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Case Report Recurrent Recalcitrant Gingival Hyperplasia and Plasminogen Deficiency: A Case Report Lakshmanan Suresh,* Alfredo Aguirre,* Vijay Kumar,† Lynn W. Solomon,* Edward A. Sielski,‡ and Mirdza E. Neiders*
Background: Recurrent gingival hyperplasia due to plasminogen deficiency is a rare condition due to fibrin deposition in the connective tissue. Only eight cases have previously been reported in the English literature, and all cases were diagnosed before the age of 35 years. This paper presents an older patient with recurrent gingival hyperplasia due to plasminogen deficiency (hypoplasminogenemia). Methods: A 59-year-old woman presented with recurrent gingival swelling of 6 years’ duration. Multiple biopsies performed at various time periods were histologically reported to be gingival hyperplasia with chronic inflammation. Routine hematoxylin and eosin (H & E) staining and direct immunofluorescence were performed. Results: H & E-stained sections showed subepithelial, eosinophilic, amorphous, acellular deposits. Direct immunofluorescence showed positive staining for fibrin, immunoglobulin (Ig) G, IgA, and IgM. Functional plasminogen and plasminogen activator inhibitor-1 assays were done and found to be deficient. A diagnosis of gingival hyperplasia due to plasminogen deficiency (hypoplasminogenemia) was rendered. Conclusions: Recurrent gingival hyperplasia due to plasminogen deficiency (hypoplasminogenemia) is a newly recognized and rare condition. H&E staining, direct immunofluorescence, and assessment of functional plasminogen levels are essential to differentiate this condition from other conditions in which subepithelial, eosinophilic, amorphous materials are deposited. J Periodontol 2003;74:1508-1513. KEY WORDS Gingival hyperplasia; hypoplasminogenemia; plasminogen deficiency.
* Department of Oral Diagnostic Sciences, School of Dental Medicine, University at Buffalo, Buffalo, NY. † IMMCO Diagnostics Inc., Buffalo, NY; Departments of Microbiology and Dermatology, University at Buffalo. ‡ Private practice, Cheektowaga, NY.
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Gingival hyperplasia and ulceration due to deposits of fibrin in the connective tissue are unusual and rare occurrences that were first reported by Fridmodt-Moller in 1973.1 Since then, only 21 cases of this condition have been reported in the English literature.1-8 In most cases, gingival hyperplasia occurred in association with an eye condition termed ligneous conjunctivitis. Ligneous conjunctivitis is a rare eye disease first described in children by Bouisson in 18479 that exhibits an autosomal recessive pattern of inheritance.2,10 The disease presents clinically as an acute or chronic recurrent conjunctivitis. The conjunctiva acquires a pseudomembrane with an indurate consistency due to fibrin deposits.2,11 The term conjunctivitis lignosa was first introduced by Borel12 in 1933. The term lignosa derives from the Latin root “ligneous,” which means “resembling wood.” Recently, the cause of this disease was determined to be a deficiency of Type I plasminogen.13-15 In addition to the eyes, ligneous conjunctivitis can also affect the oral, nasopharyngeal, auditory, tracheobranchial, and vaginal mucous membranes.2,10,16-21 Recently, the association of gingival hyperplasia with ligneous conjunctivitis and plasminogen deficiency was established.7,8 Previous reports of oral mucosal involvement in ligneous conjunctivitis have been described in patients under the age of 35 years. In this report, we present a case of an older adult patient with recurrent gingival hyperplasia and fibrin deposition in the connective tissue secondary to plasminogen deficiency. CASE REPORT In December 1996, a 59-year-old female underwent restorative dental care for teeth #30 and #14. Shortly after temporary crowns were placed, the patient developed gingival hyperplasia around the buccal gingival margins of tooth #30. Similar lesions were present on the palatal gingival margin of tooth #14. The patient was referred to a periodontist for consultation, and a biopsy was recommended. An excisional biopsy of the gingival lesions adjacent to teeth #14 and #30 was performed in January 1997. The microscopic diagnosis rendered was hyperplastic mucosa with chronic inflammation and focal foreign body reaction. The biopsy site did not heal well, and the primary dentist decided to refer the patient to an oral pathologist for consultation in February 1997. After clinical
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Case Report examination and review of the histology, the oral pathologist concluded that this condition could be related to corrosive products from the amalgam restorations and new crowns, since the patient also had dermatological reactions from her jewelry. A recommendation was made to test the patient for a type IV hypersensitivity reaction. The lesions resolved in the interim, and allergy testing was not followed up. One month later, there was a recurrence of the lesions on the mesio-palatal and lingual gingival margins of tooth #30, followed by spontaneous resolution within 1 month’s time. This remission lasted about 20 months. The patient developed another episode of gingival hyperplasia, this time around the buccal margins of teeth #7 and #19. The periodontist suggested that the condition might be hormonally related. The patient’s follicular stimulating hormone (FSH) and luteinizing hormone (LH) levels were assessed and found to be within normal limits. Additional tests for rheumatoid factor and Helicobacter pylori to rule out rheumatoid arthritis and gastric ulcer were negative. Pain and bleeding from the gingiva prompted the periodontist to obtain a second biopsy in August 1999. Tissue from the labial gingiva of tooth #7 was taken. This biopsy was reported as “ulceration, with mild gingival hyperplasia.” The oral lesions became quiescent after the biopsy. The patient remained symptom free for nearly 2 years until she developed the current lesions. She was then referred to the oral medicine clinic at the University at Buffalo School of Dental Medicine for evaluation by an oral pathologist. At this time, the patient complained of episodic inflammation and painful lesions on her gums. Previous medical history included hypertension, mitral valve prolapse with mild regurgitation, asthma, duodenal ulcers, early macular degeneration, and allergies to meperidine hydrochloride,§ molds, and dust. Surgical history included a hysterectomy and foot surgery. She did not use tobacco and denied any alcohol or recreational drug use. Her medications included metoprolol tartrate, estropipate,¶ ranitidine hydrochloride,# clemastine fumarate,** and fluticasone propionate.†† The clinical examination revealed bilateral prominent lingual tori and multiple areas of amalgam tattoos. In addition, she had hyperplasia of the free gingival margins on teeth #2, 3, 4, 5, 14, 15, 25, and 31. The hyperplasia followed two patterns. One type of hyperplasia showed bulbous, rolled gingival margins, with facial areas showing a pebbled surface; the second pattern showed a swelling with detachment of the buccal free gingiva (Fig. 1). These gingival changes occurred despite excellent oral hygiene. Upon consultation with her primary care physician, one of the patient’s medications, estropipate, was changed to synthetic conjugated estrogens‡‡ because
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Figure 1. Gingival hyperplasia of the attached gingiva above teeth #14 and 15.
one of the listed side effects of estropipate was gingivitis and gingival bleeding. This did not resolve the patient’s problem, so a biopsy was done in July 2002 to rule out the possibility of various ulcerative and vesiculobullous conditions. The biopsy was submitted for hematoxylin and eosin (H & E) examination and direct immunofluorescence. H & E-stained sections showed surface ulceration covered by a fibrin mesh. The subjacent connective tissue exhibited large deposits of eosinophilic material resembling amyloid or fibrin. In addition, the fibrous connective tissue stroma also showed scattered chronic inflammatory cells (Fig. 2). The microscopic diagnosis was chronic hyperplastic gingivitis with ulceration and fibrinoid material. Histochemical staining for amyloidosis using Congo red was negative. Periodic acid Schiff staining proved negative as well. Direct immunofluorescence of the specimen revealed a positive staining for amorphous deposits in the lamina propria for antibodies to fibrin, immunoglobulin (Ig) G, IgM, and IgA (Fig. 3). H & E slides of the two previous biopsies were requested for review, and both revealed similar eosinophilic, amorphous deposits in the connective tissue. This indicated that previous episodes of the recalcitrant gingival hyperplasia represented the same entity; fibrin deposits had been present in all of the biopsies taken. A recommendation was made to evaluate plasminogen activity. The functional plasminogen assay § Demerol, Sanofi-Synthelabo, New York, NY. Lopressor HCT, Novartis Pharmaceuticals, East Hanover, NJ. ¶ Ogen, Pfizer Inc., New York, NY. # Zantac, Pfizer Inc. ** Tavist, Novartis Pharmaceuticals. †† Flonase, GlaxoSmithKline, Research Triangle Park, NC. ‡‡ Cenestine, Duramed Pharmaceuticals, Pomona, NY.
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Figure 2. Gingival biopsy showing subepithelial, homogeneous, amorphous, and eosinophilic deposits with scattered inflammation (H & E stain; original magnification ×200).
Figure 3. Subepithelial deposits showing positive staining in the lamina propria for fibrin (DIF; original magnification ×200).
and plasminogen activator inhibitor-1 assay were performed. The patient had a low functional plasminogen level of 54 (reference range, 70 to 143) and an increased plasminogen activator inhibitor-1 level of 73 (reference range, 4 to 43). Based on this, a diagnosis of recurrent gingival hyperplasia with ulceration due to plasminogen deficiency was rendered. After the diagnosis was made, the patient was referred to an ophthalmologist, who did not find any evidence of ligneous conjunctivitis. Although replacement therapy was considered, as of September 2003, no pharmacological intervention has been started, and the patient continues to present asymptomatic oral lesions.
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Figure 4. The fibrinolytic system.
DISCUSSION Plasminogen is a component of the fibrinolytic system, a system that is involved in the lysis of clots and clearance of extravasated fibrin.22 Plasminogen is present in blood and extracellular fluids as an inactive enzyme that is converted into its active form, plasmin, by plasminogen activators (PAs). There are two plasminogen activators: tissue plasminogen activator (tPA) and urokinase plasminogen activator (u-PA). The latter is found in urine. Inhibitory regulation of plasminogen is controlled by plasminogen activator inhibitor-1 (PAI-1).23 Impaired fibrinolysis leading to tissue accumulation of fibrin can be the result of plasminogen deficiency, decreased release of plasminogen activators, or an increase of plasminogen activator inhibitor. Figure 4 summarizes the fibrinolytic system. Plasminogen deficiency is a rare condition that is prevalent in about 0.4% of the general population.24 This deficiency can be classified into two types, i.e., type I (hypoplasminogenemia) and type II (dysplasminogenemia). Hypoplasminogenemia was first described by Hasegawa et al.25 in 1982. In this type, the functional plasminogen level and plasminogen antigen are both reduced. Dysplasminogenemia was first described by Aoki et al.26 in 1978 and consists of a molecular defect characterized by a single amino-acid substitution whereby threonine replaces alanine at the active site. This single amino-acid replacement results in a functionally deficient plasminogen that exhibits normal or only slightly reduced quantity levels.27 There are different laboratory assays that can be
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Case Report Table 1. used to evaluate the fibrinolytic system (Table 1). These assays are either qualitative or quantitative. In Laboratory Evaluation of the Fibrinolytic our case, we used functional assays, which revealed System a low level of plasminogen activity and an increased level of PAI-1. We did not determine whether the patient Analyte Evaluation Tests had hypoplasminogenemia or dysplasminogenemia, as molecular genetic tests were not done. Plasminogen 1. Functional assay – Recurrent gingival hyperplasia and ulceration due Chromogenic method to fibrin in the connective tissue have been only 2. Antigen assay – 8 recently associated with hypoplasminogenemia. To Electroimmunoassay the best of our knowledge, there have been only 21 Tissue-type plasminogen 1. Functional assay – cases reported in the English-language literature on (t-PA) and urokinase-type Chromogenic method fibrin-like material accumulation in the oral connective plasminogen (u-PA) 2. Antigen assay – tissue. Including our case, only nine patients out of ELISA method the 21 documented cases had confirmed plasminogen deficiency. This condition generally tends to affect young patients, with an age range at the onset of 5 to 24 years. In contrast, our patient first presented oral Plasminogen activator 1. Functional assay – manifestations of plasminogen deficiency at the age of inhibitor (PAI) Chromogenic method 59 years. A striking female predilection is evidenced 2. Antigen assay – by the fact that of the nine documented plasminogen ELISA method deficiency cases reported, eight were females. Collectively, these nine doc- Table 2. umented plasminogen defi- Histochemical and Direct Immunofluorescence Features of ciency cases also reveal that Subepithelial Gingival Deposits in Various Conditions in addition to the oral mucosa, the ocular conjunctiva and the Investigations laryngeal and vaginal mucous membranes may also exhibit Amyloid Lipid Immunosimultaneous lesions associGlycogen (Congo (Sudan globulins Plasminogen ated with fibrin deposits. HowLesions (PAS) red) black) (IgG) Fibrin assay ever, they are less frequent Lipid proteinosis + − + − − Normal than the oral lesions. Eye-oral lesions are seen in about 22% Oral amyloidosis − + − − − Normal of patients, while simultaneOral hypoplasmino− − − Variable* + Lower than ous laryngeal-vaginal-oral genemia normal levels lesions are observed in approximately 11% of subjects.8 Infantile systemic + − − − − Normal Our patient did not have any hyalinosis eye lesions or any other + Positive. mucosal involvement. − Negative. The etiological factor(s) * Direct immunofluorescence studies were not performed in all cases. In cases where immunoglobulin detection was performed, more than half of the cases were negative. contributing to the local development of this condition is not clear. Minor trauma, infection, or hypersensitivity have Histologically, the deposition of eosinophilic, amorbeen proposed as possible predisposing factors. In the phous, hyaline-like material in the papillary lamina affected patients, any of these factors may lead to escape propria with interspersed acute and chronic inflamof fibrin from the blood vessels and its subsequent depomatory cells should raise the suspicion of a possible sition into the surrounding connective tissue.2,14 Lack of plasminogen deficiency. The other conditions, which fibrin degradation due to the plasminogen deficiency histologically may look similar to fibrin deposits, are results in its stromal accumulation. This creates a physamyloidosis, lipid proteinosis, and infantile systemic ical impediment to cell migration, leading to microvashyalinosis (Table 2). Amyloidosis is Congo red posicular thrombosis and delayed tissue repair.28-30
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Case Report tive, while lipid proteinosis and infantile systemic hyalinosis are PAS positive. The present case stained negatively for both Congo red and PAS; thus, amyloidosis, lipid proteinosis, and infantile systemic hyalinosis were ruled out. Direct immunofluorescence (DIF) studies of lesions due to hypoplasminogenemia show a positive staining for fibrin. Our case showed that the amorphous, eosinophilic deposits observed in the lamina propria of H & E sections corresponded to the positive fibrin signals seen in DIF studies. In addition, DIF studies on our patient revealed that the fibrin pools trapped IgG, IgM, and IgA, a finding that has been previously reported.5,6,10,31 Conservative treatment should be pursued for gingival hyperplasia associated with plasminogen deficiency. Because it has been speculated that leakage of fibrin from the blood vessels is due to inflammation, meticulous oral hygiene should be sufficient in mild to moderate lesions. However, in severe lesions, surgical excision followed by strict oral hygiene should be implemented. Administration of low-dose plasminogen extracts have been used successfully in treating ligneous conjunctivitis,28 but their efficacy in treating oral lesions is yet to be elucidated, as plasminogen concentrates are expensive and not widely available. Because it is believed that inflammation plays a central role in the pathogenesis of this condition, it is tempting to speculate that topical corticosteroids may prove valuable to treat the condition by reducing inflammation and thereby promoting healing. All previously reported cases developed oral lesions at an early age (between the first and fourth decades), in contrast to the present case (sixth decade). This patient may have developed her oral lesions much later in life because of her excellent oral hygiene. The local trauma to the gingival tissues that occurred during crown preparation might have been the precipitating factor for development of her oral lesions. ACKNOWLEDGMENTS Dr. Vijay Kumar is Director at IMMCO Diagnostics Inc. REFERENCES 1. Frimodt-Moller J. Conjunctivitis ligneosa combined with a dental affection. Report of a case. Acta Ophthalmol 1973;51:34-38. 2. Hidayat AA, Riddle PJ. Ligneous conjunctivitis. A clinicopathological study of 17 cases. Ophthalmology 1987; 94:949-959. 3. Diamond JP, Chandna C, Williams C, et al. Tranexamic acid-associated ligneous conjunctivitis with gingival and peritoneal lesions. Br J Ophthalmol 1991;75:753-754. 4. Nussgens Z, Roggenkamper P. Ligneous conjunctivitis. Ten years follow-up. Ophthalmic Paediatr Genet
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1993;14:137-140. 5. Gunhan O, Celasun B, Perrini B, et al. Generalized gingival enlargement due to accumulation of amyloid-like material. J Oral Pathol 1994;23:423-428. 6. Gunhan O, Gunhan M, Berker E, Gurgan CA, Yildirim H. Destructive membranous periodontal disease (ligneous periodontitis). J Periodontol 1999;70:919-925. 7. Gokbuget AY, Mutlu S, Scully C, et al. Amyloidaceous ulcerated gingival hyperplasia: A newly described entity related to ligneous conjunctivitis. J Oral Pathol Med 1997;26:100-104. 8. Scully C, Gokbuget AY, Allen C, et al. Oral lesions indicative of plasminogen deficiency (hypoplasminogenemia). Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91:334-337. 9. Bouisson M. Painful eyes with formation of pseudomembranes on the surface of the conjunctiva (in French). Ann Oculist 1847;17:100-104. 10. Bateman JB, Petitit TH, Isenberg SJ, Simons KB. Ligneous conjunctivitis. An autosomal recessive disorder. J Pediatr Ophthalmol Strabismus 1986;23: 137-140. 11. Eagle RC, Brooks JSJ, Katowitz JA, Weinberg JC, Perry HD. Fibrin as a major constituent of ligneous conjunctivitis (letter). Am J Ophthalmol 1986;101: 493-494. 12. Borel G. A new palpebral syndrome (in French). Bull Soc Ophthalmol Fr 1933;48:168-180. 13. Schuster V, Zeitler P, Serengard S, et al. Homozygous and compound-heterozygous type I plasminogen deficiency is a common cause of ligneous conjunctivitis. Thromb Haemost 2001;85:1004-1010. 14. Schuster V, Mingers AM, Seidenspinner S, et al. Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis. Blood 1997;90:958-966. 15. Mingers AM, Heimburger N, Zeitler P, Kreth HW, Schuster V. Homozygous type I plasminogen deficiency. Semin Thromb Hemost 1997;23:259-269. 16. Rubin A, Buck D, MacDonald MR. Ligneous conjunctivitis involving the cervix. Case report. Br J Obstet Gynaecol 1989;96:1228-1230. 17. Scurry J, Planner R, Fortune DW, Lee CS, Rode J. Ligneous (pseudomembranous) inflammation of the female genital tract. A report of two cases. J Reprod Med 1993;38:407-412. 18. Cohen SR. Ligneous conjunctivitis: An ophthalmic disease with potentially fatal tracheobronchial obstruction. Laryngeal and tracheobronchial features. Ann Otol Rhinol Laryngol 1990;99:509-512. 19. Firat T. Ligneous conjunctivitis. Am J Ophthalmol 1974;78:679-688. 20. Cooper TJ, Kazdan JJ, Cutz E. Ligneous conjunctivitis with tracheal obstruction. A case report with light and electron microscopy findings. Can J Ophthalmol 1979;14:57-62. 21. Chambers JD, Blodi FC, Golden B, McKee AP. Ligneous conjunctivitis. Trans Am Acad Ophthalmol Otolaryngol 1969;73:996-1004. 22. Collen D, Lijnen HR. Basic and clinical aspects of fibrinolysis and thrombolysis. Blood 1991;78:3114-3124. 23. Girolami A, Simioni P, Scarano L, Girolami B. Venous and
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Case Report arterial thrombophilia. Haematologica 1997;82:96-100. 24. Biasiutti FD, Sulzer I, Stucki B, Wuillemin WA, Furlan M, Lammie B. Is plasminogen deficiency a thrombotic risk factor? A study on 23 thrombophilic patients and their family members. Thromb Haemost 1998;80:167-170. 25. Girolami A, Marafioti F, Rubertelli M, Cappellato MG. Congenital heterozygous plasminogen deficiency associated with a severe thrombotic tendency. Acta Haematol 1986;75:54-57. 26. Aoki N, Moroi M, Sakata Y, Yoshida N, Matsuda M. Abnormal plasminogen. J Clin Invest 1978;61:1186-1195. 27. Azuma H, Nobuaki M, Kazumasa M, et al. Molecular pathogenesis of Type I congenital plasminogen deficiency: Expression of recombinant human mutant plasminogens in mammalian cells. Blood 1997;89:183-190. 28. Schott D, Dempfle CE, Beck P, et al. Therapy with purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency. N Engl J Med 1998;339:1679-1686. 29. Bugge TH, Flick MJ, Daugherty CC, Degen JL. Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction. Genes Dev 1995;9:794-807. 30. Pohl JF, Melin-Aldana H, Sabla G, Begen JL, Bezerra JA. Plasminogen deficiency leads to an impaired lobular reorganization and matrix accumulation after chronic liver injury. Am J Pathol 2001;159:2179-2186.
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31. Holland EJ, Chan C-C, Kuwabara T, Palestine AG, Rowsey JJ, Nussenblatt RB. Immunohistochemical findings and results of treatment with cyclosporine in ligneous conjunctivitis. Am J Ophthalmol 1989;107: 160-166. Correspondence: Dr. Alfredo Aguirre, 355 Squire Hall, Department of Oral Diagnostic Sciences, School of Dental Medicine, University at Buffalo, Buffalo, NY 14214. Fax: 716/829-3554; e-mail:
[email protected]. Accepted for publication March 19, 2003.
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