Experimental Commonly

oral foreign body reactions

employed

Carol hf. Stewart,

dental

materials

DDS, MS,” and Ronald E. Watson, DDS, IUAE,~ Gainesville,

Fla.

Foreign bodies and tissue reactions to foreign materials are commonly encountered in the oral cavity. The more common lesions include apical deposition of endodontic materials, mucosal amalgam and graphite tattoos, myospherulosis, oil granulomas, and traumatically introduced dental materials and instruments. Since many foreign materials are unidentifiable histologically, commonly used dental materials were experimentally implanted subcutaneously in rats to assess local host responses and characterize the nature of these materials microscopically. The histologic characteristics of these foreign body reactions are detailed herein. The implanted materials corresponded to reactions seen in human subjects. (ORAL

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umerous foreign substances have been identified and described in the tissues of the oral cavity. Dental materials, instrument and tooth fragments are responsible for a significant percent of oral foreign body reactions.lm4 Silver amalgam is most often identified in the oral soft tissues being deposited during placement or removal of amalgam restorations.5* 6 Suture material, dental impression compounds, and oil base materials are occasionally observed in mucosal tissues, bone or the maxillary sinus because of iatrogenic deposition.‘.’ Starch granules from rubber gloves have been reported as producing foreign body granulomas, usually after tooth extraction; the lesions manifest clinically as submucosal nodules. lo, ’ ’ Endodontic materials are also commonly found in soft tissue, bone, the maxillary sinus, and the inferior alveolar foramen because of filling beyond the apical foramen, and these materials are often noted during histologic examination.iZ-‘8 Particulate materials are seen in routine microscopic sections but their exact nature is often equivocal. Studies have been undertaken to definitely identify some of these particulate materials by means of ultrastructural techniques.‘” Two common particulate materials, amalgam and graphite, resemble each other clinically, yet can best be differentiated histotogically by employing an ammonium sulfide staining reaction; amalgam will exhibit birefringence ‘Oral Diagnostic Medicme Division. bOral gency 7-14-19428

Scicnccs. Lniversity

:Zshistlint of Florida

Profwor; College

Director. of Dentistry.

Oral

Diagnostic Scicnccs. Associate Professor; Director, EmerDental Clinic. University of Florida College of Dentistry.

under polarized light whereas graphite will remain unchanged.20 Assorted foreign bodies found in the jaw are often visualized radiographically. One survey of 1000 radiographs reported the presence of 28 different foreign bodies. These included such objects as broken instruments, impression material, gutta-percha, tooth fragments, and common household items.2’ Oral pathology services must often report on the presence of these unusual, oftentimes unidentifiable foreign materials with the causative agent being described only as a foreign body, not otherwise specified. Our purpose in pursuing this study was to evaluate the histologic appearance of foreign materials and the host responses to them with the use of an animal model. In another report, we evaluated the response to common foodstuffs. This article will focus on reactions to commonly used dental compounds. MATERIAL

AND METHODS

The oral surgical pathology files at the University of Florida were reviewed to select the more common foreign body reactions in oral tissues among human subjects. These specimens were represented by postendodontic apical lesions, intraosseous lesions unrelated to endodontic procedures, soft tissue mucosal swellings, and discolorations. On the basis of the aforementioned survey of foreign bodies in human subjects, we elected to implant similar selected dental materials subcutaneously in rats to document host reactions and assess the morphologic nature of these substances histologically. Four Sprague-Dawley male rats weighing 250 to 300 gm were anesthetized with pentobarbital sodium 713

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Fig. 1. Implanted dental materials.A, Zinc phosphatecement. (Hematoxylin and eosinstain. Original magnification,X400.) B, Zinc phosphatecement.(Polarization. Original magnification,X100.) C, N2 paste. (Hematoxylin and eosinstain. Original magnification,x400.) D, Endodonticsealer.(Hematoxylin andeosin stain. Original magnification, x400.) E, Handpieceoil. (Hematoxylin and eosinstain. Original magnification, XlOO.)F, Copal varnish. (Hematoxylin and eosinstain. Original magnification, X400.)

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Fig. 2. Implanted dental materials.A, Compositeresin. (Hematoxylin and eosinstain. Original magnification, X400.) B, Compositeresin. (Polarization. Original magnification, X100.) C, Glassionomercement. (Hematoxylin and eosinstain. Original magnification, X100.) D, Glassionomercement.(Hematoxylin and eosinstain. Original magnification, x400.) E, Graphite. (Hematoxylin and eosinstain. Original magnification, X100.)

(40 mg/kg intraperitoneally). Hair was removed with clippers and the skin was swabbed with Betadine (Purdue Frederick Company, Norwalk, Connecticut) solution. Seven separate incisions, 5 mm long, and two injection sites were made in the dorsal skin with subcutaneous implantation of the following dental restorative materials: zinc phosphate cement (L.D. Caulk Company Division, Dentsply International, Milford, Delaware), N2 endodontic paste, Grossman’s endodontic sealer (Sultan Chemists, Englewood, New Jersey), handpiece oil (Midwest, Division of Sybron Corp., Des Plaines, Illinois), Copalite (Cooley & Cooley Ltd., Houston, Texas), self-curing composite resin (Concise, 3M Co. Dental Products Division, St. Paul, Minnesota), glass ionomer cement (Ketac, ESPE-Premier Sales Corporation, Norristown, Pennsylvania), lead pencil graphite, and dental amalgam (Tytin, S.S. White Products International,

Philadelphia, Pennsylvania). By means of aseptic technique, the experimental materials were mixed according to the manufacturer’s directions. The formula for the N2 paste consisted of zinc oxide powder (74%), titanium dioxide (2.0%), bismuth salts (17%), paraformaldehyde (7.0%): and liquid eugenol. The materials were allowed to set for 30 minutes, then pulverized before being implanted. Portions from 0.3 to 0.5 cm in diameter of amalgam, zinc phosphate cement, endodontic sealer, endodontic paste, composite resin, glass ionomer cement, and graphite from a pencil were implanted into separate sites. By means of a syringe, 0.2 ml of copal varnish and handpiece oil were separately injected subcutaneously. The surgical implant sites were subsequently closed with 4-O gut suture. The animals were maintained on standard chow and water ad libitum for 6 weeks. All animals were killed by a lethal dose of intraperitoneal pento-

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barbital. At autopsy, blocks of epidermis with subcutaneous tissues containing implanted materials were placed in neutral buffered formalin with subsequent routine histopathologic processing. Paraffin sections were hydrated and stained with hematoxylin and eosin. The foreign materials were assessed by routine light microscopy as well as polarization microscopy. RESULTS

Table I summarizes the findings from the implantation studies. Three of the implanted dental materials, namely zinc phosphate cement, N2 paste, and endodontic sealer, induced similar host responses. Alternatively, the morphologic characteristics of the material particles were dissimilar. Zinc phosphate cement was characterized by rounded yellow crystals, 10 to 50 pm in diameter, that displayed rose and yellow birefringence under polarized light (Fig. 1, A and B). The tissue response consisted of a sparse mononuclear cell infiltrate, consisting primarily of histiocytes and an occasional multinucleated giant cell. Implanted N2 paste consisted of two distinct components. Aggregates of basophilic amorphous material were distributed throughout the lesion. The second component consisted of large dense clumbs of minute yellow-brown punctate granules, each less than 0.2 pm in diameter. These particles were not refractile with the use of polarization lenses. The host response consisted of a sparse mononuclear cell infiltrate of lymphocytes, histiocytes, and an occasional giant cell (Fig. 1, C). The endodontic sealer consisted of rhomboid and rectangular-shaped yellow crystals on hematoxylin and eosin stain that exhibited rose and yellow birefringence under polarized light. The crystals were located in a background of basophilic amorphous material similar to that seen in the N2 paste. Fibroblasts were organized around the material with an inflammatory infiltrate composed of histiocytes, plasma cells, lymphocytes, and an occasional multinucleated giant cell. No acute reaction was observed (Fig. 1, D) . Implanted handpiece oil was characterized by round and oval vacuolated spaces, varying in size from 50 to 300 Frn; histiocytes were compressed around the empty vacuoles. No significant multinucleated giant cell formation was observed (Fig. 1, E). Copal varnish was very similar histologically to handpiece oil, characterized by the formation of large vacuoles with a mild inflammatory cell reaction consisting of lymnhnmter ?rs-l h;ct;nrvtz=c No multinucleated giant ,“.“““‘J ‘%.. cells ‘were present (Fig. 1, fl. Composite resin as observed on hematoxylin and eosin stain was found to be represented by “glassy” yellow polymorphic crystals, sometimes in the shape

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of rings, a polygonal structure, or a white laminated band. The resin crystals were markedly birefringent, white in color. The infiltrate consisted of eosinophils as well as histiocytes, and a significant number of multinucleated giant cells could be identified (Fig. 2, A and B). Glass ionomer cement was similar histologically to composite, but demonstrated a distinct crinkled rather than a glassy appearance. Furthermore, these crystals failed to show birefringence under polarizing lenses. The inflammatory infiltrate consisted of histiocytes with minimal multinucleated giant cells (Fig. 3, C and D). Examination of the graphite implant revealed black particulate matter in angular clumps. No discrete particle shape could be discerned and the material was nonrefractile. The inflammatory reaction was very mild with few histiocytes; no multinucleated giant cells were observed (Fig. 2, E). Amalgam presented as a black-amorphous conglomerate with brown particles oriented along collagen and reticulin fibers. The particles were also observed in blood vessel walls. A mild histiocytic, lymphocytic infiltrate was present with a rare multinucleated giant cell. DISCUSSION

In this investigation, the tissue response of rats to most of the implanted dental materials was similar. Of significance was the demonstration of unique histologic characteristics of the implanted materials themselves, which could establish individual identification for nearly all of them. The tissue response to zinc phosphate cement, N2 paste, and endodontic sealer consisted of a sparse mononuclear cell infiltrate of histiocytes and an occasional multinucleated giant cell. Other investigators have recorded adverse reactions to root canal filling materials that were inadvertently extended beyond the apical foramen. Paresthesia in the second and third divisions of the trigeminal nerve is more commonly associated with paraformaldehyde containing pastes such as N2 and Endomethasone.22-2g The histopathologic findings often show necrosis associated with granular foreign material, foreign body giant cell reaction, and suppurative inflammation of varying intensity. Particulate material is frequently difficult if not impossible to identify. Eugenol, a phenol derivative, can coagulate protein and initiate tissue reactions if present in sufficient quantity. Studies have demonstrated that root canal sealers containing zinc oxide-eugenol can be cytotoxic. 30*31 Implantation of pellets of zinc oxideeugenol cement into soft tissues and bones of rats elicited a mild inflammatory response at 30 and 80 days.32 Yesilsoy and coworkers33 implanted six varieties of root canal sealers into dorsal subdermal tissue

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I. Implanted Implanted

dental material

1. Zinc phosphate

cement

2. N2 paste 3. Endodontic

4. Handpiece

sealer

response

Morphologic

Sparse

histiocytes,

occasional

MGC

Sparse

histiocytes,

occasional

MGC

Sparse histiocytes, plasma lymphocytes, occasional

cells,

and

MGC

8. Graphite

Compressed histiocytes around vacuolated spaces, no significant MGC Compressed histiocytes around vacuolated spaces, no significant MGC Mononuclear infiltrate with eosinophils, frequent MGC Mononuclear infiltrate, occasional MGC Mild mononuclear infiltrate

9. Amalgam

Mild

5. Copal

oil

varnish

6. Composite

resin

7. Glass ionomer

MGC,

multinucleated

7I 7

foreign body reactions Host

material

oral foreign body reactions

mononuclear

infiltrate

characteristics

Black ovoid particles, rounded crystals with rose and yellow birefringence Yellowish-brown particles, punctate granules forming conglomerates, nonrefractile Basophilic conglomerates with yellow rectangular/ rhomboidal crystals with foci of rose and yellow birefringence Vacant vacuoles

Vacant

vacuoles

Yellow glassy crystals polymorphic with white laminated birefringence Irregular crystals with a “crinkled” surface, no birefringence Black punctate granules, nonrefractile Black punctate granules, nonrefractile

crystals

giant cell.

sites of guinea pigs. The standard sealers evaluated were Grossman’s sealer, containing zinc oxide and eugenol, and eucapercha, containing eucalyptol and gutta-percha. The newer sealers evaluated were Endo-Fill (Lee Pharmaceuticals, South El Monte, California) containing injectable silicone resin, CRCS (The Hygenic Corporation, Akron, Ohio) containing calcium hydroxide and eugenol, Sealapex (Kerr Manufacturing Company, Division of Sybron Corporation, Romulus, Michigan) containing calcium hydroxide and a polymeric resin, and HypoCal (Ellman International Manufacturing Inc., Hewlett, New York) containing calcium hydroxide. Analysis of tissue response showed that overall, Sealapex and EndoFill had less severe inflammatory reactions than any of the others. Grossman’s sealer, CRCS, and Hypocal showed principally severe inflammatory responses at 6 and 15 days, but mild reactions at 80 days. Overall, eucapercha showed less severe inflammatory responses than Grossman’s sealer, CRCS, and Hypocal. Both Grossman’s sealer and CRCS did not have overall favorable histologic reactions; however, they have been used successfully in the clinical setting. Therefore, our results disclosed only mild inflammatory reactions as opposed to other studies previously discussed. However, in other investigations, the reactions were observed within 15 days of implantation and our animals were killed after 6 weeks. The implanted materials could be differentiated from one another on the basis of morphologic features. The distinguishing features of zinc phosphate cement were the round yellow crystals, 10 to 50 pm

in diameter, that displayed rose and yellow birefringence under crossed polarizing lenses. These crystals were admixed with clumps of basophilic amorphous material. The N2 paste also showed conglomerates of amorphous basophilic material that could not be differentiated from that of zinc phosphate; however, the crystalline particles differed, being yellow-brown punctate granules, less than 0.2 pm, that were arranged in dense clumps. These particles were nonrefractile. Endodontic sealer resembled the N2 paste; however, the crystalline particles were unique, being birefringent and geometrically angulated. Implanted handpiece oil and copal varnish were so similar in histologic findings and tissue response that unique features could not be determined. Empty vacuoles of varying size and a mild inflammatory cell infiltrate were observed in both. Although handpiece oil granulomas are often seen, particularly in old extraction sites, a unique foreign body reaction myospherulosis sometimes results from the placement of a nonsterile petrolatum-based antibiotic ointment. The condition is believed to be induced by the action of lipid substances on extravasated erythrocytes. This process may be asymptomatic, occurring in nonhealing extraction sites, or less commonly, a soft tissue nodule may be seen. The radiographic appearance is often a unilocular radiolucency. Most cases of myospherulosis have evolved subsequent to postoperative placement of tetracycline petrolatum-based vehicle or Terra-Cortril (Pfizer) (oxytetracycline hydrochloride-hydrocortisone acetate), impregnated Gelfoam (Upjohn Company), or Oxycel (Parke-Davis and

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Company).“4-‘” Aggregates of altered erythrocytes and pseudocysts are surrounded by variable numbers of macrophages and foreign-body-type giant cells, forming small granulomas. In hematoxylin and eosinstained sections, foreign debris has a distinctive brown-to-black color because of the formation of acid hematin from decomposed hemoglobin.36 Composite resin crystals were easily differentiated from those of glass ionomer cement by shape and birefringence. Composite resin crystals were found, polygonal, or rectangular in shape with white laminated birefringence. The glass ionomer crystals were more triangular and exhibited no birefringence. The inflammatory cell response to glass ionomer cement consisted of histiocytes and minimal multinucleated giant cells. In contrast, the inflammatory cell infiltrate elicited by composite resin was the only one to contain moderate numbers of eosinophils and a significant number of multinucleated giant cells in addition to histiocytes. The finishing process of composite restorations may produce fine particles of composite resin material. The composite “dust” may contain irritating silica as it is often used as a filler in resin products. When inadvertent tissue injury occurs during preparation, filling, or finishing of a composite restoration, there is potential for introduction of those particles into the soft tissues. The histologic response from such an injury would range from an early foreign body reaction with little or no foreign body response to a typical granulomatous reaction. A nodular and sometimes pigmented silica granuloma may appear after an asymptomatic period of 15 or more years after the initial trauma.37 Compared with other dental materials (zinc phosphate cement, a silicate cement, and zinc oxide eugenol), Meryon and Browne38 reported Concise to be least cytotoxic of the four materials. On histologic examination, the foreign material has been reported to have a brownish crystalline appearance exhibiting birefringence under polarized light.39 Some studies reporting tissue response to glass ionomer cements have been conducted. A glass ionomer-silver cement (Ketac) was implanted into the bone and soft connective tissues of rats to assess tissue compatability. At 30 days, Ketac produced moderate inflammation in half of the soft tissue samples, but mild inflammation in bone. Foreign body giant cell promotion was mild in most samples.32 Callis and Santini4’ reported no inflammatory response using Ketacfil (Espe Fabrik Pharmazeutischer Praparate, +Pf?ld,‘Qherl;\ay, West Germany) for apicoectomies of ferret canines after 30 days. Although implanted graphite and amalgam shared many similarities, they could be differentiated. The

1990

tissue was stained macroscopically in both implant sites, and the tissue inflammatory response was mild. This is consistent with human histology in that oral amalgam tattoos rarely produce significant tissue inflammation unless the amalgam is contaminated with another material. Microscopically, both materials presented as black or black-brown particulate matter within the tissues. Orientation along fibers enveloping blood vessel walls was a characteristic unique to amalgam. Toxicity in freshly triturated alloy has been reported to be greater with zinc-containing alloys such as Velvalloy (S.S. White Products International, Philadelphia, Pennsylvania) and Dispersalloy (Johnson & Johnson, East Windsor, New Jersey) than with zinc-free alloys such as Sybraloy (Kerr Manufacturing Co., Detroit, Michigan) and Tytin (S.S. White Products International) because of rapid zinc release.4’* 42 Even zinc-free alloys, however, exhibited some toxicity up to 1 month after setting, according to one study. 41 When powdered dental amalgam is implanted subcutaneously in guinea pigs, it produces a blue-black discoloration closely resembling the amalgam tattoo that occurs on the oral mucosa of human beings. 43y44 Chronic granulomata develop around the implants, and particles are degraded within macrophages and giant cells. Vast numbers of minute secondary particles containing silver and sulphur become widely distributed throughout the lesions and are responsible for the macroscopic tattooing.4s% 46 Histologically, the dental materials implanted subcutaneously into rats in this study resembled human tissue reactions observed in biopsy specimens. Microscopic findings in human periapical lesions associated with endodontically involved teeth were consistent with implanted zinc phosphate, endodontic sealer, and N2 paste. Handpiece oil and copal varnish implants were similar to cases of oil granulomas in human beings. The implanted amalgam and graphite (lead pencil) duplicated amalgam and graphite tattoos seen in human tissues. The pathogenesis of foreign body reactions in the oral cavity can often be traced to accidental implantation of dental materials into an existing wound or extraction site, or to iatrogenic trauma induced during endodontic and restorative procedures. Despite efforts by the dentist to prevent such occurrences, they will persist. The oral pathologist will be asked to characterize the lesional tissue. The significance of this report lies in offering some specific histomorphologic features for identification of commonly used dental materials that may contribute to a more definitive microscopic characterization.

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REFERENCES Cataldo foreign Barclay MED

27 E, Santis H. Response of the oral tissue to exogenous materials. J Periodontol 1974;45:93-106. JK. Root in the maxillary sinus. ORAL SLRG ORAL

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1987;64:

Koppang HS, Koppang R, Solheim T, AArnes H, Stolen SO. Identification of cellulose fibers in oral biopsies. Stand J Dent Res 1987;95: 165-73. Althouse H. Foreign bodies in the maxillary sinus. Quint Int 1973;2:29-30. Cataldo E, Santis HR. A clinico-pathologic presentation. Amalgam pigmentation. J Mass Dent Sot 1987;36:1 12. Weaver T, Auclair PL, Taybox GM. An amalgam tattoo causing local and systemic disease’? ORAL SURGE ORAL MED

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7 Owen M, Macansh J. Foreign body (impression material) in the maxillary antrum. Clin Radio1 1965;16:284-8. 8 Winstock D, Warnakulasuriya S. Impression material presenting in the maxillary antrum as a foreign body. Br Dent J 1986;160(2):54-5. 9. Silvers JE, Johnson CK. Adverse soft tissue response to impression procedures: report of case. J Am Dent Assoc 1988;116:58-60. 10. Peters E, Gardner DG, Altini M, Crooks J. Granular cell reaction to surgical glove powder. J Oral Path01 1986;15:454-8. 11. Sheikh KMA Duggal K, Relfson M, Gignac S, Rowden G. An experimental histopathological study of surgical glove powders. Arch Surg 1984;l 19:215-9. 12. Shelton DW. Recovery of zinc oxide and eugenol impression paste from the maxillary sinus. ORAL SURG ORAL MED ORAL PATHOL

1964;18:126-9.

13. Minkow B, Laufer D, Gutman D. Acute maxillary sinusitis caused by gutta-percha point. Isr J Dent Med 1977;26:33-4, 23-4. 14. Bjornland T, Haanaes HR, Margrethe E, Beyer-Olsen S. Sinusitis caused by endodontic materials displaced into the maxillary sinus. Endod Dent Traumatol 1987;3:37-40. 15. Westermark AH. Spontaneous removal of foreign bodies from the maxillary sinus: report of a case. J Oral Maxillofac Surg 1989;41:75-7. 16. Evans AW. Removal of endodontic paste from the inferior alveolar nerve by sagittal splitting of the mandible. Br Dent J 1988;164: 18-20. 17. Ruprecht A, Wagner H. Extrusion of endodontic tilling material into the inferior alveolar canal. Can Dent Assoc J 1988;54:683-5. 18. Neaverth EJ. Disabling complications following inadvertent overextension of root canal filling material. J Endod 1989; 15:135-9. 19. Harrison JD, Davies KJ. A method for the identification of particulate materials in biopsies of the oral tissues. Br Dent J 1982:153:327-9. 20. Peters E, Gardner DG. A method of distinguishing between amalgam and graphite in tissue. ORAL SLRG ORAL MED OR.AL PATHOI I.ittiler

1986;62:73-6. .MM. Kaffe

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24. Grossman

A. Foreign

bodic\

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33

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Orstavik D, Brodin P. Aas E. Paresthesia following endodontic treatment: survey of the literature and report of a case. Int Endod J 1983; 16: 167-72. Fanibunda KB. Adverse response to endodontic material containing paraformaldehyde. Br Dent J 1984; 157(7):23 l-5. Orr DL. Paresthesia of the second division of the trigeminal nerve secondary to endodontic manipulation with N2. Headache 1987;27:21-2. Nakamura H. Sakakibara F, Matsumoto Y, et al. Study on the cytotoxicity of root canal filling materials. J Endod 1986; 12: 156-60. Matsumoto D, lnoue K, Matsumoto A. The effect of newly developed root canal sealers on rat dental pulp cells in primary culture. J Endod 1989:15:60-7 Blackman R, Gross M, Seltzer S. An evaluation of the biocompatibility of a glass ionomer-silver cement in rat connective tissue. J Endod 1989;15:76-9. Yesilsoy C, Koren LZ, Morse DR. Kobayashi C. A comparative tissue toxicity evaluation of established and newer root canal sealers. ORAL SURG ORAL MED ORAL PATHOL. 1988; 651459-67. Dunlap CL, Barker BJ. Myospherulosis of the jaws. ORAL SURC

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35. Bright C. Russel D, Keyes G. Myospherulosis. J Oral Maxillofac Surg 1982;40:509I 2. 36. Lynch DP, Newland JR, McClendon JL. Myospherulosis of the oral hard and soft tissues. J Oral Maxillofac Surg 1984;42:349-55. 37. Hannon SM. Pickett AB, Frost JM. Foreign-body (silica) granuloma of the lip. J Oral Maxillofac Surg 1983;41:470-2. 38. Meryon SD, Browne RM. Evaluation of the cytotoxicity of four dental materials in vitro assessed by cell viability and enzyme cytochemistry. J Oral Rehab 1983;10:363-72. 39 Moore DL, Barker BF. A foreign body lesion of the gingiva subsequent to the placement of composite resin restoration. Quintessence Int 1986;17:785-7. 40 Callis PD, Santini A. Tissue response to retrograde root fillings in the ferret canine: a comparison of a glass ionomer cement and gutta-percha with sealer. ORAL SURC ORAI MED ORAL

41 42. 43.

44.

45.

in the implanted conventianai and high copper amalgam powders in the guinea pig \rch Oral Biol 1987;32:257-63. requests

to:

Dr. Carol M. Stewart Oral Diagnostic Sciences Director, Oral Medicine Division Box J-414 JHMHC University of Florida College of Dentistry Gainesville, FL 32610