystalline form is not evident from these studies. There are three important findings arising from the present study which support the hypothesis that cholesterol in odontogenic cysts takes its origin from haemorrhage at sites of inflammation in the cyst capsule. The first observation is the different incidence of cholesterol in the various types of odontogenic cyst. The dental cyst invariably arises from epithelial proliferation within a periapical inflammatory lesion and hence is always associated with inflammation during its development and expansion. The capsule of the dental cyst usually contains an inflammatory infiltrate throughout. In the present series inflammation was present in the cyst capsule in all but one of the dental cysts which contained cholesterol. Dentigerous cysts arise either from the breakdown of the reduced enamel epithelium covering the crown of the unerupted tooth, or from the migration of a dental cyst in the apical region of an erupted tooth on to the crown of an underlying unerupted tooth. In either case, some degree of inflammatory change is usually present in the cyst capsule. In the present series, inflammation was present in the cyst capsule in all but one of the dentigerous cysts which contained cholesterol. The proportion of cysts containing cholesterol was very similar in both the dental and dentigerous cysts, namely 43 *5 and 39 -0 per cent respectively. On the other hand, the odontogenic keratocyst is developmental in origin (SOSKOLNEand SHEAR, 1967; TOLLER, 1967; BROWNE,1969) and only shows occasional areas of focal inflammation in the capsule. Although such foci were present in the cyst capsule in all but one of the odontogenic keratocysts which contained cholesterol, the proportion of them containing cholesterol was much lower, namely 17 - 1 per cent. The fact that cholesterol is more common in odontogenic cysts of inflammatory origin than in those of other origins in which inflammatory changes are less frequent suggests a close relationship between the two. The second observation is that the incidence of cholesterol in the cyst capsule is greater than that in the cyst cavity. This finding confirms that of SHEAR(1963) and suggests that in the first instance the cholesterol is deposited in the cyst capsule. Support for this hypothesis arises from the fact that cholesterol crystals are not infrequently found in periapical granulomas and abscesses in the absence of cyst formation. As has been mentioned, the dental cyst invariably arises from such lesions. The third observation is the close correlation between the presence of cholesterol clefts and haemosiderin. Haemosiderin is frequently found in sites of chronic inflammation. In such sites, minute haemorrhages into the tissues are likely to occur. Whereas in many parts of the body the iron released from the breakdown of haemoglobin from the red blood corpuscles is stored in the tissues as haemosiderin, the other components of the haemorrhage, in particular cholesterol, are removed from the site by macrophages and the lymphatic vessels. Hence cholesterol clefts are not often observed. However, chronic inflammatory and cystic lesions arising within bone may be relatively inaccessible to its normal lymphatic drainage (TOLLER,1967). This being so, in addition to the usual deposition of haemosiderin, the extravasated cholesterol would stagnate in the tissues and eventually crystallize. Presumably once the process
111
THEORIGtNOPCHOLESTEROLINODONTOGENICCYSTS
of crystallization had commenced it would be self-propagating. Such a hypothesis may explain the frequent occurrence of cholesterol clefts in periapical granulomas and dental cysts in the mandible and maxilla and in granulomas of the middle ear in the temporal bone. Several authors have put forward the hypothesis that the cholesterol in cholesterol granulomas of the middle ear arises from repeated haemorrhages (SIMPSON,1954; RANGER, 1949; ALTES,1966). They have suggested that the cholesterol released from disintegrating red blood cells is in a form that would more readily crystallize in the tissues. Some support for this hypothesis arises from the close correlation between the presence of haemosiderin and cholesterol found in the present Chronic
Hemorrhage
mto
m+lamma?ory _-...p
-_ tlssuc
Cholesterol
bodv
inflammatory
crystals lymg cyst cavity
Cryslallisatlon wth foreiqn
qiant
cells
in cyst wa!l body reaction
in
Exfoliation
of
foreiqn
body
FIG. 3. A diagrammatic summary of the hypothesis for the origin of cholesterol in odontogenic cysts.
study. It may also explain the lack of correlation between the level of the serum cholesterol and the presence of cholesterol both in periapical granulomas and dental cysts (HERTZ, 1963) and in cholesterol granulomas of the middle ear (SIMPSON,1954; DA& 1967), although Kmsc~ (1956) states that in most instances of jaw cysts the serum cholesterol is raised. On the basis of these observations, it is possible to form the following hypothesis, which is summarized in Fig. 3. At sites of inflammation in the walls of odontogenic cysts there are repeated small haemorrhages. The extravasated red blood corpuscles undergo breakdown and haemosiderin is deposited in the tissues. In addition cholesterol both from the erythrocyte breakdown and also from the serum accumulates in
112
R. M. BROWN@
the tissues because of its relative inaccessibility from normal lymphatic drainage. Thereafter the cholesterol crystallizes and forms the characteristic clefts. Because of its close association with haemosiderin, it is suggested that it is the cholesterol released from the erythrocytes rather than that in the extravasated serum which is the most important source. Once the crystals have formed, the body reacts to them as it does to any crystalline foreign body and a foreign body reaction develops around them. This is characterized on microscopical section by the presence of multinucleate giant cells which lie against the clefts left by dissolved crystals (Fig. 2). In addition, the body attempts to exfoliate the crystals on to the nearest external surface. In this respect, the cavity of a cyst can be considered to be an external surface which is separated from the body by its epithelial lining. By a combination of the proliferation of the epithelium around the crystals and its breakdown over their surface (Fig. 4), the crystals together with the intervening tissue are eventually shed into the cyst cavity. Large masses in the process of exfoliation can be observed macroscopically on the cyst walls (Fig. 5). Such masses or mural nodules are composed of large numbers of cholesterol clefts among which there are numerous multinucleate giant cells and chronic inflammatory cells (Fig. 6). As the final stage in the cycle, the cyst lumen contains the cholesterol crystals lying free in the cyst fluid. On aspiration of the cyst contents, these are present as the characteristic rhomboid-shaped crystals (Fig. 7) which contribute to its shimmering appearance. Thus, depending on the stage of development of the cycle, cholesterol clefts may be present in the capsule of the cyst alone, in both the capsule and the cavity or in the cavity alone, This hypothesis is similar to that put forward by SHEAR(1963) except that in the present one it is postulated that the cholesterol arises predominantly from the red blood cells rather than from the plasma. It is of interest to draw attention to the similar arguments which have been put forward for the accumulation of cholesterol in the intima of large blood vessels in atherosclerosis. In his review, FRENCH (1962) stresses the importance of the relative inaccessibility of the intima of large arteries to lymphatic access. However ,unlike the odontogenic cyst, the majority of the lipid in this lesion is present in the cytoplasm of macrophages and it is only in advanced lesions that free cholesterol crystals are present. It may be that its suspected predominant origin from the plasma rather than from the red blood cells accounts for this difference. The evidence presented in this paper does not discount the possible origin of cholesterol from epithelial or tissue cell-breakdown. For instance, the greater incidence of cholesterol in dental and dentigerous cysts compared with the odontogenic keratocyst may be explained on the basis that in the former the epithelial cells degenerate while in the latter they undergo maturation to form keratin. On the other hand, there is no real support for such a hypothesis and the positive correlations between the presence of haemosiderin and cholesterol clefts demonstrated in this study form strong support for the haematogenous origin of cholesterol in odontogenic cysts.
THEOIUOINOFCHOLlZ.WROLIN ODONTOGENICCYSTS
113
(1)
Une &de histologique est r&disc% au niveau de 537 kystes odonto&nes et la pr&xnce d’inclusions de cholest&ol et d’h&mosid&ine a &te &xii&z. (2) Des inclusions de cholest&ol sont visibles dans 43,5 pour cent des kystes dentaires, dans 39,0 pour cent de kystes dentigkres et dans 17,l pour cent de kystes odontogkniques & &olution corn&. (3) une corr&lation statistiquement significative (P < 0,Ol) a tt8 constat& entre le cholest&ol et l’h6mosid&ine des kystes odontog&nes. (4) L’ensemble des r&ultats semble indiquer que le chol&erol des kystes odontog&es est hkmatog&ne. Zusammenfassung(1) 537 odontogene Zysten wurden histologisch untersucht und das Vorkommen von Cholesterinnadeln und Haemosiderin beobachtet. (2) Cholesterinnadeln waren bei 43,5 Prozent der Zahnzysten, 39,0 Prozent der Zahnkeimzysten und 17,l Prozent der odontogenen Keratozysten vorhanden. (3) Zwischen der Gegenwart von Cholesterin und Haemosiderin in odontogenen Zysten gab es eine statistisch signi6kante Korrelation (P < 0,Ol). (4) Auf der Grundlage dieser Ergebnisse wird die Hypothese unterstiitzt, daD das Cholesterin in odontogenen Zysten haematogenen Ursprungs ist.
REFERENCES ALTas, A. J. K. 1966. Cholesterol granuloma in the tympanic cavity. J. Luryng. 80,690-698. BROW, R. M. 1969. The pathogen&s of the odontogenic keratocyst. CouNsELL, A. C. 1932. The pathology of dental cysts. Br. dent. J. 53,69-75. DARLIN~T~N, C. C. 1933. So-called tumours of special interest to the dentist. Dent. Cosmos. 75, 652-662. DA& G. N. 1967. Chronic ear disease in the state of Orissa. J. Luryng. 81, 1099-1108. FAIRHURST,R. 1944.The rootgranuloma, dental or radicular, and dentigerous or follicular cysts. Dent. Rec. 64,223-233. FRENCH,J.E. 1962.Atherosclerosis in General Pathology, (Edited by FUIREY, Sir H.) Third Edn, pp. 4184l8. Lloyd-Luke Ltd., London. HERTZ, R. S. 1963. An investigation into the relationship between blood serum cholesterol and the cholesterol content of periapical dental lesions. J. sth. Culif. St. dent. Ass., 51,41-46. JACOBS,M. H. and STONE,H. 1940. Cysts of the jaws. Am. J. Orthod. 26,690-711. -xxi, T. 1952. Uber die Beziehungen des Cholesterinspiegels in Blut mm Cholesteringehalt in Kieferzysten und fiber das Verhalten des Blutspiegels nach operativer Behandhmg der Zysten. Dt. zahniirtzl. Z 7, 630-637. HIRSCH,T. 1956. Uber das Verhalten des Cholesterinspiegels im Blut nach operativer Behandlung von Kieferzysten. Stoma 9,115-124. RANGER, D. 1949. Idiopathic “haemotympanum’. J. Luryng. 63,672-681. SHBAR,M. 1963. Cholesterol in dental cysts. Oral Surg. 16,1464-1473. SIMPSON,R. R. 1954. The heritage of British otology. Proc. R. Sot. Med. 47,205-214. SOSKOLNE,W. A. and SHEAR, M. 1967. Observations on the pathogenesis of primordial cysts. Br. dent. J. 321-326. THOMA, K. H. and GOLDMAN,H. M. 1960. Oral Pathology, Fifth edition p. 418. C. V. Mosby, St. Louis. TOLLER,P. A. 1967. Origin and growth of cysts of the jaws. Ann. R. CON. Surg. 40,306-336.
PLAW
A.O.B. 16/l-~
1 AND 2 OVERLEAP
THE ORIGIN OF CHOLESTEROL
IN ODONTOGENIC
CYSTS
FIG. I. Part
of the capsule of a dental cyst demonstrating the close relationship between cholesterol clefts and the black granules of haemosiderin. Per-l’s method x 80 FIG. 2. Part of the capsule of a dental cyst demonstrating the multinucleate giant cells closely opposed to the surfaces of the cholesterol clefts. Haematoxylin and eosin. x 325 FIG. 4. A part of the capsule of a dental cyst illustrating epithelial proliferation among a group of cholesterol clefts. Haematoxylin and eosin. :: 42 PLATE
A.O.B.
I
f.p. I I4
FIG. 5. A part of the capsule of a dental cyst with a mural nodule. in Fig. 5, showing it to contain FU3. 6. A section through the mural nodule illustrated large numbers of cholesterol clefts. Haematoxylin and eosin. x 9 crystals in the aspirated fluid of a dental cyst viewed under transFrc T. 7. Cholesterol mitted (left) and polarised (right) light. x 80 PLATE 2