In Microscopy, As in Nature, One Recognizes Only What One Already Knows.

Non-Microbial Endodontic Disease
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8. Non-Microbial Endodontic Disease - P.N.R. NAIR Introduction "In microscopy, as in nature, one recognizes only what one already knows."1 Apical periodontitis is an inflammatory disorder of periradicular tissues caused by irritants of endodontic origin, mostly of persistent microbes living in the root canal system of the affected tooth.2,3 It is primarily a disease of infection. But unlike classical infectious diseases of single, specific etiologic agents, apical periodontitis is caused by a consortium of microbial species living in the root canal in an ecologically balanced community form of living4 referred to as biofilms.5 The microbial etiology of the disease has been discussed in Chapter 7, "Microbiology of Endodontic Disease." The purpose of this chapter is to provide a comprehensive overview of the nonmicrobial aspects of the disease, which are generally associated with asymptomatic persistent periapical radiolucencies, also referred to as endodontic failures. Cystic Apical Periodontitis INTRODUCTION By definition, a cyst is a closed pathologic cavity, lined by epithelium that contains a liquid or semisolid material.6 The term cyst is derived from the Greek word Kystis meaning sac or bladder. There are several varieties of cystic lesions in the body that are commonly referred to as congenital, neoplastic, parasitic, retention, implantation, and inflammatory types. A periapical cyst is an inflammatory jaw cyst of the periodontium of a tooth with infected and necrotic pulp and has been extensively reviewed.1,7,8 INCIDENCE OF PERIAPICAL CYSTS The epidemiology and global distribution of the disease are not yet known. Anatomically, periapical cysts are the most common of all jaw cysts and comprise about 52%7 to 68%9 of all the cysts affecting the human jaws. The prevalence of periapical cysts is highest among patients in their third decade of life7,10,11 and higher among males than females.7,10 Periapical cysts occur in all tooth-bearing sites of the jaws but are more frequent in maxillary than mandibular teeth. In the maxilla, the anterior region appears to be more affected with cysts whereas in the mandible the radicular cysts occur more frequently in the premolar region.12 DIAGNOSIS OF PERIAPICAL CYSTS The clinical diagnosis of periapical cysts from other forms of apical periodontitis has been extensively debated.13 Several radiographic features have been proposed to support a diagnosis, including size of the lesion and the presence of a radioopaque rim14 demarcating the lesion. Although the statistical probability of cyst occurrence may be higher among larger lesions,15 a conclusive relationship between the size of the lesion and cystic condition has not yet been substantiated by histologic data. Albeit the claim,16 periapical lesions cannot be differentially diagnosed into cystic and noncystic lesions based on radiographic features.10,17-21 In a recent histologic investigation, it has been conclusively shown that no correlation existed between the presence of a radioopaque rim and the histologic diagnosis of the cysts.22 Assuming
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that cystic cavities may have a lower density than other apical periodontitis lesions, computer tomography23 and densitometry16 have been used to differentiate these conditions, but without success. Echography, ultrasonic imaging technique, has been recently introduced as a periapical diagnostic method.24,25 The technique can detect fluid, soft tissue, and the real-time blood flow. In spite of the safety of ultrasound and the relative ease of use, the sonic waves do not pass through bone but are reflected back to the sensor, thereby enabling only detection of lesions that are not enclosed in bone. Currently, therefore, histologic serial sectioning of the lesions in toto remains to be the only reliable diagnostic method of periapical cysts.1,8,26 This has been conclusively shown in a recent histologic investigation.22 Histologic diagnosis, however, can only be applied after surgical removal of the root tip with the attached periapical lesion, thus making it a post hoc diagnosis. ORIGIN OF THE CYST EPITHELIUM The lesions of apical periodontitis often contain epithelial cells27-38 that are generally believed to be derived from the cell rests of Malassez.27 The cells proliferate in some lesions and serve as the major source of the stratified squamous epithelium7,8 that lines the lumen of lesions that develop into cysts. In rare instances, apical cysts have also been found to be lined by ciliated columnar or muco-secretory cells of respiratory origin.38-46 In one investigation,46 3 of the 256 apical periodontitis lesions examined were cysts lined with ciliated columnar epithelium (Figures 1 and 2). However, the origin of ciliated epithelium in radicular cysts has not yet been satisfactorily clarified. Currently, there are three explanations43 for the presence of ciliated cells in radicular cysts: (1) migration of epithelial cells from the maxillary sinus or the nasal cavity; (2) metaplasia of the stratified squamous epithelium; and (3) differentiation of pluripotent cells within the jaw. Most of the reported ciliated cell-lined cysts were affecting maxillary teeth. The anatomic proximity of the periapical inflammatory lesion to the maxillary sinus may result in rarefaction of the sinus floor, perforation into the sinus cavity,38,40 and maxillary sinusitis.47-49 The lumen of such a periapical cyst can communicate with the sinus cavity, as has been convincingly demonstrated in photomicrographs by Kronfeld.40 Once direct communication is established, a developing apical cyst can be lined with ciliary epithelium of sinus origin. Figure 1. A photomicrograph A, of a cystic apical periodontitis (AP) of the left maxillary second premolar of a 34-year-old male patient. Note the two diverticula of a small cystic lumen magnified in B, and part of the epithelial lining enlarged in C. The lumen (LU) is lined with columnar epithelial cells (CEP) with distinct cilia (arrow heads). D = dentine. Original magnifications: A 19, B 44, C 500. Reproduced with permission from Nair.46 Figure 2. A transmission electron micrograph of ciliated columnar epithelial cells (CEP) lining of the cystic lumen of the lesion presented in Figure 8-1. Note the distinct cilia (CI) and the neutrophilic gametocytes (NG). FI = fibroblasts. Original magnification 3,690. Reproduced with permission from Nair.46 PREVALENCE OF CYSTS AMONG PERIAPICAL LESIONS There have been many studies on the prevalence of periapical cysts among apical periodontitis lesions (Table 1). In this literature, the prevalence of cysts varies from 6% to 55%. However, accurate histopathologic diagnosis of radicular cysts is possible only through serial sectioning or step-serial sectioning of the lesions removed in toto.50 There are only three studies31,50,51 in which either one of those essential
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techniques was used, whereas most of the others (Table 1) analyzed specimens obtained from wide sources for routine histopathologic reports. The statistically impressive 2,308 lesions in Bhaskar's study10 had been obtained from 314 contributors and the 800 biopsies of Lalonde and Luebke21 originated from 134 sources. Such histopathologic diagnostic specimens, often derived through apical curettage, do not represent lesions in toto. In random sections from fragmented and epithelialized lesions, part of the specimens can give the appearance of epitheliumlined cavities that do not exist in reality. Indeed, another author52 defined a typical radicular cyst as one in which "a real or imagined lumen was lined with stratified squamous epithelium." It should be pointed out that the photomicrographic illustrations (Figure 3) in several studies10,21 represent only magnified views of selected small segments of epithelialized lesions. They are not supported by overview pictures of lesser magnifications of sequential sections derived from different axial planes of the lesions in question. The wide variation in the reported incidence of periapical cysts is most probably due to the difference in the histopathologic interpretation of the sections. When the histopathologic diagnosis is based on random or limited number of serial sections, most of epithelialized periapical [Figure 1. A photomicrograph A, of a cystic apical periodontitis (AP) of the left maxillary second premolar of a 34-year-old male patient. Note the two diverticula of a small cystic lumen magnified in B, and part of the epithelial lining enlarged in C. The lumen (LU) is lined with columnar epithelial cells (CEP) with distinct cilia (arrow heads). D = dentine. Original magnifications: A 19, B 44, C 500.] [Figure 2. A transmission electron micrograph of ciliated columnar epithelial cells (CEP) lining of the cystic lumen of the lesion presented in Figure 8-1. Note the distinct cilia (CI) and the neutrophilic gametocytes (NG). FI = fibroblasts. Original magnification 3,690.] [Table 1. The Prevalence of Radicular Cysts Among Apical Periodontitis Lesions] [Figure 3. Roentgenogram (top) and photomicrograph (bottom) of a "radicular cyst." Original illustrations reprinted from Bhaskar.10 Note the small selected segment of an epithelialized lesion. It is not supported by overview pictures of lesser magnification of sequential sections derived from different axial planes of the lesion.] lesions would be wrongly categorized as radicular cysts. This view is substantiated by the results of a study50 in which an overall 52% of the lesions (n = 256) were found to be epithelialized but only 15% were actually periapical cysts. Figure 3. Roentgenogram (top) and photomicrograph (bottom) of a "radicular cyst." Original illustrations reprinted from Bhaskar.10 Note the small selected segment of an epithelialized lesion. It is not supported by overview pictures of lesser magnification of sequential sections derived from different axial planes of the lesion. Reproduced with permission from Elsevier. HISTOPATHOLOGY OF PERIAPICAL CYSTS
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The structure of a periapical cyst in relation to the root canal of the affected teeth has not been taken into account in routine histopathologic diagnosis. The major reason for this has been the nature of the biopsy itself. Apical specimens removed by curettage do not contain the root tips of the diseased teeth making structural reference to the root canals of the affected teeth impossible. In 1980 Simon51 has pointed out that there are two distinct categories of radicular cysts namely, those containing cavities completely enclosed in epithelial lining and those containing epithelium-lined cavities that are open to the root [Figure 4. Root apices in cavities lined by epithelium (E in top). Original illustrations reprinted from Simon.51 Note the severe damage of the microanatomic relationship between the root apices and the cyst epithelia that might have influenced critics to wonder whether the "bay cysts"51 are histologic artifacts. Original magnification 25.] canals. The latter was designated as "bay cysts"51 and later renamed as "pocket cysts."50 It seems that Simon51 has observed only the large type of such lesions with voluminous cavities, into which the root apices of the affected teeth appeared to protrude. The photomicrographs in the publication reveal severe damage of the microanatomic relationship between the root apices and the cyst epithelia (Figure 4). This might have influenced critics to wonder whether the "bay cysts"51 are histologic artifacts. We50 analyzed 256 periapical lesions obtained in toto with extracted teeth. The specimens were processed by a modern plastic-embedding technique, and meticulous serial or step-serial sections were prepared and evaluated based on predefined histopathologic criteria. Of the 256 specimens, 35% were found to be periapical abscesses, 50% were periapical granulomas, and only 15% were periapical cysts. Equally significant was the finding that two distinct classes of radicular cysts the apical true cysts, with cavities completely enclosed in epithelial linings (Figure 5), and the apical pocket cysts, with cyst lumina open to the root canals (Figure 6) could be observed at the periapex when the lesions were analyzed in relation to the root canals. An overall 9% of the 256 lesions were apical true cysts and 6% were periapical pocket cysts. Figure 4. Root apices in cavities lined by epithelium (E in top). Original illustrations reprinted from Simon.51 Note the severe damage of the microanatomic relationship between the root apices and the cyst epithelia that might have influenced critics to wonder whether the "bay cysts"51 are histologic artifacts. Original magnification 25. Reproduced with permission from Williams & Wilkins. Figure 5. Periapical true cyst. Photomicrograph A, of an axial section passing through the apical foramen (AF). The lower half of the lesion and the epithelium (EP in B) are magnified in B, and C, respectively. Note the cystic lumen (LU) with cholesterol clefts (CC) completely enclosed in EP having no communication to the root canal. Original magnifications: A 15, B 30, C 180. Reproduced with permission from Nair.1 Figure 6. Periapical pocket cyst. Axial sections passing peripheral to the root canal A, B, give the false impression of the presence of a cyst lumen (LU) completely enclosed in epithelium. Sequential section C, passing through axial plane of the root canal clearly reveals the continuity of the LU with the root canal (RC in D. The apical foramen with the LU of the section C, are magnified in D. Note the pouch-like LU of the pocket cyst with the epithelium (EP)
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forming a collar at the root apex. Original magnifications: A, B, C 15; D 50. D = dentine. Reproduced with permission from Nair.1 GENESIS OF TRUE CYSTS The periapical true cyst may be defined as a chronic inflammatory lesion at the periapex that contains an epithelium lined, closed pathological cavity (Figure 5). The pathogenesis of true cysts has been described by various authors.8,28,50,53-59 An apical cyst is a direct sequel to apical granuloma, although a granuloma need not always develop into a cyst. Owing to still unknown reasons, only a small fraction (<10%) of the periapical lesions change into true radicular cysts.10,21 The pathogenesis of the true cyst has been described in three phases.7 During the first phase, the dormant cell-rests of Malassez begin to proliferate as a direct effect of inflammation,57,60 probably under the influence of bacterial antigens,61 epidermal growth factors,62-64 cell mediators, and metabolites that are released by various cells residing in the periapical lesion. During the second phase, an epithelium lined cavity comes into existence. There are two main theories regarding the formation of the cyst cavity: (1) the "nutritional deficiency theory" and (2) the "abscess theory." The "nutritional deficiency theory" is based on the assumption that the central cells of the epithelial strands become removed from their source of nutrition and undergo necrosis and liquefactive degeneration.57,65-67 The accumulating products in turn attract neutrophilic granulocytes into the necrotic area. Such microcavities containing degenerating epithelial cells, infiltrating mobile cells, and tissue fluid coalesce to form the cyst cavity lined by stratified epithelium. The "abscess theory" postulates that the [Figure 5. Periapical true cyst. Photomicrograph A, of an axial section passing through the apical foramen (AF). The lower half of the lesion and the epithelium (EP in B) are magnified in B, and C, respectively. Note the cystic lumen (LU) with cholesterol clefts (CC) completely enclosed in EP having no communication to the root canal. Original magnifications: A 15, B 30, C 180.] [Figure 6. Periapical pocket cyst. Axial sections passing peripheral to the root canal A, B, give the false impression of the presence of a cyst lumen (LU) completely enclosed in epithelium. Sequential section C, passing through axial plane of the root canal clearly reveals the continuity of the LU with the root canal (RC in D. The apical foramen with the LU of the section C, are magnified in D. Note the pouch-like LU of the pocket cyst with the epithelium (EP) forming a collar at the root apex. Original magnifications: A, B, C 15; D 50. D = dentine.] proliferating epithelium lines an abscess cavity formed by tissue necrosis and lysis because of the innate nature of the epithelial cells to cover exposed connective tissue surfaces.29,33 During the third phase the cyst grows, by which exact mechanism is still unknown. It is generally believed to be by osmosis. The presence of necrotic tissue in the cyst lumen attracts neutrophilic granulocytes, which extravasate and transmigrate through the epithelial lining (Figures 7 and 8) into the cyst cavity where they perish. The lytic products of the dying cells in the cyst lumen release a greater number of molecules. As a result, the osmotic pressure of the cyst fluid rises to a level higher than that of the tissue fluid.68 The latter diffuses into the cyst cavity so as to raise the intraluminal hydrostatic pressure well above the capillary pressure. The increased intracyst pressure may lead to bone resorption and expansion of the cyst. However, the fact that an apical pocket cyst with lumen open to the necrotic root canal can
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become larger50,59 suggests against osmotic pressure as a potential factor in the development of radicular cysts. Furthermore, there is increasing evidence in support of a molecular mechanism for cyst expansion.59 The T-lymphocytes69 and macrophages in the cyst wall may provide a continuous source of bone resorptive metabolites70 and cytokines. The presence of effector molecules such as matrix metalloproteinases 1 and 2 have also been reported in the cyst walls.71 Figure 7. Composite transmission electron micrograph showing neutrophils (NG, arrowheads) apparently in the process of transmigration through the epithelial wall of a cyst (EP) into the cyst lumen (LU). ST = subepithelial tissue; PC = plasma cells; MA = macrophages. Original magnification 1,600. Modified from Nair.59 Figure 8. An intramural scanning electron microscopic view of a cyst luminal wall (LU, in A) enlarged in stages (B, C, D). Note the flat epithelial cells (EP) and the globular neutrophilic granulocytes (NG). The latter emerge through the interepithelial cell spaces into the cyst lumen. Original magnifications: A 20, B 230, C 670, D 1,300. Reproduced with permission from Nair.1 GENESIS OF POCKET CYSTS The periapical pocket cyst contains an epithelium-lined pathologic cavity that is open to the root canal of the affected tooth (Figure 6). As mentioned previously, such lesions were originally described as "bay cysts."51 It has been postulated that biologically, a pocket cyst constitutes an extension of the infected root canal space into the periapex. The microluminal space becomes enclosed in a stratified squamous epithelium that grows and forms an epithelial collar (Figure 9) around the root tip. The epithelial collar forms an "epithelial attachment"37 to the root surface that seals off the infected root canal and the micro-cystic lumen from the periapical milieu and the rest of the body (Figure 9 C and D). The presence of microorganisms at the apical foramen (Figure 10) attracts neutrophilic granulocytes by chemotaxis into the microlumen. However, the pouch-like lumenbiologically outside the body milieu acts as a "death trap" to the externalized neutrophils. As the necrotic tissue and microbial products accumulate, the sac-like lumen enlarges to accommodate the debris, forming a voluminous diverticulum of the root canal [Figure 7. Composite transmission electron micrograph showing neutrophils (NG, arrowheads) apparently in the process of transmigration through the epithelial wall of a cyst (EP) into the cyst lumen (LU). ST = subepithelial tissue; PC = plasma cells; MA = macrophages. Original magnification 1,600.] [Figure 8. An intramural scanning electron microscopic view of a cyst luminal wall (LU, in A) enlarged in stages (B, C, D). Note the flat epithelial cells (EP) and the globular neutrophilic granulocytes (NG). The latter emerge through the interepithelial cell spaces into the cyst lumen. Original magnifications: A 20, B 230, C 670, D 1,300.] [Figure 9. Overview photomicrograph A, of an apical periodontitis lesion (AP). The resorbed root tip with widened apical foramen is magnified in B. Note the bacterial plaque (white arrow head, BA) at the apical foramen and the micro-abscess (MA) externalized by an epithelial (EP) ring attached to the root tip. The rectangular demarcated area in A, is magnified in C. Note the numerous subepithelial blood
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vessels (BV) that are further magnified in D. The bacteria (BA) attract neutrophils (NG) to form the micro-abscess in front of the apical foramen which probably is the initiation of a periapical pocket cyst. D = dentine. Original magnifications: A 20, B 40, C 130, D 310.] [Figure 10. High-magnification photomicrographs (A-D) of the bacterial plaque (BA) shown in Figure 8-9 and the micro-abscess containing clusters of bacterial colonies (BA) apparently held back by a wall of neutrophils (NG). D = dentine; EP = epithelium. Original magnifications: A, C, D 800; B 520.] [Figure 11. Photomicrograph of a well-developed pocket cyst A. Note the sac-like epithelial lumen (LU), enlarged in B. A sequential, axial serial section C, passing through the apical foramen in the root canal plane (RC) shows the continuity of the lumen to the root canal. D = dentine. Original magnification: A, C 16; B, D 40.] space into the periapical area (Figures 11 and 12). It has been pointed out50 that from the pathogenic, structural, tissue dynamic, host-benefit, and protection stand points, the epithelium-lined pouch-like extension of the root canal space of such lesions has much in common with a marginal periodontal pocket. This appears to justify the terminology of "periapical pocket cyst" as opposed to the biologically meaningless term "bay cyst."51 In this context, it is interesting to note that cystic lesions with morphologic features identical to those of pocket cysts have been histologically illustrated by Seltzer in a text book72 [Figure 12. Macrophotographs A, B, of a large apical periodontitis lesion removed in toto by apical surgery A. The specimen after decalcification and axial subdivision B, shows a voluminous lumen into which the root canal opens.] and also experimentally induced in monkeys by Valderhaug.60,73 However, these authors neither differentiated nor interpreted the lesions in relation to the root canals of the involved teetha reminder that in microscopy, as in nature, one recognizes only what one already knows. Figure 9. Overview photomicrograph A, of an apical periodontitis lesion (AP). The resorbed root tip with widened apical foramen is magnified in B. Note the bacterial plaque (white arrow head, BA) at the apical foramen and the microabscess (MA) externalized by an epithelial (EP) ring attached to the root tip. The rectangular demarcated area in A, is magnified in C. Note the numerous subepithelial blood vessels (BV) that are further magnified in D. The bacteria (BA) attract neutrophils (NG) to form the micro-abscess in front of the apical foramen which probably is the initiation of a periapical pocket cyst. D = dentine. Original magnifications: A 20, B 40, C 130, D 310. Reproduced with permission from Nair.1 Figure 10. High-magnification photomicrographs (A-D) of the bacterial plaque (BA) shown in Figure 8-9 and the micro-abscess containing clusters of bacterial colonies (BA) apparently held back by a wall of neutrophils (NG). D = dentine; EP = epithelium. Original magnifications: A, C, D 800; B 520. Reproduced with permission from Nair.1 Figure 11. Photomicrograph of a well-developed pocket cyst A. Note the saclike epithelial lumen (LU), enlarged in B. A sequential, axial serial section C,
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passing through the apical foramen in the root canal plane (RC) shows the continuity of the lumen to the root canal. D = dentine. Original magnification: A, C 16; B, D 40. Reproduced with permission from Nair.1 Figure 12. Macrophotographs A, B, of a large apical periodontitis lesion removed in toto by apical surgery A. The specimen after decalcification and axial subdivision B, shows a voluminous lumen into which the root canal opens. Reproduced with permission from Nair.1 CYSTS AND PERIAPICAL HEALING The occurrence of two distinct classes of radicular cysts and the low prevalence of true cysts (<10%) are both significant considerations in clinical management of primary and particularly posttreatment apical periodontitis. Many clinicians hold the view that cysts do not heal and thus must be removed by surgery. It should be pointed out with emphasis that apical periodontitis lesions cannot be differentially diagnosed into cystic and noncystic lesions based on radiographs.10,11,17-20,74 However, routine histopathologic diagnostic reports and publications based on retrospective reviewing of such have perpetuated the notion that nearly half of all periapical lesions are radicular cysts. As a result, a disproportionately large number of apical surgeries are performed at the tooth apex to "enucleate" lesions that are clinically diagnosed as "cysts." In fact, studies based on meticulous serial sections have shown that the incidence of true cysts is less than 10% of all periapical lesions.31,50,51 This would imply that most of the cases in which apical surgery has been performed based on radiographic diagnosis of cysts might have resolved by nonsurgical root canal therapy. The endodontic literature suggests that a great majority of cysts heal after nonsurgical root canal therapy. "Success rates" of 85% to 90% have been reported.75-77 However, the histologic status of any apical radiolucent lesion at the time of treatment is unknown to the clinician, who is also unaware of the differential diagnostic status of the "successful" and "failed" cases. Most of the cystic lesions must heal if one should reconcile the high healing rate after non-surgical root canal treatment and the claimed high prevalence of radicular cysts. This conclusion is based purely on a deductive logic in the absence of any histologic basis. It must be noted that several investigators listed in Table 1 reached the erroneous conclusion on high prevalence of cyst based on an incorrect interpretation of epithelialized apical periodontitis lesions. CLINICAL RELEVANCE OF CYSTS IN PRIMARY AND POSTTREATMENT APICAL PERIODONTITIS The aim of nonsurgical root canal therapy is the elimination of infection from the root canal and the prevention of re-infection by root filling. Periapical pocket cysts, particularly the smaller ones, may heal after root canal therapy.51 The tissue dynamics of a true cyst is self-sustaining as the lesion is no longer dependent on the presence or absence of root canal infection.50,51 Therefore, the true cysts, particularly the large ones, are less likely to be resolved by nonsurgical root canal therapy. This has been shown in a long-term radiographic follow-up (Figure 13) of a case and subsequent histologic analysis of the surgical block biopsy.26 It can be argued that the prevalence of cysts in posttreatment apical periodontitis should be substantially higher than that in primary apical periodontitis. However, this suggestion has not been supported by data based on a statistically reliable number of specimens. Nevertheless, investigations26,78,79 of 16 histologically reliable block biopsies of posttreatment apical
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periodontitis lesions (Table 2) revealed 2 cystic specimens (13%), possibly true cysts, which is well above the 9% of true cysts observed in a large study50 on mostly primary apical periodontitis lesions. The presence of two distinct structural forms of cystic apical periodontitis and the low prevalence of periapical cysts would question the rationale behind some of the current diagnostic and therapeutic concepts such as (1) disproportionate application of apical surgery based on unfounded radiographic diagnosis of apical lesions as cysts, and (2) the widely held opinion that majority of cysts heal after nonsurgical root canal therapy. Nevertheless, it should be recognized that periapical cysts could sustain persistent apical [Figure 13. Longitudinal radiographs A-D, of a periapically affected central maxillary incisor of a 37-year-old woman for a period of 4 years and 9 months. Note the large radiolucent asymptomatic lesion before A, 44 months after root filling B, and immediately after periapical surgery C. The periapical area shows distinct bone healing D, after 1 year postoperatively. Histopathologic examination of the surgical specimen by modern tissue processing and step-serial sectioning technique confirmed that the lesion was a true radicular cyst that also contained cholesterol clefts. Selected radiographs from Nair et al.26] [Table 2. The Prevalence of Cysts Among Post-treatment Apical Periodontitis Lesions] radiolucencies. Therefore, clinicians should consider the option of apical surgery, particularly when previous orthograde re-treatment has not resulted in radiographic healing. Figure 13. Longitudinal radiographs A-D, of a periapically affected central maxillary incisor of a 37-year-old woman for a period of 4 years and 9 months. Note the large radiolucent asymptomatic lesion before A, 44 months after root filling B, and immediately after periapical surgery C. The periapical area shows distinct bone healing D, after 1 year postoperatively. Histopathologic examination of the surgical specimen by modern tissue processing and stepserial sectioning technique confirmed that the lesion was a true radicular cyst that also contained cholesterol clefts. Selected radiographs from Nair et al.26 CHOLESTEROL AND APICAL PERIODONTITIS The presence of cholesterol clefts in apical periodontitis has been a common histopathologic observation. Yet, its etiologic significance to posttreatment apical periodontitis has been appreciated only recently.26,80,81 Endogenous substances of crystalline fine particulate nature can be tissue irritating. The crystals induce cytokinenetwork-mediated inflammation, hard tissue resorption, and soft tissue damage. Endogenous crystalline substances that have been shown to cause pathogenic tissue reaction include monosodium urate (gout), calcium phosphate dihydrate (pseudogout), basic calcium phosphate (hydroxyapatite), and cholesterol. Cholesterol6 is a steroid lipid present in all animal tissues. The term is derived from Chole-stereos meaning "bile-solid" because of its occurrence in gall stones. Cholesterol has the characteristic core of the "cyclopentanoperhydrophenanthrene" ring (Figure 14). It is abundant in "membrane-rich" tissues (myelin) and secretory
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cells and is the precursor of bile acids, provitamin D3, and several hormones.82 Cholesterol is essential to life and most of the body cholesterol is produced in the liver. The entire body requirement of cholesterol can be met by endogenous production. Nevertheless, dietary cholesterol is absorbed from the intestine and metabolized. Cholesterol, being insoluble in aqueous solution, is transported by the circulation as conjugates of lipoproteins. Figure 14. The parent compound of all steroids is Cyclopentanoperhydrophenanthrine with four saturated rings that are designated alphabetically as shown A. The structural formula of cholesterol B. Note the four cyclohexane rings and the standard numbering system of all the carbon atoms. Reproduced with permission from Nair.81 CHOLESTEROL IN DISEASE High blood level of cholesterol is suspected to play a role in atherosclerosis as a result of its deposition in the vascular walls.82,83 Atherosclerosis is a chronic, progressive, multifactorial disease that begins as an intracellular deposition of cholesterol in previously damaged sites on the inner arterial walls. The lesions eventually become fibrous calcified plaques. The consequent hardening and narrowing of the arteries promote the formation of intravascular blood clots and infarction of the dependent tissue. Although atheromas can develop in many different blood vessels, they are most common in the coronary arteries. The resultant myocardial infarction is usually fatal and is the most common cause of death in western industrialized nations.84 Deposition of crystalline cholesterol also occurs in other tissues and organs, as in the case of otitis media and the "pearly tumor" of the cranium.85 In the oral region, accumulation of cholesterol crystals occurs in apical periodontitis lesions10,26,55,86-89 with clinical significance in endodontics and oral surgery.26,90 [Figure 14. The parent compound of all steroids is Cyclopentanoperhydrophenanthrine with four saturated rings that are designated alphabetically as shown A. The structural formula of cholesterol B. Note the four cyclohexane rings and the standard numbering system of all the carbon atoms.] CHOLESTEROL IN APICAL PERIODONTITIS Apical periodontitis lesions often contain deposits of cholesterol crystals appearing as narrow, elongated tissue clefts in histopathologic sections. The crystals dissolve in fat solvents used for the tissue processing and leave behind the spaces they occupied as clefts. The reported prevalence of cholesterol clefts in apical periodontitis varies from 18% to 44%.55,86,88,89 The crystals are believed to be formed from cholesterol released by: (1) disintegrating erythrocytes of stagnant blood vessels within the lesion,88 (2) lymphocytes, plasma cells, and macrophages that die in great numbers and disintegrate in chronic periapical lesions,89 and (3) the circulating plasma lipids.55 All these sources may contribute to the concentration and crystallization of cholesterol in the periapical area. Nevertheless, inflammatory cells that die and disintegrate within the lesion may be the major source of cholesterol, as a result of its release from membranes of such cells in long-standing lesions.26,72 The crystals are initially formed in the inflamed periapical connective tissue, where they act as foreign bodies and provoke a giant cell reaction.
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In histologic sections, numerous multinucleated giant cells can be observed around the cholesterol clefts (Figure 15). When a large number of crystals accumulate in the inflamed connective tissue, they passively move in the direction of least resistance. If the lesion happens to be a radicular cyst, the crystals move in the direction of the epithelium-lined cyst cavity, as the outer collagenous capsule of the lesion is much tougher for the crystals to move through. The slow "glacier-like" movement of the crystal mass erodes the epithelial lining and empties the crystals into the cyst lumen (Figure 15). [Figure 15. Cholesterol crystals and cystic condition of apical periodontitis as potential causes for endodontic failures. Overview of a histologic section (upper inset) of an asymptomatic apical periodontitis that persisted after conventional root canal treatment. Note the vast number of cholesterol clefts (CC) surrounded by giant cells (GC) of which a selected one with several nuclei (arrowheads) is magnified in the lower inset. D = dentine; CT = connective tissue; NT = necrotic tissue. Original magnifications: 68; upper inset 11; lower inset 412.] Radicular cysts91 and apical granulomas10 in which cholesterol clefts form a major component are referred to as "cholesteatoma." The term originates from general pathology where it refers to a local accumulation of cholesterol crystals that cause discomfort and dysfunction of the affected organs.85 Therefore, the term should be used more specifically as "apical cholesteatoma" so as to distinguish the condition from cholesteatoma affecting other tissues and organs. Figure 15. Cholesterol crystals and cystic condition of apical periodontitis as potential causes for endodontic failures. Overview of a histologic section (upper inset) of an asymptomatic apical periodontitis that persisted after conventional root canal treatment. Note the vast number of cholesterol clefts (CC) surrounded by giant cells (GC) of which a selected one with several nuclei (arrowheads) is magnified in the lower inset. D = dentine; CT = connective tissue; NT = necrotic tissue. Original magnifications: 68; upper inset 11; lower inset 412. Reproduced with permission from Nair.81 TISSUE REACTION TO CHOLESTEROL Cholesterol crystals are intensely sclerogenic.92,93 They induce granulomatous lesions in dogs,94 mice,92,93,95-97 and rabbits.95,98,99 The cholesterol was applied in those studies by direct injection of its suspension into arterial walls,94 by subcutaneous deposition of cholesterol crystals,92,93,96,97 or by subcutaneous implantation of absorbable gelatin sponge that had been saturated with cholesterol in ether, and the solvent was allowed to evaporate before the implantation.95,99 These studies consistently showed that the cholesterol crystals were densely surrounded by macrophages and giant cells. There appears to be only one experimental study reported in the literature that specifically addressed the potential association of cholesterol crystals and nonresolving apical periodontitis lesions.80 In this study in guinea pigs, the tissue reaction to cholesterol crystals was investigated by using a Teflon cage model100 that facilitated the intact surgical retrieval of the cholesterol crystals with the surrounding host tissue after the experimentation. The study was to answer the question as to whether aggregates of cholesterol crystals would induce and sustain a granulomatous tissue reaction in guinea pigs. Pure cholesterol crystals, prepared to a mushy form,
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were placed in Teflon cages that were implanted subcutaneously in guinea pigs. The cage contents were retrieved after 2, 4, and 32 weeks of implantation and processed for light and correlative transmission electron microscopy. The cages revealed delicate soft connective tissue that grew in through perforations on the cage wall. The crystals were densely surrounded by numerous macrophages and multinucleated giant cells (Figures 16 and 17), forming a well circumscribed area of tissue reaction. The cells, [Figure 16. Photomicrograph A, of guinea pig tissue reaction to aggregates of cholesterol crystals after an observation period of 32 weeks. The rectangular demarcated areas in A, B, and C, are magnified in B, C, and D, respectively. Note that rhomboid clefts left by cholesterol crystals (CC) surrounded by giant cells (GC) and numerous mononuclear cells (arrowheads in D). AT = adipose tissue; CT = connective tissue. Original magnifications: A 10, B 21, C 82, and D 220.] [Figure 17. Ultrastructure of guinea pig tissue reaction to cholesterol crystals (CC) in cages that were removed 32 weeks after implantation. Note a large multinucleated (N) giant cell (GC) and numerous macrophages (MA) around the crystals. Original magnification: 4,600.] however, were unable to eliminate the crystals during an observation period of 8 months. The congregation of macrophages and giant cells around cholesterol crystals in the absence of other inflammatory cells such as neutrophils, lymphocytes, and plasma cells suggests that the crystals induced a typical foreign body reaction.101-103 Whereas most of the macrophages may be freshly recruited blood monocyte population,104,105 the giant cells are of local origin. Radioactive labeling studies106,107 have conclusively shown that giant cells are monocyte derivatives formed by fusion of macrophages. Investigations on the cytogenesis of multinucleate giant cells around cholesterol crystals in subcutaneous implants suggest that they are formed by a process of "circumfusion"93 of macrophages around individual crystals. Once formed, the giant cells can also enlarge in size by synchronous division of their nuclei.108 Figure 16. Photomicrograph A, of guinea pig tissue reaction to aggregates of cholesterol crystals after an observation period of 32 weeks. The rectangular demarcated areas in A, B, and C, are magnified in B, C, and D, respectively. Note that rhomboid clefts left by cholesterol crystals (CC) surrounded by giant cells (GC) and numerous mononuclear cells (arrowheads in D). AT = adipose tissue; CT = connective tissue. Original magnifications: A 10, B 21, C 82, and D 220. Reproduced with permission from Nair.81 Figure 17. Ultrastructure of guinea pig tissue reaction to cholesterol crystals (CC) in cages that were removed 32 weeks after implantation. Note a large multinucleated (N) giant cell (GC) and numerous macrophages (MA) around the crystals. Original magnification: 4,600. Reproduced with permission from Nair.81 BODY CELLS CANNOT ELIMINATE CHOLESTEROL CRYSTALS Tissue degradation of cholesterol crystals, if any, should happen via the phagocytic and/or biochemical pathways. Macrophages are efficient phagocytes109 capable of
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ingesting and killing microorganisms, scavenging dead cells and necrotic tissue, and removing small foreign particles.110 Cells belonging to the mononuclear phagocytic system111 are involved in lipid uptake.112 Macrophages have been shown to internalize cholesterol crystals in vitro.93,112 Fine suspensions of cholesterol crystals administered intraperitoneally in rats were found in sternal lymph node macrophages.113,114 In this apparently-phagocytic intake of particulate cholesterol, the size of the crystals must have been appropriately small for the macrophages to ingest them. However, when macrophages encounter larger foreign particles,101,103 or cholesterol crystals,92-96,99 they form multinucleate giant cells. The presence of giant cells in cholesterol granuloma is a clear sign of the large size of the crystals in relation to macrophages. However, the giant cells are poor phagocytes,107,115 their phagocytic efficiency declining with increasing size of the cells.116,117 The degradative power of multinucleate giant cells is mainly vested in their ability to resorb intrinsic and extrinsic substrates. Resorption is a highly specialized cellular activity in which the destruction of suitable substrates occurs extracellularly at the specialized cell/substrate interface by biochemical means. In order to degrade tissue deposits of cholesterol crystals, the surrounding cells should have the ability to attack the crystals chemically so as to disperse them into the surrounding tissue fluid or to make them accessible to the cells themselves. Cholesterol crystals are highly hydrophobic, and their dispersal would necessitate making them hydrophilic and "soluble" in an aqueous medium.92 The granulomatous and sclerogenic effects of cholesterol crystals can be prevented by the incorporation of phospholipids into subcutaneous implants of cholesterol.96 This beneficial effect of phospholipids has been attributed to their "detergent" property and their role as donors of polyunsaturated fatty acids during esterification of the cholesterol.92,97 The giant cells and macrophages are known to esterify and mobilize cholesterol in a lipid droplet form.93 Macrophages can convert particulate cholesterol into a soluble form by incorporating it into a lipoprotein vehicle,112,118 so that the cholesterol can be readily esterified or added into the lipoprotein pool in circulation. These cell biologic findings obviously support the possible ability of macrophages and giant cells to degrade particulate cholesterol. But they are not consistent with the histopathologic observation of spontaneous10,26,28 and experimentally-induced92-96,99 cholesterol granulomas. The characteristic feature of such lesions is the accumulation of macrophages and giant cells around the cholesterol clefts and their persistence for long periods of time. Therefore, it is to be assumed that the macrophages and the multinucleate giant cells that congregate around cholesterol crystals are unable to destroy the crystals in a way beneficial to the host.80 Therefore, massive accumulation of cholesterol crystals in apical periodontitis is clinically significant. The macrophages and giant cells that surround cholesterol crystals are not only unable to degrade the crystalline cholesterol but are major sources of apical inflammatory and bone resorptive mediators. Bone-resorbing activity of cholesterol-exposed macrophages due to enhanced expression of interleukin-1 has been experimentally shown.119 Based on these considerations, it was concluded in a long-term longitudinal follow-up of a case that "the presence of vast numbers of cholesterol crystals . . . would be sufficient to sustain the lesion indefinitely."26 The experimental results and other evidence presented from the literature substantiate that assumption. FOREIGN BODIES
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Foreign materials trapped in periapical tissues can cause pathologic tissue reaction. Particles of root-filling materials, other endodontic materials,101,120 and portions of foods121 can reach the periapical tissues and initiate a foreign body reaction that may be associated with periapical radiolucency.101 The most widely used solid root canal filling material is prepared from (transpolyisoprene), the coagulated exudate from Plaquium gutta tree of Asia or from similar latex derived from the Mimisops globsa tree of South America.122 Cones are composed of about 20% gutta-percha, 60% to 75% zinc oxide, and varying amounts of metal sulfates for radioopacity, waxes, and coloring agents. Based on implantation experiments in animals, cones are considered to be biocompatible and well tolerated by human tissues.123-125 This view has not been consistent with the observation that the presence of extruded gutta-percha is associated with delayed healing of the periapex.76,77,101,126,127 In general, bulk form of sterile materials with smooth surfaces placed within bone or soft tissue evoke a fibrous tissue encapsulation, while particulate materials induce a foreign body and chronic inflammatory reaction.128-132 Apart from the particle size, the chemical composition of gutta-percha is also of significance. Leaching zinc oxide from gutta-percha cones has been shown to be cytotoxic in vitro,133,134 tissue irritating in vivo, and associated with adjacent inflammatory reaction.103,135 Tissue response to gutta-percha was studied103 using subcutaneously implanted Teflon cages in which the gutta-percha evoked two distinct types of tissue reaction. Large pieces of gutta-percha were encapsulated by collagen and the surrounding tissue was free of inflammation (Figure 18). But, fine particles of gutta-percha induced an intense, localized tissue response (Figure 19), characterized by the presence of macrophages and giant cells. The [Figure 18. Guinea pig tissue reaction to gutta-percha (GP) by 1 month after subcutaneous implantation A. Large pieces of gutta-percha are well encapsulated by collagen fibers that run parallel to the surface of the gutta-percha particle. The interface of the gutta-percha particle and the host tissue (arrow) is magnified in stages in B, and C. The gap between the implant and the collagen capsule is artifactual. Note the noninflamed, healthy soft delicate connective tissue. Original magnifications: A 17, B 80, C 200.] [Figure 19. Disintegrated gutta-percha as potential for maintaining posttreatment apical periodontitis. As clusters of fine particles (A, B,) they induce intense circumscribed tissue reaction (TR) around. Note that the fine particles of gutta-percha (* in C, GP in D) are surrounded by numerous mononuclear cells (MNC). Original magnifications: A 30, B 80, C 200, D 750.] [Figure 20. Two longitudinal radiographs (inset and A) of a root-filled and periapically affected left central maxillary incisor of a 54-year-old man. The first radiograph (inset) taken immediately after root filling in 1977 shows a small excess filling that protrudes into the periapex (arrowhead in inset). Note the excess filling has disappeared in the radiograph taken 10 years later (arrowhead in A) and shortly before surgery was performed. The apical block biopsy removed by surgery does not show any excess filling, as is evident from the macrophotograph of the decalcified and axially subdivided piece of the biopsy, B. RF = root filling; D = dentine; GR = granuloma. Original magnification: B 10.]
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accumulation of macrophages in conjunction with the fine particles of gutta-percha is significant for the clinically observed impairment in the healing of apical periodontitis, when teeth are root filled with excess of gutta-percha. Pieces of guttapercha cones in periapical tissue can gradually fragment into fine particles that in turn can induce a typical foreign body reaction101-103 and activate macrophages.136 The latter release a battery of intercellular mediators that include proinflammatory cytokines and modulators that are involved in bone resorption.137-140 In addition, commercial gutta-percha cones may become contaminated with tissueirritating substances that can initiate a foreign body reaction at the periapex. In a follow-up study of nine asymptomatic persistent apical periodontitis lesions that were removed as surgical block biopsies and analyzed by correlative light and transmission electron microscopy, one biopsy (Figure 20) revealed the involvement of talc contaminated gutta-percha.101 The radiographic lesion persisted asymptomatically and grew in size during a decade of posttreatment follow-up. The lesion was characterized by the presence of vast numbers of multinucleate giant cells with birefringent inclusion bodies (Figure 21). In transmission electron microscope, the birefringent bodies were found to be highly electron dense (Figure 22). Energy dispersive X-ray microanalysis of the [Figure 21. A bright-field photomicrograph of a plastic-embedded semithin (2 mm thick) section of the apical area shown in Figure 20 B. Note the large apical periodontitis lesion (AP) A. The same field when viewed in polarized lights B. Note the birefringent bodies distributed throughout the lesion B. The apical foramen is magnified in C, and the dark arrow-headed cells in C, are further enlarged in D. Note the birefringence (BB) emerging from slit-like inclusion bodies in multinucleated (N) giant cells. B = bone; D = dentine. Original magnifications: A, B 23; C 66; D 300.] [Figure 22. Low-magnification transmission electron micrograph showing the profiles of several giant cells within the apical periodontitis shown in Figures 20 and 21. Note the presence of many slit-like inclusion bodies (BB1 to BB6), which contain a highly electron-dense material. This material may remain intact within the inclusion body or may be pushed away from its original site (BB2) or may appear disintegrated (BB3 and BB4) by the tissue processing. Note the lines of artifacts AL, which are created by portions of the electron-dense material having been carried away by the knife edge, leaving tracts behind. Original magnification: 1,880.] inclusion bodies using scanning transmission electron microscopy (STEM) revealed the presence of magnesium and silicon (Figure 23). These elements are presumably the remnants of talc-contaminated gutta-percha that protruded into the periapex and had been resorbed during the follow-up period. Figure 18. Guinea pig tissue reaction to gutta-percha (GP) by 1 month after subcutaneous implantation A. Large pieces of gutta-percha are well encapsulated by collagen fibers that run parallel to the surface of the gutta-percha particle. The interface of the gutta-percha particle and the host tissue (arrow) is magnified in stages in B, and C. The gap between the implant and the collagen capsule is artifactual. Note the noninflamed, healthy soft delicate connective tissue. Original magnifications: A 17, B 80, C 200. Reproduced with
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permission from Nair.163 Figure 19. Disintegrated gutta-percha as potential for maintaining posttreatment apical periodontitis. As clusters of fine particles (A, B,) they induce intense circumscribed tissue reaction (TR) around. Note that the fine particles of guttapercha (* in C, GP in D) are surrounded by numerous mononuclear cells (MNC). Original magnifications: A 30, B 80, C 200, D 750. From P.N.R. Nair, Pathobiology of the periapex. In: S. Cohen and R.C. Burns, editors, Pathways of the pulp, 8th ed., St Louis, 2002 Mosby. Figure 20. Two longitudinal radiographs (inset and A) of a root-filled and periapically affected left central maxillary incisor of a 54-year-old man. The first radiograph (inset) taken immediately after root filling in 1977 shows a small excess filling that protrudes into the periapex (arrowhead in inset). Note the excess filling has disappeared in the radiograph taken 10 years later (arrowhead in A) and shortly before surgery was performed. The apical block biopsy removed by surgery does not show any excess filling, as is evident from the macrophotograph of the decalcified and axially subdivided piece of the biopsy, B. RF = root filling; D = dentine; GR = granuloma. Original magnification: B 10. Reproduced with permission from Nair.101 Figure 21. A bright-field photomicrograph of a plastic-embedded semithin (2 mm thick) section of the apical area shown in Figure 20 B. Note the large apical periodontitis lesion (AP) A. The same field when viewed in polarized lights B. Note the birefringent bodies distributed throughout the lesion B. The apical foramen is magnified in C, and the dark arrow-headed cells in C, are further enlarged in D. Note the birefringence (BB) emerging from slit-like inclusion bodies in multinucleated (N) giant cells. B = bone; D = dentine. Original magnifications: A, B 23; C 66; D 300. From Nair, Pathology of apical periodontitis. In: D. Orstavik and T.R. PittFord, editors, Essential Endodontology, Oxford, 1998, Blackwell. Figure 22. Low-magnification transmission electron micrograph showing the profiles of several giant cells within the apical periodontitis shown in Figures 20 and 21. Note the presence of many slit-like inclusion bodies (BB1 to BB6), which contain a highly electron-dense material. This material may remain intact within the inclusion body or may be pushed away from its original site (BB2) or may appear disintegrated (BB3 and BB4) by the tissue processing. Note the lines of artifacts AL, which are created by portions of the electron-dense material having been carried away by the knife edge, leaving tracts behind. Original magnification: 1,880. From P.N.R. Nair et al.27 Reproduced with permission from Nair.101 Figure 23. High-magnification transmission electron micrograph C, of the intact birefringent body labeled BB1 in Figure 22. Note the distinct delimiting membrane around the birefringent body (BB). Energy-dispersive X-ray microanalysis of the electron-dense material done in scanning transmission electron microscope (STEM: done at the point where the two hairlines perpendicular to each other cross in the left inset) revealed the presence of silicon (Si), magnesium (Mg), and lead (Pb) in A, whereas another site in the neighboring cytoplasm of the same giant cell (arrowhead in right inset) does not show the presence of Si and Mg B. Lead and uranium (U) are used for section contrasting, and emission in copper (Cu) is from the section-supporting grid
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made of copper. Original magnification 11,000; insets 3,300. Reproduced with permission from Nair.101 ORAL PULSE GRANULOMA It denotes a foreign body reaction to particles of vegetable foods, particularly leguminous seeds such as peas, beans, and lentils (pulses) that get lodged in the oral tissues. The lesions are also referred to as the giant cell hyaline angiopathy,141,142 vegetable granuloma,143 and [Figure 23. High-magnification transmission electron micrograph C, of the intact birefringent body labeled BB1 in Figure 22. Note the distinct delimiting membrane around the birefringent body (BB). Energy-dispersive X-ray microanalysis of the electron-dense material done in scanning transmission electron microscope (STEM: done at the point where the two hairlines perpendicular to each other cross in the left inset) revealed the presence of silicon (Si), magnesium (Mg), and lead (Pb) in A, whereas another site in the neighboring cytoplasm of the same giant cell (arrowhead in right inset) does not show the presence of Si and Mg B. Lead and uranium (U) are used for section contrasting, and emission in copper (Cu) is from the sectionsupporting grid made of copper. Original magnification 11,000; insets 3,300.] food-induced granuloma.144 Pulse granuloma has been reported in lungs,145 stomach walls, and peritoneal cavities.146 Experimental lesions have been induced in animals by intratracheal, intraperitoneal, and submucous introduction of leguminous seeds.147,148 Periapical pulse granulomas are associated with teeth grossly damaged by caries and with the history of endodontic therapy.121,149 Pulse granuloma is characterized by the presence of intensely iodine and periodic acidSchiff-positive hyaline rings/bodies surrounded by giant cells and inflammatory cells.121,148-150 The cellulose in plants has been suggested to be the granuloma-inducing agent.147 However, leguminous seeds are the most frequently involved vegetable in such granulomatous lesions. This indicates that other components in pulses, such as antigenic proteins and mitogenic phytohemagglutinins, may also be involved in the pathologic tissue response.147 The pulse granulomas are clinically relevant because particles of vegetable foods can reach the periapical tissues via root canals of teeth exposed to the oral cavity by trauma, caries, or endodontic procedures.121 However, the incidence of pulse-induced apical periodontitis may be low, as only two such cases have been reported in the literature.121,150 CELLULOSE GRANULOMA Cellulose granuloma is pathologic tissue reaction to particles of predominantly cellulose-containing materials that are used in endodontic practice.151-154 Endodontic paper points are utilized for microbial sampling and drying of root canals. Medicated cotton wool has been used in root canals as well. Particles of these thermo-sterilized materials can easily dislodge or get pushed into the periapical tissue154 so as to induce a foreign body reaction at the periapex. Presence of cellulose fibers in periapical biopsies with a history of previous endodontic treatment has been reported.151-153 The overall incidence of cellulose-induced apical periodontitis is unknown. This may be partly due to the inconspicuous nature of cellulose material in periapical biopsies and the difficulty to identify them without the application of special stains or techniques. In two investigations in which 13 biopsies of posttreatment apical periodontitis were histologically examined, all displayed material consistent with cellulose fibers.151,152
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The endodontic paper points and cotton wool consists of cellulose, which is neither digested by humans nor degraded by the body cells. They remain in tissues for long periods of time153 and evoke a foreign body reaction around them. The particles, when viewed in polarized light, reveal birefringence due to the regular structural arrangement of the molecules within cellulose.151 Paper points infected with intraradicular micro-organisms can project through the apical foramen into the periapical tissue (Figure 24) and allow a biofilm to grow around the paper point (Figure 24). Figure 24. A massive paper-point granuloma affecting a root-canal-treated human tooth A. The demarcated area in B, is magnified in C, and that in the same is further magnified in D. Note the tip of the paper point (FB) projecting into the apical periodontitis lesion and the bacterial plaque (BP) adhering to the surface of the paper point. RT = root tip; EP = epithelium; PC = plant cell. Original magnifications: A 20, B 40, C 60, D 150. From P.N.R. Nair, Pathobiology of the periapex. In: S. Cohen and R.C. Burns, editors, Pathways of the pulp, 8th edition, St Louis, 2002 Mosby. OTHER FOREIGN MATERIALS Endodontic sealer cements, amalgam, and calcium salts derived from periapically extruded calcium hydroxide also occur in periapical tissues. In a histologic and X-ray microanalytic investigation of 29 apical biopsies, 31% of the specimens were found to contain materials compatible with amalgam and endodontic sealer components.120 However, an etiologic significance of these materials has not been conclusively shown by experiments. It is possible that these materials might have been coexisting with unidentified etiologic agents such as the presence of intraradicular infection in those cases. [Figure 24. A massive paper-point granuloma affecting a root-canal-treated human tooth A. The demarcated area in B, is magnified in C, and that in the same is further magnified in D. Note the tip of the paper point (FB) projecting into the apical periodontitis lesion and the bacterial plaque (BP) adhering to the surface of the paper point. RT = root tip; EP = epithelium; PC = plant cell. Original magnifications: A 20, B 40, C 60, D 150.] Scar Tissue healing There is evidence10,52,79,155 that unresolved periapical radiolucencies may occasionally be due to healing of the lesion by scar tissue (Figure 25) that may be misdiagnosed as a radiographic sign of failed endodontic treatment. Certain deductions can be made from the [Figure 25. Periapical scar (SC) of a root canal (RC)-treated tooth after 5-year followup and surgery. The rectangular demarcated areas in B-D, are magnified in C-E, respectively. The scar tissue reveals bundles of collagen fibers (CO), blood vessels (BV), and erythrocytes due to hemorrhage. Infiltrating inflammatory cells are notably absent. Original magnifications: A 14, B 35, C 90, D 340, E 560.] data available on normal healing and guided regeneration of the marginal periodontium. Several cell populations participate in the periodontal healing process. The pattern of healing depends on several factors, two of which are decisive. They are
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the regeneration potential and the speed with which the tissue cells bordering the defect react.156-159 A periapical scar probably develops because precursors of soft connective tissue colonize both the root tip and periapical tissue; this may occur before the appropriate cells, which have the potential to restore various structural components of the apical periodontium, are able to do so.79 Figure 25. Periapical scar (SC) of a root canal (RC)-treated tooth after 5-year follow-up and surgery. The rectangular demarcated areas in B-D, are magnified in C-E, respectively. The scar tissue reveals bundles of collagen fibers (CO), blood vessels (BV), and erythrocytes due to hemorrhage. Infiltrating inflammatory cells are notably absent. Original magnifications: A 14, B 35, C 90, D 340, E 560. Modified from Nair et al.79 Concluding Remarks The presence of an intraradicular infection is the essential cause of primary apical periodontitis and the major cause of persistent apical radiolucencies.160,161 This means that microbial infection is not the only etiologic agent of apical radiolucencies persisting posttreatment. The nonmicrobial factors, discussed in this chapter, include (1) true cystic lesions, (2) extruded root canal filling or other exogenous materials that cause a foreign body reaction; (3) accumulation of endogenous cholesterol crystals that irritate periapical tissues; and (4) scar tissue healing of the lesion. Although true cysts, foreign body reaction, and scar tissue healing are of rare occurrence, they are of clinical significance. Most of the cysts, particularly larger cysts, may not be amenable to root canal treatment alone. Whereas smaller pocket cysts are likely to heal after root canal treatment, very large pocket cysts and most of the true cysts may not heal. But there are no individual statistics on them. Cysts, nevertheless, represent only a small fraction of persistent apical radiolucencies. The fact that persistent apical radiolucencies cannot be differentially diagnosed based on etiology is of no clinical significance but of academic interest only. This is because it is not guaranteed that root canal re-treatment of an otherwise well-treated tooth will result in the removal of intraradicular microbes located in the apical canal system, which is the single most important cause of persisting radiolucencies. Furthermore, apical radiolucencies persisting because of extraradicular factors discussed in this chapter, such as foreign body reaction, including those due to cholesterol crystals, cystic condition, and scar tissue are beyond root canal system and cannot be managed by root canal re-treatment. Therefore, with cases of asymptomatic, persistent radiolucencies, clinicians should consider the necessity of removing the extraradicular factors by an apical surgery,162 in order to improve the long-term result of treatment. An apical surgery enables to remove the extraradicular agents that sustain the radiolucency posttreatment and also allows a retrograde access to any infection in the apical portion of the root canal system that can also be removed or sealed within the canal by a retrograde root-end filling.163 References
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1. Nair PNR. Non-microbial etiology: periapical cysts sustain post-treatment apical periodontitis. Endod Topics 2003;6:114-34. 2. Kakehashi S, Stanley HR, Fitzgerald RJ. The effects of surgical exposures of dental pulps in germ-free and conventional laboratory rats. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1965;20:340-9. 3. Sundqvist G. Bacteriological studies of necrotic dental pulps [Dr. Odont. Thesis]. Umea, Sweden: University of Umea; 1976. 4. Nair PNR. Light and electron microscopic studies of root canal flora and periapical lesions. J Endod 1987;13:29-39. 5. Costerton W, Veeh R, Shirtliff M, et al. The application of biofilm science to the study and control of chronic bacterial infections. J Clin Invest 2003;112:1466-77. 6. Taylor E. Dorland's illustrated medical dictionary. 27th ed. Philadelphia: W.B. Saunders Co.; 1988. p. 324. 7. Shear M. Cysts of the oral regions. 3rd ed. Oxford: Wright; 1992. pp. 136-70. 8. Nair PNR. New perspectives on radicular cysts: do they heal? Int Endod J 1998;31:155-60. 9. Killey HC, Kay LW, Seward GR. Benign cystic lesions of the jaws, their diagnosis and treatment. 3rd ed. Edinburgh and London: Churchill Livingston; 1977. 10. Bhaskar SN. Periapical lesiontypes, incidence and clinical features. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1966;21:657-71. 11. Mortensen H, Winther JE, Birn H. Periapical granulomas and cysts. Scand J Dent Res 1970;78:241-50. 12. Borg G, Persson G, Thilander H. A study of odontogenic cysts with special reference to comparisons between keratinizing and nonkeratinizing cysts. Swed Dent J 1974;67:311-25. 13. Huumonen S, Orstavik D. Radiological aspects of apical periodontitis. Endod Topics 2002;1:3-25. 14. Sewerin IP. Radiographic examination. In: Bergenholtz G, Horsted-Bindslav P, and Reit C, editors. Textbook of endodontology. Oxford: Blackwell Munksgaard; 2003. pp. 215-35. 15. White SC, Sapp JP, Seto BG, et al. Absence of radiometric differentiation between periapical cyst and granulomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1994;78:650-4. 16. Shrout M, Hall J, Hildeblot C. Differentiation of periapical granulomas and radicular cysts by digital radiometric analysis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1993;76:356-61.
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17. Priebe WA, Lazansky JP, Wuehrmann AH. The value of the roentgenographic film in the differential diagnosis of periapical lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1954;7:979-83. 18. Baumann L, Rossman SR. Clinical, roentgenologic and histologic findings in teeth with apical radiolucent areas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1956;9:1330-6. 19. Wais FT. Significance of findings following biopsy and histologic study of 100 periapical lesions. Oral Surg Ora Med Oral Pathol Oral Radiol Endod 1958;11:650-3. 20. Linenberg WB, Waldron CA, DeLaune GF. A clinical roentgenographic and histopathologic evaluation of periapical lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1964;17:467-72. 21. Lalonde ER, Luebke RG. The frequency and distribution of periapical cysts and granulomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1968;25:861-8. 22. Ricucci D, Mannocci F, Pitt Ford TR. A study of periapical lesions correlating the presence of a radioopaque lamina with histological findings. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;101:389-94. 23. Trope M, Pettigrew J, Petras J, et al. Differentiation of radicular cysts and granulomas using computerized tomography. Endod Dent Traumatol 1989;5:69-72. 24. Cotti E, Campisi G, Garau V, et al. A new technique for the study of periapical bone lesions: ultrasound real time imaging. Int Endod J 2002;35:148-52. 25. Cotti E, Campisi G, Garau V, et al. Ultrasound real-time imaging in the differential diagnosis of periapical lesions. Int Endod J 2003;36:556-63. 26. Nair PNR, Sjogren U, Schumacher E, et al. Radicular cyst affecting a root-filled human tooth: a long-term post-treatment follow-up. Int Endod J 1993;26:225-33. 27. Malassez ML. Sur l'existence de masses epitheliales dans le ligament alveolodentaire chez l'homme adulte et a l'etat normal. Comp Rend Soc Biol 1884;36:241-4. 28. Thoma KH. A histo-pathological study of the dental granuloma and diseased root apex. J Natl Dent Assoc 1917;4:1075-90. 29. McConnell G. The histo-pathology of dental granulomas. J Natl Dent Assoc 1921;8:390-8. 30. Freeman N. Histopathological investigation of dental granuloma. J Dent Res 1931;11:176-200. 31. Sonnabend E, Oh C-S. Zur Frage des Epithels im apikalen Granulationsgewebe (Granulom) menschlicher Zahne. Dtsch Zahnarztl Z 1966;21:627-43.
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32. Seltzer S, Soltanoff W, Bender IB. Epithelial proliferation in periapical lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1969;27:111-21. 33. Summers L. The incidence of epithelium in periapical granulomas and the mechanism of cavitation in apical dental cysts in man. Arch Oral Biol 1974;19:117780. 34. Summers L, Papadimitriou J. The nature of epithelial proliferation in apical granulomas. J Oral Pathol 1975;4:324-9. 35. Langeland MA, Block RM, Grossman LI. A histopathologic and histobacteriologic study of 35 periapical endodontic surgical specimens. J Endod 1977;3:8-23. 36. Yanagisawa W. Pathologic study of periapical lesions. I. Periapical granulomas: clinical, histologic and immunohistopathologic studies. J Oral Pathol 1980;9:288300. 37. Nair PNR, Schroeder HE. Epithelial attachment at diseased human tooth-apex. J Periodont Res 1985;20:293-300. 38. Nair PNR, Schmid-Meier E. An apical granuloma with epithelial integument. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1986;62:698-703. 39. Turner J. Dental cysts. Brit Dent J 1898;19:711-34. 40. Kronfeld R. Histopathology of the teeth and their surrounding structures. Philadelphia: Lea & Febiger; 1939. pp. 210-11. 41. Stafne E, Millhon J. Periodontal cysts. J Oral Surg 1945;3:102-11. 42. Gorlin R. Potentialities of oral epithelium manifest by mandibular dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1957;10:271-84. 43. Shear M. Secretory epithelium in the lining of dental cysts. J Dent Assoc South Africa 1960;15:117-22. 44. Marsland E, Browne R. Two odontogenic cysts, partially lined with ciliated epithelium. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1965;19:502-7. 45. Fujiwara K, Watanabe T. Mucous producing cells and ciliated epithelial cells in mandibular radicular cysts: an electron microscopic study. J Oral Maxillofac Surg 1988;46:149-51. 46. Nair PNR, Pajarola G, Luder HU. Ciliated epithelium lined radicular cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:485-93. 47. Berry G. Dental caries in paranasal sinus infections. Arch Otolaryngol 1929;8:698-706. 48. Stevensson W. Chronic maxillary sinusitis. Arch Otolaryngol 1931;13:505-31.
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