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  • Overfilling of calcium hydroxide– based paste Calcipex II produced a foreign body granuloma without acute inflammatory reaction Jin Woo Kim, DDS, PhD,a Kyung Mo Cho, DDS, PhD,a Se Hee Park, DDS, MSD, PhD,a Seung Gon Song, DDS,a Mi Sun Park, DDS,b Hye Rim Jung, DDS,b Ji Yong Song, BS,b Yeon Sook Kim, DDS, PhD,b and Suk Keun Lee, DDS, PhD,b Gangneung, Korea COLLEGE OF DENTISTRY, KANGNUNG NATIONAL UNIVERSITY A patient, a 62-year-old man, received endodontic treatment of the lower left canine complicated by apicaloverfilling of Calcipex II. At the second day after the root canal filling, the 14th day after placement of Calcipex IIintracanal medication, he complained of a gingival swelling in the treated area. The incisional biopsy of the gingivalswelling revealed a foreign body granuloma infiltrated with macrophages engulfing the fine Calcipex II granules butwith polymorphonuclear leukocytes (PMNs). However, the gingival swelling was healed uneventfully, and the toothwas free of symptoms at 4 months’ follow-up. This study first reports the Calcipex II–induced reaction in humanperiodontium. In the immunohistochemistry using antisera of lysozyme, CD31, CD68, interleukin-8 (IL-8), andpoly(ADP-ribose) polymerase 1 (PARP-1), the granule-laden cells are positive for lysozyme, CD31, CD68, and PARP-1,but negative for IL-8. Thus, it is presumed that the granule-laden cells belong to the macrophages/monocytes ratherthan the PMNs, and that they gradually undergo the apoptotic processes. These data suggest that the canal dressingmaterial, Calcipex II, is able to be widely dispersed into the periodontal tissues, primarily engulfed by macrophages,and resulted in the foreign body granuloma in the absence of acute inflammatory reaction. (Oral Surg Oral Med OralPathol Oral Radiol Endod 2009;107:e73-e76)CASE REPORT through the apical foramen (Fig. 1, b). On the third visit, the A 62-year-old man was referred from a private dental clinic working length of the root canal was recalculated and theto the Department of Conservative Dentistry in Kangnung apical preparation enlarged to size #55. A root canal fillingNational University (KNU) Dental Hospital. The chief com- with gutta-percha cone and AH-26 sealer (DeTrey/Dentsply,plaint was vestibular swelling in the lower left canine (#22) Konstanz, Germany) was placed. The root canal was wellarea. The patient’s dentomedical history was noncontributory. obturated, and the overfilling of Calcipex II was reduced inPulp test revealed that tooth #22 was unresponsive to cold and amount (Fig. 1, c).electric pulp testing, whereas the adjacent teeth responded At the day after the root canal filling (the 14th day afterwithin normal limits. The tooth was very sensitive to percus- Calcipex II placement), the patient came back complaining ofsion and palpation. Pus was discharged from the labial gin- a gingival swelling in the area of tooth #22 (Fig. 1, d). Thegival sulcus of the tooth. Purulent exudate was also noted on gingival swelling showed no pus discharge in the gingivalaccess opening of the tooth. The root canal was irrigated with sulcus, and the tooth was not tender to touch. An incisional3% sodium hypochlorite and 2% chlorhexidine in conjunction biopsy was done and the specimen fixed in 10% neutralwith root canal instrumentation after radiographic determina- formalin. The biopsy was subsequently embedded in paraffin,tion of root canal length (Fig. 1, a). and sectioned in 4 m thickness. The usage of the biopsy On the second visit, the exudates and swelling had de- specimen filed in the Department of Oral Pathology, KNUcreased and Calcipex II (Nishika, Shimonoseki, Japan) was Dental Hospital, was approved by the Life Ethics Committeeused as an intracanal dressing as suggested by the manufac- of KNU. The histologic sections were routinely stained withturer. The Calcipex II was, however, slightly overfilled hematoxylin and eosin, and also used for immunohistochem- istry using antisera of lysozyme, CD31, CD68, interleukin-8 (IL-8), and poly(ADP-ribose) polymerase 1 (PARP-1) (SantaSupported by research grants from the Korean Science and Engineer- Cruz Biotechnology, Santa Cruz, CA). In addition, the Cal-ing Foundation (R11-2002-001-03003-0 and R01-2003-000- cipex II material was dispersed in water and smeared on glass10891-0) and the Korean Research Foundation (KRF-2007-013). slide for the microscopic observation. Every microscopica Department of Conservative Dentistry. image was recorded with a digital camera (Olympus DP-70,b Department of Oral Pathology. Tokyo, Japan).Received for publication Jul 9, 2008; accepted for publication Oct 21,2008. The microsections of the gingival swelling showed a gran-1079-2104/$ - see front matter ulomatous lesion heavily infiltrated with fine granular mate-© 2009 Mosby, Inc. All rights reserved. rials, engulfed mostly by macrophages and slightly by stromaldoi:10.1016/j.tripleo.2008.10.019 fibroblasts (Fig. 2, a, 1-3). The Calcipex II granules were not e73
  • OOOOEe74 Kim et al. March 2009Fig. 1. Standard radiographs during the endodontic treatment of the lower left canine. a, X-ray for initial working lengthdetermination. b, On the second visit, Calcipex II was overfilled into the periapical area (arrows). c, After root canal filling, someCalcipex II remained periapical but reduced in amount (arrows). d, At the second day after canal filling, when the gingivalswelling occurred, the canal filling looked fine and there was no change in periapical area (arrows).localized in the granuloma lesion but gradually dispersed root canal is filled in a single-session treatment.1-3across the border of the granuloma into the adjacent connec- Calcipex II is a calcium hydroxide water-based pastetive tissue (Fig. 2, a, 4 and 5). The fine granular materials for root canal dressing, which is easy to handle and thewere identical to the Calcipex II granules smeared on the most easily removed. Great care had to be taken toglass slide, exhibiting slightly translucent and fine granular avoid extrusion via the apical foramen compared withaggregation but no calcification or polymerization (Fig. 2, b).The Calcipex II granules were mainly engulfed by macro- the silicon oil– based Vitapex.4 In the present study, thephages, and also slightly localized at the cytoplasms of fibro- Calcipex II used as an intracanal dressing material wasblasts. Still a lot of the fine Calcipex II granules were freely overfilled into the periapical area, and its fine granulardispersed in the stromal fibrous tissue, but rarely in the lumen materials were rapidly migrated up through the gingivalof capillaries. In the immunohistochemistry using antisera of tissue. The Calcipex II granules were not calcified norlysozyme, CD31, CD68, IL-8, and PARP-1, the Calcipex II polymerized in the gingival tissue; rather, they weregranule–laden cells were positive for lysozyme, CD31, and diffusely scattered throughout the collagenous fibrousCD68, indicating that the cells belonged to the lineage of tissue, were rapidly engulfed by the macropahges, andmacrophage/histiocyte/monocyte and were in the apoptotic resulted in a foreign body granuloma. The granulomaprocesses (Fig. 2, c-e). On the other hand, the Calcipex IIgranule–laden cells were negative for IL-8, which is a che- was mainly infiltrated with macrophages, and only amokine usually positive in neutrophils (Fig. 2, f), similar to few lymphocytes were found, but exclusive of PMNs.the negative control staining (Fig. 2, h). Under the micro- In the immunohistochemistry, the Calcipex II granule–scopic observation in routine hematoxylin and eosin stain, the laden cells were strongly positive for lysozyme, CD31,macrophages filled with the Calcipex II granules could not and CD68, which are markers for the macrophages,readily dissolve the fine granules; rather, they were gradually including histiocytes and monocytes,5-11 whereas theydestroyed by the rupture of their cell membrane. Nevertheless were negative for the antibody of IL-8, which is athere appeared no acute inflammatory reaction. The Calcipex marker for PMNs.12 However, the inflammatory degen-II–laden macrophages were strongly positive for PARP-1,indicating that the cells were undergoing the apoptotic pro- eration or necrosis by cytotoxic chemokine IL-8 wascesses, possibly due to the overload of Calcipex II (Fig. 2, g). not observed in the Calcipex II–induced foreign bodyEventually, the Calcipex II induced a foreign body granuloma macrophages, but no acute inflammation by PMNs. The Calcipex II granules were too small, 500 nm, to be localized in the root canal, so that they were easilyDISCUSSION overflowed and dispersed into the periapical tissues The use of a calcium hydroxide– based intracanal depending on the dynamic pressure that occurred dur-dressing is important for periapical repair in teeth with ing canal filling and biting. The fine Calcipex II gran-periapical lesion. Dressing with calcium hydroxide ules were rapidly engulfed by macrophages and evenpaste results in better periapical repair than when the endocytosed by stromal fibroblasts. However, the Cal-
  • OOOOEVolume 107, Number 3 Kim et al. e75Fig. 2. Photomicrographs of the Calcipex II-induced foreign body granuloma. a, Hematoxylin and eosin stain. a1, Lowmagnification of main lesion: The Calcipex II granules were diffusely observed in the stromal cells. a2-a5, High magnification.a2, Most of the Calcipex II granules were engulfed by macrophages (arrows), only a few lymphocytes (arrowheads) wereinfiltrated but not PMN. a3, Some Calcipex II granules were also endocytosed by stromal fibroblasts (arrowheads); no CalcipexII granules were found in the lumen of capillaries (C). a4, Note the massive dispersion of the Calcipex II granules in the fibrousconnective tissue; many Calcipex II granules were found in the cytoplasms of fibroblasts (arrowheads). a5, Border area betweenthe fibrous connective tissue and granulomatous lesion. The Calcipex II granules were diffusely dispersed; note many macro-phages infiltrated into the border area. b, Calcipex II paste smeared on the slide glass. b1, Low magnification: The Calcipex IIgranules were well dispersed and aggregated (arrows). b2, High magnification: The fine granules of Calcipex II was very small,measuring 500 nm in diameter. c-g, Immunohistochemistry. c, Lysozyme antibody, positive in the Calcipex II granule–ladencells (arrows). d, CD31 antibody, positive in the Calcipex II granule–laden cells (arrows). e, CD68 antibody, positive in theCalcipex II granule–laden cells (arrows). f, Interleukin-8 antibody, negative in the Calcipex II granule–laden cells (arrows). g,Poly(ADP-ribose) polymerase 1 antibody, positive in the Calcipex II granule–-laden cells (arrows). h, Negative control stainedwithout antisera. View slide
  • OOOOEe76 Kim et al. March 2009cipex II granules seem to be not readily degraded in the giant cell granuloma. An immunohistochemical and ultra-cytoplasms of macrophages; rather, the macrophages structural study. Oral Dis 1995;1:20-5. 7. Macarenco RS, do Canto AL, Gonzalez S. Angiolymphoid hy-overfilled with the Calcipex II granules tend to be perplasia with eosinophilia showing prominent granulomatousdestroyed with the positive reaction of PARP-1, which and fibrotic reaction: a morphological and immunohistochemicalis a marker of cellular apoptosis.13,14 However, the study. Am J Dermatopathol 2006;28:514-7.features of cytotoxic degeneration and the allergic hy- 8. Yuan K, Wing LY, Lin MT. Pathogenetic roles of angiogenicpersensitivity by the immune reactions of PMNs and factors in pyogenic granulomas in pregnancy are modulated by female sex hormones. J Periodontol 2002;73:701-8.lymphocytes were not observed in the Calcipex II– 9. Knoess M, Krukemeyer MG, Kriegsmann J, Thabe H, Otto M,induced foreign body granuloma. Krenn V. Colocalization of C4d deposits/CD68 macrophages in In this study, the overfilling of Calcipex II in end- rheumatoid nodule and granuloma annulare: immunohistochem-odontic treatment produced a foreign body granuloma ical evidence of a complement-mediated mechanism in fibrinoidin the nearby gingival tissue. Although the Calcipex II necrosis. Pathol Res Pract 2008;204:373-8. 10. Tian XF, Li TJ, Yu SF. Giant cell granuloma of the temporalwas rapidly reduced in amount in the periapical radio- bone: a case report with immunohistochemical, enzyme histo-grams after treatment, the Calcipex II material was not chemical, and in vitro studies. Arch Pathol Lab Med 2003;resorbed easily; rather, it was dispersed into adjacent 127:1217-20.soft tissue, evoking a foreign body reaction by macro- 11. Rodini CO, Lara VS. Study of the expression of CD68 mac-phages in the absence of acute inflammatory reaction. rophages and CD8 T cells in human granulomas and periapical cysts. Oral Surg Oral Med Oral Pathol Oral Radiol EndodREFERENCES 2001;92:221-7. 1. Leonardo MR, Hernandez ME, Silva LA, Tanomaru-Filho M. 12. Pilozzi E, Stoppacciaro A, Rendina E, Ruco LP. Monocyte Effect of a calcium hydroxide– based root canal dressing on chemotactic protein-1 in the inflammatory pseudotumour of the periapical repair in dogs: a histological study. Oral Surg Oral lung. Mol Pathol 1998;51:50-2. Med Oral Pathol Oral Radiol Endod 2006;102:680-5. 13. Okinaga T, Kasai H, Tsujisawa T, Nishihara T. Role of caspases 2. Berbert FL, Leonardo MR, Silva LA, Tanomaru Filho M, Bra- in cleavage of lamin A/C and PARP during apoptosis in macro- mante CM. Influence of root canal dressings and sealers on repair phages infected with a periodontopathic bacterium. J Med Mi- of apical periodontitis after endodontic treatment. Oral Surg Oral crobiol 2007;56:1399-404. Med Oral Pathol Oral Radiol Endod 2002;93:184-9. 14. Fink SL, Cookson BT. Caspase-1-dependent pore formation dur- 3. Peters LB, van Winkelhoff AJ, Buijs JF, Wesselink PR. Effects ing pyroptosis leads to osmotic lysis of infected host macro- of instrumentation, irrigation and dressing with calcium hydrox- phages. Cell Microbiol 2006;8:1812-25. ide on infection in pulpless teeth with periapical bone lesions. Int Endod J 2002;35:13-21. Reprint requests: 4. Hosoya N, Kurayama H, Iino F, Arai T. Effects of calcium hydroxide on physical and sealing properties of canal sealers. Int Suk Keun Lee, DDS, PhD Endod J 2004;37:178-84. Department of Oral Pathology 5. Stefanaki K, Tsivitanidou-Kakourou T, Stefanaki C, Valari M, College of Dentistry Argyrakos T, Konstantinidou CV, et al. Histological and immu- Kangnung National University nohistochemical study of granuloma annulare and subcutaneous 123 Chibyun-dong granuloma annulare in children. J Cutan Pathol 2007;34:392-6. Gangneung, 210-702 Korea 6. Carvalho YR, Loyola AM, Gomez RS, Araujo VC. Peripheral View slide