RESEARCH ARTICLE
Retrospective Analysis of the Histopathologic Features of 288 Cases of Reactional Lesions in Gingiva and Alveolar Ridge Felipe R. de Matos, DDS, PhD, Thaı´s G. Benevenuto, DDS, MSc, Cassiano F. W. Nonaka, DDS, PhD, Lea˜o P. Pinto, DDS, PhD, and Le´lia B. de Souza, DDS, PhD
Introduction: The aim of this study was to perform a retrospective study of histopathologic features of a series of cases of pyogenic granuloma (PG), peripheral giant cell lesion (PGCL), and peripheral ossifying fibromas (POF) that constitutes the group called reactional lesions, located in gingiva and alveolar ridge. Study Design: Cases of PG, PGCL, and POF were selected for this study. The morphological analysis of the lesions constituted the following: intensity of inflammatory infiltrate (IF), presence of vascular proliferation (VP), fibroblastic proliferation (FP), areas of ulceration (AU), bacterial colony (BC), presence of mineralization (PM), multinucleated giant cells (MGC), hemosiderin deposition (HD), hemorrhage area (HA). Results: Of the 288 cases analyzed, 162 (56.3%) were PG, 72 (25%) were PGCL, and 54 (18.8%) were POF. The IF, VP, AU, and BC were more prominent in PG (85.8%, 98.8%, 91.4%, and 46.9%, respectively) and PM in POFs (98.1%). FP was more frequent in POF (98.1%) and PGCL (100%) and MGC in PGCL (100%), although some cases of POF (7.4%) and PG (0.6%) exhibited MGC. HD was more frequent in PGCL (40.3%) and HA in PG (53.1%). Conclusions: This study demonstrated that IF, VP, AU, BC, and HA are the common features in PG, MGC, FP, and HD are the most common in PGCL, and PM associated with FP are the most common in POF, which can help in the histopathologic differential diagnosis between these lesions. In addition, it may suggest a possible development and maturation of the PG in POF with reduction in the inflammatory component and increase in the fibrous component. Key Words: pyogenic granuloma, peripheral giant cell granuloma, peripheral ossifying fibroma, histopathological features, gingiva, alveolar ridge (Appl Immunohistochem Mol Morphol 2014;22:505–510) Received for publication April 10, 2013; accepted June 1, 2013. From the Oral Pathology Department, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil. The authors declare no conflict of interest. Reprints: Le´lia B. de Souza, DDS, PhD, Departamento de Odontologia, Federal University of Rio Grande do Norte, Av. Senador Salgado Filho, 1787 Lagoa Nova, Natal, Rio Grande do Norte 59056-000, Brazil (e-mail: [email protected]). Copyright r 2013 by Lippincott Williams & Wilkins
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eactive lesions in gingiva and alveolar ridge mucosa are very common.1–3 Although there are some clinical differences among the reactive lesions, their etiology is very similar, and the presence of variable amounts of inflammatory infiltrate (IF) in all of them can determine high clinical and microscopic resemblance. These are subjected to chronic local irritation or trauma from calculus, food impaction, restorations that show irregular margins, low-grade trauma, and iatrogenic factors. Even with common etiologic factors, tissue response follows different courses in each individual lesion, reflected by their microscopical characteristics.4 The great majority of localized overgrowths of gingiva and alveolar ridge mucosa are considered to be reactive and non-neoplastic lesions,5 like peripheral giant cell lesion (PGCL), pyogenic granuloma (PG), and peripheral ossifying fibroma (POF).6 Not much difference exists in clinical appearance between these lesions. However, the knowledge of the frequency and distribution of such lesions is essential when establishing a diagnosis and planning treatment. Therefore, periodontologists and oral and maxillofacial surgeons often give the diagnostic term epulis to these lesions clinically.6 In addition, there is no consensus as to the histologic classification. Buchner et al7 cite the example that Lee’s “calcifying fibroblastic granuloma” would correspond to Bhaskar and Jacoway’s “peripheral fibroma with calcification” or to Eversole’s “peripheral ossifying fibroma.” Diagnosis of each lesion from this group (PGCL, PG, and POF) is aided by their clinical and periapical radiographic features, but histopathologic analysis is essential for final diagnosis4 because from the clinical point view these lesions do not possess specific features. They are usually oral hyperplastic lesions and present a common course, originally manifesting as an intensely red and soft mass of inflamed granulation tissue, being painless or not.2,8 Histologically, PGCL is a reactive lesion that consists of a proliferation of ovoid-shaped to spindle-shaped mesenchymal cells and multinucleated giant cells (MGC) with an associated prominent vascularity.9–11 PG is characterized by a mass of hyperplastic granulation tissue with marked proliferation of endothelial cells that line capillary channels and an infiltrate of mixed inflammatory cells.7 Finally, POF is a reactive lesion that
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includes a cellular fibroblastic tissue and formation of mineralized products like woven and lamellar bone, cementum-like material, and dystrophic calcification.7 The treatment of these lesions aims to eliminate the underlying etiologic agents and comprises surgical resection.8 Knowledge of frequency and distribution of such lesions is also essential. Despite a few studies about these lesions in Brazil,3,4 the aim of this retrospective study was to identify the clinicopathologic features of PGCL, PG, and POF diagnosed on Oral Pathology Service and their morphologic characteristics.
MATERIALS AND METHODS A retrospective study of 10,311 biopsies obtained over a period of 40 years (1970 to 2009) in the Oral Pathology Service was designed. The histologic features were studied in 5 mm wide paraffin sections stained with hematoxylin and eosin. The lesions were classified into the 3 above-described groups, that is, PGCL, PG, and POF according to the criteria that were described in the Introduction section of the study. For the morphologic study, some microscopical parameters were analyzed, according to Peralles et al,4 which are as follows: distribution of IF—classified as mild, when there were focal areas, especially on the subepithelial area, or intense, when it was disperse and deep on the connective tissue; type of IF—predominantly acute, chronic, or both; presence of vascular proliferation (VP)—presence of abundant capillary or cavernous VPs on the connective tissue (not only focal areas of increased vascularity); pattern of the oral mucosal lining epithelium—subdivided as normal, atrophic (thin epithelium with 15 to 20 cell layers) or absent (areas of ulceration); presence of MGC; presence of mineralized material—microscopically compatible with bone and/or cementum; type of connective tissue—loose or dense; the presence of fibroblastic proliferation dispersed on the connective tissue; and presence of hyaline granuloma, bacterial colony (BC), hemosiderin deposition (HD), hemorrhage area, and odontogenic epithelium.
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TABLE 1. Histopathologic Findings of 288 Reactive Gingival/ Alveolar Lesions by Histologic Subtype n (%) Parameters
PG
Epithelium Normal 1 Atrophy 59 Hyperplasia 159 Predomine (hyperplastic) 131 Ulcer 148 Connective tissue Loose 21 Dense 48 Loose and dense 93 Fibroblastic proliferation 10 Vascular proliferation 160 Type of inflammatory infiltrate Acute 1 Chronic 22 Both 139 Intensity of inflammatory infiltrate Mild 23 Intense 139 Mineralization Absent 151 Cementum-like 6 Bone/Bone-like 4 Cementum/bone 1 Multinucleated giant cell Absent 161 Present 1 Hyaline granuloma Absent 161 Present 1 Bacterial colony Absent 85 Present 76 Hemosiderin deposition Absent 158 Present 4 Hemorrhage area Absent 76 Present 86 Odontogenic epithelium Absent 157 Present 5
PGCL
POF
(0.6) (36.4) (98.1) (80.9) (91.4)
2 20 65 53 23
(2.8) (27.8) (90.3) (73.6) (31.9)
2 12 49 34 27
(3.7) (22.2) (90.7) (63) (50)
(13) (29.6) (57.4) (6.2) (98.8)
3 59 10 72 59
(4.2) (81.9) (13.9) (100) (81.9)
1 37 16 53 26
(1.9) (68.5) (29.6) (98.1) (48.1)
(0.6) (13.6) (85.8)
0 (0.0) 54 (75) 18 (25)
0 (0.0) 34 (63) 20 (37)
(14.2) (85.8)
56 (77.8) 16 (22.2)
31 (57.4) 23 (42.6)
(93.2) (3.7) (2.5) (0.6)
44 0 28 0
1 9 33 11
(99.4) (0.6)
0 (0.0) 72 (100)
50 (92.6) 4 (7.4)
(99.4) (0.6)
72 (100) 0 (0.0)
54 (100) 0 (0.0)
(52.8) (46.9)
70 (97.2) 2 (2.8)
49 (90.7) 5 (9.3)
(97.5) (2.5)
43 (59.7) 29 (40.3)
53 (98.1) 1 (1.9)
(46.9) (53.1)
50 (69.4) 22 (30.6)
53 (98.1) 1 (1.9)
(96.9) (3.1)
72 (100) 0 (0.0)
51 (94.4) 3 (5.6)
(61.1) (0.0) (38.9) (0.0)
(1.9) (16.7) (61.1) (20.4)
RESULTS
PG indicates pyogenic granuloma; PGCL, peripheral giant cell lesion; POF, peripheral ossifying fibroma.
Of the 10,311 biopsies, 288 cases (2.8%) of reaction lesions were identified. There were 162 (56.3%) PG, 72 (25%) PGCL, and 54 (18.8%) POF. Histologic parameters evaluated are described in Table 1. With respect to epithelial morphology, atrophy, ulceration, and hyperplasia were found predominantly on PG (36.4%, 91.4%, and 98.1%, respectively), although these findings were present in all other histologic types. The hyperplasia was found most frequently in all the lesions and the presence of the ulceration was most common in PG (91.4%; Fig. 1A). Connective tissue was considered loose and dense in most PG (57.4%) and, in contrast, was considered dense in most PGCL (81.9%; Fig. 1B) and POF (68.5%; Fig. 1C). Fibroblastic proliferation was commonly present in PGCL (100%) and POF (98.1%). VP was found frequently in PG (98.8%; Fig. 1D) and PGCL (81.9%; Fig. 2A). Chronic IF was found in all cases, being most common in PGCL (75%)
and POF (63%); acute infiltrate was identified in only 1 case of PG. IF was considered intense in 85.8% of cases of PG and mild in 77.8% of PGCL and 57.4% of POF. Mineralization showed marked affinity for POF, being exhibited in 16.7% of cementum-like areas (Fig. 2B), 61.1% of bone/ bone-like areas (Fig. 1C), and 20.4% of cementum/bone areas. In contrast, the mineralization was observed in 6.8% of PG (Fig. 2C) and 38.9% of PGCL (Fig. 2D). MGC were found in all cases of PGCL (Fig. 2A) being present in some cases of POF (7.4%) (Fig. 2B) and PG (0.6%). Hyaline granuloma was found in only 1 case of PG (Fig. 3A). BC was seen in epithelial and ulceration in 46.9% of PG (Fig. 1A) and absent in 97.2% of PGCL and 90.7% of POF. Hemosiderin deposition was found in 40.3% of PGCL (Fig. 3B) and hemorrhage area in 53.1% of PG and
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FIGURE 1. A, Photomicrograph of PG exhibiting ulcer area (arrow) and bacterial colony (asterisk; H&E, 40). B, Photomicrograph of peripheral giant cell lesion with dense connective tissue and some multinucleated giant cell (arrow; H&E, 200). C, Photomicrograph of peripheral ossifying fibroma characterized by the presence of a collagenized fibrous connective tissue with a proliferation of fibroblastic cells (arrow), especially in the areas of bone-like material (asterisk; H&E, 200). D, Photomicrograph of PG exhibiting transition of epithelium to ulcer area (H&E, 200). H&E indicates hematoxylin and eosin; PG, pyogenic granuloma.
30.6% of PGCL. Few cases showed odontogenic epithelium, being present in 5 (3.1%) cases of PG and 3 (5.6%) of POF. r
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DISCUSSION According to the results obtained, the most common lesion was PG (56.3%), followed by PGCL (25%) www.appliedimmunohist.com |
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FIGURE 2. A, Photomicrograph of PGCL with numerous multinucleated giant cell and blood vessels (H&E, 400). B, Photomicrograph of peripheral ossifying fibroma exhibiting one multinucleated giant cell (arrow) and cementum-like areas (arrow head) between mesenchymal cells (H&E, 400). C, Photomicrograph of pyogenic granuloma with focal area of mineralized material (H&E, 400). D, Photomicrograph of PGCL exhibiting focus of mineralized tissue (H&E, 200). H&E indicates hematoxylin and eosin; PGCL, peripheral giant cell lesion.
and POF (18.8%), in line with the literature. For PG, there was a variation of 42.7%7 to 58.8%1 in studies with reactive lesions only. It is interesting to note that the research findings are similar to those of Salum et al,3 who carried out their study in Brazil and found 57% of cases diagnosed as PG. In relation to PGCL, a higher amplitude in percentage was observed, ranging from 3.9%6 to 30.6%.1 Again, the frequency of PGCL cases in this study becomes close to the Brazilian study that identified it in 22.5% of the cases.3 Finally, the POF was found in 18.8% of the cases and is within the frequency reported in some studies, that is, 10.5%1 to 45.3%.6 PG is a reactive lesion front to an etiological traumatic factor, and the sites most likely to injuries are the gingiva and the alveolar ridge. The presence of calculus, overhanging edges, and rough restorations can act as irritant factors. These elements cause microulceration and allow the entry of microorganisms in the intimacy of the
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connective tissue.12,13 The findings of the present research endorse this theory, once the ulceration was found in 91.4% of PG cases and there was presence of bacteria colonies in 46.9%. The irritation in fibrovascular connective tissue becomes denser and begins the inflammatory response.13 Once the inflammation is triggered, growth factors and inflammatory cytokines such as vascular endothelial growth factors and interleukin-8, respectively, stimulate the proliferation of endothelial cells and the formation of new capillary beds,14 reflecting on the main morphological characteristics of PG.4,6 Not diverging from these concepts of this assertion, we identified a dense connective tissue in 29.6% and dense and loose in 57.4% of the cases, an intense and mixed IF in 85.8% of the cases, and proliferation of blood vessels was present in 98.8% of PG. In contrast, POF and PGCL observed a reduced percentage of ulceration (50% and 31.9%, respectively), followed by absence of BC r
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FIGURE 3. A, Presence of hyaline granuloma (arrow) in pyogenic granuloma (H&E, 400). B, Presence of hemosiderin deposition (arrow) next to multinucleated giant cells area in peripheral giant cell lesion (H&E, 200). H&E indicates hematoxylin and eosin.
(90.7% and 97.2%, respectively), which could explain the lightness of IF in these lesions (57.4% and 77.8%, respectively). Eleven cases (6.8%) of PG showed foci of mineralization, unusual finding for this lesion, moving away from 98.1% found in POF. Mineralization areas in POF are usually seen in the cellular zone and show considerable variation in the pattern of mineralization from small rounded calcified deposits to large trabecular bone areas surrounded by osteoblastos,15 such as that observed in the present study. In addition, PGCL may exhibit focus of mineralized tissue but less frequently. According to Capelozza et al,16 PGCL may exhibit elevated growth potential, sometimes with erosion of underlying bone. This might justify the presence of mineralized osseous tissue in 38.9% of PGCL in this study, such as that observed by Dayan et al17 (35%). Some authors suggest a possible development and maturation of the PG in POF, with reduction in the inflammatory component, increase of the fibrous component, and development of some foci of calcification, but this theory is not applied to all POF formed.4,6 In contrast, Prasad et al18 believe that the PG and the POF should not be regarded as distinct clinical entities but preferably as progressive stages of the same pathology. The results of this study may suggest this transition when comparing the percentage of POF and PG with intense IF (42.6% and 85.8%, respectively) and presence of dense fibrous connective tissue (68.5% and 29.6%, respectively), as observed by Peralles et al.4 The PGCL occurs exclusively in gingival and alveolar mucosa and microscopically is characterized by the proliferation of mesenchymal cells in the middle of the MGC, and may have extensive hemorrhagic areas and HD.4,19 The presence of fibroblast proliferation and MGC were found in 100% of the cases, hemorrhagic areas in 30.6% of the cases, and HD in 40.3% of the cases. It is believed that the MGC seen in PGCL originate r
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from the fusion of monocytic cells of CD68+ macrophage/osteoclastic lineage stimulated by the release of receptor activator of nuclear factor k-B ligand by mesenchymal cells.20 The hemosiderin pigmentation is related to the deposition of endogenous catabolic products and indicates the presence of many microhemorrhages in the lamina propria. Cells of the defense mechanism (ie, macrophages) react at the site of erythrocyte degradation; this starts “phagocytosis” and degrades the hemoglobin, producing the hemosiderin.21 Although a greater percentage of cases of PG (53.1%) exhibit hemorrhagic areas compared with the PGCL (30.6%), the hemosiderin pigmentation was most found in PGCL (40.3%). This could be explained by the fact that PGCL have a large number of cells with macrophagic phenotype.20 However, in minor frequency, the PG may contain areas that share microscopic features common to PGCL and POF, as reported by Peralles et al.4 One case (0.6%) of PG showed the presence of multinucleated giant cell and 6.8% showed mineralized areas. These findings could reinforce some microscopic features shared by the PG and POF and that might occur supposedly in some cases during the maturation process.4 Although not a common and essential component, the POF can present MGC, usually associated with the mineralized material and nests of odontogenic epithelium as representing the vestigial dental lamina.15 In 7.4% of cases of POF, we observed the presence of MGC and in 5.6%, the presence of odontogenic epithelium. Other lesions with oral manifestations and with presence of MGC that may occur in gingival and alveolar tissues are tuberculosis and paracoccidioidomycosis. Both of them take the form of an irregular ulceration or a discrete granular mass and they are often painful. The MGCs exhibit inside the microorganism and their nucleus are arranged at the cell periphery.22,23 The POF, similar to other injuries described above, occurs exclusively in gingival and alveolar tissues.3,4 www.appliedimmunohist.com |
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Garcia de Marcos et al15 conducted a study with the objective to investigate the nature of the POF by immunohistochemical analysis. The authors have strengthened the evidence of nature myofibroblastic and fibroblastic lesion, which is consistent with a possible origin in periodontal ligament. In optical microscopy, the POF is characterized by the presence of a collagenized fibrous connective tissue with a proliferation of fibroblastic cells, especially in the areas mineralized, which may be formed from bone material, similar to the cementum or dystrophic calcification. Most of the time, there is a chronic IF.7 These findings were observed in the majority of the patients studied in this research. Only 1 PG case presented hyaline granuloma. The hyaline granuloma is an eventual histologic finding characterized by deposition of eosinophilic amorphous nodular material surrounded by variable amounts of inflammatory cells and giant cells.24 The hyaline granuloma can be found in lesions of soft tissue,25 and although the exact etiopathogenesis of these hyaline structures remain unknown, there are basically 2 opposing theories, which are as follows: the first proposes an extrinsic origin, resulting from the deployment of foreign material or body (plant material, vegetables, therapeutic agents).26,27 The second theory suggests an intrinsic origin, in which the lesions develop from the collagen degeneration, degenerative changes in blood vessels walls, extravasated and fibrosed serum proteins, or changes in the natural process of resolution of periapical lesions.28 Although these lesions exhibit similar characteristics, this study demonstrated that the intense IF, VP, ulceration, the presence of BC, and hemorrhagic areas are common features in GP, whereas the MGC, fibroblast proliferation, and HD are more frequent in PGCL and the presence of mineralization associated with fibroblast proliferation in the POF, which can help in the histopathologic differential diagnosis between these lesions. In addition, the present study may suggest a possible development and maturation of the PG in POF with reduction in the inflammatory component and increase in the fibrous component. REFERENCES 1. Ababneh KT. Biopsied gingival lesions in northern Jordanians: a retrospective analysis over 10 years. Int J Periodontics Restorative Dent. 2006;26:387–393. 2. Shamim T, Varghese VI, Shameena PM, et al. A retrospective analysis of gingival biopsied lesions in South Indian population: 2001-2006. Med Oral Patol Oral Cir Bucal. 2008;13:E414–E418. 3. Salum FG, Yurgel LS, Cherubini K, et al. Pyogenic granuloma, peripheral giant cell granuloma and peripheral ossifying fibroma: retrospective analysis of 138 cases. Minerva Stomatol. 2008;57:227–232. 4. Peralles PG, Viana APB, Azevedo ALR, et al. Gingival and alveolar hyperplastic reactive lesions: clinicopathological study of 90 cases. Braz J Oral Sci. 2006;5:1085–1089.
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5. Bataineh A, Al-Dwairi ZN. A survey of localized lesions of oral tissues: a clinicopathological study. J Contemp Dent Pract. 2005; 6:30–39. 6. Zhang W, Chen Y, An Z, et al. Reactive gingival lesions: a retrospective study of 2439 cases. Quintessence Int. 2007;38:103–110. 7. Buchner A, Shnaiderman-Shapiro A, Vered M. Relative frequency of localized reactive hyperplastic lesions of the gingiva: a retrospective study of 1675 cases from Israel. J Oral Pathol Med. 2010;39:631–638. 8. Tamarit-Borras M, Delgado-Molina E, Berini-Aytes L, et al. Removal of hyperplastic lesions of the oral cavity. A retrospective study of 128 cases. Med Oral Patol Oral Cir Bucal. 2005;10:151–162. 9. Matos FR, Nonaka CF, Miguel MC, et al. Immunoexpression of MMP-9, VEGF, and vWF in central and peripheral giant cell lesions of the jaws. J Oral Pathol Med. 2011;40:338–344. 10. de Matos FR, de Moraes M, Nonaka CF, et al. Immunoexpression of TNF-alpha and TGF-beta in central and peripheral giant cell lesions of the jaws. J Oral Pathol Med. 2012;41:194–199. 11. Matos FR, Sarmento DJS, Capistrano Neto A, et al. Central giant cell lesion in pediatric patient: case report and literature review of 33 cases. Int J Clin Dent. 2012;6:33–42. 12. Al-Khateeb T, Ababneh K. Oral pyogenic granuloma in Jordanians: a retrospective analysis of 108 cases. J Oral Maxillofac Surg. 2003; 61:1285–1288. 13. Esmeili T, Lozada-Nur F, Epstein J. Common benign oral soft tissue masses. Dent Clin North Am. 2005;49:223–240, x. 14. Rundhaug JE. Matrix metalloproteinases and angiogenesis. J Cell Mol Med. 2005;9:267–285. 15. Garcia de Marcos JA, Garcia de Marcos MJ, Arroyo Rodriguez S, et al. Peripheral ossifying fibroma: a clinical and immunohistochemical study of four cases. J Oral Sci. 2010;52:95–99. 16. Capelozza ALA, Taveira LAA, Pagin O. Peripheral giant cell lesion: case report. Salusvita. 2007;26:99–104. 17. Dayan D, Buchner A, Spirer S. Bone formation in peripheral giant cell granuloma. J Periodontol. 1990;61:444–446. 18. Prasad S, Reddy SB, Patil SR, et al. Peripheral ossifying fibroma and pyogenic granuloma. Are they interrelated? N Y State Dent J. 2008;74:50–52. 19. Souza PE, Mesquita RA, Gomez RS. Evaluation of p53, PCNA, Ki-67, MDM2 and AgNOR in oral peripheral and central giant cell lesions. Oral Dis. 2000;6:35–39. 20. Florez-Moreno GA, Henao-Ruiz M, Santa-Saenz DM, et al. Cytomorphometric and immunohistochemical comparison between central and peripheral giant cell lesions of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105:625–632. 21. Takami M. Catabolism of heme moiety of hemoglobin.haptoglobin in rat liver cells in vivo. J Biol Chem. 1993;268:20335–20342. 22. Almeida OP, Jacks J Jr., Scully C. Paracoccidioidomycosis of the mouth: an emerging deep mycosis. Crit Rev Oral Biol Med. 2003; 14:377–383. 23. Eng HL, Lu SY, Yang CH, et al. Oral tuberculosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81:415–420. 24. Zhai J, Maluf HM. Peridiverticular colonic hyaline rings (pulse granulomas): report of two cases associated with perforated diverticula. Ann Diagn Pathol. 2004;8:375–379. 25. Gueiros LA, Santos Silva AR, Romanach MJ, et al. Distinctive aspects of oral hyaline ring granulomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;106:e35–e39. 26. Talacko AA, Radden BG. The pathogenesis of oral pulse granuloma: an animal model. J Oral Pathol. 1988;17:99–105. 27. LaMear WR, Estrem SA, Spollen LE. Pulse granuloma presenting as a facial mass. Otolaryngol Head Neck Surg. 1994;111:522–523. 28. Chou L, Ficarra G, Hansen LS. Hyaline ring granuloma: a distinct oral entity. Oral Surg Oral Med Oral Pathol. 1990;70:318–324.
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Retrospective Analysis of the Histopathologic Features of 288 Cases of Reactional Lesions in Gingiva and Alveolar Ridge Felipe R. de Matos, DDS, PhD, Thaı´s G. Benevenuto, DDS, MSc, Cassiano F. W. Nonaka, DDS, PhD, Lea˜o P. Pinto, DDS, PhD, and Le´lia B. de Souza, DDS, PhD
Introduction: The aim of this study was to perform a retrospective study of histopathologic features of a series of cases of pyogenic granuloma (PG), peripheral giant cell lesion (PGCL), and peripheral ossifying fibromas (POF) that constitutes the group called reactional lesions, located in gingiva and alveolar ridge. Study Design: Cases of PG, PGCL, and POF were selected for this study. The morphological analysis of the lesions constituted the following: intensity of inflammatory infiltrate (IF), presence of vascular proliferation (VP), fibroblastic proliferation (FP), areas of ulceration (AU), bacterial colony (BC), presence of mineralization (PM), multinucleated giant cells (MGC), hemosiderin deposition (HD), hemorrhage area (HA). Results: Of the 288 cases analyzed, 162 (56.3%) were PG, 72 (25%) were PGCL, and 54 (18.8%) were POF. The IF, VP, AU, and BC were more prominent in PG (85.8%, 98.8%, 91.4%, and 46.9%, respectively) and PM in POFs (98.1%). FP was more frequent in POF (98.1%) and PGCL (100%) and MGC in PGCL (100%), although some cases of POF (7.4%) and PG (0.6%) exhibited MGC. HD was more frequent in PGCL (40.3%) and HA in PG (53.1%). Conclusions: This study demonstrated that IF, VP, AU, BC, and HA are the common features in PG, MGC, FP, and HD are the most common in PGCL, and PM associated with FP are the most common in POF, which can help in the histopathologic differential diagnosis between these lesions. In addition, it may suggest a possible development and maturation of the PG in POF with reduction in the inflammatory component and increase in the fibrous component. Key Words: pyogenic granuloma, peripheral giant cell granuloma, peripheral ossifying fibroma, histopathological features, gingiva, alveolar ridge (Appl Immunohistochem Mol Morphol 2014;22:505–510) Received for publication April 10, 2013; accepted June 1, 2013. From the Oral Pathology Department, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil. The authors declare no conflict of interest. Reprints: Le´lia B. de Souza, DDS, PhD, Departamento de Odontologia, Federal University of Rio Grande do Norte, Av. Senador Salgado Filho, 1787 Lagoa Nova, Natal, Rio Grande do Norte 59056-000, Brazil (e-mail: [email protected]). Copyright r 2013 by Lippincott Williams & Wilkins
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eactive lesions in gingiva and alveolar ridge mucosa are very common.1–3 Although there are some clinical differences among the reactive lesions, their etiology is very similar, and the presence of variable amounts of inflammatory infiltrate (IF) in all of them can determine high clinical and microscopic resemblance. These are subjected to chronic local irritation or trauma from calculus, food impaction, restorations that show irregular margins, low-grade trauma, and iatrogenic factors. Even with common etiologic factors, tissue response follows different courses in each individual lesion, reflected by their microscopical characteristics.4 The great majority of localized overgrowths of gingiva and alveolar ridge mucosa are considered to be reactive and non-neoplastic lesions,5 like peripheral giant cell lesion (PGCL), pyogenic granuloma (PG), and peripheral ossifying fibroma (POF).6 Not much difference exists in clinical appearance between these lesions. However, the knowledge of the frequency and distribution of such lesions is essential when establishing a diagnosis and planning treatment. Therefore, periodontologists and oral and maxillofacial surgeons often give the diagnostic term epulis to these lesions clinically.6 In addition, there is no consensus as to the histologic classification. Buchner et al7 cite the example that Lee’s “calcifying fibroblastic granuloma” would correspond to Bhaskar and Jacoway’s “peripheral fibroma with calcification” or to Eversole’s “peripheral ossifying fibroma.” Diagnosis of each lesion from this group (PGCL, PG, and POF) is aided by their clinical and periapical radiographic features, but histopathologic analysis is essential for final diagnosis4 because from the clinical point view these lesions do not possess specific features. They are usually oral hyperplastic lesions and present a common course, originally manifesting as an intensely red and soft mass of inflamed granulation tissue, being painless or not.2,8 Histologically, PGCL is a reactive lesion that consists of a proliferation of ovoid-shaped to spindle-shaped mesenchymal cells and multinucleated giant cells (MGC) with an associated prominent vascularity.9–11 PG is characterized by a mass of hyperplastic granulation tissue with marked proliferation of endothelial cells that line capillary channels and an infiltrate of mixed inflammatory cells.7 Finally, POF is a reactive lesion that
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includes a cellular fibroblastic tissue and formation of mineralized products like woven and lamellar bone, cementum-like material, and dystrophic calcification.7 The treatment of these lesions aims to eliminate the underlying etiologic agents and comprises surgical resection.8 Knowledge of frequency and distribution of such lesions is also essential. Despite a few studies about these lesions in Brazil,3,4 the aim of this retrospective study was to identify the clinicopathologic features of PGCL, PG, and POF diagnosed on Oral Pathology Service and their morphologic characteristics.
MATERIALS AND METHODS A retrospective study of 10,311 biopsies obtained over a period of 40 years (1970 to 2009) in the Oral Pathology Service was designed. The histologic features were studied in 5 mm wide paraffin sections stained with hematoxylin and eosin. The lesions were classified into the 3 above-described groups, that is, PGCL, PG, and POF according to the criteria that were described in the Introduction section of the study. For the morphologic study, some microscopical parameters were analyzed, according to Peralles et al,4 which are as follows: distribution of IF—classified as mild, when there were focal areas, especially on the subepithelial area, or intense, when it was disperse and deep on the connective tissue; type of IF—predominantly acute, chronic, or both; presence of vascular proliferation (VP)—presence of abundant capillary or cavernous VPs on the connective tissue (not only focal areas of increased vascularity); pattern of the oral mucosal lining epithelium—subdivided as normal, atrophic (thin epithelium with 15 to 20 cell layers) or absent (areas of ulceration); presence of MGC; presence of mineralized material—microscopically compatible with bone and/or cementum; type of connective tissue—loose or dense; the presence of fibroblastic proliferation dispersed on the connective tissue; and presence of hyaline granuloma, bacterial colony (BC), hemosiderin deposition (HD), hemorrhage area, and odontogenic epithelium.
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TABLE 1. Histopathologic Findings of 288 Reactive Gingival/ Alveolar Lesions by Histologic Subtype n (%) Parameters
PG
Epithelium Normal 1 Atrophy 59 Hyperplasia 159 Predomine (hyperplastic) 131 Ulcer 148 Connective tissue Loose 21 Dense 48 Loose and dense 93 Fibroblastic proliferation 10 Vascular proliferation 160 Type of inflammatory infiltrate Acute 1 Chronic 22 Both 139 Intensity of inflammatory infiltrate Mild 23 Intense 139 Mineralization Absent 151 Cementum-like 6 Bone/Bone-like 4 Cementum/bone 1 Multinucleated giant cell Absent 161 Present 1 Hyaline granuloma Absent 161 Present 1 Bacterial colony Absent 85 Present 76 Hemosiderin deposition Absent 158 Present 4 Hemorrhage area Absent 76 Present 86 Odontogenic epithelium Absent 157 Present 5
PGCL
POF
(0.6) (36.4) (98.1) (80.9) (91.4)
2 20 65 53 23
(2.8) (27.8) (90.3) (73.6) (31.9)
2 12 49 34 27
(3.7) (22.2) (90.7) (63) (50)
(13) (29.6) (57.4) (6.2) (98.8)
3 59 10 72 59
(4.2) (81.9) (13.9) (100) (81.9)
1 37 16 53 26
(1.9) (68.5) (29.6) (98.1) (48.1)
(0.6) (13.6) (85.8)
0 (0.0) 54 (75) 18 (25)
0 (0.0) 34 (63) 20 (37)
(14.2) (85.8)
56 (77.8) 16 (22.2)
31 (57.4) 23 (42.6)
(93.2) (3.7) (2.5) (0.6)
44 0 28 0
1 9 33 11
(99.4) (0.6)
0 (0.0) 72 (100)
50 (92.6) 4 (7.4)
(99.4) (0.6)
72 (100) 0 (0.0)
54 (100) 0 (0.0)
(52.8) (46.9)
70 (97.2) 2 (2.8)
49 (90.7) 5 (9.3)
(97.5) (2.5)
43 (59.7) 29 (40.3)
53 (98.1) 1 (1.9)
(46.9) (53.1)
50 (69.4) 22 (30.6)
53 (98.1) 1 (1.9)
(96.9) (3.1)
72 (100) 0 (0.0)
51 (94.4) 3 (5.6)
(61.1) (0.0) (38.9) (0.0)
(1.9) (16.7) (61.1) (20.4)
RESULTS
PG indicates pyogenic granuloma; PGCL, peripheral giant cell lesion; POF, peripheral ossifying fibroma.
Of the 10,311 biopsies, 288 cases (2.8%) of reaction lesions were identified. There were 162 (56.3%) PG, 72 (25%) PGCL, and 54 (18.8%) POF. Histologic parameters evaluated are described in Table 1. With respect to epithelial morphology, atrophy, ulceration, and hyperplasia were found predominantly on PG (36.4%, 91.4%, and 98.1%, respectively), although these findings were present in all other histologic types. The hyperplasia was found most frequently in all the lesions and the presence of the ulceration was most common in PG (91.4%; Fig. 1A). Connective tissue was considered loose and dense in most PG (57.4%) and, in contrast, was considered dense in most PGCL (81.9%; Fig. 1B) and POF (68.5%; Fig. 1C). Fibroblastic proliferation was commonly present in PGCL (100%) and POF (98.1%). VP was found frequently in PG (98.8%; Fig. 1D) and PGCL (81.9%; Fig. 2A). Chronic IF was found in all cases, being most common in PGCL (75%)
and POF (63%); acute infiltrate was identified in only 1 case of PG. IF was considered intense in 85.8% of cases of PG and mild in 77.8% of PGCL and 57.4% of POF. Mineralization showed marked affinity for POF, being exhibited in 16.7% of cementum-like areas (Fig. 2B), 61.1% of bone/ bone-like areas (Fig. 1C), and 20.4% of cementum/bone areas. In contrast, the mineralization was observed in 6.8% of PG (Fig. 2C) and 38.9% of PGCL (Fig. 2D). MGC were found in all cases of PGCL (Fig. 2A) being present in some cases of POF (7.4%) (Fig. 2B) and PG (0.6%). Hyaline granuloma was found in only 1 case of PG (Fig. 3A). BC was seen in epithelial and ulceration in 46.9% of PG (Fig. 1A) and absent in 97.2% of PGCL and 90.7% of POF. Hemosiderin deposition was found in 40.3% of PGCL (Fig. 3B) and hemorrhage area in 53.1% of PG and
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Reactional Lesions in Gingiva and Alveolar Ridge
FIGURE 1. A, Photomicrograph of PG exhibiting ulcer area (arrow) and bacterial colony (asterisk; H&E, 40). B, Photomicrograph of peripheral giant cell lesion with dense connective tissue and some multinucleated giant cell (arrow; H&E, 200). C, Photomicrograph of peripheral ossifying fibroma characterized by the presence of a collagenized fibrous connective tissue with a proliferation of fibroblastic cells (arrow), especially in the areas of bone-like material (asterisk; H&E, 200). D, Photomicrograph of PG exhibiting transition of epithelium to ulcer area (H&E, 200). H&E indicates hematoxylin and eosin; PG, pyogenic granuloma.
30.6% of PGCL. Few cases showed odontogenic epithelium, being present in 5 (3.1%) cases of PG and 3 (5.6%) of POF. r
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DISCUSSION According to the results obtained, the most common lesion was PG (56.3%), followed by PGCL (25%) www.appliedimmunohist.com |
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FIGURE 2. A, Photomicrograph of PGCL with numerous multinucleated giant cell and blood vessels (H&E, 400). B, Photomicrograph of peripheral ossifying fibroma exhibiting one multinucleated giant cell (arrow) and cementum-like areas (arrow head) between mesenchymal cells (H&E, 400). C, Photomicrograph of pyogenic granuloma with focal area of mineralized material (H&E, 400). D, Photomicrograph of PGCL exhibiting focus of mineralized tissue (H&E, 200). H&E indicates hematoxylin and eosin; PGCL, peripheral giant cell lesion.
and POF (18.8%), in line with the literature. For PG, there was a variation of 42.7%7 to 58.8%1 in studies with reactive lesions only. It is interesting to note that the research findings are similar to those of Salum et al,3 who carried out their study in Brazil and found 57% of cases diagnosed as PG. In relation to PGCL, a higher amplitude in percentage was observed, ranging from 3.9%6 to 30.6%.1 Again, the frequency of PGCL cases in this study becomes close to the Brazilian study that identified it in 22.5% of the cases.3 Finally, the POF was found in 18.8% of the cases and is within the frequency reported in some studies, that is, 10.5%1 to 45.3%.6 PG is a reactive lesion front to an etiological traumatic factor, and the sites most likely to injuries are the gingiva and the alveolar ridge. The presence of calculus, overhanging edges, and rough restorations can act as irritant factors. These elements cause microulceration and allow the entry of microorganisms in the intimacy of the
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connective tissue.12,13 The findings of the present research endorse this theory, once the ulceration was found in 91.4% of PG cases and there was presence of bacteria colonies in 46.9%. The irritation in fibrovascular connective tissue becomes denser and begins the inflammatory response.13 Once the inflammation is triggered, growth factors and inflammatory cytokines such as vascular endothelial growth factors and interleukin-8, respectively, stimulate the proliferation of endothelial cells and the formation of new capillary beds,14 reflecting on the main morphological characteristics of PG.4,6 Not diverging from these concepts of this assertion, we identified a dense connective tissue in 29.6% and dense and loose in 57.4% of the cases, an intense and mixed IF in 85.8% of the cases, and proliferation of blood vessels was present in 98.8% of PG. In contrast, POF and PGCL observed a reduced percentage of ulceration (50% and 31.9%, respectively), followed by absence of BC r
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FIGURE 3. A, Presence of hyaline granuloma (arrow) in pyogenic granuloma (H&E, 400). B, Presence of hemosiderin deposition (arrow) next to multinucleated giant cells area in peripheral giant cell lesion (H&E, 200). H&E indicates hematoxylin and eosin.
(90.7% and 97.2%, respectively), which could explain the lightness of IF in these lesions (57.4% and 77.8%, respectively). Eleven cases (6.8%) of PG showed foci of mineralization, unusual finding for this lesion, moving away from 98.1% found in POF. Mineralization areas in POF are usually seen in the cellular zone and show considerable variation in the pattern of mineralization from small rounded calcified deposits to large trabecular bone areas surrounded by osteoblastos,15 such as that observed in the present study. In addition, PGCL may exhibit focus of mineralized tissue but less frequently. According to Capelozza et al,16 PGCL may exhibit elevated growth potential, sometimes with erosion of underlying bone. This might justify the presence of mineralized osseous tissue in 38.9% of PGCL in this study, such as that observed by Dayan et al17 (35%). Some authors suggest a possible development and maturation of the PG in POF, with reduction in the inflammatory component, increase of the fibrous component, and development of some foci of calcification, but this theory is not applied to all POF formed.4,6 In contrast, Prasad et al18 believe that the PG and the POF should not be regarded as distinct clinical entities but preferably as progressive stages of the same pathology. The results of this study may suggest this transition when comparing the percentage of POF and PG with intense IF (42.6% and 85.8%, respectively) and presence of dense fibrous connective tissue (68.5% and 29.6%, respectively), as observed by Peralles et al.4 The PGCL occurs exclusively in gingival and alveolar mucosa and microscopically is characterized by the proliferation of mesenchymal cells in the middle of the MGC, and may have extensive hemorrhagic areas and HD.4,19 The presence of fibroblast proliferation and MGC were found in 100% of the cases, hemorrhagic areas in 30.6% of the cases, and HD in 40.3% of the cases. It is believed that the MGC seen in PGCL originate r
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from the fusion of monocytic cells of CD68+ macrophage/osteoclastic lineage stimulated by the release of receptor activator of nuclear factor k-B ligand by mesenchymal cells.20 The hemosiderin pigmentation is related to the deposition of endogenous catabolic products and indicates the presence of many microhemorrhages in the lamina propria. Cells of the defense mechanism (ie, macrophages) react at the site of erythrocyte degradation; this starts “phagocytosis” and degrades the hemoglobin, producing the hemosiderin.21 Although a greater percentage of cases of PG (53.1%) exhibit hemorrhagic areas compared with the PGCL (30.6%), the hemosiderin pigmentation was most found in PGCL (40.3%). This could be explained by the fact that PGCL have a large number of cells with macrophagic phenotype.20 However, in minor frequency, the PG may contain areas that share microscopic features common to PGCL and POF, as reported by Peralles et al.4 One case (0.6%) of PG showed the presence of multinucleated giant cell and 6.8% showed mineralized areas. These findings could reinforce some microscopic features shared by the PG and POF and that might occur supposedly in some cases during the maturation process.4 Although not a common and essential component, the POF can present MGC, usually associated with the mineralized material and nests of odontogenic epithelium as representing the vestigial dental lamina.15 In 7.4% of cases of POF, we observed the presence of MGC and in 5.6%, the presence of odontogenic epithelium. Other lesions with oral manifestations and with presence of MGC that may occur in gingival and alveolar tissues are tuberculosis and paracoccidioidomycosis. Both of them take the form of an irregular ulceration or a discrete granular mass and they are often painful. The MGCs exhibit inside the microorganism and their nucleus are arranged at the cell periphery.22,23 The POF, similar to other injuries described above, occurs exclusively in gingival and alveolar tissues.3,4 www.appliedimmunohist.com |
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Garcia de Marcos et al15 conducted a study with the objective to investigate the nature of the POF by immunohistochemical analysis. The authors have strengthened the evidence of nature myofibroblastic and fibroblastic lesion, which is consistent with a possible origin in periodontal ligament. In optical microscopy, the POF is characterized by the presence of a collagenized fibrous connective tissue with a proliferation of fibroblastic cells, especially in the areas mineralized, which may be formed from bone material, similar to the cementum or dystrophic calcification. Most of the time, there is a chronic IF.7 These findings were observed in the majority of the patients studied in this research. Only 1 PG case presented hyaline granuloma. The hyaline granuloma is an eventual histologic finding characterized by deposition of eosinophilic amorphous nodular material surrounded by variable amounts of inflammatory cells and giant cells.24 The hyaline granuloma can be found in lesions of soft tissue,25 and although the exact etiopathogenesis of these hyaline structures remain unknown, there are basically 2 opposing theories, which are as follows: the first proposes an extrinsic origin, resulting from the deployment of foreign material or body (plant material, vegetables, therapeutic agents).26,27 The second theory suggests an intrinsic origin, in which the lesions develop from the collagen degeneration, degenerative changes in blood vessels walls, extravasated and fibrosed serum proteins, or changes in the natural process of resolution of periapical lesions.28 Although these lesions exhibit similar characteristics, this study demonstrated that the intense IF, VP, ulceration, the presence of BC, and hemorrhagic areas are common features in GP, whereas the MGC, fibroblast proliferation, and HD are more frequent in PGCL and the presence of mineralization associated with fibroblast proliferation in the POF, which can help in the histopathologic differential diagnosis between these lesions. In addition, the present study may suggest a possible development and maturation of the PG in POF with reduction in the inflammatory component and increase in the fibrous component. REFERENCES 1. Ababneh KT. Biopsied gingival lesions in northern Jordanians: a retrospective analysis over 10 years. Int J Periodontics Restorative Dent. 2006;26:387–393. 2. Shamim T, Varghese VI, Shameena PM, et al. A retrospective analysis of gingival biopsied lesions in South Indian population: 2001-2006. Med Oral Patol Oral Cir Bucal. 2008;13:E414–E418. 3. Salum FG, Yurgel LS, Cherubini K, et al. Pyogenic granuloma, peripheral giant cell granuloma and peripheral ossifying fibroma: retrospective analysis of 138 cases. Minerva Stomatol. 2008;57:227–232. 4. Peralles PG, Viana APB, Azevedo ALR, et al. Gingival and alveolar hyperplastic reactive lesions: clinicopathological study of 90 cases. Braz J Oral Sci. 2006;5:1085–1089.
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5. Bataineh A, Al-Dwairi ZN. A survey of localized lesions of oral tissues: a clinicopathological study. J Contemp Dent Pract. 2005; 6:30–39. 6. Zhang W, Chen Y, An Z, et al. Reactive gingival lesions: a retrospective study of 2439 cases. Quintessence Int. 2007;38:103–110. 7. Buchner A, Shnaiderman-Shapiro A, Vered M. Relative frequency of localized reactive hyperplastic lesions of the gingiva: a retrospective study of 1675 cases from Israel. J Oral Pathol Med. 2010;39:631–638. 8. Tamarit-Borras M, Delgado-Molina E, Berini-Aytes L, et al. Removal of hyperplastic lesions of the oral cavity. A retrospective study of 128 cases. Med Oral Patol Oral Cir Bucal. 2005;10:151–162. 9. Matos FR, Nonaka CF, Miguel MC, et al. Immunoexpression of MMP-9, VEGF, and vWF in central and peripheral giant cell lesions of the jaws. J Oral Pathol Med. 2011;40:338–344. 10. de Matos FR, de Moraes M, Nonaka CF, et al. Immunoexpression of TNF-alpha and TGF-beta in central and peripheral giant cell lesions of the jaws. J Oral Pathol Med. 2012;41:194–199. 11. Matos FR, Sarmento DJS, Capistrano Neto A, et al. Central giant cell lesion in pediatric patient: case report and literature review of 33 cases. Int J Clin Dent. 2012;6:33–42. 12. Al-Khateeb T, Ababneh K. Oral pyogenic granuloma in Jordanians: a retrospective analysis of 108 cases. J Oral Maxillofac Surg. 2003; 61:1285–1288. 13. Esmeili T, Lozada-Nur F, Epstein J. Common benign oral soft tissue masses. Dent Clin North Am. 2005;49:223–240, x. 14. Rundhaug JE. Matrix metalloproteinases and angiogenesis. J Cell Mol Med. 2005;9:267–285. 15. Garcia de Marcos JA, Garcia de Marcos MJ, Arroyo Rodriguez S, et al. Peripheral ossifying fibroma: a clinical and immunohistochemical study of four cases. J Oral Sci. 2010;52:95–99. 16. Capelozza ALA, Taveira LAA, Pagin O. Peripheral giant cell lesion: case report. Salusvita. 2007;26:99–104. 17. Dayan D, Buchner A, Spirer S. Bone formation in peripheral giant cell granuloma. J Periodontol. 1990;61:444–446. 18. Prasad S, Reddy SB, Patil SR, et al. Peripheral ossifying fibroma and pyogenic granuloma. Are they interrelated? N Y State Dent J. 2008;74:50–52. 19. Souza PE, Mesquita RA, Gomez RS. Evaluation of p53, PCNA, Ki-67, MDM2 and AgNOR in oral peripheral and central giant cell lesions. Oral Dis. 2000;6:35–39. 20. Florez-Moreno GA, Henao-Ruiz M, Santa-Saenz DM, et al. Cytomorphometric and immunohistochemical comparison between central and peripheral giant cell lesions of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105:625–632. 21. Takami M. Catabolism of heme moiety of hemoglobin.haptoglobin in rat liver cells in vivo. J Biol Chem. 1993;268:20335–20342. 22. Almeida OP, Jacks J Jr., Scully C. Paracoccidioidomycosis of the mouth: an emerging deep mycosis. Crit Rev Oral Biol Med. 2003; 14:377–383. 23. Eng HL, Lu SY, Yang CH, et al. Oral tuberculosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81:415–420. 24. Zhai J, Maluf HM. Peridiverticular colonic hyaline rings (pulse granulomas): report of two cases associated with perforated diverticula. Ann Diagn Pathol. 2004;8:375–379. 25. Gueiros LA, Santos Silva AR, Romanach MJ, et al. Distinctive aspects of oral hyaline ring granulomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;106:e35–e39. 26. Talacko AA, Radden BG. The pathogenesis of oral pulse granuloma: an animal model. J Oral Pathol. 1988;17:99–105. 27. LaMear WR, Estrem SA, Spollen LE. Pulse granuloma presenting as a facial mass. Otolaryngol Head Neck Surg. 1994;111:522–523. 28. Chou L, Ficarra G, Hansen LS. Hyaline ring granuloma: a distinct oral entity. Oral Surg Oral Med Oral Pathol. 1990;70:318–324.
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